US20020031505A1 - Antitumor compositions containing taxane derivatives - Google Patents
Antitumor compositions containing taxane derivatives Download PDFInfo
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- US20020031505A1 US20020031505A1 US09/813,018 US81301801A US2002031505A1 US 20020031505 A1 US20020031505 A1 US 20020031505A1 US 81301801 A US81301801 A US 81301801A US 2002031505 A1 US2002031505 A1 US 2002031505A1
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- BUNDOSUFZPKSAA-HRPTWFMTSA-N [H]C12[C@H](C)C3(O)CC(OC(=O)C(O)C(NC(C)=O)C4=CC=CC=C4)C(C)=C(C(O[Ac])C(=O)[C@@]14C[C@H]4CC1OC[C@]12O[Ac])C3(C)C Chemical compound [H]C12[C@H](C)C3(O)CC(OC(=O)C(O)C(NC(C)=O)C4=CC=CC=C4)C(C)=C(C(O[Ac])C(=O)[C@@]14C[C@H]4CC1OC[C@]12O[Ac])C3(C)C BUNDOSUFZPKSAA-HRPTWFMTSA-N 0.000 description 6
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/243—Platinum; Compounds thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/14—Peptides containing saccharide radicals; Derivatives thereof, e.g. bleomycin, phleomycin, muramylpeptides or vancomycin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- 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 doses used are between 1 and 10 mg/kg administered intraperitoneally or between 1 and 3 mg/kg administered intravenously.
- 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
- the invention relates to combinations of taxol, Taxotere and their analogues with vinca alkaloids, cyclophosphamide, 5-fluorouracil, doxorubicin, cisplatin, navelbine, camptothecin, and etoposide.
- 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)).
- 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)
- 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 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.
- mice 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.
- 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.
- 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.
- 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.
- cyclophosphamide alkylating agent
- 5-fluorouracil antimetabolite
- etoposide semisynthetic podophyllotoxin agent
- vincristine vinca alkaloid
- acetocyclopropyl taxotere 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.
- chemotherapeutic agents such as doxorubicin (antibiotic), cisplatin (platinum coordination complex), navelbine (spindle poison), and CPT-11 (topoisomerase inhibitor)
- the combination toxicity index 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 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 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 10 of each single agent can be used in combination.
- 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.
- 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-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.
- 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.
- 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.
- compositions for parental administration are generally pharmaceutically acceptable, sterile solutions or suspensions which may optionally be prepared as required at the time of use.
- 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.
- compositions for oral or intraperitoneal administration are preferably aqueous suspensions or solutions.
- 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.
- they can afford the advantage of being able to employ the constituents at considerably lower doses than those at which they are used alone.
Abstract
Description
- 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.
- 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, 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, 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:
- log10cells 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 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 Td 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 Activity of the combination Taxotere + cyclophosphamide at the optimum dose against advanced MA13/c mammary adenocarcinoma grafted subcutaneously Dose mg/kg/ Total log10 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 -
TABLE 2 Activity of the combination Taxotere + etoposide at the optimum dose against advanced B16 melonoma grafted subcutaneously Dose mg/kg/ Total log10 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 -
TABLE 3 Activity of the combination Taxotere + 5-fluorouracil at the optimum dose against advanced C38 colon adenacarcinoma grafted subcutaneously Dose mg/kg/ Total log10 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 -
TABLE 4 Activity of the combination Taxotere + vincristine at the optimum dose against advanced P388 leukemias (106 cells i.p.) Dose mg/kg/ Total log10 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 -
- 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 CTI 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 CTI 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 CTI of 2 indicates that 100% of the LD10 of 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.
TABLE 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) →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 ←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 - 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 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.
- 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.
- 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.
- 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 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).
- 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-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.
- 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 (19)
Priority Applications (21)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US09/813,018 US6441026B1 (en) | 1993-11-08 | 2001-03-21 | Antitumor compositions containing taxane derivatives |
SI200230525T SI1478355T1 (en) | 2001-03-21 | 2002-03-21 | Antitumor compositions containing taxane derivatives |
MXPA03008539A MXPA03008539A (en) | 2001-03-21 | 2002-03-21 | Antitumor compositions containing taxane derivatives. |
AT02713093T ATE355837T1 (en) | 2001-03-21 | 2002-03-21 | ANTITUMOR COMPOSITIONS CONTAINING TAXANE DERIVATIVES |
DE60218751T DE60218751T2 (en) | 2001-03-21 | 2002-03-21 | ANTITUMOR COMPOSITIONS CONTAINING TAXAN DERIVATIVES |
PCT/IB2002/000853 WO2002074289A2 (en) | 2001-03-21 | 2002-03-21 | Antitumor compositions containing taxane derivatives |
CNA2009101299448A CN101590057A (en) | 2001-03-21 | 2002-03-21 | The anti-tumor compositions that contains Taxane derivative |
JP2002572997A JP4467885B2 (en) | 2001-03-21 | 2002-03-21 | Antitumor composition containing taxane derivative |
CA2440160A CA2440160C (en) | 2001-03-21 | 2002-03-21 | Antitumor compositions containing taxane derivatives |
PCT/IB2002/002239 WO2002074232A2 (en) | 2001-03-21 | 2002-03-21 | Antitumor compositions containing taxane derivatives |
DK02713093T DK1478355T3 (en) | 2001-03-21 | 2002-03-21 | Anti-tumor compositions containing taxane derivatives |
EP02713093A EP1478355B1 (en) | 2001-03-21 | 2002-03-21 | Antitumor compositions containing taxane derivatives |
ES02713093T ES2282400T3 (en) | 2001-03-21 | 2002-03-21 | ANTITUMOR COMPOSITIONS CONTAINING DERIVATIVES OF TAXANO. |
PT02713093T PT1478355E (en) | 2001-03-21 | 2002-03-21 | Antitumor compositions containing taxane derivatives |
HU0500478A HUP0500478A2 (en) | 2001-03-21 | 2002-03-21 | Antitumor compositions containing taxane derivatives |
AU2002244877A AU2002244877B2 (en) | 2001-03-21 | 2002-03-21 | Antitumor compositions containing taxane derivatives |
EA200301047A EA006878B1 (en) | 2001-03-21 | 2002-03-21 | Antitumor compositions containing taxane derivatives |
BR0208274-8A BR0208274A (en) | 2001-03-21 | 2002-03-21 | Antitumor compositions containing taxane derivatives |
CNA028068572A CN1536995A (en) | 2001-03-21 | 2002-03-21 | Antitumor compositions containing taxane derivatives |
IL157992A IL157992A (en) | 2001-03-21 | 2003-09-18 | Pharmaceutical compositions containing a taxane derivative |
CY20071100643T CY1106582T1 (en) | 2001-03-21 | 2007-05-10 | ANTI-CANCER COMPOSITIONS CONTAINING TAXANE DERIVATIVES |
Applications Claiming Priority (8)
Application Number | Priority Date | Filing Date | Title |
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PCT/FR1993/001096 WO1994010995A1 (en) | 1992-11-10 | 1993-11-08 | Antitumour compositions containing taxane derivatives |
USPCT/FR93/01096 | 1993-11-08 | ||
US08/424,470 US5728687A (en) | 1992-11-10 | 1993-11-08 | Antitumour compositions containing taxane derivatives |
US08/967,036 US5908835A (en) | 1992-11-10 | 1997-11-10 | Anti-tumor compositions containing taxane derivatives |
US18290098A | 1998-10-30 | 1998-10-30 | |
US09/371,520 US6214863B1 (en) | 1992-11-10 | 1999-08-10 | Antitumor compositions containing taxane derivatives |
US70573900A | 2000-11-06 | 2000-11-06 | |
US09/813,018 US6441026B1 (en) | 1993-11-08 | 2001-03-21 | Antitumor compositions containing taxane derivatives |
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US70573900A Continuation-In-Part | 1992-11-10 | 2000-11-06 |
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US09/813,018 Expired - Fee Related US6441026B1 (en) | 1993-11-08 | 2001-03-21 | Antitumor compositions containing taxane derivatives |
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US (1) | US6441026B1 (en) |
EP (1) | EP1478355B1 (en) |
JP (1) | JP4467885B2 (en) |
CN (2) | CN1536995A (en) |
AT (1) | ATE355837T1 (en) |
AU (1) | AU2002244877B2 (en) |
BR (1) | BR0208274A (en) |
CA (1) | CA2440160C (en) |
CY (1) | CY1106582T1 (en) |
DE (1) | DE60218751T2 (en) |
DK (1) | DK1478355T3 (en) |
EA (1) | EA006878B1 (en) |
ES (1) | ES2282400T3 (en) |
HU (1) | HUP0500478A2 (en) |
IL (1) | IL157992A (en) |
MX (1) | MXPA03008539A (en) |
PT (1) | PT1478355E (en) |
SI (1) | SI1478355T1 (en) |
WO (2) | WO2002074289A2 (en) |
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US20060263434A1 (en) * | 2005-02-18 | 2006-11-23 | Desai Neil P | Combinations and modes of administration of therapeutic agents and combination therapy |
WO2008015578A2 (en) * | 2006-08-03 | 2008-02-07 | Sanofi-Aventis | Antitumor compositions containing acetylcyclopropyl docetaxel and trastuzumab |
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US20090304805A1 (en) * | 2005-02-18 | 2009-12-10 | Desai Neil P | Combinations and modes of administration of therapeutic agents and combination therapy |
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FR2601676B1 (en) | 1986-07-17 | 1988-09-23 | Rhone Poulenc Sante | PROCESS FOR THE PREPARATION OF TAXOL AND DESACETYL-10 TAXOL |
FR2601675B1 (en) | 1986-07-17 | 1988-09-23 | Rhone Poulenc Sante | TAXOL DERIVATIVES, THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
US4876399A (en) | 1987-11-02 | 1989-10-24 | Research Corporation Technologies, Inc. | Taxols, their preparation and intermediates thereof |
US5015744A (en) | 1989-11-14 | 1991-05-14 | Florida State University | Method for preparation of taxol using an oxazinone |
US5136060A (en) | 1989-11-14 | 1992-08-04 | Florida State University | Method for preparation of taxol using an oxazinone |
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WO1992019765A1 (en) | 1991-05-08 | 1992-11-12 | The United States Of America, As Represented By The Secretary Of The Department Of Health And Human Services | Method for designing cancer treatment regimens and methods and pharmaceutical compositions for the treatment of cancer |
US5645988A (en) | 1991-05-08 | 1997-07-08 | The United States Of America As Represented By The Department Of Health And Human Services | Methods of identifying drugs with selective effects against cancer cells |
US5284865A (en) | 1991-09-23 | 1994-02-08 | Holton Robert A | Cyclohexyl substituted taxanes and pharmaceutical compositions containing them |
US5229526A (en) | 1991-09-23 | 1993-07-20 | Florida State University | Metal alkoxides |
US5262409A (en) | 1991-10-11 | 1993-11-16 | Fred Hutchinson Cancer Research Center | Binary tumor therapy |
US5294737A (en) | 1992-02-27 | 1994-03-15 | The Research Foundation State University Of New York | Process for the production of chiral hydroxy-β-lactams and hydroxyamino acids derived therefrom |
FR2697752B1 (en) | 1992-11-10 | 1995-04-14 | Rhone Poulenc Rorer Sa | Antitumor compositions containing taxane derivatives. |
EP0982028A1 (en) * | 1998-08-20 | 2000-03-01 | Aventis Pharma S.A. | New use of taxoid derivatives |
-
2001
- 2001-03-21 US US09/813,018 patent/US6441026B1/en not_active Expired - Fee Related
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2002
- 2002-03-21 MX MXPA03008539A patent/MXPA03008539A/en active IP Right Grant
- 2002-03-21 AU AU2002244877A patent/AU2002244877B2/en not_active Ceased
- 2002-03-21 CN CNA028068572A patent/CN1536995A/en active Pending
- 2002-03-21 EA EA200301047A patent/EA006878B1/en not_active IP Right Cessation
- 2002-03-21 AT AT02713093T patent/ATE355837T1/en active
- 2002-03-21 SI SI200230525T patent/SI1478355T1/en unknown
- 2002-03-21 EP EP02713093A patent/EP1478355B1/en not_active Expired - Lifetime
- 2002-03-21 PT PT02713093T patent/PT1478355E/en unknown
- 2002-03-21 BR BR0208274-8A patent/BR0208274A/en not_active IP Right Cessation
- 2002-03-21 CN CNA2009101299448A patent/CN101590057A/en active Pending
- 2002-03-21 WO PCT/IB2002/000853 patent/WO2002074289A2/en active IP Right Grant
- 2002-03-21 CA CA2440160A patent/CA2440160C/en not_active Expired - Lifetime
- 2002-03-21 WO PCT/IB2002/002239 patent/WO2002074232A2/en not_active Application Discontinuation
- 2002-03-21 ES ES02713093T patent/ES2282400T3/en not_active Expired - Lifetime
- 2002-03-21 DK DK02713093T patent/DK1478355T3/en active
- 2002-03-21 JP JP2002572997A patent/JP4467885B2/en not_active Expired - Lifetime
- 2002-03-21 HU HU0500478A patent/HUP0500478A2/en unknown
- 2002-03-21 DE DE60218751T patent/DE60218751T2/en not_active Expired - Lifetime
-
2003
- 2003-09-18 IL IL157992A patent/IL157992A/en not_active IP Right Cessation
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- 2007-05-10 CY CY20071100643T patent/CY1106582T1/en unknown
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US20060263434A1 (en) * | 2005-02-18 | 2006-11-23 | Desai Neil P | Combinations and modes of administration of therapeutic agents and combination therapy |
US20090098210A1 (en) * | 2005-02-18 | 2009-04-16 | Desai Neil P | Combinations and modes of administration of therapeutic agents and combination therapy |
US20090304805A1 (en) * | 2005-02-18 | 2009-12-10 | Desai Neil P | Combinations and modes of administration of therapeutic agents and combination therapy |
US7758891B2 (en) | 2005-02-18 | 2010-07-20 | Abraxis Bioscience, Llc | Combinations and modes of administration of therapeutic agents and combination therapy |
US8034375B2 (en) * | 2005-02-18 | 2011-10-11 | Abraxis Bioscience, Llc | Combinations and modes of administration of therapeutic agents and combination therapy |
US8268348B2 (en) | 2005-02-18 | 2012-09-18 | Abraxis Bioscience, Llc | Combinations and modes of administration of therapeutic agents and combination therapy |
US20130195984A1 (en) * | 2005-02-18 | 2013-08-01 | Abraxis Bioscience, Llc | Combinations and modes of administration of therapeutic agents and combination therapy |
EP1913958A1 (en) * | 2006-08-03 | 2008-04-23 | Sanofi-Aventis | Antitumor compositions containing acetylcyclopropyl docetaxel and trastuzumab |
WO2008015578A3 (en) * | 2006-08-03 | 2008-04-10 | Sanofi Aventis | Antitumor compositions containing acetylcyclopropyl docetaxel and trastuzumab |
WO2008015578A2 (en) * | 2006-08-03 | 2008-02-07 | Sanofi-Aventis | Antitumor compositions containing acetylcyclopropyl docetaxel and trastuzumab |
US9393318B2 (en) | 2010-03-29 | 2016-07-19 | Abraxis Bioscience, Llc | Methods of treating cancer |
US9597409B2 (en) | 2010-03-29 | 2017-03-21 | Abraxis Bioscience, Llc | Methods of treating cancer |
US10660965B2 (en) | 2010-03-29 | 2020-05-26 | Abraxis Bioscience, Llc | Methods of enhancing drug delivery and effectiveness of therapeutic agents |
US9399072B2 (en) | 2010-06-04 | 2016-07-26 | Abraxis Bioscience, Llc | Methods of treatment of pancreatic cancer |
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US9820949B2 (en) | 2010-06-04 | 2017-11-21 | Abraxis Bioscience, Llc | Methods of treatment of pancreatic cancer |
Also Published As
Publication number | Publication date |
---|---|
US6441026B1 (en) | 2002-08-27 |
CA2440160A1 (en) | 2002-09-26 |
WO2002074289A2 (en) | 2002-09-26 |
JP2004536790A (en) | 2004-12-09 |
MXPA03008539A (en) | 2004-08-11 |
CA2440160C (en) | 2011-07-05 |
SI1478355T1 (en) | 2007-08-31 |
ES2282400T3 (en) | 2007-10-16 |
PT1478355E (en) | 2007-05-31 |
EA200301047A1 (en) | 2004-06-24 |
EP1478355B1 (en) | 2007-03-07 |
IL157992A (en) | 2008-08-07 |
HUP0500478A2 (en) | 2005-08-29 |
ATE355837T1 (en) | 2007-03-15 |
BR0208274A (en) | 2004-07-13 |
JP4467885B2 (en) | 2010-05-26 |
DK1478355T3 (en) | 2007-07-02 |
WO2002074289A3 (en) | 2004-09-02 |
EP1478355A2 (en) | 2004-11-24 |
CN101590057A (en) | 2009-12-02 |
AU2002244877B2 (en) | 2006-07-20 |
EA006878B1 (en) | 2006-04-28 |
CN1536995A (en) | 2004-10-13 |
DE60218751T2 (en) | 2007-11-22 |
CY1106582T1 (en) | 2012-01-25 |
DE60218751D1 (en) | 2007-04-19 |
WO2002074232A2 (en) | 2002-09-26 |
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