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    Summary
    EudraCT Number:2012-001947-31
    Sponsor's Protocol Code Number:TUD-CLL-X4-054
    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:2012-07-17
    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 ConcernedGermany - PEI
    A.2EudraCT number2012-001947-31
    A.3Full title of the trial
    Ofatumumab Induction and Maintenance in Elderly Patients with Poor Risk CLL in the Context of Allogeneic Transplantation: CLLX4 Trial
    Ofatumumab Induktions- und Erhaltungstherapie bei älteren Patienten mit poor risk CLL in Rahmen der allogenen Stammzelltransplantation (CLLX4-Studie)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Ofatumumab Induction and Maintenance therapy in Elderly Patients with Poor Risk chronic lymphocytic leukemia in the Context of Allogeneic Transplantation
    Induktions- und Erhaltungstherapie mit Ofatumumab bei älteren Patienten mit einer Hochrisiko Chronischen Lymphatischen Leukämie (CLL) im Rahmen der allogenen Stammzelltransplantation (CLLX4-Studie)
    A.3.2Name or abbreviated title of the trial where available
    CLL-X4
    A.4.1Sponsor's protocol code numberTUD-CLL-X4-054
    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 SponsorTechnische Universität Dresen
    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 supportGlaxoSmithKline GmbH & Co KG
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationJohannes Schetelig
    B.5.2Functional name of contact pointcoordinating investigator
    B.5.3 Address:
    B.5.3.1Street AddressFetscherstraße 74
    B.5.3.2Town/ cityDresden
    B.5.3.3Post code01307
    B.5.3.4CountryGermany
    B.5.4Telephone number+4903514585604
    B.5.5Fax number+4903514584367
    B.5.6E-mailjohannes.schetelig@uniklinikum-dresden.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 Arzerra
    D.2.1.1.2Name of the Marketing Authorisation holderGlaxo Group Ltd
    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 Yes
    D.2.5.1Orphan drug designation numberEU/3/08/581
    D.3 Description of the IMP
    D.3.1Product nameArzerra
    D.3.2Product code GSK1841157
    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 INNOfatumumab
    D.3.9.1CAS number 679818-59-8
    D.3.9.2Current sponsor codeGSK 1841157
    D.3.9.3Other descriptive nameHuMax-CD20
    D.3.9.4EV Substance CodeSUB25221
    D.3.10 Strength
    D.3.10.1Concentration unit mg/l milligram(s)/litre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    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) Yes
    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 aged >55 years with a diagnosis of CLL according to WHO criteria confirmed by flow cytometry of peripheral blood or bone marrow and a poor-risk disease according to the EBMT CLL Transplant Consensus
    Patienten im Alter > 55 Jahre mit der Diagnose einer CLL nach aktuellen WHO Kriterien (Hallek 2008) bestätigt durch eine durchflusszytometrische Untersuchung von peripherem Blut oder Knochemark und einer Hochrisiko CLL definiert nach dem EBMT CLL Transplant Consensus
    E.1.1.1Medical condition in easily understood language
    Patients aged >55 years with a diagnosis of Chronic lymphocytic leukemia and a poor-risk disease
    Patienten im Alter > 55 Jahre mit der Diagnose einer CLL mit Hochrisikocharakter
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.0
    E.1.2Level LLT
    E.1.2Classification code 10009310
    E.1.2Term CLL
    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 study the safety and efficacy of anti-CD20 blockade with ofatumumab in the context of allogeneic HCT in CLL.
    Es soll die Sicherheit und Effektivität einer anti CD 20 Blockade mit Ofatumumab im Rahmen der allogenen Transplantation bei Patienten mit CLL geprüft werden.
    E.2.2Secondary objectives of the trial
    - rate of patients who reach allogeneic HCT
    - rates of grade III/IV adverse drug reactions
    - Overall and event and progression-free survival
    - relapse incidence
    - non-relapse mortality for the ITT population and transplanted patients
    - Incidences of acute and chronic GVHD
    - Rate der Patienten die allogen transplantiert werden
    - Rate an Grad III/IV unerwünschten Medikamentennebenwirkungen
    - Gesamt- Ereignis- und Progressionsfreies Überleben
    - Rezidiv Inzidenz
    - nicht-rezidiv bedingte Todesfälle für die ITT Gruppe und transplantierte Patienten
    - Inzidenz von akuter und chronischer GvHD
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Associated Research Project
    Version 2-0, August 15, 2012
    evaluation of:
    Moitoring of peptide-specific cytotoxic T-cells
    Serologic immune response
    Immunologic resistence
    Begleitforschungsprojekt
    Version 2-0, August 15, 2012
    Untersuchung von:
    Moitoring von peptid-spezifischen cytotoxischen T-Zellen
    Serologische Immunantwort
    Immunologische Resistenz
    E.3Principal inclusion criteria
    - Diagnosis of CLL according to WHO criteria confirmed by flow cytometry of peripheral blood or bone marrow
    - Age > 55 years
    - Poor-risk disease according to the EBMT CLL Transplant Consensus:
    =>Non-response or early relapse (within 12 months) after purine analogue-containing therapy
    =>Relapse (within 24 months) after purine analogue combination therapy or treatment of similar efficacy (ie, autologous stem cell transplantation)
    =>p53 deletion/mutation (del 17p-) requiring treatment
    - Measurable disease in the peripheral blood defined by a minimum clonal lymphocyte count of 0.5 GPT/L at the time of study inclusion
    - Medically fit patients eligible for allogeneic HCT
    - Informed consent for related and unrelated donor search and the goal to perform allogeneic HCT
    -Sexually mature males must agree to use adequate and medically accepted method of contraception throughout the study if their sexual partners are woman of child bearing potential (WOCBP)
    -WOCBP must be using an adequate and medically accepted method of contraception to avoid pregnancy throughout the study and for at least 3 months after the study. WOCBP includes any female that has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation or bilateral oophorectomy) or is not postmenopausal (defined as amenorrhea >12 consecutive months); or woman on hormone replacement therapy (HRT) with documented serum follicle stimulating hormone (FSH) level >35mlU/mL.
    -WOCBP must have a negative serum or urin pregnancy test prior to the start of the study.
    - Diagnose einer CLL nach aktuellen WHO Kriterien (Hallek 2008) bestätigt durch eine durchflusszytometrische Untersuchung von peripherem Blut oder Knochemark
    - Alter > 55 Jahre
    - Hochrisiko CLL definiert nach dem EBMT CLL Transplant Consensus:
    => Nichtansprechen oder frühes Rezidiv (innerhalb von 12 Monaten) nach Therapie mit Purinanalogon
    => Rezidiv (innerhalb von 24 Monaten) nach Purinanalogon Kombinationstherapie oder Behandlung mit ähnlicher Effektivität (z.B. autologe Transplantation)
    => P53 Deletion/Mutation (del 17p-) bei Patienten mit Behandlungsindikation
    => Messbare Erkrankungsaktivität im peripheren Blut definiert durch mindestens 0.5 GPT/L klonale Lymphozyten zum Zeitpunkt des Studieneinschlusses
    - Medizinisch fitte Patienten die für eine allogene Transplantation geeignet sind
    - Einverständniserklärung für die Familien- und Fremdspendersuche
    -Männer müssen effektiven und medizinisch sinnvollen kontrazeptiven Maßnahmen zur Vermeidung einer Schwangerschaft für den Studienzeitraum zustimmen, wenn Ihre Partner Frauen im gebärfähigen Alter sind.
    -Frauen im gebärfähigen Alter müssen effektiven und medizinisch sinnvollen kontrazeptiven Maßnahmen zur Vermeidung einer Schwanger-schaft für den Studienzeitraum und für mindestens 3 Monate nach Beendigung der Studienteilnahme zustimmen. Frauen im gebärfähigen Alter umfassen alle Frauen, die eine Menarche erlebt und sich nicht einer erfolgreichen chirurgischen Sterilisation (Hysterektomie, bilaterale Tuben-ligation oder bilaterale Oophorektomie) unterzogen haben oder nicht postmenopausal sind (definiert als Amenorrhö mehr als 12 aufeinanderfolgende Monate); oder Frauen mit Hormonersatztherapie (HRT) mit dokumentiertem Serum Folikel stimulierendem Hormon Spiegel (FSH)> 35 mlU/mL.
    -Frauen im gebärfähigen Alter müssen vor Studieneinschluss einen negativen Schwanger-schaftstest im Serum oder Urin nachweisen
    E.4Principal exclusion criteria
    - Richter’s transformation in current relapse or active disease
    - Prior allogeneic HCT
    - Treatment with any known non-marketed drug substance or experimental therapy within 5 terminal half lives or 4 weeks prior to enrollment, whichever is longer, or participation in any other interventional clinical study
    - Non-response to monotherapy with ofatumumab prior to study inclusion
    - Clinically significant cardiac disease including unstable angina, acute myocardial infarction within six months prior to randomization, congestive heart failure (left ventricular ejection fraction < 50%).
    - Abnormal renal function defined by an estimated GFR < 50ml/min
    - Abnormal lung function tests defined by a DLCO <50%, FEV1%VC <70% despite appropriate treatment
    - Positive serology for Hepatitis B (HB) defined as a positive test for HBsAg or HBcAb.
    - Positive serology for hepatitis C (HC) defined as a positive test for anti-HCV, confirmed by PCR.
    - Screening laboratory values:
    =>total bilirubin >1.5 times upper normal limit (unless due to AIHA or a known history of Gilbert’s disease)
    =>ALT or AST >2.5 times upper normal limit
    =>Gamma glutamyl transpeptidase (GGT) >2.5 times upper normal limit (unless due to disease involvement of the liver)
    - Other past or current hematologic or solid organ malignancy. Subjects who have been free of malignancy for at least 3 years, or have a history of completely resected non-melanoma skin cancer, or successfully treated in situ carcinoma are eligible.
    - Male subjects unable or unwilling to use adequate contraception methods from study start to one year after the last dose of protocol therapy.
    - Pregnant or lactating woman
    - Significant concurrent, uncontrolled medical condition including, but not limited to, renal, hepatic, gastrointestinal, endocrine, pulmonary, neurological, cerebral or psychiatric disease which in the opinion of the investigator may represent a risk for the patient
    - Richter-Tranformation
    - Vorherige allogene Transplantation
    - Behandlung mit jeglicher nicht zugelassenen Substanz oder experimenteller Therapie innerhalb von 5 terminalen Halbwertszeiten oder der letzten 4 Wochen vor Studieneinschluss, je nach dem welches länger ist oder Teilnahme an einer anderen interventionellen Prüfung
    - Nichtansprechen auf eine Ofatumumab Monotherapie vor Studieneinschluss
    - Klinisch signifikante Herzerkrankung, insbesondere instabile Angina, akuter Myokardinfarkt innerhalb von 6 Monten vor Studieneinschluss, Herzinsuffizienz (linksventrikuläre Ejektionsfraktion < 50%)
    - Eingeschränkte Nierenfunktion definiert durch eine GFR < 50 ml/min
    - Eingeschränkte Lungenfunktionsprüfung definiert durch DLCO <50%, FEV1%VC <70% trotz effektiver Therapie
    - Positive Hepatitis B (HB) Serologie definiert als positives HBsAG oder HBcAb
    - Positive Hepatitis C (HC) Serologie definiert als positiver Test für anti-HCV, bestätigt durch PCR
    - Laborwerte zum Zeitpunkt des Studieneinschlusses:
    => Gesamtbilirubin > 1.5 x oberer Normwert (außer durch AIHA oder bekannte Gilbert-Meulengracht Erkrankung)
    => ALT oder AST > 2.5 x oberer Normwert
    => Gamma GT > 2.5 x oberer Normwert (außer durch Infiltration der CLL bedingt)
    - Weitere aktive oder zurückliegende Krebserkrankung eines soliden Organs. Patienten die mindestens 3 Jahre krankheitsfrei waren oder an einem komplett resezierten Hauttumor (nicht Melanom) oder einem erfolgreich behandelten in-situ Karzionom litten, können eingeschlossen werden
    - Männliche Probanden die unwillig oder nicht in der Lage sind adäquate Verhütungsmethoden ein Jahr nach letzter Studienmedikamentgabe zu verwenden
    - Schwangerschaft oder stillende Frauen
    - Weitere schwerwiegende und unkontrollierte Situationen, inklusive aber nicht beschränkt auf, Nieren-, Leber-, endokrinologische , Lungen-, Neurologische, cerebrale oder psychiatrische Erkrankungen die nach Einschätzung des behandelnden Arztes ein Risiko für den Patienten darstellen
    E.5 End points
    E.5.1Primary end point(s)
    Response rate after induction therapy and rate of MRD-negative patients who did not experience relapse, progression or death within the first 14 months after study enrollment
    Ansprechrate nach Induktionstherapie und Rate an MRD-negativen Patienten die nach 14 Monaten progressions- und rezidivfrei am Leben sind.
    E.5.1.1Timepoint(s) of evaluation of this end point
    overall remission rate (CR and PR): immediately after induction therapy
    MRD-negativity: at 14 months after study inclusion
    Gesamt Remissionsrate (CR und PR): direkt nach Induktionstherapie
    MRD-negative Patienten: 14 Monate nach Studieneinschluss
    E.5.2Secondary end point(s)
    - rate of patients who reach allogeneic HCT
    - rates of grade III/IV adverse drug reactions
    - Overall, event and progression-free survival
    - relapse incidence
    - non-relapse mortality for the ITT population and transplanted patients
    - Incidences of acute and chronic GVHD
    - Rate der Patienten die allogen transplantiert werden
    - Rate an Grad III/IV unerwünschten Medikamentennebenwirkungen
    - Gesamt- Ereignis- und Progressionsfreies Überleben
    - Rezidiv Inzidenz
    - nicht-rezidiv bedingte Todesfälle für die ITT Gruppe und transplantierte Patienten
    - Inzidenz von akuter und chronischer GvHD
    E.5.2.1Timepoint(s) of evaluation of this end point
    at end of follow-up (month 14)
    am Ende der Follow up Evaluation (Monat 14)
    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 concerned10
    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 months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial 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: 71
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 71
    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 state71
    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)
    provided in the protocol (chapter 9.6 Treatment after End of Study)
    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 German Cooperative Transplant Study Group
    G.4.3.4Network Country Germany
    G.4 Investigator Network to be involved in the Trial: 2
    G.4.1Name of Organisation German CLL Study Group
    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 Decision2012-09-05
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-02-27
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2015-08-05
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