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WO2008109349A1 - Schéma posologique amélioré servant au traitement du cancer avec du 5-fluorouracile, du 5,10-méthylènetétrahydrofolate et de la capécitabine - Google Patents

Schéma posologique amélioré servant au traitement du cancer avec du 5-fluorouracile, du 5,10-méthylènetétrahydrofolate et de la capécitabine Download PDF

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Publication number
WO2008109349A1
WO2008109349A1 PCT/US2008/055324 US2008055324W WO2008109349A1 WO 2008109349 A1 WO2008109349 A1 WO 2008109349A1 US 2008055324 W US2008055324 W US 2008055324W WO 2008109349 A1 WO2008109349 A1 WO 2008109349A1
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capecitabine
treatment
patient
methylenetetrahydrofolate
administration
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PCT/US2008/055324
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English (en)
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Mark Cantwell
Joan Robbins
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Adventrx Pharmaceuticals, Inc.
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Publication of WO2008109349A1 publication Critical patent/WO2008109349A1/fr

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    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin

Definitions

  • XELODA has the potential convenience factor of an oral drug.
  • the intravenous delivery of 5-FU requires patient visits to the clinic for dosing.
  • the recommended dosing schedule (1250 mg/m 2 twice a day comprising approximately 10 tablets per dose) and patient responsibility for self-administration of XELODA contributes to patient noncompliance.
  • the safety profile of XELODA compared to 5-FU including less XELOD A-induced diarrhea, nausea, and stomatitis have also been suggested as advantages of XELODA.
  • XELODA causes hand-foot syndrome in a significant proportion of patients as soon as 11 days after initiation of treatment, requiring either dose reduction or interruption.
  • dose reduction has been shown to potentially have a negative impact on time to tumor progression.
  • 5-FU does not cause a significant amount of hand foot syndrome.
  • leucovorin has been used as a modulator of 5-fluorouracil (5-FU) for cancer treatment, and leucovorin plus 5-FU has become the standard combination therapy for many cancer types, including colorectal cancer.
  • leucovorin is inactive directly and must undergo several metabolic transformations to its active metabolite 5,10- methylenetetrahydrofolate (COF ACTOR®; or 5,10-CH 2 FH 4 ) to be effective.
  • COFACTOR supplies 5,10-methylenetetrahydrofolate directly and has demonstrated enhancement of the anti-tumor effects of 5-FU in Phase I/II human clinical trials for colorectal and breast cancer.
  • COFACTOR significantly enhances 5-FU anti-tumor activity when given as a daily treatment for 7 consecutive days. Furthermore, COFACTOR also reduced 5- FU induced weight loss compared to leucovorin in this treatment regimen.
  • the combination treatment of 5-FU plus COFACTOR and XELODA results in significantly better anti-tumor activity, prolonged animal survival, and less toxicity than XELODA treatment alone on days 1-14, or treatment with 5-FU plus leucovorin on days 1 and 8 and XELODA on days 2-7 and 9-14.
  • the present invention provides a method of potentiating the therapeutic effect of 5-fluorouracil (5-FU) and 5,10-methylenetetrahydrofolate upon tumor load in a patient hosting 5-FU sensitive tumors.
  • the first step of the method involves cyclic administering to the patient a combination of 5-FU and 5,10 methyl enetetrahydro folate.
  • the second step of the method involves administering capecitabine 1 day after the first step i where the administration of capecitabine is in an amount that potentiates the therapeutic effect of 5-fluorouracil by reducing the tumor load in the patient to a greater amount than treatment with 5-FU and 5,10-methylenetetrahydrofolate without capecitabine.
  • the capecitabine is administered at a daily dosage of between 625 and 1250 mg/m 2 twice a day.
  • the capecitabine is administered orally.
  • the administration of capecitabine occurs daily for between 1 to 6 days before the patient is again treated with 5-FU and 5, 10-methylenetetrahydrofolate.
  • the cyclic administering to the patient of a combination of 5-FU and 5,10 methyl enetetrahydrofolate occurs at least three times over a period of three weeks.
  • the present invention provides the method where the tumor is colorectal cancer.
  • the tumor is a cancer of the breast.
  • the tumor is a cancer of the pancreas, hi another embodiment, the tumor is a cancer of the stomach.
  • the present invention provides a method where the treatment further includes co-administration of a chemotherapeutic drug selected from the group consisting of cisplatin, oxaplatin, irinotecan, gemcitabine, bevacizumab and cetuximab.
  • a chemotherapeutic drug selected from the group consisting of cisplatin, oxaplatin, irinotecan, gemcitabine, bevacizumab and cetuximab.
  • the present invention provides a method where the administration of 5-FU is between 250 and 1000 mg/m 2 per treatment. In still other embodiments, the administration of 5,10 methylenetetrahydro folate is between 50 and 70 mg/m 2 per treatment.
  • the present invention provides a method of reducing adverse side effects arising from treatment of 5-fluorouracil and 5,10-methylenetetrahydrofolate in a patient hosting 5-FU sensitive tumors.
  • the first step of the method involves cyclic administering to the patient a combination of 5-FU and 5,10-methylenetetrahydrofolate.
  • the second step of the method involves administering capecitabine 1 day after the first step i where the administration of capecitabine is in an amount that potentiates the therapeutic effect of 5-fluorouracil while reducing adverse side effects in the patient compared to side effects arising from treatment with 5-FU and 5,10-methylenetetrahydrofolate without capecitabine.
  • the present invention provides the method of reducing having the preferred embodiments described above.
  • the present invention provides a method of reducing adverse side effects of a treatment regimen consisting of daily doses of capecitabine in a patient with cancer.
  • the first step of the method involves cyclic administering to the patient a combination of 5-FU and 5,10-methylenetetrahydrofolate.
  • the second step of the method involves administering capecitabine 1 day after the first step i where the cyclic administration of 5-FU and 5,10-methylenetetrahydrofolate followed by the administration of capecitabine reduces the adverse effects of a treatment regimen consisting of daily doses of capecitabine alone.
  • Figure 1 is a graphical representation of treatment regimens 1-4: 1) Water, PO daily, 14 days (days 1-14); 2) XELODA, PO daily, 14 days (days 1-14); 3) Leucovorin plus 5-FU, IP, weekly (days 1 and 8) and XELODA, PO daily, (days 2-7 and 9- 14); and 4) COFACTOR plus 5-FU, IP, weekly (days 1 and 8) and XELODA, PO daily, (days 2-7 and 9-14).
  • Figure 2 is a graphical representation showing tumor growth kinetics for all four treatment regimens.
  • the COFU ⁇ XELODA treatment (regimen no. 4) shows slower growth kinetics as compared to the other three treatment regimens.
  • Figure 3 is a graphical representation of the percent of mice surviving over time for each of the four different regimen.
  • the graph shows that COFU ⁇ XELODA treatment (regimen no. 4) prolonged mouse survival compared to the other regimens.
  • the median survival of COFU ⁇ XELODA treated mice (60 days) was significantly longer (p ⁇ 0.05) than FOFU ⁇ XELODA (regimen no. 3, 39 days) and XELODA alone (38 days).
  • the XELODA and FOFU ⁇ XELODA treatment did not significantly change survival compared to control (water) treated mice (44.5 days).
  • Figure 4 is a graphical representation of weight loss in mice, showing a small changes in body weight for COFU ⁇ XELODA treatment as compared to treatment with water alone. Treatment with FOFU ⁇ XELODA and XELODA alone, showed significantly more weight loss as compared to treatment with water.
  • Figure 5 shows a graphical representation of the NCI common toxicity criteria weight loss grading. Treatment with COFU ⁇ XELODA showed less grade 1 toxicity at day eight and no grade 2 toxicity at day 15. In contrast, both XELODA alone and FOFU ⁇ XELODA showed greater grade 1 toxicity at day 8 and up to grade 2 weight loss toxicity at day 15.
  • the present invention provides a novel regimen for potentiating the therapeutic effect of 5-FU and 5,10-CH 2 FH 4 upon tumor load in a patient hosting 5-FU sensitive tumors.
  • the method comprises a first step of cyclic administering to the patient a combination of 5- FU and 5,10-CH 2 FH 4 .
  • the second step involves administering capecitabine 1 day after the first step where the administration of capecitabine is in an amount that potentiates the therapeutic effect of 5-FU by reducing the tumor load in the patient to a greater amount than treatment with 5-FU and 5,10-CH 2 FH 4 without capecitabine.
  • One embodiment of the present invention relates to the use Of S 5 IO-CH 2 FH 4 as a modulator of 5-FU in cancer chemotherapy.
  • 5,10-CH 2 FH 4 increases response rates to 5-FU as a result of increasing the inhibition of TS by the 5-FU metabolite, FdUMP, in tumors.
  • 5,10-CH 2 FH 4 can be used to inhibit the growth of tumors when used in combination with 5-FU, or with other drugs which are metabolized to FdUMP including floxuridine (FUDR), ftorafur (tegafur), and DoxifluridineTM (5'-deoxyfluorouridine) and capecitabine.
  • FUDR floxuridine
  • ftorafur ftorafur
  • DoxifluridineTM 5'-deoxyfluorouridine
  • the mechanism of action of 5, 10-CH 2 FH 4 is promotion of TS inhibition by FdUMP in fluoropyrimidine-treated tumors, which can occur by increasing the rate of formation and stability of TS-FdUMP-5,10-CH 2 FH 4 and TS-FdUMP FH 4 ternary complexes.
  • the reduced toxicity of 5 -FU (or an analog or prodrug thereof) when combined with 5,10-CH 2 FH 4 can permit drug regimens in which 5,10-CH 2 FH 4 and 5-FU (or an analog or prodrug thereof) are used in combination with one or more additional anti-cancer drugs that would be prohibitively toxic in the absence OfCH 2 FH 4 .
  • 5-FU sensitive tumors refers to tumors that can be treated by administration of 5-FU.
  • the administration of 5-FU to the tumor results in one or more of the following: growth inhibition of the tumor; decrease in size of the tumor; abatement; remission; diminishing of symptoms or making the symptom, injury, pathology or condition more tolerable to the patient; or decreasing the frequency or duration of the symptom or condition.
  • Cyclic administering refers to a treatment protocol involving repeated administration of a primary drug treatment to a patient at set intervals.
  • the interval can be days or weeks. Preferably, the interval is several days, or about a week.
  • a secondary drug treatment can be administered to the patient.
  • cyclic administering refers to the administration of at least two primary drug treatments.
  • efficacy of an anticancer treatment or chemotherapy regimen is determined by its anti-tumor or anti-cancer cell effects and ability to improve clinical results of treatment, such as, for example, remission, time to progression, response rate, and survivorship.
  • Accepted methods of assessing the efficacy of an anticancer treatment or chemotherapy regimen are well-established in the field of cancer treatment.
  • anti-cancer effects can be assessed by detecting cancer cells or markers, for example in serum or plasma. Examples of tumor proteins or antigens that can be detected include CEA for colon cancer and CA 19-9 for pancreatic cancer.
  • anti-tumor effects can be measured by monitoring tumor size and the change in tumor size over time.
  • Patient refers to animals such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice and the like. Li certain embodiments, the patient is a human.
  • Patentiating the therapeutic effect refers to increasing or multiplying the therapeutic effect of a drug by administering the drug in combination with, or simultaneous to, another drug.
  • the method of the present invention is a method of potentiating the therapeutic effect of 5-FU and 5, 10-methylenetetrahydro folate administered in combination.
  • Toxicity refers to harmful effects of an entity on the cells, tissues, organs, or systems of the body. Toxic effects result from biochemical reactions of the entity with the cells or tissues of the subject being treated, and can be general or specific, involving a particular system or organ.
  • Toxicity can include, as non-limiting examples, increased lacrimation; mucositis; esophagopharyngitis; neurological toxicity, such as parasthesias, insomnia, and dizziness; gastrointestinal toxicity, such as nausea, vomiting, and diarrhea; weight loss toxicity; cardiac toxicity; dermatological toxicity, including alopecia, sweating, and rashes; and hematological toxicity, such as, but not limited to, neutropenia, thrombocytopenia, lymphopenia, and leucopenia.
  • Clinical definitions of toxicity parameters can be found in the National Cancer Institute's Common Toxicity Criteria (version 3) or in the World Health Organization Toxicity Criteria.
  • Tumor load refers to the amount or size of a tumor in a patient.
  • the present invention provides a novel regimen for potentiating the therapeutic effect of 5-fluorouracil (5-FU) and 5,10-methylenetetrahydrofolate (5,10-CH 2 FH 4 ) upon tumor load in a patient hosting 5-FU sensitive tumors.
  • the combination of 5-FU, 5,10-CH 2 FH 4 and capecitabine results in a synergistic effect for the treatment of 5-FU sensitive tumors.
  • the synergistic effect is afforded by the cyclic administering to a patient a combination of 5-FU and 5,10-CH 2 FH 4 .
  • the cyclic administering involves the administration of 5-FU and 5,10-CH 2 FH 4 on one day, followed by a subsequent administration of 5-FU and 5,10-CH 2 FH 4 several days later. Typically, the interval is about one week. On the days when the 5-FU and 5,10-CH 2 FH 4 are not being administered, an oral dose of capecitabine is administered.
  • Patients that benefit from the methods of the present invention are those patients suffering from a 5-FU sensitive cancer, such as, for example, colorectal carcinoma, pancreatic, breast, head and neck, esophageal cancer, or stomach cancer.
  • a 5-FU sensitive cancer such as, for example, colorectal carcinoma, pancreatic, breast, head and neck, esophageal cancer, or stomach cancer.
  • the patient has a tumor type that in current practice is not commonly treated with 5-FU, such as, but not limited to ovarian cancer or cervical cancer.
  • treating a cancer patient with 5,10- CH 2 FH 4 , 5-FU (or an analog or prodrug thereof), and capecitabine can reduce the rate of tumor growth in a cancer patient when compared with treating the patient with capecitabine in the absence of 5,10-CH 2 FH 4 and 5-FU (or an analog or prodrug thereof), or when compared with treating a patient with 5-FU (or an analog or prodrug thereof) and capecitabine in the absence of 5,10-CH 2 FH 4 .
  • treating cancer patients with 5,10-CH 2 FH 4 , 5-FU (or an analog or prodrug thereof), and capecitabine can increase the survivorship of cancer patients when compared with treating cancer patients with capecitabine in the absence Of S 5 IO-CH 2 FH 4 and 5-FU (or an analog or prodrug thereof) or when compared with treating cancer patients with 5-FU (or an analog or prodrug thereof) and capecitabine in the absence of 5,10-CH 2 FH 4 .
  • the treatment methods of the present invention provide improved treatment of cancer, lower toxicity, lower side effects and improved patient survival.
  • the synergistic effect afforded by the use of 5,10-CH 2 FH 4 and 5-FU in combination with capecitabine allows better efficacy in the treatment of cancer along with lower dosing levels of the drugs. Accordingly, patients sensitive to the side effects and toxicity of the individual drugs will benefit from the combination treatment as the cancer can be effectively treated at lower doses, thus reducing the side effects to the patient.
  • the lower side effects and toxicity afforded by the use of 5,10-CH 2 FH 4 and 5-FU in combination with capecitabine can allow dose escalation of one or more of the drugs in the treatment regimen to allow improved efficacy.
  • the use Of S 5 IO-CH 2 FH 4 and 5-FU in combination with capecitabine allows a wider dosing range of drugs while maintaining or enhancing overall efficacy of treatment.
  • Formulations of 5-FU are commercially available from American Pharmaceutical Partners, Inc. The formulations are available in a variety of sizes (10 mL to 100 mL). Typically concentrations for the formulations are 50 mg/mL. Formulations of 5-FU comprise 5-FU in water, with the pH adjusted to 9.2 using sodium hydroxide. [0038] Formulations of capecitabine are available from Roche. The formulations are available as 150 mg and 500 mg film-coated tablets. The core of the tablets comprise the following excipients: anhydrous lactose, croscarmellose sodium, hypromellose, microcrystalline cellulose and magnesium stearate. The tablet coating comprises the following excipients: titanium dioxide, yellow and red iron oxide, and talc.
  • Formulations of 5, 10-CH 2 FH 4 comprise 5, 10-CH 2 FH 4 in combination with citric acid and ascorbic acid, at an essentially neutral pH.
  • essentially neutral pH means a pH of 7.0 ⁇ 0.2.
  • the relative amounts of citric acid and ascorbic may vary, without substantially affecting the stability of the composition, from about 0.75:1 to about 2.25:1 weight ratio of citric acid to ascorbic acid. In accordance with a preferred embodiment, citric acid and ascorbic acid are present at a weight ratio of about 1.5:1.
  • the formulation of 5, 10-CH 2 FH 4 comprises the steps of (a) preparing a solution of citric acid and ascorbic acid at an essentially neutral pH; and (b) dissolving 5,10-CH 2 FH 4 in the solution.
  • the solution of citric acid and ascorbic acid is chilled to 10° C and kept chilled at this temperature until all of 5,10-CH 2 FH 4 has gone into solution.
  • the essentially neutral pH of the solution of citric acid and ascorbic acid is obtained by adjusting and/or buffering the pH of the solution in any manner known in the art, such as with NaOH or HCl.
  • the relative amounts of citric acid and ascorbic may vary, without substantially affecting the stability of the composition, from about 0.75:1 to about 2.25:1 weight ratio of citric acid to ascorbic acid.
  • the pharmaceutical compositions can be used alone, or in combination with other therapeutic or diagnostic agents.
  • the pharmaceutical compositions can be administered to the patient in a variety of ways, including topically, parenterally, intravenously, colonically, rectally or intraperitoneally.
  • the pharmaceutical compositions are administered parenterally, intravenously, or orally.
  • the additional anticancer drugs used in the combination protocols of the present invention can be administered separately or one or more of the anticancer drugs used in the combination protocols can be administered together. Where one or more anticancer drug is administered separately, the timing and schedule of administration of each drug can vary.
  • bolus injection of each drug can be given once weekly for a number of weeks.
  • 5,10-CH 2 FH 4 is administered prior to 5-FU or 5-FU analog or prodrug.
  • the patient can receive the 5,10-CH 2 FH 4 dose from about 10 minutes to about four hours prior to receiving the 5- FU dose.
  • the protocol for the combination therapy is not limiting, and can include any feasible administration protocols with respect to frequency, duration, and dosage.
  • capecitabine can be administered orally on a daily basis until the next 5,10-CH 2 FH 4 and 5-FU combination treatment, approximately about one week.
  • the treatment time for capecitabine can be as low as 1 day, and as high as 6 days.
  • capecitabine can be administered for about 6 days.
  • another treatment of 5,10-CH 2 FH 4 and 5-FU can be administered. This can be again followed by treatment with capecitabine for about as low as 1 day and as high as about 6 days. Accordingly, capecitabine can be administered only on days when the 5,10-CH 2 FH 4 and 5-FU combination are not administered.
  • One of skill in the art will appreciate that other treatment regimens are useful in the present invention.
  • a number of chemotherapy protocols that combine 5-FU with one or more anticancer drugs are known in the field of cancer therapy. "Randomized trial of intensive cyclophosphamide, epirubicin, and fluorouracil chemotherapy compared with cyclophosphamide, methotrexate, and fluorouracil in premenopausal women with node- positive breast cancer.” J Clin Oncol 1998; 16(8): 2651-8; herein incorporated by reference, particularly for disclosure of anticancer protocols that use 5-FU.)
  • Anticancer protocols that include 5-FU in combination with one or more additional drugs also include therapies for breast cancer that include cyclophosphamide, doxorubicin, and fluorouracil (see, for example, Bennett JM, Muss HB, Doroshaw JH, et al.
  • the present invention includes the addition of 5,10-CH 2 FH 4 to chemotherapy regimens such as these to reduce the toxicity of the chemotherapy regimens.
  • the regimen of the present invention can be used to treat 5-FU sensitive cancers in combination with a chemotherapeutic drug selected from platins, topoisomerase inhibitors, angiogenesis inhibitors, and epidermal growth factor receptor inhibitors (e.g., cisplatin, oxaplatins, irinotecan, bevacizumab and cetuximab).
  • a chemotherapeutic drug selected from platins, topoisomerase inhibitors, angiogenesis inhibitors, and epidermal growth factor receptor inhibitors (e.g., cisplatin, oxaplatins, irinotecan, bevacizumab and cetuximab).
  • anticancer treatment protocols include radiation therapy in addition to chemotherapy.
  • the present invention provides a treatment regimen of first administering on the same day, 5,10-CH 2 FH 4 and 5-FU.
  • capecitabine can be administered on days when 5,10-CH 2 FH 4 and 5-FU are not administered.
  • Capecitabine can be administered for at least about 1 day, or up to about 6 days.
  • capecitabine can be administered for about 6 days.
  • another treatment of 5,10-CH 2 FH 4 and 5-FU can be administered. This can be again followed by treatment with capecitabine for about as low as 1 day and as high as about 6 days.
  • capecitabine can be administered on a daily basis for about 14 days consecutive days, followed by a week without treatment of capecitabine.
  • the pharmaceutically effective amount of a composition required as a dose will depend on the route of administration, the type of cancer being treated, and the physical characteristics of the patient.
  • the dose can be tailored to achieve a desired effect, but will depend on such factors as body surface area, weight, diet, concurrent medication and other factors which those skilled in the medical arts will recognize.
  • Those skilled in the art of cancer treatment and chemotherapy would be able to determine optimal dosages and regimens for 5,10-CH 2 FH 4 , 5-FU and capecitabine using well- established protocols for evaluating toxicity and efficacy for individual patients.
  • Some preferred treatments of cancer patients with 5-FU and 5,10-CH 2 FH 4 are regimens using from 10 milligrams to 1 gram Of S 5 IO-CH 2 FH 4 per m 2 , preferably from 20 milligrams to 500 milligrams of 5,10-CH 2 FH 4 per m 2 , and more preferably from about 30 milligrams to about 250 milligrams of 5,10-CH 2 FH 4 per m 2 .
  • a preferred dose of 5,10-CH 2 FH 4 can be from about 50 to about 70 milligrams per m 2 .
  • Administration of 5-FU can be performed at a variety of dosages less than about 5 gram per m 2 , e.g., from about 25 milligrams to about 5 grams per m 2 , e.g., from about 50 milligrams to 2.5 grams per m , e.g., from about 100 milligrams to about 1 gram per m .
  • a preferred dose of 5-FU can be from about 250 to about 1000 milligrams per m 2 .
  • the daily dosage of capecitabine for example, can be less than about 7500 mg per m 2 , e.g., from about 500 mg to about 7500 mg per m 2 , e.g., from about 1000 mg to about 5000 mgs per m 2 , e.g., from about 1500 mg to about 3000 mg per m 2 .
  • the dose can be divided into one to six (preferably two) administrations per day.
  • This example provides a representative method of formulating a lyophilized composition of 5,10-CH 2 FH 4 at an essentially neutral pH comprising citric acid and ascorbic acid.
  • This Example provides a new regimen for the treatment of cancer using existing anti-cancer drugs and protocols.
  • the combination of existing drugs and protocols in a novel regimen has surprisingly resulted in improved treatment of colorectal cancer, as well as a reduction in drug toxicity and adverse side effects.
  • the novel regimen of the instant invention also improved patient survival.
  • mice were female 6-8 week old nude mice (nu/nu) were obtained from Harlan, Inc. Four mice per cage were maintained in isolated, hepa-f ⁇ lter-ventilated cages.
  • the human colon carcinoma HT-29 was obtained from American Type Culture Collection (ATCC). Cells were maintained in complete media (DMEM containing 10% fetal bovine serum, 2 mM 1-glutamine, 100 units/mL penicillin, and 100 ⁇ g/mL streptomycin) in a 37 0 C, 5% CO 2 humidified incubator. Cells were passaged every 2-3 days prior to use in vivo.
  • ATCC American Type Culture Collection
  • 5-Fluorouracil (5-FU) and leucovorin were obtained from Sigma- Aldrich.
  • COFACTOR flaxorin; 5,10- methylenetetrahydofolate
  • XELOD ATM Capecitabine
  • PBS phosphate buffered saline
  • the drugs were dosed as follows. 5-FU, Leucovorin, and COFACTOR were each injected intraperitoneally (IP) at 0.6 mg/mouse/drug (approximately 30 mg/kg body weight; 90 mg/m 2 ).
  • IP intraperitoneally
  • XELODATM was delivered by oral gavage (PO) at 7.5 mg/mouse (approximately 375 mg/kg body weight; 1125 mg/m 2 ).
  • Water 200 ⁇ L/mouse was delivered by oral gavage. Mice were randomized to four separate treatment groups (Table 1):
  • COFU- ⁇ XELODA treatment prolonged mouse survival compared to the other drug regimens.
  • the median survival of COFU ⁇ XELODA treated mice 60 days was significantly longer (p ⁇ 0.05) than FOFU ⁇ XELODA (39 days) and XELODA alone (38 days).
  • XELODA and FOFU ⁇ XELODA treatment did not significantly change survival compared to control (water) treated mice (44.5 days).
  • mice The cause of death for the majority of mice was euthanasia due to tumor ulceration or tumor diameters >2cm.
  • a small percentage of mice in the XELODA only treatment group (15%) and FOFU ⁇ XELODA (5%) died following the onset of clinical signs of illness or potentially drug-related toxicity (e.g. weight loss and lethargy), hi contrast, there were no deaths secondary to clinical signs of illness or drug-related toxicity in either the COFU ⁇ XELODA or control (water) treatment groups.
  • COFU ⁇ XELODA treatment (-5.95% and -9.66% on days 8 and 15, respectively) was less than the maximum severity of weight loss following FOFU ⁇ XELODA treatment (-9.13% and -19.58% on days 8 and 15, respectively).

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Abstract

La présente invention concerne une méthode permettant de potentialiser l'effet thérapeutique du 5-fluorouracile et du 5,10-méthylènetétrahydrofolate en cas de charge tumorale chez un patient souffrant de tumeurs sensibles au 5-FU. Cette méthode comprend une première étape comprenant l'administration cyclique au patient d'une combinaison de 5-FU et de 5,10-méthylènetétrahydrofolate, et une deuxième étape comprenant l'administration de capécitabine 1 jour après la première étape. Selon cette invention, la quantité de capécitabine administrée potentialise l'effet thérapeutique du 5-fluorouracile et réduit davantage la charge tumorale chez le patient qu'un traitement avec du 5-FU et du 5,10-méthylènetétrahydrofolate sans capécitabine.
PCT/US2008/055324 2007-03-06 2008-02-28 Schéma posologique amélioré servant au traitement du cancer avec du 5-fluorouracile, du 5,10-méthylènetétrahydrofolate et de la capécitabine WO2008109349A1 (fr)

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EP2617421A1 (fr) 2012-01-20 2013-07-24 Isofol Medical AB Tétrahydrofolates en combinaison avec les inhibiteurs EGFR dans l'utilisation pour le traitement du cancer
US10292984B2 (en) 2017-02-14 2019-05-21 Isofol Medical Ab Methods for increasing blood plasma 2′-deoxyuridine (dUrd) and thymidylate synthase inhibition
US10328079B2 (en) 2017-08-24 2019-06-25 Isofol Medical Ab [6R]-MTHF multiple bolus administration in 5-fluorouracil based chemotherapy
US11013744B2 (en) 2017-08-24 2021-05-25 Isofol Medical Ab [6R]—MTHF—an efficient folate alternative in 5-fluorouracil based chemotherapy
RU2779535C2 (ru) * 2018-01-05 2022-09-09 Исофол Медикал Аб Способы лечения колоректального и метастатического колоректального рака

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EP2617421A1 (fr) 2012-01-20 2013-07-24 Isofol Medical AB Tétrahydrofolates en combinaison avec les inhibiteurs EGFR dans l'utilisation pour le traitement du cancer
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