A Phase 1b Open Label Study Investigating the Safety and Efficacy of Blinatumomab in Combination With Pembrolizumab in Adult Subjects With Relapsed or Refractory Diffuse Large B-Cell Lymphoma (DLBCL)
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- Amgen
- 入组人数
- 31
- 试验地点
- 1
- 主要终点
- Number of Participants With Dose Limiting Toxicities (DLTs)
研究概览
简要总结
The primary objective of the study is to determine the maximum tolerated dose (MTD) of blinatumomab in combination with pembrolizumab in adults with relapsed or refractory (r/r) DLBCL.
详细描述
The study was planned as 2 parts:
- Part 1 will test the safety of up to 3 different blinatumomab target dose levels in combination with pembrolizumab in a rolling 6 design. A Dose Level Review Team (DLRT) will review the safety data to evaluate possible drug effects and dose-limiting toxicities (DLTs).
- Part 2 will consist of an expansion cohort to assess pharmacokinetics (PK), safety, and preliminary efficacy data at the chosen target dose. The part 2 dose will be determined by the totality of the clinical data from part 1 as determined by the DLRT.
Based on the results from Part 1, a decision was made not to proceed with Part 2 of this study.
Secondary objectives of the study are to evaluate the safety, efficacy, and pharmacokinetics (PK) of blinatumomab in combination with pembrolizumab. Tumor response will be evaluated according to the Revised Response Criteria for Malignant Lymphoma (Cheson et al, 2007). With implementation of Protocol Amendment 5, response will also be assessed according to the Lugano Classification (Cheson et al, 2014). Only participants enrolled after implementation of Protocol Amendment 5 (03 December 2019) will have tumor assessments using the Lugano criteria.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 100 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Have histologically confirmed diffuse large B-cell lymphoma that is either:
- •Refractory after at least one regimen of systemic chemotherapy and/or targeted therapy, or
- •In first or later relapse if have received at least 2 systemic regimens since time of diagnosis, or
- •Relapsed post-autologous or allogeneic hematopoietic stem cell transplantation (HSCT) with adequate organ function after proximity to transplantation time exclusions
- •Have measurable disease
- •Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
- •Life expectancy of ≥ 12 weeks in the opinion of the Investigator
- •Biopsy proven DLBCL (biopsy proven at least at primary diagnosis of DLBCL)
- •Other Inclusion Criteria May Apply
排除标准
- •Richter's transformation (DLBCL arising in the setting of prior chronic lymphocytic leukemia) or primary mediastinal B cell lymphoma (PMBCL)
- •History or presence of clinically relevant central nervous system pathology such as epilepsy, paresis, aphasia, stroke, severe brain injury, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome, or psychosis.
- •Has a diagnosis of immunodeficiency or has received systemic steroid therapy (in excess of 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of protocol specified therapy.
- •Has undergone prior allogeneic HSCT:
- •within the last 5 years OR
- •greater than 5 years ago but has active graft versus host disease (GvHD) requiring systemic treatment.
- •Has received autologous HSCT within 6 weeks prior to start of treatment.
- •Other Exclusion Criteria May Apply.
研究组 & 干预措施
Cohort Ia: Blinatumomab 9/28 µg/day + Pembrolizumab
Participants received blinatumomab administered as a continuous intravenous infusion (CIVI) for 8 weeks followed by a 28-day treatment-free interval. Participants with stable disease or better may have received a second 28-day consolidation cycle. The starting dose of each cycle was 9 µg/day for the first 7 days then 28 µg/day for the remaining days of treatment.
Starting on Day 15 participants also received 200 mg pembrolizumab administered by intravenous (IV) infusion every 3 weeks (Q3W) until disease progression or for up to 35 cycles.
干预措施: Blinatumomab (Drug)
Cohort Ia: Blinatumomab 9/28 µg/day + Pembrolizumab
Participants received blinatumomab administered as a continuous intravenous infusion (CIVI) for 8 weeks followed by a 28-day treatment-free interval. Participants with stable disease or better may have received a second 28-day consolidation cycle. The starting dose of each cycle was 9 µg/day for the first 7 days then 28 µg/day for the remaining days of treatment.
Starting on Day 15 participants also received 200 mg pembrolizumab administered by intravenous (IV) infusion every 3 weeks (Q3W) until disease progression or for up to 35 cycles.
干预措施: Pembrolizumab (Drug)
Cohort IIa: Blinatumomab 9/28/56 µg/day + Pembrolizumab
Participants received blinatumomab administered as a continuous intravenous infusion for 8 weeks followed by a 28-day treatment-free interval. Participants with stable disease or better may have received a second 28-day consolidation cycle. The starting dose of each cycle was 9 µg/day for the first 7 days, 28 µg/day for 7 days then 56 µg/day for the remaining days of treatment.
Starting on Day 19 participants also received 200 mg pembrolizumab administered by IV infusion Q3W until disease progression or for up to 35 cycles.
干预措施: Blinatumomab (Drug)
Cohort IIa: Blinatumomab 9/28/56 µg/day + Pembrolizumab
Participants received blinatumomab administered as a continuous intravenous infusion for 8 weeks followed by a 28-day treatment-free interval. Participants with stable disease or better may have received a second 28-day consolidation cycle. The starting dose of each cycle was 9 µg/day for the first 7 days, 28 µg/day for 7 days then 56 µg/day for the remaining days of treatment.
Starting on Day 19 participants also received 200 mg pembrolizumab administered by IV infusion Q3W until disease progression or for up to 35 cycles.
干预措施: Pembrolizumab (Drug)
Cohort IIIa: Blinatumomab 9/28/112 µg/day + Pembrolizumab
Participants received blinatumomab administered as a continuous intravenous infusion for 8 weeks followed by a 28-day treatment-free interval. Participants with stable disease or better may have received a second 28-day consolidation cycle. The starting dose of each cycle was 9 µg/day for the first 7 days, 28 µg/day for 7 days then 112 µg/day for the remaining days of treatment.
Starting on Day 19 participants also received 200 mg pembrolizumab administered by IV infusion Q3W until disease progression or for up to 35 cycles.
干预措施: Blinatumomab (Drug)
Cohort IIIa: Blinatumomab 9/28/112 µg/day + Pembrolizumab
Participants received blinatumomab administered as a continuous intravenous infusion for 8 weeks followed by a 28-day treatment-free interval. Participants with stable disease or better may have received a second 28-day consolidation cycle. The starting dose of each cycle was 9 µg/day for the first 7 days, 28 µg/day for 7 days then 112 µg/day for the remaining days of treatment.
Starting on Day 19 participants also received 200 mg pembrolizumab administered by IV infusion Q3W until disease progression or for up to 35 cycles.
干预措施: Pembrolizumab (Drug)
Expansion Cohort
This cohort will test the maximum tolerated dose of blinatumomab in combination with pembrolizumab identified in Part 1 of the study.
干预措施: Blinatumomab (Drug)
Expansion Cohort
This cohort will test the maximum tolerated dose of blinatumomab in combination with pembrolizumab identified in Part 1 of the study.
干预措施: Pembrolizumab (Drug)
结局指标
主要结局
Number of Participants With Dose Limiting Toxicities (DLTs)
时间窗: The DLT evaluation period was 42 days from initiation of pembrolizumab treatment (Day 15 for Cohort Ia and Day 19 for Cohorts IIa and IIIa)
Dose-limiting toxicities were grade 3-5 adverse events that occurred during the DLT-evaluation period that were judged by the Investigator to be possibly, probably or definitely related to study drug administration. All toxicities were graded using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0: * Grade 3: Severe or medically significant but not immediately life-threatening. * Grade 4: Life-threatening. * Grade 5: Death.
次要结局
- Objective Response Rate During the First 12 Weeks Using Revised Response Cheson Criteria(First 12 weeks of blinatumomab treatment)
- Pembrolizumab Minimum Serum Concentration(Pre-dose on pembrolizumab cycles 2, 4, 6, 8, and 12 (Study days 36, 78, 120, 162, and 246, respectively).)
- Cohort IIIa Only: Objective Response Rate During the First 12 Weeks Using the Lugano Classification(First 12 weeks of blinatumomab treatment)
- Objective Response Rate During the Treatment Period Using Revised Response Cheson Criteria(From Day 1 to 30 days after last dose of either blinatumomab or pembrolizumab administration; the overall median duration of treatment was 87 days.)
- Cohort IIIa Only: Objective Response Rate During the Treatment Period Using the Lugano Classification(From study Day 1 to 30 days after last dose of either blinatumomab or pembrolizumab administration; the overall median duration of treatment was 87 days.)
- Complete Response Rate During the First 12 Weeks Using the Revised Response Cheson Criteria(First 12 weeks of blinatumomab treatment)
- Cohort IIIa Only: Complete Response Rate During the First 12 Weeks Using the Lugano Classification(First 12 weeks of blinatumomab treatment)
- Number of Participants With Treatment-emergent Adverse Events (TEAEs)(From first dose of blinatumomab to minimum of 30 days after last dose of blinatumomab or pembrolizumab (whichever was later) or end of study: median (min, max) duration was 22.7 (1.0, 85.8) days.)
- Complete Response Rate During the Treatment Period Using the Revised Response Cheson Criteria(From Day 1 to 30 days after last dose of either blinatumomab or pembrolizumab administration; the overall median duration of treatment was 87 days.)
- Cohort IIIa Only: Complete Response Rate During the Treatment Period Using the Lugano Classification(From Day 1 to 30 days after last dose of either blinatumomab or pembrolizumab administration; the overall median duration of treatment was 87 days.)
- Progression Free Survival by the Revised Response Cheson Criteria(From first dose of blinatumomab up to the end of study. Median (min, max) time on study was 188.0 days (19.0, 1512.0).)
- Cohort IIIa Only: Progression Free Survival Using the Lugano Classification(From first dose of blinatumomab up to the end of study. Median (min, max) time on study was 188.0 days (19.0, 1512.0).)
- Overall Survival(From first dose of blinatumomab up to the end of study. Median (min, max) time on study was 188.0 days (19.0, 1512.0).)
- Duration of Response for Participants Who Achieved CR/PR Using the Revised Response Cheson Criteria(From first dose of blinatumomab up to the end of study. Median (min, max) time on study was 188.0 days (19.0, 1512.0).)
- Cohort IIIa Only: Duration of Response for Participants Who Achieved CMR/PMR Using the Lugano Classification(From first dose of blinatumomab up to the end of study. Median (min, max) time on study was 188.0 days (19.0, 1512.0).)
- Blinatumomab Steady State Concentration (Css)(Day 2 for 9 µg/day Css (all cohorts), days 10, 15, 22, 29, and 43 for 28 µg/day Css (Cohort Ia), day 10 for 28 µg/day Css (Cohorts IIa and IIIa), and days 19, 26, and 40 for 56 µg/day and 112 µg/day Css (Cohorts IIa and IIIa respectively).)
- Blinatumomab Clearance(Day 2 for 9 µg/day Css (all cohorts), days 10, 15, 22, 29, and 43 for 28 µg/day Css (Cohort Ia), day 10 for 28 µg/day Css (Cohorts IIa and IIIa), and days 19, 26, and 40 for 56 µg/day and 112 µg/day Css (Cohorts IIa and IIIa respectively).)
- Pembrolizumab Peak Serum Concentration(Within approximately 30 minutes after the end of the infusion in cycle 1 (study day 15 for Cohort Ia, study day 19 for Cohorts IIa and IIIa) and cycle 8 (study day 162 for Cohort Ia and day 166 for Cohorts IIa and IIIa).)