FR2968557A1 - ANTITUMOR COMBINATION COMPRISING A DRIFT OF THE COMBRETASTATIN FAMILY AND THE CETUXIMAB - Google Patents

Abstract

The invention relates to a pharmaceutical antitumor combination comprising a combretastatin family derivative, such as ombrabulin, which may be in base form or in the form of a pharmaceutically acceptable salt, and cetuximab.

Description

ANTITUMOR COMBINATION COMPRISING A DRIFT OF THE COMBRETASTATIN FAMILY AND THE CETUXIMAB

The present invention relates to an antitumor combination comprising a combretastatin family derivative such as AVE8062 (ombrabulin), which may be in base form or in the form of a salt of a pharmaceutically acceptable acid, and cetuximab, this combination being effective in the treatment of cancers and more particularly of solid tumors. Derivatives of the combretastatin family, such as AVE8062, are inhibitors of cell microtubule polymerization. These compounds are Vascular Disrupting Agent (VDA) agents and cetuximab is a monoclonal antibody directed against the human Epidermal Growth Factor Receptor (EGFR) receptor.

[Prior art] Combinations including AVE8062 are described in the following patent documents: - WO 2007/077309 discloses the combination between AVE8062 and VEGF Trap (or aflibercept), an agent preventing tumor angiogenesis. WO 99/51246 describes the combination of AVE8062 and platinum salts. WO 2004/037258 describes the combination between AVE8062 and various antitumor agents selected from taxanes including taxol and taxotere, alkylating agents such as cyclophosphamide, or isosfamide, antimetabolites such as 5-FU or cytarabine, epidophyllotoxin, antibiotics including doxorubicin and vinca alkaloids. EP 1407784 describes the combination of AVE8062 with dexamethasone.

25 On the EMEA website, the Summary of Product Characteristics of cetuximab, marketed under the trade name Erbitux® (http://www.ema.europa.edu/docs/en_GB/document_library/ EPAR _-_ ProductInformation / human / 000558 / WC50 0029119.pdf) indicates that cetuximab may be combined with other anti-cancer treatments such as radiotherapy and platinum-based chemotherapy. The invention relates to a pharmaceutical antitumor combination comprising: a derivative of the combretastatin family, such as AVE8062 of formula OMe MeO OMe, and cetuximab (Erbitux®), an antibody Chimeric monoclonal IgG1 directed against human epidermal growth factor receptor (EGFR). The derivative of the combretastatin family, such as AVE8062, may be in base form or in the form of a salt of a pharmaceutically acceptable acid. The combination comprises an effective amount of a combretastatin family derivative, such as AVE8062, and an effective amount of cetuximab.

The combination may be intended to be administered to a patient during a cycle of from 1 to 4 weeks, more particularly 3 weeks, comprising administration of a combretastatin family derivative such as AVE8062 and three cetuximab administrations. The combination can be shifted in time or concomitantly.

According to one of the preferred embodiments of the invention, the AVE8062 is administered to a patient in an intermittent pattern with a time interval between two administrations (duration of a cycle) ranging from 1 to 4 weeks, for example Three weeks. Cetuximab can be administered to a patient in an intermittent pattern with an interval of one week between two administrations. The invention also relates to the use of a combretastatin family derivative such as AVE8062 and cetuximab for the preparation of the antitumor combination described above.

[Description of the invention] Definitions - pharmaceutically acceptable acid: organic or inorganic acid with low toxicity (see "Pharmaceutical salts" J.Pharm.Sci., 1977, 66, 1-19); a pharmaceutical compound producing an effect on the treated tumor. By derivatives of the family of combretastatins, or derivatives of stilbene, the derivatives of the following general formula: (I) in which A represents a hydroxyl group or an amino group and its pharmaceutically acceptable salts. Among the salts, mention may be made of hydrochloride, acetate, phosphate and methanesulphonate. When the compound or A is an amino group it may also be coupled to amino acids to yield amides as well as their pharmaceutically acceptable salts.

The synthesis of combretastatines, which may be in base form or a pharmaceutically acceptable salt, as well as the pharmaceutical compositions containing them, are described in US Patents 4,996,237; US 5,525,632; US 5,731,353 and US 5,674,906. These patents describe combretastatins and their metabolites and describe their anticancer activity in vitro and in vivo.

Derivatives of the combretastatin family are inhibitors of the polymerization of microtubules of cells.

One of these derivatives, the AVE8062 has the formula: OMe MeO OMe OH NH2 (Isomer Z) It is a tumor-destroying agent (or VDA for "Vascular Disrupting Agent"). It has the chemical name: (Z) -N- [2-methoxy-5- [2- (3,4,5-trimethoxyphenyl) vinyl] phenyl] -L-serinamide. This compound, which is described in EP 731085 B1, can be prepared according to the process described in WO 03/084919.

AVE8062 can 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: OMe MeO OMe Once administered , the AVE8062 in vivo releases the active metabolite (Z) -1- (3-amino-4-methoxyphenyl) -2- (3,4,5-trimethoxyphenyl) ethene which has the formula: OMe We can also substitute AVE8062 another combretastatin of formula OMe MeO OMe OMe N HY in base form or in the form of a salt of a pharmaceutically acceptable acid, wherein Y represents an amino acid, which releases in vivo this metabolite.

Cetuximab is marketed under the trademark Erbitux®. It is a chimeric monoclonal antibody that specifically binds to the extracellular domain of the human epidermal growth factor receptor (EGFR). It is composed of the Fv region of an anti-EGFR murine antibody and human IgG1 constant regions (heavy and kappa chains). It is produced by cell culture of murine myeloma. The EGFR signaling pathways are involved in the control of cell survival, cell cycle progression, angiogenesis, migration, cell invasion, and metastatic cell potential. Cetuximab blocks the binding of endogenous EGFR ligands resulting in inhibition of receptor function.

With regard to the combination, this consists in combining in the form of two separate pharmaceutical preparations a derivative of the combretastatin family, such as AVE8062, and cetuximab. OMe NH2 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) ,. ..). The protocol can be determined by any specialist in oncology.

Thus, the combination may be intended to be administered to a patient during a cycle of from 1 to 4 weeks, more particularly 3 weeks, comprising administration of a combretastatin family derivative, such as AVE8062, and three cetuximab administrations. The combination can be shifted in time or concomitantly.

According to one of the preferred embodiments of the invention, the AVE8062 is administered to a patient in an intermittent pattern with a time interval between two administrations (duration of a cycle) ranging from 1 to 4 weeks, for example 3 weeks . Cetuximab can be administered to a patient in an intermittent pattern with an interval of one week between two administrations. The combination is therefore intended to be administered to a patient during a cycle of from 1 to 4 weeks, more particularly 3 weeks, comprising administration of AVE8062 and three administrations of cetuximab. The combination can be shifted in time or concomitantly.

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. Parenterally, 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. In a particular embodiment, the derivative of the combretastatin family, such as AVE8062, is administered parenterally, such as by intravenous, bolus or infusion administration, and cetuximab is administered parenterally such as the intravenous route. .

A galenic form of AVE8062 adapted to the parenteral route is that in which AVE8062 is in solution in water. A dosage form of cetuximab adapted to the intravenous route is for example that marketed under the Erbitux® brand as a solution for infusion.

The doses of AVE8062 and cetuximab each administered to a patient depend on various parameters such as the nature and stage of the cancer to be treated and the patient to be treated (age, weight, previous treatment (s), ...). AVE8062 can be administered once every 3 weeks at a tolerated dose of 5 to 60 mg / m2 (defined dose for each administration). Cetuximab can be administered at a tolerated dose of between 250 and 400 mg / m2 (defined dose for each administration).

The combination may be effective in the treatment of cancers, more particularly solid tumors in general, preferentially in the treatment of colorectal, head and neck cancers, sarcomas, lung or ovarian cancers.

The effectiveness of a combination can be demonstrated in pre-clinical animal models by determining its therapeutic synergy.

A combination exhibits therapeutic synergy if it is therapeutically superior to the best agent used alone at its optimal dose (T. H. 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. Finally, the synergy in combination can be demonstrated by statistical comparison of the tumor volumes in the different groups. The sum of the effects of the products alone is compared to the effect of combining the products at the same doses using estimates obtained from a two-way analysis of variance (MIXED procedure of the SAS software). It is this latter mode of evaluation which has been used in the experimental tests described hereinafter, carried out in mice with the combination according to the invention.

In these mouse assays, the antitumor activity can be determined according to different parameters such as the dose (in mg / kg) the mode of administration, the time of administration, the toxicity, the variation of tumor weight in the group treated versus the control group on a given day (% ATIAC), the median percentage of tumor regression on a given day, the median time of onset (TC) of a target tumor weight in the treated group (T) compared to the control group (C), and the number of partial tumor regressions (PR = regression of 50% of initial tumor size) and complete (CR = regression below the threshold of palpation). In the experimental tests described below, antitumor activity is reported for AT / AC <40%.

The antitumor activity on solid tumors is experimentally determined as follows: Experimented animals are female SCID mice which are grafted bilaterally subcutaneously with 30 to 60 mg of a primary human tumor fragment. colon, IMM-COLOI, at day 0. This primary tumor overexpressing EGFR has a wild-type K-ras genotype predisposing to respond to cetuximab. The animals carrying tumors having reached a defined tumor size and greater than 120 mg, are distributed in the different groups of treatments and controls, so that the range of tumor size is comparable from one group to the other. other .. Generally, chemotherapy starts from 3 to 22 days after the transplant, depending on the type of tumor and the desired tumor size. The animals are observed and weighed daily. A dose inducing a weight loss of 20% or more on the day when weight loss is maximal (nadir - group average) or a mortality of 10% or more is considered toxic. The evaluation of antitumor activity is carried out at the highest non-toxic dose (HNTD for "Highest Non Toxic Dose"), or at the highest dose tested (HDT for "Highest Tested Dose"), in the context of a non-cytotoxic agent. Tumors are measured 2 or 3 times a week until they reach 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.

In the following studies, AVE8062 in hydrochloride form is formulated in water with 0.9% NaCl. Cetuximab is formulated in phosphate buffer free of calcium and magnesium at a pH of 7.4.

In this study, in which the tumors are treated at an advanced stage, the AVE8062 was administered intravenously on days 21, 25 and 29 following the implantation of the tumor. Cetuximab was administered intraperitoneally on days 21, 25 and 29. When the two agents were administered in combination, the same regimens as those used for the agents alone were resumed, the combination of the two agents being performed at 4 hours apart (AVE8062 administered first) on days 21, 25 and 29.

The loss of body weight is reported on the first day after the end of treatment (D30). The change in tumor weight in the treatment group compared to the control group as well as the median regression percentage are reported 3 days after the last treatment (J32) and the delay is reached for a target tumor weight of 500 mg. Statistical studies compare the times to reach 500mg in the treated groups compared to the control group or compared to the best agent alone. Synergy is evaluated by comparing tumor volumes over a period of 13 days after the end of treatment.

Table I presents the experimental results of the study. The doubling time of the tumor was 4.9 days.

The median tumor weight at the start of treatment was 182 to 195 mg, the control having reached a tumor weight of 500 mg, 29 days after tumor grafting.

The highest dose tested (HDT) of AVE8062 is 58 mg / kg per injection, for a total dose of 174 mg / kg. At this dose, AVE8062 is active with 6/6 partial regressions (PR) and no complete regression (CR). AVE8062 maintains activity at both lower dose levels. The growth time compared to the control group is between 7 and 11 days.

Cetuximab at its highest dose tested (HDT) of 12.5 mg / kg per administration, ie a total dose of 37.5 mg / kg, is active with 1/6 PR and a growth time of 13 days. The lower dose level does not allow the antitumor activity to be retained.

The highest non-toxic dose (HNTD) of the combination was determined at the dose of 58 mg / kg by administration of AVE8062 combined with that of 3.1 mg / kg by administration of cetuximab, the higher doses of the combination being been found toxic. At this HNTD, the combination is very active with 100% partial regressions (6/6 PR) and 33% complete regressions (2/6 CR) of the tumor. Lower doses of the combination are also active, inducing 2-dose CRs and RAs at all dose levels tested. The growth time relative to the control group ranges from 14 days at the lowest dose to 32 days at the HNTD.

Table II presents the statistical analysis of the results of the study. Synergy is observed at day 36 for all combination groups and extends to day 42 for the 3 highest dose levels.

In conclusion, the combination of AVE8062 with cetuximab induces complete tumor regressions, unobserved for the agents alone. These complete regressions in combination are observed at several dose levels. The growth time in combination is consistently higher than that observed in monotherapy and synergy is observed at different dose levels. The combination of AVE8062 with cetuximab thus confers a statistically significant therapeutic benefit in an experimental model of primary human colon tumor.

I. Evaluation of AVE8062 in combination with cetuximab in SCID female mice with human colon archinoma IMM-COLOI: experimental results figent, route Diagram Mortality% bwc% AT / OC% regression Median day TC regressions comments ig / kg / adm (in mg / kg) (day of average to median to median to reach in days deaths) day 30a day 32 day 32 500 mg days partial complete V Cetuximab IP 21,25,29 0/6 -5.4 < 0 53 39.4 10.6 6/6 0/6 HDT, active 0/6 -2.0 <0 40 37.4 8.6 4/6 0/6 Assets 0/6 -7.5 <0 5 36.1 7.3 1/6 0/6 Assets 0/6 -3.7 +40 - 33.9 5.1 0/6 0/6 Inactive 12.5 (37.5) 21, 25, 29 0/6 -7.6 +2 42.3 13.5 1/6 0/6 HDT, active 3.1 (9.3) 0/6 -8.6 +43 35.0 6.2 0/6 0/6 Inactive 12.5 (37.5) 21,25,29 1/6 (30) -1.0 - - - - - - Toxic 3.1 (9.3) 0/6 -3.0 <0 78 60.6 31.8 6 / 6 2/6 HNTD, very active 12.5 (37.5) 0/6 +0.2 <0 92 56.8 28.0 6/6 2/6 Highly active 3.1 (9.3) 0/6 -0.2 <0 80 57.4 28.6 6/6 1 / 6 Very active 12.5 (37.5) 0/6 +2.6 <0 82 59.2 30.4 6/6 0/6 Very active f 3.1 (9.3) 0/6 +0.6 <0 81 50.5 21.7 6/6 0/6 Highly Active 12.5 (37.5) 0/6 +0.6 <0 74 53.5 24.7 6/6 0/6 Highly Active 12.5 (37.5) 0 / 6 -1.0 <0 6 42.4 13.6 1/6 0/6 Double the tumor = 4.9 days. Median tumor weight at start of treatment = 181.5 - 194.5 mg. Median time to reach 500 mg at 28.8 days. Duration of treatment: cetuximab = 9 days, AVE8062 = 9 days. on: AVE8062 in water with 0.9% NaCl; cetuximab in phosphate buffer without calcium or magnesium at pH 7.4) ns: bwc = change in body weight, AT / AC = change in tumor weight in the treated group compared to the control group, TC = time to reach the oral target in the treated group versus the control group, HNTD = highest non-toxic dose, HDT = highest dose tested ison areas of weight loss in the control group (-8.5% at day 30), variations in Body weights are calculated the day after the last treatment 1 II. Evaluation of AVE8062 in combination with cetuximab in SCID female mice with human colon archinoma IMM-COLOI: Statistical analysis froze,% AT / OC% regression path Day statistical statistics on tumor volumes for median comments on times for the evaluation of the therapeutic synergy ig / kg / adm (in mg / kg) Median diagram at the median to reach 500mg in days day 32 day 32 to reach p-value p-valueb J32 p-value J36 p-value J38 p- value J42 p-value 500 mg V Cetuximab IP 21,25,29 <0 53 39.4 P = 0.0026 Active <0 40 37.4 P = 0.0026 Active <0 5 36.1 P = 0.0026 Active +40 - 33.9 P = 0.0015 Inactive 12.5 (37.5 ) 21, 25, 29 +2 - 42.3 P = 0.0026 Active 3.1 (9.3) +43 - 35.0 P = 0.0026 Inactive 12.5 (37.5) 21,25,29 - - - - - - - - - Toxic 3.1 (9.3) < 0 78 60.6 P = 0.0026 P = 0.0228 NS P = 0.0096 P <0.0001 P <0.0001 Synergy at J36, 38 and 12.5 (37.5) <0 92 56.8 P = 0.0026 P = 0.0035 NS P <0.0001 P <0.0001 P = 0.0004 Synergy at D36, 38 and 3.1 (9.3) <0 80 57.4 P = 0.0026 P = 0.0094 P = 0 .0456 P = 0.0006 P = 0.0008 P = 0.0002 Synergy on D32, 36, 38 E 12.5 (37.5) <0 82 59.2 P = 0.0026 P = 0.0239 NS P = 0.0254 NS NS Synergy on D36 3.1 (9.3) <0 81 50.5 P = 0.0026 NS NS P = 0.0041 P = 0.0215 NS Synergy at J36 and 3 £ 12.5 (37.5) <0 74 53.5 P = 0.0026 P = 0.0228 NS P = 0.0259 NS NS Synergy at J36 12.5 (37.5) <0 6 42.4 P = 0.0026 NS active edian of achievement of 500 mg in control = 28.8 days. areas: Log-rank multiple comparisons with Bonferroni-Holm corrections, reported in the group controls multiple log-rank comparisons with Bonferroni-Holm corrections, reported in the cetuximab agent alone group at 12.5 mg / kg / NOVA 2 factors with repeated measures. p-value at the specified day. Ability less than 5% (p-value <0.05) is considered statistically significant. NS = not statistically significant

Claims (7)

REVENDICATIONS1. Antitumor pharmaceutical combination comprising a combretastatin family derivative, which may be in base form or in the form of a pharmaceutically acceptable salt, and cetuximab. The combination of claim 1 wherein the combretastatin family derivative is AVE8062 of formula OMe MeO OMe OMe O ~ OH N H2 10, which may be in base form or in the form of a pharmaceutically acceptable salt. The combination of claim 1 or 2 comprising an effective amount of a combretastatin family derivative and an effective amount of cetuximab. 4. Combination according to one of claims 1 to 3 wherein the combretastatin derivative is in the form of hydrochloride. 2 0 Combination according to one of claims 1 to 4 for its application as a medicament in the treatment of a solid tumor. Combination according to one of claims 1 to 5 for its application as a medicament in the treatment of sarcomas, lung cancers, head and neck, ovarian cancers or colorectal cancers. 7. Use of a derivative of the combretastatin and cetuximab family for the preparation of an antitumor combination as described in one of claims 1 to 6.