A Study of INCB099280 in Combination With Adagrasib in Adults With Advanced Solid Tumors Harboring a KRASG12C Mutation

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to evaluate the safety and tolerability of INCB099280 in combination with adagrasib and to establish the MTD or identify RDE(s) for the combination of INCB099280 and adagrasib.

Official Title
-----------------
A Phase 1 Study of INCB099280 in Combination With Adagrasib in Adults With Advanced Solid Tumors Harboring a KRASG12C Mutation

Conditions
-----------------
Advanced Solid Tumors

Intervention / Treatment
-----------------
* Drug: INCB099280
* Drug: adagrasib


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: KRASG12C-mutated solid malignancy determined by a sponsor-approved assay using either tumor tissue or ctDNA. Histologically confirmed malignant solid tumor with locally advanced and/or metastatic disease. Only participants with NSCLC will be enrolled into Part 2 Cohort A. Only participants with CRC will be enrolled into Part 2 Cohort B. Part 1: Disease progression on or after at least 1 prior systemic treatment. Part 2 (Cohort A - NSCLC): Received an anti-PD-(L)1-containing regimen and platinum based chemotherapy regimen either concurrently or sequentially Part 2 (Cohort B - CRC): Received at least 1 line of systemic therapy that includes the combination of fluoropyrimidine-based chemotherapy (in combination with oxaliplatin and/or irinotecan) and either a vascular endothelial growth factor-targeting monoclonal antibody or an anti-epidermal growth factor receptor monoclonal antibody (if RAS wild type). Participants with MSI-H/dMMR CRC must also have received a prior immune checkpoint inhibitor approved for this indication. Measurable disease according to RECIST v1.1. Eastern Cooperative Oncology Group performance status of 0 or 1. Estimated life expectancy > 3 months. Willingness to avoid pregnancy. Exclusion Criteria: Known additional malignancy that is progressing or requires active treatment. Central nervous system (CNS) metastases requiring treatment and/or leptomeningeal disease. Part 2 only: Prior treatment with an approved or investigational agent targeting KRASG12C. Toxicity from prior therapy that has not recovered to protocol-defined limits. Received thoracic radiation of > 30 Gy within 6 months of the first dose of study treatment. Participation in another interventional clinical study. History or evidence of interstitial lung disease, including noninfectious pneumonitis. Presence of gastrointestinal condition that may affect drug absorption. Active autoimmune disease requiring systemic treatment, including corticosteroids exceeding a daily dose of 10 mg of prednisone or equivalent. Diagnosis of immunodeficiency or receiving chronic systemic steroid therapy exceeding a daily dose of 10 mg of prednisone or equivalent. Active infection requiring systemic therapy. History of organ transplantation, including allogeneic stem cell transplantation. Receipt of systemic antibiotics within 28 days of the first dose of study treatment. Probiotic usage is prohibited during screening and throughout the study treatment period. Received a live vaccine within 28 days of the planned start of study drug. Laboratory values outside the Protocol-defined ranges. Other protocol-defined Inclusion/Exclusion Criteria may apply.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1: Dose Finding<br>INCB099280 administered in combination with adagrasib in participants with previously treated KRAS glutamine to cysteine mutation at codon 12 (KRASG12C) mutant advanced solid tumors, will be evaluated to identify dose(s) for further evaluation in the dose expansion phase of the study. | Drug: INCB099280<br>* Administered as specified in the treatment arm description<br>Drug: adagrasib<br>* Administered as specified in the treatment arm description<br>* Other names: KRAZATI;|
| Experimental: Part 2: Dose Expansion<br>Up to 80 participants will be enrolled in 1 of 2 disease-specific cohorts: Cohort A: previously treated KRASG12C mutated non-small cell lung cancer (NSCLC) Cohort B: previously treated KRASG12C-mutated colorectal cancer (CRC). Up to 3 doses may be selected from Part 1: Dose Finding for the Part 2: Dose Expansion. | Drug: INCB099280<br>* Administered as specified in the treatment arm description<br>Drug: adagrasib<br>* Administered as specified in the treatment arm description<br>* Other names: KRAZATI;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: 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. | 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 |
| --- | --- | --- |
| INCB099280 and adagrasib plasma concentrations. | PK parameters will be calculated from the blood plasma concentrations of INCB099280 and adagrasib using standard noncompartmental (model independent) PK methods. | Up to 2 years | 
| Objective response rate (ORR) | Defined as having a best overall response of complete response (CR) or partial response (PR) assessed per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 by the investigator. | Up to 2 years | 
| Disease Control Rate (DCR) | Defined as having a best overall response of CR, PR, or stable disease (SD) ≥ 15 weeks (from the start of treatment) assessed per RECIST v1.1 by the investigator. | Up to 2 years | 
| Duration of Response (DOR) | Defined as the time from the first CR or PR until disease progression (assessed per RECIST v1.1 by the investigator) or death from any cause, whichever occurs earlier. | Up to 2 years | 
| Progression-free survival (PFS) | Defined as absence of disease progression (assessed per RECIST v1.1 by the investigator) or death from any cause from start of treatment. | Up to 12 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
KRASG12C mutation, non-small cell lung cancer (NSCLC), colorectal cancer (CRC)