An Open-label Phase 1b/2 Study of Binimetinib Administered in Combination With Nivolumab or Nivolumab Plus Ipilimumab in Patients With Previously Treated Microsatellite-stable (MSS) Metastatic Colorectal Cancer With RAS Mutation
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- Pfizer
- 入组人数
- 75
- 试验地点
- 49
- 主要终点
- Phase 2: Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors (RECIST) Version (v) 1.1
研究概览
简要总结
This is a multicenter, open-label, Phase 1B/2 study to evaluate the safety and assess the preliminary anti-tumor activity of binimetinib administered in combination with nivolumab or nivolumab + ipilimumab in adult patients with advanced metastatic colorectal cancer (mCRC) with microsatellite stable (MSS) disease and presence of a RAS mutation that have received at least one prior line of therapy and no more than 2 prior lines of therapy. The study contains a Phase 1b period to determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) and schedule of binimetinib followed by a randomized Phase 2 period to assess the efficacy of the combinations.
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
- 未提供
排除标准
- 未提供
研究组 & 干预措施
Phase 2 / Arm 2B
binimetinib + nivolumab + ipilimumab
干预措施: binimetinib (Drug)
Phase 2 / Arm 2B
binimetinib + nivolumab + ipilimumab
干预措施: nivolumab (Drug)
Phase 1b / Arm 1A
binimetinib + nivolumab
干预措施: binimetinib (Drug)
Phase 1b / Arm 1A
binimetinib + nivolumab
干预措施: nivolumab (Drug)
Phase 1b / Arm 1B
binimetinib + nivolumab + ipilimumab
干预措施: binimetinib (Drug)
Phase 1b / Arm 1B
binimetinib + nivolumab + ipilimumab
干预措施: nivolumab (Drug)
Phase 1b / Arm 1B
binimetinib + nivolumab + ipilimumab
干预措施: ipilimumab (Drug)
Phase 2 / Arm 2A
binimetinib + nivolumab
干预措施: binimetinib (Drug)
Phase 2 / Arm 2A
binimetinib + nivolumab
干预措施: nivolumab (Drug)
Phase 2 / Arm 2B
binimetinib + nivolumab + ipilimumab
干预措施: ipilimumab (Drug)
结局指标
主要结局
Phase 2: Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors (RECIST) Version (v) 1.1
时间窗: From start of the treatment until disease progression, death or initiation of new anticancer therapy, whichever occurred first (Phase 2: maximum up to 26 months approximately)
ORR was defined as the percentage of participants who achieved a best overall response (BOR) of complete response (CR) or partial response (PR) as determined by investigator per RECIST v1.1. As per RECIST v1.1, CR was defined as disappearance of target and non-target lesions and normalization of tumor markers. Pathological lymph nodes must have short axis measures less than (\<)10 millimeter (mm). PR was defined as at least a 30% decrease in the sum of measures (longest diameter for tumor lesions and short axis measure for nodes) of target lesions, taking as reference baseline sum of diameters. Non-target lesions must be non-progressive disease (PD). PD was defined as at least a 20% increase in sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions was considered progression.
Phase 1b: Number of Participants With Dose-Limiting Toxicities (DLT)
时间窗: Cycle 1: Day 1 up to Day 28
DLT:Adverse event(AE)/abnormal laboratory assessed unrelated-disease,disease progression,intercurrent illness/concomitant medication/therapies resulting inability tolerate 75% dose intensity in Cycle 1.Total bilirubin(TBL)grade(G)\>=3 (\>3.0\*upper limit of normal\[ULN)\]);AST/ALT\>5-8\*ULN\>5 days,\>8\*ULN,\>3\*ULN concurrent TBL\>2\*ULN;G\>=3 serum creatinine,CK elevation,ECG QTcF prolonged,G3 troponin,electrolyte\>72 hours,G3/4 amylase/lipase.G4 ANC,platelet count\>7 days;G3/4 platelet count,other AE except lymphopenia.G\>=3 retinopathy,other disorder\>21 days;G2 uveitis/eye pain/blurred vision/decreased visual acuity;G4 other disorder.Decrease LVEF\>10% G\>=3 cardiac disorders.G3/4 hypertension.G3 fatigue\>=7 days,hypersensitivity,infusion reaction,fever\>=72 hours/hemodynamic compromise,endocrinopathy.G\>=2 interstitial lung disease/pneumonitis;G3 bronchospasm.G3/4 rash,hand foot skin reaction,photosensitivity.G3 colitis;G3/4 diarrhea,nausea/vomiting.Neurologic G3.Other hematologic/nonhematolic G\>=3 AE.
次要结局
- Number of Participants With Abnormal Hepatic Laboratory Values(Phase 1b: Baseline up to 30 days after last dose (maximum up to 9 months approximately), Phase 2: Baseline up to 30 days after last dose (maximum up to 26 months approximately))
- Number of Participants With Shift From Baseline in Laboratory Parameter Values Based on CTCAE v4.03: Chemistry(Phase 1b: Baseline up to 30 days after last dose (maximum up to 9 months approximately), Phase 2: Baseline up to 30 days after last dose (maximum up to 26 months approximately))
- Number of Participants With Shift From Baseline in Laboratory Parameter Values Based on Common Terminology Criteria for Adverse Events (CTCAE) v4.03: Hematology and Coagulation(Phase 1b: Baseline up to 30 days after last dose (maximum up to 9 months approximately), Phase 2: Baseline up to 30 days after last dose (maximum up to 26 months approximately))
- Percentage of Participants With Complete Response as Per RECIST v1.1(From start of the treatment until disease progression, death or initiation of new anticancer therapy, whichever occurred first (Phase 1b: maximum up to 9 months approximately and Phase 2: maximum up to 26 months approximately))
- Phase 1b: Objective Response Rate (ORR) Per RECIST v1.1(From start of the treatment until disease progression, death or initiation of new anticancer therapy, whichever occurred first (Phase 1b: maximum up to 9 months approximately))
- Duration of Response (DOR) as Per RECIST v1.1(From date of first documented CR/PR to date of first documented PD, death or initiation of new anticancer therapy, whichever occurred first (Phase 1b: maximum up to 9 months approximately, Phase 2: maximum up to 26 months approximately))
- Number of Participants With Treatment-Emergent Adverse Events (TEAE) Based on Common Terminology Criteria for Adverse Events (CTCAE) v4.03(From start of the treatment up to 30 days after last dose or start of new anticancer therapy minus 1 day, whichever occurred first (Phase 1b: maximum up to 9 months approximately and Phase 2: maximum up to 26 months approximately))
- Number of Participants With Shift From Baseline in Laboratory Parameter Values Based on Normal Range: Hematology and Coagulation(Phase 1b: Baseline up to 30 days after last dose (maximum up to 9 months approximately), Phase 2: Baseline up to 30 days after last dose (maximum up to 26 months approximately))
- Concentration Versus Time Summary of Plasma Concentration of Binimetinib(1.5 hours post dose of binimetinib on Day 1, 15 of Cycle 1; pre dose of binimetinib on Day 15 of Cycle 1, 2, 3, 4, 5)
- Number of Participants With Shift From Baseline in Laboratory Parameter Values Based on Normal Range: Chemistry and Thyroid Function(Phase 1b: Baseline up to 30 days after last dose (maximum up to 9 months approximately), Phase 2: Baseline up to 30 days after last dose (maximum up to 26 months approximately))