ES2363064T3 - TREATMENT OF HUMAN BODY CANCER USING ET743. - Google Patents

Abstract

ET743 for use in the treatment of cancer in the human body, which comprises administering ET743 by intravenous infusion at a dose of 1500 micrograms per m of body surface area, for 24 hours, where the cancer is a sarcoma, leading to clinical improvement

Description

Treatment of human body cancers using ET743.

The present invention relates to the claim 1.

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Background of the invention

The cancer comprises a group of neoplasms malignant that can be divided into two categories, carcinoma, which It comprises most of the cases observed in the clinic, and others less frequent cancers, including leukemia, lymphoma, tumors of the central nervous system and sarcoma. Carcinomas have their origin in epithelial tissues while sarcomas are develop in connective tissues and their structures have their origin in mesodermal tissues. Sarcomas can affect, for example, the muscle or bone and occur in the bones, bladder, kidneys, liver, lung, parotid or spleen.

Cancer is invasive and tends to metastasize in New sites It extends directly to surrounding tissues and it can also be disseminated through the lymphatic systems and circulatory. Many cancer treatments are affordable, including surgery and radiation for localized disease, as well as drugs. However, the effectiveness of treatments Available in many types of cancers is limited, and are required new improved forms of treatments that show a benefit clinical. This is especially true for those patients who have an advanced and / or metastatic disease. It's also true for patients who relapse with progressive disease after having previously been treated with established therapies for that an additional treatment with the same therapy is mostly ineffective part due to the appearance of resistance or limitations in the administration of therapies due to associated toxicities

Chemotherapy plays a significant part in the treatment of cancer, as required for the treatment of advanced cancers with distant metastases and a It often helps to reduce tumors before surgery, and they have developed many anti-cancer drugs based on Different modes of action.

Ecteinascidines are marine alkaloids and some of them have potent antitumor activity in vitro . Several ecteinascidines have been described previously in the scientific and patent literature.

For example, US Pat. UU. No. 5,089,273 describes new compositions of matter extracted from the tropical marine invertebrate, Ecteinascidia turbinata , and have been designated as ecteinascidins 729, 743, 745, 759A, 759B and 770. These compounds are useful as antibacterial and / or antitumor agents. in mammals

U.S. Patent UU. No. 5,256,663 describes pharmaceutical compositions comprising matter extracted from the tropical marine invertebrate, Ecteinascidia turbinata , and which are referred to herein as ecteinascidines, and the use of said compositions as antibacterial, anti-viral, and / or antitumor agents in mammals.

U.S. Patent UU. No. 5,478,932 describes ecteinascidines isolated from the Caribbean tunicate Ecteinascidia turbinata , which provide in vivo protection against P388 lymphoma, B16 melanoma, M5076 ovarian sarcoma, Lewis lung carcinoma, and LX- human lung carcinoma xenografts. 1 and human breast MX-1.

U.S. Patent UU. No. 5,654,426 describes different ecteinascidines isolated from the Caribbean tunicate Ecteinascidia turbinata , which provide in vivo protection against P388 lymphoma, B16 melanoma, M5076 ovarian sarcoma, Lewis lung carcinoma, and LX human lung carcinoma xenografts -1 and human breast MX-1.

U.S. Patent UU. No. 5,721,352 describes a synthetic procedure for the formation of compounds of ecteinascidin and related structures.

Additional background that is illustrative can be found in: EJ Corey, J. Am. Chem. Soc., 1996, 118, p. 9202-9203; Rinehart et al., Journal of National Products, 1990, "Bioactive Compounds from Aquatic and Terrestrial Sources", vol. 53, p. 771-792; Rinehart et al., Puré and Appl. Chem., 1990, "Biologically active natural producís", vol. 62, p. 1277-1280; Rinehart et al., J. Org. Chem., 1990, "Ecteinascidins 729, 743, 745, 759A, 759B, and 770; Potent Antitumor Agents from the Caribbean tunicate Ecteinascidia turbinata ", vol. 55, 4512-4515; Wright et al., J. Org. Chem., 1990, "Antitumour Tetrahydroisoquinoline Alkaloids from the Colonial Ascidian Ecteinascidia turbinata ", vol. 55, pp. 4508-4512; Sakai et al., Proc. Natl Acad. Sci. USA 1992, "Additional antitumor ecteinascidins from a Caribbean tunicate: Crystal structures and activities in vivo ", vol. 89, 11456-11460; Science 1994, "Chemical Prospectors Scour the Seas fro Promising Drugs", vol. 266, p. 1324; KE Koenig, "Asymmetric Synthesis", ed. Morrison, Academic Press, Inc., Orlando, FL, vol. 5, 1985, p. 71; Bailón et al., J. Chem. Soc. Perkin Trans., 1, 1982, "Synthesis and Properties of a Series of Sterically Hindered Guanidine Bases", p. 2085; Fukuyama et al., J. Am. Chem. Soc., 1982, "Stereocontrolled Total Synthesis of (+) - Saframycin B", vol. 104, p. 4957; Fukuyama et al., J. Am. Chem. Soc., 1990, "Total Synthesis of (+) - Saframycin A", vol. 112, p. 3712; Saito et al., J. org. Chem., 1989, "Synthesis of Saframycins. Preparation of a Key Tricyclic Lactam Intermediate to Saframycin A", vol. 54, 5391; Still et al., J. Org. Chem., 1978, "Rapid Chromatographic Technique for Preparative Separations with Moderate Resolution", vol. 43, p. 2923; WG Kofron, LM Baclawski, J. Org. Chem., 1976, vol. 41, 1879; Guan et al., J. Biomolec. Struc & Dynam., Vol. 10, pp 793-817 (1993); Shamma et al., "Carbon-13 NMR Shift Assignments of Amines and Alkalolds", p. 206 (1979); Lown et al., Biochemistry, 21, 419-428 (1982); Zmijewski et al., Chem. Biol. Interactions, 52, 361-375 (1985); Ito, CRC CRIT. Anal Rev. Chem., 17, 65-143 (1986); Rinehart et al., "Topics in Pharmaceutical Sciences 1989" p. 613-626, DD Breimer, DJA Cromwelin, KK Midha, Eds., Amsterdam medical Press BV, Noordwijk, The Netherlands 81989); Rinehart et al., "Biological mass Spectrometry", 223-258 eds. Burlingame et al., Elsevier Amsterdam (1990); Guan et al., Jour. Biomolec Struct. & Dynam., Vol. 10 pages 793-817 (1993); Nakagawa et al., J. Amer. Chem. Soc., 111: 2721-2722 (1989); Llchter et al., "Food and Drugs from the Sea Proceedings" (1972), Marine Technology Society, Washington, DC 1973, 117-127; Sakai et al., J. Amer. Chem. Soc., 1996, 118, 9017; García-Roccha et al., Brit. J. Cancer, 1996, 73: 875-883; and Pommier et al., Biochemistry, 1996, 35: 13303-13309.

In particular, it has been found that the ecteinascidin 743 also shows a promising action when it tested in animal models, such as when evaluated against breast cancer xenografts, non-cell lung Small, melanoma and ovarian cancer.

An article on the in vitro antitumor activity of the new marine agent, Ecteinascidin-743 (ET-743, NSC-648766) against explanted human tumors of patients, Annals of Oncology, 9: 981-987, 1988, is typical of In vivo descriptions. The authors conclude from their data that continuous or prolonged exposure may intensify activity. In the same issue of that publication, on pages 989-993, an article on the in vitro temporary dependence of myelotoxicity and the cytotoxicity of Ecteinascidin 743 (ET-743) concludes that prolonged exposure may represent the best administration regimen .

Lansiaux (Bull. Du Cancer, 86, (2), 1999, pages 139-141) refers to ET-743 and its mechanism of action. The results of the Phase 1 clinical trial. Taamma et al. (Proc. Am. Cnc. Res., 39, 1998, page 323) discloses the study on dose increase of ET-743. Rosing et al. (Proc. Am. Ass. Cnc. Res., 40, 1999, page 81) also shows phase 1 studies with data related to pharmacokinetic experiments.

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Summary of the Invention

The invention relates to ET-743 for use in the treatment of cancers of the human body, comprising the administration of ET-743 by Intravenous infusion at a dose of 1500 micrograms per m2 of body surface area, for a period of 24 hours, in the That cancer is sarcoma, which leads to clinical improvement.

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Embodiments of the Invention

Thus, the present invention provides the claim 1.

Administration in accordance with this invention is by intravenous infusion over a period of 24 hours. The infusion can be performed at appropriate intervals between 1 and 6 weeks. Later in this report they are provided additional guidelines

The ET743 compound and the compositions of the The present invention can be used with other drugs for Provide a combination therapy. The other drugs can be part of the same composition, or they can be provided as a separate composition for administration at the same time or at different times. The identity of other drugs is not Particularly limited, and suitable candidates include:

a) drugs with antifungal effects, especially those that are aimed at elements cytoskeletals, including microtubule modulators such as taxanes (such as taxol, paclitaxel, taxotere, docetaxel), podophyllotoxins or alkaloids of vinca (vincristine, vinblastine);

b) antimetabolite drugs (such as 5-fluorouracil, cytarabine, gemcitabine, analogues purine such as pentostatin, methotrexate);

c) alkylating agents or nitrogen mustards (such as nitrosoureas, cyclophosphamide or ifosfamide);

d) DNA-directed drugs such as anthracycline drugs adriamycin, doxorubicin, farmorubicin or epicubicin;

e) drugs directed to topoisomerases such as the etoposide:

f) hormones and agonists or antagonists of hormones such as estrogens, antiestrogens (tamoxifen and related compounds) and androgens, flutamide, leuprorelin, goserelin, cyprotron or octreotide;

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g) drugs targeting the transduction signal in tumor cells including antibody derivatives such as herceptin;

h) alkylating agents such as drugs of platinum (cis-platinum, carboplatin, oxaliplatin, paraplatin) or nitrosoureas;

i) drugs that potentially affect the metastasis of tumors such as metalloproteinase inhibitors of the matrix;

j) gene therapy and antisense agents;

k) antibody therapeutic agents;

l) other bioactive compounds of marine origin, mainly didemnins such as aplidine;

m) spheroid analogues, in particular dexamethasone;

n) anti-inflammatory drugs, including non-steroidal agents (such as acetaminophen or ibuprofen) or steroids and their derivatives in particular the dexamethasone; Y

o) antiemetic drugs, including inhibitors of 5HT-3 (such as the granisetron or the ondansetron), and steroids and their derivatives in particular the dexamethasone.

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The present invention also extends to compounds described herein for use in a method of treatment, and the use of the compounds in the preparation of a composition for the treatment of sarcoma.

Patient responses have been observed in clinical trials with ET-743, demonstrating the Usefulness of the treatment method.

Phase I clinical studies and analyzes Pharmacokinetics demonstrate that ET-743 presents a positive therapeutic window with a manageable toxicity in the dose range required for clinical efficacy in the Treatment of cancer patients.

The use consists of drug administration by intravenous infusion over a period of 24 h at the level of Recommended dose (RD) with or without combination with other agents therapeutic

The ET-743 is supplied and stores as a sterile lyophilized product, which consists of ET-743 and excipient in a formulation suitable for therapeutic use, in particular a formulation containing mannitol and a phosphate salt buffered at a suitable pH.

A preferred formulation, which shows a improved stability at a higher storage temperature, is the obtained from 1000 ml of 0.9% sodium chloride or other vehicle of suitable infusion, 250 µg of ET-743 with 250 mg of mannitol, 34 mg of monopotassium phosphate and phosphoric acid for adjust to a pH between 4.00 and 6.00, the pH being 4.80 the preferred one. The product is lyophilized and stored in refrigerator, between + 4ºC and -20ºC and protected from light until its use.

The preparation of the reconstituted solution is carried out under aseptic conditions by adding water distilled in the amount of 5 ml for every 250 µg of ET-743 and stirring for a short time to Dissolve the solids.

The preparation of the infusion solution It is also carried out under aseptic conditions by removing the volume of the reconstituted solution, corresponding to the dose calculated for each patient, and slow injection of the solution reconstituted in an infusion bag or bottle containing 100 and 1000 ml of a 0.9% sodium chloride solution, after which homogenizes the total content by slow manual agitation. The infusion solution of ET-743 should be administered intravenously, as soon as possible, within 48 hours after its preparation. The systems of PVC and polyethylene infusion, as well as transparent glass they are the preferred materials for the container and the conduit.

Administration takes place in cycles, an infusion being given in the preferred application method intravenous ET734 to patients the first week of each cycle, allowing patients to recover in the rest of the cycle. The preferred duration of each cycle is both 3 and 4 weeks; multiple cycles may occur in case it is necessary. The drug can also be administered each of the First days of each cycle. Dosage delays and / or are carried out dose reductions and regimen adjustments in the case where specify depending on the patient's individual tolerance to treatments, in particular dose reductions are recommended for those patients with serum levels of transaminases or alkaline phosphatase from the liver, or bilirubin, higher than normal

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The Recommended Dose (RD) is the highest dose that can be safely administered to a patient producing a tolerable, manageable and reversible toxicity, in accordance with the common toxicity criteria established by the National Cancer Institute, (USA) so that no more than 2 out of a total of 6 patients present any dose-limiting toxicity (DLT). Guidelines for cancer therapy frequently call for the administration of chemotherapeutic agents at the highest safe dose at which toxicity is manageable in order to achieve maximum efficacy (VT DeVita Jr., S. Hellman and SA Rosenberg, Cancer: Principies and Practice of Oncology, 3rd ed., 1989, Lipincott, Philadelphia).

The DLTs for ET743 were determined using this method of treatment in clinical studies were those of myelosuppression and discomfort. These studies established a recommended dose level of 1500 micrograms per m2 area body surface for infusions of 24 hours or 1650 micrograms per m2 of body surface for infusions every 3 hours. Doses of 1800 micrograms per m2 or higher resulted in a too large fraction of patients who they presented DLT and thus it was determined that they were too Toxic for safe administration.

Although a response case of a Breast cancer described in June 98 at a dose level of 1800 micrograms / m2, a level considered unsafe at any infusion rate because 2 of 4 patients presented severe dose-limiting toxic responses. Another case previously described involved a response in a patient of melanoma after an infusion of 1 hour, whose method does not allow reach the recommended dose level without thrombocytopenia and fatigue dose limiting.

ET-743 can be safely administered at a dose level of or below the Recommended Dose (RD).

In particular the invention relates to the intravenous infusion for 24 hours at a dose level of 1500 micrograms per, m 2 of body surface area preferably between 1000 and 1650 micrograms.

When the ET-743 is used in combination with other therapeutic agents, it may be necessary to adjust the doses of both agents.

Previously, the only biological responses described with the administration of ET743 had been observed in animals or in vitro models, known to be notoriously inaccurate regarding their usefulness in predicting responses in human patients, or in human patients in experimental settings when a study was not available. effective and safe method of treatment (whether the dose used was a significantly high toxic dose compared to the recommended dose or the administration regimen was not appropriate).

In clinical trials using the method of present invention appropriate plasma levels were achieved in RD patients, and more importantly, the measured responses objectively demonstrated evidence of clinical benefits to patients

Definitions for the responses of patients were adopted from the WHO Common Toxicity Criteria and were determined the responses following standard medical practice in this field.

The objective responses were obtained in patients with advanced and / or metastatic cancers refractory to previous treatments, which included soft tissue sarcoma, of bone and gastrointestinal stroma, breast cancer and melanoma. The activity evidence, using a variety of regimens suboptimal which has also been observed in ocular melanoma advanced and mesothelioma, and a positive response to the clinical marker in ovarian cancer suggests that the method of this invention also It will be useful in the treatment of these diseases.

In particular, treatment with this method has showed responses in cancer patients with disease advanced and / or metastatic, which showed progressive disease after having been previously treated with therapies established.

A preferred method of this invention therefore implies the identification of cancer patients who have been treated for cancer, particularly patients who have received chemotherapy, and their treatment with ET-743.

In particular the treatment with this procedure has also shown responses in patients with sarcomas including soft tissue, bone and bone sarcomas gastrointestinal stroma In particular the treatment with this method has shown responses in patients with tissue sarcomas soft. In particular the treatment with this method has shown responses in patients with bone sarcomas. In particular the Treatment with this method has shown responses in patients with gastrointestinal stromal sarcomas. In particular the treatment with this procedure he has shown answers in patients with breast cancers

The table, Figure 1, shows the answers observed with this method of treatment.

The invention is further illustrated by The following examples that are related to clinical trials in humans

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Example 1

The test data were analyzed with 24 hours of continuous intravenous infusion of ET-743 every 3 or 4 weeks at 1500 µg / m2. The Pharmacokinetics of ET-743 in all patients during the first cycle of therapy to assess variability between patients and possible correlations with the activity clinical or toxicity.

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Patient population

16 patients with soft tissue sarcoma advanced / metastatic (STS).

12 patients with soft tissue sarcoma with No previous chemotherapy treatment.

8 patients with stromal tumor advanced / metastatic gastrointestinal (GIST).

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Safety / Observed toxicities

The tolerability of the treatment was very good

Nausea was essentially eliminated by Dexamethasone use as a prophylactic antiemetic.

Myelosuppression

Temporary / asymptomatic transaminitis.

Fatigue.

The data showed no differences. significant with the first phase I data.

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Effectiveness

- 6 of the 10 evaluable STS patients without no previous chemotherapy treatment have shown disease Stable or lower responses after 2 cycles of therapy.

- 4 of the 12 STS patients evaluable with Previous chemotherapy treatment have shown stable disease or minor responses after 2 cycles of therapy.

- Preliminary evidence of activity was observed in liposarcoma, leiomyosarcoma, and synovial sarcoma.

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Example 2

(For purposes only illustrative)

Data from one trial were analyzed with continuous intravenous infusion for 24 hours of ET-743 every 3 weeks in 20 patients previously treated, with advanced / metastatic breast cancer, at a level of 1500 µg / m2 dose.

Characteristics of the patient population

20 women,

presenting all of them measurable disease and progressive at the time of study entry

Age between 33 and 64 years (average 50 years)

minimum number of organs involved: 2 (range 1-6)

disease sites:

cutaneous

12 (60%)

liver

10 (50%)

bones

9 (45%)

nodules lymphatic

6 (30%)

pulmonary pleura

6 (30%)

Minimum number of previous chemotherapy treatments

2 (1-6)

Patients previously treated with anthracyclines

twenty

Patients previously treated with taxanes

16

Patients resistant to Anthracyclines and Taxanes

5

Resistant patients only to taxanes

2

Resistant patients only to anthracyclines

3

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Safety / toxicities

Total number of cycles administered

56

Minimum number of cycles per patient

2 (range of 1-8)

Number of grade 3 or 4 toxicities described per cycle

Neutropenia

25 (50%)

Thrombocytopenia

4 (2%)

Transaminitis predictable

34 (60%)

Asthenia (grade 2/3)

13 (23%)

The data showed no differences. significant with the data of the previous phase I.

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Effectiveness

In the 16 evaluable patients, they were observed two partial responses (involvement of the pleuropulmonary skin and thoracic) lasting 3.5 and over 2 months in patients without primary resistance to any of the treatment drugs previous. Six patients achieved stabilization of the disease (above 2, 3, 3, above 3, 4, 5 and by over 6 months) including two with a sustained decrease in CA 15-3 a marker for this disease.

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Example 3

Data from one trial were analyzed with continuous intravenous infusion for 24 hours of ET-743 every 3 weeks in 20 treated patients previously, with advanced / metastatic soft tissue sarcoma, being all of them, except two patients, treated at a level of 1500 µg / m2 dose

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Characteristics of the patient population

39 patients / 22 women

35 soft tissue sarcomas (STS)

3 osteosarcoma (OS)

1 Ewing sarcoma (ES)

22 patients had advanced disease at study entry, with a 56% progression of the disease under the previous regime

Age 16 to 71 years (average 45 years)

general condition of the patient 0 (0-2) (ECOG criteria)

Minimum number of previous treatments of Chemotherapy 2 (1-7)

Most patients had received anthracyclines and alkylating agents as chemotherapy treatments previous.

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Safety / toxicities

Total number of cycles administered

137

Minimum number of cycles per patient

2 (interval 1-12)

Number of grade 3 or 4 toxicities described per cycle

Neutropenia

34%, with 6.5% fever

Thrombocytopenia

5%

Reversible transaminitis, sharp

44%

Asthenia (grade 2/3)

13 823%)

The data showed no differences. significant with the data of the previous phase I.

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Effectiveness

In 34 evaluable patients,

4 partial responses were observed (11.7%), two of which were full answers after the surgery

3 minor responses were observed, one of the which was a complete post surgery response to 11 stabilizations of the disease, most of which lasted 3 months or more.

Responses were observed in several types histological, including 2 out of 3 osteosarcomas, in all disease sites, including visceral metastases, in advanced and non-advanced disease, and in refractory tumors and not anthracycline refractory.

Claims (16)

1. ET743 for use in the treatment of cancer in the human body, which comprises administering ET743 by intravenous infusion at a dose of 1500 micrograms per m area of body surface, for 24 hours, where cancer is a sarcoma, leading to clinical improvement. 2. ET743 for use in cancer treatment in the human body according to claim 1, wherein the Cancer is soft tissue sarcoma. 3. ET743 for use in cancer treatment in the human body according to claim 1, wherein the Cancer is liposarcoma, leiomyosarcoma or synovial sarcoma. 4. ET743 for use in cancer treatment in the human body according to claim 1, wherein the cancer is gastrointestinal stromal sarcoma or sarcoma of bones. 5. ET743 for use in cancer treatment in the human body according to any of the previous claims, wherein the ET743 is administered in cycles, at intervals of 1 to 6 weeks. 6. ET743 for use in cancer treatment in the human body according to claim 5, wherein ET743 is administered during the first week of each cycle. 7. ET743 for use in cancer treatment in the human body according to claim 6, wherein the ET743 is administered on each first day of each cycle. 8. ET743 for use in cancer treatment in the human body according to any one of the claims 6 to 7, wherein the patients are allowed to recover during the rest of the cycle. 9. ET743 for use in cancer treatment in the human body according to any one of the claims 5 to 8, wherein the cycle is 3 weeks. 10. ET743 for use in the treatment of cancer in the human body according to any one of the claims 5 to 8, wherein the cycle is 4 weeks. 11. ET743 for use in the treatment of cancer in the human body according to any of the previous claims, comprising administering a dose of 1500 micrograms per m2 of body surface area per intravenous infusion for 24 hours, given in multiple cycles of 3 at 4 weeks, each with a single administration of the drug the First day of each cycle. 12. ET743 for use in the treatment of cancer in the human body according to any of the previous claims, wherein the patient has cancer advanced and 10 metastatic. 13. ET743 for use in the treatment of a cancer in the human body according to any of the previous claims, in which the human has been previously Treated with cancer with chemotherapy. 14. ET743 for use in the treatment of a cancer in the human body according to any of the previous claims, wherein the treatment includes combination therapy 15. ET743 for use in the treatment of a cancer in the human body according to any of the previous claims, wherein the treatment includes administer another drug, selected from: a) a drug with antimitotic effect; b) an antimetabolite drug; c) an alkylating agent or a mustard nitrogen; d) a drug that targets DNA; e) a drug that targets a topoisomerase; f) a hormone or an agonist or antagonist of hormone; g) a drug that targets the signal of transduction in tumor cells; h) an alkylating drug; i) a drug that potentially affects the tumor metastasis; j) a gene therapy or antisense agents; k) an antibody therapeutic agent; l) other bioactive compound of origin Marine; m) a spheroid analog; n) an anti-inflammatory drug; or o) an antiemetic drug.

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16. ET743 for use in the treatment of a cancer in the human body according to claim 15, in the one that the other drug is dexamethasone.