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    EudraCT Number:2021-002639-48
    Sponsor's Protocol Code Number:54767414AMY2009
    National Competent Authority:Germany - PEI
    Clinical Trial Type:EEA CTA
    Trial Status:Trial now transitioned
    Date on which this record was first entered in the EudraCT database:2021-12-15
    Trial results
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    A. Protocol Information
    A.1Member State ConcernedGermany - PEI
    A.2EudraCT number2021-002639-48
    A.3Full title of the trial
    A Phase 2, Multicohort Study of Daratumumab-Based Therapies in Participants with Amyloid Light Chain (AL) Amyloidosis
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase 2, Multicohort Study of Daratumumab-Based Therapies in Participants with Amyloid Light Chain (AL) Amyloidosis
    A.3.2Name or abbreviated title of the trial where available
    A.4.1Sponsor's protocol code number54767414AMY2009
    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.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 CM
    B.5.4Telephone number+31 715242166
    B.5.5Fax number+31 715242110
    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. name DAZARLEX
    D. of the Marketing Authorisation holderJanssen-Cilag International NV
    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/3/18/2020
    D.3 Description of the IMP
    D.3.1Product nameDaratumumab co-formulated with recombinant human hyaluronidase (rHuPH20)
    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. cell therapy medicinal product No
    D. therapy medical product No
    D. Engineered Product No
    D. ATIMP (i.e. one involving a medical device) No
    D. 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. 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
    Amyloid Light Chain Amyloidosis
    E.1.1.1Medical condition in easily understood language
    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 23.0
    E.1.2Level LLT
    E.1.2Classification code 10083938
    E.1.2Term Amyloid light-chain amyloidosis
    E.1.2System Organ Class 100000004870
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    - to characterize cardiac safety of different D-VCd treatment regimens in newly diagnosed systemic AL amyloidosis with cardiac involvement
    - to identify potential mitigation strategies for cardiac toxicity
    - to characterize the PK of SC daratumumab, among racial and ethnic minorities with newly diagnosed systemic AL amyloidosis treated with D-VCd
    E.2.2Secondary objectives of the trial
    - to evaluate efficacy measures
    - to assess the safety profile, including cardiac events
    - to characterize the PK of SC daratumumab
    - to assess the immunogenicity of SC daratumumab
    - to monitor the clinical signs and symptoms of cardiac AL amyloidosis to identify possible predictive factors for cardiac events

    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - ≥18 years of age.
    - New diagnosis of systemic AL amyloidosis based on both: (a) tissue deposition of amyloid in any organ other than bone marrow and (b) an underlying clonal plasma cell disorder as demonstrated by any one of the following:
    • Clonal plasma cells in the bone marrow
    • Monoclonal gammopathy in the serum or urine
    • Abnormal free light chain ratio
    - Measurable disease at screening defined by one of the following:
    • difference between iFLC and uninvolved FLC (dFLC) ≥40mg/L per central laboratory
    • serum M-protein ≥0.5 g/dL
    - Cohort 1: Cardiac involvement (AL amyloidosis Mayo Cardiac Stage II and Stage IIIa; see Appendix 6) with or without other organ(s) involved
    - Cohort 2: One or more organs impacted by systemic AL amyloidosis according to consensus guidelines
    - Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0, 1 or 2.
    - Pre-treatment clinical laboratory values meeting the following criteria during the Screening Phase:
    • Hemoglobin ≥8.0 g/dL (≥5 mmol/L); red blood cell transfusion allowed until 7 days before randomization/enrollment
    • Platelets ≥50×109/L; platelet transfusions are allowed until 7 days before randomization/enrollment
    • Absolute Neutrophil count ≥1.0×109/L
    • Aspartate aminotransferase and alanine aminotransferase ≤2.5× ULN
    • Total bilirubin ≤1.5 × ULN; except in participants with congenital bilirubinemia, such as Gilbert syndrome (in which case direct bilirubin ≤2×ULN is required)
    • Estimated glomerular filtration rate ≥20 mL/min/1.73 m2
    - A female participant of childbearing potential must have a negative serum or urine test at screening and within 72 hours of the first dose of study treatment and must agree to further serum or urine pregnancy tests during the study.
    - A female participant must be either of the following:
    a. Not of childbearing potential
    b. Of childbearing potential and practicing true abstinence or have a sole partner who is vasectomized or practicing at least 1 highly effective user independent method of contraception
    Contraception must begin 4 weeks prior to dosing and continue for 1 year after discontinuation of cyclophosphamide or 100 days after discontinuation of daratumumab, whichever is longer.
    - A male participant must wear a condom (with or without spermicidal foam/gel/film/cream/suppository) when engaging in any activity that allows for passage of ejaculate to another person during the study and for 6 months after discontinuation of cyclophosphamide or 100 days after discontinuation of daratumumab, whichever is longer. His female partner, if of childbearing potential, must also be practicing a highly effective method of contraception.
    If the male participant is vasectomized, he still must wear a condom (with or without spermicidal foam/gel/film/cream/suppository), but his female partner is not required to use contraception.
    - A female participant must agree not to donate eggs (ova, oocytes) or freeze for future use, for the purposes of assisted reproduction during the study and for a period of least 1 year after the last dose of cyclophosphamide or 100 days after discontinuation of daratumumab, whichever is longer.
    - A male participant must agree not to donate sperm for the purpose of reproduction during the study and for a minimum of 6 months after receiving the last dose of cyclophosphamide or 100 days after discontinuation of daratumumab, whichever is longer.
    - Signed an informed consent form (ICF).
    - Cohort 2 only: self-identified racial and ethnic minorities, including Black or African American.
    E.4Principal exclusion criteria
    - Prior therapy for systemic AL amyloidosis or multiple myeloma including medications that target CD38, with the exception of 160 mg dexamethasone or equivalent corticosteroid maximum exposure prior to randomization/enrollment.
    - Previous or current diagnosis of symptomatic multiple myeloma per International Myeloma Working Group (IMWG) Criteria.
    - Participant received any of the following therapies:
    a. treatment with an investigational drug or used an invasive investigational medical device within 14 days or at least 5 half-lives, whichever is less.
    b. vaccinated with an investigational vaccine (except for COVID-19, live attenuated or replicating viral vector vaccines < 4 weeks prior to randomization/enrollment.
    - Stem cell transplantation – Planned stem cell transplant during the first 9 cycles of protocol therapy are excluded. Stem cell collection during the first 9 cycles of protocol therapy is permitted.
    - Grade 2 sensory or Grade 1 painful peripheral neuropathy.
    - Evidence of significant cardiovascular conditions (as specified in protocol)
    - History of malignancy (other than AL amyloidosis) within 3 years before the date of randomization
    - Contraindications or life-threatening allergies, hypersensitivity, or intolerance to any component of study treatment or its excipients, including bortezomib, boron, mannitol, or cyclophosphamide or any of its metabolites
    - Known allergies, hypersensitivity, or intolerance to monoclonal antibodies, hyaluronidase, human proteins, or their excipients, or known sensitivity to mammalian-derived products
    - Pregnant or breastfeeding or planning to become pregnant while enrolled in this study or within 1 year after discontinuation of cyclophosphamide or 100 days after the last dose of daratumumab, whichever is longer
    - Plans to father a child while enrolled in this study or within 6 months after discontinuation of cyclophosphamide or 100 days after the last dose of daratumumab, whichever is longer
    - Chronic obstructive pulmonary disease (COPD) with a Forced Expiratory Volume in 1 second (FEV1) <50% of predicted normal
    - Moderate or severe persistent asthma within the past 2 years, or currently has uncontrolled asthma of any classification
    - Participant is known to be positive for human immunodeficiency virus (HIV), with 1 or more of the following:
    • Not receiving highly active antiretroviral therapy (ART)
    • Had a change in ART within 6 months of the start of screening
    • Receiving ART that may interfere with study treatment (consult Sponsor for review of medication prior to enrollment)
    • CD4 count <350 at screening
    • Acquired immunodeficiency syndrome (AIDS)-defining opportunistic infection within 6 months of start of screening
    • Not agreeing to start ART and be on ART >4 weeks plus having HIV viral load <400 copies/mL at end of 4-week period (to ensure ART is tolerated and HIV controlled)
    - Seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen [HbsAg]). (Conditions for resolved infection are specified in protocol)
    - 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).
    - Any serious underlying medical or psychiatric 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, such as:
    • Evidence of serious active viral or bacterial infection, requiring systemic antimicrobial therapy, or uncontrolled systemic fungal infection.
    • Active autoimmune disease or a history of autoimmune disease within 2 years. EXCEPTION: Participants with vitiligo, type I diabetes, and prior autoimmune thyroiditis that is currently euthyroid based on clinical symptoms and laboratory testing are eligible regardless of when these conditions were diagnosed.
    • Disabling psychiatric conditions (eg, alcohol or drug abuse), severe dementia, or altered mental status.
    - Any other issue that would impair the ability of the participant to receive or tolerate the planned treatment at the study site, to understand informed consent or any condition for which, in the opinion of the investigator, participation would not be in the best interest of the participant or that could prevent, limit, or confound the protocol-specified assessments.
    - Major surgical procedure within 2 weeks before randomization/enrollment or has not fully recovered from an earlier surgical procedure, or has major surgical procedure planned during the time the participant is expected to participate in the study.
    - Any form of non-AL amyloidosis, including ATTR amyloidosis.
    E.5 End points
    E.5.1Primary end point(s)
    - incidence of any toxicity grade of cardiac events
    - C[trough]
    E.5.1.1Timepoint(s) of evaluation of this end point
    Cohort 1: approximately 12-months after 120 participants have been randomized.

    Cohort 2: cycle 3 day 1 predose
    E.5.2Secondary end point(s)
    - Overall HemCR and HemCR rate at 6 months
    - Rate of VGPR or better
    - Time to HemCR (or VGPR or better)
    - Duration of response (HemCR and VGPR or better)
    - Organ response rate (OrRR) at 6 months and 12 months for kidney, heart, liver
    - Overall survival (OS)
    - Time to next treatment (TNT)
    - Incidence and severity of AEs
    - Pharmacokinetic profile of daratumumab
    - Immunogenicity of daratumumab and rHuPH20
    - Clinical signs and symptoms of cardiac AL amyloidosis
    E.5.2.1Timepoint(s) of evaluation of this end point
    HemCR rate at 6 months
    OrRR at 6 and 12 months
    All other secondary end points during the conduct 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 No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    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. trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E. trial design description
    Cohort 2 is not randomized
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E. description
    Cohort 1: different treatment schedule. VCd starting at cycle 1 day 1 or at cycle 4 day 1.
    E.8.2.4Number of treatment arms in the trial3
    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 concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA21
    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
    United States
    United Kingdom
    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
    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 days14
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months10
    E.8.9.2In all countries concerned by the trial days14
    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: 80
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 70
    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 state11
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 78
    F.4.2.2In the whole clinical trial 150
    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)
    Subjects will be instructed that study drug will not be available to them after they have completed/discontinued treatment and that they should return to their primary physician to determine standard of care (Prot Sect 6.7).Patients receiving daratumumab and who continue to benefit from the study treatment when study is over will have the option to continue on daratumumab treatment for a max of 2 year from the start of the study. Sponsor plans to provide study medication to these patients.
    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 Decision2022-03-07
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2022-07-25
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
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