WO2004073719A1

WO2004073719A1 - A combined therapy comprising an indolopyrrolocarbazole derivative and another antitumor agent

Info

Publication number: WO2004073719A1
Application number: PCT/EP2004/050130
Authority: WO
Inventors: Marina Ciomei; Enrico Pesenti
Original assignee: Pharmacia Italia S.P.A.
Priority date: 2003-02-21
Filing date: 2004-02-16
Publication date: 2004-09-02
Also published as: TW200500073A; BRPI0407642A; EP1599210A1; ITMI20030317A1; MXPA05008879A; JP2006518355A; CL2004000319A1; CA2516097A1; AR043241A1

Abstract

The present invention relates to a method for treating cancer in a subject in need of such a treatment, said method comprising the administration to the patient of a therapeutically effective amount of edotecarin together with capecitabine or docetaxel.

Description

TITLE

A COMBINED THERAPY COMPRISING AN INDOLOPYRROLOCARBAZOLE DERIVATIVE AND ANOTHER ANTITUMOR AGENT

DESCRIPTION OF THE INVENTION

The present invention relates to the field of the neoplastic diseases therapy. In particular, this invention relates to a method for treating cancer in a subject in need of such a treatment, said method comprising the administration to the patient of a therapeutically effective amount of an indolopyrrolocarbazole derivative together with another antitumor agent. The present invention further relates to pharmaceutical compositions and packaging units, which comprise an indolopyrrolocarbazole derivative and another antitumoral agent.

Cancer is one of the major causes of death in humans and animals; surgery, radiation and chemotherapy are the useful means to fight cancer.

In particular, combined chemotherapy, designed to treat cancer using more than one drug in combination or in association, is a well-known modality to optimise the treatment regimen of neoplastic diseases .

There is therefore a need of selecting new antitumor combinations of known pharmaceutical agents that are particularly suitable for treating patients suffering from a cancer.

The present invention meets this need by providing a pharmaceutical combination comprising an indolopyrrolocarbazole derivative,- i.e. edotecarin or a pharmaceutically acceptable salt thereof and another antitumor agent chosen between docetaxel and capecitabine .

It has now been found that the efficacy of the combination according to the invention is greater than the efficacy that could have been achieved with either type of combination partner administered alone.

Therefore, it is an object of the present invention a combined preparation for simultaneous, separate or sequential use in cancer treatment, comprising a pharmaceutical composition comprising edotecarin or a pharmaceutically acceptable salt thereof and at least a pharmaceutically acceptable excipient and a pharmaceutical composition comprising docetaxel and at least a pharmaceutically acceptable excipient.

A further object of the present invention is a combined preparation for simultaneous, separate or sequential use in cancer treatment, comprising a pharmaceutical composition comprising edotecarin and at least a pharmaceutically acceptable excipient and a pharmaceutical composition comprising capecitabine and at least a pharmaceutically acceptable excipient.

Edotecarin (CAS RN 174402-32-5), i.e. 12-β-D- glucopyranosyl-2, 10-dihydroxy-6-{ [2-hydroxy-l- hydroxymethyl) ethyl] amino}-12, 13-dihydro-6H-indolo [2,3- a]pyrrole [3, 4-c] carbazole-5, 7-dione, is an indolopyrrolocarbazole derivative also known as ED-749 or J-107088 having the following formula:

Edotecarin can be prepared, for example, according to the method described in the European Patent no. 545,195, in the European patent application No. 95917506 both to Banyu Pharm. CO. LTD., or in Tetrahedron (2001) 57, 8917-23.

According to the present invention, edotecarin can be present in the form of a pharmaceutically acceptable salt. A pharmaceutically acceptable salt is, according to the present invention, any salt of acid or basic addition which maintains the biological effectiveness and the properties of edotecarin and which is formed by a suitable non toxic acid or base. Examples of pharmaceutically acceptable salts of addition with acids, both with inorganic acids, such as hydrochloric and methansulfonic acid and with organic acids, such as acetic, citric, tartaric and maleic acid.

Capecitabine (CAS RN 154361-50-9) having the following formula

is a pro-drug of 5-fluorouracyl, which Hoffmann-La Roche has developed and launched for the treatment of breast and colon-rectum cancer in major worldwide markets .

Capecitabine can be prepared, for example, following the methods described in the European patent No. 602,454 and US patent No. 5,472,949, both to Hoffmann- La Roche . Capecitabine is commercially available as XELODA^®.

Docetaxel (CAS RN 114977-28-5) having the following formula:

is a synthetic derivative of paclitaxel, developed and launched by Aventis Pharma. The preparation of docetaxel is described, for example, in the European Patents No. 253,738 and 253,739 and in the International patent application WO 92/09589, all to Rhone-Poulenc . Docetaxel is commercially available as TAXOTERE^®.

The terms "treating" or "to treat" mean to alleviate symptoms, eliminate the causation either on a temporary or permanent basis, or to prevent or slow the appearance of symptoms. The term "treatment" includes, according to the present invention, alleviation, elimination, of the cause and prevention of the cancer.

Besides being useful for human treatment, these combinations are also useful for the treatment of other mammals, among them horses, dogs, cats, mice, ovines, swine, etc.

The combined preparations according to the present invention can be used in cancer treatment.

The term "cancer" according to the present invention includes all types of cancer, as those listed in the National Cancer Institute (NCI) Web Site, at the following Internet address: http: //www.nci .nih.gov/cancerinfo/types/ and comprises, for instance, breast cancer, colon cancer, colorectal cancer, liver cancer, pancreatic cancer, renal cancer, uterine cancer, head and neck cancer, brain cancer, ovarian cancer, prostate cancer, testicular cancer, kidney cancer, lung cancer, stomach cancer, oesophageal cancer, bladder cancer, bone cancer, skin cancer, limphoma, malignant melanoma, neuroblastoma, glioma, multiform glioblastoma and the like.

The term "therapeutically-effective" is intended to qualify the amount of each agent for use in the combination therapy, which will achieve the goal of improvement in disease severity and the frequency of incidence over treatment of each agent by itself, and/or of amelioration of adverse side effects typically associated with alternative therapies.

The administration of the constituents of the combined preparation according to the present invention can be made simultaneously, separately or sequentially in any order. Namely, the present invention intends to embrace administration of edotecarin or a pharmaceutically acceptable salt thereof with capecitabine or docetaxel in a sequential manner in a regimen that will provide beneficial effects of the drug combination, and intends as well to embrace co-administration of these agents in a substantially simultaneous manner, such as in a single dosage unit having a fixed ratio of these active agents or in multiple, separate dosage units for each agent, where the separate dosage units can be taken together contemporaneously, or taken within a period of time sufficient to receive a beneficial effect from both of the constituents of the combination.

Therefore, it is an additional object of the present invention the use of edotecarin or of a pharmaceutically acceptable salt thereof and of capecitabine in the preparation of a medicament for use against cancer, wherein edotecarin or a pharmaceutically acceptable salt thereof and capecitabine are administered simultaneously, separately or sequentially.

It is yet another object of the present invention the use of edotecarin or a pharmaceutically acceptable salt thereof and of docetaxel in the preparation of a medicament for use against cancer, wherein edotecarin or a pharmaceutically acceptable salt thereof and docetaxel are administered simultaneously, separately or sequentially.

The constituents of the combined preparation according to the present invention can be administered to the patient in any manner that is medically acceptable from the medical viewpoint, including orally, parenterally and with loco-regional therapeutic approaches, such as implants . Oral administration includes the administration of the constituents of the combined preparation according to the invention in a suitable pharmaceutical form for oral use, such as tablets, capsules, suspensions, solutions, emulsions, powders, granules, syrups and the like.

Parenteral administration includes the administration of the constituents of the combined preparation according to the invention in a suitable pharmaceutical form for sub-cutaneous, intramuscular or intravenous use. Implants include, for example, intrarterial implants .

For example, edotecarin or a pharmaceutically acceptable salt thereof may be administered in a suitable pharmaceutical form for intravenous use, docetaxel may be administered in a suitable pharmaceutical form for intravenous use and capecitabine may be administered in a suitable pharmaceutical form for oral use.

In any case, the selection of the route, of the dosage, of the time interval and of the order of administration of the constituents of the combined preparation according to the present invention can be determined by a person skilled in the medical art. Such selection can vary, inter alia, according to the particular pharmaceutical composition of edotecarin or of a pharmaceutically acceptable salt thereof which is used, according to the particular pharmaceutical composition of capecitabine which is used or according to the particular pharmaceutical composition of docetaxel which is used, on the type, severity and extension of the cancer being treated, on the sex, age, and on the particular clinical conditions of the patient at the time of the treatment. When edotecarin or a pharmaceutically acceptable salt thereof and capecitabine or docetaxel are provided together with a pharmaceutically acceptable carrier, a pharmaceutical composition is formed. Said pharmaceutical composition which therefore comprises edotecarin or a pharmaceutically acceptable salt thereof and capecitabine or docetaxel as active agents, a carrier or a pharmaceutically acceptable excipient, is suitable for treating cancer.

Therefore, it is a further object of the present invention a pharmaceutical composition, which comprises edotecarin or a pharmaceutically acceptable salt thereof and capecitabine or docetaxel as active agents, and at least a carrier or a pharmaceutically acceptable excipient, for cancer treatment.

Pharmaceutically acceptable carriers or excipients to be used in the preparation of a pharmaceutical composition according to the invention are well known to a skilled person in the art of formulating compounds in the form of pharmaceutical compositions. For example, said pharmaceutical compositions can usually contain, for instance, pharmaceutically acceptable salts, buffering agents, preservatives and/or compatible carriers .

The terms "pharmaceutically acceptable carrier" refers herein to one or more conventional compatible solid or liquid filling agents, diluting substances or encapsulating substances which are suitable for administration to mammals, among them humans.

Pharmaceutical compositions suitable for parenteral administration are formulated in a sterile form. The amount of active ingredient contained in the aforesaid pharmaceutical compositions according to the present invention may vary, depending quite amply on many factors such as the route of administration and the vehicle; for example, a single dosage unit may contain from 0.5 to 500 mg of edotecarin or a pharmaceutically acceptable salt thereof and from 10 to 1,000 mg of capecitabine or from 1 mg to 100 mg of docetaxel .

The technique for the preparation of the pharmaceutical compositions according to the present invention is to be considered conventional and well known by those skilled in the art.

A further aspect of the present invention relates to a method for the treatment of cancer, which comprises administering to a mammal a therapeutically effective amount of edotecarin or of a pharmaceutically acceptable salt thereof and capecitabine, in amounts effective to produce a synergistic anti-cancer effect. In a particular aspect, the present invention relates to a method for treating a cancer in a patient in need thereof, said method comprising the administration to said patient of edotecarin or a pharmaceutically acceptable salt thereof and of capecitabine, in amounts effective to produce a synergistic anti-cancer effect.

Yet another aspect of the present invention relates to a method for the treatment of cancer, which comprises administering to a mammal a therapeutically effective amount of edotecarin or of a pharmaceutically acceptable salt thereof and docetaxel, in amounts effective to produce a synergistic anti-cancer effect. In another particular aspect, the present invention relates to a method for treating a cancer in a patient in need thereof, said method comprising the administration to said patient of edotecarin or a pharmaceutically acceptable salt thereof and of docetaxel, in amounts effective to produce a synergistic anti-cancer effect.

The terms "a synergistic anti-cancer effect" refers to a greater than additive anti-cancer effect which is produced by a combination of two active and which exceeds that which .would otherwise results from individual administration of either active alone.

In the method according to the present invention the amount of edotecarin or a pharmaceutically acceptable salt thereof together with the amount of capecitabine or docetaxel constitute an amount effective for the treatment of cancer.

In the method of the present invention, the administration of edotecarin or of a pharmaceutically acceptable salt thereof can vary from about 0.1 mg/m² to about 100 mg/m² per body surface area of an adult, preferably from about 10 mg/m² to about 50 mg/m² per body surface area of an adult.

In the method of the present invention, the administration of capecitabine can vary from about 10 mg/m² to about 10000 mg/m² per body surface area of an adult, preferably from about 500 mg/m² to about 2500 mg/m² per body surface area of an adult.

In the method of the present invention, the administration of docetaxel can vary from about 0.5 mg/m² to about 500 mg/m² per body surface area of an adult, preferably from about 10 mg/m² to about 100 mg/m² per body surface area of an adult. The present invention also provides a therapeutic kit which comprises, in suitable packaging units, a pharmaceutical composition comprising edotecarin or a pharmaceutically acceptable salt thereof and a pharmaceutical composition comprising capecitabine or docetaxel, present within individual packaging units or within distinct packaging units .

As a particular example, a kit according to ^■ the invention comprises a pharmaceutical composition comprising edotecarin or a pharmaceutically acceptable salt thereof and a pharmaceutical composition comprising capecitabine or docetaxel, within distinct packaging units .

The kits according to the invention are intended for use in anti-cancer therapy, as defined above.

The efficacy of the combined preparations according to the invention can be demonstrated by determining a therapeutic synergy among the constituents of the combination, for example as set out in the experimental part that follows .

EXPERIMENTAL PART

Immune depressed (Nu/Nu) mice, bearing human SKBR-3 human breast carcinoma implanted sub-cutaneously, were treated with the compounds in question with following treatment scheme:

Edotecarin 3 mg/Kg was administered intravenously on day 9 and 16;

Docetaxel 5 mg/Kg was administered intravenously on day

8, 12 and 15;

Capecitabine 370 mg/Kg was administered orally from day

10 to day 23. The treatments started when the tumors were measurable (day 8 from tumor cell injection: tumor weight mean for all the groups was 0.18 g) .

Tumour measurements were taken by a calliper 1-2 times a week. These tumor measurements were converted to mg tumor weight by following formula:

_ , length (mm) x width ² (mm) Tumour weight =

Statistical analysis were carried out on the tumor weights measured at different days in the mice treated with the combination of edotecarin + capecitabine or edotecarin + docetaxel in comparison with the measurements obtained in mice treated with the corresponding drugs as single agents . P values resulted from a Mann Whitney test always <0.01, indicated a therapeutic advantage (synergism) of the combined treatments in comparison of the administration of each . compound alone .

Antitumor response to the actives alone or in combination was also assessed by evaluating the tumor growth delay, namely the time taken by the tumours of the different treatment groups to reach the predetermined weight of (1 g) (T-C) .

The obtained results are reported in the Table below. Table

* treatments IV on day 9 and 16 ** treatments IV on day 8, 12, 15 *** treatments OS from day 10 to day 23

Edotecarin combined with docetaxel produced a synergistic effect: the T-Cs was higher than that expected by the simple addition of the T-Cs obtained with the two compounds as single agent (20.3 days when the expected T-Cs was 10.5 days) . Also the result obtained for the combination with capecitabine was considered as synergistic (T-C = 34.9 days in comparison with an expected T-C = 29.5). The above-reported data show that the administration of edotecarin in combination with docetaxel or capecitabine result in a synergistic anti-cancer effect by providing an unexpected increase in the tumor of growth delay.

Claims

1. A pharmaceutical combination comprising edotecarin or a pharmaceutically acceptable salt thereof and docetaxel.

2. A pharmaceutical combination comprising edotecarin or a pharmaceutically acceptable salt thereof and capecitabine .

3. A combined preparation for simultaneous, separate or sequential use in the treatment of cancer, comprising a pharmaceutical composition comprising edotecarin or a pharmaceutically acceptable salt thereof and at least a pharmaceutically acceptable excipient and a pharmaceutical composition comprising docetaxel and at least a pharmaceutically acceptable excipient.

4. A combined preparation for simultaneous, separate or sequential use in the treatment of cancer, comprising a pharmaceutical composition comprising edotecarin and at least a pharmaceutically acceptable excipient and a pharmaceutical composition comprising capecitabine and at least a pharmaceutically acceptable excipient.

5. Use of edotecarin or of a pharmaceutically acceptable salt thereof and of capecitabine in the preparation of a medicament for use against cancer, wherein edotecarin or a pharmaceutically acceptable salt thereof and capecitabine are administered simultaneously, separately or sequentially.

6. Use of edotecarin or of a pharmaceutically acceptable salt thereof and of docetaxel in the preparation of a medicament for use against cancer wherein edotecarin or a pharmaceutically acceptable salt thereof and docetaxel are administered simultaneously, separately or sequentially.

7. A pharmaceutical composition comprising edotecarin or a pharmaceutically acceptable salt thereof and capecitabine as active agents, and a carrier or a pharmaceutically acceptable excipient, for the treatment of cancer.

8. A pharmaceutical composition comprising edotecarin or a pharmaceutically acceptable salt thereof and docetaxel as active agents, and a carrier or a pharmaceutically acceptable excipient, for the treatment of cancer.

9. A method for the treatment of cancer, which comprises administering to a mammal a therapeutically effective amount of edotecarin or of a pharmaceutically acceptable salt thereof and capecitabine, in amounts effective to produce a synergistic anti-cancer effect.

10. A method for the treatment of cancer, which comprises administering to a mammal a therapeutically effective amount of edotecarin or of a pharmaceutically acceptable salt thereof and docetaxel, in amounts effective to produce a synergistic anti-cancer effect.

11. A method for the treatment of cancer, which comprises administering to a patient in need thereof a therapeutically effective amount of edotecarin and capecitabine, wherein edotecarin and capecitabine are administered simultaneously, separately or sequentially to provide a synergistic anticancer effect, and wherein the cancer is sensitive to the synergistic combination.

12. A method for the treatment of cancer which comprises administering to a patient in need thereof a therapeutically effective amount of edotecarin and docetaxel, wherein edotecarin and docetaxel are administered simultaneously, separately or sequentially to provide a synergistic anticancer effect, and wherein the cancer is sensitive to the synergistic combination.

13. A therapeutic kit comprising, in suitable packaging units, a pharmaceutical composition which comprises edotecarin or a pharmaceutically acceptable salt thereof and a pharmaceutical composition which comprises capecitabine, present within a single packaging unit or within distinct packaging units .

14. The therapeutic kit comprising, in suitable packaging units, a pharmaceutical composition which comprises edotecarin or a pharmaceutically acceptable salt thereof and a pharmaceutical composition which comprises docetaxel, present within a single packaging unit or within distinct packaging units .

15. The kit as claimed in claim 13, wherein a pharmaceutical composition comprising edotecarin or a pharmaceutically acceptable salt thereof and a pharmaceutical composition comprising capecitabine are within distinct packaging units.

16. The kit as claimed in claim 14, wherein a pharmaceutical composition comprising edotecarin or a pharmaceutically acceptable salt thereof and a pharmaceutical composition comprising docetaxel are within distinct packaging units .

17. The kit as claimed in one of the claims from 13 to 16, for use in the treatment of cancer.