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    Summary
    EudraCT Number:2014-000255-85
    Sponsor's Protocol Code Number:54767414MMY3004
    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:2014-07-15
    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 number2014-000255-85
    A.3Full title of the trial
    Phase 3 Study Comparing Daratumumab, Bortezomib and Dexamethasone (DVd) vs Bortezomib and Dexamethasone (Vd) in Subjects With Relapsed or Refractory Multiple Myeloma
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Addition of Daratumumab to Combination of Bortezomib and Dexamethasone in Participants with Relapsed or Refractory Multiple Myeloma
    A.4.1Sponsor's protocol code number54767414MMY3004
    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 SponsorJanssen-Cilag International N.V.
    B.1.3.4CountryBelgium
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportJanssen Research & Development, LLC
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationJanssen-Cilag International N.V.
    B.5.2Functional name of contact pointClinical Registry group
    B.5.3 Address:
    B.5.3.1Street AddressArchimedesweg 29
    B.5.3.2Town/ cityLeiden
    B.5.3.3Post code2333
    B.5.3.4CountryNetherlands
    B.5.4Telephone number+31 715242166
    B.5.5Fax number+31 715242110
    B.5.6E-mailClinicalTrialsEU@its.jnj.com
    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 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.3.9.3Other descriptive nameHUMAX-CD38
    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.IMP: 2
    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 JNJ-54767414
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous 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
    D.3.9.3Other descriptive nameHuMax-CD38, 3003-005
    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 number120
    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
    Multiple myeloma
    E.1.1.1Medical condition in easily understood language
    Multiple myeloma
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    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 Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To compare the efficacy of daratumumab when combined with VELCADE and dexamethasone (DVd) to that of VELCADE and dexamethasone (Vd), in terms of progression-free survival (PFS) in subjects with relapsed or refractory multiple myeloma.
    E.2.2Secondary objectives of the trial
    The major secondary objectives are as follows:
    - To evaluate clinical outcomes including time to disease progression (TTP), overall response rate (ORR), and overall survival (OS).
    - To evaluate the proportion of subjects with a response of very good partial response (VGPR) or better.
    - To evaluate duration of and time to response.
    - To assess the safety and tolerability of daratumumab when administered in combination with Vd.
    - To assess Minimal Residual Disease (MRD) in subjects who achieve ≥VGPR.
    - To assess the pharmacokinetics of daratumumab in combination with Vd.
    - To assess the immunogenicity of daratumumab.
    - To assess the immunogenicity of rHuPH20 in subjects receiving daratumumab SC.
    - To evaluate treatment effects on patient reported outcomes (PROs) including the EuroQol-5 Dimensions (EQ-5D-5L) and EORTC QLQ-C30.
    - To evaluate clinical efficacy of DVd in high risk molecular subgroups (del17p, t(4;14), t(14;20), UAMS-70).
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Subject must be at least 18 years of age.
    2.Subject must have had documented multiple myeloma as defined by the criteria below:
    ● Monoclonal plasma cells in the bone marrow 10% at some point in their disease history, or presence of a biopsy-proven plasmacytoma.
    ●Measurable disease at Screening as defined by any of the following:
    -IgG multiple myeloma: Serum monoclonal paraprotein (M-protein) level ≥1.0 g/dL or urine M-protein level ≥200 mg/24 hours; or
    -IgA, IgD, IgE, IgM multiple myeloma: serum M-protein level ≥0.5 g/dL or urine M-protein level ≥200 mg/24 hours; or
    - Light chain multiple myeloma without measurable disease in the serum or the urine:
    Serum immunoglobulin free light chain ≥10 mg/dL and abnormal serum immunoglobulin kappa lambda free light chain ratio.
    3. Subject must have received at least 1 prior line of therapy for multiple myeloma (refer to Attachment 1). NOTE: A "line of therapy" is defined as 1 or more cycles of a planned treatment program.
    4. Subject must have documented evidence of progressive disease (PD) based on investigator’s determination of response by the IMWG criteria on or after their last regimen.
    5.Subject must have achieved a response (partial response [PR] or better based on investigator’s determination of response by the IMWG criteria) to at least 1 prior regimen in the past (refer to Attachment 1).
    6. Subject must have an ECOG Performance Status score of 0, 1, or 2 (refer to Attachment 2).
    7. For subjects experiencing toxicities resulting from previous therapy (including peripheral neuropathy), the toxicities must be resolved or stabilized to ≤Grade 1.
    8. Women of childbearing potential must commit to either abstain continuously from heterosexual sexual intercourse or to use 2 methods of reliable birth control simultaneously. This includes one highly effective form of contraception (tubal ligation, intrauterine device [IUD], hormonal [birth control pills, injections, hormonal patches, vaginal rings or implants]
    or partner’s vasectomy) and one additional effective contraceptive method (male latex or synthetic condom, diaphragm, or cervical cap). Contraception must begin 4 weeks prior to dosing. Reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy
    9. A woman of childbearing potential must have a negative urine or serum pregnancy test at screening within 14 days prior to randomization.
    10. Each subject (or their legally acceptable representative) must sign an Informed Consent Form (ICF) indicating that he or she understands the purpose of and procedures required for the study and are willing to participate in the study. Subjects must be willing and able to adhere to the prohibitions and restrictions specified in this protocol, as referenced in the ICF.
    E.4Principal exclusion criteria
    1. Subject has received daratumumab or other anti-CD38 therapies previously.
    2.Subject is refractory to VELCADE, or another PI, like ixazomib and carfilzomib (ie, subject had progression of disease while receiving VELCADE therapy or within 60 days of ending VELCADE therapy, or another PI therapy, like ixazomib and carfilzomib).
    3. Subject is intolerant to VELCADE (ie, discontinued due to any adverse event while on VELCADE treatment.
    4.Subject has received anti-myeloma treatment within 2 weeks or 5 pharmacokinetic halflives of the treatment, whichever is longer, before the date of randomization. The only exception is emergency use of a short course of corticosteroids (equivalent of dexamethasone 40 mg/day for a maximum of 4 days) before treatment. A list of anti-myeloma treatments with the corresponding pharmacokinetic half-lives is provided in the Site Investigational Product Procedures Manual (SIPPM).
    5. Subject has received ASCT within 12 weeks before the date of randomization, or the subject has previously received an allogenic stem cell transplant (regardless of timing).
    6. Subjects planning to undergo a stem cell transplant prior to progression of disease on this study, ie, these subjects should not be enrolled in order to reduce disease burden prior to transplant.
    7.Subject has a history of malignancy (other than multiple myeloma) within 3 years before the date of randomization (exceptions are squamous and basal cell carcinomas of the skin and carcinoma in situ of the cervix, or breast, or other non-invasive lesion, that in the opinion of the investigator, with concurrence with the sponsor's medical monitor, is considered cured with minimal risk of recurrence within 3 years).
    8. Subject has known meningeal involvement of multiple myeloma.
    9.Subject has peripheral neuropathy or neuropathic pain Grade 2 or higher, as defined by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCICTCAE) most recent version.
    10.Subject has either of the following:
    a. 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 subjects suspected of having COPD and subjects must be excluded if FEV1 <50% of predicted normal.
    b. Known moderate or severe persistent asthma, or a history of asthma within the last 2 years (see Attachment 8), or currently has uncontrolled asthma of any classification.
    (Note that subjects who currently have controlled intermittent asthma or controlled mild persistent asthma are allowed to participate in the study).
    11.Subject is known to be seropositive for human immunodeficiency virus (HIV) or known to have hepatitis B surface antigen positivity, or known to have a history of hepatitis C.
    12. Subject has any concurrent medical condition or disease (eg, active systemic infection) that is likely to interfere with study procedures or results, or that in the opinion of the investigator would constitute a hazard for participating in this study.
    13.Subject has clinically significant cardiac disease, including:
    ● Myocardial infarction within 6 months before date of randomization, or unstable or uncontrolled disease/condition related to or affecting cardiac function (eg, unstable angina, congestive heart failure, New York Heart Association Class III-IV).
    ● Uncontrolled cardiac arrhythmia (Common Terminology Criteria for Adverse Events [CTCAE] [most recent version] Grade 2 or higher) or clinically significant ECG abnormalities.
    ● Screening 12-lead ECG showing a baseline QT interval as corrected by Fridericia’s formula (QTcF) >470 msec.
    14.Subject has any of the following laboratory test results during the Screening Phase:
    ●Absolute neutrophil count ≤1.0 × 109/L;
    ●Hemoglobin level ≤7.5 g/dL (≤5 mmol/L) (it is not permissible to transfuse a subject to reach this level);
    ● Platelet count <75 × 109/L for subjects in whom <50% of bone marrow nucleated cells are plasma cells; otherwise platelet count <50 × 109/L (it is not permissible to transfuse a subject to reach this level);
    ● Alanine aminotransferase level ≥2.5 times the upper limit of normal (ULN);
    ● Aspartate aminotransferase ≥2.5 x ULN
    ●Total bilirubin level ≥1.5 × ULN, (except for Gilbert Syndrome: direct bilirubin 1.5 × ULN);
    ● Creatinine clearance ≤20 mL/min/1.73 m2 (may be calculated using the Cockcroft-Gault formula, Modification of Diet in Renal Disease [MDRD] formula or Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] formula, provided in Attachment 3), or measured);
    ● Serum calcium corrected for albumin >14.0 mg/dL (>3.5 mmol/L), or free ionized calcium 6.5 mg/dL (>1.6 mmol/L)
    18. Subject is a woman who is pregnant or breastfeeding or planning to become pregnant while enrolled in this study or within 3 months after the last dose of study drug.

    Please refer to protocol for complete overview of exclusion criteria
    E.5 End points
    E.5.1Primary end point(s)
    Percentage of participants with progression-free survival (PFS)
    E.5.1.1Timepoint(s) of evaluation of this end point
    Baseline, up to the end of the study
    E.5.2Secondary end point(s)
    1. Time to disease progression (TTP)
    2. Percentage of Participants With Overall Response
    3. Duration of response
    4. Time to Response
    5. Percentage of participants with a very good partial response (VGPR) or better
    6. Percentage of participants with Minimal Residual Disease (MRD)
    7. Percentage of participants with overall survival (OS)
    E.5.2.1Timepoint(s) of evaluation of this end point
    - For all secondary end points except 4 is Baseline, up to the end of the study
    - for secondary end point 4 is Baseline until first documented response
    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 No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic Yes
    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) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    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 concerned8
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA78
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Australia
    Brazil
    Korea, Republic of
    Mexico
    Russian Federation
    Turkey
    Ukraine
    United States
    Germany
    Hungary
    Italy
    Netherlands
    Poland
    Spain
    Sweden
    Czechia
    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 following is included in the protocol : The study is considered completed after 320 deaths have occurred.
    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 months10
    E.8.9.1In the Member State concerned days27
    E.8.9.2In all countries concerned by the trial years6
    E.8.9.2In all countries concerned by the trial months10
    E.8.9.2In all countries concerned by the trial days27
    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: 192
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 288
    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 state42
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 300
    F.4.2.2In the whole clinical trial 480
    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)
    Daratumumab will be provided to patients who are benefiting from the drug at the end of study .
    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 Decision2014-07-15
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-09-30
    P. End of Trial
    P.End of Trial StatusCompleted
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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