MXPA98002620A - Combination of temozolomide and alpha-ifn, for the treatment of avanz cancer - Google Patents

Abstract

The present invention relates to the use of temozolomide and alpha-interferon separately for the preparation of a medicament for use in the treatment of advanced cancer in a combination therapy in patients in need of this treatment. The drug containing temozolomide and alpha-interferon separately is adapted to be administrable in combination, in sufficient quantities to achieve a clinical response.

Description

"COMBINATION OF TEMOZOLOMIDE AND ALPHA-IFN, FOR ADVANCED C NCER TREATMENT" 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 which they do not conventional therapies are available that offer some reasonable hope of cure, or significant mitigation. This invention is the use of two known anti-tumor agents in combination therapy to provide a positive effect in these advanced cancers. It should also be expected that the combination therapy will allow the administration of two agents against tumors in amounts that do not result in intolerable side effects. Temozolomide is known due to its effects against tumors. For example, in one study, clinical responses were achieved in 17 percent of patients with advanced melanoma (ES Newlands, and others Br J Cancer 65 (2) 287-2981, 1992). In another study, a clinical response was achieved in 21 percent of patients with advanced melanoma (Journal of Clinical Oncology, Volume 13, Number 4 (April), 1995, pages 910 to 913). However, temozolomide is not always effective and has dose-limiting side effects, such as haematological toxicity, myelosuppression, anemia, leukopenia, etc. Alpha-interferon is also known to have effects against cancer. See, for example, Emstoff et al., Intravenous (IV) Recombinant a-2 Interferon in Metastatic Melanoma, Proc. ASCO 2:57 (C-222), 1983. However, this treatment is not always effective and sometimes results in intolerable side effects related to dosing and duration of therapy. There is a need for a method to treat advanced cancers with higher response regimens or with reduced side effects, or both.

COMPENDIUM OF THE INVENTION This invention can be summarized as a method for treating advanced cancer in patients in need of this treatment, which comprises administering temozolomide and alpha-interferon in amounts sufficient to achieve a clinical response. Temozolomide is administered to the patient in combination with alpha-interferon, that is, doses of temozolomide and alpha-interferon are administered during the same period of time. Preferred specific dosage programs are provided below.

DETAILED DESCRIPTION All references cited herein are incorporated herein by reference. The term "temozolomide" is intended to mean the compound having the formula A chemical name for temozolomide is 3, -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., J. Med. Chem, 1984, 27, 196-201 and from Wang et al., J. Chem. Soc, Chem. Commun., 1994, pages 1687-1688. The term "alpha interferon" as used herein means the family of highly specific proteins for the homologous species that inhibit viral duplication and cell proliferation and modulate the immune response. Typical appropriate alpha-interferons include but are not limited to alpha-2b recombinant interferon such as interferon Intron-A, which can be obtained from Schering Corporation of Kenilworth, NJ, alpha-2a recombinant interferon such as interferon Roferon A which can obtained from Hoffmann-La Roche, of Nutley, NJ, alpha-2C recombinant interferon such as alpha-2 interferon Berofor obtainable from Boehringer Ingelheim Pharmaceutical, Inc., of Ridgefield, CT., alpha-nl-interferon, a purified mixture of natural alpha-interferons for example Sumiferon obtainable from Sumitomo, Japan or as alpha-nl interferon ellferon (INS) obtainable from Glaxo-Wellcome Ltd., of London, Great Britain, or a consensual alpha-interferon obtainable from Amgen, Inc., of Newbury Park, CA, or alpha-n3 interferon a mixture of natural alpha-interferons made by Interferon Sciences and obtainable from Purdue Frederick Co. , of Norwalk, CT., under the name of Alferon Factory. The use of alpha-2a and alpha-2b interferon is preferred. Alpha-2b interferon is especially preferred. The manufacture of alpha-2b interferon is described in U.S. Patent No. 4,530,901. Of course the term alpha-interferon includes the obvious equivalents to it such as certain beta-interferons that are known to have properties similar to alpha-interferon. Advanced cancers treatable 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, prostate cancer, and other cancers that it is known that they respond at least partially to treatment with alpha-interferon or temozolomide, 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 symptoms or signs: (a) presence of a cancerous tumor, (b) fatigue, (c) pain, (d) current state of diminished performance of the load of the tumor, and (e) the well-known symptoms associated with each specific cancer. To practice the invention, temozolomide and alpha interferon are administered to the patient exhibiting one or more of the aforementioned symptoms or signals in sufficient amounts to eliminate at least alleviating one or more of the symptoms or signals.

The preferred dosage of temozolomide for carrying out the combination therapy of this invention is 50 to 400 milligrams per square meter of the surface area of the patient's body per day, more preferably 75 to 300 milligrams per square meter and especially so preferred 100 to 200 milligrams per square meter per day. It is preferred that the daily dosage of temozolomide be administered once per day for a period of 2 to 10 days, more preferably for a period of 3 to 8 days and especially preferably for a period of 5 days. The dosage periods of temozolomide can be repeated in cycles of 28 to 42 days, more preferably 28 to 35 days, and especially preferably for 28 days. That is, from 28 to 42 days after the first day of the administration of temozolomide, another period of administration of temozolimide can be started. Alternatively, the temozolomide may be administered for a much longer period at reduced dosage. For example, temozolomide could be administered daily for 11 days to six weeks, at a dosage of 50 to 150 milligrams per square meter per day. Temozolomide can be administered orally in the form of capsules where it is mixed with conventional pharmaceutical carriers. Preferred temozolomide capsule formulations are: Ingredient milligram / Capsule temozolomide 5 20 100 250 Lactose Anhydrous 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 Stearic Acid NF 3.0 4.4 6.0 13.5 Capsule Size * 3 2 1 0 * Two-piece hard gelatin capsules, free of preservation agent, 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 alpha interferon is preferably administered by intravenous or subcutaneous injection beginning on day one of the first period of administration of temozolomide. However, unlike temozolomide, alpha interferon is administered more or less regularly through combination therapy. Alpha interferon can be administered 1 to 7 times per week, more preferably 2 to 5 times per week, and especially preferably three times per week or every third day. The dose amount of alpha interferon can be from 1 million to 25 million international units (IU) per square meter of the surface area of the patient's body, more preferably from 5 million to 15 million IU per square meter especially so preferred from 7.5 million to 12.5 million IU per square meter. The treatment can be continued until a clinical response is achieved or until intolerable side effects are found. The dosages of temozolomide and / or alpha interferon can be increased with each new treatment cycle, as long as no intolerable side effects are found. The dosages can also be decreased, if intolerable side effects are found. A common but tolerable side effect of temozolomide is nausea and vomiting. This can be improved by administering an anti-emetic along with the temozolomide. It is preferred that the anti-emetic Ondansetron is provided p.o. in a dose of approximately 8 milligrams to approximately 30 minutes before the administration of temozolomide. Of course, other anti-emetics such as Haldonl, Bernadryl and Ativan can be used as necessary. A common, but usually tolerable, side effect of alpha-interferon is flu-like symptoms. These can usually be improved with acetaminophen and other medicines similar to common aspirin. Of course, other forms of administration of both active ingredients are proposed as they become available, such as by nasal spraying, transdermally, by suppository, by dosage form sustained release ediatne intravenous injection, etc. Any form of administration will work as long as the appropriate dosages 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 measurable or evaluable tumors 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. An evaluable tumor is one that can be measured in one dimension, such as a lung tumor not completely surrounded by an aerated lung or a palpable abdominal mass or soft tissue that can be measured in one dimension. Markers of tumors that have been shown to be highly correlated with the extent of the disease will also be taken into account to provide an evaluable disease 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 means that provides the most accurate measurement such as CT scan, MRI scan, Ultrasonography, etc. New tumors or lack thereof in previously irradiated fields can also be used to evaluate the response against tumors. The criteria for evaluating the response will be similar to that of the HO Handbook for Reporting the Results of Cancer Treatment, WHO Offset Publication 1979, 49-World Health Organization, Geneva. The following results are defined for measurable tumors uni- and bi-dimensionally. Complete Response: The complete disappearance of all clinically detectable malignant disease determined by two observations at no less than four separate weeks. Partial Response: (a) for bi-dimensionally measurable tumors, a decrease of at least 50 percent in the sum of the products of the largest perpendicular diameters of all measurable tumors, as determined by two observations at no less than four separate weeks. (b) for one-dimensionally measurable tumors, a decrease by at least 50 percent in the sum of the largest diameters of all tumors, is determined by two observations of not less than four weeks apart. In cases where the patient has multiple tumors, it is not necessary that all tumors have returned to achieve a partial response as defined herein, but no tumor should have advanced and no new tumor should appear. Stable disease: (a) for bi-dimensionally measurable tumors, less than 50 percent decrease to less than 25 percent increase in the sum of the products of the largest perpendicular diameters of all measurable tumors. (b) for uni-dimensionally measurable tumors, less than a 50 percent decrease to less than a 25 percent increase in the sum of the diameters of all tumors. For (a) and (b) new tumors should not appear. No clinical response, ie a progressive disease is defined as an increase of more than 50 percent in the product of the largest perpendicular diameters for at least one measurably measurable tumor, or an increase of more than 25 percent in the dimension measurable of at least one uni-dimensionally measurable tumor. For patients who have both uni- and bi-dimensionally measurable tumors, the total response will be determined according to the following table.

Answer in Response in Response Disease Total Illness two-dimensionally measurable measurable PD any PD Any 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 elimination or alleviation of other known symptoms or signs of advanced cancer, especially those previously indicated may also be used to evaluate the efficacy of this invention.

Advanced cancers should be evaluated, that is, tumors, etc., should be measured, no more than 14 days before the start of treatment. These cancers should be re-evaluated approximately 28 days after day 1 of administration of the first doses of temozolomide and alpha interferon. Twenty-eight days after this initial administration, another administration period may be carried out, and evaluations may be carried out twenty-eight days after the start of this second cycle. The treatment cycles can be continued until a clinical response is achieved or unacceptable toxicity is found. Another aspect of this invention is the treatment of advanced cancer with reduced side effects normally associated with temozolomide and alpha interferon. It is believed that this effect can be achieved by administration of lower doses of the two active ingredients, or by shorter duration of dosage achieved by the synergistic effect of the combination. The most common side effect of temozolomide is hematologic toxicity. The dose limiting toxicity for temozolomide is defined herein as Quality CTC Neutropenia 4 (absolute neutrophil count, including bands of less than 0.5 x 10-mm) which does not resolve in five days or Quality CTC Anemia 4 ( hemoglobin less than 6.5 grams per day), or CTC Thrombocytopenia Quality 3 (platelet count less than 50 X 10-Vmir) or CTC Thrombocytopenia Quality 4 (platelet count less than 25 X. The most common side effects of alpha interferon are: • influenza-like syndrome Neurotoxicity, including neuropsychiatric, neurosensory, and neuromotor, • cardiopulmonary • Gastrointestinal, including nausea, vomiting and / or diarrhea • Hepatotoxicity, including elevations of bilirubin, transaases or alkaline phosphatase • Nephrotoxicity .

Claims (9)

CLAIMS:

1. The use of temozolomide and alpha-interferon in combination for the preparation of a drug for the treatment of cancer.

The use of claim 1, wherein the temozolomide is administered at a rate of 50 to 400 milligrams 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 alpha interferon administered is from 1 million to 25 million IU per square meter of the surface area of the patient's body that is administered intravenously or subcutaneously 1 to 7 times per week.

3. The method of any of the claims cited above wherein the amount of temozolomide administered is 75 to 300 milligrams per square meter for a period of 3 to 8 days, and the amount of alpha interferon administered is from 5 million to 15 million of UI per square meter of the surface area of the patient's body, administered intravenously or subcutaneously.

4. The use of any of the aforementioned claims wherein the amount of temozolomide administered is 100 to 200 milligrams per square meter of the patient's body surface area per day, over a period of 5 days and the amount of alpha interferon administered. it is 7.5 to 12.5 million IU per square meter of the surface area of the patient's body, administered intravenously or subcutaneously.

5. The use of any of the aforementioned claims, wherein starting from 28 to 42 days after the first day of the period of administration of temozolomide, administrations of temozolomide are repeated.

6. The use of any of the aforementioned claims, wherein the onset of approximately 28 to 35 days after the first day of the period of administration of temozolomide is repeated in administrations of temozolomide.

The method of any of the aforementioned claims wherein the temozolomide is administered orally after the patient has fasted from food and liquids other than water for 4 hours before the administration of temozolomide, and for 2 hours after the administration of temozolomide.

The method of any of the claims cited above, wherein the temozolomide is orally administered for a period of six days to six weeks.

9. The method of any of the preceding claims wherein the interferon is interferon 2b.