A Single-Arm, Open-Label, Multicenter Phase 1/2 Study to Evaluate the Efficacy, Safety, and Pharmacokinetics of BCL2 Inhibitor BGB-11417 in Patients With Relapsed or Refractory Mantle Cell Lymphoma
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 发起方
- 入组人数
- 125
- 试验地点
- 65
- 主要终点
- Part 1: Number of Participants Experiencing Dose-limiting Toxicities (DLTs)
研究概览
简要总结
The study consists of two parts. Part 1 determines the safety and tolerability of sonrotoclax monotherapy, the maximum tolerated dose, and the recommended Phase 2 dose of sonrotoclax monotherapy for relapsed or refractory mantle cell lymphoma. Part 2 evaluates efficacy of sonrotoclax monotherapy at the recommended Phase 2 dose with recommended ramp-up schedule from Part 1.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non 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
- •Histologically confirmed diagnosis of MCL
- •Prior systemic treatments for MCL (at least one line of anti-cluster of differentiation 20 (anti-CD20) based immune or chemoimmunotherapy and at least one kind of covalent or non-covalent adequate Bruton Tyrosine Kinase (BTK) inhibitor).
- •Relapsed/refractory disease
- •Presence of measurable disease
- •Availability of archival tissue confirming diagnosis of MCL, or willing to undergo fresh tumor biopsy
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0,1 or
- •Adequate organ function
排除标准
- •Known central nervous system involvement by lymphoma
- •Prior malignancy other than MCL within the past 3 years, except for curatively treated basal or squamous cell skin cancer, superficial bladder cancer, carcinoma in situ of the cervix or breast, or localized Gleason score 6 prostate cancer.
- •Prior exposure to a BCL-2 inhibitor (eg, venetoclax/ABT-199).
- •Prior autologous stem cell transplant within the last 3 months; or prior autologous chimeric antigen receptor T-cell therapy within the last 3 months; or prior allogeneic stem cell transplant within the last 6 months or currently has an active graft-vs-host disease requiring the use of immunosuppressants.
- •Clinically significant cardiovascular disease.
- •Major surgery or significant injury ≤ 4 weeks prior to start of study treatment.
- •Active fungal, bacterial or viral infection requiring systemic treatment.
- •Note: Other protocol defined Inclusion/Exclusion criteria may apply.
研究组 & 干预措施
Part 1: Sonrotoclax 320 mg (Daily Ramp-up)
Participants received sonrotoclax at the target dose of 320 mg orally once a day after an approximately 4-week ramp-up schedule starting at 1 mg with daily dose increases until the target dose was reached. Participants received sonrotoclax until disease progression, unacceptable toxicity, or consent withdrawal.
干预措施: Sonrotoclax (Drug)
Part 2: Sonrotoclax 320 mg (Twice-weekly Ramp-up)
Participants received sonrotoclax at the target dose of 320 mg orally once a day after an approximately 4-week ramp-up schedule starting at 1 mg with twice-weekly dose increases until the target dose was reached. Participants received sonrotoclax until disease progression, unacceptable toxicity, or consent withdrawal.
干预措施: Sonrotoclax (Drug)
Part 1: Sonrotoclax 160 mg (Daily Ramp-up)
Participants received sonrotoclax at the target dose of 160 mg orally once a day (QD) after an approximately 4-week ramp-up schedule starting at 1 mg with daily dose increases until the target dose was reached. Participants received sonrotoclax until disease progression, unacceptable toxicity, or consent withdrawal.
干预措施: Sonrotoclax (Drug)
Part 2: Sonrotoclax 320 mg (Daily Ramp-up)
Participants received sonrotoclax at the target dose of 320 mg orally once a day after an approximately 4-week ramp-up schedule starting at 1 mg with daily dose increases until the target dose was reached. Participants received sonrotoclax until disease progression, unacceptable toxicity, or consent withdrawal.
干预措施: Sonrotoclax (Drug)
结局指标
主要结局
Part 1: Number of Participants Experiencing Dose-limiting Toxicities (DLTs)
时间窗: From first dose in the ramp-up period through the first 3 weeks of treatment at the target dose (approximately 7 weeks)
DLTs included the following events without a clear alternative cause other than study drug: Hematologic Toxicity: * Grade ≥ 3 febrile neutropenia; * Grade ≥ 3 thrombocytopenia lasting \> 7 days or resulting in clinically significant bleeding; * Any Grade ≥ 4 hematological toxicities, except for Grade 4 neutropenia lasting ≤ 7 days with or without treatment, Grade 4 lymphopenia, or Grade 4 leukopenia. Nonhematologic Toxicity: • Any Grade ≥ 3 nonhematologic toxicity with the following exceptions: * Laboratory tumor lysis syndrome (TLS) defined by the Howard criteria that resolves (≤ Grade 1 or baseline) in ≤ 3 days; * Individual TLS-related laboratory adverse events that resolve (≤ Grade 1or baseline) in ≤ 3 days with or without treatment; * Grade 3 gastrointestinal toxicity that resolves to ≤ Grade 2 following therapeutic intervention in ≤ 7 days; * Asymptomatic biochemical laboratory abnormalities that resolve (≤ Grade 1 or baseline) in ≤ 7 days with or without supportive care.
Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Adverse Events Leading to Treatment Discontinuation
时间窗: From first dose of study drug up to 30 days after last dose or the primary analysis data cut-off date, whichever occurred earlier; maximum duration of treatment was 31 months.
An adverse event is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study drug, whether considered related to study drug or not. A serious adverse event is any untoward medical occurrence that, at any dose: * Resulted in death * Was life-threatening * Required hospitalization or prolongation of existing hospitalization. * Resulted in disability/incapacity. * Was a congenital anomaly/birth defect. * Was considered a significant medical adverse event by the investigator or sponsor based on medical judgment.
Part 1: Number of Participants Experiencing Tumor Lysis Syndrome (TLS) Adverse Events
时间窗: From first dose of study drug up to 30 days after last dose or the primary analysis data cut-off date, whichever occurred earlier; maximum duration of treatment was 31 months.
Tumor lysis syndrome (TLS) occurs when large numbers of cancer cells die rapidly, releasing their contents (such as potassium, phosphorus, and nucleic acids) into the bloodstream faster than the kidneys can filter them out. This rapid breakdown causes a dangerous chain reaction of metabolic and electrolyte imbalances.
Part 2: Overall Response Rate (ORR) as Assessed by the Independent Review Committee (IRC)
时间窗: Response was assessed 8 and 16 weeks after the first dose, then every 12 weeks up to 1 year, every 24 weeks for 2 years, and yearly thereafter; median (range) time on follow-up in efficacy-evaluable participants in Part 2 was 14.2 (0.3-24.9) months.
ORR is defined as the percentage of participants who achieved a complete response (CR) or partial response (PR) per the Lugano Classification for non-Hodgin lymphoma.
次要结局
- Part 1: Area Under the Plasma Concentration-Time Curve From Time 0 to the Last Measurable Concentration (AUClast) of Sonrotoclax at Steady-State(Target Dose Week 4 Day 1 at predose, 2, 4, 6, and 8 hours post-dose)
- Part 1: Time to Maximum Observed Concentration of Sonrotoclax (Tmax) After a Single Dose(Ramp-up Week 1 Day 1 at predose, 2, 4, 6, and 8 hours post-dose)
- Part 1: Time to Maximum Observed Concentration of Sonrotoclax (Tmax) at Steady State(Target Dose Week 4 Day 1 at predose, 2, 4, 6, and 8 hours post-dose)
- Part 1: Maximum Observed Plasma Concentration (Cmax) of Sonrotoclax After a Single Dose(Ramp-up Week 1 Day 1 at predose, 2, 4, 6, and 8 hours post-dose)
- Part 1: Maximum Observed Plasma Concentration (Cmax) at Steady State(Target Dose Week 4 Day 1 at predose, 2, 4, 6, and 8 hours post-dose)
- Part 1: Trough Plasma Concentration (Ctrough) at Steady State(Target Dose Week 4 Day 1 at predose)
- Part 1: Area Under the Plasma Concentration-Time Curve From Time 0 to the Last Measurable Concentration (AUClast) of Sonrotoclax After a Single Dose(Ramp-up Week 1 Day 1 at predose, 2, 4, 6, and 8 hours post-dose)
- Part 1: Overall Response Rate Assessed by the Independent Review Committee (IRC)(Response was assessed 8 and 16 weeks after the first dose, then every 12 weeks up to one year, every 24 weeks for 2 years, and yearly thereafter; median (range) time on follow-up in efficacy-evaluable participants in Part 1 was 10.7 (0.1-31.6) months.)
- Part 1: Overall Response Rate Assessed by the Investigator(Response was assessed 8 and 16 weeks after the first dose, then every 12 weeks up to one year, every 24 weeks for 2 years, and yearly thereafter; median (range) time on follow-up in efficacy-evaluable participants in Part 1 was 10.7 (0.1-31.6) months.)
- Part 1: Duration of Response (DOR) Assessed by the IRC(Response was assessed 8 and 16 weeks after the first dose, then every 12 weeks up to one year, every 24 weeks for 2 years, and yearly thereafter; median (range) time on follow-up in efficacy-evaluable participants in Part 1 was 10.7 (0.1-31.6) months.)
- Part 1: Duration of Response Assessed by the Investigator(Response was assessed 8 and 16 weeks after the first dose, then every 12 weeks up to one year, every 24 weeks for 2 years, and yearly thereafter; median (range) time on follow-up in efficacy-evaluable participants in Part 1 was 10.7 (0.1-31.6) months.)
- Part 1: Progression Free Survival (PFS) Assessed by the IRC(From first dose until the data cut-off date; median (range) time on follow-up in efficacy-evaluable participants in Part 1 was 10.7 (0.1-31.6) months.)
- Part 1: Progression-free Survival Assessed by the Investigator(From first dose until the data cut-off date; median (range) time on follow-up in efficacy-evaluable participants in Part 1 was 10.7 (0.1-31.6) months.)
- Part 1: Time to Response (TTR) as Assessed by the IRC(Response was assessed 8 and 16 weeks after the first dose, then every 12 weeks up to one year, every 24 weeks for 2 years, and yearly thereafter; median (range) time on follow-up in efficacy-evaluable participants in part 1 was 10.7 (0.1-31.6) months.)
- Part 1: Time to Response Assessed by the Investigator(Response was assessed 8 and 16 weeks after the first dose, then every 12 weeks up to one year, every 24 weeks for 2 years, and yearly thereafter; median (range) time on follow-up in efficacy-evaluable participants in Part 1 was 10.7 (0.1-31.6) months.)
- Part 1: Overall Survival (OS)(From first dose until the data cut-off date; median (range) time on follow-up in efficacy-evaluable participants in Part 1 was 10.7 (0.1-31.6) months.)
- Part 2: Overall Response Rate (ORR) Assessed by the Investigator(Response was assessed at 8 and 16 weeks after the first dose, then every 12 weeks up to 1 year, every 24 weeks for 2 years, and yearly thereafter; median (range) time on follow-up in efficacy-evaluable participants in Part 2 was 14.2 (0.3-24.9) months.)
- Part 2: Duration of Response Assessed by the IRC(Response was assessed at 8 and 16 weeks after the first dose, then every 12 weeks up to 1 year, every 24 weeks for 2 years, and yearly thereafter; median (range) time on follow-up in efficacy-evaluable participants in Part 2 was 14.2 (0.3-24.9) months.)
- Part 2: Duration of Response Assessed by the Investigator(Response was assessed at 8 and 16 weeks after the first dose, then every 12 weeks up to 1 year, every 24 weeks for 2 years, and yearly thereafter; median (range) time on follow-up in efficacy-evaluable participants in Part 2 was 14.2 (0.3-24.9) months.)
- Part 2: Progression-free Survival Assessed by the IRC(From first dose of study drug until the data cut-off date; median (range) time on follow-up in efficacy-evaluable participants in Part 2 was 14.2 (0.3-24.9) months.)
- Part 2: Progression-free Survival Assessed by the Investigator(From first dose of study drug until the data cut-off date; median (range) time on follow-up in efficacy-evaluable participants in Part 2 was 14.2 (0.3-24.9) months.)
- Part 2: Time to Response Assessed by the IRC(Response was assessed at 8 and 16 weeks after the first dose, then every 12 weeks up to 1 year, every 24 weeks for 2 years, and yearly thereafter; median (range) time on follow-up in efficacy-evaluable participants in Part 2 was 14.2 (0.3-24.9) months.)
- Part 2: Time to Response Assessed by the Investigator(Response was assessed at 8 and 16 weeks after the first dose, then every 12 weeks up to 1 year, every 24 weeks for 2 years, and yearly thereafter; median (range) time on follow-up in efficacy-evaluable participants in Part 2 was 14.2 (0.3-24.9) months.)
- Part 2: Overall Survival(From first dose of study drug until the data cut-off date; median (range) time on follow-up in efficacy-evaluable participants in Part 2 was 14.2 (0.3-24.9) months.)
- Part 2: Change From Baseline in National Comprehensive Cancer Network - Functional Assessment of Cancer Therapy Lymphoma Symptom Index-18 (NFlymSI-18) Disease Related Symptoms-Physical (DRS-P) Sub-scale Score(Baseline and Weeks 4, 12, and 24)
- Part 2: Change From Baseline in National Comprehensive Cancer Network - Functional Assessment of Cancer Therapy Lymphoma Symptom Index-18 (NFlymSI-18) Treatment Side-Effects (TSE) Sub-scale Score(Baseline and Weeks 4, 12, and 24)
- Part 2: Change From Baseline in European Quality of Life 5 Dimension (EQ-5D) Visual Analog Scale (VAS) Score(Baseline and Weeks 4, 12, and 24)
- Part 2: Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Adverse Events Leading to Treatment Discontinuation(From first dose of study drug up to 30 days after last dose or the data cut-off date, whichever occurred earlier; maximum duration of treatment in Part 2 was 24.8 months.)