A Study to Evaluate KIN-2787 in Participants With BRAF and/or NRAS Mutation Positive Solid Tumors

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety, tolerability, pharmacokinetics (PK), and preliminary efficacy of KIN-2787 in adults with BRAF/NRAS-mutated advanced or metastatic solid tumors.

Detailed Description
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This is a two-part, open-label, multi-center, dose escalation and dose expansion study in participants with BRAF mutation-positive and/or NRAS mutation-positive tumors designed to evaluate the safety, tolerability, and pharmacokinetics (PK) of KIN-2787, a RAF small molecule kinase inhibitor, to determine a recommended Phase 2 dose (RP2D) of KIN-2787, and to assess the objective response to KIN-2787 therapy alone and in combination with binimetinib, a mitogen-activated protein kinase (MEK) inhibitor. The dose expansion phase (Part B) will assess the safety and efficacy of KIN-2787 at the recommended dose and schedule in patients with cancers that contain BRAF Class I, II or III mutations, including lung cancer, melanoma, and other selected solid tumors.

Official Title
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A Phase 1/1b Open-label, Multicenter Study to Investigate the Safety, Tolerability, Pharmacokinetics, and Antitumor Activity of KIN-2787 in Participants With BRAF and/or NRAS Mutation-positive Solid Tumors.

Conditions
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Solid Tumor, Adult, Non-small Cell Lung Cancer, Melanoma

Intervention / Treatment
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* Drug: KIN-2787
* Drug: KIN-2787 and binimetinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provide written informed consent prior to initiation of any study-specific procedures. Metastatic or advanced stage solid tumor Known BRAF Class I, Class II, or Class III alteration or melanoma with an NRAS mutation as confirmed by previous genomic analysis of tumor tissue or ctDNA. Measurable (Part A and B) or evaluable (Part A only) disease by RECIST v1.1. ECOG performance status 0-1 Adequate organ function, as measured by laboratory values (criteria listed in protocol). Able to swallow, retain, and absorb oral medications. Exclusion Criteria: Known participants who have received local therapy with either surgery and/or radiation therapy (participants with asymptomatic untreated brain metastasis may be eligible if met with certain criteria) In Part B Dose Expansion, previous treatment with any approved or in-development small molecule BRAF-, MEK-, or MAPK-directed inhibitor therapy. GI tract disease causing an inability to take oral medication, malabsorption syndrome, requirement for intravenous alimentation, or uncontrolled inflammatory GI disease. Active, uncontrolled bacterial, fungal, or viral infection. Participant with a positive test result for SARS-CoV2 infection, is known to have asymptomatic infection or is suspected of having SARS-CoV2, is excluded Women who are lactating or breastfeeding, or pregnant. Participants with any other active treated malignancy within 3 years prior to enrollment Complete inclusion and exclusion criteria are listed in the clinical study protocol.

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: Dose Escalation Monotherapy (Part A1)<br>Dose escalation of KIN-2787 | Drug: KIN-2787<br>* KIN-2787 will be administered orally twice daily in 28-day cycles<br>* Other names: exarafenib;|
| Experimental: Dose Escalation Combination therapy (Part A2)<br>Dose escalation of KIN-2787 and binimetinib | Drug: KIN-2787 and binimetinib<br>* KIN-2787 and binimetinib will be administered orally twice daily in 28-day cycles<br>* Other names: exarafenib and binimetinib;|
| Experimental: Dose Expansion Monotherapy (Part B1)<br>Dose expansion evaluating the recommended phase 2 dose (RP2D) of KIN-2787 | Drug: KIN-2787<br>* KIN-2787 will be administered orally twice daily in 28-day cycles<br>* Other names: exarafenib;|
| Experimental: Dose Escalation Combination therapy (Part B2)<br>Dose expansion evaluating the recommended phase 2 dose (RP2D) of KIN-2787 and binimetinib | Drug: KIN-2787 and binimetinib<br>* KIN-2787 and binimetinib will be administered orally twice daily in 28-day cycles<br>* Other names: exarafenib and binimetinib;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A1 Dose escalation monotherapy: | To determine the safety and tolerability of oral administration of KIN-2787 including dose-limiting toxicities (DLTs), and to identify the maximum tolerated dose (MTD) and/or the appropriate dose for further clinical investigation in Part B Dose Expansion. | Initiation of study drug through 28 days after last dose (up to approximately 18 months) | 
| Part A2 Dose Escalation: KIN-2787 + Binimetinib Combination | To determine the safety and tolerability of oral administration of KIN-2787 + binimetinib including DLTs, and to identify the MTD and/or the appropriate dose for further clinical investigation. | Initiation of study drug through 28 days after last dose (up to approximately 18 months) | 
| In Part B (Dose Expansion) - objective response rate (ORR) using RECIST v1.1. | To assess preliminary evidence of the anti-cancer activity of KIN-2787 and for (B2) KIN-2787 + binimetinib | Initiation of study drug until disease progression (up to approximately 36 months) | 
| In Part B (Dose Expansion) - disease control rate (DCR). |  | Initiation of study drug until disease progression (up to approximately 36 months) | 
| In Part B (Dose Expansion) - duration of overall response (DOR). | Measure of clinical benefit, defined as the time from initial tumor response to documented tumor progression | Initiation of study drug until disease progression (up to approximately 36 months) | 
| In Part B (Dose Expansion) - duration of stable disease. |  | Initiation of study drug until disease progression (up to approximately 36 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A1 Dose Escalation: Characterization of PK properties and effect of food on PK of KIN-2787 including, but not limited to tmax. |  | Initiation of study drug through Cycle 5, where each cycle is 28 days (up to approximately 4 months) | 
| Part A1 Dose Escalation: Characterization of PK properties and effect of food on PK of KIN-2787 including, but not limited to AUC. |  | Initiation of study drug through Cycle 5, where each cycle is 28 days (up to approximately 4 months) | 
| Part A1 Dose Escalation: Characterization of PK properties and effect of food on PK of KIN-2787 including, but not limited to Cmax. |  | Initiation of study drug through Cycle 5, where each cycle is 28 days (up to approximately 4 months) | 
| Part A2 Dose Escalation: characterization of PK properties of KIN-2787 and binimetinib in combination including, but not limited to Cmax. |  | Initiation of study drug through Cycle 5, where each cycle is 28 days (up to approximately 4 months) | 
| Part A2 Dose Escalation: characterization of PK properties of KIN-2787 and binimetinib in combination including, but not limited to AUC. |  | Initiation of study drug through Cycle 5, where each cycle is 28 days (up to approximately 4 months) | 
| Part A2 Dose Escalation: characterization of PK properties of KIN-2787 and binimetinib in combination including, but not limited to tmax. |  | Initiation of study drug through Cycle 5, where each cycle is 28 days (up to approximately 4 months) | 
| Part B Dose Expansion: characterization of PK properties of KIN-2787, and for (B2) KIN-2787 + binimetinib including, but not limited to AUC. |  | Initiation of study drug through Cycle 5, where each cycle is 28 days (up to approximately 4 months) | 
| Part B Dose Expansion: characterization of PK properties of KIN-2787, and for (B2) KIN-2787 + binimetinib including, but not limited to Cmax. |  | Initiation of study drug through Cycle 5, where each cycle is 28 days (up to approximately 4 months) | 
| Part B Dose Expansion: characterization of PK properties of KIN-2787, and for (B2) KIN-2787 + binimetinib including, but not limited to tmax. |  | Initiation of study drug through Cycle 5, where each cycle is 28 days (up to approximately 4 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CRC, BRAF inhibitor, BRAF, pan-RAF, pan-RAF inhibitor, RAF1, ARAF, BRAF alteration, BRAF Class II, BRAF Class III, V600, tumor growth inhibitor (TGI), melanoma, NSCLC, solid tumor, targeted therapy, BRAF Class I, NRAS, Metastatic, Unresectable, ATC, Colon, Thyroid, Advanced, Exarafenib, binimetinib