A Study of Daratumumab-Based Therapies in Participants With Amyloid Light Chain (AL) Amyloidosis
- Conditions
- Amyloidosis
- Interventions
- Registration Number
- NCT05250973
- Lead Sponsor
- Janssen Research & Development, LLC
- 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).
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 150
- 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
-
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:
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Cohort1 (Arm A): Daratumumab + Immediate Cyclophosphamide, Bortezomib and Dexamethasone (VCd) Daratumumab 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 or IV, 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). Cohort1 (Arm A): Daratumumab + Immediate Cyclophosphamide, Bortezomib and Dexamethasone (VCd) Cyclophosphamide 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 or IV, 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). Cohort1 (Arm A): Daratumumab + Immediate Cyclophosphamide, Bortezomib and Dexamethasone (VCd) Bortezomib 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 or IV, 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). Cohort1 (Arm A): Daratumumab + Immediate Cyclophosphamide, Bortezomib and Dexamethasone (VCd) Dexamethasone 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 or IV, 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). Cohort1 (Arm B): Daratumumab + Deferred VCd Daratumumab 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 or IV, 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). Cohort1 (Arm B): Daratumumab + Deferred VCd Cyclophosphamide 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 or IV, 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). Cohort1 (Arm B): Daratumumab + Deferred VCd Bortezomib 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 or IV, 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). Cohort1 (Arm B): Daratumumab + Deferred VCd Dexamethasone 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 or IV, 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). Cohort 2: Daratumumab + VCd Daratumumab 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 or IV, 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). Cohort 2: Daratumumab + VCd Cyclophosphamide 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 or IV, 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). Cohort 2: Daratumumab + VCd Bortezomib 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 or IV, 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). Cohort 2: Daratumumab + VCd Dexamethasone 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 or IV, 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).
- Primary Outcome Measures
Name Time Method 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.
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.
- Secondary Outcome Measures
Name Time Method 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).
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.
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.
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.
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.
Trial Locations
- Locations (45)
West Penn Hospital
🇺🇸Pittsburgh, Pennsylvania, United States
University of Washington
🇺🇸Seattle, Washington, United States
University College Hospital
🇬🇧London, United Kingdom
Hosp Clinico Univ de Salamanca
🇪🇸Salamanca, Spain
Leicester Royal Infirmary - Haematology
🇬🇧Leicester, United Kingdom
Clinica Univ. de Navarra
🇪🇸Pamplona, Spain
West China Hospital Si Chuan University
🇨🇳Chengdu, China
UMC Utrecht
🇳🇱Utrecht, Netherlands
Hospital Maastricht University Medical Center
🇳🇱Maastricht, Netherlands
Barbara Ann Karmanos Cancer Institute
🇺🇸Detroit, Michigan, United States
Moffitt Cancer Center
🇺🇸Tampa, Florida, United States
Winship Cancer Institute Emory University
🇺🇸Atlanta, Georgia, United States
Tufts Medical Center
🇺🇸Boston, Massachusetts, United States
Levine Cancer Institute
🇺🇸Charlotte, North Carolina, United States
University Hospital of Cleveland
🇺🇸Cleveland, Ohio, United States
UT Southwestern Medical Center
🇺🇸Dallas, Texas, United States
Ohio Health Research Institute
🇺🇸Columbus, Ohio, United States
VCU Medical Center
🇺🇸Richmond, Virginia, United States
Cross Cancer Institute
🇨🇦Edmonton, Alberta, Canada
University Health Network UHN Princess Margaret Cancer Centre
🇨🇦Toronto, Ontario, Canada
Peking University First Hospital
🇨🇳Beijing, China
Peking University People s Hospital
🇨🇳Beijing, China
First affiliated Hospital of Zhejiang University
🇨🇳Hangzhou, China
Ruijin Hospital Shanghai Jiao Tong University
🇨🇳Shanghai, China
CHU de Limoges
🇫🇷Limoges Cedex, France
Centre hospitalier Lyon-Sud
🇫🇷Pierre Benite cedex, France
CHU De Poitiers
🇫🇷Poitiers, France
CHU Rangueil
🇫🇷Toulouse, France
Universitatsklinikum Essen
🇩🇪Essen, Germany
Charite Campus Benjamin Franklin
🇩🇪Berlin, Germany
Alexandra General Hospital of Athens
🇬🇷Athens, Greece
Universitaetsklinikum Heidelberg Medizinische Klinik V
🇩🇪Heidelberg, Germany
Università Degli Studi Di Napoli Federico Ii
🇮🇹Napoli, Italy
Fondazione IRCCS Policlinico San Matteo
🇮🇹Pavia, Italy
DIPARTIMENTO DI BIOTECNOLOGIE CELLULARI ED EMATOLOGIA - UNIVERSITà ''LA SAPIENZA''
🇮🇹Roma, Italy
University Medical Center Groningen
🇳🇱Groningen, Netherlands
Hosp Univ Vall D Hebron
🇪🇸Barcelona, Spain
Hosp. Univ. Germans Trias I Pujol
🇪🇸Badalona, Spain
Boston University Medical Center
🇺🇸Boston, Massachusetts, United States
Hosp Clinic de Barcelona
🇪🇸Barcelona, Spain
City of Hope
🇺🇸Duarte, California, United States
Smilow Cancer Hospital/Yale Cancer Center
🇺🇸New Haven, Connecticut, United States
Memorial Sloan Kettering
🇺🇸New York, New York, United States
Tom Baker Cancer Center
🇨🇦Calgary, Alberta, Canada
Wake Forest University - Baptist Medical Center
🇺🇸Winston-Salem, North Carolina, United States