Clinical trial NCT03947385: Study of IDE196 in Patients with Solid Tumors Harboring GNAQ/11 Mutations or PRKC Fusions
Official title: A Phase 1/2 Study of IDE196 in Patients with Solid Tumors Harboring GNAQ/11 Mutations or PRKC Fusions
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Metastatic Uveal Melanoma
Cutaneous Melanoma
Colorectal Cancer
Other Solid Tumors
Keywords: Metastatic Uveal Melanoma
Uveal Melanoma
Protein Kinase C
Ophthalmology
Ocular Oncology
Darovasertib
IDE196
Ocular Melanoma
Lead sponsor: IDEAYA Biosciences
Sponsor class: INDUSTRY
First posted: 2019-05-13
Enrollment: 341
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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

Primary outcomes:
measure: Dose-limiting Toxicity (DLT)
timeFrame: 28 days following first dose of IDE196 as monotherapy, in combination with Binimetinib, or in combination with Crizotinib
measure: Maximum Tolerated Dose (MTD)
timeFrame: 28 days following first dose of IDE196 as monotherapy, in combination with Binimetinib, or in combination with Crizotinib
measure: Recommended Phase 2 Dose (RP2D) as monotherapy, in combination with Binimetinib, or in combination with Crizotinib
timeFrame: Approx. 6 months
measure: Plasma Concentrations of IDE196 as monotherapy, in combination with Binimetinib, or in combination with Crizotinib
timeFrame: Approx. 6 months
measure: Plasma Concentrations of Crizotinib administered in combination with IDE196
timeFrame: Approx. 6 months
measure: Plasma Concentrations of Binimetinib administered in combination with IDE196
timeFrame: Approx. 6 months
measure: Overall Response Rate (ORR) for combination with Binimetinib or in combination with Crizotinib Dose Expansion by Blinded Independent Review Committee
timeFrame: Approx. 48 months
measure: Duration of Response for combination with Binimetinib or in combination with Crizotinib Dose Expansion by Blinded Independent Review Committee
timeFrame: Approx. 48 months
Secondary outcomes:
measure: Overall Response Rate (ORR) for combination with Binimetinib or in combination with Crizotinib in Dose Escalation and all combination cohorts by Blinded Independent Review Committee
timeFrame: Approx. 48 months
measure: Duration of Response for combination with Binimetinib or in combination with Crizotinib in Dose Escalation and in all combination cohorts by Blinded Independent Review Committee
timeFrame: Approx. 48 months
measure: ORR by Investigator
timeFrame: Approx. 48 months
measure: Duration of Response by Investigator
timeFrame: Approx. 48 months
measure: Disease Control by Investigator
timeFrame: Approx. 48 months
measure: Numbers of Participants with Adverse Events
timeFrame: Approx. 48 months
measure: Treatment-related pharmacodynamic effect in all patients
timeFrame: Approx. 48 months
Other outcomes:
measure: Progression-Free Survival
timeFrame: Approx. 48 months
measure: Overall Survival
timeFrame: Approx. 48 months
measure: Reduction in tumor burden by total volumetric measurement
timeFrame: Approx. 48 months
measure: Treatment-related gene signatures and/or molecular profiling
timeFrame: Approx. 48 months
measure: Treatment-related changes in tumor tissue or cell-free DNA from blood
timeFrame: Approx. 48 months
Locations:
city: Los Angeles
country: United States
facility: UCLA Medical Center
state: California
city: San Francisco
country: United States
facility: San Francisco Oncology Associates
state: California
city: New York
country: United States
facility: Columbia University Medical Center - Herbert Irving Pavilion
state: New York
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Cincinnati
country: United States
facility: University of Cincinnati Cancer Center
state: Ohio
city: Philadelphia
country: United States
facility: Sidney Kimmel Cancer Center at Thomas Jefferson University
state: Pennsylvania
city: Nashville
country: United States
facility: The Sarah Cannon Research Institute/Tennessee Oncology
state: Tennessee
city: Houston
country: United States
facility: The University of Texas MD Anderson Cancer Center
state: Texas
city: Sydney
country: Australia
facility: Westmead Hospital
state: New South Wales
city: Toronto
country: Canada
facility: Princess Margaret Cancer Centre
state: Ontario
Study officials:
affiliation: gcole@ideayabio.com
name: George Cole Jr., MD
role: STUDY_DIRECTOR
References: