GFH375 Monotherapy and Combination Therapy as First-Line Treatment for Advanced KRAS G12D-Mutant Non-Small Cell Lung Cancer

A Multicenter, Open-label, Randomized Clinical Study to Evaluate the Efficacy, Pharmacokinetics, Safety and Tolerability of GFH375 Monotherapy and Combination Therapy as First-line Treatment in Patients With Advanced Non-small Cell Lung Cancer Harboring KRAS G12D Mutation.

This study is a multicenter, open-label, randomized clinical trial aimed at exploring the efficacy and safety of three treatment regimens for treatment-naive advanced NSCLC patients with KRAS G12D mutation: GFH375 monotherapy (Cohort 1), GFH375 combined with cetuximab (Cohort 2), and GFH375 combined with pemetrexed (Cohort 3).Every cohort will recruit 30 participants.

Study Overview

• Status: Not yet recruiting
• Conditions: NSCLC (Advanced Non-small Cell Lung Cancer)
• Intervention / Treatment: Drug: ArmA:GFH375; Drug: Arm B:GFH375; Drug: Arm C:GFH375

Detailed Description

This study is a multicenter, open-label, randomized clinical trial designed to evaluate the efficacy and safety of three treatment regimens in patients with previously untreated advanced NSCLC harboring KRAS G12D mutations: GFH375 monotherapy (Cohort 1), GFH375 combined with cetuximab (Cohort 2), and GFH375 combined with pemetrexed (Cohort 3).

The study population consists of participants with advanced, previously untreated NSCLC carrying KRAS G12D mutations. Participants must not have received any prior systemic anti-tumor therapy. After enrollment, participants will be randomized to one of the following cohorts:

Cohort 1: GFH375 monotherapy (600 mg, QD, oral), approximately 30 participants. Cohort 2: GFH375 (600 mg, QD, oral) combined with cetuximab (500 mg/m², Q2W, intravenous), approximately 30 participants.

Cohort 3: GFH375 (600 mg, QD, oral) combined with pemetrexed (500 mg/m², Q3W, intravenous), approximately 30 participants.

A total of approximately 90 participants will be enrolled in this study, and each participant will be randomized to only one cohort.

• Study Type: Interventional
• Enrollment (Estimated): 90
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Yolanda Zeng; Phone Number: +8618073129952; Email: yaozeng@genfleet.com
• Study Contact Backup: Name: Dandan Li; Phone Number: +8615357948985; Email: ddli@genfleet.com

Study Locations

• China
  • Guangdong
    • Guangzhou, Guangdong, China
      • Guangdong Provincial People's Hospital
      • Contact: Chongrui Xu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Voluntarily agree to participate in this study and sign the written informed consent form.
2. Male or female, aged 18 to 75 years at the time of signing the informed consent form.
3. Pathologically (histologically or cytologically) confirmed advanced (Stage IV) or locally advanced non-squamous non-small cell lung cancer that is not amenable to radical surgery or radiotherapy.
4. Have a written report confirming KRAS G12D mutation positive.
5. Able to provide an archival tumor tissue sample [formalin-fixed, paraffin-embedded (FFPE) block or unstained FFPE tumor sections] or to undergo a tumor biopsy prior to treatment.
6. No prior systemic anti-tumor therapy for advanced disease; or not eligible for standard of care therapy; or in the investigator's judgment, may benefit more from GFH375 monotherapy or combination therapy than from available standard therapy.
7. Have at least one measurable lesion outside the central nervous system (CNS) per RECIST v1.1. Lesions that have received prior local radiotherapy can be considered measurable only if they have demonstrated clear progression after radiotherapy; otherwise, they are not considered measurable.
8. Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of 0 or 1.

9.Life expectancy of at least 3 months as assessed by the investigator. 10.Adequate organ function.

Exclusion Criteria:

1. Has had another invasive malignancy that progressed or required treatment within 3 years prior to randomization, except adequately treated basal cell carcinoma or squamous cell carcinoma of the skin, squamous cell carcinoma in situ, superficial bladder cancer, carcinoma in situ of the cervix, ductal carcinoma in situ of the breast, or papillary thyroid carcinoma.
2. Pathologically (histologically or cytologically) confirmed squamous cell lung cancer, adenosquamous carcinoma, neuroendocrine carcinoma (including small cell lung cancer and large cell neuroendocrine carcinoma), or mixed small cell lung cancer.
3. Known to harbor other targetable driver gene alterations.
4. Has active or symptomatic brain metastases, leptomeningeal metastases, or spinal cord compression.
5. Has clinically significant severe cardiovascular disease.
6. Has had a stroke or other serious cerebrovascular event within 6 months prior to randomization.
7. Has a history of deep vein thrombosis or other severe thromboembolism within 3 months prior to randomization.
8. Has pleural effusion, ascites, or pericardial effusion requiring frequent drainage (≥2 times per month) or associated with moderate to severe symptoms.
9. Has clinically significant interstitial lung disease, radiation pneumonitis, or immune-related pneumonitis requiring treatment.
10. At high risk of gastrointestinal bleeding or perforation.
11. Has pyloric obstruction, persistent or recurrent vomiting (≥3 episodes within 24 hours); is unable or unwilling to swallow tablets; or has other impaired gastrointestinal function or gastrointestinal disease that may significantly affect the absorption of GFH375.
12. History of chronic diarrhea.
13. Has a major acute or chronic infectious disease.
14. Has other uncontrolled systemic medical conditions.
15. Planned major surgery as determined by the investigator.
16. History of organ transplantation or preparing to undergo organ transplantation (except corneal transplantation).
17. Known allergy to the investigational drug or its components.
18. Received or planned to receive a live attenuated vaccine within 28 days prior to randomization or during the administration of the investigational drug.
19. Having severe mental or psychological disorders, a history of substance abuse, or a history of severe alcoholism.
20. Pregnant or breastfeeding women.
21. Other conditions deemed by the investigator to be inappropriate for participation in the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm A:GFH375; Arm A :will enroll participants with previously untreated advanced NSCLC harboring KRAS G12D mutations.	Drug: ArmA:GFH375; GFH375 once daily (QD) 28 days as a cycle.; Other Names: GFH375
Experimental: Arm B:GFH375 in combination with Cetuximab; Arm B will enroll participants with previously untreated advanced NSCLC harboring KRAS G12D mutations.	Drug: Arm B:GFH375; GFH375 once daily (QD) .Cetuximab will be administered via intravenous infusion at a dose of 500 mg/m² every 2 weeks.; Other Names: Cetuximab
Experimental: Arm C:GFH375 in combination with Pemetrexed; Arm C will enroll participants with previously untreated advanced NSCLC harboring KRAS G12D mutations.	Drug: Arm C:GFH375; GFH375 once daily (QD) .Pemetrexed disodium will be administered via intravenous infusion at a dose of 500 mg/m² every 3 weeks.; Other Names: Pemetrexed disodium

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
the efficacy of GFH375 as monotherapy and in combination therapy	Objective response rate (ORR) assessed by RECIST 1.1 according to researchers	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

Collaborators and Investigators

• Sponsor: Genfleet Therapeutics (Shanghai) Inc.
• Investigators: Study Chair: Yilong Wu, Guangdong Provincial People's Hospital

Study record dates

Study Major Dates

• Study Start (Estimated): May 20, 2026
• Primary Completion (Estimated): April 30, 2027
• Study Completion (Estimated): April 30, 2028

Study Registration Dates

• First Submitted: April 21, 2026
• First Submitted That Met QC Criteria: April 21, 2026
• First Posted (Actual): April 28, 2026

Study Record Updates

• Last Update Posted (Actual): April 28, 2026
• Last Update Submitted That Met QC Criteria: April 21, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: KRAS G12D Mutations
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Respiratory Tract Diseases; Lung Diseases; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Carcinoma, Non-Small-Cell Lung; Amino Acids, Peptides, and Proteins; Proteins; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Guanine; Hypoxanthines; Purinones; Purines; Glutamates; Amino Acids, Acidic; Amino Acids; Amino Acids, Dicarboxylic; Pemetrexed; Cetuximab
• Other Study ID Numbers: GFH375X1302

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No