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

Official title

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

Overview

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

Detailed description

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.

Interventions

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

Primary outcome measures

• Phase Ib:Incidence of Dose-Limiting Toxicity (DLT) Events [Time frame: First 28 days (21 days for AG （3-week cycle）)]
• Phase Ib:Incidence and Severity of Adverse Events (AE) and Serious Adverse Events (SAE) [Time frame: From the first dose until 30 days after the last dose, assessed up to 24 months]
• Phase II:Objective Response Rate (ORR) [Time frame: 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]
• Phase Ib: Number of participants with abnormality in hematology laboratory parameters [Time frame: up to 24 months]
• Phase Ib: Number of participants with abnormality in clinical chemistry laboratory assessments [Time frame: up to 24 months]
• Phase Ib: Number of participants with abnormality in body temperature [Time frame: up to 24 months]
• Phase Ib: Number of participants with abnormality in blood pressure [Time frame: up to 24 months]
• Phase Ib: Number of participants with abnormality in Physical Examination Findings [Time frame: up to 24 months]
• Phase Ib: Number of participants with abnormality in PR interval [Time frame: up to 24 months]
• Phase Ib: Number of participants with abnormality in corrected QT interval using Frederica's formula (QTcF) [Time frame: up to 24 months]

Secondary outcome measures (9)

• Phase II: Incidence and Severity of AE and SAE [Time frame: From the first dose until 30 days after the last dose, assessed up to 24 months]
• DCR [Time frame: 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 [Time frame: 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 [Time frame: 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 [Time frame: 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 [Time frame: From the first dose until date of death from any cause, assessed up to 24 months]
• Time to peak plasma concentration（Tmax） of GFH276 [Time frame: up to 6 months]
• Maximum plasma concentration of GFH276 [Time frame: up to 6 months]
• Area Under the Curve from time zero to 24 hours of GFH276 [Time frame: up to 6 months]

Eligibility criteria

Inclusion criteria

• 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

Exclusion criteria

• 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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

China · 11 centers

• Peking Union Medical College Hospital — Beijing
• Sun Yat-sen Memorial Hospital, Sun Yat-sen University — Guangzhou
• The Third Affiliated Hospital (Cancer Hospital) of Harbin Medical University — Harbin
• The First Affiliated Hospital of Zhengzhou University — Zhengzhou
• Union Hospital, Tongji Medical College, Huazhong University of Science and Technology — Wuhan
• The First Affiliated Hospital of China Medical University — Shenyang
• The First Affiliated Hospital of Xi'an Jiaotong University — Xi'an
• Shandong First Medical University Affiliated Tumor Hospital — Jinan
• … and 3 more centers

Australia · 6 centers

• Concord Cancer Centre, Concord Repatriation General Hospital, Sydney Local Health District — Concord
• Macquarie University / Clinical Trials Unit — North Ryde
• The Queen Elizabeth Hospital — Woodville South
• Monash Health (Monash Medical Centre) — Clayton
• Northern Health — Epping
• PASO Medical — Frankston

Identifiers

NCT: NCT07678593 · GFH276X0201

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗