WO2013014107A1 - Sémuloparine pour l'amélioration de la survie de patients atteints d'un cancer - Google Patents

Sémuloparine pour l'amélioration de la survie de patients atteints d'un cancer Download PDF

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Publication number
WO2013014107A1
WO2013014107A1 PCT/EP2012/064343 EP2012064343W WO2013014107A1 WO 2013014107 A1 WO2013014107 A1 WO 2013014107A1 EP 2012064343 W EP2012064343 W EP 2012064343W WO 2013014107 A1 WO2013014107 A1 WO 2013014107A1
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patients
cancer
survival
molecular weight
vte
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Francesca Lawson
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Aventis Pharma SA
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Aventis Pharma SA
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Priority claimed from EP11305957A external-priority patent/EP2548561A1/fr
Priority claimed from EP12305479.3A external-priority patent/EP2656851A1/fr
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Publication of WO2013014107A1 publication Critical patent/WO2013014107A1/fr
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    • 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
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
    • A61K31/727—Heparin; Heparan
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors

Definitions

  • the invention relates to the use of semuloparin or a pharmaceutically acceptable salt thereof as a prophylactic antithrombotic agent in specific groups of patients receiving chemotherapy, wherein said use improves the survival of said patients.
  • Semuloparin belongs to a new generation of hemisynthetic heparins. It is a new ultra-low molecular weight heparin (ULMWH), with an average molecular weight of 2000-3000 Daltons and a novel antithrombotic profile resulting from high anti-Factor Xa activity (-160 U/mg) and residual anti-Factor lla activity ( ⁇ 2 U/mg). It is obtained by selective and controlled depolymerization of heparin by a phosphazene base, as described for example in Journal of Thrombosis and Haemostasis, 2009, vol. 7, 1 143-1 151 .
  • Semuloparin in the form of its sodium salt, is in clinical development for venous thromboembolism (VTE) prevention in cancer patients receiving chemotherapy (see for example G. Agnelli et al. in J. Clin. Oncol., 201 1 , vol. 29, suppl. abstr. LBA9014 and Hyer R. in Oncology Report, June 20, 201 1 ).
  • VTE venous thromboembolism
  • the Applicant has shown, based on a large phase III trial, that semuloparin, when used for venous thromboembolism prophylaxis in cancer patients receiving chemotherapy, improves the survival of some subgroups of patients, namely those having locally advanced cancer of the lungs and those having a VTE risk score equal to or greater than 3.
  • the subject-matter of the invention is an ultra-low molecular weight heparin with an average molecular weight of 2000 to 3000 Daltons, an anti-FXa activity of about 160 U/mg and an anti-Flla activity of about 2 U/mg, for use in improving the survival of patients with cancer receiving chemotherapy, said patients being selected from the group of patients having locally advanced cancer of the lungs and of patients having a VTE risk score equal to or greater than 3.
  • the anti-FXa and anti-Flla activities described above are measured using amidolytic methods on a chromogenic substrate as adapted from the monograph on Low Molecular Weight Heparins (LMWHs) of the European Pharmacopeia in force, using as reconstitution buffer a tris-NaCI pH 7.4 buffer comprising PEG6000 (polyethylene glycol 6000) instead of albumin, and an ULMWH reference substance with an anti-FXa activity of 159 U/mg and an anti-Flla activity of 2.9 U/mg.
  • the potencies are expressed in units per mg due to the use of an internal ULMWH reference standard.
  • the above ULMWH is semuloparin and the subject-matter of the invention is therefore semuloparin for use in improving the survival of patients with cancer receiving chemotherapy, said patients being selected from the group of patients having locally advanced cancer of the lungs and of patients having a VTE risk score equal to or greater than 3.
  • VTE risk score has been developed and validated for cancer patients receiving chemotherapy by Khorana A.A. et al. in Blood, 2008, vol. 1 1 1 , 4902-7. According to such a risk score, the following patients are assigned a risk score of 3 or higher:
  • hemoglobin less than 100 g/L or requiring red cell growth factors
  • BMI body mass index
  • the ULMWH is administered as a prophylactic antithrombotic agent.
  • the administration of semuloparin in such a prophylactic setting is accompanied, in the groups of cancer patients described above, by a beneficial effect on the survival of said patients.
  • the subject-matter of the invention is therefore an ULMWH with an average molecular weight of 2000 to 3000 Daltons, an anti-FXa activity of about 160 U/mg and an anti-Flla activity of about 2 U/mg, for use as an antithrombotic agent for the prophylaxis of venous thromboembolism in cancer patients receiving chemotherapy, wherein said use improves the survival of patients with locally advanced cancer of the lungs or of patients having a VTE risk score equal to or greater than 3.
  • the term "semuloparin”, in the framework of the instant invention encompasses any pharmaceutically acceptable salt thereof, in particular its sodium salt.
  • the term “semuloparin” shall therefore be understood herein as "semuloparin or any pharmaceutically acceptable salt thereof".
  • the terms below have the following meanings:
  • cancer patients are defined as patients having malignant solid tumors and being under chemotherapy treatment.
  • said "cancer patients” may be ambulatory patients (outpatients) or hospitalized patients;
  • prophylaxis refers to the administration of a therapy to an individual who is considered as being at risk for a thromboembolic pathology such as venous thromboembolism (including deep vein thrombosis, which may lead to pulmonary embolism), i.e. to an individual who does not already have symptoms of an established venous thromboembolic state;
  • VTE venous thromboembolism
  • thrombus inside a blood vessel, obstructing the flow of blood through the circulatory system
  • phase III clinical trial refers, in the framework of the instant invention, to a multinational, randomized, double-blinded study involving a large patients group (more than 3000, as it will be described in details below), as defined by the health authorities and the regulatory laws and guidelines, aiming at being the definitive assessment of how effective and safe the drug is.
  • said phase III clinical trial is performed in cancer patients, more specifically in cancer patients at high risk for VTE and who are undergoing chemotherapy for solid tumors.
  • the use of the ULMWH with an average molecular weight of 2000 to 3000 Daltons, an anti-FXa activity of about 160 U/mg and an anti-Flla activity of about 2 U/mg, as defined above improves the survival rate of the patients.
  • the use of the ULMWH with an average molecular weight of 2000 to 3000 Daltons, an anti-FXa activity of about 160 U/mg and an anti-Flla activity of about 2 U/mg, as defined above improves the survival duration of the patients, more particularly their median overall survival.
  • the ULMWH is administered at a prophylactic dose, namely at a 20 mg daily dose.
  • the ULMWH is administered once daily.
  • administration of the ULMWH is advantageously started at the initiation of a course of chemotherapy and continued once daily for 3 months. If chemotherapy is definitely discontinued, then treatment with the ULMWH should also be discontinued.
  • the patients to which the ULMWH is administered do not display severe renal impairment, which means that their estimated creatinine clearance (CLcr) value, calculated using the well-known Cockroft-Gault formula, shall not be less than 30 mL/min.
  • CLcr estimated creatinine clearance
  • the invention therefore also relates to the use of an ULMWH as defined above for the manufacture of a medicament useful in improving the survival of patients with cancer receiving chemotherapy, said patients being selected from the group of patients having locally advanced cancer of the lungs and of patients having a VTE risk score equal to or greater than 3. All the embodiments and features described above also apply to said use.
  • the invention also relates to an article of manufacture comprising:
  • the invention also relates to a method for promoting the use of an ULMWH with an average molecular weight of 2000 to 3000 Daltons, an anti-FXa activity of about 160 U/mg and an anti-Flla activity of about 2 U/mg, in particular semuloparin or a pharmaceutically acceptable salt thereof, the method comprising the step of conveying to a recipient at least one message chosen from: - said ULMWH improves the survival of patients with locally advanced cancer of the lungs;
  • DVT deep vein thrombosis
  • PE pulmonary embolism
  • LMWH low molecular weight heparin
  • VTE venous thromboembolism
  • the SAVE-ONCO phase III study A multinational, randomized, double blind, placebo-controlled study to evaluate the efficacy and safety of AVE5026 in the prevention of venous thromboembolism (VTE) in cancer patients at high risk for VTE and who are undergoing chemotherapy. 1 ) Study objectives
  • the primary objective of the study was to compare the efficacy of once daily (q.d.) subcutaneous (s.c.) injections of 20 mg AVE5026 with placebo in the prevention of VTE in cancer patients at high risk for VTE and who are undergoing chemotherapy.
  • the secondary objectives of the study comprised the evaluation of the safety of
  • Cancer patients at high VTE risk defined as patients with a metastatic or locally-advanced solid tumor of the lung, pancreas, stomach, colon/rectum, bladder or ovary and who are undergoing chemotherapy, were randomly assigned to receive once daily s.c. injection of either AVE5026 or placebo :
  • Randomized treatment was allocated to eligible patients through a centralized randomization system using an Interactive Voice Response System (IVRS).
  • IVRS Interactive Voice Response System
  • a dynamic allocation was used taking into account three factors: the localization of the primary site of tumor (lung, pancreas, stomach, colon/rectum, bladder or ovary), the stage of the cancer (metastatic versus locally-advanced) and the geographical region (North America, South America, Western Europe, Eastern Europe, Asia and rest of the world).
  • the randomization call occurred on the first day of the chemotherapy or the day after at the latest and as close as possible prior to the first IP injection.
  • a follow-up visit was scheduled one month ⁇ 1 week after the end of treatment visit. During this visit, information regarding adverse events (including bleedings and VTE) was collected.
  • survival status (alive, dead, or lost to follow up) was collected for all patients either one year after randomization or at the end of the study (i.e. 7 months following randomization of the last patient at the latest), whichever came first.
  • the duration of study participation per patient was variable and depended on the duration of chemotherapy.
  • the duration of study period is the duration of study treatment followed by a one month follow-up period after the end of treatment visit.
  • patients were screened within 3 weeks prior to the start of chemotherapy.
  • the study end date was at the latest seven months (6 months treatment period and one month follow-up) following the randomization of the last patient.
  • Chemotherapy is herein defined as any conventional cytotoxic treatment. Biological agents used alone were not considered as chemotherapy, but could be associated with cytotoxic agents.
  • Contra-indications to anticoagulation - active or recent ( ⁇ 3 months) significant bleeding, including gastrointestinal bleeding or peptic ulcer;
  • aPTT - activated partial thromboplastin time
  • UH - parenteral anticoagulants
  • LMWH enoxaparin, dalteparin, nadroparin..., or other agents such as fondaparinux, bivalirudin, hirudin
  • saline flushing solutions are highly recommended. However, if it is local practice, flushing solutions with small amounts of heparin (max 500 units) are allowed.
  • the AVE5026 syringe contained 20 mg of AVE5026 in a 0.5 mL pre-filled syringe containing 0.4 mL of a sterile, isotonic solution with sodium chloride 0.9% and water for injection corresponding to a concentration of 50 mg/mL.
  • the matching placebo syringe was strictly identical in appearance, containing the same volume but without active component.
  • AVE5026 or its placebo was administered subcutaneously.
  • Study medication (AVE5026 or its placebo) started as close as possible after the randomization, which should take place as close as possible to the start of chemotherapy.
  • the first injection was done at site under direct supervision.
  • the investigator decided whether injections at home could be performed by the patient (self-injection) or by a relative, or whether it should be supported by a health care professional.
  • Study medication was administered once daily s.c. at approximately 24 hours apart. The time of the day was upon investigator's or patient's preference. However it was recommended to keep the same timing during the study. 5) Assessment of investigational product
  • the primary efficacy criterion was the time-to-first occurrence of any component of the composite endpoint of the following documented outcome results, confirmed by the CIAC (composed of thrombosis and bleeding experts, blinded to study medication assignment), from randomization up to 3 calendar days after last IP injection:
  • VTE-related deaths including fatal PE and unexplained deaths.
  • VTE diagnosis needed to be confirmed or ruled out by objective investigations, described as follows.
  • DVT of the lower limbs the clinical diagnosis must be confirmed by compression ultrasound (CUS) or venography performed within 72 hours after the clinical suspicion. DVT was confirmed if the CUS was abnormal or if there was an intraluminal filling defect on the venography.
  • CUS compression ultrasound
  • DVT of the upper limbs thrombosis of the central line was not considered a priori as a suspicion of DVT unless a patient presented symptoms such as arm swelling, erythema, pain, distal paresthesias, neck swelling, headache, and congestion of subcutaneous collateral veins.
  • the clinical diagnosis must be confirmed by ultrasound (US) or venography performed within 72 hours after the clinical suspicion. DVT was confirmed if the US is abnormal or if there was an intraluminal filling defect on the venography.
  • Pulmonary embolism the clinical diagnosis must be confirmed by ventilation / perfusion lung scan, pulmonary angiogram or spiral Computer Tomography (CT) lung scan within 72 hours after the clinical suspicion. PE was confirmed in case of:
  • the patient population used in the analysis of the primary efficacy endpoint was the Intent-To-Treat (ITT) population, which included all randomized patients. Patients were analyzed in the treatment group to which they were allocated by the IVRS (i.e. "as randomized" regardless of treatment actually received).
  • the safety analysis period was defined as the period from the first IP injection up to the last IP injection plus 3 calendar days (called “on-treatment period”).
  • the safety population was defined as all randomized patients exposed to the study medication, regardless of the amount of treatment administered.
  • Symptomatic bleeding in a critical area or organ such as intracranial, intraspinal, intraocular, retroperitoneal, intraarticular or pericardial, or intramuscular with compartment syndrome, and/or • Bleeding causing a fall in hemoglobin level of 2 g/dL (1 .24 mmol/L) or more, or leading to transfusion of two or more units of whole blood or red cells
  • the median duration of study treatment was around 3.5 months in the two groups, with most of patients receiving 3 to 6 months of study treatment: 48.8% in the semuloparin group and 48.3% in the placebo group.
  • the primary analysis of the primary endpoint consisted of the comparison of the two treatment groups (AVE5026 and placebo) using the two-sample test of Gray for comparing Cumulative Incidence Functions (CIFs), at a significant level of 0.05 (2-sided).
  • An estimation of the treatment effect was provided using Fine and Gray regression model for CIFs.
  • CIFs were estimated separately for the two treatment groups with Prentice non- parametric estimator using a model of cause-specific hazards; corresponding 95% 2-sided Cls were computed by Keiding and Andersen formula with variance computed using the delta method.
  • Table 1 describes the incidences of the primary efficacy endpoint of SAVE-ONCO study by treatment groups.
  • Table 2 describes the results for each component of the primary efficacy endpoint and table 3 describes the key subgroups analyses by cancer stage and location of primary tumor.
  • Table 1 Any VTE or VTE-related death during the efficacy analysis period (time to first VTE event) - Primary efficacy analysis - Intent-To-Treat population AVE5026 Placebo
  • N number of patients in the primary efficacy population
  • n number of patients showing a given event
  • n/N (%) 1 1/1608 (0.7%) 34/1604 (2.1 %) 0.32 95% mid-p CI (0.4 to 1 .2) (1.5 to 2.9) (0.15 to 0.62)
  • risk reduction compared to placebo was 64% for any VTE or VTE-related death (primary endpoint), 68% for DVT (67% for DVT of the upper limbs and 68% for DVT of the lower limbs) and 59% for PE.
  • Table 4 describes the incidence of any treatment emergent clinically relevant bleeding, major bleeding and clinically relevant non-major bleeding in the safety population of the SAVE-ONCO study.
  • Table 4 Number of patients with treatment emergent clinically relevant bleedings, major bleedings and non-major bleedings - Safety population
  • N number of patients in the safety population
  • n number of patients with bleedings
  • Tables 5 and 6 describe the subgroup analyses on survival (survival rate on table 5, median overall survival on table 6), based on stage of cancer. These tables show a favourable trend for semuloparin on the survival rate of patients with locally advanced cancer. There was no heterogeneity according to tumor site (interaction p- value of 0.2042).
  • Table 5 Number of deaths - Subgroup analysis - Stratification factors - Intent-To- Treat population
  • N number of patients in the Intent-To-Treat population
  • n number of deaths
  • Table 7 Subgroups analysis - Number of deaths - Kaplan Meier survival estimates by location site of primary tumor - Intent-To-Treat population - Patients with locally advanced cancer
  • n number of deaths
  • Table 8 Subgroups analysis - Overall survival (months) - Kaplan Meier survival estimates by location site of primary tumor - Intent-To-Treat population - Patients with locally advanced cancer
  • Table 9 Analysis of the numbers of deaths and of the overall survival according to the VTE risk score of the patients is detailed table 9. The results in table 9 show the benefit of the treatment with semuloparin on survival, both in terms of number of deaths and of median overall survival, in the subgroup of cancer patients with a VTE risk score ⁇ 3. Table 9: Subgroups analysis - Number of deaths and overall survival (months) according to VTE risk score - Intent-To-Treat population

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Abstract

L'invention concerne une héparine à poids moléculaire ultra-faible ayant un poids moléculaire moyen de 2000 à 3000 Daltons, une activité anti-FXa d'environ 160 U/mg et une activité anti-FIIa d'environ 2 U/mg, en particulier une sémuloparine, pour l'utilisation en tant qu'agent antithrombotique prophylactique chez des patients atteints d'un cancer recevant une chimiothérapie pour des tumeurs solides avancées localement, ladite utilisation étant accompagnée par une amélioration de la survie des patients atteints d'un cancer des poumons avancé localement ou ayant un score de risque de thrombo-embolie veineuse égal ou supérieur à 3.
PCT/EP2012/064343 2011-07-22 2012-07-20 Sémuloparine pour l'amélioration de la survie de patients atteints d'un cancer Ceased WO2013014107A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP11305957A EP2548561A1 (fr) 2011-07-22 2011-07-22 Sémuloparine pour améliorer la survie de patients atteints d'un cancer localement avancé
EP11305957.0 2011-07-22
EP12305479.3A EP2656851A1 (fr) 2012-04-27 2012-04-27 Semuloparin permettant d'améliorer la survie de patients atteints de cancer
EP12305479.3 2012-04-27

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015028919A1 (fr) * 2013-08-29 2015-03-05 Daiichi Sankyo Company, Limited Agent pour le traitement et la prévention du cancer

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"Venous Thromboembolic Disease, V.2.2011", INTERNET CITATION, 7 April 2011 (2011-04-07), pages 1 - 95, XP008139961, Retrieved from the Internet <URL:http://www.nccn.org/professionals/physician_gls/f_guidelines.asp> [retrieved on 20110726] *
AGNELLI G ET AL: "The ultra-low molecular weight heparin (ULMWH) semuloparin for prevention of venous thromboembolism (VTE) in patients with cancer receiving chemotherapy: SAVE ONCO study", INTERNET CITATION, 3 June 2011 (2011-06-03), pages 1 - 3, XP007919132, Retrieved from the Internet <URL:http://www.asco.org/ascov2/Meetings/Abstracts?&vmview=abst_detail_view&confID=102&abstractID=80129> [retrieved on 20110722] *
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015028919A1 (fr) * 2013-08-29 2015-03-05 Daiichi Sankyo Company, Limited Agent pour le traitement et la prévention du cancer

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