|E.1 Medical condition or disease under investigation |
|E.1.1||Medical condition(s) being investigated || |
|Amyloid Light Chain Amyloidosis |
|E.1.1.1||Medical condition in easily understood language || |
|E.1.1.2||Therapeutic area ||Diseases [C] - Immune System Diseases [C20] |
|MedDRA Classification |
|E.1.2 Medical condition or disease under investigation |
|E.1.2||Version ||23.0 |
|E.1.2||Level ||LLT |
|E.1.2||Classification code ||10083938 |
|E.1.2||Term ||Amyloid light-chain amyloidosis |
|E.1.2||System Organ Class ||100000004870 |
|E.1.3||Condition being studied is a rare disease || Yes |
|E.2 Objective of the trial |
|E.2.1||Main objective of the trial || |
|Cohort 1: |
- 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.2.2||Secondary 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.2.3||Trial contains a sub-study || No |
|E.3||Principal 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 difference between iFLC and uninvolved FLC (dFLC) ≥40mg/L per central laboratory
- 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 3 months 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 3 months 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 3 months 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 3 months after discontinuation of daratumumab, whichever is longer.
- Signed an informed consent form (ICF).
12Cohort 2 only: self-identified racial and ethnic minorities, including Black or African American.
|E.4||Principal 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 within 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 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 100 days after the last dose of study treatment
- 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 wild type or mutated (ATTR) amyloidosis.
|E.5 End points |
|E.5.1||Primary end point(s)|| |
|Cohort 1: |
- incidence and severity of cardiac events
|E.5.1.1||Timepoint(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.5.2||Secondary 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.5.2.1||Timepoint(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.6||Scope of the trial |
|E.6.1||Diagnosis|| No |
|E.6.2||Prophylaxis|| No |
|E.6.3||Therapy|| No |
|E.6.4||Safety|| Yes |
|E.6.5||Efficacy|| Yes |
|E.6.6||Pharmacokinetic|| Yes |
|E.6.7||Pharmacodynamic|| No |
|E.6.8||Bioequivalence|| No |
|E.6.9||Dose response|| No |
|E.6.10||Pharmacogenetic|| No |
|E.6.11||Pharmacogenomic|| No |
|E.6.12||Pharmacoeconomic|| No |
|E.6.13||Others|| No |
|E.7||Trial type and phase |
|E.7.1||Human pharmacology (Phase I)|| No |
|E.7.1.1||First administration to humans|| No |
|E.7.1.2||Bioequivalence study|| No |
|E.7.1.3||Other|| No |
|E.18.104.22.168||Other trial type description|| |
|E.7.2||Therapeutic exploratory (Phase II)|| Yes |
|E.7.3||Therapeutic confirmatory (Phase III)|| No |
|E.7.4||Therapeutic use (Phase IV)|| No |
|E.8 Design of the trial |
|E.8.1||Controlled|| Yes |
|E.8.1.1||Randomised|| Yes |
|E.8.1.2||Open|| Yes |
|E.8.1.3||Single blind|| No |
|E.8.1.4||Double blind || No |
|E.8.1.5||Parallel group|| Yes |
|E.8.1.6||Cross over || No |
|E.8.1.7||Other|| Yes |
|E.22.214.171.124||Other trial design description|| |
|Cohort 2 is not randomized |
|E.8.2|| Comparator of controlled trial |
|E.8.2.1||Other medicinal product(s)|| No |
|E.8.2.2||Placebo || No |
|E.8.2.3||Other|| Yes |
|E.126.96.36.199||Comparator description|| |
|Cohort 1: different treatment schedule. VCd starting at cycle 1 day 1 or at cycle 4 day 1. |
|E.8.2.4||Number of treatment arms in the trial||3 |
|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.8.4.1||Number of sites anticipated in Member State concerned||2 |
|E.8.5||The trial involves multiple Member States|| Yes |
|E.8.5.1||Number of sites anticipated in the EEA||21 |
|E.8.6 Trial involving sites outside the EEA |
|E.8.6.1||Trial being conducted both within and outside the EEA|| Yes |
|E.8.6.2||Trial being conducted completely outside of the EEA|| No |
|E.8.6.3||If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned|| |
|United Kingdom |
|United States |
|E.8.7||Trial 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.8.9.1||In the Member State concerned years||3 |
|E.8.9.1||In the Member State concerned months||8 |
|E.8.9.1||In the Member State concerned days||0 |
|E.8.9.2||In all countries concerned by the trial years||3 |
|E.8.9.2||In all countries concerned by the trial months||10 |
|E.8.9.2||In all countries concerned by the trial days||14 |