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

PHASE2PHASE3RECRUITING

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).

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Study details:

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.

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Eligibility criteria

Researchers look for people who fit a certain description, called eligibility criteria. See if you qualify.

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
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    Eligibility

    Age eligible for study : 18 and older

    Healthy volunteers accepted : No

    Gender eligible for study: All

    Things to know

    Study dates

    Study start: 2023-10-31

    Primary completion: 2027-01-15

    Study completion finish: 2028-01-15

    study type

    Study type

    TREATMENT

    phase

    Phase

      PHASE2

      PHASE3

    trial

    Trial ID

    NCT05987332

    Intervention or treatment

    DRUG: IDE196

    DRUG: Crizotinib

    DRUG: Pembrolizumab

    DRUG: Ipilimumab

    DRUG: Nivolumab

    DRUG: Dacarbazine

    Conditions

    • Metastatic Uveal Melanoma

    Find a site

    Closest Location:

    Westmead Hospital

    Research sites nearby

    Select from list below to view details:

    • Westmead Hospital

      Sydney, New South Wales, Australia

    • Peter MacCallum Cancer Centre

      Melbourne, Victoria, Australia

    • Princess Alexander Hospital

      Brisbane, Queensland, Australia

    • Alfred Health

      Melbourne, Victoria, Australia

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    Study Plan

    This section provides details of the study plan, including how the study is designed and what the study is measuring.

    How is the study designed?

    Participant Group/ArmIntervention/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
    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
    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

    What is the study measuring?

    Primary outcome

    Primary Outcome MeasurePrimary Outcome DescriptionPrimary Outcome Time Frame
    Progression-Free Survival (PFS) by blinded independent central review (BICR) of IDE196 + Crizotinib compared to investigator's choice of treatmentPFS per RECIST 1.1Approximately 2 years
    Overall Survival (OS) of IDE196 + Crizotinib compared to investigator's choice of treatmentOS from randomization to date of death due to any causeApproximately 4 years

    Secondary outcome

    Secondary Outcome MeasureSecondary Outcome DescriptionSecondary Outcome Time Frame
    Safety of IDE196 + Crizotinib: Incidence of Adverse EventsTreatment 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 V5.0Approximately 2 years
    Phase 2a: Dose exposure response of IDE196Dose-exposure-response of IDE196 as measured by concentration of IDE196 in plasmaApproximately 5 months
    Phase 2a: Dose exposure response of CrizotinibDose-exposure-response of Crizotinib as measured by concentration of Crizotinib in plasmaApproximately 5 months
    Progression-Free Survival (PFS) per Investigator of IDE196 + Crizotinib compared to investigator's choice of treatmentPFS per RECIST 1.1Approximately 2 years
    Objective Response Rate (ORR) per BICR and Investigator assessment of IDE196 + Crizotinib compared to investigator's choice of treatmentORR per RECIST 1.1Approximately 2 years
    Duration of Response (DOR) per BICR and Investigator assessment of IDE196 + Crizotinib compared to investigator's choice of treatmentDOR per RECIST 1.1Approximately 2 years
    Change from baseline over time and between treatment arms in EORTC QLQ-C30Global 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 scoresGeneral 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

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    References

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

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