A Study to Evaluate GFH375 Versus Docetaxel in Participants With Non-Small Cell Lung Cancer With KRAS G12D Mutation

Official title

A Phase III, Randomized, Open-Label, Multicenter Study to Evaluate GFH375 Versus Docetaxel in Participants With Locally Advanced and Unresectable or Metastatic Non-Small Cell Lung Cancer With KRAS G12D Mutation Failed Prior Standard Therapy

Overview

The purpose of this study is to compare the effectiveness, safety and tolerability of GFH375 versus docetaxel in participants with KRAS G12D-mutant non-small cell lung cancer (NSCLC). GFH375 is an oral, highly selective, non-covalent small-molecule inhibitor targeting the KRAS G12D mutation. Preclinical studies showed GFH375 strongly blocks KRAS-driven signaling and cancer cell growth, and demonstrated anti-tumor activity in NSCLC animal models. Docetaxel is a chemotherapy drug for locally advanced or metastatic NSCLC. This is an open-label, randomized controlled trial. Both participant and study doctor will know which study medication each participant receives. After enrollment, participant will be randomly assigned to either the GFH375 group or docetaxel group by chance. Neither participant nor study doctor can pick your treatment group. You have a two-thirds chance to receive GFH375 and a one-third chance to receive docetaxel. * GFH375 group: Take GFH375 tablets by mouth once daily as scheduled; each treatment cycle lasts 21 days. * Docetaxel group: Receive docetaxel via intravenous infusion at 75 mg/m² once every 3 weeks. Study treatment will continue until cancer gets worse, participant can't tolerate the study treatment, or other conditions make participant unable to keep receiving study treatment. Some participants on docetaxel may be able to switch to GFH375 during the study if their cancer becomes worse. There will be safety checks at each visit, and the doctors will continue to check for medical problems and participant 's wellbeing throughout the study. Participants will continue to have scans of their tumor every 6 weeks for the first year, then every 9 weeks until their cancer becomes worse. After participant's cancer becomes worse, clinic staff will telephone participant every 3 mouths to check on their cancer.

Interventions

• Drug GFH375
  GFH375 administered orally at the protocol-specified dose once daily. Each treatment cycle is 21 days.
• Drug Docetaxel
  Receive docetaxel via intravenous infusion at 75 mg/m² once every 3 weeks.

Primary outcome measures

• Objective Response Rate(ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. as assessed by blinded independent central review (BICR) [Time frame: From the first dose until the date of first documented CR or PR, assessed up to 24 months]
• Progression-Free Survival (PFS) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. as assessed by blinded independent central review (BICR) [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.]
• Overall Survival (OS) [Time frame: From the first dose until the date of death from any cause, whichever came first, assessed up to 36~48 months]

Secondary outcome measures (12)

• Objective Response Rate (ORR) per RECIST v1.1, as assessed by the investigator [Time frame: From the first dose until the date of first documented CR or PR,assessed up to 24 months.]
• PFS per RECIST v1.1. as assessed by the investigator [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.]
• DCR per RECIST v 1.1 as assessed by the investigator and the BICR [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 per RECIST v 1.1 as assessed by the investigator and the BICR [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 per RECIST v 1.1 as assessed by the investigator and the BICR [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.]
• Number of Participants with Adverse Events (AEs) [Time frame: From the first dose until 30 days after the last dose, assessed up to 24 months.]
• Severity of Adverse Events(AEs) [Time frame: From the first dose until 30 days after the last dose, assessed up to 24 months.]
• Incidence of AEs that result in treatment discontinuation, treatment interruption, or dose reduction. [Time frame: From the first dose until 30 days after the last dose, assessed up to 24 months.]
• Severity of adverse events (AEs) leading to treatment discontinuation, treatment interruption, and dose reduction. [Time frame: From the first dose until 30 days after the last dose, assessed up to 24 months.]
• Time to deterioration in NSCLC symptoms evaluated via European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Lung Cancer Module (EORTC QLQ-LC13) items [Time frame: From the first dose until 30 days after the last dose, assessed up to 24 months.]
• Time to Worsening measured by European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) items [Time frame: From the first dose until 30 days after the last dose, assessed up to 24 months.]
• Change from baseline in EORTC QLQ-C30 [Time frame: From the first dose to week12.]

Eligibility criteria

Inclusion criteria

• 1\. Voluntary participation in the study and signed informed consent form (ICF).
• 2\. Age ≥ 18 years at the time of signing the ICF; male or female.
• 3\. Histologically or cytologically confirmed locally advanced unresectable or metastatic non small cell lung cancer (NSCLC).
• 4\. Participants must provide adequate and qualified tumor tissue slides samples or agree to undergo tumor biopsy to obtain tissue samples for central laboratory confirmation of KRAS G12D mutation.
• 5\. Disease progression or intolerance to toxicity after at least one prior line of platinum based chemotherapy and anti PD 1/PD L1 antibody therapy.
• 6\. At least one measurable target lesion according to RECIST version 1.1.
• 7\. Investigator assessed life expectancy ≥ 12 weeks.
• 8\. Adequate organ function.
• 9\. Ability to communicate well, comply with scheduled follow up visits, and adhere to protocol requirements.

Exclusion criteria

• 1\. Presence of other driver gene mutations in NSCLC, or concurrent other KRAS or RAS mutations.
• 2\. Other malignancy that has progressed or required treatment within 3 years prior to randomization.
• 3\. Leptomeningeal metastasis, or symptomatic or progressive central nervous system (CNS) metastasis.
• 4\. Existing or potential severe bone injury due to bone metastasis, or uncontrolled pain related to bone metastasis.
• 5\. Prior treatment with KRAS G12D targeted therapy or pan RAS/KRAS targeted therapy.
• 6\. Prior treatment with docetaxel as part of systemic therapy.
• 7\. Radiotherapy within 4 weeks prior to randomization, or other local anti tumor therapy within 4 weeks prior to randomization.
• 8\. Other anti tumor therapy within 28 days or 5 half lives prior to randomization, or cell therapy within 3 months prior to randomization.
• 9\. Clinically significant severe cardiovascular disease.
• 10\. Stroke or other severe cerebrovascular disease within 6 months prior to randomization.
• 11\. Major acute or chronic infectious disease.
• 12\. Other poorly controlled systemic diseases.
• 13\. Severe psychiatric or psychological disorder, or history of drug abuse, or severe alcohol abuse.
• 14\. Pregnancy or breastfeeding.
• 15\. Any other condition that, in the investigator's judgment, makes the participant unsuitable for the study.

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

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• Shanghai Lung Cancer Center, Shanghai Key Laboratory of Thoracic Tumor Biotherapy, Shangha — Shanghai

Identifiers

NCT: NCT07668752 · GFH375X1303

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗