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

Study Overview
=================
Brief Summary
-----------------
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).

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.

Official Title
-----------------
A Phase 2, Multicohort Study of Daratumumab-Based Therapies in Participants With Amyloid Light Chain (AL) Amyloidosis

Conditions
-----------------
Amyloidosis

Intervention / Treatment
-----------------
* Drug: Daratumumab
* Drug: Cyclophosphamide
* Drug: Bortezomib
* Drug: Dexamethasone


Participation Criteria
=================
Eligibility Criteria
-----------------
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: treatment with an investigational drug or used an invasive investigational medical device within 14 days or at least 5 half-lives, whichever is less; 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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort1 (Arm A): Immediate Daratumumab + Cyclophosphamide, Bortezomib and Dexamethasone (VCd)<br>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<br>* Daratumumab will be administered subcutaneously.<br>* Other names: JNJ-54767414;Drug: Cyclophosphamide<br>* Cyclophosphamide will be administered either orally or IV.<br>Drug: Bortezomib<br>* Bortezomib will be administered by SC injection.<br>Drug: Dexamethasone<br>* Dexamethasone will be administered orally or IV.<br>|
| Experimental: Cohort1 (Arm B): Daratumumab + Deferred VCd<br>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<br>* Daratumumab will be administered subcutaneously.<br>* Other names: JNJ-54767414;Drug: Cyclophosphamide<br>* Cyclophosphamide will be administered either orally or IV.<br>Drug: Bortezomib<br>* Bortezomib will be administered by SC injection.<br>Drug: Dexamethasone<br>* Dexamethasone will be administered orally or IV.<br>|
| Experimental: Cohort 2: Daratumumab + VCd<br>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<br>* Daratumumab will be administered subcutaneously.<br>* Other names: JNJ-54767414;Drug: Cyclophosphamide<br>* Cyclophosphamide will be administered either orally or IV.<br>Drug: Bortezomib<br>* Bortezomib will be administered by SC injection.<br>Drug: Dexamethasone<br>* Dexamethasone will be administered orally or IV.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants with Cardiac Events of Any Toxicity Grade | Number of participants with cardiac events of any toxicity grade will be reported. | Up to 12 months | 
| Observed Concentration Immediately Prior to the Next Study Treatment Administration (Ctrough) | Ctrough is defined as the observed concentration immediately prior to the next study treatment administration. | Cycle 3 Day 1 predose (each cycle is of 28 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Complete Hematologic Response (HemCR) Rate | Overall HemCR rate is defined as percentage of participants who achieve HemCR during or after the study treatment. | Up to 3 years | 
| HemCR Rate | HemCR rate at 6 month is defined as percentage of participants who achieve HemCR at 6 month during or after the study treatment. | At 6 months | 
| Very Good Partial Response (VGPR) or Better Rate | Hematologic greater than or equal to (>=) VGPR rate is defined as percentage of participants who achieve hematologic response of VGPR or better. | Up to 3 Years | 
| Time to HemCR or (VGPR or Better) | For participants who achieve HemCR (or >=VGPR), time to HemCR (or >=VGPR) is defined as the time between the date of randomization (Cohort1)/first treatment (Cohort 2) and the first efficacy evaluation at which the participant has met all criteria for hematologic complete response (CR) (or >=VGPR). | Up to 3 years | 
| Duration of Response (HemCR and VGPR or Better) | 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. | Up to 3 years | 
| Organ Response Rate (OrRR) | Organ response rate is defined as the percentage of participants who achieve organ response in each corresponding organ (kidney, heart, liver). | Up to 3 years | 
| Overall Survival (OS) | OS is measured from the date of randomization (Cohort 1)/first treatment (Cohort 2) to the date of the participant's death. | Up to 3 years | 
| Time to Next Treatment (TNT) | TNT for amyloid light chain (AL) amyloidosis is defined as the time from the date of randomization (Cohort1)/first treatment (Cohort 2) to the start date of subsequent AL amyloidosis (non-protocol) treatment. | Up to 3 Years | 
| Number of Participants with Adverse Events (AEs) by Severity | 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. | Up to 3 Years | 
| Serum Concentration of Daratumumab | Serum samples will be analyzed to determine concentrations of daratumumab. | Up to 3 Years | 
| Number of Participants with Antibodies to Daratumumab | Number of participants with antibodies to daratumumab will be reported. | Up to 3 years | 
| Number of Participants with Antibodies to Recombinant Human Hyaluronidase PH20 Enzyme (rHuPH20) | Number of participants with antibodies to rHuPH20 will be reported. | Up to 3 years | 
| Change from Baseline in Clinical Signs and Symptoms Score of Cardiac AL Amyloidosis | Change from baseline in clinical signs and symptoms score of cardiac AL amyloidosis will be reported. | Baseline up to 3 Years |