Classifications

• • 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
  • A61K31/16—Amides, e.g. hydroxamic acids
  • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
  • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
• • 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
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
• • 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
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • 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 an antitumor combination combining AVE8062 and sorafenib effective in the treatment of cancers, more particularly solid tumors.
• WO 2007/077309 discloses the combination of antiviral AVE8062 (or VDA, Vascular Disrupting Agent) and antiangiogenic VEGF Trap.
• WO 99910779 describes the combination AVE8062 / platinum salt.
• WO 2004/037258 describes the combination AVE8062 with various antitumor agents chosen from taxanes (taxol, taxotere), alkylating agents (cyclophosphamide, isosfamide, etc.), antimetabolites (5-FU, cytarabine, etc.), epidophylloptoxin, antibiotics (doxorubicin, %), vinca alkaloids.
• EP 1407784 describes the combination AVE8062 / dexamethasone.
• the Nexavar ® (sorafenib tosylate) may be combined with different anti-cancer agents such as gemcitabine, oxaliplatin, doxorubicin, irinotecan or docetaxel.
• different anti-cancer agents such as gemcitabine, oxaliplatin, doxorubicin, irinotecan or docetaxel.
• the invention relates to a pharmaceutical antitumor combination comprising I AVE8062
• antitumour agents can be formulated in base form or in the form of a salt of a pharmaceutically acceptable acid.
• the combination comprises an effective amount of I ⁇ VE8062 and an effective amount of sorafenib.
• the combination is intended to be administered to a patient during a cycle comprising administration of AVE8062 marking the onset of said cycle and multiple administrations of sorafenib, the combination being time-shifted and non-concomitant, I ⁇ VE8062 being administered prior to any first administration of sorafenib.
• LVE8062 can be administered on the same day as sorafenib with a delay of 1 to 4 hours before the first administration of sorafenib.
• LVE8062 can also be given the day before the very first administration of sorafenib, especially with a delay of at least 24 hours.
• the cycle is repeated, the interval between two administrations of AVE8062 ranging from 1 to 4 weeks.
• the invention also relates to the use of AVE8062 and sorafenib for the preparation of the antitumor combination described above.
• Effective amount amount of a pharmaceutical compound producing an effect on the treated tumor.
• I ⁇ VE8062 that belongs to the combretastatin family and has the formula:
• LVE8062 may be administered in base form (see formula above) or in the form of a salt of a pharmaceutically acceptable acid, for example in the form of the hydrochloride, represented below:
• I ⁇ VE8062 releases in vivo the active metabolite (Z) -1- (3-amino-4-methoxyphenyl) -2- (3,4,5-trimethoxyphenyl) ethene which has the formula:
• Sorafenib is marketed by Bayer HealthCare under the brand name Nexavar ® .
• Sorafenib is a multikinase inhibitor targeting VEGF and BRAF receptors that has the chemical formula: and is chemically named: 4- [4 - [[4-chloro-3- (trifluoromethyl) phenyl] carbamoylamino] phenoxy] -N-methyl-pyridine-2-carboxamide. It is an antiangiogenic agent. This compound is described in WO 00/42012 and WO 00/41698.
• Sorafenib may be administered in base form (see formula above) or in the form of a salt of a pharmaceutically acceptable acid, for example in the form of tosylate.
• this consists of combining two separate pharmaceutical preparations I ⁇ VE8062 and sorafenib.
• the combination is administered repeatedly over several cycles according to a protocol that depends on the nature and stage of the cancer to be treated and the patient to be treated (age, weight, previous treatment (s), ... ).
• Each cycle begins with the administration of I ⁇ VE8062 and includes in addition to this one, several administrations of sorafenib (a cycle is thus characterized by an administration of AVE8062 marking the beginning of this cycle and several administrations of sorafenib).
• LVE8062 is administered to a patient in an intermittent regimen with an interval between two administrations (duration of a cycle) ranging from 1 to 4 weeks, for example 3 weeks (note: in the context of the tests on mice, the I intervalleVE8062 administration interval was 4 or 5 days).
• Sorafenib can be administered to a patient on a daily schedule for a certain period of the cycle. Sorafenib may possibly be administered until the end of a cycle.
• the mode of administration may be the parenteral route and / or the oral route and depends on the dosage form used for the antitumor agent.
• the antitumor agent may be administered intravenously as a bolus or prepared in an intravenous infusion bag, with pharmaceutically acceptable carriers by various methods known to those skilled in the art.
• AVE8062 is administered parenterally, such as by intravenous, bolus or infusion administration, and sorafenib is administered orally.
• a galenic form of I ⁇ VE8062 adapted to the parenteral route is that in which I ⁇ VE8062 is in solution in water.
• a dosage form of sorafenib adapted to the oral route is for example that marketed under the trademark Nexavar ® in the form of tablets containing 274 mg of sorafenib in the form of sorafenib tosylate (equivalent to 200 mg of active principle).
• LVE8062 may be administered at a tolerated dose of 5 to 100, 5 and 60, 10 and 50, 20 and 42, 20 and 40 mg / m 2 (body weight / area, defined dose for each administration).
• Sorafenib can be administered at a tolerated dose of 200 to 600 mg, 300 and 500 mg (defined dose for each administration). Sorafenib can be taken twice a day at a dose of active ingredient of 200 mg, which corresponds to a daily dose of 400 mg.
• the combination is effective in treating cancers, particularly solid tumors in general, more particularly sarcoma, lung, ovarian, kidney or liver cancers.
• I AVE8062 is administered on the same day and with a delay of 1 to 4 hours before the first administration of sorafenib.
• I AVE8062 is administered the day before the very first administration of sorafenib.
• the time between the administration of I ⁇ VE8062 and all 1 st administration of sorafenib is at least 24 hours.
• the effectiveness of a combination can be demonstrated by the determination of its therapeutic synergy.
• a combination exhibits therapeutic synergy if it is therapeutically superior to the best agent used alone at its optimal dose (TH Corbett et al., Cancer Treatment Reports 1982, 66, 1187).
• the effectiveness of a combination can also be demonstrated by comparing the maximum tolerated dose of the combination with the maximum tolerated dose of each of the separate components in the study in question.
• logio of the killed cells TC (days) / 3.32 x T d in which TC represents the tumor growth delay, which is the average time in days for the tumors of the treated group (T) to reach a predetermined value (1 g for example) and for the tumors of the control group (C) to reach the same value and T d represents the time in days necessary for tumor volume of the dual control group during the exponential phase of tumor growth (TH Corbett et al, Cancer, 1977, 40, 2660-2680, FM Schabel et al., Cancer Drug Development, Part B, Methods in Cancer Research 1979 , 17, 3-51, New York, Academy Press Inc.).
• a product is considered active if the logio of the cells killed is greater than or equal to 0.7.
• a product is considered very active if the logio is greater than 2.8.
• the activity in this case is declared for a positive net log cell kill (> 0).
• a cytostatic activity corresponds to a net log cell kill of 0, i.e., the duration of treatment is equal to the duration of the antitumor effect.
• 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 a therapeutic synergy when the logio of the killed cells is at least 1 log it is compared to the logio value of the killed cells of the best constituent when administered alone.
• the effectiveness of the combinations on solid tumors can be determined experimentally as follows:
• the animals under experiment are female SCID mice that are grafted bilaterally subcutaneously with 30 to 60 mg of a tumor fragment. non-small cell lung cancer, NCI-H460 (ATCC # HTB-177) at day 0.
• NCI-H460 non-small cell lung cancer
• the implanted animals are distributed randomly into different groups intended to receive or not (checks), the treatment (s).
• the animals, tumor carriers having reached a defined tumor size and greater than 150 mg are distributed in the different groups, treatments and controls, so that the tumor size range is comparable from one group to another.
• Non-tumor bearing animals may also be subjected to the same treatments as tumor bearing animals in order to be able to dissociate the toxic effect from the specific effect on the tumor.
• chemotherapy begins 3 to 22 days after the transplant, depending on the type of tumor and tumor size desired. The animals are observed and weighed daily. A dose inducing a weight loss of 20% or more in nadir (group average) or a mortality of 10% or more is considered toxic.
• the evaluation of the tumor activity is carried out at the highest non-toxic dose, or at the highest dose tested, as part of a non-cytotoxic agent.
• Tumors are measured 2 or 3 times a week until the tumor reaches approximately 2 g or until the animal dies if it occurs before the tumor reaches 2 g. The animals are autopsied when they are sacrificed.
• the antitumor activity is determined according to various recorded parameters such as the dose (mg / kg), the mode of administration, the administration time, the toxicity and the log-10 of the killed cells which is a function of the growth time. tumoral as well as the doubling time of the tumor.
• I AVE8062 as hydrochloride is formulated in water with 0.9% NaCl.
• Sorafenib is formulated with 12.5% ethanol, 12.5% polysorbate 80 and 75% glucose 5% in water.
• the doubling time of the tumor was two days.
• the median tumor weight at the start of treatment was 219 to 234 mg, with control reaching a tumor weight of 1000 mg, 12.8 days after tumor grafting.
• HED The highest dose tested (HED) of I ⁇ VE8062 is 58 mg / kg per injection, for a total dose of 116 mg / kg.
• the highest non-toxic dose (HNTD) of the combination was determined at a dose of 36 mg / kg by administration of AVE8062 combined with that of 62 mg / kg by administration of sorafenib, the higher doses of the combination being found toxic.
• HNTD non-toxic dose
• the combination is active with 2.4 log cell kill, and 0.0 log cell kill net. However, no partial regression was obtained at this dose.
• the lower doses of the combination are also active (2.2 to 2.5 log cell kill), without inducing either tumor regression.
• LVE8062 was administered intravenously on days 10 and 14 following tumor implantation. Sorafenib was administered orally from day 10 to day 14. The two agents were administered in combination, according to the same regimens as those used for the agents alone, but the administration of sorafenib having been shifted one hour after the administration of I ⁇ VE8062.
• the doubling time of the tumor was 1, 6 days.
• the median tumor weight at the start of treatment was 431 to 458 mg, the control having reached a tumor weight of 1500 mg, 13.2 days after tumor grafting.
• the 2 highest doses of AVE8062 were toxic and the highest non-toxic dose (HNTD) was 22.3 mg / kg per injection, for a total dose of 44.6 mg / kg.
• HNTD non-toxic dose
• I ⁇ VE8062 is active with 1.1 log-10 of killed cells (log cell kill), without inducing tumor regression.
• the HNTD of the combination was determined at the dose of 58 mg / kg by administration of AVE8062 combined with that of 38.4 mg / kg by administration of sorafenib, the higher doses of the combination being found to be toxic.
• the combination is active with 2.1 log cell kill, which is 1 log cell kill more than the agents only 1, 1 log cell kill for each).
• Five lower doses of the combination are also active, with a log cell kill of 1, 9 to 1, 5, and inducing PR at 4 dose levels.
• LVE8062 was administered intravenously on days 9 and 14 following the implantation of the NCI-H460 lung tumor in female SCID mice. Sorafenib was administered orally from day 9 to day 20. When the 2 agents were administered in combination, the same regimens were used as for the agents alone, but sorafenib administrations were started 24 hours after I ⁇ VE8062.
• the doubling time of the tumor was 1.5 days.
• the median tumor weight at the start of treatment was 217-235 mg, with control reaching a tumor weight of 1000 mg, 13.6 days post-tumor.
• HNTD non-toxic dose
• the HNTD of the combination was determined at the dose of 36 mg / kg by administration of AVE8062 combined with that of 100 mg / kg by administration of sorafenib, the higher doses of the combination having been found to be toxic.
• the combination is very active with 3.1 log cell kill, and 0.3 log cell kill net.
• Tumor doubling time 2 days.
• Median tumor weight at the start of treatment 219 - 234 mg.
• HED highest dose evaluated
• HNTD highest non-toxic dose
• HDT highest dose tested
• PR partial regressions
• CR full regressions.
• Tumor doubling time 1.6 days.
• Median tumor weight at the start of treatment 431 - 458 mg.
• Median time to reach 1500 mg at control 13.2 days.
• HNTD highest non-toxic dose
• HDT highest dose tested
• BWC change in body weight
• Tumor doubling time 1.5 days.
• Median tumor weight at the start of treatment 217-235 mg.
• Median time to reach 1000 mg at control 13.6 days.
• HNTD highest non-toxic dose
• HDT highest dose tested
• PR partial regressions
• CR full regressions.

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