Antitumor compositions containing taxane derivatives

Details Antitumor compositions containing taxane derivatives Antitumor compositions containing taxane derivatives

1999-08-10

2001-04-10

Krass, Frederick (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S002600, C514S008100, C514S033000, C514S034000, C514S279000, C514S283000, C514S299000, C514S300000, C514S410000, C514S413000, C514S414000, C514S415000, C514S422000, C514S459000

Reexamination Certificate

active

06214863

ABSTRACT:

The present invention relates to combinations of taxol, Taxotere and their analogues and substances which are therapeutically useful in the treatment of neoplas tic diseases.
Taxol, Taxotere and their analogues, which possess noteworthy antitumour and antileukaemic properties, are especially useful in the treatment of cancers of the 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, hexamethylmelamine, thiotepa or dacarbazine, antimetabolites such as pyrimidine analogues, for instance 5-fluorouracil and cytarabine or its analogues such as 2-fluorodeoxycytidine, 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, doxorubicin, 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 and etoposide.
The improved efficacy of a combination according to the invention may be demonstrated by determination of the therapeutic synergy.
The efficacy of a combination according to the invention may also be characterized by adding the actions of each constituent.
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 log
10
cells killed, which is determined according to the following formula:
log
10
cells killed=
T−C
(days)/3.32
×T
d
in which T−C represents the time taken for the cells to grow, which is the mean time in days for the tumours of the treated group (T) and the tumours 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 tumour 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 log
10
cells killed is greater than or equal to 0.7. A product is considered to be very active if log
10
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 log
10
cells killed is greater than the value of the log
10
cells killed of the best constituent when it is administered alone.
The efficacy of the combinations on solid tumours 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 tumour fragment on day 0. The animals bearing tumours are mixed before being subjected to the various treatments and controls. In the case of treatment of advanced tumours, tumours are allowed to develop to the desired size, animals having insufficiently developed tumours being eliminated. The selected animals are distributed at random to undergo the treatments and controls. Animals not bearing tumours may also be subjected to the same treatments as the tumour-bearing animals in order to be able to dissociate the toxic effect from the specific effect on the tumour. Chemotherapy generally begins from 3 to 22 days after grafting, depending on the type of tumour, 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 tumours are measured 2 or 3 times a week until the tumour reaches approximately 2 g, or until the animal dies if this occurs before the tumour reaches 2 g. The animals are autopsied when sacrificed.
The antitumour activity is determined in accordance with the different parameters recorded.
For a study of the combinations on leukaemias, 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 leukaemia.
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
Activity of the combination Taxotere + cyclophosphamide at the
optimum dose against advanced MA13/c mammary adenocarcinoma
grafted subcutaneously
Dose
Total
log
10
mg/kg/injection
Administration
dose
cells
Product
i.v.
on days:
mg/kg
killed
Taxotere
15
14, 17, 20
45
2.8
Cylcophos-
118
14
118
1.3
phamide
Taxotere
7.5
14, 17, 20, 14
22.5
3.4
+
90.0
90
cyclophos
phamide
TABLE 2
Activity of the combination Taxotere + etoposide at the optimum
dose against early B16 melanoma grafted subcutaneously
Dose
Total
log
10
mg/kg/injection
Administration
dose
cells
Product
i.v.
on days:
mg/kg
killed
Taxotere
17.5
4, 7, 10, 13
70
2.8
Etoposide
46.2
4, 7, 10, 13
184.8
2.8
Taxotere
15.7
4, 7, 10, 13
62.8
4.1
+
13.8
(simultaneous)
55.2
etoposide
TABLE 3
Activity of the combination Taxotere + 5-fluorouracil at the
optimum dose against advanced C38 colon adenocarcinoma grafted
subcutaneously
Dose
Total
log
10
mg/kg/injec-
Administration
dose
cells
Product
tion i.v.
on days:
mg/kg
killed
Taxotere
2

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