This study is an open-label Phase 1/Phase 2 evaluation of INCB001158 as a single agent and in combination with immune checkpoint therapy in patients with advanced/metastatic solid tumors.
This study is an open-label Phase 1 evaluation of INCB001158 as a single agent and in combination with immune checkpoint therapy in patients with advanced/metastatic solid tumors. Single Agent INCB001158: Patients with advanced/metastatic solid tumors will be enrolled into escalating monotherapy dose cohorts to determine the Recommended Phase 2 Dose (RP2D) of INCB001158. Additional patients with NSCLC, Colorectal Cancer (CRC), and other tumors including SCCHN, RCC, Gastric, Bladder and Melanoma will be enrolled at the single agent RP2D. Combination Treatment: Patients with advanced/metastatic NSCLC, Melanoma, Urothelial, Microsatellite Instability (MSI)/ Microsatellite Stable (MSS) CRC, Gastric, SCCHN and Mesothelioma will be enrolled into separate cohorts of combination therapy (INCB001158 and Pembrolizumab) to determine the RP2D. In the dose expansion phase, additional patients with NSCLC, Melanoma, Urothelial, MSI/MSS CRC, Gastric, SCCHN and Mesothelioma will be treated with the combination of INCB001158 and Pembrolizumab at the RP2D. All patients will be assessed for safety, pharmacokinetics, biomarkers and tumor response.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
260
Arginase Inhibitor
PD-1 Inhibitor
University of South Alabama
Mobile, Alabama, United States
Honor Health/Pinnacle Oncology Hematology
Scottsdale, Arizona, United States
University of Arizona
Tucson, Arizona, United States
Georgetown
Washington D.C., District of Columbia, United States
Johns Hopkins
Baltimore, Maryland, United States
BIDMC
Boston, Massachusetts, United States
DFCI
Boston, Massachusetts, United States
Henry Ford
Detroit, Michigan, United States
Sarah Cannon Research Institute at Tennessee Oncology
Nashville, Tennessee, United States
Vanderbilt
Nashville, Tennessee, United States
...and 10 more locations
Number of Participants With Any Treatment-emergent Adverse Event (TEAE)
An adverse event (AE) was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related, that occurred after a participant provided informed consent. Abnormal laboratory values or test results occurring after informed consent constituted AEs only if they induced clinical signs or symptoms, were considered clinically meaningful, required therapy (e.g., hematologic abnormality that required transfusion), or required changes in the study treatment(s). A TEAE was defined as any adverse event that started or worsened after the first dose of study drug.
Time frame: up to study completion (up to approximately 3.5 years)
Recommended Phase 2 Dose (RP2D) of INCB001158
The RP2D was determined by a traditional 3+3 dose-escalation design of single-agent INCB001158 in participants with advanced/metastatic solid tumors at doses of 50, 75, 100, or 150 mg.
Time frame: 12 weeks
RP2D of INCB001158 in Combination With Pembrolizumab
INCB001158 was dosed orally BID.
Time frame: 12 weeks
Objective Response Rate (ORR)
ORR was defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (v1.1) as the percentage of participants with a confirmed best overall response of complete response (CR) or partial response (PR) at any post-Baseline visits prior to first disease progression and alternative cancer therapy use. 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. Pleural mesothelioma was evaluated using modified RECIST criteria. Confidence intervals were calculated based on the exact method for binomial distributions (Clopper Pearson). Two participants evaluable for PFS were not evaluable for response.
Time frame: Until disease progression/study discontinuation (up to approximately 5 years)
Percentage of Participants With the Indicated Best Overall Response (BOR)
BOR was evaluated per RECIST v1.1. 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. Stable disease (SD): no change in target lesions to qualify for CR, PR, or progressive disease (PD). PD: progression of a target or non-target lesion or presence of a new lesion. Missing: participant had a missing BOR because there were no post-Baseline tumor assessments. Pleural mesothelioma was evaluated using modified RECIST criteria.
Time frame: Until disease progression/study discontinuation (up to approximately 5 years)
Duration of Response (DOR)
DOR was defined as the number of months from the date of the first documentation of an objective response (CR or PR per RECIST v1.1) to the date of the first documentation of disease progression or death, whichever occurred first. 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. Pleural mesothelioma will be evaluated using modified RECIST criteria. Kaplan-Meier (KM) product-limit estimates with a log-log transformation were used for 95% confidence interval calculation.
Time frame: Until disease progression/study discontinuation (up to approximately 5 years)
Progression-free Survival (PFS)
PFS was defined as the length of time between the date of the first dose and the earlier of death or progressive disease as assessed by RECIST v1.1. Pleural mesothelioma was evaluated using modified RECIST criteria. Participants enrolled in Part 1c had renal impairment. These participants received INCB001158 50 mg + pembrolizumab, which was half the recommended Phase 2 dose of INCB001158. In renally impaired participants, the 50 mg dose has comparable exposure to 100 mg in participants with normal renal function. It was pre-specified to combine Part 1c and Part 3 participants for efficacy analysis based on planned comparable dosing according to renal function.
Time frame: Until disease progression/study discontinuation (up to approximately 5 years)
Cmax of INCB001158 Following Single Escalating Doses for Part 1A
Cmax was defined as the maximum observed concentration of INCB001158.
Time frame: Cycle 1 Day 1: predose; 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-dose
Tmax of INCB001158 Following Single Escalating Doses for Part 1A
tmax was defined as the time of the maximum observed concentration of INCB001158.
Time frame: Cycle 1 Day 1: predose; 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-dose
AUC0-t of INCB001158 Following Single Escalating Doses for Part 1A
AUC0-t was defined as the area under the concentration-time curve from dosing (time 0) of INCB001158 to time t.
Time frame: Cycle 1 Day 1: predose; 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-dose
AUC0-inf of INCB001158 Following Single Escalating Doses for Part 1A
AUC0-inf was defined as the area under the concentration-time curve from dosing (time 0) of INCB001158 extrapolated to infinity.
Time frame: Cycle 1 Day 1: predose; 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-dose
t1/2 of INCB001158 Following Single Escalating Doses for Part 1A
t1/2 was defined as the half-life of INCB001158.
Time frame: Cycle 1 Day 1: predose; 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-dose
CL/F of INCB001158 Following Single Escalating Doses for Part 1A
CL/F was defined as the apparent oral dose clearance of INCB001158.
Time frame: Cycle 1 Day 1: predose; 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-dose
Vz/F of INCB001158 Following Single Escalating Doses for Part 1A
Vz/F was defined as the apparent volume of distribution of INCB001158.
Time frame: Cycle 1 Day 1: predose; 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-dose
Cmax of INCB001158 Following Multiple Escalating Doses for Part 1A
Cmax was defined as the maximum observed concentration of INCB001158.
Time frame: Cycle 1 Day 15: predose; 0.5, 1, 2, 4, 6, 8, and 12 hours post-dose
Tmax of INCB001158 Following Multiple Escalating Doses for Part 1A
tmax was defined as the time of the maximum observed concentration of INCB001158.
Time frame: Cycle 1 Day 15: predose; 0.5, 1, 2, 4, 6, 8, and 12 hours post-dose
AUC0-t of INCB001158 Following Multiple Escalating Doses for Part 1A
AUC0-t was defined as the area under the concentration-time curve from dosing (time 0) of INCB001158 to time t.
Time frame: Cycle 1 Day 15: predose; 0.5, 1, 2, 4, 6, 8, and 12 hours post-dose
AUC0-tau of INCB001158 Following Multiple Escalating Doses for Part 1A
AUC0-tau was defined as the area under the concentration-time curve from dosing (time 0) of INCB001158 to the end of the dosing period.
Time frame: Cycle 1 Day 15: predose; 0.5, 1, 2, 4, 6, 8, and 12 hours post-dose
t1/2 of INCB001158 Following Multiple Escalating Doses for Part 1A
t1/2 was defined as the half-life of INCB001158.
Time frame: Cycle 1 Day 15: predose; 0.5, 1, 2, 4, 6, 8, and 12 hours post-dose
CL/F of INCB001158 Following Multiple Escalating Doses for Part 1A
CL/F was defined as the apparent oral dose clearance of INCB001158.
Time frame: Cycle 1 Day 15: predose; 0.5, 1, 2, 4, 6, 8, and 12 hours post-dose
Vz/F of INCB001158 Following Multiple Escalating Doses for Part 1A
Vz/F was defined as the apparent volume of distribution of INCB001158.
Time frame: Cycle 1 Day 15: predose; 0.5, 1, 2, 4, 6, 8, and 12 hours post-dose
Cmax of INCB001158 in the Fed and Fasted States Following Multiple Doses for Part 1A to Assess the Effect of Food
Cmax was defined as the maximum observed concentration of INCB001158.
Time frame: Fasted: Cycle 1 Day 15: predose; 0.5, 1, 2, 4, 6, 8, and 12 hours post-dose. Fed: Cycle 2 Day 8: predose; 0.5, 1, 2, 4, 6, and 8 hours post-dose
Tmax of INCB001158 in the Fed and Fasted States Following Multiple Doses for Part 1A to Assess the Effect of Food
tmax was defined as the time of the maximum observed concentration of INCB001158.
Time frame: Fasted: Cycle 1 Day 15: predose; 0.5, 1, 2, 4, 6, 8, and 12 hours post-dose. Fed: Cycle 2 Day 8: predose; 0.5, 1, 2, 4, 6, and 8 hours post-dose
AUC of INCB001158 in the Fed and Fasted States Following Multiple Doses for Part 1A to Assess the Effect of Food
AUC was defined as the area under the concentration-time curve of INCB001158.
Time frame: Fasted: Cycle 1 Day 15: predose; 0.5, 1, 2, 4, 6, 8, and 12 hours post-dose. Fed: Cycle 2 Day 8: predose; 0.5, 1, 2, 4, 6, and 8 hours post-dose
Cmax of INCB001158 for Capsules Versus Tablets for Part 2D to Assess the Effect of Formulation
Cmax was defined as the maximum observed concentration of INCB001158.
Time frame: Tablet: Cycle 1 Day 15 (Tablet) and Cycle 2 Day 1 (Capsule): predose; 0.5, 1, 2, 4, 6, 8, and 10 hours post-dose
Tmax of INCB001158 for Capsules Versus Tablets for Part 2D to Assess the Effect of Formulation
tmax was defined as the time of the maximum observed concentration of INCB001158.
Time frame: Tablet: Cycle 1 Day 15 (Tablet) and Cycle 2 Day 1 (Capsule): predose; 0.5, 1, 2, 4, 6, 8, and 10 hours post-dose
AUC0-t of INCB001158 for Capsules Versus Tablets for Part 2D to Assess the Effect of Formulation
AUC0-t was defined as the area under the concentration-time curve from dosing (time 0) of INCB001158 to time t.
Time frame: Tablet: Cycle 1 Day 15 (Tablet) and Cycle 2 Day 1 (Capsule): predose; 0.5, 1, 2, 4, 6, 8, and 10 hours post-dose
AUC0-tau of INCB001158 for Capsules Versus Tablets for Part 2D to Assess the Effect of Formulation
AUC0-tau was defined as the area under the concentration-time curve from dosing (time 0) of INCB001158 to the end of the dosing period.
Time frame: Tablet: Cycle 1 Day 15 (Tablet) and Cycle 2 Day 1 (Capsule): predose; 0.5, 1, 2, 4, 6, 8, and 10 hours post-dose
Cmax of INCB001158 in Participants With Renal Impairment (Part 1C) and Normal Renal Function (Part 1A)
Cmax was defined as the Maximum observed concentration of INCB001158.
Time frame: Cycle 1 Day 1: predose; 0.5, 1, 2, 4, 6, 8, 12, and 24 (Part 1A only) hours post-dose.
Tmax of INCB001158 in Participants With Renal Impairment (Part 1C) and Normal Renal Function (Part 1A)
tmax was defined as the time of the maximum observed concentration of INCB001158.
Time frame: Cycle 1 Day 1: predose; 0.5, 1, 2, 4, 6, 8, 12, and 24 (Part 1A only) hours post-dose.
AUC0-8h of INCB001158 in Participants With Renal Impairment (Part 1C) and Normal Renal Function (Part 1A)
AUC0-8h was defined as the area under the concentration-time curve from dosing (time 0) of INCB001158 to 8 hours post-dose.
Time frame: Cycle 1 Day 1: predose; 0.5, 1, 2, 4, 6, and 8 hours post-dose
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