A Study of GFH276 Combined With Cetuximab or Chemotherapy in Participants With Solid Tumors and Pancreatic Ductal Adenocarcinoma (PDAC) Harboring RAS Mutation

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.

• GFH276 (Drug): Oral GFH276 administered once daily in combination with other study drugs.
• Cetuximab (Drug): Intravenous cetuximab at a dose of 500 mg/m²
• Nab paclitaxel (Drug): Intravenous nab-paclitaxel at a dose of 125 mg/m².
• Gemcitabine (Drug): Intravenous Gemcitabine at a dose of 1000 mg/m².
• Fluorouracil (Drug): Intravenous Fluorouracil at a dose of 2400 mg/m² via 46-hour infusion.Dosing may follow the above regimen or local institutional standards.
• Leucovorin (Drug): Intravenous leucovorin at a dose of 400 mg/m².Dosing may follow the above regimen or local institutional standards.
• Irinotecan (Drug): Intravenous irinotecan at a dose of 150 mg/m².Dosing may follow the above regimen or local institutional standards.
• Oxaliplatin (Drug): Intravenous oxaliplatin at a dose of 85 mg/m².Dosing may follow the above regimen or local institutional standards.

Primary outcomes

• Phase Ib:Incidence of Dose-Limiting Toxicity (DLT) Events [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) [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) [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 [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 [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 [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 [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 [up to 24 months]: Number of participants with abnormality in Physical Examination Findings
• Phase Ib: Number of participants with abnormality in PR interval [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) [up to 24 months]: Number of participants with abnormality incorrected QT interval using Frederica's formula (QTcF)

Secondary outcomes

• 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]: Incidence and Severity of AE and SAE，Assessed according to CTCAE 6.0
• 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]: Disease Control Rate (DCR)
• 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]: Duration of Response assessed by investigators
• 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]: Time To Response assessed by investigators
• 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]: Progression-Free Survival (PFS) per Response Evaluation Criteria according to RECIST 1.1, as Determined by investigators
• OS [From the first dose until date of death from any cause, assessed up to 24 months]: Overall Survival
• Time to peak plasma concentration（Tmax） of GFH276 [up to 6 months]: Plasma concentrations of GFH276 and relevant pharmacokinetic parameters including Tmax were evaluated.
• Maximum plasma concentration of GFH276 [up to 6 months]: Plasma concentrations of GFH276 and relevant pharmacokinetic parameters including Cmax were evaluated.
• Area Under the Curve from time zero to 24 hours of GFH276 [up to 6 months]: Plasma concentrations of GFH276 and relevant pharmacokinetic parameters including AUC0-24 were evaluated.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

1. Age ≥ 18 years
2. Histologically or cytologically confirmed locally advanced or metastatic solid tumor and PDAC with RAS mutation or KRAS amplification
3. At least one measurable lesion according to RECIST v1.1
4. ECOG performance status 0 or 1
5. Life expectancy > 3 months
6. Adequate organ function
7. Willing to provide written informed consent
8. Fertile participants must use effective contraception

Exclusion Criteria:

1. Other active malignancy within 3 years
2. Symptomatic brain metastases, leptomeningeal disease, spinal cord compression, or primary brain tumor
3. History of active clinically significant cardiovascular dysfunction
4. For participants with known concomitant second oncodriver for PDAC or for solid tumors.
5. With active infection (HIV, HBV, HCV, syphilis)
6. The presence of clinical or radiological evidence of intestinal obstruction.
7. Prior anticancer therapy within 28 days or 5 half-lives
8. Diagnosis of deep vein thrombosis or pulmonary embolism within 3 months
9. Hypersensitivity to study drugs, or inability to swallow tablets or comply with study procedures.
10. History of central nervous system (CNS)disease
11. Presence of clinically significant interstitial lung disease, radiation pneumonitis, or immune-related pneumonia that requires treatment.
12. With uncontrollable or symptomatic pleural effusion, ascites, or pericardial effusion.