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    Summary
    EudraCT Number:2014-003740-13
    Sponsor's Protocol Code Number:RC14_0048
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:GB - no longer in EU/EEA
    Date on which this record was first entered in the EudraCT database:2015-12-23
    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 ConcernedUK - MHRA
    A.2EudraCT number2014-003740-13
    A.3Full title of the trial
    A phase I/II trial of Obinutuzumab, ABT-199 (GDC-0199) plus Ibrutinib in Relapsed/Refractory Mantle Call Lymphoma patients (OAsIs)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A phase I/II trial of Obinutuzumab, ABT-199 (GDC-0199) plus Ibrutinib in RElasped/Refractory Mantle Cell Lymphoma patients - OasIs
    A.3.2Name or abbreviated title of the trial where available
    OAsIs
    A.4.1Sponsor's protocol code numberRC14_0048
    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 SponsorCentre Hospitalier Universiaire de Nantes
    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 supportROCHE
    B.4.2CountrySwitzerland
    B.4.1Name of organisation providing supportJANSSEN
    B.4.2CountryBelgium
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationCHU de Nantes
    B.5.2Functional name of contact pointMaelle Ningre
    B.5.3 Address:
    B.5.3.1Street Address5, allee de l'isle Gloriette
    B.5.3.2Town/ cityNANTES
    B.5.3.3Post code44093
    B.5.3.4CountryFrance
    B.5.4Telephone number0033253482430
    B.5.6E-mailbp-prom-regl@chu-nantes.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 IMBRUVICA
    D.2.1.1.2Name of the Marketing Authorisation holderJANSSEN
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/13/1115
    D.3 Description of the IMP
    D.3.1Product nameIBRUTINIB
    D.3.2Product code PRD2480669
    D.3.4Pharmaceutical form Capsule
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    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 GAZIVARO
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Registration Ltd
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/12/1054
    D.3 Description of the IMP
    D.3.1Product nameOBINUTUZUMAB
    D.3.2Product code PRD2480532
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    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 No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/12/1080
    D.3 Description of the IMP
    D.3.1Product nameGDC-0199
    D.3.2Product code PRD2518219
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Mantle Cell Lymphoma
    E.1.1.1Medical condition in easily understood language
    Mantle Cell Lymphoma
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10061275
    E.1.2Term Mantle cell lymphoma
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective is to determine the Maximal Tolerated Dose of the novel combination of Obinutuzumab(GA101), ABT199(GDC-0199) and Ibrutinib in relapsed/refractory Mantle Cell Lymphoma by using a Continual Reassessment Model.
    E.2.2Secondary objectives of the trial
    The Secondary Objectives are:
    To determine the efficacy of the combination of Obinutuzumab(GA101), Ibrutinib and ABT199(GDC-0199) in terms of beneficial clinical response (overall response rate, complete response rate and partial response rate Cheson 99 and 07 criteria, and Working Group Revised Response Criteria for malignant Lymphomas 14) overall survival , progression free survival.
    To describe the safety & tolerability of the novel combination of ABT199(GDC-0199), Obinutuzumab(GA101) and Ibrutinib
    To establish a biobank to further explore biomarkers and the mechanisms of action including resistance.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • Age >16 (UK patient criteria).
    • Relapsed or refractory Mantle Cell Lymphoma. The diagnosis has to be confirmed by phenotypic expression of CD5, CD20 and cyclin D1 or the t(11;14) translocation.
    • At least one prior line of treatment.
    • Stage II-IV in need of treatment.
    • ECOG performance status of 0 – 2.
    • Haematology values must be within the following limits:
    a. Absolute neutrophil count (ANC) ≥1000/mm3 independent of growth factor support
    b. Platelets≥100,000/mm3 or ≥ 50,000/mm3 if bone marrow involvement and independent of transfusion support in either situation
    • Biochemical values within the following limits:
    a. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 x upper limit of normal (ULN)
    b. Total bilirubin ≤ 1.5 x ULN unless bilirubin rise is due to Gilbert’s syndrome or of non-hepatic origin
    c. Serum creatinine ≤ 2 x ULN or estimated Glomerular Filtration Rate (Cockroft Gault) ≥ 50 mL/min.
    • HIV, anti-HBc, HbsAg test negative
    • Life expectancy of more than 3 months.
    • Women of childbearing potential and men who are sexually active must be practicing a highly effective method of birth control during and after the study consistent with local regulations regarding the use of birth control methods for subjects participating in clinical trials. Men must agree to not donate sperm during and after the study. For females, these restrictions apply for 18 month after the last dose of study drug. For males, these restrictions apply for 3 months after the last dose of study drug.
    • Women of childbearing potential must have a negative serum or urine pregnancy test at Screening. Women who are pregnant or breastfeeding are ineligible for this study.
    • Written signed informed consent form.
    E.4Principal exclusion criteria
    • Clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of Screening, or any Class 3 (moderate) or Class 4 (severe) cardiac disease as defined by the New York Heart Association Functional Classification.
    • Major surgery within 4 weeks of randomization.
    • Known central nervous system lymphoma.
    • History of stroke or intracranial hemorrhage within 6 months prior to randomization.
    • Requires anticoagulation with warfarin or equivalent vitamin K antagonists.
    • Impaired liver, renal (GFR<50ml/min) or other organ function which will interfere with the treatment.
    • Requires treatment with strong CYP3A inhibitors.
    • Vaccinated with live, attenuated vaccines within 4 weeks of randomization.
    • Known history of human immunodeficiency virus (HIV) or active Hepatitis C Virus or active Hepatitis B Virus infection or any uncontrolled active systemic infection requiring intravenous (IV) antibiotics. (patients HbsAg+and/or antiHBc+ and/or HIV+ are excluded)
    • Any life-threatening illness, medical condition, or organ system dysfunction which, in the investigator’s opinion, could compromise the subject’s safety, interfere with the absorption or metabolism of ibrutinib capsules, or put the study outcomes at undue risk.
    • Known hypersensitivity to study treatment (GA101, Ibrutinib, GDC-0199) or to any of the excipients.
    • Known allergy to xanthine oxidase inhibitors and rasburicase
    • Severe prior reactions to monoclonal antibodies or with prior significant toxicity (other than thrombocytopenia) from Bcl-2 inhibitor
    • History of prior other malignancy with the exception of: Curatively treated basal cell carcinoma or squamous cell carcinoma of the skin or carcinoma in situ of the cervix at any time prior to study
    • Other cancers not specified above which have been curatively treated by surgery alone and from which subject is disease-free for ≥5 years without further treatment.
    • Psychiatric illness or condition which could interfere with their ability to understand the requirements of the study.
    • Pregnancy/lactation
    • Men or women of reproductive potential not agreeing to use acceptable method of birth control during treatment and for heighten months after completion of treatment for the women and three months for the men. .
    • Use of any standard or experimental anti-cancer drug therapy within 28 days prior to the first dose of study drug.
    E.5 End points
    E.5.1Primary end point(s)
    Step A Primary Outcome measure:
    The occurrence of unacceptable toxicity (as defined in the protocol) of the combination of GA101 and Ibrutinib during the first cycle of treatment.

    Step B will only proceed on condition that no unacceptable toxicity in patients in step A is observed.

    Step B Primary Outcome measure:
    The occurrence of unacceptable toxicity of the combination of Obutinuzumab (GA101) and Ibrutinib plus ABT199(GDC-0199) during the first two cycles of treatment in terms of Dose-Limiting Toxicities (DLTs) of the studied combination to establish the Recommended Phase 2 Dose (RP2D).
    E.5.1.1Timepoint(s) of evaluation of this end point
    Step A outcomes will be continually assessed until 9 patients have completed Step A.
    Step B outcomes will be assessed at each grouped inclusion during the dose escalation phase, and after LPLV.
    E.5.2Secondary end point(s)
    Secondary End points Step A
    • Safety (type, frequency, severity, and relationship of adverse events to study treatment).
    • Incidence of Serious Adverse Event (SAE), Adverse Event (AE) and laboratory abnormalities.
    • Incidence and severity of tumor lysis syndrome
    • Time to progression and overall survival
    • Response (CR, PR, SD, PD) and overall response (CR+ PR) rates

    Secondary Endpoints Step B
    • Safety (type, frequency, severity, and relationship of adverse events to study treatment).
    • Incidence of Serious Adverse Event (SAE), Adverse Event (AE) and laboratory abnormalities.
    • Incidence and severity of tumor lysis syndrome
    • Time to progression and overall survival
    • Response (CR, PR, SD, PD) and overall response (CR+ PR) rates
    E.5.2.1Timepoint(s) of evaluation of this end point
    Step A secondary outcomes will be continually assessed until 9 patients have completed Step A
    Step B outcomes will be assessed at each grouped inclusion during the dose escalation phase, and after LPLV for the study as a whole.
    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 Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    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
    combination of 3 molecules including one with escalating dose
    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.8.2.4Number of treatment arms in the trial2
    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 concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA4
    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 years10
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days1
    E.8.9.2In all countries concerned by the trial years10
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days1
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1Number of subjects for this age range: 0
    F.1.1.1In Utero No
    F.1.1.1.1Number of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.2.1Number of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F.1.1.3.1Number of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.4.1Number of subjects for this age range: 0
    F.1.1.5Children (2-11years) No
    F.1.1.5.1Number of subjects for this age range: 0
    F.1.1.6Adolescents (12-17 years) No
    F.1.1.6.1Number of subjects for this age range: 0
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 15
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 18
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    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 state15
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 33
    F.4.2.2In the whole clinical trial 33
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    At the end of treatment the patients will be followed for two years after the end of treatment or until progression. Obinutuzumab (GA101) and ABT199(GDC-0199) will be stopped after 2 years of treatment. Ibrutinib will continue until progression according to local practice and the investigators discretion.
    At the end of the research the patient's medical care will be discussed between the investigator and patient.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2016-02-19
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-03-23
    P. End of Trial
    P.End of Trial StatusGB - no longer in EU/EEA
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