TW201306833A - Combination comprising a derivative of the family of the combretastatins and cetuximab - Google Patents

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

Contains a combination of the COMBRETASTATINS derivative and Cetuximab (CETUXIMAB)

The present invention relates to a composition comprising a combretastatin family derivative such as AVE8062 (ombrabulin, which may be in the form of a base or a salt of a pharmaceutically acceptable acid) and Citadel An anti-tumor combination of cetuximab. This combination is effective in the treatment of cancer and, more specifically, solid tumors. The compstatin derivative (such as AVE8062) is an inhibitor of cellular microtubule polymerization. It is a preparation for destroying tumor blood vessels ("Vascular Disrupting Agent", abbreviated as VDA), and cetuximab is a monoclonal antibody directed against human epidermal growth factor receptor (EGFR).

The combination including AVE8062 has been described in the following patent documents:

- WO 2007/077309 describes a combination between AVE8062 and VEGF Trap (or ablibercept), an agent that blocks tumor angiogenesis.

- WO 99/51246 describes a combination of AVE8062 and a platinum salt.

-WO 2004/037258 describes a combination between AVE8062 and a plurality of antineoplastic agents selected from taxanes, including paclitaxel and taxotere, alkylating agents such as cyclophosphamide or isocyclic phosphorus Indoleamine), antimetabolite (such as 5-FU or cytarabine), epidophyllotoxin, antibiotics (including doxorubicin), and vinca alkaloids.

-EP 1407784 describes a combination of AVE8062 and glucocorticoids (Dexamethason).

On the EMA website, take Erbitux An overview of the product characteristics of cetuximab sold under the trademark (http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_Product_Information/human/000558/WC500029119.pdf) indicating that cetuximab can be combined with Other anti-cancer therapeutic combinations, such as platinum-based radiation therapy and chemotherapy.

The present invention relates to an anti-tumor pharmaceutical combination comprising:

- a compstatin derivative, such as AVE8062, and

- Cetuximab (Erbitux) ), a monoclonal antibody directed against the human epidermal growth factor receptor (EGFR).

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

The combination comprises an effective amount of a cebritastatin derivative (such as AVE8062) and an effective amount of cetuximab.

This combination is suitable for administration to patients over a period of 1 to 4 weeks (more specifically, 3 weeks), including administration of one cebritastatin derivative such as AVE8062, and administration of cetuximab three times. . This combination can be adjusted over time or in parallel.

In accordance with one of the preferred embodiments of the present invention, AVE8062 is administered to a patient based on an intermittent dosing regimen between 1 and 4 weeks (e.g., 3 weeks) between administrations (within one cycle). Regarding the portion of cetuximab, it can be administered to patients based on an intermittent course of administration between the two administrations.

The invention also relates to the use of a sultastatin derivative (such as AVE8062) and cetuximab for the preparation of the above antitumor combination.

definition

• pharmaceutically acceptable acids: organic or inorganic acids with low toxicity (see "Pharmaceutical salts", J. Pharm. Sci., 1977, 66, 1-19);

• Effective amount: The amount of pharmaceutical compound used to effect an effect on the tumor being treated.

The term "combrittastatin derivative" or "stilbene derivative" is understood to mean a derivative of the following formula:

Wherein A represents a hydroxyl group or an amine group, and a pharmaceutically acceptable salt thereof.

In addition to these salts, hydrochloride, acetate, phosphate or methanesulfonate can also be mentioned.

When A is an amine group, the compound of formula (I) can also be coupled to an amino acid to form a guanamine and a pharmaceutically acceptable salt thereof. A method of synthesizing competatstatin in the form of a base or a pharmaceutically acceptable salt, and a pharmaceutical composition thereof, is described in U.S. Patent Nos. 4,996,237, 5,525,632, 5,731,353, and 5,674,906. These patents describe compostatin and its metabolites and describe their anticancer activity in vitro and in vivo.

The cateretstatin derivative is an inhibitor of cellular microtubule polymerization.

One of these derivatives, AVE8062, has the following formula:

This is a drug that destroys tumor blood vessels (or "Vascular Disrupting Agent", abbreviated as VDA). Its chemical name is: (Z)-N-[2-methoxy-5-[2-(3,4,5-trimethoxyphenyl)vinyl]phenyl]-L-silylamine. The compound described in EP 731085 B1 can be prepared according to the method described in WO 03/084919.

AVE8062 can be administered in the form of a base (see above) or a salt of a pharmaceutically acceptable acid, for example in the form of a hydrochloride, as follows:

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

Thus, another alternative form of combretastatin (combretastatin) in the form of a base or a salt of a pharmaceutically acceptable acid may be used instead of AVE8062:

Wherein Y represents an amino acid which releases the metabolite in vivo.

Cetuximab is based on Erbitux Trademarks are sold. It is a chimeric monoclonal antibody that specifically binds to the extracellular domain of the human epidermal growth factor receptor (EGFR). It consists of the Fv region of the mouse anti-EGFR antibody and the human IgG1 constant region (heavy chain and kappa chain). It is produced by cell culture of mouse myeloma.

The EGFR signaling pathway involves controlling cell survival, cell cycle progression, angiogenesis, migration, cell invasion, and cellular metabolic potential. Cetuximab blocks the binding of EGFR endogenous ligands, resulting in inhibition of the function of the receptor.

With regard to this combination, the latter involves the incorporation of a compstatin derivative (e.g., AVE8062) and cetuximab in the form of two different pharmaceutical preparations.

Depending on the nature and stage of the cancer to be treated and the course of treatment (age, weight, prior treatment and the like), the combination is suitable for repeated administration over several cycles. This course of treatment can be determined by any physician who specializes in oncology. Thus, the combination is suitable for administration to a patient during a period of between 1 and 4 weeks (more specifically 3 weeks), including administration of a one-time compostatin derivative (such as AVE8062), and administration three times. Cetuximab. This combination can be adjusted over time or in parallel.

In accordance with one of the preferred embodiments of the present invention, AVE8062 is administered to a patient based on an intermittent course of treatment between 1 and 4 weeks (e.g., 3 weeks) between the two administrations (cycle duration). The portion of the cetuximab can be administered to the patient based on an intermittent course of treatment that is one week apart between the two administrations. Thus, the combination is suitable for administering to a patient during a period of between 1 and 4 weeks (more specifically 3 weeks), including administration of AVE8062 once and administration of cetuximab three times. This combination can be adjusted over time or in parallel.

In accordance with certain embodiments, the present invention is directed to a medical kit intended to specifically treat cancer and, more particularly, solid tumors (eg, colorectal cancer, head cancer, neck cancer, sarcoma, lung cancer, and ovarian cancer), including:

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

(ii) a second pharmaceutical dosage formulation comprising cetuximab, the two pharmaceutical dosage formulations (i) and (ii) being independent of each other, and may be administered separately, simultaneously or at intervals.

The method of administration may be a parenteral route and/or an oral route, and will depend on the pharmaceutical dosage form used for the anti-cancer agent. The anti-cancer agent employing a parenteral route can be administered by intravenous rapid injection route, or can be prepared as a continuous intravenous infusion by a variety of methods known to those skilled in the art using pharmaceutically acceptable carriers. Depending on the particular form, the cebritastatin derivative (eg AVE8062) is administered by parenteral route, such as by intravenous injection via intravenous injection or via continuous infusion, and cetuximab It is administered by a parenteral route, such as an intravenous route.

The pharmaceutical dosage form of AVE8062 suitable for the parenteral route allows AVE8062 to be dissolved in water to form a solution. A pharmaceutical dosage form of cetuximab suitable for intravenous routes (for example) to Erbitux A trademarked form of a solution for continuous infusion.

The dose of AVE8062 and cetuximab administered to patients in each case depends on various parameters, such as the nature and stage of the cancer to be treated, and the patient to be treated (age, weight, prior treatment, etc.) condition). The AVE8062 can be administered once every 3 weeks with a tolerated dose between 5 and 60 mg/m ² (for each dose defined). The portion of the cetuximab can be administered to a tolerated dose between 250 and 400 mg/m ² (for a dose defined for each administration).

This combination is effective in the treatment of cancer, more particularly in general solid tumors, for example in the treatment of colorectal cancer, head cancer, neck cancer, sarcoma, lung cancer or ovarian cancer.

The effectiveness of this combination can be demonstrated in clinical animal models by measuring its therapeutic synergy.

If a combination is therapeutically superior to the effect of the optimal agent alone at the optimal dose, the combination shows therapeutic synergy (T. H. Corbett et al, Cancer Treatment Reports, 1982, 66, 1187).

The effectiveness of the combination can also be confirmed by comparing the maximum tolerated dose of the combination with the maximum tolerated dose of each of the individual components in the relevant study.

Finally, the synergy of the combination can be confirmed by statistical comparison of tumor volumes in each group. The effects obtained by two-way analysis of variance (the MIXED program of the SAS software) were used to compare the effects of the sum of the effects of the individual products with the combination of the same dose of the products. The latter evaluation method was used in the following experimental experiments, and the mice were tested using the combination according to the present invention.

In these mouse experiments, the anti-tumor activity can be determined according to various parameters, such as dosage (in mg/kg), administration method, administration time, toxicity, tumor weight change of the treatment group compared to the control group on the specified date. (ΔT/△C%), the median value of the percentage of tumor regression on the specified date, the intermediate value of the waiting time (TC) of the target tumor weight of the treatment group (T) compared with the control group (C), and partial tumor regression The number (PR = 50% from the initial tumor volume) and complete tumor regression (CR = regression to below the palpation threshold). In the following experimental tests, the antitumor activity claimed ΔT/ΔC < 40%.

The anti-tumor activity of solid tumors was determined experimentally in the following manner: the experimental animals were female SCID mice on day 0, using 30 to 60 mg of IMM-COLO1 human colon primary tumor. Fragments were injected bilaterally by subcutaneous injection. This overexpressing primary tumor of EGFR exhibits the genotype of the K-ras wild type, which makes it easy to respond to cetuximab. The animals with tumors that had reached a predetermined tumor size of more than 120 mg were divided into different treatment groups and control groups such that each group had a similar tumor size range with each other.

In general, chemotherapy is initiated 3 to 22 days after transplantation depending on the type of tumor and the size of the tumor required. The animals were observed daily and weighed. The dose at which the weight loss was 20% or more or the mortality rate was 10% or more was considered to be a toxic dose on the day when the weight loss was the highest (the lowest point of the group average). When a non-cytotoxic agent is used, the anti-tumor activity is assessed at the highest non-toxic dose (HNTD) or at the highest test dose (HDT). The tumors were measured 2 or 3 times a week until they reached about 2 g or until the animal died (if the tumor reached 2 g before it died). An autopsy was performed after sacrificing the animals.

In the following study, AVE8062 in the form of the hydrochloride salt was formulated in water containing 0.9% NaCl. Cetuximab is formulated in a pH 7.4 calcium-free and magnesium-free phosphate buffer.

In this study, AVE8062 was administered intravenously on days 21, 25, and 29 after tumor transplantation when these tumors were treated in advanced stages. Cetuximab was administered intraperitoneally on days 21, 25 and 29. When the two agents are administered in combination, they are administered in the same course of treatment for the individual agents, and the combination of the two agents has been carried out at intervals of 4 hours (first dose of AVE8062) on days 21, 25 and 29 days.

Body weight loss was calculated relative to the first day after the end of treatment (D30). The median value of tumor weight change and regression percentage of the treatment group compared to the control group was presented 3 days after the final treatment (D32) and the waiting time was calculated for the target tumor weight of 500 mg. These statistical studies compared the treatment group to a time of 500 mg compared to the control group or compared to the use of the preferred agent alone. The synergy was assessed by comparing tumor volumes over a period of 13 days after the end of treatment.

The experimental results of this study are shown in Table 1. The tumor was doubled for 4.9 days.

The median tumor weight at the start of treatment was 182 to 195 mg, and after 29 days after tumor transplantation, the control group had reached a tumor weight of 500 mg. The highest dose of AVE8062 (HDT) is 58 mg/kg per injection, which is the total dose of 174 mg/kg. At this dose, the AVE8062 is active, causing a partial regression (PR) of 6/6 but not complete regression (CR). AVE8062 retains its activity at both lower dose levels. Tumor growth was delayed by 7 to 11 days compared to the control group.

Cetuximab was active at a maximum dose of 12.5 mg/kg (HDT), a total dose of 37.5 mg/kg, resulting in a 1/6 PR and delayed growth for 13 days. Lower dose levels do not maintain their antitumor activity.

The highest non-toxic dose (HNTD) of this combination was determined by each dose of AVE8062 at a dose of 58 mg/kg administered at a dose of 3.1 mg/kg cetuximab. It has been found that higher doses of this combination are toxic. . At this HNTD, the combination was extremely active, causing the tumor to resolve 100% (6/6 PR) and 33% completely (2/6 CR). The lower dose of this combination is also active, CR occurs at both dose levels, and PR occurs at all test dose levels. Tumor growth was delayed by 14 days (at the lowest dose) to 32 days (under HNTD) compared to the control group.

The statistical analysis results of this study are shown in Table II.

Synergy was observed on day 36 in all combination treatment groups and continued to day 42 at the three highest dose levels.

In conclusion, the combination of AVE8062 and cetuximab caused complete tumor regression, which was not observed when the agent was used alone. These combinations showed complete regression at several dose levels. This combination resulted in a consistently greater delay in tumor growth than monotherapy, and synergy was observed at different dose levels. Thus, the combination of AVE8062 and cetuximab provides a statistically significant therapeutic advantage in an experimental model of primary colon cancer in humans.

Claims (18)

A pharmaceutical combination comprising a combretastatin family derivative (which may be in the form of a base or a pharmaceutically acceptable salt) and cetuximab (cetuximab). As in the combination of claim 1, wherein the ebretretatin derivative is AVE8062: It may be in the form of a base or a pharmaceutically acceptable salt. A combination of claim 1 or 2 comprising an effective amount of a compstatin derivative and an effective amount of cetuximab. A combination of claim 1 or 2, wherein the compostatin derivative is in the form of a hydrochloride. A combination of claim 1 or 2, which is suitable for administering a drug to a patient during the cycle, comprising administering a cebritastatin derivative once and administering cetuximab three times, the combination being adjusted over time or Parallel administration. As in the combination of claim 5, it is suitable for administration to a patient during the cycle, wherein the cycle is repeated, with an interval of between 1 and 4 weeks between the two administrations of the cebritastatin derivative. A combination of claims 1 or 2, which is suitable for administration of a compstatin derivative by parenteral route and/or administration of cetuximab via a parenteral route. A pharmaceutical combination for treating cancer comprising a compstatin derivative (which may be in the form of a base or a pharmaceutically acceptable salt), and cetuximab. The pharmaceutical combination of claim 8, wherein the cateracestatin derivative is AVE8062: The pharmaceutical combination of claims 8 and 9 comprising an effective amount of AVE8062 and an effective amount of cetuximab. A pharmaceutical combination according to claim 8 or 9, wherein AVE8062 is in the form of a hydrochloride. A pharmaceutical combination according to claim 8 or 9 for use in the treatment of a solid tumor. A pharmaceutical combination according to claim 8 or 9, for use in the treatment of sarcoma, lung cancer, head cancer, neck cancer, ovarian cancer or colorectal cancer. A pharmaceutical combination comprising: a quesretatinstat derivative, which may be in the form of a base or a pharmaceutically acceptable salt, and cetuximab, which is used in the manufacture of a medicament for the treatment of cancer. A use of a sirtustatin derivative and cetuximab for the preparation of an anti-tumor combination as described in any one of claims 1 to 14. A medical kit comprising: (i) a first pharmaceutical dosage formulation comprising ombrabulin or AVE8062 in the form of a base or a pharmaceutically acceptable salt, (ii) comprising cetuximab A second pharmaceutical dosage formulation, (i) and (ii), which are independent of one another, can be administered separately, simultaneously or at intervals. The medical kit of claim 16 for use in treating a solid tumor. A medical kit according to any one of claims 16 and 17 for use in the treatment of sarcoma, lung cancer, head cancer, neck cancer, ovarian cancer or colorectal cancer.