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    Summary
    EudraCT Number:2014-005164-15
    Sponsor's Protocol Code Number:ALTERNATIVE
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2015-09-17
    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 ConcernedGermany - BfArM
    A.2EudraCT number2014-005164-15
    A.3Full title of the trial
    A prospective multicenter Phase 2 Study of the Chemotherapy-free Combination of the Bruton's Tyrosine Kinase Inhibitor, PCI-32765
    (Ibrutinib) in Combination with Obinutuzumab (GA 101) in Patients with Previously Untreated Follicular Lymphoma (FL) and a High Tumor
    Burden
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Chemotherapy-free combination of PCI-32765 (Ibrutinib) with Obinutuzumab (GA 101) in Patients with Previously Untreated Follicular Lymphoma (FL) and High Tumor Burden
    A.3.2Name or abbreviated title of the trial where available
    ALTERNATIVE
    A.4.1Sponsor's protocol code numberALTERNATIVE
    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 SponsorKlinikum der Universität München, Medizinische Klinik und Poliklinik III
    B.1.3.4CountryGermany
    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 supportJanssen-Cilag GmbH
    B.4.2CountryGermany
    B.4.1Name of organisation providing supportF. Hoffmann - La Roche Ltd
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationKlinikum der Universität München - Medizinische Klinik und Poliklinik III - Leitung der Studienzentrale für Hämatologie
    B.5.2Functional name of contact pointDr. rer. nat. Michael Unterhalt
    B.5.3 Address:
    B.5.3.1Street AddressMarchioninistr. 15
    B.5.3.2Town/ cityMunich
    B.5.3.3Post code81377
    B.5.3.4CountryGermany
    B.5.4Telephone number+4989440074900
    B.5.5Fax number+4989440077900
    B.5.6E-mailstudyce@med.uni-muenchen.de
    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 Research & Development, LCC and Pharmacyclics, LCC
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    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/3/12/984 and EU/3/13/1115
    D.3 Description of the IMP
    D.3.1Product nameIbrutinib
    D.3.2Product code PCI-32765
    D.3.4Pharmaceutical form Capsule, hard
    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 INNIbrutinib
    D.3.9.1CAS number 936563-96-1
    D.3.9.3Other descriptive nameIBRUTINIB
    D.3.9.4EV Substance CodeSUB120863
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number140
    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 GAZYVARO
    D.2.1.1.2Name of the Marketing Authorisation holderF. Hoffmann-La Roche, Ltd
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    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 / RO5072759
    D.3.2Product code GA 101
    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.3.9.3Other 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 typeMonoclonal Antibody
    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
    Stage II - IV follicular lymphoma grade 1 - 3a and a high tumor burden not previously treated
    E.1.1.1Medical condition in easily understood language
    Follicular Lymphoma in need of treatment
    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 20.0
    E.1.2Level PT
    E.1.2Classification code 10016908
    E.1.2Term Follicle centre lymphoma, follicular grade I, II, III stage II
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10016910
    E.1.2Term Follicle centre lymphoma, follicular grade I, II, III stage IV
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10016909
    E.1.2Term Follicle centre lymphoma, follicular grade I, II, III stage III
    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
    The primary objective of this study is to evaluate the efficacy of the chemotherapy-free combination of ibrutinib and obinutuzumab (GA 101) in patients with previously untreated follicular lymphoma (FL) and a high tumor burden. Primary endpoint is the rate of progression free survival one year after registration. Progression-free survival (PFS) is chosen as primary endpoint since it represents besides overall survival the most relevant parameter for patients. PFS is defined as the time from registration to lymphoma progression or death from any cause.
    E.2.2Secondary objectives of the trial
    Overall survival, complete response rate, overall response rate ORR and SD rates at end of induction, one year after start of therapy and after end of maintenance therapy, PFS (continuous observation), duration of response, 3-year-PFS, percentage of progression during induction and during maintenance therapy, percentage of progression during induction and during maintenance therapy, safety, percentage of MRD negative patients during induction therapy (midterm), after induction therapy and after maintenance therapy, duration of molecular remission for MRD negative patients after the end of induction and after end of maintenance, rate of secondary transformation to aggressive lymphoma, time to next anti-lymphoma therapy and time to next chemotherapy based treatment, percentage of secondary malignancies, time to first secondary malignancy, percentage of patients with compliance to therapy after 1, 2 and 3 years and patient-reported lymphoma symptoms and concerns as measured by FACT-Lym.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Histologically confirmed follicular lymphoma grade 1, 2 or 3a with a biopsy performed within 12 months before study entry and with material available for central review and complimentary scientific analyses
    2. Ann Arbor Stage III/IV, or stage II not suitable for radiotherapy, or stage II bulky disease (nodal or extra nodal mass >7 cm)
    3. Age ≥ 18 years
    4. No prior lymphoma therapy
    5. Need for start of therapy as defined by:
    - bulky disease at study entry according to the GELF criteria (nodal or extra nodal mass >7 cm in its greater diameter)
    - and/or B symptoms (fever, drenching night sweats, or unintentional weight loss of >10% of normal body weight over a period of 6 months or less)
    - and/or hematopoietic insufficiency (granulocytopenia < 1.500/µl, Hb < 10 g/dl, thrombocytopenia < 100.000/µl)
    - and/or compressive syndrome
    - and/or pleural/peritoneal effusion caused by lymphoma
    - and/or symptomatic extra nodal manifestations.
    6. At least one bi-dimensionally measurable lesion (> 2 cm in its largest dimension by CT scan or MRI)
    7. Performance status ≤2 on the ECOG scale
    8. Adequate hematologic function (unless abnormalities are related to NHL), defined as
    follows:
    - hemoglobin ≥ 9.0 g/dl
    - absolute neutrophil count ≥ 1500 /µL
    - platelet count ≥ 75000 /µl.
    9. Women are not breast feeding, are using highly effective contraception, are not pregnant and agree not to become pregnant during participation in the trial and during the 18 months thereafter (pregnancy testing is mandatory for premenopausal women)
    10. Men agree not to father a child during participation in the trial and during the 18 months thereafter
    11. Written informed consent
    E.4Principal exclusion criteria
    1. Transformation to high-grade lymphoma (secondary to “low grade” FL)
    2. Grade 3b follicular lymphoma
    3. Presence or history of CNS disease (either CNS lymphoma or leptomeningeal lymphoma).
    4. Known hypersensitivity to any of the study drugs
    5. Known sensitivity to murine products
    6. Regular use of corticosteroids during the last 4 weeks, unless administered at a dose equivalent to < 20 mg/day prednisone.
    7. Concomitant use of strong CY3A4 inhibitors and / or oral anticoagulants (warfarin and/or phenprocoumon)
    8. Prior or concomitant malignancies except:
    - non-melanoma skin cancer or adequately treated in carcinoma in situ of the cervix
    - other malignant diseases not specified above which have been curatively treated by surgery alone and from which subject is disease-free for ≥5 years without further treatment.
    9. Serious disease interfering with a regular therapy according to the study protocol:
    - 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.
    - pulmonary (e.g. chronic lung disease with hypoxemia)
    - endocrine (e.g. severe, not sufficiently controlled diabetes mellitus)
    - renal insufficiency (unless caused by the lymphoma): creatinine > 2x upper normal value and/or creatinine clearance < 50 ml/min)
    - impairment of liver function (unless caused by the lymphoma): transaminases > 3x normal or bilirubin > 2.0 mg/dl (unless caused by known Morbus Meulengracht [Gilbert-Meulengracht-Syndrome]).
    10. Positive test results for chronic HBV infection (defined as positive HBsAg serology) Patients with occult or prior HBV infection (defined as negative HBsAg and positive total HBcAb) may be included if HBV DNA is undetectable, provided that they are willing to undergo monthly DNA testing. Patients who have protective titers of hepatitis B surface antibody (HBsAb) after vaccination or prior but cured hepatitis B are eligible.
    11. Positive test results for hepatitis C (hepatitis C virus [HCV] antibody serology testing). Patients positive for HCV antibody are eligible only if PCR is negative for HCV RNA.
    12. Known history of HIV seropositive status
    13. Patients with a history of confirmed PML
    14. Vaccination with a live vaccine within 28 days prior to registration
    15. Recent major surgery (within 4 weeks prior to the start of Cycle 1)
    16. History of stroke or intracranial hemorrhage within 6 months prior to registration
    17. Serious underlying medical conditions, which could impair the ability of the patient to undergo the treatment offered in the study (e.g. ongoing infection, gastric ulcers, active autoimmune disease)
    18. Treatment within a clinical trial within 30 days prior to trial entry
    19. Prior organ, bone marrow or peripheral blood stem cell transplantation
    20. Known or persistent abuse of medication, drugs or alcohol
    21. Any other co-existing medical or psychological condition that will preclude participation in the study or compromise ability to give informed consent.
    E.5 End points
    E.5.1Primary end point(s)
    Progression-free survival (PFS) is chosen as primary endpoint for most phase III trials in FL, since it represents beside overall survival the most clinical relevant parameter for patients. PFS is in this trial defined as the time from registration to lymphoma progression or death from any cause. Since an early readout for efficacy is needed in this phase II trial, the rate of patients achieving a progression free survival of more than one year after registration (one year PFS) will be the primary endpoint of this trial. The use of this non-standard endpoint is well justified by the observation of progression free survival in former trials, showing a nearly linear shape of the Kaplan-Meier-estimates for PFS and a proportional hazard for different treatments.
    E.5.1.1Timepoint(s) of evaluation of this end point
    One year after registration
    E.5.2Secondary end point(s)
    - Rate of patients achieving a progression free survival of more than three years
    - Progression free survival after start of therapy (continuous observation)
    - CR, PR and SD rates after induction therapy, one year after start of therapy and after end of maintenance therapy (at 30 months after start of therapy: CR30)
    - Duration of Response
    - Percentage of progression during induction and during maintenance therapy
    - Time to treatment failure after start of therapy (failure defined by missing CR/PR or progression after CR or PR or death in remission)
    - Time to next anti-lymphoma therapy and time to next chemotherapy based treatment
    - Safety including treatment associated adverse events
    - Percentage of MRD negative patients during induction therapy (midterm), after induction therapy and after maintenance therapy
    - Duration of molecular remission for MRD negative patients after the end of induction and after end of maintenance
    - Percentage of secondary transformation to aggressive lymphoma
    - Percentage of secondary malignancies
    - Time to first secondary malignancy
    - Overall survival
    - Percentage of patients with compliance to therapy after 1, 2 and 3 years
    - patient-reported lymphoma symptoms and concerns (FACT-Lym).
    E.5.2.1Timepoint(s) of evaluation of this end point
    The time to event parameters survival, progression free survival, time to treatment failure, time to first secondary malignancy and time to next anti-lymphoma therapy/chemotherapy will be evaluated starting at registration in this trial. If an event has not been observed at evaluation, the parameter will be censored at the last documented event-free observation.
    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 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 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 concerned40
    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 years6
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days0
    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: 49
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 49
    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 state98
    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)
    Patients will be treated according to the local standard care.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation Deutsche Studiengruppe Niedrig Maligne Lymphome e.V. (German Low Grade Lymphoma Study Group - GLSG)
    G.4.3.4Network Country Germany
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2015-12-22
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-11-18
    P. End of Trial
    P.End of Trial StatusOngoing
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