WO2025076007A1

WO2025076007A1 - Methods of treating high-risk non-muscle invasive bladder cancer unresponsive to bacillus calmette-guérin therapy

Info

Publication number: WO2025076007A1
Application number: PCT/US2024/049485
Authority: WO
Inventors: Hussein SWEITI; Christopher CUTIE; Kiran Patel; Sumeet BHANVADIA
Original assignee: Taris Biomedical Llc
Priority date: 2023-10-02
Filing date: 2024-10-01
Publication date: 2025-04-10

Abstract

The present invention provides methods for treatment of papillary-only high-risk non-muscle invasive bladder cancer that is unresponsive or experienced to BCG therapy by locally administering gemcitabine to the bladder. Also provided herein are kits and articles of manufacture for treating high-risk non-muscle invasive bladder cancer that is unresponsive to BCG.

Description

METHODS OF TREATING HIGH-RISK NON-MUSCLE INVASIVE BLADDER

CANCER UNRESPONSIVE TO BACILLUS CALMETTE-GUERIN THERAPY

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to and the benefit of U.S. Provisional Application Nos. 63/587,385, filed October 2, 2023; 63/618,179, filed January 5, 2024; and 63/640,779, filed April 30, 2024, the contents of each of which are incorporated herein by reference in their entirety.

FIELD

[0002] The present disclosure relates to methods of treating papillary-only high-risk non-muscle invasive bladder cancer in patients that are unresponsive to or have experienced Bacillus Calmette-Guerin (BCG) therapy.

BACKGROUND

[0003] Bladder cancer is a significant medical problem, and currently available treatment options are unsatisfactory for a number of reasons. According to the Pharma Intelligence database (Citeline), as of the filing date of this application, there had more than 1300 clinical trials looking to identify safe and effective treatments for bladder cancer. Of those trials, more than 1000 either failed to meet their outcome, were terminated, or were otherwise discontinued. There remains a significant unmet medical need for patients with bladder cancer and the subject matter described and claimed herein is a significant step to helping meet that need.

[0004] Systemic neoadjuvant chemotherapy, transurethral resection of bladder tumor (TURBT) followed by intravesical treatment with Bacillus Calmette-Guerin (BCG) therapy, and radical cystectomy are among the currently available treatment options for bladder cancer patients, depending on the stage of bladder cancer.

[0005] Systemic chemotherapy is associated with significant toxicity, risks overtreatment in a significant proportion of patients, and up to 80% of patients may refuse or be ineligible for neoadjuvant and/or adjuvant regimens (Haseebuddin et al. J Urol. 2015;139(4S):e852-e853). Furthermore, while BCG therapy can be successful at preventing early tumor recurrences in patients with high-risk non-muscle invasive bladder cancer (NMIBC), most patients do not maintain sustained remissions (Shelley et al. Cochrane Database Syst Rev. 2000;

(4):CD001986). BCG treatment eventually fails in up to 50% of patients; almost 50% of these failures occur within the first 6 months (Lightfoot et al. Scientific World J. 2011 Mar 7; 11 :602- 613). Thus, many patients will ultimately develop BCG-unresponsive disease.

[0006] Radical cystectomy is associated with high morbidity (up to 60%) and negatively affects health related quality of life. These complications occur even in high-volume centers of excellence and regardless of surgical technique or approach (Shabsigh et al. Eur Urol. 2009; 55: 164-176). The procedure itself has a mortality rate of 3% (Stein et al. J Clin Oncol. 2001; 19:666-67). Hence, some patients refuse surgery. Additionally, some patients are medically unfit for surgery due to such factors as age, functional status, American Society of Anesthesiologists Class Score, co-morbidities, and body mass index.

[0007] Thus, there exists a significant clinical need for alternative treatment options. The present application addresses these and other needs.

[0008] The disclosures of all publications, patents, patent applications and published patent applications referred to herein are hereby incorporated herein by reference in their entirety.

BRIEF SUMMARY

[0009] In some aspects, provided herein is a method of treating papillary-only high-risk nonmuscle invasive bladder cancer (HR-NMIBC) in an individual comprising administering to the individual about 225 mg of gemcitabine about every three weeks (Q3W) for at least about 24 weeks.

[0010] In some aspects, provided herein is a method of treating papillary-only high-risk nonmuscle invasive bladder cancer (HR-NMIBC) in an individual comprising administering to the individual about 256 mg of gemcitabine hydrochloride (equivalent to about 225 mg gemcitabine free-base) about every three weeks (Q3W) for at least about 24 weeks.

[0011] In other aspects, provided herein is a method of treating papillary-only high-risk nonmuscle invasive bladder cancer (HR-NMIBC) in an individual comprising administering gemcitabine to the bladder of the individual about every three weeks (Q3W) for at least about 24 weeks during eight administration periods, wherein each administration period comprises a delivery period of at least about seven days when gemcitabine is released from an intravesical drug delivery system, wherein the concentration of gemcitabine in the urine of the individual is at least about 4 pg/mL during each delivery period. In some embodiments, the method comprises administering gemcitabine hydrochloride to the bladder of the individual.

[0012] In other aspects, provided herein is a method of bladder sparing in an individual having papillary-only high-risk non-muscle invasive bladder cancer (HR-NMIBC) comprising administering to the individual about 225 mg of gemcitabine about every three weeks (Q3W) for at least about 24 weeks, wherein the individual does not receive a radical cystectomy.

[0013] In other aspects, provided herein is a method of treating papillary-only high-risk nonmuscle invasive bladder cancer (HR-NMIBC) in an individual who is eligible for radical cystectomy, the method comprising administering to the individual about 225 mg of gemcitabine about every three weeks (Q3W) for at least about 24 weeks.

[0014] In other aspects, provided herein is a method of treating papillary-only high-risk nonmuscle invasive bladder cancer (HR-NMIBC) in an individual comprising administering to the individual about 225 mg of gemcitabine about every three weeks (Q3W) for at least about 24 weeks, wherein such treatment results in an increased disease-free survival compared to a standard of care treatment.

[0015] In other aspects, provided herein is a method of treating papillary-only high-risk nonmuscle invasive bladder cancer (HR-NMIBC) in a patient comprising (a) administering to the individual about 225 mg of gemcitabine about every three weeks (Q3W) for at least about 24 weeks during eight administration periods, (b) administering to the individual about 225 mg of gemcitabine about every 12 weeks (Q12W) for at least about 60 weeks during six administration periods, (c) extending disease-free survival in the individual by at least about 9 months; wherein each administration period comprises a delivery period of at least about seven days.

[0016] In other aspects, provided herein is a method of treating papillary-only high-risk nonmuscle invasive bladder cancer (HR-NMIBC) in an individual who is eligible for radical cystectomy, the method comprising administering to the individual about 256 mg of gemcitabine HC1 (equivalent to about 225 mg gemcitabine free base) about every three weeks (Q3W) for at least about 24 weeks.

[0017] In other aspects, provided herein is a method of treating papillary-only high-risk nonmuscle invasive bladder cancer (HR-NMIBC) in an individual comprising administering to the individual about 256 mg of gemcitabine HC1 (equivalent to about 225 mg gemcitabine free base) about every three weeks (Q3W) for at least about 24 weeks, wherein such treatment results in an increased disease-free survival compared to a standard of care treatment.

[0018] In other aspects, provided herein is a method of treating papillary-only high-risk nonmuscle invasive bladder cancer (HR-NMIBC) in a patient comprising (a) administering to the individual about 256 mg of gemcitabine HC1 (equivalent to about 225 mg gemcitabine free base) about every three weeks (Q3W) for at least about 24 weeks during eight administration periods, (b) administering to the individual about 256 mg of gemcitabine HC1 (equivalent to about 225 mg gemcitabine free base) about every 12 weeks (Q12W) for at least about 60 weeks during six administration periods, (c) extending disease-free survival in the individual by at least about 9 months; wherein each administration period comprises a delivery period of at least about seven days.

[0019] In other aspects, provided herein is a method of increasing the disease-free survival for treating papillary-only high-risk non-muscle invasive bladder cancer (HR-NMIBC) in an individual comprising administering to the individual about 225 mg of gemcitabine about every three weeks (Q3W) for at least about 24 weeks, wherein such treatment results in an increased median disease-free survival compared to the median disease-free survival achieved by intravesical mitomycin C (MMC) or intravesical gemcitabine.

[0020] In some embodiments, the concentration of gemcitabine in the urine of the individual is between about 4 pg/mL and about 50 pg/mL during each administration period.

[0021] In some embodiments, the individual has BCG-unresponsive or BCG-experienced NMIBC.

[0022] In some embodiments, the papillary-only high-risk non-muscle invasive bladder cancer comprises high grade Ta or any T1 disease not comprising CIS. In some embodiments, the individual does not have CIS. In some embodiments, the individual does not have N+ and/or M+ bladder cancer.

[0023] In some embodiments, the gemcitabine administered to the individual is a monotherapy for treatment of the papillary-only HR-NMIBC that is unresponsive to intravesical BCG therapy or BCG-experienced.

[0024] In some embodiments, the median disease-free survival in the population of patients is improved compared to the standard of care, optionally wherein the median disease-free survival in the population of patients is improved at least 40% compared to the disease-free survival for the standard of care.

[0025] In some embodiments, the median disease-free survival in the population of patients is improved compared to a systemic chemotherapeutic agent therapy, optionally wherein the disease-free survival is improved at least 40% compared to the disease-free survival for the systemic chemotherapeutic agent therapy.

[0026] In some embodiments, the median disease-free survival in the population of patients is improved compared to treatment with intravesical mitomycin C (MMC) or intravesical gemcitabine, optionally wherein the median disease-free survival is improved at least 40% compared to the disease-free survival for intravesical mitomycin C (MMC) or intravesical gemcitabine.

[0027] In some embodiments, such treatment results in a disease-free survival of at least 9 months.

[0028] In some embodiments, such treatment results in an increased recurrence-free survival compared to the standard of care treatment, optionally wherein the recurrence-free survival is improved at least 40% compared to the recurrence-free survival for intravesical mitomycin C (MMC) or intravesical gemcitabine.

[0029] In some embodiments, such treatment results in an increased time to next intervention compared to the standard of care treatment, optionally wherein the time to next intervention is improved at least 40% compared to the time to next intervention for intravesical mitomycin C (MMC) or intravesical gemcitabine.

[0030] In some embodiments, such treatment results in a time to next intervention of at least 9 months.

[0031] In some embodiments, such treatment results in an increased time to disease worsening compared to the standard of care treatment, optionally wherein the time to disease worsening is improved at least about 40% compared to the time to disease worsening for intravesical mitomycin C (MMC) or intravesical gemcitabine.

[0032] In some embodiments, such treatment results in a time to disease worsening of at least about 9 months.

[0033] In some embodiments, such treatment results in an increased time to progression compared to the standard of care treatment, optionally wherein the time to progression is improved at least 40% compared to the time to progression for intravesical mitomycin C (MMC) or intravesical gemcitabine.

[0034] In some embodiments, such treatment results in a time to progression of at least 9 months.

[0035] In some embodiments, such treatment results in an increased disease-free survival rate compared to the standard of care treatment, optionally wherein the disease-free survival rate is improved by at least 20% compared to the disease-free survival rate for intravesical mitomycin C (MMC) or intravesical gemcitabine.

[0036] In some embodiments, the disease-free survival rate is a 12-month disease-free survival rate. [0037] In some embodiments, such treatment results in a 12- month disease-free survival rate of at least about 60%.

[0038] In some embodiments, the disease-free survival rate is a 24-month disease-free survival rate.

[0039] In some embodiments, such treatment results in a 24-month disease-free survival rate of at least about 30%.

[0040] In some embodiments, such treatment results in an increased overall survival compared to the standard of care treatment.

[0041] In some embodiments, such treatment results in an increased all-cause disease-free survival compared to the standard of care treatment, optionally wherein the all-cause disease-free survival is increased by at least 40% compared to the all-cause disease-free survival for intravesical mitomycin C (MMC) or intravesical gemcitabine.

[0042] In some embodiments, such treatment results in an all-cause disease-free survival of at least about 9 months.

[0043] In some embodiments, such treatment results in an increased cancer-specific survival compared to the standard of care treatment.

[0044] In some embodiments, such treatment results in an increased time to cystectomy compared to the standard of care treatment.

[0045] In some embodiments, such treatment results in a time to cystectomy of at least about 12 months.

[0046] In some embodiments, such treatment results in an increased disease-free survival at 2 years compared to the standard of care treatment.

[0047] In some embodiments, the intravesical gemcitabine is administered to the individual as a monotherapy for treatment of the papillary-only high-risk non-muscle invasive bladder cancer (HR-NMIBC) that is unresponsive to intravesical Bacillus Calmette-Guerin (BCG) therapy.

[0048] In some embodiments, the individual is administered gemcitabine within 12 months of completion of the last dose of BCG therapy.

[0049] In some embodiments, the individual has received i) a minimum of five of six full doses of an induction course of BCG; and ii) two or three doses of a maintenance course, or two of six doses of a second induction course of BCG therapy.

[0050] In some embodiments, the individual has Ta stage bladder cancer, and/or wherein the population of patients comprises one or more individuals with Ta stage bladder cancer. In some embodiments, the individual has high grade Ta stage bladder cancer and/or wherein the population of patients comprises one or more individuals with high grade Ta stage bladder cancer.

[0051] In some embodiments, the individual has T1 stage bladder cancer and/or wherein the population of patients comprises one or more individuals with T1 stage bladder cancer. In some embodiments, the individual has high grade T1 stage bladder cancer and/or wherein the population of patients comprises one or more individuals with high grade T1 stage bladder cancer.

[0052] In some embodiments, the individual has a mixed histology tumor and/or wherein the population of patients comprises one or more individuals with a mixed histology tumor.

[0053] In some embodiments, the individual is ineligible or elected not to undergo radical cystectomy. In some embodiments, the individual elected not to undergo radical cystectomy due to bladder preservation or concern about quality of life after bladder removal.

[0054] In some embodiments, the bladder cancer does not have neuroendocrine, micropapillary, signet ring cell, plasmacytoid, or sarcomatoid features.

[0055] In some embodiments, the individual does not have a urothelial carcinoma or histological variant at any site outside of the urinary bladder.

[0056] In some embodiments, performing a transurethral resection of bladder tumors (TURBT) if the individual has papillary bladder cancer. In some embodiments, the bladder cancer is fully resected following TURBT.

[0057] In some embodiments, following treatment with gemcitabine, the individual is monitored for recurrence.

[0058] In some embodiments, following treatment with gemcitabine, the individual does not receive valrubicin, systemic gemcitabine, docetaxel, pembrolizumab or paclitaxel for treating the papillary-only high-risk non-muscle invasive bladder cancer (HR-NMIBC) that is unresponsive to intravesical Bacillus Calmette-Guerin (BCG) therapy.

[0059] In some embodiments, treatment with gemcitabine causes tumor ablation.

[0060] In some embodiments, following treatment with gemcitabine, the individual does not receive a transurethral resection of bladder tumors (TURBT).

[0061] In some embodiments, the individual does not progress to muscle-invasive bladder cancer.

[0062] In some embodiments, the quality-of-life score of the individual is maintained or increases following treatment with gemcitabine. [0063] In some embodiments, the individual has asymptomatic macrohematuria or dysuria prior to the treatment with gemcitabine.

[0064] In some embodiments, administering gemcitabine comprises inserting an intravesical drug delivery system comprising about 225 mg gemcitabine into the bladder of the individual and removing the intravesical drug delivery system about three weeks later. In some embodiments, administering gemcitabine comprises inserting an intravesical drug delivery system comprising about 256 mg gemcitabine HC1 into the bladder of the individual and removing the intravesical drug delivery system about three weeks later.

[0065] In some embodiments, the method comprises i) inserting an intravesical drug delivery system comprising about 225 mg of gemcitabine into the bladder of the individual; ii) removing the intravesical drug delivery system about three weeks later; iii) inserting a new intravesical drug delivery system comprising about 225 mg of gemcitabine into the bladder on the day that the intravesical drug delivery system is removed in step ii), and iv) removing the new intravesical drug delivery system about three weeks later; wherein steps ii) and iii) are completed seven times.

[0066] In some embodiments, the method comprises a dosing schedule of at least about 24 weeks comprising i) inserting a first intravesical drug delivery system into the bladder in week 0, and removing the first intravesical drug delivery system in week 3; ii) inserting a second intravesical drug delivery system into the bladder in week 3 after removing the first intravesical drug delivery system, and removing the second intravesical drug delivery system in week 6; iii) inserting a third intravesical drug delivery system into the bladder in week 6 after removing the second intravesical drug delivery system, and removing the third intravesical drug delivery system in week 9; iv) inserting a fourth intravesical drug delivery system into the bladder in week 9 after removing the third intravesical drug delivery system, and removing the fourth intravesical drug delivery system in week 12; v) inserting a fifth intravesical drug delivery system into the bladder in week 12 after removing the fourth intravesical drug delivery system, and removing the fifth intravesical drug delivery system in week 15; vi) inserting a sixth intravesical drug delivery system into the bladder in week 15 after removing the fifth intravesical drug delivery system, and removing the sixth intravesical drug delivery system in week 18; vii) inserting a seventh intravesical drug delivery system into the bladder in week 18 after removing the sixth intravesical drug delivery system, and removing the seventh intravesical drug delivery system in week 21; and viii) inserting an eighth intravesical drug delivery system into the bladder in week 21 after removing the seventh intravesical drug delivery system, and removing the eighth intravesical drug delivery system in week 24; wherein each intravesical drug delivery system comprises an intravesical device comprising about 225 mg of gemcitabine. In some embodiments, the intravesical drug delivery system comprises about 256 mg of gemcitabine HC1.

[0067] In some embodiments, the method further comprises a maintenance therapy phase, wherein the maintenance therapy phase comprises administering about 225 mg of gemcitabine to the bladder of the individual for about three weeks about every two to four months.

[0068] In some embodiments, the maintenance therapy phase comprises administering about 225 mg gemcitabine to the bladder of the individual for about three weeks about every three months. [0069] In some embodiments, the maintenance therapy phase begins at least about 30 weeks after the start of treatment with gemcitabine. In some embodiments, the maintenance therapy begins about 36 weeks after the start of treatment with gemcitabine.

[0070] In some embodiments, the maintenance therapy comprises administering about 225 mg to the bladder of the individual during weeks 36-39, 48-51, 60-63, 72-75, 84-87, and 96-99.

[0071] In some embodiments, the method further comprises i) inserting an intravesical drug delivery system into the bladder of the individual on about week 36 and removing the intravesical drug delivery system on about week 39; ii) inserting an intravesical drug delivery system into the bladder of the individual on about week 48 and removing the intravesical drug delivery system on about week 51; iii) inserting an intravesical drug delivery system into the bladder of the individual on about week 60 and removing the intravesical drug delivery system on about week 63; iv) inserting an intravesical drug delivery system into the bladder of the individual on about week 72 and removing the intravesical drug delivery system on about week 75; v) inserting an intravesical drug delivery system into the bladder of the individual on about week 84 and removing the intravesical drug delivery system on about week 87; and vi) inserting an intravesical drug delivery system into the bladder of the individual on about week 96 and removing the intravesical drug delivery system on about week 99; wherein the intravesical drug delivery system comprises an intravesical device comprising about 225 mg of gemcitabine. [0072] In some embodiments, gemcitabine is delivered from the intravesical device during a delivery period.

[0073] In some embodiments, the delivery period is about one to about three weeks.

[0074] In some embodiments, the concentration of gemcitabine in the urine is from about 1 pg/mL to about 25 pg/mL or from about 4 pg/mL to about 50 pg/mL during the delivery period. [0075] In some embodiments, the intravesical drug delivery system releases gemcitabine at a rate of about 10 to about 45 mg/day for the first seven days of administration.

[0076] In some embodiments, the intravesical drug delivery system comprises an intravesical device that comprises a housing which contains and controllably releases the gemcitabine and is elastically deformable between a retention shape configured to retain the intravesical device in the individual’s bladder and a deployment shape for passage of the intravesical device through the individual’s urethra. In some embodiments, the intravesical device comprises a dual lumen silicone part with a single laser-machined orifice. In some embodiments, the dual lumen silicone part comprises a large lumen and a small lumen. In some embodiments, the small lumen comprises a super-elastic nitinol wire. In some embodiments, the super-elastic nitinol wire is in a predefined form to provide retention of the system in the bladder.

[0077] In some embodiments, the large lumen of the dual lumen silicone part comprises the gemcitabine.

[0078] In some embodiments, the large lumen of the dual lumen silicone part comprises osmotic minitablets. In some embodiments, the osmotic minitablets contain urea as an osmotic agent.

[0079] In some embodiments, the intravesical drug delivery system is deployed into the bladder of the individual by a urinary placement catheter.

[0080] In other aspects, provided herein is a kit comprising an intravesical drug delivery system comprising about 225 mg of gemcitabine and instructions for use. In some embodiments, the kit further comprises a urinary placement catheter. In some embodiments, the urinary placement catheter comprises a catheter and a stylet. In some embodiments, the kit further comprises a lubricant and/or a syringe.

[0081] In other aspects, provided herein is an article of manufacture comprising an intravesical drug delivery system comprising an intravesical device comprising about 225 mg of gemcitabine and a package insert comprising instructions for use.

[0082] In other aspects, provided herein is an intravesical drug delivery system comprising an intravesical device comprising about 225 mg gemcitabine.

[0083] In other aspects, provided herein is gemcitabine for use according to the method comprising administering to the individual about 225 mg of gemcitabine about every three weeks (Q3W) for at least about 24 weeks.

[0084] In other aspects, provided herein is use of gemcitabine for treating papillary-only high- risk non-muscle invasive bladder cancer (HR-NMIBC) in an individual comprising administering to the individual about 225 mg of gemcitabine about every three weeks (Q3W) for at least about 24 weeks, wherein such treatment results in an improved disease-free survival in a population of patients who have received such treatment compared to a standard of care treatment.

[0085] In some embodiments, the individual has BCG-unresponsive or BCG-experienced NMIBC.

[0086] In some embodiments, the gemcitabine is a gemcitabine free base equivalent (FBE). [0087] In other aspects, provided herein are minitablets comprising gemcitabine for use according to the method comprising administering to the individual about 225 mg of gemcitabine about every three weeks (Q3W) for at least about 24 weeks.

[0088] In other aspects, provided herein is gemcitabine for use with an intravesical device, for use according to the method comprising administering to the individual about 225 mg of gemcitabine about every three weeks (Q3W) for at least about 24 weeks.

[0089] In other aspects, provided herein is gemcitabine for use according to the method comprising administering to the individual about 225 mg of gemcitabine about every three weeks (Q3W) for at least about 24 weeks, in combination with an intravesical device.

[0090] In other aspects, provided herein is gemcitabine for use according to the method comprising administering to the individual about 225 mg of gemcitabine about every three weeks (Q3W) for at least about 24 weeks, wherein the gemcitabine is administered by an intravesical device.

[0091] In some embodiments, the amount of gemcitabine administered to the individual is a clinically effective amount of gemcitabine.

[0092] In some embodiments, gemcitabine is administered to the individual in a clinically effective amount.

[0093] In some embodiments, the individual is ineligible for radical cystectomy due to age, high American Society of Anesthesiologists class score, or medical and surgical comorbidities.

[0094] In some embodiments, the individual elects not to undergo a radical cystectomy to preserve their bladder, to preserve sexual function, concern about quality of life after cystectomy, or concern about mortality and morbidity risk associated with radical cystectomy. [0095] In some embodiments, the individual has recurrent, papillary-only high-risk non-muscle invasive bladder cancer (HR-NMIBC).

[0096] In some aspects, described herein is a method of treating recurrent BCG-unresponsive or BCG-experienced papillary-only HR-NMIBC in an individual comprising: inserting an intravesical drug delivery system comprising about 225 mg of gemcitabine into the bladder of the individual about once every three weeks (Q3W) for a total of up to 24 weeks following starting treatment, wherein each intravesical drug delivery system is removed from the bladder about three weeks after insertion into the bladder and wherein each intravesical drug delivery system is removed prior to insertion of another intravesical drug delivery system. In some embodiments, gemcitabine is administered as a free base equivalent (FBE). In some embodiments, the gemcitabine FBE is a pharmaceutically acceptable salt of gemcitabine. In some embodiments, the gemcitabine FBE is gemcitabine hydrochloride (HC1). In some embodiments, about 256 mg of gemcitabine HC1 is administered to the individual.

[0097] In some aspects, described herein is a method of treating recurrent BCG-unresponsive or BCG-experienced papillary-only HR-NMIBC in an individual comprising: inserting an intravesical drug delivery system comprising gemcitabine HC1 into the bladder of the individual about once every three weeks (Q3W) for a total of up to 24 weeks following starting treatment, wherein each intravesical drug delivery system is removed from the bladder about three weeks after insertion into the bladder and wherein each intravesical drug delivery system is removed prior to insertion of another intravesical drug delivery system.

[0098] In some aspects, described herein in a method of treating recurrent BCG-unresponsive or BCG-experienced papillary-only HR-NMIBC in an individual comprising: inserting an intravesical drug delivery system comprising about 225 mg of gemcitabine into the bladder of the individual about once every three weeks (Q3W) for a total of up to 24 weeks following starting treatment, followed by inserting an intravesical drug delivery system comprising about 225 mg of gemcitabine into the bladder of the individual about once every 12 weeks (Q12W) for up to an additional 75 weeks after the first 24 weeks of treatment, wherein each intravesical drug delivery system is removed from the bladder about three weeks after insertion into the bladder and wherein each intravesical drug delivery system is removed prior to insertion of another intravesical drug delivery system.

[0099] In some embodiments, administering gemcitabine comprises inserting an intravesical drug delivery system comprising about 225 mg gemcitabine into the bladder of the individual and removing the intravesical drug delivery system about 7 to about 10 days later.

[0100] In some embodiments, the intravesical device comprises: a housing configured for intravesical insertion, the housing defining a drug reservoir lumen and a retention frame lumen, the drug reservoir lumen having a release orifice; a retention frame comprising an elastic wire located in the retention frame lumen; a first unit contained within the drug reservoir lumen, the first unit comprising gemcitabine tablets; a second unit contained within the drug reservoir lumen in a position distinct from the first unit, the second unit comprising urea tablets; wherein the housing is configured to release gemcitabine from the drug reservoir lumen through the release orifice via osmotic pressure generated by the urea tablets; wherein the housing is elastically deformable between a retention shape configured to retain the device in the individual’s bladder and a deployment shape configured for passage of the device through the individual’s urethra. In some embodiments, the first unit comprises gemcitabine HC1 tablets.

BRIEF DESCRIPTION OF THE DRAWINGS

[0101] The drawings illustrate certain features and advantages of this disclosure. These embodiments are not intended to limit the scope of the appended claims in any manner.

[0102] FIGs. 1A-1B show an exemplary intravesical drug delivery system, TAR-200. TAR-200 is an intravesical drug delivery system comprising two components: (i) the drug constituent, which consists of gemcitabine minitablets (comprising 256 mg gemcitabine hydrochloride (equivalent to 225 mg of gemcitabine free base) and osmotic minitablets containing urea as the osmotic agent; and (ii) the intravesical device constituent, which is comprised of a dual lumen silicone part with a single laser-machined orifice and a superelastic nitinol wire (“wireform”). The large lumen of the silicone part contains the gemcitabine and urea minitablets and serves as an elementary osmotic pump to release drug in a controlled manner. The smaller lumen contains the nitinol wire in a predefined form to provide retention of the system in the bladder during the indwelling period. In FIG. 1A, TAR-200 is shown in an exemplary retention shape (e.g., in a so- called “pretzel shape” or a bi-oval shape) suited to retain the intravesical system within the bladder. The retention shape provides, among other things, that the intravesical drug delivery system resists becoming entrained in urine and excreted when the individual voids. In FIG. IB, a close-up view is shown to highlight the drug constituent and wireform of TAR-200.

[0103] FIG. 2 shows the size of the intravesical drug delivery system, TAR-200, compared to a US 25-cent coin and 2-Euro coin.

[0104] FIGS. 3A-3D show an exemplary intravesical drug delivery system, TAR-200, in accordance with some aspects. FIG. 3A illustrates the intravesical drug delivery system in a bioval retention shape, in accordance with some aspects. FIG. 3B illustrates an enlarged view of the silicone spacers and silicone adhesive at the ends of the housing of the intravesical drug delivery system of FIG. 3 A, in accordance with some aspects. FIG. 3C illustrates a cross- sectional view of the housing of the intravesical drug delivery system along line C-C in FIG. 3 A, in accordance with some aspects. FIG. 3D is a schematic depicting the intravesical drug delivery system of FIGS. 3A-3C in its elongated, uncoiled form, in accordance with some aspects. [0105] FIGs. 4A-4B show exemplary insertion devices for use with intravesical drug delivery systems provided herein, such as TAR-200, called a urological placement catheter (Urinary Placement Catheter or Inserter) for the transurethral placement of the intravesical drug delivery systems. The UPC comprises a catheter and stylet, as shown in FIG. 4A. In FIG. 4B, a close-up view is shown to highlight the depth markings present on the catheter shaft.

[0106] FIGs. 5A-5F are pictures of an exemplary sequence of loading TAR-200 into the Urinary Placement Catheter and deploying it therefrom. In FIG. 5A, TAR-200 is depicted next to the Urinary Placement Catheter and in the retention shape, suited to retain the device within the bladder. FIG. 5B shows a healthcare provider inserting TAR-200 into the catheter shaft of the Urinary Placement Catheter. FIG.5C shows the healthcare provider pushing TAR-200 through the catheter shaft with the stylet of the Urinary Placement Catheter. FIG. 5D shows TAR-200 beginning to emerge from an exit port of the catheter shaft as the stylet is further pushed by the healthcare provider. FIG. 5E shows TAR-200 as it continues to exit from the exit port of the catheter shaft as the stylet is even further pushed by the healthcare provider. FIG. 5F shows TAR-200 just prior to complete deployment from the catheter shaft, where it has substantially resumed the retention shape.

[0107] FIG. 6 shows the percentage of gemcitabine released from the intravesical drug delivery system (TAR-200) over three weeks in vitro. The line represents an average from twelve intravesical drug delivery systems.

[0108] FIG. 7 shows estimated gemcitabine urine concentrations over 7 days using TAR-200 delivery compared to instillation.

[0109] FIGS. 8A-8B show average urine concentration of gemcitabine in minipigs following transurethral intravesical deployment of TAR-200 for 7 days (FIG. 8A) and 28 days (FIG. 8B), respectively.

[0110] FIGS. 9A-9B show mean (SD) urine concentration of gemcitabine after intravesical administration of TAR-200 in combination with 360 mg of IV cetrelimab (Group 1), or TAR- 200 alone (Group 2). FIG. 9A shows results from a first gemcitabine dosing cycle of three weeks. FIG. 9B shows results from a second, third, or fourth three-week dosing cycle (individuals provided samples for one of these dosing cycles).

[0111] FIGS. 10A-10B show mean (SD) Gemcitabine Related Components (GRC, Gemcitabine + dFdU) in mg-equivalents of gemcitabine after intravesical administration of TAR-200 in combination with 360 mg of IV cetrelimab (Group 1), or TAR-200 alone (Group 2). FIG. 10A shows results from the first gemcitabine dosing cycle. FIG. 10B shows results from the second, third, or fourth dosing cycles (individuals provided samples for one of these dosing cycles). [0112] FIG. 11 shows the amount of gemcitabine that is released from TAR-200 in vitro vs. in vivo, as measured in human urine each day for seven days. The percentage reported is the percentage of the initial gemcitabine contained in the TAR-200 drug delivery system (225 mg) that was released each day.

[0113] FIG. 12 shows the study design for an open-label, multi-center, randomized study evaluating the efficacy and safety of TAR-200 versus investigator’s choice of intravesical chemotherapy in participants who received Bacillus Calmette-Guerin (BCG) and recurred with high-risk non-muscle-invasive bladder cancer (HR-NMIBC) and who are ineligible for or elected not to undergo radical cystectomy.

[0114] FIG. 13 shows the criteria for participants to be classified as BCG-unresponsive or BCG- experienced.

DETAILED DESCRIPTION

[0115] Prior to the present invention, few therapies were available to treat individuals with papillary-only HR-NMIBC that were unresponsive to BCG therapy, and the available therapies were relatively ineffective. Individuals with high-risk non-muscle invasive bladder cancer are typically initially treated with BCG, however up to 50% of patients eventually experience recurrence. A subset of patients may receive a radical cystectomy, however the utility of radical cystectomy is limited due to high morbidity and decreased quality of life. In some aspects, the present therapy is significantly more effective than the currently available treatment for such patients, such as intravesical Mitomycin C and intravesical gemcitabine. In significant contrast, local and continuous delivery of gemcitabine to the bladder over a period of time to individuals with papillary-only HR-NMIBC unresponsive to BCG therapy, is now shown to significantly improve the disease-free survival in a population of patients receiving such treatment. In some embodiments, the present methods prolong disease-free survival as compared to intravesical chemotherapy in patients who recur with papillary-only HR-NMIBC after BCG therapy and refuse or are unfit for radical cystectomy.

[0116] In another aspect, the gemcitabine is administered as a monotherapy for treatment of papillary-only HR-NMIBC that is unresponsive to BCG therapy. Prior to the present invention, it was considered that local delivery of gemcitabine to the bladder may not be adequately effective for treating papillary-only HR-NMIBC that is unresponsive to BCG therapy, and therefore local delivery of gemcitabine to the bladder should be combined with other therapies, such as checkpoint therapies, in order to generate a sufficient immune response to cause an antitumor response.

[0117] Accordingly, provided herein, in some aspects, are methods of treating individuals with papillary-only high-risk non-muscle invasive bladder cancer by administering gemcitabine locally to the bladder of the individual, wherein each gemcitabine administration comprises delivering gemcitabine continuously to the bladder for at least 7 days during a gemcitabine delivery period. In some embodiments, gemcitabine is administered to the bladder about every three weeks for up to about the first six months and administered about every three months thereafter. In some embodiments, gemcitabine is administered to the bladder for about six months with no rest periods. In some embodiments, gemcitabine is administered to the bladder about every three weeks for the first 24 weeks and then about every three months thereafter for a total of about 2 years. In some embodiments, gemcitabine is administered to the bladder for about 24 weeks without a rest period and then is administered for three weeks at a time with a three month rest period between administrations. In some embodiments, about 225 mg of gemcitabine is administered during each administration. In some embodiments, the about 225 mg gemcitabine is in the form of about 256 mg gemcitabine hydrochloride (HC1). In some embodiments, the individual has papillary-only BCG-unresponsive non-muscle invasive bladder cancer. In some embodiments, the individual has papillary-only BCG-experienced high-risk non- muscle invasive bladder cancer. In some embodiments, the individual has refused or is ineligible for radical cystectomy.

Definitions

[0118] Reference to “about” a value or parameter herein includes (and describes) variations that are directed to that value or parameter per se. For example, description referring to “about X” includes description of “X”.

[0119] “Administration” or “administering” as used herein refers to providing a therapeutic agent to an individual. Administration can be subcutaneous, intravenous, or intravesical, for example. In some embodiments, a particular amount of drug is administered to the individual, however only a portion of the drug is delivered (or released). In other embodiments, a particular amount of drug is administered to the individual and the entire amount administered is delivered (or released) from the intravesical drug delivery system. In certain embodiments, an administration period is a period during which an intravesical drug delivery system comprising a drug component, such as gemcitabine, remains in the individual’s bladder. [0120] “Delivery” is used herein to refer to release of a drug. For example, a delivery period is a period during which an effective amount or clinically effective amount, of a drug, such as gemcitabine, is released from, for example, an intravesical drug delivery system.

[0121] “Dosing cycle” as used herein refers to a total period until a subsequent dose is administered to an individual. For example, one dosing cycle can be the time from the insertion of a first intravesical drug delivery system to the time of insertion of a second intravesical drug delivery system, regardless of when the first intravesical drug delivery system was removed. [0122] “Indwelling period” as used herein refers to a period during which an intravesical drug delivery system is present in the bladder of an individual. For example, an intravesical drug delivery system that is removed from a bladder three weeks after insertion has a three-week indwelling period.

[0123] As used herein, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. For example, “a” or “an” means “at least one” or “one or more.”

[0124] The term “continuous” or “continuously” as used herein refers to sustained or extended administration of a therapeutic agent (such as gemcitabine) over a sustained or extended period of time. Continuous includes different release rates over a period of time. For example, a drug is continuously released over a period of seven days if the drug is released at a faster rate over the first three days and a slower rate over a period of the last four days.

[0125] The term “individual” as used herein refers to a human.

[0126] Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. For example, “about three weeks” includes 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 and 28 days.

[0127] The term “about X-Y” used herein has the same meaning as “about X to about Y .” [0128] As used herein, “treatment” or “treating” is an approach for obtaining beneficial or desired results including clinical results. For purposes of this invention, beneficial or desired clinical results include, but are not limited to, one or more of the following: alleviating one or more symptoms resulting from the disease, diminishing the extent of the disease, stabilizing the disease (e.g., preventing or delaying the worsening of the disease), suppressing or delaying the spread (e.g., metastasis) of the disease, preventing or delaying the recurrence of the disease, delaying or slowing the progression of the disease, ameliorating the disease state, providing a remission (partial or total) of the disease, decreasing the dose of one or more other medications required to treat the disease, delaying the progression of the disease, increasing or improving the quality of life, increasing weight gain, and/or prolonging survival. “Treatment” includes administering intravesical drug delivery systems to prevent, alleviate, or eliminate the symptoms, complications, or disease itself. Treatment can be curative or ameliorating. Also encompassed by "treatment" is a reduction of pathological consequence of cancer. The methods of the invention contemplate any one or more of these aspects of treatment. In some embodiments, “treatment” encompasses one or more clinical endpoints such as disease-free survival, recurrence-free survival, time to next intervention, time to disease worsening, time to progression, overall survival, all-cause disease-free survival, cancer-specific survival, time to cystectomy, and/or quality of life.

[0129] The term "methods of treatment" used herein is intended to be synonymous with “medical use”. For example, disclosure of "a method of treating HR-NMIBC comprising administering gemcitabine to a patient" is equivalent to and includes "use of gemcitabine for treating HR-NMIBC in a patient".

[0130] The term “effective amount” used herein refers to an amount of a compound or composition sufficient to treat a specified disorder, condition or disease such as to ameliorate, palliate, lessen, and/or delay one or more of its symptoms. In reference to cancers, an effective amount comprises an amount sufficient to cause a tumor to shrink and/or to decrease the growth rate of the tumor (such as to suppress tumor growth) and/or to suppress, or delay other unwanted cell proliferation and/or to treat or suppress tumor metastasis and/or to reduce (such as eradiate) preexisting tumor metastasis and/or to reduce incidence or burden of preexisting tumor metastasis and/or to suppress or delay tumor metastasis and/or to inhibit tumor cells and/or to induce an immune response against a tumor cell. An effective amount can be administered in one or more administrations, for example, the effective amount of the drug or composition may: (i) reduce the number of cancer cells; (ii) reduce tumor size; (iii) inhibit, retard, slow to some extent and preferably stop cancer cell infiltration into peripheral organs; (iv) inhibit (i.e., slow to some extent and preferably stop) tumor metastasis; (v) inhibit tumor growth; (vi) suppress or delay occurrence and/or recurrence of tumor; and/or (vii) relieve to some extent one or more of the symptoms associated with the cancer.

[0131] The term “month” used herein refers to about 28 days to about 31 days. The term “month” may also refer to a period of about four weeks to about five weeks.

[0132] “BCG-unresponsive” high-risk NMIBC as used herein means that the individual has at least one of the following: persistent disease despite adequate BCG therapy; disease recurrence after initially achieving a tumor-free state after adequate BCG; or T1 tumors following a single induction course of BCG. Specifically, “BCG-unresponsive” high-risk NMIBC as used herein means that the individual has received 5 or 6 doses of BCG induction therapy and either 2 or 3 doses of maintenance BCG or 2 or more doses of a second induction course. Disease recurrence must be high-grade T1 at the first disease assessment after induction, or high-grade Ta or any T1 disease within 6 months of completing adequate BCG therapy.

[0133] “BCG-experienced” high-risk NMIBC as used herein means that the individual has had an adequate BCG induction course defined as a minimum of 5 of 6 doses of an induction course with or without at least one dose of a BCG maintenance course.

[0134] “Adequate BGC therapy” as used herein means a) at least 5 of 6 doses of an induction course plus b) at least 2 of 3 doses or a maintenance course or at least 2 of 6 doses of a second induction course.

[0135] “Monotherapy” as used herein means use of a treatment regimen, such as treatment comprising local administration of gemcitabine to the bladder, as the single active ingredient for treating HR-NMIBC. In some embodiments, the individual receiving monotherapy receives one or more therapy to treat a disease other than HR-NMIBC or a side effect of the monotherapy. Gemcitabine may be provided in the form of a pharmaceutically acceptable salt.

[0136] Gemcitabine can be administered to an individual as a gemcitabine free base equivalent, such as a pharmaceutically acceptable salt of gemcitabine (e.g., gemcitabine hydrochloride). For example, 256 mg of gemcitabine hydrochloride is equivalent to 225 mg gemcitabine free-base.

Amounts of gemcitabine are on free base basis, unless indicated otherwise. Thus, as would be understood by the ordinarily-skilled artisan, unless indicated otherwise, the dosage amounts of gemcitabine as used herein refer to the dosage amount of gemcitabine free base. An individual may be administered a free base equivalent, such as a pharmaceutically acceptable salt thereof. It is understood that a corresponding free base equivalent of a pharmaceutically acceptable salt of gemcitabine may be readily determined. For a given amount of gemcitabine free base, the free base equivalent of a pharmaceutically acceptable salt may be determined as shown below:

mg gem FBE

[0137] To illustrate, the amount of gemcitabine HC1 that corresponds to about 225 mg of gemcitabine free base may be calculated as follows

225

255.65 mg gem FBE [0138] Thus, about 256 mg gemcitabine hydrochloride (also referred to as gemcitabine HC1;

CAS Registry No. 122111-03-9) corresponds to, and is the free base equivalent of, about 225 mg gemcitabine free base (CAS Registry No. 95058-81-4, having the chemical structure

Similar calculations may be done for other salts or forms of gemcitabine to determine the amount of gemcitabine salt that corresponds to the free base dosage amount.

[0139] “Recurrence” as used herein is defined as positive urine cytology for high grade urothelial carcinoma, or biopsy proven HR-NMIBC.

[0140] As used herein, “non-muscle invasive bladder cancer” and “non-muscle invasive urothelial carcinoma of the bladder” may be used interchangeably.

[0141] It is further to be understood that the terms “includes, “including,” “comprises,” and/or “comprising,” when used herein, specify the presence of stated features, integers, steps, operations, elements, components, and/or units but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, units, and/or groups thereof.

I. Methods of Treatment

[0142] The various aspects and embodiments described in this section in the context of a method of treatment also apply to gemcitabine for use according to the methods described herein, and minitablets comprising gemcitabine for use according to the methods described herein, unless indicated otherwise. Similarly, the various aspects and embodiments described in this section in the context of a method of treatment also apply to gemcitabine for use with an intravesical drug delivery system, according to the methods described herein, and gemcitabine for use according to the methods described herein, in combination with an intravesical drug delivery system, and gemcitabine for use according to the methods described herein, wherein the gemcitabine is administered by an intravesical drug delivery system.

A. Patient Populations

[0143] The present invention in some aspects provides a method of treating papillary-only HR- NMIBC bladder cancer that is experienced or unresponsive to BCG therapy in an individual. In some embodiments, papillary-only HR-NMIBC is defined as high-grade Ta disease or any T1 disease not comprising carcinoma in situ (CIS). In some embodiments, papillary-only is defined as disease not comprising CIS. In some embodiments, the individual does not have carcinoma in situ (CIS). In some embodiments, the individual has no CIS at time of papillary recurrence. [0144] In some embodiments, the individual is unfit or not eligible for a cystectomy or has refused a cystectomy. In some embodiments, the individual is ineligible for radical cystectomy under the National Comprehensive Cancer Network (NCCN) guidelines. For example, the individual is unfit for curative therapy due to frailty. Prior to the present methods, such individuals typically received palliative radiation without chemotherapy (3.5 Gy/fraction - 10 treatments; or 7 Gy/fraction - 7 treatments; TURBT; or no treatment). In some embodiments, the individual cannot tolerate radical cystectomy based upon the American Society of Anesthesiology (ASA) guidelines. For example, the individual who cannot tolerate radial cystectomy may be deemed medically unfit for surgery requiring general or epidural anesthesia. In some embodiments, the individual is ineligible for or elected not to undergo radical cystectomy.

[0145] In other embodiments, the individual may not be suitable for radical cystectomy due to a lack of post-operative care infrastructure (e.g., as determined by the Comprehensive Geriatric Assessment provided by the American Society of Anesthesiologists). In some embodiments, an individual is not suitable for radical cystectomy due to frailty (e.g., as determined by the Comprehensive Geriatric Assessment provided by the American Society of Anesthesiologists). Under these guidelines, an individual is deemed frail if he or she shows abnormal independent activities of daily living, severe malnutrition, cognitive impairment, or comorbidities cumulative illness rating scale for geriatrics (CISR-G) grades 3-4. Furthermore, under current guidelines, subjects must be deemed unfit for radical cystectomy (RC) due to comorbid conditions with a risk of mortality >5% as estimated by the American College of Surgeons risk calculator using the current procedure terminology code 51595 or 51596 for cystectomy.

[0146] In some embodiments, the individual is eligible for a radical cystectomy but elects not to undergo the radical cystectomy due to quality-of-life considerations. In some embodiments, the quality-of-life impacts of radical cystectomy include, but are not limited to, mortality, incontinence, decreased sexual function, subfertility or infertility, and decreased bowel function. [0147] In some aspects, the individual has non-muscle invasive bladder cancer (NMIBC). In some embodiments, NMIBC can be risk stratified into low, intermediate and high-risk groups depending on the probability of recurrence and progression to muscle-invasive disease. In some embodiments, the individual has high-risk NMIBC (HR-NMIBC). In some embodiments, the individual has papillary-only high-risk unresponsive to prior intravesical Bacillus Calmette- Guerin (BCG) therapy. In some embodiments, the individual is either ineligible for or has elected not to undergo radical cystectomy (RC). In some embodiments, the individual has BCG- unresponsive high-risk NMIBC after treatment with adequate BCG therapy defined as a minimum of 5 of 6 doses of an induction course (adequate induction) plus 2 of 3 doses of a maintenance course, or 2 of 6 doses of a second induction course. In some embodiments, the individual is eligible for a radical cystectomy. In some embodiments, the individual has BCG- experienced papillary-only high-risk NMIBC after treatment with adequate BCG induction therapy defined as a minimum of 5 of 6 doses and with or without at least 1 dose of a BCG maintenance course.

[0148] In some embodiments, the NMIBC is staged using the tumor, node, metastasis (TNM) staging system. In some embodiments, Ta stage bladder cancer is defined as a non-invasive papillary carcinoma. In some embodiments, Ta stage bladder cancer has grown toward the hollow center of the bladder but has not grown into the connective tissue or muscle of the bladder wall. In some embodiments, Ta stage bladder cancer is further delineated into either low- grade (LG) or high-grade (HG) subtypes, with LG referring to a slow growing, less aggressive form of the disease and HG referring to a rapidly growing, more aggressive form of the disease. In some embodiments, CIS is defined as a flat lesion comprising of cytologically malignant cells which may involve either full or partial thickness of the urothelium. In some embodiments, the NMIBC is identified by clinical staging (cTa, cTl) based on endoscopic surgery (biopsy or TURBT).

[0149] In some embodiments, the individual has undergone prior BCG therapy. In some embodiments, the prior BCG treatment comprises intravesical instillations of hundreds of millions of Mycobacterium bovis Bacillus Calmette-Calmette-Guerin bacilli applied weekly over the course of a six week induction treatment. In some embodiments, the bladder cancer is resected following the six-week BCG induction treatment. In some embodiments, the prior BCG therapy further comprises a maintenance treatment consisting of six-week periods of intravesical BCG instillation every three months for one to three years.

[0150] In some embodiments, the individual has recurrent, papillary only HR-NMIBC. In some embodiments, the individual has recurrent, papillary only HR-NMIBC following BCG therapy or in the event of a BCG shortage. In some embodiments, the individual has high grade Ta or any Tl, and does not have CIS.

[0151] In some embodiments, the individual has undergone between 3 and 6 courses of BCG induction treatment. In some embodiments, the individual has undergone at least 1 to 2, 2 to 3, 3 to 4, 4 to 5, or 5 to 6 prior courses of BCG induction treatment. In some embodiments, the individual has undergone 5 courses of BCG induction treatment during the prior BCG therapy. In some embodiments, the individual has undergone at least 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 prior courses of BCG therapy. In some embodiments, adequate BCG therapy is defined as a minimum of 5 of 6 full doses of an induction course plus 2 of 3 doses of a maintenance course, or at least 2 of 6 doses of a second induction course. In some embodiments, individuals receiving BCG therapy receive screening endoscopic surgeries (biopsies or TURBTs) about every 3 months to monitor for disease progression.

[0152] In some embodiments, the individual has BCG-unresponsive HR-NMIBC. In some embodiments, BCG-unresponsive HR-NMIBC is defined as persistent disease despite adequate BCG therapy, disease recurrence after initially achieving a tumor-free state after adequate BCG, or T1 tumors following a single induction course of BCG. In some embodiments, an individual becomes aware of BCG-unresponsive HR-NMIBC after experiencing painful urination (dysuria). In some embodiments, an individual becomes aware of BCG-unresponsive HR-NMIBC after experiencing blood in the urine without pain (asymptomatic microhematuria). In some embodiments, BCG-unresponsive disease is defined as recurrent high-grade Ta or any T1 disease within 6 months of completion of adequate BCG therapy, or T1 high-grade disease at the first disease assessment following an induction BCG course.

[0153] In some embodiments, the individual has BCG-experienced HR-NMIBC. In some embodiments, BCG-experienced HR-NMIBC is defined as persistent disease despite minimum BCG therapy. In some embodiments, minimum BCG therapy comprises adequate BCG induction therapy defined as a minimum of 5 or 6 doses of an induction course with or without at least one dose of a BCG maintenance course. In some embodiments BCG-experienced disease recurrence is defined as recurrent high-grade Ta or any T1 disease within 12 months of completion of minimum BCG therapy.

[0154] In some embodiments, the bladder cancer is resected prior to administration of the gemcitabine. In some embodiments, the individual undergoes a TURBT prior to administration of the gemcitabine to the bladder. In some embodiments, gemcitabine is administered within seven days following a TURBT. In some embodiments, the tumor is maximally resected prior to administration of the gemcitabine such that no visible tumor is present. In some embodiments, the tumor is non-maximally resected prior to administration of the gemcitabine. In some embodiments, the tumor is non-maximally resected prior to administration of the gemcitabine such that residual tumor is present. In some embodiments, the patient is TO after TURBT. In some embodiments, the individual undergoes TURBT at week 24 and/or week 48 of treatment with gemcitabine.

[0155] In some embodiments, the individual has undergone TURBT and has residual tumor at the site of resection. In some embodiments, the individual has stage Ta, or Tis cancer following TURBT.

[0156] In some embodiments, the individual does not have lymph node involvement (N+) and/or metastases (M+) per Blinded Independent Central Review of CT/MR Urography. In some embodiments, the individual does not have active malignancies other than the disease being treated under study. In some embodiments, active malignancies are defined as malignancies progressing or requiring treatment change in the last 24 months.

[0157] In some embodiments, the individual does not have CIS at any point from the time of diagnosis of papillary-only HR-NMIBC recurrence to randomization. In some embodiments, the individual has history of CIS greater than or equal to 12 months prior to time of diagnosis of papillary-only HR-NMIBC recurrence to randomization. In some embodiments, the individual does not have presence or a history of histologically confirmed, muscle-invasive, locally advanced, nonresectable, or metastatic urothelial carcinoma, for example T2, T3, T4, N+, and/or M+ disease.

[0158] In some embodiments, the individual must not currently have urothelial carcinoma or histological variant at any site outside of the urinary bladder. In some embodiments, the induvial may have urothelial carcinoma of the upper urinary tract (including renal pelvis and ureter) if treated with complete nephroureterectomy more than 24 months prior to randomization with no evidence of recurrence.

B. Dosing Regimens

[0159] The following section describes various aspects (embodiments) of dosing and treatment regimens, any and all of which apply to the methods described herein. The various aspects (embodiments) of dosing and treatment regimens also apply to gemcitabine for use according to the methods described herein, and minitablets comprising gemcitabine for use according to the methods described herein. Similarly, the various aspects (embodiments) of dosing and treatment regimens also apply to gemcitabine for use with an intravesical drug delivery system, according to the methods described herein, and gemcitabine for use according to the methods described herein, in combination with an intravesical drug delivery system, and gemcitabine for use according to the methods described herein, wherein the gemcitabine is administered by an intravesical drug delivery system. [0160] The present application in one aspect provides a method of treating bladder cancer in an individual comprising administering gemcitabine locally to the bladder of the individual, wherein each gemcitabine administration comprises delivering gemcitabine continuously to the bladder for at least 7 days during a gemcitabine delivery period. In some embodiments, gemcitabine is administered as a monotherapy.

[0161] In some embodiments, the gemcitabine is administered by inserting an intravesical drug delivery system into the bladder of the individual, wherein the administration period is the time that the device is maintained in the bladder. In some embodiments, the gemcitabine is delivered from the device into the urine in the bladder during a delivery period that is less than the entire administration period. For example, in some embodiments, the methods provided herein comprise a three week administration period during which the intravesical drug delivery system resides in the bladder, wherein the intravesical drug delivery system releases gemcitabine for at least one week, but less than three weeks.

[0162] In some embodiments, the method comprises inserting an intravesical drug delivery system comprising about 225 mg gemcitabine into the bladder of the individual and removing the intravesical drug delivery system about 7 to about 10 days later. In some embodiments, the intravesical drug delivery system comprises about 256 mg of gemcitabine HC1 (equivalent to about 225 mg gemcitabine FBE). In some aspects, provided herein is a method of treating a bladder cancer in an individual comprising administering gemcitabine locally to the bladder of the individual about every 3 weeks, wherein each gemcitabine administration comprises delivering gemcitabine continuously to the bladder for at least 7 days during a gemcitabine delivery period. In some embodiments, about 225 mg of gemcitabine is administered. In some embodiments, administering gemcitabine comprises inserting an intravesical drug delivery system comprising about 150 mg to about 300 mg, about 200 mg to about 250 mg, or about 225 mg of gemcitabine into the bladder and removing the intravesical drug delivery system about three weeks later. In some embodiments, administering gemcitabine comprises inserting an intravesical drug delivery system comprising about 171 mg to about 342 mg, about 228 mg to about 285 mg, or about 256 mg of gemcitabine HC1 into the bladder and removing the intravesical drug delivery system about three weeks later. In some embodiments, gemcitabine in the intravesical drug delivery system is in the form of a pharmaceutically acceptable salt. In some embodiments, gemcitabine is in the form of gemcitabine HC1. In some embodiments, the intravesical device comprises about 256 mg gemcitabine HC1. [0163] In some embodiments, the delivery period comprises local and continuous delivery of gemcitabine to the bladder. In some embodiments, the concentration of the gemcitabine or active metabolite thereof in the plasma of the individual is at a subtherapeutic level during portions of the delivery period.

[0164] In some embodiments, gemcitabine is administered to the individual about every three weeks. In some embodiments, administration of gemcitabine comprises inserting an intravesical drug delivery system and removing the intravesical drug delivery system about three weeks later. In some embodiments, the intravesical system delivers gemcitabine during a gemcitabine delivery period which comprises at least a portion of the about three week administration period. In some embodiments, the gemcitabine delivery period is at least one week. In some embodiments, the gemcitabine delivery period is at least two weeks. In some embodiments, the gemcitabine delivery period is at least about three weeks. In some embodiments, the gemcitabine delivery period is at least about two to about three weeks. In some embodiments, the gemcitabine delivery period is about one week to about three weeks. In some embodiments, the length of the gemcitabine delivery period is the same or about the same for each delivery period. In some embodiments, there is an effective concentration of gemcitabine in the urine of the individual during the gemcitabine delivery period.

[0165] In some of embodiments, each delivery period is about three weeks. In some embodiments, each delivery period is about 14 to about 21 days. In some embodiments, the gemcitabine is delivered multiple times over a period of more than six weeks. In some embodiments, the gemcitabine is delivered multiple times over a period of more than 12 weeks. In some embodiments, gemcitabine is delivered multiple times over a period of more than 15 weeks. In some embodiments, gemcitabine is delivered multiple times over a period of more than 18 weeks. In some embodiments, the gemcitabine is delivered multiple times over a period of more than 21 weeks. In some embodiments, gemcitabine is delivered multiple times over a period of about 24 weeks.

[0166] In some embodiments, provided herein is a method of treating papillary-only high-risk non-muscle invasive bladder cancer (HR-NMIBC) in a patient comprising (a) administering to the individual about 225 mg of gemcitabine about every three weeks (Q3W) for at least about 24 weeks during eight administration periods, and (b) administering to the individual about 225 mg of gemcitabine about every 3 months (Q3M) for at least about 60 weeks during six administration periods. In some embodiments, about 256 mg of gemcitabine HC1 is administered to the individual. [0167] In some embodiments, provided herein is a method of treating papillary-only high-risk non-muscle invasive bladder cancer (HR-NMIBC) in a patient comprising (a) administering to the individual about gemcitabine about every three weeks (Q3W) for at least about 24 weeks during eight administration periods, and (b) administering to the individual about 225 mg of gemcitabine about every 3 months (Q3M) for at least about 60 weeks during six administration periods.

[0168] In some embodiments, provided herein is a method of treating papillary-only high-risk non-muscle invasive bladder cancer (HR-NMIBC) in a patient comprising (a) administering to the individual about 256 mg of gemcitabine HC1 about every three weeks (Q3W) for at least about 24 weeks during eight administration periods, and (b) administering to the individual about 256 mg of gemcitabine HC1 about every 3 months (Q3M) for at least about 60 weeks during six administration periods.

[0169] In some embodiments, provided herein is a method of treating papillary-only recurrent high-risk non-muscle invasive bladder cancer (HR-NMIBC) in a patient comprising (a) administering to the individual about 225 mg of gemcitabine about every three weeks (Q3W) for at least about 24 weeks, and (b) administering to the individual about 225 mg of gemcitabine about every 12 weeks (Q12W) beginning at week 36 through week 99.

[0170] In some embodiments, provided herein is a method of treating papillary-only recurrent high-risk non-muscle invasive bladder cancer (HR-NMIBC) in a patient comprising (a) administering to the individual about 256 mg of gemcitabine HC1 about every three weeks (Q3W) for at least about 24 weeks, and (b) administering to the individual about 256 mg of gemcitabine HC1 about every 12 weeks (Q12W) beginning at week 36 through week 99.

[0171] In some embodiments, provided herein a method of treating papillary-only recurrent high-risk non-muscle invasive bladder cancer (HR-NMIBC) in a patient comprising (a) administering to the individual about 225 mg of gemcitabine about every three weeks (Q3W) for at least about 24 weeks in 8 doses, and (b) administering to the individual about 225 mg of gemcitabine about every 12 weeks (Q12W) beginning at week 36 through week 99 in 10 doses. [0172] In some embodiments, provided herein a method of treating papillary-only recurrent high-risk non-muscle invasive bladder cancer (HR-NMIBC) in a patient comprising (a) administering to the individual about 256 mg of gemcitabine HC1 about every three weeks (Q3W) for at least about 24 weeks in 8 doses, and (b) administering to the individual about 256 mg of gemcitabine HC1 about every 12 weeks (Q12W) beginning at week 36 through week 99 in 10 doses. [0173] In some embodiments, the gemcitabine is continuously delivered to the bladder for about 7, 8, 9, 10, 11, 12, 13 or 14 days. In some embodiments, the gemcitabine is continuously delivered to the bladder for up to 21 days (e.g., for about 15, 16, 17, 18, 19, 20, or 21 days). In some embodiments, the majority of the gemcitabine is delivered to the bladder within the first 14 days following insertion of the intravesical drug delivery system.

[0174] In some embodiments, the majority of gemcitabine within the intravesical drug delivery system is released in the first seven days of indwelling. In some embodiments, about 35% to about 55% of the 225 mg gemcitabine in the intravesical drug delivery system is released into the urine by day seven (after insertion into the bladder). In some embodiments, about 70% of the 225 mg gemcitabine in the intravesical drug delivery system is released into the urine by day seven (after insertion into the bladder). In some embodiments, the intravesical drug delivery system releases gemcitabine at a slower rate following the first seven days of indwelling. In some embodiments, about 70% to about 90% of the 225 mg gemcitabine in the intravesical drug delivery system is released into the urine by day 21 (after insertion into the bladder). In some embodiments, about 3% to about 20% of the 225 mg gemcitabine in the intravesical drug delivery system is released each day for the first seven days. In some embodiments, the gemcitabine is at a subtherapeutic level in the urine after day 7. In some embodiments, the gemcitabine is at a subtherapeutic level in the urine after day 10.

[0175] In some embodiments, the majority of gemcitabine within the intravesical drug delivery system is released in the first seven days of indwelling. In some embodiments, about 35% to about 55% of the 256 mg gemcitabine HC1 in the intravesical drug delivery system is released into the urine by day seven (after insertion into the bladder). In some embodiments, about 70% of the 256 mg gemcitabine HC1 in the intravesical drug delivery system is released into the urine by day seven (after insertion into the bladder). In some embodiments, the intravesical drug delivery system releases gemcitabine at a slower rate following the first seven days of indwelling. In some embodiments, about 70% to about 90% of the 256 mg gemcitabine HC1 in the intravesical drug delivery system is released into the urine by day 21 (after insertion into the bladder). In some embodiments, about 3% to about 20% of the 256 mg gemcitabine HC1 in the intravesical drug delivery system is released each day for the first seven days. In some embodiments, the gemcitabine is at a subtherapeutic level in the urine after day 7. In some embodiments, the gemcitabine is at a subtherapeutic level in the urine after day 10.

[0176] It may be advantageous to continuously deliver gemcitabine locally to the bladder more than once. For example, in some embodiments, the gemcitabine is delivered locally to the bladder of an individual at least twice, at least 3 times, at least 4 times, at least 5 times, or at least 10 times. In some embodiments, gemcitabine is delivered multiple times over a period of at least 12 weeks, at least 15 weeks, at least 18 weeks, at least 21 weeks, at least 24 weeks, at least 27 weeks, or at least 30 weeks. In some embodiments, gemcitabine is delivered multiple times over a period of at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 12 months, or at least 18 months. For example, in some embodiments, gemcitabine is delivered locally to the bladder of an individual twice, 3 times, 4 times, 5 times, or 10 times. In some embodiments, gemcitabine is delivered multiple times over a period of one month, one month to 18 months, 2 months to 18 months, 3 months to 18 months, or one month to 6 months.

[0177] In some embodiments, during the gemcitabine delivery period, there is an effective amount of gemcitabine in the urine of the individual for treating a bladder cancer. In some embodiments, the urine concentration of gemcitabine during the delivery period is about 1 pg/mL to about 25 pg/mL, about 1 pg/mL to about 20 pg/mL, about 1 pg/mL to about 15 pg/mL, about 1 pg/mL to about 10 pg/mL. In some embodiments, the urine concentration of gemcitabine during the delivery period is about 18.4 pg/mL. In some embodiments, the maximum urine concentration of gemcitabine during the delivery period is about 18.4 pg/mL. In some embodiments, the urine concentration of gemcitabine during the delivery period is about 16.1 pg/mL. In some embodiments, the urine concentration of gemcitabine during the delivery period is about 8.9 pg/mL. In some embodiments, the urine concentration of gemcitabine during the delivery period is about 6.9 pg/mL. In some embodiments, the urine concentration is at least 4-5 pg/mL for at least one week. In some embodiments, the urine concentration peaks on day 2 following insertion of an intravesical drug delivery system into the bladder of the individual. In some embodiments, the urine concentration peaks on day 4 following insertion of an intravesical drug delivery system into the bladder of the individual. In some embodiments, the urine concentration of gemcitabine ranges between about 4 pg/mL to about 40 pg/mL over the delivery period. In some embodiments, the urine concentration of gemcitabine ranges between about 4 pg/mL to about 40 pg/mL over about seven days. In some embodiments, the delivery period is less than three weeks. In some embodiments, the delivery period is one to three weeks. In some embodiments, the delivery period is one to two weeks. In some embodiments, administering gemcitabine comprises inserting an intravesical drug delivery system comprising gemcitabine into the bladder of the individual and removing the intravesical drug delivery system about three weeks later. In some embodiments, the concentration of the gemcitabine or active metabolite thereof in the plasma of the individual is at a subtherapeutic level during the delivery period. In some embodiments, upon delivery of gemcitabine the ratio of gemcitabine in the urine to gemcitabine in the plasma of the individual during the period of continuous delivery is greater than about 500: 1. In some embodiments, the main metabolite of gemcitabine is 2’, 2’ difluorodeoxyuridine (dFdU). In some embodiments, the plasma concentration of dFdU is less than 0.3 pg/mL upon delivery of the gemcitabine. In some embodiments, the plasma concentration of dFdU is less than 0.2 pg/mL upon delivery of the gemcitabine. In some embodiments, the plasma concentration of dFdU is less than 0.1 pg/mL upon delivery of the gemcitabine. In some embodiments, the plasma concentration of dFdU is between 0.1 and 0.3 pg/mL upon delivery of the gemcitabine.

[0178] In some embodiments, the method comprises administering gemcitabine locally to the bladder of the individual every three weeks or about every three weeks during an induction phase. In some embodiments, the dosing regimen comprises a maintenance phase following the induction phase. In some embodiments, the maintenance phase comprises administering an effective amount of gemcitabine locally to the bladder of the individual about every three months following the induction phase. In some embodiments, about 225 mg of gemcitabine is administered during each about three week period. In some embodiments, administering gemcitabine comprises inserting an intravesical drug delivery system comprising about 150 mg to about 300 mg, about 200 mg to about 250 mg, or about 225 mg of gemcitabine into the bladder and removing the intravesical drug delivery system about three weeks later. In some embodiments, administering gemcitabine comprises inserting an intravesical drug delivery system comprising about 171 mg to about 342 mg, about 228 mg to about 285 mg, or about 256 mg of gemcitabine HC1 into the bladder and removing the intravesical drug delivery system about three weeks later. In some embodiments, the intravesical drug delivery system comprises about 256 mg of gemcitabine HC1.

[0179] In some embodiments, the method comprises administering gemcitabine locally to the bladder of the individual every three weeks or about every three weeks during a first phase. In some embodiments, the dosing regimen comprises a second phase following the first phase. In some embodiments, the second phase comprises administering an effective amount of gemcitabine locally to the bladder of the individual about every three months following the first phase. In some embodiments, about 225 mg of gemcitabine is administered during each about three week period. In some embodiments, administering gemcitabine comprises inserting an intravesical drug delivery system comprising about 150 mg to about 300 mg, about 200 mg to about 250 mg, or about 225 mg of gemcitabine into the bladder and removing the intravesical drug delivery system about three weeks later. In some embodiments, administering gemcitabine comprises inserting an intravesical drug delivery system comprising about 171 mg to about 342 mg, about 228 mg to about 285 mg, or about 256 mg of gemcitabine HC1 into the bladder and removing the intravesical drug delivery system about three weeks later. In some embodiments, the intravesical drug delivery system comprises about 256 mg of gemcitabine HC1.

[0180] In some embodiments, the induction phase is between or between about 12 and 30 weeks long. In some embodiments, the induction phase is about 12 weeks long. In some embodiments, the induction phase is about 15 weeks long. In some embodiments, the induction phase is about 18 weeks long. In some embodiments, the induction phase is at least 21 weeks long. In some embodiments, the induction phase is about 24 weeks long.

[0181] In some embodiments, the first phase is between or between about 12 and 30 weeks long. In some embodiments, the first phase is about 12 weeks long. In some embodiments, the first phase is about 15 weeks long. In some embodiments, the first phase is about 18 weeks long. In some embodiments, the first phase is at least 21 weeks long. In some embodiments, the first phase is about 24 weeks long.

[0182] In some embodiments, the induction phase comprises multiple consecutive administrations of gemcitabine without interruption. In some embodiments, the induction phase comprises at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, or 8 consecutive administrations without a rest period. In some embodiments, each administration comprises inserting an intravesical drug delivery system comprising about 150 mg to about 300 mg, about 200 mg to about 250 mg, or about 225 mg of gemcitabine into the bladder and removing the intravesical drug delivery system about three weeks later. In some embodiments, administering gemcitabine comprises inserting an intravesical drug delivery system comprising about 171 mg to about 342 mg, about 228 mg to about 285 mg, or about 256 mg of gemcitabine HC1 into the bladder and removing the intravesical drug delivery system about three weeks later. In some embodiments, the intravesical drug delivery system comprises about 256 mg of gemcitabine HC1. In some embodiments, gemcitabine is continuously delivered during the induction phase. In some embodiments, the induction phase precedes the maintenance phase. In some embodiments the total of up to 24 weeks ends with removal of an intravesical drug delivery system on week 24.

[0183] In some embodiments, the first phase comprises multiple consecutive administrations of gemcitabine without interruption. In some embodiments, the first phase comprises at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, or 8 consecutive administrations without a rest period. In some embodiments, each administration comprises inserting an intravesical drug delivery system comprising about 150 mg to about 300 mg, about 200 mg to about 250 mg, or about 225 mg of gemcitabine into the bladder and removing the intravesical drug delivery system about three weeks later. In some embodiments, administering gemcitabine comprises inserting an intravesical drug delivery system comprising about 171 mg to about 342 mg, about 228 mg to about 285 mg, or about 256 mg of gemcitabine HC1 into the bladder and removing the intravesical drug delivery system about three weeks later. In some embodiments, the intravesical drug delivery system comprises about 256 mg of gemcitabine HC1. In some embodiments, gemcitabine is continuously delivered during the first phase. In some embodiments, the first phase precedes the second phase. In some embodiments the total of up to 24 weeks ends with removal of an intravesical drug delivery system on week 24.

[0184] In some aspects, described herein are methods of treating recurrent HR-NMIBC in patients that are unresponsive to or have experienced BCG therapy comprising: inserting an intravesical drug delivery system comprising about 225 mg of gemcitabine into the bladder of the individual about once every three weeks (Q3W) for a total of up to 24 weeks following starting treatment, wherein each intravesical drug delivery system is removed from the bladder about three weeks after insertion into the bladder and wherein each intravesical drug delivery system is removed prior to insertion of another intravesical drug delivery system. In some embodiments the total of up to 24 weeks ends with removal of an intravesical drug delivery system on week 24. In some embodiments, the individual has papillary only HR-NMIBC. In some aspects, described herein are methods of treating papillary-only HR-NMIBC in patients that are unresponsive to or have experienced BCG therapy comprising: inserting an intravesical drug delivery system comprising about 225 mg of gemcitabine into the bladder of the individual about once every three weeks (Q3W) for a total of up to 24 weeks following starting treatment, followed by inserting an intravesical drug delivery system comprising about 225 mg of gemcitabine into the bladder of the individual about once every 12 weeks (Q12W) for up to an additional 6 months after the first 24 weeks of treatment, wherein each intravesical drug delivery system is removed from the bladder about three weeks after insertion into the bladder and wherein each intravesical drug delivery system is removed prior to insertion of another intravesical drug delivery system.. In some embodiments, the intravesical drug delivery system comprises about 256 mg of gemcitabine HC1. [0185] In some aspects, described herein are methods of treating recurrent BCG-unresponsive or BCG-experienced HR-NMIBC in an individual comprising inserting an intravesical drug delivery system comprising about 225 mg of gemcitabine into the bladder of the individual about once every three weeks (Q3W) for a total of up to 24 weeks following starting treatment, followed by inserting an intravesical drug delivery system comprising about 225 mg of gemcitabine into the bladder of the individual about once every 12 weeks (Q12W) for up to an additional 75 weeks after the first 24 weeks of treatment, wherein each intravesical drug delivery system is removed from the bladder about three weeks after insertion into the bladder and wherein each intravesical drug delivery system is removed prior to insertion of another intravesical drug delivery system. In some embodiments, the intravesical drug delivery system comprises about 256 mg of gemcitabine HC1.

[0186] In some embodiments, the method comprises administering to the bladder of the individual a plurality of intravesical drug delivery systems during a first phase. In some embodiments, administering the plurality of intravesical drug delivery systems during a first phase comprises two or more three-week dosing cycles of gemcitabine comprising (i) inserting one of the plurality of intravesical drug delivery systems into the bladders about once every three weeks (Q3W); and (ii) removing the intravesical drug delivery system from the bladder about three weeks after insertion; wherein in each dosing cycle of gemcitabine steps (i) and (ii) of the dosing cycle of gemcitabine are repeated with a new intravesical drug delivery system of the plurality of intravesical drug delivery systems for up to about 24 weeks. In some embodiments, the first phase starts in week 0 with insertion of an intravesical drug delivery system and ends with removal of an intravesical drug delivery system on about week 24. In some embodiments, steps (i) and (ii) are performed eight times. In some embodiments, steps (i) and (ii) are performed eight times in a first phase. In some embodiments, steps (i) and (ii) are performed eight times in an induction phase. In some embodiments, the method comprises a first phase comprising eight doses of gemcitabine, each dose comprising administering an intravesical drug delivery system comprising about 225 mg gemcitabine to the bladder. In some embodiments, the intravesical drug delivery system comprises about 256 mg of gemcitabine HC1.

[0187] In some embodiments, a maintenance phase follows the induction phase. In some embodiments, the maintenance phase comprises administering gemcitabine periodically with rest periods between each administration. In some embodiments, there is a rest phase between the induction phase and the maintenance phase. In some embodiments, the rest phase before the maintenance phase is about 1 month, about 2 months, about 3 months, about 4 months, or about 5 months. In some embodiments, the rest phase between administrations in the maintenance phase is about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, or about 6 months. In some embodiments, the maintenance phase comprises administering gemcitabine quarterly, such as about every three months. In some embodiments, the maintenance phase starts on about week 36 following the start of treatment. In some embodiments, the maintenance phase ends on about week 99 following the start of treatment.

[0188] In some embodiments, a second phase follows the first phase. In some embodiments, the second phase comprises administering gemcitabine periodically with rest periods between each administration. In some embodiments, there is a rest phase between the first phase and the second phase. In some embodiments, the rest phase before the second phase is about 1 month, about 2 months, about 3 months, about 4 months, or about 5 months. In some embodiments, the rest phase between administrations in the second phase is about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, or about 6 months. In some embodiments, the second phase comprises administering gemcitabine quarterly, such as about every three months. In some embodiments, the second phase starts on about week 36 following the start of treatment. In some embodiments, the second phase ends on about week 99 following the start of treatment.

[0189] In some embodiments, the maintenance phase continues for at least 6 months, at least 12 months, at least 18 months, or at least 2 years. In some embodiments, the maintenance phase continues for about 12 months or about 18 months. In some embodiments, the total treatment with gemcitabine including the induction phase and the maintenance phase is about two years. In some embodiments, the total treatment with gemcitabine including the induction phase and the maintenance phase comprises 14 doses of gemcitabine, each dose comprising administering an intravesical drug delivery system comprising about 225 mg gemcitabine to the bladder. In some embodiments, the total treatment with gemcitabine including the induction phase and the maintenance phase comprises 14 doses of gemcitabine, each dose comprising administering an intravesical drug delivery system comprising about 256 mg gemcitabine HC1 to the bladder.

[0190] In some embodiments, the second phase continues for at least 6 months, at least 12 months, at least 18 months, or at least 2 years. In some embodiments, the second phase continues for about 12 months or about 18 months. In some embodiments, the total treatment with gemcitabine including the first phase and the second phase is about two years. In some embodiments, the total treatment with gemcitabine including the first phase and the second phase comprises 14 doses of gemcitabine, each dose comprising administering an intravesical drug delivery system comprising about 225 mg gemcitabine to the bladder. In some embodiments, the total treatment with gemcitabine including the first phase and the second phase comprises 14 doses of gemcitabine, each dose comprising administering an intravesical drug delivery system comprising about 256 mg gemcitabine HC1 to the bladder. In some embodiments, the second phase comprises Q12W dosing of gemcitabine beginning at Week 36, through Week 99 (Year 2), with last intravesical drug delivery system insertion at Week 96 and removal at Week 99. [0191] In some aspects, provided herein is a method of treating a bladder cancer in an individual comprising i) administering gemcitabine locally to the bladder of the individual about every three weeks for about at least 9 weeks, at least 15 weeks, at least 18 weeks, at least 21 weeks, or about 24 weeks during an induction phase; ii) administering an effective amount of gemcitabine locally to the bladder of the individual about every three months during a maintenance phase following the induction phase; wherein each administration of gemcitabine comprises continuously delivering gemcitabine to the bladder for at least 7 days during a gemcitabine delivery period. In some embodiments, about 225 mg of gemcitabine is administered. In some embodiments, administering gemcitabine comprises inserting an intravesical drug delivery system comprising about 150 mg to about 300 mg, about 200 mg to about 250 mg, or about 225 mg of gemcitabine into the bladder and removing the intravesical drug delivery system about three weeks later. In some embodiments, administering gemcitabine comprises inserting an intravesical drug delivery system comprising about 171 mg to about 342 mg, about 228 mg to about 285 mg, or about 256 mg of gemcitabine HC1 into the bladder and removing the intravesical drug delivery system about three weeks later. In some embodiments, the intravesical drug delivery system comprises about 256 mg of gemcitabine HC1.

[0192] In some aspects, provided herein is a method of treating a bladder cancer in an individual comprising i) administering gemcitabine locally to the bladder of the individual about every three weeks for about at least 9 weeks, at least 15 weeks, at least 18 weeks, at least 21 weeks, or about 24 weeks during a first phase; ii) administering an effective amount of gemcitabine locally to the bladder of the individual about every three months during a second phase following the first phase; wherein each administration of gemcitabine comprises continuously delivering gemcitabine to the bladder for at least 7 days during a gemcitabine delivery period. In some embodiments, about 225 mg of gemcitabine is administered. In some embodiments, administering gemcitabine comprises inserting an intravesical drug delivery system comprising about 150 mg to about 300 mg, about 200 mg to about 250 mg, or about 225 mg of gemcitabine into the bladder and removing the intravesical drug delivery system about three weeks later. In some embodiments, administering gemcitabine comprises inserting an intravesical drug delivery system comprising about 171 mg to about 342 mg, about 228 mg to about 285 mg, or about 256 mg of gemcitabine HC1 into the bladder and removing the intravesical drug delivery system about three weeks later. In some embodiments, the intravesical drug delivery system comprises about 256 mg of gemcitabine HC1.

[0193] In some embodiments, the method comprises (i) placing an intravesical drug delivery system into the bladder of the individual, wherein the intravesical drug delivery system remains in the bladder for about three weeks (e.g., 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 or 28 days) and wherein gemcitabine is continuously delivered to the bladder for at least seven days. In some embodiments, provided herein is a method of treating bladder cancer in an individual comprising (i) placing an intravesical drug delivery system into the bladder of the individual, wherein the intravesical drug delivery system remains in the bladder for about three weeks (e.g., 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 or 28 days) and wherein the intravesical drug delivery system delivers the gemcitabine passively. In some embodiments, provided herein is a method of treating bladder cancer in an individual comprising (i) placing a first intravesical drug delivery system into the bladder of the individual on day 0, (ii) removing the first intravesical drug delivery system about 3 weeks (e.g., 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 or 28 days) later, (iii) placing a second intravesical drug delivery system in the bladder of the individual on the same day as the removing of the first intravesical drug delivery system, and (iv) removing the second intravesical drug delivery system three weeks or about three weeks later. In some embodiments, the intravesical drug delivery system comprises about 225 mg of gemcitabine. In some embodiments, the intravesical drug delivery system comprises about 256 mg of gemcitabine HC1. In some embodiments, the subsequent intravesical drug delivery system is inserted on the same day that the previous intravesical drug delivery system is removed. In some embodiments, the subsequent intravesical drug delivery system is inserted within 1, within 2, within 3, within 4 or within 5 hours of removal of the previous intravesical drug delivery system. In some embodiments, the subsequent intravesical drug delivery system is inserted on a different day than the day that the previous intravesical drug delivery system is removed. In some embodiments, the subsequent intravesical drug delivery system is inserted within 1 day, within 2 days, within 3 days, within 4 days, within 5 days, within 6 days, or within 7 days of removal of the previous intravesical drug delivery system.

[0194] In some embodiments, the method comprises (i) placing an intravesical drug delivery system into the bladder of the individual, wherein the intravesical drug delivery system remains in the bladder for about three weeks (e.g., 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 or 28 days) and wherein the gemcitabine is continuously delivered to the bladder for at least 7 days. In some embodiments, provided herein is a method of treating bladder cancer in an individual comprising (i) using a urinary placement catheter, transurethrally deploying an intravesical drug delivery system into the bladder of the individual, wherein the intravesical drug delivery system remains in the bladder for about three weeks (e.g., 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 or 28 days) and wherein the intravesical drug delivery system delivers the gemcitabine passively. In some embodiments, provided herein is a method of treating bladder cancer in an individual comprising (i) using a urinary placement catheter, transurethrally deploying a first intravesical drug delivery system into the bladder of the individual on day 0, (ii) using a cystoscope, removing the first intravesical drug delivery system at about three weeks (e.g., 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 or 28 days) later, (iii) using a urinary placement catheter, transurethrally deploying a second intravesical drug delivery system in the bladder of the individual on the same day as the removing of the first intravesical drug delivery system, and (iv) using a cystoscope, removing the second intravesical drug delivery system three weeks or about three weeks later.

[0195] In some embodiments, gemcitabine is administered to the bladder of the individual via an intravesical drug delivery system comprising an intravesical device comprising about 225 mg of gemcitabine. In some embodiments, the intravesical drug delivery system comprises about 256 mg of gemcitabine HC1. In some embodiments, the intravesical delivery device comprises a housing defining a reservoir; a first unit (minitablet) contained within the reservoir, the first unit (minitablet) comprising an antimetabolite; and a second unit (minitablet) contained within the reservoir in a position distinct from the first unit (minitablet), wherein the second unit (minitablet) comprises a functional agent that facilitates in vivo release of the antimetabolite from the housing. In some embodiments, the intravesical device comprises a housing which contains and controllably releases the gemcitabine and is elastically deformable between a retention shape configured to retain the intravesical device in the individual’s bladder and a deployment shape for passage of the intravesical device through the individual’s urethra.

[0196] In some embodiments the intravesical device comprises a housing configured for intravesical insertion and a dosage form comprising gemcitabine, wherein the housing holds the dosage form and is configured to release gemcitabine in an amount effective for the treatment of high-risk non-muscle invasive bladder cancer. In some embodiments, the intravesical device comprises a housing defining a reservoir, a first unit contained within the reservoir comprising gemcitabine, and a second unit (minitablet) comprising a functional agent that facilitates in vivo release of gemcitabine from the housing. In some embodiments, the agent that facilitates release is urea. In some embodiments, the intravesical device comprises about 150 mg to about 300 mg, about 200 mg to about 250 mg, or about 225 mg gemcitabine. In some embodiments, the intravesical device comprises about 171 mg to about 342 mg, about 228 mg to about 285 mg, or about 256 mg of gemcitabine HC1. In some embodiments, the intravesical drug delivery system comprises about 256 mg of gemcitabine HC1.

[0197] In some embodiments, the intravesical drug delivery system releases gemcitabine at a rate of about 0.5 mg/day to about 50 mg/day, about 1 mg/day to about 40 mg/day, about 3 mg/day to about 30 mg/day, about 5 mg/day to about 20 mg/day, about 10 mg/day to about 40 mg/day, or about 1 mg/day to about 15 mg/day. In some embodiments, the intravesical drug delivery system releases gemcitabine at a rate of about 0.5 mg/day to about 50 mg/day, about 1 mg/day to about 40 mg/day, about 3 mg/day to about 30 mg/day, about 5 mg/day to about 20 mg/day, about 10 mg/day to about 40 mg/day, or about 1 mg/day to about 15 mg/day. In some embodiments, the intravesical device is elastically deformable between a retention shape configured to retain the intravesical device in the individual’s bladder and a deployment shape for passage of the intravesical device through the individual’s urea. In some embodiments, the retention shape is a pretzel or bi-oval shape. In some embodiments, the deployment shape is suitable for deployment through a catheter. In some embodiments, the intravesical device can be retrieved using a cytoscope and forceps. In some embodiments, gemcitabine is administered to the bladder about every three weeks during the induction phase and then every three months thereafter during the maintenance phase. In some embodiments, gemcitabine is administered to the bladder about every three weeks during the first phase and then every three months thereafter during the second phase.

[0198] In some embodiments, provided herein are methods of treating individuals with papillary-only high-risk non-muscle invasive bladder cancer comprising administering gemcitabine locally to the bladder of the individual, wherein each gemcitabine administration comprises delivering gemcitabine continuously to the bladder for at least seven days during a gemcitabine delivery period. In some embodiments, gemcitabine is administered to the bladder about every three weeks for up to the first six months and every three months thereafter. In some embodiments, gemcitabine is administered to the bladder about every three weeks for the first 21 weeks and then every three months thereafter for a total of about 2 years. In some embodiments, gemcitabine is administered to the bladder about every three weeks for the first 24 weeks and then every three months thereafter for a total of about 2 years. In some embodiments, about 225 mg of gemcitabine is administered during each administration. In some embodiments, about 256 mg gemcitabine HC1 is administered during each administration. In some embodiments, the individual has BCG-unresponsive papillary-only non-muscle invasive bladder cancer. In some embodiments, the individual has refused or is ineligible for radical cystectomy.

[0199] In some embodiments, the method of treating individuals with papillary-only high-risk non-muscle invasive bladder cancer comprises an induction phase and a maintenance phase. In some embodiments, the induction phase comprises administering gemcitabine locally to the bladder multiple times, without interruption. In some embodiments, each gemcitabine administration comprises a gemcitabine delivery period of at least seven days, during which a therapeutically effective amount of gemcitabine is released into the bladder. In some embodiments, administering gemcitabine comprises inserting an intravesical drug delivery system comprising gemcitabine and removing the intravesical drug delivery system about three weeks later. In some embodiments, the gemcitabine delivery period is less than three weeks. For example, in some embodiments, the induction phase comprises administering gemcitabine to the bladder every three weeks without interruption, wherein gemcitabine is delivered to the bladder for two to three weeks. In some embodiments, the induction phase comprises administering gemcitabine to the bladder every three weeks without interruption, wherein gemcitabine is delivered to the bladder for one to three weeks. In some embodiments, gemcitabine is administered to the bladder eight consecutive times without interruption during the induction phase. In some embodiments, gemcitabine is administered to the bladder eight times without interruption during the first phase for a total of about 24 weeks. In some embodiments, gemcitabine is delivered to the bladder by release from an intravesical drug delivery system. In some embodiments, the induction phase is about six months, such as about 24 weeks. In some embodiments, gemcitabine is administered about every three weeks for about 24 weeks during the induction phase. In some embodiments, about 225 mg gemcitabine is administered during each administration In some embodiments, the individual has BCG-unresponsive papillary-only non-muscle invasive bladder cancer. In some embodiments, the individual has refused or is ineligible for radical cystectomy.

[0200] In some embodiments, the method of treating individuals with papillary-only high-risk non-muscle invasive bladder cancer comprises a first phase and a second phase. In some embodiments, the first phase comprises administering gemcitabine locally to the bladder multiple times, without interruption. In some embodiments, each gemcitabine administration comprises a gemcitabine delivery period of at least seven days, during which a therapeutically effective amount of gemcitabine is released into the bladder. In some embodiments, administering gemcitabine comprises inserting an intravesical drug delivery system comprising gemcitabine and removing the intravesical drug delivery system about three weeks later. In some embodiments, the gemcitabine delivery period is less than three weeks. For example, in some embodiments, the first phase comprises administering gemcitabine to the bladder every three weeks without interruption, wherein gemcitabine is delivered to the bladder for two to three weeks. In some embodiments, the first phase comprises administering gemcitabine to the bladder every three weeks without interruption, wherein gemcitabine is delivered to the bladder for one to three weeks. In some embodiments, gemcitabine is administered to the bladder eight consecutive times without interruption during the first phase. In some embodiments, gemcitabine is administered to the bladder eight times without interruption during the first phase for a total of about 24 weeks. In some embodiments, gemcitabine is delivered to the bladder by release from an intravesical drug delivery system. In some embodiments, the first phase is about six months, such as about 24 weeks. In some embodiments, gemcitabine is administered about every three weeks for about 24 weeks during the first phase. In some embodiments, about 225 mg gemcitabine is administered during each administration. In some embodiments, gemcitabine is administered as a free base equivalent (FBE). In some embodiments, the gemcitabine FBE is a pharmaceutically acceptable salt of gemcitabine. In some embodiments, the gemcitabine FBE is gemcitabine hydrochloride (HC1). In some embodiments, about 256 mg of gemcitabine HC1 is administered to the individual during each administration. In some embodiments, the individual has BCG-unresponsive papillary-only non-muscle invasive bladder cancer. In some embodiments, the individual has refused or is ineligible for radical cystectomy.

[0201] In some embodiments, the induction phase comprises administering gemcitabine on weeks 0, 3, 6, 9, 12, 15, 18, and 21. In some embodiments, the induction phase comprises inserting an intravesical drug delivery system comprising gemcitabine on weeks 0, 3, 6, 9, 12, 15, 18, and 21 and removing each intravesical drug delivery system about three weeks later on weeks 3, 6, 9, 12, 15, 18, 21, and 24. In some embodiments, the induction phase comprises inserting a first intravesical drug delivery system comprising gemcitabine into the bladder in week 0 and removing the first intravesical drug delivery system in week 3, inserting a second intravesical drug delivery system comprising gemcitabine into the bladder in week 3 and removing the second intravesical drug delivery system in week 6, inserting a third intravesical drug delivery system comprising gemcitabine into the bladder in week 6 and removing the third intravesical drug delivery system in week 9, inserting a fourth intravesical drug delivery system comprising gemcitabine into the bladder in week 9 and removing the intravesical drug delivery system device in week 12, inserting a fifth intravesical drug delivery system comprising gemcitabine into the bladder in week 12 and removing the fifth intravesical drug delivery system in week 15, inserting a sixth intravesical drug delivery system comprising gemcitabine into the bladder in week 15 and removing the sixth intravesical drug delivery system in week 18, inserting a seventh intravesical drug delivery system comprising gemcitabine into the bladder in week 18 and removing the seventh intravesical drug delivery system in week 21, inserting an eighth intravesical drug delivery system in week 21 and removing the eighth intravesical drug delivery system in week 24. In some embodiments, the intravesical drug delivery system comprises about 150 mg to about 300 mg, about 200 mg to about 250 mg, or about 225 mg gemcitabine. In some embodiments, the intravesical drug delivery system comprises about 150 mg to about 300 mg, about 200 mg to about 250 mg, or about 225 mg gemcitabine. In some embodiments, the intravesical drug delivery system comprises about 171 mg to about 342 mg, about 228 mg to about 285 mg, or about 256 mg of gemcitabine HC1. In some embodiments, the intravesical drug delivery system comprises about 256 mg gemcitabine HC1. In some embodiments, the intravesical drug delivery system remains in the bladder for about three weeks. In some embodiments, the individual has BCG-unresponsive non-muscle invasive bladder cancer. In some embodiments, the individual has refused or is ineligible for radical cystectomy. [0202] In some embodiments, the first phase comprises administering gemcitabine on weeks 0, 3, 6, 9, 12, 15, 18, and 21. In some embodiments, the first phase comprises inserting an intravesical drug delivery system comprising gemcitabine on weeks 0, 3, 6, 9, 12, 15, 18, and 21 and removing each intravesical drug delivery system about three weeks later on weeks 3, 6, 9, 12, 15, 18, 21, and 24. In some embodiments, the previous intravesical drug delivery system is removed prior to insertion of the new intravesical drug delivery system such that there are not two intravesical drug delivery systems in the bladder at the same time.

[0203] In some embodiments, the first phase comprises inserting a first intravesical drug delivery system comprising gemcitabine into the bladder in week 0 and removing the first intravesical drug delivery system in week 3, inserting a second intravesical drug delivery system comprising gemcitabine into the bladder in week 3 and removing the second intravesical drug delivery system in week 6, inserting a third intravesical drug delivery system comprising gemcitabine into the bladder in week 6 and removing the third intravesical drug delivery system in week 9, inserting a fourth intravesical drug delivery system comprising gemcitabine into the bladder in week 9 and removing the intravesical drug delivery system device in week 12, inserting a fifth intravesical drug delivery system comprising gemcitabine into the bladder in week 12 and removing the fifth intravesical drug delivery system in week 15, inserting a sixth intravesical drug delivery system comprising gemcitabine into the bladder in week 15 and removing the sixth intravesical drug delivery system in week 18, inserting a seventh intravesical drug delivery system comprising gemcitabine into the bladder in week 18 and removing the seventh intravesical drug delivery system in week 21, inserting an eighth intravesical drug delivery system in week 21 and removing the eighth intravesical drug delivery system in week 24. In some embodiments, the intravesical drug delivery system comprises about 225 mg gemcitabine. In some embodiments, the intravesical drug delivery system comprises about 256 mg of gemcitabine HC1. In some embodiments, the individual has BCG-unresponsive nonmuscle invasive bladder cancer. In some embodiments, the individual has refused or is ineligible for radical cystectomy.

[0204] In some embodiments, the intravesical drug delivery system remains in the bladder for about three weeks. In some embodiments, the intravesical drug delivery system remains in the bladder for about 14 days to about 28 days. In some embodiments, the intravesical drug delivery system remains in the bladder for about 7 to about 10 days.

[0205] In some embodiments, a maintenance phase follows the induction phase. In some embodiments, there is a rest period between the induction phase and the maintenance phase, during which gemcitabine is not administered. In some embodiments, the rest period is about three to about five months. In some embodiments, the rest period is about 12 weeks. In some embodiments, gemcitabine is administered less frequently in the maintenance phase than in the induction phase. In some embodiments, the maintenance phase comprises rest periods during which no gemcitabine is delivered to the bladder of the individual. In some embodiments, the maintenance phase comprises delivering gemcitabine to the bladder of the individual quarterly or about every three months. In some embodiments, the intravesical drug delivery system comprises about 150 mg to about 300 mg, about 200 mg to about 250 mg, or about 225 mg gemcitabine. In some embodiments, the intravesical drug delivery system comprises about 171 mg to about 342 mg, about 228 mg to about 285 mg, or about 256 mg of gemcitabine HC1. In some embodiments, the intravesical drug delivery system comprises about 256 mg of gemcitabine HC1. In some embodiments, the individual has BCG-unresponsive papillary-only non-muscle invasive bladder cancer. In some embodiments, the individual has refused or is ineligible for radical cystectomy. [0206] In some embodiments, a second phase follows the first phase. In some embodiments, there is a rest period between the first phase and the second phase, during which gemcitabine is not administered. In some embodiments, the rest period is about three to about five months. In some embodiments, the rest period is about 12 weeks. In some embodiments, gemcitabine is administered less frequently in the second phase than in the first phase. In some embodiments, the second phase comprises rest periods during which no gemcitabine is delivered to the bladder of the individual. In some embodiments, the second phase comprises delivering gemcitabine to the bladder of the individual quarterly or about every three months. In some embodiments, the intravesical drug delivery system comprises 225 mg gemcitabine, some embodiments, the individual has BCG-unresponsive papillary-only non-muscle invasive bladder cancer. In some embodiments, the individual has refused or is ineligible for radical cystectomy.

[0207] In some embodiments, the maintenance phase comprises inserting an intravesical drug delivery system comprising gemcitabine into the bladder of the individual about every three months. In some embodiments, the intravesical drug delivery system remains in the bladder for about three weeks. In some embodiments, the intravesical drug delivery system comprises about 150 mg to about 300 mg, about 200 mg to about 250 mg, or about 225 mg gemcitabine. In some embodiments, the intravesical drug delivery system comprises about 171 mg to about 342 mg, about 228 mg to about 285 mg, or about 256 mg of gemcitabine HC1. In some embodiments, gemcitabine is administered to the bladder six times during the maintenance phase over the course of about 63 weeks. In some embodiments, the maintenance phase comprises administering gemcitabine to the bladder of the individual in weeks 36, 48, 60, 72, 84, and 96 of a dosing schedule. In some embodiments, the maintenance phase comprises inserting an intravesical drug delivery system comprising gemcitabine to the bladder of the individual in weeks 36, 48, 60, 72, 84, and 96 of a dosing schedule, and removing the intravesical drug delivery system in weeks 39, 51, 63, 75, 87, and 99 after an about three week indwelling period. In some embodiments, the individual has BCG-unresponsive non-muscle invasive bladder cancer. In some embodiments, the individual has refused or is ineligible for radical cystectomy. [0208] In some embodiments, the second phase comprises inserting an intravesical drug delivery system comprising gemcitabine into the bladder of the individual about every three months. In some embodiments, the intravesical drug delivery system remains in the bladder for about three weeks. In some embodiments, the intravesical drug delivery system comprises about 225 mg gemcitabine. In some embodiments, gemcitabine is administered as a free base equivalent (FBE). In some embodiments, the gemcitabine FBE is a pharmaceutically acceptable salt of gemcitabine. In some embodiments, the gemcitabine FBE is gemcitabine hydrochloride (HC1). In some embodiments, about 256 mg of gemcitabine HC1 is administered to the individual. In some embodiments, gemcitabine is administered to the bladder six times during the second phase over the course of about 63 weeks. In some embodiments, the second phase comprises administering gemcitabine to the bladder of the individual in weeks 36, 48, 60, 72, 84, and 96 of a dosing schedule. In some embodiments, the second phase comprises inserting an intravesical drug delivery system comprising gemcitabine to the bladder of the individual in weeks 36, 48, 60, 72, 84, and 96 of a dosing schedule, and removing the intravesical drug delivery system in weeks 39, 51, 63, 75, 87, and 99 after an about three week indwelling period. In some embodiments, the individual has BCG-unresponsive non-muscle invasive bladder cancer. In some embodiments, the individual has refused or is ineligible for radical cystectomy.

[0209] Also provided herein is a method of treating papillary-only high-risk non-muscle invasive bladder cancer in an individual comprising administering gemcitabine locally to the bladder of the individual about every 12 weeks, such as quarterly. In some embodiments, each gemcitabine administration is about three weeks. In some embodiments, each gemcitabine administration comprises a gemcitabine delivery period of at least seven days, during which a therapeutically effective amount of gemcitabine is released into the bladder. In some embodiments, administering gemcitabine comprises inserting an intravesical drug delivery system comprising gemcitabine and removing the intravesical drug delivery system about three weeks later. In some embodiments, gemcitabine is administered about every 12 weeks for at least six months. In some embodiments, gemcitabine is administered every about 12 weeks for at least one year. In some embodiments, gemcitabine is administered every about 12 weeks for about 18 months. In some embodiments, about 225 mg of gemcitabine is administered to the individual during each administration. In some embodiments, the individual has BCG-unresponsive papillary-only non- muscle invasive bladder cancer. In some embodiments, the individual has refused or is ineligible for radical cystectomy.

[0210] Also provided herein is a method of treating papillary-only high-risk non-muscle invasive bladder cancer in an individual comprising a dosing schedule of at least 21 weeks comprising administering about 225 mg gemcitabine locally to the bladder about every three weeks. In some embodiments, administering about 225 mg gemcitabine about every three weeks comprises inserting an intravesical drug delivery system into the bladder and removing the intravesical drug delivery system about three weeks later, wherein the intravesical drug delivery system comprises about 150 mg to about 300 mg, about 200 mg to about 250 mg, or about 225 mg gemcitabine. In some embodiments, administering about 225 mg gemcitabine about every three weeks comprises inserting an intravesical drug delivery system into the bladder and removing the intravesical drug delivery system about three weeks later, wherein the intravesical drug delivery system comprises about 171 mg to about 342 mg, about 228 mg to about 285 mg, or about 256 mg of gemcitabine HC1. In some embodiments, the intravesical drug delivery system continuously delivers gemcitabine to the bladder during a gemcitabine delivery period. In some embodiments, the gemcitabine delivery period is at least 7 days. In some embodiments, the gemcitabine delivery period is about three weeks or less. In some embodiments, the gemcitabine delivery period is at least one week or at least two weeks. In some embodiments, the gemcitabine delivery period is about one to about two weeks. In some embodiments, less than 225 mg of gemcitabine is delivered to the individual. In some embodiments, not all of the gemcitabine contained in the intravesical drug delivery system is released into the bladder. In some embodiments, the individual has BCG-unresponsive papillary-only non-muscle invasive bladder cancer. In some embodiments, the individual has refused or is ineligible for radical cystectomy.

[0211] In some embodiments, provided herein is a method of treating high-risk non-muscle invasive bladder cancer in an individual comprising inserting an intravesical drug delivery system comprising about 150 mg to about 300 mg, about 200 mg to about 250 mg, or about 225 mg gemcitabine into the bladder and removing the intravesical drug delivery system about three weeks later, wherein on the day that the intravesical drug delivery system is removed, a new intravesical drug delivery system comprising 225 mg gemcitabine is inserted into the bladder. In some embodiments, provided herein is a method of treating high-risk non-muscle invasive bladder cancer in an individual comprising inserting an intravesical drug delivery system comprising about 171 mg to about 342 mg, about 228 mg to about 285 mg, or about 256 mg of gemcitabine HC1 into the bladder and removing the intravesical drug delivery system about three weeks later, wherein on the day that the intravesical drug delivery system is removed, a new intravesical drug delivery system comprising 256 mg gemcitabine HC1 is inserted into the bladder. In some embodiments, an intravesical drug delivery system is inserted and removed eight consecutive times, without interruption. For example, in some embodiments, an intravesical drug delivery system is inserted in week 0, 3, 6, 9, 12, 15, 18, and 21 and the intravesical drug delivery system is removed in weeks 3, 6, 9, 12, 15, 18, 21, and 24. In some embodiments, the individual has BCG-unresponsive papillary-only non-muscle invasive bladder cancer. In some embodiments, the individual has refused or is ineligible for radical cystectomy. [0212] In some embodiments, the method comprises administering gemcitabine on weeks 0, 3, 6, 9, 12, 15, 18, 21, 36, 48, 60, 72, 84, and 96. In some embodiments, the method comprises inserting a first intravesical drug delivery system comprising gemcitabine into the bladder in week 0 and removing the first intravesical drug delivery system in week 3, inserting a second intravesical drug delivery system comprising gemcitabine into the bladder in week 3 and removing the second intravesical drug delivery system in week 6, inserting a third intravesical drug delivery system comprising gemcitabine into the bladder in week 6 and removing the third intravesical drug delivery system in week 9, inserting a fourth intravesical drug delivery system comprising gemcitabine into the bladder in week 9 and removing the intravesical drug delivery system device in week 12, inserting a fifth intravesical drug delivery system comprising gemcitabine into the bladder in week 12 and removing the fifth intravesical drug delivery system in week 15, inserting a sixth intravesical drug delivery system comprising gemcitabine into the bladder in week 15 and removing the sixth intravesical drug delivery system in week 18, inserting a seventh intravesical drug delivery system comprising gemcitabine into the bladder in week 18 and removing the seventh intravesical drug delivery system in week 21, inserting an eighth intravesical drug delivery system in week 21 and removing the eighth intravesical drug delivery system in week 24, inserting a ninth intravesical drug delivery system in week 36 and removing the ninth intravesical drug delivery system in week 39, inserting a tenth intravesical drug delivery system in week 48 and removing the tenth intravesical drug delivery system in week 51, inserting an eleventh intravesical drug delivery system in week 60 and removing the eleventh intravesical drug delivery system in week 63, inserting a twelfth intravesical drug delivery system in week 72 and removing the twelfth intravesical drug delivery system in week 75, inserting a thirteenth intravesical drug delivery system in week 84 and removing the thirteenth intravesical drug delivery system in week 87, inserting a fourteenth intravesical drug delivery system in week 96 and removing the fourteenth intravesical drug delivery system in week 99. In some embodiments, the intravesical drug delivery system comprises about 225 mg gemcitabine. In some embodiments, administering gemcitabine comprises inserting an intravesical drug delivery system comprising gemcitabine into the bladder and removing the intravesical drug delivery system about three weeks later. In some embodiments, the intravesical drug delivery system comprises about 150 mg to about 300 mg, about 200 mg to about 250 mg, or about 225 mg gemcitabine. In some embodiments, the intravesical drug delivery system comprises about 171 mg to about 342 mg, about 228 mg to about 285 mg, or about 256 mg of gemcitabine HC1. In some embodiments, the intravesical drug delivery system releases gemcitabine during a gemcitabine delivery period of at least one week. In some embodiments, the gemcitabine delivery period is at least two weeks. In some embodiments, the gemcitabine delivery period is less than three weeks. In some embodiments, the individual has BCG- unresponsive papillary-only non-muscle invasive bladder cancer. In some embodiments, the individual has refused or is ineligible for radical cystectomy.

[0213] In some embodiments, provided herein is a method of treating papillary-only HR- NMIBC comprising administering about 225 mg of gemcitabine per Q3W dosing cycle for 8 cycles (through Week 24, with last intravesical drug delivery system insertion at Week 21 and removal at Week 24), followed by Q12W TAR-200 maintenance dosing (6 doses) beginning at Week 36, through Week 99 (Year 2), with last intravesical drug delivery system insertion at Week 96 and removal at Week 99.

[0214] In some embodiments, provided herein is a method of treating papillary-only high-risk non-muscle invasive bladder cancer in an individual comprising administering gemcitabine locally to the bladder of the individual, wherein gemcitabine administration comprises delivering gemcitabine continuously to the bladder for at least 7 days during a gemcitabine delivery period, wherein during the gemcitabine delivery period, there is an effective amount of gemcitabine in the urine of the individual for treating high-risk non-muscle invasive bladder cancer. In some embodiments, the urine concentration of gemcitabine during the delivery period is about 1 pg/mL to about 25 pg/mL, about 1 pg/mL to about 20 pg/mL, about 1 pg/mL to about 15 pg/mL, about 1 pg/mL to about 10 pg/mL. In some embodiments, the urine concentration of gemcitabine during the delivery period is about 18.4 pg/mL. In some embodiments, the maximum urine concentration of gemcitabine during the delivery period is about 18.4 pg/mL. In some embodiments, the urine concentration of gemcitabine during the delivery period is about 16.1 pg/mL. In some embodiments, the urine concentration of gemcitabine during the delivery period is about 8.9 pg/mL. In some embodiments, the urine concentration of gemcitabine during the delivery period is about 6.9 pg/mL. In some embodiments, the delivery period is less than three weeks. In some embodiments, the delivery period is about one to about three weeks. In some embodiments, the delivery period is about one to about two weeks. In some embodiments, administering gemcitabine comprises inserting an intravesical drug delivery system comprising gemcitabine into the bladder of the individual and removing the intravesical drug delivery period about three weeks later. In some embodiments, gemcitabine is administered to the bladder about every three weeks for the first 24 weeks and then every three months thereafter for a total of about two years. In some embodiments, 225 mg of gemcitabine is administered during each administration some embodiments, the individual has BCG-unresponsive papillary-only nonmuscle invasive bladder cancer. In some embodiments, the individual has refused or is ineligible for radical cystectomy.

[0215] In some embodiments, provided herein is a method of treating papillary-only high-risk non-muscle invasive bladder cancer in an individual comprising administering gemcitabine locally to the bladder of the individual, wherein gemcitabine administration comprises delivering gemcitabine continuously to the bladder for at least 7 days during a gemcitabine delivery period, wherein the gemcitabine is delivered via an intravesical drug delivery system comprising an intravesical device and a drug, such as gemcitabine. In some embodiments the intravesical device comprises a housing configured for intravesical insertion and a dosage form comprising gemcitabine, wherein the housing holds the dosage form and is configured to release gemcitabine in an amount effective for the treatment of papillary-only high-risk non-muscle invasive bladder cancer. In some embodiments, the intravesical device comprises a housing defining a reservoir, a first unit contained within the reservoir comprising gemcitabine, and a second unit comprises a functional agent that facilitates in vivo release of gemcitabine from the housing. In some embodiments, the agent that facilitates release is urea. In some embodiments, the intravesical device comprises about 150 mg to about 300 mg, about 200 mg to about 250 mg, or about 225 mg gemcitabine. In some embodiments, the intravesical drug delivery system comprises about 171 mg to about 342 mg, about 228 mg to about 285 mg, or about 256 mg of gemcitabine HC1. In some embodiments, the intravesical drug delivery system comprises about 256 mg of gemcitabine HC1. In some embodiments, the intravesical drug delivery system releases about 0.5 mg/day to about 50 mg/day, about 1 mg/day to about 40 mg/day, about 3 mg/day to about 30 mg/day, about 5 mg/day to about 20 mg/day or about 1 mg/day to about 15 mg/day. In some embodiments, the intravesical device is elastically deformable between a retention shape configured to retain the intravesical device in the individual’s bladder and a deployment shape for passage of the intravesical device through the individual’s urea. In some embodiments, the retention shape is a pretzel or bi-oval shape. In some embodiments, the deployment shape is suitable for deployment through a catheter. In some embodiments, the intravesical device can be retrieved using a cytoscope and forceps. In some embodiments, gemcitabine is administered to the bladder about every three weeks for the first 24 weeks and then every three months thereafter for a total of about 2 years. In some embodiments, 225 mg of gemcitabine is administered during each administration. In some embodiments, the individual has BCG-unresponsive papillary-only non-muscle invasive bladder cancer. In some embodiments, the individual has refused or is ineligible for radical cystectomy.

[0216] In some embodiments, provided herein is a method of treating papillary-only high-risk non-muscle invasive bladder cancer in an individual comprising administering gemcitabine locally to the bladder of the individual, wherein gemcitabine administration comprises delivering gemcitabine continuously to the bladder for at least 7 days during a gemcitabine delivery period, wherein the individual has carcinoma in situ. In some embodiments, the individual has high grade disease. In some embodiments, the individual has high grade Ta or T1 disease. In some embodiments, the individual has papillary disease. In some embodiments, gemcitabine is administered to the bladder about every three weeks for the first 24 weeks and then about every three months thereafter for a total of about two years. In some embodiments, about 225 mg of gemcitabine is administered during each administration. In some embodiments, the individual has BCG-unresponsive papillary-only non-muscle invasive bladder cancer. In some embodiments, the individual has received previous intravesical BCG therapy. In some embodiments, BCG therapy comprises repeated instillations of BCG over the course of three or six weeks.

[0217] In some embodiments, the individual with papillary-only high-risk non muscle invasive bladder cancer is ineligible for or has elected not to undergo a radical cystectomy. In some embodiments, gemcitabine is administered to the bladder of the individual every about three weeks for the first 24 weeks and then about every three months thereafter for a total of about two years. In some embodiments, about 225 mg of gemcitabine is administered during each administration. In some embodiments, the individual has BCG-unresponsive papillary-only non- muscle invasive bladder cancer. In some embodiments, the individual has refused or is ineligible for radical cystectomy.

[0218] In some embodiments, the present methods comprising locally administering gemcitabine to the bladder result in reduced side effects compared to alternative treatments for papillary-only high-risk non muscle invasive bladder cancer. In some embodiments, the methods reduce the incidence of adverse effects, micturition urgency, pollakiuria, dysuria, noninfective cystitis, urinary tract infection, pruritus, and/or diarrhea compared to alternative therapies.

[0219] In some embodiments, the individual is ineligible for radical cystectomy under the National Comprehensive Cancer Network (NCCN) guidelines. For example, the individual may be unfit for curative therapy due to frailty. Prior to the present methods, such individuals typically received palliative radiation without chemotherapy (3.5 Gy/fraction - 10 treatments; or 7Gy/fraction - 7 treatments; TURBT; or no treatment).

[0220] In some embodiments, the individual cannot tolerate radical cystectomy based upon the American Society of Anesthesiology (ASA) guidelines. For example, the individual who cannot tolerate radial cystectomy may be deemed medically unfit for surgery requiring general or epidural anesthesia.

[0221] In other embodiments, the individual may not be suitable for radical cystectomy due to a lack of post-operative care infrastructure (e.g., as determined by the Comprehensive Geriatric Assessment provided by the American Society of Anesthesiologists). In some embodiments, an individual is not suitable for radical cystectomy due to frailty (e.g., as determined by the Comprehensive Geriatric Assessment provided by the American Society of Anesthesiologists). Under these guidelines, an individual is deemed frail if he or she shows abnormal independent activities of daily living, severe malnutrition, cognitive impairment, or comorbidities cumulative illness rating scale for geriatrics (CISR-G) grades 3-4.

C. Endpoints

[0222] The various aspects and embodiments described in this section in the context of a method of treatment comprising administering gemcitabine also apply to gemcitabine for use according to the methods described herein, and minitablets comprising gemcitabine for use according to the methods described herein. Similarly, the various aspects and embodiments described in this section in the context of a method of treatment comprising administering gemcitabine also apply to gemcitabine for use with an intravesical drug delivery system, according to the methods described herein, and gemcitabine for use according to the methods described herein, in combination with an intravesical drug delivery system, and gemcitabine for use according to the methods described herein, wherein the gemcitabine is administered by an intravesical drug delivery system.

[0223] In some embodiments, provided herein is a method of treating papillary-only high-risk non-muscle invasive bladder cancer in an individual comprising administering gemcitabine locally to the bladder of the individual, wherein gemcitabine administration comprises delivering gemcitabine continuously to the bladder for at least 7 days during a gemcitabine delivery period, wherein the individual experiences improved disease-free survival compared to a standard of care treatment. In some embodiments, the standard of care treatment comprises single agent intravesical chemotherapy comprising intravesical Mitomycin C therapy or intravesical gemcitabine therapy. In some embodiments, disease-free survival is measured as the time from randomization to either the time of the first recurrence of HR disease (HG Ta, any T1 or CIS), progression, or death due to any cause, whichever occurs first. In some embodiments, disease- free survival rate is measured as the percentage of participants with disease-free survival. In some embodiments, recurrence and progression events will be determined by central disease assessments of cytology, pathology, or imaging, as applicable. In some embodiments, gemcitabine is administered to the bladder of the individual about every three weeks for the first 24 weeks and then about every three months thereafter for a total of about two years. In some embodiments, about 225 mg of gemcitabine is administered during each administration. In some embodiments, gemcitabine is administered as a free base equivalent (FBE). In some embodiments, the gemcitabine FBE is a pharmaceutically acceptable salt of gemcitabine. In some embodiments, the gemcitabine FBE is gemcitabine hydrochloride (HC1). In some embodiments, about 256 mg of gemcitabine HC1 is administered to the individual. In some embodiments, the individual has BCG-unresponsive high-risk non-muscle invasive bladder cancer. In some embodiments, the individual has recurrent papillary-only high-risk non-muscle invasive bladder cancer. In some embodiments, the individual has refused or is ineligible for radical cystectomy. In some embodiments, “improved” disease-free survival is a longer duration of disease-free survival in an individual.

[0224] In some embodiments, provided herein is a method of treating papillary-only high-risk non-muscle invasive bladder cancer in an individual comprising administering gemcitabine locally to the bladder of the individual, wherein gemcitabine administration comprises delivering gemcitabine continuously to the bladder for at least 7 days during a gemcitabine delivery period, wherein the individual experiences prolonged disease-free survival compared to a standard of care treatment. In some embodiments, the standard of care treatment comprises single agent intravesical chemotherapy comprising intravesical Mitomycin C therapy or intravesical gemcitabine therapy. In some embodiments, disease-free survival is measured as the time from randomization to either the time of the first recurrence of HR disease (HG Ta, any T1 or CIS), progression, or death due to any cause, whichever occurs first. In some embodiments, recurrence and progression events will be determined by central disease assessments of cytology, pathology, or imaging, as applicable. In some embodiments, gemcitabine is administered to the bladder of the individual about every three weeks for the first 24 weeks and then about every three months thereafter for a total of about two years. In some embodiments, about 225 mg of gemcitabine is administered during each administration. In some embodiments about 256 mg of gemcitabine HC1 is administered during each administration. In some embodiments, the individual has BCG- unresponsive high-risk non-muscle invasive bladder cancer. In some embodiments, the individual has recurrent papillary-only high-risk non-muscle invasive bladder cancer. In some embodiments, the individual has refused or is ineligible for radical cystectomy.

[0225] In some embodiments, provided herein is a method of treating papillary-only high-risk non-muscle invasive bladder cancer (HR-NMIBC) in a patient comprising (a) administering to the individual about 225 mg of gemcitabine about every three weeks (Q3W) for at least about 24 weeks during eight administration periods, (b) administering to the individual about 225 mg of gemcitabine about every 3 months (Q3M) for at least about 60 weeks during six administration periods, (c) extending disease-free survival in the individual by at least about 9 months; wherein each administration period comprises a delivery period of at least seven days. In some embodiments, extending disease-free survival is increasing the length of time an individual experiences disease-free survival. In some embodiments about 256 mg of gemcitabine HC1 is administered during each administration.

[0226] In some embodiments, provided herein is a method of treating papillary-only high-risk non-muscle invasive bladder cancer (HR-NMIBC) in a patient comprising (a) administering to the individual about 225 mg of gemcitabine about every three weeks (Q3W) for at least about 24 weeks during eight administration periods, (b) administering to the individual about 225 mg of gemcitabine about every 12 weeks (Q12W) for at least about 60 weeks during six administration periods, (c) extending disease-free survival in the individual by at least about 9 months; wherein each administration period comprises a delivery period of at least seven days. In some embodiments, extending disease-free survival is increasing the length of time an individual experiences disease-free survival. In some embodiments about 256 mg of gemcitabine HC1 is administered during each administration.

[0227] In some embodiments, provided herein is a method of treating papillary-only high-risk non-muscle invasive bladder cancer (HR-NMIBC) in a patient comprising (a) administering to the individual about 225 mg of gemcitabine about every three weeks (Q3W) for at least about 24 weeks during eight administration periods, (b) administering to the individual about 225 mg of gemcitabine about every 12 weeks (Q12W) for at least about 60 weeks during six administration periods, (c) extending disease-free survival in the individual by at least about 9 months; wherein each administration period comprises a delivery period of at least seven days. In some embodiments about 256 mg of gemcitabine HC1 is administered during each administration.

[0228] In some embodiments, provided herein is a method of treating papillary-only high-risk non-muscle invasive bladder cancer in a population of patients comprising administering gemcitabine locally to the bladder of each patient, wherein gemcitabine administration comprises delivering gemcitabine continuously to the bladder for at least 7 days during a gemcitabine delivery period, wherein such treatment results in an improved 1-year disease-free survival rate in a population of patients who have received such treatment of at least 40% longer than in a population of patients who have received standard of care therapy. In some embodiments, such treatment results in a disease-free survival of at least about 9 months. In some embodiments, the population of patients comprises individuals with papillary-only high-risk non-muscle invasive bladder cancer. In some embodiments, the population of patients comprises individuals who have received BCG between 1 and 22 months prior to the start of treatment with gemcitabine. In some embodiments, the population of patients comprises individuals who do not receive a radical cystectomy. In some embodiments, the majority of individuals in the population of patients declined radical cystectomy. In some embodiments, the therapy is a bladder sparing therapy. In some embodiments, the individual does not receive a radical cystectomy.

[0229] In some embodiments, provided herein is a method of treating papillary-only high-risk non-muscle invasive bladder cancer in a population of patients comprising administering gemcitabine locally to the bladder of each patient, wherein gemcitabine administration comprises delivering gemcitabine continuously to the bladder for at least 7 days during a gemcitabine delivery period, wherein such treatment results in an increased median disease-free survival in a population of patients who have received such treatment compared to a population of patients who have received standard of care therapy. In some embodiments, such treatment results in a median disease-free survival of at least about 9 months. In some embodiments, median disease- free survival is measured as the median amount of time during which individuals experience disease-free survival. In some embodiments, the population of patients comprises individuals with papillary-only high-risk non-muscle invasive bladder cancer. In some embodiments, the population of patients comprises individuals who have received BCG between 1 and 22 months prior to the start of treatment with gemcitabine. In some embodiments, the population of patients comprises individuals who do not receive a radical cystectomy. In some embodiments, the majority of individuals in the population of patients declined radical cystectomy. In some embodiments, the therapy is a bladder sparing therapy. In some embodiments, the individual does not receive a radical cystectomy. In some embodiments, gemcitabine is delivered locally to the bladder about every three weeks (Q3W) for up to about 24 weeks followed by 12 weeks (Q12W) for up to 18 months. [0230] In some embodiments, provided herein is a method of treating papillary-only high-risk non-muscle invasive bladder cancer in a population of patients comprising administering gemcitabine locally to the bladder of each patient, wherein gemcitabine administration comprises delivering gemcitabine continuously to the bladder for at least 7 days during a gemcitabine delivery period, wherein such treatment results in increased recurrence-free survival (RFS) in a population of patients compared to the standard of care treatment. In some embodiments, provided herein is a method of treating papillary-only high-risk non-muscle invasive bladder cancer in a population of patients comprising administering gemcitabine locally to the bladder of each patient, wherein gemcitabine administration comprises delivering gemcitabine continuously to the bladder for at least 7 days during a gemcitabine delivery period, wherein such treatment results in recurrence-free survival (RFS) in a population of patients who have received such treatment of at least 40% longer than in a population of patients who have received standard of care therapy. In some embodiments, such treatment results in a recurrence-free survival of at least about 9 months. In some embodiments, RFS is measured as the time from randomization to the time of the first recurrence of HR disease including high-grade Ta bladder cancer, or any T1 or CIS bladder cancer, or death due to any cause, whichever occurs first. In some embodiments, the population of patients comprises individuals with papillary-only high-risk non-muscle invasive bladder cancer. In some embodiments, the population of patients comprises individuals who have received BCG between 1 and 22 months prior to the start of treatment with gemcitabine. In some embodiments, the population of patients comprises individuals who do not receive a radical cystectomy. In some embodiments, the majority of individuals in the population of patients declined radical cystectomy. In some embodiments, the therapy is a bladder sparing therapy. In some embodiments, the individual does not receive a radical cystectomy. In some embodiments, gemcitabine is delivered locally to the bladder about every three weeks (Q3W) for up to about 24 weeks followed by 12 weeks (Q12W) for up to 18 months.

[0231] In some embodiments, provided herein is a method of treating papillary-only high-risk non-muscle invasive bladder cancer in a population of patients comprising administering gemcitabine locally to the bladder of each patient, wherein gemcitabine administration comprises delivering gemcitabine continuously to the bladder for at least 7 days during a gemcitabine delivery period, wherein such treatment results in time to next intervention (TTNI) in a population of patients who have received such treatment of at least 40% longer than in a population of patients who have received standard of care therapy. In some embodiments, such treatment results in a time to next intervention of at least about 9 months. In some embodiments, TTNI is measured from the date of randomization to the date of next localized intervention or systemic intervention for the treatment of bladder cancer. In some embodiments, the population of patients comprises individuals with papillary-only high-risk non-muscle invasive bladder cancer. In some embodiments, the population of patients comprises individuals who have received BCG between 1 and 22 months prior to the start of treatment with gemcitabine. In some embodiments, the population of patients comprises individuals who do not receive a radical cystectomy. In some embodiments, the majority of individuals in the population of patients declined radical cystectomy. In some embodiments, the therapy is a bladder sparing therapy. In some embodiments, the individual does not receive a radical cystectomy. In some embodiments, the individual is ineligible for or elected not to undergo radical cystectomy. In some embodiments, gemcitabine is delivered locally to the bladder about every three weeks (Q3W) for up to about 24 weeks followed by 12 weeks (Q12W) for up to 18 months.

[0232] In some embodiments, provided herein is a method of treating papillary-only high-risk non-muscle invasive bladder cancer in a population of patients comprising administering gemcitabine locally to the bladder of each patient, wherein gemcitabine administration comprises delivering gemcitabine continuously to the bladder for at least 7 days during a gemcitabine delivery period, wherein such treatment results in an increased time to disease worsening (TTDW) in a population of patients who have received such treatment compared to those who have received standard of care therapy. In some embodiments, provided herein is a method of treating papillary-only high-risk non-muscle invasive bladder cancer in a population of patients comprising administering gemcitabine locally to the bladder of each patient, wherein gemcitabine administration comprises delivering gemcitabine continuously to the bladder for at least 7 days during a gemcitabine delivery period, wherein such treatment results in a time to disease worsening (TTDW) in a population of patients who have received such treatment of at least 40% longer than in a population of patients who have received standard of care therapy. In some embodiments, such treatment results in a time to disease worsening of at least about 9 months. In some embodiments, TTDW is measured from the date of randomization to the date of cystectomy, systemic therapy, or radiation therapy (treatments of disease worsening). In some embodiments, the population of patients comprises individuals with papillary-only high-risk non- muscle invasive bladder cancer. In some embodiments, the population of patients comprises individuals who have received BCG between 1 and 22 months prior to the start of treatment with gemcitabine. In some embodiments, the population of patients comprises individuals who do not receive a radical cystectomy. In some embodiments, the majority of individuals in the population of patients declined radical cystectomy. In some embodiments, the therapy is a bladder sparing therapy. In some embodiments, the individual does not receive a radical cystectomy. In some embodiments, gemcitabine is delivered locally to the bladder about every three weeks (Q3W) for up to about 24 weeks followed by 12 weeks (Q12W) for up to 18 months.

[0233] In some embodiments, provided herein is a method of treating papillary-only high-risk non-muscle invasive bladder cancer in a population of patients comprising administering gemcitabine locally to the bladder of each patient, wherein gemcitabine administration comprises delivering gemcitabine continuously to the bladder for at least 7 days during a gemcitabine delivery period, wherein such treatment results in time to progression (TTP) in a population of patients who have received such treatment of at least about 40% longer than in a population of patients who have received standard of care therapy. In some embodiments, such treatment results in a time to progression of at least about 9 months. In some embodiments, TTP is measured as the time from randomization to the date of first documented evidence of disease progression (e.g., HG Ta to Tl, MIBC, nodal or distant metastasis) or death due to disease progression, whichever occurs first. In some embodiments, the population of patients comprises individuals with papillary-only high-risk non-muscle invasive bladder cancer. In some embodiments, the population of patients comprises individuals who have received BCG between 1 and 22 months prior to the start of treatment with gemcitabine. In some embodiments, the population of patients comprises individuals who do not receive a radical cystectomy. In some embodiments, the majority of individuals in the population of patients declined radical cystectomy. In some embodiments, the therapy is a bladder sparing therapy. In some embodiments, the individual does not receive a radical cystectomy. In some embodiments, gemcitabine is delivered locally to the bladder about every three weeks (Q3W) for up to about 24 weeks followed by 12 weeks (Q12W) for up to 18 months.

[0234] In some embodiments, provided herein is a method of treating papillary-only high-risk non-muscle invasive bladder cancer in a population of patients comprising administering gemcitabine locally to the bladder of each patient, wherein gemcitabine administration comprises delivering gemcitabine continuously to the bladder for at least 7 days during a gemcitabine delivery period, wherein such treatment results in a disease-free survival (DFS) at 12 months in a population of patients who have received such treatment of at least about 20% longer than in a population of patients who have received standard of care therapy. In some embodiments, such treatment results in a disease-free survival (DFS) at 24 months in a population of patients who have received such treatment of at least 20% longer than in a population of patients who have received standard of care therapy. In some embodiments, such treatment results in a 12- month disease-free survival rate of at least about 60%. In some embodiments, such treatment results in a 24- month disease-free survival rate of at least about 30%. In some embodiments, the 12-month DFS rate is defined as the percentage of participants with DFS at 12 months. In some embodiments, the 24-month DFS rate is defined as the percentage of participants with DFS at 24 months. In some embodiments, the population of patients comprises individuals with papillary- only high-risk non-muscle invasive bladder cancer. In some embodiments, the population of patients comprises individuals who have received BCG between 1 and 22 months prior to the start of treatment with gemcitabine. In some embodiments, the population of patients comprises individuals who do not receive a radical cystectomy. In some embodiments, the majority of individuals in the population of patients declined radical cystectomy. In some embodiments, the therapy is a bladder sparing therapy. In some embodiments, the individual does not receive a radical cystectomy. In some embodiments, gemcitabine is delivered locally to the bladder about every three weeks (Q3W) for up to about 24 weeks followed by 12 weeks (Q12W) for up to 18 months.

[0235] In some embodiments, provided herein is a method of treating papillary-only high-risk non-muscle invasive bladder cancer in a population of patients comprising administering gemcitabine locally to the bladder of each patient, wherein gemcitabine administration comprises delivering gemcitabine continuously to the bladder for at least 7 days during a gemcitabine delivery period, wherein such treatment results in an increased overall survival (OS) in a population of patients who have received such treatment compared to a population of patients who have received standard of care therapy. In some embodiments, OS is defined as the time from randomization to death, due to any cause. In some embodiments, the population of patients comprises individuals with papillary-only high-risk non-muscle invasive bladder cancer. In some embodiments, the population of patients comprises individuals who have received BCG between 1 and 22 months prior to the start of treatment with gemcitabine. In some embodiments, the population of patients comprises individuals who do not receive a radical cystectomy. In some embodiments, the majority of individuals in the population of patients declined radical cystectomy. In some embodiments, the therapy is a bladder sparing therapy. In some embodiments, the individual does not receive a radical cystectomy. In some embodiments, gemcitabine is delivered locally to the bladder about every three weeks (Q3W) for up to about 24 weeks followed by 12 weeks (Q12W) for up to 18 months.

[0236] In some embodiments, provided herein is a method of treating papillary-only high-risk non-muscle invasive bladder cancer in a population of patients comprising administering gemcitabine locally to the bladder of each patient, wherein gemcitabine administration comprises delivering gemcitabine continuously to the bladder for at least 7 days during a gemcitabine delivery period, wherein such treatment results in an all-cause disease-free survival (aDFS) in a population of patients who have received such treatment of at least about 40% longer than in a population of patients who have received standard of care therapy. In some embodiments, such treatment results in an all-cause disease-free survival of at least about 9 months. In some embodiments, aDFS is defined as the time from randomization until the date of the recurrence of or progression to any of the following, whichever is reported first: any grade of Ta or T1 disease or higher, CIS, N+, M+, or death. In some embodiments, the population of patients comprises individuals with papillary-only high-risk non-muscle invasive bladder cancer. In some embodiments, the population of patients comprises individuals who have received BCG between 1 and 22 months prior to the start of treatment with gemcitabine. In some embodiments, the population of patients comprises individuals who do not receive a radical cystectomy. In some embodiments, the majority of individuals in the population of patients declined radical cystectomy. In some embodiments, the therapy is a bladder sparing therapy. In some embodiments, the individual does not receive a radical cystectomy. In some embodiments, gemcitabine is delivered locally to the bladder about every three weeks (Q3W) for up to about 24 weeks followed by 12 weeks (Q12W) for up to 18 months.

[0237] In some embodiments, provided herein is a method of treating papillary-only high-risk non-muscle invasive bladder cancer in a population of patients comprising administering gemcitabine locally to the bladder of each patient, wherein gemcitabine administration comprises delivering gemcitabine continuously to the bladder for at least 7 days during a gemcitabine delivery period, wherein such treatment results in an increased cancer-specific survival (CSS) in a population of patients who have received such treatment compared to a population of patients who have received standard of care therapy. In some embodiments, CSS will be measured as the time from randomization to the date of death due to bladder cancer. In some embodiments, the population of patients comprises individuals who have received BCG between 1 and 22 months prior to the start of treatment with gemcitabine. In some embodiments, the population of patients comprises individuals who do not receive a radical cystectomy. In some embodiments, the majority of individuals in the population of patients declined radical cystectomy. In some embodiments, the therapy is a bladder sparing therapy. In some embodiments, the individual does not receive a radical cystectomy. In some embodiments, gemcitabine is delivered locally to the bladder about every three weeks (Q3W) for up to about 24 weeks followed by 12 weeks (Q12W) for up to 18 months.

[0238] In some embodiments, provided herein is a method of treating papillary-only high-risk non-muscle invasive bladder cancer in a population of patients comprising administering gemcitabine locally to the bladder of each patient, wherein gemcitabine administration comprises delivering gemcitabine continuously to the bladder for at least 7 days during a gemcitabine delivery period, wherein such treatment results in an increased time to cystectomy (TTC) in a population of patients who have received such treatment compared to a population of patients who have received standard of care therapy. In some embodiments, such treatment results in a time to cystectomy of at least about 12 months. In some embodiments, TTC will be measured as the time from randomization to the date of the cystectomy. In some embodiments, the population of patients comprises individuals who have received BCG between 1 and 22 months prior to the start of treatment with gemcitabine. In some embodiments, gemcitabine is delivered locally to the bladder about every three weeks (Q3W) for up to about 24 weeks followed by 12 weeks (Q12W) for up to 18 months.

[0239] In some embodiments, provided herein is a method of treating papillary-only high-risk non-muscle invasive bladder cancer in a population of patients comprising administering gemcitabine locally to the bladder of each patient, wherein gemcitabine administration comprises delivering gemcitabine continuously to the bladder for at least 7 days during a gemcitabine delivery period, wherein such treatment results in an increased disease-free survival at 2 years (DFS2) in a population of patients who have received such treatment compared to a population of patients who have received standard of care therapy. In some embodiments, DFS2 is defined as the time from randomization until the date of recurrence of HR disease, progression, or death due to any cause on the first subsequent anticancer treatment, whichever occurs first. In some embodiments, the population of patients comprises individuals who have received BCG between 1 and 22 months prior to the start of treatment with gemcitabine. In some embodiments, the population of patients comprises individuals who do not receive a radical cystectomy. In some embodiments, the majority of individuals in the population of patients declined radical cystectomy. In some embodiments, the therapy is a bladder sparing therapy. In some embodiments, the individual does not receive a radical cystectomy. In some embodiments, gemcitabine is delivered locally to the bladder about every three weeks (Q3W) for up to about 24 weeks followed by 12 weeks (Q12W) for up to 18 months.

[0240] In some embodiments, provided herein is a method of treating papillary-only high-risk non-muscle invasive bladder cancer in a population of patients comprising administering gemcitabine locally to the bladder of each patient, wherein gemcitabine administration comprises delivering gemcitabine continuously to the bladder for at least 7 days during a gemcitabine delivery period, wherein a two-year surveillance period begins at about 24 to 47 days after the first administration of gemcitabine. In some embodiments, cystoscopy and cytology assessments are performed at about week 12, about week 24, about week 36, about week 48, about week 60, about week 72, about week 84, about week 96, about week 120, and about week 144 during treatment. In some embodiments, a complete response is observed during a scheduled cystoscopy and cytology assessment during treatment. In some embodiments, gemcitabine is delivered locally to the bladder about every three weeks (Q3W) for about 24 weeks. In some embodiments, gemcitabine is delivered locally to the bladder about every three weeks (Q3W) for about 24 weeks during an induction phase and then about every three months during a maintenance phase. In some embodiments, gemcitabine is delivered locally to the bladder about every three weeks (Q3W) for up to about 24 weeks followed by 12 weeks (Q12W) for up to 18 months. In some embodiments, the therapy is a bladder sparing therapy. In some embodiments, the individual does not receive a radical cystectomy.

[0241] In some embodiments, provided herein is a method of treating papillary-only high-risk non-muscle invasive bladder cancer that is unresponsive to or experienced intravesical Bacillus Calmette-Guerin (BCG) therapy in a population of patients comprising administering gemcitabine locally to the bladder of each patient, wherein gemcitabine administration comprises delivering gemcitabine continuously to the bladder for at least 7 days during a gemcitabine delivery period, wherein such treatment results in an improved disease-free survival compared to a standard of care treatment. In some embodiments, the standard of care treatment comprises radical cystectomy. In some embodiments, the standard of care treatment comprises a systemic or intravesical chemotherapy. In some embodiments, the standard of care treatment comprises mitomycin C therapy. In some embodiments, the standard of care treatment comprises Valrubicin. In some embodiments, the standard of care treatment comprises pembrolizumab. In some embodiments, the standard of care treatment comprises paclitaxel. In some embodiments, the standard of care treatment comprises an immune checkpoint therapy such as pembrolizumab. In some embodiments, the standard of care treatment includes an adjuvant chemotherapy such as mitomycin C, epirubicin, or doxorubicin. In some embodiments, the standard of care treatment comprises a systemic or intravesical combination chemotherapy. In some embodiments, the combination intravesical chemotherapy is composed of gemcitabine and docetaxel. In some embodiments, gemcitabine is delivered locally to the bladder about every three weeks (Q3W) for about 24 weeks. In some embodiments, gemcitabine is delivered locally to the bladder about every three weeks (Q3W) for about 24 weeks during an induction phase and then about every three months during a maintenance phase. In some embodiments, gemcitabine is delivered locally to the bladder about every three weeks (Q3W) for up to about 24 weeks followed by 12 weeks (Q12W) for up to 18 months. In some embodiments, the therapy is a bladder sparing therapy. In some embodiments, the individual does not receive a radical cystectomy.

[0242] In some embodiments, provided herein is a method of treating papillary-only high-risk non-muscle invasive bladder cancer comprising administering gemcitabine to an individual, wherein gemcitabine administration comprises delivering gemcitabine continuously to the bladder for at least 7 days during a gemcitabine delivery period, wherein following such treatment the individual exhibits no evidence of bladder cancer. In some embodiments, following such treatment, the individual has a biopsy-proven benign or low-grade NMIBC. In some embodiments, the biopsy-proven benign or low-grade NMIBC comprises a low-grade Ta bladder cancer. In some embodiments, the low-grade NMIBC is a non-invasive papillary (Ta) tumor. In some embodiments, gemcitabine is delivered locally to the bladder about every three weeks (Q3W) for about 24 weeks. In some embodiments, gemcitabine is delivered locally to the bladder about every three weeks (Q3W) for about 24 weeks during an induction phase and then about every three months during a maintenance phase. In some embodiments, gemcitabine is delivered locally to the bladder about every three weeks (Q3W) for up to about 24 weeks followed by 12 weeks (Q12W) for up to 18 months. In some embodiments, the therapy is a bladder sparing therapy. In some embodiments, the individual does not receive a radical cystectomy.

[0243] In some embodiments, the methods provided herein result in bladder sparing in an individual with papillary-only HR-NIMBC that is unresponsive to BCG therapy. In some embodiments, the bladder sparing methods provided herein result in significant improvements on quality of life for treated individuals. In some embodiments, a quality-of-life score is calculated for treated individuals based on results from the European Organization for Research and Treatment of Cancer-Quality of Life Questionnaire-Core (EORTC-QLQ-C30), European Organization for Research and Treatment of Cancer -Non-Muscle Invasive Bladder Cancer Questionnaire (EORTC-QLQ-NMIBC24), or the 5-level EQ-5D (EQ-5D-5L) questionnaire. In some embodiments, the quality-of-life score of the individual is maintained or increases following treatment by the methods provided herein. In some embodiments, quality of life improvements include avoiding the risks of mortality and morbidity associated with radical cystectomy, as well as maintaining continence, sexual function, fertility, and bowel function. In some embodiments, gemcitabine is delivered locally to the bladder about every three weeks (Q3W) for about 24 weeks. In some embodiments, gemcitabine is delivered locally to the bladder about every three weeks (Q3W) for about 24 weeks during an induction phase and then about every three months during a maintenance phase. In some embodiments, gemcitabine is delivered locally to the bladder about every three weeks (Q3W) for up to about 24 weeks followed by 12 weeks (Q12W) for up to 18 months. In some embodiments, the individual does not receive a radical cystectomy.

[0244] In some embodiments, the EORTC-QLQ-C30 is a core questionnaire for evaluating the quality of life of participants participating in cancer clinical studies. In some embodiments, the EORTC-QLQ-C30 is a 30-item questionnaire with 9 multi-item subscales and 6 single items. In some embodiments, the EORTC-QLQ-C30 incorporates 5 functional scales (physical, role, cognitive, emotional, and social functioning), 3 symptom scales (fatigue, pain, and nausea or vomiting), and a global health status or quality of life scale. In some embodiments, the single items assess dyspnea, appetite loss, sleep disturbance, constipation, diarrhea, and perceived financial impact of disease and treatment. Ratings for each item range from 1 (not at all) to 4 (very much). In some embodiments, the EORTC-QLQ-C30 is designed to be used across cancer populations and takes about 11 minutes to complete.

[0245] In some embodiments, the EORTC-QLQ-NMIBC24 is a 24-item questionnaire for evaluating the quality of life of participants with superficial (non-muscle invasive) bladder cancer. In some embodiments, the questionnaire is designed to supplement the QLQ-C30 and incorporates 6 multi-item scales and 5 single items. In some embodiments, ratings for each item in the EORTC-QLQ-NMIBC24 range from 1 (not at all) to 4 (very much). In some embodiments, the scales cover urinary symptoms, malaise, worries about the future, bloating and flatulence, sexual function, and male sexual problems. In some embodiments, the single items assess intravesical treatment issues, sexual intimacy, sexual enjoyment, risk of contaminating partner, and female sexual problems. In some embodiments, the EORTC-QLQ-NMIBC24 takes about 8 minutes to complete. I Intravesical drug delivery systems

[0246] The various aspects and embodiments described in this section in the context of a method of treatment comprising administering gemcitabine using an intravesical drug delivery system also apply to gemcitabine for use according to the methods described herein, and minitablets comprising gemcitabine for use according to the methods described herein. In particular, the aspects and embodiments described in this section also relate to gemcitabine for use with an intravesical drug delivery system for use in the methods provided herein, wherein the method comprises continuous delivery of gemcitabine to the bladder by an intravesical drug delivery system comprising the intravesical device, and to gemcitabine for use according to the methods described herein, wherein the gemcitabine is administered by an intravesical drug delivery system.

[0247] As described herein, administering gemcitabine can include the use of an intravesical drug delivery system that comprises the gemcitabine and is insertable into the bladder for extended or sustained release of the gemcitabine. An exemplary intravesical drug delivery system 100 is shown in and described below with respect to FIGS. 1 A-B, 2, and 3A-3D, and may otherwise be referred to herein as “TAR-200” or “gemcitabine targeted releasing system”. When inserted into the bladder, the intravesical drug delivery system is submerged and freely mobile in the urine during the indwelling period.

[0248] In some embodiments, the intravesical drug delivery system is a sterile, non-resorbable, flexible, intravesical system containing 256 mg gemcitabine HC1 (equivalent to 225 mg free base). Once administered, the intravesical drug delivery system retains its bi-oval shape and is free-moving within the bladder.

[0249] Gemcitabine HC1 (a nucleoside metabolic inhibitor) is also called 2’ -deoxy -2’, 2’- difluorocytidine monohydrochloride (P-isomer). The molecular formula for gemcitabine HC1 is C9H11F2N3O4 • HC1, the molecular weight is 299.66, and the structural formula is:

[0250] In some embodiments, the intravesical drug delivery system comprises gemcitabine minitablets (which may appear as solid material) and osmotic minitablets (for osmotic performance), and are contained within the bi-oval shaped device constituent. The color of the minitablets may vary but that has no effect on the potency of the intravesical drug delivery system. The minitablets contain the following ingredients: [0251] Gemcitabine minitablets: containing a total dose of 225 mg of the active ingredient gemcitabine (as free-base equivalent), and the following inactive ingredients: polyethylene glycol 8000 (8 mg), povidone K30 (13.4 mg), urea (42.6 mg).

[0252] Osmotic (urea) minitablets: contain no active ingredient, and the following inactive ingredients: urea (648 mg), polyethylene oxide 600,000 (72 mg), FD&C Blue No.1 (0.0042 mg). [0253] The bi-oval shaped tube consists of a dual lumen silicone part, a superelastic nitinol wire in a predefined shape (wireform), silicone spacers, and silicone adhesive. The minitablets are surrounded by a semipermeable membrane that contains a single delivery orifice. In some embodiments, the intravesical drug delivery system’s coiled dimensions are approximately 6 cm wide x 5 cm high.

[0254] In some embodiments, the methods provided herein include administering gemcitabine 104 using an intravesical drug delivery system 100. Any intravesical drug delivery system 100 comprises an intravesical device and gemcitabine 104. In some embodiments, the intravesical device is capable of delivering the gemcitabine 104 within the bladder in suitable amounts, at suitable rates, and over suitable durations.

[0255] In some embodiments, the intravesical device is configured to be deployed into the bladder through the working channel of a catheter, cystoscope, or other deployment instrument positioned in the urethra. In some embodiments, the intravesical device is elastically deformable between a deployment shape for passage through the deployment instrument and a bladder retention shape in which the device (i) resists becoming entrained in urine and excreted when the individual voids, and (ii) intended to be tolerable to the individual, e.g., does not overly press on the bladder wall, or enter the ureter orifices. Such intravesical devices are known in the art. In some embodiments, the intravesical drug delivery system or intravesical device is one described in one or more of U.S. Patent No. 10,543,166, U.S. Patent No. 9,283,361, U.S. Patent No.

8,679,094, U.S. Patent No. 10,857,336, U.S. Patent No. 9,457,176, U.S. Patent No. 8,690,840, U.S. Patent No. 9,107,816, U.S. Patent No. 10,137,287, U.S. Patent No. 9,814,671, U.S. Patent No. 10,729,823, U.S. Patent No. 10,315,019, U.S. Patent No. 10,933,170, U.S. Patent No.

10,737,078, U.S. Patent No. 10,894,150, and U.S. Patent No. 11,020,575, which are incorporated herein by reference in their entirety.

[0256] In various embodiments, the intravesical drug delivery system 100 may release the gemcitabine continuously or intermittently to achieve a concentration of the drug in the bladder that produces an extended, sustained, and/or therapeutically effective concentration of the drug in urine in the bladder as described in the methods provided herein. In certain embodiments, the intravesical drug delivery system may release the gemcitabine in an amount of about 0.5 mg/day to about 50 mg/day, about 1 mg/day to about 40 mg/day, about 3 mg/day to about 30 mg/day, about 5 mg/day to about 20 mg/day, or about 1 mg/day to about 15 mg/day. In certain embodiments, the intravesical drug delivery system may release the gemcitabine in an amount (such as a maximum amount) of about 42 mg/day. In certain embodiments, the intravesical drug delivery system may release the gemcitabine in an amount of about 12 mg/day. In certain embodiments, these release rates are provided over a treatment period as described herein. In certain embodiments, these release rates are provided over a delivery period from 14 days to 21 days. In certain embodiments, these release rates are provided over a delivery period of about 7 days. In certain embodiments, these release rates are provided over a delivery period of about 14 days. In some embodiments, the intravesical drug delivery system releases gemcitabine at a maximum rate of 42 mg FBE/day on day two and a rate of 12 mg FBE/day on day 7.

[0257] In some embodiments, the intravesical device include a device body, which may be a housing 102, and a drug payload which includes a suitable amount of the gemcitabine 104. The drug payload may be referred to herein as a dosage form. The drug payload may be contained in a drug reservoir lumen 110, or reservoir, within the device body. The device body, in combination with the form and formulation of the drug payload, may control release/delivery of the gemcitabine into the bladder. The release of gemcitabine 104 from the intravesical drug delivery systems described herein may be driven and controlled by different mechanisms of action. In various embodiments, the gemcitabine 104 may be released from the intravesical device by diffusion through a wall of the housing 102, by diffusion through one or more defined apertures in a wall of the housing, by osmotic pressure through an aperture in the housing, by osmotic pressure through one or more transiently formed microchannels in the housing, by erosion of a drug formulation in contact with urine in the bladder, by diffusion through a drug- permeable polymer or matrix component defining part of the device housing, or by a combination thereof. The intravesical drug delivery system 100 can include a single delivery orifice 108 that controllably releases the gemcitabine 104 from the drug reservoir lumen 110 through the delivery orifice 108. The delivery orifice 108 may be a laser-drilled delivery orifice. In some examples, the diameter of the delivery orifice 108 can be between about 25-300 pm, such as between about 50-250 pm, or about 100-200 pm (e.g., about 150 pm). In FIG. 3A, the delivery orifice 108 is positioned centrally between the two ovals making up the bi-oval shape of the system for maximum, controlled release of the gemcitabine 104 from the delivery orifice 108, as described in greater detail below. Examples of such intravesical devices or intravesical drug delivery systems are described in the above-listed U.S. patents incorporated by reference. [0258] Following in vivo deployment, the intravesical drug delivery system releases the gemcitabine. Release may occur, as described above, due to an osmotic pressure gradient between the interior and exterior of the intravesical device, the drug passing through one or more orifices or passing pores in the intravesical device under the force of osmotic pressure. Release may also occur by diffusion, whereby the drug passes through one or more orifices or passing pores in the intravesical device and/or through a drug-permeable wall of the intravesical device, due to a drug concentration gradient between the interior and exterior of the intravesical device. Combinations of these release modes within a single intravesical device are possible, and in some embodiments are preferred in order to achieve an overall drug release profile not readily achievable from either mode individually.

[0259] In some embodiments, at least some of the material(s) used to form the device body may be water permeable so that solubilizing fluid (e.g., urine) can diffuse into the intravesical device to contact the drug payload, e.g., enter a drug reservoir portion to solubilize the non-liquid forms of the gemcitabine (and/or any immunomodulating agent, additional therapeutic agent, functional agent, or a combination thereof also) contained within the intravesical device following its deployment into the bladder. For example, silicone, certain thermoplastic polyurethanes, or other biocompatible elastomeric materials may be used. In other embodiments, the device body may be formed, at least in part, of a water-impermeable material.

[0260] The drug payload may be housed in the intravesical device in various forms, which may depend on the particular mechanism by which the intravesical drug delivery system controllably releases the gemcitabine into fluid (e.g., urine) in the bladder. In some embodiments, the drug is provided in a solid, semi-solid, or other non-liquid form, which advantageously may facilitate stable storage of the drug before the intravesical device is used and advantageously may enable the drug payload of the intravesical device to be stored in smaller volume than would be possible if the drug were housed in the form of a liquid solution. In some embodiments, the non-liquid form is selected from tablets, granules, pellets, powders, semisolids (e.g., an ointment, cream, paste, or gel), capsules, and combinations thereof. In some embodiments, the intravesical device body includes a drug reservoir lumen. In some of these embodiments, the drug reservoir lumen holds one or several drug tablets or other solid drug units, wherein at least a portion of the tablets/units includes gemcitabine. In some embodiments, the intravesical device holds from about 10 to 100 cylindrical drug tablets, such as mini -tablets. In certain embodiments, the mini- tablets each have a diameter of about 1.0 to about 3.3 mm, such as about 1.5 to about 3.1 mm, and a length of about 1.5 to about 4.7 mm, such as about 2.0 to about 4.5 mm. In one embodiment, the drug is in the form of a plurality of tablets, such as mini-tablets described in U.S. Patent No. 8,343,516 and 11,040,005, which are incorporated by reference herein.

[0261] In some other embodiments, the gemcitabine may be provided in the intravesical device as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the gemcitabine may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution, for constitution with a suitable vehicle, e.g., sterile, pyrogen-free water, before use. [0262] In some particular embodiments, the intravesical drug delivery system is configured to provide controlled release of the gemcitabine by osmotic pressure, as described, for example, in U.S. Patent No. 10,729,823, which as noted above is incorporated by reference herein. In some of these embodiments, the intravesical device includes a housing defining a reservoir; a first unit (e.g., a first plurality of tablets) contained within the reservoir, the first unit comprising gemcitabine; and a second unit (e.g., a second plurality of tablets) contained within the reservoir, the second unit comprising a functional agent and not comprising gemcitabine. One or more of the first unit tablets may fill a length from about 1 cm to about 5 cm of the lumen of the tube, and one or more of the second unit tablets may fill a length from about 10 cm to about 14 cm of the lumen of the tube. The functional agent is a substance that facilitates in vivo release of the drug from the housing. For example, it may be an osmotic agent, such as urea. In some embodiments, the housing is in the form of an elongated elastomeric tube having a lumen (i.e., the reservoir) in which all of the first and second tablets are aligned and contained, wherein the elastomeric tube includes one or more apertures or microchannels configured to provide release of the gemcitabine in vivo by osmotic pressure.

[0263] In some embodiments, the intravesical drug delivery system contains a unit concentration of about 225 mg of gemcitabine. In some of these embodiments, the intravesical drug delivery system is configured to deliver about 100 to about 225 mg of gemcitabine (e.g., about 140 mg, about 160 mg, about 180 mg, about 200 mg, or about 220 mg of gemcitabine) to the individual over at least about or about a seven day period, at least about or about a fourteen-day period, or at least about or about a three-week period. In some embodiments, the intravesical drug delivery system is configured to deliver about 114 to about 256 mg of gemcitabine HC1 (e.g., about 159 mg, about 182 mg, about 205 mg, about 228 mg, or about 250 mg of gemcitabine HC1) to the individual over at least about or about a seven day period, at least about or about a fourteen-day period, or at least about or about a three-week period.

[0264] In some embodiments, the intravesical drug delivery system is a TAR-200/gemcitabine product (hereafter, TAR-200), an intravesical drug delivery system consisting of two components: (i) the drug constituent, which consists of gemcitabine minitablets (225 mg, free base equivalent) and osmotic minitablets containing urea as the osmotic agent; and (ii) the intravesical device constituent, which is comprised of a dual lumen silicone part with a single laser-machined orifice and a superelastic nitinol wire (as shown in FIG. 1). The large lumen of the silicone part contains the gemcitabine and urea minitablets and serves as an osmotic pump to release drug in a controlled manner. The smaller lumen contains a nitinol wire in a predefined coil form to provide retention of the intravesical drug delivery system in the individual’s bladder during the indwelling period. In some embodiments, the intravesical drug delivery system comprises minitablets comprising about 256 mg of gemcitabine HC1 (equivalent to about 225 mg gemcitabine free base).

[0265] The minitablets (including the gemcitabine minitablets and the osmotic minitablets) may be arranged serially within the housing 102, as shown at least in FIG. 3D. In the arrangement illustrated in FIG. 3D, the plurality of minitablets including gemcitabine 104 are flanked on either side by the plurality of minitablets including osmotic agent 114. This arrangement of gemcitabine minitablets and osmotic minitablets may be beneficial controlling and/or maximizing osmotic release of the gemcitabine 104 from the delivery orifice 108.

[0266] In some examples, the first unit including the gemcitabine 104 may further include an osmotic agent (i.e., in addition to or in place of the second unit including osmotic agent). The osmotic agent may include urea. In some examples, the first unit may include at least 50 percent by weight gemcitabine, at least 60 percent by weight gemcitabine, at least 75 percent by weight gemcitabine, from about 60 to about 99 percent by weight gemcitabine, or from about 75 to about 95 percent by weight gemcitabine.

[0267] In some examples, the second unit may include at least 80 percent by weight osmotic agent, at least 85 percent by weight osmotic agent, at least 90 percent by weight osmotic agent, from about 80 to about 99 percent by weight osmotic agent, or from about 85 to about 95 percent by weight osmotic agent. The remainder of the first unit and/or second unit may include excipients such as pharmaceutical lubricants, stabilizing agents, or binding agents, for example oil-based lubricants, polyethylene glycol (PEG), or polyvinylpyrrolidone (PVP). The excipients may also include a viscosity enhancing (e.g., release delay) agent, for example polyethylene oxide (PEO). For example, a viscosity enhancing agent could be provided in a portion of the first unit, a portion of the second unit, or both the first and second unit to further control release of the gemcitabine. In some embodiments, the first unit comprises 80% by weight gemcitabine HC1, 13.3% by weight urea, 2.5% by weight polyethylene glycol (PEG), and 4.2% by weight polyvinylpyrrolidone. In some embodiments, the PEG comprises PEG 8000.

[0268] In some embodiments, the second unit may include about 90 percent by weight urea and about 10 percent by weight oil-based pharmaceutical lubricant LUBRITAB ®. In some embodiments, the second unit may include about 90 percent by weight urea and about 10 percent by weight polyethylene oxide (PEO). In a particular embodiment, the first unit contains at least 75 percent by weight gemcitabine HC1, such as about 80 percent by weight gemcitabine HC1. In a particular embodiment, the second unit contains at least 85 percent by weight urea, such as about 90 percent by weight urea.

[0269] The housing 102 may be formed of a semi -permeable membrane that is permeable to water/urine and impermeable to the gemcitabine 104 and osmotic agent 114 contained therein. In this manner, substantially no amount of the solubilized gemcitabine 104 or the osmotic agent 114 can diffuse through the housing 102 over the dosing cycle in which the intravesical drug delivery system 100 is inserted into the bladder. When inserted into the bladder, the intravesical drug delivery system 100 can operate as an osmotic pump. Water or urine in the individual’s bladder can diffuse through the housing 102 into the drug reservoir lumen 110 to contact and solubilize the minitablets of gemcitabine 104 and minitablets of osmotic agent 114, creating an osmotic pressure to drive the solubilized drug from the drug delivery system through delivery orifice 108. [0270] As shown in FIGS. 3A-3B the end portions 150 of the intravesical drug delivery system 100 can include silicone spacers 116 disposed at each end of the housing 102 to close or plug the drug reservoir lumen 110. In some embodiments, the opposed ends of the retention frame 106 can overlay the respective silicone spacers 116. In some examples, a silicone adhesive 118 can be injected into the drug reservoir lumen 110 to secure the silicone spacers 116 within the ends of the drug reservoir lumen 110. Separately, the retention frame lumen 112 can be sealed using a silicone adhesive 120. Once the silicone adhesive is injected to the housing 102, any extra housing 102 at the ends can be trimmed.

[0271] As noted above, the intravesical drug delivery system 100 may be flexible between a bioval, or coiled, shape (retention shape), and an uncoiled shape (insertion shape). In the coiled shape, the intravesical drug delivery system 100 may have a width of about 4-7 cm, about 4.5- 6.5 cm, or about 5-6 cm (e.g., 5.5 cm or 6 cm). In the coiled shape, the intravesical drug delivery system 100 may have a height of about 3-6 cm, about 3.5-5.5 cm, or about 4-5 cm (e.g., about 4.5 cm or 5 cm). In the uncoiled shape, the intravesical drug delivery system 100 may have a length between about 15-20 cm, such as about 16-19 cm or about 17-18 cm (e.g., 17 cm). [0272] In some embodiments, the intravesical drug delivery system is provided in a kit with a urological placement catheter configured to facilitate deployment of the intravesical device into the bladder of an individual. In some embodiments, the urological placement catheter is described in U.S. Patent No. 10,064,980, which is incorporated herein by reference. In some embodiments, TAR-200 is kitted with a urological placement catheter (Urinary Placement Catheter), for the transurethral placement of intravesical drug delivery systems, as shown in FIG. 4A and FIG. 4B. In some embodiments, TAR-200 is removed from the bladder transurethrally via cystoscopy and endoscopic graspers.

III. Articles of Manufacture

[0273] In some aspects, provided herein is an article of manufacture comprising a packaging material and an intravesical drug delivery system comprising 225 mg gemcitabine and a package insert comprising instructions for use according to the methods disclosed herein. In some embodiments, the article of manufacture further comprises a urinary placement catheter. In some embodiments, the urinary placement catheter comprises a catheter and a stylet. In some embodiments, the article of manufacture further comprises a lubricant and/or a syringe. In some embodiments, the instructions for use provide instructions for administering the intravesical drug delivery system comprising 225 mg gemcitabine according to the methods provided herein. In some embodiments, gemcitabine is administered as a free base equivalent (FBE). In some embodiments, the gemcitabine FBE is a pharmaceutically acceptable salt of gemcitabine. In some embodiments, the gemcitabine FBE is gemcitabine hydrochloride (HC1). In some embodiments, the intravesical drug delivery system comprises about 256 mg of gemcitabine HC1.

[0274] In some embodiments, the article of manufacture comprises an intravesical drug delivery system comprising about 150 mg to about 300 mg, about 200 mg to about 250 mg, or about 225 mg gemcitabine. In some embodiments, the article of manufacture comprises an intravesical drug delivery system comprising about 171 mg to about 342 mg, about 228 mg to about 285 mg, or about 256 mg of gemcitabine HC1. In some embodiments, the article of manufacture further comprises a urinary placement catheter. In some embodiments, the urinary placement catheter comprises a catheter and a stylet. In some embodiments, the article of manufacture further comprises a lubricant and/or a syringe. In some embodiments, the instructions for use provide instructions for administering the intravesical drug delivery system comprising 225 mg gemcitabine according to the methods provided herein. In some embodiments, gemcitabine is administered as a free base equivalent (FBE). In some embodiments, the gemcitabine FBE is a pharmaceutically acceptable salt of gemcitabine. In some embodiments, the gemcitabine FBE is gemcitabine hydrochloride (HC1). In some embodiments, the intravesical drug delivery system comprises about 256 mg of gemcitabine HC1.

[0275] In some embodiments, the article of manufacture comprises a packaging material, a TAR-200 intravesical drug delivery system as shown in FIGs. 1 A-1B and a urinary placement catheter comprising a catheter and a stylet as shown in FIGs. 4A-4B. TAR-200 is an intravesical drug delivery system consisting of two components: (i) the drug constituent, which consists of gemcitabine minitablets (225 mg, free base equivalent) and osmotic minitablets containing urea as the osmotic agent; and (ii) the intravesical device constituent, which is comprised of a dual lumen silicone part with a single laser-machined orifice and a superelastic nitinol wire (“wireform”). The large lumen of the silicone part contains the gemcitabine and urea minitablets and serves as an elementary osmotic pump to release drug in a controlled manner. The smaller lumen contains the nitinol wire in a predefined form to provide retention of the system in the bladder during the indwelling period. In some embodiments, the intravesical device comprises a deployment shape. In some embodiments, the intravesical drug delivery system and the urinary placement catheter are packaged in separate pouches (e.g., Tyvek pouches). In some embodiments, the intravesical drug delivery system and the urinary placement catheter are packaged together in the same pouch (e.g., a Tyvek pouch).

[0276] In some embodiments, the package insert provides instructions for insertion and/or removal of the intravesical drug delivery system. In some embodiments, the package insert provides instructions for the intravesical drug delivery system to be inserted transurethrally into the bladder using the Urinary Placement Catheter and removed from the bladder using endoscopic non-cutting grasping forceps and a standard flexible or rigid cystoscope. In some embodiments, the package insert provides instructions for inserting the intravesical drug delivery system, comprising: (1) Prepare for Placement: gather supplies, including Inserter, TAR-200, and two 10 mL slip tip syringes filled with water-based lubricant. If needed, fill syringes manually. Open TAR-200 outer foil pouch at tear notch. Open TAR-200 and Inserter Tyvek pouches from chevron side; (2) Introduce Empty Catheter into Bladder: (a) Lubricate tip of empty Catheter; (b) Introduce empty Catheter (without stylet) into urethra and advance until urine return. Note depth marking printed on Catheter to maintain position during procedure; (3) After Placing Catheter into Bladder, Inject Lubricant and Insert TAR-200: (a) Using first lubricant syringe, inject 2-3 mL of lubricant into Catheter’s end; (b) Load either end of TAR-200 into Catheter and advance until completely uncoiled inside Catheter; (c) Using second lubricant syringe, inject another 2-3 mL of lubricant into Catheter’s end; (d) Slowly insert stylet completely into Catheter until stylet hub is in flush contact with Catheter’s end. This will ensure TAR-200 completely exits Catheter into bladder; (e) Remove Catheter and stylet from urethra together. TAR-200 should remain inside bladder. Note: If TAR-200 cannot be advanced due to resistance, remove catheter and stylet completely. Ensure TAR-200 is removed as well. Do not attempt to place the removed TAR-200 again.

[0277] In some embodiments, the package insert provides instructions for inserting the intravesical drug delivery system, comprising: (1) Gather supplies, including the UPC and two sterile 10 ml slip tip syringes filled with sterile water-based lubricant. If needed, fill syringes manually; (2) Inspect all UPC device pouches for damage. DO NOT USE any product that is damaged or has damaged packaging; (3) After preparation of the urethral meatus, lubricate the tip of the empty catheter shaft. NOTE: Depth markings are aligned with upward direction of coude tip; (4) Introduce empty catheter shaft (without green stylet) into urethra and advance until urine return. Note depth marking printed on catheter shaft to maintain position during procedure; (5) Refer to the instructions for use provided with the intravesical drug delivery system on how to load the intravesical drug delivery system into the UPC; (6) Once the intravesical drug delivery system is loaded into the UPC, slowly insert the green stylet until the white stylet hub is in flush contact with the catheter’s end. This will ensure that the intravesical drug delivery system completely exits the UPC into the bladder; (7) After withdrawing the catheter shaft, visually confirm that the intravesical drug delivery system is no longer in the UPC.

[0278] In some embodiments, the package insert provides instructions for removing the intravesical drug delivery system, comprising: Insert Cystoscope and Grasp TAR-200: (a) Introduce cystoscope into bladder and visualize TAR-200, (b) Introduce grasping forceps through cystoscope’ s working channel, (c) Grasp TAR-200 over silicone tubing and wireform. Do not grasp on or near ends of TAR-200; and Remove TAR-200: (a) While grasping TAR-200, remove cystoscope and forceps out of urethra together to remove TAR-200 under direct vision. Do not remove TAR-200 through cystoscope’s working channel. Doing so can damage TAR-200 and/or cystoscope; (b) After removal, inspect TAR-200 to confirm it is intact and unbroken. [0279] In some embodiments, the package insert provides instructions for dosing TAR-200 (225 mg gemcitabine) in a 21 day dosing cycle, wherein a TAR-200 intravesical drug delivery system is inserted transurethrally into the bladder, remains indwelling for three weeks, and is then removed and replaced with a new TAR-200 intravesical drug delivery system every 3 weeks for the duration of the dosing period. In some embodiments, insertion and/or removal of the TAR- 200 intravesical drug delivery system is inserted every 3 weeks ±7 days.

[0280] In some embodiments, the package insert provides instructions for a method of treating individuals with high-risk non-muscle invasive bladder cancer comprising administering gemcitabine locally to the bladder of the individual, wherein each gemcitabine administration comprises delivering gemcitabine continuously to the bladder for at least 7 days during a gemcitabine delivery period. In some embodiments, gemcitabine is administered to the bladder about every three weeks for up to the first about six months and about every three months thereafter. In some embodiments, gemcitabine is administered to the bladder about every three weeks for about the first 24 weeks and then about every three months thereafter for a total of about two years. In some embodiments, about 225 mg of gemcitabine is administered during each administration. In some embodiments, the individual has BCG-unresponsive non-muscle invasive bladder cancer. In some embodiments, the individual has refused or is ineligible for radical cystectomy.

Kits

[0281] In some aspects, provided herein are kits for carrying out any methods described herein. [0282] In some embodiments, provided herein is a kit comprising an intravesical drug delivery system containing 225-mg free base equivalents of gemcitabine, such as the TAR-200 device illustrated in FIGs. 1A-1B. In some embodiments, gemcitabine is administered as a free base equivalent (FBE). In some embodiments, the gemcitabine FBE is a pharmaceutically acceptable salt of gemcitabine. In some embodiments, the gemcitabine FBE is gemcitabine hydrochloride (HC1). In some embodiments, the intravesical drug delivery system comprises about 256 mg of gemcitabine HC1. In some embodiments, the kit further comprises a Urinary Placement Catheter (“Inserter”) consisting of a clear catheter and a colored or opaque stylet (e.g., a green stylet), such as the catheter and stylet as shown in FIGs. 4A-4B. In some embodiments, the intravesical drug delivery system comprises a deployment shape. In some embodiments, the intravesical drug delivery system and the urinary placement catheter are packaged in separate pouches (e.g., Tyvek pouches). In some embodiments, the intravesical drug delivery system and the urinary placement catheter are packaged together in the same pouch (e.g., a Tyvek pouch). In some embodiments, the kit further comprises instructions for inserting the intravesical drug delivery system into the bladder of an individual, and/or instructions for removing the intravesical drug delivery system. In some embodiments, the instructions require use of water-based lubricant, syringes, non-cutting, grasping forceps, and/or a flexible or rigid cystoscope. In some embodiments, the water-based lubricant, syringes, non-cutting, grasping forceps, and/or a flexible or rigid cystoscope are not included in the kit. In some embodiments, the kit comprises instructions for using the intravesical drug delivery system according to any of the methods provided herein.

[0283] In some embodiments, the kit provides instructions for inserting the intravesical drug delivery system, comprising: (1) Prepare for Placement: gather supplies, including Inserter, TAR-200, and two 10 mL slip tip syringes filled with water-based lubricant. If needed, fill syringes manually. Open TAR-200 outer foil pouch at tear notch. Open TAR-200 and Inserter Tyvek pouches from chevron side; (2) Introduce Empty Catheter into Bladder: (a) Lubricate tip of empty Catheter; (b) Introduce empty Catheter (without stylet) into urethra and advance until urine return. Note depth marking printed on Catheter to maintain position during procedure; (3) After Placing Catheter into Bladder, Inject Lubricant and Insert TAR-200: (a) Using first lubricant syringe, inject 2-3 mL of lubricant into Catheter’s end; (b) Load either end of TAR-200 into Catheter and advance until completely uncoiled inside Catheter; (c) Using second lubricant syringe, inject another 2-3 mL of lubricant into Catheter’s end; (d) Slowly insert stylet completely into Catheter until stylet hub is in flush contact with Catheter’s end. This will ensure TAR-200 completely exits Catheter into bladder; (e) Remove Catheter and stylet from urethra together. TAR-200 should remain inside bladder. Note: If TAR-200 cannot be advanced due to resistance, remove catheter and stylet completely. Ensure TAR-200 is removed as well. Do not attempt to place the removed TAR-200 again.

[0284] In some embodiments, the kit provides instructions for inserting the intravesical drug delivery system, comprising: (1) Gather supplies, including the UPC and two sterile 10 ml slip tip syringes filled with sterile water-based lubricant. If needed, fill syringes manually; (2) Inspect all UPC device pouches for damage. DO NOT USE any product that is damaged or has damaged packaging; (3) After preparation of the urethral meatus, lubricate the tip of the empty catheter shaft. NOTE: Depth markings are aligned with upward direction of coude tip; (4) Introduce empty catheter shaft (without green stylet) into urethra and advance until urine return. Note depth marking printed on catheter shaft to maintain position during procedure; (5) Refer to the instructions for use provided with the intravesical drug delivery system on how to load the intravesical drug delivery system into the UPC; (6) Once the intravesical drug delivery system is loaded into the UPC, slowly insert the green stylet until the white stylet hub is in flush contact with the catheter’s end. This will ensure that the intravesical drug delivery system completely exits the UPC into the bladder; (7) After withdrawing the catheter shaft, visually confirm that the intravesical drug delivery system is no longer in the UPC.

[0285] In some embodiments, the kit provides instructions for removing the intravesical drug delivery system, comprising: Insert Cystoscope and Grasp TAR-200: (a) Introduce cystoscope into bladder and visualize TAR-200, (b) Introduce grasping forceps through cystoscope’ s working channel, (c) Grasp TAR-200 over silicone tubing and wireform. Do not grasp on or near ends of TAR-200; and Remove TAR-200: (a) While grasping TAR-200, remove cystoscope and forceps out of urethra together to remove TAR-200 under direct vision. Do not remove TAR-200 through cystoscope’ s working channel. Doing so can damage TAR-200 and/or cystoscope; (b) After removal, inspect TAR-200 to confirm it is intact and unbroken.

[0286] In some aspects, provided herein is a kit comprising an intravesical drug delivery system provided herein. In some embodiments, the intravesical drug delivery system comprises an intravesical drug delivery system comprising 225-mg free base equivalents of gemcitabine. In some embodiments, the intravesical drug delivery system comprises a deployment shape and a retention shape. For example, the intravesical drug delivery system may be elastically deformable between a relatively straightened or uncoiled shape suited for insertion through a lumen (e.g., the urethra) into the bladder of the individual (the deployment shape) and a retention shape suited to retain the intravesical drug delivery system within the bladder (FIG. 2). For the purposes of this disclosure, terms such as “relatively expanded shape,” “relatively higher-profile shape,” or “retention shape” generally denote any shape suited for retaining the intravesical drug delivery system in the intended implantation location, including but not limited to a pretzel or bioval shape or other coiled shape (e.g., comprising overlapping coils) that is suited for retaining the intravesical drug delivery system in the bladder. In some embodiments, the relatively expanded shape is a pretzel or bi-oval shape. In some embodiments, the kit further comprises a Urinary Placement Catheter.

[0287] In some embodiments, the kit further comprises instructions for administering the intravesical drug delivery system according to any of the methods disclosed herein.

[0288] In some embodiments, the kit comprises instructions for a method of treating individuals with high-risk non-muscle invasive bladder cancer comprising administering gemcitabine locally to the bladder of the individual, wherein each gemcitabine administration comprises delivering gemcitabine continuously to the bladder for at least 7 days during a gemcitabine delivery period. In some embodiments, gemcitabine is administered to the bladder about every three weeks for about the first six months and about every three months thereafter. In some embodiments, gemcitabine is administered to the bladder about every three weeks for about the first 24 weeks and then about every three months thereafter for a total of about two years. In some embodiments, about 225 mg of gemcitabine is administered during each administration. In some embodiments, gemcitabine is administered as a free base equivalent (FBE). In some embodiments, the gemcitabine FBE is a pharmaceutically acceptable salt of gemcitabine. In some embodiments, the gemcitabine FBE is gemcitabine hydrochloride (HC1). In some embodiments, the intravesical drug delivery system comprises about 256 mg of gemcitabine HC1. In some embodiments, the individual has BCG-unresponsive non-muscle invasive bladder cancer. In some embodiments, the individual has refused or is ineligible for radical cystectomy.

EMBODIMENTS

[0289] Various embodiments of the methods, systems, articles of manufacture, and kits for treating papillary-only high-risk non-muscle invasive bladder cancer in an individual provided herein are included in the following non-limiting list of embodiments.

[0290] 1. A method of treating papillary-only high-risk non-muscle invasive bladder cancer (HR-NMIBC) in an individual comprising administering to the bladder of individual about 225 mg of gemcitabine about every three weeks (Q3W) for at least about 24 weeks.

[0291] 2. A method of treating papillary-only high-risk non-muscle invasive bladder cancer (HR-NMIBC) in an individual comprising administering gemcitabine to the bladder of the individual about every three weeks (Q3W) for at least about 24 weeks during eight administration periods, wherein each administration period comprises a delivery period of at least about seven days when gemcitabine is released from an intravesical drug delivery system, wherein the concentration of gemcitabine in the urine of the individual is at least about 4 pg/mL during each delivery period.

[0292] 3. A method of bladder sparing in an individual having papillary-only high-risk non- muscle invasive bladder cancer (HR-NMIBC) comprising administering to the individual about 225 mg of gemcitabine about every three weeks (Q3W) for at least about 24 weeks, wherein the individual does not receive a radical cystectomy.

[0293] 4. A method of treating papillary-only high-risk non-muscle invasive bladder cancer (HR-NMIBC) in an individual who is eligible for radical cystectomy, the method comprising administering to the bladder of the individual about 225 mg of gemcitabine about every three weeks (Q3W) for at least about 24 weeks. [0294] 5. A method of treating papillary-only high-risk non-muscle invasive bladder cancer (HR-NMIBC) in an individual comprising administering to the bladder of the individual about 225 mg of gemcitabine about every three weeks (Q3W) for at least about 24 weeks, wherein such treatment results in an increased disease-free survival compared to a standard of care treatment.

[0295] 6. A method of treating papillary-only high-risk non-muscle invasive bladder cancer (HR-NMIBC) in an individual comprising (a) administering to the bladder of the individual about 225 mg of gemcitabine about every three weeks (Q3W) for at least about 24 weeks during eight administration periods, (b) administering to the bladder of the individual about 225 mg of gemcitabine about every 3 months (Q3M) for at least about 60 weeks during six administration periods, and (c) extending disease-free survival in the individual by at least about 9 months; wherein each administration period comprises a delivery period of at least about seven days.

[0296] 7 A method of increasing the disease-free survival for papillary-only high-risk non- muscle invasive bladder cancer (HR-NMIBC) in an individual comprising administering to the bladder of the individual about 225 mg of gemcitabine about every three weeks (Q3W) for at least about 24 weeks, wherein such treatment results in an increased median disease-free survival compared to the median disease-free survival achieved by intravesical mitomycin C (MMC) or intravesical gemcitabine.

[0297] 8. The method of any one of embodiments 1-7, wherein the concentration of gemcitabine in the urine of the individual is between about 4 pg/mL and about 50 pg/mL during each administration period.

[0298] 9. The method of any one of embodiments 1-8, wherein the individual has BCG- unresponsive or BCG-experienced NMIBC.

[0299] 10. The method of any one of embodiments 1-9, wherein the papillary-only high-risk non-muscle invasive bladder cancer comprises high grade Ta or any T1 disease not comprising CIS.

[0300] 11. The method of any one of embodiments 1-10, wherein the individual does not have CIS.

[0301] 12. The method of any one of embodiments 1-11, wherein the individual does not have N+ and/or M+ bladder cancer.

[0302] 13. The method of any one of embodiments 1-12, wherein the gemcitabine administered to the individual is a monotherapy for treatment of the papillary-only HR-NMIBC that is unresponsive to intravesical BCG therapy or that is BCG-experienced. [0303] 14. The method of any one of embodiments 1-13, wherein the median disease-free survival in a population of patients who have received such therapy is improved compared to the standard of care, optionally wherein the median disease-free survival in the population of patients is improved at least about 40% compared to the disease-free survival for the standard of care.

[0304] 15. The method of any one of embodiments 1-14, wherein the median disease-free survival in a population of patients who have received such therapy is improved compared to a systemic chemotherapeutic agent therapy, optionally wherein the disease-free survival is improved at least about 40% compared to the disease-free survival for the systemic chemotherapeutic agent therapy.

[0305] 16. The method of any one of embodiments 1-15, wherein the median disease-free survival in a population of patients who have receive such therapy improved compared to treatment with intravesical mitomycin C (MMC) or intravesical gemcitabine, optionally wherein the median disease-free survival is improved at least about 40% compared to the disease-free survival for intravesical mitomycin C (MMC) or intravesical gemcitabine.

[0306] 17. The method of any one of embodiments 1-16, wherein such treatment results in a disease-free survival of at least about 9 months.

[0307] 18. The method of any one of embodiments 1-17 wherein such treatment results in an increased recurrence-free survival compared to the standard of care treatment, optionally wherein the recurrence-free survival is improved at least about 40% compared to the recurrence- free survival for intravesical mitomycin C (MMC) or intravesical gemcitabine.

[0308] 19. The method of any one of embodiments 1-18, wherein such treatment results in an increased time to next intervention compared to the standard of care treatment, optionally wherein the time to next intervention is improved at least about 40% compared to the time to next intervention for intravesical mitomycin C (MMC) or intravesical gemcitabine.

[0309] 20. The method of any one of embodiments 1-19, wherein such treatment results in a time to next intervention of at least about 9 months.

[0310] 21. The method of any one of embodiments 1-20, wherein such treatment results in an increased time to disease worsening compared to the standard of care treatment, optionally wherein the time to disease worsening is improved at least about 40% compared to the time to disease worsening for intravesical mitomycin C (MMC) or intravesical gemcitabine.

[0311] 22. The method of any one of embodiments 1-21, wherein such treatment results in a time to disease worsening of at least about 9 months. [0312] 23. The method of any one of embodiments 1-22, wherein such treatment results in an increased time to progression compared to the standard of care treatment, optionally wherein the time to progression is improved at least about 40% compared to the time to progression for intravesical mitomycin C (MMC) or intravesical gemcitabine.

[0313] 24. The method of any one of embodiments 1-23, wherein such treatment results in a time to progression of at least about 9 months.

[0314] 25. The method of any one of embodiments 1-24, wherein such treatment results in an increased disease-free survival rate compared to the standard of care treatment, optionally wherein the disease-free survival rate is improved by at least about 20% compared to the disease- free survival rate for intravesical mitomycin C (MMC) or intravesical gemcitabine.

[0315] 26. The method of embodiment 25, wherein the disease-free survival rate is a 12-month disease-free survival rate.

[0316] 27. The method of embodiment 26, wherein such treatment results in a 12- month disease-free survival rate of at least about 60%.

[0317] 28. The method of embodiment 25, wherein the disease-free survival rate is a 24-month disease-free survival rate.

[0318] 29. The method of embodiment 28, wherein such treatment results in a 24-month disease- free survival rate of at least about 30%.

[0319] 30. The method of any one of embodiments 1-29, wherein such treatment results in an increased overall survival compared to the standard of care treatment.

[0320] 31. The method of any one of embodiments 1-30, wherein such treatment results in an increased all-cause disease-free survival compared to the standard of care treatment, optionally wherein the all-cause disease-free survival is increased by at least about 40% compared to the all-cause disease-free survival for intravesical mitomycin C (MMC) or intravesical gemcitabine. [0321] 32. The method of any one of embodiments 1-31, wherein such treatment results in an all-cause disease-free survival of at least about 9 months.

[0322] 33. The method of any one of embodiments 1-32, wherein such treatment results in an increased cancer-specific survival compared to the standard of care treatment.

[0323] 34. The method of any one of embodiments 1-33, wherein such treatment results in an increased time to cystectomy compared to the standard of care treatment.

[0324] 35. The method of any one of embodiments 1-34, wherein such treatment results in a time to cystectomy of at least about 12 months. [0325] 36. The method of any one of embodiments 1-35, wherein such treatment results in an increased disease-free survival at 2 years compared to the standard of care treatment.

[0326] 37. The method of any one of embodiments 1-36, wherein the intravesical gemcitabine is administered to the individual as a monotherapy for treatment of the papillary-only high-risk non-muscle invasive bladder cancer (HR-NMIBC) that is unresponsive to intravesical Bacillus Calmette-Guerin (BCG) therapy.

[0327] 38. The method of any one of embodiments 1-37, wherein the individual is administered gemcitabine within 12 months of completion of the last dose of BCG therapy.

[0328] 39. The method of any one of embodiments 1-38, wherein the individual has received i) a minimum of five of six full doses of an induction course of BCG; and ii) two or three doses of a maintenance course, or two of six doses of a second induction course of BCG therapy.

[0329] 40. The method of any one of embodiments 1-39, wherein the individual has Ta stage bladder cancer, and/or wherein the population of patients comprises one or more individuals with Ta stage bladder cancer.

[0330] 41. The method of embodiment 40, wherein the individual has high grade Ta stage bladder cancer and/or wherein the population of patients comprises one or more individuals with high grade Ta stage bladder cancer.

[0331] 42. The method of any one of embodiments 1-41, wherein the individual has T1 stage bladder cancer and/or wherein the population of patients comprises one or more individuals with T1 stage bladder cancer.

[0332] 43. The method of embodiment 42, wherein the individual has high grade T1 stage bladder cancer and/or wherein the population of patients comprises one or more individuals with high grade T1 stage bladder cancer.

[0333] 44. The method of any one of embodiments 1-43, wherein the individual has a mixed histology tumor and/or wherein the population of patients comprises one or more individuals with a mixed histology tumor.

[0334] 45. The method of any one of embodiments 1-44, wherein the individual is ineligible or elected not to undergo radical cystectomy.

[0335] 46. The method of embodiment 45, wherein the individual elected not to undergo radical cystectomy due to bladder preservation or concern about quality of life after bladder removal.

[0336] 47. The method of any one of embodiments 1-46, wherein the bladder cancer does not have neuroendocrine, micropapillary, signet ring cell, plasmacytoid, or sarcomatoid features. [0337] 48. The method of any one of embodiments 1-47, wherein the individual does not have a urothelial carcinoma or histological variant at any site outside of the urinary bladder.

[0338] 49. The method of any one of embodiments 1-48, comprising performing a transurethral resection of bladder tumors (TURBT) if the individual has papillary bladder cancer.

[0339] 50. The method of embodiment 49, wherein the bladder cancer is fully resected following TURBT.

[0340] 51. The method of any one of embodiments 1-50, wherein following treatment with gemcitabine, the individual is monitored for recurrence.

[0341] 52. The method of any one of embodiments 1-51, wherein following treatment with gemcitabine, the individual does not receive valrubicin, systemic gemcitabine, docetaxel, pembrolizumab or paclitaxel for treating the papillary-only high-risk non-muscle invasive bladder cancer (HR-NMIBC) that is unresponsive to intravesical Bacillus Calmette-Guerin (BCG) therapy.

[0342] 53. The method of any one of embodiments 1-52, wherein treatment with gemcitabine causes tumor ablation.

[0343] 54. The method of any one of embodiments 1-53, wherein following treatment with gemcitabine, the individual does not receive a transurethral resection of bladder tumors (TURBT).

[0344] 55. The method of any one of embodiments 1-54, wherein the individual does not progress to muscle-invasive bladder cancer.

[0345] 56. The method of any one of embodiments 1-55, wherein the quality-of-life score of the individual is maintained or increases following treatment with gemcitabine.

[0346] 57. The method of any one of embodiments 1-56, wherein the individual has asymptomatic macrohematuria or dysuria prior to the treatment with gemcitabine.

[0347] 58. The method of any one of embodiments 1-57, wherein administering gemcitabine comprises inserting an intravesical drug delivery system comprising about 225 mg gemcitabine into the bladder of the individual and removing the intravesical drug delivery system about three weeks later.

[0348] 59. The method of any one of embodiments 1-58 comprising i) inserting an intravesical drug delivery system comprising about 225 mg of gemcitabine into the bladder of the individual; ii) removing the intravesical drug delivery system about three weeks later; iii) inserting a new intravesical drug delivery system comprising about 225 mg of gemcitabine into the bladder on the day that the intravesical drug delivery system is removed in step ii), and iv) removing the new intravesical drug delivery system about three weeks later; wherein steps ii) and iii) are completed seven times.

[0349] 60. The method of any one of embodiments 1-59 comprising a dosing schedule of at least about 24 weeks comprising i) inserting a first intravesical drug delivery system into the bladder in week 0, and removing the first intravesical drug delivery system in week 3; ii) inserting a second intravesical drug delivery system into the bladder in week 3 after removing the first intravesical drug delivery system, and removing the second intravesical drug delivery system in week 6; iii) inserting a third intravesical drug delivery system into the bladder in week 6 after removing the second intravesical drug delivery system, and removing the third intravesical drug delivery system in week 9; iv) inserting a fourth intravesical drug delivery system into the bladder in week 9 after removing the third intravesical drug delivery system, and removing the fourth intravesical drug delivery system in week 12; v) inserting a fifth intravesical drug delivery system into the bladder in week 12 after removing the fourth intravesical drug delivery system, and removing the fifth intravesical drug delivery system in week 15; vi) inserting a sixth intravesical drug delivery system into the bladder in week 15 after removing the fifth intravesical drug delivery system, and removing the sixth intravesical drug delivery system in week 18; vii) inserting a seventh intravesical drug delivery system into the bladder in week 18 after removing the sixth intravesical drug delivery system, and removing the seventh intravesical drug delivery system in week 21; and viii) inserting an eighth intravesical drug delivery system into the bladder in week 21 after removing the seventh intravesical drug delivery system, and removing the eighth intravesical drug delivery system in week 24; wherein each intravesical drug delivery system comprises an intravesical device comprising about 225 mg of gemcitabine.

[0350] 61. The method of any one of embodiments 1-60, further comprising a maintenance therapy phase, wherein the maintenance therapy phase comprises administering about 225 mg of gemcitabine to the bladder of the individual for about three weeks about every two to four months.

[0351] 62. The method of embodiment 61, wherein the maintenance therapy phase comprises administering about 225 mg gemcitabine to the bladder of the individual for about three weeks about every three months.

[0352] 63. The method of embodiment 61 or 62, wherein the maintenance therapy phase begins at least about 30 weeks after the start of treatment with gemcitabine.

[0353] 64. The method of embodiment 63, wherein the maintenance therapy begins about 36 weeks after the start of treatment with gemcitabine. [0354] 65. The method of any one of embodiments 61-64, wherein the maintenance therapy comprises administering about 225 mg to the bladder of the individual during weeks 36-39, 48- 51, 60-63, 72-75, 84-87, and 96-99.

[0355] 66. The method of any one of embodiments 60-65, comprising i) inserting an intravesical drug delivery system into the bladder of the individual on about week 36 and removing the intravesical drug delivery system on about week 39; ii) inserting an intravesical drug delivery system into the bladder of the individual on about week 48 and removing the intravesical drug delivery system on about week 51; iii) inserting an intravesical drug delivery system into the bladder of the individual on about week 60 and removing the intravesical drug delivery system on about week 63; iv) inserting an intravesical drug delivery system into the bladder of the individual on about week 72 and removing the intravesical drug delivery system on about week 75; v) inserting an intravesical drug delivery system into the bladder of the individual on about week 84 and removing the intravesical drug delivery system on about week 87; and vi) inserting an intravesical drug delivery system into the bladder of the individual on about week 96 and removing the intravesical drug delivery system on about week 99; wherein the intravesical drug delivery system comprises an intravesical device comprising about 225 mg of gemcitabine.

[0356] 67. The method of any one of embodiments 58-66, wherein gemcitabine is delivered from the intravesical device during a delivery period.

[0357] 68. The method of embodiment 67, wherein the delivery period is about one to about three weeks.

[0358] 69. The method of embodiment 68, wherein the concentration of gemcitabine in the urine is from about 1 pg/mL to about 25 pg/mL or from about 4 pg/mL to about 50 pg/mL during the delivery period.

[0359] 70. The method of any one of embodiments 1-69, wherein the intravesical drug delivery system releases gemcitabine at a rate of about 10 to about 45 mg/day for about the first seven days of administration.

[0360] 71. The method of any one of embodiments 1-70, wherein the intravesical drug delivery system comprises an intravesical device that comprises a housing which contains and controllably releases the gemcitabine and is elastically deformable between a retention shape configured to retain the intravesical device in the individual’s bladder and a deployment shape for passage of the intravesical device through the individual’s urethra.

[0361] 72. The method of embodiment 71, wherein the intravesical device comprises a dual lumen silicone part with a single laser-machined orifice. [0362] 73. The method of embodiment 72, wherein the dual lumen silicone part comprises a large lumen and a small lumen.

[0363] 74. The method of embodiment 73, wherein the small lumen comprises a super-elastic nitinol wire.

[0364] 75. The method of embodiment 74, wherein the super-elastic nitinol wire is in a predefined form to provide retention of the system in the bladder.

[0365] 76. The method of any one of embodiments 73-75, wherein the large lumen of the dual lumen silicone part comprises the gemcitabine.

[0366] 77. The method of any one of embodiments 73-76, wherein the large lumen of the dual lumen silicone part comprises osmotic minitablets.

[0367] 78. The method of embodiment 77, wherein the osmotic minitablets contain urea as an osmotic agent.

[0368] 79. The method of any one of embodiments 1-78, wherein the intravesical drug delivery system is deployed into the bladder of the individual by a urinary placement catheter.

[0369] 80. A kit comprising an intravesical drug delivery system comprising about 225 mg of gemcitabine and instructions for use comprising the method of any one of embodiments 1-79. [0370] 81. The kit of embodiment 80, further comprising a urinary placement catheter.

[0371] 82. The kit of embodiment 81, wherein the urinary placement catheter comprises a catheter and a stylet.

[0372] 83. The kit of any one of embodiments 80-82, further comprising a lubricant and/or a syringe.

[0373] 84. An article of manufacture comprising an intravesical drug delivery system comprising an intravesical device comprising about 225 mg of gemcitabine and a package insert comprising instructions for use according to the method of any one of embodiments 1-79.

[0374] 85. An intravesical drug delivery system comprising an intravesical device comprising about 225 mg gemcitabine for use in the method of any one of embodiments 1-79.

[0375] 86. Gemcitabine for use according to the method of any one of embodiments 1-79.

[0376] 87. Use of gemcitabine for treating papillary-only high-risk non-muscle invasive bladder cancer (HR-NMIBC) in an individual comprising

[0377] administering to the individual about 225 mg of gemcitabine about every three weeks (Q3W) for at least about 24 weeks,

[0378] wherein such treatment results in an improved disease-free survival in a population of patients who have received such treatment compared to a standard of care treatment. [0379] 88. The use of embodiment 87, wherein the individual has BCG-unresponsive or BCG- experienced NMIBC.

[0380] 89. The method of any one of embodiments 1-79 and 87-88, wherein the gemcitabine is gemcitabine free base equivalent (FBE).

[0381] 90. Minitablets comprising gemcitabine for use according to the method of any one of embodiments 1-79, or 87-89.

[0382] 91. Gemcitabine for use with an intravesical device, for use according to the method of any one of embodiments 1-79, or 87-89.

[0383] 92. Gemcitabine for use according to the method of any one of embodiments 1-79, or 87-89, in combination with an intravesical device.

[0384] 93. Gemcitabine for use according to the method of any one of embodiments 1-79, or 87-89, wherein the gemcitabine is administered by an intravesical device.

[0385] 94. The method of any one of embodiments 1-79, or 87-89, wherein amount of gemcitabine administered to the individual is a clinically effective amount of gemcitabine.

[0386] 95. The method of any one of embodiments 1-79, or 87-89, or 94, wherein the individual is ineligible for radical cystectomy due to age, high American Society of Anesthesiologists class score, or medical and surgical comorbidities.

[0387] 96. The method of any one of embodiments 1-79, or 87-89, or 94-95, wherein the individual elects not to undergo a radical cystectomy to preserve their bladder, to preserve sexual function, concern about quality of life after cystectomy, or concern about mortality and morbidity risk associated with radical cystectomy.

[0388] 97. The method of any one of embodiments 1-79, or 87-89, or 94-96, wherein the individual has recurrent, papillary-only high-risk non-muscle invasive bladder cancer (HR- NMIBC).

[0389] 98. A method of treating papillary-only high-risk non-muscle invasive bladder cancer (HR-NMIBC) in an individual comprising administering to the bladder of the individual gemcitabine about every three weeks (Q3W) for up to about 24 weeks.

[0390] 99. A method of treating recurrent BCG-unresponsive or BCG-experienced papillary- only HR-NMIBC in an individual comprising: inserting an intravesical drug delivery system comprising about 225 mg of gemcitabine into the bladder of the individual about once every three weeks (Q3W) for a total of up to 24 weeks following starting treatment, wherein each intravesical drug delivery system is removed from the bladder about three weeks after insertion into the bladder and wherein each intravesical drug delivery system is removed prior to insertion of another intravesical drug delivery system.

[0391] 100. A method of treating recurrent BCG-unresponsive or BCG-experienced papillary- only HR-NMIBC in an individual comprising: inserting an intravesical drug delivery system comprising about 225 mg of gemcitabine into the bladder of the individual about once every three weeks (Q3W) for a total of up to 24 weeks following starting treatment, followed by inserting an intravesical drug delivery system comprising about 225 mg of gemcitabine into the bladder of the individual about once every 12 weeks (Q12W) for up to an additional 75 weeks after the first 24 weeks of treatment, wherein each intravesical drug delivery system is removed from the bladder about three weeks after insertion into the bladder and wherein each intravesical drug delivery system is removed prior to insertion of another intravesical drug delivery system. [0392] 101. The method of any one of embodiments 1-7, wherein administering gemcitabine comprises inserting an intravesical drug delivery system comprising about 225 mg gemcitabine into the bladder of the individual and removing the intravesical drug delivery system about 7 to about 10 days later.

[0393] 102. The method of any one of embodiments 1-7 or 101, comprising i) inserting an intravesical drug delivery system comprising about 225 mg of gemcitabine into the bladder of the individual; ii) removing the intravesical drug delivery system about 7 days to about 10 days later; iii) inserting a new intravesical drug delivery system comprising about 225 mg of gemcitabine into the bladder on the day that the intravesical drug delivery system is removed in step ii), and iv) removing the new intravesical drug delivery system about 7 days to about 10 days later; wherein steps ii) and iii) are completed seven times.

[0394] 103. The method of embodiment 72 or 73, wherein the dual lumen comprises a drug reservoir lumen containing the gemcitabine and a retention frame lumen containing a predefined shaped retention frame.

[0395] 104. The method of embodiment 103, wherein the drug reservoir lumen comprises a single delivery orifice that controllably releases the gemcitabine from the drug reservoir lumen through the delivery orifice.

[0396] 105. The method of embodiment 104, wherein the delivery orifice is a laser-drilled delivery orifice.

[0397] 106. The method of any one of embodiments 103-105, wherein the intravesical drug delivery system comprises a first unit contained within the drug reservoir lumen and comprising the gemcitabine and a second unit contained within the drug reservoir lumen in a position distinct from the first unit, the second unit comprising an osmotic agent.

[0398] 107. The method of embodiment 106, wherein the osmotic agent comprises urea mini tablets.

[0399] 108. The method of embodiment 106 or 107, wherein the first unit further comprises urea.

[0400] 109. The method of any one of embodiments 106-108, wherein the first unit contains at least 75 percent by weight gemcitabine HC1.

[0401] 110. The method of any one of embodiments 106-109, wherein the second unit contains at least 85 percent by weight urea.

[0402] 111. The method of any one of embodiments 71-110, wherein the housing is elastically deformable between a retention shape configured to retain the intravesical drug delivery system in the individual’s bladder and a deployment shape configured for passage of the intravesical drug delivery system through the individual’s urethra.

[0403] 112. The method of any one of embodiments 1-111, wherein the gemcitabine is in the form of minitablets.

[0404] 113. The method of any one of embodiments 1-112, wherein the intravesical device comprises: a housing configured for intravesical insertion, the housing defining a drug reservoir lumen and a retention frame lumen, the drug reservoir lumen having a release orifice; a retention frame comprising an elastic wire located in the retention frame lumen; a first unit contained within the drug reservoir lumen, the first unit comprising gemcitabine tablets; a second unit contained within the drug reservoir lumen in a position distinct from the first unit, the second unit comprising urea tablets; wherein the housing is configured to release gemcitabine from the drug reservoir lumen through the release orifice via osmotic pressure generated by the urea tablets; wherein the housing is elastically deformable between a retention shape configured to retain the device in the individual’s bladder and a deployment shape configured for passage of the device through the individual’s urethra.

[0405] 114. A method of treating papillary-only high-risk non-muscle invasive bladder cancer in an individual comprising: inserting an intravesical drug delivery system comprising about 256 mg gemcitabine hydrochloride into the bladder of the individual about once every three weeks (Q3W) for a total of up to 24 weeks following starting treatment, followed by inserting an intravesical drug delivery system comprising about 256 mg gemcitabine hydrochloride into the bladder of the individual about once every 12 weeks (Q12W) for up to an additional 75 weeks after the first 24 weeks of treatment, wherein each intravesical drug delivery system is removed from the bladder about three weeks after insertion into the bladder and wherein each intravesical drug delivery system is removed prior to insertion of another intravesical drug delivery system. [0406] 115. A method of treating papillary-only high-risk non-muscle invasive bladder cancer in an individual comprising: inserting an intravesical drug delivery system comprising about 256 mg gemcitabine hydrochloride into the bladder of the individual about once every three weeks (Q3W) for a total of up to 24 weeks following starting treatment, followed by inserting an intravesical drug delivery system comprising about 256 mg gemcitabine hydrochloride into the bladder of the individual about once every 12 weeks (Q12W) for up to an additional 75 weeks after the first 24 weeks of treatment, wherein each intravesical drug delivery system is removed from the bladder about seven days to about 10 days after insertion into the bladder and wherein each intravesical drug delivery system is removed prior to insertion of another intravesical drug delivery system.

EXAMPLES

[0407] The following examples are included for illustrative purposes only and are not intended to limit the scope of the present disclosure.

Example 1: In vitro release rate of gemcitabine following administration of TAR-200 [0408] FIG. 6 depicts the percent of gemcitabine released from the TAR-200 intravesical drug delivery system in vitro. The intravesical drug delivery system containing 225 mg gemcitabine (256 gemcitabine HC1) was placed in 300 mL ultrapure water at 37 degrees C. 1 mL samples were taken at 1, 2, 3, 4, 7, 10, 14, 17, and 21 days after the device was placed in water. Samples were then analyzed using an Acquity UPLC® (CSH C18 1.7-pm particle size, 50x2.1 mm i.d.) to quantify gemcitabine released from the intravesical device. The results suggest that approximately 70% of the gemcitabine was released from the intravesical device by day 7, and that approximately 90% of the gemcitabine was released by day 21.

Example 2: Bladder Concentrations of Gemcitabine Following Administration of TAR-200 [0409] Nonclinical studies have demonstrated that bladder concentrations of gemcitabine following administration of TAR-200 in minipigs are sufficient to achieve tissue concentrations that are expected to be tumoricidal.

[0410] A non-Good Laboratory Practice (non-GLP) toxicology study of TAR-200 in minipigs demonstrated that average bladder urine concentrations of 10 pg/mL and above were achieved over a 7-day dosing cycle, resulting in no or low plasma levels of gemcitabine. In this study, minimal changes in hematological tests, clinical chemistry tests, and urinalyses were noted in animals treated with 1 deployment of TAR-200 or 2 sequential 7-day deployments of TAR-200. Administration of 2 TAR-200 simultaneously in this study resulted in greater urinary concentrations and more pronounced clinical and histopathological findings.

[0411] A GLP toxicology study comparing TAR-200 to placebo demonstrated that quantifiable urine gemcitabine concentrations occurred within 24 hours and levels at or above 10 pg/mL were generally maintained over a 7-day dosing cycle in minipigs (FIG 8A). No quantifiable levels of gemcitabine were observed in plasma. Administration of TAR-200 was associated primarily with mild urothelial inflammation in the bladder based on the hematology, clinical chemistry, gross pathology, and microscopic observations. The urothelial changes tended to be mild in severity and transient as complete resolution was observed following the 14-day recovery period.

[0412] Use of TAR-200 for up to 21 days is based on the biphasic release properties observed in vitro and confirmed by in vivo minipig studies. In minipigs, during the first 7-day period, approximately 70% to 80% of the total gemcitabine content in TAR-200 is released, with <20% being released over the following 14-day period (FIG. 8B).

Example 3: Urine concentrations of gemcitabine in individuals following administration of TAR-200

[0413] Referring to FIGS. 9A and 9B, pharmacokinetics of gemcitabine in plasma and urine were measured in individuals receiving TAR-200 (225 mg gemcitabine) (Group 1) or TAR-200 in combination with intravenous cetrelimab (360 mg) (Group 1) for three-week dosing cycles of gemcitabine. After administration of gemcitabine via the TAR-200 intravesical drug delivery system, maximum gemcitabine concentration in urine was reached at a median T_max of 2 to 4 days and appeared to be similar for TAR-200 + cetrelimab and TAR-200 alone. Mean gemcitabine concentration in urine exceeded the tumoricidal concentrations of 3 pg/mL (FIG. 9A-9B). Mean cumulative excreted gemcitabine in urine expressed as percentage of the administered dose from 0-168 hours ranged between 36.2-53.8%. Meanwhile, maximum dFdU concentration in urine was reached at median T_max between 3 and 6 days. Mean cumulative excreted dFdU amount in urine expressed as percentage of the administered dose from 0-168 hours ranged between 11.1-23.3%. The total excreted gemcitabine and dFdU was further converted to GRC in mg-equivalents gemcitabine (mg-Eq. gemcitabine) and are calculated as follows: GRC (mg-Eq. gemcitabine) = Gemcitabine in mg + dFdU in mg * (263.20/264.18). Mean cumulative excreted GRC amount in urine expressed as percentage of the administered dose from 0-168 hours was approximately 60% which appeared to be comparable for Group 1 and Group 2 for all weeks (FIG. 10A-10B). Plasma gemcitabine concentrations of all available samples were below the limit of quantitation [LOQ 0.1 pg/mL] which confirms that there is no systemic exposure of gemcitabine. Plasma dFdU concentrations of all except 2 samples were below the limit of quantitation [LOQ 0.1 pg/mL] which confirms that there is negligible systemic exposure of dFdU (<0.397 pg/mL).

[0414] This example demonstrates that TAR-200 continuously releases gemcitabine into the urine at concentrations sufficient to treat tumors over a period of at least seven days or more and supports use of TAR-200 in a three week dosing cycle to treat bladder cancer.

Example 4: A Phase 3 Study to Investigate TAR-200 Versus Investigator’s Choice of Intravesical Chemotherapy in Participants Who Received Bacillus Calmette-Guerin (BCG) and Recurred with High-Risk Non-Muscle-Invasive Bladder Cancer and Who Are Not Eligible for or Choose Not to Undergo Surgery

[0415] The following example describes a Phase 3, open-label, multi-center, randomized study evaluating the efficacy and safety of TAR-200 versus investigator’s choice of intravesical chemotherapy in participants who received Bacillus Calmette-Guerin (BCG) and recurred with high-risk non-muscle-invasive bladder cancer (HR-NMIBC) and who are ineligible for or elected not to undergo radical cystectomy.

[0416] TAR-200 is an innovative advancement in the field of urologic drug delivery that has the potential to provide extended, sustained local dosing without systemic absorption and ultimately provide more effective treatment than urethral catheterization for the delivery of gemcitabine to the bladder. As an intravesical drug delivery system, the TAR 200 approach may: minimize systemic exposure and associated adverse events of current therapies gemcitabine due to a continuous, low dose release of gemcitabine profile, lower rate of tumor recurrence, and/or maximize targeted drug gemcitabine exposure within the bladder.

Study Design

[0417] This is a randomized, open-label, active-controlled (superiority), multi -center, Phase 3 study evaluating the efficacy and safety of intravesical TAR-200 versus Investigator’s choice of single agent intravesical chemotherapy (intravesical mitomycin C (MMC) or gemcitabine) in participants who received BCG and recurred with papillary-only HR-NMIBC (HG Ta or any Tl, no CIS) and who are either ineligible for or elect not to undergo radical cystectomy (RC) (Table 1). Participants must have received a minimum of adequate BCG induction (5 of 6 doses) and recurred within 1 year of last dose of BCG (i.e., BCG-experienced or BCG-unresponsive) (FIG. 12). [0418] Participants are stratified based on prior BCG treatment (experienced or unresponsive) and based on T-stage (HG Ta or any Tl). Participants who meet the definition of BCG- unresponsive disease will not be stratified as BCG-experienced (FIG. 13).

[0419] A target of up to approximately 250 participants are randomly assigned (1 : 1) in this study to treatment with either TAR-200 or Investigator’s choice of single agent intravesical MMC or gemcitabine.

[0420] As shown in FIG. 12, for participants in Group A, TAR-200 is dosed every 21 days (Q21D) through Week 24 (8 induction doses). Maintenance dosing of TAR-200 will then occur every 12 weeks (Q12W) beginning at Week 24 through Week 96 (Year 2).

[0421] For participants in Group B, MMC or gemcitabine is dosed once weekly (QW) for 6 weeks (6 induction doses), then once monthly (QM) for at least 12 months (total of 10 maintenance doses). This may be followed by an optional second year of additional maintenance at the Investigator’s discretion.

[0422] All participants will undergo cystoscopy and urine cytology at weeks 12, 24, 36, 48, 60, 72, 84, and 96. Additionally, all participants will receive a CT Urogram/MR Urogram at weeks 48, 96, and at any time as deemed clinically indicated.

[0423] In all groups, the Treatment Phase will be followed by a Follow-up Phase.

[0424] The primary endpoint is disease-free survival (DFS) in participants who received BCG and recurred with HR-NMIBC and who are either ineligible for or elect not to undergo RC, receiving TAR-200 versus Investigator’s choice of single agent intravesical chemotherapy (MMC or gemcitabine). DFS is measured as the time from randomization to either the time of the first recurrence of HR disease (HG Ta, any Tl or CIS), progression, or death due to any cause, whichever occurs first. Recurrence and progression events are determined by central disease assessments of cytology, pathology, or imaging as applicable. Local cystoscopy is used to screen for suspected local recurrence; however, a suspicious cystoscopy finding will not alone be considered an event until pathologic confirmation.

[0425] Once a DFS event is reached, participants are required to discontinue from study treatment.

[0426] Key secondary endpoints include recurrence-free survival (RFS), time to next intervention (TTNI), time to disease worsening (TTDW), time to progression (TTP), and overall survival (OS).

[0427] In the event of a positive study result at any of the planned analyses, and upon further notification by the Sponsor, participants in the control arm (Group B) with confirmed recurrence of papillary only HR-NMIBC (HG Ta or any Tl, no CIS) will have the opportunity to receive TAR 200 for up to 2 years.

Pharmaceutical Properties and Formulation of TAR-200 - Drug and Device Elements [0428] TAR-200 is a drug-device combination product and consists of a drug constituent (comprising both gemcitabine HC1 minitablets and osmotic minitablets) and a device constituent. The device constituent consists of a dual lumen silicone part, a superelastic nitinol wire in a predefined shape (wireform), silicone spacers, and silicone adhesive. The dual lumen silicone part has a large lumen, which houses the drug constituent and serves as the osmotic pump. The second, smaller lumen of the silicone part contains the nitinol wireform, which provides the bladder-retentive property of the system. The TAR-200 system is not made with natural latex rubber.

[0429] This device constituent acts as an elementary osmotic pump (or single chamber osmotic pump) that delivers the therapeutic agent at a controlled rate by an osmotic process. The therapeutic agent is surrounded by a semipermeable membrane that contains a single delivery orifice. In its simplest form, the rate of delivery is controlled by water permeability of a semipermeable membrane and the osmotic properties of said therapeutic and osmotic agents.

Gemcitabine 225 mg Intravesical Delivery System (TAR-200) Minitablets Formulation [0430] Gemcitabine hydrochloride, USP/Ph.Eur. is used as the active drug substance for TAR- 200. The formulation components are compendial materials with an established use history in pharmaceutical products.

[0431] The TAR-200 drug constituent includes both gemcitabine minitablets (as active drug) and osmotic (urea) minitablets (for osmotic performance). The gemcitabine minitablets consist of gemcitabine HC1, USP/Ph.Eur., Kollidon 30 (povidone), polyethylene glycol (PEG) 8000, and urea. The osmotic minitablets consist of urea, polyethylene oxide (PEO) 600,000 molecular weight, and US Food, Drug, & Cosmetic (FD&C) Blue No. 1 colorant (<0.001% w/w).

TAR-200 Drug Delivery System

[0432] TAR-200, an investigational, intravesical drug-device combination product, comprising 2 components: 1) the drug constituent contains both gemcitabine HC1 (225 mg FBE) and osmotic (urea) minitablets, that provide the osmotic properties required to achieve the desired release rate, and 2) the device constituent consists of the dual lumen silicone.

[0433] TAR-200 is flexible bi-oval shaped tube. The product size (<5 cm on the long axis), is visually compared to the size of a US 25-cent coin and a 2-Euro coin in FIG. 2. [0434] The ends of TAR-200 are contained in clear plastic sleeves; the system is packaged in a Tyvek pouch and a protective foil pouch, and then terminally sterilized.

[0435] TAR-200 is co-packaged with the Urinary Placement Catheter (UPC), which has been specifically developed for the transurethral placement of the drug delivery system into the bladder. The UPC is a sterile, single-use, transient contact medical device for use solely with specified intravesical delivery systems, such as TAR 200 (FIGs. 4A-4B). The UPC will be in contact with a participant only for the duration of the product insertion procedure (on average <5 minutes).

[0436] TAR-200 is loaded linearly into the clear shaft of the UPC and then inserted into the bladder by advancing the system through the clear shaft of the UPC with a stylet. TAR-200 returns to its original bi-oval form after exiting from the UPC when it is fully inserted into the bladder. A benchtop illustration of the loading and deployment of TAR-200 is provided in FIGs. 5A-5F

[0437] A post insertion cystoscopy is not mandated but may be performed and is suggested for those utilizing the TAR-200 and UPC for the first time. A performed post-insertion cystoscopy would provide a visual assessment of TAR-200 to safeguard that the gemcitabine 225 mg intravesical delivery system is in its “bi-oval” shape and fully contained within the bladder. When placing the UPC, confirm position within the bladder with urine return, then block the opening of the catheter to allow urine to remain in the bladder. This creates a space within the bladder that may facilitate delivery of TAR-200 within the bladder. Alternatively, flexible cystoscopy after insertion of TAR-200 can confirm that it is freely floating within the bladder. The bladder should not be completely empty when TAR-200 is inserted. Consider administering anticholinergics, nonsteroidal anti inflammatory drugs (NSAIDS), and bladder analgesics such as phenopyrazidine, pre- or post-TAR-200 insertion. After insertion of TAR-200, the participant should be counseled to consume adequate liquids as reduced fluid consumption may exacerbate urinary symptoms.

[0438] TAR-200 is removed from the bladder using either a flexible or rigid cystoscope with non-cutting grasping forceps after a defined indwelling period.

TAR-200 In Vitro Release Profile

[0439] The in vitro gemcitabine release profile indicates that approximately 70% of the total gemcitabine is released from TAR-200 in the first 7 days; and approximately 90% of the total gemcitabine is released from TAR-200 by Day 21 (FIG. 6). MMC Dose Selection

[0440] The dose of intravesical Mitomycin C (MMC) is 40 mg. MMC is administered at the site QW for 6 weeks of induction and then QM for up to 12 months (total of 10 doses) of maintenance (Di Stasi 2003). This may be followed by an optional second year of additional maintenance at the Investigator’s discretion.

[0441] MMC is indicated for intravesical infusion at the dose of 40 mg/40mL and the European Urological Association Guidelines recommend 20 to 40 mg as the standard dose of MMC for patients for whom BCG has failed in NMIBC (Babjuk 2022, SmPC Mitomycin 2019).

Hypothesis

[0442] The primary hypothesis of this study is that treatment with TAR-200 intravesical drug delivery system in participants with HR-NMIBC (HG Ta, any Tl, no CIS) who have recurred within 12 months of adequate induction BCG (with or without maintenance) may result in prolonged disease-free survival (DFS) as compared to participants treated with either intravesical MMC or gemcitabine.

Gemcitabine Intravesical Infusion Dose Selection

[0443] The dose of intravesical gemcitabine infusion is 2,000 mg. Intravesical gemcitabine infusion is administered at the site QW for 6 weeks of induction and then QM for up to 12 months (total of 10 doses) of maintenance (Skinner 2013, Addeo 2010). This may be followed by an optional second year of additional maintenance at the Investigator’s discretion.

End of Study Definition

[0444] The end of study is considered as 5 years after the last participant is randomized in the study. This will ensure a minimum of 3 years of disease assessments following the final dose of study drug. The final data from the study site will be sent to the Sponsor (or designee) after completion of the final participant assessment at that study site, in the time frame specified in the clinical trial agreement.

[0445] A participant will be considered to have completed the study if they have completed the treatment and Follow-up Phases or died before the end of treatment (EOT) or Follow-up Phases. Participants who have been lost to follow-up or have withdrawn consent for study participation before the end of the Follow-up Phase will not be considered to have completed the study.

[0446] Participants who prematurely discontinue study treatment for any reason will remain in the study and all efforts will be made to continue to follow those participants for assessments/procedures outlined for the Follow-up Phase (e.g., recurrence, progression, OS, subsequent anti-cancer therapies, other malignancies, procedures [e.g., cystectomy]. The only exception to this is when a participant specifically withdraws consent for any further contact with him/her or persons previously authorized by participant to provide this information. All reasonable efforts should be made to maintain the participant on study to ensure accurate assessment of all protocol-specified endpoints. Those participants who do prematurely discontinue study treatment for any reason before completion of the Treatment Phase will not be considered to have completed the study treatment.

Table 1 : Summary of Group A Study Drug and Group B Study Drug Comparators

Study Population

[0447] Screening for eligible participants will be performed within 42 days before randomization and administration of the study treatment. For participants who require repeat biopsy/TURBT and/or repeat imaging during the Screening Phase, the Screening Phase may be extended from 42 days to 60 days. If repeat biopsy/TURBT and/or repeat imaging is conducted, the results must be available prior to randomization.

Inclusion Criteria [0448] 1) Be >18 years of age (or the legal age of majority in the jurisdiction in which the study is taking place, whichever is greater) at the time of informed consent.

[0449] 2) Histologically confirmed diagnosis by local pathology (within 90 days of documented informed consent) of recurrent, papillary-only HR-NMIBC (defined as HG Ta or any Tl). Or 2a) Participants with variant histologic subtypes are allowed if tumor(s) demonstrate urothelial (transitional cell histology) predominance. However, neuroendocrine, and small cell variants will be excluded.

[0450] 3) All visible tumor completely resected prior to randomization. Urine cytology must not be positive or suspicious for HG urothelial carcinoma before randomization. For participants with lamina propria invasion (Tl) on the screening biopsy /TURBT, muscularis propria must be present to rule out MIBC.

[0451] 4) Participants must have received at least 5 of 6 induction doses of BCG (adequate induction) with or without maintenance therapy.

[0452] 5) Diagnosis of papillary-only HR-NMIBC (defined as HG Ta or any Tl, no CIS) must be within 12 months of the last dose of BCG therapy.

[0453] 6) Participants must be ineligible for or have elected not to undergo RC.

[0454] 7) All AEs associated with any prior surgery and/or intravesical therapy must have resolved to CTCAE version 5.0 Grade <2 prior to screening.

[0455] 8) Have an Eastern Cooperative Oncology Group (ECOG) performance status Grade of 0, 1, or 2 (Table 2).

[0456] 9) Adequate bone marrow, liver, and renal function. Bone marrow function (without the support of cytokines or erythropoiesis stimulating agent in preceding 2 weeks): Absolute neutrophil count (ANC) >1.0>< 10³/pL, Platelet count >75* 10³/pL, Hemoglobin >8.0 g/dL. Liver function: total bilirubin <2 x upper limit normal (ULN) OR direct bilirubin <ULN and total bilirubin <3.0 mg/dL for participants with congenital nonhemolytic hyperbilirubinemia (such as Gilbert’s Syndrome). Alanine aminotransferase (ALT) per serum glutamic-pyruvic transferase and aspartate aminotransferase (AST) per serum glutamic-oxaloacetic transaminase <3 x institutional ULN. Renal function: eGFR of >30 mL/min, based on MDRD 4-variable formula. [0457] 10) Contraceptive use by participants should be consistent with local regulations regarding the use of contraceptive methods of participants participating in clinical studies. Investigators will advise participants on the options for banking of gametes for reproductive conservation. A participant of childbearing potential must agree not to be pregnant, breastfeeding, or planning to become pregnant while enrolled in this study or within 6 months after the last dose of study treatment. A partner must be either of the following; not of childbearing potential, or of childbearing potential and practicing true abstinence, or have a sole partner who is vasectomized, or is practicing at least 1 highly effective user independent method of contraception. Participants must agree to continue the above throughout the study and for 6 months after the EOT.

[0458] 11) A participant of childbearing potential (POCBP) must have a negative highly sensitive serum (e.g., beta-human chorionic gonadotropin [P-hCG]) pregnancy test (at screening) and must agree to further serum or urine pregnancy tests during the study.

[0459] 12) Participants must sign an Informed Consent Form (ICF) (or their legally acceptable representative must sign) indicating that the participant understands the purpose of, and procedures required for, the study and is willing to participate in the study and agreement to store samples when applicable.

[0460] Participants must be willing to comply with and able to undergo all study procedures (e.g., multiple cystoscopies from Screening through the end of study and TURBT/bladder biopsy for assessment of recurrence/progression) and willing and able to adhere to the lifestyle restrictions specified in this protocol.

Exclusion Criteria

[0461] Any potential participant who meets any of the following criteria will be excluded from participating in the study:

[0462] 1) Presence of CIS at any point from time of diagnosis of papillary-only HR-NMIBC recurrence to randomization; however, history of CIS >12 months prior is acceptable. Additionally, presence or history of histologically confirmed, muscle-invasive, locally advanced, nonresectable, or metastatic urothelial carcinoma (i.e., T2, T3, T4, N+, and/or M+).

[0463] 2) Must not currently have urothelial carcinoma or histological variant at any site outside of the urinary bladder. Urothelial carcinoma of the upper urinary tract (including renal pelvis and ureter) is allowable if treated with complete nephroureterectomy more than 24 months prior to randomization with no evidence of recurrence.

[0464] 3) N+ and/or M+ per blinded independent central review (BICR) of computed CT/MR Urography.

[0465] 4) Active malignancies (i.e., progressing or requiring treatment change in the last 24 months) other than the disease being treated under study. Allowed recent second or prior malignancies include the following. Any malignancy that was not progressing nor requiring treatment change in the last 12 months (and not considered at HR of recurrence requiring systemic therapy). Malignancies treated within the last 12 months and considered at very low risk for recurrence: Non-melanoma skin cancers treated with curative therapy or localized melanoma treated with curative surgical resection alone, Non-invasive cervical cancer, Breast cancer: adequately treated lobular CIS or ductal CIS, localized breast cancer and receiving antihormonal agents. Localized prostate cancer (NO, MO) with a Gleason score <7 a, treated locally only (radical prostatectomy [RP]/radiation therapy [RT]/focal treatment), Other malignancy that is considered at minimal risk of recurrence.

[0466] 5) Presence of any bladder or urethral anatomic feature that, in the opinion of the Investigator, may prevent the safe placement, indwelling use, or removal of TAR-200. Participants with tumors involving the prostatic urethra in men will be excluded.

[0467] 6) A history of clinically significant polyuria with recorded 24-hour urine volumes >4,000 mL.

[0468] 7) History of uncontrolled cardiovascular disease including any of the following in the preceding 3 months prior to Screening: unstable angina, myocardial infarction, ventricular fibrillation, Torsades de Pointes, cardiac arrest, or known congestive New York Heart Association Class III-IV heart failure, cerebrovascular accident, or transient ischemic attack. History of pulmonary embolism or other venous thromboembolism within the preceding 2 months.

[0469] 8) Pyeloureteral tube externalized to the skin is exclusionary. Unilateral nephrostomy tube or ureteral stent is permitted if it does not interfere with either insertion or retention of TAR-200 into the bladder. Bilateral ureteral stents are exclusionary.

[0470] 9) Participants who have not recovered from the effects of major surgery or significant traumatic injury at least 14 days before randomization (TURBT is not considered major surgery). [0471] 10) Indwelling catheters are not permitted; however, intermittent catheterization is acceptable.

[0472] 11) Concurrent urinary tract infection (UTI), defined as a symptomatic infection with a positive urine culture with a bacterial count of >10⁵ colony forming units (CFU)/mL in urine voided from women, or >10⁴ CFU/mL in urine voided from men, or in straight catheter urine from women that cannot be cleared with antibiotic therapy. Additionally, any active infection requiring systemic IV or intramuscular (IM) therapy within 14 days prior to randomization. [0473] 12) Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, or psychiatric illness/social situation that would limit compliance with study requirements. [0474] 13) As determined by the Investigator, contraindications to the use of TAR-200, MMC, or gemcitabine per local prescribing information. Known hypersensitivity to any study component including: Gemcitabine (or other drug excipients) or chemically related drugs, TAR- 200 device constituent materials, TAR-200 UPC materials, MMC (or other drug excipients) or chemically related drugs.

[0475] 14) Received a live virus vaccine within 30 days prior to randomization. Inactivated (non live or non-replicating) vaccines approved or authorized for emergency use (e.g., Coronavirus disease 2019 [COVID-19]) by local health authorities are allowed.

[0476] 15) Received serial intravesical therapy or systemic therapy from the time of histologic diagnosis of recurrent HR-NMIBC to date of randomization. Immediate post-TURBT singledose per-operative intravesical chemotherapy is allowed in accordance with institutional guidelines.

[0477] 16) Previous treatment with TAR-200.

[0478] 17) Currently participating or has participated in a study and received an investigational agent or investigational device within 4 weeks prior to screening.

[0479] 18) Participants with evidence of bladder perforation during cystoscopy. Participants are eligible if perforation has resolved prior to dosing.

[0480] 19) Bladder post-void residual (PVR) volume >350 mL at screening after second voided urine.

[0481] 20) Any condition for which, in the opinion of the Investigator, participation would not be in the best interest of the participant (e.g., compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments.

Primary Endpoint(s)

[0482] The primary efficacy endpoint is DFS, which is measured as the time from date of randomization to the date of either first recurrence of HR disease (HR-NMIBC (HG Ta, any T1 or CIS)), progression, or death due to any cause, whichever occurs first.

[0483] Recurrence of HR disease is defined as: positive urine cytology for HG urothelial cancer, or biopsy-proven HR-NMIBC.

[0484] Progression is defined as: an increase of stage from Ta to Tl, OR progression to MIBC (T>2), lymph node (N+), or distant disease (M+).

[0485] Patients with suspicious cytology will be considered to have DFS event if the subsequent cytology is positive, i.e., the previous suspicious cytology will be imputed based on the subsequent cytology. If the subsequent urine cytology is negative, this will not be considered a DFS event.

[0486] The full analysis set will be used for the primary analysis for DFS. The distribution (median and Kaplan-Meier curves) of DFS will be provided using Kaplan-Meier estimate. Treatment difference will be compared using a 2-sided stratified log-rank test as the primary analysis. The estimate of hazard ratio and its 95% CI will be based on stratified Cox proportional hazard model with study intervention as the sole explanatory variable.

[0487] In addition, DFS rate at prespecified landmarks (e.g., 6 months, 1-year , and 2-year) with 95% CI will be estimated by Kaplan-Meier method and reported for each treatment group.

Secondary Endpoint(s)

[0488] RFS is measured as the time from randomization to the date of the first recurrence of HR disease (HG Ta, any Tl, or CIS), or death due to any cause, whichever occurs first. RFS rate at 6, 12, and 24 months will also be evaluated by each treatment group. Similar censoring rule as DFS will be applied to RFS, except those participants who had progression without recurrence prior to the progression will be censored at the date of last disease assessment before progression.

[0489] TTNI (e.g., TURBT, RC, radiation therapy or chemotherapy) is measured as the time from the date of randomization to the date of the next intervention (localized or systemic) for the treatment of bladder cancer. Participants who did not receive next intervention will be censored at the last study assessment.

[0490] TTDW is measured as the time from randomization to cystectomy, systemic therapy, or radiation therapy (treatments of disease worsening).

[0491] TTP is measured as the time from randomization to the date of first documented evidence of disease progression (i.e., HG Ta to Tl, MIBC, nodal [T>2], lymph node [N+], or distant metastasis [M+]), or death due to disease progression, whichever occurs first. Participants last known to be alive and free from progression will be censored at the date of last disease assessment. Participants who received subsequent anticancer therapy will not be censored and continued to be monitored until progression, death, or the end of study.

[0492] OS is defined as the time from the randomization to death from any cause. Participants known to be alive in the study will be censored at the date when they are last known to be alive. [0493] The same analysis methods that will be performed for DFS will be applied to RFS, TTNI, TTDW, TTP, and OS. [0494] Other secondary endpoints include the following. The 12-month and 24-month DFS rate. The safety and tolerability of TAR-200 and Investigators choice of chemotherapy will be assessed by frequency and grade of AEs (according to CTCAE version 5.0) and laboratory abnormalities: CTCAE grades comparing baseline to the worst post-baseline value; other safety data, such as vital signs, will be considered as appropriate. Change from baseline in EORTC QLQ-C30 and EORTC QLQ-NMIBC24 scores, and proportion of participants with meaningful change in EORTC QLQ-C30 and EORTC QLQ NMIBC24 scores.

Exploratory Endpoint(s)

[0495] TTC is measured as the time from the date of randomization to the date of the RC. Participants who did not have cystectomy will be censored at the last study assessment.

[0496] aDFS is measured as the time from the date of randomization to either the time of DFS or any recurrence of HR-NMIBC (any grade Ta, any grade Tl, or CIS), progression, or death due to any cause, whichever occurs first. Same censoring rule as DFS will be applied to aDFS, by including the non-HR-NMIBC in the recurrence.

[0497] DFS2 is measured as the time from randomization to the date of recurrence of HR disease, progression, or death due to any cause on the first subsequent anticancer treatment, whichever occurs first. Same censoring rule as DFS will be applied to DFS2.

[0498] CSS is measured as the time from randomization to the date of death due to bladder cancer. Participants known to be alive in the study will be censored at the date when they are last known to be alive.

[0499] The same analysis methods that will be performed for DFS will be applied to TTNI, TTC, aDFS, DFS2, and CSS.

[0500] Other exploratory endpoints include the following. To evaluate the PK of gemcitabine and its major metabolite, dFdU, in urine following administration of TAR-200. To evaluate patient-reported general HRQoL. To evaluate healthcare resource utilization and hospitalizations. To identify response and resistance biomarkers that are associated with DFS or other disease endpoints. To identify changes in biomarkers during treatment with TAR-200 compared to control treatment.

Disease Assessments

Cystoscopy

[0501] Cystoscopy will be performed for a visual assessment of the bladder urothelium. Whenever possible, the same individual should perform cystoscopy throughout the study for a given participant. Cystoscopy technology for bladder visualization (e.g., white light, blue light) will be documented in the eCRF. Every effort should be made to use the same technology with a given participant throughout the study. Assessment cystoscopy during Screening may be required to ensure bladder accessibility is adequate for insertion of TAR-200. Repeat cystoscopy within Screening is required for participants referred from an outside institution, different health care provider from study Investigator, and/or if previous assessment was not done within 42 days prior to randomization.

[0502] During treatment and follow-up, a positive (i.e., suspicious) cystoscopy will lead to pathologic evaluation of biopsy /TURBT.

Urine Cytology

[0503] Urine specimens will be collected throughout the course of the study at specified timepoints and reported according to the Paris System (The Paris System for Reporting Urinary Cytology 2015).

[0504] At screening, local results will be used for randomization. A sample will be sent for central review; however, results are not required prior to randomization.

[0505] During the Treatment Phase and the Follow-up Phase, urine cytology will be evaluated by local and central pathology laboratory. Treatment decisions should be based off the central cytopathological diagnosis. Sites should consult with the Sponsor in the event of a positive local urine cytology and absent/pending central cytopathology review before discontinuing study treatment.

TURBT/Bladder Biopsy

[0506] In accordance with the protocol, a cystoscopic biopsy is defined as a TURBT and/or a cystoscopic cold-cup biopsy.

[0507] For participants with lamina propria invasion (Tl) on the Screening biopsy/TURBT, muscularis propria must be present to rule out MIBC.

[0508] A TURBT will be required during screening to remove any residual disease. During treatment and follow-up, a TURBT/bladder biopsy will be conducted if positive cystoscopy or positive urine cytology or as deemed clinically indicated. Specimens from any time point should be submitted to central laboratory.

[0509] During the Treatment Phase and the Follow-up Phase, samples will be evaluated by local review and will be submitted for central review for disease status. Treatment decisions should be based off central pathological diagnosis.

CT Urography /MR Urography Scan [0510] At all imaging time points it is preferred that a CT Urography Scan of the abdomen and pelvis (with IV contrast) be acquired instead of MR Urography. However, if a CT Urography Scan cannot be done, MR Urography may be used. If iodinated IV contrast is contraindicated, perform a magnetic resonance imaging (MRI) scan of the abdomen and pelvis using Gadolinium IV contrast, unless contraindicated. Use the same modality(ies) and methodology for disease assessment at baseline and throughout the course of the study whenever possible.

Patient Reported Outcomes

EORTC QLQ-C30

[0511] The EORTC QLQ-C30 (Version 3), is a self-administered, 30-item questionnaire measuring the HRQoL of participants with cancer. The recall period for most items is the past week. EORTC QLQ-C30 includes 5 functional scales (physical, role, cognitive, emotional, and social), 3 symptom scales (fatigue, pain, and nausea and vomiting), a global health status / quality of life scale, and 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). Responses to items 1-28 are rated on a 4-point Likert response scale ranging from 1 “Not at all” to 4 “Very much”. Two global health status items are rated on a 7- point numeric rating scale from 1 “Very Poor” to 7 “Excellent.” Higher scores indicate greater functioning, better global health status, and or more severe symptoms The EORTC QLQ-C30 can generally be completed in 5 minutes. (Aaronson 1988, Aaronson 1991, Aaronson 1993).

EORTC QLQ-NMIBC24

[0512] The EORTC QLQ-NMIBC24, is a self-administered, 24-item questionnaire measuring the HRQoL of participants with NMIBC. The questionnaire is a supplementary module to be employed in conjunction with the QLQ-C30. The recall period for most items is the past week, although some items are rated based on the past 4 weeks. There are 6 multi-item scales (urinary symptoms, malaise, future worries, bloating and flatulence, sexual function and male sexual problems) and 5 single items (intravesical treatment issues, sexual intimacy, worries about risk of contaminating partner, sexual enjoyment, and female sexual problems). Responses for all items are rated on a 4-point Likert response scale ranging from 1 “Not at all” to 4 “Very much”. Higher scores represent a high level of symptomatology or problems, with the exception of sexual function and sexual enjoyment where a higher score represents a higher level of functioning. The EORTC QLQ-NMIBC24 takes about 5 minutes to complete (Blazeby 2014).

PGI-S

[0513] The PGI-S is a self-administered, single-item questionnaire measuring patients’ impression of disease severity. The recall period is the past week. Response options are “none,” “mild,” “moderate,” and “severe.” A higher PGI-S score indicates more severe disease. The PGI- S can generally be completed in less than 1 minute.

EQ-5D-5L

[0514] The EQ-5D-5L is a self-administered, standardized measure of health status in a wide range of health conditions and treatments. It provides a descriptive profile and a single index value for health status that can be used in the clinical and economic evaluation of health care. The recall period for all items is ‘Today’. The EQ-5D-5L consists of a descriptive system and VAS. The descriptive system is composed of 5 items across 5 dimensions (mobility, self care, usual activities, pain/discomfort and anxiety/depression) rated on a 5-point Likert scale ranging from “No problems” to “Extreme problems”. The VAS is a single item asking participants to rate their own health on that day on a 0 (“worst imaginable health state”) to 100 (“best imaginable health state”) scale. The EQ-5D-5L can generally be completed in 2-3 minutes. (EuroQoL 2019, Herdman 2011, Janssen 2013).

Adverse Events (AEs)

[0515] An AE is any untoward medical occurrence in a clinical study participant administered a pharmaceutical (investigational or non investigational) product. An AE does not necessarily have a causal relationship with the treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal finding), symptom, or disease temporally associated with the use of a medicinal (investigational or non investigational) product, whether or not related to that medicinal (investigational or non investigational) product.

[0516] Serious adverse events (SAEs) are any untoward medical occurrence that at any dose: results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization or prolongation of existing hospitalization, results in persistent or significant disability or incapacity, is a congenital anomaly/birth defect, is a suspected transmission of any infectious agent via a medicinal product, or is medically important.

Analysis Sets

[0517] The enrolled analysis set comprises participants who signed ICF.

[0518] The Full Analysis Set comprises all participants who were randomized in the study, (i.e., intent-to-treat).

[0519] The Safety Analysis Set comprises all participants who received at least 1 dose of any study intervention.

Sample Size Determination [0520] This study will randomize approximately 250 participants in a 1 : 1 randomization ratio. The primary efficacy analysis for DFS will be performed after 125 DFS events have been observed. The 1-year DFS rate in the control group is anticipated to be 40% (i.e., median DFS of 9 months). Assuming 20% absolute improvement in 1 year DFS rate over the control (from 40% to 60%, translating to a hazard ratio of 0.55 and an improvement of median DFS from 9 months to 16 months), this study will provide over 90% power to achieve a statistically significant difference between the treatment groups (2-sided alpha = 0.05). This assumes a 20.5-month accrual, 12 months of additional follow up, and a 5% annual dropout rate.

Table 2: ECOG Performance Status Scale

Claims

CLAIMS What is claimed is:

1. A method of treating papillary-only high-risk non-muscle invasive bladder cancer (HR- NMIBC) in an individual comprising administering to the bladder of the individual about 225 mg of gemcitabine about every three weeks (Q3W) for up to about 24 weeks.

2. A method of treating papillary-only high-risk non-muscle invasive bladder cancer (HR- NMIBC) in an individual comprising administering gemcitabine to the bladder of the individual about every three weeks (Q3W) for up to about 24 weeks during eight administration periods, wherein each administration period comprises a delivery period of at least about seven days when gemcitabine is released from an intravesical drug delivery system, wherein the concentration of gemcitabine in the urine of the individual is at least about 4 pg/mL during each delivery period.

3. A method of bladder sparing in an individual having papillary-only high-risk non-muscle invasive bladder cancer (HR-NMIBC) comprising administering to the individual about 225 mg of gemcitabine about every three weeks (Q3W) for up to about 24 weeks, wherein the individual does not receive a radical cystectomy.

4. A method of treating papillary-only high-risk non-muscle invasive bladder cancer (HR- NMIBC) in an individual who is eligible for radical cystectomy, the method comprising administering to the bladder of the individual about 225 mg of gemcitabine about every three weeks (Q3W) for up to about 24 weeks.

5. A method of treating papillary-only high-risk non-muscle invasive bladder cancer (HR- NMIBC) in an individual comprising administering to the bladder of the individual gemcitabine about every three weeks (Q3W) for up to about 24 weeks.

6. A method of treating papillary-only high-risk non-muscle invasive bladder cancer (HR- NMIBC) in an individual comprising administering to the bladder of the individual about 225 mg of gemcitabine about every three weeks (Q3W) for up to about 24 weeks, wherein such treatment results in an increased disease-free survival compared to a standard of care treatment.

7. A method of treating papillary-only high-risk non-muscle invasive bladder cancer (HR- NMIBC) in an individual comprising

(a) administering to the bladder of the individual about 225 mg of gemcitabine about every three weeks (Q3W) for up to about 24 weeks during eight administration periods,

(b) administering to the bladder of the individual about 225 mg of gemcitabine about every 12 weeks (Q12W) for at least about 60 weeks during six administration periods,

(c) extending disease-free survival in the individual by at least about 9 months; wherein each administration period comprises a delivery period of at least about seven days.

8. A method of increasing the disease-free survival for papillary-only high-risk non-muscle invasive bladder cancer (HR-NMIBC) in an individual comprising administering to the bladder of the individual about 225 mg of gemcitabine about every three weeks (Q3W) for up to about 24 weeks, wherein such treatment results in an increased median disease-free survival compared to the median disease-free survival achieved by intravesical mitomycin C (MMC) or intravesical gemcitabine.

9. A method of treating recurrent BCG-unresponsive or BCG-experienced papillary-only HR- NMIBC in an individual comprising: inserting an intravesical drug delivery system comprising about 225 mg of gemcitabine into the bladder of the individual about once every three weeks (Q3W) for a total of up to 24 weeks following starting treatment, wherein each intravesical drug delivery system is removed from the bladder about three weeks after insertion into the bladder and wherein each intravesical drug delivery system is removed prior to insertion of another intravesical drug delivery system.

10. A method of treating recurrent BCG-unresponsive or BCG-experienced papillary-only HR- NMIBC in an individual comprising: inserting an intravesical drug delivery system comprising about 225 mg of gemcitabine into the bladder of the individual about once every three weeks (Q3W) for a total of up to 24 weeks following starting treatment, followed by inserting an intravesical drug delivery system comprising about 225 mg of gemcitabine into the bladder of the individual about once every 12 weeks (Q12W) for up to an additional 75 weeks after the first 24 weeks of treatment, wherein each intravesical drug delivery system is removed from the bladder about three weeks after insertion into the bladder and wherein each intravesical drug delivery system is removed prior to insertion of another intravesical drug delivery system.

11. The method of any one of claims 1-10, wherein the concentration of gemcitabine in the urine of the individual is between about 4 pg/mL and about 50 pg/mL during each administration period.

12. The method of any one of claims 1-11, wherein the papillary-only high-risk non-muscle invasive bladder cancer comprises high grade Ta or any T1 disease not comprising CIS.

13. The method of any one of claims 1-12, wherein the individual does not have CIS.

14. The method of any one of claims 1-13, wherein the individual does not have N+ and/or M+ bladder cancer.

15. The method of any one of claims 1-14, wherein the gemcitabine administered to the individual as a monotherapy for treatment of papillary-only HR-NMIBC.

16. The method of any one of claims 1-15, wherein median disease-free survival in a population of patients who have received such therapy is improved compared to the standard of care, optionally wherein the median disease-free survival in the population of patients is improved at least about 40% compared to the disease-free survival for the standard of care.

17. The method of any one of claims 1-15, wherein median disease-free survival in a population of patients who have received such therapy is improved compared to a systemic chemotherapeutic agent therapy, optionally wherein the disease-free survival is improved at least about 40% compared to the disease-free survival for the systemic chemotherapeutic agent therapy.

18. The method of any one of claims 1-15, wherein median disease-free survival in a population of patients who have receive such therapy is improved compared to treatment with intravesical mitomycin C (MMC) or intravesical gemcitabine, optionally wherein the median disease-free survival is improved at least about 40% compared to the disease-free survival for intravesical mitomycin C (MMC) or intravesical gemcitabine.

19. The method of any one of claims 1-18, wherein such treatment results in an increased recurrence-free survival compared to the standard of care treatment, optionally wherein the recurrence-free survival is improved at least about 40% compared to the recurrence-free survival for intravesical mitomycin C (MMC) or intravesical gemcitabine.

20. The method of any one of claims 1-19, wherein such treatment results in an increased time to next intervention compared to the standard of care treatment, optionally wherein the time to next intervention is improved at least about 40% compared to the time to next intervention for intravesical mitomycin C (MMC) or intravesical gemcitabine.

21. The method of any one of claims 1-20, wherein such treatment results in an increased time to disease worsening compared to the standard of care treatment, optionally wherein the time to disease worsening is improved at least about 40% compared to the time to disease worsening for intravesical mitomycin C (MMC) or intravesical gemcitabine.

22. The method of any one of claims 1-21, wherein such treatment results in an increased time to progression compared to the standard of care treatment, optionally wherein the time to progression is improved at least about 40% compared to the time to progression for intravesical mitomycin C (MMC) or intravesical gemcitabine.

23. The method of any one of claims 1-22, wherein such treatment results in an increased disease-free survival rate compared to the standard of care treatment, optionally wherein the disease-free survival rate is improved by at least about 20% compared to the disease-free survival rate for intravesical mitomycin C (MMC) or intravesical gemcitabine.

24. The method of claim 23, wherein the disease-free survival rate is a 24-month disease-free survival rate.

25. The method of any one of claims 1-24, wherein such treatment results in an increased overall survival compared to the standard of care treatment.

26. The method of any one of claims 1-25, wherein such treatment results in an increased cancerspecific survival compared to the standard of care treatment.

27. The method of any one of claims 1-26, wherein such treatment results in an increased time to cystectomy compared to the standard of care treatment.

28. The method of any one of claims 1-27, wherein such treatment results in a time to cystectomy of at least about 12 months.

29. The method of any one of claims 1-28, wherein such treatment results in an increased disease-free survival at 2 years compared to the standard of care treatment.

30. The method of any one of claims 1-29, wherein the individual has BCG-experienced HR- NMIBC.

31. The method of claim 30, wherein the individual has received five of six doses of an induction phase of BCG and has recurred with high grade Ta or any T1 disease within 12 months.

32. The method of any one of claims 1-29, wherein the individual has BCG-unresponsive HR- NMIBC.

33. The method of claim 32, wherein the individual has received i) a minimum of five of six full doses of an induction course of BCG; and

I l l ii) two or three doses of a maintenance course, or two of six doses of a second induction course of BCG therapy.

34. The method of claim 32 or claim 33, wherein the individual has i) high grade T1 disease at a first disease assessment after induction or ii) high grade Ta or any T1 disease within six months.

35. The method of any one of claims 1-34, wherein the individual is administered gemcitabine within 12 months of completion of a last dose of BCG therapy.

36. The method of any one of claims 1-35, wherein such treatment results in a disease-free survival of at least 9 months.

37. The method of any one of claims 1-36, wherein the individual is ineligible for or elected not to undergo radical cystectomy.

38. The method of claim 37, wherein the individual elected not to undergo radical cystectomy due to bladder preservation or concern about quality of life after bladder removal.

39. The method of claims 37 or 38, wherein the individual elected not to undergo a radical cystectomy to preserve their bladder, to preserve sexual function, or concern about mortality and morbidity risk associated with radical cystectomy.

40. The method of claim 37, wherein the individual is ineligible for radical cystectomy due to age, high American Society of Anesthesiologists class score, or medical and surgical comorbidities.

41. The method of any one of claims 1-8 or 11-40, wherein the individual and/or the population of patients comprise one or more individuals that has recurrent, papillary-only high-risk nonmuscle invasive bladder cancer (HR-NMIBC).

42. The method of any one of claims 1-41, wherein the individual has Ta stage bladder cancer, and/or wherein the population of patients comprises one or more individuals with Ta stage bladder cancer.

43. The method of claim 42, wherein the individual has high grade Ta stage bladder cancer and/or wherein the population of patients comprises one or more individuals with high grade Ta stage bladder cancer.

44. The method of any one of claims 1-41, wherein the individual has T1 stage bladder cancer and/or wherein the population of patients comprises one or more individuals with T1 stage bladder cancer.

45. The method of claim 44, wherein the individual has high grade T1 stage bladder cancer and/or wherein the population of patients comprises one or more individuals with high grade T1 stage bladder cancer.

46. The method of any one of claims 1-45, wherein the individual has a mixed histology tumor and/or wherein the population of patients comprises one or more individuals with a mixed histology tumor.

47. The method of any one of claims 1-46, wherein the bladder cancer does not have neuroendocrine, micropapillary, signet ring cell, plasmacytoid, or sarcomatoid features.

48. The method of any one of claims 1-47, wherein the individual does not have a urothelial carcinoma or histological variant at any site outside of the urinary bladder.

49. The method of any one of claims 1-48, comprising performing a transurethral resection of bladder tumor (TURBT) prior to treatment with gemcitabine.

50. The method of claim 49, wherein the bladder cancer is fully resected following TURBT.

51. The method of any one of claims 1-50, wherein following treatment with gemcitabine, the individual is monitored for recurrence.

52. The method of any one of claims 1-51, wherein following treatment with gemcitabine, The individual does not receive valrubicin, systemic gemcitabine, docetaxel, pembrolizumab or paclitaxel for treating the papillary-only high-risk non-muscle invasive bladder cancer (HR- NMIBC) that is unresponsive to intravesical Bacillus Calmette-Guerin (BCG) therapy.

53. The method of any one of claims 1-52, wherein treatment with gemcitabine causes tumor ablation.

54. The method of any one of claims 1-53, wherein following treatment with gemcitabine, the individual does not receive a transurethral resection of bladder tumors (TURBT).

55. The method of any one of claims 1-54, wherein the individual does not progress to muscle- invasive bladder cancer.

56. The method of any one of claims 1-55, wherein the quality-of-life score of the individual is maintained or increases following treatment with gemcitabine.

57. The method of any one of claims 1-56, wherein the individual has asymptomatic macrohematuria or dysuria prior to the treatment with gemcitabine.

58. The method of any one of claims 1-8 or 11-57, wherein administering gemcitabine comprises inserting an intravesical drug delivery system comprising about 225 mg gemcitabine into the bladder of the individual and removing the intravesical drug delivery system about three weeks later.

59. The method of any one of claims 1-8 or 11-57, wherein administering gemcitabine comprises inserting an intravesical drug delivery system comprising about 225 mg gemcitabine into the bladder of the individual and removing the intravesical drug delivery system about 7 to about 10 days later.

60. The method of any one of claims 1-8 or 11-58, comprising i) inserting an intravesical drug delivery system comprising about 225 mg of gemcitabine into the bladder of the individual; ii) removing the intravesical drug delivery system about three weeks later; iii) inserting a new intravesical drug delivery system comprising about 225 mg of gemcitabine into the bladder on the day that the intravesical drug delivery system is removed in step ii), and iv) removing the new intravesical drug delivery system about three weeks later; wherein steps ii) and iii) are completed seven times.

61. The method of any one of claims 1-8, 11-57, or 59 comprising i) inserting an intravesical drug delivery system comprising about 225 mg of gemcitabine into the bladder of the individual; ii) removing the intravesical drug delivery system about 7 days to about 10 days later; iii) inserting a new intravesical drug delivery system comprising about 225 mg of gemcitabine into the bladder on the day that the intravesical drug delivery system is removed in step ii), and iv) removing the new intravesical drug delivery system about 7 days to about 10 days later; wherein steps ii) and iii) are completed seven times.

62. The method of any one of claims 1-8 or 10-61, comprising a dosing schedule of up to about 24 weeks comprising: i) inserting a first intravesical drug delivery system into the bladder in week 0, and removing the first intravesical drug delivery system in week 3; ii) inserting a second intravesical drug delivery system into the bladder in week 3 after removing the first intravesical drug delivery system, and removing the second intravesical drug delivery system in week 6; iii) inserting a third intravesical drug delivery system into the bladder in week 6 after removing the second intravesical drug delivery system, and removing the third intravesical drug delivery system in week 9; iv) inserting a fourth intravesical drug delivery system into the bladder in week 9 after removing the third intravesical drug delivery system, and removing the fourth intravesical drug delivery system in week 12; v) inserting a fifth intravesical drug delivery system into the bladder in week 12 after removing the fourth intravesical drug delivery system, and removing the fifth intravesical drug delivery system in week 15; vi) inserting a sixth intravesical drug delivery system into the bladder in week 15 after removing the fifth intravesical drug delivery system, and removing the sixth intravesical drug delivery system in week 18; vii) inserting a seventh intravesical drug delivery system into the bladder in week 18 after removing the sixth intravesical drug delivery system, and removing the seventh intravesical drug delivery system in week 21; and viii) inserting an eighth intravesical drug delivery system into the bladder in week 21 after removing the seventh intravesical drug delivery system, and removing the eighth intravesical drug delivery system in week 24; wherein each intravesical drug delivery system comprises an intravesical device comprising about 225 mg of gemcitabine.

63. The method of any one of claims 1-8 or 10-62, further comprising a second phase, the second phase comprising administering about 225 mg gemcitabine to the bladder of the individual every 12 weeks (Q12W).

64. The method of claim 63, wherein the second phase comprises administering about 225 mg gemcitabine to the bladder of the individual for about 7 days to about 10 days about every three months.

65. The method of any one of claims 9 or 63-64, wherein the second phase comprises administering about 225 mg gemcitabine to the bladder of the individual during weeks 36-39, 48-51, 60-63, 72-75, 84-87, and 96-99.

66. The method of any one of claims 9 or 63-65, comprising i) inserting an intravesical drug delivery system into the bladder of the individual on about week 36 and removing the intravesical drug delivery system on about week 39; ii) inserting an intravesical drug delivery system into the bladder of the individual on about week 48 and removing the intravesical drug delivery system on about week 51; iii) inserting an intravesical drug delivery system into the bladder of the individual on about week 60 and removing the intravesical drug delivery system on about week 63; iv) inserting an intravesical drug delivery system into the bladder of the individual on about week 72 and removing the intravesical drug delivery system on about week 75; v) inserting an intravesical drug delivery system into the bladder of the individual on about week 84 and removing the intravesical drug delivery system on about week 87; and vi) inserting an intravesical drug delivery system into the bladder of the individual on about week 96 and removing the intravesical drug delivery system on about week 99; wherein the intravesical drug delivery system comprises an intravesical device comprising about 225 mg of gemcitabine.

67. The method of any one of claims 9 or 63-66, wherein the method comprises up to fourteen total doses of gemcitabine.

68. The method of any one of claims 1-67, wherein gemcitabine is delivered from an intravesical drug delivery system during a delivery period.

69. The method of claim 68, wherein the delivery period is about one to about three weeks.

70. The method of claim 68 or claim 69, wherein the concentration of gemcitabine in the urine is from about 1 pg/mL to about 25 pg/mL or from about 4 pg/mL to about 50 pg/mL during the delivery period.

71. The method of any one of claims 2, 9, 10, or 58-70, wherein the intravesical drug delivery system releases gemcitabine at a rate of about 10 to about 45 mg/day for about the first seven days of administration.

72. The method of any one of claims 2, 9, 10, or 58-71, wherein the intravesical drug delivery system is deployed into the bladder of the individual by a urinary placement catheter.

73. The method of any one of claims 1, 3-10, or 58-72, wherein about 256 mg of gemcitabine hydrochloride (HC1) is administered to the individual.

74. The method of any one of claims 2, 9, 10, or 58-73, wherein the intravesical drug delivery system comprises about 256 mg of gemcitabine HC1.

75. The method of any one of claims 8, 9, or 58-74, wherein the intravesical drug delivery system comprises a flexible, bi-oval shaped housing comprising a dual lumen.

76. The method of claim 75, wherein the dual lumen comprises a drug reservoir lumen containing the gemcitabine and a retention frame lumen containing a predefined shaped retention frame.

77. The method of claim 76, wherein the retention frame is a super-elastic nitinol wire.

78. The method of claim 76 or 77, wherein the drug reservoir lumen comprises silicone part comprising a single delivery orifice that controllably releases the gemcitabine from the drug reservoir lumen through the delivery orifice.

79. The method of claim 78, wherein the delivery orifice is a laser-drilled delivery orifice.

80. The method of any one of claims 76-79, wherein the intravesical drug delivery system comprises a first unit contained within the drug reservoir lumen and comprising the gemcitabine and a second unit contained within the drug reservoir lumen in a position distinct from the first unit, the second unit comprising an osmotic agent.

81. The method of claim 80, wherein the osmotic agent comprises urea minitablets.

82. The method of claim 80 or 81, wherein the first unit further comprises urea.

83. The method of any one of claims 80-82, wherein the first unit contains at least 75 percent by weight gemcitabine HC1.

84. The method of any one of claims 80-83, wherein the second unit contains at least 85 percent by weight urea.

85. The method of any one of claims 75-84, wherein the housing is configured to release the gemcitabine from the drug reservoir lumen through the delivery orifice via osmotic pressure generated by the osmotic agent.

86. The method of any one of claims 75-85, wherein the housing is elastically deformable between a retention shape configured to retain the intravesical drug delivery system in the individual’s bladder and a deployment shape configured for passage of the intravesical drug delivery system through the individual’s urethra.

87. The method of claim 80, wherein the gemcitabine is in the form of minitablets.

88. The method of any one of claims 9, 10, or 58-87, wherein the intravesical device comprises: a housing configured for intravesical insertion, the housing defining a drug reservoir lumen and a retention frame lumen, the drug reservoir lumen having a release orifice; a retention frame comprising an elastic wire located in the retention frame lumen; a first unit contained within the drug reservoir lumen, the first unit comprising gemcitabine tablets; a second unit contained within the drug reservoir lumen in a position distinct from the first unit, the second unit comprising urea tablets; wherein the housing is configured to release gemcitabine from the drug reservoir lumen through the release orifice via osmotic pressure generated by the urea tablets; wherein the housing is elastically deformable between a retention shape configured to retain the device in the individual’s bladder and a deployment shape configured for passage of the device through the individual’s urethra.

89. A kit comprising an intravesical drug delivery system comprising about 225 mg of gemcitabine and instructions for use comprising the method of any one of claims 1-88.

90. The kit of claim 89, further comprising a urinary placement catheter.

91. The kit of claim 90, wherein the urinary placement catheter comprises a catheter and a stylet.

92. The kit of any one of claims 88-90, further comprising a lubricant and/or a syringe.

93. An article of manufacture comprising an intravesical drug delivery system comprising an intravesical device comprising about 225 mg of gemcitabine and a package insert comprising instructions for use according to the method of any one of claims 1-88.

94. An intravesical drug delivery system comprising an intravesical device comprising about 225 mg gemcitabine for use in the method of any one of claims 1-88.

95. Gemcitabine for use according to the method of any one of claims 1-88.

96. Use of gemcitabine for treating papillary-only high-risk non-muscle invasive bladder cancer (HR-NMIBC) in an individual comprising administering to the individual about 225 mg of gemcitabine about every three weeks (Q3W) for up to about 24 weeks, wherein such treatment results in an improved disease-free survival in a population of patients who have received such treatment compared to a standard of care treatment.

97. The use of claim 96, wherein the individual has BCG-unresponsive or BCG-experienced NMIBC.

98. Minitablets comprising gemcitabine for use according to the method of any one of claims 1- 88.

99. Gemcitabine for use with an intravesical device, for use according to the method of any one of claims 1-88.

100. Gemcitabine for use according to the method of any one of claims 1-88, in combination with an intravesical device.

101. Gemcitabine for use according to the method of any one of claims 1-88, wherein the gemcitabine is administered by an intravesical device.

102. A method of treating papillary-only high-risk non-muscle invasive bladder cancer in an individual comprising: inserting an intravesical drug delivery system comprising about 256 mg gemcitabine hydrochloride into the bladder of the individual about once every three weeks (Q3W) for a total of up to 24 weeks following starting treatment, followed by inserting an intravesical drug delivery system comprising about 256 mg gemcitabine hydrochloride into the bladder of the individual about once every 12 weeks (Q12W) for up to an additional 75 weeks after the first 24 weeks of treatment, wherein each intravesical drug delivery system is removed from the bladder about three weeks after insertion into the bladder and wherein each intravesical drug delivery system is removed prior to insertion of another intravesical drug delivery system.

103. A method of treating papillary-only high-risk non-muscle invasive bladder cancer in an individual comprising: inserting an intravesical drug delivery system comprising about 256 mg gemcitabine hydrochloride into the bladder of the individual about once every three weeks (Q3W) for a total of up to 24 weeks following starting treatment, followed by inserting an intravesical drug delivery system comprising about 256 mg gemcitabine hydrochloride into the bladder of the individual about once every 12 weeks (Q12W) for up to an additional 75 weeks after the first 24 weeks of treatment, wherein each intravesical drug delivery system is removed from the bladder about seven days to about 10 days after insertion into the bladder and wherein each intravesical drug delivery system is removed prior to insertion of another intravesical drug delivery system.

104. The method of claim 102 or 103, wherein the individual has BCG-experienced HR- NMIBC.

105. The method of claim 104, wherein the individual has received five of six doses of an induction phase of BCG and has recurred with high grade Ta or any T1 disease within 12 months.

106. The method of claim 102 or 103, wherein the individual has BCG-unresponsive HR- NMIBC.

107. The method of claim 106, wherein the individual has received i) a minimum of five of six full doses of an induction course of BCG; and ii) two or three doses of a maintenance course, or two of six doses of a second induction course of BCG therapy