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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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)

Conditions
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Metastatic Uveal Melanoma

Intervention / Treatment
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* Drug: IDE196
* Drug: Crizotinib
* Drug: Pembrolizumab
* Drug: Ipilimumab
* Drug: Nivolumab
* Drug: Dacarbazine


Participation Criteria
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Eligibility Criteria
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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, or 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 Active HIV infection or 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 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

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: Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

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

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) by blinded independent central review (BICR) of IDE196 + Crizotinib compared to investigator's choice of treatment | PFS per RECIST 1.1 | Approximately 2 years | 
| 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, 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 | Approximately 2 years | 
| Phase 2a: Dose exposure response of IDE196 | Dose-exposure-response of IDE196 as measured by concentration of IDE196 in plasma | Approximately 5 months | 
| Phase 2a: Dose exposure response of Crizotinib | Dose-exposure-response of Crizotinib as measured by concentration of Crizotinib in plasma | Approximately 5 months | 
| Progression-Free Survival (PFS) per Investigator of IDE196 + Crizotinib compared to investigator's choice of treatment | PFS per RECIST 1.1 | 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 1.1 | 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 1.1 | Approximately 2 years | 
| Change from baseline over time and between treatment arms in EORTC QLQ-C30 | 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. | Approximately 2 years | 
| Change from baseline over time and between treatment arms in EuroQoL (EQ)-5D-5L scores | 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. | Approximately 2 years | 

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