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

• Sponsor: Incyte Corporation (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT02959437
• Collaborator: (none)
• Enrollment: 70
• Locations: 12
• Arms: 3
• Actual Duration (Months): 36.1
• Patients Per Site: 5.8
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Solid Tumors; Advanced Malignancies; Metastatic Cancer	Drug: Azacitidine; Drug: Pembrolizumab; Drug: Epacadostat; Drug: INCB057643; Drug: Pembrolizumab; Drug: Epacadostat; Drug: INCB059872	Phase 1/Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 70 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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)
• Actual Study Start Date: Feb 27, 2017
• Actual Primary Completion Date: Feb 15, 2019
• Actual Study Completion Date: Mar 2, 2020

Arms and Interventions

Arm	Intervention/Treatment
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.

Outcome Measures

Primary Outcome Measures

1. Part 1 and 2 : Number of Participants With Treatment Emergent Adverse Events [Baseline through 42-49 days after end of treatment, estimated up to 27 months (24 months with 100 day FU period).]

   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).

2. Part 1 and 2: Objective Response Rate Based on Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) [Every 9 weeks for the duration of study participation; estimated minimum of 6 months.]

   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.

Secondary Outcome Measures

1. Parts 1 and 2: Percentage of Responders Determined by Immunohistochemistry [Baseline to Week 5/6 or week 8/9]

   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.

2. Parts 1 and 2: Progression-free Survival Based on RECIST v1.1. [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]

   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.

3. Parts 1 and 2: Duration of Response Based on RECIST v1.1 [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]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: 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).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	City of Hope National Medical Center	Duarte	California	United States	91010
2	University of California San Diego	La Jolla	California	United States	92093
3	The University of Chicago	Chicago	Illinois	United States	60637
4	University of Pennsylvania Health System	Philadelphia	Pennsylvania	United States	19014
5	Sarah Cannon	Nashville	Tennessee	United States	37203
6	Vanderbilt-Ingram Cancer Center	Nashville	Tennessee	United States	37232
7	MD Anderson Cancer Center	Houston	Texas	United States	77030
8	University of Washington	Seattle	Washington	United States	98109
9	Vall D Hebron Univ	Barcelona		Spain	08035
10	Univ De Navarra	Pamplona		Spain	31008
11	University College London Hospitals (Uclh)	London		United Kingdom	W1t7ha
12	Churchill Hospital	Oxford		United Kingdom	Ox37le

Sponsors and Collaborators

• Incyte Corporation

Investigators

• Study Director: Kevin O'Hayer, MD, Incyte Corporation

Study Documents (Full-Text)

• Study Protocol - Aug 30, 2018
• Statistical Analysis Plan - Jul 18, 2018

More Information

Publications

None provided.

• Responsible Party: Incyte Corporation
• ClinicalTrials.gov Identifier: NCT02959437
• Other Study ID Numbers: INCB 24360-206 / ECHO-206
• First Posted: Nov 9, 2016
• Last Update Posted: May 6, 2021
• Last Verified: Apr 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Incyte Corporation: Solid tumors; NSCLC; CRC
• Additional relevant MeSH terms: Neoplasms; Neoplasm Metastasis; Pembrolizumab; Azacitidine; INCB057643

Study Results

Participant Flow

Recruitment Details	The study was conducted at 8 study sites in United States, 2 sites in UK and 1 site in Spain.
Pre-assignment Detail	A total of 70 participants were enrolled in the study. Study enrollment was permanently discontinued on 15-Feb-2019 as a strategic decision. No patients were enrolled in Treatment Group B and Treatment Group C.

Arm/Group Title	Treatment Group A :100mg of INCB24360	Treatment Group A :300mg of INCB24360	Treatment Group B :INCB057643+Pembrolizumab+Epacadostat	Treatment Group C :INCB059872+Pembrolizumab+Epacadostat
Arm/Group Description	In Treatment Group A, subjects will receive the DNMT inhibitor azacitidine in combination with the PD-1 inhibitor pembrolizumab and the IDO1 inhibitor epacadostat at 100mg. Due to early termination of study subjects from dose escalation and dose expansion are combined.	In Treatment Group A, subjects will receive the DNMT inhibitor azacitidine in combination with the PD-1 inhibitor pembrolizumab and the IDO1 inhibitor epacadostat at 300mg.	In Treatment Group B, subjects will receive INCB057643 in combination with the PD-1 inhibitor pembrolizumab and the IDO1 inhibitor epacadostat at 100mg.	In Treatment Group C, subjects will receive INCB059872 in combination with the PD-1 inhibitor pembrolizumab and the IDO1 inhibitor epacadostat at 100mg.
Period Title: Overall Study
STARTED	62	8	0	0
COMPLETED	0	0	0	0
NOT COMPLETED	62	8	0	0

Baseline Characteristics

Arm/Group Title	Treatment Group A :100mg of INCB24360	Treatment Group A :300mg of INCB24360	Treatment Group B :INCB057643+Pembrolizumab+Epacadostat	Treatment Group C :INCB059872+Pembrolizumab+Epacadostat	Total
Arm/Group Description	In Treatment Group A, subjects will receive the DNMT inhibitor azacitidine in combination with the PD-1 inhibitor pembrolizumab and the IDO1 inhibitor epacadostat at 100mg. Due to early termination of study subjects from dose escalation and dose expansion are combined.	In Treatment Group A, subjects will receive the DNMT inhibitor azacitidine in combination with the PD-1 inhibitor pembrolizumab and the IDO1 inhibitor epacadostat at 300mg.	In Treatment Group B, subjects will receive INCB057643 in combination with the PD-1 inhibitor pembrolizumab and the IDO1 inhibitor epacadostat at 100mg.	In Treatment Group C, subjects will receive INCB059872 in combination with the PD-1 inhibitor pembrolizumab and the IDO1 inhibitor epacadostat at 100mg.	Total of all reporting groups
Overall Participants	62	8	0	0	70
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	57.0 (11.92)	53.0 (11.31)	56.5 (11.84)
Sex: Female, Male (Count of Participants)
Female	19 30.6%	4 50%	23 Infinity
Male	43 69.4%	4 50%	47 Infinity
Race/Ethnicity, Customized (Count of Participants)
White/Caucasian	56 90.3%	5 62.5%	61 Infinity
Black/African-American	3 4.8%	0 0%	3 Infinity
Asian	2 3.2%	0 0%	2 Infinity
American-Indian/Alaska Native	0 0%	0 0%	0 NaN
Native Hawaiian/Pacific Islander	0 0%	0 0%	0 NaN
Other	1 1.6%	3 37.5%	4 Infinity
Race/Ethnicity, Customized (Count of Participants)
Hispanic or Latino	4 6.5%	2 25%	0 NaN	0 NaN	6 8.6%
Not Hispanic or Latino	54 87.1%	6 75%	0 NaN	0 NaN	60 85.7%
Unknown	4 6.5%	0 0%	0 NaN	0 NaN	4 5.7%

Outcome Measures

1. Primary Outcome

Title	Part 1 and 2 : Number of Participants With Treatment Emergent Adverse Events
Description	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).

Outcome Measure Data

Analysis Population Description

The safety population includes all subjects enrolled in the study who received at least 1 dose of study drug.

Arm/Group Title	Treatment Group A :100mg of INCB24360	Treatment Group A :300mg of INCB24360	Treatment Group B :INCB057643+Pembrolizumab+Epacadostat	Treatment Group C :INCB059872+Pembrolizumab+Epacadostat
Arm/Group Description	In Treatment Group A, subjects will receive the DNMT inhibitor azacitidine in combination with the PD-1 inhibitor pembrolizumab and the IDO1 inhibitor epacadostat at 100mg. Due to early termination of study subjects from dose escalation and dose expansion are combined.	In Treatment Group A, subjects will receive the DNMT inhibitor azacitidine in combination with the PD-1 inhibitor pembrolizumab and the IDO1 inhibitor epacadostat at 300mg.	In Treatment Group B, subjects will receive INCB057643 in combination with the PD-1 inhibitor pembrolizumab and the IDO1 inhibitor epacadostat at 100mg.	In Treatment Group C, subjects will receive INCB059872 in combination with the PD-1 inhibitor pembrolizumab and the IDO1 inhibitor epacadostat at 100mg.
Measure Participants	62	8	0	0
Count of Participants [Participants]	62 100%	8 100%

2. Primary Outcome

Title	Part 1 and 2: Objective Response Rate Based on Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1)
Description	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.

Outcome Measure Data

Analysis Population Description

The response evaluable population includes all subjects enrolled in the study who received at least 1 dose of study drug, completed a baseline scan and have at least 1 post baseline scan, or has been on study for a minimum of 70 days of follow-up or who discontinued treatment. No participants enrolled in part 2 of the study due to early termination of study

Arm/Group Title	Treatment Group A :100mg of INCB24360	Treatment Group A :300mg of INCB24360	Treatment Group B :INCB057643+Pembrolizumab+Epacadostat	Treatment Group C :INCB059872+Pembrolizumab+Epacadostat
Arm/Group Description	In Treatment Group A, subjects will receive the DNMT inhibitor azacitidine in combination with the PD-1 inhibitor pembrolizumab and the IDO1 inhibitor epacadostat at 100mg. Due to early termination of study subjects from dose escalation and dose expansion are combined.	In Treatment Group A, subjects will receive the DNMT inhibitor azacitidine in combination with the PD-1 inhibitor pembrolizumab and the IDO1 inhibitor epacadostat at 300mg.	In Treatment Group B, subjects will receive INCB057643 in combination with the PD-1 inhibitor pembrolizumab and the IDO1 inhibitor epacadostat at 100mg.	In Treatment Group C, subjects will receive INCB059872 in combination with the PD-1 inhibitor pembrolizumab and the IDO1 inhibitor epacadostat at 100mg.
Measure Participants	62	8	0	0
Count of Participants [Participants]	3 4.8%	1 12.5%	0 NaN	0 NaN

3. Secondary Outcome

Title	Parts 1 and 2: Percentage of Responders Determined by Immunohistochemistry
Description	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

Outcome Measure Data

Analysis Population Description

All subjects enrolled in the study who received at least 1 dose of study drug, who had evaluable baseline and on treatment biopsies. No participants enrolled in part 2 of the study due to early termination of study.

Arm/Group Title	Treatment Group A :100 or 300mg of INCB24360	Treatment Group B :INCB057643+Pembrolizumab+Epacadostat	Treatment Group C :INCB059872+Pembrolizumab+Epacadostat
Arm/Group Description	Treatment Group A :100mg of INCB24360 In Treatment Group A, subjects will receive the DNMT inhibitor azacitidine in combination with the PD-1 inhibitor pembrolizumab and the IDO1 inhibitor epacadostat at 100mg or 300mg. Due to early termination of study subjects from dose escalation and dose expansion are combined.	In Treatment Group B, subjects will receive INCB057643 in combination with the PD-1 inhibitor pembrolizumab and the IDO1 inhibitor epacadostat at 100mg.	In Treatment Group C, subjects will receive INCB059872 in combination with the PD-1 inhibitor pembrolizumab and the IDO1 inhibitor epacadostat at 100mg.
Measure Participants	19	0	0
Intratumoral CD8+ T cells	14 22.6%
CD8+:FoxP3+ ratios	10 16.1%

4. Secondary Outcome

Title	Parts 1 and 2: Progression-free Survival Based on RECIST v1.1.
Description	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

Outcome Measure Data

Analysis Population Description

All subjects enrolled in the study who received at least 1 dose of study drug, completed a baseline scan and have at least 1 post baseline scan, or has been on study for a minimum of 70 days of follow-up or who discontinued treatment. No participants enrolled in part 2 of the study due to early termination of study

Arm/Group Title	Treatment Group A :100mg of INCB24360	Treatment Group A :300mg of INCB24360	Treatment Group B :INCB057643+Pembrolizumab+Epacadostat	Treatment Group C :INCB059872+Pembrolizumab+Epacadostat
Arm/Group Description	In Treatment Group A, subjects will receive the DNMT inhibitor azacitidine in combination with the PD-1 inhibitor pembrolizumab and the IDO1 inhibitor epacadostat at 100mg. Due to early termination of study subjects from dose escalation and dose expansion are combined.	In Treatment Group A, subjects will receive the DNMT inhibitor azacitidine in combination with the PD-1 inhibitor pembrolizumab and the IDO1 inhibitor epacadostat at 300mg.	In Treatment Group B, subjects will receive INCB057643 in combination with the PD-1 inhibitor pembrolizumab and the IDO1 inhibitor epacadostat at 100mg.	In Treatment Group C, subjects will receive INCB059872 in combination with the PD-1 inhibitor pembrolizumab and the IDO1 inhibitor epacadostat at 100mg.
Measure Participants	62	8	0	0
Median (95% Confidence Interval) [Months]	2.07	2.64

5. Secondary Outcome

Title	Parts 1 and 2: Duration of Response Based on RECIST v1.1
Description	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

Outcome Measure Data

Analysis Population Description

All subjects enrolled in the study who received at least 1 dose of study drug, completed a baseline scan and have at least 1 post baseline scan, or has been on study for a minimum of 70 days of follow-up or who discontinued treatment. No participants enrolled in part 2 of the study due to early termination of study.

Arm/Group Title	Treatment Group A :100mg of INCB24360	Treatment Group A :300mg of INCB24360	Treatment Group B :INCB057643+Pembrolizumab+Epacadostat	Treatment Group C :INCB059872+Pembrolizumab+Epacadostat
Arm/Group Description	In Treatment Group A, subjects will receive the DNMT inhibitor azacitidine in combination with the PD-1 inhibitor pembrolizumab and the IDO1 inhibitor epacadostat at 100mg. Due to early termination of study subjects from dose escalation and dose expansion are combined.	In Treatment Group A, subjects will receive the DNMT inhibitor azacitidine in combination with the PD-1 inhibitor pembrolizumab and the IDO1 inhibitor epacadostat at 300mg.	In Treatment Group B, subjects will receive INCB057643 in combination with the PD-1 inhibitor pembrolizumab and the IDO1 inhibitor epacadostat at 100mg.	In Treatment Group C, subjects will receive INCB059872 in combination with the PD-1 inhibitor pembrolizumab and the IDO1 inhibitor epacadostat at 100mg.
Measure Participants	3	1	0	0
Median (95% Confidence Interval) [Months]	2.63	1.22

Adverse Events

Time Frame	Baseline through 42-49 days after end of treatment, estimated up to 27 months (24 months with 100 day FU period).
Adverse Event Reporting Description	The safety population included all participants enrolled in the study who received at least 1 dose of study drug. Data is presented for Group A only, no participants enrolled in Treatment Groups B and C.
Arm/Group Title	Treatment Group A :100mg of INCB24360		Treatment Group A :300mg of INCB24360
Arm/Group Description	In Treatment Group A, subjects will receive the DNMT inhibitor azacitidine in combination with the PD-1 inhibitor pembrolizumab and the IDO1 inhibitor epacadostat at 100mg. Due to early termination of study subjects from dose escalation and dose expansion are combined.		In Treatment Group A, subjects will receive the DNMT inhibitor azacitidine in combination with the PD-1 inhibitor pembrolizumab and the IDO1 inhibitor epacadostat at 300mg.
All Cause Mortality
	Treatment Group A :100mg of INCB24360		Treatment Group A :300mg of INCB24360
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	41/62 (66.1%)		4/8 (50%)
Serious Adverse Events
	Treatment Group A :100mg of INCB24360		Treatment Group A :300mg of INCB24360
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	28/62 (45.2%)		3/8 (37.5%)
Blood and lymphatic system disorders
Anemia	2/62 (3.2%)		0/8 (0%)
Leukocytosis	0/62 (0%)		1/8 (12.5%)
Cardiac disorders
Atrial fibrillation	1/62 (1.6%)		0/8 (0%)
Sinua tachycardia	0/62 (0%)		1/8 (12.5%)
Endocrine disorders
Hyperthyroidism	1/62 (1.6%)		0/8 (0%)
Gastrointestinal disorders
Abdominal Pain	2/62 (3.2%)		1/8 (12.5%)
Ascites	1/62 (1.6%)		0/8 (0%)
Diarrhoea	1/62 (1.6%)		0/8 (0%)
Intra-abdominal haemorrhage	1/62 (1.6%)		0/8 (0%)
Intussusception	1/62 (1.6%)		0/8 (0%)
Nausea	4/62 (6.5%)		1/8 (12.5%)
Small Intestinal Obstruction	3/62 (4.8%)		0/8 (0%)
Vomiting	2/62 (3.2%)		1/8 (12.5%)
General disorders
Asthenia	0/62 (0%)		1/8 (12.5%)
Disease Progression	8/62 (12.9%)		0/8 (0%)
Fatigue	2/62 (3.2%)		0/8 (0%)
Non-cardiac Chest Pain	0/62 (0%)		1/8 (12.5%)
Pain	1/62 (1.6%)		0/8 (0%)
Pyrexia	1/62 (1.6%)		0/8 (0%)
Infections and infestations
Infection	0/62 (0%)		1/8 (12.5%)
Urinary tract Infection	1/62 (1.6%)		0/8 (0%)
Injury, poisoning and procedural complications
Head Injury	0/62 (0%)		1/8 (12.5%)
Wound Haemorrhage	0/62 (0%)		1/8 (12.5%)
Metabolism and nutrition disorders
Dehydration	1/62 (1.6%)		0/8 (0%)
Musculoskeletal and connective tissue disorders
Back Pain	3/62 (4.8%)		0/8 (0%)
Bone Pain	1/62 (1.6%)		0/8 (0%)
Muscular Weakness	1/62 (1.6%)		0/8 (0%)
Pain in Extremity	1/62 (1.6%)		0/8 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Malignant Neoplasm Progression	1/62 (1.6%)		0/8 (0%)
Rectal Cancer Metastatic	1/62 (1.6%)		0/8 (0%)
Lymphangiosis Carcinomatosa	1/62 (1.6%)		0/8 (0%)
Nervous system disorders
Brain Injury	1/62 (1.6%)		0/8 (0%)
Brain Oedema	1/62 (1.6%)		0/8 (0%)
Dizziness	0/62 (0%)		1/8 (12.5%)
Dysmetria	1/62 (1.6%)		0/8 (0%)
Headache	1/62 (1.6%)		0/8 (0%)
Hemiparesis	1/62 (1.6%)		0/8 (0%)
Hypoaesthesia	1/62 (1.6%)		0/8 (0%)
Loss of Consciousness	0/62 (0%)		1/8 (12.5%)
Peroneal Nerve Palsy	1/62 (1.6%)		0/8 (0%)
Seizure	2/62 (3.2%)		0/8 (0%)
Psychiatric disorders
Confusional State	1/62 (1.6%)		1/8 (12.5%)
Mental Status Changes	1/62 (1.6%)		0/8 (0%)
Renal and urinary disorders
Urinary Retention	1/62 (1.6%)		0/8 (0%)
Respiratory, thoracic and mediastinal disorders
Acute Respiratory Failure	1/62 (1.6%)		0/8 (0%)
Cough	1/62 (1.6%)		0/8 (0%)
Dyspnoea	1/62 (1.6%)		0/8 (0%)
Haemoptysis	1/62 (1.6%)		0/8 (0%)
Hypoxia	1/62 (1.6%)		0/8 (0%)
Pneumonitis	1/62 (1.6%)		0/8 (0%)
Pulmonary Embolism	1/62 (1.6%)		0/8 (0%)
Respiratory Failure	1/62 (1.6%)		0/8 (0%)
Other (Not Including Serious) Adverse Events
	Treatment Group A :100mg of INCB24360		Treatment Group A :300mg of INCB24360
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	59/62 (95.2%)		8/8 (100%)
Blood and lymphatic system disorders
Anaemia	11/62 (17.7%)		2/8 (25%)
Cardiac disorders
Sinus Tachycardia	0/62 (0%)		1/8 (12.5%)
Gastrointestinal disorders
Abdominal Distension	2/62 (3.2%)		2/8 (25%)
Abdominal pain	12/62 (19.4%)		1/8 (12.5%)
Abdominal pain lower	1/62 (1.6%)		1/8 (12.5%)
Constipation	16/62 (25.8%)		3/8 (37.5%)
Dyspepsia	3/62 (4.8%)		1/8 (12.5%)
Gastrooesophageal reflux disease	4/62 (6.5%)		1/8 (12.5%)
Nausea	34/62 (54.8%)		3/8 (37.5%)
Vomiting	21/62 (33.9%)		2/8 (25%)
Diarrhoea	12/62 (19.4%)		3/8 (37.5%)
General disorders
Chills	4/62 (6.5%)		1/8 (12.5%)
Fatigue	28/62 (45.2%)		6/8 (75%)
Injection site erythema	5/62 (8.1%)		0/8 (0%)
Injection site pain	4/62 (6.5%)		0/8 (0%)
Injection site reaction	13/62 (21%)		0/8 (0%)
Local swelling	1/62 (1.6%)		1/8 (12.5%)
Oedema peripheral	6/62 (9.7%)		1/8 (12.5%)
Pyrexia	6/62 (9.7%)		0/8 (0%)
Infections and infestations
Herpes zoster	0/62 (0%)		1/8 (12.5%)
Mastoiditis	0/62 (0%)		1/8 (12.5%)
Upper respiratory tract infection	3/62 (4.8%)		1/8 (12.5%)
Injury, poisoning and procedural complications
Ligament sprain	0/62 (0%)		1/8 (12.5%)
Investigations
Alanine aminotransferase increased	4/62 (6.5%)		2/8 (25%)
Aspartate aminotransferase increased	5/62 (8.1%)		3/8 (37.5%)
Blood alkaline phosphatase increased	7/62 (11.3%)		2/8 (25%)
Blood creatinine increased	4/62 (6.5%)		0/8 (0%)
Blood phosphorus decreased	0/62 (0%)		1/8 (12.5%)
Electrocardiogram QT prolonged	0/62 (0%)		1/8 (12.5%)
Platelet count decreased	2/62 (3.2%)		1/8 (12.5%)
White blood cell count decreased	3/62 (4.8%)		1/8 (12.5%)
Metabolism and nutrition disorders
Decreased appetite	12/62 (19.4%)		5/8 (62.5%)
Hypercalcaemia	0/62 (0%)		1/8 (12.5%)
Hyperkalaemia	4/62 (6.5%)		0/8 (0%)
Hypoalbuminaemia	4/62 (6.5%)		1/8 (12.5%)
Hypokalaemia	4/62 (6.5%)		0/8 (0%)
Hypomagnesaemia	0/62 (0%)		1/8 (12.5%)
Hyponatraemia	3/62 (4.8%)		1/8 (12.5%)
Musculoskeletal and connective tissue disorders
Arthralgia	7/62 (11.3%)		1/8 (12.5%)
Back pain	6/62 (9.7%)		2/8 (25%)
Flank pain	1/62 (1.6%)		1/8 (12.5%)
Muscle spasms	1/62 (1.6%)		1/8 (12.5%)
Musculoskeletal chest pain	2/62 (3.2%)		1/8 (12.5%)
Musculoskeletal discomfort	0/62 (0%)		1/8 (12.5%)
Musculoskeletal pain	0/62 (0%)		2/8 (25%)
Myalgia	4/62 (6.5%)		2/8 (25%)
Neck pain	1/62 (1.6%)		1/8 (12.5%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cancer pain	1/62 (1.6%)		1/8 (12.5%)
Nervous system disorders
Headache	4/62 (6.5%)		4/8 (50%)
Neuropathy peripheral	2/62 (3.2%)		1/8 (12.5%)
Peroneal nerve palsy	0/62 (0%)		1/8 (12.5%)
Psychiatric disorders
Anxiety	3/62 (4.8%)		1/8 (12.5%)
Insomnia	5/62 (8.1%)		1/8 (12.5%)
Renal and urinary disorders
Haematuria	0/62 (0%)		1/8 (12.5%)
Pneumaturia	0/62 (0%)		1/8 (12.5%)
Terminal dribbling	0/62 (0%)		1/8 (12.5%)
Respiratory, thoracic and mediastinal disorders
Cough	9/62 (14.5%)		2/8 (25%)
Dyspnoea	8/62 (12.9%)		1/8 (12.5%)
Dyspnoea exertional	4/62 (6.5%)		0/8 (0%)
Productive cough	2/62 (3.2%)		2/8 (25%)
Wheezing	0/62 (0%)		1/8 (12.5%)
Skin and subcutaneous tissue disorders
Acne	0/62 (0%)		1/8 (12.5%)
Dermatitis acneiform	0/62 (0%)		1/8 (12.5%)
Pruritus	6/62 (9.7%)		1/8 (12.5%)
Rash	9/62 (14.5%)		2/8 (25%)
Vascular disorders
Hypotension	2/62 (3.2%)		1/8 (12.5%)

Limitations/Caveats

[Not Specified]

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Clinical Study Agreement