Purpose

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.

Conditions

Eligibility

Eligible Ages
Over 18 Years
Eligible Genders
All
Accepts Healthy Volunteers
No

Inclusion Criteria

  • Willingness to provide written informed consent for the study. - Willingness to undergo a pretreatment and on-treatment tumor biopsy to obtain tumor tissue. - Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. - Part 1: Subjects with histologically or cytologically confirmed advanced or metastatic solid tumors that have failed prior standard therapy (disease progression; subject refusal or intolerance is also allowable). - Part 2: *Note: Subjects must have failed available therapies that are known to confer clinical benefit as indicated below, unless they are ineligible, intolerant, or refused standard treatment. - Subjects with histologically or cytologically confirmed NSCLC: - Metastatic (Stage IV) or recurrent NSCLC (according to American Joint Committee on Cancer 7th edition guidelines) who have had disease progression after available therapies for advanced or metastatic disease that are known to confer clinical benefit, been intolerant to treatment, or refused standard treatment. - Prior systemic regimens must include previously approved therapies, including a platinum-containing chemotherapy regimen; a tyrosine kinase inhibitor for tumors with driver mutations; and checkpoint inhibitors where approved. - Must have disease progression on a prior PD-1-pathway targeted agent. - Subjects with recurrent (unresectable) or metastatic CRC: - Have histologically confirmed microsatellite stable (MSS) CRC. - Stage IV MSS CRC (according to American Joint Committee on Cancer 7th edition guidelines) who have had disease progression after available therapies for advanced or metastatic disease that are known to confer clinical benefit, been intolerant to treatment, or refused standard treatment. - Prior systemic regimens must include previously approved therapies, including fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy; an anti-VEGF therapy (if no contraindication); and if negative for KRAS, NRAS, and BRAF mutations and no contraindication, an anti-epidermal growth factor receptor (EGFR) therapy; and progressed after the last administration of approved therapy. - Subjects with HNSCC: - Histologically confirmed squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx. - Carcinomas of the nasopharynx, salivary gland, or nonsquamous cell histology are excluded. - Must have received prior treatment with a platinum-based therapy - Must have had documented disease progression while on a prior PD-1 pathway-targeted agent. - Subjects with melanoma: - Histologically or cytologically confirmed melanoma. - Unresectable Stage III or Stage IV melanoma, as per American Joint Committee on Cancer staging system not amenable to local therapy. - Subjects with urothelial carcinoma: - Histologically or cytologically confirmed urothelial carcinoma of the renal pelvis, ureter, urinary bladder, or urethra that is transitional cell or mixed transitional/nontransitional (predominantly transitional) cell type. - Stage IV locally advanced or metastatic urothelial carcinoma (according to American Joint Committee on Cancer 7th edition guidelines) with documented disease progression while on a PD-1 pathway targeted therapy.

Exclusion Criteria

  • Laboratory parameters not within the protocol-defined range. - Receipt of anticancer medications or investigational drugs within a defined interval before the first administration of study drug. - Has not recovered from toxic effects of prior therapy to ≤ Grade 1. - Active or inactive autoimmune disease or syndrome. - Active infection requiring systemic therapy. - Known active central nervous system (CNS) metastases and/or carcinomatous meningitis. - History or presence of an abnormal ECG that, in the investigator's opinion, is clinically meaningful. - Has received a live vaccine within 30 days of planned start of study therapy. - Prior receipt of an IDO inhibitor. - Subjects with uncontrolled type I or type II diabetes mellitus (defined as HgbA1c > 8). - Prior receipt of a BET inhibitor (Treatment Group B only). - Subjects with a history of bleeding related to cancer under study requiring a medical intervention (eg, embolization procedure, RBC transfusion, or hospitalization) within 30 days of study enrollment (Treatment Groups B and C only). - Clinically significant bleeding within 14 days of Cycle 1 Day 1 (Treatment Groups B and C only). - Prior receipt of an LSD1 inhibitor including INCB059872 (Treatment Group C only).

Study Design

Phase
Phase 1/Phase 2
Study Type
Interventional
Allocation
Non-Randomized
Intervention Model
Single Group Assignment
Primary Purpose
Treatment
Masking
None (Open Label)

Arm Groups

ArmDescriptionAssigned Intervention
Experimental
Treatment Group A: Azacitidine + Pembrolizumab + Epacadostat
Part 1 is an open-label 3 + 3 + 3 dose-escalation design based on observing each dose level for a period of 21 days. Part 2 will evaluate the recommended dose determined in Part 1.
  • Drug: Azacitidine
    Five doses of azacitidine will be administered by subcutaneous injection or intravenously (IV) over Days 1 to 7 in Cycles 1 through 6.
  • Drug: Pembrolizumab
    Pembrolizumab will be administered in a 30-minute IV infusion every 3 weeks on Day 1 of each 21-day cycle.
  • Drug: Epacadostat
    Epacadostat tablets will be administered orally twice daily.
Experimental
Treatment Group B: INCB057643 + Pembrolizumab + Epacadostat
Part 1 is an open-label 3 + 3 + 3 dose-escalation design based on observing each dose level for a period of 42 days. Part 1 will also contain dose-expansion cohorts in previously treated NSCLC and MSS CRC. Part 2 will evaluate the recommended dose determined in Part 1.
  • Drug: INCB057643
    INCB057643 will be orally self- administered once daily beginning on Cycle 1 Day 1 and continuously thereafter in 21-day cycles.
  • Drug: Pembrolizumab
    Pembrolizumab will be administered in a 30-minute IV infusion every 3 weeks of each 21-day cycle starting on Cycle 2 Day 1.
  • Drug: Epacadostat
    Epacadostat tablets will be administered orally twice daily starting at Cycle 2 Day 1.
Experimental
Treatment Group C: INCB059872 + Pembrolizumab + Epacadostat
Part 1 is an open-label 3 + 3 + 3 dose-escalation design based on observing each dose level for a period of 42 days. Part 1 will also contain dose-expansion cohorts in previously treated NSCLC and MSS CRC. Part 2 will evaluate the recommended dose determined in Part 1.
  • Drug: Pembrolizumab
    Pembrolizumab will be administered in a 30-minute IV infusion every 3 weeks of each 21-day cycle starting on Cycle 2 Day 1.
  • Drug: Epacadostat
    Epacadostat tablets will be administered orally twice daily starting at Cycle 2 Day 1.
  • Drug: INCB059872
    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.

More Details

Status
Terminated
Sponsor
Incyte Corporation

Study Contact

Notice

Study information shown on this site is derived from ClinicalTrials.gov (a public registry operated by the National Institutes of Health). The listing of studies provided is not certain to be all studies for which you might be eligible. Furthermore, study eligibility requirements can be difficult to understand and may change over time, so it is wise to speak with your medical care provider and individual research study teams when making decisions related to participation.