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    Summary
    EudraCT Number:2017-003950-18
    Sponsor's Protocol Code Number:ΕΑΕ-2017/ΜΜ02
    National Competent Authority:Greece - EOF
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2017-11-28
    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 ConcernedGreece - EOF
    A.2EudraCT number2017-003950-18
    A.3Full title of the trial
    Efficacy of Daratumumab in Patients with Relapsed/Refractory Myeloma with Renal Impairment
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Efficacy of Daratumumab in Patients with Relapsed/Refractory Myeloma with Renal Impairment
    A.3.2Name or abbreviated title of the trial where available
    The DARE study
    A.4.1Sponsor's protocol code numberΕΑΕ-2017/ΜΜ02
    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 SponsorHellenic Society of Hematology
    B.1.3.4CountryGreece
    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 supportJanssen Pharmaceutica NV
    B.4.2CountryBelgium
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationHealth Data Specialists Ireland Limited
    B.5.2Functional name of contact pointHealth Data Specialists Ireland
    B.5.3 Address:
    B.5.3.1Street Address77 SIR JOHN ROGERSON'S QUAY, BLOCK C, GRAND CANAL DOCKLANDS
    B.5.3.2Town/ cityDublin
    B.5.3.3Post codeD02 NP08
    B.5.3.4CountryIreland
    B.5.4Telephone number00353906480600
    B.5.6E-mailinfo@heads-research.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.2.1.1.1Trade name DARZALEX
    D.2.1.1.2Name of the Marketing Authorisation holderJanssen-Cilag International N.V
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/13/1153
    D.3 Description of the IMP
    D.3.1Product nameDaratumumab
    D.3.2Product code Daratumumab
    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.3.9.4EV 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
    Relapsed and /or Refractory 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
    The primary objective of this study is to evaluate progression free survival (PFS) in subjects with relapsed or refractory multiple myeloma and renal impairment treated with daratumumab and dexamethasone.
    E.2.2Secondary objectives of the trial
    The Secondary objectives of the study are the following:
    To evaluate Overall Response Rates (ORR)
    To evaluate Renal Response Rates (RRR)
    To evaluate duration of response in patients (DoR) with RI.
    To evaluate time to next therapy (TNT).
    To evaluate Overall Survival (OS).
    To assess the safety and tolerability of Daratumumab with dexamethasone in patients with RRMM and RI.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1.Males and females at least 18 years of age.
    2.Voluntary written informed consent before performance of any study-related procedure.
    3.Subject must have documented multiple myeloma as defined by the criteria below:
    Monoclonal plasma cells in the bone marrow ≥ 10% or presence of a biopsy proven plasmacytoma.
    AND any or more of the following myeloma defining events:
    •Evidence of end organ damage that can be attributed to the underlying plasma cell
    proliferative disorder, specifically:
    • Hypercalcaemia: serum calcium >0.25 mmol/L (>1 mg/dL) higher than the
    upper limit of normal or >2.75 mmol/L (>11 mg/dL)
    • Renal insufficiency: creatinine clearance <40 mL per min or serum creatinine >177 μmol/L (>2 mg/dL)
    • Anaemia: haemoglobin value of >20 g/L below the lower limit of normal, or a
    haemoglobin value <100 g/L
    • Bone lesions: one or more osteolytic lesions on skeletal radiography, CT, or PET-CT
    •Any one or more of the following biomarkers of malignancy:
    • Clonal bone marrow plasma cell percentage ≥60%
    • Involved:uninvolved serum free light chain ratio ≥100
    • >1 focal lesions on MRI studies
    4.Prior treatment with at least two lines of treatment that included both bortezomib- and lenalidomide-based regimens.
    5.Documented evidence of progressive disease (PD) as defined by the modified IMWG criteria (see Appendix 4) on or after the last regimen if the patient responded to previous regimens.
    6.Subjects must have measurable disease as defined by any of the following:
    •Serum monoclonal paraprotein (M-protein) level ≥ 1.0 g/dL (except for IgA subtype: ≥ 0.5 g/dL) or urine M-protein level ≥ 200 mg/24 hours; or
    •Light chain multiple myeloma: Serum immunoglobulin free light chain ≥ 10 mg/dL (100 mg/L) and abnormal serum immunoglobulin kappa lambda free-light-chain ratio.
    7.Renal impairment defined as eGFR < 30 ml/min/1.73 m2 (calculated with the CKD-EPI formula, see section 7.1.1.9) or in need for dialysis. Patients who undergo intraperitoneal dialysis may also be included.
    8.Eastern Cooperative Oncology Group (ECOG) performance status score of ≤ 2.
    9.Willingness and ability to participate in study procedures.
    10.Reproductive Status
    a)Women of childbearing potential (WOCBP) must have two negative serum or urine pregnancy tests, one 10-14 days prior to start of the study drug and one within 24 hours prior to the start of study drug. Females are not of reproductive potential if they have been in natural menopause for at least 24 consecutive months, or have had a hysterectomy and/or bilateral oophorectomy.
    b)Women must not be breastfeeding.
    c)WOCBP must agree to follow instructions for methods of contraception for 4 weeks before the start of treatment with study drugs, for the duration of treatment with study drugs, and for 3 months after cessation of study treatment.
    d)Males who are sexually active must always use a latex or synthetic condom during any sexual contact with females of reproductive potential, even if they have undergone a successful vasectomy. They must also agree to follow instructions for methods of contraception for 4 weeks before the start of treatment with study drugs, for the duration of treatment with study drugs, and for a total of 90 days post-treatment completion. on. The additional contraception of female partners of childbearing potential should also be considered.
    e)Male patients must not donate sperm for up to 90 days post treatment completion.
    f)Female patients must not donate eggs for up to 90 days post treatment completion.
    g)Azoospermic males and WOCBP who are not heterosexually active are exempt from contraceptive requirements. However, WOCBP will still undergo pregnancy testing as described in this section.

    Highly effective methods of contraception have a failure rate of < 1% when used consistently and correctly. Subjects must agree to the use of two methods of contraception, with one method being highly effective (tubal ligation, intrauterine device [IUD], hormonal [birth control pills, injections, hormonal patches, vaginal rings or implants] or partner’s vasectomy) and the other method being additionally effective (male latex or synthetic condom, diaphragm, or cervical cap).
    E.4Principal exclusion criteria
    1.Previous therapy with daratumumab or other anti-CD38 therapy.
    2.Anti-myeloma treatment within 2 weeks prior to Cycle 1, Day 1.
    3.Cumulative dose of corticosteroids greater than or equal to the equivalent of 140mg prednisone for ≥ 4 days or a dose of corticosteroids greater than or equal to the equivalent of 40 mg/day of dexamethasone for ≥ 4 days within the 2-week period prior to Cycle 1, Day 1.
    4.Previous allogenic stem cell transplant; or Autologous Stem Cell Transplantation (ASCT) within 12 weeks before Cycle 1, Day 1.
    5.Clinical signs of meningeal involvement of multiple myeloma.
    6.Subject has either of the following:
    a.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 (see Appendix 7), within 2 years from C1D1, 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.
    7.Clinically significant cardiac disease, including:
    a)Myocardial infarction within 1 year, or unstable or uncontrolled condition (e.g., unstable angina, congestive heart failure, New York Heart Association Class III-IV).
    b)Uncontrolled cardiac arrhythmia (CTCAE Grade 2 or higher) (atrial fibrillation with controlled ventricular rate is allowed) or clinically significant ECG abnormalities.
    c)ECG showing a baseline QT interval as corrected by Fridericia’s formula (QTcF) >470 msec.
    8.Any of the following:
    a. Known active hepatitis A
    b. Patient is seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen [HBsAg]). Subjects with resolved infection (ie, subjects who are HBsAg negative but positive for antibodies to hepatitis B core antigen [anti-HBc] and/or antibodies to hepatitis B surface antigen [anti-HBs]) must be screened using real-time polymerase chain reaction (PCR) measurement of hepatitis B virus (HBV) DNA levels. Those who are PCR positive will be excluded. EXCEPTION: Subjects with serologic findings suggestive of HBV vaccination (anti-HBs positivity as the only serologic marker) AND a known history of prior HBV vaccination, do not need to be tested for HBV DNA by PCR.
    c. Known to be seropositive for hepatitis C (except in the setting of a sustained virologic response [SVR], defined as aviremia at least 12 weeks after completion of antiviral therapy).
    9.Known to be seropositive for human immunodeficiency virus (HIV).
    10.Amyloidosis, or any prior or concurrent malignancy, except for the following:
    a)Adequately treated basal cell or squamous cell skin cancer.
    b)Any cancer (other than in-situ) from which the subject has been disease-free for 3 years prior to study entry.
    11.Any of the following laboratory test results during Screening:
    a)Absolute neutrophil count ≤ 1.0 × 109/L;
    b)Hemoglobin level ≤ 7.5 g/dL (≤ 4.65 mmol/L);
    c)Platelet count < 75 × 109/L in patients in whom < 50% of bone marrow nucleated cells are plasma cells and < 50x109/L in patients in whom more than 50% of bone marrow nucleated cells are plasma cells;
    d)Alanine aminotransferase level ≥ 2.5 times the upper limit of normal (ULN);
    12.Pregnant or nursing women.
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint of this study is Progression-free survival
    E.5.1.1Timepoint(s) of evaluation of this end point
    The whole duration of the study
    E.5.2Secondary end point(s)
    The secondary endpoints of this study are the following:
    - Overall response rate
    - Renal Response rate
    - Duration of response
    - Time to next therapy
    - Overall survival
    - Safety (adverse events)
    E.5.2.1Timepoint(s) of evaluation of this end point
    The whole duration of the study
    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 Information not present in EudraCT
    E.8.1.2Open Information not present in EudraCT
    E.8.1.3Single blind No
    E.8.1.4Double blind Information not present in EudraCT
    E.8.1.5Parallel group Information not present in EudraCT
    E.8.1.6Cross over Information not present in EudraCT
    E.8.1.7Other Information not present in EudraCT
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Information not present in EudraCT
    E.8.2.2Placebo Information not present in EudraCT
    E.8.2.3Other Information not present in EudraCT
    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 concerned6
    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 No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months1
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months1
    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: 11
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 27
    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 Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    The following subject categories are permitted:
    The study participant cannot read or write.
    The study participant is incapacitated or with partial ability to enter legal transactions.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state36
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 38
    F.4.2.2In the whole clinical trial 38
    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 Decision2017-12-15
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-12-01
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2021-03-22
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