A Phase 1b/2 Study of Blinatumomab in Japanese Subjects With Relapsed/Refractory B-precursor Acute Lymphoblastic Leukemia (ALL) (Horai Study)
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- Amgen
- 入组人数
- 66
- 试验地点
- 16
- 主要终点
- Phase 2: Percentage of Participants With a Best Response of Complete Remission or Complete Remission With Only Partial Hematological Recovery Within 2 Cycles of Treatment
研究概览
简要总结
This is an open-label, combined 2-part multicenter study to evaluate the efficacy, safety, and tolerability of blinatumomab in adult and pediatric Japanese patients with relapsed/refractory B-precursor ALL.
详细描述
The Phase 1b part will investigate the safety, efficacy, pharmacokinetics (PK) and pharmacodynamics (PD) of blinatumomab to determine the maximum tolerated dose (MTD) in both adult and pediatric Japanese patients with relapsed/refractory B-precursor ALL. The Phase 2 part will assess the safety and efficacy of the recommended dose level of blinatumomab identified in the Phase 1b portion of the study in the adult study population.
In June 2017 protocol amendment 4 extended the study to include an expansion cohort of approximately 65 participants to investigate the safety of blinatumomab in participants who did not participate in Phase 1b or Phase 2 of the study. Adult and pediatric patients in the expansion cohort may receive up to 5 cycles of investigational blinatomumab and may receive commercial blinatomumab after a minimum of 2 cycles of the investigational drug.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 0 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age ≥ 18 years old at enrollment
- •Subjects with Philadelphia-negative B-precursor ALL, with any of the following:
- •Relapsed or refractory after first line therapy with first remission duration ≤ 12 months; or
- •Relapsed or refractory after first salvage therapy; or
- •Relapsed or refractory within 12 months of allogeneic hematopoietic stem cell transplant (alloHSCT)
- •Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or
- •Greater than 5% blasts in bone marrow
- •Pediatric Subjects Key Inclusion Criteria:
- •Age < 18 years old at enrollment
- •Relapsed/refractory disease, defined as one of the following:
- •second or later bone marrow relapse;
- •any marrow relapse after alloHSCT; or
- •Refractory to other treatments:
- •For subjects in first relapse: failure to achieve a complete response (CR) following a full standard reinduction chemotherapy regimen
- •For subjects who have not achieved a first remission: failure to achieve remission following a full standard induction regimen
- •Greater than 5% blasts in bone marrow
- •Karnofsky performance status ≥ 50% for subjects ≥ 16 years
- •Lansky performance status ≥ 50% for subjects < 16 years
- •Key Exclusion Criteria
- •Subjects with Burkitt´s Leukemia according to World Health Organization (WHO) classification
- •History or presence of clinically relevant central nervous system (CNS) pathology such as epilepsy, seizure, paresis, aphasia, stroke, severe brain injuries, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome, psychosis; with the exception of well-controlled CNS leukemia
- •Active ALL in the CNS or testes
- •Current autoimmune disease or history of autoimmune disease with potential CNS involvement
- •Autologous HSCT within 6 weeks prior to start of blinatumomab treatment
- •AlloHSCT within 12 weeks prior to start of blinatumomab treatment
- •Any active acute Graft-versus-Host Disease (GvHD) grade 2-4 according to Glucksberg criteria or active chronic GvHD requiring systemic treatment
排除标准
- 未提供
研究组 & 干预措施
Blinatumomab 9-28 µg/day Phase 1b Adult Population
Participants received blinatumomab by continuous intravenous (CIV) infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose for adults was 9 µg/day for the first week of cycle 1, escalated to 28 µg/day starting from Week 2 and all cycles thereafter.
干预措施: Blinatumomab (Drug)
Blinatumomab 5-15 µg/m^2/day Phase 1b Pediatric Population
Participants received blinatumomab by CIV infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. For pediatric participants the initial dose was 5 µg/m²/day for the first week of cycle 1, escalated to 15 µg/m²/day starting from week 2 and all cycles thereafter.
干预措施: Blinatumomab (Drug)
Blinatumomab 9-28 µg/day Phase 2 Adult Population
Participants received blinatumomab by CIV infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose for adults was 9 µg/day for the first week of cycle 1, escalated to 28 µg/day starting from Week 2 and all cycles thereafter.
干预措施: Blinatumomab (Drug)
Blinatumomab 9-28 µg/day Adult Expansion Population
Participants received blinatumomab by CIV infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose for adults was 9 µg/day for the first week of cycle 1, escalated to 28 µg/day starting from Week 2 and all cycles thereafter.
干预措施: Blinatumomab (Drug)
Blinatumomab 5-15 µg/m^2/day Pediatric Expansion Population
Participants received blinatumomab by CIV infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. For pediatric participants the initial dose was 5 µg/m²/day for the first week of cycle 1, escalated to 15 µg/m²/day starting from week 2 and all cycles thereafter.
干预措施: Blinatumomab (Drug)
结局指标
主要结局
Phase 2: Percentage of Participants With a Best Response of Complete Remission or Complete Remission With Only Partial Hematological Recovery Within 2 Cycles of Treatment
时间窗: Within the first 2 cycles of treatment, 12 weeks
Hematological assessments were performed from bone marrow biopsy samples. All hematological assessments of bone marrow were reviewed in a central reference laboratory. Hematological remissions were defined by the following criteria: * Complete Remission (CR) is defined as ≤ 5% blasts in the bone marrow, no evidence of disease, and full recovery of peripheral blood counts: platelets \> 100,000/µl and absolute neutrophil count (ANC) \> 1,000/µl. * Complete Remission With Partial Hematological Recovery (CRh\*) is defined as ≤ 5% blasts in the bone marrow, no evidence of disease, and partial recovery of peripheral blood counts: platelets \> 50,000/µl and ANC \> 500/µl.
Phase 1b: Number of Participants With Dose-limiting Toxicities
时间窗: Days 1 to 14
Dose-limiting toxicities (DLTs) were defined as any Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 grade ≥ 3 adverse event related to blinatumomab, excluding specific CTCAE grade ≥ 3 adverse events considered consistent with the current known safety profile of blinatumomab, CTCAE grade ≥ 3 fever or infection, and laboratory parameters of CTCAE grade ≥ 3 not considered clinically relevant and/or responding to routine medical management.
Expansion Cohort: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related TEAEs
时间窗: From the start of the first infusion to 30 days after the end of the last infusion; median (min, max) treatment duration was 55.6 (25, 140) and 28.0 (8, 56) days in the adult and pediatric expansion cohorts, respectively.
TEAEs are defined as those that start between the start of the first infusion of blinatumomab and 30 days after the end of the last infusion during the treatment period. The severity of adverse events was assessed by the investigator according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 as follows: Grade 1 - Mild AE; Grade 2 - Moderate AE; Grade 3 - Severe AE; Grade 4 - Life-threatening or disabling AE; Grade 5 - Death. The investigator used medical judgment to determine if there was a causal relationship (ie, related, unrelated) between an adverse event and blinatumomab.
次要结局
- Phase 1b and Phase 2: Duration of Response(Median (minimum [min], maximum [max]) follow-up time was 6.3 (2.4, 13.6) months for Phase 1b and 26.7 (3.0, 28.5) months for Phase 2.)
- Phase 1b and Phase 2: Terminal Half-life of Blinatumomab(Cycle 1 day 1 predose, 2, 6 (adults), 10, 24 hours; day 8 (prior to dose step) 0 hour (adults); day 15 any time during infusion; day 29 prior to end of infusion, 1 (adults), 2, 4 (adults), 6 hours after end of infusion)
- Phase 1b and Phase 2: Number of Participants Who Developed Anti-Blinatumomab Antibodies(Day 1 before first dose; cycles 1 and 2 day 29, 6 hours after end of infusion; 30 days after last dose.)
- Phase 2: Best Overall Response Within 2 Cycles of Treatment(Within the first 2 cycles of treatment, 12 weeks)
- Phase 1b and Phase 2: Volume of Distribution of Blinatumomab(Cycle 1 day 1 predose, 2, 6 (adults), 10, 24 hours; day 8 (prior to dose step) 0 hour (adults); day 15 any time during infusion; day 29 prior to end of infusion, 1 (adults), 2, 4 (adults), 6 hours after end of infusion)
- Expansion Cohort Adult: Percentage of Participants With a Best Response of Complete Remission or Complete Remission With Only Partial Hematological Recovery Within 2 Cycles of Treatment(Within the first 2 cycles of treatment, 12 weeks)
- Phase 2: Percentage of Participants Who Received an Allogeneic Hematopoietic Stem Cell Transplant (HSCT) During Blinatumomab Induced Remission(Median (min, max) follow-up time was 26.7 (3.0, 28.5) months.)
- Phase 2: 100-Day Mortality After Allogeneic HSCT(100 days, from the date of allogeneic HSCT; median (min, max) follow-up time was 26.7 (3.0, 28.5))
- Phase 1b and Phase 2: Serum Blinatumomab Concentration at Steady State(After 24 hours from the start of infusion: Cycle 1 (before dose step) day 2; Cycle 1 (after dose step) days 15 and 29; Cycle 2 onwards day 8 (pediatric and adult), days 15 and 29 (adult).)
- Phase 1b and Phase 2: Interleukin-10 Concentration(Adults: cycle 1, day 1: 2, 6, 10, 24 hrs after infusion start; day 8: 2, 6, 10 hrs after dose step. Cycles 2-5, day 1: 6 hrs after infusion start. Pediatric: cycle 1, day 1: 6, 10, 24 hrs after infusion start; Cycles 2-5, day 1: 6 hrs after infusion start)
- Phase 1b and Phase 2: Tumor Necrosis Factor-Alpha (TNFα) Concentration(Adults: cycle 1, day 1: 2, 6, 10, 24 hrs after infusion start; day 8: 2, 6, 10 hrs after dose step. Cycles 2-5, day 1: 6 hrs after infusion start. Pediatric: cycle 1, day 1: 6, 10, 24 hrs after infusion start; Cycles 2-5, day 1: 6 hrs after infusion start)
- Phase 1b Adults: Percentage of Participants With a Best Response of Complete Remission or Complete Remission With Only Partial Hematological Recovery Within 2 Cycles of Treatment(Within the first 2 cycles of treatment, 12 weeks)
- Phase 1b Pediatric: Percentage of Participants With M1 Remission Within 2 Cycles of Treatment(The first 2 cycles of treatment, 12 weeks)
- Phase 1b and Phase 2: Relapse-free Survival(Median (min, max) follow-up time was 6.3 (2.4, 13.6) months for Phase 1b and 26.7 (3.0, 28.5) months for Phase 2.)
- Phase 1b and Phase 2: Overall Survival(Median (min, max) follow-up time was 6.3 (2.4, 13.6) months for Phase 1b and 26.7 (3.0, 28.5) months for Phase 2.)
- Phase 1b and Phase 2: Systemic Clearance of Blinatumomab(After 24 hours from the start of infusion: Cycle 1 (before dose step) day 2; Cycle 1 (after dose step) days 15 and 29; Cycle 2 onwards day 8 (pediatric and adult), days 15 and 29 (adult).)
- Phase 1b and Phase 2: Interleukin-2 Concentration(Adults: cycle 1, day 1: 2, 6, 10, 24 hrs after infusion start; day 8: 2, 6, 10 hrs after dose step. Cycles 2-5, day 1: 6 hrs after infusion start. Pediatric: cycle 1, day 1: 6, 10, 24 hrs after infusion start; Cycles 2-5, day 1: 6 hrs after infusion start)
- Phase 1b and Phase 2: Number of Participants With TEAEs(From the start of the first infusion to 30 days after the end of the last infusion; median (min, max) treatment duration was 108 (56, 140), 56.0 (5, 84), and 56.0 (11, 115) days in adult phase 1b, adult phase 2 and pediatric phase 1b cohort respectively.)
- Phase 1b and Phase 2: Interleukin-6 Concentration(Adults: cycle 1, day 1: 2, 6, 10, 24 hrs after infusion start; day 8: 2, 6, 10 hrs after dose step. Cycles 2-5, day 1: 6 hrs after infusion start. Pediatric: cycle 1, day 1: 6, 10, 24 hrs after infusion start; Cycles 2-5, day 1: 6 hrs after infusion start)
- Phase 1b and Phase 2: Interferon Gamma (IFN-γ) Concentration(Adults: cycle 1, day 1: 2, 6, 10, 24 hrs after infusion start; day 8: 2, 6, 10 hrs after dose step. Cycles 2-5, day 1: 6 hrs after infusion start. Pediatric: cycle 1, day 1: 6, 10, 24 hrs after infusion start; Cycles 2-5, day 1: 6 hrs after infusion start)
- Expansion Cohort Pediatric: Percentage of Participants With M1 Remission Within 2 Cycles of Treatment(Within the first 2 cycles of treatment, 12 weeks)