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    Summary
    EudraCT Number:2014-000580-40
    Sponsor's Protocol Code Number:CLL2-BAG
    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:2015-01-22
    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 number2014-000580-40
    A.3Full title of the trial
    A prospective, open-label, multicentre phase-II-trial to evaluate the efficacy and safety of a sequential regimen of Bendamustine followed by GA101 (Obinutuzumab) and ABT-199 (Venetoclax) followed by ABT-199 and GA101 maintenance in CLL patients
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A prospective, open-label, multicentre phase-II-trial to evaluate the efficacy and safety of a sequential regimen of Bendamustine followed by GA101 (Obinutuzumab) and ABT-199 (Venetoclax) followed by ABT-199 and GA101 maintenance in CLL patients
    A.3.2Name or abbreviated title of the trial where available
    CLL2-BAG
    A.4.1Sponsor's protocol code numberCLL2-BAG
    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 SponsorUniversity of Cologne
    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 supportF.Hoffmann - La Roche
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationGerman CLL Study Group
    B.5.2Functional name of contact pointInformation Desk
    B.5.3 Address:
    B.5.3.1Street AddressGleueler Str. 176 - 178
    B.5.3.2Town/ cityKöln
    B.5.3.3Post code50935
    B.5.3.4CountryGermany
    B.5.4Telephone number00490221478 88220
    B.5.5Fax number00490221478 86886
    B.5.6E-mailcllstudie@uk-koeln.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 Bendamustin (Levact)
    D.2.1.1.2Name of the Marketing Authorisation holderAstellas Pharma GmbH
    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 nameBendamustine hydrochloride
    D.3.4Pharmaceutical form Concentrate and solvent for 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: 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 holderRoche / Genentech
    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 / GA101
    D.3.2Product code RO5072759
    D.3.4Pharmaceutical form Concentrate and solvent 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 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 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 Yes
    D.3.11.13.1Other medicinal product typeRO5072759 is a humanized and glycoengineered monoclonal antibody (mAB), targets and kills CD20 + B-cells
    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 Yes
    D.2.1.1.1Trade name venclyxto
    D.2.1.1.2Name of the Marketing Authorisation holderAbbvie
    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/3/12/1080
    D.3 Description of the IMP
    D.3.1Product nameABT-199, Venetoclax
    D.3.4Pharmaceutical form Film-coated 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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Fit and unfit patients with previously untreated or relapsed/refractory CLL requiring treatment
    E.1.1.1Medical condition in easily understood language
    Fit and unfit patients with previously untreated or relapsed/refractory CLL requiring treatment
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level PT
    E.1.2Classification code 10008958
    E.1.2Term Chronic lymphocytic leukaemia
    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 results of the CLL2-BAG trial, evaluating an optional debulking with bendamustine followed by an induction and a maintenance treatment with obinutuzumab and venetoclax were promising: Overall response rate was 95% and additionally, the minimal residual disease negativity rate in peripheral blood was 87%.Toxicity was generally acceptable and manageable. It is scientifically important to collect further data in this study, to analyze the duration of response and the further course of MRD. Risk factors for early progression may be identified. Consecutive blood samples will be analyzed for venetoclax resistance and clonal evolution.
    The planned re-treatment with venetoclax and obinutuzumab in case of a progression will investigate the efficacy of a re-treatment. Up to 10 patients each from the relapsed/refractory and the first-line cohort may be treated with obinutuzumab and. Start of the re-treatment should not be later than two years before planned end of the trial.
    E.2.2Secondary objectives of the trial
    Secondary endpoints to assess the efficacy of the re-treatment are: ORR and (clinical) CR/CRi rate at the final restaging of re-treatment phase and at end of re-treatment maintenance phase, as well as MRD levels in peripheral blood and bone marrow. Furthermore, it is aimed to evaluate the safety of re-treatment with venetoclax and obinutuzumab by assessment of type, frequency, and severity of AEs and their relationship to study treatment.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Documented CLL requiring treatment (irrespective if first or relapse treatment) according to iwCLL criteria
    In case of previously treated patients, these must have recovered from acute toxicities and treatment regimen must be stopped within the following time periods before start of study treatment in the CLL2-BAG trial:
    • chemotherapy within ≥ 28 days
    • antibody treatment within ≥ 14 days
    • kinase inhibitors, BCL2-antagonists or immunmodulatory agents within ≥ 3 days
    • corticosteroids may be applied until the start of the BAG-regimen, these have to be reduced to an equivalent of ≤ 20mg prednisolon during treatment
    2. Adequate renal function, as indicated by a creatinine clearance ≥30ml/min calculated according to the modified formula of Cockcroft and Gault or directly measured with 24 hr. urine collection
    3. Adequate hematologic function as indicated by a platelet count ≥ 25 x 10 9/L, a neutrophil count ≥ 1,0 x 10 9/L and a hemoglobin value ≥ 8.0 g/dL, unless directly attributable to the patient´s CLL (e.g. bone marrow infiltration)
    4. Adequate liver function as indicated by a total bilirubin ≤2x, AST/ALT ≤2.5x the institutional ULN value, unless directly attributable to the patient’s CLL or to Gilbert’s Syndrome
    5. Negative serological testing for hepatitis B (HBsAg nega-tive and anti-HBc negative, patients positive for anti-HBc may be included if PCR for HBV DNA is negative and HBV-DNA PCR is performed every month until 1 year after last dosage of obinutuzumab), negative testing for hepatitis-C RNA and negative HIV test within 6 weeks prior to registration
    6. Age ≥ 18 years
    7. ECOG 0 to 2, ECOG 3 is only permitted if related to CLL (e.g. due to anemia or severe constitutional symptoms)
    8. Life expectancy ≥ 6 months
    9. Ability and willingness to provide written informed consent and to adhere to the study visit schedule and other protocol requirements
    Inclusion criteria for extended follow-up and re-treatment (Amendment 4):
    1.Patients must have participated in the CLL2-BAG trial and must have benefitted from study treatment
    2.Only patients with a confirmed progression of CLL who are in need of treatment according to iwCLL 2008 criteria are eligible for retreatment with veneto-clax and obinutuzumab
    Please note: Patients with a MRD conversion from nega-tive/intermediate to positive without clinical signs of pro-gression should not (yet) receive a retreatment in the trial
    E.4Principal exclusion criteria
    1. Transformation of CLL (i.e. Richter’s transformation, pro-lymphocytic leukemia)
    2. Known central nervous system (CNS) involvement
    3. Patients with confirmed PML
    4. Malignancies other than CLL currently requiring systemic therapies
    5. Uncontrolled infection requiring systemic treatment
    6. Any comorbidity or organ system impairment rated with a CIRS (cumulative illness rating scale) score of 4, excluding the eyes/ears/nose/throat/larynx organ system or any other life-threatening illness, medical condition or organ system dysfunction that – in the investigator´s opinion - could compromise the patients safety or interfere with the absorption or metabolism of the study drugs (e.g, inability to swallow tablets or impaired resorption in the gastro-intestinal tract)
    7. Requirement of therapy with strong CYP3A4 inhibitors/inducers or anticoagulant with warfarin, phenprocoumon (marcumar) or other vitamin K-antagonists
    8. Use of investigational agents which would interfere with the study drug within 28 days prior to registration
    9. Known hypersensitivity to obinutuzumab, venetoclax or any of the excipients
    Please note: Patients with a known hypersensitivity to bendamustine are allowed to participate but will not receive a debulking with bendamustine
    10. Pregnant women and nursing mothers (a negative pregnancy test is required for all women of childbearing potential within 7 days before start of treatment, on day one of every debulking and induction cycle (monthly) and on day one of every maintenance cycle (every three months))
    11. Fertile men or women of childbearing potential unless:
    - surgically sterile or ≥ 2 years after the onset of menopause, or
    - willing to use two methods of reliable contraception including one highly effective (Pearl Index <1) and one additional effective (barrier) method during study treatment and for 18 months after end of study treatment.
    12. Vaccination with a live vaccine ≤ 28 days prior to registration
    13. Legal incapacity
    14. Prisoners or subjects who are institutionalized by regulatory or court order
    15. Persons who are in dependence to the sponsor or an investigator
    Exclusion criteria for extended follow-up and re-treatment (Amendment 4):
    3.Patients who received any subsequent treatment for CLL outside the study are ineligible
    E.5 End points
    E.5.1Primary end point(s)
    Overall response rate (ORR)
    E.5.1.1Timepoint(s) of evaluation of this end point
    at final restaging (RE) 12 weeks after the start of the last course of induction therapy
    E.5.2Secondary end point(s)
    Type, frequency, severity of AEs + AESI + their relationship to study treatment
    MRD in peripheral blood at
    - final restaging after end of induction in patients responding to study treatment and
    - every 12 weeks during maintenance if patient has achieved a (clinical) CR(i) or
    - every 24 weeks during the maintenance phase if the patient has achieved a PR
    - every 24 weeks during follow up
    - MRD in BM optionally in patients with (clinical) CR(i) 3 months after achievement of MRD- in peripheral blood
    - BRR until 6 months after RE
    - ORR after debulking
    - ORR after end/maintenance
    - ORR in two strata of previously untreated and relapsed/refractory pats, fit + unfit patients for mentioned response definitions
    - ORR in biological defined risk groups
    - PFS
    - EFS
    - OS
    - Duration of response in patients with:
    - (clinical) CR,
    - (clinical) CRi,
    - PR with/without lymphocytosis
    - Time to next CLL treatment
    - relationship between baseline markers and clinical outcome parameters
    - Efficacy of re-treatment with venetoclax and obinutuzumab (in case of a clinical progression after termination of mainte-nance therapy):
    - ORR and (clinical) CR/CRi rate assessed by the in-vestigator at the final restaging of re-treatment phase (12 weeks after the start of the last re-treatment in-duction cycle) and at the end of re-treatment mainte-nance phase
    - MRD levels measured in peripheral blood by four-color flow cytometry every 3 months during re-treatment and every 6 months during thefollow-up thereafter
    - MRD levels measured in bone marrow (optionally in patients with (clinical) CR/CRi and MRD negativity in peripheral blood)
    - Safety evaluation of re-treatment: Type, frequency, and severity of
    - adverse events (AE) leading to dose reductions, treatment interruption and/or discontinuation,
    - adverse events of special interest (AESI) and
    - serious adverse events (SAEs)
    and their relationship to study treatment.
    E.5.2.1Timepoint(s) of evaluation of this end point
    ongoing evaluation during the trial
    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.8.2.4Number of treatment arms in the trial1
    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 concerned20
    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 years8
    E.8.9.1In the Member State concerned months
    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: 62
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 62
    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 state62
    F.4.2 For a multinational trial
    F.4.2.2In the whole clinical trial 62
    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)
    After participation in the trial has ended no special treatment or care is needed.
    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 Decision2015-03-31
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-04-23
    P. End of Trial
    P.End of Trial StatusOngoing
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