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    Summary
    EudraCT Number:2013-000182-37
    Sponsor's Protocol Code Number:BREACH
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2014-08-25
    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 ConcernedFrance - ANSM
    A.2EudraCT number2013-000182-37
    A.3Full title of the trial
    BRENTUXIMAB VEDOTIN ASSOCIATED WITH CHEMOTHERAPY IN UNTREATED PATIENTS WITH STAGE I/II UNFAVOURABLE HODGKIN LYMPHOMA - A RANDOMIZED PHASE II LYSA-FIL-EORTC INTERGROUP STUDY
    Brentuximab vedotin associé à la chimiothérapie chez des patients atteints de lymphome de hodgkin stade I/II défavorable au diagnostic.
    Une étude randomisée de phase II de l’intergroupe LYSA-FIL-EORTC.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    BRENTUXIMAB VEDOTIN ASSOCIATED WITH CHEMOTHERAPY IN UNTREATED PATIENTS WITH STAGE I/II UNFAVOURABLE HODGKIN LYMPHOMA - A RANDOMIZED STUDY
    Brentuximab vedotin associé à la chimiothérapie chez des patients atteints de lymphome de hodgkin stade I/II défavorable au diagnostic.
    Une étude randomisée.
    A.3.2Name or abbreviated title of the trial where available
    BREACH
    A.4.1Sponsor's protocol code numberBREACH
    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 SponsorLYSARC
    B.1.3.4CountryFrance
    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 supportMillennium: The Takeda Oncology Company
    B.4.2CountryUnited States
    B.4.1Name of organisation providing supportLYSARC
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationDr Luc-Matthieu Fornecker
    B.5.2Functional name of contact pointCo-coordinating Investigator
    B.5.3 Address:
    B.5.3.1Street AddressCHU Strasbourg, Service Hématologie Hautepierre, Hôpital de Hautepierre, BP. 428
    B.5.3.2Town/ cityStrasbourg
    B.5.3.3Post code67098
    B.5.3.4CountryFrance
    B.5.4Telephone number33388127676
    B.5.5Fax number33388127681
    B.5.6E-mailluc-matthieu.fornecker@chru-strasbourg.fr
    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 No
    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 nameBrentuximab vedotin
    D.3.2Product code SGN-35
    D.3.4Pharmaceutical form Powder 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 typeequal
    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
    Untreated patients with histologically confirmed CD30+ classical Hodgkin lymphoma (stage I/II), aged > or = 18 and < or = 60 years old, with at least one unfavourable clinical pronostic factor
    E.1.1.1Medical condition in easily understood language
    Patients from 18 to 60 years old, with Hodgkin lymphoma CD30+, with one unfavourable clinical pronostic factor
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 17.0
    E.1.2Level LLT
    E.1.2Classification code 10020328
    E.1.2Term Hodgkin's lymphoma
    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 17.0
    E.1.2Level SOC
    E.1.2Classification code 10029104
    E.1.2Term Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    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
    To assess the efficacy of the combination AVD+brentuximab vedotin in untreated patients with stage I/II unfavourable Hodgkin lymphoma, as measured by the rate of PET negativity after two cycles of immuno chemotherapy, PET assessment based on central review.
    E.2.2Secondary objectives of the trial
    To assess the efficacy and safety of AVD+brentuximab vedotin as measured by:
    • Secondary efficacy endpoints:
    - CR rate (according to Cheson 2007) at the end of treatment
    - Progression-free survival
    - Overall survival

    • Secondary safety endpoint:
    - Toxicity of Brentuximab vedotin in combination with combined modality treatment will be assessed.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Analysis on tumor tissue biopsy to determine factors that influence treatment response based on PET scan assessment and prognosis
    E.3Principal inclusion criteria
    • Histologically confirmed CD30+ classical Hodgkin lymphoma according to local evaluation
    • Supradiaphragmatic Ann Arbor clinical stage I or II
    • Previously untreated
    • PET scan without IV contrast at diagnosis available for central review with at least one hypermetabolic lesion
    • Unfavourable (U) characteristics according to the classic EORTC/LYSA clinical prognostic factors. Unfavourable (U) subset includes patients with at least one of the following factors:
    o CSII ≥ 4 nodal areas
    o age ≥ 50 yrs
    o M/T ratio ≥ 0.35
    o ESR ≥ 50 (without B-symptoms) or ESR ≥ 30 with B-symptoms
    • ECOG performance status 0-2
    • Life expectancy > 6 months
    • Age 18 to 60 years (≥ 18 years to ≤ 60 years)
    • Patients must be available for periodic blood sampling, study-related assessments, and management of toxicity at the treating institution.
    • Female patients who:
    o Are postmenopausal for at least 1 year before the screening visit, OR are surgically sterile,
    OR
    o If they are of childbearing potential, agree to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent through 6 months after the last dose of study drug, or agree to completely abstain from heterosexual intercourse
    • Male patients, even if surgically sterilized (ie, status postvasectomy), who:
    o Agree to practice effective barrier contraception during the entire study treatment period and through 6 months after the last dose of study drug, or agree to completely abstain from heterosexual intercourse.
    • Patients must give written informed consent. A copy of the informed signed consent form will be retained in the patient’s chart.
    • Required baseline laboratory data:
    o Absolute neutrophil count ≥ 1,500/µL
    o Platelet count ≥ 75,000/ µL
    o Hemoglobin ≥ 8g/dL
    o Serum total bilirubin ≤ 1.5 X ULN unless the elevation is known to be due to Gilbert syndrome.
    o Serum creatinine ≤ 2.0 mg/dL and/or calculated creatinine clearance > 40 mL/minute (Cockcroft-Gault formula or MDRD)
    o Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 X ULN
    E.4Principal exclusion criteria
    • Histological diagnosis different from classical Hodgkin Lymphoma. Nodular lymphocyte predominant subtypes (nodular paragranuloma or Poppema paragranuloma) are excluded.
    • Known cerebral or meningeal disease of any etiology, including signs or symptoms of PML
    • Any sensory or motor peripheral neuropathy ≥ Grade 2
    • Known history of any of the following cardiovascular conditions
    o Myocardial infarction within 2 years of randomization
    o New York Heart Association (NYHA) Class III or IV heart failure (see Appendix 14)
    o Evidence of current uncontrolled cardiovascular conditions, including cardiac arrhythmias, congestive heart failure (CHF), angina, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities
    o Recent evidence (within 30 days before first dose of study drug) of a left-ventricular ejection fraction <50%
    • Unstable diabetes mellitus (to avoid uninterpretable FDG-PET scan).
    • Known HIV positive
    • HCV positive
    • HBV positive. This means:
    o HBsAg positive
    o HBsAg negative, anti-HBs positive and/or anti-HBc positive and detectable viral DNA
    o Note:
     Patients who are HBsAg negative and viral DNA negative are eligible
     Patients who are seropositive due to a history of hepatitis B vaccine are eligible.
    • Any history of cancer during the last 5 years, with the exception of non-melanoma skin tumors. Carcinoma in situ of any type are not excluded if they have undergone complete resection.
    • Dementia or altered mental status that would preclude compliance with drug delivery
    • Pregnancy or breastfeeding. Females of childbearing potential having a positive β-HCG pregnancy test result during screening or a positive pregnancy test (urinary or blood) within 1 day before start of treatment.
    • Previous treatment with any anti-CD30 antibody.
    • Known hypersensitivity to any excipients contained in the brentuximab vedotin formulation or known contra-indication to any drug contained in the chemotherapy regimens (for ex.: pulmonary or neurological disease grade ≥ 2)
    • Treatment with corticosteroids before baseline PET scan (PET 0)
    • Patients with known active viral, bacterial, or fungal infection requiring treatment with antimicrobial therapy or with untreated known active Grade 3 viral, bacterial, or fungal infection, within 2 weeks prior to the first dose of brentuximab vedotin
    • Treatment with any investigational drug within 30 days before planned first cycle of chemotherapy or immune-chemotherapy
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint is the PET response rate according to the Deauville criteria based on central review assessed after 2 cycles of chemotherapy or immuno-chemotherapy (ABVD or AVD/Brentuximab vedotin).
    E.5.1.1Timepoint(s) of evaluation of this end point
    The categorization of the patients according to PET results will be performed as follows:
    - 1, 2 or 3: PET negative = Responder
    - 4- 5: PET positive =Non-responder.
    - Missing PET evaluation (for whatever reason) : Non-responder
    As sensitivity analysis will be performed on the Evaluable Set.
    E.5.2Secondary end point(s)
    The secondary endpoints are the efficacy and the safety
    E.5.2.1Timepoint(s) of evaluation of this end point
    Secondary efficacy endpoints will include:
    • COMPLETE RESPONSE RATES ACCORDING TO PET RESPONSE AT END OF TREATMENT
    Disease response evaluation at end of treatment (after radiotherapy) will be used to determine the Response Rate.
    • PET RESPONSE RATE (ACCORDING TO DEAUVILLE CRITERIA) AT END OF TREATMENT
    PET evaluation will be performed at end of treatment.
    • PROGRESSION FREE SURVIVAL (PFS)
    PFS is defined as the time from randomization into the study to the first observation of documented disease progression or death due to any cause. If a subject has not progressed or died, PFS will be censored at the time of last visit assessment.
    • OVERALL SURVIVAL (OS)
    Overall survival will be measured from date of randomization into the study to the date of death from any cause.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis Yes
    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 Yes
    E.6.13.1Other scope of the trial description
    To assess the rate of PET negativity after two cycles of immunochemotherapy
    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 Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group Yes
    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) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    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 concerned43
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA105
    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
    The end of the study is defined as the last patient's last visit and will occur approximately 6 years and 8 months (80 months) after the first patient is enrolled to allow patients to have a minimum of 5 years of follow-up post treatment.
    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 months8
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years6
    E.8.9.2In all countries concerned by the trial months8
    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: 170
    F.1.3Elderly (>=65 years) No
    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 state100
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 170
    F.4.2.2In the whole clinical trial 170
    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)
    Patients who receive the complete treatment won't be treated after this study, except in case of relapse. Patients who withdraw from the study will receive a salvage therapy.
    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 Decision2014-08-13
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-08-29
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2022-06-02
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