AU2002244877A1

AU2002244877A1 - Antitumor compositions containing taxane derivatives

Info

Publication number: AU2002244877A1
Application number: AU2002244877A
Authority: AU
Inventors: Marie-Christine Bissery
Original assignee: Aventis Pharma SA
Current assignee: Aventis Pharma SA
Priority date: 2001-03-21
Filing date: 2002-03-21
Publication date: 2003-03-27
Anticipated expiration: 2022-03-21

Description

ANTITUMOR COMPOSITIONS CONTAINING

TAXANE DERIVATIVES

This application is a continuation-in-part of U.S. Patent Application No.

09/705,739, filed November 6, 2000, which is a divisional application of

Application No. 09/371 ,520, filed August 10, 1999, which is a continuation

application of Application No. 09/182,900, filed October 30, 1998, now

abandoned, which is a divisional application of Application No. 08/967,036, filed

November 10, 1997, now U.S. Patent No. 5,908,835, which is a divisional

application of Application No. 08/424,470, filed May 9, 1995, now U.S. Patent

No. 5,728,687.

The present invention relates to combinations of taxol, Taxotere and their

analogues and substances which are therapeutically useful in the treatment of

neoplastic diseases.

Taxol, Taxotere and their analogues, which possess noteworthy antitumor

and antileukemic properties, are especially useful in the treatment of cancers of

the colon, ovary, breast or lung.

The preparation of taxol, Taxotere and their derivatives form the subject,

for example, of European Patents EP 0,253,738 and EP 0,253,739 and

International Application PCT WO 92/09,589. Generally, the doses used, which depend on factors distinctive to the

subject to be treated, are between 1 and 10 mg/kg administered intraperitoneally

or between 1 and 3 mg/kg administered intravenously.

It has now been found, and this forms the subject of the present invention,

that the efficacy of taxol, Taxotere and their analogues may be considerably

improved when they are administered in combination with at least one substance

which is therapeutically useful in anticancer treatments and has a mechanism

identical to or different from this of taxane derivatives.

Among substances which may be used in association or in combination

with taxol, Taxotere or their analogues, there may be mentioned alkylating

agents such as cyclophosphamide, isosfamide, melphalan, hexametyl-

melamine, thiotepa or dacarbazine, antimetabolites such as pyrimidine

analogues, for instance 5-fluarouracil and cytarabine, or its analogues such as 2-

flourodeoxycytidine, or folic acid analogues such as methotrexate, idatrexate or

trimetrexate, spindle poisons including vinca alkaloids such as vinblastine or

vincristine or their synthetic analogues such as navelbine, or estramustine or

taxoids, epidophylloptoxins such as etoposide or teniposide, antibiotics such as

daunorubicine, doxόrubicin, bleomycin or mitomycin, enzymes such as L-

asparaginase, topoisomerase inhibitors such as camptothecin derivatives

chosen from CPT-11 and topotecan or pyridobenzoindole derivatives, and

various agents such as procarbazine, mitoxantrone, platinum coordination complexes such as cisplatin or carboplatin, and biological response modifiers or

growth factor inhibitors such as interferons or interleukins.

Moreover, since the activity of the products depends on the doses used, it

is possible to use higher doses and to increase the activity while decreasing the

toxicity phenomena or delaying their onset by combining growth factors of the

haematopoietic type such as G-CSF or GM-CSF or certain interleukins with

taxol, Taxotere, their analogues or their combinations with other therapeutically

active substances.

The combinations or associations according to the invention enable the

phenomena of pleiotropic resistance or "multi-drug resistance" to be avoided to

delayed.

More especially, the invention relates to combinations of taxol, Taxotere

and their analogues with vinca alkaloids, cyclophosphamide, 5-fluorouracil,

doxorubicin, cisplatin, navelbine, camptothecin, and etoposide.

The improved efficacy of a combination according to the invention may be

demonstrated by determination of the therapeutic synergy. A combination

manifests therapeutic synergy if it is therapeutically superior to one or other of

the constituents used at its optimum dose (T.H. Corbett et al., Cancer Treatment

Reports, 66: 1187 (1982)).

To demonstrate the efficacy of a combination, it may be necessary to

compare the maximum tolerated dose of the combination with the maximum

tolerated dose of each of the separate constituents in the study in question. This efficacy may be quantified, for example, by the log₁₀ cells killed, which is

determined according to the following formula:

log₁₀ cells killed = T-C (days)/3.32 x T_d

in which T - C represents the time taken for the cells to grow, which is the mean

time in days for the tumors of the treated group (T) and the tumors of the treated

group (C) to have reached a predetermined value (1 g for example) , and T_d

represents the time in days needed for the volume of the tumor to double in the

control animals [T.H. Corbett et al., Cancer. 40, 2660-2680 (1977); F.M. Schabel

et al., Cancer Drug Development, Part B, Methods in Cancer Research. 17, 3-

51 , New York, Academic Press Inc. (1979)]. A product is considered to be active

if log₁₀ cells killed is greater than or equal to 0.7. A product is considered to be

very active if log₁₀ cells killed is greater than 2.8.

The combination, used at its own maximum tolerated dose, in which each

of the constituents will be present at a dose generally not exceeding its

maximum tolerated dose, will manifest therapeutic synergy when the log₁₀ cells

killed is greater than the value of the log₁₀ cells killed of the best constituent

when it is administered alone.

The efficacy of the combinations on solid tumors may be determined

experimentally in the following manner:

The animals subjected to the experiment, generally mice, are

subcutaneously grafted bilaterally with 30 to 60 mg of a tumor fragment on day

0. The animals bearing tumors are mixed before being subjected to the various treatments and controls. In the case of treatment of advanced tumors, tumors

are allowed to develop to the desired size, animals having insufficiently

developed tumors being eliminated. The selected animals are distributed at

random to undergo the treatments and controls. Animals not bearing tumors

may also be subjected to the same treatments as the tumor-bearing animals in

order to be able to dissociate the toxic effect from the specific effect on the

tumor. Chemotherapy generally begins from 3 to 22 days after grafting,

depending on the type of tumor, and the animals are observed every day. The

different animal groups are weighed 3 or 4 times a week until the maximum

weight loss is attained, and the groups are then weighed at least once a week

until the end of the trial.

The tumors are measured 2 or 3 times a week until the tumor reaches

approximately 2 g, or until the animal dies if this occurs before the tumor reaches

2 g. The animals are autopsied when sacrificed.

The antitumor activity is determined in accordance with the different

parameters recorded.

For a study of the combinations on leukemias the animals are grafted with

a particular number of cells, and the antitumour activity is determined by the

increase in the survival time of the treated mice relative to the controls. The

product is considered to be active if the increase in survival time is greater than

27%, and is considered to be very active if it is greater than 75% in the case of

P388 leukemias. The results obtained with combinations of Taxotere and various

chemotherapeutic agents, such as cyclophosphamide (alkylating agent), 5-

fluorouracil (antimetabolite), etoposide (semisynthetic podophyllotoxin agent)

and vincristine (vinca alkaloid), the combinations being used at their optimum

dose, are given as examples in the following tables.

TABLE 1

TABLE 2

TABLE 3

TABLE 4

Experiments were also conducted using a taxotere analogue, N-

debenzoyl-N-t-butoxy-carbonyl-7-deoxy-8-desmethyl-7, 8-cyclopropataxotere (hereinafter acetocyclopropyl taxotere) with several chemotherapeutic agents.

The structure of acetocyclopropyl taxotere is as follows:

Combinations of acetocyclopropyl taxotere and various chemotherapeutic

agents, such as doxorubicin (antibiotic), cisplatin (platinum coordination

complex), navelbine (spindle poison), and CPT-11 (topoisomerase inhibitor),

were evaluated in mice bearing s.c. transplantable tumors. The tumor model

used to evaluate each drug combination was selected, in general, on the basis of

its responsiveness to each of the agents when used as monotherapy. Using i.v.

intermittent schedules, full dose response trials were conducted for each single

agent and each combination.

In addition to the parameters described above, the combination toxicity

index (CTI) was determined. See Corbett, T.H., et al., Response of

transplantable tumors of mice to anthracenedione derivatives alone and in combination with clinically useful agents, Cancer Treat. Rep. 66: 1187-1200

(1982). The CTl represents the sum of the fractions of the lethal dose 10% (LD₁₀)

of each single agent used in the optimal combination. It indicates the extent in

host toxicity overlap. For example, a CTl of 1 indicates that only 50% of the LD₁₀

of each single agent (or any of the ratios, 70:30, 40:60, etc ...) can be used in

combinations without incurring additional toxicity, whereas a CTl of 2 indicates

that 100% of the LD₁₀of each single agent can be used in combination.

The following table summarizes for each combination the therapeutic

response and highest non toxic dose of each arm of the study, the single agents

and the combination.

Abbreviations use : = tumor ou ling time; bwl = body weight loss; TFS = tumor free survivors; CTl «= combination toxicity; IV = intravenous; PO = by month; CR = Complete Response. In combination with doxorubicin, the optimal combination produced a log

cell kill of 5.3 in MA13/C bearing mice and induced 100% complete regressions

(no cures) whereas the single agents produced lower log cell kill, i.e.,

acetocyclopropyl taxotere had a log cell kill of 2.9 and doxorubicin-3.0. The

combination toxicity index was 1.42 indicating that approximately 70% of the

HNTD of each single agent can be combined without additional toxicity.

With cisplatin, the optimal combination produced 3.6 log cell kill and 2/7

tumor free survivors on day 122 in Colon 51 bearing mice whereas the single

agents produced 1.4 log cell kill for acetocyclopropyl taxotere and 2.7 log cell kill

for cisplatin with no tumor free survivors. There was an important overlap in host

recovery with a CTl of 0.68 indicating that less than 35% of each of the single

agent can be administered in combination. However, the mice were not

hyperhydrated when receiving cisplatin which may explain this degree of toxicity.

The combination of acetocyclopropyl taxotere with CPT-11 was found to

be at least as good as the best single agent in the combinations (1.7 log cell kill

for the combination, versus 1.5 for acetocyclopropyl taxotere and 1.1 for

CPT-11 ). However, CTl of 0.6 indicates an important overlap in host toxicity.

Finally, there was a very good synergistic effect between acetocyclopropyl

taxotere and navelbine in MA17/A bearing mice with a 8.1 log cell kill (and 2

tumor free survivors on day 123) for the combination, 4.8 for acetocyclopropyl

taxotere and 5.5 for navelbine. The combination produced a modest overlap in host toxicity with a CTl of 1.42.

Overall, the four acetocyclopropyl taxotere combinations tested were all

found synergistic i.e., the antitumor activity was greater in the combination arm

than in single agent arm at highest non toxic dose.

In terms of tolerance, the combination of acetocyclopropyl taxotere with

doxorubicin or navelbine, were well tolerated with a CTl of approximately 1.4,

whereas dose reduction would be needed in the case of combination of

cyclopropataxol with cisplatin or with CPT-11 (CTl < 1 ).

The present invention also relates, therefore, to pharmaceutical compositions containing the combinations according to the invention.

The constituents of which the combination are composed may be

administered simultaneously, semi-εimultaneously, separately, or spaced out

over a period of time so as to obtain the maximum efficacy of the combination; it

being possible for each administration to vary in its duration from a rapid

administration to a continuous perfusion.

As a result, for the purposes of the present invention, the combinations

are not exclusively limited to those which are obtained by physical association of

the constituents, but also to those which permit a separate administration, which

can be simultaneous or spaced out over a period of time.

The compositions according to the invention are preferably compositions

which can be administered parentally. However, these compositions may be

administered orally or intraperitoneally in the case of localized regional therapies. The compositions for parental administration are generally

pharmaceutically acceptable, sterile solutions or suspensions which may

optionally be prepared as required at the time of use. For the preparation of

non-aqueous solutions or suspensions, natural vegetable oils such as olive oil,

sesame oil or liquid petroleum or injectable organic esters such as ethyl oleate

may be used. The sterile aqueous solutions can consist of a solution of the

product in water. The aqueous solutions are suitable for intravenous

administration provided the pH is appropriately adjusted and the solution is made

isotonic, for example with a sufficient amount of sodium chloride or glucose. The

sterilization may be carried out by heating or by any other means which does not

adversely affect the composition. The combinations may also take the form of

liposomes or the form of an association with carriers as cyclodextrins or

polyethylene glycols.

The compositions for oral or intraperitoneal administration are preferably

aqueous suspensions or solutions.

In the combinations according to the invention, the application of the

constituents of which may be simultaneous, separate or spaced out over a

period of time, it is especially advantageous for the amount of taxane derivative

to represent from 10 to 90% by weight of the combination, it being possible for

this content to vary in accordance with the nature of the associated substance,

the efficacy sought and the nature of the cancer to he treated.

The combinations according to the invention are especially useful in the treatment of cancers of the colon, breast, ovary or lung, as well as melanoma

and leukemia. In particular, they can afford the advantage of being able to

employ the constituents at considerably lower doses than those at which they

are used alone.

Claims

1. A pharmaceutical composition comprised of the compound of

formula 1

or a derivatve thereof, and at least one of an alkylating agent, an antimetabolite,

a spindle poison, an epidophyllotoxin, an antibiotic, an enzyme, a topoisomerase

inhibitor, a platinum coordination complex, a biological response modifier or a

growth factor inhibitor.

2. The pharmaceutical composition according to claim 1 wherein the

antibiotic agent is chosen from daunorubicin, doxorubicin, bleomycin and

mitomycin.

3. The pharmaceutical composition according to claim 1 wherein the

spindle poison is chosen from vinca alkaloids, their synthetic or semi-synthetic

analogues, estramustine or navelbine.

4. The pharmaceutical composition according to claim 1 wherein the

topoisomerase inhibitor is chosen from camptothecin and its derivatives including

CPT-11 , topotecan and pyridobenzoindole derivatives.

5. The pharmaceutical composition according to claim 1 wherein the

platinum coordinating complex is chosen from cisplatin and carboplatin.

6. The pharmaceutical composition according to anyone of claims 2

to 5, further comprising growth factors of the haematopoietic type.

7. A method of administering the constituents of the composition as

claimed in any one of claims 2 to 5, wherein said administration is separate and

simultaneous.

8. A method of administering the constituents of the composition as

sequential.

9. A method of administering the constituents of the composition as

spaced out over time.

10. A pharmaceutical composition having therapeutic synergy in the

treatment of neoplastic disease comprising a compound of the formula:

and doxorubicin.

11. A pharmaceutical composition having therapeutic synergy in the treatment of neoplastic disease comprising a compound of the formula:

and navelbine.

12. A pharmaceutical composition having therapeutic synergy in the

treatment of neoplastic disease comprising a compound of the formula:

and cisplatin.

13. A pharmaceutical composition having therapeutic synergy in the

treatment of neoplastic disease comprising a compound of the formula:

and CPT H.

14. The pharmaceutical composition of any one of claims 10 to 13

wherein the constituents of the composition are administered simultaneously.

15. The pharmaceutical composition of any one of claims 10 to 13

wherein the constituents of the composition are administered separately and

simultaneously.

16. The pharmaceutical composition of any one of claims 10 to 13

wherein the constituents of the composition are administered separately and

semi-simultaneously.

17. The pharmaceutical composition of any one of claims 10 to 13

wherein the constituents of the composition are administered separately and

sequentially.

18. The pharmaceutical composition of claim 10 or claim 11 wherein the

neoplastic disease is breast cancer.

19. The pharmaceutical composition of claim 12 or claim 13 wherein the

neoplastic disease is colon cancer.