Ripretinib in Combination With Binimetinib in Patients With Gastrointestinal Stromal Tumor (GIST)

Study Overview
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Brief Summary
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Multicenter, open-label Phase 1b/2 study of ripretinib in combination with binimetinib in patients with gastrointestinal stromal tumor (GIST). There will be 2 distinct parts in this study: Dose Escalation (Phase 1) and Expansion (Phase 2).

Official Title
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A Phase 1b/2, Open-label, Multicenter Study to Evaluate the Safety, Tolerability, Efficacy, and Pharmacokinetics of Ripretinib in Combination With Binimetinib in Patients With Gastrointestinal Stromal Tumor (GIST)

Conditions
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Gastrointestinal Stromal Tumors

Intervention / Treatment
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* Drug: Ripretinib
* Drug: binimetinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients ≥18 years of age with advanced GIST (unresectable or metastatic). Must have at least progressed on imatinib or have documented intolerance to imatinib. Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1. Patients must have a histologic diagnosis of GIST. If a female of childbearing potential, must have a negative pregnancy test. Adequate organ function and bone marrow function Exclusion Criteria: Received prior anticancer therapy within 14 days or 5× the half-life whichever is longer) prior to the first dose. Ongoing or prior participation in the DCC-2618-03-002 study. Prior therapy with ripretinib. Prior therapy with MEK inhibitor. History of certain ocular disorders. History of clinically significant hepatobiliary disease. Known active central nervous system metastases. History or presence of clinically relevant cardiovascular abnormalities. Systemic arterial or venous thrombotic or embolic events within 6 months of first dose. History of acute or chronic pancreatitis History of chronic inflammatory bowel disease or Crohn's disease requiring intervention within 12 months of first dose. Gastrointestinal abnormalities including but not limited to: inability to take oral medication, malabsorption syndromes

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: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Escalation<br>Escalation Phase: Increasing doses of ripretinib in combination with increase doses of binimetinib in patients with advanced GIST who have progressed on at least imatinib or are intolerant to imatinib and are ripretinib naïve in repeated 28-day cycles. Participants may remain on treatment until disease progression, unacceptable toxicity, or withdrawal of consent | Drug: Ripretinib<br>* 50 mg tablets<br>* Other names: DCC-2618, QINLOCK;Drug: binimetinib<br>* 15 mg tablets<br>* Other names: Mektovi;|
| Experimental: Expansion<br>Ripretinib in combination with binimetinib at the recommended Phase 2 dose (RP2D) in patients with advanced GIST who have progressed on imatinib or are intolerant to imatinib and are naïve. Participants may remain on treatment until disease progression, unacceptable toxicity, or withdrawal of consent | Drug: Ripretinib<br>* 50 mg tablets<br>* Other names: DCC-2618, QINLOCK;Drug: binimetinib<br>* 15 mg tablets<br>* Other names: Mektovi;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety/tolerability of oral ripretinib in combination with binimetinib: incidence of adverse events | Adverse events [TEAEs, SAEs, AESIs], dose reduction, dose interruption, or discontinuation, vital signs (heart rate [beats/min], and changes in laboratory parameters (chemistry, hematology, urinalysis, coagulation). | Approximately 12 months | 
| Determination of the Maximum Tolerated Dose and the Recommended Phase 2 Dose |  | Approximately 12 months | 
| Expansion Phase Only: Evaluate the objective response rate (ORR) of ripretinib in combination with binimetinib by modified RECIST | Measure ORR | Approximately 36 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine the time to maximum observed concentration (tmax) profile of oral ripretinib in combination with binimetinib | Measure Tmax | Cycle 1 Day 1, and Cycle 1 Day15 (pre-dose and at multiple time points [up to 8 hours] post-dose). Each cycle is 28 days | 
| Determine the maximum observed concentration (Cmax) profile of oral ripretinib in combination with binimetinib | Measure Cmax | Cycle 1 Day 1, and Cycle 1 Day15 (pre-dose and at multiple time points [up to 8 hours] post-dose). Each cycle is 28 days | 
| Determine the minimum observed concentration (Cmin) profile of oral ripretinib in combination with binimetinib | Measure Cmin | Cycle 1 Day 1, and Cycle 1 Day15 (pre-dose and at multiple time points [up to 8 hours] post-dose). Each cycle is 28 days | 
| Determine the area under the concentration-time curve (AUC) profile of oral ripretinib in combination with binimetinib | Measure AUC | Cycle 1 Day 1, and Cycle 1 Day15 (pre-dose and at multiple time points [up to 8 hours] post-dose). Each cycle is 28 days | 
| Evaluate the objective response rate (ORR) of ripretinib in combination with binimetinib by modified RECIST (escalation phase only) and Choi criteria (escalation and expansion phases) | Measure ORR | Approximately 36 months | 
| Evaluate the progression-free survival (PFS) of ripretinib in combination with binimetinib | Measure PFS | Approximately 36 months | 
| Evaluate the overall survival (OS) of ripretinib in combination with binimetinib | Measure OS | Approximately 36 months | 
| Evaluate the duration of response (DOR) of ripretinib in combination with binimetinib | Measure DOR | Approximately 36 months | 
| Evaluate the clinical benefit rate (CBR) of ripretinib in combination with binimetinib | Measure CBR | Approximately 36 months | 
| Evaluate the time to response (TTR) of ripretinib in combination with binimetinib | Measure TTR | Approximately 36 months |