MXPA05012889A - Combined use of ecteinascidin-743 and platinum antineoplastic compounds - Google Patents

Abstract

ET-743 can be used to mitigate resistance to and potentiate the cytotoxic effects of a platinum coordination complex anti-neoplastic agent in a human cancer patient.

Description

COMBINED USE OF ECTEINASIDINE-743 AND PLATINUM ANTINEOPLASTIC COMPOUNDS Field of the Invention The present invention relates to a treatment, more particularly to the improved use of antitumor compounds in cancer therapy. The present invention is directed to the use of ecteinasidin 743 and to products containing this compound for cancer therapy, in particular to the use of ecteinasidine 743 in combination with an antineoplastic platinum coordination complex in the treatment of cancer. BACKGROUND OF THE INVENTION Cancer comprises a group of malignant neoplasms that can be divided into two categories: carcinoma, which comprises most of the cases observed in the clinics, and other less frequent cancers, which include leukemia, lymphoma, tumors in the nervous system central and sarcomas. Carcinomas have their origin in epithelial tissue, while sarcomas develop from connective tissues and those structures that have their origin in mesodermal tissues. Sarcomas can affect, for example, the muscles or bones and arise in the bones, bladder, kidneys, liver, lung, parotid, spleen, etc. Cancer is invasive and tends to metastasize to new sites. It disperses directly into surrounding tissues, and can also be spread through the lymphatic and circulatory systems. Many cancer treatments are available, including surgery and radiation for localized disease and drugs. However, the efficacy of the treatments available in many types of cancer is limited, and new and improved forms of treatment that show clinical benefit are needed. This is especially true for those patients who present with advanced and / or metastatic disease. It is also real for patients with recurrence to progressive disease after having been previously treated with established therapies for which additional treatment with the same therapy is in most cases ineffective, due to the acquisition of resistance or limitations in the administration of therapies due to associated toxicities. Chemotherapy plays an important part in the treatment of cancer, since it is required for the treatment of advanced cancers with distant metastases, and often helps to reduce the tumor before surgery. Many anti-cancer drugs have been developed based on several modes of action. The most commonly used types of anti-cancer agents include: alkylating agents-DNA (eg, cyclophosphamide, ifosamide), antimetabolites (eg, methotrexate, a folate antagonist and 5-fluorouracil, a pyrimidine antagonist), microtubule switches (eg vincristine, vinblastine, paclitaxel), DNA intercalators (eg, doxorubicin, daunomycin, cisplatin) and hormone therapy (eg, tamoxifen, flutamide). The ideal antineoplastic drug could selectively kill cancer cells, with a broad therapeutic index, in relation to their toxicity towards non-malignant cells. It may also retain its effectiveness against malignant cells, even after prolonged exposure to the drug. Unfortunately, none of the normal chemotherapies has an ideal profile. Most have very narrow therapeutic indices and, in almost every case, cancer cells exposed to slightly sub-lethal concentrations of a chemotherapeutic agent will develop resistance to that agent, and very often cross-resistance to various other antineoplastic agents. Combination therapy using drugs with different mechanisms of action is an accepted treatment method that helps prevent the development of resistance by the treated tumor. The ecteinascidinas (abbreviated here as ET or ET's) are extremely potent antitumor agents isolated from the marine tunicate turbinate of Ecteinascidia. Several ecteinascidins have been previously reported in scientific patents and literatures. See, for example, US Patent No. 5, 089,273, which describes novel compounds of extracted matter of tropical marine invertebrates, Ecteinascidia turbinata, and designated in said patent as ecteinascidinas 729, 743, 745, 759A, 759B and 770. These compounds are useful as antibacterial and / or anti-bacterial agents. -tumors in mammals. U.S. Patent No. 5,478,932 describes ecteinascidins isolated from Caribbean tunicate Ecteinascidia turbinata that provides in vivo protection against P388 lymphoma, B16 melanoma, M5076 ovarian sarcoma, Lewis lung carcinoma and LX-1 human lung carcinoma xenografts and mammary carcinoma. Human MX-1 One of them, ecteinascidin-743 (ET-743), is a novel tetrahydroisoquinoline alkaloid isolated from Ecteinascidia turbinata ascidian marina that has considerable antitumor activity in vitro and in vivo in murine and human tumors, and is currently in clinical trials. Potent antitumor activity has been demonstrated in a wide range of tumor models in vivo including human tumor xenografts in live mice. ET-743 has a novel complex mechanism of action at the level of kinetic transcription. ET-743 binds to guanine-cytosine-rich sequences in the minor DNA slot and guanine residues of alkylates in the N2 position. An in vitro bone marrow assay using human, murine and canine progenitor cells showed equal sensitivity of erythroid and myeloid cells to ET-743. Prolonged or repeated exposure to the drug proved more toxic to hematopoietic progenitors than a one-hour exposure. The therapeutic index of ET-743 was more favorable with prolonged exposure. A program of clinical development of ET-743 in cancer patients, began with phase I studies investigating intravenous infusion programs of 1 hour, 3 hours, 24 hours and 72 hours and a program of 1 hour daily for 5 days (dx5 ). In Phase I and Phase II clinical trials, ET-743 has shown significant antitumor activity against several human malignancies, including soft tissue sarcomas and ovarian carcinomas. In WO 0069441, incorporated herein by reference, additional details are provided with respect to the use of ET-743 for the treatment of human body cancer. A well-known and used family of anti-cancer agents are the platinum compounds. Cisplatin (cis-diaminadichloroplatinum (II)) is a platinum coordination complex, first identified in 1965 as a cytotoxic agent. It has broad activity as an antineoplastic agent and is especially useful in the treatment of epithelial malignancies. Other platinum coordination complexes that have been evaluated in clinical trials include carboplatin, tetraplatin ormiplatine, iproplatin, and oxaliplatin. In the last decade, it has substantially increased the treatment of cancer patients with antineoplastic agents of platinum coordination complex, such as cisplatin or carboplatine. Cisplatin has been shown to be useful in the treatment of multiple malignancies, including testicular cancer, ovarian cancer and small cell lung cancer, while carboplatin has proved useful in brain tumors, endometrial cancer, germ cell tumors and Head and neck cancer. The mechanism of action is not normally known, although it may be related to the ability of these compounds to bind to DNA and form various types of inter-strand and inter-strand cross-links, which possibly interfere with the synthesis of both DNA and RNA. Patients with cancer eventually become resistant to treatment with platinum coordination complexes, such as cisplatin or carboplatin. The mechanism of resistance to these compounds is not clear, but may be related to the decreased drug accumulation, elevation of intracellular concentrations of metallothioneins and glutathione, which bind and deactivate the drug., or to the formation or repair of adducts of diminished DNA-drug. Therefore, there is a need to develop effective therapies that overcome this resistance. In cancer cell lines growing in vitro, the combination of ET-743 and cisplatin showed an additive or synergistic effect evaluated by sobologram analysis. This synergistic effect has been confirmed in vivo: Erba, E. and associates "ET-743 and cisplatin (DDP) shown in vitro and in vivo synergy against human sarcoma and ovarian carcinoma cells", Proceed. AACR-NCI-EORTC nov. 2001, abstract 406; Faircloth, Glynn Thomas, Jr., and Associates. "In vivo combinations of chemotherapeutic agents with Ecteinascidin 743 (Et743) against solid tumors", Proceed. AACR-NCI-EORTC nov. 2001, abstract 387; D'lncalci M. and associates: "The combination of ET-743 and cisplatin (DDP): from a molecular pharmacology study to a clinical trial phase.", Proceed. AACR March 2002, abstract 404; D'lncalci, M. and associates. "In human tumor xenografts the resistance to ET-743 or cisplatin" can be overeóme by giving the two drugs in combination. "Proceed, AACR-NCI-EORTC, Nov. 2002, abstract 97. The combination therapy comprising ET-743 , it is also the object of the publication WO 02 36135, which is incorporated in its entirety to the present invention as a specific reference It is an object of the present invention to provide methods and products effective to prevent resistance or overcome the established resistance to agents Antineoplastic Agents of the Platinum Coordination Complex in Human Patients It is another object of the present invention to provide an effective method and products for enhancing the cytotoxic effects of the antineoplastic agents of the platinum coordination complex in the clinical environment Summary of the Invention Unexpectedly, We discovered that when it is provided in combination, the maximum dose of ET-743 and a platinum compound, particularly The cisplatin or carboplatine may be administered without an increase or addition of toxicity. This has been confirmed in clinical trials, in which the full dose of cisplatin and carboplatin has been successfully administered with a dose scale of ET-743. Therefore, the present invention relates to a novel treatment regimen for cancer patients, whereby the platinum compound is administered in combination with ET-743. The present invention further provides a method of treating a patient with human cancer comprising the administration of a platinum compound and ET-743, wherein the amount of platinum compound is at least 50%, at least 75% , at least 85%, at least 90%, at least 95% or at least 100% of the recommended dose for the platinum compound in the absence of ET-743, and the amount of ET-743 is at less 50%, at least 75%, at least 85%, at least 90%, at least 95% or at least 100% of the recommended dose for ET-743 in the absence of the platinum compound. The recommended doses are based on studies of Toxicity that limits the dose. Preferably, the amounts of platinum compound and ET-743, both are at least 85%, at least 90%, at least 95% or at least 100% of the respective recommended dose. In another aspect, the present invention is directed to the use of ET-743 in the preparation of a medicament for the effective treatment of a human cancer patient by combination therapy employing ET-743 with a platinum compound, characterized in that the combination overcomes the resistance to platinum antineoplastic compounds without increasing the toxicity of each drug. In a related aspect, the present invention provides a method for treating a human cancer patient with a platinum compound, wherein ET-743 is administered as a combination therapy without a compensation fall in the platinum compound dose.

In yet another embodiment of the present invention, there is provided a method of reducing resistance to platinum antineoplastic compounds in an individual having a neoplastic disease, wherein the method comprises administering to an individual ET-743 and the platinum compound in a dosage range which is the same as the dose administered, if each of ET-743 and the platinum compound were administered alone. The present invention also provides a pharmaceutical composition containing a recommended dose of ET-743 for weekly administration in combination with a platinum compound and a pharmaceutically acceptable carrier. In a further aspect of the present invention, a medical team is provided for administering ET-743 in combination with an antineoplastic platinum compound, wherein the medical team comprises printed instructions for administering ET-743 in accordance with the dosing schedules that are administered. will be set forth below, and the supply of ET-743 in dosage units of at least one cycle, wherein each dosage unit contains the appropriate amount of ET-743 for the treatments as defined above and a pharmaceutically acceptable carrier.

Detailed Description of the Invention ET-743 is a natural compound represented by the following formula: The term "ET-743" also intends to cover here any salt, ester, solvate, hydrate or any other pharmaceutically acceptable compound, which at the time of administration to the recipient, has the ability to provide (directly or indirectly) the compound such as described here. However, it will be appreciated that non-pharmaceutically acceptable salts are also within the scope of the present invention, since these may be useful in the preparation of pharmaceutically acceptable salts. The preparation of salts and prodrugs and derivatives can be carried out by methods known in the art. ET-743 is supplied and stored in the form of a sterile lyophilized product, consisting of ET-743 and an excipient in a formulation suitable for therapeutic use.

The combinations of the present invention comprise ET-743 and an antineoplastic platinum compound, preferably a coordination complex. Preferred complexes include cisplatin, carboplatin, tetraplatin, ormiplatine, iproplatin, oxaliplatin, and the like.

Preferably, the platinum coordination complex is cisplatin or carboplatin, more preferably, cisplatin. The two drugs can be provided simultaneously or one after the other in any sequence, preferably in a sequence. As mentioned, the present invention provides a method of treatment for a patient with human cancer. Preferably the patients are patients with recidivism or resistance to previous chemotherapy. More preferably, patients have ovarian cancer, head and neck cancer, NSCL carcinoma or melanoma. In a particularly preferred embodiment, patients are patients with ovarian cancer and the previous therapy comprises treatment with platinum compounds. In addition, the present invention provides a method for treating cancer in humans, wherein the method comprises the step of intravenous infusion of a composition comprising ET-743 in a human having cancer, in a continuous dose in a period of up to 4 hours. followed or preceded by intravenous infusion of a composition comprising an antineoplastic compound of platinum in a human having cancer in a continuous dosage, wherein the infusion step is repeated weekly or on a cyclic basis. The infusion step is usually repeated on a cyclic basis. The cyclic basis comprises two phases, the weekly infusion phase and a non infusion phase, referred to as a rest phase. In the rest phase patients are allowed to recover. Normally the cycle is worked in weeks, and therefore the cycle comprises one or more weeks of an infusion phase, and one or more weeks of a rest phase. The rest period may be longer or shorter than the infusion phase. The preferred duration of each cycle is 2 to 4 weeks; can be administered, as necessary, multiple cycles. Most preferred are cycles of 3 or 4 weeks with 1 or 2 weeks of infusion. When ET-743 is administered in combination with cisplatin, the dosage amount of ET-743 is preferably less than 700 μg / m2 / day on day 1 and 8 in a program every 3 or 4 weeks, preferably approximately 400 up to about 650 μg / m2 / day, more preferably from about 500 to about 650 μg / m2 / day, even more preferably from about 550 to about 650 μg / m2 / day. In this case, the most preferred program is the administration of both compounds on days 1 and 8 every 4 weeks. On the other hand, when ET-743 is administered in combination with carboplatine, the dose of ET-743 is preferably less than 1200 μg / m2 / day on day 1 in a program every 3 weeks, preferably between 650 and 1200 μg / m2 / day, more preferably between 800 and 1000 μg / m2 / day, even more preferably between 800 and 900 μg / m2 / day. The amount of cisplatin dose is the total dose range that is used according to the type of program determined. Preferably it is from about 30 to 60 μg / m2 / day, or more preferably from about 40 to 50 μg / m / day, even more preferably about 40 μg / m2 / day. The carboplatin dose amount is the total dose range that is used according to the type of program determined. Preferably it is from about 200 to 400 μg / m2 / day, more preferably about 250 to 300 μg / m2 / day. In a particular modality, the infusion time of ET-743 is between 1 and 3 hours, preferably between 2 and 3 hours, especially preferred is a time of about 3 hours. The above programs and dosages allow effective combination therapy for cancer in humans, and at the same time avoid toxicities. We have discovered that ET-743 in combination with cisplatin or carboplatin is effective in the treatment of several types of cancer, including advanced or metastatic cancer. Preferably, the combination of ET-743 with a platinum compound is used according to the programs and doses above for the treatment of sarcoma, osteosarcoma, ovarian cancer, breast cancer, melanoma, head and neck cancer, colorectal cancer , mesothelioma, kidney cancer, endometrial cancer and lung cancer. Depending on the type of tumor and the stage of development of the disease, the treatments of the present invention are useful for: preventing the risk of tumor development, promoting the regression of tumors, stopping tumor growth and / or preventing metastasis. Although the guide for the dose was determined above, the correct dosage of the compound will vary according to the particular formulation, the mode of application and the site, host and tumor being treated in particular. Other factors that should be taken into account are age, body weight, sex, diet, time of administration, range of excretion, host conditions, drug combinations, reaction sensitivities and severity of the disease. The administration can be carried out continuously or periodically within the maximum tolerated dose. EXAMPLES Example 1 In order to evaluate the effects of the combination of ET-743 and cisplatin (DDP) in vivo, we selected some xenografts relatively resistant to a single dose of PDD and moderately sensitive to a single dose of ET-743. For the administration of the drugs, suitable vehicles were injected using the same program and injection route as the drug therapies. ET-743 and DDP were administered with one hour of separation in sequences or simultaneously. In sc transplanted xenografts, tumor growth was monitored and tumor weight (TW) was determined by measuring the diameters of the tumor with a Vernier caliper every 2 to 4 days and using the formula TW = d2 x D / 2 (where dy D represent the shortest and longest diameter, respectively.The only maximum iv dose of DDP and ET-743 that did not cause toxic death was, respectively, 12 mg / kg and 0.2 mg / kg. The same dose of each drug it can be administered when the two drugs are administered in combination with a tolerable toxicity, with a maximum weight loss ranging from 10 to 26% in different experiments (n = 14) with an average value of 15%.

Surprisingly, treatment with the combination resulted in only a slightly greater weight loss than with treatment with each drug alone. The toxicity did not seem different when the two drugs were administered simultaneously, or was provided one after the other with an interval of one hour in either of the two sequences. The antitumor activity of the combination was greater than that of each drug alone in all models. In rhabdomyosarcoma TE-671 and neuroblastoma SK-N-DZ, the three combinations were compared (for example ET-743 was administered one hour before DDP or at the same time or 1 hour after DDP) and no significant differences were observed in the antitumor activity. Also in H & N FADU, in NSCLC LX-1, in melanoma H-187 and in SKOV of ovary, where the two sequences were compared, no consistent differences were found related to the sequence. Collectively, all data indicate that the antitumor activity of the combination was greater than that of each drug alone, and the sequence did not influence the efficacy and toxicity of the treatment in a consistent manner. Example 2 The observation that the toxicity of the combination seemed very modest, stimulated us to test the effect of the combination of ET-743 and DDP, dividing the dose of both drugs in three administrations with an interval of 4 days.

The ovarian carcinoma xenografts 1A9 were relatively resistant to the two drugs used as monotherapy. In contrast to DDP at 4 mg / Kg. (Q4x3) for a total dose of 12 mg / Kg. administered simultaneously with ET-743 in a dose of (Q4x3) for a total dose of 0.3 mg / Kg. induced a significant TWI of 73%.

Again we observed non-toxic deaths or severe toxicity with the combination (average body weight loss 16%) compared to the drugs alone (14% and 12% with ET-743 and DDP, respectively). Therefore, combination therapy allows higher doses and even, in tumors in which the two drugs produced a non-significant activity administered alone, there was evidence of activity of the combination of each of the drugs. The combination is particularly successful in overcoming ovarian carcinoma xenograft resistance. Example 3 In patients with ovarian carcinoma the tumor was dispersed in the peritoneal cavity. Therefore, to mimic clinical disease, we selected a human ovarian xenograft, HOC 8, which was transplanted intraperitoneally from ascites and disseminated in the peritoneal cavity. This tumor is partially sensitive to DDP (ILS = 139%) and insensitive to ET-743 (ILS = 21% and 23% with 0.05% and 0.15 mg / Kg., Q4x3). When two drugs were combined, the effect was much greater than when each drug was administered as a single agent, obtaining a dramatic increase in survival. Both the low dose (ILS = 258% versus vehicle) and the high dose (ILS = 322% versus vehicle) of ET-743 combined with DDP, increased the survival time of the mice containing HOC8, which was significantly improved in comparison with DDP as monotherapy (ILS = 49% and 76% versus PDD with high and low doses of ET-743 respectively). Three animals remained alive for 12 months, two of them belonging to the group receiving the high ET-743 dose. They were sacrificed and a detailed macroscopic and microscopic pathological evaluation was carried out. The mouse that belonged to the group that received the low ET-743 dose was apparently cured, since microscopic analyzes of liver, spleen, pancreas, bone marrow, diaphragm, uterus omentum of ovary and several lymph nodes were negative. The other mice that survived in the long term showed a residual tumor at a level of omentum, and one of them, a single metastasis in the uterus, while in the other organs no metastasis was detected. This example shows the potential of the combination in ovarian cancer, even if there was metastasis. Example 4 A multicenter dose discovery assay was designed, in a program on day 1 and 8 of every three weeks, with increasing doses of ET administered as a 3-hour infusion with spheroid and antiemetic prophylaxis, followed by 30 minutes After a 1-hour infusion of cisplatin at a fixed dose of 40 mg / m2 with 2-L NS hydration, 36 patients were admitted (15 with ovarian cancer, 6 with uterine cancer, 14 with soft tissue sarcoma, 1 with another type of tumor). Before the treatments, patients were registered in the following way: The dose levels of ET-743 were 300, 400, 500, 600 and 700 μg / m2 / day; 3 to 6 patients were treated per dose level according to the toxicity.

The scale of ET-743 was uneventful up to 500 μg / m2; patients with doses of μg / m2 were grouped into two separate risk groups according to the degree of previous chemotherapy: low risk regimen 1 (LR); high risk regimens > 2 (HR). The table below illustrates the haematological toxicity found: * 7 days duration of neutropenia G4? DLT. • 1 patient with 500 and one patient with 600 failed to recover from neutropenia using > what d35? DLT. # 1 patient enrolled in 500 received 400 in cycle 1. The table below illustrates the non-haematological toxicity found: The table below illustrates other non-haematological toxicities found: Toxicities that limit the dose (DLTs): • 500: 1 of 7 treated patients failed to recover on day 35 • 600: 3 of 15 treated patients: • 1 failed to recover hematological toxicity on day 35 • 1 ALT grade 3, was not recovered for B / L • 1 failed to be treated again on day 8 with bilirubin grade 1, ALT grade 3. • 700: 2 of 7 patients treated ANC grade 4 took more than 7 days (one patient also had Gr 4 thrombocytopenia concomitant and failed in the recovery of hematological toxicity on day 35). The table below illustrates the effectiveness observed: (PR: partial response, PD: progressive disease, CR: complete response, NC: no change, AD: adjuvant, NE: not evaluable, TTP: progress time) From this study we conclude that: • In this population, BAT is 700 μg / m2 in patients previously treated on days 1 and 8 every 4 weeks.

• Recommended dose (RD) in previously treated patients is 500 μg / m2 day 1 and 8 every 4 weeks. • DLT is myelosuppression, particularly neutropenia. • In doses = 600 μg / m2 day 1 and 8 every 3 weeks, delayed recovery of neutropenia that was observed in most patients. • The main non-haematological toxicities are nausea and vomiting dependent on the dose (NyV), asthenia and liver toxicity (always reversible and moderate up to 600 μg / m2 / day). • The main non-hematological toxicities were NyV and asthenia dependent on the dose. • The optimal interval of the new treatment is day 28. Example 5 We designed a trial to find the multicenter dose, in a program on day 1 every 3 weeks, with carboplatin administered in a fixed dose of 300 mg / m2 in the form of an infusion of 1 hour followed by an increased dose of ET administered as a 3-hour infusion with prophylaxis of spheroids and antiemetics. 11 patients were admitted (6 with ovarian cancer, 1 with lung cancer, 4 with soft tissue sarcoma). The previous treatments of the patients were as indicated below: The ET-743 dose levels were 500. 650 and 800 μg / m2 / day; 3 to 6 patients were treated by dose level according to the toxicity. The maximum tolerated dose (MTD) was defined as the highest dose level tested of the combination in which at least two patients experienced DLT in cycle 1. If a patient was found to have dose-induced DLT during either the cycle 1 or 2, you can treat up to 6 patients at that level. If DLT was not observed in additional patients, new patients may be treated at the next higher dose level. The hematological toxicities of cycle 1 for platelets and absolute neutrophil count (ANC), are reported in the following table: Two patients developed DLT during the first course with grade 3 thrombopenia at dose level 3. Both patients had ovarian carcinoma previously treated with carboplatin. The table below shows hematological toxicities for platelets and ANC for the three courses administered, as well as the number of cycles without hematologic recovery on day 21 and 28.

* All after dose reduction; (1) 8 after dose reduction; (2) 1 after dose reduction.

* All after dose reduction; (1) 8 after dose reduction; (2) 1 after dose reduction.

And the number of patients with delayed (and reduced) doses in cycle 2, the reason for this delay being reported in the following table, for each dose level: As can be inferred from the data of cycle 1 of 11 patients treated: In this population the MTD is 800 μg / m2 of ET-743 with carboplatin in a fixed target (300 mg / m2) - DLTs consists of thrombocytopenia grade 3. - In this population in the second dose level, 100% of patients had a dose delay with dose reduction in the second cycle, due to haematological toxicity.

- In the third dose level, 50% of the patients had a dose delay with dose reduction in the second cycle, due to haematological toxicity. Due to this long-term safety profile, moderate neutropenia is considered to be avoided by achieving an adequate dose intensity of ET-743, and the two DLTs consisting of grade 3 thrombocytopenia in two patients with ovarian carcinoma previously treated. With carboplatin, the following program can be inferred: In patients previously treated with carboplatin: The administration of carboplatin in the fixed target (250 mg / m2) during a 1-hour infusion followed by ET-743 by iv infusion for 3 hours in the day 1 every 3 weeks. In patients not previously treated with carboplatin: The administration of carboplatin in a fixed target (300 mg / m2) through a 1-hour infusion followed by ET-743 by iv infusion for 3 hours on day 1 every 3 weeks.

Claims (18)

1. R E I V I N D I C A C I O N S 1. A method for mitigating resistance to the antineoplastic agent of the platinum coordination complex in a human cancer patient, characterized in that the method comprises administering to the patient an antineoplastic agent of the platinum coordination complex and ET-743.
2. 2. A method for enhancing the cytotoxic effects of an antineoplastic agent of the platinum coordination complex in a human cancer patient, characterized in that the method comprises administering to the patient an antineoplastic agent of the platinum coordination complex and ET-743.
3. 3. A method according to claim 1 or 2, characterized in that ET-743 is administered as a combination therapy with the antineoplastic agent of platinum without a drop in compensation in the dose of platinum antineoplastic agent.
4. 4. A method according to claim 1 or 2, characterized in that it comprises administering to an individual the antineoplastic agent of platinum and ET-743 in amounts of doses that are in the same range as the dose that would be administered, if each of ET-743 and the platinum compound will be administered alone.
5. 5. A method according to claim 4, characterized in that the amounts of the antineoplastic agent of platinum and ET-743 are both at least 90% of the respective recommended dose.
6. 6. A method according to any of the preceding claims, characterized in that the platinum antineoplastic agent is selected from cisplatin, carboplatin, tetraplatin, ormiplatine, iproplatin, oxaliplatin.
7. 7. A method according to claim 6, characterized in that the antineoplastic agent of platinum is cisplatin or carboplatin.
8. 8. A method according to claim 7, characterized in that the platinum antineoplastic agent is cisplatin.
9. 9. A method according to any of the preceding claims, characterized in that the antineoplastic agent of platinum and ET-743 are administered in sequences.
10. A method according to claim 9, characterized in that it comprises the step of infusing intravenously a composition comprising ET-743 in the patient in a continuous dose for a period of up to 4 hours, followed or preceded by intravenous infusion of a composition comprising an antineoplastic agent of platinum in the patient in a continuous dose, and weekly repeating the infusion steps on a cyclic basis.
11. 11. A method according to claim 10, characterized in that the cyclic base comprises two phases, a weekly infusion phase, referred to as an infusion phase, and a non-infusion phase, referred to as a rest phase wherein the cycle comprises one or more weeks of an infusion phase, and one or more weeks of a rest phase.
12. 12. A method according to any of the preceding claims, characterized in that the patient is relapsing or resisting prior chemotherapy.
13. 13. A method according to any of the preceding claims, characterized in that the patient has a cancer selected from sarcoma, osteosarcoma, ovarian cancer, breast cancer, NSCL carcinoma, melanoma, head and neck cancer, colorectal cancer, mesothelioma, kidney cancer, endometrial cancer and lung cancer.
14. A method according to any of the preceding claims, characterized in that the patient has a cancer selected from ovarian cancer, NSCL carcinoma, melanoma, head and neck cancer.
15. 15. A pharmaceutical composition for weekly administration, containing a recommended dose of an antineoplastic agent of the platinum coordination complex and a recommended dose of ET-743.
16. 16. The use of an antineoplastic agent of the platinum coordination complex in the preparation of a medicament for a method according to any of claims 1 to 14.
17. 17. The use of ET-743 in the preparation of a medicament for a method according to any one of claims 1 to 14.
18. 18. A medical team to administer an antineoplastic agent of platinum in combination with ET-743, wherein the medical team comprises the supply of ET-743 in dosage units for at least one cycle, wherein each dosage unit contains the appropriate amount of ET-743 and a pharmaceutically acceptable carrier, and printed instructions for administering ET- 743 according to the dosing schedule. R E S U M E N ET-743 can be used to mitigate resistance to, and potentiate the cytotoxic effects of an antineoplastic agent of the platinum coordination complex in a human cancer patient.