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WO2013018017A1 - Combinaison antitumorale comprenant de l'ombrabuline et du cisplatine, associée à la radiothérapie - Google Patents

Combinaison antitumorale comprenant de l'ombrabuline et du cisplatine, associée à la radiothérapie Download PDF

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Publication number
WO2013018017A1
WO2013018017A1 PCT/IB2012/053879 IB2012053879W WO2013018017A1 WO 2013018017 A1 WO2013018017 A1 WO 2013018017A1 IB 2012053879 W IB2012053879 W IB 2012053879W WO 2013018017 A1 WO2013018017 A1 WO 2013018017A1
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WO
WIPO (PCT)
Prior art keywords
cisplatin
ave8062
ombrabulin
radiotherapy
administration
Prior art date
Application number
PCT/IB2012/053879
Other languages
English (en)
Inventor
Chantal Carrez
Céline CLEMENSON
Eric Deutsch
Original Assignee
Sanofi
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sanofi filed Critical Sanofi
Publication of WO2013018017A1 publication Critical patent/WO2013018017A1/fr

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Classifications

    • 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
    • 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
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/243—Platinum; Compounds thereof
    • 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 cisplatin 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
  • 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 cisplatin, 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 cisplatin 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 cisplatin 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.
  • It also relates to the use of ombrabulin or AVE8062 and of cisplatin 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 comprising ombrabulin or AVE8062 in the form of a base or in the form of a pharmaceutically acceptable salt, and cisplatin, 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 cisplatin, 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 cisplatin, comprises an effective amount of ombrabulin or AVE8062 and an effective amount of cisplatin.
  • 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.
  • the inventors have in fact noted that the triple administration of ombrabulin, of cisplatin and of radiotherapy produces antitumour effects which are enhanced in comparison with those obtained by means of monotherapy with ombrabulin alone, or else by means of bitherapy with ombrabulin and cisplatin, ombrabulin and radiotherapy or cisplatin and radiotherapy, as attested to by the results discussed in the experimental section.
  • Ombrabulin 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:
  • Cisplatin Cisplatin or cis-diamrninedichloroplatinum(II) (CDDP) is sold in France in particular under the brand cisplatyl®. It is a platinum-based complex used in the treatment of various cancers, such as sarcomas, carcinomas or lymphomas. It belongs to the DNA- alkylating compound class. Cisplatin binds selectively to the purine bases of DNA and induces a variation in the local conformation of the DNA double strand. This deformation inhibits the replication and transcription of the DNA to RNA, and induces cell death.
  • said combination can be in the form of a unit pharmaceutical preparation.
  • said combination can consist in combining ombrabulin or AVE8062 and cisplatin 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 cisplatin 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:
  • 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:
  • 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 an administration of cisplatin.
  • the administration of the ombrabulin and of the cisplatin may be simultaneous or at different times.
  • 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 example 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 cisplatin 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 cisplatin which is suitable for the intravenous route is, for example, that sold under the brand Cisplatine ® or Cisplatyl ® 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 intravenously, as a bolus or by drip and for administration of the cisplatin intravenously.
  • the doses of AVE8062 and of cisplatin 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 cisplatin can be administered, for its part, at a tolerated dose of between 10 and 120 mg/m 2 (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 cisplatin 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 ⁇ /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 cisplatin 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 AVE8062 in hydrochloride form is formulated in water with 0.9% NaCl.
  • the cisplatin is also formulated in water with 0.9% NaCl, at pH 4.5.
  • the locoregional radiotherapy is carried out at a dose rate of 0.35 Gy/min.
  • AVE8062 and the cisplatin were administered intravenously, at a sub-optimal dose, on days 13 and 17 following tumour implantation. Likewise, the animals were irradiated at a sub-optimal dose on days 13 and 17. In the combination groups, the same schemes and doses as those used for the agents alone were repeated, with treatment of the animals on days 13 and 17. The combination of the two chemotherapy agents is performed 2 hours apart (cisplatin administered first). In the groups treated with cisplatin and irradiated, the radiotherapy is performed one hour after the administration of the cisplatin. In the groups treated with AVE8062 and irradiated, the animals receive the 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 (D24) and the delay in reaching a target tumour weight of 1000 mg is calculated.
  • the statistical studies compare the times to reach 1000 mg and 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). For the tumour volume comparison, the benefit of the combinations is evaluated over a period of 21 days after the end of the treatment (up to D38).
  • 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 342 to 433 mg, the control having reached a tumour weight of 1000 mg 19.6 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 inactive with a median %AT/AC of 43.5% and no partial regression (0% PR). The delay in growth compared with the control group is 5.3 days.
  • Cisplatin is tested at the dose of 4 mg/kg per administration, i.e. a total dose of 8 mg/kg. At this dose, cisplatin is active with a median %AT/AC of 2.7%, no tumour regression (0% PR) and a delay in growth of 13.4 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%, no tumour regression (0%> PR) and a delay in growth of 10.0 days.
  • AVE8062 combined with radiotherapy is highly active with a negative median %AT/AC, a median tumour regression of 15%, but no partial tumour regression (0%) PR).
  • the delay in tumour growth in this group is 13.6 days.
  • Cisplatin combined with radiotherapy is also highly active with a negative median %AT/AC and a median tumour regression of 40%.
  • the delay in tumour growth in this group is 22.4 days.
  • AVE8062 combined with cisplatin is highly active with a negative median at %AT/AC and a median tumour regression of 68%. Five animals out of seven exhibit complete tumour regression (71% CR) and one additional animal exhibits a partial regression (86% PR). The delay in tumour growth in this group reaches 23.0 days.
  • Combinations of the three agents at the same doses The triple combination of AVE8062, cisplatin 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 100%. All the animals of this group exhibit complete tumour regression during the study (100% CR). The delay in tumour growth in this group reaches 40.7 days.
  • Table II shows the statistical analysis of the results of the study. The statistical analysis relating to the times to reach the target tumour size of 1000 mg, and also that relating to the tumour volumes, show 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 double combination of the two chemotherapies is statistically different from each of the chemotherapies with agent alone (p ⁇ 0.0001),
  • Agent related nadir day of % ⁇ / ⁇ 0 regression
  • Cisplatin IV 7ml/kg 4.0 (8.0) 13, 17 0/7 10.8 (20) ⁇ 0 40 42.0 22.4 3/7 0/7 Highly active IR 3 Gy (6 Gy) 13, 17
  • Cisplatin IV 7ml/kg 4.0 (8.0) 13, 17 0/7 12.1 (20) ⁇ 0 100 60.2 40.7 7/7 7/7 Highly active IR 3 Gy (6 Gy) 13, 17
  • Tumour doubling time ⁇ 8 days.
  • Median tumour weight at the beginning of treatments 342 - 433 mg.
  • Treatment duration 5 days.
  • a probability of less than 5% is considered to be statistically significant.

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  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Inorganic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pain & Pain Management (AREA)
  • Dermatology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une combinaison pharmaceutique antitumorale comprenant de l'ombrabuline ou AVE8062, qui peut se trouver sous la forme d'une base ou sous la forme d'un sel pharmaceutiquement acceptable, et du cisplatine, et destinée à être utilisée en tant qu'agent antitumoral pour des patients qui sont également traités par radiothérapie, notamment souffrant de cancers et plus particulièrement de tumeurs solides.
PCT/IB2012/053879 2011-08-01 2012-07-30 Combinaison antitumorale comprenant de l'ombrabuline et du cisplatine, associée à la radiothérapie WO2013018017A1 (fr)

Applications Claiming Priority (2)

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FR1157040 2011-08-01
FR1157040A FR2978662A1 (fr) 2011-08-01 2011-08-01 Combinaison antitumorale comprenant l'ombrabuline et le cisplatine, associee a la radiotherapie

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WO2013018017A1 true WO2013018017A1 (fr) 2013-02-07

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AR (1) AR087392A1 (fr)
FR (1) FR2978662A1 (fr)
TW (1) TW201313225A (fr)
UY (1) UY34232A (fr)
WO (1) WO2013018017A1 (fr)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
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
WO2005110426A1 (fr) * 2004-05-14 2005-11-24 Angiogene Pharmaceuticals Ltd Agents de dommage vasculaire pour une administration sous forme de perfusion intraveineuse
WO2007077309A1 (fr) 2005-12-22 2007-07-12 Aventis Pharma S.A. Combinaison comprenant de la combretastatine et des agents anticancereux
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

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
EP1068870A1 (fr) * 1998-04-03 2001-01-17 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
WO2005110426A1 (fr) * 2004-05-14 2005-11-24 Angiogene Pharmaceuticals Ltd Agents de dommage vasculaire pour une administration sous forme de perfusion intraveineuse
WO2007077309A1 (fr) 2005-12-22 2007-07-12 Aventis Pharma S.A. Combinaison comprenant de la combretastatine et des agents anticancereux
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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Title
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KATSUYOSHI HORI ET AL.: "Tumor blood flow interruption after radiotherapy strongly inhibits tumor regrowth", JAPANESE CANCER ASSOCIATION, July 2008 (2008-07-01)
MARCU LOREDANA ET AL: "Cisplatin and radiotherapy in the treatment of locally advanced head and neck cancer--a review of their cooperation.", ACTA ONCOLOGICA (STOCKHOLM, SWEDEN) 2003 LNKD- PUBMED:12899503, vol. 42, no. 4, 2003, pages 315 - 325, XP009161333, ISSN: 0284-186X *
PATTERSON ET AL: "Vascular Damaging Agents", CLINICAL ONCOLOGY, W.B. SAUNDERS, AMSTERDAM, NL, vol. 19, no. 6, 2 July 2007 (2007-07-02), pages 443 - 456, XP022137687, ISSN: 0936-6555, DOI: 10.1016/J.CLON.2007.03.014 *

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AR087392A1 (es) 2014-03-19
UY34232A (es) 2013-02-28
TW201313225A (zh) 2013-04-01
FR2978662A1 (fr) 2013-02-08

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