IDE196 (Darovasertib) in Combination With Crizotinib as First-line Therapy in Metastatic Uveal Melanoma

Phase 2

Recruiting

• Conditions: Metastatic Uveal Melanoma
• Interventions: Drug: IDE196; Drug: Pembrolizumab; Drug: Crizotinib; Drug: Ipilimumab; Drug: Nivolumab; Drug: Dacarbazine

• Registration Number: NCT05987332
• Lead Sponsor: IDEAYA Biosciences

Brief Summary

This is a Phase 2/3, multi-arm, multi-stage, open-label study of human leukocyte antigen (HLA)-A\*02:01 negative participants with metastatic uveal melanoma (MUM) who will be randomized to receive either IDE196 + crizotinib or investigator's choice of treatment (pembrolizumab, ipilimumab + nivolumab, or dacarbazine).

Detailed Description

This study is designed as a multi-stage Phase 2 study within a Phase 3 study to evaluate the safety, tolerability, pharmacokinetics, dose-exposure relationship, and anti-tumor activity of IDE196 in combination with crizotinib compared to the comparator arm of investigator's choice of treatment (pembrolizumab, ipilimumab + nivolumab, or dacarbazine).

The Phase 2a dose optimization stage will evaluate two doses of IDE196 in combination with crizotinib compared to the comparator arm. Participants will be randomized to the three treatment arms. At the point of optimal IDE196 + crizotinib dose selection, the other dose arm will be dropped with discontinuation of enrollment to that arm. Participants receiving the IDE196 dose (in combination with crizotinib) that is not selected, will be offered the choice to remain on the same dose or change to the chosen optimal dose.

The optimal dose will be chosen to complete the Phase 2b portion. The Phase 2b part of the study will continue to enroll the chosen combination dose of IDE196 + crizotinib compared with the comparator arm. Participants will be randomized to the two treatment arms.

The Phase 3 part of the study will continue to enroll the chosen combination dose of IDE196 + crizotinib compared with the comparator arm. Participants will be randomized to the two treatment arms.

Study Timeline

• Study First Submitted: 2023-07-12
• Study First Submitted QC: 2023-08-03
• Study First Posted: 2023-08-14
• Study Start: 2023-10-31
• Status Verified: 2025-03
• Last Update Submitted: 2025-06-05
• Last Update Posted: 2025-06-10
• Primary Completion: 2027-01-15
• Study Completion: 2028-01-15

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 420

Inclusion Criteria

• Histological or cytological confirmed Metastatic Uveal Melanoma
• HLA-A*02:01 negative
• No prior systemic therapy in the metastatic or advanced setting or regional or liver-directed therapy. Ablations or surgical resection of oligometastatic disease, and neoadjuvant or adjuvant therapy is allowed
• Measurable disease per RECIST 1.1
• Able to be safely administered and absorb study therapy
• ECOG performance status 0 or 1
• Life expectancy of ≥3 months
• Adequate organ function

Exclusion Criteria

• Previous treatment with a PKC inhibitor (including prior treatment with IDE196), an inhibitor directly targeting MET, or an inhibitor directly targeting GNAQ/11
• Concurrent malignant disease
• AEs from prior anti-cancer therapy that have not resolved to Grade ≤1
• Symptomatic or untreated central nervous system (CNS) metastases, or CNS metastases that require corticosteroids
• High risk of syncope
• Known AIDS related illness or active Hep B/C
• Active adrenal insufficiency, active colitis, or active inflammatory bowel disease
• History of interstitial lung disease, active pneumonitis, or history of pneumonitis
• Active infection requiring systemic antibiotic therapy
• Use of hematopoietic colony-stimulating factors (CSF) prior to start of study drug
• Females who are pregnant or breastfeeding
• History of severe hypersensitivity reactions (eg, anaphylaxis) to other biologic drugs or monoclonal antibodies
• Contraindication for treatment with investigator's choice therapies as per applicable labelling
• History of stroke within the last 6 months of the first dose of study drug
• Has any other condition that may increase the risk associated with study participation or may interfere with the interpretation of study results and, in the opinion of the investigator, would make the participant inappropriate for entry into the study, including institutionalization on the basis of an official or court order

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Phase 2a / 2b / 3 Comparator Arm	Nivolumab	Participants will receive investigator's choice of Pembrolizumab, Ipilimumab + Nivolumab, or Dacarbazine.
Phase 2b / 3 Chosen Combination dose of IDE196 + crizotinib	IDE196	Chosen combination dose of IDE196 + crizotinib will be tested in additional participants.
Phase 2a / 2b / 3 Comparator Arm	Pembrolizumab	Participants will receive investigator's choice of Pembrolizumab, Ipilimumab + Nivolumab, or Dacarbazine.
Phase 2a Dose Optimization of IDE196 + crizotinib	Crizotinib	Multiple doses of IDE196 will be tested in combination with fixed dose of crizotinib to identify the optimal combination dose.
Phase 2a / 2b / 3 Comparator Arm	Dacarbazine	Participants will receive investigator's choice of Pembrolizumab, Ipilimumab + Nivolumab, or Dacarbazine.
Phase 2a Dose Optimization of IDE196 + crizotinib	IDE196	Multiple doses of IDE196 will be tested in combination with fixed dose of crizotinib to identify the optimal combination dose.
Phase 2b / 3 Chosen Combination dose of IDE196 + crizotinib	Crizotinib	Chosen combination dose of IDE196 + crizotinib will be tested in additional participants.
Phase 2a / 2b / 3 Comparator Arm	Ipilimumab	Participants will receive investigator's choice of Pembrolizumab, Ipilimumab + Nivolumab, or Dacarbazine.

Primary Outcome Measures

Name	Time	Method
Progression-Free Survival (PFS) by blinded independent central review (BICR) of IDE196 + Crizotinib compared to investigator's choice of treatment	Approximately 2 years	PFS per RECIST 1.1
Overall Survival (OS) of IDE196 + Crizotinib compared to investigator's choice of treatment	Approximately 4 years	OS from randomization to date of death due to any cause

Secondary Outcome Measures

Name	Time	Method
Progression-Free Survival (PFS) per Investigator of IDE196 + Crizotinib compared to investigator's choice of treatment	Approximately 2 years	PFS per RECIST 1.1
Duration of Response (DOR) per BICR and Investigator assessment of IDE196 + Crizotinib compared to investigator's choice of treatment	Approximately 2 years	DOR per RECIST 1.1
Phase 2a: Dose exposure response of IDE196	Approximately 5 months	Dose-exposure-response of IDE196 as measured by concentration of IDE196 in plasma
Objective Response Rate (ORR) per BICR and Investigator assessment of IDE196 + Crizotinib compared to investigator's choice of treatment	Approximately 2 years	ORR per RECIST 1.1
Safety of IDE196 + Crizotinib: Incidence of Adverse Events	Approximately 2 years	Treatment emergent adverse events will be summarized by all AEs, all Grade 3-4-5 AEs, all treatment related AEs, all AEs leading to study drug modifications or discontinuations, all SAEs as measured by CTCAE V5.0
Phase 2a: Dose exposure response of Crizotinib	Approximately 5 months	Dose-exposure-response of Crizotinib as measured by concentration of Crizotinib in plasma
Change from baseline over time and between treatment arms in EORTC QLQ-C30	Approximately 2 years	Global health status and quality of life will be assessed using the EORTC QLQ-C30 questionnaire. The score range for the EORTC QLQ-C30 is from 0 to 100, with higher scores indicating better functioning and better global health status and health-related quality of life. A positive change indicates improvement.
Change from baseline over time and between treatment arms in EuroQoL (EQ)-5D-5L scores	Approximately 2 years	General health status will be assessed using the EQ-5D,5L questionnaire, which includes five dimensions (5D): mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has 3 scoring levels, where 1 indicates a better health state (no problems) and 3 indicates a worse health state. A positive change indicates improvement.

Trial Locations

Locations (67)

Honor Health; 🇺🇸 Scottsdale, Arizona, United States

Moores Cancer Center; 🇺🇸 La Jolla, California, United States

UCLA Medical Center; 🇺🇸 Los Angeles, California, United States

The Angeles Clinic and Research Institute; 🇺🇸 Los Angeles, California, United States

California Pacific Medical Center (CPMC); 🇺🇸 San Francisco, California, United States

University of California San Francisco; 🇺🇸 San Francisco, California, United States

University of Colorado Cancer Center; 🇺🇸 Aurora, Colorado, United States

SCRI at HealthONE; 🇺🇸 Denver, Colorado, United States

University of Miami Sylvester Comprehensive Cancer Center; 🇺🇸 Miami, Florida, United States

Moffitt Cancer Center; 🇺🇸 Tampa, Florida, United States

Scroll for more (57 remaining)