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    Summary
    EudraCT Number:2012-003097-45
    Sponsor's Protocol Code Number:NL40688.018.12
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2014-01-23
    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 ConcernedNetherlands - Competent Authority
    A.2EudraCT number2012-003097-45
    A.3Full title of the trial
    Phase I/II feasibility study combining Brentuximab Vedotin (Adcetris) with second line salvage chemotherapy (DHAP) in Hodgkin lymphoma patients refractory to first line chemotherapy or in first relapse who are eligible for high dose treatment followed by autologous peripheral blood stem cell transplantation
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Phase I/II feasibility study combining Brentuximab Vedotin (Adcetris) with second line salvage chemotherapy (DHAP) in Hodgkin lymphoma patients refractory to first line chemotherapy or in first relapse who are eligible for high dose treatment followed by autologous peripheral blood stem cell transplantation
    A.3.2Name or abbreviated title of the trial where available
    Transplant BRaVE
    A.4.1Sponsor's protocol code numberNL40688.018.12
    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 SponsorAcedemic Medical Center
    B.1.3.4CountryNetherlands
    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 supportAcademic Medical Center
    B.4.2CountryNetherlands
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAcademic Medical Center
    B.5.2Functional name of contact pointEdith van Dijkman
    B.5.3 Address:
    B.5.3.1Street AddressMeibergdreef 9
    B.5.3.2Town/ cityAmsterdam
    B.5.3.3Post code1105 AZ
    B.5.3.4CountryNetherlands
    B.5.4Telephone number0031205668136
    B.5.6E-maile.e.vandijkman@amc.nl
    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.2.5The 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 nameSGN-35
    D.3.2Product code SGN-35
    D.3.4Pharmaceutical form Powder 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.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNBrentuximab vedotin
    D.3.9.1CAS number 914088-09-8
    D.3.9.3Other descriptive nameBRENTUXIMAB VEDOTIN
    D.3.9.4EV Substance CodeSUB32397
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeup to
    D.3.10.3Concentration number5
    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
    Hodgkin lymphoma
    E.1.1.1Medical condition in easily understood language
    Hodgkin lymphoma
    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 HLGT
    E.1.2Classification code 10025319
    E.1.2Term Lymphomas Hodgkin's disease
    E.1.2System Organ Class 10005329 - Blood and lymphatic system disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Phase I
    • To identify the feasibility and RDL (recommended dose level) of BV in combination with DHAP, in a 21-day schedule

    Phase II

    • To demonstrate the efficacy and safety of BV in combination with DHAP as salvage treatment (establish the fraction of responding patients – metabolic CR – as judged by PET-CT after the third cycle, and establish the rate of grade ¾ non-hematological toxicity, including neurotoxicity).

    E.2.2Secondary objectives of the trial
    Phase I
    • To assess the toxicity of BV in combination with DHAP
    • To assess the success rate of autologous peripheral blood stem cell harvest after 2 courses of BV-DHAP

    Phase II
    • To assess the ORR (CR and PR) after 3 cycles of BV-DHAP and after auto-PBSCT
    • To assess the toxicity profile of BV in combination with DHAP
    • To assess hematological recovery after each cycle of BV-DHAP
    • To assess the feasibility of harvesting an autologous peripheral blood stem cell graft after 2 cycles of BV-DHAP
    • To assess the fraction of patients (CR/PR) eligible for auto-PBSCT who actually undergo auto-PBSCT
    • To assess peripheral blood neutrophil and platelet recovery after auto-SCT
    • To evaluate PFS, EFS and OS with this treatment regimen
    • To identify predictive factors for response, PFS, EFS and OS (exploratory analysis)
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • Histologically confirmed CD30+ classical HL (central pathology review; results not required to enroll the patient in the study), primarily refractory to first line chemotherapy or in first relapse after any polychemotherapy regimen (e.g. ABVD, baseline BEACOPP or escalated BEACOPP, or other induction regimens)
    • In case of relapse, the relapse must be histologically confirmed. In case histology is not possible, at least confirmation of the relapse by FNA is required.
    • Measurable disease, as defined in Appendix C i.e. CT scans showing at least 2 or more clearly demarcated lesions with a long axis ≥ 1.5 cm and a short axis diameter ≥ 1.0 cm, or 1 clearly demarcated lesion with a long axis ≥ 2.0 cm and a short axis diameter ≥ 1.0 cm. These lesions must be FDG-positive
    • Age ≥ 18 years (upper age limit for auto-PBSCT at the discretion of the participating center)
    • WHO ≤ 2 (see appendix A)
    • Life expectancy of > 3 months with treatment
    • No major organ dysfunction, unless HL-related
    • Total bilirubin < 1.5x ULN (unless due to lymphoma involvement of the liver or a known history of Gilbert’s syndrome; in that case ALT/AST may be elevated up to 5 x ULN)
    • ALT/AST < 3x ULN (unless due to lymphoma involvement of the liver)
    • GFR > 60 ml/min as estimated by the Cockroft&Gault formula (appendix D)
    • Absolute neutrophil count ≥ 1.5x109/L, unless caused by diffuse bone marrow infiltration by the HL
    • Platelets ≥ 100x109/L, unless caused by diffuse bone marrow infiltration by the HL
    • Hemoglobin must be >8 g/dL
    • Written informed consent
    • Able to adhere to the study visit schedule and other protocol requirements
    • Female patient is either post-menopausal for at least 1 year before the screening visit or surgically sterile or if of childbearing potential, agrees to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent through 30 days after the last dose of study drug, or agrees to completely abstain from heterosexual intercourse.
    • Male patients, even if surgically sterilized, (i.e., status post vasectomy) agree to practice effective barrier contraception during the entire study period and through 6 months after the last dose of study drug, or agrees to completely abstain from heterosexual intercourse.
    • Eligible for high dose chemotherapy and autologous peripheral blood stem cell transplantation
    • Resolution of toxicities from first-line therapy
    E.4Principal exclusion criteria
    • Peripheral sensory or motor neuropathy grade ≥ 2
    • Known cerebral or meningeal disease (HL or any other etiology), including signs or symptoms of PML
    • Symptomatic neurologic disease compromising normal activities of daily living or requiring medications
    • Patients who have been using other investigational agents within at least 5 half lives of the most recent agent used prior to enrollment in the study
    • Patients who were treated with myelosuppressive chemotherapy or biological therapy ≤ 4 weeks before study inclusion
    • Female patients who are both lactating and breast feeding or have a positive serum pregnancy test during the screening period or a positive pregnancy test on Day 1 before first dose of study drug or adults of reproductive potential who are not using effective birth control methods.
    • Patients with any active systemic viral, bacterial, or fungal infection requiring systemic antibiotics within 2 weeks prior to first study drug dose
    • Patients who have a history of another primary malignancy less than 3 years before study inclusion or previously diagnosed with another malignancy and have evidence of residual disease, with the exception of non-melanoma skin cancer, completely resected melanoma TNMpT1 and carcinoma in situ of the uterine cervix
    • Patients with known hypersensitivity to recombinant proteins, murine proteins, or to any excipient contained in the drug formulation of brentuximab vedotin.
    • Patients with known HIV seropositivity, known hepatitis B surface antigen-positivity, or known or suspected active hepatitis C infection
    • Patients receiving radiation therapy within 8 weeks prior to start of protocol treatment. Emergency radiation therapy is allowed, as long as measurable disease (at non-irradiated sites) persists.
    • Patients with a serious psychiatric disorder that could, in the investigator’s opinion, potentially interfere with the completion of treatment according to the protocol
    • Patients who have any severe and/or uncontrolled medical condition or other conditions that could affect their participation in the study such as:
    – unstable angina pectoris, symptomatic congestive heart failure (NYHA II, III, IV), myocardial infarction ≤ 6 months prior to first study drug, serious uncontrolled cardiac arrhythmia, cerebrovascular accidents ≤ 6 months before study drug start
    – severely impaired pulmonary function as defined as spirometry and DLCO (diffusing capacity of the lung for carbon monoxide) that is 50% or less of the normal predicted value and/or O2 saturation that is 90% or less at rest on room air
    – any active (acute or chronic) or uncontrolled infection/disorders that impair the ability to evaluate the patient or for the patient to complete the study
    • nonmalignant medical illnesses that are uncontrolled or whose control may be jeopardized by this study drug, such as severe hypertension that is not controlled with medical management and thyroid abnormalities when thyroid function cannot be maintained in the normal range by medication
    E.5 End points
    E.5.1Primary end point(s)
     The rate of patients with severe toxicity (defined as DLT’s, see paragraph 7.2) during cycle I-III of the combination treatment (BV + DHAP)
     RDL of BV-DHAP for the phase II part of the study
     Metabolic CR rate (PET-CT) after the third cycle of BV-DHAP reinduction therapy
    E.5.1.1Timepoint(s) of evaluation of this end point
    • At entry
    • Prior to each cycle of BV-DHAP
    • After the second cycle of BV-DHAP
    • After the 3rd cycle of BV-DHAP
    • 6 weeks after ASCT
    • End of protocol treatment
    E.5.2Secondary end point(s)
     (Severe) Adverse Events during the combination treatment
     Time to hematological recovery after each cycle of BV + DHAP
     Time to recovery from non-hematological toxicity after each cycle of BV + DHAP.
     Administration of treatment: dose reductions, interval between cycles, discontinuation rate
     Rate of successful PBSC collection (≥ 2x106 CD34+ cells/kg) after the second cycle of BV- DHAP
     Overall response rate (PR + CR) after the third cycle of BV-DHAP reinduction therapy (based on the results of the FDG-PET/CT scan)
     Overall response rate (PR + CR) after auto-PBSCT (based on the results of the FDG-PET/CT scan)
     Metabolic CR rate (PET-CT) after auto-PBSCT
     Fraction of patients (CR/PR) eligible for auto-PBSCT who actually undergo auto-PBSCT
     Progression free survival (PFS) and event free survival (EFS)
     Overall survival (OS)
    E.5.2.1Timepoint(s) of evaluation of this end point
    • At entry
    • Prior to each cycle of BV-DHAP
    • After the second cycle of BV-DHAP
    • After the 3rd cycle of BV-DHAP
    • 6 weeks after ASCT
    • End of protocol treatment
    • During follow up every 3 months for 2 years and every 6 months thereafter until 5 years after last treatment
    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 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) Yes
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other Yes
    E.7.1.3.1Other trial type description
    safety
    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 concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA8
    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 years7
    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 years7
    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: 74
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 24
    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 state30
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 74
    F.4.2.2In the whole clinical trial 74
    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)
    none
    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 Decision2014-01-30
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-01-20
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2020-09-21
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