A Study to Evaluate INCB186748 in Participants With Advanced or Metastatic Solid Tumors With KRAS G12D Mutation

Phase 1

Recruiting

• Conditions: Solid Tumors
• Interventions: Drug: INCB186748; Drug: Cetuximab; Drug: GEMNabP; Drug: mFOLFIRINOX

• Registration Number: NCT06818812
• Lead Sponsor: Incyte Corporation

Brief Summary

The purpose of this study is to evaluate INCB186748 in Participants With Advanced or Metastatic Solid Tumors With KRAS G12D Mutation.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2025-02-05
• Study First Submitted QC: 2025-02-05
• Study First Posted: 2025-02-10
• Study Start: 2025-03-27
• Status Verified: 2025-04
• Last Update Submitted: 2025-04-11
• Last Update Posted: 2025-04-15
• Primary Completion: 2027-03-27
• Study Completion: 2027-03-27

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 308

Inclusion Criteria

• ≥18 years old.

• Locally advanced or metastatic solid tumor with KRAS G12D mutation.

• For Part 1 and Part 2 Combination Group 1: Disease progression on or after prior standard treatment, or intolerance to or ineligibility for standard treatment, or no standard available treatment to improve the disease outcome.

• For Part 2 Combination Groups 2 and 3: No more than 1 prior standard treatment.

• Cohort-specific requirements as follows:

  • Parts 1a and 1d: histologically or cytologically confirmed malignant solid tumor of any tissue origin.

  • Part 1b

    • Disease Group 1: diagnosis of PDAC and at least 1 but no more than 2 prior standard systemic regimens for pancreatic cancer.
    • Disease Group 2: diagnosis of CRC.

  • Part 1c: Confirmed diagnosis of PDAC or CRC.

  • Parts 2a and 2b

    • Combination Group 1 (INCB186748 in combination with cetuximab):

      • Diagnosis of PDAC or

      • Diagnosis of CRC and ∘ Prior treatment in the advanced setting with a fluoropyrimidine-based chemotherapy regimen containing either oxaliplatin or irinotecan and

        • In Part 2a: ≤ 3 prior standard regimens.
        • In Part 2b: ≤ 2 prior standard regimens.

    • Combination Group 2 (INCB186748 in combination with GEMNabP) and

    • Combination Group 3 (INCB186748 in combination with mFOLFIRINOX):

      • Diagnosis of PDAC.
      • ≤ 1 prior standard systemic regimen for pancreatic cancer.

• Measurable disease according to RECIST v1.1.

• ECOG performance status score of 0 or 1.

Exclusion Criteria

• Prior treatment with any KRAS inhibitor.
• Known additional invasive malignancy within 1 year of the first dose of study drug.
• History of organ transplant, including allogeneic stem cell transplantation.
• Significant, uncontrolled medical condition.
• History or presence of an ECG abnormality.
• Inadequate organ function.

Other protocol-defined Inclusion/Exclusion Criteria may apply.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Part 1b: Dose Expansion monotherapy	INCB186748	INCB186748 at the protocol-defined dose strength based on cohort assignment.
Part 1d: Food-Effect	INCB186748	Evaluate food effect on drug exposure as defined in the protocol.
Part 2a: Dose Escalation combination	Cetuximab	INCB186748 in combination at the protocol-defined dose strength based on cohort assignment.
Part 2a: Dose Escalation combination	GEMNabP	INCB186748 in combination at the protocol-defined dose strength based on cohort assignment.
Part 2a: Dose Escalation combination	mFOLFIRINOX	INCB186748 in combination at the protocol-defined dose strength based on cohort assignment.
Part 2b: Dose Expansion combination	Cetuximab	INCB186748 in combination at the protocol-defined dose strength based on cohort assignment.
Part 2b: Dose Expansion combination	GEMNabP	INCB186748 in combination at the protocol-defined dose strength based on cohort assignment.
Part 2b: Dose Expansion combination	mFOLFIRINOX	INCB186748 in combination at the protocol-defined dose strength based on cohort assignment.
Part 1a: Dose Escalation monotherapy	INCB186748	INCB186748 at the protocol-defined dose strength based on cohort assignment.
Part 1c: Pharmacodynamic cohort	INCB186748	INCB186748 at the protocol-defined dose strength based on cohort assignment.
Part 2a: Dose Escalation combination	INCB186748	INCB186748 in combination at the protocol-defined dose strength based on cohort assignment.
Part 2b: Dose Expansion combination	INCB186748	INCB186748 in combination at the protocol-defined dose strength based on cohort assignment.

Primary Outcome Measures

Name	Time	Method
Number of participants with Dose Limiting Toxicities (DLTs)	Up to 28 days	Dose-limiting toxicity will be defined as the occurrence of any of the toxicities as per protocol.
Number of participants with Treatment-emergent Adverse Events (TEAEs)	Up to approximately 12 months and 60 days	Defined as adverse events reported for the first time or worsening of a pre-existing event occurring after the first dose of study drug up to 30 days (for INCB186748 as monotherapy and in combination with GEMNabP or mFOLFIRINOX) and 60 days (for INCB186748 in combination with cetuximab) after the last dose of INCB186748.
Number of participants with TEAEs leading to dose modification or discontinuation	Up to approximately 12 months and 60 days	Number of participants with TEAEs leading to dose modification or discontinuation.

Secondary Outcome Measures

Name	Time	Method
Objective Response Rate (ORR)	Up to approximately 12 months	Defined as having a best overall Complete Response (CR) or Partial Response (PR), as determined by the investigator by radiographic disease assessment according to RECIST v1.1.
Disease Control Response (DCR)	Up to approximately 12 months	Defined as having a best overall response of CR, PR, or Stable Disease (SD) as determined by the investigator by radiographic disease assessment according to RECIST v1.1.
INCB186748 pharmacokinetic (PK) in Plasma	Up to approximately 12 months	INCB186748 concentration in plasma.
Duration of Response (DOR)	Up to approximately 12 months	Defined as the time from earliest date of disease response (Completed Response or Partial Response) until earliest date of disease progression as determined by the investigator by radiographic disease assessment according to RECIST v1.1 or death due to any cause if occurring sooner than progression.

Trial Locations

Locations (9)

Florida Cancer Specialists; 🇺🇸 Sarasota, Florida, United States

UCLA Healthcare Hematology-Oncology; 🇺🇸 Santa Monica, California, United States

Sidney Kimmel Comprehensive Cancer Center At Johns Hopkins; 🇺🇸 Baltimore, Maryland, United States

Sarah Cannon Research Institue At Healthone; 🇺🇸 Denver, Colorado, United States

Georgetown University Hospital; 🇺🇸 Washington, District of Columbia, United States

Hackensack University Medical Center; 🇺🇸 Hackensack, New Jersey, United States

Jefferson University Hospitals; 🇺🇸 Philadelphia, Pennsylvania, United States

Scri Oncology Partners; 🇺🇸 Nashville, Tennessee, United States

Md Anderson Cancer Center; 🇺🇸 Houston, Texas, United States