U.S. patent application number 09/813018 was filed with the patent office on 2002-03-14 for antitumor compositions containing taxane derivatives.
Invention is credited to Bissery, Marie-Christine.
Application Number | 20020031505 09/813018 |
Document ID | / |
Family ID | 25211230 |
Filed Date | 2002-03-14 |
United States Patent
Application |
20020031505 |
Kind Code |
A1 |
Bissery, Marie-Christine |
March 14, 2002 |
Antitumor compositions containing taxane derivatives
Abstract
A pharmaceutical composition comprised of acetocyclopropyl
taxotere 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 is described.
Inventors: |
Bissery, Marie-Christine;
(Vitry Sur Seine, FR) |
Correspondence
Address: |
Finnegan, Henderson, Farabow,
Garrett & Dunner, L.L.P.
1300 I Street, N.W.
Washington
DC
20005-3315
US
|
Family ID: |
25211230 |
Appl. No.: |
09/813018 |
Filed: |
March 21, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09813018 |
Mar 21, 2001 |
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09705739 |
Nov 6, 2000 |
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09705739 |
Nov 6, 2000 |
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09371520 |
Aug 10, 1999 |
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6214863 |
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09371520 |
Aug 10, 1999 |
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09182900 |
Oct 30, 1998 |
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09182900 |
Oct 30, 1998 |
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08967036 |
Nov 10, 1997 |
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5908835 |
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08967036 |
Nov 10, 1997 |
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08424470 |
May 9, 1995 |
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5728687 |
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Current U.S.
Class: |
424/94.1 ;
424/649; 514/27; 514/283; 514/449 |
Current CPC
Class: |
A61K 31/4745 20130101;
A61K 31/337 20130101; A61K 38/14 20130101; A61K 33/243 20190101;
A61P 43/00 20180101; A61P 35/00 20180101; A61K 45/06 20130101; A61K
31/337 20130101; A61K 2300/00 20130101; A61K 33/24 20130101; A61K
2300/00 20130101; A61K 38/14 20130101; A61K 2300/00 20130101; A61K
31/4745 20130101; A61K 2300/00 20130101 |
Class at
Publication: |
424/94.1 ;
424/649; 514/27; 514/283; 514/449 |
International
Class: |
A61K 038/43; A61K
033/24; A61K 031/337; A61K 031/375 |
Foreign Application Data
Date |
Code |
Application Number |
Nov 8, 1993 |
US |
PCT/FR93/01096 |
Claims
1. A pharmaceutical composition comprised of the compound of 2or 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
claimed in any one of claims 2 to 5, wherein said administration is
separate and sequential.
9. 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 spaced out over time.
10. A pharmaceutical composition having therapeutic synergy in the
treatment of neoplastic disease comprising a compound of the
formula: 3and doxorubicin.
11. A pharmaceutical composition having therapeutic synergy in the
treatment of neoplastic disease comprising a compound of the
formula: 4and navelbine.
12. A pharmaceutical composition having therapeutic synergy in the
treatment of neoplastic disease comprising a compound of the
formula: 5and cisplatin.
13. A pharmaceutical composition having therapeutic synergy in the
treatment of neoplastic disease comprising a compound of the
formula: 6and CPT 11.
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.
Description
[0001] This application is a continuation-in-part of U.S. patent
application Ser. No. 09/705,739, filed Nov. 6, 2000, which is a
divisional application of application Ser. No. 09/371,520, filed
Aug. 10, 1999, which is a continuation application of application
Ser. No. 09/182,900, filed Oct. 30, 1998, now abandoned, which is a
divisional application of application Ser. No. 08/967,036, filed
Nov. 10, 1997, now U.S. Pat. No. 5,908,835, which is a divisional
application of application Ser. No. 08/424,470, filed May 9, 1995,
now U.S. Pat. No. 5,728,687.
[0002] The present invention relates to combinations of taxol,
Taxotere and their analogues and substances which are
therapeutically useful in the treatment of neoplastic diseases.
[0003] 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.
[0004] 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.
[0005] 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.
[0006] 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.
[0007] 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, 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.
[0008] 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.
[0009] The combinations or associations according to the invention
enable the phenomena of pleiotropic resistance or "multi-drug
resistance" to be avoided to delayed.
[0010] 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.
[0011] 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)).
[0012] 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.sub.10 cells killed, which is
determined according to the following formula:
log.sub.10cells killed=T-C(days)/3.32.times.T.sub.d
[0013] 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.sub.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 log.sub.10 cells
killed is greater than or equal to 0.7. A product is considered to
be very active if log.sub.10 cells killed is greater than 2.8.
[0014] 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.sub.10 cells killed is greater than the value
of the log.sub.10 cells killed of the best constituent when it is
administered alone.
[0015] The efficacy of the combinations on solid tumors may be
determined experimentally in the following manner:
[0016] 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.
[0017] 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.
[0018] The antitumor activity is determined in accordance with the
different parameters recorded.
[0019] 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.
[0020] 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.
1TABLE 1 Activity of the combination Taxotere + cyclophosphamide at
the optimum dose against advanced MA13/c mammary adenocarcinoma
grafted subcutaneously Dose mg/kg/ Total log.sub.10 injection
Administration dose cells Product i.v. on days: mg/kg killed
Taxotere 15 14, 17, 20 45 2.8 Cylcophosphamide 118 14 118 1.3
Taxotere + 7.5 14, 17, 20, 14 22.5 3.4 cyclophosphamide 90.0 90
[0021]
2TABLE 2 Activity of the combination Taxotere + etoposide at the
optimum dose against advanced B16 melonoma grafted subcutaneously
Dose mg/kg/ Total log.sub.10 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 1.3 Taxotere + 15.7 4, 7, 10,
13 62.8 4.1 etoposide 13.8 (simultaneous) 55.5
[0022]
3TABLE 3 Activity of the combination Taxotere + 5-fluorouracil at
the optimum dose against advanced C38 colon adenacarcinoma grafted
subcutaneously Dose mg/kg/ Total log.sub.10 injection
Administration dose cells Product i.v. on days: mg/kg killed
Taxotere 22 21, 25, 29, 33 88.0 1.4 5-fluorouracil 43.4 21, 25, 29,
33 173.6 1.1 Taxotere + 17.6 21, 25, 29, 33 70.4 4.8 5-fluorouracil
27.0 (simultaneous) 108.0
[0023]
4TABLE 4 Activity of the combination Taxotere + vincristine at the
optimum dose against advanced P388 leukemias (10.sup.6 cells i.p.)
Dose mg/kg/ Total log.sub.10 injection Administration dose cells
Product i.v. on days: mg/kg killed Taxotere 17.5 4, 7, 10, 13 70
2.8 vincristine 46.2 4, 7, 10, 13 184.8 2.8 Taxotere + 21.75 1, 4,
7 65.25 62 vincristine 1.2 (simultaneous) 3.6 Taxotere + 21.75 1,
4, 7 65.25 77 vincristine 1.2 (4 hours apart) 3.6
[0024] Experiments were also conducted using a taxotere analogue,
N-debenzoyl-N-t-butoxy-carbonyl-7-deoxy-8-desmethyl-7,8-cyclopropataxoter-
e (hereinafter acetocyclopropyl taxotere) with several
chemotherapeutic agents. The structure of acetocyclopropyl taxotere
is as follows: 1
[0025] 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.
[0026] 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 CTI represents the sum of the fractions of the lethal dose 10%
(LD.sub.10) of each single agent used in the optimal combination.
It indicates the extent in host toxicity overlap. For example, a
CTI of 1 indicates that only 50% of the LD.sub.10 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
CTI of 2 indicates that 100% of the LD.sub.10 of each single agent
can be used in combination.
[0027] 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.
5TABLE Cyclopropatoxol combination trials at optimal dose.
Treatment Therapeutic Response Agent Tumor Dose Total % bwl log
(route of (implantation mg/kg/in Schedule dose loss at nadir T/C
cell administration) site) j (days) mg/kg (day of nadir) % kill
Responses CTI CR acetocyclopropyl Adv. MA13/C 34.0 15, 22 68.0 2.4
(19) -- 2.9 3/5 taxotere (IV) Doxorubicin (IV) (SC) 11.0 15, 22
22.0 7.0 (26) -- 3 0 3/5 acetocyclopropyl 34.0 simult. 68 0 13.4
(27) -- 5.3 5/5 1.4 taxotere A + 2 Doxorubicin 11.0 22.0 Td = 2.6
days Median tumor size 81-116 mg TFS acetocyclopropyl Early C51
30.0 5, 12 60.0 10.7 (17) 0 1.4 0/7 taxotere (IV) Cisplatinum (SC)
.fwdarw.3.1 6.2 4.8 (7) 0 2.7 0/7 acetocyclopropyl 13.6 simult.
26.5 12.5 (16) 0 3.6 2/7 0.6 taxotere A + 8 Cisplatinum 2.0 4 0 Td
= 2.5 days CPT-11 (PO) Early C51 42.5 5, 9 2x/d 425.0 3 7 (7) 0 1.1
-- acetocyclopropyl (SC) 21.1 5, 9 42.2 8.6 (13) 0 1.5 -- taxotere
A (IV) CPT-11 (PO) + 21.0 simult. 210.0 8.3 (13) 0 1.7 -- 0.6
acetocyclopropyl 11.9 23.8 taxotere (IV) Td = 2 days TFS
acetocyclopropyl Early MA 40.3 5, 12 80.6 3.5 (28) 0 4.8 0/7
taxotere (IV) 17/C Navelbine (SC) 16.0 5, 12 .rarw.320 11.8 (14) 0
5.5 0/6 acetocyclopropyl 25.0 5, 12 50.0 6 2 (17) 0 8.1 2/7 1.4
taxotere A + 2 Navelbine 16.0 simult. 32.0 Td = 1 day Abbreviations
used: Td = tumor doubling time; bwl = body weight loss; TFS = tumor
free survivors; CTI = combination toxicity; IV intravenous; PO = by
month; CR = Complete Response.
[0028] 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.
[0029] 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 CTI 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.
[0030] 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, CTI of 0.6
indicates an important overlap in host toxicity.
[0031] 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 CTI of 1.42.
[0032] 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.
[0033] In terms of tolerance, the combination of acetocyclopropyl
taxotere with doxorubicin or navelbine, were well tolerated with a
CTI of approximately 1.4, whereas dose reduction would be needed in
the case of combination of cyclopropataxol with cisplatin or with
CPT-11 (CTI<1).
[0034] The present invention also relates, therefore, to
pharmaceutical compositions containing the combinations according
to the invention.
[0035] The constituents of which the combination are composed may
be administered simultaneously, semi-simultaneously, 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.
[0036] 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.
[0037] 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.
[0038] 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.
[0039] The compositions for oral or intraperitoneal administration
are preferably aqueous suspensions or solutions.
[0040] 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.
[0041] 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.
* * * * *