Study of IDE196 in Patients with Solid Tumors Harboring GNAQ/11 Mutations or PRKC Fusions

Ideaya Biosciences

Status and phase: Enrolling; Phase 2; Phase 1

Conditions: Other Solid Tumors; Metastatic Uveal Melanoma; Colorectal Cancer; Cutaneous Melanoma

Treatments: Drug: IDE196; Drug: Binimetinib; Drug: Crizotinib

Study type: Interventional

Funder types: Industry

Identifiers

NCT03947385

IDE196-001

Details and patient eligibility

About

This is a Phase 1/2, 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 metastatic uveal melanoma (MUM), cutaneous melanoma, colorectal cancer, and other solid tumors.

Phase 1 (dose escalation - monotherapy) will assess safety, tolerability and pharmacokinetics of IDE196 via standard dose escalation scheme and determine the recommended Phase 2 dose. Safety and anti-tumor activity will be assessed in the Phase 2 (dose expansion) part of the study.

Phase 1 (dose escalation - binimetib combination) will assess safety, tolerability and pharmacokinetics of IDE196 and binimetinib via standard dose escalation scheme and determine the recommended Phase 2 dose. Safety and anti-tumor activity will be assessed in the Phase 2 (dose expansion) part of the study.

Phase 1 (dose escalation - crizotinib combination) will assess safety, tolerability and pharmacokinetics of IDE196 and crizotinib via standard dose escalation scheme and determine the recommended Phase 2 dose. Safety and anti-tumor activity will be assessed in the Phase 2 (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, Phase 1, Phase 2 dose expansion in IDE196 monotherapy, and Phase 2 dose expansion of IDE196 in combination with binimetinib have been fully enrolled. There were no patients enrolled in the crizotinib monotherapy cohorts.

Enrollment: 341 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Sequential Assignment

Masking: None (Open label)

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341 participants in 9 patient groups

Dose Escalation Monotherapy

Experimental group

Description:

IDE196 dosed orally, twice daily (BID) for each 28-day cycle

Treatment:

Drug: IDE196

Dose Expansion Monotherapy

Experimental group

Description:

RP2D in MUM and non-MUM tumors harboring GNAQ/11 mutations or PRKC fusions (cutaneous melanoma, CRC, other solid tumors)

Treatment:

Drug: IDE196

Dose Escalation Binimetinib Combination

Experimental group

Description:

IDE196 dosed orally, twice daily (BID) for each 28-day cycle and Binimetinib dosed orally, twice daily (BID) for each 28-day cycle

Treatment:

Drug: Binimetinib

Drug: IDE196

Dose Expansion Binimetinib Combination

Experimental group

Description:

RP2D in MUM and non-MUM tumors harboring GNAQ/11 mutations (cutaneous melanoma, CRC, other solid tumors)

Treatment:

Drug: Binimetinib

Drug: IDE196

Dose Escalation Crizotinib Combination

Experimental group

Description:

IDE196 dosed orally, twice daily (BID) for each 28-day cycle and Crizotinib dosed orally, twice daily (BID) for each 28-day cycle

Treatment:

Drug: Crizotinib

Drug: IDE196

Dose Expansion Crizotinib Combination

Experimental group

Description:

RP2D in MUM and non-MUM tumors harboring GNAQ/11 mutations (cutaneous melanoma, CRC, other solid tumors) Previously treated MUM, Treatment naïve MUM, MUM patients with human leukocyte antigen (HLA)-A\*02:01 positive status

Treatment:

Drug: Crizotinib

Drug: IDE196

Dose Optimization Crizotinib Combination

Experimental group

Description:

IDE196 dosed orally, twice daily (BID) for each 28-day cycle and Crizotinib dosed orally, twice daily (BID) for each 28-day cycle

Treatment:

Drug: Crizotinib

Drug: IDE196

Crizotinib Monotherapy with Crossover to Combination

Experimental group

Description:

Crizotinib dosed orally, twice daily (BID) for each 28-day cycle until disease progression then IDE196 added and dosed orally, twice daily (BID) for each 28-day cycle

Treatment:

Drug: Crizotinib

Drug: IDE196

PK Substudy with Pravastatin (OBTP1B1 Substrate)

Experimental group

Description:

A PK substudy with approximately 18 patients will be nested within the IDE196 and crizotinib combination expansion cohort to evaluate the impact on the pravastatin PK profile by the steady state exposures of IDE196.

Treatment:

Drug: Crizotinib