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WO2013018018A1 - Combinaison antitumorale comprenant l'ombrabuline et le cétuximab, associée à une radiothérapie - Google Patents

Combinaison antitumorale comprenant l'ombrabuline et le cétuximab, associée à une radiothérapie Download PDF

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Publication number
WO2013018018A1
WO2013018018A1 PCT/IB2012/053881 IB2012053881W WO2013018018A1 WO 2013018018 A1 WO2013018018 A1 WO 2013018018A1 IB 2012053881 W IB2012053881 W IB 2012053881W WO 2013018018 A1 WO2013018018 A1 WO 2013018018A1
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WO
WIPO (PCT)
Prior art keywords
cetuximab
ombrabulin
ave8062
radiotherapy
administration
Prior art date
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Ceased
Application number
PCT/IB2012/053881
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English (en)
Inventor
Chantal Carrez
Céline CLEMENSON
Eric Deutsch
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sanofi SA
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Sanofi SA
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Filing date
Publication date
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Publication of WO2013018018A1 publication Critical patent/WO2013018018A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to a combination therapy for treating cancer, in particular involving solid tumours, implementing a coadministration of ombrabulin, of cetuximab and of radiotherapy.
  • WO 2007/077309 describes the combination of AVE8062 and VEGF Trap (or aflibercept), an agent which prevents tumour angiogenesis.
  • WO 2004/037258 describes the combination of 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 also vinca alkaloids.
  • WO 2010/128259 describes an antitumour combination comprising AVE8062 and sorafenib.
  • VDA tumour vascular disrupting agent
  • RTKs receptor tyrosine kinases
  • cetuximab can be combined with other anticancer treatments such as radiotherapy and platinum-salt-based chemotherapy.
  • the invention relates to a combination therapy for treating cancer, in particular involving solid tumours.
  • the invention relates more particularly to a pharmaceutical combination comprising ombrabulin or AVE8062 in the form of a base or in the form of a pharmaceutically acceptable salt, and cetuximab, for use thereof as an antitumour agent intended for patients who are also treated with radiotherapy, in particular suffering from cancers and even more particularly suffering from solid tumours.
  • ombrabulin, of cetuximab and of radiotherapy can be separate, simultaneous or spread out over time.
  • the invention also relates to the use of ombrabulin or AVE8062 and of cetuximab for preparing an antitumour combination intended for treating patients who are also treated with radiotherapy, in particular patients suffering from cancers and even more particularly suffering from solid tumours.
  • ombrabulin or AVE 8062 and of cetuximab for preparing an antitumour combination intended to be administered in association, simultaneously, separately or spread out over time, with radiotherapy.
  • ombrabulin or AVE8062 and of cetuximab for preparing a medicament intended to be used simultaneously, separately or spread out over time, with radiotherapy, for treating cancer and more particularly solid tumours.
  • the present invention relates to a pharmaceutical combination
  • a pharmaceutical combination comprising ombrabulin or AVE8062 in the form of a base or in the form of a pharmaceutically acceptable salt, and cetuximab, for separate administration, administration spread out over time or simultaneous administration to patients who are also treated with radiotherapy, in particular patients suffering from cancers and even more particularly suffering from solid tumours.
  • the present invention relates to a pharmaceutical combination
  • a pharmaceutical combination comprising ombrabulin or AVE8062 in the form of a base or in the form of a pharmaceutically acceptable salt, and cetuximab, for use thereof as an antitumour agent, said combination being administered in association with radiotherapy.
  • the combination which, in the context of the present invention, means the combination of ombrabulin or AVE8062 in the form of a base or in the form of a pharmaceutically acceptable salt and of cetuximab, comprises an effective amount of ombrabulin or AVE8062 and an effective amount of cetuximab.
  • the radiotherapy is also administered at an effective dose.
  • the separate administration, simultaneous administration or administration spread out over time of a medicinal combination means that the elementary constituents of the combination, and in the present case, including the ionizing radiations, can be administered at the same time, each in one go at distinct moments, or repeatedly, or else at different moments, in particular during cycles.
  • the elementary constituents can, in order to do this, be formulated as mixtures, only if they are administered simultaneously, or else formulated separately for the other administration schemes.
  • Ombrabulin or AVE8062 can be in the form of a base or in the form of a pharmaceutically acceptable acid salt.
  • salts mention may be made of the hydrochloride, acetate, phosphate or methanesulfonate.
  • Ombrabulin or AVE8062 has the formula:
  • tumour vascular disrupting agent or VDA
  • ombrabulin or AVE8062 can be administered in the form of a base (cf. formula above) or in the form of a pharmaceutically acceptable acid salt, for example in the form of the hydrochloride, represented below:
  • Cetuximab is sold under the brand Erbitux ® . It is a chimeric monoclonal antibody which binds specifically 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 IgGl constant regions (heavy and kappa chains). It is produced by cell culture of a murine myeloma.
  • EGFR epidermal growth factor receptor
  • the EGFR signalling pathways are involved in the control of cell survival, of cell cycle progression, of angiogenesis, of migration, of cell invasion and of the metastatic potential of cells.
  • Cetuximab blocks the binding of the endogenous ligands of the EGFR, resulting in an inhibition of the function of the receptor.
  • said combination can be in the form of a unit pharmaceutical preparation.
  • said combination can consist in combining ombrabulin or AVE8062 and cetuximab in the form of two pharmaceutical preparations.
  • the combination can be in the form of a combination kit or product.
  • the pharmaceutical combination of ombrabulin and cetuximab can in particular take the form of a kit comprising:
  • the combination can be administered repeatedly over the course of several cycles according to a protocol which depends on the nature and on the stage of the cancer to be treated and also on the patient to be treated (age, weight, previous treatment(s), etc.).
  • the protocol can be determined by any practitioner specializing in oncology.
  • the present invention relates to a pharmaceutical kit, in particular intended for treating cancer and more particularly solid tumours, comprising: (i) a first galenical formulation comprising ombrabulin or AVE8062 in the form of a base or of a pharmaceutically acceptable salt,
  • the two galenical formulations (i) and (ii) being intended to be administered separately, simultaneously or spread out over time with respect to one another, of use for a joint administration of radiotherapy, the two galenical formulations (i) and (ii) being intended to be administered independently of one another, separately, simultaneously or spread out over time with respect to said administration of radiotherapy.
  • the present invention relates to a pharmaceutical kit, in particular intended for treating cancer and more particularly solid tumours, comprising:
  • the two galenical formulations (i) and (ii) being intended to be administered separately, simultaneously or spread out over time with respect to one another, said kit being administered in association with radiotherapy, the radiotherapy being itself intended to be administered separately, simultaneously or spread out over time with said kit.
  • Radiotherapy is a method of locoregional treatment of cancers, using radiation to destroy the cancer cells by blocking their ability to multiply.
  • Radiotherapy in the context of the present invention, consists in particular of the therapeutic use of ionizing radiation.
  • Said radiotherapy and the associated ionizing radiation are those commonly used and known to those skilled in the art.
  • Radiotherapy includes in particular the use of ionizing radiation, for example ⁇ -rays, X-rays and/or radiation emanating from radioisotopes. In the context of the present invention, it is more particularly X-ray radiation.
  • the combination may be intended to be administered to a patient over the course of a cycle that can range from 1 to 4 weeks, more particularly 3 weeks.
  • the cycle defines the interval between the beginning and the end of an administration scheme for the combination in accordance with the present invention.
  • this cycle comprises an administration of ombrabulin or AVE8062, and three administrations of cetuximab.
  • the administration of the ombrabulin and of the first dose of cetuximab may be simultaneous or at different times.
  • the first dose of cetuximab may be delayed by one or two days after the administration of ombrabulin, the taking of which starts the duration of the cycle.
  • cetuximab can be administered in three intakes, with one week between intakes.
  • the radiotherapy may, for its part, be administered in fractionated form during one or more cycles such as defined above.
  • the radiotherapy may in particular be administered at a rate of one daily irradiation, 5 days out of 7, for 7 weeks.
  • the administration mode may be the parenteral route and/or the oral route and depends on the galenical form used for the antitumour agent.
  • the antitumour agent may be administered intravenously, as a bolus or prepared in an intravenous drip bag, with pharmaceutically acceptable vectors by means of various methods known to those skilled in the art.
  • the ombrabulin or AVE8062 is administered parenterally, such as by intravenous administration, as a bolus or by drip, and the cetuximab is administered parenterally, such as the intravenous route.
  • One galenical form of ombrabulin or AVE8062 which is suitable for the parenteral route is that in which the ombrabulin or AVE8062 is in solution in water.
  • One galenical form of cetuximab which is suitable for the intravenous route is, for example, that sold under the brand Erbitux ® in the form of a drip solution.
  • the invention relates to a combination as defined previously, suitable for parenteral administration, and more particularly suitable for administration of the ombrabulin or AVE8062 intravenously, as a bolus or by drip and for administration of the cetuximab intravenously.
  • the doses of AVE8062 and of cetuximab administered each time to a patient depend on various parameters, such as the nature and stage of the cancer to be treated, and also on the patient to be treated (age, weight, previous treatment(s), etc.).
  • the AVE8062 can be administered once every 3 weeks at a tolerated dose of between 5 and 60 mg/m 2 of body surface (dose defined for each administration).
  • the cetuximab can be administered, for its part, at a tolerated dose of between 250 and 400 mg/m 2 of body surface (dose defined for each administration).
  • the radiotherapy doses depend on the type of tumour and can range from 45 to more than 75 gray (Gy), more specifically from 50 to 60 Gy, over the total duration of the treatment.
  • the doses may, for example, be 10 Gy per week at a rate of five sessions of 2 Gy per day.
  • the combination can be effective in the treatment of cancers, more particularly of solid tumours in general, preferentially in the treatment of head and neck cancer, lung cancer, cervical cancer or stomach cancer.
  • the present application also relates to a method for prevention or therapeutic treatment of cancers and more particularly solid tumours, consisting in administering to patients, in need thereof, an effective amount of ombrabulin or AVE8062, an effective amount of cetuximab and an effective dose of radiotherapy, it being possible for their administration to be carried out separately, simultaneously or spread out over time.
  • an antitumour activity is declared for AT/AC ⁇ 40%.
  • the antitumour activity on solid tumours is determined experimentally in the following way: the animals subjected to the experiment are NMRI female mice which are subcutaneously inoculated unilaterally with 3 million cells of the FaDu tumour line originating from a human hypopharyngeal tumour, on day 0. This tumour, representative of head and neck squamous cell carcinomas, is sensitive to cetuximab and to irradiation.
  • the animals, bearing tumours having reached a tumour size previously defined and greater than 100 mg, are distributed in the various treatment and control groups, in such a way that the tumour size range is comparable from one group to the other.
  • the chemotherapy begins from 3 to 22 days after the graft, depending on the type of tumour and the tumour size desired.
  • the animals are observed and weighed every day.
  • a dose which induces a weight loss of 20% or more on the day the weight loss is at a maximum (nadir - mean of the group) or a mortality of 10% or more is considered to be toxic.
  • the tumours are measured two or three times per week until they reach approximately 2 g or until the animal dies if that occurs before the tumour reaches 2 g.
  • the animals are autopsied when they are sacrificed.
  • the ombrabulin or AVE8062 in hydrochloride form is formulated in water with 0.9% NaCl.
  • the cetuximab is formulated in a calcium- and magnesium-free phosphate buffer, at pH 7.4.
  • the locoregional radiotherapy is carried out at a dose rate of 0.35 Gy/min.
  • the ombrabulin or AVE8062 was administered intravenously, at a sub-optimal dose, on days 15 and 19 following tumour implantation.
  • the cetuximab was administered intraperitoneally, at a sub-optimal dose, on the same days.
  • the animals were irradiated at a sub-optimal dose on days 15 and 19.
  • the combination of the two chemotherapy agents is performed 5 hours apart (cetuximab administered first).
  • the radiotherapy is performed 4 hours after the administration of the cetuximab.
  • the animals receive the ombrabulin or AVE8062 one hour after irradiation.
  • the loss of body weight is reported for each group on the day it reaches its nadir.
  • the change in tumour weight in the treated group compared with the control group and also the median regression percentage are reported 7 days after the final treatment (D26) and the delay in reaching a target tumour weight of 1000 mg is calculated.
  • the statistical studies compare the tumour volumes in the treated groups compared with the control group (for the irradiation alone), compared with the chemotherapy agents alone (for the combinations in doublet) or compared with the doublets (for the triple combination). The benefit of the combinations is evaluated over a period of 21 days after the end of the treatment (up to D40).
  • Table I gives the experimental results of the study.
  • the tumour doubling time was approximately 8 days.
  • the median tumour weight at the beginning of the treatments was from 308 to 456 mg, the control having reached a tumour weight of 1000 mg 23.2 days after the tumour graft.
  • the dose tested for AVE8062 is 36 mg/kg per injection, i.e. a total dose of 72 mg/kg. At this dose, AVE8062 is marginally active with a median %AT/AC of 37% and one partial regression (14% PR). The delay in growth compared with the control group is 4.8 days.
  • Cetuximab is tested at the dose of 20 mg/kg per administration, i.e. a total dose of 40 mg/kg. At this dose, cetuximab is active with a median %AT/AC of 23.8%, no tumour regression (0% PR) and a delay in growth of 12.2 days.
  • the irradiation at the dose of 3 Gy per session i.e. a total dose of 6 Gy, exhibits a marginal antitumour activity with a median %AT/AC of 36.8%, no tumour regression (0% PR) and a delay in growth of 7.0 days.
  • AVE8062 combined with radiotherapy is highly active with a negative median % ⁇ / AC, a median tumour regression of 16%, and two partial tumour regressions (29%> PR).
  • the delay in tumour growth in this group is 13.8 days.
  • Cetuximab combined with radiotherapy is also highly active with a negative median %AT/AC of 0.1%, but no partial tumour regression (0% PR). The delay in tumour growth in this group is 13.3 days.
  • AVE8062 combined with cetuximab is highly active with a negative median at %AT/AC and a median tumour regression of 42%. Five animals out of eight exhibit a partial regression (62% PR), none exhibiting complete tumour regression (0%) CR). The delay in tumour growth in this group reaches 18.2 days.
  • the triple combination of AVE8062, cetuximab and irradiation shows the maximum antitumour activity in this study.
  • the treatment is highly active with a negative median %AT/AC and a median tumour regression of 50%.
  • Four animals out of seven exhibit a partial tumour regression (57% PR) and one animal exhibits complete tumour regression (14% CR).
  • the delay in tumour growth in this group reaches 23.3 days.
  • Table II shows the statistical analysis of the results of the study.
  • the statistical analysis relating to the tumour volumes shows that:
  • the irradiated group differs significantly from the control group (p ⁇ 0.0001), the double combinations of chemotherapy with radiotherapy are significantly different from the chemotherapies with agent alone (p ⁇ 0.0001),
  • the combination of AVE8062 with cetuximab and radiotherapy induces partial tumour regressions, also observed in the double combinations containing AVE8062, and a complete tumour regression, only observed in this treatment group.
  • the delay in growth for the triple combination is greater than that observed in the double combinations, making the triple combination the best arm of treatment in this study.
  • the combination of AVE8062 with cetuximab and radiotherapy therefore confers a statistically significant therapeutic advantage in an experimental model of head and neck tumour.
  • Table I Evaluation of AVE8062 in combination with cetuximab and radiotherapy on NMRI female mice bearing the FaDu head and neck squamous cell carcinoma: experimental results
  • Agent related nadir day of % ⁇ / ⁇ 0 regression
  • Median tumour weight at the beginning of treatments 308 - 456 mg.
  • bwc body weight change
  • ⁇ / ⁇ change in tumour weight in the treated group compared with the control group
  • T-C delay in reaching the target tumour weight in the treated group compared with the control group
  • IV intravenous route
  • IP intraperitoneal route

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  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
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  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract

La présente invention concerne une combinaison pharmaceutique antitumorale comprenant l'ombrabuline ou l'AVE8062, qui peut se présenter sous la forme d'une base ou d'un sel pharmaceutiquement acceptable, et le cisplatine, destinée à être utilisée comme agent antitumoral prévu pour des patients traités également par radiothérapie, souffrant plus particulièrement de cancers et même souffrant plus particulièrement de tumeurs solides.
PCT/IB2012/053881 2011-08-01 2012-07-30 Combinaison antitumorale comprenant l'ombrabuline et le cétuximab, associée à une radiothérapie Ceased WO2013018018A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR1157044A FR2978663A1 (fr) 2011-08-01 2011-08-01 Combinaison antitumorale comprenant l'ombrabuline et le cetuximab, associee a la radiotherapie
FR1157044 2011-08-01

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WO2013018018A1 true WO2013018018A1 (fr) 2013-02-07

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AR (1) AR087393A1 (fr)
FR (1) FR2978663A1 (fr)
TW (1) TW201315461A (fr)
UY (1) UY34233A (fr)
WO (1) WO2013018018A1 (fr)

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WO2003084919A2 (fr) 2002-04-11 2003-10-16 Aventis Pharma S.A. Procedes de preparation de combretastatines
EP1407784A1 (fr) 2001-06-25 2004-04-14 Ajinomoto Co., Inc. Agents antitumoraux
WO2004037258A1 (fr) 2001-03-15 2004-05-06 Aventis Pharma S.A. Combinaison comprenant de la combretastatine et des agents anticancereux
WO2007077309A1 (fr) 2005-12-22 2007-07-12 Aventis Pharma S.A. Combinaison comprenant de la combretastatine et des agents anticancereux
US20090209496A1 (en) * 2008-02-15 2009-08-20 David Chaplin Methods and compositions for enhancing the efficacy of rtk inhibitors
WO2010128259A1 (fr) 2009-05-07 2010-11-11 Sanofi-Aventis Combinaison antitumorale comprenant l'ave8062 et le sorafenib

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EP0031085A2 (fr) 1979-12-20 1981-07-01 General Electric Company Appareil de traitement de signaux à transfert de charges
WO1999051246A1 (fr) 1998-04-03 1999-10-14 Ajinomoto Co., Inc. Agents antitumoraux
WO2004037258A1 (fr) 2001-03-15 2004-05-06 Aventis Pharma S.A. Combinaison comprenant de la combretastatine et des agents anticancereux
EP1407784A1 (fr) 2001-06-25 2004-04-14 Ajinomoto Co., Inc. Agents antitumoraux
WO2003084919A2 (fr) 2002-04-11 2003-10-16 Aventis Pharma S.A. Procedes de preparation de combretastatines
WO2007077309A1 (fr) 2005-12-22 2007-07-12 Aventis Pharma S.A. Combinaison comprenant de la combretastatine et des agents anticancereux
US20090209496A1 (en) * 2008-02-15 2009-08-20 David Chaplin Methods and compositions for enhancing the efficacy of rtk inhibitors
WO2009103076A1 (fr) 2008-02-15 2009-08-20 Oxigene, Inc. Méthodes et compositions pour améliorer l'efficacité des inhibiteurs des récepteurs tyrosine kinases (rtk)
WO2010128259A1 (fr) 2009-05-07 2010-11-11 Sanofi-Aventis Combinaison antitumorale comprenant l'ave8062 et le sorafenib

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BONNER JAMES A ET AL: "Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck.", THE NEW ENGLAND JOURNAL OF MEDICINE 9 FEB 2006 LNKD- PUBMED:16467544, vol. 354, no. 6, 9 February 2006 (2006-02-09), pages 567 - 578, XP002680334, ISSN: 1533-4406 *
CHARGARI C ET AL: "Etat des lieux des associations chimioradiotherapeutiques et place potentielle des therapies ciblees dans les cancers bronchiques non a petites cellules", CANCER RADIOTHERAPIE, ELSEVIER, PARIS, FR, vol. 13, no. 2, 1 April 2009 (2009-04-01), pages 114 - 122, XP025977246, ISSN: 1278-3218, [retrieved on 20090120], DOI: 10.1016/J.CANRAD.2008.08.273 *
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FR2978663A1 (fr) 2013-02-08
UY34233A (es) 2013-02-28
TW201315461A (zh) 2013-04-16
AR087393A1 (es) 2014-03-19

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