A Multi-center, Open-label Phase Ib/II Study Exploring the Safety/Tolerability, Pharmacokinetics, and Efficacy of GFH276 in Combination With Cetuximab or Chemotherapy in the Treatment of Patients With Advanced Solid Tumors and Pancreatic Ductal Adenocarcinoma (PDAC) Harboring RAS Mutation
试验速览
- 阶段
- 1 期
- 状态
- 尚未招募
- 入组人数
- 222
- 试验地点
- 17
- 主要终点
- Phase Ib:Incidence of Dose-Limiting Toxicity (DLT) Events
研究概览
简要总结
A Study of GFH276 Combined With Cetuximab or Chemotherapy in Participants With Solid Tumors and Pancreatic Ductal Adenocarcinoma (PDAC) Harboring RAS Mutation
详细描述
This is an open-label, multicenter Phase Ib/II clinical trial to evaluate the safety, tolerability, and preliminary anti-tumor efficacy of oral GFH276 in combination with cetuximab or standard chemotherapy in adult patients with locally advanced or metastatic RAS-mutated solid tumors and pancreatic ductal adenocarcinoma (PDAC).
Participants will be enrolled into three treatment arms with different combination regimens.
In the Phase Ib stage, dose escalation of GFH276 will be performed in each combination arm to identify the optimal recommended Phase 2 dose (RP2D) based on dose-limiting toxicity (DLT) and the overall safety profile. After RP2D determination, Phase II expansion cohorts will enroll eligible patients to further evaluate the anti-tumor efficacy and long-term safety of each combination regimen. Study-related assessments will include tumor imaging, laboratory tests, adverse event monitoring, and pharmacokinetic sampling throughout the treatment period.
Participants will continue their assigned study treatment until confirmed disease progression, intolerable toxicity, withdrawal of consent, or study closure.
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
- •Age ≥ 18 years
- •Histologically or cytologically confirmed locally advanced or metastatic solid tumor and PDAC with RAS mutation or KRAS amplification
- •At least one measurable lesion according to RECIST v1.1
- •ECOG performance status 0 or 1
- •Life expectancy > 3 months
- •Adequate organ function
- •Willing to provide written informed consent
- •Fertile participants must use effective contraception
排除标准
- •Other active malignancy within 3 years
- •Symptomatic brain metastases, leptomeningeal disease, spinal cord compression, or primary brain tumor
- •History of active clinically significant cardiovascular dysfunction
- •For participants with known concomitant second oncodriver for PDAC or for solid tumors.
- •With active infection (HIV, HBV, HCV, syphilis)
- •The presence of clinical or radiological evidence of intestinal obstruction.
- •Prior anticancer therapy within 28 days or 5 half-lives
- •Diagnosis of deep vein thrombosis or pulmonary embolism within 3 months
- •Hypersensitivity to study drugs, or inability to swallow tablets or comply with study procedures.
- •History of central nervous system (CNS)disease
- •Presence of clinically significant interstitial lung disease, radiation pneumonitis, or immune-related pneumonia that requires treatment.
- •With uncontrollable or symptomatic pleural effusion, ascites, or pericardial effusion.
研究组 & 干预措施
Arm A: GFH276 + Cetuximab
GFH276 once daily; cetuximab 500 mg/m² intravenous infusion every 2 weeks.
干预措施: GFH276 (Drug)
Arm B: GFH276 + AG
GFH276 once daily; nab-paclitaxel 125 mg/m² + gemcitabine 1000 mg/m² (AG regimen); 4-week cycle (D1, D8, D15) or 3-week cycle (D1, D8) in China
干预措施: Gemcitabine (Drug)
Arm B: GFH276 + AG
GFH276 once daily; nab-paclitaxel 125 mg/m² + gemcitabine 1000 mg/m² (AG regimen); 4-week cycle (D1, D8, D15) or 3-week cycle (D1, D8) in China
干预措施: Nab paclitaxel (Drug)
Arm C: GFH276 + mFOLFIRINOX
GFH276 once daily; mFOLFIRINOX :Fluorouracil 2400 mg/m²(46 h), Leucovorin 400 mg/m², Irinotecan 150 mg/m², Oxaliplatin 85 mg/m², IV D1, every 2 weeks .
The mFOLFIRINOX regimen may be administered per the above dosage, or in accordance with national or institutional guidelines.
干预措施: Fluorouracil (Drug)
Arm C: GFH276 + mFOLFIRINOX
GFH276 once daily; mFOLFIRINOX :Fluorouracil 2400 mg/m²(46 h), Leucovorin 400 mg/m², Irinotecan 150 mg/m², Oxaliplatin 85 mg/m², IV D1, every 2 weeks .
The mFOLFIRINOX regimen may be administered per the above dosage, or in accordance with national or institutional guidelines.
干预措施: Irinotecan (Drug)
Arm A: GFH276 + Cetuximab
GFH276 once daily; cetuximab 500 mg/m² intravenous infusion every 2 weeks.
干预措施: Cetuximab (Drug)
Arm C: GFH276 + mFOLFIRINOX
GFH276 once daily; mFOLFIRINOX :Fluorouracil 2400 mg/m²(46 h), Leucovorin 400 mg/m², Irinotecan 150 mg/m², Oxaliplatin 85 mg/m², IV D1, every 2 weeks .
The mFOLFIRINOX regimen may be administered per the above dosage, or in accordance with national or institutional guidelines.
干预措施: Leucovorin (Drug)
Arm C: GFH276 + mFOLFIRINOX
GFH276 once daily; mFOLFIRINOX :Fluorouracil 2400 mg/m²(46 h), Leucovorin 400 mg/m², Irinotecan 150 mg/m², Oxaliplatin 85 mg/m², IV D1, every 2 weeks .
The mFOLFIRINOX regimen may be administered per the above dosage, or in accordance with national or institutional guidelines.
干预措施: Oxaliplatin (Drug)
Arm B: GFH276 + AG
GFH276 once daily; nab-paclitaxel 125 mg/m² + gemcitabine 1000 mg/m² (AG regimen); 4-week cycle (D1, D8, D15) or 3-week cycle (D1, D8) in China
干预措施: GFH276 (Drug)
Arm C: GFH276 + mFOLFIRINOX
GFH276 once daily; mFOLFIRINOX :Fluorouracil 2400 mg/m²(46 h), Leucovorin 400 mg/m², Irinotecan 150 mg/m², Oxaliplatin 85 mg/m², IV D1, every 2 weeks .
The mFOLFIRINOX regimen may be administered per the above dosage, or in accordance with national or institutional guidelines.
干预措施: GFH276 (Drug)
结局指标
主要结局
Phase Ib:Incidence of Dose-Limiting Toxicity (DLT) Events
时间窗: First 28 days (21 days for AG （3-week cycle）)
The incidence of DLT events
Phase Ib:Incidence and Severity of Adverse Events (AE) and Serious Adverse Events (SAE)
时间窗: From the first dose until 30 days after the last dose, assessed up to 24 months
The incidence and severity of AEs and SAEs，according to NCI CTCAE，v6.0
Phase II:Objective Response Rate (ORR)
时间窗: From the first dose until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 24 months
Assessed by investigators according to RECIST 1.1
Phase Ib: Number of participants with abnormality in hematology laboratory parameters
时间窗: up to 24 months
Number of participants with abnormality in hematology laboratory parameters，Hematology assessments will include hemoglobin, white blood cell count, differential white blood cell counts and platelet count
Phase Ib: Number of participants with abnormality in clinical chemistry laboratory assessments
时间窗: up to 24 months
Number of participants with abnormality in clinical chemistry laboratory assessments， assessments will include serum chemistry (such as sodium, potassium, urea, creatinine) and liver function parameters, including alanine aminotransferase (ALT), aspartate aminotransferase (AST) and bilirubin.
Phase Ib: Number of participants with abnormality in body temperature
时间窗: up to 24 months
Number of participants with abnormality in body temperature(°C), throughout the study.
Phase Ib: Number of participants with abnormality in blood pressure
时间窗: up to 24 months
Number of participants with abnormality in blood pressure, including systolic blood pressure (mmHg) and diastolic blood pressure (mmHg)
Phase Ib: Number of participants with abnormality in Physical Examination Findings
时间窗: up to 24 months
Number of participants with abnormality in Physical Examination Findings
Phase Ib: Number of participants with abnormality in PR interval
时间窗: up to 24 months
Number of participants with abnormality in electrocardiogram (ECG) parameters, including PR interval
Phase Ib: Number of participants with abnormality in corrected QT interval using Frederica's formula (QTcF)
时间窗: up to 24 months
Number of participants with abnormality incorrected QT interval using Frederica's formula (QTcF)
次要结局
- Phase II: Incidence and Severity of AE and SAE(From the first dose until 30 days after the last dose, assessed up to 24 months)
- DCR(From the first dose until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 24 months)
- DoR(From the first dose until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 24 months)
- TTR(From the first dose until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 24 months)
- PFS(From the first dose until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 24 months)
- OS(From the first dose until date of death from any cause, assessed up to 24 months)
- Time to peak plasma concentration（Tmax） of GFH276(up to 6 months)
- Maximum plasma concentration of GFH276(up to 6 months)
- Area Under the Curve from time zero to 24 hours of GFH276(up to 6 months)