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

Phase 3RecruitingNCT07668752

Genfleet Therapeutics (Shanghai) Inc.300 enrolled

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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.

Outcomes

Primary Outcomes

Objective Response Rate(ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. as assessed by blinded independent central review (BICR)

ORR is the proportion of participants whose best response is either complete response (CR) or partial response (PR) per RECIST v1.1 assessed by 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)

PFS is defined as the time from the date of randomization until the date of documented radiographic disease progression per RECIST v1.1, as assessed by BICR or until death due to any cause, whichever comes first.

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)

OS is defined as the time from the date of randomization until the date of death from any cause.

Time frame: From the first dose until the date of death from any cause, whichever came first, assessed up to 36~48 months

Secondary Outcomes

Objective Response Rate (ORR) per RECIST v1.1, as assessed by the investigator

ORR is defined as the proportion of participants whose best overall response (BOR) is rated as confirmed complete response (CR) or confirmed partial response (PR) 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

PFS is defined as the time from the date of randomization until the date of documented radiographic disease progression per RECIST v1.1 as assessed by the investigator or until death due to any cause, whichever comes first.

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

DCR is defined as the proportion of participants whose best overall response is rated as CR, confirmed PR or SD per RECIST v1.1 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

DOR is defined as the time from the date of first documented response (CR or PR subsequently confirmed) to the date of first documented PD per RECIST v1.1 as assessed by the investigator and the BICR or death due to any cause, whichever occurs first.

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

TTR is defined as the time from the date of randomization to the first documentation of objective response (confirmed CR or confirmed PR) per RECIST v1.1. 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)

An AE is any untoward medical occurrence in a patient or clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention.