MXPA98001585A - Combined therapy for advanced cancer, which includes temozolomide and cispla - Google Patents

Abstract

A method for treating advanced cancer in patients in need of such treatment is disclosed. Temozolomide and cisplatin are administered in combination, in sufficient amounts to achieve a clinical response.

Description

COMBINED THERAPY FOR ADVANCED CANCER. COMPRISING TEMOZOLOMIDE AND CISPLATIN Despite numerous advances in cancer treatment, well-known lifestyle changes that can greatly reduce the risk of cancer and the early warning signs that some cancers provide, many patients still develop advanced cancer for cancer. which are not available conventional therapies, which offer any reasonable hope of cure or significant relief. This invention relates to the use of two known agents against tumors, in combination therapy to provide a positive effect in these advanced cancers. It is also expected that the combination therapy allows administration of the two agents against tumors in amounts that do not result in intolerable side effects. Temozolomide is known for its effects against tumors. For example, in one study, clinical responses were achieved in 17% of patients who had advanced melanomas (Newlands ES, et al., Br J Cancer 65 (2) 287-2981, 1992). In another study, clinical responses were achieved in 21% of patients with advanced melanoma (Journal of Clinical Oncology, Vol. 13, No. 4 (April), 1995, pages 910-913). However, temozolomide has side effects that limit its dose, such as haematological toxicity, ie, suppression, anemia, leukopenia, etc. The cisplatin is known to have properties against tumors (see, for example, B. Rosenberg et al, Wature 205, 698 (1965) and 222, 385 (1972).) However, it also has side effects that limit its dose, such as Nephrotoxicity and ototoxicity There is a need for a method of treating advanced cancers with higher response regimens or reduced side effects, or both.

COMPENDIUM OF THE INVENTION This invention can be summarized as a method to treat advanced cancer in patients in need of this treatment, which comprises administering temozolomide and cisplatin in sufficient quantities to achieve a clinical response. The temozolomide is administered to the patient in combination with the cisplatin, that is, doses of temozolomide and cisplatin are administered during the same period of time. Specific preferred dosage schedules are listed below.

DETAILED DESCRIPTION All references cited herein are incorporated by reference.

The term "temozolomide" is intended to mean a compound having the formula: A chemical name for temozolomide is 3,4-dihydro-3-methyl-4-oxoimidazo- [5, 1-d] -1,2,3,4-tetrazin-8-carboximide. The synthesis of temozolomide is well known. See, for example, Stevens et al., In J. Med. Chem., 1984, 27, 196-201 and ang et al., In J. Chem. Soc., Chem. Commun. , 1984, pages 1687-1688. The cisplatin (cis-diaminodichloroplatininium, compound number 2319 of the Merck index, edition), has the formula: Cl KH3 Ft Advanced cancers, which can be treated by this invention, include malignant melanoma, malignant metastasized melanoma, lung cancer, breast cancer, brain cancer, ovarian cancer, cancer of the head and / or neck , sarcoma, cancer of the prostate and other known cancers that are, at least partially, sensitive to the treatment of cisplatin, which have advanced to a stage where conventional therapy is unlikely to provide a cure. A person suffering from advanced cancer may exhibit one or more of the following signs or symptoms. (a) the presence of a cancerous tumor, (b) fatigue, (c) pain, (d) decreased performance status from the burden of the tumor, and (e) the well-known symptoms associated with each specific cancer. To practice the invention, temozolomide and cisplatin are administered to the patient, who exhibits one or more of the above signs or symptoms, in amounts sufficient to eliminate, or at least alleviate, one or more of the signs or symptoms.

The preferred dose of the temozolomide for practicing the combination therapy of this invention is from 50 to 400 mg per square meter of the surface area of the patient's body per day, more preferably from 75 to 300 mg / m2 and especially preferred from 100 to 200 mg. / m2 / day. It is preferred that the daily dose of the temozolomide be administered once a day for a period of 2 to 10 days, more preferably, a period of 3 to 8 days and especially preferred a period of 5 days. Alternatively, the temozolomide can be administered for a much longer period with a reduced dose. For example, temozolomide can be administered daily for 11 days up to six weeks, at a dose of 50 to 150 mg / m2 / day. Temozolomide can be administered orally in the form of capsules, in which it is mixed with conventional pharmaceutical carriers. Preferred formulations of temozolomide capsules are: Ingredient mg / Capsule Temozolomide 20 100 250 Anhydrous lactose NF 132.8 182.2 175.7 154.3 Sodium starch glycolate NF 7.5 11.0 15.0 22.5 Colloidal silicon dioxide NF 0.2 0.2 0.3 0.7 Tartaric acid NF 1.5 2.2 3.0 9.0 Steric acid NF 3.0 4.4 6.0 13.5 Size of the capsule * 0 * Hard gelatin capsules, two pieces, condom-free, opaque, white.

It is especially preferred that the patient fast from all food or drink, except water, for four hours before the administration of the temozolomide and for two hours thereafter. The cisplatin is preferably administered with a single intravenous infusion on day one of the period of administration of the temozolomide, approximately four hours after the administration of the first day of the temozolomide. To maintain sufficient hydration, one liter of a normal saline solution with 20 meq of KCl / liter and 1 g of magnesium sulfate, at a rate of approximately 250 ml / hour, was administered before and after the infusion of cisplatin. The amount of the cisplatin in the infusion is preferably from 25 to 300 mg per square meter of the surface area of the patient's body, more preferably from 50 to 150 mg / m2 and especially preferred from 75 to 100 mg / m2. Additional fluid can be supplied to maintain adequate urine production. The cisplatin is preferably administered with 500 ml of the normal saline, which contains 12.5 g of mannitol in a period of one hour. Alternatively, the dose of cisplatin, listed in the previous paragraph, can be administered in a period of 2 to 5 days. Up to 100 mg / day / m2 of the surface area of the patient's body can be administered daily for 5 consecutive days. After a period of approximately 28 to 42 days, preferably 28 days, from the first day of the period of administration of the temozolomide, another cycle of administration can be performed, with the temozolomide being administered on day one and on each subsequent day of the administration period, and the cisplatin being administered on day one, or less preferably in a period of 2 to 5 days. For example, for a period of administration of the temozolomide of five days, the period of administration of the cisplatin of one day, and a cycle of treatment of 28 days, the treatment will take place during the five days (the treatment of the temozolomide in the days 1 and 5 and treatment of cisplatin on day 1), followed by 28-5 = 23 days, during which treatment is not provided, followed by five more days of treatment, as the start of the second cycle. The treatment cycles can be continued until a clinical response is obtained or until intolerable side effects are found. The doses of temozolomide and / or cisplatin may be increased with each new treatment cycle, provided that no intolerable side effects occur. Doses can also be decreased, if intolerable side effects occur. It is currently preferred to gradually adjust the dose of temozolomide while keeping the cisplatin dose constant. A common side effect, but tolerable, both temozolomide and cisplatin are nausea and vomiting. These can be alleviated by the administration of an anti-emetic in conjunction with temozolomide. It is preferable that the anti-emetic Ondansetron be administered p.o., in a dose of about 8 mg for about 30 minutes before the administration of the temozolomide. Similarly, it is preferred to administer Ondansetron, 32 mg in an intravenous (IV) or Granisetron, 1 mg IV and Decadron 10 mg, IV form, 30 minutes before the infusion of cisplatin. Of course, other anti-ethics can also be used, such as Haldol, Benadryl and Ativan, as necessary. Of course, other forms of administration of both active ingredients, as available, are considered, such as nasal sprays, transdermally, by suppositories, by sustained release dosage forms, by intravenous (IV) injection, etc. Any form of administration will work as long as the appropriate doses are delivered, without destroying the active ingredient. The effectiveness of the treatment can be determined by controlled clinical trials. Patients who have advanced cancer with tumors that can be measured and evaluated will be included in the study. A measurable tumor is one that can be measured in at least two dimensions, such as a tumor of the lung surrounded by the aerated lung, a skin nodule, or a superficial lymph node. A tumor that can be evaluated is one that can be measured in one dimension, such as a lung tumor, not completely surrounded by the aerated lung or a mass of soft tissue or palpable abdominal tissue, which can be measured in one dimension. The tumor markers that have been shown to be highly correlated with the extent of the disease will also be considered to supply a disease that can be evaluated, such as PSA for prostate cancer, CA-125 for ovarian cancer, CA-15-3 for breast cancer, etc. The tumor will be measured or evaluated before and after treatment by any resource that provides the most accurate measurement, such as CT scan, MRI scan, Ultrasonography, etc. New tumors or their lack in previously irradiated fields can also be used to assess the response against the tumor. The criteria for evaluating the response will be similar to those in the WHO Handbook of Results of Cancer Treatment Reports, WHO Offset Publication 1979, 49-Wold Health Organization, Geneva, Switzerland. The following results are defined for tumors that can be measured uni- and bi-dimensionally.

Complete answer: The complete disappearance of all malignant disease, which can be detected clinically, determined by the two observations separated by no less than four weeks.

Partial response: (a) for tumors that can be measured bi-dimensionally, a decrease of at least 50% in the sum of the products of the largest perpendicular diameters of all measurable tumors, as determined by two observations separated by not less than four weeks; (b) for tumors that can be measured one-dimensionally, a decrease of at least 50% in the sum of the largest diameters of all tumors, as determined by two observations separated by no less than four weeks. In cases where the patient has multiple tumors, it is not necessary for all tumors to regress, to achieve a partial response, as defined herein, but no tumor should have progressed and no new tumor should have appeared.

Stable disease (a) for tumors that can be measured bidimensionally, less than a 50% decrease to less than a 25% increase in the sum of the products of the largest perpendicular diameters of all measurable tumors; (b) for tumors that can be measured one-dimensionally, less than a 50% decrease to less than a 25% increase in the sum of the diameters of all tumors. For (a) and (b), no new tumor must have appeared.

No clinical response, ie progressive disease, is defined as an increase of more than 50% in the product of the largest perpendicular diameters for at least one tumor that can be measured bi-dimensionally, or an increase of more than 25% in the measurable dimension of at least one tumor that can be measured one-dimensionally. For patients who have tumors that can be measured both uni- and bi-dimensionally, the overall response will be determined according to the following table.

Disease response Disease response Measurable response measurable bi General dimensionally one-dimensional PD some PD Some PD PD SD SD or PR SD SD CR PR PR SD or PR or CR PR CR SD or PR PR CR CR CR Abbreviations: PD: Progressive disease CR: Complete response PR: Partial response SD: Stable disease Of course, the removal or alleviation of other known signs or symptoms of advanced cancer, especially those previously listed, may also be used to evaluate the effectiveness of this invention. Advanced cancers should be evaluated, that is, measured tumors, etc., no more than 14 days before the start of treatment. These cancers should be re-evaluated approximately 28 days after day 1 of the administration of the first dose of temozolomide and cisplatin. Twenty-eight days after this initial administration, another administration period can be made, and the evaluations carried out 28 days after the start of this second cycle. The treatment cycles can be continued until clinical responses are achieved or unacceptable toxicity is found. Another aspect of this invention is the treatment of advanced cancer with reduced side effects, usually associated with temozolomide and cisplatin. It is believed that this objective can be achieved by the administration of lower doses of the two active ingredients or by shorter duration of the dosage, by the synergistic effect of the combination. The most serious side effect of temozolomide is haematological toxicity. The dose-limiting toxicity for temozolomide is defined here as Grade 4 Neutropenia of CTC (absolute neutrophil counts, which include bands, less than 0.5 x 103 / mm3) that do not resolve in days or Anemia Grade 4 CTC (hemoglobin less than 6.5 g / dl) or Grade 3 thrombocytopenia of CTC (platelet count less than 50 x 103 / mm3) or Grade 4 thrombocytopenia of CTC (platelet count less than 25) x 103 / mm3). The most common side effect of cisplatin is nephrotoxicity. The toxicity that limits the dose will cause serum creatinine of more than 2.2 mg / dl, which persists for more than 2 weeks from the time of dosing.

Claims (17)

1. CLAIMS 1. A method to treat advanced cancers in patients in need of such treatment, this method comprises administering temozolomide and cisplatin in sufficient quantities to achieve a clinical response. The method of claim 1, wherein the amount of the temozolomide administered is 50 to 400 mg per square meter of the surface area of the patient's body per day, for a period of 2 to 10 days, and the amount of the cisplatin. administered is 25 to 300 mg per square meter of the surface area of the patient's body, as a single dose on the first day of administration of temozolomide. 3. The method of claim 2, wherein starting at 28 to 42 days after the first day of the administration period of temozolomide, administrations of temozolomide and cisplatin are repeated. The method of claim 2, wherein the amount of the temozolomide administered is 75 to 300 mg per m2 of the surface area of the patient's body per day, for a period of 3 to 8 days, and the amount of the cisplatin administered it is 50 to 150 mg per m2 of the surface area of the patient's body, as a single dose, on the first day of administration of temozolomide. 5. The method of claim 4, wherein beginning at 28 to 35 days after the first day of the period of administration of temozolomide, the administrations of temozolomide and cisplatin are repeated. The method of claim 4, wherein the amount of the temozolomide administered is 100 to 200 mg per m2 of the surface area of the patient's body per day, over a period of 5 days, and the amount of the cisplatin administered is 75 to 100 mg per 2 of the surface area of the patient's body, as a single dose on the first day of administration of temozolomide. The method of claim 6, wherein beginning 28 days after the first day of the administration period of temozolomide, the administrations of temozolomide and cisplatin are repeated. The method of claim 1, wherein the temozolomide is administered orally, after the patient has fasted from food and liquids, apart from water, for 4 hours before administration of the temozolomide and for 2 hours after administration of temozolomide, and cisplatin is administered by intravenous infusion. The method of claim 2, wherein the temozolomide is administered orally after the patient has fasted from food and liquids, in addition to water, for 4 hours before administration of the temozolomide and for 2 hours after this administration of temozolomide, and cisplatin is administered by intravenous infusion. The method of claim 3, wherein the temozolomide is administered orally, after the patient has fasted from food and liquids, apart from water, for 4 hours, before the administration of the temozolomide and for 2 hours after this administration of temozolomide, and cisplatin is administered by intravenous infusion. The method of claim 4, wherein the temozolomide is administered orally, after the patient has fasted from food and liquids, apart from water, for 4 hours, before administration of the temozolomide and for 2 hours after this administration of temozolomide, and cisplatin is administered by intravenous infusion. The method of claim 5, wherein the temozolomide is administered orally, after the patient has fasted from food and liquids, apart from water, for 4 hours, before the administration of the temozolomide and for 2 hours after this administration of temozolomide, and cisplatin is administered by intravenous infusion. 13. The method of claim 6, wherein the temozolomide is administered orally, after the patient has fasted from food and liquids, apart from water, for 4 hours, before the administration of the temozolomide and for 2 hours after this administration of temozolomide, and the cisplatin is administered by intravenous infusion. The method of claim 7, wherein the temozolomide is administered orally, after the patient has fasted from food and liquids, apart from water, for 4 hours, before administration of the temozolomide and for 2 hours after this administration of temozolomide, and cisplatin is administered by intravenous infusion. 15. The method of claim 1, wherein the temozolomide is orally administered for a period of 6 days up to six weeks. 16. The method of claim 1, wherein the cisplatin is administered by intravenous infusion over a period of 2 to 5 days. The method of claim 16, wherein the temozolomide is administered orally for a period of 6 days to six weeks.