A Study of Daratumumab-Based Therapies in Participants With Amyloid Light Chain (AL) Amyloidosis

Purpose

The purpose of this study is to characterize cardiac safety of Daratumumab, Cyclophosphamide, Bortezomib, and Dexamethasone (D-VCd) treatment regimens (Arm A: immediate daratumumab + VCd treatment and Arm B: daratumumab + deferred VCd) in newly diagnosed systemic amyloid light chain (AL) amyloidosis with cardiac involvement and to identify potential mitigation strategies for cardiac toxicity (cohort 1); to characterize the pharmacokinetics of subcutaneous (SC) daratumumab, among racial and ethnic minorities, including Black or African American, with newly diagnosed AL amyloidosis treated with D-VCd (cohort 2).

Condition

  • Amyloidosis

Eligibility

Eligible Ages
Over 18 Years
Eligible Genders
All
Accepts Healthy Volunteers
No

Inclusion Criteria

  • Cohort 1: Cardiac involvement (amyloid light chain [AL] amyloidosis Mayo Cardiac Stage II and Stage IIIa) 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 - 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 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 - Cohort 2 only: self-identified racial and ethnic minorities, including Black or African American

Exclusion Criteria

  • Prior therapy for systemic AL amyloidosis or multiple myeloma including medications that target cluster of differentiation 38 (CD38), with the exception of 160 milligrams(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: 1. treatment with an investigational drug or used an invasive investigational medical device within 14 days or at least 5 half-lives, whichever is less; 2. vaccinated with an investigational vaccine (except for COVID-19) live, attenuated or replicating viral vector vaccines less than (<) 4 weeks prior to randomization/enrollment. Participants who are taking strong Cytochrome P450 3A4(CYP3A4) inducers must discontinue their use at least 5 half-lives prior to the first dose of bortezomib - 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

Study Design

Phase
Phase 2
Study Type
Interventional
Allocation
Randomized
Intervention Model
Parallel Assignment
Primary Purpose
Treatment
Masking
None (Open Label)

Arm Groups

ArmDescriptionAssigned Intervention
Experimental
Cohort1 (Arm A): Immediate Daratumumab + Cyclophosphamide, Bortezomib and Dexamethasone (VCd) 		Participants with newly diagnosed systemic amyloid light chain (AL) amyloidosis with Mayo Cardiac Stage II and IIIa cardiac involvement will receive daratumumab 1800 milligrams (mg) subcutaneously (SC) starting on Day 1 once weekly (q1w) up to Day 22 for cycles 1-2, on Days 1 and 15 for cycles 3-6, and on Day 1 for cycles 7-24 of a 28-day cycle. Participants will also receive VCd (cyclophosphamide 300 milligrams per meter square [mg/m^2] either orally or intravenously [IV], bortezomib 1.3 mg/m^2 SC, dexamethasone 40 mg weekly either orally or IV) weekly starting at Cycle 1 Day 1 up to Day 22 in every 28-day cycle for a maximum of 6 cycles (Cycle 6 Day 22).
  • Drug: Daratumumab
    Daratumumab will be administered subcutaneously.
    Other names:
    • JNJ-54767414
  • Drug: Cyclophosphamide
    Cyclophosphamide will be administered either orally or IV.
  • Drug: Bortezomib
    Bortezomib will be administered by SC injection.
  • Drug: Dexamethasone
    Dexamethasone will be administered orally or IV.
Experimental
Cohort1 (Arm B): Daratumumab + Deferred VCd 		Participants with newly diagnosed systemic AL amyloidosis with Mayo Cardiac Stage II and IIIa cardiac involvement will receive SC daratumumab 1800mg on Day 1 once weekly (q1w) up to Day 22 for cycles 1-2, on Days 1 and 15 for cycles 3-6, and on Day 1 for cycles 7-24 of a 28-day cycle. Participants will also receive VCd (Cyclophosphamide 300 mg/m^2 either orally or IV, Bortezomib 1.3 mg/m^2 SC, Dexamethasone 40 mg weekly either orally or IV) starting at Cycle 4 Day 1, weekly (Days 1, 8, 15, 22) in every 28-day cycle for a maximum of 6 cycles (Cycle 9 Day 22).
  • Drug: Daratumumab
    Daratumumab will be administered subcutaneously.
    Other names:
    • JNJ-54767414
  • Drug: Cyclophosphamide
    Cyclophosphamide will be administered either orally or IV.
  • Drug: Bortezomib
    Bortezomib will be administered by SC injection.
  • Drug: Dexamethasone
    Dexamethasone will be administered orally or IV.
Experimental
Cohort 2: Daratumumab + VCd 		Participants with racial and ethnic minorities, including Black or African American participants, with newly diagnosed AL amyloidosis will receive SC injection of daratumumab 1800 mg SC on Day 1 once weekly (q1w) up to Day 22 for cycles 1-2, on Days 1 and 15 for cycles 3-6, and on Day 1 for cycles 7-24 of a 28-day cycle. Participants will also receive VCd (cyclophosphamide 300 milligrams per meter square [mg/m^2] either orally or intravenously [IV], bortezomib 1.3 mg/m^2 SC, dexamethasone 40 mg weekly either orally or IV) weekly starting at Cycle 1 Day 1 up to Day 22 in every 28-day cycle for a maximum of 6 cycles (Cycle 6 Day 22).
  • Drug: Daratumumab
    Daratumumab will be administered subcutaneously.
    Other names:
    • JNJ-54767414
  • Drug: Cyclophosphamide
    Cyclophosphamide will be administered either orally or IV.
  • Drug: Bortezomib
    Bortezomib will be administered by SC injection.
  • Drug: Dexamethasone
    Dexamethasone will be administered orally or IV.

Recruiting Locations

Boston University Medical Center
Boston, Massachusetts 02118

More Details

Status
Recruiting
Sponsor
Janssen Research & Development, LLC

Study Contact

Study Contact
844-434-4210
Participate-In-This-Study@its.jnj.com

Detailed Description

AL amyloidosis is a rare disorder caused by clonal plasma cells that secrete immunoglobulin light chains that misfold into insoluble amyloid. The insoluble amyloid gets deposited in vital organs which results in serious and life-threatening organ dysfunction. Daratumumab is a human immunoglobulin (IgG1K) monoclonal antibody (mAb) that binds with high affinity to a unique epitope on cluster of differentiation 38 (CD38), a transmembrane glycoprotein. It is a targeted immunotherapy directed towards tumor cells that overexpress CD38. Participants will be enrolled into 2 cohorts based on cardiac involvement at baseline for cohort 1 and racial or ethnic minority with at least one organ involved for cohort 2. This study aims to generate data on risk factors for cardiac toxicity and to evaluate the cardiac safety of the proposed treatment regimens and identify potential mitigation strategies for cardiac toxicity such as deferred VCd treatment, The study will consist of screening phase (up to 28 days) and treatment phase with up to 24 treatment cycles (each cycle is 28 days). Safety assessment will include adverse events (AEs), serious adverse events (SAEs), physical examinations, Eastern Cooperative Oncology Group (ECOG) criteria for performance status, laboratory tests and vital signs. The overall duration of the study will be up to 3 years and 8 months.