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    Summary
    EudraCT Number:2016-002059-89
    Sponsor's Protocol Code Number:GAZAI
    National Competent Authority:Germany - PEI
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2017-06-12
    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 - PEI
    A.2EudraCT number2016-002059-89
    A.3Full title of the trial
    Therapy of Nodal Follicular Non-Hodgkin Lymphoma (WHO grade 1/2) in Clinical Stage I/II using Response Adapted Involved Site Radiotherapy in Combination with Gazyvaro
    A.3.2Name or abbreviated title of the trial where available
    GAZyvaro and response Adapted Involved-site Radiotherapy
    A.4.1Sponsor's protocol code numberGAZAI
    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 SponsorRuprecht-Karls-University Heidelberg, Medical Faculty represented by University Hospital Heidelberg
    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 supportRoche Pharma AG
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAbteilung Radioonkologie & Strahlentherapie, Universitätsklinikum Heidelberg
    B.5.2Functional name of contact pointProf. Dr. med. Klaus Herfarth
    B.5.3 Address:
    B.5.3.1Street AddressIm Neuenheimer Feld 400
    B.5.3.2Town/ cityHeidelberg
    B.5.3.3Post code69120
    B.5.3.4CountryGermany
    B.5.4Telephone number0049622156 8202
    B.5.5Fax number0049622156 5353
    B.5.6E-mailKlaus.Herfarth@med.uni-heidelberg.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 GAZYVARO®
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Pharma AG
    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 No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameGAZYVARO
    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.3.9.4EV 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 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
    nodal follicular lymphoma grade 1 or grade 2 in the clinical stage I or II (Ann Arbor classification)
    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 23.0
    E.1.2Level PT
    E.1.2Classification code 10029602
    E.1.2Term Non-Hodgkin's lymphoma stage I
    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 23.0
    E.1.2Level PT
    E.1.2Classification code 10029603
    E.1.2Term Non-Hodgkin's lymphoma stage II
    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 rate of metabolic CR after low-dose radiotherapy in combination with Gazyvaro (Obinutuzumab) for early stage nodal follicular lymphoma will be assessed. In addition, the feasibility of a response adapted approach using FDG-PET/CT regarding success (PFS, rates of remission, analysis of recurrences) and safety in combination with Gazyvaro will be assessed.
    The results will be historically compared to the results of the MIR trial regarding morphologic response in week 7 and the quality of life (secondary endpoints). Additional secondary endpoints are PFS, the site of recurrences in the three subgroups (1. PET negative after initial staging; 2. PET negative in week 18; 3. PET positive in week 18).

    Primary
    Evaluation of the rate of metabolic CR after low-dose involved site radiotherapy in combination with Gazyvaro (Obinutuzumab) in early stage nodal follicular lymphoma in order to avoid conventional full dose IF radiotherapy.
    E.2.2Secondary objectives of the trial
    Secondary
    Efficacy and safety of a response adapted radiation dose treatment schedule.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • Centrally reviewed CD20-positive follicular lymphoma grade 1/2 based on WHO classification (2008)
    • Untreated (radiation-, chemo- or immunotherapy) nodal lymphoma (including involvement of Waldeyer´s ring)
    • Age: ≥18 years
    • ECOG: 0-2
    • Stage: clinical stage I or II (Ann Arbor classification)
    • Risk profile: Largest diameter of the lymphoma * 7 cm (sectional images)
    • Written informed consent and willingness to cooperate during the course of the trial
    • Adequate hematologic function (unless abnormalities are related to NHL), defined as follows: Hemoglobin ≥ 9.0 g/dL; absolute neutrophil count ≥ 1.5 × 109/L, Platelet count ≥ 75 × 109/L
    • Capability to understand the intention and the consequences of the clinical trial
    • Adequate contraception for men and women of child-bearing age during therapy and 18 months thereafter
    • Patients with non-active hepatitis B infection (HBsAg neg/HBcAB pos/HBV DNA neg) under 1-year prophylactic anti-viral therapy (e.g. Entecavir® or Tenofovir®) possible (see also 5.6. Prior and Concomitant Disease)
    E.4Principal exclusion criteria
    • Extra nodal manifestation
    • Secondary cancer in the patients medical history (exclusion: basalioma, spinalioma, melanoma in situ, bladder cancer T1a, non-metastasized solid tumor in constant remission, which was diagnosed >3 years ago
    • Concomitant diseases: congenital or acquired immune-deficiency syndromes, active infections including viral hepatitis (serology positive for HBsAg or HBcAb in combination positive HBV DNA), uncontrolled concomitant diseases including significant cardiovascular or pulmonary disease (see also 5.6. Prior and Concomitant Disease)
    • Severe psychiatric disease
    • Pregnancy / lactation
    • Known hypersensitivity against Gazyvaro (Obinutuzumab) or drugs with similar chemical structure or any other additive of the pharmaceutical formula of the study drug
    • Participation in another interventional trial or follow-up period of a competing trial which can influence the results of this current trial
    • Creatinine > 1.5 times the upper limit of normal (ULN) (unless creatinine clearance normal), or calculated creatinine clearance < 40 mL/min
    • AST or ALT > 2.5 × ULN
    • Total bilirubin ≥ 1.5 × ULN
    • INR > 1.5 × ULN
    • PTT or aPTT > 1.5 × the ULN
    E.5 End points
    E.5.1Primary end point(s)
    Metabolic complete response (CR) in patients with initially remaining lymphoma judged by FDG-PET/CT
    E.5.1.1Timepoint(s) of evaluation of this end point
    in week 18
    E.5.2Secondary end point(s)
    • Morphologic CR, PR, SD, PD in week 7, week 18 and month 6 in patients with initially remaining lymphoma judged by CT/MRI
    • Historical comparison of the morphologic response with MIR data (using MabThera); The comparison of the CR rate in week 7 will allow for a comparison of the two different CD20 antibodies. Due to the restricted patient numbers no matched pair analysis will be possible
    • Progression free survival (PFS) of all treated patients (2 years after individual treatment start)
    • Toxicity (NCI-CTC criteria, version 4.03) of all patients
    • Relapse rate and pattern of recurrence of all treated patients at all follow-up visits.
    • Overall survival (OS) of all treated patients (2 years)
    • Quality of life according EORTC QLQ C30 and FACT-Lym questionnaires at inclusion and in week 18, month 12, and 24 (all treated patients)
    • MRD response in peripheral blood: initially, week 18, months 6, 12, 18 and 24 (all treated patients). MRD is evaluated by the laboratory of C. Pott (Kiel) using at least the markers: t(14:18) PCR for MBR, 3’mbr, 5’mcr and MCR; clonal IGH rearrangements (FR1-3); clonal IGL rearrangements (IGK and Kappa-KDE)
    E.5.2.1Timepoint(s) of evaluation of this end point
    • Morphologic CR, PR, SD, PD in week 7, week 18 and month 6
    • Historical comparison of the morphologic response with MIR data in week 7
    • Progression free survival 2 years after individual treatment start
    • Relapse rate and pattern of recurrence at all follow-up visits
    • Overall survival (OS) (2 years)
    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 Yes
    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) 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 concerned15
    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 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: 19
    F.1.3Elderly (>=65 years) No
    F.1.3.1Number of subjects for this age range: 74
    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 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 state93
    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)
    Follow-up procedures and possible further treatments after the trial (early ending or after month 30) should be performed according to local standard procedures at each site. The results of this extended follow-up should be collected with the consent of the patient as in a register. It is the goal to analyze these long time follow-up data retrospectively in the future.
    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 Decision2017-11-02
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-11-02
    P. End of Trial
    P.End of Trial StatusOngoing
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