MXPA06005359A - Combination therapy comprising the use of et-743 and paclitaxel for treating cancer - Google Patents

Abstract

Methods of treating a human body for cancer are provided. In one aspect, an effective therapeutic amount of paclitaxel is administered in combination with ET-743 in a dose range between 0.5 and 1 mg/m2. In a related aspect, an effective therapeutic amount of ET-743 is administered in combination with paclitaxel in a dose range between 80 and 140 mg/m2.

Description

COMBINATION THERAPY COMPRISING THE USE OF ET-743 AND PACLITAXEL TO TREAT CANCER The invention relates to a combination therapy, more particularly a combination therapy for cancer.

FIELD OF THE INVENTION The present invention is directed to the use of ecteinascidin 743 and products that contain this compound for cancer therapy. In particular, the present invention is directed to the use of ecteinascidin 743 in combination with paclitaxel for the treatment of cancer.

BACKGROUND OF THE INVENTION Cancer comprises a group of malignant neoplasms that can be divided into two categories, carcinoma, comprising a majority of the cases observed in the clinics, and other less frequent cancers, including leukemia, lymphoma, tumors of the central nervous system and sarcoma. The carcinomas have their origin in epithelial tissues e the sarcomas developed from the connective tissues and those structures that had their origin in mesodermal tissues. Sarcomas can affect, for example, the muscle or bone and occur in the bones, gallbladder, kidneys, liver, lung, parotid, spleen, etc. Cancer is invasive and tends to metastasize to new sites It spreads directly into surrounding tissues and can also spread through the circulatory and lymphatic systems. Several treatments are available for cancer, including surgery and radiation for localized disease, and drugs. However, the effectiveness of the treatments available in various types of cancer is limited, and new, improved forms of treatment that show clinical benefit are necessary. This is especially true for those patients who present with metastatic and / or advanced disease. It is also true for patients who relapse with the progressive disease after having previously been treated with established therapies for h the greatest treatment with the same therapy is largely ineffective due to the acquisition of resistance or limitations in the administration of the therapies due to the associated toxicities. Chemotherapy plays an important part in the treatment of cancer, as it is required for the treatment of advanced cancers with distant metastases and frequently useful for tumor reduction before surgery, and several anti-cancer drugs have been developed on the basis of to different modes of action. The most commonly used types of anti-cancer agents include: DNA alkylating agents (e.g., cyclophosphamide, ifosfamide), antimetabolites (e.g., metrotrexate, a folate antagonist, and 5-fluorouracil, a pyrimidine antagonist), microtubule disruptors (by example, vincristine, vinblastine, paclitaxel), DNA intercalators (eg, doxorubicin, daunomycin, cisplatin), and hormone therapy (eg, tamoxifen, flutamide). The ideal antineoplastic drug could kill cancer cells selectively, with a broad therapeutic index relative to its toxicity towards non-malignant cells. It could also retain its effectiveness against malignant cells, even after prolonged exposure to the drug. Unfortunately, none of the current chemotherapies has an ideal configuration. Most have very narrow therapeutic indices and, in almost every case, cancer cells exposed to slightly sublethal concentrations of a chemotherapeutic agent will develop resistance to that agent, and very often cross-resistance to various other antineoplastic agents. The ecteinascidinas (hereinafter abbreviated ETs) are powerful antitumor agents in excess isolated from the marine tunicate Ecte 'inascidia turbinata. Several ecteinascidins have been previously reported in the patent and specific literature. See, for example, Pat. from the USA No. 5,089,273, h describes new compounds extracted from the tropical marine invertebrate, Ecteinascidia turbinata, and designated herein as ecteinascidins 729, 743, 745, 759A, 759B and 770. These compounds are useful as antibacterial and / or antitumor agents in the mammals. Pat. from the USA No. 5,478,932 describes ecteinascidins isolated from the Caribbean tunicate Ecteinascidia turbinata, which provide in vivo protection against P388 lymphoma, B16 melanoma, M5076 ovarian sarcoma, Lewis lung carcinoma, and human lung LX-1 and human mammalian carcinoma xenografts MX-1. One of the ETs, ecteinascidin-743 (ET-743), is a new tetrahydroisoquinoline alkaloid with antitumor activity! considerable in tumors, murine and human, in vitro and in vivo, and is currently in clinical trials. ET-743 possesses potent antineoplastic activity against a variety of human tumor xenografts grown in athymic mice, including melanoma and breast and ovarian carcinoma. A clinical development program of ET-743 in cancer patients began with phase I studies investigating 1-hour, 3-hour, 24-hour and 72-hour intravenous infusion schedules and a 1-hour daily schedule x 5 (dx5). Promising responses were observed in patients with sarcoma and ovarian and breast carcinoma. Therefore, this new drug is currently under intense investigation in several phase I clinical trials in cancer patients with a variety of neoplastic diseases. Further detail in the use of ET-743 for the treatment of the human body for cancer is given in WO 0069441, incorporated herein by reference in its entirety. On pages 8 and 9, this patent specification indicates that ET-743 can be used in combination therapy with another drug.

A list of candidates for the other drug is given, and it mentions paclitaxel. A current review of ET-743, its chemistry, mechanism of action and preclinical and clinical development can be found in van Kesteren, Ch. Et al. , 2003, Anti-Cancer Drugs, 14 (7), pages 487-502: "Yondelis (trabectedin, ET-743): the development or fan anticancer agent of marine origin", and references in the present. Combination therapy that uses drugs with different mechanisms of action is an accepted method of treatment that helps prevent the development of resistance by the treated tumor. The in vitro activity of ET-743 in combination with other anti-cancer agents has been studied, see for example, WO 02 36135, incorporated herein by reference in its entirety. In particular, WO 0236135 mentions the combination of ET-743 with paclitaxel. A synergistic effect is indicated in tests on animal models. Takahashi et al. in Clinical Cancer Research, 7: 3251 -3257, 2001, reported in Sequence-dependent Enhancement of Cytotoxicity Produced by Ecteinascidin 743 (ET-743) with Doxorubicin or Paclitaxel in Soft Tissue Sarcoma Cells. They used two strains of soft tissue sarcoma cell, and report that ET-743 and paclitaxel result in strong cytotoxic synergism when paclitaxel is administered before ET-743, but less than aive toxicity when ET-743 is added concomitantly or before paclitaxel .

In Cancer Research 62: 6909-6915, 2002, Takahashi et al. , describe the work in Sequence-dependent Enhancement of Cytotoxicity Produced by Ecteinascidin 743 (ET-743) and Paclitaxel in Human Breast Canee Cell Lines in vitro and in vivo. They found that pretreatment with paclitaxel before ET-743 was the most effective combination in three breast cancer cell lines, and that sequential treatment with paclitaxel followed by ET-743 enhances the antitumor effects in nude mice carrying carcinoma xenografts , without increasing toxicity. An object of the invention is to provide an effective cancer combination treatment based on ET-743 with doxorubicin.

BRIEF DESCRIPTION OF THE INVENTION According to the present invention, we provide a combination therapy for the treatment of cancer using ecteinascidin 743 and paclitaxel, using a cyclic dosing protocol. Typical dosing protocols for combination therapy are provided. From phase I clinical trials, we have determined that a combination of ET-743 and doxorubicin is tolerable and viable, with evidence of antitumor activity. We also provide a method to treat a patient with cancer, which comprises administering ET-743 and doxorubicin. ET-743 and paclitaxel are preferably administered on the same day as a predetermined cycle. We also provide the use of ET-743 in the preparation of a medication to carry out the treatment method. We also provide the use of paclitaxel, in the preparation of a medication to carry out the treatment method. We provide the use of ET-743 and paclitaxel, in the preparation of a medication to carry out the treatment method.

DETAILED DESCRIPTION ET-743 is a natural compound represented by the following formula: As used herein, the term "ET-743" extends to natural and synthetic ET-743 and also covers any pharmaceutically acceptable salt, ester, solvate, hydrate, or prodrug compound which, upon administration to the container, is capable of providing (directly or indirectly) the compound ET-743. The preparation of salts and other derivatives, and prodrugs, can be carried out by methods known in the art. ET-743 is typically supplied and stored as a sterile lyophilized product, with ET-743 and excipient in a formulation suitable for therapeutic use, in particular a formulation containing mannitol and a phosphate salt regulated at a suitable pH. The dose will be selected according to the dosing schedule, taking into account the existing data in the Dosage Limiting Toxicity, in which see for example, the incorporated WO patent specifications, and also see van Kesteren, Ch. Et al. , 2003, Anti-Cancer Drugs, 14 (7), pages 487-502; "Yondelis (trabectedin, ET-743): The development of an anticancer agent of marine origin". This article is incorporated herein in its entirety and for specific reference. For a single administration of ET-743 at the start of each cycle or twice per cycle, we prefer a dose in the range 0.2 to 2 mg / m2, more preferably 0.4 to 1.4 mg / m2, more preferably 0.5 to 1 mg / m2. In one embodiment, the dose of ET-743 is approximately 0.58-0.9 mg / m2. In this stage, we currently prefer a dose of approximately 0.65 mg / m2, approximately 0.775 mg / m2 or approximately 0.9 mg / m2. The lower amounts are adequate where there is a repeated dosage on a weekly or daily schedule. As noted in the article incorporated by van Kesteren, the combination of ET-743 with dexamethasone gives unexpected benefits. It has a role in liver prophylaxis. Therefore, we prefer to administer dexamethasone to the patient, typically at approximately the infusion time of ET-743. For example, we prefer to give dexamethasone before ET-743 on the same day. The administration of dexamethasone can be extended, for example, to one or more days preceding or following ET-743. Paclitaxel is used for the treatment of. various cancers, including for example, breast cancer, metastatic ovarian cancer, neck and head cancer, non-small lung cancer, small cell lung cancer, and gallbladder cancer. The dosing amount of doxorubicin is preferably in the range of 50 to 200 mg / m2 / day, more preferably 60 to 150 mg / m / day. At this stage, we currently prefer a dose of approximately 80 mg / m2 / day, approximately 120 mg / m2 / day or approximately 140 mg / m2. In the present invention, ET-743 and paclitaxel are administered in combination as part of an antitumor therapy. It is preferred to administer the combination by infusion. ET-743 and paclitaxel can be provided as separate medicaments for administration at the same time or at different times. Preferably, ET-743 and paclitaxel are provided as separate medicaments for administration at different times. When administered separately and at different times, it is preferable to administer paclitaxel followed by ET-743. The infusion step is typically repeated on a cyclic basis, which may be repeated as suitable for eg 1 to 35 cycles. The cycle includes an infusion phase of the combination, and usually also a non-infusion phase of the combination.

Typically, the cycle is worked in weeks, and in this way the cycle usually comprises one or more weeks of drug infusion phase, and one or more weeks to complete the cycle. Usually, a cycle can be from 1 to 6 weeks. In one embodiment, a 2-week cycle is preferred. The infusion phase can by itself be a single administration in each cycle ie 1 72 hours, more usually about 1, 3 or 24 hours. When paclitaxel and ET-743 are provided as separate medications for administration at different times, the infusion times for each may differ. Infusion times for paclitaxel are generally up to 6 hours, more preferably 1 -3 hours, with 1 hour more preferred. Infusion times for ET-743 are generally up to 24 hours, more preferably about 1, about 3 or about 24 hours. The short infusion times that allow the treatment to be carried out without a stay during I last night in the hospital are especially desirable. Thus, for example, a single administration of paclitaxel on day 1 followed by a single administration of ET-743 on day 2 of a week 2 cycle is preferred. Other administration protocols can be designed having consideration to this modality. Premedication and support medication can occur. Mention is already made of dexamethasone with ET-743, but additional options include dexamethasone premedicated by paclitaxel, diphydramine premedicated by paclitaxel, ranitidine premedicated by paclitaxel, premedicated 5-HTs antagonist or supportive medication for ET-743. Depending on the type of tumor and the stage of development of the disease, the treatments of the invention are useful in the prevention of the risk of developing tumors, in the promotion of tumor regression, in the arrest of tumor growth and / or in the prevention of metastasis. In particular, the method of the invention is suitable for human patients, especially those who relapse or are refractory to prior chemotherapy. First-line therapy is also contemplated. Preferably, the combination therapy is used according to the schedules and dosages above for the treatment of sarcoma, osteosarcoma, ovarian cancer, breast cancer, melanoma, colorectal cancer, mesothelioma, kidney cancer, endometrial cancer and lung cancer. More preferably, patients are sarcoma patients, especially those with a soft tissue sarcoma and breast cancer. Ovarian cancer and breast cancer are preferably suitable for combination therapy. In a further aspect of the present invention, medical equipment for administering ET-743 in combination with paclitaxel is provided, comprising printed instructions for administering ET-743 according to the dosing schedules set forth above, and a supply of ET-743 in the dosing units by 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 vehicle. Although the guide for the dosage is given above, the correct dosage of the compounds will vary according to the particular formulation, the mode of application, and the particular site, host and tumor to be treated. Other factors such as age, body weight, sex, diet, time of administration, rate of excretion, condition of the host, drug combinations, reaction sensitivities and severity of the disease should be taken into account. The administration can be carried out continuously or periodically within the maximum tolerated dose.

EXAMPLE: Phase I Clinical Trial A phase I trial combining paclitaxel and trabectedin was performed. The objective of this study was to determine the maximum tolerated dose, safety configuration and tolerability of the paclitaxel sequence administration as a 1 hour infusion followed by ET-743 as a 3-hour infusion, 24 hours later, every 2 weeks in patients with advanced solid tumors. All the patients registered in the study met the following criteria: Histological diagnosis of advanced solid tumor, They had at least 4 weeks since the chemotherapy (6 weeks from nitrosureas and mitomycin C), immunotherapy, hormone therapy or any anti-tumor therapy or Research agents and wide field radiation including > 25% bone marrow reserve, Age of at least 18, ANC > 1500 / mm3, PLT > 100.00 / mm3 and Hgb > 8.5 g / dL, Adequate renal function: calculated creatinine clearance > 50 ml / min, Suitable liver function: albumin > 2.5 g / dL, total bilirubin < L OxULN, AST & ALT < 3xULN, total ALKP < 1 .5xULN, State of Performance (PS) of Northeast Cooperative Oncology Group (ECOG) 0-2 record, Life expectancy > 3 months, CNS metastases asymptomatic or treated, - Absence of any of the concurrent serious medical illnesses, which may increase the patient's risk during therapy, Absence of previous ET-743 exposure or documented allergy to ET-743, - They had < 1 peripheral neuropathy 1 . Administration of Paclitaxel: Premedication: Dexamethasone 20 mg i.v. , diphenhydramine 50 mg i.v. and ranitidine 50 mg i.v. 30-60 minutes before the administration of paclitaxel, - Paclitaxel was administered as a 1 hour infusion on day 1 of each cycle, except in cycle 1 in which it was administered on day 7 (7 days before cycle 1 day 1). 2. Administration of ET-743: Premedication: Dexamethasone 10 mg i.v. and 5-HT3 antagonist i.v. 30-60 minutes before the administration of ET-743, ET-743 was administered as a 3-hour infusion on day 2 of each cycle through a central venous catheter, Supporting drug: 5-HT3 antagonist was given beginning 24 hours after ET-743 for 3 days. The dose limiting toxicity (DLT) was defined during the first 2 treatment cycles as: ANC <; 500 / μL for more than 5 days, ANC < 1000 / μL with fever (> 38.5 ° C) - PLT < 25,000 / μL, Grade 3 by > 7 days of transaminitis grade 4 leading to delayed union, Any grade 3 or 4 non-haematological toxicity except nausea or vomiting inadequately treated. - Delay in the beginning of the subsequent cycle by > 1 week due to toxicity, Any grade 4 transaminitis. A total of 1 8 patients were recorded in the first 5 dose levels. Patient characteristics are tabulated as shown: Average age (range) 39 (18-67) Male: Female 1 1: 7 Heavily slightly Pre-treated 13: 5 Average number of previous chemotherapy, Regimens (range) 3 (1 -5) No. of patients with adjuvant chemotherapy 8 No. of patients with non-adjuvant chemotherapy 4 Ifosfamide / Previous doxorubicin 1 3 No. of patients with anterior autologous BMT 2 No. of patients with previous radiation 6 Tumor Type Soft Tissue Sarcoma 17 Melanoma 1 Average No. of Cycles of ET-743 / Paclitaxel (Range) 4 (1 -28) Table 1 shows the number of patients exposed in each dose of Paclitaxel / ET-743 and the dose-limiting toxicities observed. Table 1 Table 2 shows the drug-related toxicities frequently reported. In order to define the degree of toxicity, the common NCI criterion is used.

Table 2 Table 2 (cont.) Regarding the antitumor activity of the combination, positive responses (PR) were observed in a patient with doxorubicin / liposarcoma resistant to ifosfamide after Cycle 8 until Cycle 16 and in a patient with primitive neuroectodermal tumor (pNET) after Cycle 4. In addition, Prolonged Stabilization Disease (SD> 24 weeks) was observed in a patient with primitive neuroectodermal tumor (pNET) (28 cycles), in a patient with melanoma (26 cycles) and in a patient with liposarcoma (20 cycles). In conclusion, except one leiomyosarcoma pre-treated heavily in cohort 5 experienced DLT with delay of Cycle 3 due to ANC < 1.5 for more than 1 week, this sequential combination of paclitaxel and ET-743 every 2 weeks is tolerated very well. Some antitumor activity is observed in a doxorubicin / liposarcoma resistant to ifosfamide and in a pNET and prolonged stable disease is also observed in a pNET, in a melanoma and in a liposarcoma.

Claims (16)

1. CLAIMS 1. A method for treating a human body for cancer comprising administering an effective therapeutic amount of paclitaxel, in combination with ET-743 in a dose range between 0.5 and 1 mg / m2 for ET-743.
2. 2. A method for treating a human body for cancer comprising administering a therapeutically effective amount of ET-743, in combination with paclitaxel in a dose range between 80 and 140 mg / m2 for paclitaxel.
3. The method according to claim 1 or 2, wherein paclitaxel and ET-743 are provided as separate medicaments for administration at different times.
4. 4. The method according to claim 3, wherein paclitaxel is administered prior to administration of ET-743.
5. The method according to claim 4, wherein paclitaxel and ET-743 are administered by intravenous injection.
6. The method according to claim 5, wherein the infusion time for intravenous injection is up to 3 hours for paclitaxel and up to 24 hours for ET-743.
7. The method according to claim 6, wherein the infusion time for intravenous injection is about 1 hour for paclitaxel and about 3 hours for ET-743.
8. The method according to claim 7, wherein the infusions are carried out in a range of 1 to 6 weeks.
9. 9. The method according to claim 8, wherein the infusions are carried out in a 2 week interval.
10. The method according to claim 9, wherein paclitaxel is administered in a dose of up to 120 mg / m2, followed by ET-743 which is administered in a dose of up to 0.775 mg / m2. eleven .
11. The method according to claim 10, wherein paclitaxel is administered in a dose of approximately 120 mg / m2, followed by ET-743 which is administered in a dose of approximately 0.650 mg / m2.
12. A method according to any preceding claim, wherein the patient has a cancer selected from sarcoma, osteosarcoma, ovarian cancer, breast cancer, melanoma, colorectal cancer, mesothelioma, renal cancer, endometrial cancer and lung cancer. 3.
13. A method according to claim 12, in which the patient has a cancer selected from sarcoma, ovarian cancer, endometrial cancer and breast cancer.
14. 14. The use of paclitaxel in the preparation of a medicament for a method according to any of claims 1 to 13.
15. 15. The use of ET-743 in the preparation of a medicament for a method according to any of claims 1 to 1.
16. 16. A medical team to administer ET-743 in combination with doxorubicin, comprising a supply of ET- 743 in units of doses for at least one cycle, wherein each dose unit contains the appropriate amount of ET-743 for the treatments and a pharmaceutically acceptable vehicle, and printed instructions for administering ET-743 according to a dosing schedule.