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).
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
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
420
Dosed orally, twice daily
Dosed orally, twice daily
IV administration every 3 weeks
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.
Time frame: 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
Time frame: 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
Time frame: Approximately 4 years
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.
Time frame: 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.
Time frame: 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
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IV administration every 3 weeks for 4 Cycles
IV administration every 3 Weeks for 4 Cycles, thereafter every 4 Weeks maintenance
IV administration every 3 Weeks
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
...and 58 more locations
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: Approximately 2 years
Change from baseline over time and between treatment arms in
EuroQoL (EQ)-5D-5L scores
Time frame: 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
Time frame: 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
Time frame: Approximately 2 years
Time to response as assessed by Investigator and BICR
Time to response per RECIST v1.1
Time frame: Approximately 2 years