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    Summary
    EudraCT Number:2015-004364-11
    Sponsor's Protocol Code Number:69HCL15_0321
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2016-04-27
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedFrance - ANSM
    A.2EudraCT number2015-004364-11
    A.3Full title of the trial
    ENDOLA

    A PHASE I/II TRIAL TO ASSESS THE SAFETY AND EFFICACY OF METRONOMIC CYCLOPHOSPHAMIDE, METFORMIN AND OLAPARIB IN RECURRENT ADVANCED/METASTATIC ENDOMETRIAL CANCER PATIENTS
    ENDOLA

    Essai de phase I/II visant à évaluer la tolérance et l’efficacité de l’association ENDOxan métronomique, metformine et OLAparib dans les cancers de l’ENDOmètre métastatiques ou avancés en rechute
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A TRIAL TO ASSESS THE SAFETY AND EFFICACY OF METRONOMIC CYCLOPHOSPHAMIDE, METFORMIN AND OLAPARIB IN ENDOMETRIAL CANCER PATIENTS
    Essai visant à évaluer la tolérance et l’efficacité de l’association ENDOxan métronomique, metformine et OLAparib dans les cancers de l’ENDOmètre
    A.3.2Name or abbreviated title of the trial where available
    ENDOLA
    ENDOLA
    A.4.1Sponsor's protocol code number69HCL15_0321
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorHospices Civils de Lyon
    B.1.3.4CountryFrance
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportInstitut National du Cancer
    B.4.2CountryFrance
    B.4.1Name of organisation providing supportHospices Civils de Lyon
    B.4.2CountryFrance
    B.4.1Name of organisation providing supportAstra Zeneca
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationHospices Civils de Lyon
    B.5.2Functional name of contact pointProject manager
    B.5.3 Address:
    B.5.3.1Street Address3 Quai des Célestins
    B.5.3.2Town/ cityLyon Cedex 02
    B.5.3.3Post code69229
    B.5.3.4CountryFrance
    B.5.4Telephone number0033472406841
    B.5.5Fax number0033472115190
    B.5.6E-mailsylvie.galvain@chu-lyon.fr
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name LYNPARZA
    D.2.1.1.2Name of the Marketing Authorisation holderAstra Zeneca AB
    D.2.1.2Country which granted the Marketing AuthorisationSweden
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Capsule
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNolaparib
    D.3.9.1CAS number 763113-22-0
    D.3.9.3Other descriptive nameOLAPARIB
    D.3.9.4EV Substance CodeSUB32234
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number25 to 150
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Endoxan
    D.2.1.1.2Name of the Marketing Authorisation holderBAXTER
    D.2.1.2Country which granted the Marketing AuthorisationFrance
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNCYCLOPHOSPHAMIDE
    D.3.9.1CAS number 50-18-0
    D.3.9.4EV Substance CodeSUB06859MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 3
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Information not present in EudraCT
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameMetformine
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNMETFORMIN
    D.3.9.1CAS number 657-24-9
    D.3.9.4EV Substance CodeSUB08831MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number500 to 1000
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    - Patients with histologically and/or cytologically documented endometrial carcinoma (type I or type II), recurrent after platinum-based chemotherapy
    - Patientes présentant un cancer de l’endomètre (type I ou type II) histologiquement et/ou cytologiquement documenté, en rechute après une chimiothérapie à base de platine
    E.1.1.1Medical condition in easily understood language
    Advanced cancerous disease and resistant to standard therapy, at the internal mucosa of the uterus
    maladie cancéreuse avancée et résistante au traitement standard , portant sur la muqueuse interne de l'utérus
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.0
    E.1.2Level PT
    E.1.2Classification code 10014736
    E.1.2Term Endometrial cancer recurrent
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To assess the safety and recommended phase 2 trial dose (RP2D) of olaparib combined to metronomic cyclophosphamide and metformin in patients with recurrent advanced/metastatic endometrial carcinomas
    Evaluer la tolérance et la dose recommandée de l’olaparib pour les essais de phase 2 (RP2D) combiné au cyclophosphamide métronomique et à la metformine chez des patientes atteintes de cancer de l’endomètre avancé/métastatique.
    E.2.2Secondary objectives of the trial
    - To assess the efficacy of olaparib combined to metronomic cyclophosphamide and metformin in patients with advanced/metastatic endometrial carcinomas;
    - To assess the safety of the combination throughout the study;
    - To obtain data on the respective pharmacodynamic effects of the 3 drugs on involved signaling pathways (PI3K-AKT-mTor-S6K; PARP1 and IGF1R in PBMCs, tumor samples and in baseline blood samples) along with potential pharmacodynamic interactions;
    - To obtain data on the kinetics of circulating pharmacodynamic biomarkers, including CA-125, IGF-1, insulin and circulating tumor DNA, to be related with treatments effects;
    - To obtain data about impact of DNA damage repair system alterations on treatment effects: homologous recombination, Lynch syndrome and other DNA repair genes.
    - Evaluer l’efficacité de l’olaparib combiné au cyclophosphamide métronomique et à la metformine chez des patientes atteintes de cancer de l’endomètre avancé/métastatique
    - Evaluer la tolérance sur toute l’étude de l’olaparib combiné au cyclophosphamide métronomique et à la metformine chez des patientes atteintes de cancer de l’endomètre avancé/métastatique
    - Obtenir des données sur les effets pharmacodynamiques (PD) des 3 médicaments combinés sur les voies de signalisation impliquées , et sur le risque d’interaction pharmacodynamique
    - Obtenir des données sur les cinétiques de biomarqueurs circulants tels que CA-125, insuline, IGF-1 et ADN tumoral circulant, à relier avec les effets thérapeutiques de la combinaison
    - Obtenir des données sur l’impact d’anomalies constitutionnelles ou somatiques du système de réparation de l’ADN sur les effets thérapeutiques de la combinaison
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Woman older than 18 years and younger than 81 year old
    - Patients with histologically and/or cytologically documented endometrial carcinoma (type I or type II), recurrent after platinum-based chemotherapy.
    - Patients with Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
    - Archival tumor tissue available, or tumor lesion biopsy feasible
    - There is no limitation to prior number of therapies
    - Patients who have measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1
    - Femmes âgées de plus de 18 ans et de moins de 81 ans
    - Présentant un cancer de l’endomètre (type I ou type II) histologiquement et/ou cytologiquement documenté, en rechute après une chimiothérapie à base de platine
    - ECOG PS ≤ 2
    - Pas de limitation dans le nombre antérieur de traitements
    - Présentant une maladie mesurable selon les critères d'évaluation de réponse dans les tumeurs solides (critères RECIST v1.1)
    E.4Principal exclusion criteria
    - Illness, incompatible with metformin treatment, in particular those associated with a risk of hypoperfusion or hypoxia (not limited to): acute or chronic renal failure (creatinine clearance < 60 ml/min); lactic acidocetosis; septic shock; congestive heart failure; respiratory distress; liver failure; chronic alcoholism; uncontrolled seizures; age > 80 years; allergy/hypersensitivity to metformin.
    - Previous treatment with cyclophosphamide; or allergy/hypersensitivity to cyclophosphamide.
    - Any previous treatment with a PARP inhibitor, including olaparib.
    - Patients with second primary cancer, except: adequately treated non-melanoma skin cancer, curatively treated in-situ cancer of the cervix, or other solid tumours curatively treated with no evidence of disease for ≥ 5 years.
    - Pathologies incompatibles avec la metformine, en particulier celles associées à un risque d'hypoperfusion ou d’hypoxie : insuffisance rénale aiguë ou chronique (clairance de la créatinine <60 ml / min); acidocétose lactique; choc septique; insuffisance cardiaque congestive; détresse respiratoire; insuffisance hépatique; alcoolisme chronique; épilepsie non contrôlée; âge> 80 ans; allergie / hypersensibilité à la metformine
    - Traitement antérieur par cyclophosphamide et/ou allergie / hypersensibilité au cyclophosphamide
    - Tout traitement antérieur avec un inhibiteur de PARP, y compris olaparib
    - Patientes présentant un deuxième cancer primitif ; à l'exception des cancers de la peau non-mélanomes ayant été traités, des cancers in situ du col utérin ayant bénéficié d’un traitement curatif ou d'autres tumeurs solides ayant bénéficiées d’un traitement curatif, avec aucun signe de maladie depuis au moins 5 ans
    E.5 End points
    E.5.1Primary end point(s)
    Safety including nature, number and grade of adverse events according to NCI-CTAE v.4 criteria in order to determine the phase 2 trial recommended dose (RP2D). RP2D is defined as the highest dose level at which less than 20% of patients experienced dose limiting toxicities during the first 6 week treatment.
    Tolérance comprenant le nombre, le grade, et la nature des effets indésirables cotés selon le NCI-CTAE v.4 pour déterminer la dose recommandée pour les essais de phase 2 (RP2D). La RP2D est définie comme la plus haute dose à laquelle moins de 20% des patientes présenteront des toxicités dose limitante (DLT) sur les 6 premières semaines de traitement.
    E.5.1.1Timepoint(s) of evaluation of this end point
    the first 6 week treatment
    sur les 6 premières semaines de traitement.
    E.5.2Secondary end point(s)
    - 1/Non progression rate at 10 weeks
    - 2/Rate of best response (RECIST v.1.1) during the whole treatment period
    - 3/Safety throughout the study
    - 1/Taux de non progression à 10 semaines
    - 2/ Taux de meilleure réponse selon les critères RECIST v1.1 durant la période de traitement
    - 3/ Tolérance sur l’ensemble de l’étude
    E.5.2.1Timepoint(s) of evaluation of this end point
    - 1/ at 10 weeks
    - 2/ during the whole treatment period
    - 3/ throughout the study
    - 1/ à 10 semaines
    - 2/durant la période de traitement
    - 3/Tolérance sur l’ensemble de l’étude
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) Yes
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other Yes
    E.7.1.3.1Other trial type description
    assess the safety and recommended phase 2 trial dose (RP2D) of three combined treatments
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned7
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months43
    E.8.9.1In the Member State concerned days
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 22
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 14
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male No
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state36
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2016-03-07
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-01-08
    P. End of Trial
    P.End of Trial StatusCompleted
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