A Phase 1b Study to Assess Safety, Tolerability and Antitumor Activity of the Combination of BGB 3111 With Obinutuzumab in Subjects With B-Cell Lymphoid Malignancies
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 119
- 试验地点
- 14
- 主要终点
- Part 1: Number Of Participants Experiencing Dose-limiting Toxicity (DLT)
研究概览
简要总结
This study evaluated the safety and preliminary efficacy of BGB-3111 (zanubrutinib) in combination with obinutuzumab in participants with B-cell lymphoid malignancies.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 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
- •Aged ≥18 years, able and willing to provide written informed consent and to comply with the study protocol.
- •Laboratory parameters as specified below:
- •Hematologic: Platelet count >40x10^9/liter (L) (may be post-transfusion); absolute neutrophil count >1.0x10^9/L (growth factor use is allowed to bring pre-treatment neutrophils to >1.0x10^9 cells/L if marrow infiltration is involved).
- •Hepatic: Total bilirubin <3 x upper limit normal (ULN); and aspartate aminotransferase and alanine transaminase ≤3 x ULN.
- •Renal: Creatinine clearance ≥50 milliliters/minute (as estimated by the Cockcroft Gault equation or as measured by nuclear medicine scan or 24-hour urine collection); participants requiring hemodialysis will be excluded.
- •Anticipated survival of at least 6 months.
- •Eastern Cooperative Oncology Group performance status of 0 to
- •Female participants of childbearing potential and non-sterile males must have agreed to practice at least one of the following methods of birth control with partner(s) throughout the study and for ≥3 months after discontinuing zanubrutinib or ≥18 months following obinutuzumab treatment, whichever was longer: total abstinence from sexual intercourse, double barrier contraception, intra uterine device or hormonal contraceptive initiated at least 3 months prior to first administration of study drug.
- •Male participants must have not donated sperm from first study drug administration, until 3 months after zanubrutinib discontinuation or 18 months following obinutuzumab treatment, whichever is longer.
排除标准
- •Known central nervous system lymphoma or leukemia.
- •Known prolymphocytic leukemia or history of, or currently suspected, Richter's syndrome.
- •Uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenia purpura.
- •History of significant cardiovascular disease.
- •Severe or debilitating pulmonary disease.
- •History of severe allergic or anaphylactic reactions to monoclonal antibody therapy.
- •Prior Bruton tyrosine kinase inhibitor treatment.
- •Used medications which were strong cytochrome P450 (CYP) 3A inhibitors and strong CYP3A inducers.
- •Vaccination with a live vaccine within 28 days of the initiation of treatment.
- •Allogeneic stem cell transplantation within 6 months, or had active graft versus host disease requiring ongoing immunosuppression.
- •Receipt of the following treatment prior to first administration of zanubrutinib, corticosteroids given with anti-neoplastic intent within 7 days, chemotherapy or radiotherapy within 3 weeks, monoclonal antibody within 4 weeks.
- •Participated in any investigational drug study within 28 days of study entry, or not recovered from non-hematologic toxicity of any prior chemotherapy up to ≤ Grade 1 (except for alopecia).
- •History of other active malignancies within 2 years of study entry.
- •Major surgery in the past 4 weeks.
- •Active symptomatic fungal, bacterial and/or viral infection including evidence of infection with human immunodeficiency virus, human T cell lymphotropic virus seropositive status.
- •Inability to comply with the study procedures.
- •Pregnant or nursing women.
- •Any illness or condition that in the opinion of the investigator may have affected the safety of treatment or evaluation of any study's endpoints.
研究组 & 干预措施
Zanubrutinib and Obinutuzumab
In the dose-escalation part, dose levels and regimens were evaluated. In the indication-specific expansion cohorts, participants were assigned to different cohorts based on histology type.
干预措施: Zanubrutinib (Drug)
Zanubrutinib and Obinutuzumab
In the dose-escalation part, dose levels and regimens were evaluated. In the indication-specific expansion cohorts, participants were assigned to different cohorts based on histology type.
干预措施: Obinutuzumab (Drug)
结局指标
主要结局
Part 1: Number Of Participants Experiencing Dose-limiting Toxicity (DLT)
时间窗: Day 1 (first dose) through 4 years and 8 months
Dose-limiting toxicities were defined as a toxicity or AE occurring during the DLT assessment period (first 29 days of treatment), which is not clearly attributable to a cause other than zanubrutinib and/or obinutuzumab (such as disease progression, underlying illness, concurrent illness or concomitant medication) and meets one of the following criteria: * Grade 3 or 4 drug-related non-hematologic toxicity (excluding Grade 3 nausea, vomiting, hypertension, and asymptomatic laboratory abnormalities), * Grade 4 drug-related hematologic toxicity persisting for \>14 days, * any grade toxicity, which in the judgment of the investigator or Sponsor, required removal of the participant from the study.
Part 1: Number Of Participants With Clinical Laboratory Abnormalities
时间窗: Day -28 to -1 (predose) through 4 years and 8 months
Laboratory results are reported as participants with shifts towards (high directionality) or away (low directionality) from Grade 3 or Higher Toxicity.
Part 1 and Part 2: Number Of Participants Achieving A Best Response Of Partial Response
时间窗: Day 1 (first dose) through 4 years and 8 months
Partial response was defined as follows: * ≥ 50% reduction of serum IgM from baseline, * reduction in lymphadenopathy/splenomegaly (if present at baseline). For response assessments that occurred during cycles where a CT scan was not required, then results from prior scans (up to 12 weeks during the first 48 weeks and up to 24 weeks thereafter) could be carried forward in those participants with extramedullary disease at baseline.
Part 1: Number Of Deaths
时间窗: Day 1 (first dose) through 4 years and 8 months
An AE was defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product (zanubrutinib in combination with obinutuzumab). An AE could therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of study drug. An SAE was 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.
Part 1 : Number Of Participants Experiencing Adverse Events
时间窗: Day 1 (first dose) through 4 years and 8 months
An AE was defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product (zanubrutinib in combination with obinutuzumab). An AE could therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of the study drug. A serious AE (SAE) was 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.
次要结局
- Part 1 and Part 2: Steady State AUClast Of Zanubrutinib(Day 1 Cycle 1, Predose (within 3 hours), hours 1, 2, 4 and 7)
- Part 1: Area Under The Plasma Concentration-time Curve From Time 0 To The Time Of The Last Measurable Concentration (AUClast) Of Zanubrutinib(Day 1 Cycle 1, Predose (within 3 hours), hours 1, 2, 4 and 7)
- Part 1: Terminal Elimination Half-life (t1/2) Of Zanubrutinib(Day 1 Cycle 1, Predose (within 3 hours), hours 1, 2, 4 and 7)
- Part 1 and Part 2: Number Of Participants Achieving A Best Response Of Complete Response(Day 1 (first dose) through 4 years and 8 months)
- Part 1 and Part 2: Duration Of Response (DOR)(Day 1 (first dose) through 4 years and 8 months)
- Part 1 and Part 2: Time To Response (TTR)(Day 1 (first dose) through 4 years and 8 months)
- Part 1 and Part 2: Overall Survival (OS)(Day 1 (first dose) through 4 years and 8 months)
- Part 1: Apparent Volume Of Distribution (Vz/F) Of Zanubrutinib(Day 1 Cycle 1, Predose (within 3 hours), hours 1, 2, 4 and 7)
- Part 1: Maximum Plasma Concentration (Cmax) Of Zanubrutinib(Day 1 Cycle 1, Predose (within 3 hours), hours 1, 2, 4 and 7)
- Part 1 and Part 2: Steady State Cmax of Zanubrutinib(Day 1 Cycle 1, Predose (within 3 hours), hours 1, 2, 4 and 7)
- Part 1 and Part 2: Hematologic Improvement In Participants With CLL(Day 1 (first dose) through 4 years and 8 months)
- Part 1: Area Under The Plasma Concentration-time Curve From Time 0 To Infinity Time (AUC) Of Zanubrutinib(Day 1 Cycle 1, Predose (within 3 hours), hours 1, 2, 4 and 7)
- Part 1: Time To Maximum Plasma Concentration (Tmax) Of Zanubrutinib(Day 1 Cycle 1, Predose (within 3 hours), hours 1, 2, 4 and 7)
- Part 1: Apparent Clearance (CL/F) Of Zanubrutinib(Day 1 Cycle 1, Predose (within 3 hours), hours 1, 2, 4 and 7)
- Part 1 and Part 2: Steady State Tmax Of Zanubrutinib(Day 1 Cycle 1, Predose (within 3 hours), hours 1, 2, 4 and 7)
- Part 2: Number Of Participants Experiencing Adverse Events(Day 1 (first dose) through 4 years and 8 months)
- Part 2: Number Of Participants With Clinical Laboratory Abnormalities(Day -28 to -1 (predose) through 4 years and 8 months)
- Part 1 and Part 2: Progression-free Survival (PFS)(Day 1 (first dose) through 4 years and 8 months)
- Part 2: Number Of Deaths(Day 1 (first dose) through 4 years and 8 months)