Amyloidosis
Conditions
Brief summary
The purpose of this study is to characterize cardiac safety of Daratumumab, Cyclophosphamide, Bortezomib, and Dexamethasone (D-VCd) treatment regimens (Arm A: daratumumab + immediate 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).
Interventions
DRUGDaratumumab
Daratumumab will be administered subcutaneously.
DRUGCyclophosphamide
Cyclophosphamide will be administered either orally or IV.
DRUGBortezomib
Bortezomib will be administered by SC injection or IV.
DRUGDexamethasone
Dexamethasone will be administered orally or IV.
Sponsors
Janssen Research & Development, LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Participants of Cohort 1 will be randomized to either Arm A or Arm B of Cohort 1 in a 2:1 ratio. For Cohort 2, participants will be enrolled without randomization.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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 * Measurable disease at screening defined by one of the following: Difference between iFLC and uninvolved FLC (dFLC) \>= 40mg/L per central laboratory Serum involved free light chain (iFLC) \>= 40 mg/L with an abnormal kappa:lambda ratio Serum M-protein \>= 0.5 g/dL
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, including the presence of lytic bone disease, plasmacytomas, \>=60% plasma cells in the bone marrow, or hypercalcemia related to myeloma. * 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Observed Concentration Immediately Prior to the Next Study Treatment Administration (Ctrough) of Daratumumab | Cycle 3 Day 1 predose (each cycle is of 28 days) | Ctrough is defined as the observed concentration immediately prior to the next study treatment administration. |
| Number of Participants with Cardiac Events of Any Toxicity Grade | Up to 12 months | Number of participants with cardiac events of any toxicity grade will be reported. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Serum Concentration of Daratumumab | Up to 3 years | Serum samples will be analyzed to determine concentrations of daratumumab. |
| Number of Participants with Antibodies to Daratumumab | Up to Cycle 12 or Month 12 (whichever occurs later) | Number of participants with antibodies to daratumumab will be reported. |
| Number of Participants with Antibodies to Recombinant Human Hyaluronidase PH20 Enzyme (rHuPH20) | Up to Cycle 12 or Month 12 (whichever occurs later) | Number of participants with antibodies to rHuPH20 will be reported. |
| Change from Baseline in Clinical Signs and Symptoms Score of Cardiac AL Amyloidosis | Up to Cycle 12 or Month 12 (whichever occurs later) | Change from baseline in clinical signs and symptoms score of cardiac AL amyloidosis will be reported. |
| Overall Complete Hematologic Response (HemCR) Rate | Up to Cycle 12 or Month 12 (whichever occurs later) | Overall HemCR rate is defined as percentage of participants who achieve HemCR during or after the study treatment. |
| HemCR Rate | At 6 months | HemCR rate at 6 month is defined as percentage of participants who achieve HemCR at 6 month during or after the study treatment. |
| Very Good Partial Response (VGPR) or Better Rate | Up to Cycle 12 or Month 12 (whichever occurs later) | Hematologic greater than or equal to (\>=) VGPR rate is defined as percentage of participants who achieve hematologic response of VGPR or better. |
| Time to HemCR or (VGPR or Better) | Up to Cycle 12 or Month 12 (whichever occurs later) | For participants who achieve HemCR (or \>=VGPR), time to HemCR (or \>=VGPR) is defined as the time between the date of first study treatment and the first efficacy evaluation at which the participant has met all criteria for hematologic complete response (CR) (or \>=VGPR). |
| Duration of Response (HemCR and VGPR or Better) | Up to Cycle 12 or Month 12 (whichever occurs later) | For participants who achieve HemCR (or \>=VGPR), duration of HemCR (or \>=VGPR) is defined as the time between the date of initial documentation of HemCR (or \>=VGPR) to the date of first documented evidence of hematologic progressive disease or death, whichever comes first. |
| Organ Response Rate (OrRR) | Up to Cycle 12 or Month 12 (whichever occurs later) | Organ response rate is defined as the percentage of participants who achieve organ response in each corresponding organ (kidney, heart, liver). |
| Time to Subsequent Therapy | Up to Cycle 12 or Month 12 (whichever occurs later) | Time to subsequent therapy for amyloid light chain (AL) amyloidosis is defined as the time from the date of first study treatment to the start date of subsequent AL amyloidosis (non-protocol) treatment. |
| Overall Survival (OS) | Until Cycle 12 or Month 12 (whichever occurs later) | OS is measured from the date of first study treatment to the date of the participant's death. |
| Number of Participants with Adverse Events (AEs) by Severity | Up to Cycle 12 or Month 12 (whichever occurs later) | Number of participants with AEs by severity will be reported. An AE is any untoward medical occurrence in a participant participating in a clinical study that does not necessarily have a causal relationship with the pharmaceutical/ biological agent under study. |
Countries
Canada, China, France, Germany, Greece, Italy, Netherlands, Spain, United Kingdom, United States
Contacts
STUDY_DIRECTORJanssen Research & Development, LLC Clinical Trial
Janssen Research & Development, LLC
Outcome results
None listed