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    Summary
    EudraCT Number:2015-000568-32
    Sponsor's Protocol Code Number:CLLTX1
    National Competent Authority:Germany - PEI
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2016-11-01
    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 number2015-000568-32
    A.3Full title of the trial
    Obinutuzumab containing conditioning regimen for CLL patients and patients with Richter`s transformation requiring an allogeneic stem cell transplantation
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Obinutuzumab containing conditioning regimen for CLL patients and patients with Richter`s transformation requiring an allogeneic stem cell transplantation
    A.4.1Sponsor's protocol code numberCLLTX1
    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 SponsorUniversität Köln
    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 organisationGerman CLL Study Group
    B.5.2Functional name of contact pointCLLTX1
    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 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 nameObinutuzumab
    D.3.2Product code RO5072759
    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 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
    Patients with poor risk CLL and Richter`s transformation requiring an allogeneic stem cell transplantation
    E.1.1.1Medical condition in easily understood language
    Patients with poor risk CLL and Richter`s transformation requiring an allogeneic stem cell transplantation
    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 10008958
    E.1.2Term Chronic lymphocytic leukaemia
    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 10058728
    E.1.2Term Richter's syndrome
    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 the study is to evaluate the feasibility, efficacy and safety of an Obinutuzumab containing conditioning regimen for CLL patients and patients with Richter`s transformation requiring an allogeneic stem cell transplantation.
    E.2.2Secondary objectives of the trial
    • Rate of patients free from disease progression at 12 months post-transplant
    • MRD negativity rate at different time points (days +60, +90, +180, +270 and months 12, 18 and 24 post transplant)
    • Overall response rate following treatment at 6 months post-transplant
    • Progression-free survival
    • Event-free survival
    • Overall survival
    • Chimerism at day 100 post-transplant
    • Non relapse mortality and relapse related mortality
    • Engraftment post-transplant defined as > 0.50 x 109/L Neutrophils and Platelets > 20 x 109/L without transfusion requirement at 30 days post-transplant
    • Incidences of grade III/IV adverse drug reactions
    • Incidence and severity of acute GvHD at 100 and 365 days post transplant
    • Incidence and severity of chronic GvHD within the first year post transplant
    • Correlation between MRD and PFS
    • Evaluation of relationship between various baseline markers and clinical outcome parameters
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Have documented CLL according to iwCLL criteria
    2. a) CLL requiring transplant according to the consensus statement 2014:1
    • Non-response or early relapse within 24 months after purine analogue combination therapy or treatment of similar efficacy plus high risk CLL TP53 deletion/mutation (del 17p-) and/or del 11 plus response to kinase inhibitors or other small molecules
    or
    • Non-response or early relapse within 24 months after purine analogue combination therapy or treatment of similar efficacy and refractory to or non-tolerating kinase inhibitors or other small molecules
    or
    b) Transformation of CLL to aggressive NHL (Richter’s transformation)
    The CLL patients should have at least one therapy with the newer targeted agents such as BCL-2 inhibitors or BCR targeting agents. Both poor risk CLL patients and patients with Richter`s transformation should achieve the best possible response defined as disease sensitivity measured as CR, PR or SD prior to transplant with an available salvage therapy
    3. Availability of a suitable fully matched (10/10) sibling or unrelated donor
    4. Must have an Eastern Cooperative Oncology Group (ECOG) performance status score of ≤ 1.
    5. Hematology values within the following limits unless cytopenia is caused by the underlying disease, i.e., no evidence of additional bone marrow dysfunction (e.g. myelodysplastic syndrome 2, hypoplastic bone marrow):
    • Absolute neutrophil count ≥ 1.0 x 109/L
    • Platelets ≥ 50 x 109/L and more than 7 days since last transfusion
    6. Adequate liver function as indicated by a total bilirubin AST, and ALT ≤1.5 the institutional ULN value, unless directly attributable to the patient’s CLL
    7. Negative serological testing for hepatitis B (HBsAg negative 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
    8. 18 years of age or older but not older then 70 years
    9. Able and willing to provide written informed consent and to comply with the study protocol procedures
    10. Patient agrees to inform other physicians about study participation
    E.4Principal exclusion criteria
    11. Previous allogeneic stem cell transplant
    12. Known central nervous system (CNS) involvement
    13. Patients with a history of confirmed PML
    14. Clinically significant cardiac disease including unstable angina, acute myocardial infarction withinsix months prior to randomization, congestive heart failure (left ventricular ejection fraction < 50%).
    15. Organ dysfunction DLCO < 50%, TLC < 70%, FEV1 < 70% and or receiving supplementary oxygen, Inadequate renal function: Creatinine clearance < 50ml/min
    16. Patients with active fungal infections with radiological progression despite treatment with Ambisome or active Triazole for more than a month
    17. History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies. Known sensitivity or allergy to murine products
    18. Hypersensitivity to Obinutuzumab or to any of the excipients such as for example Mannitol
    19. Participation in another experimental drug trial (including chemotherapy, antibody treatment, kinase inhibitors, BCL2-antagonists or immunmodulatory agents) with start of the conditioning regimen/first Obinutuzumab application.
    20. Pregnant women and nursing mothers (a negative pregnancy test is required for all women of childbearing potential within 7 days before start of treatment)
    21. Fertile men or women of childbearing potential unless:
    • Surgically sterile or ≥ 2 years after the onset of menopause
    • Willing to use a highly effective contraceptive method (Pearl Index < 1) such as oral hormonal contraceptives, intrauterine device, sexual abstinence or barrier method of contraception in conjunction with spermicidal jelly during study treatment and for 12 months after end of study treatment.
    22. Vaccination with a live vaccine a minimum of 28 days prior to randomization
    23. Prisoners or patients who are institutionalized by regulatory or court order or persons who are in dependence to the sponsor or an investigator
    E.5 End points
    E.5.1Primary end point(s)
    For this study there will be no formal primary endpoint which is connected to sample size calculation and confirmatory testing. According to the main study objective, the following key efficacy endpoint will be considered:
    • Rate of patients free from disease progression (PD-free rate) at 12 months post-transplant
    Moreover the following additional endpoints will be evaluated:
    Other efficacy endpoints
    • CLL patients: MRD negativity rate at different time points (days 60, 90, 180, 270 and months 12, 18 and 24 post-transplant)
    • Overall response rate (ORR) following treatment at 6 months post-transplant
    • Progression-free survival (PFS)
    • Event-free survival (EFS)
    • Overall survival (OS)
    Safety endpoints
    • Non relapse mortality (NRM) and relapse related mortality
    • Engraftment post-transplant defined as > 0,50 x 109/L Neutrophils and Platelets > 20 x 109/L without transfusion requirement at 30 days post-transplant
    • Chimerism at day 100 post-transplant
    • Incidences of grade III/IV adverse drug reactions
    • Incidence and severity of acute GvHD at 100 and 365 days post transplant
    • Incidence and severity of chronic GvHD within the first year post transplant
    Health-related quality of life by EORTC QLQ-C30 questionnaire
    Explorative endpoints
    • Correlation between MRD and PFS
    • Evaluation of relationship between various baseline markers and clinical outcome parameters
    E.5.1.1Timepoint(s) of evaluation of this end point
    Analysis of key efficacy end point: Q1 2020
    Final study report: Q1 2022

    E.5.2Secondary end point(s)
    not applicable
    E.5.2.1Timepoint(s) of evaluation of this end point
    not applicable
    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 concerned6
    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
    40 patients shall be enrolled in the study. With an accrual rate of 1-2 patients per month the accrual duration will last 24 months (2 years). The additional time required from the time of last patient enrolled until the key efficacy endpoint is reached is approximately 12 months (1 year) followed by an additional observation time point at 24 months post transplantation for MRD and response resulting in total study duration of approximately 48 months (4 years).
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    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: 40
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 40
    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 state40
    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 Decision2017-03-30
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-11-07
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2019-09-30
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
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