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

Overview

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.

Interventions

• Drug IDE196
  IDE196 dosed orally, twice daily for each 28-day cycle
• Drug Binimetinib
  Binimetinib dosed orally, twice daily for each 28-day cycle
• Drug Crizotinib
  Crizotinib dosed orally, twice daily for each 28-day cycle

Primary outcome measures

• Dose-limiting Toxicity (DLT) [Time frame: 28 days following first dose of IDE196 as monotherapy, in combination with Binimetinib, or in combination with Crizotinib]
• Incidence of Adverse Events [Time frame: Approx. 8 months]
• Maximum Tolerated Dose (MTD) [Time frame: 28 days following first dose of IDE196 as monotherapy, in combination with Binimetinib, or in combination with Crizotinib]
• Recommended Phase 2 Dose (RP2D) as monotherapy, in combination with Binimetinib, or in combination with Crizotinib [Time frame: Approx. 6 months]
• Plasma Concentrations of IDE196 as monotherapy, in combination with Binimetinib, or in combination with Crizotinib [Time frame: Approx. 6 months]
• Plasma Concentrations of Crizotinib administered in combination with IDE196 [Time frame: Approx. 6 months]
• Plasma Concentrations of Binimetinib administered in combination with IDE196 [Time frame: Approx. 6 months]
• Overall Response Rate (ORR) of IDE196 monotherapy, in combination with Binimetinib, and in combination with Crizotinib in Dose Expansion cohorts by Investigator response assessment [Time frame: Approx. 8 months]
• Duration of Response (DOR) of IDE196 monotherapy, in combination with Binimetinib, and in combination with Crizotinib in Dose Expansion cohorts by Investigator response assessment [Time frame: Approx. 8 months]

Secondary outcome measures (11)

• Progression Free Survival (PFS) of IDE196 monotherapy, in combination with Binimetinib, and in combination with Crizotinib in Dose Expansion cohorts by Investigator response assessment [Time frame: Approx. 18 months]
• Overall Response Rate (ORR) of IDE196 monotherapy, in combination with Binimetinib, and in combination with Crizotinib in Dose Expansion cohorts and by prior treatment status (pretreated or treatment naive) by Investigator response assessment [Time frame: Approx. 18 months]
• Duration of Response (DOR) of IDE196 monotherapy, in combination with Binimetinib, and in combination with Crizotinib in Dose Expansion cohorts by prior treatment status (pretreated or treatment naive) by Investigator response assessment [Time frame: Approx. 18 months]
• Disease Control Rate (DCR) by Investigator [Time frame: Approx. 18 months]
• Area under the plasma concentration versus time curve (AUC) [Time frame: Approx. 8 months]
• Area under the plasma concentration curve from time zero extrapolated to infinity (AUCinf) [Time frame: Approx. 8 months]
• Area under the plasma concentration curve from time zero to the last measurable concentration time (AUC0-t) [Time frame: Approx. 8 months]
• Area under the plasma concentration curve extrapolating the percentage of total drug exposure (AUC%extra) [Time frame: Approx. 8 months]
• Peak Plasma Concentration (Cmax) [Time frame: Approx. 8 months]
• Time to maximum plasma concentration (Tmax) [Time frame: Approx. 8 months]
• Elimination half-life of Plasma Concentration levels (T1/2) [Time frame: Approx. 8 months]

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

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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 12 centers

• UCLA Medical Center — Los Angeles
• San Francisco Oncology Associates — San Francisco
• SCRI - Denver — Denver
• University of Iowa — Iowa City
• Cancer Hematology Centers Western Michigan — Grand Rapids
• Columbia University Medical Center - Herbert Irving Pavilion — New York
• Duke University Medical Center — Durham
• University of Cincinnati Cancer Center — Cincinnati
• … and 4 more centers

Australia · 2 centers

• Westmead Hospital — Sydney
• Queensland — Woolloongabba

Canada · 1 center

• Princess Margaret Cancer Centre — Toronto

Identifiers

NCT: NCT03947385 · IDE196-001

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗