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    Summary
    EudraCT Number:2018-004333-33
    Sponsor's Protocol Code Number:EMN22/54767414AMY2005
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2019-07-08
    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 ConcernedNetherlands - Competent Authority
    A.2EudraCT number2018-004333-33
    A.3Full title of the trial
    Phase 2 study of daratumumab monotherapy in previously untreated patients with stage 3B light chain (AL) amyloidosis
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Phase 2 study of daratumumab monotherapy in previously untreated patients with stage 3B light chain (AL) amyloidosis
    A.4.1Sponsor's protocol code numberEMN22/54767414AMY2005
    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 SponsorEuropean Myeloma Network
    B.1.3.4CountryNetherlands
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportJanssen Pharmaceutica NV
    B.4.2CountryBelgium
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationEuropean Myeloma Network
    B.5.2Functional name of contact pointEuropean Myeloma Network
    B.5.3 Address:
    B.5.3.1Street Addresss-Gravendijkwal 230
    B.5.3.2Town/ cityRotterdam
    B.5.3.3Post code3015 CE
    B.5.3.4CountryNetherlands
    B.5.4Telephone number0031010703 3123
    B.5.6E-mails.lonergan@erasmusmc.nl
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade 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 JNJ-54767414
    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.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 Yes
    D.2.1.1.1Trade name Velcade
    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 No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameBortezomib
    D.3.2Product code 26866138
    D.3.4Pharmaceutical form Powder for 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 INNBORTEZOMIB
    D.3.9.1CAS number 179324-69-7
    D.3.9.4EV Substance CodeSUB20020
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    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 No
    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 typeProteosoma Inhibitor
    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
    Patients with newly diagnosed stage 3B AL amyloidosis
    E.1.1.1Medical condition in easily understood language
    Patients with newly diagnosed stage 3B AL amyloidosis
    E.1.1.2Therapeutic area Diseases [C] - Immune System Diseases [C20]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10002022
    E.1.2Term Amyloidosis
    E.1.2System Organ Class 10021428 - Immune system disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the overall survival (OS) rate at 6 months following treatment with daratumumab in frontline AL patients with stage 3B disease
    E.2.2Secondary objectives of the trial
    • To evaluate the overall (ORR), very good partial (VGPR) and complete (CR) hematologic response rates at 3 and 6 months
    • To evaluate the Major Organ Deterioration Progression-Free Survival (MOD-PFS). Will be defined from the start of study treatment until any one of the following events (whichever occurs first)
    - Death
    - Clinical manifestation of cardiac failure:
    - Clinical manifestation of renal failure:
    - Development of hematologic progression of disease (PD) as per consensus guidelines
    • To evaluate PFS based on all-cause mortality and progression of disease
    • To evaluate the organ response rate (OrRR)
    o Heart
    o Kidney
    o Liver
    • To evaluate treatment effects on patient-reported outcomes (PROs) such as SF-36, EQ-5D-5L and EORTC QLQ-C30
    • To characterize time to and duration of response
    • To assess the safety and tolerability of daratumumab in patients with stage 3B AL amyloidosis
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Men or women 18 years of age or older.
    2. Diagnosis of amyloidosis, AL type, based on:
    a. Histopathological diagnosis of amyloidosis based on detection by immunohistochemistry and polarizing light microscopy of green bi-refringent material in Congo Red stained tissue specimens (excluding bone marrow) or characteristic electron microscopy appearance
    AND
    b. Measurable disease of amyloid light chain amyloidosis as defined by at least ONE of the following:
    - serum monoclonal protein ≥0.5 g/dL by protein electrophoresis (routine serum protein electrophoresis and immunofixation performed at local lab)
    - serum free light chain (FLC) ≥2.0 mg/dL (20 mg/L) with an abnormal kappa:lambda ratio or the difference between involved and uninvolved free light chains (dFLC) ≥2mg/dL (20 mg/L). Serum FLCs will be measured using the Freelite assay at a central laboratory.
    - Note: Measurable disease by Urine Bence-Jones Proteinuria is not sufficient for study enrolment.
    AND
    c. Cardiac involvement by AL amyloidosis according to consensus guidelines (See ATTACHMENT 3)
    3. Mayo Stage 3B disease, defined as both A. increased cardiac troponin (hsTnT >54 pg/ml) AND B. increased NT-proBNP ≥ 8500 pg/ml
    4. For subjects with congestive heart failure, symptoms should be optimally managed and clinically stable with no cardiovascular-related hospitalizations within 2 weeks prior to Cycle 1 Day 1, as assessed by the Principal Investigator. [See also exclusion criteria 3]
    5. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0, 1,2 or 3 (ATTACHMENT 1)
    6. Subject must have pre-treatment clinical laboratory values meeting the following criteria during the Screening Phase:
    a. Absolute neutrophil count ≥1.0 × 109/L;
    b. Hemoglobin level ≥10.0 g/dL (≥5 mmol/L)
    c. Platelet count ≥75 × 109/L; platelet transfusions are NOT acceptable
    d. Alanine aminotransferase level (ALT) ≤2.5 x ULN;
    e. Aspartate aminotransferase (AST) ≤2.5 x ULN
    f. Total bilirubin level ≤1.5 × ULN, except for subjects with history of Gilbert Syndrome, in which case direct bilirubin ≤ 2 × ULN
    g. Estimated Glomerular Filtration Rate (eGFR) ≥20 mL/min; Please note that the eGFR is measured by using the CKD-EPI equation
    7. Women of childbearing potential must commit to either abstain continuously from heterosexual sexual intercourse (if this is the preferred and usual lifestyle of the subject) or to use 2 methods of reliable birth control simultaneously. This includes one highly effective form of contraception (tubal ligation, intrauterine device, 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 prior to dosing and continue for 3 months after discontinuation of daratumumab. Reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy or bilateral oophorectomy.
    8. During the study and for 3 months after receiving the last dose of daratumumab, female subjects must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction.
    9. A man who is sexually active with a woman of childbearing potential and has not had a vasectomy must agree to use a barrier method of birth control, e.g. either condom with spermicidal foam/gel/film/cream/suppository or partner with occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository during and up to 3 months after discontinuation of daratumumab. All men must not donate sperm during the study and for 3 months after discontinuation of daratumumab.
    10. Female subjects of childbearing potential must have a negative serum or urine pregnancy tests within 14 days prior to Cycle 1 Day 1. For requirements during the Treatment Phase, please see the Time and Events Schedule.
    11. Each subject must sign an informed consent form (ICF) indicating that he or she understands the purpose of the 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.Prior therapy for AL amyloidosis or multiple myeloma with the exception of 160 mg dexamethasone (or equivalent steroid) maximum exposure prior to Cycle 1 Day 1.
    2.Previous or current diagnosis of symptomatic multiple myeloma including the presence of lytic bone disease, plasmacytomas, ≥ 60% plasma cells in the bone marrow, and/or hypercalcemia.
    3.Evidence of significant cardiovascular conditions as specified below:
    a. New York Heart Association (NYHA) classification of heart failure, stages IIIB or IV
    b. Heart failure that in the opinion of the investigator due to ischemic heart disease or uncorrected valvular disease, and not due to AL amyloid cardiomyopathy.
    c. Hospitalization for unstable angina or myocardial infarction or percutaneous cardiac intervention with recent stent or coronary artery bypass grafting, all within the last 6 months prior to the first dose
    d. Subjects with a history of sustained ventricular tachycardia or aborted ventricular fibrillation or with a history of atrioventricular (AV) nodal or sinoatrial (SA) nodal dysfunction for which a pacemaker/ICD is indicated but will not be placed (subjects who do have a pacemaker/ICD are allowed in the study)
    e. Screening 12-lead ECG showing a baseline QT interval as corrected by Fridericia’s formula (QTcF) >500 msec. Subjects who have pacemaker may be included regardless of calculated QTc interval.
    f. Supine systolic blood pressure <90 mmHg, or symptomatic orthostatic hypotension, defined as a decrease in systolic blood pressure upon standing of >20 mmHg despite medical management in the absence of volume depletion
    4. Subjects planning to undergo a stem cell transplant during the first 6 cycles of protocol therapy are excluded. Stem cell collection during the first 6 cycles of protocol therapy is permitted.
    5. Diagnosed or treated for malignancy other than AL, except:
    a. Malignancy treated with curative intent and with no known active disease present for ≥24 months before Cycle 1 Day 1
    b. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
    c. Adequately treated carcinoma in situ (e.g. cervical, breast) with no evidence of disease
    6. Subject has 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
    7. Subject has known moderate or severe persistent asthma within the past 2 years or currently has uncontrolled asthma of any classification. (Note that subjects who currently have controlled intermittent asthma or controlled mild persistent asthma are allowed in the study).
    8. Subject is known to be seropositive for human immunodeficiency virus (HIV). HIV positive subjects who are stable on highly active antiretroviral therapy (HAART) with no opportunistic infections within the last 6 months are eligible.
    9. Subjects known:
    a. To be seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen [HBsAg]). Subjects with resolved infection (ie, subjects who are positive for antibodies to hepatitis B core antigen [antiHBc] and/or antibodies to hepatitis B surface antigen [antiHBs]) 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.
    b. To be seropositive for hepatitis C
    10. Subject has any concurrent medical condition or disease 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.
    11. Any form of non-AL amyloidosis, including wild type or mutated (ATTR) amyloidosis.
    12. Subject has known allergies, hypersensitivity, or intolerance to monoclonal antibodies or human proteins, or their excipients, or known sensitivity to mammalian-derived products.
    13. Subject is known or suspected of not being able to comply with the study protocol or the subject has any condition for which, in the opinion of the investigator, participation would not be in the best interest of the subject or that could prevent, limit, or confound the protocol-specified assessments.
    14. Subject is a woman who is pregnant or breastfeeding or planning to become pregnant while enrolled in this study or within 3 months following discontinuation of daratumumab.
    15. Subject has received an investigational drug or used an invasive investigational medical device within 4 weeks prior to Cycle 1 Day 1
    16. Subject has had major surgery within 2 weeks prior to Cycle 1, Day 1, or will not have fully recovered from surgery, or has surgery planned during the time the subject is expected to participate in the study or within 2 weeks after the last dose of study drug administration
    E.5 End points
    E.5.1Primary end point(s)
    Overall survival rate
    E.5.1.1Timepoint(s) of evaluation of this end point
    6 months
    E.5.2Secondary end point(s)
    Overall (ORR), very good partial (VGPR) and complete (CR) hematologic response rates (3 & 6 months), Major Organ Deterioration Progression-Free Survival (MOD-PFS), PFS based on all-cause mortality and progression of disease (PD), organ response rate (OrRR), to evaluate treatment effects on patient related outcomes (PROs), to characterize time to and duration of response, and to asses the safety and tolerability of daratumumab in patients with stage 3B AL amyloidosis
    E.5.2.1Timepoint(s) of evaluation of this end point
    For the entire 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 Yes
    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.8.2.4Number of treatment arms in the trial1
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA3
    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
    2 years after the last subject is enrolled
    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 months6
    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 months6
    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: 20
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 20
    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 state10
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 40
    F.4.2.2In the whole clinical trial 40
    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 Decision2019-07-08
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-07-24
    P. End of Trial
    P.End of Trial StatusOngoing
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