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

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

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.

Study Overview

• Status: Terminated
• Conditions: Advanced Solid Tumors
• Intervention / Treatment: Drug: INCB099280; Drug: adagrasib

• Study Type: Interventional
• Enrollment (Actual): 6
• Phase: Phase 1

Contacts and Locations

Study Locations

• Italy
  • Candiolo, Italy, 10060
    • Fondazione Del Piemonte Per L Oncologia Ircc Candiolo
  • Rozzano, Italy, 20089
    • Irccs Istituto Clinico Humanitas
  • Verona, Italy, 37124
    • Centro Ricerche Cliniche Di Verona (Crc)
• Spain
  • Barcelona, Spain, 08035
    • Hospital General Universitario Vall D Hebron
  • Barcelona, Spain, 08023
    • Hospital HM Nou Delfos
  • Pozuelo de Alarcón, Spain, 28223
    • Hospital Universitario Quironsalud Madrid
  • Seville, Spain, 41009
    • Hospital Universitario Virgen Macarena
• United Kingdom
  • London, United Kingdom, W12 0HS
    • Hammersmith Hospital
  • London, United Kingdom, SE1 9RT
    • Guys Hospital
• United States
  • California
    • Los Angeles, California, United States, 90067
      • Valkyrie Clinical Trials
  • Colorado
    • Greeley, Colorado, United States, 80631
      • Banner MD Anderson Cancer Center
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Henry Ford Health System
  • Texas
    • Dallas, Texas, United States, 75251
      • Mary Crowley Cancer Research Centers McCrc Headquarters
  • Virginia
    • Falls Church, Virginia, United States, 22042
      • Inova Schar Cancer Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part 1: Dose Finding; 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; Administered as specified in the treatment arm description; Drug: adagrasib; Administered as specified in the treatment arm description; Other Names: KRAZATI
Experimental: Part 2: Dose Expansion; 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; Administered as specified in the treatment arm description; Drug: adagrasib; Administered as specified in the treatment arm description; Other Names: KRAZATI

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Dose-limiting Toxicities (DLTs)	DLTs were defined as protocol-defined toxicities occurring up to and including on Day 28, except those with a clear alternative explanation. Toxicities with a clear alternative explanation (e.g., due to disease progression) or transient (≤72 hours) abnormal laboratory values without associated clinically significant signs or symptoms based on investigator determination could have been deemed non-DLTs.	up to Day 28
Number of Participants With Treatment-emergent Adverse Events (TEAEs)	An adverse event (AE) was defined any untoward medical occurrence associated with the use of a drug in humans, whether or not it is considered drug-related. An AE could therefore have been any unfavorable or unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of study treatment. A TEAE was defined as any AE either reported for the first time or the worsening of a pre-existing event after the first dose of either study drug until 104 days after the last dose of study treatment or start of new anticancer therapy.	up to 574 days
Number of Participants With TEAEs Leading to Treatment Interruptions, Dose Reductions, and Permanent Discontinuation of INCB099280 and Adagarsib	An AE was defined any untoward medical occurrence associated with the use of a drug in humans, whether or not it is considered drug-related. An AE could therefore have been any unfavorable or unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of study treatment. A TEAE was defined as any AE either reported for the first time or the worsening of a pre-existing event after the first dose of either study drug until 104 days after the last dose of study treatment or start of new anticancer therapy.	up to 574 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Concentration of INCB099280	During the lead-in period, INCB099280 was administered as monotherapy. During the treatment period, INCB099280 and adagrasib were coadministered.	Lead-in Period Day -1 and Cycle 1 Day 8: predose and 0.5, 1, 2, 3, 4, 6, 8, and 12 hours postdose; predose on Day 1 of Cycles 1, 2, 4, and 6
Cmax of INCB099280 When Administered Alone and in Combination With Adagrasib	During the lead-in period, INCB099280 was administered as monotherapy. During the treatment period, INCB099280 and adagrasib were coadministered. Cmax was defined as the maximum plasma concentration of INCB099280. Lead-in Period: Day -1 and Cycle 1 Day 8: predose and 0.5, 1, 2, 3, 4, 6, 8, and 12 hours postdose; predose on Day 1 of Cycles 1, 2, 4, 6, 8, 12, and every fourth cycle thereafter. Without Lead-in Period: Cycle 1 Day 8: predose and 1, 2, and 4 hours postdose; predose on Day 1 of Cycles 1, 2, 4, 6, 8, 12, and every fourth cycle thereafter.	Day -1; Cycle 1 Day 8; Day 1 of Cycles 1, 2, 4, 6, 8, 12, and every fourth cycle thereafter
Cmax,ss of INCB099280 When Administered Alone and in Combination With Adagrasib	During the lead-in period, INCB099280 was administered as monotherapy. During the treatment period, INCB099280 and adagrasib were coadministered. Cmax,ss was defined as the maximum plasma concentration of INCB099280 at steady state. Lead-in Period: Day -1 and Cycle 1 Day 8: predose and 0.5, 1, 2, 3, 4, 6, 8, and 12 hours postdose; predose on Day 1 of Cycles 1, 2, 4, 6, 8, 12, and every fourth cycle thereafter. Without Lead-in Period: Cycle 1 Day 8: predose and 1, 2, and 4 hours postdose; predose on Day 1 of Cycles 1, 2, 4, 6, 8, 12, and every fourth cycle thereafter.	Day -1; Cycle 1 Day 8; Day 1 of Cycles 1, 2, 4, 6, 8, 12, and every fourth cycle thereafter
Cmin,ss of INCB099280 When Administered Alone and in Combination With Adagrasib	During the lead-in period, INCB099280 was administered as monotherapy. During the treatment period, INCB099280 and adagrasib were coadministered. Cmin,ss was defined as the minimum plasma concentration of INCB099280 at steady state. Lead-in Period: Day -1 and Cycle 1 Day 8: predose and 0.5, 1, 2, 3, 4, 6, 8, and 12 hours postdose; predose on Day 1 of Cycles 1, 2, 4, 6, 8, 12, and every fourth cycle thereafter. Without Lead-in Period: Cycle 1 Day 8: predose and 1, 2, and 4 hours postdose; predose on Day 1 of Cycles 1, 2, 4, 6, 8, 12, and every fourth cycle thereafter.	Day -1; Cycle 1 Day 8; Day 1 of Cycles 1, 2, 4, 6, 8, 12, and every fourth cycle thereafter
Tmax of INCB099280 When Administered Alone and in Combination With Adagrasib	During the lead-in period, INCB099280 was administered as monotherapy. During the treatment period, INCB099280 and adagrasib were coadministered. tmax was defined as the time to the maximum concentration of INCB099280. Lead-in Period: Day -1 and Cycle 1 Day 8: predose and 0.5, 1, 2, 3, 4, 6, 8, and 12 hours postdose; predose on Day 1 of Cycles 1, 2, 4, 6, 8, 12, and every fourth cycle thereafter. Without Lead-in Period: Cycle 1 Day 8: predose and 1, 2, and 4 hours postdose; predose on Day 1 of Cycles 1, 2, 4, 6, 8, 12, and every fourth cycle thereafter.	Day -1; Cycle 1 Day 8; Day 1 of Cycles 1, 2, 4, 6, 8, 12, and every fourth cycle thereafter
AUC0-tau of INCB099280 When Administered Alone and in Combination With Adagrasib	During the lead-in period, INCB099280 was administered as monotherapy. During the treatment period, INCB099280 and adagrasib were coadministered. AUC0-tau was defined as the area under the steady-state plasma or serum concentration-time curve over 1 dose interval of INCB099280. Lead-in Period: Day -1 and Cycle 1 Day 8: predose and 0.5, 1, 2, 3, 4, 6, 8, and 12 hours postdose; predose on Day 1 of Cycles 1, 2, 4, 6, 8, 12, and every fourth cycle thereafter. Without Lead-in Period: Cycle 1 Day 8: predose and 1, 2, and 4 hours postdose; predose on Day 1 of Cycles 1, 2, 4, 6, 8, 12, and every fourth cycle thereafter.	Day -1; Cycle 1 Day 8; Day 1 of Cycles 1, 2, 4, 6, 8, 12, and every fourth cycle thereafter
CLss/F of INCB099280 When Administered Alone and in Combination With Adagrasib	During the lead-in period, INCB099280 was administered as monotherapy. During the treatment period, INCB099280 and adagrasib were coadministered. CLss/F was defined as the apparent oral dose clearance of INCB099280 at steady state. Lead-in Period: Day -1 and Cycle 1 Day 8: predose and 0.5, 1, 2, 3, 4, 6, 8, and 12 hours postdose; predose on Day 1 of Cycles 1, 2, 4, 6, 8, 12, and every fourth cycle thereafter. Without Lead-in Period: Cycle 1 Day 8: predose and 1, 2, and 4 hours postdose; predose on Day 1 of Cycles 1, 2, 4, 6, 8, 12, and every fourth cycle thereafter.	Day -1; Cycle 1 Day 8; Day 1 of Cycles 1, 2, 4, 6, 8, 12, and every fourth cycle thereafter
Objective Response	Objective response was defined as having a best overall response of complete response (CR) or partial response (PR) assessed per Response Evaluation Criteria in Solid Tumours version 1.1 (RECIST v1.1) by the investigator. CR: disappearance of all target and non-target lesions and no appearance of any new lesions. Any pathological lymph nodes (whether target or non-target) must have a reduction in the short axis to <10 millimeters (mm). PR: complete disappearance or at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference the baseline sum diameters, no new lesions, and no progression of non-target lesions.	up to 470 days
Disease Control	Disease control was defined as 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. CR: disappearance of all target and non-target lesions and no appearance of any new lesions. Any pathological lymph nodes (whether target or non-target) must have a reduction in the short axis to <10 mm. PR: complete disappearance or at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference the baseline sum diameters, no new lesions, and no progression of non-target lesions. PD: progression of a target or non-target lesion or presence of a new lesion. SD: no change in target lesions to qualify for CR, PR, or PD.	up to 470 days
Duration of Response	Duration of response was 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 occurred earlier. CR: disappearance of all target and non-target lesions and no appearance of any new lesions. Any pathological lymph nodes (whether target or non-target) must have a reduction in the short axis to <10 millimeters (mm). PR: complete disappearance or at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference the baseline sum diameters, no new lesions, and no progression of non-target lesions.	up to 470 days
Kaplan-Meier Estimate of ≥6-month and ≥12-month Progression-free Survival (PFS)	≥6-month and ≥12-month PFS was defined as the absence of disease progression (assessed per RECIST v1.1 by the investigator) or death from any cause from the start of treatment to ≥6 or ≥12 months after treatment. A Kaplan-Meier estimate of PFS is an estimate of the probability that a participant will remain alive and free from disease progression (or relapse) at a given time point after starting treatment.	≥6-months and ≥12-months (up to 470 days)

Collaborators and Investigators

• Sponsor: Incyte Corporation
• Collaborators: Mirati Therapeutics Inc.
• Investigators: Study Director: Incyte Medical Monitor, Incyte Corporation

Study record dates

Study Major Dates

• Study Start (Actual): December 28, 2023
• Primary Completion (Actual): April 11, 2025
• Study Completion (Actual): July 11, 2025

Study Registration Dates

• First Submitted: September 8, 2023
• First Submitted That Met QC Criteria: September 8, 2023
• First Posted (Actual): September 15, 2023

Study Record Updates

• Last Update Posted (Actual): September 8, 2026
• Last Update Submitted That Met QC Criteria: September 3, 2026
• Last Verified: September 1, 2026

More Information

Terms related to this study

• Keywords: colorectal cancer (CRC); non-small cell lung cancer (NSCLC); KRASG12C mutation
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Intestinal Diseases; Respiratory Tract Diseases; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Lung Diseases; Respiratory Tract Neoplasms; Thoracic Neoplasms; Colonic Diseases; Lung Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Colorectal Neoplasms; Carcinoma, Non-Small-Cell Lung; Antineoplastic Agents; adagrasib
• Other Study ID Numbers: INCB99280-204; 2023 (U.S. NIH Grant/Contract: GRAMMY Museum Foundation); 2023-503223-26-00 (Registry Identifier: EU CT number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Incyte shares data with qualified external researchers after a research proposal is submitted. These requests are reviewed and approved by a review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. The trial data availability is according to the criteria and process described on https://www.incyte.com/our-company/compliance-and-transparency
• IPD Sharing Time Frame: Data will be shared after the primary publication or 2 years after the study has ended for market authorized products and indications.
• IPD Sharing Access Criteria: Data from eligible studies will be shared with qualified researchers according to the criteria and process described in the Data Sharing section of the www.incyteclinicaltrials.com website. For approved requests, the researchers will be granted access to anonymized data under the terms of a data sharing agreement.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No