A Dose Escalation Study of HBI-2438 in Patients With Solid Tumors Harboring KRAS G12C Mutation

Study Overview
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Brief Summary
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A Phase 1 dose escalation study in patients with advanced solid tumors harboring KRAS G12C mutation to determine the maximum tolerated dose and recommended Phase II dose of HBI-2438 and characterize its pharmacokinetic profile.

Detailed Description
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A Phase 1, Open-Label, Dose Escalation of HBI-2438 in Patients with Advanced Malignant Solid Tumors Harboring KRAS G12C Mutation. The primary and secondary objectives are: To determine the MTD and recommended Phase 2 dose (RP2D) of HBI-2438 as an oral monotherapy for advanced solid tumors harboring KRAS G12C mutation. To characterize the PK of HBI-2438 in subjects with advanced malignant solid tumors harboring KRAS G12C mutation. HBI-2438 is an orally administered KRAS G12C Inhibitor and will be dosed once daily throughout the escalation and expansion phase. Up to 44 subjects will be enrolled sequentially into the 3+3 dose escalation and monitored throughout the study for safety and tolerability. The dose escalation phase will consist of 6 cohorts, with doses ranging from 150 to 1200mg. Once the MTD of RP2D is established, an additional 6-8 subjects with brain metastases will be enrolled into the expansion phase at that dose level.

Official Title
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A Phase 1, Open Label, Dose Escalation of HBI-2438 in Patients With Advanced Malignant Solid Tumors Harboring KRAS G12C Mutation

Conditions
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Lung Cancer, Non Small Cell Lung Cancer, Colorectal Cancer, Cancer of Pancreas, Colon Cancer, Solid Tumor, Cancer

Intervention / Treatment
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* Drug: HBI-2438


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Key Inclusion Criteria: Male or female at least 18 years of age at the time of signing the ICF prior to initiation of any study specific activities/procedures Advanced malignant solid tumors with KRAS G12C mutation- as determined by genetic testing Must have failed or refused standard of care therapy, are not eligible for standard of care therapy, or cannot benefit from standard of care therapy, in the opinion of the Investigator At least 1 measurable target lesion that meets the definition of RECIST v1.1 ECOG Performance Status of 0 or 1 Demonstrate adequate organ function Expected survival time > 3 months in the opinion of the investigator Must be able to swallow oral medications and must not have gastrointestinal abnormalities that significantly affect drug absorption Exclusion Criteria: Key Exclusion Criteria: History of another concurrent malignancy within 3 years prior to study entry, unless the malignancy was treated with curative intent and the likelihood of relapse is <5% in 2 years Note: Subjects with a history of squamous or basal cell carcinoma of the skin or carcinoma in the situ of the cervix may be enrolled Untreated or symptomatic central nervous system (CNS) metastases Note: Subjects with asymptomatic treated CNS metastases are eligible provided they have been clinically stable and not requiring steroids for at least 4 weeks Clinically significant cardiovascular disease, including stroke or myocardial infarction within 6 months prior to first dose of HBI-2438; or the presence of unstable angina or congestive heart failure of New York Heart Association Grade 2 or higher Any unresolved Grade 2 or greater toxicity from previous anti-cancer therapy, except alopecia, within 4 weeks of first study treatment administration Active autoimmune diseases or history of autoimmune diseases that may relapse Pregnant or nursing Prior treatment with any KRAS G12C inhibitors Any condition that required systemic treatment with either corticosteroids (>10 mg daily of prednisone or equivalent) or other immunosuppressive medication ≤14 days before the first study treatment administration Treatment with other investigational drugs/devices within 4 weeks prior to first study treatment administration

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Interventional Model Description: 3+3 Dose Escalation Design with Expansion
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Escalation and Expansion<br>HBI-2438 will be given orally in ascending doses (escalation cohort), until the maximum tolerated dose or recommended Phase 2 dose is reached. Up to 6-8 patients will then be enrolled in the expansion cohort at the recommended dose. | Drug: HBI-2438<br>* KRAS G12C Inhibitor<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To determine the maximum tolerated dose (MTD) | Safety endpoints: Incidence of dose-limiting toxicities (DLTs) | Up to 36 months | 
| adverse events (AEs), and serious adverse events (SAEs) overall | Safety endpoints: adverse events (AEs), and serious adverse events (SAEs) overall | Up to 36 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| maximum plasma concentration (Cmax) | Pharmacokinetic variables including maximum plasma concentration (Cmax) | Cycle 1 (21 days) | 
| minimum plasma concentration (Cmin) | Pharmacokinetic variables including minimum plasma concentration (Cmin) | Cycle 1 (21 days) | 
| Area Under the Curve (AUC) | Pharmacokinetic variables including Area Under the Curve (AUC) | Cycle 1 (21 days) | 
| Pharmacokinetic variables including clearance | Pharmacokinetic variables including clearance | Cycle 1 (21 days) | 
| Pharmacokinetic variables including serum half-life | Pharmacokinetic variables including serum half-life | Cycle 1 (21 days) | 
| Pharmacokinetic variables including volume of distribution | Pharmacokinetic variables including volume of distribution | Cycle 1 (21 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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KRAS G12C, FIH