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

IDE196 (Darovasertib) in Combination With Crizotinib Versus Investigator's Choice of Treatment as First-line Therapy in HLA-A2 Negative Metastatic Uveal Melanoma (DAR-UM-2)

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).

Study Overview

• Status: Active, not recruiting
• Conditions: Metastatic Uveal Melanoma
• Intervention / Treatment: Drug: IDE196; Drug: Crizotinib; Drug: Pembrolizumab; Drug: Ipilimumab; Drug: Nivolumab; Drug: 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 to evaluate the primary endpoint of overall survival (OS).

• Study Type: Interventional
• Enrollment (Estimated): 420
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Australia
  • Adelaide, Australia
    • Queen Elizabeth Hospital
  • New South Wales
    • Sydney, New South Wales, Australia, 2145
      • Westmead Hospital
  • Queensland
    • Brisbane, Queensland, Australia, 4102
      • Princess Alexander Hospital
  • Victoria
    • Melbourne, Victoria, Australia, 3000
      • Peter MacCallum Cancer Centre
    • Melbourne, Victoria, Australia, 3168
      • Alfred Health
  • Washington
    • Perth, Washington, Australia, 6009
      • Sir Charles Gairdner Hospital
• Belgium
  • Brussels, Belgium, 1200
    • Cliniques Universitaires Saint Luc
  • Leuven, Belgium, 3000
    • Algemene Medische Oncologie UZ
• Canada
  • Alberta
    • Edmonton, Alberta, Canada, T6G 1Z2
      • Cross Cancer Institute, University of Alberta
  • British Columbia
    • Vancouver, British Columbia, Canada, V5Z4C2
      • BC Cancer Agency
  • Ontario
    • Toronto, Ontario, Canada, M5G 2M9
      • Princess Margaret Cancer Centre
  • Quebec
    • Montreal, Quebec, Canada, H2X 0C1
      • Centre Hospitalier de l'Universite de Montreal- CHUM
• France
  • Lyon, France
    • The Leon Berard Center
  • Paris, France, 75005
    • Institut Curie
• Germany
  • Berlin, Germany, 12203
    • Charite - Universitatsmedizin Berlin
  • Baden-Wurttemberg
    • Heidelberg, Baden-Wurttemberg, Germany, 69120
      • NCT Heidelberg
  • North Rhine-Westphalia
    • Cologne, North Rhine-Westphalia, Germany, 50937
      • Universitätsklinikum Köln
    • Essen, North Rhine-Westphalia, Germany, 45147
      • Universitatsklinikum Essen (Aor)
  • Saxony
    • Dresden, Saxony, Germany, 1307
      • Universitätsklinikum Carl Gustav Carus Dresden
• Israel
  • Jerusalem, Israel, 91120
    • Hadassah Medical Center
  • Ramat Gan, Israel, 52621
    • Sheba Medical Center
• Italy
  • Milan, Italy, 20133
    • Fondazione IRCCS Istituto Nazionale dei Tumori
  • Napoli, Italy, 80131
    • Istituto Nazionale dei Tumori Fondazione Pascale
  • Roma, Italy, 00168
    • Fondazione Policlinico Gemelli IRCCS
  • Siena, Italy, 53100
    • AOUS Policlinico Le Scotte
• Netherlands
  • Leiden, Netherlands, 2333 ZA
    • LUMC (Leids Universitair Medisch Centrum)
• Poland
  • Gdansk, Poland, 80-214
    • Ośrodek Badań Klinicznych Wczesnych Faz, Uniwersyteckie Centrum Kliniczne w Gdańsku
  • Warsaw, Poland, 02-781
    • Narodowy Instytut Onkologii im. Marii Skłodowskiej-Curie Państwowy Instytut Badawczy
• Spain
  • L'Hospitalet de Llobregat, Spain, 8908
    • Catalan Institute of Oncology
  • Madrid, Spain, 28046
    • Hospital Universitario La Paz
  • Santiago de Compostela, Spain, 15706
    • Hospital Clinico Universitario de Santiago de Compostela
  • Seville, Spain, 41009
    • Hospital Universitario Virgen Macarena
  • Valencia, Spain, 46014
    • Hospital General Universitario Valencia
• Switzerland
  • Zurich, Switzerland, 8058
    • Dermatologische Klinik, USZ Flughafen Geschoss 7 - Klinische Forschung
• United Kingdom
  • Glasgow, United Kingdom, G12 0YN
    • The Beatson West of Scotland Cancer Centre
  • Metropolitan Borough of Wirral, United Kingdom, CH63 4JY
    • The Clatterbridge Cancer Centre NHS Foundation Trust
  • Northwood, United Kingdom, HA6 2RN
    • Mount Vernon Cancer Centre East & North Herts NHS Trust
• United States
  • Arizona
    • Scottsdale, Arizona, United States, 85258
      • Honor Health
  • California
    • La Jolla, California, United States, 92093
      • Moores Cancer Center
    • Los Angeles, California, United States, 90025
      • The Angeles Clinic and Research Institute
    • Los Angeles, California, United States, 90024
      • UCLA Medical Center
    • San Francisco, California, United States, 94143
      • University of California San Francisco
    • San Francisco, California, United States, 94115
      • California Pacific Medical Center (CPMC)
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Cancer Center
    • Denver, Colorado, United States, 80218
      • SCRI at HealthOne
  • Florida
    • Miami, Florida, United States, 33136
      • University of Miami Sylvester Comprehensive Cancer Center
    • Tampa, Florida, United States, 33612
      • Moffitt Cancer Center
  • Georgia
    • Atlanta, Georgia, United States, 30342
      • Northside Hospital Atlanta
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
    • Boston, Massachusetts, United States, 02215
      • Dana Farber Cancer Institute
  • Michigan
    • Grand Rapids, Michigan, United States, 49546
      • The Cancer and Hematology Centers
  • Minnesota
    • Burnsville, Minnesota, United States, 55337
      • Minnesota Oncology Hematology, P.A.
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • Missouri
    • St Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • New York
    • Buffalo, New York, United States, 14263
      • Roswell Park Cancer Institute
    • Manhasset, New York, United States, 11030
      • Northwell Health
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Center
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Health System
  • Ohio
    • Cincinnati, Ohio, United States, 45267
      • University of Cincinnati
    • Cleveland, Ohio, United States, 44195
      • The Cleveland Clinic Foundation
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • Thomas Jefferson University
    • Pittsburgh, Pennsylvania, United States, 15232
      • University of Pittsburgh Medical Center
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • SCRI Oncology Partners
  • Texas
    • Dallas, Texas, United States, 75390
      • UT Southwestern Medical Center
    • Dallas, Texas, United States, 75246
      • Texas Oncology- DFW
    • Houston, Texas, United States, 77030
      • MD Anderson Cancer Center
    • Houston, Texas, United States, 77030
      • Houston Methodist Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Histological or cytological confirmed Metastatic Uveal Melanoma
• HLA-A*02:01 negative
• No prior systemic therapy in the metastatic or advanced setting 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 or falls
• Known AIDS related illness
• Active adrenal insufficiency, active colitis, or active inflammatory bowel disease
• History of interstitial lung disease, active pneumonitis, or history of pneumonitis requiring steroids
• Active infection requiring systemic antibiotic therapy or active Hepatitis B/C
• Major surgery, radiotherapy, or use of hematopoietic colony-stimulating factors (CSF) within 2 weeks 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
• Impaired Cardiac function or clinically significant cardiac diseases, including angina pectoris or acute myocardial infarction <= 6 months prior to start of study treatment
• 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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Phase 2a Dose Optimization of IDE196 + crizotinib; Multiple doses of IDE196 will be tested in combination with fixed dose of crizotinib to identify the optimal combination dose.	Drug: IDE196; Dosed orally, twice daily; Other Names: Darovasertib; Drug: Crizotinib; Dosed orally, twice daily; Other Names: XALKORI
Experimental: Phase 2b / 3 Chosen Combination dose of IDE196 + crizotinib; Chosen combination dose of IDE196 + crizotinib will be tested in additional participants.	Drug: IDE196; Dosed orally, twice daily; Other Names: Darovasertib; Drug: Crizotinib; Dosed orally, twice daily; Other Names: XALKORI
Active Comparator: Phase 2a / 2b / 3 Comparator Arm; Participants will receive investigator's choice of Pembrolizumab, Ipilimumab + Nivolumab, or Dacarbazine.	Drug: Pembrolizumab; IV administration every 3 weeks; Other Names: Keytruda; Drug: Ipilimumab; IV administration every 3 weeks for 4 Cycles; Other Names: Yervoy; Drug: Nivolumab; IV administration every 3 Weeks for 4 Cycles, thereafter every 4 Weeks maintenance; Other Names: Opdivo; Drug: Dacarbazine; IV administration every 3 Weeks; Other Names: DTIC-Dome

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase 2a: To determine the optimal dose of IDE196 + Crizotinib combination for Phase 2B and Phase 3 by evaluating the following:	dose exposure response (safety and efficacy) relationship, plasma concentration profiles and pharmacokinetic (PK) parameters, treatment-emergent Adverse Events (TEAEs), laboratory abnormalities, electrocardiogram (ECG), and vital sign changes and study treatment discontinuation due to AEs.	Approximately 5 months
Phase 2 Progression-Free Survival (PFS)	by blinded independent central review (BICR) of IDE196 + Crizotinib compared to investigator's choice of treatment per RECIST v1.1	Approximately 2 years
Phase 3 Overall Survival (OS) of IDE196 + Crizotinib compared to investigator's choice of treatment.	OS from randomization to date of death due to any cause	Approximately 4 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety of IDE196 + Crizotinib: Incidence of Adverse Events	Treatment emergent adverse events will be summarized by all AEs, including by Grade ≥3, all treatment related AEs, all AEs leading to study drug modifications or discontinuations, all SAEs as measured by CTCAE v5.0.	Approximately 2 years
Phase 2a: Dose-exposure-response of IDE196 as measured by correlating the concentration of IDE196 in plasma with safety and efficacy.	Dose exposure response of IDE196.	Approximately 5 months
Phase 2a: Dose-exposure-response of Crizotinib measured by correlating the concentration of Crizotinib in plasma with safety and efficacy.	Dose exposure response of Crizotinib	Approximately 5 months
Phase 2b + 3: Progression-Free Survival (PFS) per Investigator Assessment of IDE196 + Crizotinib compared to investigator's choice of treatment .	PFS per RECIST v1.1	Approximately 2 years
Objective Response Rate (ORR) per BICR and Investigator assessment of IDE196 + Crizotinib compared to investigator's choice of treatment	ORR per RECIST v1.1	Approximately 2 years
Duration of Response (DOR) per BICR and Investigator assessment of IDE196 + Crizotinib compared to investigator's choice of treatment	DOR per RECIST v1.1	Approximately 2 years
Change from baseline over time and between treatment arms in 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 in EORTC QLQ-C30 scores	Approximately 2 years
Change from baseline over time and between treatment arms in	EuroQoL (EQ)-5D-5L scores	Approximately 2 years
Best Objective Response (BOR) per BICR and Investigator Assessment of IDE196 + Crizotinib compared to Investigator's choice of treatment	Best Objective Response (BOR) per RECIST v1.1	Approximately 2 years
Disease Control Rate (DCR) per BICR and Investigator Assessment of IDE196 + Crizotinib compared to investigator's choice of treatment.	Disease Control Rate (DCR) per RECIST v1.1	Approximately 2 years
Time to response as assessed by Investigator and BICR	Time to response per RECIST v1.1	Approximately 2 years

Collaborators and Investigators

• Sponsor: IDEAYA Biosciences
• Investigators: Study Director: Hetal Patel, MD, MSHS, CHCQM, IDEAYA Biosciences

Study record dates

Study Major Dates

• Study Start (Actual): October 31, 2023
• Primary Completion (Estimated): January 15, 2027
• Study Completion (Estimated): January 15, 2028

Study Registration Dates

• First Submitted: July 12, 2023
• First Submitted That Met QC Criteria: August 3, 2023
• First Posted (Actual): August 14, 2023

Study Record Updates

• Last Update Posted (Actual): February 17, 2026
• Last Update Submitted That Met QC Criteria: February 12, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Keywords: Melanoma; Ophthalmology; Ocular Oncology; Ocular melanoma; Crizotinib; Metastatic Uveal Melanoma; Protein Kinase C; Darovasertib; IDE196
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Neoplasms by Histologic Type; Eye Diseases; Skin Diseases; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Nevi and Melanomas; Skin Neoplasms; Eye Neoplasms; Uveal Diseases; Skin and Connective Tissue Diseases; Uveal Neoplasms; Melanoma; Uveal Melanoma; Amino Acids, Peptides, and Proteins; Proteins; Organic Chemicals; Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Azoles; Triazenes; Imidazoles; Piperidines; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Aminopyridines; Nivolumab; Ipilimumab; Crizotinib; Dacarbazine; pembrolizumab
• Other Study ID Numbers: IDE196-002

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No