A Randomized, Open-label, Phase 3 Study Comparing Once-weekly vs Twice-weekly Carfilzomib in Combination With Lenalidomide and Dexamethasone in Subjects With Relapsed or Refractory Multiple Myeloma (A.R.R.O.W.2)
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 发起方
- Amgen
- 入组人数
- 454
- 试验地点
- 108
- 主要终点
- Overall Response Rate (ORR) Per International Myeloma Working Group Uniform Response Criteria (IMWG-URC)
研究概览
简要总结
Compare efficacy of 56 mg/m2 carfilzomib administered once-weekly in combination with lenalidomide and dexamethasone (KRd 56 mg/m2) to 27 mg/m2 carfilzomib administered twice-weekly in combination with lenalidomide and dexamethasone (KRd 27 mg/m2) in subjects with relapsed or refractory multiple myeloma (RRMM) with 1 to 3 prior lines of therapy.
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 99 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Multiple myeloma with documented relapse or progression after most recent myeloma treatment. Subjects refractory to the most recent line of therapy are eligible, unless last treatment contained proteasome inhibitor (PI) or lenalidomide and dexamethasone. Refractory is defined as disease that is nonresponsive or progresses within 60 days of last therapy.
- •Subjects must have at least PR to at least 1 line of prior therapy.
- •Subjects must have received at least 1 but not more than 3 prior lines of therapy for multiple myeloma (induction therapy followed by stem cell transplant and consolidation maintenance therapy will be considered as 1 line of therapy).
- •Prior therapy with a PI or the combination of lenalidomide and dexamethasone are allowed if the patient had at least a PR to the most recent treatment with a PI or lenalidomide and dexamethasone, neither PI or lenalidomide and dexamethasone containing treatment were ceased due to toxicity, the patient has not relapsed within 60 days of discontinuation of the PI or lenalidomide and dexamethasone containing treatment. A history of prior neuropathy is permitted if this was not grade 3, grade 4 or grade 2 with pain and if not resolved within the 14 days before enrollment, is less than or equal to grade 2 without pain. Patients are permitted to have received single agent lenalidomide as maintenance therapy within 60 days of enrollment.
- •Previous treatment with a lenalidomide and dexamethasone containing regimen is allowed, as long as the subject did not progress during the first 3 months after initiating lenalidomide and dexamethasone containing therapy.
- •Measurable disease with at least 1 of the following assessed within 21 days prior to randomization:
- •Immunoglobulin G (IgG) multiple myeloma: serum monoclonal protein (M-protein) level ≥ 1.0 g/dL
- •Immunoglobulin A (IgA), Immunoglobulin D (IgD), Immunoglobulin E (IgE) multiple myeloma: serum M-protein level ≥ 0.5 g/dL
- •Urine M-protein ≥ 200 mg per 24 hours
- •In subjects without measurable serum or urine M-protein, serum-free light chain (SFLC) ≥ 100 mg/L (involved light chain) and an abnormal serum kappa lambda ratio
- •Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 ≤ 2
- •Other inclusion criteria may apply
排除标准
- •Waldenström macroglobulinemia.
- •Multiple myeloma of Immunoglobulin M (IgM) subtype.
- •Plasma cell leukemia (> 2.0 × 10^9 /L circulating plasma cells by standard differential).
- •Uncontrolled hypertension, defined as a subject whose blood pressure is greater than or equal to 160 mmHg systolic or greater than or equal to 100 mmHg diastolic when taken in accordance with the European Society of Hypertension/European Society of Cardiology 2018 guidelines (Section 12.10; Williams et al, 2018).
- •Active congestive heart failure (New York Heart Association Class III to IV), symptomatic ischemia, uncontrolled arrhythmias, screening ECG with corrected QT interval (QTc) of > 470 msec, pericardial disease, or myocardial infarction within 4 months prior to randomization.
- •Calculated or measured creatinine clearance < 30 mL/min (calculation must be based on the Cockcroft and Gault formula) within 28 days prior to randomization.
- •Other exclusion criteria may apply
研究组 & 干预措施
Carfilzomib once-weekly
Carfilzomib, lenalidomide, dexamethasone (KRd) regimen using once-weekly carfilzomib 56 mg/m2
干预措施: Carfilzomib (Drug)
Carfilzomib once-weekly
Carfilzomib, lenalidomide, dexamethasone (KRd) regimen using once-weekly carfilzomib 56 mg/m2
干预措施: Lenalidomide (Drug)
Carfilzomib once-weekly
Carfilzomib, lenalidomide, dexamethasone (KRd) regimen using once-weekly carfilzomib 56 mg/m2
干预措施: Dexamethasone (Drug)
Carfilzomib twice-weekly
Carfilzomib, lenalidomide, dexamethasone (KRd) regimen using twice-weekly carfilzomib 27 mg/m2
干预措施: Carfilzomib (Drug)
Carfilzomib twice-weekly
Carfilzomib, lenalidomide, dexamethasone (KRd) regimen using twice-weekly carfilzomib 27 mg/m2
干预措施: Lenalidomide (Drug)
Carfilzomib twice-weekly
Carfilzomib, lenalidomide, dexamethasone (KRd) regimen using twice-weekly carfilzomib 27 mg/m2
干预措施: Dexamethasone (Drug)
结局指标
主要结局
Overall Response Rate (ORR) Per International Myeloma Working Group Uniform Response Criteria (IMWG-URC)
时间窗: Cycle 1 Day 1 up to approximately 12 months (cycle = 28 days); median treatment duration for the twice-weekly arm was 47.00 weeks and for the once-weekly arm was 47.14 weeks.
ORR was defined as the percentage of participants with a best overall response of stringent complete response (sCR), complete response (CR), very good partial response (VGPR), or partial response (PR) per IMWG-URC. CR: negative immunofixation on serum and urine, soft tissue plasmacytomas disappearance, \< 5% plasma cells in bone marrow (BM). sCR: CR and normal serum free light chain ratio and no clonal cells in BM by immunohistochemistry. VGPR: Serum and urine M-protein detectable by immunofixation or ≥ 90% reduction in serum M-protein (urine M-protein level \< 100 mg/24-hours). PR: ≥ 50% reduction of serum M-protein and reduction in 24-hours urinary M-protein by ≥ 90% or to \< 200 mg/24-hours. The ORR 95% confidence intervals (CIs) were estimated using the Clopper-Pearson method.
次要结局
- Kaplan-Meier Estimate of Progression-free Survival (PFS) Rate at 12 Months(12 months)
- Percentage of Participants Who Reported Convenience as Measured by the Patient-reported Convenience With Carfilzomib-dosing Schedule Question(Day 28 of Cycle 4)
- Number of Participants With Treatment-emergent Adverse Events (TEAEs)(Cycle 1 Day 1 up to end of Cycle 12 + 30 days, where each cycle was 28 days; median treatment duration (any study treatment) was 47.00 weeks in the twice-weekly KRd group and 47.14 weeks in the once-weekly KRd group)
- Time to Response (TTR)(Cycle 1 Day 1 up to approximately 12 months (cycle = 28 days); median treatment duration for the twice-weekly arm was 47.00 weeks and for the once-weekly arm was 47.14 weeks.)
- Patient-reported Treatment Satisfaction as Measured by the Cancer Therapy Satisfaction Questionnaire (CTSQ)(Cycle 5 Day 1, Cycle 12 Day 1, and safety follow-up (30 days after last dose))
- Kaplan-Meier Estimate of Duration of Response (DOR)(Cycle 1 Day 1 up to approximately 12 months (cycle = 28 days); median treatment duration for the twice-weekly arm was 47.00 weeks and for the once-weekly arm was 47.14 weeks.)
- Percentage of Participants With Minimal Residual Disease Negativity (MRD[-]) by IRC Per IMWG-URC at 12 Months(Cycle 1 Day 1 up to 12 months (cycle = 28 days))
- Kaplan-Meier Estimate of Time to Progression (TTP)(Cycle 1 Day 1 up to approximately 12 months (cycle = 28 days); median treatment duration for the twice-weekly arm was 47.00 weeks and for the once-weekly arm was 47.14 weeks.)
- Percentage of Participants Who Achieved Minimal Residual Disease Negative Complete Response (MRD[-]CR) by Independent Review Committee (IRC) Per IMWG-URC(Cycle 1 Day 1 up to approximately 12 months (cycle = 28 days); median treatment duration for the twice-weekly arm was 47.00 weeks and for the once-weekly arm was 47.14 weeks.)
- Change From Baseline in EORTC QLQ-C30 Role Functioning Scale(Baseline (Cycle 1 Day 1), Cycle 3 Day 1, Cycle 5 Day 1, Cycle 7 Day 1, Cycle 9 Day 1, Cycle 12 Day 1, and safety follow-up (30 days after last dose))
- Kaplan-Meier Estimate of Overall Survival (OS)(Cycle 1 Day 1 up to approximately 12 months (cycle = 28 days); median treatment duration for the twice-weekly arm was 47.00 weeks and for the once-weekly arm was 47.14 weeks.)
- Change From Baseline in European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire (EORTC QLQ)-Core 30 (C30) Physical Functioning Scale(Baseline (Cycle 1 Day 1), Cycle 3 Day 1, Cycle 5 Day 1, Cycle 7 Day 1, Cycle 9 Day 1, Cycle 12 Day 1, and safety follow-up (30 days after last dose))