A Phase 2, Multicohort Study of Daratumumab-Based Therapies in Participants With Amyloid Light Chain (AL) Amyloidosis
试验速览
- 阶段
- 2 期
- 状态
- 进行中（未招募）
- 入组人数
- 151
- 试验地点
- 90
- 主要终点
- Number of Participants with Cardiac Events of Any Toxicity Grade
研究概览
简要总结
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).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
Cohort1 (Arm A): Daratumumab + Immediate 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 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).
干预措施: Daratumumab (Drug)
Cohort1 (Arm A): Daratumumab + Immediate 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 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).
干预措施: Dexamethasone (Drug)
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 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).
干预措施: Daratumumab (Drug)
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 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).
干预措施: Cyclophosphamide (Drug)
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 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).
干预措施: Bortezomib (Drug)
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 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).
干预措施: Cyclophosphamide (Drug)
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 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).
干预措施: Bortezomib (Drug)
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 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).
干预措施: Dexamethasone (Drug)
Cohort1 (Arm A): Daratumumab + Immediate 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 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).
干预措施: Cyclophosphamide (Drug)
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 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).
干预措施: Dexamethasone (Drug)
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 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).
干预措施: Daratumumab (Drug)
Cohort1 (Arm A): Daratumumab + Immediate 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 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).
干预措施: Bortezomib (Drug)
结局指标
主要结局
Number of Participants with Cardiac Events of Any Toxicity Grade
时间窗: 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
时间窗: 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.
次要结局
- Number of Participants with Antibodies to Daratumumab(Up to Cycle 12 or Month 12 (whichever occurs later))
- Number of Participants with Antibodies to Recombinant Human Hyaluronidase PH20 Enzyme (rHuPH20)(Up to Cycle 12 or Month 12 (whichever occurs later))
- Change from Baseline in Clinical Signs and Symptoms Score of Cardiac AL Amyloidosis(Up to Cycle 12 or Month 12 (whichever occurs later))
- Very Good Partial Response (VGPR) or Better Rate(Up to Cycle 12 or Month 12 (whichever occurs later))
- Overall Complete Hematologic Response (HemCR) Rate(Up to Cycle 12 or Month 12 (whichever occurs later))
- HemCR Rate(At 6 months)
- Duration of Response (HemCR and VGPR or Better)(Up to Cycle 12 or Month 12 (whichever occurs later))
- Time to HemCR or (VGPR or Better)(Up to Cycle 12 or Month 12 (whichever occurs later))
- Organ Response Rate (OrRR)(Up to Cycle 12 or Month 12 (whichever occurs later))
- Overall Survival (OS)(Until Cycle 12 or Month 12 (whichever occurs later))
- Time to Subsequent Therapy(Up to Cycle 12 or Month 12 (whichever occurs later))
- Number of Participants with Adverse Events (AEs) by Severity(Up to Cycle 12 or Month 12 (whichever occurs later))
- Serum Concentration of Daratumumab(Up to 3 years)