A Phase Ib/II, Multi-Center, Open-Label Study to Evaluate the Safety/Tolerability, Pharmacokinetics, and Efficacy of GFH925 in Combination with Cetuximab in Previously Untreated Advanced NSCLC Harboring KRAS G12C Mutation

Trial ID: 2022-501451-87-00
Protocol: GFH925X0201
Sponsor: Zhejiang Genfleet Therapeutics Co. Ltd.

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Diseases & Conditions

Non-small cell lung cancer metastatic

Objectives

The primary objective of this study is to evaluate the **safety** and **tolerability** of GFH925 in combination with Cetuximab in patients with advanced KRAS G12C-mutant non-small cell lung cancer (NSCLC). This is clinically relevant as it aims to determine the potential adverse effects and overall acceptability of the treatment regimen, which is crucial for ensuring patient safety and guiding dosage adjustments.

Secondary objectives include:

Characterizing the **pharmacokinetics** of GFH925 in combination with Cetuximab, which will provide insights into the absorption, distribution, metabolism, and excretion of the drug, informing optimal dosing strategies.
Evaluating the preliminary **efficacy** of the combination therapy, which will help assess the potential therapeutic benefits in reducing tumor burden or slowing disease progression.
Assessing the overall **efficacy** of GFH925 in combination with Cetuximab, which is essential for understanding the treatment's impact on disease outcomes.
Evaluating the **safety** of the combination therapy, ensuring that any adverse effects are identified and managed appropriately.
Evaluating the pharmacokinetic parameters of GFH925 at scheduled time points, which will further refine understanding of the drug's behavior in the body over time.

Participants

The clinical trial involves participants diagnosed with **previously untreated advanced non-small cell lung cancer (NSCLC) harboring the KRAS G12C mutation**. The study population includes both male and female subjects aged 18 years and older, with an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 1, indicating they are ambulatory and capable of all self-care. Participants are required to have a life expectancy of more than three months, as judged by the investigator. The trial does not specify the total number of participants, as this information was not provided by the sponsor. The selection criteria include individuals with histologically or cytologically confirmed advanced NSCLC who have not received prior systemic antitumor therapy for advanced or metastatic disease. Participants must have adequate organ function and be willing to provide tumor tissue and plasma for biomarker analysis. Both genders are included, and the trial considers vulnerable populations. Lifestyle factors such as diet and physical activity are not specified in the trial data. The trial population was selected based on specific medical and health criteria, including the absence of other targetable oncogenic driver mutations or alterations.

Plans and Procedures

The clinical trial is designed as a **Phase Ib/II, multi-center, open-label study** to evaluate the safety, tolerability, pharmacokinetics, and efficacy of GFH925 in combination with **Cetuximab** in patients with previously untreated advanced non-small cell lung cancer (NSCLC) harboring the KRAS G12C mutation. The trial is not randomized or blinded, as it is open-label, allowing both researchers and participants to know the treatment being administered. The study is expected to commence recruitment on February 26, 2023, and conclude by March 26, 2025, with the overall duration of participant involvement varying based on individual response and progression.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on specific criteria, such as age, performance status, and organ function. Following successful screening, participants will enter the treatment phase, where they will receive GFH925 orally and Cetuximab via intravenous infusion. Regular follow-up visits will be scheduled to monitor safety, collect pharmacokinetic data, and evaluate treatment efficacy through assessments such as overall response rate and disease control rate. The end-of-study visit will occur after the completion of the treatment regimen or upon early termination.

Participant involvement is expected to last until disease progression, unacceptable toxicity, or withdrawal of consent. Conditions that may lead to early termination include adverse events, serious adverse events, or any significant changes in laboratory parameters, vital signs, or electrocardiogram results. The primary endpoints focus on the incidence of adverse events and overall response rate, while secondary endpoints include pharmacokinetic parameters and survival outcomes. The study aims to provide valuable insights into the potential benefits of combining GFH925 with Cetuximab for this specific patient population.

Treatment

The clinical trial involves the administration of **Cetuximab**, marketed under the name Erbitux, which is provided as a 5 mg/mL **solution for infusion**. This experimental medication is administered via **intravenous infusion**. Cetuximab is a protein-based therapeutic agent, specifically classified under the ATC code L01FE01. The pharmaceutical form remains unchanged except for overlabeling modifications. The administration schedule and dosage are determined based on the study protocol, and participant compliance is monitored through regular assessments.

In addition to Cetuximab, the trial includes the experimental medication **Fulzerasib**, which contains the active substance GFH925. Fulzerasib is formulated as a **tablet** and is administered **orally**. This chemical-based drug is developed by Zhejiang Genfleet Therapeutics Co., Ltd. The dosing schedule for Fulzerasib is outlined in the study protocol, with adherence monitored through participant reporting and pill counts. Both medications are used in combination to evaluate their safety, tolerability, and efficacy in treating advanced non-small cell lung cancer (NSCLC) with the KRAS G12C mutation.

Efficacy

The efficacy of the investigational combination of GFH925 and **Cetuximab** in the treatment of advanced non-small cell lung cancer (NSCLC) with KRAS G12C mutation will be assessed through several primary and secondary endpoints. The primary efficacy endpoint is the overall response rate (ORR), which will be evaluated to determine the proportion of patients achieving a predefined level of tumor size reduction. Secondary endpoints include the best overall response (BOR), duration of response (DoR), time to response (TTR), progression-free survival (PFS), and overall survival (OS). These parameters will be assessed according to the Response Evaluation Criteria in Solid Tumor (RECIST) 1.1 guidelines.

Data collection for these endpoints will occur at specified intervals throughout the trial, with assessments conducted via imaging studies and clinical evaluations. The pharmacokinetic (PK) profile of GFH925 will also be analyzed, including parameters such as maximum concentration (Cmax), time to reach maximum concentration (Tmax), area under the curve (AUC), and half-life (T1/2). These PK parameters will be measured at various time points to understand the drug's behavior in the body. The study will also monitor the plasma concentration of GFH925 to correlate with efficacy outcomes. The trial is designed to provide comprehensive data on the efficacy of the drug combination in this specific patient population.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Patient has provided informed consent form (ICF) prior to initiation of any study specific activities/procedures. For patients who are incapable of giving consent, they also be allowed if they have legal representative to consent on their behalf.
Males or females aged ≥ 18 years.
Eastern Cooperative Oncology Group (ECOG) Performance Status of 0~1.
Life expectancy > 3 months judged by the investigator
Willing to provide archival or new tumor tissue and plasma for the analysis of biomarkers.
Have histologically or cytologically confirmed advanced NSCLC with no prior systemic antitumor therapy given as primary therapy for advanced or metastatic disease; and meet all the following requirements: 1) Unwilling to receive immunochemotherapy, or with a potential to benefit from treatment with the combination of GFH925 and cetuximab as compared to available standard treatment (i.e. immunochemotherapy) as judged by investigator. 2) Have documented KRAS G12C mutation 3) Without other targetable oncogenic driver mutation or alteration, i.e., EGFR active mutation, ALK/ROS1 rearrangements, RET rearrangements. 4) Have received prior neo-adjuvant, adjuvant chemotherapy, or chemoradiotherapy with curative intent for non-metastatic disease must have experienced a treatment-free interval of at least 6 months prior to initiation of study treatment since the last chemotherapy or completion of chemoradiotherapy.
Have at least one measurable lesion except for patients only have CNS metastases per RECIST 1.1.
Have sufficient organ functions, including: 1) Adequate hematopoietic functions: absolute neutrophil count (ANC) ≥ 1.5 × 109 /L, platelet count ≥ 75 × 109 /L, hemoglobin ≥ 9 g/dL, without blood transfusion or treatment with hematopoietic stimulating factors within 14 days prior to screening. 2) Adequate liver functions: i. Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) < 2.5 ×upper limit of normal (ULN) (if liver metastases are present, < 5 × ULN). ii. Total bilirubin (TBIL) < 1.5 × ULN (< 2 × ULN for patients with documented Gilbert's syndrome or < 3 × ULN for extrahepatic obstruction). 3) Adequate renal functions: serum creatinine (SCr) ≤ 1.5 × ULN, or creatinine clearance (CrCl) ≥ 60 mL/min (calculated by Cockcroft-Gault formula) if SCr > 1.5 × ULN. 4) Prothrombin time (PT) or activated partial thromboplastin time (APTT) < 1.5 ×ULN, along with international normalized ratio (INR) < 1.5 or within target range if on prophylactic anticoagulation therapy. 5) Level of Magnesium is within normal limits
With toxicities left from prior anti-tumor therapy resolved to baseline or CTCAE Grade 1 (neurotoxicity or alopecia ≤ Grade 2).
Women of childbearing potential (WOCBP) and male patients with WOCBP partners must agree to use effective contraception method during the study period and within 30 days after the last dose of GFH925 or within 2 months after the last dose of Cetuximab, whichever is longer. WOCBP must have negative pregnancy test results within 1 week (inclusive) prior to initiation of study treatment.

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Exclusion Criteria

Patients with any other malignancies that have progressed or have required active treatment within the last 3 years prior to be enrolled, except for carcinoma in situ or basal or squamous cell skin cancer that has undergone potentially curation therapy.
With clinically significant cardiovascular diseases: - Clinically significant cardiovascular events within 6 months before the first study treatment, such as myocardial infarction, severe/unstable angina, heart failure (New York Heart Association class III or IV), arrhythmia requiring medication, angioplasty, stent implantation, and coronary artery bypass grafting. - QT/QTcF prolongation (QTcF > 470 ms for females or QTcF > 450 ms for males.
Active central nervous system (CNS) metastases and/or carcinomatous meningitis that require therapeutic intervention or are causing clinical symptoms. Patients with previously treated brain metastases may participate provided the participants are stable at least 7 days prior to the initiation of the study treatment.
With clinically significant gastrointestinal diseases, such as intractable hiccup, ≥ grade 2 nausea, ≥ grade 2 vomiting, severe peptic ulcer and liver cirrhosis, active gastrointestinal bleeding, or other conditions that interfere swallowing the tablets or significantly alter the absorption; patients with liver metastases who have severe portal hypertension due to Budd-Chiari syndrome or portal vein thrombosis.
With active infections, including: 1) Positive human immunodeficiency virus antibody (HIV-Ab). 2) Active hepatitis B virus infection (positive HBsAg with positive HBV-DNA). 3) Active hepatitis C virus infection (positive HCV-Ab with positive HCV-RNA). 4) Active infections requiring systemic treatment.
With uncontrollable or symptomatic pleural effusion, ascites, or pericardial effusion.
With uncontrolled systemic diseases, such as hypertension or diabetes.
With conjunctivitis and keratitis within 4 weeks prior to initiation of study treatment.
Prior treatment with an inhibitor specific to KRAS G12C.
Therapeutic or palliative radiation therapy within 2 weeks prior to first study treatment. Except for bone metastasis which is not the target lesion within 2 weeks prior to initiation of study treatment.
Major surgery within 4 weeks prior to initiation of study treatment.
Use of proton pump inhibitors or H2 antagonists within 7 days prior to the initiation of the study treatment.
Use of strong inhibitors or strong inducers of CYP3A4 or P-gp within 14 days or 5 half-lives (whichever is longer); or herbal medicine/or grapefruit juice or grapefruit containing products within 7 days prior to initiation of study treatment (refer to protocol Table 9).
Use of sensitive substrates of CYP3A4 or CYP2D6 (with a narrow therapeutic window), within 14 days or 5 half-lives (whichever is longer) prior to initiation of study treatment that was not reviewed and approved by the principal investigator and sponsor (refer to protocol Table 10).
With known allergies to the study drugs or components.
With history of interstitial lung diseases or pulmonary fibrosis.
Pregnant or lactating females, or female patients intend to become pregnant during participation.
Other conditions judged by the investigator as inappropriate to participate in the study.