Phase 1b/2 Study of Futibatinib in Combination With Binimetinib in Patients With Advanced KRAS Mutant Cancer

Study Overview
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Brief Summary
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Phase 1b/2 study to evaluate the FGFRi futibatinib in combination with the MEKi binimetinib in patients with advanced KRASmt tumors.

Detailed Description
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This is an open-label, nonrandomized, uncontrolled Phase 1b/2 study to determine the recommended phase 2 dose (RP2D) of futibatinib in combination with binimetinib and to explore the preliminary antitumor activity of futibatinib in combination with binimetinib in patients with advanced KRASmt tumors. The study will consist of two parts: Part 1: Dose-Escalation part to determine the RP2D and dosing schedule of futibatinib in combination with binimetinib in patients with advanced cancer disease Part 2: Dose-Expansion part to evaluate the preliminary antitumor activity of futibatinib in combination with binimetinib at the RP2D in patients with advanced KRASmt NSCLC Patients will receive study treatment until progressive disease or any other discontinuation or withdrawal criterion is met.

Official Title
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A Phase 1b/2 Open-label, Nonrandomized Study of FGFR Inhibitor Futibatinib in Combination With MEK-inhibitor Binimetinib in Patients With Advanced KRAS Mutant Cancer

Conditions
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Advanced or Metastatic Solid Tumors Irrespective of Gene Alterations, Non-Small Cell Lung Cancer, KRAS Gene Mutation

Intervention / Treatment
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* Drug: Futibatinib and Binimetinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed advanced cancer of any tumor type (Part 1) or NSCLC with a confirmed KRAS mutation as determined by local results (Part 2) Appropriate candidate for experimental therapy For patients in Part 2 only: Patient has radiographically measurable disease per RECIST 1.1 criteria. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. Adequate cardiac function (Left ventricular ejection fraction (LVEF) ≥50% ) Adequate organ function Must have tumor tissue specimen available (optional for patients in Part 1) Exclusion Criteria: History or current evidence of calcium and phosphate hemostasis disorder or systemic mineral imbalance with ectopic calcification of soft tissues Current evidence or history of clinically significant corneal or retinal disorder as confirmed by ophthalmologic examination. Known untreated central nervous system (CNS) metastases or history of uncontrolled seizures. Significant gastrointestinal disorder(s) that could interfere with absorption of futibatinib/binimetinib Patients who have neuromuscular disorders that are associated with elevated creatinine kinase (CK)

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
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Futibitanib in combination with binimetinib<br>Dose escalation: Futibitanib in combination with binimetinib in patients with advanced cancer disease. Dose expansion: Futibatinib in combination with binimetinib at the RP2D in patients with advanced KRASmt NSCLC | Drug: Futibatinib and Binimetinib<br>* Patients will receive futibatinib once daily in combination with binimetinib twice daily by oral administration on a 21-day cycle<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recommended Phase 2 Dose (RP2D) in Part 1 | Determine RP2D of futibatinib in combination with binimetinib based on Dose Limiting Toxicities | 12 months | 
| Objective Response Rate (ORR) in Part 2 | proportion of patients who have achieved a PR or complete response (CR) according to RECIST 1.1. | approximately 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics (PK): Maximum plasma concentration (Cmax) of futibatinib, binimetinib, and AR00426032 | Plasma concentrations of futibatinib, binimetinib, and AR00426032 | approximately 24 months | 
| PK: Area under the plasma concentration-time curve (AUC) of futibatinib, binimetinib, and AR00426032 | Plasma concentrations of futibatinib, binimetinib, and AR00426032 | approximately 24 months | 
| PK: Time to reach maximum plasma concentration (Tmax) of futibatinib, binimetinib, and AR00426032 | Plasma concentrations of futibatinib, binimetinib, and AR00426032 | approximately 24 months | 
| PK: Terminal elimination half-life (T1/2) of futibatinib, binimetinib, and AR00426032 | Plasma concentrations of futibatinib, binimetinib, and AR00426032 | approximately 24 months | 
| PK: Minimum plasma concentration before administration (Cmin) of futibatinib, binimetinib, and AR00426032 | Plasma concentrations of futibatinib, binimetinib, and AR00426032 | approximately 24 months | 
| PK: Accumulation ratio of Cmax and AUC (R) of futibatinib, binimetinib, and AR00426032 | Plasma concentrations of futibatinib, binimetinib, and AR00426032 | approximately 24 months | 
| Duration of response (DOR) | DOR is defined as the length of time between first response and the date of objectively documented progression of disease or death | approximately 24 months | 
| Progression-free survival (PFS) | PFS is defined as the time from date of first dose to objectively documented progression of disease or death | approximately 24 months | 
| Disease control rate (DCR) at 24 months | DCR is defined as the percentage of patients who have achieved a CR, PR, or SD. | approximately 24 months | 
| Number of patients with treatment-emergent adverse events as assessed by CTCAE v5.0 | Evaluate safety and tolerability of futibatinib in combination with binimetinib based on treatment-emergent adverse events per CTCAE v5.0(including serious adverse events),clinical laboratory parameters, ECGs, and vital signs | Approximately 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Futibatinib, Binimetinib, MEKi, FGFR, FGFRi, TAS-120, KRASmt, NSCLC