Azacitidine Combined With Pembrolizumab and Epacadostat in Subjects With Advanced Solid Tumors (ECHO-206)

Study Overview
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Brief Summary
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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.

Official Title
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A Phase 1/2 Study Exploring the Safety, Tolerability, Effect on the Tumor Microenvironment, and Efficacy of Azacitidine in Combination With Pembrolizumab and Epacadostat in Subjects With Advanced Solid Tumors and Previously Treated Stage IIIB or Stage IV Non-Small Cell Lung Cancer and Stage IV Microsatellite-Stable Colorectal Cancer (ECHO-206)

Conditions
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Solid Tumors, Advanced Malignancies, Metastatic Cancer

Intervention / Treatment
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* Drug: Azacitidine
* Drug: Pembrolizumab
* Drug: Epacadostat
* Drug: INCB057643
* Drug: Pembrolizumab
* Drug: Epacadostat
* Drug: INCB059872


Participation Criteria
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Eligibility Criteria
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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).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment Group A: Azacitidine + Pembrolizumab + Epacadostat<br>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<br>* Five doses of azacitidine will be administered by subcutaneous injection or intravenously (IV) over Days 1 to 7 in Cycles 1 through 6.<br>Drug: Pembrolizumab<br>* Pembrolizumab will be administered in a 30-minute IV infusion every 3 weeks on Day 1 of each 21-day cycle.<br>Drug: Epacadostat<br>* Epacadostat tablets will be administered orally twice daily.<br>|
| Experimental: Treatment Group B: INCB057643 + Pembrolizumab + Epacadostat<br>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<br>* INCB057643 will be orally self- administered once daily beginning on Cycle 1 Day 1 and continuously thereafter in 21-day cycles.<br>Drug: Pembrolizumab<br>* Pembrolizumab will be administered in a 30-minute IV infusion every 3 weeks of each 21-day cycle starting on Cycle 2 Day 1.<br>Drug: Epacadostat<br>* Epacadostat tablets will be administered orally twice daily starting at Cycle 2 Day 1.<br>|
| Experimental: Treatment Group C: INCB059872 + Pembrolizumab + Epacadostat<br>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<br>* Pembrolizumab will be administered in a 30-minute IV infusion every 3 weeks of each 21-day cycle starting on Cycle 2 Day 1.<br>Drug: Epacadostat<br>* Epacadostat tablets will be administered orally twice daily starting at Cycle 2 Day 1.<br>Drug: INCB059872<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | 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. | Every 9 weeks for the duration of study participation; estimated minimum of 6 months. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 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. | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CRC, Solid tumors, NSCLC