A Phase IB, Open-Label, Dose-Escalation Study Evaluating the Safety, Tolerability and Pharmacokinetics of Vemurafenib in Combination With GDC-0973 (Cobimetinib) When Administered in BRAFV600E Mutation-Positive Patients Previously Treated (But Without Prior Exposure to BRAF or MEK Inhibitor Therapy) or Previously Untreated for Locally Advanced/Unresectable or Metastatic Melanoma or Those Who Have Progressed After Treatment With Vemurafenib
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 131
- 试验地点
- 10
- 主要终点
- Cmax of Cobimetinib on Day 14 (Steady State), Cycle 1
研究概览
简要总结
This open-label, dose-escalation study of vemurafenib in combination with cobimetinib will evaluate the safety, tolerability and pharmacokinetics in participants with BRAFV600 mutation-positive metastatic melanoma. Participants with previously untreated, BRAFV600E mutation-positive, locally advanced/unresectable or metastatic melanoma or those who have progressed on vemurafenib monotherapy immediately prior to enrolling in this trial are eligible. Participants will be assigned to different cohorts with escalating oral doses of vemurafenib and cobimetinib. This study consists of 2 stages, Stage 1 (Dose Escalation Stage [DES] and Cohort Expansion Stage [CES]) and the anticipated time on study treatment is until disease progression, unacceptable toxicity or any other discontinuation criterion is met.
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
- •Participants with histologically confirmed melanoma (unresectable Stage IIIc and Stage IV metastatic melanoma, as defined by American Joint Committee on Cancer [AJCC])
- •Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) Version (V) 1.1
- •Eastern Cooperative Oncology Group (ECOG) Performance Status of less than or equal to (</=) 1
- •Participants must
- •be previously untreated for locally advanced/unresectable or metastatic melanoma or
- •previously treated but without prior exposure to any BRAF or MEK inhibitor therapy or
- •progressed on vemurafenib while participating in a Phase I (including clinical pharmacology studies), II, or III clinical study or expanded access programs (EAP) immediately prior to enrollment in this study or
- •progressed on vemurafenib administered in a postmarketing setting immediately prior to enrollment in this study.
- •Life expectancy >/=12 weeks
排除标准
- •History of prior significant toxicity from another RAF or MEK pathway inhibitor requiring discontinuation of treatment
- •Palliative radiotherapy within 2 weeks prior to first dose of study drug treatment
- •Experimental therapy within 4 weeks prior to first dose of study drug treatment except vemurafenib
- •Major surgery within 4 weeks of first dose of study drug treatment or planning a major surgery during the study
研究组 & 干预措施
DES (Cohort 1): 60 mg Cobimetinib + 720 mg Vemurafenib
Participants will receive oral 60 milligrams (mg) cobimetinib once daily (QD) on Days 1-14, followed by 14 days off on Days 15-28 (14/14 dosing schedule) and oral 720 mg vemurafenib twice daily (BID) on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.
干预措施: Cobimetinib (Drug)
DES (Cohort 1): 60 mg Cobimetinib + 720 mg Vemurafenib
Participants will receive oral 60 milligrams (mg) cobimetinib once daily (QD) on Days 1-14, followed by 14 days off on Days 15-28 (14/14 dosing schedule) and oral 720 mg vemurafenib twice daily (BID) on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.
干预措施: vemurafenib (Drug)
DES (Cohort 1A): 60 mg Cobimetinib + 720 mg Vemurafenib
Participants will receive oral 60 mg cobimetinib QD on Days 1-21, followed by 7 days off on Days 22-28 (21/7 dosing schedule) and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.
干预措施: Cobimetinib (Drug)
DES (Cohort 1A): 60 mg Cobimetinib + 720 mg Vemurafenib
Participants will receive oral 60 mg cobimetinib QD on Days 1-21, followed by 7 days off on Days 22-28 (21/7 dosing schedule) and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.
干预措施: vemurafenib (Drug)
DES (Cohort 1B): 60 mg Cobimetinib + 960 mg Vemurafenib
Participants will receive oral 60 mg cobimetinib QD on 21/7 dosing schedule and oral 960 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.
干预措施: Cobimetinib (Drug)
DES (Cohort 1B): 60 mg Cobimetinib + 960 mg Vemurafenib
Participants will receive oral 60 mg cobimetinib QD on 21/7 dosing schedule and oral 960 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.
干预措施: vemurafenib (Drug)
DES (Cohort 1C): 60 mg Cobimetinib + 720 mg Vemurafenib
Participants will receive oral 60 mg cobimetinib QD on Days 1-28 (28/0 dosing schedule) and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.
干预措施: Cobimetinib (Drug)
DES (Cohort 1C): 60 mg Cobimetinib + 720 mg Vemurafenib
Participants will receive oral 60 mg cobimetinib QD on Days 1-28 (28/0 dosing schedule) and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.
干预措施: vemurafenib (Drug)
DES (Cohort 1D): 60 mg Cobimetinib + 960 mg Vemurafenib
Participants will receive oral 60 mg cobimetinib QD on 28/0 dosing schedule and oral 960 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.
干预措施: Cobimetinib (Drug)
DES (Cohort 1D): 60 mg Cobimetinib + 960 mg Vemurafenib
Participants will receive oral 60 mg cobimetinib QD on 28/0 dosing schedule and oral 960 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.
干预措施: vemurafenib (Drug)
DES (Cohort 2): 80 mg Cobimetinib + 720 mg Vemurafenib
Participants will receive oral 80 mg cobimetinib QD on 14/14 dosing schedule and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.
干预措施: Cobimetinib (Drug)
DES (Cohort 2): 80 mg Cobimetinib + 720 mg Vemurafenib
Participants will receive oral 80 mg cobimetinib QD on 14/14 dosing schedule and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.
干预措施: vemurafenib (Drug)
DES (Cohort 2A): 100 mg Cobimetinib + 720 mg Vemurafenib
Participants will receive oral 100 mg cobimetinib QD on 14/14 dosing schedule and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.
干预措施: Cobimetinib (Drug)
DES (Cohort 2A): 100 mg Cobimetinib + 720 mg Vemurafenib
Participants will receive oral 100 mg cobimetinib QD on 14/14 dosing schedule and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.
干预措施: vemurafenib (Drug)
DES (Cohort 3): 60 mg Cobimetinib + 960 mg Vemurafenib
Participants will receive oral 60 mg cobimetinib QD on 14/14 dosing schedule and oral 960 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.
干预措施: Cobimetinib (Drug)
DES (Cohort 3): 60 mg Cobimetinib + 960 mg Vemurafenib
Participants will receive oral 60 mg cobimetinib QD on 14/14 dosing schedule and oral 960 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.
干预措施: vemurafenib (Drug)
DES (Cohort 4): 80 mg Cobimetinib + 960 mg Vemurafenib
Participants will receive oral 80 mg cobimetinib QD on 14/14 dosing schedule and oral 960 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.
干预措施: Cobimetinib (Drug)
DES (Cohort 4): 80 mg Cobimetinib + 960 mg Vemurafenib
Participants will receive oral 80 mg cobimetinib QD on 14/14 dosing schedule and oral 960 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.
干预措施: vemurafenib (Drug)
Cobimetinib Monotherapy (100 mg or 60 mg)
Participants will receive oral 60 mg cobimetinib QD on 21/7 dosing schedule, or oral 100 mg cobimetinib QD on 14/14 dosing schedule of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.
干预措施: Cobimetinib (Drug)
CES (Cohort 1A): 60 mg Cobimetinib + 720 mg Vemurafenib
Participants will receive oral 60 mg cobimetinib QD on 21/7 dosing schedule and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.
干预措施: Cobimetinib (Drug)
CES (Cohort 1A): 60 mg Cobimetinib + 720 mg Vemurafenib
Participants will receive oral 60 mg cobimetinib QD on 21/7 dosing schedule and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.
干预措施: vemurafenib (Drug)
CES (Cohort 1B): 60 mg Cobimetinib + 960 mg Vemurafenib
Participants will receive oral 60 mg cobimetinib QD on 21/7 dosing schedule and oral 960 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.
干预措施: Cobimetinib (Drug)
CES (Cohort 1B): 60 mg Cobimetinib + 960 mg Vemurafenib
Participants will receive oral 60 mg cobimetinib QD on 21/7 dosing schedule and oral 960 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.
干预措施: vemurafenib (Drug)
结局指标
主要结局
Cmax of Cobimetinib on Day 14 (Steady State), Cycle 1
时间窗: Cycle 1: predose (0 hr) on Days 8, 14; 0.5, 1, 2, 4, 6 hr postdose on Day 14
Cmax of Vemurafenib on Day -1, Cycle 1 of Cohorts 1C and 2A in Participants Previously Treated With Vemurafenib Prior to Enrollment Into This Study
时间窗: Predose (0 hr) on Day -1, 1; 2, 4, 6, 8 hr postdose on Day -1
Tmax of Vemurafenib on Day -1, Cycle 1 in Participants Previously Treated With Vemurafenib Prior to Enrollment Into This Study
时间窗: Predose (0 hr) on Day -1, 1; 2, 4, 6, 8 hr postdose on Day -1
Cmax of Vemurafenib on Day 1, Cycle 1 in BRAFi-naïve Participants
时间窗: Predose (0 hr) on Day 1, 2; 0.5, 1, 2, 4, 6 hr postdose on Day 1
Cmax of Vemurafenib on Day 1, Cycle 1 in Cohort 1A in BRAFi-naïve Participants
时间窗: Predose (0 hr) on Day 1, 2; 0.5, 1, 2, 4, 6 hr postdose on Day 1
Tmax of Vemurafenib on Day 1, Cycle 1 in BRAFi-naïve Participants
时间窗: Predose (0 hr) on Day 1, 2; 0.5, 1, 2, 4, 6 hr postdose on Day 1
Cmax of Vemurafenib on Day 14, Cycle 1
时间窗: Predose (0 hr) on Days 14, 15; 0.5, 1, 2, 4, 6, 8 hr postdose on Day 14
Tmax of Vemurafenib on Day 14, Cycle 1
时间窗: Predose (0 hr) on Days 14, 15; 0.5, 1, 2, 4, 6, 8 hr postdose on Day 14
Cmax of Cobimetinib on Day 1, Cycle 1 in Cohort 3
时间窗: Cycle 1: predose (0 hr) on Days 1, 2; 0.5, 1, 2, 4, 6 hr postdose on Day 1
Number of Participants With Dose-Limiting Toxicities (DLTs) During DES in Combination Cohorts
时间窗: 28 Days
DLT is defined as 1 of the following toxicities considered by the investigator to be related to study treatment: a) Grade 3 nausea, vomiting or diarrhea that resolved to Grade less than or equal to (≤) 1 within 7 days, b) Grade 3 rash or photosensitivity that resolved to Grade ≤2 within 7 days, c) Grade 3 cutaneous squamous cell carcinoma (cuSCC) that was subsequently resected, d) Grade greater than or equal to (≥) 3 fatigue or hyperuricemia that resolved to Grade ≤2 within 7 days, e) Grade 3 fever, f) Grade 3 or 4 elevation of serum creatine phosphokinase (CPK) levels, which is asymptomatic, deemed by the investigator to be clinically insignificant and that returned to Grade ≤2 during the 14-day cobimetinib treatment holiday, g) Grade ≥3 febrile neutropenia, h) Grade ≥4 neutropenia (absolute neutrophil count \[ANC\] less than \<500/microliter \[μL\]), i) Grade ≥4 thrombocytopenia, j) Grade ≥4 anemia, k) Grade ≥3 elevation of total bilirubin, hepatic transaminase or alkaline phosphatase.
Maximum Tolerated Doses (MTD) of Vemurafenib and Cobimetinib When Administered in Combination in DES
时间窗: 28 Days
The highest dose level(s) at which fewer than one-third of participants experienced a DLT was declared the MTD. DLT is defined as 1 of the following toxicities considered by the investigator to be related to study treatment: a) Grade 3 nausea, vomiting or diarrhea that resolved to Grade ≤1 within 7 days, b) Grade 3 rash/photosensitivity that resolved to Grade ≤2 within 7 days, c) Grade 3 cuSCC that was subsequently resected, d) Grade ≥3 fatigue/hyperuricemia that resolved to Grade ≤2 within 7 days, e) Grade 3 fever, f) Grade 3 or 4 elevation of serum CPK levels, which is asymptomatic, deemed to be clinically insignificant and returns to Grade ≤2 during the 14-day cobimetinib treatment holiday, g) Grade ≥3 febrile neutropenia, h) Grade ≥4 neutropenia (ANC \<500/ μL), i) Grade ≥4 thrombocytopenia, j) Grade ≥4 anemia, k) Grade ≥3 elevation of total bilirubin, hepatic transaminase or alkaline phosphatase.
Maximum Plasma Concentration (Cmax) of Cobimetinib on Day 1, Cycle 1
时间窗: Cycle 1: predose (0 hours [hr]) on Days 1, 2; 0.5, 1, 2, 4, 6 hr postdose on Day 1
Time Taken to Reach Maximum Plasma Concentration (Tmax) of Cobimetinib on Day 1, Cycle 1
时间窗: Cycle 1: predose (0 hr) on Days 1, 2; 0.5, 1, 2, 4, 6 hr postdose on Day 1
Area Under Concentration Versus Time Curve (AUC) Over a Period of 24 Hours (AUC0-24) of Cobimetinib on Day 1, Cycle 1
时间窗: Cycle 1: predose (0 hr) on Days 1, 2; 0.5, 1, 2, 4, 6 hr postdose on Day 1
AUC0-24 of Cobimetinib on Day 1, Cycle 1 of Cohort 3
时间窗: Cycle 1: predose (0 hr) on Days 1, 2; 0.5, 1, 2, 4, 6 hr postdose on Day 1
AUC0-24 of Cobimetinib on Day 14, Cycle 1
时间窗: Cycle 1: predose (0 hr) on Days 8, 14; 0.5, 1, 2, 4, 6 hr postdose on Day 14
Clearance (CL) of Cobimetinib on Day 14 (Steady State), Cycle 1
时间窗: Cycle 1: predose (0 hr) on Days 8, 14; 0.5, 1, 2, 4, 6 hr postdose on Day 14
Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes.
Tmax of Cobimetinib on Day 14 (Steady State), Cycle 1
时间窗: Cycle 1: predose (0 hr) on Days 8, 14; 0.5, 1, 2, 4, 6 hr postdose on Day 14
Cmax of Vemurafenib on Day -1, Cycle 1 in Participants Previously Treated With Vemurafenib Prior to Enrollment Into This Study
时间窗: Predose (0 hr) on Days -1, 1; 2, 4, 6, 8 hr postdose on Day -1
次要结局
- Percentage of Participants With an Objective Response of Complete Response (CR) or Partial Response (PR) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version (V) 1.1(Assessed at screening (within 28 days prior to initiation of Cycle 1), every 6 weeks thereafter until disease progression (up to 82 months))
- Percentage of Participants With Disease Progression According to RECIST V 1.1(Assessed at screening (within 28 days prior to initiation of Cycle 1), every 6 weeks thereafter until disease progression or death (up to 82 months))
- Median Duration of Response (DOR)(Time from first occurrence of objective response until the time of disease progression or death from any cause (up to 82 months))
- Overall Survival (OS)(Assessed at screening (within 28 days prior to initiation of Cycle 1), every 6 weeks thereafter until disease progression or death (up to 82 months))
- Average Percent Change From Baseline in Fluorodeoxyglucose-positron Emission Tomography (FDG-PET) at Cycle 1 and Cycle 2(Cycle 1 (Days 10 to 14), Cycle 2 (Days 14+7))
- Pharmacodynamics: Number of Participants With Mitogen-Activated Protein Kinase (MAPK) Inhibition, as Assessed by Immunohistochemistry (IHC)(At baseline; Cycle 1: Day 14; at disease progression (Up to 32 months))