A Phase 1b/2 Trial to Evaluate the Safety and Efficacy of Radium-223 Dichloride (BAY88-8223) in Combination With Bortezomib and Dexamethasone in Early Relapsed Multiple Myeloma
试验速览
- 阶段
- 1 期
- 状态
- 撤回
- 发起方
- Bayer
- 主要终点
- Progression-free survival (PFS) in Phase 2, defined as the time (in days) from date of randomization to disease progression
研究概览
简要总结
This study will be conducted in 2 parts. The phase 1b part will be an international, phase 1b, open-label, dose-escalation assessment of radium-223 dichloride administered with bortezomib and dexamethasone in subjects with relapsed multiple myeloma. The primary endpoint of the phase 1b part is to determine the optimal dose of radium-223 dichloride in combination with bortezomib/dexamethasone for the Phase 2 portion of the study.
The phase 2 part will be an international, phase 2, double-blind, randomized, placebo-controlled assessment of radium-223 dichloride versus placebo administered with bortezomib and dexamethasone, in subjects with relapsed multiple myeloma. Randomization (1:1) in the phase 2 part will be stratified by:
- Prior bortezomib treatment (yes, no)
- Prior treatment (1 prior line of treatment, >1 prior line of treatment) Approximately 30 subjects (10 subjects per cohort) will be enrolled in the phase 1b part of the study and approximately 196 subjects will be enrolled in the phase 2 part of the study.
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
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
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
- •Cytologically or histologically confirmed diagnosis of multiple myeloma
- •Subjects must have received at least 1 and not more than 3 previous lines of treatment and have had a response to treatment (i.e., achieved a minimal response [MR] or better) according to the International Myeloma Working Group (IMWG) uniform response criteria
- •Subjects must have had progressive disease according to the IMWG uniform response criteria following the last multiple myeloma treatment
- •Subjects must have measurable disease defined as at least 1 of the following (according to central laboratory results):
- •Serum M-protein ≥1 g/dL
- •Urine M-protein ≥200 mg/24 hours
- •Serum free light chain (FLC) ≥10 mg/dL with abnormal ratio
- •≥1 bone lesion identifiable by radiograph, computed tomography, magnetic resonance imaging, or bone scintigraphy
- •Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0-2
- •Subjects must be nonrefractory to bortezomib and had no progression during or within 60 days after completion of bortezomib
- •Absolute neutrophil count (ANC) ≥1.5 × 10e9/L, hemoglobin (Hb) ≥9.0 g/dL, and platelet count ≥75.0 × 10e9/L independent of transfusion of red blood cells (RBC) or platelet concentrates and independent of granulocyte colony stimulating factor (G-CSF) or granulocyte macrophage colony stimulating factor (GM-CSF)
排除标准
- •Systemic glucocorticoid therapy (prednisone >10 mg/day orally or equivalent) within the last 4 weeks prior to first dose, unless tapered and on a stable dose ≤10 mg/day for at least 1 week
- •Subjects with known POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes) or light chain (AL) amyloidosis
- •Plasma cell leukemia
- •Systemic anti-cancer therapy within 4 weeks prior to first dose
- •Radiation therapy in the previous 4 weeks prior to first dose except if given for pain management and involves less than 10% of the bone marrow
- •Prior treatment with radium-223 dichloride or any experimental radiopharmaceutical
- •Congestive heart failure (New York Heart Association [NYHA] class III to IV), symptomatic cardiac ischemia, cardiomyopathy, clinically relevant ventricular arrhythmia, pericardial disease, unstable angina or myocardial infarct in the previous 6 months prior to first dose, left ventricular ejection fraction <40%
- •Neuropathy ≥ Grade 2 or Grade 1 with pain
研究组 & 干预措施
Radium-223 dichloride [Phase 1, dose 1]
Phase 1: Radium-223 dichloride; 30 kiloBecquerel (kBq)/kg body weight (33 kBq/kg after implementation of National Institute of Standards and Technology [NIST] update) every 4 weeks for a total of 6 radium-223 dichloride doses plus SOC bortezomib/dexamethasone.
干预措施: Radium-223 dichloride (Xofigo, BAY88-8223) (Drug)
Radium-223 dichloride [Phase 1, dose 1]
Phase 1: Radium-223 dichloride; 30 kiloBecquerel (kBq)/kg body weight (33 kBq/kg after implementation of National Institute of Standards and Technology [NIST] update) every 4 weeks for a total of 6 radium-223 dichloride doses plus SOC bortezomib/dexamethasone.
干预措施: Bortezomib (Drug)
Radium-223 dichloride [Phase 1, dose 1]
Phase 1: Radium-223 dichloride; 30 kiloBecquerel (kBq)/kg body weight (33 kBq/kg after implementation of National Institute of Standards and Technology [NIST] update) every 4 weeks for a total of 6 radium-223 dichloride doses plus SOC bortezomib/dexamethasone.
干预措施: Dexamethasone (Drug)
Radium-223 dichloride [Phase 1, dose 2]
Phase 1: Radium-223 dichloride; 50 kBq/kg body weight (55 kBq/kg after implementation of NIST update) every 4 weeks for a total of 6 radium-223 dichloride doses plus SOC bortezomib/dexamethasone.
干预措施: Radium-223 dichloride (Xofigo, BAY88-8223) (Drug)
Radium-223 dichloride [Phase 1, dose 2]
Phase 1: Radium-223 dichloride; 50 kBq/kg body weight (55 kBq/kg after implementation of NIST update) every 4 weeks for a total of 6 radium-223 dichloride doses plus SOC bortezomib/dexamethasone.
干预措施: Bortezomib (Drug)
Radium-223 dichloride [Phase 1, dose 2]
Phase 1: Radium-223 dichloride; 50 kBq/kg body weight (55 kBq/kg after implementation of NIST update) every 4 weeks for a total of 6 radium-223 dichloride doses plus SOC bortezomib/dexamethasone.
干预措施: Dexamethasone (Drug)
Radium-223 dichloride [Phase 1, dose 3]
Phase 1: Radium-223 dichloride; 80 kBq/kg body weight (88 kBq/kg after implementation of NIST update) every 4 weeks for a total of 6 radium-223 dichloride doses plus SOC bortezomib/dexamethasone.
干预措施: Radium-223 dichloride (Xofigo, BAY88-8223) (Drug)
Radium-223 dichloride [Phase 1, dose 3]
Phase 1: Radium-223 dichloride; 80 kBq/kg body weight (88 kBq/kg after implementation of NIST update) every 4 weeks for a total of 6 radium-223 dichloride doses plus SOC bortezomib/dexamethasone.
干预措施: Bortezomib (Drug)
Radium-223 dichloride [Phase 1, dose 3]
Phase 1: Radium-223 dichloride; 80 kBq/kg body weight (88 kBq/kg after implementation of NIST update) every 4 weeks for a total of 6 radium-223 dichloride doses plus SOC bortezomib/dexamethasone.
干预措施: Dexamethasone (Drug)
Placebo +SoC [Phase 2]
Phase 2: Matching placebo (isotonic saline) every 4 weeks for a total of 6 doses plus SoC (Standard of care) bortezomib/dexamethasone.
干预措施: Placebo (Drug)
Placebo +SoC [Phase 2]
Phase 2: Matching placebo (isotonic saline) every 4 weeks for a total of 6 doses plus SoC (Standard of care) bortezomib/dexamethasone.
干预措施: Bortezomib (Drug)
Placebo +SoC [Phase 2]
Phase 2: Matching placebo (isotonic saline) every 4 weeks for a total of 6 doses plus SoC (Standard of care) bortezomib/dexamethasone.
干预措施: Dexamethasone (Drug)
Radium-223 dichloride + SoC [Phase 2]
Phase 2: Phase 1b-selected dose of radium-223 dichloride every 4 weeks for 6 doses plus SOC bortezomib/dexamethasone
干预措施: Radium-223 dichloride (Xofigo, BAY88-8223) (Drug)
Radium-223 dichloride + SoC [Phase 2]
Phase 2: Phase 1b-selected dose of radium-223 dichloride every 4 weeks for 6 doses plus SOC bortezomib/dexamethasone
干预措施: Bortezomib (Drug)
Radium-223 dichloride + SoC [Phase 2]
Phase 2: Phase 1b-selected dose of radium-223 dichloride every 4 weeks for 6 doses plus SOC bortezomib/dexamethasone
干预措施: Dexamethasone (Drug)
结局指标
主要结局
Progression-free survival (PFS) in Phase 2, defined as the time (in days) from date of randomization to disease progression
时间窗: Up to 25 months
Joint positive adjudication of safety summary in Phase 1b by steering committee, investigator and sponsor (Yes/No)
时间窗: At 13 months
次要结局
- Objective Response Rate (ORR) in Phase 2(Up to 25 months)
- Number of participants with adverse events in phase 2(Up to 25 months)
- Duration of response in Phase 1b, defined as the time (in days) from the date of first response to treatment (CR, sCR, VGPR, PR) to the date of disease progression or death(Approximately 12 months)
- Overall survival (OS) in Phase 2, defined as the time (in days) from date of randomization until death from any cause(Up to 25 months)
- Symptomatic skeletal event free survival in Phase 2, defined as the time from randomization to the occurrence of 1 of the following: First on-study SSE or Death from any cause if death occurs before a documented SSE(Up to 25 months)
- Objective response rate (ORR) in Phase 1b, in the proportion of subjects in the analysis population who have complete response (CR), stringent complete response (sCR), very good partial response (VGPR), partial response (PR), or stable disease (SD)(Approximately 12 months)
- Time to Symptomatic Skeletal Event (SSE) in Phase 2, defined as the time (days) from the date of randomization to the date of the first on-study SSE(Up to 25 months)
- Time to pain progression in Phase 2(Up to 25 months)
- Duration of response in Phase 2(Up to 25 months)