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    Summary
    EudraCT Number:2013-004635-69
    Sponsor's Protocol Code Number:VU-HEM-ZR-OBI-2014
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2014-03-26
    Trial results View 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 ConcernedNetherlands - Competent Authority
    A.2EudraCT number2013-004635-69
    A.3Full title of the trial
    A phase II study of obinutuzumab monotherapy
    in rituximab-refractory follicular lymphoma
    Obinutuzumab monotherapie voor rituximab-refractair folliculair lymfoom
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A phase II study of obinutuzumab monotherapy
    in rituximab-refractory follicular lymphoma
    Obinutuzumab monotherapie voor rituximab-refractair folliculair lymfoom
    A.4.1Sponsor's protocol code numberVU-HEM-ZR-OBI-2014
    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 SponsorVU University Medical Center
    B.1.3.4CountryNetherlands
    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 supportVU University Medical Center
    B.4.2CountryNetherlands
    B.4.1Name of organisation providing supportRoche Nederland B.V.
    B.4.2CountryNetherlands
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationVU University Medical Center
    B.5.2Functional name of contact pointTrial office dept. of Haematology
    B.5.3 Address:
    B.5.3.1Street AddressDe Boelelaan 1117
    B.5.3.2Town/ cityAmsterdam
    B.5.3.3Post code1081HV
    B.5.3.4CountryNetherlands
    B.5.4Telephone number0031204449265
    B.5.5Fax number0031204443650
    B.5.6E-mailm.leidekker@vumc.nl
    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 No
    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 nameobinutuzumab
    D.3.2Product code RO5072759
    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.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNobinutuzumab
    D.3.9.1CAS number 949142-50-1
    D.3.9.2Current sponsor codeRO5072759
    D.3.9.3Other descriptive nameOBINUTUZUMAB
    D.3.9.4EV Substance CodeSUB32751
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1000
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    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 Yes
    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 Yes
    D.3.11.13.1Other medicinal product typeobinutuzumab is a humanized and glyco-engineered monoclonal antibody
    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 No
    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 nameobinutuzumab-N-succinyl-desferal-zirconium-89
    D.3.2Product code 89Zr-obinutuzumab
    D.3.4Pharmaceutical form Solution for injection/infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNobinutuzumab
    D.3.9.1CAS number 949142-50-1
    D.3.9.2Current sponsor codeRO5072759
    D.3.9.3Other descriptive nameOBINUTUZUMAB
    D.3.9.4EV Substance CodeSUB32751
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    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 Yes
    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 Yes
    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
    rituximab refractory follicular lymphoma
    E.1.1.1Medical condition in easily understood language
    rituximab refractory follicular lymphoma
    E.1.1.2Therapeutic area Diseases [C] - Blood and lymphatic diseases [C15]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 16.1
    E.1.2Level LLT
    E.1.2Classification code 10016896
    E.1.2Term Follicle centre lymphoma diffuse small cell lymphoma NOS
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    •To determine the efficacy (defined as overall response) of obinutuzumab monotherapy given in cycles of 4 weekly infusions to rituximab-refractory follicular lymphoma patients
    E.2.2Secondary objectives of the trial
    •To determine the efficacy (defined as progression free survival, overall survival, duration of response, duration of stable disease, time to next treatment) of obinutuzumab monotherapy given as 4 weekly infusions to rituximab-refractory follicular lymphoma patients.
    •To investigate the relationship between tumour uptake on immuno-PET and tumour response to obinutuzumab
    •To compare tumour uptake using immuno-PET as a novel imaging biomarker to “standard imaging technique” (18F-PET/CT, contrast enhanced CT)
    •To investigate the biodistribution and dosimetry in normal tissue of 89Zr-obinutuzumab
    •To determine the value of FDG-PET-CT scanning in response assessment of follicular lymphoma patients
    •To assess safety data by monitoring all adverse and serious adverse events (AEs/SAEs) according to the NCI CTCAE v.4.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    •Biopsy-proven rituximab refractory follicular lymphoma (defined as disease progression while on rituximab maintenance therapy). Patients are required to have received a minimum of 2 infusions of rituximab maintenance therapy and/or be on a maintenance schedule for a minimum of 3 months (measured from the time of first maintenance infusion). Disease progression must have occurred before the last maintenance infusion.
    •No clinical or pathological evidence of transformation to high-grade or diffuse large B-cell lymphoma (e.g. B symptoms, fast-growing tumour, or increasing lactate dehydrogenase level)
    •Patients must have radiographically documented measurable disease, defined as 2 or more clearly demarcated lesions with a largest diameter of at least 1.5 cm or 1 clearly demarcated lesion with a largest diameter of at least 2.0 cm by computed tomography scan. All radiology studies must be performed within 14 days prior to registration.
    •Adult patients, >=18 years of age
    •Clinical indication for treatment as determined by the “treating physician”
    •ECOG performance status of 0, 1 or 2.
    •Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial
    •Before patient registration, written informed consent must be given according to GCP, and national regulations.
    E.4Principal exclusion criteria
    •Known central nervous system involvement
    •Concurrent use of other anti-cancer agents
    •All other lymphoma treatment (except rituximab maintenance therapy) during the last 6 months.
    •Concurrent use of glucocorticoids (>10mg/day prednisolone or equivalent), or glucocorticoids (>10mg/day prednisolone or equivalent) within 4 weeks of first infusion
    •Prior use of any investigational monoclonal antibody within 6 months of study start
    •Prior use of any anti-cancer vaccine
    •Previous allogeneic stem cell transplantation at any time or previous autologous stem cell transplantation within 6 months of first infusion
    •More than 1 previous radioimmunotherapy
    •Radioimmunotherapy within 3 months of first infusion
    •Other active malignancy or history of other active malignancy. However patients who have been free of malignancy for at least 5 years, or have a history of completely resected non-melanoma skin cancer, or successfully treated in situ carcinoma are eligible.
    •Intolerance of exogenous protein administration
    •Pregnant and breastfeeding women and those of childbearing potential who are not able or willing to use adequate and effective contraception.
    Definition of adequate and effective contraception: use of two reliable forms of contraception.
    For women, effective contraception is required to continue for ≥ 12 months after the last dose of obinutuzumab. For men, effective contraception is required to continue for ≥ 3 months after the last dose of obinutuzumab.
    •Life expectancy < (less than) 6 months
    •Clinical significant cardiovascular disease, such as New York Heart Association Class III or IV cardiac disease, myocardial infarction within the last 6 months, unstable arrhythmias, or unstable angina)
    •Active infectious disease, requiring systemic treatment:
    o Positive test results for chronic hepatitis B virus (HBV) infection (defined as positive hepatitis B virus surface antigen [HBsAg] and/or hepatitis B core antibody [HBcAb] serology)
    o Positive test results for hepatitis C (hepatitis C virus [HCV] antibody serology testing) Patients positive for HCV antibody are eligible only if polymerase chain reaction is negative for HCV RNA
    o Vaccination with a live vaccine within 28 days prior to the start of study drug (Cycle 1, Day 1)
    o Known HIV or HTLV-1 infection
    •Any of the following abnormal laboratory values:
    oCreatinine >1.5 times the upper limit of normal (unless creatinine clearance normal), or creatinine clearance <40 ml/min
    oAspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2.5 times the upper limit of normal
    oTotal bilirubin >3 x ULN
    oNeutrophil count <1.5 x 109/L (unless due to underlying disease, as established by extensive bone marrow involvement)
    oHemoglobin <8 g/dL (unless due to underlying disease, as established by extensive bone marrow involvement)
    E.5 End points
    E.5.1Primary end point(s)
    •Overall response using the Revised Response Criteria for Malignant Lymphoma (RRMCML) for disease assessment (10)
    E.5.1.1Timepoint(s) of evaluation of this end point
    week 10-12 after start study treatment
    E.5.2Secondary end point(s)
    •Progression-free survival
    •Overall survival
    •Duration of response, in responders
    •Duration of stable disease
    •Time to next anti-lymphoma treatment
    •The detection of tumour lesions employing contrast enhanced CT-scan
    •The detection of tumour lesions employing 18F-FDG-PET
    •The detection of tumour lesions employing 89Zr-obinutuzumab immuno-PET
    •The detection of 89Zr-obinutuzumab in normal tissue
    •The description of safety data: all adverse events and serious adverse events (AEs/SAEs) according to to the NCI CTCAE v.4.


    E.5.2.1Timepoint(s) of evaluation of this end point
    PFS+duration of response+uration of stable disease +The detection of tumour lesions employing contrast enhanced CT-scan
    6,9,12 months
    Os+time to next treatment: every 2 months up to one year
    •The detection of tumour lesions employing 18F-FDG-PET: month 6
    •The detection of tumour lesions employing 89Zr-obinutuzumab immuno-PET: day 1,4,7
    •The detection of 89Zr-obinutuzumab in normal tissue: day 1,4,7
    •The description of safety data: every visit
    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 No
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    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) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    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 Yes
    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 Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    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 No
    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 years3
    E.8.9.1In the Member State concerned months1
    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: 25
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 5
    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 Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    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 state25
    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)
    None
    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 Decision2014-03-26
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-11-05
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2019-10-25
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