A New Two-Drug Combination (IDE196 + Crizotinib) for 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)
In Plain English
This trial is testing whether two drugs taken together—IDE196 and crizotinib—work better than standard treatments for uveal melanoma that has spread to other parts of your body. Both drugs are pills you take by mouth twice a day. The study will compare your results on this new combination against patients who receive one of three standard treatments (pembrolizumab, a combination of ipilimumab and nivolumab, or dacarbazine). The trial has three stages. First, doctors will test two different doses of IDE196 combined with crizotinib to find the best dose that works well and is safe. Once they pick the winning dose, more patients will be enrolled to confirm it works. Finally, the largest stage will compare this combination head-to-head with standard treatments, measuring how long patients survive. The main goal is to see if this new combination helps people with metastatic uveal melanoma live longer. **Important: You can only join this trial if you have a specific genetic marker called HLA-A*02:01 negative.** This means you'll need a blood test to check if you qualify before enrolling. This genetic difference affects how your immune system responds to these drugs.
What This Trial Does
This is a /3, multi-arm, multi-stage, open-label study of human leukocyte antigen (HLA)-A\*02:01 negative participants with uveal melanoma (MUM) who will be randomized to receive either IDE196 + crizotinib or investigator's choice of treatment (pembrolizumab, ipilimumab + nivolumab, or dacarbazine).
How It Works
This study is designed as a multi-stage study within a 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 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).
Who Can Join
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
Treatments
IDE196 (DRUG)
Dosed orally, twice daily
Crizotinib (DRUG)
Dosed orally, twice daily
Pembrolizumab (DRUG)
IV administration every 3 weeks
Ipilimumab (DRUG)
IV administration every 3 weeks for 4 Cycles
Nivolumab (DRUG)
IV administration every 3 Weeks for 4 Cycles, thereafter every 4 Weeks maintenance
Dacarbazine (DRUG)
IV administration every 3 Weeks
Trial Sites (68)
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
Northside Hospital Atlanta
Atlanta, Georgia, United States
University of Iowa
Iowa City, Iowa, United States
Massachusetts General Hospital
Boston, Massachusetts, United States
Dana Farber Cancer Institute
Boston, Massachusetts, United States
The Cancer and Hematology Centers
Grand Rapids, Michigan, United States
Minnesota Oncology Hematology, P.A.
Burnsville, Minnesota, United States
Mayo Clinic
Rochester, Minnesota, United States
Washington University School of Medicine
St Louis, Missouri, United States
Roswell Park Cancer Institute
Buffalo, New York, United States
Northwell Health
Manhasset, New York, United States
Memorial Sloan Kettering Cancer Center
New York, New York, United States
Duke University Health System
Durham, North Carolina, United States
University of Cincinnati
Cincinnati, Ohio, United States
The Cleveland Clinic Foundation
Cleveland, Ohio, United States
Thomas Jefferson University
Philadelphia, Pennsylvania, United States
University of Pittsburgh Medical Center
Pittsburgh, Pennsylvania, United States
SCRI Oncology Partners
Nashville, Tennessee, United States
Texas Oncology- DFW
Dallas, Texas, United States
UT Southwestern Medical Center
Dallas, Texas, United States
Houston Methodist Cancer Center
Houston, Texas, United States
MD Anderson Cancer Center
Houston, Texas, United States
Westmead Hospital
Sydney, New South Wales, Australia
Princess Alexander Hospital
Brisbane, Queensland, Australia
Peter MacCallum Cancer Centre
Melbourne, Victoria, Australia
Alfred Health
Melbourne, Victoria, Australia
Sir Charles Gairdner Hospital
Perth, Washington, Australia
Queen Elizabeth Hospital
Adelaide, Australia
Cliniques Universitaires Saint Luc
Brussels, Belgium
Algemene Medische Oncologie UZ
Leuven, Belgium
Cross Cancer Institute, University of Alberta
Edmonton, Alberta, Canada
BC Cancer Agency
Vancouver, British Columbia, Canada
Princess Margaret Cancer Centre
Toronto, Ontario, Canada
Centre Hospitalier de l'Universite de Montreal- CHUM
Montreal, Quebec, Canada
The Leon Berard Center
Lyon, France
Institut Curie
Paris, France
NCT Heidelberg
Heidelberg, Baden-Wurttemberg, Germany
Universitätsklinikum Köln
Cologne, North Rhine-Westphalia, Germany
Universitätsklinikum Essen (AöR)
Essen, North Rhine-Westphalia, Germany
Universitätsklinikum Carl Gustav Carus Dresden
Dresden, Saxony, Germany
Charité - Universitätsmedizin Berlin
Berlin, Germany
Hadassah Medical Center
Jerusalem, Israel
Sheba Medical Center
Ramat Gan, Israel
Fondazione IRCCS Istituto Nazionale dei Tumori
Milan, Italy
Istituto Nazionale dei Tumori Fondazione Pascale
Naples, Italy
Fondazione Policlinico Gemelli IRCCS
Roma, Italy
AOUS Policlinico Le Scotte
Siena, Italy
LUMC (Leids Universitair Medisch Centrum)
Leiden, Netherlands
Ośrodek Badań Klinicznych Wczesnych Faz, Uniwersyteckie Centrum Kliniczne w Gdańsku
Gdansk, Poland
Narodowy Instytut Onkologii im. Marii Skłodowskiej-Curie Państwowy Instytut Badawczy
Warsaw, Poland
Catalan Institute of Oncology
L'Hospitalet de Llobregat, Spain
Hospital Universitario La Paz
Madrid, Spain
Hospital Clínico Universitario de Santiago de Compostela
Santiago de Compostela, Spain
Hospital Universitario Virgen Macarena
Seville, Spain
Hospital General Universitario Valencia
Valencia, Spain
Dermatologische Klinik, USZ Flughafen Geschoss 7 - Klinische Forschung
Zurich, Switzerland
The Beatson West of Scotland Cancer Centre
Glasgow, United Kingdom
The Clatterbridge Cancer Centre NHS Foundation Trust
Metropolitan Borough of Wirral, United Kingdom
Mount Vernon Cancer Centre East & North Herts NHS Trust
Northwood, United Kingdom