This is an open-label, Phase 1/2 study in subjects with advanced or metastatic solid tumors. The study has three separate treatment groups where separate epigenetic agents are evaluated with an immunotherapy combination. Treatment Group A will evaluate the DNA methyltransferase inhibitor azacitidine in combination with the programmed death receptor-1 (PD-1) inhibitor pembrolizumab and the indoleamine 2,3-dioxygenase (IDO-1) inhibitor epacadostat; Treatment Group B will evaluate the bromodomain and extra-terminal (BET) inhibitor INCB057643 with pembrolizumab and epacadostat; and Treatment Group C will evaluate the lysine-specific demethylase 1A (LSD1) inhibitor INCB059872 with pembrolizumab and epacadostat. The study will be divided into 2 parts (Part 1 and 2). Part 1 is a dose-escalation assessment to evaluate the safety and tolerability of the combination therapies. Once the recommended doses have been determined, subjects with previously treated NSCLC, microsatellite-stable colorectal cancer (CRC), head and neck squamous cell carcinoma, urothelial carcinoma, and melanoma will be enrolled into expansion cohorts in Part 2.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
70
Five doses of azacitidine will be administered by subcutaneous injection or intravenously (IV) over Days 1 to 7 in Cycles 1 through 6.
Pembrolizumab will be administered in a 30-minute IV infusion every 3 weeks on Day 1 of each 21-day cycle.
Epacadostat tablets will be administered orally twice daily.
INCB057643 will be orally self- administered once daily beginning on Cycle 1 Day 1 and continuously thereafter in 21-day cycles.
Pembrolizumab will be administered in a 30-minute IV infusion every 3 weeks of each 21-day cycle starting on Cycle 2 Day 1.
Epacadostat tablets will be administered orally twice daily starting at Cycle 2 Day 1.
INCB059872 will be orally self- administered once daily OR every other day beginning on Cycle 1 Day 1 and continuously thereafter in 21-day cycles.
City of Hope National Medical Center
Duarte, California, United States
University of California San Diego
La Jolla, California, United States
The University of Chicago
Chicago, Illinois, United States
University of Pennsylvania Health System
Philadelphia, Pennsylvania, United States
Sarah Cannon
Nashville, Tennessee, United States
Vanderbilt-Ingram Cancer Center
Nashville, Tennessee, United States
MD Anderson Cancer Center
Houston, Texas, United States
University of Washington
Seattle, Washington, United States
Vall D Hebron Univ
Barcelona, Spain
Univ De Navarra
Pamplona, Spain
...and 2 more locations
Part 1 and 2 : Number of Participants With Treatment Emergent Adverse Events
A treatment-emergent AE was defined as an event occurring after exposure to at least 1 dose of study drug. A treatment-related AE was defined as an event with a definite, probable, or possible causality to study medication. A serious AE is an event resulting in death, hospitalization, persistent or significant disability/incapacity, or is life threatening, a congenital anomaly/birth defect or requires medical or surgical intervention to prevent 1 of the outcomes above. The intensity of an AE was graded according to the National Cancer Institute common terminology criteria for adverse events (NCI-CTCAE) version 4.03: Grade 1 (Mild); Grade 2 (Moderate); Grade 3 (Severe); Grade 4 (life-threatening).
Time frame: Baseline through 42-49 days after end of treatment, estimated up to 27 months (24 months with 100 day FU period).
Part 1 and 2: Objective Response Rate Based on Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1)
ORR was defined as the percentage of participants having a complete response (CR) or partial response (PR) as determined by investigator assessment of radiographic disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. CR is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR is at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. A participant was considered as an objective responder if the participant had a best overall response of CR or PR.
Time frame: Every 9 weeks for the duration of study participation; estimated minimum of 6 months.
Parts 1 and 2: Percentage of Responders Determined by Immunohistochemistry
Responder is defined as an increase in the number of tumor-infiltrating lymphocytes or the ratio of CD8+ lymphocytes to T regulatory cells infiltrating tumor post-treatment versus pretreatment with pembrolizumab and epacadostat in combination with azacitidine.
Time frame: Baseline to Week 5/6 or week 8/9
Parts 1 and 2: Progression-free Survival Based on RECIST v1.1.
Defined as the time from date of first dose of study drug until the earliest date of disease progression per RECIST v1.1, or death due to any cause, if occurring sooner than progression.
Time frame: Every 9 weeks from date of randomization until the date of first documented progression or date of death from any cause whichever came first, assessed up to 24 months
Parts 1 and 2: Duration of Response Based on RECIST v1.1
Defined as the time from earliest date of disease response until the earliest date of disease progression per RECIST v1.1, or death due to any cause, if occurring sooner than progression.
Time frame: Every 9 weeks from date of randomization until the date of first documented progression or date of death from any cause whichever came first, assessed up to 24 months
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