Study of IDE196 in Patients With Solid Tumors Harboring GNAQ/11 Mutations or PRKC Fusions

Study Overview
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Brief Summary
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This is a Phase 1/2, multi-center, open-label basket study designed to evaluate the safety and anti-tumor activity of IDE196 in patients with solid tumors harboring GNAQ or GNA11 (GNAQ/11) mutations or PRKC fusions, including metastatic uveal melanoma (MUM), cutaneous melanoma, colorectal cancer, and other solid tumors. Phase 1 (dose escalation - monotherapy) will assess safety, tolerability and pharmacokinetics of IDE196 via standard dose escalation scheme and determine the recommended Phase 2 dose. Safety and anti-tumor activity will be assessed in the Phase 2 (dose expansion) part of the study. Phase 1 Tablet and Food Effect Pharmacokinetic (PK) Substudy will assess the PK profile of IDE196 tablet and evaluate the effects of food on the PK profile of IDE196 tablet Phase 1 (dose escalation - binimetib combination) will assess safety, tolerability and pharmacokinetics of IDE196 and binimetinib via standard dose escalation scheme and determine the recommended Phase 2 dose. Safety and anti-tumor activity will be assessed in the Phase 2 (dose expansion) part of the study. Phase 1 (dose escalation - crizotinib combination) will assess safety, tolerability and pharmacokinetics of IDE196 and crizotinib via standard dose escalation scheme and determine the recommended Phase 2 dose. Safety and anti-tumor activity will be assessed in the Phase 2 (dose expansion) part of the study. Evaluation of safety and efficacy across multiple doses may be explored in the dose optimization part of the study. Crizotinib monotherapy with crossover to combination cohort may be assessed for safety and to show the contribution of each study drug to anti-tumor activity.

Official Title
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A Phase 1/2 Study of IDE196 in Patients With Solid Tumors Harboring GNAQ/11 Mutations or PRKC Fusions

Conditions
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Metastatic Uveal Melanoma, Cutaneous Melanoma, Colorectal Cancer, Other Solid Tumors

Intervention / Treatment
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* Drug: IDE196
* Drug: Binimetinib
* Drug: Crizotinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient must be ≥18 years of age Diagnosis of one of the following: MUM: Uveal melanoma with histological or cytological confirmed metastatic disease. Or Non-MUM: Advanced cutaneous melanoma, colorectal cancer, or other solid tumor that has progressed following prior standard therapies or that has no satisfactory alternative therapies and has evidence of GNAQ/11 hotspot mutation Measurable disease Eastern Cooperative Oncology Group ≤1 and expected life expectancy of > 3 months Adequate organ function at screening Adequate contraceptive measures for non-sterilized male and female patients of childbearing potential Binimetinib Combination Additional Inclusion Criteria: • Adequate cardiac function represented by left ventricular ejection fraction (LVEF) ≥ 50% Crizotinib Combination Additional Inclusion Criteria: Prior chemotherapy other therapies as applicable or major surgeries must have been completed at least 4 weeks prior to initiation of crizotinib Patients with preexisting peripheral neuropathy can be included if it is Grade 1 or lower, prior to initiation of crizotinib Exclusion Criteria: Known symptomatic brain metastases Previous treatment with a PKC inhibitor Known MSI-H/dMMR tumors who have not previously received immune checkpoint inhibitors Adverse events from prior anti-cancer therapy that have not resolved Known acquired immunodeficiency syndrome (AIDS)-related illness, hepatitis B virus, or hepatitis C virus Active infection requiring ongoing therapy Recent surgery or radiotherapy Prior gastrectomy or upper bowel removal or any other gastrointestinal disorder or defect Females who are pregnant or breastfeeding Impaired cardiac function Treatment with prohibited medications that cannot be discontinued prior to study entry For patients receiving IDE196 powder-in-capsule (PIC) formulation or crizotinib, allergy to mammalian meat products and gelatin Binimetinib Combination Additional Exclusion Criteria Prior treatment with a MEK inhibitor History or current evidence of retinal vein occlusion (RVO) or current risk factors for RVO History of interstitial lung disease History of thromboembolic or cerebrovascular events ≤ 12 weeks prior to first dose Concurrent neuromuscular disorders that are associated with elevated creatine phosphokinase (CPK) Uncontrolled arterial hypertension despite medical treatment Allergy to binimetinib or its components History of syncope Crizotinib Combination Additional Exclusion Criteria: Prior therapy directly targeting ALK, MET, or ROS1 Spinal cord compression History of pneumonitis or interstitial lung disease History of syncope

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<br>IDE196 dosed orally, twice daily (BID) for each 28-day cycle | Drug: IDE196<br>* IDE196 dosed orally, twice daily for each 28-day cycle<br>* Other names: Protein Kinase C (PKC) Inhibitor;|
| Experimental: Dose Expansion Monotherapy<br>RP2D in MUM and non-MUM tumors harboring GNAQ/11 mutations or PRKC fusions (cutaneous melanoma, CRC, other solid tumors) | Drug: IDE196<br>* IDE196 dosed orally, twice daily for each 28-day cycle<br>* Other names: Protein Kinase C (PKC) Inhibitor;|
| Experimental: Dose Escalation Binimetinib Combination<br>IDE196 dosed orally, twice daily (BID) for each 28-day cycle and Binimetinib dosed orally, twice daily (BID) for each 28-day cycle | Drug: IDE196<br>* IDE196 dosed orally, twice daily for each 28-day cycle<br>* Other names: Protein Kinase C (PKC) Inhibitor;Drug: Binimetinib<br>* Binimetinib dosed orally, twice daily for each 28-day cycle<br>* Other names: MEKTOVI;|
| Experimental: Dose Expansion Binimetinib Combination<br>RP2D in MUM and non-MUM tumors harboring GNAQ/11 mutations (cutaneous melanoma, CRC, other solid tumors) | Drug: IDE196<br>* IDE196 dosed orally, twice daily for each 28-day cycle<br>* Other names: Protein Kinase C (PKC) Inhibitor;Drug: Binimetinib<br>* Binimetinib dosed orally, twice daily for each 28-day cycle<br>* Other names: MEKTOVI;|
| Experimental: Dose Escalation Crizotinib Combination<br>IDE196 dosed orally, twice daily (BID) for each 28-day cycle and Crizotinib dosed orally, twice daily (BID) for each 28-day cycle | Drug: IDE196<br>* IDE196 dosed orally, twice daily for each 28-day cycle<br>* Other names: Protein Kinase C (PKC) Inhibitor;Drug: Crizotinib<br>* Crizotinib dosed orally, twice daily for each 28-day cycle<br>* Other names: XALKORI;|
| Experimental: Dose Expansion Crizotinib Combination<br>RP2D in MUM and non-MUM tumors harboring GNAQ/11 mutations (cutaneous melanoma, CRC, other solid tumors) | Drug: IDE196<br>* IDE196 dosed orally, twice daily for each 28-day cycle<br>* Other names: Protein Kinase C (PKC) Inhibitor;Drug: Crizotinib<br>* Crizotinib dosed orally, twice daily for each 28-day cycle<br>* Other names: XALKORI;|
| Experimental: Dose Optimization Crizotinib Combination<br>IDE196 dosed orally, twice daily (BID) for each 28-day cycle and Crizotinib dosed orally, twice daily (BID) for each 28-day cycle | Drug: IDE196<br>* IDE196 dosed orally, twice daily for each 28-day cycle<br>* Other names: Protein Kinase C (PKC) Inhibitor;Drug: Crizotinib<br>* Crizotinib dosed orally, twice daily for each 28-day cycle<br>* Other names: XALKORI;|
| Experimental: Crizotinib Monotherapy with Crossover to Combination<br>Crizotinib dosed orally, twice daily (BID) for each 28-day cycle until disease progression then IDE196 added and dosed orally, twice daily (BID) for each 28-day cycle | Drug: IDE196<br>* IDE196 dosed orally, twice daily for each 28-day cycle<br>* Other names: Protein Kinase C (PKC) Inhibitor;Drug: Crizotinib<br>* Crizotinib dosed orally, twice daily for each 28-day cycle<br>* Other names: XALKORI;|
| Experimental: Tablet PK Substudy<br>IDE196 dosed orally, once on Cycle 1 Day 1; thereafter, twice daily (BID) for each 28-day cycle | Drug: IDE196<br>* IDE196 dosed orally, twice daily for each 28-day cycle<br>* Other names: Protein Kinase C (PKC) Inhibitor;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose-limiting Toxicity (DLT) | Determine DLT of IDE196 as monotherapy, in combination with Binimetinib, or in combination with Crizotinib | 28 days following first dose of IDE196 as monotherapy, in combination with Binimetinib, or in combination with Crizotinib | 
| Maximum Tolerated Dose (MTD) | Determine MTD of IDE196 as monotherapy, in combination with Binimetinib, or in combination with Crizotinib | 28 days following first dose of IDE196 as monotherapy, in combination with Binimetinib, or in combination with Crizotinib | 
| Recommended Phase 2 Dose (RP2D) as monotherapy, in combination with Binimetinib, or in combination with Crizotinib | Determine RP2D of IDE196 as monotherapy, in combination with Binimetinib, or in combination with Crizotinib | Approx. 6 months | 
| Plasma Concentrations of IDE196 as monotherapy, in combination with Binimetinib, or in combination with Crizotinib | Pharmacokinetics of IDE196 as monotherapy, in combination with Binimetinib, or in combination with Crizotinib | Approx. 6 months | 
| Plasma Concentrations of Crizotinib administered in combination with IDE196 | Pharmacokinetics of Crizotinib in combination with IDE196 | Approx. 6 months | 
| Plasma Concentrations of Binimetinib administered in combination with IDE196 | Pharmacokinetics of Binimetinib in combination with IDE196 | Approx. 6 months | 
| Overall Response Rate (ORR) for combination with Binimetinib or in combination with Crizotinib Dose Expansion by Blinded Independent Review Committee | Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (v1.1) criteria | Approx. 48 months | 
| Duration of Response for combination with Binimetinib or in combination with Crizotinib Dose Expansion by Blinded Independent Review Committee | RECIST v1.1 | Approx. 48 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) for combination with Binimetinib or in combination with Crizotinib in Dose Escalation and all combination cohorts by Blinded Independent Review Committee | Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (v1.1) criteria | Approx. 48 months | 
| Duration of Response for combination with Binimetinib or in combination with Crizotinib in Dose Escalation and in all combination cohorts by Blinded Independent Review Committee | RECIST v1.1 | Approx. 48 months | 
| ORR by Investigator | RECIST v1.1 | Approx. 48 months | 
| Duration of Response by Investigator | RECIST v1.1 | Approx. 48 months | 
| Disease Control by Investigator | RECIST v1.1 | Approx. 48 months | 
| Numbers of Participants with Adverse Events | Safety and tolerability of IDE196 either as monotherapy, in combination with Binimetinib, or in combination with Crizotinib | Approx. 48 months | 
| Treatment-related pharmacodynamic effect in all patients | Modulation of signaling proteins in PKC, MAPK, and MET pathways | Approx. 48 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Metastatic Uveal Melanoma, Uveal Melanoma, Protein Kinase C, Ophthalmology, Ocular Oncology, Darovasertib, IDE196, Ocular Melanoma