WO2012076688A1

WO2012076688A1 - Combination comprising a derivative of the family of the combretastatins and cetuximab

Info

Publication number: WO2012076688A1
Application number: PCT/EP2011/072310
Authority: WO
Inventors: Chantal Carrez; Brigitte Demers; Yvette Ruffin; Patricia Vrignaud
Original assignee: Sanofi
Priority date: 2010-12-09
Filing date: 2011-12-09
Publication date: 2012-06-14
Also published as: FR2968557A1; TW201306833A; AR084169A1; UY33789A

Abstract

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

Description

COMBINATION COMPRISING A DERIVATIVE OF THE FAMILY OF THE

COMBRETASTATINS AND CETUXIMAB

The present invention relates to an antitumour combination comprising a derivative of the family of the combretastatins, such as AVE8062 (ombrabulin), which can be in the form of the base 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 solid tumours. Derivatives of the family of the combretastatins, such as AVE8062, are inhibitors of the polymerization of the microtubules of the cells. These compounds are agents which destroy tumour vessels (VDA for "Vascular Disrupting Agent") and cetuximab is a monoclonal antibody directed against the human epidermal growth factor receptor (EGFR).

[Prior art]

Combinations including AVE8062 are described in the following patent documents:

- WO 2007/077309 describes the combination between AVE8062 and VEGF Trap (or aflibercept), an agent which prevents tumour angiogenesis.

- WO 99/51246 describes the combination of AVE8062 and platinum salts.

- WO 2004/037258 describes the combination between AVE8062 and various antitumour agents chosen from taxanes, including taxol and taxotere, alkylating agents, such as cyclophosphamide or ifosfamide, antimetabolites, such as 5-FU or cytarabine, epidophyllotoxin, antibiotics, including doxorubicin, and vinca alkaloids.

- EP 1407784 describes the combination of AVE8062 with dexamethasone.

On the EMA site, the Summary of Product Characteristics for cetuximab, sold under the Erbitux® brand, (http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_- _Product_lnformation/human/000558/WC5000291 19.pdf) indicates that cetuximab can be combined with other anticancer treatments, such as radiotherapy and chemotherapy based on platinum salts.

[Brief description of the invention]

The invention relates to an antitumour pharmaceutical combination comprising:

- a derivative of the family of the combretastatins, such as AVE8062 of formula

, and - cetuximab (Erbitux^®), a chimeric \gG<_\ monoclonal antibody directed against the human epidermal growth factor receptor (EGFR).

The derivative of the family of the combretastatins, such as AVE8062, can be in the form of the base or in the form of a salt of a pharmaceutically acceptable acid.

The combination comprises an effective amount of a derivative of the family of the combretastatins, such as AVE8062, and an effective amount of cetuximab. The combination is suitable for administration to a patient during a cycle which can range from 1 to 4 weeks, more particularly 3 weeks, comprising one administration of a derivative of the family of the combretastatins, such as AVE8062, and three administrations of cetuximab. The combination can be offset in time or concomitant. According to one of the preferred implementations of the invention, AVE8062 is administered to a patient according to an intermittent scheme with an interval between two administrations (duration of a cycle) which can range from 1 to 4 weeks, for example 3 weeks. The cetuximab can, for its part, be administered to a patient according to an intermittent scheme with an interval of one week between two administrations.

The invention also relates to the use of a derivative of the family of the combretastatins, such as AVE8062, and of cetuximab in the preparation of the antitumour combination described above. [Description of the invention]

Definitions

• Pharmaceutically acceptable acid: organic or inorganic acid exhibiting a low toxicity (see "Pharmaceutical salts", J. Pharm. Sci., 1977, 66, 1-19);

• effective amount: amount of a pharmaceutical compound which produces an effect on the tumour treated.

The term "derivatives of the family of the combretastatins" or "stilbene derivatives" is understood to mean a derivative of the following general formula:

in which A represents a hydroxyl group or an amino group, and their pharmaceutically acceptable salts.

Mention may be made, among the salts, of the hydrochloride, acetate, phosphate or methanesulphonate.

When A is an amino group, the compound of formula (I) can also be coupled to amino acids in order to result in amides and their pharmaceutically acceptable salts.

The synthesis of the combretastatins, which can be in the form of the base or of a

pharmaceutically acceptable salt, and the pharmaceutical compositions which comprise them are described in Patents US 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 in vitro and in vivo anticancer activity.

The derivatives of the family of the combretastatins are inhibitors of the polymerization of the microtubules of the cells.

One of these derivatives, AVE8062, has the formula:

(Z isomer)

This is an agent which destroys tumour vessels (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 the form of the base (cf. above formula) or in the form of a salt of a pharmaceutically acceptable acid, for example in the form of the hydrochloride, represented below:

Once administered, AVE8062 releases in vivo the active metabolite (Z)-1-(3-amino- 4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl)ethene, which has the formula:

It is thus also possible to replace AVE8062 with another combretastatin of formula:

in the form of the base or in the form of a salt of a pharmaceutically acceptable acid, in which Y represents an amino acid, which releases this metabolite in vivo. Cetuximab is sold under the Erbitux^® brand. It is a chimeric monoclonal antibody which specifically binds to the extracellular domain of the human epidermal growth factor receptor (EGFR). It is composed of the Fv region of a murine anti-EGFR antibody and of the human lgG1 constant regions (heavy and kappa chains). It is produced by cell culturing of a murine myeloma.

EGFR signalling pathways are involved in the control of cell survival, the progression of the cell cycle, angiogenesis, migration, cell invasion and cell metastatic potential. Cetuximab blocks the binding of EGFR endogenous ligands, resulting in inhibition of the function of the receptor. As regards the combination, the latter consists in combining, in the form of two distinct pharmaceutical preparations, a derivative of the family of the combretastatins, such as AVE8062, and cetuximab.

The combination is suitable for an administration which is repeated during several cycles according to a protocol which depends on the nature and the stage of the cancer to be treated and on the patient to be cared for (age, weight, previous treatment(s), and the like). The protocol can be determined by any practitioner who is a specialist in oncology.

Thus, the combination is suitable for the administration to a patient during a cycle which can range from 1 to 4 weeks, more particularly 3 weeks, comprising one administration of the derivative of the family of the combretastatins, such as AVE8062, and three administrations of cetuximab. The combination can be offset in time or concomitant.

According to one of the preferred implementations of the invention, AVE8062 is administered to a patient according to an intermittent scheme with an interval between two administrations (duration of a cycle) which can range from 1 to 4 weeks, for example 3 weeks. The cetuximab can, for its part, be administered to a patient according to an intermittent scheme with an interval of one week between two administrations. The combination is thus suitable for the administration to a patient during a cycle which can range from 1 to 4 weeks, more particularly 3 weeks, comprising one administration of AVE8062 and three administrations of cetuximab. The combination can be offset in time or concomitant.

According to a specific embodiment, the present invention relates to a pharmaceutical kit intended in particular to treat cancers and more particularly solid tumours, for example colorectal cancer, head cancer, neck cancer, sarcomas, lung cancer or ovarian cancer, comprising:

(i) a first pharmaceutical dosage formulation comprising ombrabulin or AVE8062 in the form of the base or of a pharmaceutically acceptable salt,

(ii) a second pharmaceutical dosage formulation comprising cetuximab, the two pharmaceutical dosage formulations (i) and (ii) being intended to be administered independently of one another, separately, simultaneously or spread out over time with respect to one another.

The method of administration can be the parenteral route and/or the oral route and depends on the pharmaceutical dosage form used for the antitumour agent. By the parenteral route, the antitumour agent can be administered by the intravenous bolus route or can be prepared in an intravenous infusion bag, with pharmaceutically acceptable vectors, by various processes known to a person skilled in the art. According to a specific form, the derivative of the family of the combretastatins, such as AVE8062, is administered by the parenteral route, such as by intravenous administration, as a bolus or by infusion, and the cetuximab is administered by the parenteral route, such as the intravenous route.

A pharmaceutical dosage form of AVE8062 suitable for the parenteral route is that where AVE8062 is in solution in water. A pharmaceutical dosage form of cetuximab suitable for the intravenous route is, for example, that sold under the Erbitux^® brand in the form of a solution for infusion.

The doses of AVE8062 and cetuximab administered on each occasion to a patient depend on various parameters, such as the nature and the stage of the cancer to be treated and also the patient to be cared for (age, weight, previous treatment(s), and the like). The AVE8062 can be administered once every 3 weeks at a tolerated dose of between 5 and 60 mg/m² (dose defined for each administration). The cetuximab can, for its part, be administered at a tolerated dose of between 250 and 400 mg/m² (dose defined for each administration). The combination may be effective in the treatment of cancers, more particularly solid tumours in general, for example in the treatment of colorectal cancer, head cancer, neck cancer, sarcomas, lung cancer or ovarian cancer.

The effectiveness of a combination can be demonstrated in preclinical animal models by the determination of its therapeutic synergy.

A combination displays a 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, 1 187).

The effectiveness of a combination can also be demonstrated by comparison of the maximum tolerated dose of the combination with the maximum tolerated dose of each of the separate constituents in the study in question.

Finally, the combination synergy can be demonstrated by statistical comparison of the tumour volumes in the various groups. The sum of the effects of the products alone is compared with the effect of the combination of the products at the same doses using valuations obtained from a two-factor analysis of variance (MIXED procedure of the SAS software). It is the latter method of evaluation which was used in the experimental trials described below, carried out on mice with the combination according to the invention.

In these trials on mice, the antitumour activity can be determined in accordance with various parameters, such as the dose (in mg/kg), the method of administration, the administration time, the toxicity, the variation in tumour weight in the treated group in comparison with the control group on a given day (%ΔΤ/ΔΟ), the median percentage of tumour regression on a given day, the median waiting time (T-C) for a target tumour weight in the treated group (T) in comparison with the control group (C), and the number of partial tumour regressions (PR = regression of 50% of the initial tumour size) and complete tumour regressions (CR = regression below the palpation threshold). In the experimental trials described below, an antitumour activity is claimed for ΔΤ/ΔΟ < 40%. The antitumour activity with regard to solid tumours is determined experimentally in the following way: the animals subjected to the experiment are female SCID mice which are bilaterally grafted subcutaneously with from 30 to 60 mg of a fragment of IMM-COL01 human colon primary tumour on day 0. This primary tumour, which overexpresses EGFR, exhibits a genotype of K-ras wild type which predisposes it to respond to cetuximab. The animals carrying tumours which have reached a predefined tumour size of greater than 120 mg are distributed into different groups, treatment groups and control groups, so that the range of tumour size is comparable from one group to the other.

Generally, the chemotherapy is begun from 3 to 22 days after grafting, according to the type of tumour and the desired tumour size. The animals are observed and weighed every day. A dose which induces a loss in weight of 20% or more on the day where the loss in weight is maximum (nadir - mean of the group) or a mortality of 10% or more is regarded as toxic. The antitumour activity is evaluated at the highest nontoxic dose (HNTD) or at the highest dose tested (HDT), in the context of a noncytotoxic agent. The tumours are measured 2 or 3 times weekly until they reach approximately 2 g or until the animal dies, if this occurs before the tumour reaches 2 g. The animals are autopsied when they are sacrificed.

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

In this study, where the tumours are treated at an advanced stage, the AVE8062 was administered intravenously on days 21 , 25 and 29 following the implantation of the tumour. The cetuximab was administered intraperitoneally on days 21 , 25 and 29. When the two agents were administered in combination, the same schemes as those used for the agents alone were adopted, the combination of the two agents having been carried out at an interval of 4 hours (AVE8062 administered first) on days 21 , 25 and 29.

The loss in body weight is with respect to the first day following the end of the treatment (D30). The variation in tumour weight in the treated group in comparison with the control group and the median percentage of regression are reported 3 days after the final treatment (D32) and the waiting time is calculated for a target tumour weight of 500 mg. The statistical studies compare the times to reach 500 mg in the treated groups in comparison with the control group or in comparison with the better agent alone. The synergy is evaluated by comparing the tumour volumes over a period of 13 days after the end of the treatment.

The experimental results of the study are presented in Table I. The doubling time for the tumour was 4.9 days. The median tumour weight at the beginning of the treatments was from 182 to 195 mg, the control having reached a tumour weight of 500 mg 29 days after the tumour graft.

The highest dose tested (HDT) of the AVE8062 is 58 mg/kg per injection, i.e. a total dose of 174 mg/kg. At this dose, the AVE8062 is active with 6/6 partial regressions (PR) and no complete regression (CR). The AVE8062 retains its activity at the two lower dose levels. The growth delay in comparison with the control group ranges between 7 and 1 1 days.

Cetuximab at its highest dose tested (HDT) of 12.5 mg/kg per administration, i.e. a total dose of 37.5 mg/kg, is active with 1/6 PR and a growth delay of 13 days. The lower dose level does not make it possible to retain the antitumour activity.

The highest nontoxic dose (HNTD) of the combination was determined at the dose of 58 mg/kg per administration of AVE8062 combined with that of 3.1 mg/kg per administration of cetuximab, the higher doses of the combination having been found to be toxic. At this HNTD, the combination is very active with 100% of partial regressions (6/6 PR) and 33% of complete regressions (2/6 CR) of the tumour. The lower doses of the combination are also active, bringing about CRs at 2 dose levels and PRs at all the dose levels tested. The growth delay in comparison with the control group ranges between 14 days, at the lowest dose, and 32 days, at the HNTD.

The statistical analysis of the results of the study are presented in Table II.

A synergy is observed on day 36 for all the combination groups and persists up to day 42 for the 3 highest dose levels. In conclusion, the combination of AVE8062 with cetuximab brings about complete tumour regressions, nonobserved for the agents alone. These combination complete regressions are observed at several dose levels. The combination growth delay is systematically greater than that observed in monotherapy and a synergy is observed at different dose levels. The combination of AVE8062 with cetuximab thus confers a statistically significant therapeutic advantage in a human colon primary tumour experimental model. Table I. Evaluation of AVE8062 in connbination with cetuximab with regard to female SCID mice carrying the IMM-COL01 human colon adenocarcinoma: experimental results

Mortality Mean % Median % Median % Median day for Regressions

Agent, Route Scheme T-C in

(day of bwc on ΔΤ/ΔΟ on regression on reaching Comments Dose in mg/kg/adm (in mg kg) in days days

death) day 30" day 32 day 32 500 mg

Partial Complete

AVE8062 IV Cetuximab IP

58.0 (174.0) 21,25,29 0/6 -5.4 <0 53 39.4 10.6 6/6 0/6 HDT, active

36.0 (108.0) 0/6 -2.0 <0 40 37.4 8.6 4/6 0/6 Active

22.3 (66.9) 0/6 -7.5 <0 5 36.1 7.3 1/6 0/6 Active

13.8 (41.4) 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

58.0 (174.0) 12.5 (37.5) 21,25,29 1/6 (30) -1.0 - - - - - - Toxic

58.0 (174.0) 3.1 (9.3) 0/6 -3.0 <0 78 60.6 31.8 6/6 2/6 HNTD, very active

36.0 (108.0) 12.5 (37.5) 0/6 +0.2 <0 92 56.8 28.0 6/6 2/6 Very active

36.0 (108.0) 3.1 (9.3) 0/6 -0.2 <0 80 57.4 28.6 6/6 1/6 Very active

22.3 (66.9) 12.5 (37.5) 0/6 +2.6 <0 82 59.2 30.4 6/6 0/6 Very active

22.3 (66.9) 3.1 (9.3) 0/6 +0.6 <0 81 50.5 21.7 6/6 0/6 Very active

13.8 (41.4) 12.5 (37.5) 0/6 +0.6 <0 74 53.5 24.7 6/6 0/6 Very active

8.6 (25.8) 12.5 (37.5) 0/6 -1.0 <0 6 42.4 13.6 1/6 0/6 Active

Doubling time of the tumour = 4.9 days. Median tumour weight at the beginning of the treatments = 181.5 - 194.5 mg. Median waiting time for 500 mg in the control = 28.8 days. Duration of the treatment: cetuximab = 9 days, AVE8062 = 9 days.

Formulation: AVE8062 in water with 0.9% NaCI; cetuximab in a calcium-free and magnesium-free phosphate buffer at pH 7.4.

Abbreviations: bwc = body weight change, ΔΤ/AC = variation in tumour weight in the treated group in comparison with the control group, T-C = waiting time for the target tumour weight in the treated group in comparison with the control group, HNTD = highest nontoxic dose, HDT = highest dose tested.

Comments:

a = due to the loss in weight in the control group (-8.5% on day 30), the body weight changes are calculated the day after the final treatment

Table II. Evaluation of AVE8062 in combination with cetuximab with regard to female SCID mice carrying the IMM-COL01 human colon adenocarcinoma: statistical analysis

Statistics Statistics with regard to the tumour volumes for Comments

Median

Median % Median % with regard to the the evaluation of the therapeutic synergy

Agent, Route Scheme day for

ΔΤ/ΔΟ on regression times for reaching

Dose in mg/kg/adm (in mg/kg) in days reaching

day 32 on day 32 500 mg

500 mg

p-vakje° p-value¹" D32p-value^c Γ-Οδρ-νε*^ D38 revalue' D42 p-value^c

AVE8062 IV Cetuximab IP

58.0 (174.0) 21,25,29 <0 53 39.4 P=0.0026 - - Active

36.0 (108.0) <0 40 37.4 P=0.0026 - - - Active

22.3 (66.9) <0 5 36.1 P=0.0026 - - - Active

13.8 (41.4) +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

58.0 (174.0) 12.5 (37.5) 21,2529 - - - - - - - Toxic

58.0 (174.0) 3.1 (9.3) <0 78 60.6 P=0.0026 P=0.0228 NS P=0.0096 P<0.0001 PO.0001 Synergy at 036, 38 and 42

36.0 (108.0) 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 42

36.0 (108.0) 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 at D32, 36, 38 and

42

22.3 (66.9) 12.5 (37.5) <0 82 59.2 P=0.0026 P=0.0239 NS P=0.0254 NS NS Synergy at D36

22.3 (66.9) 3.1 (9.3) <0 81 50.5 P=0.0026 NS NS P=0.0041 P=0.0215 NS Synergy at D36 and 38

13.8 (41.4) 12.5 (37.5) <0 74 53.5 P=0.0026 P=0.0228 NS P=0.0259 NS NS Synergy at D36

8.6 (25.8) 12.5 (37.5) <0 6 42.4 P=0.0026 NS - - Active

Median waiting time for 500 mg in the control = 28.8 days.

Comments:

a = Log-rank multiple comparisons tests with Bonferroni-Holm corrections, with respect to the control group

b = Log-rank multiple comparisons tests with Bonferroni-Holm corrections, with respect to the cetuximab group (agent alone) at the dose of 12.5 mg/kg

c = 2-factor ANOVA test with repeated measurements, p-value on the day D specified.

A probability of less than 5% (p-value < 0.05) is regarded as statistically significant. NS = not statistically significant

Claims

1. Pharmaceutical combination comprising a derivative of the family of the combretastatins, which can be in the form of the base or in the form of a pharmaceutically acceptable salt, and cetuximab.

2. Combination according to Claim 1 , in which the derivative of the family of the combretastatins is AVE8062 of formula:

which can be in the form of the base or in the form of a pharmaceutically acceptable salt.

3. Combination according to Claim 1 or 2, comprising an effective amount of a derivative of the family of the combretastatins and an effective amount of cetuximab.

4. Combination according to one of Claims 1 to 3, in which the derivative of the combretastatins is in the hydrochloride form.

5. Combination according to any one of Claims 1 to 4, suitable for administration to a patient during a cycle comprising one administration of a derivative of the family of the combretastatins and three administrations of cetuximab, the combination being offset in time or concomitant.

6. Combination according to Claim 5, suitable for administration to a patient during a cycle for which the cycle is repeated, the interval between two administrations of the derivative of the family of the combretastatins ranging from 1 to 4 weeks.

7. Combination according to one of Claims 1 to 6, suitable for administration of the derivative of the family of the combretastatins by the parenteral route and/or of cetuximab by the parenteral route.

8. Pharmaceutical combination comprising a derivative of the family of the combretastatins, which can be in the form of the base or in the form of a pharmaceutically acceptable salt, and cetuximab for the use thereof in the treatment of cancers.

9. Combination for the use thereof according to Claim 8, in which the derivative of the family of the combretastatins is AVE8062 of formula:

10. Combination for the use thereof according to either of Claims 8 and 9, comprising an effective amount of AVE8062 and an effective amount of cetuximab.

11. Combination for the use thereof according to one of Claims 8 to 10, in which the AVE8062 is in the hydrochloride form.

12. Combination according to one of Claims 8 to 1 1 for the use thereof in the treatment of a solid tumour.

13. Combination according to one of Claims 8 to 12 for the use thereof in the treatment of sarcomas, lung cancer, head cancer, neck cancer, ovarian cancer or colorectal cancer.

14. Pharmaceutical combination, comprising:

- a derivative of the family of the combretastatins, which can be in the form of the base or in the form of a pharmaceutically acceptable salt,

- and cetuximab,

in the preparation of a medicament for the treatment of cancers.

15. Use of a derivative of the family of the combretastatins and cetuximab in the preparation of an antitumour combination as described in one of Claims 1 to 14.

16. Pharmaceutical kit, comprising: (i) a first pharmaceutical dosage formulation comprising ombrabulin or AVE8062 in the form of the base or of a pharmaceutically acceptable salt,

(ii) a second pharmaceutical dosage formulation comprising cetuximab,

the two pharmaceutical dosage formulations (i) and (ii) being intended to be administered independently of one another, separately, simultaneously or spread out over time with respect to one another.

17. Pharmaceutical kit according to Claim 16, for the use thereof in the treatment of a solid tumour.

18. Pharmaceutical kit according to either of Claims 16 and 17, for the use thereof in the treatment of sarcomas, lung cancer, head cancer, neck cancer, ovarian cancer or colorectal cancer.