Testing IDE196 to Target the Genetic Mutations That Drive Uveal Melanoma
A Phase 1/2 Study of IDE196 in Patients With Solid Tumors Harboring GNAQ/11 Mutations or PRKC Fusions
In Plain English
This trial is testing a new drug called IDE196 that targets a specific genetic flaw found in many uveal melanomas. Your cancer cells likely have mutations in genes called GNAQ or GNA11—think of these as broken instructions that tell your cancer cells to grow. IDE196 is designed to block the faulty signal these mutations create, which may slow or stop your cancer from growing. The trial has two main phases. In Phase 1, doctors test different doses of IDE196 alone, or combined with other drugs (binimetinib or crizotinib), to find the safest and most effective dose. In Phase 2, they give more patients the best dose found in Phase 1 to see how well it actually works against the cancer. You'll take the drug by mouth twice a day in 28-day cycles. The trial is currently enrolling patients for Phase 2, and some parts are already full. Before you can join, you'll need a genetic test to confirm your tumor has one of these specific mutations. This test is essential because the drug only works if your cancer has this particular flaw.
What This Trial Does
This is a /2, multi-center, open-label basket study designed to evaluate the safety and anti-tumor activity of IDE196 in patients with solid tumors harboring GNAQ or GNA11 (GNAQ/11) mutations or PRKC fusions, including uveal melanoma (MUM), cutaneous melanoma, colorectal cancer, and other solid tumors. (dose escalation - monotherapy) will assess safety, tolerability and pharmacokinetics of IDE196 via standard dose escalation scheme and determine the recommended dose. Safety and anti-tumor activity will be assessed in the (dose expansion) part of the study. (dose escalation - binimetib combination) will assess safety, tolerability and pharmacokinetics of IDE196 and binimetinib via standard dose escalation scheme and determine the recommended dose. Safety and anti-tumor activity will be assessed in the (dose expansion) part of the study. (dose escalation - crizotinib combination) will assess safety, tolerability and pharmacokinetics of IDE196 and crizotinib via standard dose escalation scheme and determine the recommended dose. Safety and anti-tumor activity will be assessed in the (dose expansion) part of the study. Evaluation of safety and efficacy across multiple doses may be explored in the dose optimization part of the study. Crizotinib monotherapy with crossover to combination cohort may be assessed for safety and to show the contribution of each study drug to anti-tumor activity. As of Protocol Amendment 10, , dose expansion in IDE196 monotherapy, and dose expansion of IDE196 in combination with binimetinib have been fully enrolled. There were no patients enrolled in the crizotinib monotherapy cohorts.
Who Can Join
Inclusion Criteria
- Patient must be ≥18 years of age and able to provide written informed consent
- Diagnosis of the following:
- o MUM: Uveal melanoma with histological or cytological confirmed metastatic disease. Metastatic disease may be treatment naïve or have progressed on or after most recent therapy. If the most recent therapy was an immune-oncology agent, PD must be confirmed.
- \- If a patient is treatment naïve and human leukocyte antigen (HLA)-A\*02:01 positive\*\*\*, documentation is required to provide rationale why treatment with tebentafusp is not the ideal firstline treatment approach or of the patient's intolerance to tebentafusp.
- \*\*\*To be enrolled in the HLA-A\*02:01 positive cohort, HLA status must be documented by test results from a CAP/CLIA-certified laboratory.
- Measurable disease per RECIST v1.1
- Eastern Cooperative Oncology Group ≤1 and expected life expectancy of \> 3 months
- Adequate organ function at screening
- Adequate contraceptive measures for non-sterilized male and female patients of childbearing potential
- Crizotinib Combination Additional Inclusion Criteria:
- Prior chemotherapy other therapies as applicable or major surgeries must have been completed at least 4 weeks prior to initiation of crizotinib
- Patients with preexisting peripheral neuropathy can be included if it is Grade 1 or lower, prior to initiation of crizotinib Biopsy-eligible patients
- Accessible lesion(s) that permit a total of at least two biopsies without unacceptable risk of a significant procedural complication.
Exclusion Criteria
- Previous treatment with a PKC inhibitor
- Known MSI-H/dMMR tumors who have not previously received immune checkpoint inhibitors
- Known symptomatic brain metastases
- Adverse events from prior anti-cancer therapy that have not resolved
- Known acquired immunodeficiency syndrome (AIDS)-related illness, hepatitis B virus, or hepatitis C virus
- Active infection requiring ongoing therapy
- Recent surgery or radiotherapy
- Prior gastrectomy or upper bowel removal or any other gastrointestinal disorder or defect
- Females who are pregnant or breastfeeding
- Impaired cardiac function
- Treatment with prohibited medications that cannot be discontinued prior to study entry
- For patients receiving IDE196 powder-in-capsule (PIC) formulation or crizotinib, allergy to mammalian meat products and gelatin
- Crizotinib Combination Additional Exclusion Criteria:
- Prior therapy directly targeting ALK, MET, or ROS1
- Spinal cord compression
- History of pneumonitis or interstitial lung disease
- History of syncope
- History of thromboembolic or cerebrovascular events ≤12 weeks prior to first dose of study treatment
- PK Substudy (optional) with Pravastatin Additional Exclusion Criteria:
- Taken any dose of statin or inhibitor of organic anion transporting polypeptide within 7 days prior to enrollment in the study and cannot refrain from them through C2D1
- Taken drugs that interfere with the absorption, metabolism, or elimination of pravastatin
- Any contraindication associated to the use of statins or hypersensitivity component of pravastatin
- Active liver disease
- DDI Cocktail Substudy Additional Exclusion Criteria:
- Treatment with bupropion, repaglinide, flurbiprofen, omeprazole, esomeprazole, midazolam, and dabigatran etexilate within 7 days prior to Cycle 1 Day -1.
- Intake of vitamin supplements containing Vitamin B6 (pyridoxine), grapefruit/grapefruit juice, or Seville orange juice within 7 days prior to Cycle 1 Day -1.
- Intake of any strong or moderate inhibitor of CYP2B6, CYP2CI, CYP2C9, CYP2C10 and OAT3 is prohibited within 7 days or within 5 half-lives, whichever is longer, of Cycle 1 Day -1.
- Moderate and strong inhibitors of CYP2A4/5 or P-gp are prohibited within 7 days, or within 5 half-lives, whichever is longer, of Cycle 1 Day -1.
- Intake of strong or moderate inducers of CYP3A4/5, CYP2B6, CYP2C9, CYP2C19, or OAT3 is prohibited during 15 days, or 5 half-lives, whichever is longer, prior to Cycle 1 Day -1.
Treatments
IDE196 (DRUG)
IDE196 dosed orally, twice daily for each 28-day cycle
Binimetinib (DRUG)
Binimetinib dosed orally, twice daily for each 28-day cycle
Crizotinib (DRUG)
Crizotinib dosed orally, twice daily for each 28-day cycle
Trial Sites (15)
UCLA Medical Center
Los Angeles, California, United States
Bartosz Chmielowski, MD · BChmielowski@mednet.ucla.edu
RecruitingSan Francisco Oncology Associates
San Francisco, California, United States
Active Not RecruitingSCRI - Denver
Denver, Colorado, United States
Ryan Weight, MD · ryan.weight@theskincancerinstitute.com
RecruitingUniversity of Iowa
Iowa City, Iowa, United States
Active Not RecruitingCancer Hematology Centers Western Michigan
Grand Rapids, Michigan, United States
Active Not RecruitingColumbia University Medical Center - Herbert Irving Pavilion
New York, New York, United States
Active Not RecruitingDuke University Medical Center
Durham, North Carolina, United States
Carol A Wiggs · cao13@duke.edu
RecruitingUniversity of Cincinnati Cancer Center
Cincinnati, Ohio, United States
RecruitingThe Cleveland Clinic Foundation
Cleveland, Ohio, United States
Active Not RecruitingSidney Kimmel Cancer Center at Thomas Jefferson University
Philadelphia, Pennsylvania, United States
Marlana Orloff, MD · marlana.orloff@jefferson.edu
RecruitingThe Sarah Cannon Research Institute/Tennessee Oncology
Nashville, Tennessee, United States
askSARAH
RecruitingThe University of Texas MD Anderson Cancer Center
Houston, Texas, United States
Jordi Ahnert, MD · JRodon@mdanderson.org
RecruitingWestmead Hospital
Sydney, New South Wales, Australia
Active Not RecruitingQueensland
Woolloongabba, Australia
Active Not RecruitingPrincess Margaret Cancer Centre
Toronto, Ontario, Canada
Active Not Recruiting