A Phase 3 Randomized, Open-Label, Multicenter Clinical Study of CGT9486+Sunitinib vs. Sunitinib in Subjects With Locally Advanced, Unresectable, or Metastatic Gastrointestinal Stromal Tumors
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 入组人数
- 482
- 试验地点
- 238
- 主要终点
- Part 1a - pharmacokinetics - Cmax
研究概览
简要总结
This is a Phase 3, open-label, international, multicenter study of CGT9486 in combination with sunitinib. This is a multi-part study that will enroll approximately 482 patients. Part 1 consists of two evaluations: 1) confirming the dose of an updated formulation of CGT9486 to be used in subsequent parts in approximately 20 patients who have received at least one prior line of therapy for Gastrointestinal Stromal Tumors (GIST) and 2) evaluating the potential for drug-drug interactions between CGT9486 and sunitinib in approximately 18 patients who have received at least two prior tyrosine kinase inhibitors (TKIs) for GISTs. The second part of the study will enroll approximately 388 patients who are intolerant to, or who failed prior treatment with imatinib only and will compare the efficacy of CGT9486 plus sunitinib to sunitinib alone with patients being randomized in a 1:1 manner. This study also contains two substudies: 1) a drug-drug interactions (DDI) substudy will investigate the potential for CGT9486 to be a Cytochrome P450 (CYP)3A4 inducer in approximately 16 patients who have received at least one prior line of therapy for GIST and 2) a substudy intended to test the efficacy of bezuclastinib and sunitinib as first-line (1L) treatment of GIST in approximately 40 participants with KIT exon 9 mutations and no prior systemic therapy (with the exception of up to 10 subjects with ongoing imatinib therapy of ≤4 weeks).
研究设计
- 研究类型
- Interventional
- 分配方式
- 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 locally advanced, metastatic, and/or unresectable GIST. Molecular pathology report must be available for Part 2; if molecular pathology report is unavailable or inadequate, an archival or fresh tumor tissue sample will be required to evaluate mutational status prior to randomization. (GIST 1L Substudy: must have documented mutation in KIT Exon 9 with an available molecular pathology report; archival or fresh tumor tissue sample will be required)
- •Documented disease progression on or intolerance to imatinib (Part 1a, Part 1b, Part 2, DDI Substudy)
- •Subjects must have received the following treatment:
- •DDI Substudy/Part 1a: Treatment with ≥1 prior lines of therapy for GIST
- •Part 1b: Treatment with ≥2 prior TKI for GISTs
- •Part 2: Prior treatment with imatinib only
- •GIST 1L Substudy: No prior systemic therapy for GIST including adjuvant therapy. Exception: up to 10 subjects with ongoing imatinib therapy of ≤4 weeks
- •Have at least 1 measurable lesion according to mRECIST v1.1 (Part1a, Part 1b, Part 2, GIST 1L Substudy)
- •Eastern Cooperative Oncology Group (ECOG) Status
- •0 to 2 (Part 1a, Part 1b, Part 2, DDI Substudy)
- •0 to 1 (GIST 1L Substudy)
- •Have clinically acceptable local laboratory screening results (clinical chemistry and hematology) within certain limits
排除标准
- •Known Platelet-Derived Growth Factor Receptor (PDGFR) driving mutations or known succinate dehydrogenase deficiency (Part 1a, Part 1b, Part 2, DDI Substudy)
- •Clinically significant cardiac disease
- •Major surgeries (eg, abdominal laparotomy) within 4 weeks of the first dose of study drug (Part 1a, Part 1b, Part 2, DDI Substudy)
- •Gastrointestinal abnormalities including, but not limited to, significant nausea and vomiting, malabsorption, external biliary shunt, or significant bowel resection that would preclude adequate absorption
- •Any active bleeding excluding hemorrhoidal or gum bleeding
- •Seropositive for HIV 1 or 2, or positive for hepatitis B surface antigen or hepatitis C virus (HCV) antibody.
- •Active, uncontrolled, systemic bacterial, fungal, or viral infections at Screening
- •Received strong CYP3A4 inhibitors or inducers (Part 1a, Part 1b, Part 2, DDI Substudy)
- •Received sunitinib within 3 weeks (Part 1a, Part 1b, DDI Substudy)
研究组 & 干预措施
Part 2 - Control Group
sunitinib 37.5 mg QD
干预措施: Sunitinib (Drug)
DDI Substudy (Midazolam)
Midazolam, CGT9486, sunitinib
干预措施: Midazolam (Drug)
Part 1b - DDI Cohort 2
sunitinib 37.5 mg QD plus CGT9486
干预措施: Sunitinib (Drug)
GIST 1L Substudy
CGT9486, sunitinib
干预措施: Sunitinib (Drug)
Part 1a
CGT9486 plus sunitinib 37.5 mg QD
干预措施: CGT9486 (Drug)
Part 1a
CGT9486 plus sunitinib 37.5 mg QD
干预措施: Sunitinib (Drug)
Part 2 - Experimental Group
CGT9486 plus sunitinib 37.5 mg QD
干预措施: CGT9486 (Drug)
Part 2 - Experimental Group
CGT9486 plus sunitinib 37.5 mg QD
干预措施: Sunitinib (Drug)
Part 1b - DDI Cohort 1
CGT9486 plus sunitinib 37.5 mg QD
干预措施: Sunitinib (Drug)
Part 1b - DDI Cohort 2
sunitinib 37.5 mg QD plus CGT9486
干预措施: CGT9486 (Drug)
DDI Substudy (Midazolam)
Midazolam, CGT9486, sunitinib
干预措施: CGT9486 (Drug)
DDI Substudy (Midazolam)
Midazolam, CGT9486, sunitinib
干预措施: Sunitinib (Drug)
GIST 1L Substudy
CGT9486, sunitinib
干预措施: CGT9486 (Drug)
Part 1b - DDI Cohort 1
CGT9486 plus sunitinib 37.5 mg QD
干预措施: CGT9486 (Drug)
结局指标
主要结局
Part 1a - pharmacokinetics - Cmax
时间窗: 16 days
Maximum plasma concentration (Cmax)
Part 1a - pharmacokinetics - AUC
时间窗: 16 days
Area under the plasma concentration-time curve (AUC)
Part 1b - pharmacokinetics - Cmax
时间窗: 14 days
Maximum plasma concentration (Cmax)
Part 1b - pharmacokinetics - AUC
时间窗: 14 days
Area under the plasma concentration-time curve (AUC)
Part 1b - pharmacokinetics - Tmax
时间窗: 14 days
Time to maximum observed plasma concentration (Tmax)
Part 2 - Progression Free Survival (PFS)
时间窗: Approximately 48 months
Time from first dose to documented disease progression or death due to any cause, whichever occurs first
DDI Substudy - pharmacokinetics - AUC
时间窗: 16 days
Area under the plasma concentration-time curve (AUC)
DDI Substudy - pharmacokinetics - Cmax
时间窗: 14 days
Maximum plasma concentration (Cmax)
次要结局
- All Study Parts - observing the safety of each treatment regimen.(Approximately 48 months)
- Part 1a, Part 1b, Part 2 - Overall Survival (OS)(Approximately 48 months)
- Part 1a, Part 1b, Part 2 - Objective Response Rate (ORR)(Approximately 48 months)
- Part 1a, Part 1b, Part 2 - Disease Control Rate (DCR)(Approximately 48 months)
- Part 1a, Part 1b. Part 2 - Time to response (TTR)(Approximately 48 months)
- Part 1a, Part 1b, Part 2 - Duration of Response (DOR)(Approximately 48 months)
- Part 2 Only - European Organisation for Research and Treatment of Cancer Quality of Life (EORTC-QLQ-30)(Approximately 48 months)