A Study to Evaluate INCB161734 in Participants With Advanced or Metastatic Solid Tumors With KRAS G12D Mutation

Study Overview
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Brief Summary
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This study is conducted to determine the safety and tolerability of INCB161734 as a single agent or in combination with other anticancer therapies.

Official Title
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A Phase 1, Open-Label, Multicenter Study of INCB161734 in Participants With Advanced or Metastatic Solid Tumors With KRAS G12D Mutation

Conditions
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Solid Tumors

Intervention / Treatment
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* Drug: INCB161734
* Drug: Cetuximab
* Drug: Retifanlimab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ≥18 years old Locally-advanced or metastatic solid tumor with KRAS G12D mutation Disease progression on prior standard treatment, intolerance to or ineligibility for standard treatment, or no available standard treatment to improve the disease outcome Cohort specific requirements as follows: Part 1A: Histologically or cytologically confirmed malignant solid tumor of any tissue origin Part 1B Disease group 1: diagnosis of PDAC Disease group 2: diagnosis of CRC Disease group 3: diagnosis of NSCLC Disease group 4: diagnosis of other advanced solid tumor and not part of Disease groups 1, 2 and 3 Parts 2A and 2B Combination 1: Diagnosis of CRC or CRC Combination 2: Diagnoses of PDAC, CRC or NSCLC Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 Exclusion Criteria: Prior treatment with any KRAS G12D 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1a: Dose Escalation monotherapy<br>INCB161734 at the protocol-defined dose strength based on cohort assignment. | Drug: INCB161734<br>* INCB161734 will be administered at protocol defined dose.<br>|
| Experimental: Part 1b: Dose Expansion monotherapy<br>INCB161734 at the protocol-defined dose strength based on cohort assignment. | Drug: INCB161734<br>* INCB161734 will be administered at protocol defined dose.<br>|
| Experimental: Part 1c: Pharmacodynamic cohort<br>INCB161734 at the protocol-defined dose strength based on cohort assignment. | Drug: INCB161734<br>* INCB161734 will be administered at protocol defined dose.<br>|
| Experimental: Part 2a: Dose Escalation combination<br>INCB161734 in combination at the protocol-defined dose strength based on cohort assignment. | Drug: INCB161734<br>* INCB161734 will be administered at protocol defined dose.<br>Drug: Cetuximab<br>* Cetuximab will be administered at protocol defined dose.<br>Drug: Retifanlimab<br>* Retifanlimab will be administered at protocol defined dose.<br>|
| Experimental: Part 2b: Dose Expansion combination<br>INCB161734 in combination at the protocol-defined dose strength based on cohort assignment. | Drug: INCB161734<br>* INCB161734 will be administered at protocol defined dose.<br>Drug: Cetuximab<br>* Cetuximab will be administered at protocol defined dose.<br>Drug: Retifanlimab<br>* Retifanlimab will be administered at protocol defined dose.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with Dose Limiting Toxicities (DLTs) | Dose-limiting toxicity will be defined as the occurrence of any of the toxicities as per protocol. | Up to 28 days | 
| Number of participants with Treatment-emergent Adverse Events (TEAEs) | Defined as adverse events reported for the first time or worsening of a pre-existing event after first dose of study drug monotherapy and in combination with cetuximab and retifanlimab. | Up to 2 years and 90 days | 
| Number of participants with TEAEs leading to dose modification or discontinuation | Number of participants with TEAEs leading to dose modification or discontinuation. | Up to 2 years and 90 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| INCB161734 pharmacokinetic (PK) in Plasma | INCB161734 concentration in plasma. | Up to approximately 90 days | 
| Objective Response Rate (ORR) | 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. | Up to 2 years | 
| Disease Control Response (DCR) | 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. | Up to 2 years | 
| Duration of Response (DOR) | 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. | Up to 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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INCB161734, KRASG12D Mutation, pancreatic ductal adenocarcinoma (PDAC), colorectal cancer (CRC), non-small cell lung cancer (NSCLC)