A Dose Escalation Study of SHP2 Inhibitor in Patients With Solid Tumors Harboring KRAS of EGFR Mutations

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 or EGFR mutations to determine the maximum tolerated dose and recommended Phase II dose of HBI-2376 and characterize its pharmacokinetic profile.

Detailed Description
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A Phase 1, Open-Label, Dose Escalation of HBI-2376 in Patients with Advanced Malignant Solid Tumors Harboring KRAS or EGFR Mutations. The primary and secondary objectives are: To determine the MTD and recommended Phase 2 dose (RP2D), of HBI-2376 as an oral monotherapy for advanced solid tumors harboring KRAS or EGFR mutations To characterize the PK of HBI-2376 in subjects with advanced malignant solid tumors harboring KRAS or EGFR mutations HBI-2376 is a SHP2 Inhibitor and will be dosed once daily throughout the escalation and expansion phase. Up to 42 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 6 to 40mg. Once the MTD of RP2D is established, additional 6 subjects 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-2376 in Patients With Advanced Malignant Solid Tumors Harboring KRAS or EGFR Mutations

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

Intervention / Treatment
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* Drug: HBI-2376


Participation Criteria
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Eligibility Criteria
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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 or EGFR mutations diagnosed by histology or cytology Relapsed or refractory to, or intolerant of, or refuse approved or standard of care established therapy known to provide clinical benefit for disease 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 Must be able to swallow oral medications and must not have gastrointestinal abnormalities that significantly affect drug absorption 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 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 SHP2 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-2376 will be given orally in ascending doses (escalation cohort), until the maximum tolerated dose or recommended Phase 2 dose is reached. Up to 6 patients will then be enrolled in the expansion cohort at the recommended dose. | Drug: HBI-2376<br>* SHP2 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) and recommended Phase 2 dose (RP2D), of HBI-2376 as an oral monotherapy for advanced solid tumors harboring KRAS or EGFR mutations. | Safety endpoints: Incidence of dose-limiting toxicities (DLTs), adverse events (AEs), and serious adverse events (SAEs) overall, by severity, by relationship to HBI-2376, and those that led to discontinuation of HBI-2376 | Up to 36 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetic variables including maximum plasma concentration (Cmax) | Pharmacokinetic variables including maximum plasma concentration (Cmax) | Cycle 1 (28 days) | 
| Pharmacokinetic variables including minimum plasma concentration (Cmin) | Pharmacokinetic variables including minimum plasma concentration (Cmin) | Cycle 1 (28 days) | 
| Pharmacokinetic variables including Area Under the Curve (AUC) | Pharmacokinetic variables including Area Under the Curve (AUC) | Cycle 1 (28 days) | 
| Pharmacokinetic variables including clearance | Pharmacokinetic variables including clearance | Cycle 1 (28 days) | 
| Pharmacokinetic variables including serum half-life | Pharmacokinetic variables including serum half-life | Cycle 1 (28 days) | 
| Pharmacokinetic variables including volume of distribution | Pharmacokinetic variables including volume of distribution | Cycle 1 (28 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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KRAS, EGFR, SHP2, FIH