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

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

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).

Study Overview

• Status: Recruiting
• Conditions: Amyloidosis
• Intervention / Treatment: Drug: Daratumumab; Drug: Cyclophosphamide; Drug: Bortezomib; Drug: Dexamethasone

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.

• Study Type: Interventional
• Enrollment (Estimated): 150
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Study Contact; Phone Number: 844-434-4210; Email: Participate-In-This-Study@its.jnj.com

Study Locations

• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 4N2
      • Recruiting
      • Tom Baker Cancer Center
    • Edmonton, Alberta, Canada, T6G 1Z2
      • Recruiting
      • Cross Cancer Institute
  • Ontario
    • Toronto, Ontario, Canada, M5G 2M9
      • Recruiting
      • University Health Network (UHN) Princess Margaret Cancer Centre
• China
  • Beijing, China, 100034
    • Recruiting
    • Peking University First Hospital
  • Beijing, China, 100044
    • Recruiting
    • Peking University People's Hospital
  • Chengdu, China, 610041
    • Recruiting
    • West China Hospital, Si Chuan University
  • Hangzhou, China, 310020
    • Recruiting
    • First Affiliated Hospital of Zhejiang University
  • Shanghai, China, 200025
    • Recruiting
    • Ruijin Hospital, Shanghai Jiao Tong University
• France
  • Limoges Cedex, France, 87042
    • Recruiting
    • CHU de Limoges
  • Pierre Benite cedex, France, 69495
    • Recruiting
    • Centre Hospitalier Lyon-Sud
  • Poitiers, France, 86000
    • Recruiting
    • CHU de Poitiers
  • Toulouse, France, 31400
    • Recruiting
    • CHU Rangueil
• Germany
  • Berlin, Germany, 12203
    • Recruiting
    • Charite Campus Benjamin Franklin
  • Essen, Germany, 45122
    • Completed
    • Universitätsklinikum Essen
  • Heidelberg, Germany, 69120
    • Recruiting
    • Universitaetsklinikum Heidelberg Medizinische Klinik V
• Greece
  • Athens, Greece, 11528
    • Recruiting
    • Alexandra General Hospital of Athens
• Italy
  • Napoli, Italy, 80131
    • Recruiting
    • Università degli Studi di Napoli Federico II
  • Pavia, Italy, 27100
    • Recruiting
    • Fondazione IRCCS Policlinico San Matteo
  • Roma, Italy, 00161
    • Completed
    • DIPARTIMENTO DI BIOTECNOLOGIE CELLULARI ED EMATOLOGIA - UNIVERSITà ''LA SAPIENZA''
• Netherlands
  • Groningen, Netherlands, 9713 GZ
    • Recruiting
    • University Medical Center Groningen
  • Maastricht, Netherlands, 6229 HX
    • Recruiting
    • Hospital Maastricht University Medical Center
  • Utrecht, Netherlands, 3584 CX
    • Recruiting
    • UMC Utrecht
• Spain
  • Badalona, Spain, 08916
    • Recruiting
    • Hosp. Univ. Germans Trias I Pujol
  • Barcelona, Spain, 08035
    • Recruiting
    • Hosp. Univ. Vall D Hebron
  • Barcelona, Spain, 08036
    • Recruiting
    • Hosp. Clinic de Barcelona
  • Madrid, Spain, 28027
    • Recruiting
    • Clinica Univ. de Navarra
  • Pamplona, Spain, 31008
    • Recruiting
    • Clinica Univ. de Navarra
  • Salamanca, Spain, 37007
    • Recruiting
    • Hosp. Clinico Univ. de Salamanca
• United Kingdom
  • Leicester, United Kingdom, LE1 5WW
    • Recruiting
    • Leicester Royal Infirmary - Haematology
  • London, United Kingdom, NW1 2PG
    • Recruiting
    • University College Hospital
• United States
  • California
    • Duarte, California, United States, 91010
      • Recruiting
      • City of Hope
  • Connecticut
    • New Haven, Connecticut, United States, 06510
      • Recruiting
      • Smilow Cancer Hospital/Yale Cancer Center
  • Florida
    • Tampa, Florida, United States, 33612
      • Recruiting
      • Moffitt Cancer Center
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Recruiting
      • Winship Cancer Institute Emory University
  • Massachusetts
    • Boston, Massachusetts, United States, 02111
      • Recruiting
      • Tufts Medical Center
    • Boston, Massachusetts, United States, 02118
      • Recruiting
      • Boston University Medical Center
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Recruiting
      • Barbara Ann Karmanos Cancer Institute
  • New York
    • New York, New York, United States, 10021
      • Recruiting
      • Memorial Sloan Kettering
  • North Carolina
    • Charlotte, North Carolina, United States, 28204
      • Recruiting
      • Levine Cancer Institute
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • Recruiting
      • University Hospital of Cleveland
    • Columbus, Ohio, United States, 43214
      • Recruiting
      • Ohio Health Research Institute
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15224
      • Recruiting
      • West Penn Hospital
  • Washington
    • Seattle, Washington, United States, 90805
      • Recruiting
      • University of Washington

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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.

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

Collaborators and Investigators

• Sponsor: Janssen Research & Development, LLC
• Investigators: Study Director: Janssen Research & Development, LLC Clinical Trial, Janssen Research & Development, LLC

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2022
• Primary Completion (Estimated): November 29, 2024
• Study Completion (Estimated): December 31, 2027

Study Registration Dates

• First Submitted: February 11, 2022
• First Submitted That Met QC Criteria: February 11, 2022
• First Posted (Actual): February 22, 2022

Study Record Updates

• Last Update Posted (Actual): March 27, 2024
• Last Update Submitted That Met QC Criteria: March 26, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Metabolic Diseases; Proteostasis Deficiencies; Amyloidosis; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Anti-Inflammatory Agents; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Dexamethasone; Cyclophosphamide; Daratumumab; Bortezomib
• Other Study ID Numbers: CR109160; 2021-002639-48 (EudraCT Number); 54767414AMY2009 (Other Identifier: Janssen Research & Development, LLC)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The data sharing policy of the Janssen Pharmaceutical Companies of Johnson & Johnson is available at www.janssen.com/clinical-trials/transparency. As noted on this site, requests for access to the study data can be submitted through Yale Open Data Access (YODA) Project site at yoda.yale.edu

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No