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    Summary
    EudraCT Number:2015-002221-19
    Sponsor's Protocol Code Number:2015_29
    National Competent Authority:Belgium - FPS Health-DGM
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2016-02-02
    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 ConcernedBelgium - FPS Health-DGM
    A.2EudraCT number2015-002221-19
    A.3Full title of the trial
    A Multicenter Open label Phase II study of Daratumumab in combination with dexamethasone in Multiple Myeloma resistant or refractory to Bortezomib and Lenalidomide and Pomalidomide – an IFM 2014-04 study
    Etude Multicentrique En-Ouvert de Phase 2 du Daratumumab en combinaison avec la Dexamethasone dans le Myélome Multiple résistant ou réfractaire au Bortezomib et Lenalidomide et Pomalidomide – IFM2014-04
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Daratumumab in treatment of resistant or refractory Multiple myeloma
    le Daratumumab dans le traitement du myélome multiple resistant ou réfrataire
    A.3.2Name or abbreviated title of the trial where available
    IFM2014-04
    IFM2014-04
    A.4.1Sponsor's protocol code number2015_29
    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 SponsorCHRU of Lille
    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 supportJansen Research & Devellopment, LLC
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationClinical reserach federation
    B.5.2Functional name of contact pointChanaz LOUNI / Ohyba BELLA (CRA)
    B.5.3 Address:
    B.5.3.1Street Address6 rue du Professeur Laguesse
    B.5.3.2Town/ citylille
    B.5.3.3Post code59037
    B.5.3.4CountryFrance
    B.5.4Telephone number0033320444145
    B.5.5Fax number0033320445711
    B.5.6E-mailfrc@chru-lille.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 Yes
    D.2.5.1Orphan drug designation numberEU/3/13/1153
    D.3 Description of the IMP
    D.3.1Product nameDaratumumab
    D.3.2Product code HuMax-CD38
    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 INNDARATUMUMAB
    D.3.9.1CAS number 945721-28-8
    D.3.9.2Current sponsor codeJNJ-54767414 (daratumumab)
    D.3.9.4EV Substance CodeSUB175772
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    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) 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 Yes
    D.3.11.13.1Other medicinal product typehuman monoclonal antibody
    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
    Multiple Myeloma resistant or refractory to Bortezomib and Lenalidomide and Pomalidomide
    myélome multiple resistant ou réfractaire au Bortézomib, Lenalidomide et Pomalidomid
    E.1.1.1Medical condition in easily understood language
    Multiple Myeloma
    Myélome multiple
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.1
    E.1.2Level LLT
    E.1.2Classification code 10028228
    E.1.2Term Multiple myeloma
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    • To determine the best overall Response rate to Daratumumab plus Dexamethasone in myeloma patients resistant or refractory to Bortezomib and Lenalidomide and Pomalidomide
    • Determine the Overall Response Rate (ORR), including Partial Response (PR), Very Good Partial Response (VGPR), Complete Response (CR) to Daratumumab plus Dexamethasone in patients with RRMM resistant or refractory to Bortezomib and Lenalidomide, and Pomalidomide, using the International Myeloma Working Group (IMWG) response criteria.
    • Déterminer le taux de meilleures réponses globales au Daratumumab chez les patients atteint d’un MM résistant et / ou réfractaire au Bortézomib, Lénalidomide et Pomalidomide
    • Déterminer le taux de réponse globale (ORR), incluant les taux de réponse partielle (PR), de très bonne réponse partielle (VGPR), de réponse complète (CR), et de réponse complète avec un ratio FLC normal (CR+) du Daratumumab et du Dexaméthasone chez les patients atteints de MM préalablement exposée au Bortézomib, Lénalidomide, et Pomalidomide selon les critères de réponse de l’IMWG (groupe de travail international sur le myélome).
    E.2.2Secondary objectives of the trial
    • To determine Safety of Daratumumab (type, frequency, severity, and relationship of adverse events to study treatment). Incidence of Treatment Emergent Adverse Event (TEAE), Serious Adverse Event (SAE) and laboratory abnormalities using National Cancer Institute (NCI) common toxicity criteria.
    • To determine VGPR and CR rate (IMWG criteria)
    • To determine the clinical benefit rate (CBR, Minor response (MR) or better). MR will be determined using the criteria of the European Organisation for Blood and Marrow Transplantation (EBMT) criteria.
    • To determine ORR including Partial Response (PR), Very Good Partial Response (VGPR), Complete Response (CR) and minor response (MR) to Daratumumab plus Dexamethasone at 3 months and 6 months of treatment.
    • To determine progression-free survival (PFS),
    • To determine time to progression (TTP).
    • To determine time to response (TTR)
    • To determine the Duration of Response (DOR)
    • To determine Overall Survival (OS)
    • ...
    • Déterminer les données de sécurité du Daratumumab (type, fréquence, sévérité, relation de causalité au traitement à l’étude), ainsi que l’incidence des évènements indésirables liés au traitement (TEAE), évènements indésirables graves, résultats d’analyses de laboratoires anormales gradés en utilisant le guideline de l’institut national du cancer sur les critères communs de toxicité (CCTAE V4).
    • Déterminer le taux de VGPR et CR (critères de l’IMWG)
    • Déterminer le taux de réponse clinique bénéfique (CBR, réponse mineure (MR) ou meilleure). La MR sera déterminée en utilisant les critères de l’Organisation Européenne pour la transfusion de sang et la Transplantation de la moëlle (EBMT).
    • Déterminer le taux de réponses globales incluant les réponses partielles (PR), les très bonnes réponses partielles (VGPR), les réponses complètes (CR) et minimales (MR) au Daratumumab plus Déxamethasone à 3 mois et 6 mois de traitement.
    • Déterminer la survie sans progression (PFS),
    • Déter...
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Must be able to understand and voluntarily sign an informed consent form
    2. Must be able to adhere to the study visit schedule and other protocol requirements
    3. Age ³ 18 years
    4. Life expectancy > 6 months
    5. Patients must have relapsed myeloma, and previously treated with Bortezomib, Lenalidomide, and Pomalidomide treatment, and being resistant or refractory to Bortezomib and Lenalidomide and Pomalidomide treatment. 6. Patients must have a clearly detectable and quantifiable monoclonal M-component value:
     IgG (serum M-component > 10g/l)
     IgA (serum M-component >5g/l)
     IgD (serum M-component > 0.5g/l)
     Light chain (serum M-component >1g/l or Bence Jones > 200mg/24H)
     In patients without measurable serum and urine M-protein levels when the absolute serum FreeLight chain (sFLC) is ≥100 mg/l and an abnormal sFLC K/λ ratio (<0.26 and >1.65) is found (Dispenzieri, 2008).
    7. Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2
    8. Adequate bone marrow function within 5 days prior to 1st drug intake (cycle1, day 1, C1D1), without transfusion nor growth factor support within 5 days prior to 1st drug intake , defined as:
     Absolute neutrophils ≥ 1000/mm3
     Platelets ≥ 50000/mm3
     Haemoglobin ≥ 8.5g/dl
    9. Adequate organ function defined as:
     Serum creatinine clearance (Cockcroft-Gault formula) ≥30 ml/min
     Serum SGOT or SGPT < 3.0 X upper limit of normal (ULN)
     Serum total bilirubin < 2.0 mg/dL
    10. Wash out period of at least 2 weeks from previous antitumor therapy or any investigational treatment or 5 half-lives from previous antibodies.
    11. Women who are partners of men and of childbearing potential must be practicing one of the following methods of birth control: subcutaneous hormonal implant, levonorgestrel releasing intra-uterine system, medroxyprogesterone acetate depot, tubal sterilization, ovulation inhibitory progesterone only pills, or sexual intercourse with a vasectomized male partner (vasectomy must be confirmed by 2 negative semen analyses). Or women will commit to absolute and continuous abstinence confirmed to her physician on a monthly basis. Childbearing potential*. Contraception will start during therapy including dose interruptions, for 4 months after discontinuation of Daratumumab.
    *: Criteria for women of childbearing potential :
    This protocol defines a female of childbearing potential as a sexually mature woman who:
    1) has not undergone a hysterectomy or bilateral oophorectomy or
    2) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (ie, has had menses at any time in the preceding 24 consecutive months)

    12. A woman of childbearing potential must have 2 negative serum or urine pregnancy tests at Screening, first within 28 days prior to dosing and the second within 48 hours prior to dosing, and remain on a highly effective method of birth control. The two methods of reliable contraception must include one highly effective method and one additional effective (barrier) method. FCBP must be referred to a qualified provider of contraceptive methods if needed. The following are examples of highly effective and additional effective methods of contraception:
    • Highly effective methods:
    o Intrauterine device (IUD)
    o Hormonal (birth control pills, injections, implants)
    o Tubal ligation
    o Partner’s vasectomy
    • Additional effective methods:
    o Male condom
    o Diaphragm
    o Cervical Cap

    13. Serum (urine in the case where serum is not possible in a timely manner) pregnancy test to be performed for all women of childbearing potential regularly during the study,. In addition, a pregnancy test may be done at any time during the study at the discretion of the investigator if a subject misses a period or has unusual menstrual bleeding.
    14. A woman of childbearing potential must remain on a highly effective method of birth control. Contraception must begin 4 weeks before initiating treatment with Daratumumab, during therapy, during dose interruptions and continuing for 4 months following discontinuation of Daratumumab. Reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy.
    15. A man who has not had a vasectomy and who is sexually active with a woman of childbearing potential must agree to use a barrier method of birth control eg, condom with spermicidal foam/gel/film/cream/suppository, and all men must also not donate sperm during the study, for 4 months following discontinuation of Daratumumab. The exception to this restriction is that if the subject’s female partner is surgically sterile, a second method of birth control is not required.
    16. Subjects affiliated with an appropriate social security system.
    1. Doit être capable de comprendre et de signer volontairement un consentement éclairé
    2. Doit être capable d’adhérer au programme de visites pour l’étude et aux autres impératifs du protocole
    3. Age  18 ans
    4. Espérance de vie > 6 mois
    5. Les patients doivent avoir un myélome en rechute, précédemment traités par Bortezomib, Lénalidomide et Pomalidomide, et être résistants ou réfractaires aux traitements par Bortezomib, Lénalidomide et Pomalidomide
    (Cf. protocole)
    6. Les patients doivent avoir un composant monoclonal clairement détectable et quantifiable (Cf. protocole)
    7. Statut ECOG (performance status) évalué à 0, 1, ou 2
    8. Fonction médullaire adéquate sans transfusion dans les 5 jours précédant la première prise de traitement (C1J1) sans facteurs de croissance défini (Cf. protocole)
    9. Paramètres biochimiques :
    - Clairance de la créatinine sérique (formule de Cockcroft-Gault) ≥ 30 ml/min
    - SGOT ou SGPT < 3 x la limite supérieure de la normale (LSN)
    - Bilirubine totale < 2,0 mg/dL
    10. Période sans traitement d’au moins 2 semaines après toute autre thérapeutique anti-tumorale y compris traitement investigationnel ou période de 5 demi vie après un traitement par un anticorps.
    11. Les femmes ayant un partenaire masculin et en âge de procréer devront utiliser l’une des méthodes contraceptives suivantes: implant hormonal sous-cutané, dispositif intra-utérin à libération de lévonorgestrel, acétate de demédroxyprogestérone, stérilisation tubaire, pilules contraceptives bloquant l’ovulation ne contenant que de la progestérone, ou rapports sexuels avec un partenaire masculin vasectomisé (la vasectomie doit être confirmée par deux spermogrammes négatifs). Ou toute femme s’engageant à une abstinence absolue et continue confirmée mensuellement par son médecin. La contraception débutera 4 semaines avant le début du traitement et durant les 4 mois suivant l’arrêt du Daratumumab.
    12. Les femmes en âge de procréer doivent avoir 2 tests de grossesse sanguins ou urinaires négatifs, le premier dans les 28 jours avant la première administration du produit expérimental et le second dans les 48 h qui précèdent la première perfusion du Daratumumab, et comprendre la nécessité et accepter d’utiliser simultanément deux méthodes fiables et distinctes de contraception efficaces ou de pratiquer l’abstinence totale : 1) pendant 28 jours avant l’initiation du médicament de l’étude 2) pendant que le patient prend le médicament de l’étude 3) pendant les interruptions de dose du médicament de l’étude 4) pendant au moins 28 jours après l’arrêt du médicament de l’étude (Cf. protocole).

    13. Un test de grossesse est à faire pour toutes les femmes en âge de procréer régulièrement durant l’étude. De plus, un test de grossesse est à faire en cas de règles irrégulières ou d’aménorrhée, à la discrétion de l’investigateur.

    14. Les hommes non vasectomisés et qui ont des relations sexuelles avec leurs partenaires en âge de procréer doivent utiliser une méthode de contraception de type barrière, exemple : préservatif avec spermicides en mousse/gelée/film/crème ou suppositoire. Tous les hommes s’engagement à ne pas donner leurs sperme au cours de l'étude et durant 4 mois après l'arrêt du traitement par Daratumumab. L’exception à cette restriction est que si le partenaire féminin est chirurgicalement stérile, la deuxième méthode n’est pas nécessaire.
    15. Patient bénéficiant d’un régime de protection sociale.
    E.4Principal exclusion criteria
    Patients meeting any of the following exclusion criteria are not eligible to enrol in this study:
    1. Target disease exceptions:
    o Solitary bone/solitary extramedullary plasmocytoma
    o Patients with non-secretory MM and non-measurable MM
    o Evidence of central nervous system (CNS) involvement

    2. Medical history and Concurrent disease:
    o Subjects with prior (≤ 5 years) or concurrent invasive malignancies except the following:
     Adequately treated basal cell or squamous cell skin cancer
     Incidental finding of low grade (Gleason 3+3 or less) prostate cancer
     Any cancer from which the subject has been disease free for at least 3 years.
    o Subject with known/underlying medical conditions that, in the investigator’s opinion would make the administration of the study drug hazardous (ie: uncontrolled diabetes or uncontrolled coronary artery disease)
    o Any uncontrolled or severe cardiovascular or pulmonary disease determined by the investigator including:
     NYHA functional classification III or IV congestive heart failure
     LVEF ( Left Ventricular Ejection Fraction) ≥45%
     Uncontrolled angina, hypertension or arrhythmia
     Myocardial infarction in the past 6 months
    o Subjects with grade 2 or greater peripheral neuropathy (as per NCI-CTCAEv4.0)
    o Subject is a woman who is pregnant, or breast-feeding, or planning to become pregnant while enrolled in this study or within 4 months after the last dose of any component of the treatment regimen. Or, subject is a man who plans to father a child while enrolled in this study or within 4 months after the last dose of any component of the treatment regimen.
    o Known positive for HIV or active hepatitis B or C.
    o Subjects with psychiatric illnesses or social situations that would preclude them understanding the informed consent, study compliance or the ability to tolerate study procedures and/or study therapy
    o Subjects with known chronic obstructive pulmonary disease (COPD) with a Forced Expiratory Volume in 1 second (FEV1) < 50% of predicted normal. Note that FEV1 testing is required for patients suspected of having COPD and subjects must be excluded if FEV1 <50% of predicted normal.
    o Subjects with a history of moderate or severe persistent asthma within the past 2 years (see appendix), or with uncontrolled asthma of any classification at the time of screening (Note that subjects who currently have controlled intermittent asthma or controlled mild persistent asthma are allowed in the study).
    3. Physical and laboratory test findings:
    o Patients on dialysis or with a Creatinine clearance < 30mL/min
    o SGOT or SGPT >3ULN
    4. Prohibited prior therapies
    o Prior local irradiation within two weeks before first dose
    o Previous anti-CD38 therapy.
    5. Allergies and Adverse Drug Reaction:
    o Hypersensitivity to Dexamethasone that would prohibit treatment with study therapy
    6. Refusal to consent or protected by a legal regime (guardianship, trusteeship)
    Les patients répondant à l'un des critères d'exclusion suivants ne sont pas éligibles dans cette étude:
    1. Exceptions pathologiques:
    1.1. Plasmocytome osseux / plasmocytome extramédullaire solidaire
    1.2. Patients avec un MM non sécrétant et non mesurable.
    1.3. Résultat prouvant l’atteinte du système nerveux central (CNS)
    2. Antécédents et maladie associés:
    2.1. Sujets ayants des antécècedents de tumeurs malignes invasives (≤ 5 ans) ou concomitants à l'exception de ce qui suit:
    2.2. Carcinome basocellulaire ou spinocellulaire de la peau en rémission.
    2.3. Découverte fortuite de cancer de la prostate de bas grade (Gleason 3+3 ou moins).
    2.4. Tout cancer guéri depuis au moins 3 ans.
    2.5. Sujets dont les conditions médicales connues/ suspectées, selon l’avis de l’investigateur, pourraient rendre l’administration du traitement dangereux (pathologies non contrôlées : diabète/ ou maladie artérielle coronarienne).
    2.6. Toute pathologie cardiovasculaire sévère ou pulmonaire non contrôlée, selon le jugement de l’investigateur, incluant (Cf. protocole):
    2.7. Sujets ayant une neuropathie périphérique grade 2 ou plus (selon le NCI-CTCAEv4.0).
    2.8. Femmes enceintes ou allaitantes ou désirant avoir un enfant au cours de l’étude ou dans les 4 mois après la dernière prise du traitement. Si le sujet est un homme qui planifie d’être père au cours de l’étude ou dans les 4 mois après la dernière prise de traitement.
    2.9. Infection HIV ou hépatite virale active B ou C
    2.10. Sujets atteints d’une maladie psychiatrique ou dans une situation sociale qui ne lui pas de comprendre le consentement éclairé, d’être compliant, ou d’adhérer au programme des visites, aux procédures et ou au traitement à l’étude.
    2.11. Sujets atteint de broncho-pneumopathie chronique obstructive (BPCO) avec un volume expiratoire maximale en 1 seconde (VEMs) < 50% de la norme. A noter que le VEMs est nécessaire pour les patients suspectés d’avoir une BPCO. Les patients avec un VEMs< 50% de la valeur normale attendue doivent être exclus.
    2.12. Sujets ayant un antécédent d’asthme modéré à sévère dans les 2 ans précèdent l’inclusion (voir appendix 7 du protocole), ou un asthme non contrôlé quel que soit sa classification. (à noter que les sujets qui ont un asthme intermittent ou contrôlé sont autorisés à participer à l’étude).
    3. Paramètres biochimiques
    3.1. Patients dialysés ou avec une clairance de la créatinine < 30mL/min
    3.2. SGOT ou SGPT >3ULN
    4. Traitements antérieurs interdits
    4.1. Irradiation localisée dans les deux semaines la première administration du traitement à l’étude.
    4.2. Patients ayant reçu un anticorps anti-CD38 lors d’une précédente ligne thérapeutique.
    5. Allergie et effets indésirables liés au traitement à l’étude:
    5.1. Hypersensibilité à la Dexamethasone qui interdirait le traitement
    6. Refus de participation à l’étude ou protégée par un régime juridique (tutelle, curatelle)
    E.5 End points
    E.5.1Primary end point(s)
    • The primary endpoint is the Overall Response Rate (ORR, PR or better) using the IMWG response criteria.
    • Le critère principal est le taux de réponse global (ORR, RP ou mieux) en utilisant les critères de réponse de l’IMWG.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Throughout the study using the IMWG response criteria.
    Tout au long de l'étude
    E.5.2Secondary end point(s)
    • Assess safety by type, frequency, severity, relationship of adverse events to study treatment and changes in vital signs, physical exams. Incidence of Treatment Emergent Adverse Event (TEAE), Serious Adverse Event (SAE) and laboratory abnormalities using National Cancer Institute (NCI) common toxicity criteria (CCTAE V4).
    • Response rate (VGPR and CR) to Daratumumab and Dexamethasone in the study population using IMWG response criteria. VGPR + CR rate and CR+- rate (complete response with normal FLC ratio) will also be determinate using IWMG criteria [1]. Determine the Clinical Benefit Rate (CBR = CR+ + CR + PR + MR), and duration of Clinical Benefit using EBMT criteria at 3 months and six months..
    • Determine the OS (from the date of inclusion to last date of follow-up) of patients treated with Daratumumab+ Dexamethasone, Progression-free Survival (PFS), Event-free Survival (EFS) and time to progression (TTP).
    • Secondary efficacy variables for study treatment include:
    o Time to progression (TTP) obtained with study treatment versus the patient’s TTP(s) on prior therapies for MM
    o Duration of Response (DOR)
    • Assess QoL using EORTC QLQ30, MY20 and EQ5D-3L
    • Determine the Clinical Benefit Rate (CBR = CR+ + CR + PR + MR), and duration of CBR Determine the Disease Control Rate (DCR = CBR + stable disease [SD; for a minimum of 4 weeks]), as well as duration of DCR.
    • Compare PFS, ORR, DOR, DCR, and OS obtained with Daratumumab and Dexamethasone in patients with International Staging System (ISS) Stages II/III versus ISS Stage I
    Exploratory Endpoints
    • Compare response and survival with regards to chromosome copy numbers and chromosomal structural abnormalities present in tumour cells
    • Evaluation of ORR, DOR, PFS, and OS in patient with free light chain (FLC) MM treated with Daratumumab plus Dexamethasone
    • Correlational studies to evaluate response according to chromosome copy numbers and chromosomal structural abnormalities such as del(17p), t(4;14), t(14;16), t(14;20), amp(1q) and del(1p).
    • Evaluation des données de sécurité par type, fréquence, sévérité, relation de causalité au traitement à l’étude, ainsi que des changements dans les signes vitaux, les examens physiques, incidence des évènements indésirables liés au traitement (TEAE), évènements indésirables graves, résultats d’analyses de laboratoires anormales gradés en utilisant le guideline de l’institut national du cancer sur les critères communs de toxicité (CCTAE V4).
    • Evaluation du taux de réponse (TBRP et RC) au Daratumumab et à la Dexamethasone dans la population d’étude en utilisant les critères de réponse de l’IMWG. Les taux de TBRP+ RC et de RC+ seront aussi déterminés en utilisant les critères de l’IMWG.
    • Déterminer le taux de Bénéfice clinique (CBR=CR++ CR + PR + MR), et la durée de la CBR en utilisant les critères de l’EBMT.
    • Taux de réponses (VGPR et CR) au Daratumumab et Dexamethasone dans la population de l’étude en utilisant les critères de réponses IMWG. Le taux de VGPR, CR et CR+ (réponse complète avec un taux de FLC normal) sera aussi déterminé en utilisant les critères IMWG. Déterminer le taux du bénéfice clinique (CBR = CR+ + CR + PR + MR), et la durée du bénéfice Clinique en utilisant les critères EBMT à 3 et 6 mois.
    • Déterminer la survie globale (OS) des patients traités par Daratumumab + Dexamethasone, la survie sans progression (PFS), la survie sans évènement (EFS) et le lapse de temps jusqu’à progression (TTP).
    • Les variables Secondaires d’efficacité pour l’étude:
    o le temps jusqu’à progression obtenu avec le traitement à l’étude versus celui sans traitement pour le myélome.
    o la durée de la réponse
    • Evaluer la qualité de vie en utilisant des questionnaires: EORTC QLQ30, MY20 et EQ5D-3L
    • Déterminer le taux de contrôle de la maladie (DCR = CBR + maladie stable [SD; pour un minimum de 4 semaines]), ainsi que la durée de stabilisation de la maladie.
    • Comparer la PFS, le taux de réponse globale, la durée de la réponse, la stabilisation de la maladie, et la survie globale obtenu avec la combinaison Daratumumab + Dexaméthasone chez les patients ayant un MM de stade III versus I ou II selon le système de classement international (ISS)
    Exploratoire
    • Comparaison de la réponse et de la survie en regards des anomalies du chromosome : nombre de copie et anomalie structurale présent dans les cellules tumorales.
    • Evaluation du taux de réponse globale, la durée de la réponse, la survie sans progression, et de la survie globale chez les patients dont le MM est mesurable sur les chaînes libres légères (CLL) traités par Daratumumab plus dexamethasone
    E.5.2.1Timepoint(s) of evaluation of this end point
    As specified for each end point
    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 concerned5
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA60
    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 years5
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years5
    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: 50
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 14
    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 No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Information not present in EudraCT
    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 state10
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 54
    F.4.2.2In the whole clinical trial 64
    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)
    If patient stop study, he will start another treatment of myeloma according to his doctor
    si un patientarrete l'etude, il entamera un autre traitement du myélome multiple en concertation avec son medecin
    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 Decision2016-04-18
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-04-25
    P. End of Trial
    P.End of Trial StatusOngoing
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