A Phase 1b/2, Open-label, Multicenter Study to Evaluate the Safety, Tolerability, Efficacy, and Pharmacokinetics of Ripretinib in Combination With Binimetinib in Patients With Gastrointestinal Stromal Tumor (GIST)
试验速览
- 阶段
- 1 期
- 状态
- 撤回
- 主要终点
- Safety/tolerability of oral ripretinib in combination with binimetinib: incidence of adverse events
研究概览
简要总结
Multicenter, open-label Phase 1b/2 study of ripretinib in combination with binimetinib in patients with gastrointestinal stromal tumor (GIST). There will be 2 distinct parts in this study: Dose Escalation (Phase 1) and Expansion (Phase 2).
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 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients ≥18 years of age with advanced GIST (unresectable or metastatic).
- •Must have at least progressed on imatinib or have documented intolerance to imatinib.
- •Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or
- •Patients must have a histologic diagnosis of GIST.
- •If a female of childbearing potential, must have a negative pregnancy test.
- •Adequate organ function and bone marrow function
排除标准
- •Received prior anticancer therapy within 14 days or 5× the half-life whichever is longer) prior to the first dose.
- •Ongoing or prior participation in the DCC-2618-03-002 study.
- •Prior therapy with ripretinib.
- •Prior therapy with MEK inhibitor.
- •History of certain ocular disorders.
- •History of clinically significant hepatobiliary disease.
- •Known active central nervous system metastases.
- •History or presence of clinically relevant cardiovascular abnormalities.
- •Systemic arterial or venous thrombotic or embolic events within 6 months of first dose.
- •History of acute or chronic pancreatitis
- •History of chronic inflammatory bowel disease or Crohn's disease requiring intervention within 12 months of first dose.
- •Gastrointestinal abnormalities including but not limited to:
- •inability to take oral medication,
- •malabsorption syndromes
研究组 & 干预措施
Escalation
Escalation Phase: Increasing doses of ripretinib in combination with increase doses of binimetinib in patients with advanced GIST who have progressed on at least imatinib or are intolerant to imatinib and are ripretinib naïve in repeated 28-day cycles.
Participants may remain on treatment until disease progression, unacceptable toxicity, or withdrawal of consent
干预措施: Ripretinib (Drug)
Escalation
Escalation Phase: Increasing doses of ripretinib in combination with increase doses of binimetinib in patients with advanced GIST who have progressed on at least imatinib or are intolerant to imatinib and are ripretinib naïve in repeated 28-day cycles.
Participants may remain on treatment until disease progression, unacceptable toxicity, or withdrawal of consent
干预措施: binimetinib (Drug)
Expansion
Ripretinib in combination with binimetinib at the recommended Phase 2 dose (RP2D) in patients with advanced GIST who have progressed on imatinib or are intolerant to imatinib and are naïve.
Participants may remain on treatment until disease progression, unacceptable toxicity, or withdrawal of consent
干预措施: Ripretinib (Drug)
Expansion
Ripretinib in combination with binimetinib at the recommended Phase 2 dose (RP2D) in patients with advanced GIST who have progressed on imatinib or are intolerant to imatinib and are naïve.
Participants may remain on treatment until disease progression, unacceptable toxicity, or withdrawal of consent
干预措施: binimetinib (Drug)
结局指标
主要结局
Safety/tolerability of oral ripretinib in combination with binimetinib: incidence of adverse events
时间窗: Approximately 12 months
Adverse events \[TEAEs, SAEs, AESIs\], dose reduction, dose interruption, or discontinuation, vital signs (heart rate \[beats/min\], and changes in laboratory parameters (chemistry, hematology, urinalysis, coagulation).
Determination of the Maximum Tolerated Dose and the Recommended Phase 2 Dose
时间窗: Approximately 12 months
Expansion Phase Only: Evaluate the objective response rate (ORR) of ripretinib in combination with binimetinib by modified RECIST
时间窗: Approximately 36 months
Measure ORR
次要结局
- Determine the minimum observed concentration (Cmin) profile of oral ripretinib in combination with binimetinib(Cycle 1 Day 1, and Cycle 1 Day15 (pre-dose and at multiple time points [up to 8 hours] post-dose). Each cycle is 28 days)
- Evaluate the progression-free survival (PFS) of ripretinib in combination with binimetinib(Approximately 36 months)
- Evaluate the duration of response (DOR) of ripretinib in combination with binimetinib(Approximately 36 months)
- Determine the time to maximum observed concentration (tmax) profile of oral ripretinib in combination with binimetinib(Cycle 1 Day 1, and Cycle 1 Day15 (pre-dose and at multiple time points [up to 8 hours] post-dose). Each cycle is 28 days)
- Determine the maximum observed concentration (Cmax) profile of oral ripretinib in combination with binimetinib(Cycle 1 Day 1, and Cycle 1 Day15 (pre-dose and at multiple time points [up to 8 hours] post-dose). Each cycle is 28 days)
- Determine the area under the concentration-time curve (AUC) profile of oral ripretinib in combination with binimetinib(Cycle 1 Day 1, and Cycle 1 Day15 (pre-dose and at multiple time points [up to 8 hours] post-dose). Each cycle is 28 days)
- Evaluate the objective response rate (ORR) of ripretinib in combination with binimetinib by modified RECIST (escalation phase only) and Choi criteria (escalation and expansion phases)(Approximately 36 months)
- Evaluate the overall survival (OS) of ripretinib in combination with binimetinib(Approximately 36 months)
- Evaluate the clinical benefit rate (CBR) of ripretinib in combination with binimetinib(Approximately 36 months)
- Evaluate the time to response (TTR) of ripretinib in combination with binimetinib(Approximately 36 months)