WO2008036954A1 - Procédés et compositions pour le traitement du cancer - Google Patents
Procédés et compositions pour le traitement du cancer Download PDFInfo
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- WO2008036954A1 WO2008036954A1 PCT/US2007/079244 US2007079244W WO2008036954A1 WO 2008036954 A1 WO2008036954 A1 WO 2008036954A1 US 2007079244 W US2007079244 W US 2007079244W WO 2008036954 A1 WO2008036954 A1 WO 2008036954A1
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/243—Platinum; Compounds thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/244—Lanthanides; Compounds thereof
Definitions
- the present invention relates to N-[5-[[[5-(l,l-dimethylethyl)-2- 5 oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide, compositions thereof, and methods for its use to treat cancer.
- Compound I is suitable as an inhibitor of protein kinases such as the cyclin dependent kinases (cdks), for example, cdc2 (cdkl), cdk2, cdk3, cdk4, cdk5, cdk6, cdk7, cdk8, and cdk9.
- cdks protein kinases
- cdc2 cyclin dependent kinases
- Flavopiridol the first nonselective CDK inhibitor to enter clinical trials, has had disappointing activity against solid tumors in part due to unacceptable toxicity and poor PK properties.
- Other CDK inhibitors with improved tolerability profiles and pharmaceutical properties have the potential to meet a large unmet medical need.
- Compound I is a potent and selective inhibitor of CDKs, in particular CDK2, CDK7, and CDK9.
- CDK2 is a cell cycle-regulated kinase that controls the entry into and normal progression through DNA synthesis. Inappropriate activation of CDK2 occurs in many human cancers and is associated with a poorer prognosis for patients.
- CDK2 Activation of CDK2 in several cancer types including breast, NSCLC, and ovarian cancers is mediated through either overexpression of the associated activating subunit (cyclin E) or underexpression of the CDK2-inhibitor, p27.
- cyclin E activating subunit
- p27 underexpression of the CDK2-inhibitor
- CDK7 and CDK9 are not cell cycle regulated kinases, but are required for transcriptional control, particularly of short half-life mRNAs, many of which encode antiapoptotic and growth regulatory genes.
- the deregulation of CDK7 or 9 in cancers has not been widely studied to date.
- an inhibitor of CDKs 2, 7 and 9 in tumor cells may be expected to cause cell cycle arrest and induce apoptosis in tumors both as a single agent and in combination with chemotherapy.
- compositions comprising administering to a mammal in need thereof a dose of N-[5-[[[5-(l,l-dimethylethyl)-2- oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide, referred to herein as Compound I, of about 1 mg/m 2 - 150 mg/m 2 .
- the dose is given on a daily schedule.
- Compound I is dosed on a once daily for 5 days every three weeks schedule.
- Compound I is dosed on a once every three weeks schedule.
- kits for use with the 1 mg/m 2 - 150 mg/m 2 dose of Compound I comprise use of the dose Compound I and another cancer therapy such as, for example, surgery or radiation.
- the combinations comprise Compound I and a second active agent.
- the second active agents are anticancer cytoxics such as cisplatin or carboplatin.
- Compound I and the second active agent are each administered on a weekly schedule.
- pharmaceutical compositions comprising 1 mg -300 mg dosage forms of Compound I.
- the pharmaceutical dosage forms comprise N- [5 - [ [ [5 -( 1 , 1 -dimethyl ethyl)-2-oxazolyl]methyl] thio] -2-thiazo IyI] -4- piperidinecarboxamide hemi-L-tartrate, also referred to herein as "Compound I API”. 4. BRIEF DESCRIPTION OF THE FIGURES
- Figure 1 illustrates the structures of Compound I (top) and Compound I API (bottom).
- Figure 2 illustrates the effect of combining Compound I with carboplatin on tumor growth volume over time in the A2780 mouse xenograft model. Shown are vehicle (squares); 75 mg/kg IV carboplatin on a q4d ⁇ 2 schedule (circles); 60 mg/kg IP Compound I on a q4d ⁇ 2 schedule (triangles); 30 mg/kg IP Compound I on a qd ⁇ 8 schedule (inverted triangles); and a combination of 75 mg/kg IV carboplatin on a q4d x 2 schedule with 60 mg/kg IP Compound I (diamonds) on a q4d ⁇ 2 schedule administered 24 hours after the respective carboplatin doses.
- Figure 3 illustrates the effect of combining Compound I with cisplatin on tumor growth volume over time in the A2780 mouse xenograft model. Shown are vehicle (squares); 5 mg/kg IV cisplatin on a q4d ⁇ 2 schedule (circles); 30 mg/kg IP Compound I on a q4d ⁇ 2 schedule (triangles); and a combination of 5 mg/kg IV carboplatin on a q4d ⁇ 2 schedule with 30 mg/kg IP Compound I (diamonds) on a q4d ⁇ 2 schedule administered 24 hours after the respective cisplatin doses. 5. DESCRIPTION
- methods for using Compound I comprise administering Compound I in a dose of about 1 mg/m 2 - 150 mg/m 2 .
- methods for using Compound I comprise daily administration of Compound I for at least 2 days. In other embodiments, Compound I is administered daily for at least 3 days. In other embodiments, Compound I is administered daily for at least 4 days. In other embodiments, Compound I is administered daily for at least 5 days. In still other embodiments, Compound I is administered daily for 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, and 14 days. In another aspect of the present invention, methods of using Compound I comprise administering Compound I as a 1 -hour infusion. In other embodiments, Compound I is administered as a 3-hour infusion. In other embodiments, Compound I is administered as a 6-hour infusion. In other embodiments, Compound I is administered as an 8 -hour infusion. In still other embodiments, Compound I is administered as a 24-hour infusion.
- the method of treating cancer comprises administering a daily dose of Compound I of 10-50 mg/m 2 as a 1-hour infusion for five days every three weeks.
- the daily dose of Compound I is 10-20 mg/m 2 .
- the daily dose of Compound I is 15-25 mg/m 2 .
- the daily dose is 20-30 mg/m 2 .
- the daily dose of Compound I is 25-35 mg/m 2 .
- the daily dose of Compound I is 30-40 mg/m 2 .
- the daily dose of Compound I is 35-45 mg/m 2 .
- the daily dose of Compound I is 40-50 mg/m 2 .
- a method of treating cancer comprising administering to a mammal a dose of Compound I of about 40 mg/m 2 - 150 mg/m 2 every three weeks, wherein the mammal receives at least two doses of Compound I.
- Compound I is adminstered as a 1 -hour infusion.
- Compound I is administered as a 24-hour infusion.
- a method of treating cancer comprising administering to a mammal a dose of
- Compound I is administered as a 1 -hour infusion.
- Compound I is administered as a 24-hour infusion.
- a method of treating cancer comprising administering to a mammal a dose of Compound I of about 75 mg/m 2 - 150 mg/m 2 every three weeks, wherein the mammal receives at least two doses of Compound I.
- Compound I is administered as a 1 -hour infusion.
- Compound I is administered as a 24-hour infusion.
- the dose is 75-85 mg/m 2 and Compound I is administered as a 1 -hour infusion once every three weeks, wherein the mammal receives at least two doses of Compound I.
- the dose is 80-90 mg/m 2 and Compound I is administered as a 1 -hour infusion once every three weeks.
- the dose is 85-95 mg/m 2 and Compound I is administered as a 1-hour infusion once every three weeks.
- the dose is 90-100 mg/m 2 and Compound I is administered as a 1 -hour infusion once every three weeks.
- the dose is 75 mg/m 2 , and Compound I is administered as a 1- hour infusion once every three weeks, wherein the mammal receives at least two doses of Compound I.
- the dose is 80 mg/m 2 , and Compound I is administered as a 1-hour infusion once every three weeks.
- the dose is 85 mg/m 2 , and Compound I is administered as a 1-hour infusion once every three weeks.
- the dose is 90 mg/m 2 , and Compound I is administered as a 1-hour infusion once every three weeks.
- the dose is 95 mg/m 2 , and Compound I is administered as a 1 -hour infusion once every three weeks.
- the dose is 100 mg/m , and Compound I is administered as a 1-hour infusion once every three weeks. In another embodiment the dose is 1 10 mg/m 2 , and Compound I is administered as a 1 -hour infusion once every three weeks. In another embodiment the dose is 120 mg/m 2 , and Compound I is administered as a 1-hour infusion once every three weeks. In another embodiment the dose is 130 mg/m 2 , and Compound I is administered as a 1-hour infusion once every three weeks. In another embodiment the dose is 140 mg/m 2 , and Compound I is administered as a 1 -hour infusion once every three weeks. In another embodiment the dose is 150 mg/m 2 , and Compound I is administered as a 1-hour infusion once every three weeks.
- the dose is 90-130 mg/m 2 , and Compound I is administered as a 24-hour infusion once every three weeks, wherein the mammal receives at least two doses of Compound I.
- the dose is 90-100 mg/m 2 , and Compound I is administered as a 24-hour infusion once every three weeks.
- the dose is 100- 110 mg/m 2 , and Compound I is administered as a 24- hour infusion once every three weeks.
- the dose is 1 10-120 mg/m 2 and Compound I is administered as a 24-hour infusion once every three weeks.
- the dose is 120-130 mg/m 2 and Compound I is administered as a 24-hour infusion once every three weeks.
- a method of treating cancer comprising administering to a mammal a dose of Compound I of about 1 mg/m 2 -150 mg/m 2 once a week as a 1-hour infusion, wherein the mammal receives at least two doses of Compound I.
- the cancer is a solid tumor.
- cancers that can be treated, prevented or managed using methods provided herein include, but are not limited to solid tumors and blood borne tumors.
- cancer can be disease of skin tissues, organs, blood, and vessels, including, but not limited to, cancers of the bladder, bone or blood, brain, breast, cervix, chest, colon, endrometrium, esophagus, eye, head, kidney, liver, lung, mouth, neck, ovaries, pancreas, prostate, rectum, stomach, testis, throat, uterus and hematologic malignancies, such as leukemias, lymphomas and myelomas.
- the myeloma is multiple myeloma.
- the lymphoma is Non-Hodgkin's Lymphoma, B-cell lymphoma, mantle cell lymphoma, and Hodgkin's disease (also called Hodgkin's Lymphoma).
- the leukemia is chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphocytic leukemia (ALL), acute myelogenous leukemia and acute myeloblastic leukemia (AML).
- the cancer comprises solid tumor.
- the cancer comprises blood borne tumor cells released from a primary tumor.
- the cancer comprises a hematological maligancy.
- the cancer can be relapsed, refractory or resistant to conventional therapy.
- Forms of Compound I that can be used in the compositions and methods provided herein include, but are not limited to the following salts: hydrochloride, dihydrochloride, sulfate, trifluoroacetate, mixture of trifluoroacetate and hydrochloride, tartrate, fumarate, succinate, maleate, citrate, methanesulfonate, bromate and iodate salts.
- These salts include racemic forms as well as enantiomers and diastereomers (such as, for example, D-tartrate and L-tartrate salts).
- the salt of Compound l is a hemi-L-tartrate salt.
- Compound I is formulated for intravenous (IV) administration, which is currently under development for the treatment of cancer. Its chemical structure is shown in Figure 1 (top).
- the active pharmaceutical ingredient (API) of Compound I is a 2: 1 salt of Compound I as a free base with L-tartaric acid (Compound I API), and is manufactured under Good Manufacturing Practice (GMP) controls.
- the molecular formula of Compound I API is Ci 7 H 24 N 4 O 2 S 2 ⁇ (C 4 H 6 O 6 )Iz 2 and its molecular weight is 455.5 Daltons.
- the structure of Compound I API is also shown in Figure 1 (bottom).
- Compound I API is a white non-hygroscopic powder with lumps and melts between 233 0 C and 240 0 C.
- Compound I API is slightly soluble in water, propylene glycol and methanol, very slightly soluble in ethanol and polyethylene glycol 400 (PEG 400), and practically insoluble in acetone and acetonitrile.
- the pH of a saturated solution of Compound I API in water at 25 0 C is 5.1. Based on the pH-solubility profile at 25 0 C, the Compound I API pKa values are estimated to be 8.4 and 11.
- Dosage amounts used in the compositions and methods provided herein are based on the molecular weight of Compound I API (i.e. 455.5 Da). It is routine for one of skill in the art to calculate molecular weights of other salts of Compound I in order to determine corresponding amounts of the salt necessary for use in the methods provided herein, or for use for the pharmaceutical compositions provided herein.
- Compound I may be used as a single agent according to methods of the invention, or alternatively other therapies, chemotherapeutic agents or other anti-cancer agents may be used in combination with Compound I to treat proliferative diseases and cancer.
- the invention is directed to a method of treating cancer comprising administering to a mammal in need thereof a dose of Compound I of about 1 mg/m 2 -150 mg/m and a second active agent.
- the intravenous administration may be in the same IV line, or in separate IV lines.
- the 1 mg/m 2 -150 mg/m 2 dose of Compound I is administered once every four days.
- the 1 mg/m 2 - 150 mg/m 2 dose of Compound I is administered once a week.
- the method using Compound I in combination with a second active agent the 1 mg/m 2 - 150 mg/m 2 dose of Compound I is administered once every two weeks.
- the method using Compound I in combination with a second active agent the 1 mg/m 2 - 150 mg/m 2 dose of Compound I is administered once every three weeks.
- the 1 mg/m 2 - 150 mg/m 2 is administered once every four weeks.
- the second active agent may be administered at a different frequency than the 1 mg/m 2 - 150 mg/m 2 dose of Compound I, or it may be administered at the same frequency as the 1 mg/m 2 - 150 mg/m 2 dose of Compound I.
- the second active agent is administered at the same frequency as Compound I, but on a staggered schedule as compared with Compound I.
- a staggered schedule refers to a waiting period between the end of administration of the second active agent or Compound I and the start of administration of Compound I or the second active agent, respectively.
- the second active agent may be administered prior to the start of administration of Compound I, subsequently to the completion of the administration of Compound I, concurrently with Compound I, or simultaneously with Compound I.
- the administration of the second active agent is completed 24 hours prior to administration of Compound I.
- the administration of the second active agent is completed 48 hours prior to administration of Compound I.
- the administration of the second active agent is completed 72 hours prior to administration of Compound I.
- both Compound I and the second active agent are present at the same time in the subject.
- the second active agent is administered on the same day as (i.e. within 24 hours of) the 1 mg/m 2 -150 mg/m 2 dose of Compound I.
- the second active agent is administered immediately prior to Compound I. In another embodiment, the second active agent is administered immediately after Compound I. In one example where Compound I is given as a 1-hour infusion, the infusion of Compound I would start immediately after administration of the second active agent is complete.
- the second active agent administered in combination with Compound I is an anticancer cytotoxic agent.
- Compound I is administered on a staggered schedule with respect to the anticancer cytotoxic agent.
- Compound I is admininistered 24 hours after the end of the administration of the anticancer cytotoxic agent.
- the second active agent may be administered using a different length infusion than is used for Compound I.
- the second active agent is administered in a 10- 15 minute intravenous infusion.
- the second active agent is administered as a 1-hour infusion.
- the second active agent is administered as a 24-hour infusion.
- the second active agent administered in combination with Compound I is a DNA-damaging agent. In another embodiment, the second active agent administered in combination with Compound I is cisplatin. In another embodiment, the second active agent administered in combination with Compound I is carboplatin.
- the invention is directed to a method of treating cancer comprising administering to a mammal in need thereof a dose of Compound I of 1 mg/m 2 - 150 mg/m 2 once a week, and a dose of a second active agent given at least once every four weeks.
- the second active agent given at least once every four weeks is cisplatin.
- the second active agent given at least once every four weeks is carboplatin.
- the method for treating cancer comprises administering to a mammal in need thereof a dose of Compound I of 1 mg/m 2 - 150 mg/m 2 once a week, and a dose of cisplatin of 1 mg/m -30 mg/m 2 administered once a week.
- the method for treating cancer comprises administering to a mammal in need thereof a dose of Compound I of 10 mg/m -120 mg/m once a week, and a dose of cisplatin of 1 mg/m 2 -30 mg/m 2 administered once a week.
- Compound I and cisplatin are administered once a week for two weeks.
- Compound I and cisplatin are administered once a week for three weeks. In another embodiment, Compound I and cisplatin are administered once a week for four weeks. In another embodiment, Compound I and cisplatin are administered once a week for five weeks. In another embodiment, Compound I and cisplatin are administered once a week for six weeks.
- the dose of Compound I is 30 mg/m 2 -90 mg/m 2 administered once a week, and the dose of cisplatin is 1 mg/m 2 -30 mg/m 2 administered once a week.
- the dose of Compound I is 30 mg/m 2 -40 mg/m 2 administered once a week, and the dose of cisplatin is 1 mg/m 2 -30 mg/m 2 administered once a week.
- the dose of Compound I is 40 mg/m 2 -50 mg/m 2 administered once a week, and the dose of cisplatin is 1 mg/m 2 - 30 mg/m 2 administered once a week.
- the dose of Compound I is 50 mg/m 2 -60 mg/m 2 administered once a week, and the dose of cisplatin is 1 mg/m 2 -30 mg/m 2 administered once a week. In another embodiment, the dose of Compound I is 60 mg/m 2 -70 mg/m 2 administered once a week, and the dose of cisplatin is 1 mg/m 2 -30 mg/m 2 administered once a week. In another embodiment, the dose of Compound I is 70 mg/m -80 mg/m 2 administered once a week, and the dose of cisplatin is 1 mg/m 2 -30 mg/m 2 administered once a week. In another embodiment, the dose of Compound I is 80 mg/m 2 -90 mg/m administered once a week, and the dose of cisplatin is 1 mg/m 2 -30 mg/m administered once a week.
- the dose of Compound I is 30 mg/m 2 administered once a week, and the dose of cisplatin is 1 mg/m 2 -30 mg/m 2 administered once a week. In another embodiment, the dose of Compound I is 40 mg/m administered once a week, and the dose of cisplatin is 1 mg/m -30 mg/m administered once a week. In another embodiment, the dose of Compound I is 50 mg/m 2 administered once a week, and the dose of cisplatin is 1 mg/m 2 -30 mg/m 2 administered once a week.
- the dose of Compound I is 60 mg/m 2 administered once a week, and the dose of cisplatin is 1 mg/m 2 -30 mg/m 2 administered once a week. In another embodiment, the dose of Compound I is 70 mg/m administered once a week, and the dose of cisplatin is 1 mg/m -30 mg/m administered once a week. In another embodiment, the dose of Compound I is 80 mg/m 2 administered once a week, and the dose of cisplatin is 1 mg/m 2 -30 mg/m 2 administered once a week. In another embodiment, the dose of Compound I is 90 mg/m 2 administered once a week, and the dose of cisplatin is 1 mg/m 2 -30 mg/m 2 administered once a week.
- the dose of Compound I is 30 mg/m 2 -90 mg/m 2 administered once a week, and the dose of cisplatin is 5 mg/m 2 -25 mg/m 2 administered once a week. In another embodiment, the dose of Compound I is 30 mg/m 2 -90 mg/m 2 administered once a week, and the dose of cisplatin is 10 mg/m 2 -20 mg/m 2 administered once a week.
- the dose of Compound I is 30 mg/m 2 -90 mg/m 2 administered once a week, and the dose of cisplatin is 5 mg/m 2 administered once a week. In another embodiment, the dose of Compound I is 30 mg/m -90 mg/m 2 administered once a week, and the dose of cisplatin is 10 mg/m 2 administered once a week. In another embodiment, the dose of Compound I is 30 mg/m 2 -90 mg/m 2 administered once a week, and the dose of cisplatin is 15 mg/m 2 administered once a week.
- the dose of Compound I is 30 mg/m 2 -90 mg/m 2 administered once a week, and the dose of cisplatin is 20 mg/m administered once a week. In another embodiment, the dose of Compound I is 30 mg/m -90 mg/m 2 administered once a week, and the dose of cisplatin is 25 mg/m 2 administered once a week.
- the method for treating cancer comprises administering to a mammal in need thereof a dose of Compound I of 1 mg/m 2 - 150 mg/m 2 once a week, and a dose of cisplatin of 5 mg/m 2 -60 mg/m 2 every 2 weeks.
- a dose of Compound I of 1 mg/m 2 - 150 mg/m 2 once a week comprises administering to a mammal in need thereof a dose of Compound I of 1 mg/m 2 - 150 mg/m 2 once a week, and a dose of cisplatin of 10 mg/m 2 - 100 mg/m 2 every 3 weeks.
- the method comprises administering to a mammal in need thereof a dose of Compound I of 1 mg/m 2 - 150 mg/m once a week, and a dose of cisplatin of 15 mg/m 2 - 120 mg/m 2 every 4 weeks.
- the present application is directed to a method for treating cancer comprising administering to a mammal in need thereof a dose of Compound I of 1 mg/m 2 - 150 mg/m 2 once a week, and a dose of carboplatin of 60 mg/m 2 -225 mg/m 2 administered once a week.
- the method for treating cancer comprising administering to a mammal in need thereof a dose of Compound I of 10 mg/m 2 -120 mg/m 2 once a week, and a dose of carboplatin of 60 mg/m 2 -225 mg/m 2 administered once a week.
- Compound I and carboplatin are administered once a week for two weeks.
- Compound I and carboplatin are administered once a week for three weeks. In another embodiment, Compound I and carboplatin are administered once a week for four weeks. In another embodiment, Compound I and carboplatin are administered once a week for five weeks. In another embodiment, Compound I and carboplatin are administered once a week for six weeks. In another embodiment of the method, the dose of Compound I is 30 mg/m 2 -90 mg/m 2 administered once a week, and the dose of carboplatin is 60 mg/m 2 -225 mg/m 2 administered once a week.
- the dose of Compound I is 30 mg/m 2 -40 mg/m 2 administered once a week, and the dose of carboplatin is 60 mg/m 2 - 225 mg/m 2 administered once a week. In another embodiment, the dose of Compound I is 40 mg/m 2 -50 mg/m 2 administered once a week, and the dose of carboplatin is 60 mg/m 2 -225 mg/m 2 administered once a week. In another embodiment, the dose of Compound I is 50 mg/m 2 -60 mg/m 2 administered once a week, and the dose of carboplatin is 60 mg/m -225 mg/m administered once a week.
- the dose of Compound I is 60 mg/m -70 mg/m administered once a week, and the dose of carboplatin is 60 mg/m 2 -225 mg/m 2 administered once a week. In another embodiment, the dose of Compound I is 70 mg/m 2 -80 mg/m 2 administered once a week, and the dose of carboplatin is 60 mg/m 2 -225 mg/m 2 administered once a week. In another embodiment, the dose of Compound I is 80 mg/m 2 -90 mg/m 2 administered once a week, and the dose of carboplatin is 60 mg/m 2 - 225 mg/m 2 administered once a week.
- the dose of Compound I is 30 mg/m administered once a week, and the dose of carboplatin is 60 mg/m -225 mg/m 2 administered once a week. In another embodiment, the dose of Compound I is 40 mg/m 2 administered once a week, and the dose of carboplatin is 60 mg/m 2 -225 mg/m 2 administered once a week. In another embodiment, the dose of Compound I is 50 mg/m 2 administered once a week, and the dose of carboplatin is 60 mg/m 2 -225 mg/m 2 administered once a week.
- the dose of Compound I is 60 mg/m 2 administered once a week, and the dose of carboplatin is 60 mg/m 2 -225 mg/m 2 administered once a week. In another embodiment, the dose of Compound I is 70 mg/m 2 administered once a week, and the dose of carboplatin is 60 mg/m -225 mg/m administered once a week. In another embodiment, the dose of Compound I is 80 mg/m 2 administered once a week, and the dose of carboplatin is 60 mg/m -225 mg/m administered once a week. In another embodiment, the dose of Compound I is 90 mg/m 2 administered once a week, and the dose of carboplatin is 60 mg/m 2 -225 mg/m 2 administered once a week.
- the dose of Compound I is 30 mg/m 2 -90 mg/m 2 administered once a week, and the dose of carboplatin is 65 mg/m 2 -200 mg/m 2 administered once a week. In another embodiment, the dose of Compound I is 30 mg/m 2 -90 mg/m 2 administered once a week, and the dose of carboplatin is 70 mg/m 2 - 175 mg/m 2 administered once a week. In another embodiment, the dose of Compound I is 30 mg/m 2 -90 mg/m 2 administered once a week, and the dose of carboplatin is 75 mg/m 2 - 150 mg/m 2 administered once a week. In another embodiment, the dose of Compound I is 30 mg/m -90 mg/m administered once a week, and the dose of carboplatin is 80 mg/m 2 - 125 mg/m 2 administered once a week.
- the dose of Compound I is 30 mg/m 2 -90 mg/m 2 administered once a week, and the dose of carboplatin is 75 mg/m administered once a week. In another embodiment, the dose of Compound I is 30 mg/m -90 mg/m administered once a week, and the dose of carboplatin is 85 mg/m 2 administered once a week. In another embodiment, the dose of Compound I is 30 mg/m 2 -90 mg/m 2 administered once a week, and the dose of carboplatin is 95 mg/m 2 administered once a week.
- the dose of Compound I is 30 mg/m -90 mg/m 2 administered once a week, and the dose of carboplatin is 105 mg/m 2 administered once a week. In another embodiment, the dose of Compound I is 30 mg/m 2 -90 mg/m 2 administered once a week, and the dose of carboplatin is 115 mg/m 2 administered once a week. In another embodiment, the dose of Compound I is 30 mg/m 2 -90 mg/m 2 administered once a week, and the dose of carboplatin is 125 mg/m 2 administered once a week.
- the dose of Compound I is 30 mg/m -90 mg/m administered once a week, and the dose of carboplatin is 135 mg/m 2 administered once a week. In another embodiment, the dose of Compound I is 30 mg/m 2 -90 mg/m 2 administered once a week, and the dose of carboplatin is 145 mg/m 2 administered once a week. In another embodiment, the method for treating cancer comprises administering to a mammal in need thereof a dose of Compound I of 1 mg/m 2 -150 mg/m 2 once a week, and a dose of carboplatin of 125 mg/m 2 -250 mg/m 2 every 2 weeks.
- the method comprises administering to a mammal in need thereof a dose of Compound I of 1 mg/m -150 mg/m 2 once a week, and a dose of carboplatin of 175 mg/m 2 -375 mg/m 2 every 3 weeks.
- the method comprises administering to a mammal in need thereof a dose of Compound I of 1 mg/m 2 - 150 mg/m 2 once a week, and a dose of carboplatin of 250 mg/m 2 -500 mg/m 2 every 4 weeks.
- the method for treating cancer comprises administering to a mammal in need thereof a dose of Compound I of 1 mg/m 2 - 150 mg/m 2 once a week and an amount of carboplatin sufficient to achieve an AUC of 4 mg/mL x min - 7 mg/mL x min, wherein the amount of carboplatin is administered once a week.
- the method for treating cancer comprises administering to a mammal in need thereof a dose of Compound I of 10 mg/m 2 - 120 mg/m 2 once a week and an amount of carboplatin sufficient to achieve an AUC of 4 mg/mL x min - 7 mg/mL x min, wherein the amount of carboplatin is administered once a week.
- the amount of carboplatin is sufficient to achieve an AUC of about 4 mg/mL x min. In another embodiment of the method, the amount of carboplatin is sufficient to achieve an AUC of about 5 mg/mL x min. In another embodiment of the method, the amount of carboplatin is sufficient to achieve an AUC of about 6 mg/mL x min. In another embodiment of the method, the amount of carboplatin is sufficient to achieve an AUC of about 7 mg/mL x min.
- the method for treating cancer comprises administering to a mammal in need thereof a dose of Compound I of 30 mg/m 2 -90 mg/m 2 once a week and an amount of carboplatin sufficient to achieve an area under the concentration vs time curve (AUC) of 4 mg/mL x min - 7 mg/mL x min, wherein the amount of carboplatin is administered once a week.
- AUC concentration vs time curve
- the amount of carboplatin is sufficient to achieve an AUC of about 4 mg/mL x min.
- the amount of carboplatin is sufficient to achieve an AUC of about 5 mg/mL x min.
- the amount of carboplatin is sufficient to achieve an AUC of about 6 mg/mL x min. In another embodiment of the method, the amount of carboplatin is sufficient to achieve an AUC of about 7 mg/mL x min.
- the amount of carboplatin necessary to achieve a desired AUC can be calculated using the Calvert formula for carboplatin dosing:
- Total dose (mg) [target area under the concentration vs time curve (AUC in mg/mL x min)] X [Glomerular filtration rate (GFR in mL/in) + 25].
- therapies or anticancer agents may be used in combination with Compound I, or in combination with Compound I and a second active agent.
- Non-limiting examples of such therapies include surgery, radiotherapy (in but a few examples, gamma- radiation, neutron beam radiotherapy, electron beam radiotherapy, proton therapy, brachytherapy, and systemic radioactive isotopes, to name a few), endocrine therapy, biologic response modifiers (interferons, interleukins, and tumor necrosis factor (TNF) to name a few), hyperthermia and cryotherapy, agents to attenuate any adverse effects (e.g. , antiemetics), and other approved chemotherapeutic drugs.
- chemotherapeutic drugs that may be used as a second active agent in combination with Compound I include, but are not limited to, alkylating drugs (mechlorethamine, chlorambucil, Cyclophosphamide, Melphalan, Ifosfamide), antimetabolites (Methotrexate), purine antagonists and pyrimidine antagonists (6- Mercaptopurine, 5-Fluorouracil, Cytarabile, Gemcitabine), spindle poisons (Vinblastine, Vincristine, Vinorelbine, Paclitaxel), podophyllotoxins (Etoposide, Irinotecan, Topotecan), antibiotics (Doxorubicin, Bleomycin, Mitomycin), nitrosoureas (Carmustine, Lomustine), inorganic ions (Cisplatin, Carboplatin), enzymes (Asparaginase), and hormones (Tamoxifen, Leuprolide, Flutamide, and Megestrol), Gleeve
- Some specific anticancer agents that can be used in combination with Compound I include, but are not limited to: acivicin; aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine; ambomycin; ametantrone acetate; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan; cactinomycin; calusterone; capecitabline; caracemide; carbetimer; carboplatin; carmustine; carubicin hydrochloride; carzelesin; cedef
- anti-cancer drugs that can be used in combination with Compound I include, but are not limited to: 20-epi-l,25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti-dorsalizing morphogenetic protein- 1; antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid
- SarCNU sarcophytol A; sargramostim; Sdi 1 mimetics; semustine; senescence derived inhibitor 1 ; sense oligonucleotides; signal transduction inhibitors; sizofiran; sobuzoxane; sodium borocaptate; sodium phenylacetate; solverol; somatomedin binding protein; sonermin; sparfosic acid; spicamycin D; spiromustine; splenopentin; spongistatin 1 ; squalamine; stipiamide; stromelysin inhibitors; sulfinosine; superactive vasoactive intestinal peptide antagonist; suradista; suramin; swainsonine; tallimustine; tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium; tegafur; tellurapyrylium; telomerase inhibitors; temoporfin;
- Specific second active agents include, but are not limited to, rituximab, oblimersen (Genasense ), remicade, docetaxel, celecoxib, melphalan, dexamethasone (Decadron ), steroids, gemcitabine, cisplatinum, temozolomide, etoposide, cyclophosphamide, temodar, carboplatin, procarbazine, gliadel, tamoxifen, topotecan, methotrexate, Arisa ® , taxol, taxotere, fluorouracil, leucovorin, irinotecan, xeloda, CPT-11, interferon alpha, pegylated interferon alpha (e.g., PEG INTRON-A), capecitabine, cisplatin, thiotepa, fludarabine, carboplatin, liposomal daunorubicin,
- the second active agent is a supportive care agent.
- An example of supportive care agent is an antiemetic.
- Specific antiemetic agents include, but are not limited to, phenothiazines, butyrophenones, benzodiazapines, corticosteroids, serotonin antagonists, cannabinoids, and NKi receptor antagonists.
- phenothiazine antiemetics include, but are not limited to, prochlorperazine and trimethobenzamide.
- Examples of butyophenone antiemetic include, but are not limited to, haloperidol.
- Examples of benzodiazapine antiemetic include, but are not limited to, lorazepam.
- corticosteroid antiemetic examples include, but are not limited to, dexamethasone.
- serotonin antagonist antiemetic examples include, but are not limited to, ondansetron, granisetron, and dolasetron.
- cannabinoid antiemetic examples include, but are not limited to, dronabinol.
- NKi receptor antagonists examples include, but are not limited to, aprepitant.
- compositions containing Compound I and pharmaceutically acceptable carriers such as diluents or adjuvants, or in combination with other active ingredient, such as another anti-cancer agent.
- pharmaceutically acceptable carriers such as diluents or adjuvants
- other active ingredient such as another anti-cancer agent.
- Compound I may be administered by any conventional route, including but not limited to orally, parenterally, or rectally.
- Compound I is administered by an IV injection.
- compositions for parenteral administration can be emulsions or sterile solutions. Use may be made, as solvent or vehicle, of propylene glycol, a polyethylene glycol, vegetable oils, or injectable organic esters, for example ethyl oleate. These compositions can also contain adjuvants, in particular wetting, isotonizing, emulsifying, dispersing and stabilizing agents. Sterilization can be carried out in several ways, for example using a bacteriological filter, by radiation or by heating. They can also be prepared in the form of sterile solid compositions which can be dissolved at the time of use in sterile water or any other injectable sterile medium. Pharmaceutical compositions can be used in the preparation of individual, single unit dosage forms. Pharmaceutical compositions and dosage forms comprise Compound I and one or more excipients.
- compositions and dosage forms can also comprise one or more additional active ingredients.
- additional active ingredients examples of optional second, or additional, active ingredients are disclosed herein.
- compositions and single unit dosage forms provided herein comprise a prophylactically or therapeutically effective amount of Compound I, and typically one or more pharmaceutically acceptable carriers or excipients.
- carrier refers to a diluent, adjuvant (e.g., Freund's adjuvant (complete and incomplete)), excipient, or vehicle with which the therapeutic is administered.
- Such pharmaceutical carriers can be sterile liquids, such as water and oils.
- water is a carrier when the pharmaceutical composition is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions.
- Suitable pharmaceutical carriers are described in Remington: The Science and Practice of Pharmacy, 21 st edition, Lippincott, Williams and Wilkins, Baltimore, MD (2005), the contents of which are hereby incorporated by reference in their entirety.
- Typical pharmaceutical compositions and dosage forms comprise one or more excipients.
- Suitable excipients are well-known to those skilled in the art of pharmacy, and non limiting examples of suitable excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like.
- composition or dosage form Whether a particular excipient is suitable for incorporation into a pharmaceutical composition or dosage form depends on a variety of factors well known in the art including, but not limited to, the way in which the dosage form will be administered to a subject and the specific active ingredients in the dosage form.
- the composition or single unit dosage form if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents.
- compositions and dosage forms that comprise one or more compounds that reduce the rate by which an active ingredient will decompose.
- compounds which are referred to herein as “stabilizers,” include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers.
- compositions and single unit dosage forms can take the form of solutions, suspensions, emulsion, powders and the like.
- Such compositions and dosage forms will contain a prophylactically or therapeutically effective amount of a prophylactic or therapeutic agent, in certain embodiments, in purified form, together with a suitable amount of carrier so as to provide the form for proper administration to the subject.
- the formulation should suit the mode of administration.
- the pharmaceutical compositions or single unit dosage forms are sterile and in suitable form for administration to a subject, such as a mammalian subject, such an animal subject, or in particular a human subject.
- a pharmaceutical composition provided herein is formulated to be compatible with its intended route of administration.
- routes of administration include, but are not limited to, parenteral, e.g., intravenous, intradermal, subcutaneous, intramuscular, subcutaneous, inhalation, intranasal, transdermal, topical, transmucosal, intra- tumoral, intra-synovial and rectal administration.
- the composition is formulated in accordance with routine procedures as a pharmaceutical composition adapted for intravenous, subcutaneous, intramuscular, intranasal or topical administration to human beings.
- a pharmaceutical composition is formulated in accordance with routine procedures for subcutaneous administration to human beings.
- compositions for intravenous administration are solutions in sterile isotonic aqueous buffer.
- the composition may also include a solubilizing agent and a local anesthetic such as lignocaine to ease pain at the site of the injection.
- dosage forms include, but are not limited to: liquid dosage forms suitable for parenteral administration to a subject; and sterile solids (e.g., crystalline or amorphous solids) that can be reconstituted to provide liquid dosage forms suitable for parenteral administration to a subject.
- sterile solids e.g., crystalline or amorphous solids
- compositions, shape, and type of dosage forms provided herein will typically vary depending on their use.
- a parenteral dosage form may contain smaller amounts of one or more of the active ingredients it comprises than an oral dosage form used to treat the same disease or disorder.
- specific dosage forms encompassed herein will vary from one another will be readily apparent to those skilled in the art. See, e.g., Remington: The Science and Practice of Pharmacy, 21 st edition, Lippincott, Williams and Wilkins, Baltimore, MD (2005), the contents of which are hereby incorporated by reference in their entirety.
- compositions provided herein are supplied either separately or mixed together in unit dosage form.
- the composition can be dispensed with an infusion bottle containing sterile pharmaceutical grade water or saline.
- an ampoule of sterile water for injection or saline can be provided so that the ingredients may be mixed prior to administration.
- the invention is directed to a dosage forms comprising Compound I within the range of about 1 mg to about 300 mg per vial.
- Particular dosage forms provided herein have about 1, 3, 6, 9, 10, 12, 13.5, 15, 18, 19, 21, 24, 25, 27, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 1 10, 1 15, 120, 125, 130, 135, 140, 145 150 mg of Compound I per vial.
- Other dosage forms have about 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, or 300 mg of Compound I per vial.
- the application is directed to a pharmaceutical composition
- a pharmaceutical composition comprising a 1 mg-300 mg dose of N-[5-[[[5-(l,l-dimethylethyl)-2- oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide hemi-L-tartrate.
- the pharmaceutical composition comprises a 20 mg-100 mg dose of N- [5 - [ [[5 -( 1 , 1 -dimethylethyl)-2-oxazolyl]methy 1] thio] -2-thiazolyl] -4- piperidinecarboxamide hemi-L-tartrate.
- the pharmaceutical composition comprises a 60 mg -180 mg dose of N-[5-[[[5-(l,l-dimethylethyl)-2- oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide hemi-L-tartrate.
- the pharmaceutical composition comprises a 150 mg-300 mg dose ofN-[5-[[[5-(l,l-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4- piperidinecarboxamide hemi-L-tartrate.
- Parenteral dosage forms can be administered to patients by various routes including, but not limited to, subcutaneous, intravenous (including bolus injection), intramuscular, and intraarterial. Because their administration typically bypasses patients' natural defenses against contaminants, parenteral dosage forms are preferably sterile or capable of being sterilized prior to administration to a patient. Examples of parenteral dosage forms include, but are not limited to, solutions ready for injection, dry products ready to be dissolved or suspended in a pharmaceutically acceptable vehicle for injection, suspensions ready for injection, and emulsions.
- Suitable vehicles that can be used to provide parenteral dosage forms are well known to those skilled in the art. Examples include, but are not limited to: Water for Injection USP; aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection; water-miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and nonaqueous vehicles such as, but not limited to, vegetable oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.
- water for Injection USP Water for Injection USP
- aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection
- cyclodextrin and its derivatives can be used to increase the solubility of active ingredients. See, e.g., U.S. Patent No. 5,134,127, which is incorporated herein by reference.
- the methods of treating, preventing or managing cancers provided herein comprise administering to a patient Compound I, alone or in combination with a second active agent, on the basis of body surface area.
- Body surface area calculations can be calculated for example, with the Mosteller formula wherein:
- Compound I can be administered orally or intravenously and in single or divided daily doses in an amount of about 1 to about 150 mg/m 2 .
- Certain exemplary doses per day include about 1, 3, 6, 9, 10, 12, 13.5, 15, 18, 19, 21, 24, 25, 27, 30, 38, 45, 50, 60, 63, 75, 80, 85, 90, 95, 100, 105, 1 10, 115, 120, 125, 130, 135, 140, 145 or 150 mg/m 2 .
- the dose of Compound I is about 20 mg/m 2 -30 mg/m 2 . In another embodiment the dose is about 25 mg/m 2 -35 mg/m 2 . In another embodiment the dose is about 40 mg/m 2 -50 mg/m 2 . In another embodiment the dose is about 45 mg/m 2 -55 mg/m 2 . In another embodiment the dose is about 50 mg/m 2 -60 mg/m 2 . In another embodiment the dose is about 55 mg/m 2 -65 mg/m 2 . In another embodiment the dose is about 60 mg/m 2 -70 mg/m 2 . In another embodiment the dose is about 65 mg/m -75 mg/m . In another embodiment the dose is about 70 mg/m -80 mg/m .
- the dose is about 75 mg/m 2 -85 mg/m 2 . In another embodiment the dose is about 80 mg/m 2 -90 mg/m 2 . In another embodiment the dose is about 85 mg/m 2 -95 mg/m 2 . In another embodiment the dose is about 90 mg/ni 2 -100 mg/m 2 . In another embodiment the dose is about 100 mg/m 2 -l 10 mg/m 2 . In another embodiment the dose is about 1 10 mg/m 2 - 120 mg/m 2 . In another embodiment the dose is about 120 mg/m 2 -130 mg/m 2 . In another embodiment the dose is about 130 mg/m 2 - 140 mg/m 2 . In another embodiment the dose is about 140 mg/m 2 - 150 mg/m .
- the dose is 1 mg/m 2 , 2 mg/m 2 , 3 mg/m 2 , 4 mg/m 2 , 5 mg/m 2 , 6 mg/m , 7 mg/m , 8 mg/m , 9 mg/m , 10 mg/m , 1 1 mg/m , 12 mg/m , 13 mg/m , 14 mg/m 2 , 15 mg/m 2 , 16 mg/m 2 , 17 mg/m 2 , 18 mg/m 2 , 19 mg/m 2 , 20 mg/m 2 , 21 mg/m 2 , 22 mg/m 2 , 23 mg/m 2 , 24 mg/m 2 , 25 mg/m 2 , 26 mg/m 2 , 27 mg/m 2 , 28 mg/m 2 , 29 mg/m 2 , 30 mg/m 2 , 31 mg/m 2 , 32 mg/m 2 , 33 mg/m 2 , 34 mg/m 2 , 35 mg/m 2 , 36 mg/m 2 , 37 mg/m 2
- the dose is 51 mg/m 2 , 52 mg/m 2 , 53 mg/m 2 , 54 mg/m 2 , 55 mg/m 2 , 56 mg/m , 57 mg/m 2 , 58 mg/m 2 , 59 mg/m , 60 mg/m 2 , 61 mg/m 2 , 62 mg/m 2 , 63 mg/m 2 , 64 mg/m 2 , 65 mg/m 2 , 66 mg/m 2 , 67 mg/m 2 , 68 mg/m 2 , 69 mg/m 2 , 70 mg/m 2 , 71 mg/m , 72 mg/m , 73 mg/m 2 , 74 mg/m , 75 mg/m 2 , 76 mg/m 2 , 77 mg/m 2 , 78 mg/m 2 , 79 mg/m 2 , 80 mg/m 2 , 81 mg/m 2 , 82 mg/m 2 , 83 mg/m 2 , 84
- the administered dose of Compound I can be delivered as a single dose (e.g. a single bolus IV injection) or over a 24-hour period (e.g., continuous infusion over time or divided bolus doses over time) and is repeated until the patient experiences stable disease or regression, or until the patient experiences disease progression or unacceptable toxicity.
- Stable disease or lack thereof is determined by methods known in the art, such as evaluation of patient symptoms, physical examination and other commonly accepted evaluation modalities.
- the administered dose of Compound I can be expressed in units other than as mg/m .
- doses can be expressed as mg/kg.
- One of ordinary skill in the art would know how to convert doses from mg/m to mg/kg to given either the height or weight of a subject or both (see, e.g, www.fda.gov/cder/cancer/animalframe.htm).
- Compound I is cyclically administered to a patient. Cycling therapy involves the administration of an active agent for a period of time, followed by a rest for a period of time, and repeating this sequential administration. Cycling therapy can reduce the development of resistance to one or more of the therapies, avoid or reduce the side effects of one of the therapies, and/or improves the efficacy of the treatment.
- Compound I demonstrated in vitro antiproliferative activity against a panel of human tumor cell lines covering the major solid tumor types. Compound I induced a cellular phenotype consistent with CDK-2, and CDK7/9 inhibition, based on alteration of cell cycle distribution, induction of apoptosis, and inhibition of DNA synthesis. In addition to demonstrating in vitro cytotoxic activity, Compound I showed antitumor activity in five tumor models.
- Sensitivity to Compound I was neither dependent on tumor type nor cellular p53 status, but was mediated by overexpression of the multidrug resistance protein- 1 (MDRl) mRNA.
- Transport of Compound I by P-glycoprotein (P-gp) was further substantiated in permeability studies using Caco-2 monolayers.
- the permeability coefficient (Pc) of Compound I in the apical to basolateral direction was 14 to 42 nm/sec while in the basolateral to apical direction it was 161 nm/sec. This large difference in the bidirectional transport suggests Compound I may be a P-gp substrate.
- Compound I results in abrupt inhibition of cell cycle progression followed by an apoptotic response. Clonogenic assays indicate that as little as 8 hours of drug exposure is sufficient to elicit a maximal antiproliferative response in vitro. Compound I also has been tested in vitro in combination with several anticancer cytotoxics. In particular, Compound I shows schedule-dependent synergy with both cisplatin and carboplatin and additivity with doxorubicin and paclitaxel.
- Compound I exhibited broad-spectrum antitumor activity, showing stasis or regression in multiple murine and human tumor models in vivo. These include the P388 mouse leukemia, cyclin E transgenic mouse breast carcinoma, A2780 human ovarian carcinoma, Colo205 human colorectal carcinoma, and A431 human squamous cell carcinoma. Compound I demonstrated curative efficacy at multiple dose levels in the A2780 human tumor xenograft when dosed IV on a qd x 8 schedule. Activity is dose and schedule dependent.
- Example 3 Formulation of Compound I API
- the formulation for intravenous administration is a clear, colorless to light-yellow aqueous solution (50 mg/vial (5 mg/mL) free base). It is supplied in 10 mL Type I glass vials. A 6% fill overage is included for vial-needle- syringe (VNS) withdrawal loss. Each vial contains 53.0 mg of Compound I active free base, 95.4 mg sodium chloride (tonicity agent), 3.39 mg L-tartaric acid (buffer, pH 4.0), and water.
- the vials of Compound I Injection should be stored under refrigeration (2 0 C to 8 0 C) and protected from light.
- Compound I Injection is diluted with 0.9% Sodium Chloride Injection (Normal Saline) to the desired concentrations prior to administration (Compound I API can be diluted between 0.1 and 1.0 mg/mL).
- a total of 135 patients with metastatic refractory solid tumors were treated with Compound I in three previous phase 1 studies (CA 174001, CAl 74002, and CAl 74006).
- the patient's ages ranged from 26 to 82 years with a median age of 60 years.
- a total of 464 cycles were administered to all patients treated in these three studies.
- the MTD was deemed acute renal failure.
- DLT dose-limiting toxicity
- IV intravenously
- MTD maximum tolerated dose
- PD pharmacodynamics
- PK pharmacokinetics
- PO orally. aThe syncopal episode occurred during Cycle 2, but was considered in determining the MTD.
- Study CA 174001 was a open label dose-escalation study in which Compound I was administered as a 1-hour IV infusion once every 21 days. Cohorts of at least three patients were treated at each dose level, starting at 9.6 mg/m 2 of Compound I. The dose was escalated following a modified Fibonacci scheme. Intrapatient dose escalation was allowed only after a patient had received at least two cycles. If a patient had an acceptable toxicity profile, the dose could be increased by one dose level for the next cycle, but only if all 3 patients at the next highest dose level had already completed Cycle 1 without having a DLT.
- Objective tumor response was to be evaluated in all patients with measurable disease using a modified form of the WHO criteria incorporating the use of target/nontarget lesions used in the Response evaluation criteria in solid tumors (RECIST) response criteria.
- the assessments were to be made every two cycles (six weeks) or more frequently if medically indicated. A response was considered confirmed if it was noted on two assessments at least four weeks apart.
- NSCLC NSCLC
- 59 were white, 2 black, and 3 other, with ages ranging from 26 to 82 years with a median age of 60 years.
- the 64 treated patients received a combined total of 254 Compound I treatment cycles.
- the dose levels, the number of patients by assigned dose cohort, and the number of treatment cycles administered to each dose cohort are summarized in Table 2.
- Serial ECGs were recorded for patients at dose levels ranging from 9.6 to 95.0 mg/m 2 . There were no incidences of QTc by Bazett's correction greater than 500 msec. Ten patients experienced QTcB > 450 msec during Cycle 1, and in each case the QTc corrected by Friderica's method was ⁇ 450 msec. One of these patients (CA174001- 1-121) had a change in QTc from a baseline of > 60 msec. Two patients had a QTc > 450 in Cycles 2 and later. There was no apparent dose-related trend in QTc increase.
- Clinical AEs were reported for all 64 (100%) patients who received treatment. The severity of each AE was evaluated using the National Cancer Institute Common Toxicity Criteria, version 2.0 (NCI CTC v2.0) scale. The most common AEs (regardless of relationship) reported were fatigue (89%), nausea (52%), dyspnea (47%), anorexia (39%), cough (39%), diarrhea (39%), arthralgia (31%), constipation (31%), infection without neutropenia (31%), and pain other (31%). Treatment-related AEs occurred in 54 (84%) patients. The most common treatment- related AEs were fatigue (41%) and nausea (39%). Table 3 lists treatment-related AEs reported in > 10% of patients.
- No. number of patients.
- MTD maximum administered dose
- Table 5 summarizes the reported DLTs by dose level.
- the MTD was defined as the dose level just below the MAD, providing DLT was observed in less than two of six treated patients (or fewer than one-third if more than six treated patients) at that dose level.
- DLTs were observed in 3 of 13 patients (23%). Therefore, the MTD for Compound I administered IV on Day 1 of each 21 -day treatment cycle was deemed 85 mg/m 2 .
- Study CA 174002 was an open label, dose-escalation study in which Compound I was administered as a 24-hour infusion on Day 1 of each 21 -day treatment cycle.
- the starting dose was 4.8 mg/m and the dose was increased by 50% after the first cohort, then increased by 33% after the next 6 dose levels, after which the dose was increased by only 25%.
- Intrapatient dose escalation was allowed only after a patient had received at least two cycles and had an acceptable toxicity profile. For these patients, the dose could be increased by one dose level for the next cycle, but only if all 3 patients at that next highest dose level had already completed Cycle 1 without having a DLT.
- Tumor assessments were as previously described for Study CAl 4001.
- 48 were white and 3 black, with ages ranging from 27 to 82 years and median age was 60 years.
- the Compound I dose levels, the number of patients by assigned dose cohort, and the number of treatment cycles administered to each dose cohort are summarized in Table 6.
- Treatment-related AEs were reported for 39 (76%) patients. The most common treatment-related AE was fatigue (39%). Table 7 lists treatment-related AEs reported in > 10% of patients.
- Hepatic-other CTC term for hepatic replacement by tumor b
- 18 were white and 2 black, with ages ranging from 42 to 78 years and a median age of 57 years.
- the Compound I dose levels, the number of patients by assigned dose cohort, and the number of treatment cycles administered to each dose cohort are summarized in Table 10.
- No. number of patients.
- the PK of Compound I was evaluated in three clinical trials (CA 174001 [1-hour infusion once every 3 weeks], CA 174002 [24-hour infusion once every 3 weeks], and
- CAl 74006 [1-hour infusion once every week, except the Cycle 2 Day 1 dose was administered PO]).
- Preliminary PK data are available from 63 (CA 174001), 44 (CA 174002), and 20 (CA 174006) patients treated at doses ranging from 4 to 116 mg/m .
- a validated method using liquid chromatography in tandem with mass spectrometry (LC-MS/MS) detection was used to analyze plasma samples.
- Compound I ver 1 hour. Plasma samples obtained between 0.5 and 48 hours after Cycles 1 and 2 Day 1 doses. Samples stored frozen until analysis using a validated LC-MS/MS method.
- AUC 0 . inf area under the curve from time 0 to infinity
- CL clearance
- C raax maximum measured concentration
- SD standard deviation
- T, A terminal half-life
- V ss volume of distribution at steady state. aCompound I given IV over 24 hours. Plasma samples were obtained between 2 and 74 hours after the Cycle 1 Day 1 administration. Samples were stored frozen until analysis was performed using a validated LC-MS/MS method. cThe patient treated at 1 16 mg/m 2 only had PK samples going out to 24 hours postdose.
- AUC 0 inf area under the curve from time 0 to infinity
- CL clearance
- C ma ⁇ maximum measured concentration
- SD standard deviation
- T ⁇ terminal half-life
- V ss volume of distribution at steady state
- Compound I is a generally well tolerated cytotoxic drug. Over a hundred patients with advanced solid tumors have been treated with Compound I. Patient ages ranged from 26 to 82 years. The most frequent AEs include fatigue, nausea, vomiting, and diarrhea. There appears to be some schedule and dose-dependent toxicities, including neutropenia and elevation of liver enzymes, primarily in patients with GI and liver metastasis.
- Example 5
- TGI tumor growth inhibition
- TGD tumor growth delay
- TGI Tumor Growth Inhibition
- control TV_, - control TV 1 - (treatment TV t. - treatment TV 1 ) x 100 (control TVj - control TV 1 )
- TV t is the average tumor volume on the last day the control contained at least 75% of the animals and TV 1 is the initial average tumor volume.
- ANOVA was performed to calculate statistical significance, defined as p ⁇ 0.05.
- Time To Endpoint (TTE) was calculated for each individual animal to reach the predetermined study end point where the tumor volume becomes 1200 mm 3 or 10% of body weight or a greater than 20% body weight loss for two sequential measurements. The TTE is calculated and the median value is recorded for the group.
- TTD Tumor Growth Delay
- %TGD median TTE trea t me nt - median TTE CO ntroi x 100 median TTE con troi
- Cisplatin dosed at 5 mg/kg IV q4d *2 showed efficacy compared to the vehicle group.
- the combination of Compound I dosed q4d ⁇ 2 at 30 mg/kg 24hr after cisplatin dosed at 5 mg/kg showed additional anti-tumor activity from the vehicle group and also from the activity of single agent Compound I alone.
- the combination of Compound I dosed q4d ⁇ 2 at 30 mg/kg 24hr after cisplatin dosed at 5 mg/kg significantly delayed the tumor growth compared to the vehicle. Percent TGI and p-values and TGD(Days) and p-values are shown in Table 18.
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Abstract
L'invention concerne des procédés pour le traitement du cancer comprenant l'utilisation de N-[5[[[5 (1,1-diméthyléthyl)-2-oxazolyl]méthyl]]-2-thiazolyl]-4-pipéridinecarboxamide. Des procédés pour le traitement du cancer comprenant l'utilisation du composé en association avec d'autres thérapies sont également fournis. Des compositions pharmaceutiques et des formes posologiques unitaires, qui peuvent être utilisées dans les procédés décrits ci-dessus, sont également fournies.
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Cited By (2)
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WO2008049856A3 (fr) * | 2006-10-25 | 2009-05-07 | Ingenium Pharmaceuticals Gmbh | Procédés pour le traitement de la douleur |
WO2013162745A1 (fr) | 2012-04-27 | 2013-10-31 | Albemarle Corporation | Compositions d'activateur, leur préparation et leur utilisation dans des catalyseurs |
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WO2005012875A2 (fr) * | 2003-07-29 | 2005-02-10 | Bristol-Myers Squibb Company | Biomarqueurs de modulation des kinases dependantes des cyclines |
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WO2003020272A1 (fr) * | 2001-08-31 | 2003-03-13 | Bristol-Myers Squibb Company | Compositions et methodes de traitement du cancer |
WO2005012875A2 (fr) * | 2003-07-29 | 2005-02-10 | Bristol-Myers Squibb Company | Biomarqueurs de modulation des kinases dependantes des cyclines |
WO2007146039A2 (fr) * | 2006-06-06 | 2007-12-21 | Bristol-Myers Squibb Company | Formes cristallines du n-[5-[[[5-(1,1-diméthyléthyl)-2-oxazolyl]méthyl]thio]-2-thiazolyl]-4-pipéridinecarboxamide |
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WO2008049856A3 (fr) * | 2006-10-25 | 2009-05-07 | Ingenium Pharmaceuticals Gmbh | Procédés pour le traitement de la douleur |
WO2013162745A1 (fr) | 2012-04-27 | 2013-10-31 | Albemarle Corporation | Compositions d'activateur, leur préparation et leur utilisation dans des catalyseurs |
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