Advanced Solid Tumors
Conditions
Keywords
KRASG12C mutation, non-small cell lung cancer (NSCLC), colorectal cancer (CRC)
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.
Interventions
DRUGINCB099280
Administered as specified in the treatment arm description
DRUGadagrasib
Administered as specified in the treatment arm description
Sponsors
Incyte Corporation
Mirati Therapeutics Inc.
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Dose-limiting Toxicities (DLTs) | up to Day 28 | 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. |
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) | up to 574 days | 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. |
| Number of Participants With TEAEs Leading to Treatment Interruptions, Dose Reductions, and Permanent Discontinuation of INCB099280 and Adagarsib | up to 574 days | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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, and 6 | During the lead-in period, INCB099280 was administered as monotherapy. During the treatment period, INCB099280 and adagrasib were coadministered. |
| Cmax of INCB099280 When Administered Alone and in Combination With Adagrasib | Day -1; Cycle 1 Day 8; Day 1 of Cycles 1, 2, 4, 6, 8, 12, and every fourth cycle thereafter | 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. |
| Cmax,ss of INCB099280 When Administered Alone and in Combination With Adagrasib | Day -1; Cycle 1 Day 8; Day 1 of Cycles 1, 2, 4, 6, 8, 12, and every fourth cycle thereafter | 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. |
| Cmin,ss of INCB099280 When Administered Alone and in Combination With Adagrasib | Day -1; Cycle 1 Day 8; Day 1 of Cycles 1, 2, 4, 6, 8, 12, and every fourth cycle thereafter | 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. |
| Tmax of INCB099280 When Administered Alone and in Combination With Adagrasib | Day -1; Cycle 1 Day 8; Day 1 of Cycles 1, 2, 4, 6, 8, 12, and every fourth cycle thereafter | 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. |
| AUC0-tau of INCB099280 When Administered Alone and in Combination With Adagrasib | Day -1; Cycle 1 Day 8; Day 1 of Cycles 1, 2, 4, 6, 8, 12, and every fourth cycle thereafter | 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. |
| CLss/F of INCB099280 When Administered Alone and in Combination With Adagrasib | Day -1; Cycle 1 Day 8; Day 1 of Cycles 1, 2, 4, 6, 8, 12, and every fourth cycle thereafter | 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. |
| Objective Response | up to 470 days | 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. |
| Disease Control | up to 470 days | 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. |
| Duration of Response | up to 470 days | 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. |
| Kaplan-Meier Estimate of ≥6-month and ≥12-month Progression-free Survival (PFS) | ≥6-months and ≥12-months (up to 470 days) | ≥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. |
Countries
Italy, Spain, United Kingdom, United States
Contacts
STUDY_DIRECTORIncyte Medical Monitor
Incyte Corporation
Participant flow
Pre-assignment details
This study was conducted at 5 study centers in the United Kingdom, United States, and Spain.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 54.7 years STANDARD_DEVIATION 13.01 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 6 Participants |
| Sex: Female, Male Female | 4 Participants |
| Sex: Female, Male Male | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 3 | 1 / 3 |
| other Total, other adverse events | 3 / 3 | 3 / 3 |
| serious Total, serious adverse events | 0 / 3 | 1 / 3 |
Outcome results
None listed