Clinical trial NCT02437136
Conditions: Non-Small Cell Lung Cancer Melanoma Mismatch Repair-Proficient Colorectal Cancer
Sponsor: Syndax Pharmaceuticals
Start date: 2015-08-26; Completion date: 2022-09-29
Enrollment: 191 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to determine the safety and tolerability of entinostat used in combination with pembrolizumab in participants with NSCLC. Additionally, the purpose of the study is to assess how effective entinostat and pembrolizumab are in combination in participants with NSCLC, Melanoma, and Mismatch-Repair Proficient CRC.

Detailed description:

Arms: arm 1: Participants with NSCLC will receive entinostat 3 mg administered orally weekly (Days 1, 8, and 15 of each 21-day cycle) along with pembrolizumab 200 mg via intravenous (IV) infusion once every 3 weeks (Day 1 of each 21-day cycle). arm 2: Participants with NSCLC will receive entinostat 5 mg administered orally weekly (Days 1, 8, and 15 of each 21-day cycle) along with pembrolizumab 200 mg via IV infusion once every 3 weeks (Day 1 of each 21-day cycle). arm 3: Participants with NSCLC will receive entinostat 5 mg administered orally weekly (Days 1, 8, and 15 of each 21-day cycle) along with pembrolizumab 200 mg via IV infusion once every 3 weeks (Day 1 of each 21-day cycle). arm 4: Participants with NSCLC with squamous cell or adenocarcinoma histology who had not been treated with a programmed cell death receptor-1 (PD-1)- or programmed cell death ligand-1 (PD-L1)-blocking antibody, will receive entinostat 5 mg administered orally weekly (Days 1, 8, and 15 of each 21-day cycle) along with pembrolizumab 200 mg via IV infusion once every 3 weeks (Day 1 of each 21-day cycle). arm 5: Participants with NSCLC (any histology) who has previously been treated with and unequivocally progressed on either a PD-1- or PD-L1-blocking antibody, will receive entinostat 5 mg administered orally weekly (Days 1, 8, and 15 of each 21-day cycle) along with pembrolizumab 200 mg via IV infusion once every 3 weeks (Day 1 of each 21-day cycle). arm 6: Participants with melanoma who has previously been treated with and unequivocally progressed on either a PD-1- or PD-L1-blocking antibody, will receive entinostat 5 mg administered orally weekly (Days 1, 8, and 15 of each 21-day cycle) along with pembrolizumab 200 mg via IV infusion once every 3 weeks (Day 1 of each 21-day cycle). arm 7: Participants with CRC (mismatch repair-proficient) who had not been previously treated with a PD-1- or PD-L1-blocking antibody, received entinostat 5 mg administered orally weekly (Days 1, 8, and 15 of each 21-day cycle) along with pembrolizumab 200 mg via IV infusion once every 3 weeks (Day 1 of each 21-day cycle).
Interventions: intervention 1: entinostat intervention 2: pembrolizumab
Intervention descriptions: intervention 1: An orally available histone deacetylases inhibitor (HDACs) intervention 2: A selective humanized monoclonal antibody (mAb)

Protocol documents:
Prot_000.pdf: 
Product:  Entinostat 
Protocol Number:  SNDX-275-0601 
Date:  12 April 2018 
Page 1 of 131 
CONFIDENTIAL 
SYNDAX PHARMACEUTICALS
A Phase 1b/2, Open-label, Dose Escalation Study of Entinostat in Combination with 
Pembrolizumab in Patients with Non-small Cell Lung Cancer, with Expansion Cohorts in Patients 
with Non-small Cell Lung Cancer, Melanoma, and Mismatch Repair-Proficient Colorectal Cancer
Syndax Protocol SNDX-275-0601 
Confidentiality Notice 
This document contains confidential information of Syndax Pharmaceuticals, Inc., the contents of which 
must not be disclosed to anyone other than the study staff and members of the respective Institutional 
Review Board/Ethics Committee. 
The information in this document cannot be used for any purpose other than the evaluation or conduct of 
the clinical investigation without the prior written consent of Syndax Pharmaceuticals, Inc. 
Clinical Study Sponsor: 
Syndax Pharmaceuticals, Inc. 
35 Gatehouse Drive  
Building D, Floor 3 
Waltham, MA  02451 
Key Sponsor Contacts: 
 
 
Telephone: 
 
 
Telephone:  
 
Contract Research Organization 
N/A 
Date, Version: 
12 April 2018, Version 6.0 
Amendment: 
5 
IND Number: 
125,812 
EudraCT Number: 
2016-000638-23 
NCT #: NCT02437136


Product:  Entinostat 
Protocol Number:  SNDX-275-0601 
Date:  12 April 2018 
 
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Investigator’s Agreement 
 
I have read the attached protocol entitled “A Phase 1b/2, Open-label, Dose Escalation Study of Entinostat 
in Combination with Pembrolizumab in Patients with Non-small Cell Lung Cancer, with Expansion 
Cohorts in Patients with Non-small Cell Lung Cancer, Melanoma, and Mismatch Repair-Proficient 
Colorectal Cancer” dated 12 April 2018, and agree to abide by all provisions set forth therein.  
I agree to comply with the International Council for Harmonisation Tripartite Guideline on Good Clinical 
Practice and applicable regulations of the Food and Drug Administration. 
I agree to ensure that Financial Disclosure Statements will be completed by: 
• 
me 
• 
my sub-investigators 
at the start of the study, at study completion, and for up to 1 year after the study is completed, if there are 
changes that affect my financial disclosure status. 
I agree to ensure that the confidential information contained in this document will not be used for any 
purpose other than the evaluation or conduct of the clinical investigation without the prior written consent 
of Syndax. 
 
 
 
Signature 
 
 
Name of Principal Investigator 
 
Date  


Product:  Entinostat 
Protocol Number:  SNDX-275-0601 
Date:  12 April 2018 
 
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1. 
PROTOCOL SYNOPSIS SNDX-275-0601 
Title:  A Phase 1b/2, Open-label, Dose Escalation Study of Entinostat in Combination with Pembrolizumab in 
Patients with Non-small Cell Lung Cancer, with Expansion Cohorts in Patients with Non-small Cell Lung Cancer, 
Melanoma, and Mismatch Repair-Proficient Colorectal Cancer 
Study Phase:  Phase 1b/2 
Indication:  Melanoma, Non-small Cell Lung Cancer (NSCLC), and Mismatch Repair-Proficient Colorectal 
Cancer” 
Primary Objective: 
Phase 1b (Dose Escalation/Confirmation Cohorts):  To determine the dose-limiting toxicities (DLT) and maximum 
tolerated dose (MTD) or recommended Phase 2 dose (RP2D) of entinostat (SNDX-275) given in combination with 
pembrolizumab. 
Phase 2 (Expansion Cohorts): To evaluate the preliminary efficacy of entinostat at the RP2D in combination with 
pembrolizumab in patients with melanoma, NSCLC, and mismatch repair-proficient colorectal cancer as determined 
by overall response rate (ORR), per the Immune-related Response Evaluation Criteria in Solid Tumors (irRECIST) 
in each cohort evaluated. 
Secondary Objectives:   
Efficacy:  To evaluate the efficacy of entinostat in combination with pembrolizumab in patients with melanoma, 
NSCLC, and mismatch repair-proficient colorectal cancer as determined by secondary measures of efficacy per the 
Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) and irRECIST criterion, including: 
• 
Clinical benefit rate (CBR) (i.e., complete response [CR]+partial response [PR]+stable disease [SD]) at 6 
months 
• 
Progression-free survival (PFS) status at 6 months 
• 
PFS 
• 
Overall survival (OS) 
In patients who experience a response to treatment (i.e., CR or PR): 
• 
Duration of response (DOR)  
• 
Time to response (TTR) 
Safety:  To evaluate safety and the tolerability of entinostat in combination with pembrolizumab, as measured by 
clinical adverse events (AEs), laboratory parameters, and electrocardiograms (ECGs). 
Exploratory Objectives:   
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Product:  Entinostat 
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Hypothesis:   
Entinostat has been shown in preclinical models to reduce the number and inhibit the function of host immune 
suppressor cells in order to enhance the anti-tumor activity of immune checkpoint blockade. It is hypothesized that 
entinostat combined with pembrolizumab will result in an improved response rate for the combination compared to 
either agent alone. Preclinical study data suggest that entinostat specifically targets MDSCs and thus would improve 
the response to PD-1/PD-L1-blocking antibody (i.e., pembrolizumab) treatment. The Sponsor accordingly proposes 
to evaluate populations of MDSCs and other myeloid cells in peripheral blood and tumor tissues as well as basic T-
cell function in patients, with the expectation that if the MDSC level is decreased, the response to antigens would be 
improved.  
Study Design:   
Study SNDX-275-0601 is an open-label, Phase 1b/2 study evaluating the combination of entinostat plus 
pembrolizumab in patients with advanced metastatic or recurrent NSCLC, melanoma or mismatch repair-proficient 
colorectal cancer. The study has 2 phases, a Dose Escalation/Confirmation Phase (Phase 1b) and an Expansion 
Phase (Phase 2), with the Expansion Phase utilizing a Simon 2-stage design (Simon 1989) for cohorts 1 and 4. For 
cohorts 2 and 3, the single proportion binomial test statistic is used to test for statistical significance. An additional 
cohort (Entinostat Monotherapy Immune Correlate [EMIC] Cohort) evaluating single agent entinostat followed by 
the combination will also be evaluated in patients with NSCLC in the Phase 2 expansion phase. 
Regardless of phase, patients will be screened for study eligibility within 21 days before enrollment into the study. 
Patients who are determined to be eligible, based on screening assessments, will be enrolled into the study within 3 
days of starting study treatment. With the exception of those in the EMIC cohort, patients will receive entinostat in 
combination with pembrolizumab on Cycle 1, Day 1 (C1D1), within 3 days from enrolling into the study.  
A total of 15 patients will be enrolled in an EMIC Cohort. EMIC patients will be enrolled in the study within 3 days 
of starting study treatment on Day -14 (initiation of entinostat monotherapy) and will participate in a 2-week 
entinostat monotherapy period. The purpose of this 14-day lead-in phase is to obtain pre-and post-entinostat 
monotherapy correlative data in blood and tissue. After completion of the 2-week entinostat monotherapy period, 
patients in the EMIC Cohort will start entinostat in combination with pembrolizumab on C1D1. Patients in the 
EMIC Cohort will receive entinostat beginning at 5mg weekly for the monotherapy period, and then will receive 
entinostat in combination with pembrolizumab at the RP2D as identified in the Phase 1b Dose 
Escalation/Confirmation portion of the study. 
A cycle is 21 days in length. During treatment, patients will attend study center visits and have study evaluations 
performed on C1D1, C1D8, and C1D15; D1 and D15 of C2; and on D1 of each cycle thereafter. 
Fresh tumor tissue samples will be collected during the study as follows: 
• 
During screening from all patients on a mandatory basis. 
• 
On C2D15 (+3 days) on an optional basis from patients in the Dose Escalation/Confirmation Phase. All 
patients in the Dose Escalation/Confirmation Phase will be strongly encouraged to provide an optional 
biopsy in order to help understand dose-immune correlate effects. 
o 
On C2D15 (+3 days) on a mandatory basis from the first 10 patients (in total, across cohorts) in 
Stage 1 in the Expansion Phase, the first 10 patients in the EMIC Cohort, and the first 10 patients 
in the CRC Cohort. If, based on an interim review of tumor tissue data from the initial patients in 


Product:  Entinostat 
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Date:  12 April 2018 
 
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the Expansion Phase, such data are not considered informative, then tumor tissue samples will not 
be collected from subsequent patients on C2D15 (+3 days). Alternatively, if such data are 
considered informative, these tissue samples will be collected on C2D15 (+3 days) from 
subsequent study patients in the Expansion Phase.  
Blood for immune correlates is to be collected from patients in the EMIC Cohort pre-dose on D-14, C1D1, C1D8, 
and C2D15. In all other cohorts, blood for immune correlates is to be collected pre-dose on C1D1, C2D1, and 
C2D15. Blood for protein lysine acetylation and for entinostat and pembrolizumab PK assessments will be collected 
according to the Schedule of Events. 
Patients will have radiological disease assessments performed during screening and every 6 weeks (+/-3 days) 
(Week 6, Week 12, etc.). Disease will be assessed by computed tomography (CT), magnetic resonance imaging 
(MRI), and bone scans, as appropriate, and response will be assessed by the Investigator primarily using irRECIST. 
Safety will be assessed during the study by documentation of AEs, clinical laboratory tests, physical examination, 
vital sign measurements, electrocardiograms (ECGs), and Eastern Cooperative Oncology Group (ECOG) 
performance status. 
The maximum duration of treatment for this study is planned to be 2 years. If a patient permanently discontinues 1 
of the 2 study drugs (either entinostat or pembrolizumab), the patient may continue to receive monotherapy for up to 
2 years, unless alternate therapy is started or another discontinuation criterion is met (Section 10). 
After discontinuation of both study drugs, patients will complete an End of Treatment (EOT) visit within 7 days 
after the last study drug dose and Safety Follow-up (F/U) visits 30 days and 90 days thereafter. After completion of 
the 30-day Safety F/U visit, patients who have not experienced progressive disease (PD) are to be followed every 
2 months until PD and every 3 months thereafter until death or closure of the study by the Sponsor. 
Phase 1b (Dose Escalation/Confirmation):  The Dose Escalation/Confirmation Phase of the study, in which patients 
with NSCLC will be enrolled, employs a classical 3+3 design, with the determination of DLT and the MTD and/or 
RP2D based on entinostat in combination with pembrolizumab in C1.  
Although decisions regarding dose escalation will be made primarily based on review of data from C1, safety data 
will also be collected from all patients continuing treatment and these data will be reviewed in an ongoing manner 
by the Sponsor Study Physician(s) including Medical Monitor, in consultation with the Investigators. Any detected 
cumulative toxicity may require later dose reductions and/or other changes to the dosing schedule, as appropriate, 
including further refinement of the RP2D. 
Dose Escalation:  The initial 3-6 patients will receive entinostat at a starting dose of 3mg on D1, D8, and D15 along 
with pembrolizumab 200 mg via intravenous (IV) infusion on D1 of a 21-day cycle. Assuming an acceptable safety 
profile, escalation to an entinostat dose of 5mg weekly is planned, keeping the pembrolizumab dose constant. 
However, based on evaluation of the safety and tolerability data of the previous dose level, it may also be decided 
that accrual will take place at an intermediate dose level or alternate dosing schedule. Toxicities will be assessed by 
the Investigator using the United States (US) National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events (CTCAE), Version 4.03. The decision regarding whether to proceed to the next dose level will be 
made by the Sponsor Study Physician(s) in consultation with the Investigators after the majority of the safety 
assessments for each cohort are completed.  
All patients within a cohort are to complete C1, have safety assessments performed through C2D1, and be assessed 
for DLT before enrollment of the next cohort may commence. If <33% patients within a cohort have a DLT (i.e., <2 
of up to 6), then enrollment of the next cohort may commence with approval from the Sponsor Study Physician(s) in 
consultation with the Investigators. If ≥33% (≥2 of up to 6) of patients within a cohort experience a DLT, then the 
DLT dose level will have been reached. 
Patients who experience a DLT will be allowed to remain on study if they meet the following criteria: (1) the 
investigator believes it is appropriate for patients to remain on study; (2) the event has resolved and no longer meets 
the definition of DLT; and (3) the timeline for resolution falls within the protocol guidelines for dose delays. 
Patients who complete C1 may continue on study as long as, in the Investigator’s judgment, the patient is tolerating 
study treatment, is not at an increased safety risk, and continues to meet protocol eligibility criteria.  


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Six patients will need to be treated in a dose level for that dose to be considered for the Dose Confirmation stage. 
The recommended dose for Phase 2 investigation will be the higher of either 3 or 5mg weekly by mouth (PO) that 
results in less than a 33% incidence of DLT. The final determination of the optimal RP2D  will consider both acute 
and cumulative toxicities; the incidence of required dose delays, reductions, and discontinuations; and the overall 
facility of administration in clinical practice. 
Dose Confirmation:  The prospective MTD/RP2D identified in the Dose Escalation Phase will be confirmed in 9 
patients in the Dose Confirmation Cohort, to obtain additional AE, immune correlate, and anti-tumor activity data on 
entinostat in combination with pembrolizumab.  
The decision regarding the RP2D will be made by the Sponsor Study Physician(s), based on a review of all data 
obtained from both the Dose Escalation and Confirmation Phases, with input from the Investigators. 
After completion of the Dose Escalation/Confirmation Phase of the study, with identification of the MTD/RP2D, the 
Phase 2 portion of the study will commence. 
Phase 2 (Expansion): In the Expansion Phase, entinostat in combination with pembrolizumab will be evaluated 
using the RP2D identified in the Dose Escalation/Confirmation Phase. Up to 4 Expansion Cohorts consisting of 
distinct subsets of patients with solid tumor cancers may be explored. Expansion cohorts 1 and 4 evaluated during 
the Expansion Phase will employ a Simon 2 stage design. Expansion cohorts 2 and 3 will employ single proportion 
binomial test (See Sample Size Considerations). The final decision about which Expansion Cohorts to study will 
be based on data from the Dose Escalation/Confirmation Phase, emerging clinical data from other studies, and/or 
nonclinical data. Expansion cohorts may include: 
1. Cohort 1:  NSCLC, with squamous cell or adenocarcinoma histology who have not been treated with a PD-
1 or PD-L1blocking antibody 
2. Cohort 2:  Patients with NSCLC (any histology) who have previously been treated with and unequivocally 
progressed on either a PD-1 or PD-L1-blocking antibody 
3. Cohort 3:  Patients with melanoma who have previously been treated with and unequivocally progressed on 
either a PD-1 or PD-L1-blocking antibody (i.e., pembrolizumab, nivolumab, MEDI4736, or GNE PDL1 
[MPDL3280A]) 
4. Cohort 4: Patients with CRC (mismatch repair-proficient) who have not been previously treated with a PD-
1 or PD-L1 blocking antibody 
EMIC Cohort: 
After completion of Stage 1 of Cohort 1 in the Expansion Phase, provided the criteria for continuation are met (i.e., 
at least 3 of 13 patients in Stage 1 experience a CR or PR; see Sample Size Considerations), 15 patients with 
NSCLC (either squamous cell adenocarcinoma or mixed histology) will be enrolled in an EMIC Cohort. Patients 
will be randomly assigned to Stage 2 of Cohort 1 or the EMIC Cohort on a 1:1 basis until the EMIC Cohort is fully 
enrolled. As stated previously, EMIC patients will participate in a 2-week entinostat monotherapy period prior to 
starting entinostat in combination with pembrolizumab. The purpose of this 14-day lead-in phase is to obtain pre-and 
post-entinostat monotherapy correlative data in blood and tissue. 
Sample Size Considerations: 
Dose Escalation/Confirmation Phase 
Three to 6 patients will be enrolled in each dose cohort based on a standard Phase 1 dose escalation scheme. Each 
patient will participate in only 1 dose cohort. The total number of patients to be enrolled in the Dose 
Escalation/Confirmation Phase is dependent upon the observed safety profile, which will determine the number of 
patients per dose cohort, as well as the number of dose escalations required to achieve the MTD or RP2D. 
A starting sample size of at least 3 patients per dose cohort - expanding to 6 patients in the event of a marginal DLT 
rate (33%) or to confirm a dose for the Confirmation Phase - is deemed to be a safe and conventional approach in 
the dose escalation of a novel oncologic agent. Assuming a true DLT rate of 5% or less, there would be a 3% chance 
that dose escalation would be halted in a given cohort (i.e., observing 2 or more patients with DLT). If a true DLT 
rate of 50% is assumed, then there would be an 83% chance that dose escalation would be halted in a given cohort. 


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As stated previously, a total of 9 additional patients will be enrolled at the potential RP2D in the Dose Confirmation 
Cohort to obtain additional AE, immune correlate, and anti-tumor activity data on entinostat at the MTD or other 
dose recommended for further investigation in Phase 2 (i.e., RP2D) in combination. 
Expansion Phase 
In the Expansion Phase of the study, the safety and preliminary antitumor activity of entinostat when administered at 
the RP2D with pembrolizumab will be explored in up to 4 cohorts of adult solid tumors as previously defined. Up to 
252 patients are planned to be enrolled among the 4 cohorts. Patients will be enrolled in each cohort according to a 
single-arm study design with ORR, as determined by irRECIST, as the primary endpoint. The Expansion Phase will 
be carried out in 2 stages so that enrollment for 1 or more of the cohorts evaluated can terminate early in the event 
the antitumor activity of the combination regimen is not sufficient. The decision to terminate or continue enrollment 
for each cohort will be made independently of the other. The number of patients evaluated in each stage and the 
minimum number of responders needed to continue to the next stage, as described for cohort 1, was determined 
based on the optimum version of Simon’s 2-stage design (Simon 1989), with 80% power and 1-sided significance 
level of 10%. For cohort 4, the number of patients evaluated in each stage and the minimum number of responders 
needed to continue to the next stage was determined based on optimum version of Simon’s 2-stage design, with 90% 
power and 1-sided significance level of 5%. For cohorts 2 and 3, the number of responders needed to declare the 
study a success was based on single proportion binominal test with 90% power and 1-sided significance level of 5%. 
Note that the protocol may be amended to allow for enrollment of additional or different cohorts, for example, 
patients with PD-L1-positive NSCLC, based on emerging data during study conduct. 
Syndax will conduct one administrative analysis when at least 60% (42 out of 70 patients in cohort 2, 31 out of 52 
patients in cohort 3) of patient information have accrued in cohorts 2 and 3 for decision making for late phase 
development planning. This administrative look will not lead to stopping of the study. Nonetheless, 0.01 alpha is 
being allocated to spend for the first administrative look and leaving 0.04 alpha for the final analysis.  
Cohort 1 (NSCLC patients with squamous cell and adenocarcinoma histology not previously treated with a PD-1 
or PD-L1 blocking antibody) 
A maximum of 46 patients will be enrolled in Cohort 1. A true ORR of 35% is hypothesized for both tumor types. 
An ORR greater than 20% is considered a lower threshold for antitumor activity that would warrant continued 
development. Based on the design elements specified above, up to 13 patients may be enrolled for either tumor type 
during the first stage:  if 2 or fewer patients achieve an objective response (CR or PR), confirmed or unconfirmed, 
then enrollment will terminate; otherwise, 33 additional patients will be enrolled during the second stage. Upon 
completion of the second stage, if 13 or more patients out of the 46 enrolled achieve CR or PR, then the true ORR 
for the combination therapy likely exceeds 20%, the lower threshold of acceptable antitumor activity. Alternatively, 
if 12 or fewer patients achieve an objective response at the end of the second stage, then the true ORR is likely 20% 
or lower and further evaluation of the combination therapy may not be pursued for that tumor type. If the true ORR 
is 20% or less for a tumor type, then the expected sample size is 29.4, with probability of terminating enrollment at 
the end of the first stage equal to 50%. 
Cohort 2 (Patients with NSCLC (any histology) who have previously been treated and progressed on a PD-1 or 
PD-L1-blocking antibody)  
A maximum of 70 patients will be enrolled in Cohort 2. A true ORR of 15% is hypothesized. A response rate greater 
than 5% is considered the lower threshold for antitumor activity that would warrant continued development in this 
setting. Based on the design elements specified above, the single proportion (or one sample) binomial test will be 
used. Ninety-six percent 1-sided confidence interval of the observed one sample proportion will be calculated. The 
trial will be considered a success if the lower limit of 96% confidence interval is greater than 5%.  
Syndax will conduct one administrative analysis when at least 60% (42 out of 70 patients) of patient information 
have accrued in cohort 2 for decision making for late phase development planning. This administrative look will not 
lead to stopping of the study. Nonetheless, 0.01 alpha is being allocated to spend for the first administrative look and 
leaving 0.04 alpha for the final analysis.  
 


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Cohort 3 (Patients with melanoma who have previously been treated and progressed on a PD-1 or PD-L1-
blocking antibody) 
A maximum of 52 patients will be enrolled in Cohort 3. A true ORR of 25% is hypothesized. An ORR greater than 
10% is considered the lower threshold for antitumor activity that would warrant continued development in this 
setting. Based on the design elements specified above, , the single proportion (or one sample) binomial test will be 
used. Ninety-six percent 1-sided confidence interval of the observed one sample proportion will be calculated. The 
trial will be considered a success if the lower limit of 96% confidence interval is greater than 10%. 
Syndax will conduct one administrative analysis when at least 60% (31 out of 52 patients) of patient information 
have accrued in cohort 3 for decision making for late phase development planning. This administrative look will not 
lead to stopping of the study. Nonetheless, 0.01 alpha is being allocated to spend for the first administrative look and 
leaving 0.04 alpha for the final analysis.  
Cohort 4 (Patients with CRC who have not previously been treated on a PD-1 or PD-L1-blocking antibody) 
A maximum of 84 patients will be enrolled in Cohort 4. A true ORR of 15% is hypothesized. An ORR greater than 
5% is considered the lower threshold for antitumor activity that would warrant continued development in this 
setting. Based on the design elements specified above, up to 37 patients may be enrolled during the first stage:  if 
less than or equal to 2patients achieve a CR or PR, confirmed or unconfirmed, then enrollment will terminate; 
otherwise, 47 additional patients will be enrolled during the second stage. Upon completion of the second stage, if 8 
or more patients out of the 84 enrolled achieve CR or PR, then the true ORR for the combination regimen likely 
exceeds 5%, the lower threshold of acceptable antitumor activity. Alternatively, if 7 or fewer patients achieve an 
objective response at the end of the second stage, then the true ORR is likely 5% or lower and further evaluation of 
the combination therapy may not be pursued in this setting. If the true ORR is 5% or less, then the expected sample 
size is 50.2, with probability of terminating enrollment at the end of the first stage equal to 72%.  
Endpoints 
Primary Efficacy Endpoint 
• 
ORR, as determined by the local investigator using irRECIST 
Secondary Endpoints: (analyzed in the same populations as the primary endpoint) 
• 
CBR (CR+PR+SD) at 6 months 
• 
PFS status at 6 months 
• 
PFS 
• 
OS 
In patients who experience a response to treatment (CR or PR): 
• 
DOR 
• 
TTR 
An analysis of efficacy endpoints also will be performed, with response determined using RECIST, version 1.1 and 
irRECIST. 
Safety:  
• 
Incidence of treatment-emergent AEs, SAEs, AEs resulting in the permanent discontinuation of study drug, 
and deaths occurring within 90-days of last dose of study drug 
• 
Changes from baseline in laboratory, vital signs and ECG results 
Exploratory: 
 
 
 


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Summary of Patient Eligibility Criteria:   
INCLUSION CRITERIA 
Patients meeting all of the following criteria are considered eligible to participate in the study: 
Patients with NSCLC 
1. Has histologically- or pathologically-confirmed recurrent or metastatic NSCLC. 
2. If has adenocarcinoma, required to have previously been tested for anaplastic lymphoma kinase (ALK) 
rearrangements and epidermal growth factor receptor (EGFR) (Exon 19 Deletion and Exon 21 L8585R 
Substitution) mutations, with results available for collection in this study, and, if positive, has been treated with 
prior EGFR or ALK therapy.  
3. Received at least 1 chemotherapeutic regimen in the advanced/metastatic setting and experienced documented, 
unequivocal progressive disease by either RECIST 1.1 or clinical assessment. In addition: 
• 
If patient has EGFR mutation-positive or ALK translation-positive disease, must have received an EGFR 
inhibitor or ALK inhibitor, respectively, in addition to the above chemotherapy regimen. 
• 
Patients who received adjuvant or neoadjuvant platinum-based doublet chemotherapy (after surgery and/or 
radiation therapy) and developed recurrent or metastatic disease within 6 months of completing therapy are 
eligible; in such cases, the adjuvant or neoadjuvant platinum-based doublet chemotherapy regimen will 
count as a line of therapy.  
• 
Patients with recurrent disease >6 months after adjuvant or neoadjuvant platinum-based doublet 
chemotherapy who subsequently experienced PD during or after a platinum-based doublet chemotherapy 
regimen given to treat the recurrences, are eligible; the second platinum-based doublet chemotherapy 
regimen does not count as another line of therapy.  
• 
Patients who received pemetrexed, bevacizumab, or erlotinib as maintenance therapy (non-progressors with 
platinum-based doublet chemotherapy) and subsequently progressed after maintenance therapy) are 
eligible; such therapy does not count as a line of therapy. However, if the patient received a tyrosine kinase 
inhibitor (TKI) after failure of platinum-based doublet chemotherapy, the TKI will count as an additional 
line of therapy. 
4. Patients with NSCLC enrolled in Cohort 1 of the Expansion Phase should not have been previously treated with 
a PD-1/PD-L1-blocking antibody (i.e., pembrolizumab, nivolumab, MEDI4736, or GNE PDL1 [MPDL3280A]) 
Patients in Expansion Phase, Cohorts 2 (NSCLC) and 3 (Melanoma)  
5. Previously treated with a PD-1/PD-L1-blocking antibody (i.e., pembrolizumab, nivolumab, MEDI4736, or GNE 
PDL1 [MPDL3280A]) and experienced documented, unequivocal radiographic progression of disease by 
irRECIST, or similar criteria during or within 12 weeks after last dose of such treatment. Patients must have 
received at least 6 weeks of PD-1/PD-L1 therapy for Cohort 2 and at least 8 weeks of PD-1/PD-L1 therapy for 
Cohort 3. For patients who received such agents in a clinical trial, documentation of progressive disease 


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requires a confirmatory scan. For patients who had been treated with such agents outside of a clinical trial, 
documentation of progressive disease will be based on both radiographic and clinical assessment. If the 
requirement for a confirmatory scan is deemed not to be in the patient’s best interests based upon his/her overall 
condition, including performance status and clinical symptoms, this requirement may be waived in consultation 
with the Sponsor’s Medical Monitor; however, patients who have not had a confirmatory scan because of rapid 
progression and clinical deterioration should not be enrolled onto this trial. In all cases, the scan obtained during 
the screening process may serve as the confirmatory scan. 
(Note:  Patients who are currently receiving pembrolizumab and have clear, unequivocal evidence of PD may be 
eligible. Such patients are to be discussed with the Sponsor Study Physician on a case-by-case basis prior to 
enrollment of the patient in the study.) 
Patients with Melanoma 
6. In addition to having been previously treated with a PD-1/PD-L1-blocking antibody (inclusion #5), has a 
histologically- or cytologically-confirmed diagnosis of unresectable or metastatic melanoma and experienced 
unequivocal progressive disease during treatment with a BRAF inhibitor if BRAF V600 mutation-positive. 
Treatment with BRAF inhibitor may occur AFTER treatment with the checkpoint inhibitor. 
Patients in Expansion Phase, Cohort 4 (Colorectal Cancer) 
7. Received at least 1 chemotherapeutic regimen in the advanced/metastatic setting and experienced documented, 
unequivocal progressive disease by either RECIST 1.1 or clinical assessment. Must have documented mismatch 
repair-proficient colon cancer as determined by either immunohistochemistry for mismatch repair proteins or 
PCR-based functional microsatellite instability. Patients with colorectal cancer enrolled in Cohort 4 should not 
have been previously treated with a PD-1/PD-L1-blocking antibody (i.e., pembrolizumab, nivolumab, 
MEDI36MEDI4736, or GNE PDL1 [MPDL3280A]) 
All Patients 
8. Aged 18 years or older on the day written informed consent is given. 
9. If has brain metastases, must have stable neurologic status following local therapy (surgery or radiation) for at 
least 4 weeks without the use of steroids or on stable or decreasing dose of ≤10 mg daily prednisone (or 
equivalent), and must be without neurologic dysfunction that would confound the evaluation of neurologic and 
other AEs. (Patients with a history of carcinomatous meningitis are not eligible.) 
10. Evidence of locally recurrent or metastatic disease based on imaging studies (e.g., CT, MRI) within 28 days 
before the first study drug dose: 
• 
At least 1 measurable lesion ≥20 mm by conventional techniques or ≥10 mm by spiral CT scan or MRI, 
with the last imaging performed within 28 days before the first study drug dose. If there is only 
1 measurable lesion and it is located in previously irradiated field, it must have demonstrated unequivocal 
progression according to RECIST, version 1.1.  
11. If receiving radiation therapy, has had a 2-week washout period following completion of the treatment prior to 
receiving the first study drug dose and continues to have at least 1 measurable lesion, per above criterion. 
12. ECOG performance status of 0 or 1. 


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13. Has the following laboratory parameters: 
System 
Laboratory Value 
Hematological 
Absolute neutrophil count (ANC) 
≥1.5×109/L 
Platelets 
≥100×109/L 
Hemoglobin 
≥9 g/dL or ≥5.6 mmol/L  
Renal 
Creatinine OR 
Measured or calculated1 creatinine clearance (CrCl) 
(glomerular filtration rate [GFR] can also be used in place 
of creatinine or CrCl) 
≤1.5× the upper limit of normal (ULN) OR 
≥60 mL/min for patient with creatinine levels >1.5× 
institutional ULN 
Hepatic 
Total bilirubin 
≤1.5×ULN OR 
Direct bilirubin ≤ULN for patients with total bilirubin levels 
>1.5×ULN 
Aspartate aminotransferase (AST) and alanine 
aminotransferase (ALT) 
≤2.5×ULN OR 
≤5×ULN for patients with liver metastases 
Coagulation 
International Normalized Ratio (INR) or Prothrombin 
Time (PT) 
 
Activated Partial Thromboplastin Time (aPTT) 
≤1.5×ULN unless patient is receiving anticoagulant therapy as 
long as PT or PTT is within therapeutic range of intended use 
of anticoagulants 
≤1.5×ULN unless patient is receiving anticoagulant therapy as 
long as PT or PTT is within therapeutic range of intended use 
of anticoagulants 
1 Creatinine clearance should be calculated per institutional standard. 
 
14. Female patients of childbearing potential must have a negative serum pregnancy test during screening and a 
negative urine pregnancy test within 72 hours prior to taking first dose of study drug. If a patient is of 
childbearing potential, the patient must agree to use effective contraception, as defined in the protocol (Section 
8.5.3), during the study and for 120 days after the last dose of study drug. Non-childbearing potential is defined 
as (by other than medical reasons): 
• 
≥45 years of age and has not had menses for >2 years, 
• 
Amenorrheic for <2 years without a hysterectomy and oophorectomy and a follicle-stimulating hormone 
value in the postmenopausal range upon pre-study (screening) evaluation.  
• 
Post hysterectomy, oophorectomy or tubal ligation. Documented hysterectomy or oophorectomy must be 
confirmed with medical records of the actual procedure or confirmed by an ultrasound. Tubal ligation must 
be confirmed with medical records of the actual procedure otherwise the patient must be willing to use 2 
adequate barrier methods throughout the study, starting with the screening visit through 120 days after the 
last dose of study drug. Please see Section 8.5.3, Contraception, for a list of acceptable birth control 
methods. 
15. If male, agrees to use an adequate method of contraception starting with the first dose of study drug through 120 
days after the last dose of study drug. Please see Section 8.5.3, Contraception, for a list of acceptable birth 
control methods.  
16. Experienced resolution of toxic effect(s) of the most recent prior chemotherapy to Grade 1 or less (except 
alopecia). If patient underwent major surgery or radiation therapy of >30 Gy, they must have recovered from 
the toxicity and/or complications from the intervention. 
17. Willing to have fresh tumor samples collected during screening and at other time points designated as 
mandatory, per the Schedule of Study Assessments. If patients whose only accessible lesion for biopsy is a 
solitary target lesion, it must be amenable to a core biopsy that will not compromise assessment of tumor 
measurements. 


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18. Able to understand and give written informed consent and comply with study procedures. 
EXCLUSION CRITERIA 
Patients meeting any of the following criteria are not eligible for study participation: 
1. Diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg 
daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first 
dose of study drug.  
2. Active autoimmune disease that has required systemic treatment in past 2 years (i.e., with disease modifying 
agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or 
physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of 
systemic treatment. 
3. History of interstitial lung disease (ILD). 
4. Allergy to benzamide or inactive components of entinostat.  
5. History of allergies to any active or inactive ingredients of pembrolizumab or severe hypersensitivity (>= Grade 
3) to pembrolizumab. 
6. History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results 
of the study, interfere with the patient’s participation for the full duration of the study, or is not in the best 
interest of the patient to participate, in the opinion of the treating Investigator, including, but not limited to: 
• 
Myocardial infarction or arterial thromboembolic events within 6 months prior to baseline or severe or 
unstable angina, New York Heart Association (NYHA) Class III or IV disease, or a QTc interval 
> 470 msec. 
• 
Uncontrolled heart failure or hypertension, uncontrolled diabetes mellitus, or uncontrolled systemic 
infection. 
• 
Another known additional malignancy that is progressing or requires active treatment (excluding 
adequately treated basal cell carcinoma, squamous cell of the skin, cervical intraepithelial neoplasia 
[CIN]/cervical carcinoma in situ or melanoma in situ or ductal carcinoma in situ of the breast). Prior history 
of other cancer is allowed, as long as there is no active disease within the prior 5 years. 
• 
Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.  
• 
Active infection requiring systemic therapy. 
• 
Known active central nervous system (CNS) metastases and/or carcinomatous meningitis.  
Note: Patients with previously treated brain metastases may participate provided they are stable (without 
evidence of progression by imaging [using the identical imaging modality for each assessment, either MRI 
or CT scan] for at least 4 weeks prior to the first dose of study drug and any neurologic symptoms have 
returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids 
for at least 2 weeks prior to the first dose of study drug or are on stable or decreasing dose of ≤10 mg daily 
prednisone (or equivalent). This exception does not include carcinomatous meningitis which is excluded 
regardless of clinical stability. 
7. Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of 
the study. 
8. Currently participating and receiving study therapy or has participated in a study of an investigational agent and 
received study therapy or used an investigational device within 4 weeks of the first dose of treatment. 
9. Received a live virus vaccination within 30 days of the first dose of treatment. 
10. Prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to baseline or who has not recovered (i.e., 
≤Grade 1 or at baseline) from AEs due to agents administered more than 4 weeks earlier. 


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11. Prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study 
baseline or who has not recovered (i.e., ≤Grade 1 or at baseline) from AEs due to a previously administered 
agent. 
Note:  Patients with ≤Grade 2 neuropathy or ≤Grade 2 alopecia are an exception to this criterion and may 
qualify for the study. 
Note:  If patient underwent major surgery, they must have recovered adequately from the toxicity and/or 
complications from the intervention prior to starting therapy.  
12. Received transfusion of blood products (including platelets or red blood cells) or administration of colony 
stimulating factors (including granulocyte-colony stimulating factor [G-CSF], granulocyte macrophage-colony 
stimulating factor [GM-CSF], or recombinant erythropoietin) within 4 weeks prior to the first dose of treatment.  
13. Currently receiving treatment with any other agent listed on the prohibited medication list in Section 8.5.1 such 
as valproic acid, or other systemic cancer agents within 14 days of the first dose of treatment.  
14. If female, is pregnant, breastfeeding, or expecting to conceive, or if male, expect to father children within the 
projected duration of the study, starting with the screening visit through 120 days after the last dose of study 
drug. 
15. Known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies). 
16. Known active hepatitis B (e.g., hepatitis B surface antigen-reactive) or hepatitis C (e.g., hepatitis C virus 
ribonucleic acid [qualitative]). 
17. For CRC expansion cohort, prior history of malignant bowel obstruction requiring hospitalization in the 6 
months prior to enrollment 
18. For the CRC expansion cohort, history of uncontrolled ascites, defined as symptomatic ascites and/or repeated 
paracenteses for symptom control in the past 3 months 
Investigational Product:  
Entinostat  
Entinostat is a synthetic small molecule bearing the chemical name 3-pyridylmethyl-N-{4-[(2-
aminophenyl)carbonyl] benzyl}carbamate and the molecular formula C21H20N4O3, with a molecular weight of 
376.41. Entinostat is classified as an antineoplastic agent, specifically functioning as an inhibitor of histone 
deacetylases and therefore promotes hyperacetylation of nucleosomal histones, allowing transcriptional activation of 
a distinct set of genes that leads to the inhibition of cell proliferation, induction of terminal differentiation, and/or 
apoptosis. Entinostat is supplied in two strengths of film-coated tablets containing 1 mg (pink to light red) or 5 mg 
(yellow) of active ingredient. 
Pembrolizumab 
Pembrolizumab is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-
L1 and programmed death ligand-2 (PD-L2). Pembrolizumab is an immunoglobulin G4 kappa immunoglobulin with 
an approximate molecular weight of 149 kDa. 
Pembrolizumab will be supplied as 50mg lyophilized powder for injection or 100mg/4 mL solution for injection.  
Statistical Considerations: 
The safety and efficacy analyses will be presented by study phase. For the escalation phase, tabulations will be 
provided by dose cohort and overall. For the Expansion Phase, tabulations will be provided by tumor type and 
overall. Some analyses may be performed based on the Dose Escalation/Confirmation and Expansion Phases 
combined. 


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Safety Analyses 
Safety analyses will be conducted using the Safety Analysis Set. 
Treatment-emergent AEs reported during the study will be tabulated and listed by Medical Dictionary for 
Regulatory Activities (MedDRA version 18.0) System Organ Class (SOC) and Preferred Term (PT). Tables will 
display number and percentage of patients experiencing the event for the following categories: all AEs; AEs 
considered related to study drug; AEs by severity; DLTs; AEs occasioning treatment delay or discontinuation; and 
serious adverse events (SAEs). For the Dose Escalation/Confirmation Phase, the observed DLT rate in each dose 
cohort will be calculated by the crude proportion of patients who experienced DLT with a 2-sided 95% exact 
binomial confidence interval (CI).  
Hematology and serum chemistries will be summarized using conventional summary statistics (mean, standard 
deviation, median, and range) for the following: baseline value, minimum and maximum post-baseline values, 
average post-baseline value, and last post-baseline value. Standard shift tables will also be prepared presenting worst 
post-baseline toxicity grade versus baseline. Vital signs will be summarized in a descriptive manner by calculating 
the mean, standard deviation, median, and range in the same manner described for laboratory values. The Wilcoxon 
signed rank test may be used to assist in the identification of any systematic changes. 
Efficacy Analyses 
Efficacy analyses will be conducted using the Full Analysis Set and, where appropriate, the Per-protocol Set. 
ORR will be estimated for each cohort evaluated in the Expansion Phase, assessed using irRECIST. Crude 
proportion of patients with best overall response of CR or PR, along with a 2-sided 95% CI, will be calculated. The 
width of the CI will be adjusted to account for the multistage design (Atkinson 1985). Additionally, a 90% one-sided 
CI of the form (πL, 1] will be reported since the sample size for the Expansion Phase was determined using a one-
sided significance level of 10%. CBR at 6 months will be analyzed in a similar manner.  
DOR will be calculated for patients who achieve a CR or PR and is defined as the number of months from the start 
date of the response (and subsequently confirmed) to the first date that recurrent disease or PD is documented. PFS 
is defined as the number of months from the date of the first dose of study drug to the earliest of documented PD or 
death due to any cause without prior progression. OS is defined as the number of months from the first dose of study 
drug to the date of death due to any cause. DOR, PFS, and OS will be summarized descriptively using the Kaplan-
Meier method with 95% CIs calculated using Greenwood’s formula. Median follow-up for each endpoint will be 
estimated according to the Kaplan-Meier estimate of potential follow-up. PFS rate at 6 months and corresponding 
95% CIs will be estimated using the Kaplan-Meier method. Greenwood’s formula will be used to calculate the 
standard errors of the Kaplan-Meier estimate and upper and lower limits of the 95% CI. 
Procedures:  The Schedule of Study Assessments for patients in the EMIC Cohort is included in Table 1-2. The 
Schedule of Study Assessments for all other patients is included in Table 1-1.  
 


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Table 1-1 
Schedule of Study Assessments 
Procedure 
Screening 
(D -21 to -1) 
Combination Therapy 
EOT1 
Safety 
F/U2,3 
Post-
Study 
F/U 
C1 
C2  
≥C3 
D1 
D8 
D15 
D1 
D15 
Day 1 
Visit Window 
- 
- 
±1D 
±1D 
±3D 
±3D 
±3D 
±3D 
±3D 
±5D 
Provision of written informed consent 
X 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
Medical history, including underlying disease 
history 
X 
 
 
 
 
 
 
 
 
 
Complete physical examination 
X4 
X4 
 
 
 
 
 
X 
X 
 
Symptom-directed physical examination 
 
X 
X 
X 
X 
X 
X 
 
 
 
ECG 
X 
 
 
 
 
 
X5 
X 
 
 
Vital signs and weight 
X 
X 
 
 
X 
 
X 
X 
X 
 
ECOG performance status 
X 
X 
 
 
X 
 
X 
X 
X 
 
Radiological Imaging 
X6 
 
 
 
 
 
X7 
X8 
 
 
Disease Response Assessment 
 
X 
 
 
 
 
X 
X9 
 
 
Thyroid function tests 
X10 
 
 
 
X10 
 
X10 
X 
 
 
Pregnancy testing 
X 
X11 
 
 
 
 
 
 
 
 
Hematology, coagulation studies12, and clinical 
chemistries13 
X 
X14 
X 
X 
X 
X 
X 
X 
 
 
Blood sample for immune correlates 
 
X 
 
 
X 
X15 
 
 
 
 
Blood sample for protein lysine acetylation 
 
X 
 
X 
 
X 
 
 
 
 
Tissue sample collection for immune correlates 
X16 
 
 
 
 
X16 
 
 
 
 
Entinostat self-administration 
 
Entinostat is to be self-administered by the patient weekly), starting on 
C1D1 
 
 
 


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Procedure 
Screening 
(D -21 to -1) 
Combination Therapy 
EOT1 
Safety 
F/U2,3 
Post-
Study 
F/U 
C1 
C2  
≥C3 
D1 
D8 
D15 
D1 
D15 
Day 1 
Visit Window 
- 
- 
±1D 
±1D 
±3D 
±3D 
±3D 
±3D 
±3D 
±5D 
Pembrolizumab administration 
 
X 
 
 
X 
\ 
X 
 
 
 
Blood sample for entinostat pharmacokinetics17 
 
X 
X 
X 
X 
 
 
 
 
 
Blood sample for pembrolizumab 
pharmacokinetics and anti-drug antibodies18 
 
X 
 
 
X 
 
X 
 
X 
 
Blood sample for tumor markers19 
 
X 
 
 
X 
 
X 
X 
 
 
Pre-treatment/concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Study drug compliance assessment 
 
X 
X 
X 
 
 
 
X 
 
 
Post-study treatment patient contact20 
 
 
 
 
 
 
 
 
X 
1 The EOT visit is to be conducted within 7 days of study drug discontinuation. 
2 The first Safety F/U visit is 30 days after the EOT visit. After completion of the Safety F/U visit, patients who have not experienced PD are to be followed every 2 months until PD 
and 3 months thereafter until death or closure of the study by the Sponsor. 
3 The second Safety F/U visit is 90 days after the EOT visit. 
4 If the screening physical examination was performed within 7 days before baseline (C1D1), then a symptom-directed examination may be performed at baseline. 
5 An ECG is to be performed during screening, pre-dose on C3D1 and then every 3 cycles thereafter. An ECG may be repeated anytime, as clinically indicated. 
6 Performed only if last scan was performed >28 days previously. 
7 Patients will have radiological disease assessments performed during screening and every 6 weeks (+/-3 days) (Week 6, Week 12, etc.) during treatment.  
8 Performed only if radiological progression was not previously observed on study. 
9 Disease assessments are to be performed every 6 weeks (+/-3 days) (Week 6, Week 12, etc.) during treatment. 
10 In addition to screening, thyroid function tests (thyroid-stimulating hormone [TSH, thyrotropin], free thyroxine [T4], and triiodothyronine [T3] or free triiodothyronine [FT3]) are to 
be performed every 6 weeks during treatment starting at C2. 
11 For female patients of child-bearing potential, a serum pregnancy test is to be performed during screening and a urine pregnancy test is to be performed within 72 hours prior to 
taking the first study drug dose. Pregnancy testing is to be repeated during the study any time pregnancy is suspected. 


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12 Analytes tested include white blood cell count (WBC) with differential, platelet count, red blood cell count (RBC), hemoglobin (HGB), hematocrit (HCT), and, at screening only, 
prothrombin time (PT) or international normalized ratio (INR) and activated partial thromboplastin time (aPTT). Note: it is advisable to monitor PT and INR more frequently for 
patients who receive coumarin derivatives concurrently with entinostat. 
13 Analytes tested include ALT, AST, albumin, alkaline phosphatase, total bilirubin, blood urea nitrogen (BUN), calcium, creatinine, sodium, potassium, chloride, bicarbonate, glucose, 
lactate dehydrogenase (LDH), phosphorus, total protein, and uric acid. Magnesium is to be measured at baseline only, unless clinically indicated.  
14 Performed only if screening laboratory tests performed >7 days prior to C1D1 (baseline). 
15 Pre-dose on C1D1, C2D1 and C2D15 only. 
16 Fresh tumor tissue samples will be collected during the study as follows: during screening from all patients on a mandatory basis; on C2D15 (+3 days) on an optional basis from 
patients in the Dose Escalation/Confirmation Phase; and on C2D15 (+3 days) on a mandatory basis from the first 25 patients (in total, across cohorts) in Stage 1 in the Expansion 
Phase. If, based on an interim review of tumor tissue data from the initial patients in the Expansion Phase, such data are considered informative, then tumor tissue samples will be 
collected on a mandatory basis from all subsequent patients in the Expansion Phase on C2D15 (+3 days). Alternatively, if such data are not considered informative, these samples 
will not be collected from subsequent patients. 
17 Blood samples for entinostat PK will be collected pre-dose on C1D1 as well as 2-4 hours post-dose on C1D1; on C1D8 (anytime post-dose), on C1D15 (anytime post-dose), and pre-
dose on C2D1. The date and time of entinostat administration, the start time and stop time of the pembrolizumab infusion, and the date and time of PK sample collection must be 
recorded in the eCRF. 
18 Samples for pembrolizumab PK and anti-pembrolizumab antibodies will be collected pre-dose on C1D1, C2D1, C4D1, C6D1, C8D1 and every 4 cycles thereafter, and at 30 days 
after the last pembrolizumab dose (or until the patient starts new anti-cancer therapy).  
19 CEA in CRC cohort only 
20Information regarding PD, alternate treatments, and survival status collected until study closure; every 2 months until PD, and then every 3 months thereafter. 
 


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Table 1-2 
Schedule of Study Assessments:  EMIC Cohort 
Procedure 
Screening 
(D -35 
to -15) 
Mono-
therapy 
Period 
Combination Therapy Period 
EOT1 
Safety 
F/U2,3 
Post-
Study 
F/U 
D -14 
C1 
C2 
≥C3 
D1 
D8 
D15 
D1 
D15 
Day 1 
Visit Window 
- 
- 
- 
±1D 
±1D 
±3D 
±3D 
±3D 
±3D 
±3D 
±5D 
Provision of written informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
Medical history, including underlying disease 
history 
X 
 
 
 
 
 
 
 
 
 
 
Complete physical examination 
X4 
X4 
 
 
 
 
 
 
X 
X 
 
Symptom-directed physical examination 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
ECG 
X 
 
 
 
 
 
 
X5 
X 
 
 
Vital signs and weight 
X 
X 
X 
 
 
X 
 
X 
X 
X 
 
ECOG performance status 
X 
X 
X 
 
 
X 
 
X 
X 
X 
 
Radiological Imaging 
X6 
 
 
 
 
 
 
X7 
X8 
 
 
Disease Response Assessment 
 
X 
 
 
 
 
 
X 
X9 
 
 
Thyroid function tests 
X10 
 
 
 
 
X10 
 
X10 
X 
 
 
Pregnancy testing 
X 
X11 
 
 
 
 
 
 
 
 
 
Hematology, coagulation studies12, and 
clinical chemistries13 
X 
X14 
X 
X 
X 
X 
X 
X 
X 
 
 
Blood sample for immune correlates 
 
X 
X 
X 
 
 
X 
 
 
 
 
Blood sample for protein lysine acetylation 
 
X 
X 
 
X 
 
X 
 
 
 
 
Tissue sample collection for immune 
correlates 
X15 
 
 
 
 
 
X15 
 
 
 
 


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Procedure 
Screening 
(D -35 
to -15) 
Mono-
therapy 
Period 
Combination Therapy Period 
EOT1 
Safety 
F/U2,3 
Post-
Study 
F/U 
D -14 
C1 
C2 
≥C3 
D1 
D8 
D15 
D1 
D15 
Day 1 
Visit Window 
- 
- 
- 
±1D 
±1D 
±3D 
±3D 
±3D 
±3D 
±3D 
±5D 
Entinostat self-administration 
 
Entinostat is to be self-administered by the patient weekly, starting on D-14 
 
 
 
Pembrolizumab administration 
 
 
X 
 
 
X 
 
X 
 
 
 
Pre-treatment/concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Study drug compliance assessment 
 
X 
X 
X 
X 
 
 
 
X 
 
 
Post-study treatment patient contact16 
 
 
 
 
 
 
 
 
 
X 
1 The EOT visit is to be conducted within 7 days of study drug discontinuation. 
2 The first Safety F/U visit is 30 days after the EOT visit. After completion of the Safety F/U visit, patients who have not experienced PD are to be followed every 2 months until PD 
and 3 months thereafter until death or closure of the study by the Sponsor. 
3 The second Safety F/U visit is 90 days after the EOT visit. 
4 If the screening physical examination was performed within 7 days before the Day -14 visit, then a symptom-directed examination may be performed on Day -14. 
5 An ECG is to be performed during screening, pre-dose on C3D1 and then every 3 cycles thereafter. An ECG may be repeated anytime, as clinically indicated. 
6 Performed only if last scan was performed >28 days previously. 
7 Patients will have radiological disease assessments performed during screening and every 6 weeks (+/-3 days) (Week 6, Week 12, etc.) during treatment.  
8 Performed only if radiological progression was not previously observed on study. 
9 Disease assessments are to be performed every 6 weeks (+/-3 days) (Week 6, Week 12, etc.) during treatment. 
10 In addition to screening, thyroid function tests (thyroid-stimulating hormone [TSH, thyrotropin], free thyroxine [T4], and triiodothyronine [T3] or free triiodothyronine [FT3]) are to 
be performed every 6 weeks during treatment starting at C2. 
11 For female patients of child-bearing potential, a serum pregnancy test is to be performed during screening and a urine pregnancy test is to be performed within 72 hours prior to 
taking the first study drug dose. Pregnancy testing is to be repeated during the study any time pregnancy is suspected 


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12 Analytes tested include white blood cell count (WBC) with differential, platelet count, red blood cell count (RBC), hemoglobin (HGB), hematocrit (HCT), and, at screening only, 
prothrombin time (PT) or international normalized ratio (INR) and activated partial thromboplastin time (aPTT). Note: it is advisable to monitor PT and INR more frequently for 
patients who receive coumarin derivatives concurrently with entinostat. 
13 Analytes tested include ALT, AST, albumin, alkaline phosphatase, total bilirubin, blood urea nitrogen (BUN), calcium, creatinine, sodium, potassium, chloride, bicarbonate, glucose, 
lactate dehydrogenase (LDH), phosphorus, total protein, and uric acid. Magnesium is to be measured at baseline only, unless clinically indicated. 
14 Performed only if screening laboratory tests performed >7 days prior to Day -14. 
15 Fresh tumor tissue samples are to be collected on a mandatory basis from the first 10 patients in the EMIC Cohort during screening and on C2D15 (+3 days). 
16 Information regarding PD, alternate treatments, and survival status collected until study closure; every 2 months until PD and then every 3 months thereafter. 
 


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Study Glossary 
Abbreviation/Acronym 
Definition 
ADaM 
Analysis Dataset Model 
AE 
Adverse event 
ALK 
Anaplastic lymphoma kinase 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
AZA 
5-Azacitadine 
BSA 
Body surface area 
BUN 
Blood urea nitrogen 
C 
Cycle 
CBR 
Clinical benefit rate 
CEA 
Cancer Embryonic Antigen 
CI 
Confidence interval 
CIN 
Cervical intraepithelial neoplasia 
CNS 
Central nervous system 
CR 
Complete response 
CrCl 
Creatinine clearance 
CRC 
Colorectal cancer 
CSC 
Cancer stem cell 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events  


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Abbreviation/Acronym 
Definition 
CTLA-4 
Cytotoxic T-lymphocyte-associated antigen-4 
D 
Day 
DKA 
Diabetic ketoacidosis 
DLT 
Dose-limiting toxicity 
DNA 
Deoxyribonucleic acid 
DOR 
Duration of response 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
ECI 
Events of clinical interest 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EGFR 
Epidermal growth factor receptor 
EOT 
End of Treatment 
F/U 
Follow-up 
FAS 
Full Analysis Set 
FDG 
18F-deoxyglucose 
FoxP3 
Forkhead box P3 
G-CSF 
Granulocyte-colony stimulating factor 
GFR 
Glomerular filtration rate 
GI 
Gastrointestinal 
GM-CSF 
Granulocyte macrophage-colony stimulating factor 
G-MDSCs 
Granulocytic myeloid-derived suppressor cells 
HDAC 
Histone deacetylase 
HIV 
Human immunodeficiency virus 


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Abbreviation/Acronym 
Definition 
IB 
Investigator’s Brochure 
ICH 
International Council for Harmonisation 
ID 
Identification 
IFN-γ 
Interferon-gamma 
Ig 
Immunoglobulin 
ILD 
Interstitial lung disease 
IND 
Investigational New Drug Application 
INR 
International normalized ratio 
irAE 
Immune-related adverse events 
IRB 
Institutional Review Board 
irRECIST 
Immune-related Response Evaluation Criteria in Solid Tumors 
ITIM 
Immunoreceptor tyrosine-based inhibition motif 
ITSM 
Immunoreceptor tyrosine-based switch motif 
IV 
Intravenous(ly) 
LDH 
Lactic dehydrogenase 
mAb 
Monoclonal antibody 
MDSC 
Myeloid-derived suppressor cells 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic resonance imaging 
MTD 
Maximum tolerated dose 
NCI 
National Cancer Institute 
NE 
Non- Evaluable 
NSCLC 
Non-small cell lung cancer 
NYHA 
New York Heart Association 
ORR 
Overall response rate 


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Abbreviation/Acronym 
Definition 
OS 
Overall survival 
PD 
Progressive disease 
PD-1 
Programmed death receptor-1 
PD-L1 
Programmed death ligand-1 
PD-L2 
Programmed death ligand-2 
PET 
Positron emission tomography 
PFS 
Progression-free survival 
PK 
Pharmacokinetic 
PO 
By mouth 
PP 
Per-protocol 
PR 
Partial response 
PT 
Prothrombin time 
Q2W 
Every other week (i.e., every 2 weeks) 
Q3W 
Every 3 weeks 
RBC 
Red blood cell (count) 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious adverse event 
SC 
Subcutaneous(ly) 
SDTM 
Study Data Tabulation Model 
SEER 
Surveillance, Epidemiology, and End Results 
SOC 
System organ class 
T1DM 
Type 1 diabetes mellitus 
T3 
Triiodothyronine 
T4 
Thyroxine 
TEAE 
Treatment-emergent adverse event 


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Abbreviation/Acronym 
Definition 
TGF 
Transforming growth factor 
TIL 
Tumor-infiltrating lymphocyte 
TKI 
Tyrosine kinase inhibitor 
TSH 
Thyroid stimulating hormone 
TTR 
Time to response 
ULN 
Upper limit of normal 
US 
United States 
V-type 
Variable-type 
WBC 
White blood cell (count) 
 


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TABLE OF CONTENTS 
1. 
PROTOCOL SYNOPSIS SNDX-275-0601 .......................................................................... 3 
STUDY GLOSSARY .................................................................................................................... 21 
LIST OF TABLES ......................................................................................................................... 30 
LIST OF FIGURES ....................................................................................................................... 30 
2. 
OBJECTIVES ...................................................................................................................... 31 
2.1 
Primary .................................................................................................................... 31 
2.2 
Secondary ................................................................................................................ 31 
2.3 
Exploratory .............................................................................................................. 32 
3. 
ENDPOINTS ....................................................................................................................... 33 
3.1 
Efficacy ................................................................................................................... 33 
3.2 
Safety ...................................................................................................................... 33 
3.3 
Exploratory .............................................................................................................. 33 
4. 
BACKGROUND AND RATIONALE ................................................................................ 35 
4.1 
Study Treatment ...................................................................................................... 37 
4.1.1 
Entinostat (SNDX-275) ......................................................................... 37 
4.1.2 
Pembrolizumab (MK-3475) .................................................................. 39 
4.2 
Study Rationale ....................................................................................................... 41 
4.3 
Rationale for the Dose Selection ............................................................................. 42 
4.3.1 
Entinostat............................................................................................... 42 
4.3.2 
Pembrolizumab ..................................................................................... 43 
4.4 
Hypothesis ............................................................................................................... 44 
5. 
EXPERIMENTAL PLAN .................................................................................................... 45 
5.1 
Study Design ........................................................................................................... 45 
5.2 
Number of Centers .................................................................................................. 49 
5.3 
Number of Patients .................................................................................................. 49 
5.4 
Estimated Study Duration ....................................................................................... 49 
6. 
PATIENT ELIGIBILITY .................................................................................................... 50 
6.1 
Inclusion Criteria ..................................................................................................... 50 
6.2 
Exclusion Criteria ................................................................................................... 54 
7. 
PATIENT ENROLLMENT ................................................................................................. 57 
8. 
TREATMENT PROCEDURES .......................................................................................... 58 
8.1 
Study Drug .............................................................................................................. 58 
8.1.1 
Entinostat............................................................................................... 58 


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8.1.2 
Pembrolizumab ..................................................................................... 59 
8.2 
Study Drug Dose and Administration ..................................................................... 59 
8.2.1 
Dose-escalation Phase ........................................................................... 59 
8.2.2 
Expansion Phase .................................................................................... 62 
8.3 
Treatment Duration ................................................................................................. 63 
8.4 
Dose Adjustments ................................................................................................... 63 
8.4.1 
Entinostat............................................................................................... 64 
8.4.2 
Pembrolizumab ..................................................................................... 66 
8.5 
Concomitant Therapy .............................................................................................. 72 
8.5.1 
Prohibited Medications and Medications to be Avoided During the 
Study ..................................................................................................... 72 
8.5.2 
Rescue Medications & Supportive Care Guidelines for 
Pembrolizumab ..................................................................................... 74 
8.5.3 
Diet/Activity/Other Considerations ....................................................... 75 
8.5.4 
Study Drug Use in Pregnancy ............................................................... 76 
8.5.5 
Study Drug Use in Nursing Women ..................................................... 77 
9. 
STUDY TESTS AND OBSERVATIONS ........................................................................... 78 
9.1 
Baseline Assessments.............................................................................................. 78 
9.1.1 
Demographics ....................................................................................... 78 
9.1.2 
Height .................................................................................................... 78 
9.1.3 
Medical History ..................................................................................... 79 
9.1.4 
Pregnancy Testing ................................................................................. 79 
9.2 
Safety Assessments ................................................................................................. 79 
9.2.1 
Physical Examination ............................................................................ 79 
9.2.2 
Electrocardiograms ............................................................................... 80 
9.2.3 
Vital Signs ............................................................................................. 80 
9.2.4 
Weight ................................................................................................... 80 
9.2.5 
ECOG Performance Status .................................................................... 80 
9.2.6 
Clinical Laboratory Tests ...................................................................... 81 
9.2.7 
Adverse Events ...................................................................................... 83 
9.3 
Efficacy Assessments .............................................................................................. 83 
9.3.1 
Tumor Measurements and Disease Response Assessment ................... 83 
9.4 
Protein Lysine Acetylation and Immune Correlates ............................................... 90 
9.4.1 
Blood ..................................................................................................... 90 
9.4.2 
Tumor Tissue ........................................................................................ 92 
9.5 
Pharmacokinetics .................................................................................................... 93 
9.5.1 
Entinostat............................................................................................... 93 
9.5.2 
Pembrolizumab ..................................................................................... 93 


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10. 
DISCONTINUATION AND REPLACEMENT OF PATIENTS ....................................... 95 
11. 
ADVERSE EVENTS, DATA REPORTING, AND RECORDING .................................... 96 
11.1 
Study Drugs ............................................................................................................. 96 
11.1.1 
Entinostat............................................................................................... 96 
11.1.2 
Pembrolizumab ..................................................................................... 96 
11.2 
Adverse Event Definitions ...................................................................................... 96 
11.2.1 
Adverse Events ...................................................................................... 96 
11.2.2 
Suspected Adverse Reaction ................................................................. 97 
11.2.3 
Unexpected Adverse Event ................................................................... 97 
11.2.4 
Serious Adverse Events ......................................................................... 98 
11.3 
Reporting Procedures for All Adverse Events ........................................................ 98 
11.4 
Serious Adverse Event Reporting Procedures ...................................................... 100 
11.4.1 
Pregnancy and Lactation Reporting Procedures ................................. 101 
11.4.2 
Definition of an Overdose for This Protocol and Reporting of 
Overdose to the Sponsor ..................................................................... 101 
11.4.3 
Events of Clinical Interest with Pembrolizumab ................................. 102 
11.4.4 
Follow-Up of Adverse Events ............................................................. 102 
11.4.5 
Safety Reporting to Health Authorities, Ethics 
Committees/Institutional Review Boards and Investigators ............... 102 
11.4.6 
Protocol Deviations Due to an Emergency or Adverse Event ............ 103 
11.5 
Safety Monitoring ................................................................................................. 103 
12. 
STATISTICAL CONSIDERATIONS ............................................................................... 104 
12.1 
Sample Size Estimation ......................................................................................... 104 
12.1.1 
Escalation Phase .................................................................................. 104 
12.1.2 
Expansion Phase .................................................................................. 104 
12.2 
Populations for Analysis ....................................................................................... 107 
12.3 
Analysis Schedule ................................................................................................. 107 
12.3.1 
Safety Monitoring ............................................................................... 107 
12.3.2 
Efficacy Monitoring ............................................................................ 108 
12.4 
Statistical Methods ................................................................................................ 108 
12.4.1 
Disposition of Patients ........................................................................ 108 
12.4.2 
Demographics and Baseline Characteristics ....................................... 109 
12.4.3 
Extent of Exposure .............................................................................. 109 
12.4.4 
Concomitant Medications ................................................................... 109 
12.4.5 
Efficacy Analysis ................................................................................ 109 
12.4.6 
Immune Correlate Analyses ................................................................ 110 
12.4.7 
Safety Analysis .................................................................................... 110 
12.4.8 
Pharmacokinetic, Exposure-Safety, and Anti-pembrolizumab 
Antibody Analyses .............................................................................. 112 


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12.5 
Procedures for Reporting Deviations to the Original Statistical Analysis Plan .... 112 
13. 
INVESTIGATIONAL DRUG PRODUCT ........................................................................ 113 
13.1 
Entinostat .............................................................................................................. 113 
13.1.1 
Description .......................................................................................... 113 
13.1.2 
Formulation ......................................................................................... 113 
13.1.3 
Storage and Packaging ........................................................................ 113 
13.2 
Pembrolizumab ..................................................................................................... 113 
13.3 
Accountability ....................................................................................................... 114 
14. 
REGULATORY OBLIGATIONS ..................................................................................... 115 
14.1 
Informed Consent .................................................................................................. 115 
14.2 
Institutional Review Board (IRB)/Ethics Committee (EC) ................................... 115 
14.3 
Pre-study Documentation Requirements ............................................................... 116 
14.4 
Patient Confidentiality .......................................................................................... 116 
15. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS ...................................................... 117 
15.1 
Protocol Amendments and Study Termination ..................................................... 117 
15.2 
Study Documentation and Archive ....................................................................... 117 
15.3 
Study Monitoring and Data Collection ................................................................. 118 
16. 
REFERENCES .................................................................................................................. 119 
17. 
APPENDICES ................................................................................................................... 124 
 


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LIST OF TABLES 
Table 1-1 
Schedule of Study Assessments ....................................................................15 
Table 1-2 
Schedule of Study Assessments:  EMIC Cohort .............................................18 
Table 8-1 
Study Treatment ..........................................................................................59 
Table 8-2 
Non-hematologic Toxicity:  Dose Modification for Entinostat .........................64 
Table 8-3 
Hematologic Toxicity:  Dose Modification for Entinostat ................................65 
Table 8-4 
Pembrolizumab Dose Modification and Toxicity Management Guidelines for 
Immune-Related Adverse Events ..................................................................66 
Table 8-5 
Pembrolizumab Infusion Reaction Dose Modification and Treatment Guidelines70 
Table 9-1 
Eastern Cooperative Oncology Group Performance Status Scale, with Equivalent 
Karnofsky Performance Status Scores ...........................................................81 
Table 9-2 
Imaging and Treatment After 1st Radiologic Evidence of PD ..........................88 
Table 11-1 
Standard Severity Grading Scale .................................................................100 
Table 17-1 
Examples of substrates that may be affected by entinostat .............................125 
Table 17-2 
P-gp Inhibitors and Inducers .......................................................................125 
Table 17-3 
Gastric Acid Reducing Drugsa ....................................................................126 
LIST OF FIGURES 
Figure 5-1 
Study Schema .............................................................................................45 
Figure 9-1: Imaging and Treatment for Clinically Stable Participants Treated with 
Pembrolizumab after First Radiologic Evidence of PD Assessed by the 
Investigator.................................................................................................89 
 


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2. 
OBJECTIVES 
2.1 
Primary 
The primary study objectives are: 
Phase 1b (Dose Escalation/Confirmation Cohorts):  To determine the dose-limiting toxicities (DLT) 
and maximum tolerated dose (MTD) or recommended Phase 2 dose (RP2D) of entinostat (SNDX-275) 
given in combination with pembrolizumab. 
Phase 2 (Expansion Cohorts):  To evaluate the preliminary efficacy of entinostat at the RP2D in 
combination with pembrolizumab in patients with melanoma, non-small cell lung cancer (NSCLC), and 
mismatch repair-proficient colorectal cancer (CRC), as determined by overall response rate (ORR), per 
the Immune-related Response Evaluation Criteria in Solid Tumors (irRECIST) in each cohort evaluated. 
2.2 
Secondary 
Secondary study objectives are: 
Efficacy:  To evaluate the efficacy of entinostat in combination with pembrolizumab in patients with 
melanoma NSCLC, and mismatch repair-proficient colorectal cancer as determined by secondary 
measures of efficacy per the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) and 
Immune-related Response Evaluation Criteria in Solid Tumors (irRECIST) including: 
• 
Clinical benefit rate (CBR) (complete response [CR]+partial response [PR]+stable disease [SD]) 
at 6 months 
• 
Progression-free survival (PFS) status at 6 months 
• 
PFS 
• 
Overall survival (OS) 
In patients who experience a response to treatment (i.e., CR or PR): 
• 
Duration of response (DOR) 
• 
Time to response (TTR) 
Safety:  To evaluate safety and the tolerability of entinostat in combination with pembrolizumab, as 
measured by clinical adverse events (AEs) and laboratory parameters. 


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2.3 
Exploratory 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 


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3. 
ENDPOINTS 
3.1 
Efficacy 
The primary efficacy endpoint is: 
• 
ORR, as determined by irRECIST 
Secondary Endpoints: (analyzed in the same populations as the primary endpoint) are: 
• 
CBR (i.e., CR+PR+SD at 6 months) 
• 
PFS status at 6 months 
• 
PFS 
• 
OS 
In patients who experience a response to treatment (i.e., CR or PR): 
• 
DOR 
• 
TTR 
An analysis of efficacy endpoints will be performed with response determined using RECIST, version 1.1 
as well as irRECIST. 
3.2 
Safety 
Safety endpoints are: 
• 
Incidence, severity and duration of treatment-emergent AEs, SAEs, AEs resulting in the 
permanent discontinuation of study drug, and deaths occurring within 90-days of last dose of 
study drug 
• 
Changes from baseline in laboratory, vital signs, and ECG results  
3.3 
Exploratory 
 
 
 
 
 
 


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4. 
BACKGROUND AND RATIONALE 
Despite recent advances in therapy, metastatic NSCLC, melanoma, and CRC represent oncologic 
indications with a significant unmet medical need, with affected patients having a poor prognosis. 
Lung cancer is the leading cause of cancer death in the United States (US) (SEER 2014). The National 
Cancer Institute (NCI) Surveillance, Epidemiology, and End Results (SEER) Program estimate for the 
number of new lung cancer cases in 2014 was approximately 224,210, with 159,260 deaths due to the 
disease that year (SEER 2014). The prognosis for patients with metastatic lung cancer is poor, with a low 
5-year survival rate of 4% (Howlader 2014). NSCLC constitutes approximately 80% of all lung cancers, 
and it is estimated that 40% of patients with NSCLC present with metastatic disease. Cytotoxic 
chemotherapy and tyrosine kinase inhibitors have been shown to improve survival and quality of life in 
patients with metastatic NSCLC; however, OS remains poor and more effective therapies are urgently 
needed.  
Cutaneous melanoma, arising from malignant transformation of melanocytes in the skin, is the most 
aggressive form of skin cancer. In contrast to other types of cancer, the incidence of melanoma has 
increased over the past several decades, with the incidence doubling every 10 years. The NCI, SEER 
Program, estimate for the number of new melanoma cases in 2014 was 76,100, representing 4.6% of all 
new cancer cases, with an estimated 9,710 deaths due to the disease that year (SEER 2014). Overall, the 
5-year survival rate for melanoma, regardless of disease stage, is high (91%); however, for patients who 
present with metastatic disease and receive systemic treatment, the 5-year survival rate is considerably 
lower at 16% (SEER 2014).  
Melanoma is considered to be one of the most immunogenic tumor types, due to the presence of tumor 
infiltrating lymphocytes in resected melanoma, occasional spontaneous regressions, and clinical responses 
to immune stimulation (Finn 2012). Although historically not considered to be an immunoresponsive 
tumor type, nonclinical and clinical evidence now supports the investigation of immunologic approaches 
for the treatment of NSCLC (Harvey 2014). 
CRC is the second leading cause of cancer death in the United States with greater than 40,000 deaths each 
year. Median survival at the time of diagnosis has been extended with recent advances to approximately 
30 months, but longterm survival remains dismal with 5-year overall survival at <10%. Immune 
checkpoint inhibitors have shown dramatic effect in a subset of patients with mismatch repair-deficient 
tumors (Le 2015), but this represents 3-5% of advanced CRC. In the remaining patients, immune 


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checkpoint inhibitors have been completely unsuccessful. Accordingly, there is great interest in 
combining immune checkpoint inhibitors with other classes of agents to induce immunosensitivity. Kim 
et al. demonstated entinostat therapy of immunocompetent CRC models resulting in sensitivity to 
immune checkpoint inhibition and commesurate decrease in MDSCs. 
Several regulatory mechanisms in the immune system that are exploited by cancer have been identified, 
including regulatory T cells, MDSCs, tumor-associated macrophages and neutrophils, immune checkpoint 
pathways, and immunosuppressive cytokines (Kim 2014). Recent clinical studies with immune 
checkpoint inhibitory PD-1, PD-L1, and anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) 
antibodies have demonstrated highly promising responses in a number of tumor types, including both 
NSCLC and melanoma (Harvey 2014). Expression of the PD-1 ligand PD-L1 has been detected in lung, 
ovary, renal, and colon carcinomas and in malignant melanoma, but not in normal tissues, including the 
lung, uterus, kidney, colon, or skin (Harvey 2014). Abnormal expression of PD-L1 has been reported in 
19% up to 100% of NSCLC tumors, with the variation in results dependent on the antibody, histology, 
and technique reported (Creelan 2014). 
A number of immune checkpoint inhibitors are under clinical development for the treatment of solid 
tumors (Harvey 2014). Pembrolizumab (Keytruda®), a human monoclonal antibody against the PD-1 
protein, represents the first anti-PD-1 therapy to receive regulatory approval in the US (Poole 2014). 
Pembrolizumab is indicated for the treatment of advanced (unresectable or metastatic)  melanoma in 
adults. Pembrolizumab is also indicated for the treatment of patients with metastatic NSCLC whose 
tumors express PD-L1 as determined by an FDA-approved test and who have disease progression on or 
after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should 
have disease progression on FDA-approved therapy for these aberrations prior to receiving Keytruda®. 
(Refer to Section 4.1.2 for detailed information regarding pembrolizumab.) 
Nivolumab is another checkpoint inhibitor that targets PD-1. It is approved for the treatment of 
unresectable or metastatic melanoma in patients who experience disease progression following 
ipilimumab, and if BRAF V600 mutation positive, a BRAF inhibitor; and the treatment of metastatic 
squamous NSCLC in patients who experience disease progression after platinum-based chemotherapy.  
In addition to pembrolizumab and nivolumab, there are other investigational immune checkpoint 
inhibitors targeting PD-1 or PD-L1, including MPDL3280A and MEDI-4736, which have also 
demonstrated efficacy in clinical studies in NSCLC. In particular, the anti-PD-1/PD-L1 therapies 
administered as single agent therapy in chemotherapy refractory patients have produced ORRs ranging 


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from 15 to 25%, the majority of which were rapid and ongoing 1 year after starting therapy (American 
Association for Cancer Research 2014). 
Despite these encouraging findings, there is room for improvement in the ORR, particularly the CR rate, 
with the majority of patients with metastatic melanoma, NCSLC, and CRC, populations of patients with a 
poor prognosis, remaining unresponsive to treatment with anti-PD-1/PD-L1 therapies.  
Combination approaches with anti-PD-1/PD-L1 therapies and cytotoxic chemotherapy, anti-angiogenic 
agents, alternative immune-checkpoint inhibitors, immunostimulatory cytokines, and cancer vaccines, are 
currently under investigation, with the goal of improving efficacy over that seen with monotherapy 
(Philips 2015).  
4.1 
Study Treatment 
4.1.1 
Entinostat (SNDX-275) 
SNDX-275, an orally available synthetic pyridylcarbamate licensed from Bayer Schering AG by Syndax 
Pharmaceuticals and previously named MS-275, inhibits histone deacetylases (HDACs). SNDX-275 
promotes hyperacetylation of nucleosomal histones, allowing transcriptional activation of a distinct set of 
genes. This ultimately leads to the inhibition of cell proliferation, induction of terminal differentiation, 
and/or apoptosis (Hess-Stumpp 2007). 
Deoxyribonucleic acid (DNA) within the cell nucleus combines with a class of proteins called histones to 
form chromatin. Histones have amino terminal groups that are positively charged and are hypo-acetylated 
by HDACs. The positive charge tightly binds the histones to the negatively charged DNA phosphodiester 
backbone. Gene transcription and expression are inhibited by such a condensed conformation of the 
DNA. Histone acetyltransferases acetylate the amino terminal ends and neutralize their positive charges, 
thus leading to a more open chromatin conformation, facilitating DNA transcription.  
Altered activity of HDACs and inactivation of histone acetyltransferases within transformed cells are key 
events that affect chromatin remodeling. There is evidence that HDACs are associated with a wide range 
of tumors including melanomas, neuroblastomas, lymphomas, and lung, breast, prostate, ovarian, bladder, 
and colon cancers. In a number of in vitro models, HDAC inhibitors triggered growth arrest and induced 
cell differentiation or apoptosis. In acute promyelocytic leukemia, recruitment of HDACs by aberrant 
fusion proteins repressed constitutive gene transcription and thus prevented promyelocytic differentiation.  
Entinostat inhibited HDAC in various tumor cell lines. In particular, entinostat induced accumulation of 
acetylated histones adjacent to the promoter of the transforming growth factor (TGF)-β type II receptor 


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gene, with resulting gene expression. Mutations affecting the TGF-β signaling pathway have been 
associated with development and progression of human malignancies, including carcinomas of the lung, 
breast, prostate, and colon. Entinostat also induced histone hyperacetylation and induced expression of 
various tumor suppressor genes. Various in vitro studies in a range of human cancer cell lines have 
demonstrated the antiproliferative activity of entinostat. In vivo, entinostat inhibited the growth of a range 
of human tumor xenografts, including models of lung, prostate, breast, pancreatic, renal cell, and 
glioblastoma.  
More recently, entinostat has been shown to modify the phenotype of cancer cells from a mesenchymal to 
an epithelial one, with impact on reducing the metastatic potential of the cancer cells (Shah 2014). In 
addition, there is a suggestion that entinostat may have longer term effects on cancer phenotypes, cancer 
stem cells (CSCs) or progenitor cell pool and potential sensitization to subsequent post-study treatments 
(Juergens 2011). 
4.1.1.1 
Entinostat in Patients with Solid Tumors, including Lung Cancer and Melanoma 
To date, entinostat has been investigated alone or in combination in >1055 patients with cancer in clinical 
studies, including >600 patients with solid tumors, including NSCLC and melanoma.  
Entinostat has been investigated specifically in patients with NSCLC in combination with erlotinib in 
clinical studies sponsored by Syndax and in combination with 5-azacitadine (AZA) in clinical studies 
sponsored by the NCI. Of the studies of entinostat in combination with AZA, evidence of the anti-tumor 
activity of this combination was demonstrated in an initial study (Juergens 2011), in which adults with 
metastatic NSCLC who experienced disease progression after at least 1 anticancer regimen received 7 mg 
of entinostat by mouth (PO) on Days 3 and 10 and 30 or 40 mg/m2/day of AZA subcutaneously (SC) on 
Days 1-6 and 8-10 of a 28-day cycle. Of 31 evaluable patients, 1 experienced a CR, with a duration of 14 
months; a second patient experienced a PR, with a duration of 8 months; and 10 patients experienced 
stable disease for at least 12 weeks. Furthermore, 4 patients had major objective responses to the 
immediate subsequent therapy. Based on these encouraging findings, the NCI has initiated a follow-up 
study utilizing this combination regimen to investigate the premise that epigenetic therapy can augment 
the clinical utility of cytotoxic therapy in patients with advanced disease.  
Evidence of the efficacy of entinostat also was seen in patients with Stage IV nonresectable melanoma, 
with 25% of patients experiencing disease stabilization (Hauschild 2008). Based on these encouraging 
findings, further investigation of entinostat in combination was considered warranted in patients with 
melanoma.  


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Overall, among all patients treated, entinostat has been well tolerated at the doses and schedules 
investigated. Regardless of indication and regimen, the most frequently reported AEs with entinostat 
included gastrointestinal (GI) disturbances, primarily nausea with or without vomiting and diarrhea; 
fatigue; and hematologic abnormalities, primarily anemia, thrombocytopenia, neutropenia, and 
leukopenia. Most occurrences of these events are Grade 1 or 2 in severity and non-serious. Grade 3 and 4 
hematologic abnormalities are commonly seen in patients with hematologic malignancies, but are much 
less prevalent in patients with solid tumors.  
As would be expected, the AE profile of entinostat when given in combination varies somewhat based on 
the agent with which it is given and the corresponding patient population. Entinostat in combination with 
AZA was generally associated with an increased number and rate of AEs relative to its use in 
combination with an aromatase inhibitor, erlotinib, or other agents. Consistent with the overall AE profile 
of entinostat, nausea with or without vomiting, fatigue, and anemia were the most prevalent AEs 
regardless of the patient population or the agent given in combination. 
Additional information on the chemistry, pharmacology, toxicology, preclinical findings, and clinical 
experience to date may be found in the Investigator’s Brochure (IB). 
4.1.2 
Pembrolizumab (MK-3475) 
4.1.2.1 
Background 
Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody (mAb) with high 
specificity of binding to the PD-1 receptor, thus inhibiting its interaction with PD-L1 and programmed 
cell death ligand 2 (PD-L2). Based on preclinical in vitro data, pembrolizumab has high affinity and 
potent receptor blocking activity for PD 1. Pembrolizumab has an acceptable preclinical safety profile and 
is in clinical development as an intravenous (IV) immunotherapy for advanced malignancies. Keytruda® 
(pembrolizumab) is indicated for the treatment of patients across a number of indications.  
For more details on specific indications refer to the Investigator’s Brochure (IB). 
4.1.2.2 
Pharmaceutical and Therapeutic Background 
The importance of intact immune surveillance function in controlling outgrowth of neoplastic 
transformation has been known for decades (Disis 2010). Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and prognosis in various malignancies. In 
particular, the presence of CD8+ T cells and the ratio of CD8+ effector T cells/forkhead box P3 (FoxP3)+ 
regulatory T cells seem to correlate with improved prognosis and long-term survival in solid malignancies 


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such as ovarian, colorectal, and pancreatic cancer; hepatocellular carcinoma; malignant melanoma; and 
renal cell carcinoma. Tumor-infiltrating lymphocytes can be expanded ex vivo and reinfused, inducing 
durable objective tumor responses in cancers such as melanoma (Dudley 2005; Hunder et al., 2008). 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress immune control. 
The normal function of PD-1, expressed on the cell surface of activated T cells under healthy conditions, 
is to down-modulate unwanted or excessive immune responses, including autoimmune reactions. PD-1 
(encoded by the gene Pdcd1) is an immunoglobulin (Ig) superfamily member related to cluster of 
differentiation 28 and CTLA-4, that has been shown to negatively regulate antigen receptor signaling 
upon engagement of its ligands (PD-L1 and/or PD-L2) (Greenwald 2005; Okazaki 2001).  
 The structure of murine PD-1 has been resolved (Zhang 2004). PD-1 and its family members are type I 
transmembrane glycoproteins containing an Ig-variable–type domain responsible for ligand binding and a 
cytoplasmic tail responsible for the binding of signaling molecules. The cytoplasmic tail of PD-1 contains 
2 tyrosine-based signaling motifs, an immunoreceptor tyrosine-based inhibition motif (ITIM) and an 
immunoreceptor tyrosine-based switch motif (ITSM). Following T cell stimulation, PD-1 recruits the 
tyrosine phosphatases SHP-1 and SHP-2 to the ITSM motif within its cytoplasmic tail, leading to the 
dephosphorylation of effector molecules, such as CD3 zeta, protein kinase C-theta, and zeta chain-
associated protein kinase, which are involved in the CD3 T cell signaling cascade (Okazaki 2001; 
Chemnitz 2004; Riley 2009; Sheppard 2004). The mechanism by which PD-1 down-modulates T cell 
responses is similar to, but distinct from that of CTLA-4 because both molecules regulate an overlapping 
set of signaling proteins (Parry 2005; Francisco 2010). As a consequence, the PD-1/PD-L1 pathway is an 
attractive target for therapeutic intervention in NSCLC, melanoma, and colorectal cancer. 
4.1.2.3 
Preclinical Studies 
Therapeutic studies in mouse models have shown that administration of antibodies blocking PD-1/PD-L1 
interaction enhances infiltration of tumor-specific CD8+ T cells and ultimately leads to tumor rejection, 
either as a monotherapy or in combination with other treatment modalities (Hirano 2005; Blank 2004; 
Weber 2010; Strome 2003; Spranger 2014; Curran 2010; Pilon-Thomas 2010). Anti-mouse PD-1 or anti-
mouse PD-L1 antibodies have demonstrated antitumor responses in models of squamous cell carcinoma, 
pancreatic carcinoma, melanoma, acute myeloid leukemia and colorectal carcinoma (Strome 2003; 
Curran 2010; Pilon-Thomas 2010; Nomi 2007; Zhang 2009). In such studies, tumor infiltration by CD8+ 
T cells and increased interferon-gamma (IFN-γ), granzyme B, and perforin expression were observed, 
indicating that the mechanism underlying the antitumor activity of PD-1 checkpoint inhibition involved 


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local infiltration and activation of effector T cell function in vivo (Curran 2010). Experiments have 
confirmed the in vivo efficacy of anti-mouse PD-1 antibody as a monotherapy, as well as in combination 
with chemotherapy, in syngeneic mouse tumor models (see the current pembrolizumab IB). 
4.2 
Study Rationale 
CT26 and 4T1 are syngeneic murine tumor models commonly used for the assessment of novel 
therapeutic approaches. The CT26 colon cancer model is considered to be modestly immunogenic 
whereas the 4T1 model is poorly immunogenic and highly metastatic. A nonclinical study assessed the 
effects of immune checkpoint inhibitors alone and combined with other agents in BALB/c mice bearing 
CT26 and 4T1 tumors (Kim 2014). In the CT26 model, treatment with immune checkpoint-blocking 
antibodies, either anti-CTLA-4 or anti-PD-1, resulted in retardation of tumor growth but not tumor 
eradication. Furthermore, treatment with either antibody resulted in tumor eradication in the vast majority 
of mice with moderately-sized tumors (~400 mm3), but not with tumors >600 mm3. In BALB/c mice 
bearing 4T1 tumors, limited response was seen to treatment with either anti-PD-1 or anti-CTLA-4 
antibodies. 
It was hypothesized that the tumors in animals that did not respond to treatment might have down-
regulated the expression of major histocompatibility complex-I-related genes through epigenetic silencing 
in tumor cells. To evaluate this possibility, animals bearing large CT26 tumors were treated with 
entinostat+AZA. Eradication of primary tumors was seen in 10 of 11 mice, with a 100% survival rate at 
60 days after tumor implantation. Similarly, treatment of mice with moderately-sized 4T1 tumors with 
anti-PD-1/anti-CTLA-4+entinostat+AZA resulted in complete regression of all primary tumors 3 weeks 
after treatment initiation and a 80% survival rate at 100 days after tumor implantation. Temporary, self-
limiting toxicity, as indicated by body weight changes, was observed in animals exposed to entinostat. 
Functional studies revealed that the primary targets of epigenetic modulation were MDSCs, which are 
often elevated in tumor-bearing hosts and have potent immunosuppressive activities. Specifically, 
treatment of granulocytic MDSCs (G-MDSCs) with entinostat in vitro resulted in markedly reduced 
viability in a dose-dependent fashion. In contrast, AZA had no effect at comparable concentrations. 
Importantly, entinostat had only modest effects on CD8+
 T cells, creating a large therapeutic window in 
which G-MDSCs can be depleted while sparing CD8+ T cells. 
When co-cultured with CD8+ T cells, G-MDSCs inhibited IFN-γ secretion. However, when entinostat was 
included in the culture medium, entinostat reverted this inhibition in a dose-dependent manner. These data 


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support the premise that G-MDSCs directly inhibit the function of CD8+ T cells and that entinostat 
alleviates this inhibition by directly suppressing G-MDSCs. 
In consideration of these nonclinical findings showing that entinostat reduced the number and inhibited 
the function of host immune suppressor cells, thereby enhancing the anti-tumor activity of immune 
checkpoint blockade, it is hypothesized that entinostat combined with a PD-1/PD-L1-blocking antibody 
(i.e., pembrolizumab) will result in an improved response rate for the combination compared to either 
agent alone.  
4.3 
Rationale for the Dose Selection 
4.3.1 
Entinostat 
Entinostat has been evaluated in vitro, in nonclinical in vivo studies, and in Phase 1 and 2 studies in 
patients with various solid tumors and hematological malignancies at doses between 2 and 12 mg/mP2
P and 
at dosing frequencies ranging from once daily to every 2 weeks. Increased histone acetylation was 
observed at the lowest dose evaluated with the effect persisting at least 48 hours post-dose. 
Pharmacokinetic (PK) studies of entinostat have indicated a long half-life of entinostat, ranging from 40 
hours to 120 hours. Consistent with this long half-life, entinostat concentrations were detectable 168 
hours post-dose at doses of 2 to 12 mg/mP2
P.  
The MTD for single agent entinostat in non-hematologic indications was established as 4 mg/mP2
P weekly 
x 3 and 1 week rest, or 10 mg/mP2
P every other week continuously.  
PK analyses have demonstrated ~40% variability in the clearance of entinostat. However, when clearance 
was adjusted for body surface area (BSA), the inter-patient variability was similar. A linear regression 
analysis on factors that may contribute to this variability, such as ideal body weight, lean body mass, 
body weight, and body mass index, were not significant covariates. As a result of this analysis, fixed 
dosing is considered to be as accurate as dosing based on BSA (Alao 2004).  
Entinostat given once weekly continuously at a dose of 5 mg (in combination with the aromatase inhibitor 
exemestane) in a clinical study in patients with locally advanced or metastatic breast cancer and given 
every other week continuously at a dose of 10 mg (in combination with erlotinib) in patients with stage 
IIIB/IV NSCLC was well tolerated. Entinostat’s AE profile at these dose schedules was consistent with 
previous clinical experience, with the most common AEs being fatigue and gastrointestinal disturbances, 
(nausea, vomiting, and diarrhea). 


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Based on the clinical experience with entinostat, a low, fixed dose of 3 mg given weekly has been 
selected as the starting dose for this study, with escalation to 5 mg weekly planned.  
4.3.2 
Pembrolizumab 
The dose of pembrolizumab planned to be studied in this trial is 200mg Q3W. The dose recently approved 
in the United States and several other countries for treatment of melanoma and NSCLC patients is 2mg/kg 
Q3W. Information on the rationale for selecting 200mg Q3W is summarized below. 
 KEYNOTE-001was Phase I study conducted to evaluate the safety, tolerability, pharmacokinetics (PK) 
and pharmacodynamics (PD), and anti-tumor activity of pembrolizumab when administered as 
monotherapy. The dose escalation portion of this trial evaluated three dose levels, 1mg/kg, 3mg/kg and 
10mg/kg, administered every 2 weeks (Q2W) and dose expansion cohorts evaluated 2mg/kg Q3W and 
10mg/kg Q3W in patients with advanced solid tumors. All dose levels were well tolerated and no dose-
limiting toxicities were observed. This first-in-human study of pembrolizumab showed evidence of target 
engagement and objective evidence of tumor size reduction at all dose levels. No maximum tolerated dose 
(MTD) has been identified. In addition, two randomized cohort evaluations of melanoma patients 
receiving pembrolizumab at a dose of 2mg/kg versus 10mg/kg every 3 weeks (Q3W) have been 
completed, and one randomized cohort evaluating 10 mg/kg Q3W versus 10mg/kg every 2 weeks (Q2W) 
has also been completed. The clinical efficacy and safety data demonstrate a lack of important differences 
in efficacy or safety profile across doses.  
An integrated body of evidence suggests that 200mg every 3 weeks (Q3W) is expected to provide similar 
responses to 2mg/kg Q3W, 10mg/kg Q3W, and 10mg/kg Q2W. Previously, a flat pembrolizumab 
exposure-response relationship for efficacy and safety has been found in patients with melanoma in the 
range of doses between 2mg/kg and 10mg/kg. Exposures for 200mg Q3W are expected to lie within this 
range and will be close to those obtained with 2mg/kg Q3W dose.  
A population pharmacokinetic (PK) model, which characterized the influence of body weight and other 
patient covariates on exposure, has been developed. The PK profile of pembrolizumab is consistent with 
that of other humanized monoclonal antibodies, which typically have a low clearance and a limited 
volume of distribution. The distribution of exposures from the 200mg fixed dose are predicted to 
considerably overlap those obtained with the 2mg/kg dose and importantly will maintain individual 
patient exposures within the exposure range established in melanoma as associated with maximal clinical 
response. Pharmacokinetic properties of pembrolizumab, and specifically the weight-dependency in 


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clearance and volume of distribution are consistent with no meaningful advantage to weight-based dosing 
relative to fixed dosing.   
In translating to other tumor indications, similarly flat exposure-response relationships for efficacy and 
safety as observed in subjects with melanoma can be expected, as the anti-tumor effect of pembrolizumab 
is driven through immune system activation rather than through a direct interaction with tumor cells, 
rendering it independent of the specific tumor type. In addition, available PK results in subjects with 
melanoma, NSCLC, and other tumor types support a lack of meaningful difference in pharmacokinetic 
exposures obtained at tested doses among tumor types. Thus the 200mg Q3W fixed-dose regimen is 
considered an appropriate fixed dose for other tumor indications as well.  
A fixed dose regimen will simplify the dosing regimen to be more convenient for physicians and to 
reduce potential for dosing errors. A fixed dosing scheme will also reduce complexity in the logistical 
chain at treatment facilities and reduce wastage. The existing data suggest 200mg Q3W as the appropriate 
dose for pembrolizumab. 
4.4 
Hypothesis 
Entinostat has been shown in preclinical models to reduce the number and inhibit the function of host 
immune suppressor cells in order to enhance the anti-tumor activity of immune checkpoint blockade. It is 
hypothesized that entinostat combined with pembrolizumab will result in an improved response rate for 
the combination compared to either agent alone. Preclinical study data suggest that entinostat specifically 
targets MDSC and thus would improve the response to PD-1/PD-L1-blocking antibody (i.e., 
pembrolizumab) treatment. The Sponsor accordingly proposes to evaluate populations of MDSC and 
other myeloid cells in peripheral blood and tumor tissues as well as basic T-cell function in patients, with 
the expectation that if the MDSC level is decreased, the response to antigens would be improved.  


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5. 
EXPERIMENTAL PLAN 
5.1 
Study Design 
Study SNDX-275-0601 is an open-label, Phase 1b/2 study evaluating the combination of entinostat plus 
pembrolizumab in patients with advanced metastatic or recurrent NSCLC, CRC, or melanoma. The study 
has 2 phases, a Dose Escalation/Confirmation Phase (Phase 1b) and an Expansion Phase (Phase 2), with 
the Expansion Phase utilizing a Simon 2-stage design (Simon 1989) for cohorts 1 and 4, and utilizing a 
single proportion binomial test for cohorts 2 and 3An additional cohort (Entinostat Monotherapy Immune 
Correlate Cohort (EMIC)) evaluating single agent entinostat followed by the combination in patients with 
NSCLC will also be evaluated in the Phase 2 Expansion Phase. The study schema is presented in Figure 
5-1. 
Figure 5-1 
Study Schema 
 
Regardless of phase, patients will be screened for study eligibility within 21 days before enrollment into 
the study. Patients who are determined to be eligible based on screening assessments, will be enrolled in 
the study within 3 days of starting study treatment on Cycle 1, Day 1 (C1D1) and will receive entinostat 
in combination with pembrolizumab.  


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A total of 15 patients will be enrolled in an EMIC Cohort. EMIC patients will be enrolled in the study 
within 3 days of starting of starting entinostat on Day -14 and will participate in a 2-week entinostat 
monotherapy period. The purpose of this 14-day lead-in phase is to obtain pre-and post-entinostat 
monotherapy correlative data in blood and tissue. After completion of the 2-week entinostat monotherapy 
period, patients in the EMIC Cohort will start entinostat in combination with pembrolizumab on C1D1. 
Patients in the EMIC Cohort will receive entinostat beginning at 5mg weekly for the monotherapy period, 
and then will receive entinostat in combination with pembrolizumab at the RP2D as identified in the 
Phase 1b Dose Escalation/Confirmation portion of the study. 
A cycle is 21 days in length. During treatment, patients will attend study center visits and have study 
evaluations performed on C1D1, C1D8, and C1D15; D1 and D15 of C2; and on D1 of each cycle 
thereafter. 
Fresh tumor tissue samples will be collected during the study as follows: 
• 
During screening from all patients on a mandatory basis. 
• 
On C2D15 (+3 days) on an optional basis from patients in the Dose Escalation/Confirmation 
Phase. All patients in the Dose Escalation/Confirmation Phase will be strongly encouraged to 
provide an optional biopsy in order to help understand dose-immune correlate effects. 
• 
On C2D15 (+3 days) on a mandatory basis from the first 10 patients (in total, across cohorts) 
in Stage 1 in the Expansion Phase, the first 10 patients in the EMIC Cohort, and the first 10 
patients in the CRC Cohort.  
If, based on an interim review of tumor tissue data from at least the initial in the Expansion Phase, such 
data are not considered informative, then tumor tissue samples will not be collected from subsequent 
patients on C2D15 (+3 days). Alternatively, if such data are considered informative, tumor tissue samples 
will be collected on C2D15 (+3 days) from all subsequent study patients in the Expansion Phase. 
Blood for immune correlates is to be collected from patients in the EMIC Cohort pre-dose on D-14, 
C1D1, C1D8, and C2D15. In all other cohorts, blood for immune correlates is to be collected pre-dose on 
C1D1, C2D1, and C2D15. Blood for protein lysine acetylation and for entinostat and pembrolizumab PK 
assessments will be collected according to the Schedule of Events. Blood for immune correlates and 
protein lysine acetylation is to be shipped on the same day of draw to the applicable laboratories with 
proper advanced notification according to the study laboratory manual. 
Patients will have radiological disease assessments performed during screening and every 6 weeks (+/-3 
days) (Week 6, Week 12, etc.) during treatment. Disease will be assessed by computed tomography (CT), 


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magnetic resonance imaging (MRI), and bone scans, as appropriate, and response will be assessed by the 
Investigator using irRECIST.  
Safety will be assessed during the study by documentation of AEs, clinical laboratory tests, physical 
examination, vital sign measurements, ECGs, and Eastern Cooperative Oncology Group (ECOG) 
performance status. 
The maximum duration of treatment for this study is planned to be 2 years. If a patient permanently 
discontinues 1 of the 2 study drugs (either entinostat or pembrolizumab), the patient may continue to 
receive monotherapy for up to 2 years, unless alternate therapy is started or another discontinuation 
criterion is met (Section 10). 
After discontinuation of both study drugs, patients will complete an End of Treatment (EOT) visit within 
7 days after the last study drug dose and Safety Follow-up visits 30 days and 90 days thereafter. After 
completion of the 30-day Safety Follow-up (F/U) visit, patients who have not experienced progressive 
disease (PD) are to be followed every 2 months until PD and every 3 months thereafter until death or 
closure of the study by the Sponsor. 
Phase 1b (Dose Escalation/Confirmation):  The Dose Escalation/Confirmation Phase of the study, in 
which patients with NSCLC will be enrolled, employs a classical 3+3 design, with the determination of 
DLT and the MTD and/or RP2D based on entinostat in combination with pembrolizumab in C1.  
Although decisions regarding dose escalation will be made primarily based on review of data from C1, 
safety data will also be collected from all patients continuing treatment and these data will be reviewed in 
an ongoing manner by the Sponsor Study Physician(s) in consultation with the Investigators. Any 
detected cumulative toxicity may require later dose reductions and/or other changes to the dosing 
schedule, as appropriate, including further refinement of the RP2D. 
The initial 3-6 patients will receive entinostat at a starting dose of 3 mg on D1, D8, and D15 along with 
pembrolizumab 200 mg via intravenous (IV) infusion on D1 of a 21-day cycle. Assuming an acceptable 
safety profile, escalation to an entinostat dose of 5 mg weekly is planned, keeping the pembrolizumab 
dose constant. However, based on evaluation of the safety and tolerability data of the previous dose level, 
it may also be decided that accrual will take place at an intermediate dose level or alternate dosing 
schedule. 
Toxicities will be assessed by the Investigator using the US NCI Common Terminology Criteria for 
Adverse Events (CTCAE), Version 4.03. The decision regarding whether to proceed to the next dose level 


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will be made by the Sponsor Study Physicians, in consultation with the Investigators after the majority of 
safety assessments for each cohort are completed. Refer to Section 8.2.1.1 for details regarding the dose 
escalation procedures.  
The prospective MTD/RP2D identified in the Dose Escalation Phase will be confirmed in 9 patients in 
Dose Confirmation Cohort to obtain additional AE, immune correlate, and anti-tumor activity data on 
entinostat in combination.  
Six patients will need to be treated in a dose level for that dose to be considered for the Dose 
Confirmation stage. The recommended dose for Phase 2 investigation will be the higher of either 3 or 5 
mg weekly PO that results in less than a 33% incidence of DLT. The final determination of the RP2D will 
be based on a review of all data obtained from both the Dose Escalation and Confirmation Phases and will 
consider both acute and cumulative toxicities; the incidence of required dose delays, reductions, and 
discontinuations; and the overall facility of administration in clinical practice. 
Patients who experience a DLT will be allowed to remain on study if they meet the following criteria: (1) 
the Investigator believes it is appropriate for patients to remain on study; (2) the event has resolved and no 
longer meets the definition of DLT; and (3) the timeline for resolution falls within the guidelines for dose 
delays (Section 8.4).  
Patients who complete C1 may continue on study as long as, in the Investigator’s judgment, the patient is 
tolerating study treatment, is not at an increased safety risk, and continues to meet protocol eligibility 
criteria. 
After completion of the Dose Escalation/Confirmation Phase of the study, with identification of the MTD 
or RP2D, the Phase 2 portion of the study will commence. 
Phase 2 (Expansion): In the Expansion Phase, entinostat in combination will be evaluated using the 
RP2D identified in the Dose Escalation/Confirmation Phase. Up to 4 Expansion Cohorts consisting of 
distinct subsets of patients with solid tumor cancers may be explored. Each cohort evaluated during the 
Expansion Phase will employ a Simon 2-stage design. The final decision about which Expansion Cohorts 
to study will be based on data from the Dose Escalation/Confirmation Phase, emerging clinical data from 
other studies, and/or nonclinical data. Expansion cohorts may include: 
1. Cohort 1:  NSCLC, with squamous cell or adenocarcinoma histology who have not been treated 
with a PD-1 or PD-L1 blocking antibody1 


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1 Depending upon emerging data, the Sponsor may elect, instead of histology, to evaluate NSCLC consisting of 
PD-1+ and PD-L1+ NSCLC patients. In this case, the protocol will be amended accordingly. 
2. Cohort 2:  Patients with NSCLC (any histology) who have previously been treated with and 
unequivocally progressed on either a PD-1 or PD-L1-blocking antibody 
3. Cohort 3:  Patients with melanoma who have previously been treated with and unequivocally 
progressed on either a PD-1 or PD-L1-blocking antibody (i.e., pembrolizumab, nivolumab, 
MEDI4736, or GNE PDL1 [MPDL3280A]) 
4. Cohort 4: Patients with CRC (mismatch repair-proficient) who have not been previously treated 
with a PD-1 or PD-L1 blocking antibody 
5.2 
Number of Centers 
Up to approximately 40 study centers are planned to be recruited for participation in this study. Study 
centers that do not enroll at least 1 patient within 3 months of study center initiation may be subject to 
closure. 
5.3 
Number of Patients 
In the dose-escalation phase, 3 to 6 patients will be enrolled in each dose cohort based on a standard 
“3+3” Phase 1 dose escalation scheme. Each patient will participate in only 1 dose cohort. A total of 9 
additional patients will be enrolled in the Dose Confirmation Cohort to obtain additional AE, immune 
correlate, and anti-tumor activity data on entinostat at the MTD or other dose recommended for further 
investigation in Phase 2 (i.e., RP2D) in combination. 
Thus, the total number of patients to be enrolled in the Dose Escalation/Confirmation Phase is dependent 
upon the observed safety profile, which will determine the number of patients per dose cohort, as well as 
the number of dose escalations required to achieve the MTD. 
In the Expansion Phase, up to 252 patients are planned to be enrolled among the 4 Expansion Cohorts 
(Section 5.1). 
5.4 
Estimated Study Duration 
The estimated duration of the study is approximately 30 months.  


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6. 
PATIENT ELIGIBILITY 
6.1 
Inclusion Criteria 
Patients meeting all of the following criteria are considered eligible to participate in the study: 
Patients with NSCLC: 
1. Has histologically- or pathologically-confirmed recurrent or metastatic NSCLC. 
2. If has adenocarcinoma, required to have previously been tested for anaplastic lymphoma kinase 
(ALK) rearrangements and epidermal growth factor receptor (EGFR) (Exon 19 Deletion and 
Exon 21 L8585R Substitution) mutations, with results available for collection in this study, and, 
if positive, has been treated with prior EGFR or ALK therapy.  
3. Received at least 1 chemotherapeutic regimen in the advanced/metastatic setting and experienced 
documented, unequivocal progressive disease by either RECIST 1.1 or clinical assessment. In 
addition: 
• 
If patient has EGFR mutation-positive or ALK translation-positive disease, must have 
received an EGFR inhibitor or ALK inhibitor, respectively, in addition to the above 
chemotherapy regimen. 
• 
Patients who received adjuvant or neoadjuvant platinum-based doublet chemotherapy 
(after surgery and/or radiation therapy) and developed recurrent or metastatic disease 
within 6 months of completing therapy are eligible; in such cases, the adjuvant or 
neoadjuvant platinum-based doublet chemotherapy regimen will count as a line of 
therapy.  
• 
Patients with recurrent disease >6 months after adjuvant or neoadjuvant platinum-based 
doublet chemotherapy who subsequently experienced PD during or after a platinum-
based doublet chemotherapy regimen given to treat the recurrences, are eligible; the 
second platinum-based doublet chemotherapy regimen does not count as another line of 
therapy.  
• 
Patients who received pemetrexed, bevacizumab, or erlotinib as maintenance therapy 
(non-progressors with platinum-based doublet chemotherapy) and subsequently 
progressed after maintenance therapy) are eligible; such therapy does not count as a line 
of therapy. However, if the patient received a tyrosine kinase inhibitor (TKI) after failure 


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of platinum-based doublet chemotherapy, the TKI will count as an additional line of 
therapy. 
4. Patients with NSCLC enrolled in Cohort 1 of the Expansion Phase should not have been 
previously treated with a PD-1/PD-L1-blocking antibody (i.e. pembrolizumab, nivolumab, 
MEDI4736, or GNE PDL1 [MPDL320A] 
Patients in Expansion Phase, Cohorts 2 (NSCLC) and 3 (Melanoma) 
5. Previously treated with a PD-1/PD-L1-blocking antibody (i.e., pembrolizumab, nivolumab, 
MEDI4736, or GNE PDL1 [MPDL3280A]) and experienced documented, unequivocal 
radiographic progression of disease by irRECIST, or similar criteria during or within 12 weeks 
after last dose of such treatment. Patients must have received at least 6 weeks of PD-1/PD-L1 
therapy for Cohort 2 and at least 8 weeks of PD-1/PD-L1 therapy for Cohort 3. For patients who 
received such agents in a clinical trial, documentation of progressive disease requires a 
confirmatory scan. For patients who had been treated with such agents outside of a clinical trial, 
documentation of progressive disease will be based on both radiographic and clinical assessment. 
If the requirement for a confirmatory scan is deemed not to be in the patient’s best interests based 
upon his/her overall condition, including performance status and clinical symptoms, this 
requirement may be waived in consultation with the Sponsor’s Medical Monitor; however, 
patients who have not had a confirmatory scan because of rapid progression and clinical 
deterioration should not be enrolled onto this trial. In all cases, the scan obtained during the 
screening process may serve as the confirmatory scan. 
(Note: Patients who are currently receiving pembrolizumab and have clear, unequivocal evidence of 
PD may be eligible. Such patients are to be discussed with the Medical Monitor on a case-by-case 
basis prior to enrollment of the patient in the study.) 
Patients with Melanoma 
6. In addition to previous treatment with a PD-1/PD-L1 blocking antibody (inclusion #5), has a 
histologically- or cytologically-confirmed diagnosis of unresectable or metastatic melanoma and 
experienced unequivocal progressive disease during treatment with a BRAF inhibitor if BRAF 
V600 mutation-positive. Treatment with BRAF inhibitor may occur AFTER treatment with the 
checkpoint inhibitor.  


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Patients in Expansion Phase, Cohort 4 (Colorectal Cancer) 
7. Received at least 1 chemotherapeutic regimen in the advanced/metastatic setting and experienced 
documented, unequivocal progressive disease by either RECIST 1.1 or clinical assessment. Must 
have documented mismatch-repair proficient colon cancer as determined by either 
immunohistochemistry for mismatch repair proteins or PCR-based functional microsatellite 
instability. Patients with colorectal cancer enrolled in Cohort 4 should not have been previously 
treated with a PD-1/PD-L1-blocking antibody (i.e., pembrolizumab, nivolumab, MEDI4736, or 
GNE PDL1 [MPDL3280A]) 
All Patients 
8. Aged 18 years or older on the day written informed consent is given. 
9. If has brain metastases, must have stable neurologic status following local therapy (surgery or 
radiation) for at least 4 weeks without the use of steroids or on stable or decreasing dose of 
≤10 mg daily prednisone (or equivalent), and must be without neurologic dysfunction that would 
confound the evaluation of neurologic and other AEs. (Patients with a history of carcinomatous 
meningitis are not eligible.) 
10. Evidence of locally recurrent or metastatic disease based on imaging studies (e.g., CT, MRI) 
within 28 days before the first study drug dose: 
• 
At least 1 measurable lesion ≥20 mm by conventional techniques or ≥10 mm by spiral 
CT scan or MRI, with the last imaging performed within 28 days before the first study 
drug dose. If there is only 1 measurable lesion and it is located in previously irradiated 
field, it must have demonstrated unequivocal progression according to RECIST, version 
1.1.  
11. If receiving radiation therapy, has had a 2-week washout period following completion of the 
treatment prior to receiving the first study drug dose and continues to have at least 1 measureable 
lesion, per above criterion. 
12. ECOG performance status of 0 or 1. 


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13. Has the following laboratory parameters: 
System 
Laboratory Value 
Hematological 
Absolute neutrophil count (ANC) 
≥1.5×109/L 
Platelets 
≥100×109/L 
Hemoglobin 
≥9 g/dL or ≥5.6 mmol/L  
Renal 
Creatinine OR 
Measured or calculated1 creatinine clearance 
(CrCl) 
(glomerular filtration rate [GFR] can also be used 
in place of creatinine or CrCl) 
≤1.5× the upper limit of normal (ULN) OR 
≥60 mL/min for patient with creatinine levels >1.5× 
institutional ULN 
Hepatic 
Total bilirubin 
≤1.5×ULN OR 
Direct bilirubin ≤ULN for patients with total bilirubin 
levels >1.5×ULN 
Aspartate aminotransferase (AST) and alanine 
aminotransferase (ALT) 
≤2.5×ULN OR 
≤5×ULN for patients with liver metastases 
Coagulation 
International Normalized Ratio (INR) or 
Prothrombin Time (PT) 
 
Activated Partial Thromboplastin Time (aPTT) 
≤1.5×ULN unless patient is receiving anticoagulant 
therapy as long as PT or PTT is within therapeutic range 
of intended use of anticoagulants 
≤1.5×ULN unless patient is receiving anticoagulant 
therapy as long as PT or PTT is within therapeutic range 
of intended use of anticoagulants 
 
 
1Creatinine clearance should be calculated per institutional standard. 
 
14.  Female patients of childbearing potential must have a negative serum pregnancy test during 
screening and a negative urine pregnancy test within 72 hours prior to taking first dose of study 
drug. If a patient is of childbearing potential, the patient must agree to use effective contraception 
as defined in the protocol (Section 8.5.3), during the study and for 120 days after the last dose of 
study drug. Non-childbearing potential is defined as (by other than medical reasons): 
• 
≥45 years of age and has not had menses for >2 years, 
• 
Amenorrheic for <2 years without a hysterectomy and oophorectomy and a follicle-
stimulating hormone value in the postmenopausal range upon pre-study (screening) 
evaluation. 
• 
Post hysterectomy, oophorectomy, or tubal ligation. Documented hysterectomy or 
oophorectomy must be confirmed with medical records of the actual procedure or 
confirmed by an ultrasound. Tubal ligation must be confirmed with medical records of 
the actual procedure otherwise the patient must be willing to use 2 adequate barrier 


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methods throughout the study, starting with the screening visit through 120 days after the 
last dose of study drug. Please see Section 8.5.3, Contraception, for a list of acceptable 
birth control methods.  
15. If male, agrees to use an adequate method of contraception starting with the first dose of study 
drug through 120 days after the last dose of study drug. Please see Section 8.5.3, Contraception, 
for a list of acceptable birth control methods.  
16. Experienced resolution of toxic effect(s) of the most recent prior chemotherapy to Grade 1 or less 
(except alopecia). If patient underwent major surgery or radiation therapy of >30 Gy, they must 
have recovered from the toxicity and/or complications from the intervention. 
17. Willing to have fresh tumor samples collected during screening and at other time points 
designated as mandatory, per the Schedule of Study Assessments. If patients whose only 
accessible lesion for biopsy is a solitary target lesion, it must be amenable to a core biopsy that 
will not compromise assessment of tumor measurements. 
18. Able to understand and give written informed consent and comply with study procedures. 
6.2 
Exclusion Criteria 
Patients meeting any of the following criteria are not eligible for study participation: 
1. Diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing 
exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive 
therapy within 7 days prior to the first dose of study drug.  
2. Active autoimmune disease that has required systemic treatment in past 2 years (i.e., with disease 
modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (e.g., 
thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary 
insufficiency) is not considered a form of systemic treatment. 
3. History of interstitial lung disease (ILD). 
4. Allergy to benzamide or inactive components of entinostat.  
5. History of allergies to any active or inactive ingredients of pembrolizumab or severe 
hypersensitivity (≥Grade 3) to pembrolizumab. 
6. History or current evidence of any condition, therapy, or laboratory abnormality that might 
confound the results of the study, interfere with the patient’s participation for the full duration of 


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the study, or is not in the best interest of the patient to participate, in the opinion of the treating 
Investigator, including, but not limited to: 
• 
Myocardial infarction or arterial thromboembolic events within 6 months prior to baseline or 
severe or unstable angina, New York Heart Association (NYHA) Class III or IV disease, or a 
QTc interval > 470 msec. 
• 
Uncontrolled heart failure or hypertension, uncontrolled diabetes mellitus, or uncontrolled 
systemic infection. 
• 
Another known additional malignancy that is progressing or requires active treatment 
(excluding adequately treated basal cell carcinoma, squamous cell of the skin, cervical 
intraepithelial neoplasia [CIN]/cervical carcinoma in situ or melanoma in situ or ductal 
carcinoma in situ of the breast). Prior history of other cancer is allowed, as long as there is no 
active disease within the prior 5 years. 
• 
Has a history of (non-infectious) pneumonitis that required steroids or has current 
pneumonitis. 
• 
Active infection requiring systemic therapy. 
• 
Known active central nervous system (CNS) metastases and/or carcinomatous meningitis.  
Note: Patients with previously treated brain metastases may participate provided they are stable 
(without evidence of progression by imaging [using the identical imaging modality for each 
assessment, either MRI or CT scan] for at least 4 weeks prior to the first dose of study drug and 
any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain 
metastases, and are not using steroids for at least 2 weeks prior to the first dose of study drug or 
are on stable or decreasing dose of ≤10 mg daily prednisone (or equivalent). This exception does 
not include carcinomatous meningitis which is excluded regardless of clinical stability. 
7. Known psychiatric or substance abuse disorders that would interfere with cooperation with the 
requirements of the study. 
8. Currently participating and receiving study therapy or has participated in a study of an 
investigational agent and received study therapy or used an investigational device within 4 weeks 
of the first dose of treatment. 
9. Received a live virus vaccination within 30 days of the first dose of treatment. 


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10. Prior anti-cancer mAb within 4 weeks prior to baseline or who has not recovered (i.e., ≤Grade 1 
or at baseline) from AEs due to agents administered more than 4 weeks earlier. 
11. Prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to 
study baseline or who has not recovered (i.e., ≤Grade 1 or at baseline) from AEs due to a 
previously administered agent. 
Note:  Patients with ≤Grade 2 neuropathy or ≤Grade 2 alopecia are an exception to this criterion 
and may qualify for the study. 
Note:  If patient underwent major surgery, they must have recovered adequately from the toxicity 
and/or complications from the intervention prior to starting therapy.  
12. Received transfusion of blood products (including platelets or red blood cells) or administration 
of colony stimulating factors (including granulocyte-colony stimulating factor [G-CSF], 
granulocyte macrophage-colony stimulating factor [GM-CSF], or recombinant erythropoietin) 
within 4 weeks of the first dose of study drug. 
13. Currently receiving treatment with any other agent listed on the prohibited medication list in 
Section 8.5.1 such as valproic acid, or other systemic cancer agents within 14 days of the first 
dose of treatment.  
14. If female, is pregnant, breastfeeding, or expecting to conceive, or if male, expects to father 
children within the projected duration of the study, starting with the screening visit through 120 
days after the last dose of study drug. 
15. Known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies). 
16. Known active hepatitis B (e.g., hepatitis B surface antigen-reactive) or hepatitis C (e.g., hepatitis 
C ribonucleic acid [qualitative]). 
17. For CRC expansion cohort, prior history of malignant bowel obstruction requiring hospitalization 
in the 6 months prior to enrollment 
18. For the CRC expansion cohort, history of uncontrolled ascites, defined as symptomatic ascites 
and/or repeated paracenteses for symptom control in the past 3 months 


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7. 
PATIENT ENROLLMENT 
Section 14.3 describes documentation required prior to the commencement of study enrollment. 
The screening period for a particular patient commences at the point at which the patient signs the 
informed consent form. The consent form must be signed before any study-specific tests may be 
performed.  
After a patient has been screened and successfully fulfills all eligibility criteria, a site representative will 
send eligibility information to the appropriate Syndax representative. Once the information has been 
reviewed, approved, and returned to the site, the site representative will enter the patient in the electronic 
data capture (EDC) system. This will officially enroll the patient. Additionally, this process will 
automatically assign the patient identification (ID) number that will be used to identify the patient 
throughout the clinical study. This patient ID must be used on all study documentation related to that 
patient. Refer to the Study Manual for details on this procedure. 


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8. 
TREATMENT PROCEDURES 
8.1 
Study Drug 
Regardless of study phase, all patients will receive entinostat in combination with pembrolizumab, with 
both drugs given in an open-label fashion. 
8.1.1 
Entinostat 
Patients will receive entinostat in an open-label fashion; the dose for an individual patient is dependent on 
the cohort/study phase in which the patient is enrolled (Section 8.2.1.1). 
The dose of entinostat is dependent on the cohort / study phase in which the patient is enrolled. In the 
Dose Escalation Phase, the planned entinostat doses to be investigated are: 
• 
3 mg weekly 
• 
5 mg weekly 
In the Dose Confirmation Phase, 9 patients will receive entinostat at the prospective MTD/RP2D 
identified in the Dose Escalation Phase. 
All patients will self-administer entinostat at the assigned dose and regimen PO. On study days on which 
patients receive both entinostat and pembrolizumab, entinostat is to be taken prior to pembrolizumab. 
Patients in the EMIC Cohort will first receive entinostat as monotherapy for 2 weeks (D-14 to -1) at 5mg 
weekly. After completion of the 2-week entinostat monotherapy period, EMIC patients will enter the 
combination period and will receive entinostat in combination with pembrolizumab (Section 8.1.2) at the 
RP2D as determined in the Phase 1b Dose Escalation/Confirmation phase beginning on C1D1. If an 
EMIC Cohort patient requires a dose reduction during the monotherapy period, that patient will start the 
combination period at the reduced dose (e.g. 3mg). 
Entinostat is to be taken on an empty stomach, at least 1 hour before and 2 hours after a meal.  
Entinostat is supplied as pink to light red (1 mg) or yellow (5 mg) coated tablets.  
Entinostat is to be stored at controlled room temperature (15ºC to 25ºC) in a secure, locked storage area to 
which access is limited. Entinostat is to be protected from light. Entinostat is not to be exposed to 
extremes of temperature (greater than 30ºC or less than 5ºC). 


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Unused tablets or empty bottles will be returned to the clinic for accountability purposes. Details of study 
drug storage and handling may be found in Section 13.1.3. 
8.1.2 
Pembrolizumab 
The pembrolizumab treatment to be used in this study is outlined in Table 8-1. 
Table 8-1 
Study Treatment 
Drug 
Dose/Potency 
Dose 
Frequency 
Route of 
Administration 
Regimen 
Use 
Pembrolizumab 
200 mg 
Every three 
weeks 
(Q3W) 
Intravenous 
(IV) 
Day 1 of each cycle 
(3 week cycles) 
Experimental 
 
Pembrolizumab treatment will begin on C1D1. Pembrolizumab will be administered on D1 of each 3-
week treatment cycle after all procedures and assessments have been completed as detailed on the 
Schedule of Study Assessments (Table 1-1 or, for the EMIC Cohort, Table 1-2).  
Pembrolizumab will be administered as a dose of 200 mg using a 30-minute IV infusion. Sites should 
make every effort to target infusion timing to be as close to 30 minutes as possible. However, given the 
variability of infusion pumps from site to site, a window between -5 minutes and +10 minutes is 
permitted (i.e., infusion time is 30 minutes -5 min/+10 min). 
The Pharmacy Manual contains specific instructions for the preparation of the pembrolizumab infusion 
and administration of infusion solution. 
The Investigator shall take responsibility for and shall take all steps to maintain appropriate records and 
ensure appropriate supply, storage, handling, distribution, and usage of study drug, in accordance with the 
protocol and any applicable laws and regulations. 
8.2 
Study Drug Dose and Administration 
8.2.1 
Dose-escalation Phase 
The starting dose of entinostat is 3 mg, with escalation to a dose of 5 mg planned. However, based on 
evaluation of the safety and tolerability data of the previous dose level, it may also be decided that accrual 
will take place at an intermediate dose level or alternate dosing schedule.  


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8.2.1.1 
Dose Escalation /Confirmation Procedure 
Dose Escalation 
Toxicities will be assessed by the Investigator using the NCI CTCAE, Version 4.03. The decision 
regarding whether to proceed to the next dose level will be made by the Sponsor Study Physician(s) in 
consultation with the Investigators, after the safety assessments for each cohort are completed.  
All patients within a cohort are to complete C1, have safety assessments performed through C2D1, and be 
assessed for DLT before enrollment of the next cohort may commence. If <33% patients within a cohort 
have a DLT (i.e., <2 of up to 6), then enrollment of the next cohort may commence with approval from 
the Sponsor Study Physician(s) in consultation with the Investigators. If ≥33% (≥2 of up to 6) of patients 
within a cohort experience a DLT, then the DLT dose level will have been reached and the previous lower 
dose level will be considered the MTD. Patients who experience a DLT will be allowed to remain on 
study if they meet the following criteria: (1) the investigator believes it is appropriate for patients to 
remain on study; (2) the event has resolved and no longer meets the definition of DLT; and (3) the 
timeline for resolution falls within the protocol guidelines for dose delays. 
If a DLT necessitates enrollment of additional patients into a cohort, the Sponsor Study Physician(s) in 
consultation with the Investigators, will review all safety data for that cohort after all patients have 
completed C1. 
Although decisions regarding dose escalation will be made primarily based on review of data from C1, 
safety data will also be collected from all patients continuing treatment and these data will be reviewed 
periodically by the Sponsor Study Physician(s) in consultation with the Investigators. Any detected 
cumulative toxicity may require later dose reductions and/or other changes to the dosing schedule, as 
appropriate, including further refinement of the RP2D. 
Patients who discontinue from the study for reasons other than study drug-related toxicity before 
completing C1 may be replaced. 
Patients who complete C1 may continue on study as long as, in the investigator’s judgment, the patient is 
tolerating the study treatment, is not at an increased safety risk, and continues to meet protocol eligibility 
criteria. 


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Dose Confirmation 
The prospective MTD/RP2D identified in the Dose Escalation Phase will be confirmed in 9 patients in 
Dose Confirmation Cohort to obtain additional AE, immune correlate, and anti-tumor activity data on 
entinostat in combination.  
After completion of the Dose Escalation/Confirmation Phase of the study, with identification of the MTD 
or RP2D, the Phase 2 portion of the study will commence. 
8.2.1.2 
Dose-limiting Toxicity 
DLT is defined as the occurrence of any of the following events within the first cycle of treatment (i.e., 
C1) of entinostat in combination with pembrolizumab that are considered by the Investigator to be at least 
possibly related to entinostat. A patient that experiences an adverse event meeting DLT criteria in C1 or 
who receives the full dose of pembrolizumab and all doses of entinostat during C1 without experiencing a 
DLT is considered a DLT-evaluable patient.  
• 
Grade 4 hematologic and non-hematologic (non-laboratory) toxicities of any duration 
• 
Grade 3 non-hematologic (non-laboratory) toxicity with the exception of Grade 3 nausea, 
vomiting, and diarrhea that resolve within 3 days following institution of optimal supportive care 
• 
Any Grade 3 or Grade 4 non-hematologic laboratory value if: 
• 
Medical intervention is required to treat the patient, or 
• 
The abnormality leads to hospitalization, or 
• 
The abnormality persists for >1 week. 
• 
Febrile neutropenia Grade 3 or Grade 4: 
• 
Grade 3 is defined as ANC <1.0×109/L with a single temperature of >38.3°C (101°F) or a 
sustained temperature of ≥38°C (100.4°F) for more than 1 hour 
• 
Grade 4 is defined as ANC <1.0×109/L with a single temperature of >38.3°C (101°F) or a 
sustained temperature of ≥38°C (100.4°F) for more than 1 hour, with life-threatening 
consequences and urgent intervention indicated. 


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• 
Grade 4 thrombocytopenia (i.e., platelet count <25×109/L) 
• 
Grade 3 thrombocytopenia with clinically significant bleeding  
• 
Prolonged delay (>2 weeks) in initiating Cycle 2 due to treatment-related toxicity 
• 
Any AE requiring >2 entinostat doses to be held, an entinostat dose reduction, or entinostat 
discontinuation 
• 
Concurrent elevation of transaminases and bilirubin consistent with Hy’s Law criteria 
Note: The original Hy's Law parameters for treated patients relative to comparator patients have 
been broadened over time (Kaplowitz and DeLeve 2003, Zimmerman 1999) to include additional 
parameters, but still require that these 3 criteria be met: 
i. 
injury: elevation of >3×ULN ALT or AST activity; and 
ii. function: >2×ULN total bilirubin (another clinical marker for function, such as >1.5×ULN 
INR may be acceptable if the change is clinically significant in the absence of obstruction) 
without >2×ULN alkaline phosphatase (ALP); and 
iii. clinical verification to ensure effect is health product-induced and not induced by disease or 
another cause of injury. 
• 
Grade 5 toxicity 
8.2.1.3 
Maximum Tolerated Dose 
MTD is defined as the highest dose level at which <33% of patients experience DLT in C1. 
8.2.1.4 
Recommended Phase 2 Dose 
The RP2D will be equal to or less than the preliminary MTD. The RP2D will be determined in discussion 
with the Sponsor, Medical Monitor, and Investigators. Additionally, observations related to immune 
correlates, and any cumulative toxicity observed after multiple cycles may be included in the rationale 
supporting the RP2D. 
8.2.2 
Expansion Phase 
In the Expansion Phase, all patients will receive entinostat PO at the RP2D and schedule on D1, D8, and 
D15 in combination with pembrolizumab 200 mg via IV infusion over 30 minutes on D1 every 21 days. 


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8.3 
Treatment Duration 
The maximum duration of treatment for this study is planned to be 35 treatments (approximately 2 years.)  
Patients who complete C1 may continue on study as long as, in the Investigator’s judgment, the patient is 
tolerating the study treatment, is not at an increased safety risk, and continues to meet protocol eligibility 
criteria. 
If a patient permanently discontinues 1 of the 2 study drugs (either entinostat or pembrolizumab), the 
patient may continue to receive monotherapy for up to 2 years, unless alternate therapy is started or 
another discontinuation criterion is met (Section 10). 
Patients who discontinue both study drugs will receive standard of care outside the auspices of this study 
at the Investigator’s discretion.  
After discontinuation of both study drugs, patients will complete an EOT visit within 7 days (+/- 3 days) 
after the last study drug dose and Safety Follow-up visits 30 days (+/- 3 days) and 90 days (+/- 3 days) 
thereafter. After completion of the 30-day Safety F/U visit, patients who have not experienced PD are to 
be followed every 2 months until PD and every 3 months thereafter until death or closure of the study by 
the Sponsor. The purpose of the post-treatment follow-up is to ascertain the duration of PFS for all 
patients in the study. After development of PD, surviving patients are to be followed on an every 3-month 
basis for alternate therapy and survival until closure of the study.  
8.4 
Dose Adjustments 
Although entinostat and pembrolizumab have distinct toxicity profiles, they do share some AEs such as 
fatigue and nausea. There is the theoretical possibility that 1 agent may potentiate the other and hence 
drug causality will not always be clear. In the event of uncertainty, dose reductions and/or delays will 
follow the most conservative approach (i.e., delays and/or dose reductions for both drugs) until resolution 
of the event. No dose reductions will be performed for pembrolizumab. Guidance for delays and or dose 
reductions for entinostat are presented in Section 8.4.1. Once the entinostat dose is reduced, it cannot be 
increased. Expected AEs for each agent are summarized in Section 11.1.  


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8.4.1 
Entinostat 
8.4.1.1 
Nonhematologic Toxicity at Least Possibly Related to Entinostat 
The rules outlined in Table 8-2 are to be followed for the management of non-hematologic toxicities that 
are definitely or possibly due to entinostat alone, with toxicities graded by the Investigator according to 
the NCI, CTCAE, Version 4.03.  
Table 8-2 
Non-hematologic Toxicity:  Dose Modification for Entinostat 
Toxicity 
Dose modifications 
Grade 4 
Administer symptomatic remedies/ start prophylaxis. 
Hold dose P until recovery to Grade 1 or baseline under the following 
directions: 
1. If recovered within 4 weeks of onset (i.e.: ≤3 missed doses), 
resume study drug as follows: 
• 
If receiving 5 mg, restart study drug at 3 mg 
• 
If receiving 3 mg, restart study drug at 2 mg 
• 
If receiving 2 mg, permanently discontinue study drug 
2. If not recovered within 4 weeks (i.e. 4 missed doses), permanently 
discontinue study drug. 
Grade 3 
Administer symptomatic remedies/ start prophylaxis. Hold dose P until 
recovery to Grade 1 or baseline under the following directions: 
1. If recovered within 1 week, resume study drug at prior dose. If not 
recovered within 1 week, continue to hold dose. 
2. If recovered within 2-4 weeks, resume study drug as follows:  
• 
If receiving 5 mg, restart study drug at 3 mg 
• 
If receiving 3 mg, restart study drug at 2 mg 
• 
If receiving 2 mg, permanently discontinue study drug 
3. If not recovered within 4 weeks (i.e. 4 missed doses), permanently 
discontinue study drug. 
Recurrence of the same Grade 3 
toxicity despite dose reduction 
If the same ≥ Grade 3 event recurs: 
1. Administer symptomatic remedies/ start prophylaxis. Hold1 dose until 
recovery to Grade 1 or baseline.  
2. If recovered within 2 weeks, resume study drug as follows: 
• 
If receiving 5 mg, restart study drug at 3 mg 
• 
If receiving 3 mg, restart study drug at 2 mg 
• 
If receiving 2 mg, permanently discontinue study drug 
If the same ≥ Grade 3 event recurs (i.e., third occurrence) despite 
entinostat dose reduction to 2 mg, as described above, permanently 
discontinue study drug. 


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Toxicity 
Dose modifications 
≤Grade 2 
Administer symptomatic remedies / start prophylaxis.  
Dosing of study drug may be interrupted at the Investigator’s discretion, in 
consultation with the Medical Monitor. 
• 
If dose is held for 4 consecutive weeks, permanently discontinue study 
drug.P1 
• 
If toxicity resolves, resume entinostat at the original dose. 
1If greater than 50% of doses are missed during any 6-week period, discontinue from study drug treatment.  
8.4.1.2 
Hematologic Toxicity at Least Possibly Related to Entinostat 
The guidelines in Table 8-3 will be followed for determining the timing of cycles based on hematologic 
status at the time of planned dosing. 
Table 8-3 
Hematologic Toxicity:  Dose Modification for Entinostat 
ToxicityP 
Dose modifications 
≥Grade 3 neutropenia, 
≥Grade 3 uncomplicated 
thrombocytopenia, or 
Grade 2 complicated 
thrombocytopenia 
Administer symptomatic remedies/ start prophylaxis. 
Hold dose P1 until recovery to Grade 1 or study baseline under the following 
directions:  
1. If recovered within 1 week, resume study drug at prior dose. If 
recovered within 1 week, continue to hold dose. 
2. If recovered within 2-4 weeks, resume study drug as follows: 
• 
If receiving 5 mg, restart study drug at 3 mg 
• 
If receiving 3 mg, restart study drug at 2 mg 
• 
If receiving 2 mg, permanently discontinue study drug 
If not recovered within 4 weeks (i.e. 4 missed doses), permanently 
discontinue study drug. 
Recurrence of the same hematologic 
toxicity 
If the same hematologic toxicity recurs: 
1. Administer symptomatic remedies/ start prophylaxis. Hold1 dose until 
recovery to Grade 1 or baseline. 
2. If recovered within 2 weeks, resume study drug as follows:  
• 
If receiving 5 mg, restart study drug at 3 mg 
• 
If receiving 3 mg, restart study drug at 2 mg 
• 
If receiving 2 mg, permanently discontinue study drug 
3. If the same ≥ Grade 3 event recurs (i.e., third occurrence) despite 
entinostat dose reduction to 2 mg, as described above, permanently 
discontinue study drug. 
P1If greater than 50% of doses are missed during any 6-week period, discontinue from study drug treatment.   


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8.4.2 
Pembrolizumab 
AEs associated with pembrolizumab exposure may represent an immunologic etiology. These immune-
related AEs (irAEs) may occur shortly after the first dose or several months after the last dose of 
pembrolizumab treatment and may affect more than on body system simultaneously. Therefore, early 
recognition and initiation of treatment is critical to reduce complications. Based on existing clinical study 
data, most irAEs were reversible and could be managed with interruptions of pembrolizumab, 
administration of corticosteroids and/or other supportive care. For suspected irAEs, ensure adequate 
evaluation to confirm etiology or exclude other causes. Additional procedures or tests such as 
bronchoscopy, endoscopy, skin biopsy may be included as part of the evaluation. Based on the severity of 
irAEs, withhold or permanently discontinue pembrolizumab and administer corticosteroids. Dose 
modification and toxicity management guidelines for irAEs associated with pembrolizumab are provided 
in Table 8-4. (Refer to Section 8.5.2 and the Study Manual for supportive care guidelines, including use 
of corticosteroids.) 
Table 8-4 
Pembrolizumab Dose Modification and Toxicity Management Guidelines for 
Immune-Related Adverse Events  
General instructions: 
1. 
Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 
weeks. 
2. 
For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to 
Grade 1 or 0 and corticosteroid has been tapered. Pembrolizumab should be permanently discontinued if AE does not 
resolve within 12 weeks of last dose or corticosteroids cannot be reduced to ≤10 mg prednisone or equivalent per day 
within 12 weeks.  
3. 
For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other 
immunosuppressive treatment should be initiated if irAEs cannot be controlled by corticosteroids. 
IR AEs 
Toxicity 
Grade or 
Conditions 
(CTCAEv4.0) 
Action Taken to 
Pembrolizumab 
IR AE Management with 
Corticosteroid and/or 
Other Therapies  
Monitor and Follow-up  
Pneumonitis  
Grade 2 
Withhold  
Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper 
Monitor participants for signs and 
symptoms of pneumonitis 
Evaluate participants with suspected 
pneumonitis with radiographic imaging 
and initiate corticosteroid treatment 
Add prophylactic antibiotics for 
opportunistic infections 
Grade 3 or 4, 
or recurrent 
Grade 2 
Permanently 
discontinue 
 
 


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General instructions: 
1. 
Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 
weeks. 
2. 
For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to 
Grade 1 or 0 and corticosteroid has been tapered. Pembrolizumab should be permanently discontinued if AE does not 
resolve within 12 weeks of last dose or corticosteroids cannot be reduced to ≤10 mg prednisone or equivalent per day 
within 12 weeks.  
3. 
For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other 
immunosuppressive treatment should be initiated if irAEs cannot be controlled by corticosteroids. 
IR AEs 
Toxicity 
Grade or 
Conditions 
(CTCAEv4.0) 
Action Taken to 
Pembrolizumab 
IR AE Management with 
Corticosteroid and/or 
Other Therapies  
Monitor and Follow-up  
Diarrhea / 
Colitis  
Grade 2 or 3 
Withhold 
Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper 
 
Monitor participants for signs and 
symptoms of enterocolitis (ie, diarrhea, 
abdominal pain, blood or mucus in 
stool with or without fever) and of 
bowel perforation (ie, peritoneal signs 
and ileus). 
Participants with ≥Grade 2 diarrhea 
suspecting colitis should consider GI 
consultation and performing endoscopy 
to rule out colitis.  
Participants with diarrhea/colitis should 
be advised to drink liberal quantities of 
clear fluids. If sufficient oral fluid 
intake is not feasible, fluid and 
electrolytes should be substituted via IV 
infusion. 
Grade 4 
Permanently 
discontinue 
AST / ALT 
elevation or 
Increased 
bilirubin 
Grade 2 
Withhold 
Administer corticosteroids 
(initial dose of 0.5- 1 mg/kg 
prednisone or equivalent) 
followed by taper 
Monitor with liver function tests 
(consider weekly or more frequently 
until liver enzyme value returned to 
baseline or is stable 
Grade 3 or 4  
Permanently 
discontinue 
Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper 
Type 1 
diabetes 
mellitus 
(T1DM) or 
Hyper-
glycemia 
Newly onset 
T1DM or  
Grade 3 or 4 
hyperglycemia 
associated 
with evidence 
of β-cell 
failure 
Withhold 
Initiate insulin replacement 
therapy for participants with 
T1DM  
Administer anti-
hyperglycemic in 
participants with 
hyperglycemia  
Monitor participants for hyperglycemia 
or other signs and symptoms of 
diabetes. 


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General instructions: 
1. 
Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 
weeks. 
2. 
For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to 
Grade 1 or 0 and corticosteroid has been tapered. Pembrolizumab should be permanently discontinued if AE does not 
resolve within 12 weeks of last dose or corticosteroids cannot be reduced to ≤10 mg prednisone or equivalent per day 
within 12 weeks.  
3. 
For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other 
immunosuppressive treatment should be initiated if irAEs cannot be controlled by corticosteroids. 
IR AEs 
Toxicity 
Grade or 
Conditions 
(CTCAEv4.0) 
Action Taken to 
Pembrolizumab 
IR AE Management with 
Corticosteroid and/or 
Other Therapies  
Monitor and Follow-up  
Hypophysitis 
Grade 2 
Withhold 
Administer corticosteroids 
and initiate hormonal 
replacements as clinically 
indicated.  
 
Monitor for signs and symptoms of 
hypophysitis (including hypopituitarism 
and adrenal insufficiency)  
Grade 3 or 4  
Withhold or 
permanently 
discontinue1  
 
Hyper-
thyroidism  
Grade 2 
Continue  
Treat with non-selective 
beta-blockers (e.g., 
propranolol) or thioamides 
as appropriate  
Monitor for signs and symptoms of 
thyroid disorders 
Grade 3 or 4  
Withhold or  
permanently 
discontinue1 
Hypo-
thyroidism 
Grade 2-4 
Continue  
Initiate thyroid replacement 
hormones (eg, levothyroxine 
or liothyroinine) per 
standard of care 
Monitor for signs and symptoms of 
thyroid disorders 
Nephritis and 
Renal 
dysfunction 
Grade 2 
Withhold  
Administer corticosteroids 
(prednisone 1-2 mg/kg or 
equivalent) followed by 
taper 
Monitor changes of renal function 
Grade 3 or 4  
Permanently 
discontinue 
Myocarditis 
Grade 1 or 2 
Withhold 
Based on severity of AE 
administer corticosteroids 
Ensure adequate evaluation to confirm 
etiology and/or exclude other causes 
Grade 3 or 4 
Permanently 
discontinue 


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General instructions: 
1. 
Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 
weeks. 
2. 
For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to 
Grade 1 or 0 and corticosteroid has been tapered. Pembrolizumab should be permanently discontinued if AE does not 
resolve within 12 weeks of last dose or corticosteroids cannot be reduced to ≤10 mg prednisone or equivalent per day 
within 12 weeks.  
3. 
For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other 
immunosuppressive treatment should be initiated if irAEs cannot be controlled by corticosteroids. 
IR AEs 
Toxicity 
Grade or 
Conditions 
(CTCAEv4.0) 
Action Taken to 
Pembrolizumab 
IR AE Management with 
Corticosteroid and/or 
Other Therapies  
Monitor and Follow-up  
All other IR 
AEs 
Intolerable/ 
persistent 
Grade 2 
Withhold 
Based on type and severity 
of AE administer 
corticosteroids  
Ensure adequate evaluation to confirm 
etiology and/or exclude other causes 
Grade 3 
Withhold or 
discontinue based 
on the type of 
event. Events that 
require 
discontinuation 
include and not 
limited to:  
Guillain-Barré 
Syndrome, 
encephalitis 
Grade 4 or 
recurrent 
Grade 3  
Permanently 
discontinue 
1Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician.  
NOTE:  
For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, 
pembrolizumab may be resumed when AE resolves to ≤ Grade 2 and is controlled with hormonal replacement therapy or 
achieved metabolic control (in case of T1DM).  
Pembrolizumab may cause severe or life threatening infusion-reactions including severe hypersensitivity 
or anaphylaxis. Signs and symptoms usually develop during or shortly after drug infusion and generally 
resolve completely within 24 hours of completion of infusion. Dose modification and toxicity 
management guidelines on pembrolizumab associated infusion reaction are provided in Table 8-5. 


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Table 8-5 
Pembrolizumab Infusion Reaction Dose Modification and Treatment Guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at Subsequent Dosing 
Grade 1 
Mild reaction; infusion interruption 
not indicated; intervention not 
indicated 
Increase monitoring of vital signs as medically indicated until the participant is deemed 
medically stable in the opinion of the investigator. 
None 
Grade 2 
Requires therapy or infusion 
interruption but responds promptly to 
symptomatic treatment (e.g., 
antihistamines, NSAIDs, narcotics, 
IV fluids); prophylactic medications 
indicated for ≤24 hrs. 
Stop Infusion. 
Additional appropriate medical therapy may include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDs 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as medically indicated until the participant is deemed 
medically stable in the opinion of the investigator. 
If symptoms resolve within 1 hour of stopping drug infusion, the infusion may be restarted 
at 50% of the original infusion rate (e.g. from 100 mL/hr. to 50 mL/hr.). Otherwise dosing 
will be held until symptoms resolve and the participant should be premedicated for the next 
scheduled dose. 
Participants who develop Grade 2 toxicity despite adequate premedication should be 
permanently discontinued from further study drug treatment 
Participant may be premedicated 1.5h (± 30 
minutes) prior to infusion of pembrolizumab 
with: 
Diphenhydramine 50 mg po (or equivalent dose 
of antihistamine). 
Acetaminophen 500-1000 mg po (or equivalent 
dose of analgesic). 


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NCI CTCAE Grade 
Treatment 
Premedication at Subsequent Dosing 
Grades 3 or 4 
 
Grade 3: 
Prolonged (i.e., not rapidly responsive 
to symptomatic medication and/or 
brief interruption of infusion); 
recurrence of symptoms following 
initial improvement; hospitalization 
indicated for other clinical sequelae 
(e.g., renal impairment, pulmonary 
infiltrates) 
Grade 4: 
Life-threatening; pressor or ventilator 
support indicated 
 
Stop Infusion. 
Additional appropriate medical therapy may include but is not limited to: 
Epinephrine** 
IV fluids 
Antihistamines 
NSAIDs 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Increase monitoring of vital signs as medically indicated until the participant is deemed 
medically stable in the opinion of the investigator. 
Hospitalization may be indicated. 
**In cases of anaphylaxis, epinephrine should be used immediately. 
Participant is permanently discontinued from further study drug treatment. 
No subsequent dosing 
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the period of drug administration. For further information, please refer 
to the Common Terminology Criteria for Adverse Events v4.0 (CTCAE) at http://ctep.cancer.gov  


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Pembrolizumab may be interrupted for situations other than treatment-related AEs such as medical / 
surgical events or logistical reasons not related to study therapy. Participants should be placed back on 
study therapy within 3 weeks of the scheduled interruption, unless otherwise discussed with the Sponsor. 
The reason for interruption should be documented in the patient's study record. 
8.5 
Concomitant Therapy 
All concomitant treatments and therapies, or medication, including all prescription, over-the-counter, 
herbal supplements, and IV medications and fluids, administered during the 30 days preceding the 
screening study visit must be reported in the electronic case report form (eCRF). If changes occur during 
the study period, documentation of drug dosage, frequency, route, and date may also be included on the 
eCRF. The generic name of the drug (or trade name for combination drugs) must be specified along with 
the route of administration, indication, and duration of treatment.  
Throughout the study, the Investigator may prescribe any concomitant medications or treatments deemed 
necessary to provide adequate supportive care, such as potassium and phosphorus supplements and 
antiemetics, with the exception of those listed in Section 8.5.1. Patients must notify the Investigator of all 
concomitant medications taken through completion of the study (final visit). 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed during the 
ongoing study (Section 8.5.1). If there is a clinical indication for any medication or vaccination 
specifically prohibited during the study, discontinuation from study drug may be required. The 
Investigator should discuss any questions regarding this with the Medical Monitor. The final decision on 
any supportive therapy or vaccination rests with the Investigator and/or the patient's primary physician. 
However, the decision to continue the patent on study drug requires the mutual agreement of the 
Investigator, the Sponsor, and the patient. 
8.5.1 
Prohibited Medications and Medications to be Avoided During the Study 
8.5.1.1. Prohibited Medications 
The following medications are prohibited during study participation: 
• 
Any other HDAC inhibitor, including valproic acid 
• 
DNA methyltransferase inhibitors 
• 
Antineoplastic systemic chemotherapy or biological therapy  
• 
Immunotherapy other than pembrolizumab  


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• 
Investigational agents other than entinostat and pembrolizumab 
• 
Prophylactic use of hematopoietic colony stimulating factors are not allowed during the Phase 1b 
Dose Escalation/Confirmation Phase, but can be used to treat hematological adverse events and 
for prophylaxis subsequently, per investigator discretion during the Expansion Phase. 
• 
Radiation therapy 
Note:  Radiation therapy to a symptomatic solitary lesion or to the brain may be considered on 
an exceptional case-by-case basis after consultation with Sponsor. The patient must have clear 
measurable disease outside the radiated field. Administration of palliative radiation therapy will 
be considered clinical progression for the purposes of determining PFS. 
• 
Live vaccines within 30 days prior to the first dose of study drug and while participating in the 
study. Examples of live vaccines include, but are not limited to, the following: measles, mumps, 
rubella, chicken pox, yellow fever, rabies, Bacille de Calmette et Guérin, and typhoid (oral) 
vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are 
allowed. However, intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, 
and are not allowed. 
• 
The use of systemic corticosteroids to treat disease-related complications or co-morbid medical 
conditions is strongly discouraged. In consultation with the Sponsor, systemic corticosteroids 
may be administered, at doses no greater than 10 mg prednisone or for no longer than 
7 consecutive days if at higher doses, as clinically indicated, to treat acute conditions, (e.g. 
exacerbations of COPD, pleural effusions, etc.) other than immune-mediated toxicity related to 
study drug. The corticosteroid regimens used to treat the immune-related toxicity related to study 
drug are specified in Section 8.5.2.  
The use of physiologic doses of corticosteroids for prolonged periods may be approved in 
consultation with the Sponsor. The use of inhaled steroids for the management of asthma or the 
use of prophylactic corticosteroids to avoid allergic reactions (e.g., to IV contract dye) is 
permitted. Patients who, in the assessment by the Investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the study. Patients 
may receive other medications that the Investigator deems to be medically necessary. 
The exclusion criteria (Section 6.2) describe other medications that are prohibited in this study. 


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8.5.1.2. Medications to be avoided during the Study  
Concomitant use of the drugs below with entinostat should be avoided during the study: 
• 
 Gastric acid reducing drugs (e.g., histamine receptor antagonists [H2], antacids; see Appendix 2: 
Concomitant Medications to be Avoided 
• 
Sensitive substrates of CYP1A2, CYP2C8, CYP3A with a narrow therapeutic window (refer to 
Appendix 2: Concomitant Medications to be Avoided) 
• 
Drugs that are known to inhibit or induce P-gp (refer to Appendix 2: Concomitant Medications 
to be Avoided)    
8.5.2 
Rescue Medications & Supportive Care Guidelines for Pembrolizumab 
8.5.2.1 
Supportive Care Guidelines 
Patients should receive appropriate supportive care measures as deemed necessary by the Investigator. 
Suggested supportive care measures for the management of AEs with potential immunologic etiology are 
outlined below. Where appropriate, these guidelines include the use of PO or IV treatment with 
corticosteroids as well as additional anti-inflammatory agents if symptoms do not improve with 
administration of corticosteroids. Note that several courses of steroid tapering may be necessary as 
symptoms may worsen when the steroid dose is decreased. It is also important to note that the use of 
corticosteroids for any reason other than immune-mediated toxicities is strongly discouraged, especially 
during the phase 1 and first two cycles of phase 2 of this trial. Refer to Section 8.5.1 for specific criteria 
for the allowance of corticosteroids.  
For each disorder, attempts should be made to rule out other causes such as metastatic disease or bacterial 
or viral infection, which might require additional supportive care. The treatment guidelines are intended 
to be applied when the Investigator determines the events to be related to pembrolizumab.  
Note:  if after the evaluation the event is determined not to be related, the Investigator is instructed to 
follow the Events of Clinical Interest (ECI; Section 11.4.3) reporting guidance but does not need to 
follow the treatment guidance (as outlined in the Study Manual). Refer to Section 8.4.2 for dose 
modification guidelines. 
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or skin 
photography as part of evaluation of the event.  


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8.5.3 
Diet/Activity/Other Considerations 
Diet 
Patients should maintain a normal diet unless modifications are required to manage an AE such as 
diarrhea, nausea, or vomiting. 
Contraception 
Patients (both men and women) should be informed that taking either of the study drugs may involve 
unknown risks to the fetus (unborn baby) if a pregnancy were to occur during the study. Specifically, 
Pembrolizumab may have adverse effects on a fetus in utero, and it is not known whether pembrolizumab 
has transient adverse effects on the composition of sperm. In order to participate in the study, patients 
with reproductive potential must adhere to contraception methods that result in a failure rate of < 1% per 
year (described below) from the first screening visit throughout the study period during the treatment 
period and for at least 120 days after the last dose of study treatment (as defined in Section 11.4.1). If 
there is any question that a patient will not reliably comply with the requirements for contraception, that 
patient should not be entered into the study. 
A woman is considered to be of childbearing potential if she has experienced menarche and is not yet 
post-menopausal and has not been permanently or surgically sterilized. A woman who is ≥45 years of age 
and has not had menses for greater than 1 year will be considered post-menopausal. Permanent 
sterilization includes hysterectomy and/or bilateral oophorectomy and/or bilateral salpingectomy but not 
does include bilateral tubal occlusion.  
For this trial, male patients will not be considered to have reproductive potential only if they have 
azoospermia (whether due to having had a vasectomy or due to an underlying medical condition). 
Patients with reproductive potential must agree to use acceptable contraceptive methods with a < 1% 
annual failure rate or to remain abstinent (refrain from heterosexual intercourse). The following are 
acceptable methods of contraception: 
Single method (one of the following is acceptable): 
• 
intrauterine device (IUD) 
• 
bilateral tubal ligation 
• 
vasectomy of a female subject’s male partner  
• 
contraceptive rod implanted into the skin 


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Combination method (requires use of two of the following): 
• 
diaphragm with spermicide (cannot be used in conjunction with cervical cap/spermicide) 
• 
cervical cap with spermicide (nulliparous women only)   
• 
contraceptive sponge (nulliparous women only)  
• 
male condom or female condom (cannot be used together) 
• 
hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or progestin-only 
pill), contraceptive skin patch, vaginal contraceptive ring, or subcutaneous contraceptive 
injection) 
Either two barrier methods or a barrier method plus a hormonal method to prevent pregnancy would be 
considered acceptable. 
Abstinence (relative to heterosexual activity) can be used as the sole method of contraception if it is 
consistently employed as the patient’s preferred and usual lifestyle and if considered acceptable by the 
local regulatory agencies and EC/IRBs. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or 
postovulation methods) and withdrawal are not acceptable methods of contraception. 
As discussed above, these contraceptive methods must be used for 120 days after the last dose of study 
drug. In order to participate in the study, patients must adhere to the contraception requirement (described 
above) for the duration of the study and during the follow-up period defined in Section 11.4.1. If there is 
any question that a patient will not reliably comply with the requirements for contraception, that patient 
should not be entered into the study.  
8.5.4 
Study Drug Use in Pregnancy 
If a patient inadvertently becomes pregnant while on study drug, the patient will immediately be removed 
from the study. The site will contact the patient at least monthly and document the patient’s status until 
the pregnancy has been completed or terminated. The outcome of the pregnancy will be reported to the 
Sponsor without delay and within 24 hours if the outcome is a serious adverse experience (e.g., death, 
abortion, congenital anomaly, or other disabling or life-threatening complication to the mother or 
newborn). The Investigator will make every effort to obtain permission to follow the outcome of the 
pregnancy and report the condition of the fetus or newborn to the Sponsor. If a male patient impregnates 
his female partner the study personnel at the site must be informed immediately and the pregnancy 
reported to the Sponsor and followed as described above and in Section 11.4.1. 


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8.5.5 
Study Drug Use in Nursing Women 
It is unknown whether study drug is excreted in human milk. Since many drugs are excreted in human 
milk, and because of the potential for serious adverse reactions in the nursing infant, patients who are 
breast-feeding are not eligible for enrollment.  


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9. 
STUDY TESTS AND OBSERVATIONS 
After provision of written informed consent, patients will be screened for study eligibility within 21 days 
before the first study drug dose. Patients who are determined to be eligible, based on screening 
assessments, will be enrolled in the study within 3 days of C1D1 and start entinostat in combination with 
pembrolizumab, with the exception of those in the EMIC Cohort. 
Patients in the EMIC Cohort will enrolled in the study on Day -14 and will participate in a 2-week 
entinostat monotherapy period. After completion of the 2-week entinostat monotherapy period, patients in 
the EMIC Cohort will start entinostat in combination with pembrolizumab on C1D1.  
A cycle is 21 days in length. Patients will attend study center visits and have study evaluations performed 
on C1D1, C1D8, and C1D15; D1 and D15 of C2; and on D1 of each cycle thereafter. 
Patients will have radiological disease assessments performed during screening and every 6 weeks (+/-3 
days) (Week 6, Week 12, etc.) during treatment. 
After discontinuation of all study drug, patients will complete an EOT visit within 7 days after the last 
study drug dose and Safety F/U visits 30 days and 90 days thereafter. After completion of the 30-day 
Safety F/U visit, patients who have not experienced PD are to be followed every 2 months until PD and 
every 3 months thereafter until death or closure of the study by the Sponsor. 
Protocol-required tests, observations, and procedures are summarized in Table 1-2 for the EMIC cohort 
and in Table 1-1 for all other patients.  
9.1 
Baseline Assessments 
All patients must provide written informed consent before the performance of any study-related 
procedures. 
9.1.1 
Demographics 
Patient demographics, including age, race, and ethnicity, are to be documented during screening. 
9.1.2 
Height 
Height is to be documented during screening. 


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9.1.3 
Medical History 
A relevant medical history is to be documented during screening and updated prior to administration of 
the first study drug dose at baseline. 
The medical history is to include cancer history, including date of and stage at diagnosis, method of 
diagnosis, and all previous treatments, including radiation therapy, and response to such treatment. For 
patients in Cohorts 2 and 3, who have previously been treated and responded and then progressed on 
either a PD-1 or PD-L1-blocking antibody, the details regarding the previous PD-1 or PD-L1-blocking 
antibody, date of progression, and criteria used to determine progression, are to be documented on the 
eCRF.  
For patients with NSCLC, if patient has adenocarcinoma, results of prior testing for ALK rearrangements 
and EGFR (Exon 19 Deletion and Exon 21 L8585R Substitution) mutations are to be documented. For 
patients with melanoma, result of prior testing for BRAF V600 mutation is to be documented, if available.  
For patients in Cohort 4, results of prior testing for KRAS status, NRAS status, BRAF status are to be 
documented, if available. 
Patients in Cohort 4 must have documented mismatch repair proficient status. 
9.1.4 
Pregnancy Testing 
For females of child-bearing potential, a serum pregnancy test is to be performed during screening and a 
urine pregnancy test should be performed within 72 hours prior to taking the first study drug dose. Results 
must be available and confirmed to be negative prior to study drug administration. Pregnancy testing is to 
be repeated during the study any time pregnancy is suspected. 
9.2 
Safety Assessments 
9.2.1 
Physical Examination 
A complete physical examination will be conducted for all patients during screening; at C1D1 (if the 
screening physical was performed more than 7 days before); and at the EOT (7 days post-last dose) and 
Safety F/U (30 and 90 days thereafter) visits. If the screening physical examination was performed within 
7 days of C1D1 then a symptom-directed physical examination may be performed at on C1D1.  


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Symptom-directed physical examinations will be performed for all patients on C1D1 (if the screening 
physical was performed within 7 days before), C1D8, C1D15; D1 and D15 of C2; and on D1 of each 
subsequent cycle. 
9.2.2 
Electrocardiograms 
All patients will have a 12-lead ECG performed during screening; pre-dose (i.e., before entinostat and 
pembrolizumab) on C3D1, and then every 3 cycles thereafter. A 12-lead ECG also is to be performed at 
the EOT (7 days post-last dose). A 12-lead ECG is to be repeated as clinically indicated. 
ECGs will be recorded after the patient has rested in a supine position for at least 10 minutes in each case. 
The Investigator or designated physician will review the paper copies of each of the timed 12-lead ECGs 
when they are collected. 
9.2.3 
Vital Signs 
Vital signs, including systolic and diastolic blood pressure (mmHg), pulse (beats per minute), respiration 
rate (breaths per minute), and temperature, are to be measured during screening; at D-14 (EMIC Cohort 
only); on D1 of each treatment cycle; and at the EOT (7 days post-last dose) and Safety F/U (30 and 90 
days thereafter) visits. 
Measurements are to be made after the patient has been resting in a supine position for a minimum of 5 
minutes. 
Blood pressure and pulse will be measured using a blood pressure recording device with an appropriately 
sized cuff. The units (°F or C) and mode of temperature recording will be documented (e.g., oral, 
axillary); the same units and mode should be used for a patient across all measurements. 
9.2.4 
Weight 
Weight is to be measured during screening; at D-14 (EMIC Cohort only); on D1 of each treatment cycle; 
and at the EOT (7 days post-last dose) and Safety F/U (30 and 90 days thereafter) visits. 
9.2.5 
ECOG Performance Status 
ECOG performance status is to be assessed during screening; at D-14 (EMIC Cohort only); on D1 of each 
treatment cycle; and at the EOT (7 days post-last dose) and Safety F/U (30 and 90 days thereafter) visits. 


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The ECOG performance status scale, with corresponding Karnofsky performance status score 
equivalents, is presented in Table 9-1. 
Table 9-1 
Eastern Cooperative Oncology Group Performance Status Scale, with Equivalent 
Karnofsky Performance Status Scores 
ECOG1 
Karnofsky2 
Score 
Criterion 
% 
Criterion 
0 
Normal activity 
100 
Normal; no complaints; no evidence of 
disease 
 
 
90 
Able to carry on normal activity; minor 
signs or symptoms of disease 
1 
Symptoms but ambulatory 
80 
Normal activity with effort; some signs or 
symptoms of disease 
 
 
70 
Cares for self; unable to carry on normal 
activity or do active work 
2 
In bed <50% of time 
60 
Requires occasional assistance but is able 
to care for most of his/her needs 
 
 
50 
Requires considerable assistance and 
frequent medical care 
3 
In bed >50% of time 
40 
Disabled, requires special care and 
assistance 
 
 
30 
Severely disabled; hospitalization is 
indicated though death is not imminent 
4 
100% bedridden 
20 
Very sick; hospitalization is necessary 
 
 
10 
Moribund; fatal processes progressing 
rapidly 
5 
Dead 
0 
Dead 
1 Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP. Toxicity and response criteria of the 
Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982;5:649-655. 
2 Mor V, Laliberte L, Morris JN, Wiemann M. The Karnofsky Performance Status Scale:  an examination of its reliability and 
validity in a research setting. Cancer. 1984;53:2002-2007. 
9.2.6 
Clinical Laboratory Tests  
Blood samples for hematology and clinical chemistries are to be collected and run locally during 
screening; at D-14 (EMIC Cohort only); on D1, D8, and D15 of C1; on D1 and D15 of C2; on D1 of each 
subsequent treatment cycle; and at the EOT visit (7 days post last dose). If screening hematology and 
clinical chemistry tests are performed within 7 days of C1D1, they need not be repeated at C1D1.  


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The following analytes are to be measured: 
Hematology 
 
White blood cell count (WBC) with differential 
Hemoglobin 
Red blood cell count (RBC) 
Hematocrit 
Platelet count 
 
Clinical Chemistries 
 
ALT 
AST 
ALP 
Albumin 
Total bilirubin 
Blood urea nitrogen (BUN) 
Calcium 
Creatinine 
Sodium 
Potassium 
Chloride 
Bicarbonate 
Glucose 
Lactic dehydrogenase 
Phosphorus 
Total Protein 
Uric acid 
Magnesium (screening only, unless clinically 
indicated) 
Blood samples for thyroid function tests, including thyroid-stimulating hormone (TSH), free thyroxine 
(FT4), and total or free triiodothyronine (T3 or FT3) are to be collected and run locally during screening, 
every 6 weeks thereafter during treatment starting at C2, and at the EOT visit (7 days post last dose). 
In addition, coagulation studies, including PT or INR and aPTT, are to be measured during screening 
(locally). However, if a patient is receiving coumarin derivatives concurrently with entinostat, 
Investigators are advised to monitor PT and INR every cycle or as clinically indicated, whichever is more 
frequent. 
In the CRC cohort, blood tumor marker CEA should be drawn on day 1 of each cycle. 
  
 


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Clinical laboratory evaluations are to be repeated as necessary during treatment at a schedule determined 
by the Investigator, based on the patient’s clinical status. 
Laboratory abnormalities that are considered by the Investigator to be clinically significant for a particular 
patient are to be reported as AEs. 
9.2.7 
Adverse Events 
AEs, as defined in Section 11.2.1, are to be documented from the time of signing the informed consent 
through 30 days post-last dose, with the exception of Serious Adverse Events, which must be documented 
through 90 days following cessation of treatment, or 30 days after the initiation of a new anticancer 
therapy, whichever is earlier (Section 11.4.3). Events meeting the definition of serious (including Events 
of Clinical Interest) are to be reported as such as described in Section 11.4 and Section 11.4.3. 
9.3 
Efficacy Assessments 
With the exception of OS, all efficacy endpoints in this trial (including the primary endpoint in Phase 2) 
are linked to the tumor response assessments and therefore the importance of timely and complete disease 
assessments in this study cannot be understated. Failure to perform any of the required disease 
assessments will result in the inability to determine disease status for that time point. Frequent off 
schedule or incomplete disease assessments have the potential to weaken the conclusion of this clinical 
trial. 
The schedule of tumor burden assessments should be fixed according to the calendar, regardless of 
treatment interruptions. Tumor burden assessments will be performed until progressive disease as per 
irRECIST and RECIST 1.1 regardless of the discontinuation of study treatment or the start of a 
subsequent anticancer therapy. Patients with radiographic progression only, as defined by RECIST 1.1 
should continue on study treatment until unequivocal progressive disease is determined as defined by 
irRECIST, at the discretion of the investigator. 
The same method of assessment and the same technique used for study screening (CT scan or MRI) to 
characterize each lesion must be used at each subsequent post-screening assessment.  
9.3.1 
Tumor Measurements and Disease Response Assessment 
9.3.1.1 
Baseline Tumor Measurement and Assessment 
Initial tumor imaging at screening must be performed within 28 days prior to C1D1. (Scans performed as 
part of routine clinical management are acceptable for use as initial tumor imaging if they are of 


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diagnostic quality, have been performed within 28 days prior to C1D1, and can be assessed by the central 
imaging vendor). Patients will have radiological disease assessments performed every 6 weeks (+/-3 
days) (Week 6, Week 12, etc.) during study treatment until progressive disease. If a patient comes off 
study for reasons other than progressive disease, radiological assessments will continue on this same 
study schedule until progressive disease is unequivocally documented. Images should be kept to the 
calendar schedule and not be delayed for delays in cycles or study drug administration. Disease response 
in target and non-target lesions will be assessed locally by the Investigator using irRECIST and RECIST 
1.1. 
Measurable Disease 
To be eligible for study participation, all patients must have measurable disease per RECIST 1.1 that has 
been radiologically documented within 28 days prior to initiating study drug treatment, defined as 
follows: 
At least 1 measurable lesion: 
• 
≥10 mm in longest diameter on an axial image by CT scan or MRI with ≤5 mm reconstruction 
interval 
o If slice thickness is no greater than 5 mm, longest diameter must be at least 2 times the 
thickness 
• 
≤20 mm longest diameter by chest X-ray (if clearly defined and surrounded by aerated lung); CT 
is preferred, even without contrast 
• 
Lymph nodes ≥ 15 mm in short axis on CT scan (CT slice thickness of ≤5 mm) 
If there is only 1 measurable lesion and it is located in previously irradiated field, it must have 
demonstrated progression according to RECIST 1.1. 
Non-measurable 
Non-measurable lesions are defined per RECIST 1.1 as the following and should be captured and 
followed appropriately in the eCRF according the eCRF guidelines.  
• 
Masses < 10 mm 
• 
Lymph nodes 10 – 14 mm in short axis 
• 
Leptomeningeal disease 


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• 
Ascites, pleural or pericardial effusion 
• 
Lymphangitic involvement of skin or lung 
• 
Abdominal mases or organomegaly identified by physical exam which cannot be measured by 
reproducible imaging techniques  
• 
Blastic bone lesions 
• 
Both benign and equivocal (“cannot exclude”) findings should not be included   
Target versus non-target 
• 
Target:  all measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, 
representative of all involved organs, are to be identified as target lesions and measured and 
recorded at screening. Target lesions are to be selected on the basis of their size (i.e., those with 
the longest diameter) and suitability for accurate repeated measurement. The sum of the diameters 
for all target lesions is to be calculated and recorded on the eCRF as the baseline sum diameters.  
• 
Non-target:  all other lesions not classified as target lesions (or sites of disease) are to be 
identified as non-target lesions and are to be recorded on the eCRF. Measurement of non-target 
lesions is not required. 
9.3.1.2 
Scan Procedures 
Contrast-enhanced CT scans of chest, abdomen, and, as clinically indicated, pelvis are preferred for 
evaluation of disease status for this study; however, a contrast-enhanced MRI can also be performed if a 
patient has or develops allergy to iodinated contrast agents.  
Positron emission tomography (PET) alone will not be acceptable as part of the imaging to be performed 
for this study. If PET is performed, the Investigator should not remove any patient based on PET alone, as 
there can be false positives. If he/she thinks a patient has progressed via PET, it must be confirmed with a 
CT/MRI.  
If a combined 18F-deoxyglucose (FDG) PET-CT scan is performed, the CT portion of that examination 
should not be substituted for the dedicated CT examinations required by this protocol for tumor 
measurements unless the study center can document that the CT performed as part of the FDG PET-CT is 
of identical diagnostic quality to a diagnostic CT (with IV and oral contrast). 


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CT Scan Procedures 
Study centers must acquire and submit CT scans according to the parameters below: 
• 
Use consistent scan parameters (spacing, thickness, field of view, etc.) for all assessments. Any 
alternate imaging or parameter variation from the protocol should be noted.  
• 
If a patient develops hypersensitivity to the iodinated contrast medium while on study, it is 
acceptable to perform chest CT scans without contrast. In addition, a contrast-enhanced MRI scan 
according to the parameters described in the MRI section must be performed for the remainder of 
the required anatomy.  
• 
The patient should be given oral contrast (as either positive [e.g., barium or Gastrografin] or 
negative [e.g., water or saline] contrast media, according to site standard of care) prior to the 
examination to allow for sufficient bowel opacification.  
• 
Non-ionic iodinated IV contrast with a minimum of 320 mg iodine/mL should be used for this 
study. Contrast agent volume should be according to the package insert. The same contrast agent 
with the same concentration should be used throughout the study. 
MRI Scan Procedures 
• 
If IV contrast is medically contraindicated during the study, a dynamic contrast-enhanced MRI is 
an acceptable alternative to CT scans of the abdomen and pelvis.  
• 
MRI must be performed using either 1.5T or 3.0T scanner. A change in scanner field strength is 
not allowed for an individual patient while on study (e.g., if a patient has a C2 MRI scan at 3.0T, 
all subsequent scans must be performed at 3.0T).  
• 
MRI scans should use optimized parameters to decrease motion artifact and maximize signal-to-
noise ratio and resolution. Breath-hold imaging, fast-scanning techniques, and gadolinium should 
be used to maximize lesion identification. Note: A non-contrast CT scan of the chest or digital 
chest X-ray must be acquired in addition to the MRI of the abdomen and, as applicable, pelvis. 
• 
The patient must undergo scanning with approved extracellular contrast media only (e.g., 
Magnevist, Dataram, Omniscan).  


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• 
The same equipment, field strength, sequences, scanning parameters, positioning, angulation, 
timing, field of view, and slice thickness should be utilized for all examinations acquired both 
pre- and post-contrast for a given patient over the course of the study. 
9.3.1.3 
Disease Response Assessment Criteria 
Patients will have radiological disease assessments performed every 6 weeks (±3 days) (Week 6, 
Week 12, etc.) until unequivocal progressive disease or closure of the study by the Sponsor.  
All scans will submitted electronically to a central core radiologic laboratory. Scans from patients who 
were determined by the Investigator to have a response to treatment (CR or PR) will be reviewed by the 
core radiologic laboratory to confirm response. Scans from non-responders may also be reviewed by the 
core radiologic laboratory at the direction of the Sponsor. 
Disease response in target and non-target lesions will be assessed locally by the Investigator using 
immune response RECIST (irRECIST) and RECIST 1.1.  
Partial or complete response should be confirmed by a repeat tumor imaging assessment no less than 
4 weeks from the date the response was first documented. The tumor imaging for confirmation of 
response may be performed at the earliest, 4 weeks after the first indication of response, or at the next 
scheduled scan (i.e. 6 weeks later), whichever is clinically indicated. 
When clinically stable, participants should not be discontinued until progression is confirmed by the 
Investigator, working with local radiology, according to the rules outlined in Appendix 3. This allowance 
to continue treatment despite initial radiologic PD takes into account the observation that some 
participants can have a transient tumor flare in the first few months after the start of immunotherapy, and 
then experience subsequent disease response. This data will be captured in the clinical database. 
Clinical stability is defined as the following:  
- Absence of symptoms and signs indicating clinically significant progression of disease 
- No decline in ECOG performance status  
- No requirements for intensified management, including increased analgesia, radiation, or other 
palliative care 
If repeat imaging does not confirm PD per iRECIST, as assessed by the Investigator, and the participant 
continues to be clinically stable, study treatment may continue and follow the regular imaging schedule. If 
PD is confirmed, participants will be discontinued from study treatment. 


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If a participant has confirmed radiographic progression (iCPD) as defined in Appendix 3, study treatment 
should be discontinued; however, if the participant is achieving a clinically meaningful benefit, an 
exception to continue study treatment may be considered following consultation with the Sponsor. In this 
case, if study treatment is continued, tumor imaging should continue to be performed following the 
intervals as outlined in Section 13 and submitted to the central imaging vendor.  
A description of the adaptations and iRECIST process is provided in Appendix 3, with additional details 
in the iRECIST publication (Seymour 2017). A summary of imaging and treatment requirements after 
first radiologic evidence of progression is provided in Table 9-2 and illustrated as a flowchart in Figure 
9-1. 
Table 9-2 
Imaging and Treatment After 1st Radiologic Evidence of PD 
 
Clinically Stable 
Clinically Unstable 
Imaging 
Treatment 
Imaging 
Treatment 
First radiologic 
evidence of PD by 
RECIST 1.1 
Repeat imaging at 
4 to 8 weeks to 
confirm PD. 
May continue study 
treatment at the 
Investigator’s discretion 
while awaiting 
confirmatory tumor 
imaging by site by 
iRECIST. 
Repeat imaging at 
4 to 8 weeks to 
confirm PD per 
Investigator’s 
discretion only. 
Discontinue treatment 
Repeat tumor 
imaging confirms PD 
(iCPD) by iRECIST 
per Investigator 
assessment 
No additional 
imaging required. 
Discontinue treatment 
(exception is possible 
upon consultation with 
Sponsor). 
No additional 
imaging required. 
Not applicable 
Repeat tumor 
imaging shows iUPD 
by iRECIST per 
Investigator 
assessment 
Repeat imaging at 4 
to 8 weeks to 
confirm PD. May 
occur at next 
regularly scheduled 
imaging visit. 
Continue study treatment 
at the Investigator’s 
discretion. 
Repeat imaging at 4 
to 8 weeks to 
confirm PD per 
Investigator’s 
discretion only. 
Discontinue treatment 
Repeat tumor 
imaging shows iSD, 
iPR, or iCR by 
iRECIST per 
Investigator 
assessment. 
Continue regularly 
scheduled imaging 
assessments. 
Continue study treatment 
at the Investigator’s 
discretion. 
Continue regularly 
scheduled imaging 
assessments. 
May restart study treatment 
if condition has improved 
and/or clinically stable per 
Investigator’s discretion. 
Next tumor imaging should 
occur according to the 
regular imaging schedule. 
BICR = Blinded Independent Central Review; iCPD = iRECIST confirmed progressive disease; iCR = iRECIST complete 
response; iRECIST = modified Response Evaluation Criteria in Solid Tumors 1.1 for immune-based therapeutics; iSD = 
iRECIST stable disease; iUPD = iRECIST unconfirmed progressive disease; PD = progressive disease; RECIST 1.1 = Response 


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Clinically Stable 
Clinically Unstable 
Imaging 
Treatment 
Imaging 
Treatment 
Evaluation Criteria in Solid Tumors 1.1. 
Figure 9-1: Imaging and Treatment for Clinically Stable Participants Treated with 
Pembrolizumab after First Radiologic Evidence of PD Assessed by the Investigator 
 


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NOTE: If a patient has confirmed radiographic progression (i.e., 2 scans at least 4 weeks apart 
demonstrating progressive disease), but the patient is achieving a clinically meaningful benefit, and there 
is no further increase in the tumor burden at the confirmatory tumor imaging, an exception to continue 
treatment may be considered following consultation with the Sponsor. In this case, if treatment is 
continued, tumor imaging should continue to be performed following the study intervals and be submitted 
to the central imaging vendor. 
When feasible, patients should not be discontinued until PD is confirmed. However, patients that are 
deemed clinically unstable are not required to have repeat imaging for confirmation of PD and should 
come off study treatment. 
9.4 
Protein Lysine Acetylation and Immune Correlates 
Based on preclinical studies it is suggested that entinostat may specifically target a population of MDSCs 
and thus improve the response to PD-1 or PD-L1 antibody treatment. The Sponsor plans to evaluate 
populations of MDSC and other myeloid cells in peripheral blood and tumor tissues of the patients (if 
available) and also to evaluate the basic T-cell function in patients, with the expectation that if MDSC 
level is decreased the response to antigens would be improved. 
Blood for immune correlates and protein lysine acetylation is to be shipped on the same day of draw to 
the applicable laboratories with proper advanced notification according to the laboratory manual. 
9.4.1 
Blood 
For patients in the EMIC Cohort, blood for immune correlates is to be collected pre-dose on D-14, C1D1, 
C1D8, and C2D15. For patients in all other cohorts, blood for immune correlates is to be collected pre-
dose on C1D1, C2D1, and C2D15. At these time points, 40 mL of heparinized peripheral blood is to be 
collected and shipped overnight to a central laboratory facility for analysis. 
For patients in the EMIC Cohort, blood for protein lysine acetylation is to be collected pre-dose on D-14, 
C1D1, C1D15, and C2D15. For patients in all other cohorts, blood for protein lysine acetylation is to be 
collected pre-dose on C1D1, C1D15 and C2D15. At these time points, approximately 16mL of blood is to 
be collected and shipped overnight to a central laboratory facility for analysis. 
The following immune correlate analyses will be performed on the collected samples: 
Cell Phenotype: 
• 
MDSC: Lin (CD3, CD14, CD19, CD56) negative, HLA-DR-, CD33+; 


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• 
MDSC: CD11b+CD14-CD33+; 
• 
PMN-MDSC: CD11b+CD14-CD33+CD15+; 
• 
M-MDSC: CD11b+CD14-CD33+CD15-; 
• 
M-MDSC: CD14+HLA-DR-/lo; 
• 
Monocytes: CD14+CD16+CD66b-HLA-DR+ including subsets of classical CD14hiCD16, 
intermediate CD14hiCD16+ and non-classical CD14+CD16hi; 
• 
Dendritic cells: Lin-HLA-DR+CD303+ (BDCA2) plasmacytoid; Lin-HLA-DR+CD1c+ (BDCA1) 
myeloid; Lin-HLA-DR+CD141+ (BDCA3); 
• 
Neutrophils: CD11b+CD14-CD15+/CD66b+ cells in high density fraction; 
• 
T cells: CD3+CD4+; CD3+CD8+; Regulatory T cells: CD4+CD25+FoxP3+; 
• 
B cells: CD19. 
Cell Function: 
• 
Mononuclear cells stimulated with CD3/CD28, ConA, and tetanus toxoid. Cell proliferation by 
3H-thymidine uptake will be measured. Supernatant will be collected and interleukin-2, IFN-γ, 
and GM-CSF will be measure by enzyme-linked immunosorbent assay. 
Refer to the Study Laboratory Manual for instructions on sample collection and shipment.  


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9.4.2 
Tumor Tissue 
Fresh tumor tissue samples will be collected during the study as follows: 
• 
During screening from all patients on a mandatory basis. 
• 
On C2D15 (+3 days) on an optional basis from patients in the Dose Escalation/Confirmation 
Phase. All patients in the Dose Escalation/Confirmation Phase will be strongly encouraged to 
provide an optional biopsy in order to help understand dose-immune correlate effects. 
• 
On C2D15 (+3 days) on a mandatory basis from the first 10 patients (in total, across cohorts) 
in Stage 1 in the Expansion Phase, the first 10 patients in the EMIC Cohort, and the first 10 
patients in the CRC Cohort.  
• 
If, based on an interim review of tumor tissue data from the initial patients in the Expansion 
Phase, such data are considered informative, then tumor tissue samples will be collected on a 
mandatory basis from all subsequent patients in the Expansion Phase on C2D15 (+3 days). 
Alternatively, if such data are not considered informative, these samples will not be collected 
from subsequent patients.  
If patients whose only accessible lesion for biopsy is a solitary target lesion, it must be amenable to a core 
biopsy that will not compromise assessment of tumor measurements. If patients have only one measurable 
lesion per RECIST v1.1: 
1. the biopsy specimen should be obtained from a non-target lesion  
2. this lesion should not have been in a field of prior-irradiation unless confirmed progression of 
the lesion 
Should a patient opt out of a mandatory biopsy procedure, it will be considered a protocol deviation; 
however, the patient will be allowed to continue treatment on study. 
Tissue samples will be analyzed for changes in expression of checkpoint inhibitors (PD-1/PD-L1) 
Cohorts 1, 2, and 3 only) in tumor biopsies pre- and post-therapy as well as the following immune 
correlates:  
• 
MDSC: CD33+S100A9+; 
• 
Macrophages CD163+ or CD68+ cells; 
• 
Neutrophils – Neutrophil elastase+ cells; 


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• 
Dendritic cells – DC-SIGN (CD209); 
• 
CD4, CD8, Granzyme B, and FoxP3 positive cells will be done as appropriate if the MDSC 
level in the tissues is decreased. 
Additional details regarding the processing, storage, and shipment of tissue samples for immune correlate 
assessments are provided in the Study Manual. 
9.5 
Pharmacokinetics 
9.5.1 
Entinostat 
Blood samples will be collected to assess the PK of entinostat and will be quantified by a sensitive and 
specific validated bioanalytical method. One (1) blood samples will be collected at the following time 
points: 
• 
Pre-dose C1D1 
• 
2-4 hours post dose C1D1  
• 
C1D8 (anytime post dose) 
• 
C1D15 (anytime post dose) 
• 
Pre-dose C2D1 
On each PK sample collection day, the time and date of entinostat administration, the start and stop time 
of pembrolizumab administration, and the time and date of PK sample collection should be recorded in 
the eCRF. 
Instructions for sample collection and shipment will be provided in the PK laboratory manual. 
9.5.2 
Pembrolizumab 
Samples for determination of trough pembrolizumab levels and anti-pembrolizumab antibodies will be 
collected at the following time points (all taken pre-dose): 
• 
C1D1 
• 
C2D1 
• 
C4D1 
• 
C6D1 


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• 
C8D1 
• 
Every 4 cycles thereafter until last dose of pembrolizumab 
• 
30 days after the last pembrolizumab dose (or until the patient starts new anti-cancer therapy).  
All pre-dose trough samples should be collected within 24 hours before the pembrolizumab infusion. 
On each sample collection day, the time and date of entinostat administration, the start and stop time of 
pembrolizumab administration, and the time and date of sample collection should be recorded in the 
eCRF. 
Instructions for sample collection and shipment will be provided in the laboratory manual. 


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10. 
DISCONTINUATION AND REPLACEMENT OF PATIENTS 
Patients have the right to withdraw fully or partially from the study at any time and for any reason without 
prejudice to their future medical care by the physician or at the institution.  
Withdrawal of full consent for a study means that the patient does not wish to receive further 
investigational treatment and does not wish to or is unable to continue further study participation. 
Withdrawal of partial consent means that the patient does not wish to take investigational product any 
longer but is still willing to collaborate in providing further data by continuing on study (e.g., participate 
in all subsequent study visits or procedures). Any patient may withdraw full or partial consent to 
participate in the study at any time during the study.  
Reasons for permanently discontinuing study therapy and/or observation might include: 
• 
ineligibility 
• 
withdrawal of consent 
• 
administrative decision by the Investigator or Syndax 
• 
pregnancy 
• 
significant protocol deviation or patient noncompliance 
• 
Unacceptable toxicity 
• 
Confirmed disease progression  
• 
The investigator believes it is no longer in the patient’s best interest to continue study therapy  
In the event of discontinuation of all treatment or full withdrawal from the study, the Investigator will 
complete the End of Study form and indicate the date and the appropriate reason. To the greatest extent 
possible, the Investigator will attempt to complete protocol-required follow-up tests.  
Patients who discontinue the study for reasons other than study drug-related toxicity before completing 
C1 may be replaced. 


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11. 
ADVERSE EVENTS, DATA REPORTING, AND RECORDING 
11.1 
Study Drugs 
11.1.1 
Entinostat 
Commonly encountered AEs across clinical studies of entinostat monotherapy in patients with solid 
tumors included hypoalbuminemia, fatigue, nausea, hypophosphatemia, anemia, and thrombocytopenia. 
Incidence and severity were dose- and schedule-dependent. In a Phase 2, randomized, placebo-controlled 
study in patients with lung cancer, in which patients received erlotinib+entinostat or erlotinib+placebo, 
treatment-emergent adverse events (TEAEs) occurring at a ≥10% higher incidence in entinostat-treated 
patients versus placebo-treated patients included nausea (49% versus 25%); anorexia (40% versus 16%); 
weight decreased (32% versus 18%); dyspnea (31% versus 18%); vomiting (31% versus 13%); peripheral 
edema (28% versus 13%); anemia (22% versus 11%); thrombocytopenia (15% versus 3%); hypotension 
(14% versus 2%); and stomatitis (12% versus 2%). In a Phase 2 study in patients with metastatic 
melanoma treated with entinostat monotherapy, the most common TEAEs were nausea (39%), 
hypophosphatemia (29%), pain in extremity (21%), and back pain and diarrhea (each 18%) (Hauschild 
2008).  
Additional clinical experience is summarized in the entinostat IB. As stated previously, there are no 
clinical data with entinostat in combination with pembrolizumab. 
11.1.2 
Pembrolizumab 
Please refer to the current Informed Consent, Investigator’s Brochure, and the Study Manual for the 
current safety profile and information regarding pembrolizumab. 
11.2 
Adverse Event Definitions 
11.2.1 
Adverse Events 
An AE is defined in the International Conference on Harmonisation (ICH) Guideline for Good Clinical 
Practice as “any untoward medical occurrence in a patient or clinical investigation patient administered a 
pharmaceutical product and that does not necessarily have a causal relationship with this treatment” (ICH 
E6:1.2). 


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Worsening of a pre-existing medical condition, (i.e., diabetes, migraine headaches, gout) should be 
considered an AE if there is either an increase in severity, frequency, or duration of the condition or an 
association with significantly worse outcomes. 
Interventions for pretreatment conditions (i.e., elective cosmetic surgery) or medical procedures that were 
planned before study enrollment are not considered AEs. 
Disease progression (PD) should not be recorded as an AE unless it results in hospitalization or death. If 
PD occurs, record the date first documented in the EOT visit eCRF. Also record all methods of 
assessment, i.e., 1 target/non-target lesion, tumor response assessment, and/or clinical disease assessment. 
Indicate if the patient starts new treatment. 
In the case of death, only record “Fatal” for the event causing death. AEs that are ongoing at the end of 
the study or time of death are to be noted as “continuing.” Classification of AEs is to be done by the 
Investigator is according to the NCI CTCAE, Version 4.03. The Death eCRF must also be completed. 
The Investigator is responsible for reviewing laboratory test results and determining whether an abnormal 
value in an individual patient represents a significant change from baseline. In general, abnormal 
laboratory findings without clinical significance (based on the Investigator’s judgment) should not be 
recorded as AEs; however, laboratory value changes requiring therapy or adjustment in prior therapy are 
considered AEs. 
11.2.2 
Suspected Adverse Reaction 
A suspected adverse reaction is any AE for which there is a reasonable possibility that the drug caused the 
adverse event. For the purposes of Investigational New Drug Application (IND) safety reporting, 
‘reasonable possibility’ means there is evidence to suggest a causal relationship between the drug and the 
AE. A suspected adverse reaction implies a lesser degree of certainty about causality than adverse 
reaction, which means any AE caused by a drug. 
11.2.3 
Unexpected Adverse Event 
An unexpected AE or suspected adverse reaction is considered “unexpected” if it is not listed in the 
Investigator Brochure or is not listed at the specificity or severity that has been observed; or, if an 
Investigator Brochure is not required or available, is not consistent with the risk information described in 
the General Investigational Plan or elsewhere in the current application, as amended.  


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11.2.4 
Serious Adverse Events 
An AE or suspected adverse reaction is considered “serious” if, in the view of either the Investigator or 
Sponsor, it results in any of the following outcomes:  
• 
is fatal 
• 
is life-threatening (i.e., places the patient at immediate risk of death) 
• 
requires in-patient hospitalization or prolongation of existing hospitalization 
• 
results in persistent or significant disability/incapacity 
• 
is a congenital anomaly/birth defect 
• 
is an important medical event that may not result in death, be life-threatening, or require 
hospitalization but may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, it may jeopardize the patient and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. Examples of such medical 
events include allergic bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse. 
A hospitalization meeting the regulatory definition for “serious” is any in-patient hospital admission that 
includes a minimum of an overnight stay in a health care facility. Any AE that does not meet one of the 
definitions of serious (i.e., emergency room visit, out-patient surgery, or requires urgent investigation) 
may be considered by the Investigator to meet the “other significant medical hazard” criterion for 
classification as a serious adverse event (SAE). 
11.3 
Reporting Procedures for All Adverse Events 
The Investigator is responsible for ensuring that all AEs (as defined in Section 11.2) observed by the 
Investigator or reported by patients are properly captured in the patients’ medical records and reported on 
the eCRF. The evaluation time period for all adverse events or events of clinical interest is from the time 
that the informed consent is signed to at least 30 days after the last dose of entinostat or pembrolizumab, 
or until resolution of all acute toxicities associated with study drug administration, whichever is longer, 
with the exception of SAEs, which must be documented through 90 days following cessation of 
treatment, or 30 days after the initiation of a new anticancer therapy, whichever is earlier (Section 11.4). 


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The following AE attributes must be assigned by the Investigator: event description (with detail 
appropriate to the event); seriousness; dates of onset and resolution; severity; assessment of relatedness to 
entinostat and to pembrolizumab; and the action taken. The Investigator may be asked to provide follow-
up information, discharge summaries, and extracts from medical records. 
If applicable, the study drug relationship will be assessed by means of the question: “Is there a reasonable 
possibility that the event may have been caused by one of the two drugs based on mechanism of action 
and/or toxicity profile, or by the combination of entinostat with pembrolizumab?” The causal relation 
between an AE and the study drug will be determined by the Investigator on the basis of his or her clinical 
judgment and the following definitions:  
• 
Related: event can be fully explained by administration of the study drug(s) 
• 
Possibly Related: event may be explained by administration of the study drug(s), or by the 
patient’s clinical state or other agents/therapies 
• 
Unlikely Related: event is most likely to be explained by the patient’s clinical state or other 
agents/therapies 
• 
Not Related: event can be fully explained by the patient’s clinical state or other agents/therapies 
When assessing the relationship between administration of the study drug and the AE, the following 
should be considered: follows a temporal sequence from administration of investigational product is a 
known response to the investigational product based on clinical or preclinical data could not be explained 
by the known characteristics of the patient’s clinical state, environmental or toxic factors, or other therapy 
administered to the patient disappears or decreases upon cessation or reduction of dose of investigational 
product reappears or worsens when investigational product is reinstated. 
Whenever possible, the CTCAE, Version 4.03, should be used for assessing the severity of AEs 
(http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf).  
For AEs that are not adequately addressed in the NCI CTCAE, the standard severity grading scale may be 
used (Table 11-1). 


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Table 11-1 
Standard Severity Grading Scale 
Grade 
Standard Adverse Event Severity Scoring System 
1 
Mild: 
Aware of sign or symptom, but easily tolerated. 
2 
Moderate: 
Discomfort enough to cause interference with usual activity. 
3 
Severe: 
Incapacitating with inability to work or do usual activity. 
4 
Life-Threatening: 
Refers to an event in which the patient was, in the view of the 
Investigator, at risk of death at the time of the event. (This category 
is not to be used for an event that hypothetically might have caused 
death if it were more severe.) 
5 
Fatal: 
Event resulted in death. 
It will be left to the Investigator’s clinical judgment to determine whether an AE is related and of 
sufficient severity to require the patient’s removal from treatment or from the study. A patient may also 
voluntarily withdraw from treatment due to what he/she perceives as an intolerable AE. If either of these 
situations arises, the patient should be strongly encouraged to undergo an end-of-study assessment and be 
under medical supervision until symptoms cease or the condition becomes stable. 
11.4 
Serious Adverse Event Reporting Procedures 
SAEs will be collected and recorded throughout the study period, beginning with the signing of the 
informed consent form through 90 days after the last dose of study drug or end of the study (if thought to 
be related to study drug), or 30 days after the initiation of a new anticancer therapy, whichever is earlier. 
All SAEs must be reported to Syndax or its representative within 24 hours of discovery or notification of 
the event. Initial SAE information and all amendments or additions must be recorded on a Serious 
Adverse Event Report Form and provided to Syndax or its representative. The SAE reporting procedure is 
provided in the Study Manual. 
For all deaths, available autopsy reports and relevant medical reports should be provided to Syndax or its 
representative. If a patient is permanently withdrawn from the study because of an SAE, this information 
must be included in the initial or follow-up Serious Adverse Event Report Form as well as the EOT 
eCRF.  
The Investigator should notify the IRB or EC of SAEs occurring at the site and other AE reports received 
from Syndax, in accordance with local procedures and statutes. 


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11.4.1 
Pregnancy and Lactation Reporting Procedures 
Although pregnancy and lactation are not considered AEs, it is the responsibility of Investigators or their 
designees to report any pregnancy or lactation in a patient (spontaneously reported to them) that occurs 
during the study or within 120 days of completing the study or 30 days following cessation of treatment if 
the patient initiates new anticancer therapy, whichever is earlier. All patients who become pregnant must 
be followed to the completion/termination of the pregnancy. Pregnancy outcomes of spontaneous 
abortion, missed abortion, benign hydatidiform mole, blighted ovum, fetal death, intrauterine death, 
miscarriage, and stillbirth must be reported as SAEs (Important Medical Events). If the pregnancy 
continues to term, the outcome (health of infant) must also be reported. 
Such events must be reported within 24 hours to the Sponsor either by electronic media or paper. Sponsor 
Contact information can be found in the Study Manual. 
Please refer to the Study Manual for further details on the pregnancy reporting procedure and associated 
report form.  
11.4.2 Definition of an Overdose for This Protocol and Reporting of Overdose to the Sponsor 
11.4.2.1 
Entinostat Overdose  
No information on the treatment of overdose of entinostat is currently available. Entinostat overdoses are 
defined as a single dose greater than 15mg. This overdose will not be considered an SAE unless the 
outcome of the overdose meets seriousness criteria as defined in Section 11.2.4. In the event of an 
entinostat overdose, the Sponsor should be immediately notified. The patient should be carefully 
monitored for potential adverse reactions and symptomatic treatment instituted as per institutional 
standards of care.  
11.4.2.2 
Pembrolizumab Overdose 
For this study, a pembrolizumab overdose will be defined as ≥5 times the dose for pembrolizumab (e.g., 
≥1000 mg). A pembrolizumab overdose is considered an SAE as described in Section 11.4.3. No specific 
information is available on the treatment of overdose of pembrolizumab. In the event of overdose, the 
patient should be observed closely for signs of toxicity. Appropriate supportive treatment should be 
provided if clinically indicated. 


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11.4.3 
Events of Clinical Interest with Pembrolizumab 
Selected adverse events are also known as Events of Clinical Interest (ECI) and must be reported within 
24 hours to the Sponsor according to the SAE Reporting Procedures as outlined in Section 11.4. Sponsor 
Contact information can be found in the Study Manual.  
ECIs for this study include: 
1. An overdose of pembrolizumab, as defined in Section 11.4.2, that is not associated with clinical 
symptoms or abnormal laboratory results.  
2. an elevated AST or ALT value that is ≥3×ULN and an elevated total bilirubin value that is ≥2×ULN 
and, at the same time, an alkaline phosphatase value that is <2×ULN, as determined by way of 
protocol-specified laboratory testing or unscheduled laboratory testing.* 
*Note:  These criteria are based upon available regulatory guidance documents. The purpose of the 
criteria is to specify a threshold of abnormal hepatic tests that may require an additional evaluation for an 
underlying etiology. The study site guidance for assessment and follow up of these criteria, called the 
Drug Induced Liver Injury and Overdose Guidelines, can be found in the Study Manual. 
11.4.4 
Follow-Up of Adverse Events 
The Investigator must continue to follow all SAEs and non-serious AEs considered to be reasonably or 
possibly related to study drug either until resolution or the Investigator assesses them as chronic or stable. 
This follow-up may extend after the end of the study. 
11.4.5 
Safety Reporting to Health Authorities, Ethics Committees/Institutional Review Boards 
and Investigators  
The Sponsor will send appropriate safety notifications to Health Authorities in accordance with applicable 
laws and regulations.  
The Investigator must comply with any applicable site-specific requirements related to the reporting of 
SAEs involving his/her patients to the EC/IRB that approved the trial.  
In accordance with ICH GCP guidelines, the Sponsor or designee will inform the investigator of “findings 
that could adversely affect the safety of study patients, impact the conduct of the trial, or alter the 
EC’s/IRB’s approval/favorable opinion to continue the trial.”  


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When specifically required by regulations and guidelines, the Sponsor or designee will provide 
appropriate Safety reports directly to the concerned health authority and lead EC / IRB and will maintain 
records of these notifications. When direct reporting by the Sponsor or designee is not clearly defined by 
national or site-specific regulations, the Investigator will be responsible for promptly notifying the 
concerned EC / IRB of any safety reports provided by the Sponsor or designee and of filing copies of all 
related correspondence in the Investigator Site File. 
For trials covered by the European Directive 2001/20/EC, the Sponsor’s responsibilities regarding the 
reporting of SAEs / SUSARs / Safety Issues will be carried out in accordance with that Directive and with 
the related detailed guidance. 
11.4.6 
Protocol Deviations Due to an Emergency or Adverse Event 
Departures from the protocol will be determined as allowable on a case-by-case basis and only in the 
event of an emergency. The Investigator or other physician in attendance in such an emergency must 
contact the Medical Monitor as soon as possible to discuss the circumstances of the emergency. 
The Medical Monitor, in conjunction with the Investigators, will decide whether the patient should 
continue to participate in the study. All protocol deviations and reasons for such deviations must be noted 
on the eCRF. 
11.5 
Safety Monitoring 
The safety and tolerability of the investigational treatments will be monitored throughout the course of the 
study by the Investigators and the Sponsor Study Physicians(s) including the Medical Monitor.  
The safety and tolerability data that will be reviewed will include, but are not limited to: AEs, DLTs, 
laboratory test results, and patient discontinuations. Additionally, the development of SAEs will be 
assessed by the Sponsor Study Physician(s) on a continuous basis. (Note that all SAEs must be reported 
to the Sponsor or designee within 24 hours of discovery or notification of the event [Section 11.4].)   
No formal safety stopping rules are specified in the protocol. However, if any significant safety issues 
arise, a decision to modify or terminate the study will be made by the Sponsor in collaboration with the 
Investigators. 


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12. 
STATISTICAL CONSIDERATIONS 
12.1 
Sample Size Estimation 
12.1.1 
Escalation Phase 
Three to 6 patients will be enrolled in each dose cohort based on a standard Phase 1 dose escalation 
scheme. Each patient will participate in only 1 dose cohort. The total number of patients to be enrolled in 
the Dose Escalation/Confirmation Phase is dependent upon the observed safety profile, which will 
determine the number of patients per dose cohort, as well as the number of dose escalations required to 
achieve the MTD or RP2D. 
A starting sample size of at least 3 patients per dose cohort, expanding to 6 patients in the event of a 
marginal DLT rate (33%) was deemed to be a safe and conventional approach in the dose escalation of a 
novel oncologic agent. Assuming a true DLT rate of 5% or less, there would be a 3% chance that dose 
escalation would be halted in a given cohort (i.e., observing 2 or more patients with DLT). If a true DLT 
rate of 50% is assumed, then there would be an 83% chance that dose escalation would be halted in a 
given cohort.  
A total of 9- additional patients will be enrolled in the Dose Confirmation Cohort to obtain additional AE, 
immune correlate, and anti-tumor activity data on entinostat at the MTD or RP2D in combination. 
12.1.2 
Expansion Phase 
In the Expansion Phase of the study, the safety and preliminary antitumor activity of entinostat when 
administered at the RP2D with pembrolizumab will be explored in up to 4 cohorts of adult solid tumors as 
previously defined. Up to 252 patients are planned to be enrolled among the 4 cohorts. Patients will be 
enrolled in each cohort according to a single-arm study design with ORR, as determined by irRECIST, as 
the primary endpoint. The Expansion Phase will be carried out in 2 stages so that enrollment for 1 or more 
of the cohorts evaluated can terminate early in the event the antitumor activity of the combination 
regimen is not sufficient. The decision to terminate or continue enrollment for each cohort will be made 
independently of the other. The number of patients evaluated in each stage and the minimum number of 
responders needed to continue to the next stage, as described for cohort 1, was determined based on the 
optimum version of Simon’s 2-stage design (Simon 1989), with 80% power and 1-sided significance level 
of 10%. For cohort 4, the number of patients evaluated in each stage and the minimum number of 
responders needed to continue to the next stage was determined based on the optimum version of Simon’s 


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2-stage design, with 90% power and 1-sided significance level of 5%. For cohorts 2 and 3, the number of 
responders needed to declare the study a success was based on single proportion binominal test with 90% 
power and 1-sided significance level of 5%. Note that the protocol may be amended to allow for 
enrollment of additional or different cohorts, for example, patients with PD-L1-positive NSCLC, based 
on emerging data during study conduct. 
Syndax will conduct one administrative analysis when at least 60% (42 out of 70 patients in 
cohort 2, 31 out of 52 patients in cohort 3) of patient information have accrued in cohorts 2 and 3 
for decision making for late phase development planning. This administrative look will not lead 
to stopping of the study. Nonetheless, 0.01 alpha is being allocated to spend for the first 
administrative look and leaving 0.04 alpha for the final analysis.  
Cohort 1 (NSCLC patients with squamous cell and adenocarcinoma histology who have not been 
previously treated with a PD-1 or PD-L1-blocking antibody) 
A maximum of 46 patients will be enrolled in Cohort 1. A true ORR of 35% is hypothesized for both 
tumor types. An ORR greater than 20% is considered a lower threshold for antitumor activity that would 
warrant continued development. Based on the design elements specified above, up to 13 patients may be 
enrolled for either tumor type during the first stage:  if 2 or fewer patients achieve an objective response 
(CR or PR), confirmed or unconfirmed, then enrollment will terminate; otherwise, 33 additional patients 
will be enrolled during the second stage. Upon completion of the second stage, if 13 or more patients out 
of the 46 enrolled achieve CR or PR, then the true ORR for the combination therapy likely exceeds 20%, 
the lower threshold of acceptable antitumor activity. Alternatively, if 12 or fewer patients achieve an 
objective response at the end of the second stage, then the true ORR is likely 20% or lower and further 
evaluation of the combination therapy may not be pursued for that tumor type. If the true ORR is 20% or 
less for a tumor type, then the expected sample size is 29.4, with probability of terminating enrollment at 
the end of the first stage equal to 50%. 
Cohort 2 (Patients with NSCLC (any histology) who have previously been treated and progressed on a 
PD-1 or PD-L1-blocking antibody)  
A maximum of 70 patients will be enrolled in Cohort 2. A true ORR of 15% is hypothesized. A response 
rate greater than 5% is considered the lower threshold for antitumor activity that would warrant continued 
development in this setting. Based on the design elements specified above, the single proportion (or one 
sample) binomial test will be used. Ninety-six percent 1-sided confidence interval of the observed one 


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sample proportion will be calculated. The trial will be considered a success if the lower limit of 96% 
confidence interval is greater than 5%.  
Syndax will conduct one administrative analysis when at least 60% (42 out of 70 patients) of patient 
information have accrued in cohorts 2 for decision making for late phase development planning. This 
administrative look will not lead to stopping of the study. Nonetheless, 0.01 alpha is being allocated to 
spend for the first administrative look and leaving 0.04 alpha for the final analysis. 
Cohort 3 (Patients with melanoma who have previously been treated and progressed on a PD-1 or PD-
L1-blocking antibody)  
A maximum of 52 patients will be enrolled in cohort 3. A true ORR of 25% is hypothesized. An ORR 
greater than 10% is considered the lower threshold for antitumor activity that would warrant continued 
development in this setting. Based on the design elements specified above,   the single proportion (or one 
sample) binomial test will be used. Ninety-six percent 1-sided confidence interval of the observed one 
sample proportion will be calculated. The trial will be considered a success if the lower limit of 96% 
confidence interval is greater than 10%. 
Syndax will conduct one administrative analysis when at least 60% (31 out of 52 patients) of patient 
information have accrued in cohorts 3 for decision making for late phase development planning. This 
administrative look will not lead to stopping of the study. Nonetheless, 0.01 alpha is being allocated to 
spend for the first administrative look and leaving 0.04 alpha for the final analysis.  
Cohort 4 (Patients with CRC who have not previously been treated on a PD-1 or PD-L1-blocking 
antibody) 
A maximum of 84 patients will be enrolled in Cohort 4. A true ORR of 15% is hypothesized. An ORR 
greater than 5% is considered the lower threshold for antitumor activity that would warrant continued 
development in this setting. Based on the design elements specified above, up to 37 patients may be 
enrolled during the first stage:  if less than or equal to 2  patients achieve a CR or PR, confirmed or 
unconfirmed, then enrollment will terminate; otherwise, 47 additional patients will be enrolled during the 
second stage. Upon completion of the second stage, if 8 or more patients out of the 84 enrolled achieve 
CR or PR, then the true ORR for the combination regimen likely exceeds 5%, the lower threshold of 
acceptable antitumor activity. Alternatively, if 7 or fewer patients achieve an objective response at the end 
of the second stage, then the true ORR is likely 5% or lower and further evaluation of the combination 


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therapy may not be pursued in this setting. If the true ORR is 5% or less, then the expected sample size is 
50.2, with probability of terminating enrollment at the end of the first stage equal to 72%.  
12.2 
Populations for Analysis 
The Full Analysis Set (FAS) will serve as the primary population for the analysis of tumor response and 
other efficacy-related data. The FAS is a subset of all enrolled patients, with patients excluded for the 
following reasons: 
• 
Failure to receive at least one dose of entinostat and pembrolizumab 
• 
Lack of baseline data for those analyses that require baseline data 
A supportive analysis using the Per-Protocol (PP) set may be performed by excluding patients with 
important deviations from the protocol that may substantially affect the results of the primary efficacy 
analyses. The final determination on protocol violations, and thereby the composition of the PP set, will 
be made prior to locking the clinical database and final analysis and will be documented in a separate 
memo. 
The safety population will be used for the analysis of safety data in this study. The safety population will 
consist of all patients who receive at least one dose of entinostat and pembrolizumab. At least one 
laboratory or other safety-related assessment subsequent to at least one dose of entinostat and 
pembrolizumab is required for inclusion in the analysis of a specific safety parameter. To assess change 
from baseline, a baseline measurement is also required. 
A patient that experiences an adverse event meeting DLT criteria during C1 or who receives the full dose 
of pembrolizumab and all doses of entinostat during C1 without experiencing a DLT, is considered a 
DLT-evaluable patient.  
12.3 
Analysis Schedule 
12.3.1 
Safety Monitoring 
The safety and tolerability of the investigational treatments will be monitored throughout the course of the 
study by the Investigators and Sponsor Study Physician(s) including ongoing review of serious adverse 
events and other safety trends. Frequent meetings will be held during Phase 1 to review safety aspects of 
the study and to render dose escalation decisions as applicable.  
Safety and tolerability data that will be reviewed by the Sponsor Study Physician(s) will include, but are 
not limited to: adverse events, laboratory test results, and patient discontinuations. Note that all serious 


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adverse events must be reported to the Sponsor within 24 hours of discovery or notification of the event. 
No formal safety stopping rules are specified in the protocol. However, if any significant safety issues 
arise, a decision to modify or terminate the trial will be made by the Sponsor in collaboration with the 
study’s Steering Committee.  
12.3.2 
Efficacy Monitoring 
An interim analysis of ORR will be performed for each tumor type after enrollment in the first stage is 
complete in the Expansion Phase. Patients will be followed for response for a minimum of two cycles 
following the initiation of study drug. Patients who die or discontinue treatment during the first two 
cycles because of radiographic and/or clinical evidence of disease progression will be considered 
nonresponders. Enrollment in the second stage will be initiated once enrollment in the first stage is 
complete and the minimum number of responders is observed, as described in Section 12.1.2. If the 
minimum is observed prior to the completion of enrollment, then the transition between the first and 
second stages will occur without interruption. If the minimum is not observed at the time enrollment is 
completed, then enrollment in the second stage will be held until the continuation criterion is met. 
12.4 
Statistical Methods 
The safety and efficacy analyses will be presented by study phase. For the escalation phase, tabulations 
will be provided by dose cohort and overall. For the Expansion Phase, tabulations will be provided by 
tumor type and overall. Some analyses may be performed based on the dose escalation and Expansion 
Phases combined. 
The statistical analyses for this study will be performed using SAS® version 9.2 or later (SAS Institute, 
Inc., Cary, NC). Programming specifications will be prepared which describe the datasets and variables 
created for this study. The datasets will be prepared using the most recent version of CDISC’s Study Data 
Tabulation Model (SDTM) and Analysis Dataset Model (ADaM). The source SDTM and ADaM datasets 
from which a statistical analysis is performed (including interim safety and efficacy reviews) will be 
archived with the Sponsor. 
12.4.1 
Disposition of Patients 
The number of patients included in the efficacy and safety analyses will be summarized, along with the 
reason for exclusion from one or more analysis populations. Patients discontinuing from study drug and 


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the primary reason for discontinuation will be summarized. Patients withdrawing from study and the 
primary reason for withdrawal will be summarized in a similar manner.  
12.4.2 
Demographics and Baseline Characteristics 
Descriptive summaries of demographic and baseline characteristics will be tabulated by study phase and 
overall. For the Dose Escalation/Confirmation Phase, tabulations will be provided by dose cohort and 
overall. For the Expansion Phase, tabulations will be provided by tumor type and overall.  
12.4.3 
Extent of Exposure 
The overall duration of study drug administration (in months) and the total number of cycles initiated will 
be tabulated for each patient and summarized by study phase. For the escalation phase, tabulations will be 
provided by dose cohort and overall. For the Expansion Phase, tabulations will be provided by tumor type 
and overall. For patients who receive entinostat, the average dose of entinostat (in mg) administered and 
cumulative dose (in mg) administered will be calculated. These data will be further summarized by 
calculating the mean, standard deviation, median, and range of these values. The number and proportion 
of patients with one or more dosage modification of study drug will be tabulated by treatment arm along 
with the reason for dosage modification. The primary reason for study drug discontinuation will be 
tabulated in a similar manner. 
Similar tabulations will be provided for the administration of pembrolizumab. 
12.4.4 
Concomitant Medications 
Prior and concomitant medications will be coded to generic term using the current version of the World 
Health Organization Drug Dictionary and will be tabulated and listed by patient.  
12.4.5 
Efficacy Analysis 
Efficacy analyses will be conducted using the Full Analysis Set and, where appropriate, the Per-protocol 
Set. 
ORR will be estimated for each cohort evaluated in the Expansion Phase using irRECIST, as the primary 
endpoint. Crude proportion of patients with best overall response of CR or PR, along with a 2-sided 95% 
CI, will be calculated for cohorts 1 and 4. The width of the CI will be adjusted to account for the 
multistage design (Atkinson 1985). Additionally, a 90% one-sided CI of the form (πL, 1] will be reported 
since the sample size for the Expansion Phases for cohorts 1 and 4 were determined using a one-sided 


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significance level of 10%. Crude proportion of patients with best overall response of CR or PR, along 
with a 2-sided 98% CI, will be calculated for cohorts 2 and 3. CBR at 6 months will be analyzed in a 
similar manner.  
DOR will be calculated for patients who achieve a CR or PR and is defined as the number of months from 
the start date of the response (and subsequently confirmed) to the first date that recurrent disease or PD is 
documented. PFS is defined as the number of months from the date of the first dose of study drug to the 
earliest of documented PD or death due to any cause without prior progression. OS is defined as the 
number of months from the first dose of study drug to the date of death due to any cause. DOR, PFS, and 
OS will be summarized descriptively using the Kaplan-Meier method with 95% confidence intervals 
(CIs) calculated using Greenwood’s formula. Median follow-up for each endpoint will be estimated 
according to the Kaplan-Meier estimate of potential follow-up. PFS rate at 6 months and corresponding 
95% CIs will be estimated using the Kaplan-Meier method. Greenwood’s formula will be used to 
calculate the standard errors of the Kaplan-Meier estimate and upper and lower limits of the 95% CI. 
An analysis of efficacy endpoints also will be performed, with response determined using RECIST, 
version 1.1. 
12.4.6 
Immune Correlate Analyses 
Immune correlate values will be summarized in a descriptive manner. For immune correlates measured on 
a continuous scale, the number of patients with non-missing data, mean, either the standard error or 
standard deviation, median, 25th percentile (first quartile), 75th percentile (third quartile), minimum, and 
maximum values will be presented. For discrete data, the frequency and percent distribution will be 
presented. Within-patient changes from baseline may be assessed by the Wilcoxon signed rank test and 
Fisher’s exact test, as appropriate. Analysis of covariance models may be used to explore the relationship 
between changes in immune correlates and selected measures of antineoplastic activity (e.g., maximum 
change from baseline in the sum of product diameters in measurable nodes and nodal masses). The 
association among the various immune correlates and clinical outcomes (data permitting) may be 
explored using heat map and other data visualization techniques. 
12.4.7 
Safety Analysis 
Safety will be assessed by clinical review of all relevant parameters including AEs, SAEs, laboratory 
values, vital signs, and ECG results. Unless specified otherwise, the safety analyses will be conducted for 
the safety population defined in Section 12.2.  


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Summary tables and listings will be provided for all reported TEAEs, defined as AEs that start on or after 
the first administration of study drug. The reported AE term will be assigned a standardized preferred 
term using the current version of the Medical Dictionary for Regulatory Activities (MedDRA).  
TEAEs will be summarized based on the number and percentage of patients experiencing the event by 
MedDRA (version 18.0) system organ class (SOC) and preferred term. The causal relationship between 
the occurrence of an AE and study drug will be judged by the Investigator based on the conventions 
described in Section 11.3. In the event a patient experiences repeat episodes of the same AE, then the 
event with the highest severity grade and strongest causal relationship to study drug will be used for 
purposes of incidence tabulations. 
Tabular summaries will be provided for: 
• 
DLTs (Dose Escalation/Confirmation Phase only) 
• 
all TEAEs 
• 
TEAEs by relationship to study drug and maximum severity grade 
• 
TEAEs with action of study drug delayed/interrupted or dose reduced 
• 
TEAEs with action of study drug discontinued 
• 
SAEs 
For the escalation phase, the observed DLT rate in each dose cohort will be calculated by the crude 
proportion of patients who experienced DLT with a 2-sided 95% exact binomial CI. 
All deaths that occur on study (defined as during treatment or within 90 days of treatment 
discontinuation) will be reported in a patient listing, which will include the primary cause of death and the 
number of days between the date of the last dose of study drug and death. 
Hematology, serum chemistries, and vital signs will be summarized in a descriptive manner by 
calculating the mean, standard deviation, median, and range as follows: 
• 
baseline value 
• 
minimum post-baseline value 
• 
maximum post-baseline value 
• 
average post-baseline value 


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• 
last post-baseline value 
Laboratory values will be assigned toxicity grades when available using the NCI CTCAE. Directional 
shifts in laboratory toxicity grades (comparing baseline grade with worst post-baseline grade) will be 
analyzed using standard shift tables, presenting number and proportion of patients and their maximum 
grade shift. For analytes without a toxicity grading scale, the shift table will present directional shifts from 
baseline to above or below the laboratory standard normal range using the maximum increase and/or 
decrease observed throughout the course of treatment/observation. 
Vital signs will be summarized in a descriptive manner by calculating the mean, standard deviation, 
median, and range in the same manner described for laboratory values. The Wilcoxon signed rank test 
may be used to assist in the identification of any systematic changes. 
ECG results will be listed and summarized in terms of the number and percentage of patients with 
abnormal and normal findings, as reported by the Investigator, at the time points assessed (screening and 
EOT).  
12.4.8 
Pharmacokinetic, Exposure-Safety, and Anti-pembrolizumab Antibody Analyses 
A population PK analysis will be used to describe the PK of entinostat. The effects of patient factors (e.g., 
demographics, clinical chemistries, disease) on entinostat PK will be evaluated. In addition, the 
relationship between entinostat exposure parameters and indicators of safety will be assessed.  
Specific details for these analyses as well as analyses of trough pembrolizumab levels and anti-
pembrolizumab antibodies will be provided in a separate analysis plan. 
12.5 
Procedures for Reporting Deviations to the Original Statistical Analysis Plan 
A formal statistical plan for the analysis and presentation of data from this study will be prepared before 
database lock. Deviations from the statistical analyses outlined in this protocol will be indicated in this 
plan; any further modifications will be noted in the final clinical study report. 


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13. 
INVESTIGATIONAL DRUG PRODUCT 
The study drugs being investigated in combination during this clinical trial are pembrolizumab and 
entinostat. First study treatment is to be administered within 3 days of enrollment into the study.  
The Investigator shall take responsibility for maintaining applicable records and ensuring appropriate 
supply, storage, handling, distribution, and usage of study drug, in accordance with the protocol and any 
applicable laws and regulations. 
13.1 
Entinostat 
13.1.1 
Description 
Entinostat is a synthetic small molecule bearing the chemical name 3-Pyridylmethyl N-{4-[(2-
aminophenyl)carbamoyl]benzyl}carbamate and the molecular formula C21H20N4O3, with a molecular 
weight of 376.41. Entinostat is classified as an antineoplastic agent, specifically functioning as an 
inhibitor of histone deacetylases and therefore promotes hyperacetylation of nucleosomal histones, 
allowing transcriptional activation of a distinct set of genes that leads to the inhibition of cell 
proliferation, induction of terminal differentiation, and/or apoptosis. 
13.1.2 
Formulation 
Entinostat is supplied in 2 strengths of film-coated tablets containing 1 mg (pink to light red) or 5 mg 
(yellow) of entinostat as polymorph B. Each tablet contains mannitol, sodium starch glycolate, 
hydroxypropyl cellulose, potassium bicarbonate, and magnesium stearate as inert fillers. The film coating 
consists of hypromellose, talc, titanium dioxide, and ferric oxide pigments (red and yellow) as colorants.  
Refer to the Pharmacy Manual for more details regarding entinostat. 
13.1.3 
Storage and Packaging 
Entinostat tablets may be shipped and stored at controlled room temperature, up to 25º C (77°F); 
excursions permitted to 15°C to 30°C (59 – 86°F). The pharmacist will dispense the investigational 
material to the patient at appropriate intervals throughout the study in childproof containers. 
13.2 
Pembrolizumab 
Pembrolizumab is a humanized monoclonal antibody that blocks the interaction between PD-1 and its 
ligands, PD-L1 and PD-L2. Pembrolizumab is an IgG4 kappa immunoglobulin with an approximate 
molecular weight of 149 kDa. 


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Refer to the Pharmacy Manual for details regarding pembrolizumab formulation, storage, packaging and 
supply.  
13.3 
Accountability 
The lot number(s) of the study drugs (entinostat and pembrolizumab) received at the site are to be 
recorded on Drug Accountability Log(s) maintained by the pharmacist. Additional distribution and return 
information will also be recorded at the site.  
Patient medication instructions and dosing diaries will be provided to the patient for purposes of 
recording entinostat self-administration. The diaries along with unused entinostat tablets will be returned 
to the clinic to assess compliance and for entry into the eCRF. 


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14. 
REGULATORY OBLIGATIONS 
14.1 
Informed Consent 
A sample informed consent form is provided for the Investigator to prepare the informed consent 
document to be used at his or her site. Updates to the template will be communicated by letter from 
Syndax or designee to the Investigator.  
Before a patient’s participation in the clinical study, the Investigator is responsible for obtaining written 
informed consent from the patient or legally authorized representative after adequate explanation of the 
aims, methods, anticipated benefits, and potential hazards of the study and before any protocol-specific 
screening procedures or any investigational products are administered. The acquisition of informed 
consent should be documented in the patient’s medical records, and the informed consent form should be 
countersigned by the person who conducted the informed consent discussion (not necessarily an 
Investigator). The original signed informed consent form should be retained in accordance with 
institutional policy, and a copy of the signed consent form should be provided to the patient or legally 
acceptable representative. 
14.2 
Institutional Review Board (IRB)/Ethics Committee (EC) 
A copy of the protocol, proposed informed consent form, other written patient information, and any 
proposed advertising material must be submitted to the IRB/EC for written approval. A copy of the 
written approval of the protocol and informed consent form, in addition to other essential regulatory 
documents per Section 14.3, must be received by Syndax or designee before recruitment of patients into 
the study and shipment of study drug.  
The Investigator must submit and obtain approval from the IRB/EC for all subsequent protocol 
amendments and changes to the informed consent document. The Investigator should notify the IRB/EC 
of deviations from the protocol or SAEs occurring at the site and other AE reports received from Syndax, 
in accordance with local procedures.  
The Investigator will be responsible for obtaining annual IRB/EC renewals throughout the duration of the 
study. Copies of the Investigator’s submission and the IRB/EC continuance of approval must be sent to 
Syndax or its representative. 


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14.3 
Pre-study Documentation Requirements 
The Investigator is responsible for providing the following documents to Syndax or its representative 
before study initiation can occur:  
• 
Signed and dated protocol signature page (Investigator’s Agreement). 
• 
Completed Food and Drug Administration form 1572 or equivalent per local regulatory 
requirements. 
• 
Curricula vitae of Principal Investigator and all sub-investigators (updated within 12 months). 
• 
Copy of the IRB/EC approval of the protocol, consent form, and patient information sheet. 
• 
Copies of Health Authority and Central Ethics Committee approvals, as applicable. 
• 
IRB/EC composition or written statement that the board is in compliance with regulations. 
• 
Laboratory normal ranges and documentation of laboratory certification (or equivalent). 
• 
Signed Clinical Trial Agreement between Syndax and the authorized business representative at 
the institution. 
• 
Completed Financial Disclosure statements for the Principal Investigator and all 
sub-investigators. 
14.4 
Patient Confidentiality 
The Investigator must ensure that the patient’s confidentiality is maintained. On the eCRFs or other study 
documentation submitted to Syndax or its representative, patients should be identified only by their 
initials and a patient ID number. Patient samples should be identified only by the patient ID number. 
Documents that are not for submission to Syndax or its representative (i.e., signed informed consent 
forms) should be kept in strict confidence by the Investigator.  
In compliance with federal guidelines, it is required that the Investigator and institution permit authorized 
representatives of the company, of the regulatory agency(s), and the IRB/EC direct access to review the 
patient’s original medical records for verification of study-related procedures and data. Direct access 
includes examining, analyzing, verifying, and reproducing any records and reports that are important to 
the evaluation of the study. The Investigator is obligated to inform and obtain the consent of the patient to 
permit named representatives to have access to his/her study-related records without violating the 
confidentiality of the patient. 


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15. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS 
15.1 
Protocol Amendments and Study Termination 
All protocol amendments will be implemented by Syndax and must receive IRB/EC approval before 
implementation, except where necessary to eliminate an immediate hazard to patients. The Investigator 
must send a copy of the approval letter from the IRB/EC, along with the revised Informed Consent form, 
to Syndax or its representative.  
Both Syndax and the Investigator reserve the right to terminate the study according to the study contract. 
The Investigator should notify the IRB/EC in writing of the study’s completion or early termination and 
send a copy of the notification to Syndax or its representative. 
15.2 
Study Documentation and Archive 
The Investigator must maintain a list of appropriately qualified persons to whom he/she has delegated 
study duties. All persons authorized to make entries and/or corrections on eCRFs will be included on the 
Syndax Delegation of Responsibility Form. 
Source documents are original documents, data, and records from which the patient’s eCRF data are 
obtained. These include but are not limited to hospital records, clinical and office charts, laboratory and 
pharmacy records, diaries, microfiches, radiographs, and correspondence.  
The Investigator and study staff are responsible for maintaining a comprehensive and centralized filing 
system of study-related documentation, available for inspection at any time by representatives from 
Syndax and/or applicable regulatory authorities. Elements should include:  
• 
Patient files containing informed consent forms and patient identification list. 
• 
Study files containing the Protocol with all amendments, Investigator’s Brochure, copies of pre-
study documentation (Section 14.3), and all correspondence to and from the IRB/EC and Syndax. 
• 
Investigational Product Accountability Records and all drug-related correspondence. 
In addition, all original source documents supporting entries on the eCRFs must be maintained and be 
readily available.  
No study document should be destroyed without prior written agreement between Syndax and the 
Investigator. Should the Investigator wish to assign the study records to another party or move them to 


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another location, he/she must notify Syndax in writing of the new responsible person and/or the new 
location. 
15.3 
Study Monitoring and Data Collection 
A study monitor will be responsible for contacting and visiting the Investigator for the purpose of 
inspecting the facilities; verifying the eCRFs at regular intervals throughout the study to assess adherence 
to the protocol; ensuring completeness, accuracy, and consistency of the data; and ensuring adherence to 
local regulations on the conduct of clinical research. The monitor should have access to patient medical 
records and other study-related records needed to verify the entries on the eCRFs. 
The Investigator agrees to cooperate with the monitor to ensure that any problems detected in the course 
of these monitoring visits, including delays in completing eCRFs, are resolved.  
In addition to routine monitoring and in accordance with United States 21 CFR Parts 312, 50, and 56, this 
study may be selected for audit by a designee of Syndax or its representative. Inspection of site facilities 
(i.e., pharmacy, drug storage areas, laboratories) and review of study-related records will occur to 
evaluate the study conduct and compliance with the protocol and applicable regulatory requirements. 


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17. 
APPENDICES 
Appendix 1: New York Heart Association Classification of Heart Failure 
 
Class 
Symptomatology 
I 
No symptoms. Ordinary physical activity such as walking and climbing stairs does not 
cause fatigue or dyspnea. 
II 
Symptoms with ordinary physical activity. Walking or climbing stairs rapidly, walking 
uphill, walking or stair climbing after meals, in cold weather, in wind or when under 
emotional stress causes undue fatigue or dyspnea. 
III 
Symptoms with less than ordinary physical activity. Walking 1 to 2 blocks on the level and 
climbing more than 1 flight of stairs in normal conditions causes undue fatigue or dyspnea. 
IV 
Symptoms at rest. Inability to carry on any physical activity without fatigue or dyspnea. 
 
 
 


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Appendix 2: Concomitant Medications to be Avoided 
Examples of sensitive in vivo CYP substrates and CYP substrates with narrow therapeutic range are 
summarized in Table 17-1. 
Table 17-1 
Examples of substrates that may be affected by entinostat 
CYP Enzymes 
Substrates with 
narrow therapeutic range1 
CYP1A2 
Theophylline, tizanidine 
CYP2C8 
Paclitaxel 
CYP3A2 
Alfentanil, astemizole3, cisapride4, 
cyclosporine, dihydroergotamine, 
ergotamine, fentanyl, pimozide, 
quinidine, sirolimus, tacrolimus,  
terfenadine4 
1 CYP substrates with narrow therapeutic range refers to drugs whose exposure-response relationship indicates that small 
increases in their exposure levels by the concomitant use of CYP inhibitors may lead to serious safety concerns (e.g., Torsades 
de Pointes). 
2 Because a number of CYP3A substrates (e.g., darunavir, maraviroc) are also substrates of P-gp, the observed increase in 
exposure could be due to inhibition of both CYP3A and P-gp. 
3 Withdrawn from the United States market because of safety reasons. 
Refer to Table 17-2 for examples of transporter inhibitors and inducers. 
Table 17-2 
P-gp Inhibitors and Inducers 
 
 
Inhibitor 
Inducer 
P-gp, MDR1 
Amiodarone, azithromycin, captopril, 
carvedilol, clarithromycin, conivaptan, 
diltiazem, dronedarone, felodipine, 
lopinavir, quercetin, ranolazine, ticagrelor, 
ritonavir, cyclosporine, verapamil 
erythromycin, ketoconazole, itraconazole, 
quinidine 
Avasimibe, carbamazepine, phenytoin, 
rifampin, St John’s Wort, tipranavir/ritonavir 
 
Refer to Table 17-3 for examples of gastric acid reducing drugs.  


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Table 17-3 
Gastric Acid Reducing Drugsa 
Gastric Acid Reducing Drugs 
H2 Inhibitors 
• 
Cimetidine (Tagamet) 
• 
Ranitidine (Zantac) 
• 
Famotidine (Pepcid) 
• 
Nizatidine (Axid) 
Antacids 
• 
Alka-Seltzer 
• 
Alka-2, Surpass Gum, Titralac, Tums 
• 
Milk of Magnesia 
• 
ALternaGEL, Amphojel 
• 
Gaviscon, Gelusil, Maalox, Mylanta, Rolaids 
• 
Pepto-Bismol 
 
a Gastric acid reducing drugs:  http://www.everydayhealth.com/ulcer/ulcer-treatment.aspx 
 


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Appendix 3: Description of the iRECIST Process for Assessment of Disease Progression 
Assessment at Screening and Prior to RECIST 1.1 Progression 
Until radiographic disease progression based on RECIST 1.1, there is no distinct iRECIST assessment. 
Assessment and Decision at RECIST 1.1 Progression 
For participants who show evidence of radiological PD by RECIST 1.1 as determined by the Investigator, 
the Investigator will decide whether to continue a participant on study treatment until repeat imaging is 
obtained (using iRECIST for participant management (see Table 9-2 and Figure 9-1). This decision by the 
Investigator should be based on the participant’s overall clinical condition. 
Clinical stability is defined as the following:  
• 
Absence of symptoms and signs indicating clinically significant progression of disease 
• 
No decline in ECOG performance status  
• 
No requirements for intensified management, including increased analgesia, radiation, or other 
palliative care 
Any participant deemed clinically unstable should be discontinued from study treatment. 
If the Investigator decides to continue treatment, the participant may continue to receive study treatment 
and the tumor assessment should be repeated 4 to 8 weeks later to confirm PD by iRECIST, per 
Investigator assessment. Images should continue to be sent in to the central imaging vendor for potential 
retrospective BICR. 
Tumor flare may manifest as any factor causing radiographic progression per RECIST 1.1, including: 
• 
Increase in the sum of diameters of target lesion(s) identified at baseline to ≥20% and ≥5 mm 
from nadir 
Note: the iRECIST publication uses the terminology “sum of measurements”, but “sum of 
diameters” is in this protocol, consistent with the original RECIST 1.1 terminology. 
• 
Unequivocal progression of non-target lesion(s) identified at baseline 
• 
Development of new lesion(s) 
iRECIST defines new response categories, including iUPD (unconfirmed progressive disease) and iCPD 
(confirmed progressive disease). For purposes of iRECIST assessment, the first visit showing progression 


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according to RECIST 1.1 will be assigned a visit (overall) response of iUPD, regardless of which factors 
caused the progression. 
At this visit, target and non-target lesions identified at baseline by RECIST 1.1 will be assessed as usual. 
New lesions will be classified as measurable or non-measurable, using the same size thresholds and rules 
as for baseline lesion assessment in RECIST 1.1. From measurable new lesions, up to 5 lesions total (up 
to 2 per organ), may be selected as New Lesions – Target. The sum of diameters of these lesions will be 
calculated, and kept distinct from the sum of diameters for target lesions at baseline. All other new lesions 
will be followed qualitatively as New Lesions – Non-target. 
Assessment at the Confirmatory Imaging 
On the confirmatory imaging, the participant will be classified as progression confirmed (with an overall 
response of iCPD), or as showing persistent unconfirmed progression (with an overall response of iUPD), 
or as showing disease stability or response (iSD/iPR/iCR). 
Confirmation of Progression 
Progression is considered confirmed, and the overall response will be iCPD, if ANY of the following 
occurs: 
• 
Any of the factors that were the basis for the initial iUPD show worsening 
- For target lesions, worsening is a further increase in the sum of diameters of ≥5 mm, 
compared to any prior iUPD time point 
- For non-target lesions, worsening is any significant growth in lesions overall, compared to a 
prior iUPD time point; this does not have to meet the “unequivocal” standard of RECIST 1.1 
- For new lesions, worsening is any of these: 
o An increase in the new lesion sum of diameters by ≥5 mm from a prior iUPD time point  
o Visible growth of new non-target lesions  
o The appearance of additional new lesions 
• 
Any new factor appears that would have triggered PD by RECIST 1.1 


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Persistent iUPD 
Progression is considered not confirmed, and the overall response remains iUPD, if: 
• 
None of the progression-confirming factors identified above occurs AND 
• 
The target lesion sum of diameters (initial target lesions) remains above the initial PD threshold 
(by RECIST 1.1) 
Additional imaging for confirmation should be scheduled 4 to 8 weeks from the imaging on which iUPD 
is seen. This may correspond to the next visit in the original visit schedule. The assessment of the 
subsequent confirmation imaging proceeds in an identical manner, with possible outcomes of iCPD, 
iUPD, and iSD/iPR/iCR. 
Resolution of iUPD 
Progression is considered not confirmed, and the overall response becomes iSD/iPR/iCR, if: 
• 
None of the progression-confirming factors identified above occurs, AND 
• 
The target lesion sum of diameters (initial target lesions) is not above the initial PD threshold.  
The response is classified as iSD or iPR (depending on the sum of diameters of the target lesions), or iCR 
if all lesions resolve. 
In this case, the initial iUPD is considered to be pseudo-progression, and the level of suspicion for 
progression is “reset”. This means that the next visit that shows radiographic progression, whenever it 
occurs, is again classified as iUPD by iRECIST, and the confirmation process is repeated before a 
response of iCPD can be assigned. 
Management Following the Confirmatory Imaging 
If repeat imaging does not confirm PD per iRECIST, as assessed by the Investigator, and the participant 
continues to be clinically stable, study treatment may continue and follow the regular imaging schedule. If 
PD is confirmed, participants will be discontinued from study treatment. 


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Detection of Progression at Visits After Pseudo-progression Resolves 
After resolution of pseudo-progression (i.e., achievement of iSD/iPR/iCR), iUPD is indicated by any of 
the following events: 
• 
Target lesions 
- Sum of diameters reaches the PD threshold (≥20% and ≥5 mm increase from nadir) either for 
the first time, or after resolution of previous pseudo-progression. The nadir is always the 
smallest sum of diameters seen during the entire trial, either before or after an instance of 
pseudo-progression. 
• 
Non-target lesions 
- If non-target lesions have never shown unequivocal progression, their doing so for the first 
time results in iUPD. 
- If non-target lesions have shown previous unequivocal progression, and this progression has 
not resolved, iUPD results from any significant further growth of non-target lesions, taken as 
a whole. 
• 
New lesions 
- New lesions appear for the first time 
- Additional new lesions appear 
- Previously identified new target lesions show an increase of ≥ 5 mm in the new lesion sum of 
diameters, from the nadir value of that sum 
- Previously identified non-target lesions show any significant growth 
If any of the events above occur, the overall response for that visit is iUPD, and the iUPD evaluation 
process (see Assessment at the Confirmatory Imaging above) is repeated. Progression must be confirmed 
before iCPD can occur. 
The decision process is identical to the iUPD confirmation process for the initial PD, with one exception:  
if new lesions occurred at a prior instance of iUPD, and at the confirmatory imaging the burden of new 
lesions has increased from its smallest value (for new target lesions, the sum of diameters is ≥5 mm 
increased from its nadir), then iUPD cannot resolve to iSD or iPR. It will remain iUPD until either a 


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decrease in the new lesion burden allows resolution to iSD or iPR, or until a confirmatory factor causes 
iCPD. 
Additional details about iRECIST are provided in the iRECIST publication. 

SAP_001.pdf: 
 Syndax Pharmaceuticals 
STATISTICAL ANALYSIS PLAN 
A Phase 1b/2, Open-label, Dose Escalation Study of Entinostat in 
Combination with Pembrolizumab in Patients with Non-small Cell Lung 
Cancer, with Expansion Cohorts in Patients with Non-small Cell Lung 
Cancer, Melanoma, and Mismatch Repair-Proficient Colorectal Cancer 
SNDX-275-0601 
SAP Version: 
Date of Statistical Analysis Plan: 
Version 1.0 
30 July 2019 
Version 1.1
26 September 2019 
NCT #: NCT02437136




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Table of Contents 
1 
INTRODUCTION .............................................................................................. 10 
2 
STUDY SUMMARY.......................................................................................... 12 
2.1 
STUDY OBJECTIVES ................................................................................ 12 
 Primary Objectives.................................................................................. 12 
 Secondary Objectives.............................................................................. 12 
 Exploratory Objectives ........................................................................... 13 
2.2 
STUDY ENDPOINTS ................................................................................. 14 
 Primary Efficacy Endpoint ..................................................................... 14 
 Secondary Endpoints (analyzed for the same populations as the primary 
endpoint) ............................................................................................................. 14 
 Exploratory Endpoints ............................................................................ 14 
2.3 
STUDY DESIGN ......................................................................................... 15 
 Number of Patients and Sample Size Considerations ............................. 17 
 Estimated Treatment and Study Duration ............................................... 21 
 Study Drug Treatment............................................................................. 22 
Pembrolizumab ................................................................................................... 22 
 Efficacy Assessments.............................................................................. 23 
 Treatment After Initial Radiologic Progression ...................................... 27 
 Protein Lysine Acetylation and Immune Correlates Assessments ......... 31 
Blood ................................................................................................................... 31 
Tumor Tissue ...................................................................................................... 32 


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 Pharmacokinetic Assessments ................................................................ 33 
 Safety Assessments ................................................................................. 35 
 Other Assessments .................................................................................. 35 
3 
STATISTICAL METHODS ............................................................................... 36 
3.1 
General Methods .......................................................................................... 36 
 Computing Environment ......................................................................... 36 
 Reporting of Numerical Values .............................................................. 36 
 Baseline Value and Change from Baseline ............................................. 37 
 Handling of Missing/Incomplete Values ................................................ 37 
3.2 
Analysis Sets ................................................................................................ 38 
 Full Analysis Set ..................................................................................... 38 
 Per-Protocol Analysis Set ....................................................................... 39 
 Evaluable Analysis Set ........................................................................... 39 
 Safety Analysis Set ................................................................................. 39 
 Pharmacokinetic Analysis Set................................................................. 39 
3.3 
Analysis Variables........................................................................................ 40 
 Efficacy Variables ................................................................................... 40 
 Pharmacokinetic Variables ..................................................................... 40 
 Safety Variables ...................................................................................... 41 
 Exploratory Variables ............................................................................. 42 
3.4 
Disposition and Evaluability ........................................................................ 42 
 Disposition .............................................................................................. 42 


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 Protocol Deviations ................................................................................. 43 
3.5 
Demographics and Baseline Characteristics ................................................ 43 
 Demographics ......................................................................................... 43 
 Cancer Disease History ........................................................................... 43 
 Medical History, Prior Medications, and Physical Exam ....................... 44 
3.6 
Concomitant Medications ............................................................................ 44 
3.7 
Treatment Exposure ..................................................................................... 44 
3.8 
Efficacy Analysis ......................................................................................... 45 
3.9 
Subgroup Analyses ....................................................................................... 48 
3.10 Safety Analysis ............................................................................................. 48 
 Adverse Events ..................................................................................... 48 
 Laboratory Evaluations ......................................................................... 50 
 Vital Signs ............................................................................................. 51 
 ECG....................................................................................................... 51 
3.11 Pharmacokinetic Analysis ............................................................................ 51 
3.12 Immune Correlate Analysis .......................................................................... 52 
4 
REFERENCES ................................................................................................... 53 
5 
APPENDIX ......................................................................................................... 54 
5.1 
Laboratory Test Groupings and Standard Normal Range ............................ 54 
5.2 
CTCAE Toxicity Grades: Hematology ........................................................ 57 
5.3 
CTCAE Toxicity Grades: Chemistry ........................................................... 59 
6 
Tables, Listings, and Figures .............................................................................. 64 


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6.1 
List of Tables ................................................................................................ 64 
6.2 
List of Figures .............................................................................................. 70 
6.3 
List of Listings ............................................................................................. 71 


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LIST OF ABBREVIATIONS 
Abbreviation 
Full Term 
AE 
adverse event 
ADA 
antidrug antibody 
ADaM 
Analysis Dataset Model 
AUC0-inf 
area under the plasma concentration-time curve from 
time 0 extrapolated to infinity 
AUC0-t 
area under the plasma concentration-time curve from 
time zero to the last measurable concentration  
BMI 
body mass index 
BQL 
below the quantifiable limit 
CBR 
clinical benefit rate 
CEA 
Cancer Embryonic Antigen 
CI 
confidence interval 
Cmax 
maximum plasma concentration  
CR 
complete response 
CRC 
colorectal cancer 
CT 
computed tomography 
DLT 
dose-limiting toxicity 
DOR 
duration of response 
DSMB 
Data and Safety Monitoring Board 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EMIC 
entinostat monotherapy immune correlate 


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Abbreviation 
Full Term 
EOT 
End of Treatment 
FAS 
Full Analysis Set 
HR 
hazard ratio 
irCR 
immune-related complete response 
irPR 
Immune-related partial response 
irRECIST 
immune response RECIST 
LDH 
lactate dehydrogenase 
MDSCs 
myeloid-derived suppressor cells 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
MTD 
maximum-tolerated dose 
NCI-CTCAE 
National Cancer Institute Common Terminology 
Criteria for Adverse Events 
NGS 
next-generation sequencing 
NR 
no results/not reportable 
NSCLC 
Non small cell lung cancer 
ORR 
objective response rate 
OS 
overall survival 
PD-1 
programmed death receptor-1 
PD-L1 
programmed death ligand-1 
PFS 
progression-free survival 
PK 
pharmacokinetic  
PO 
orally 


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Abbreviation 
Full Term 
PPI 
Proton Pump Inhibitor 
PR 
partial response 
PT 
preferred term 
PT/INR 
prothrombin time or international normalized ratio 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP2D 
recommended Phase 2 dose 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
stable disease 
SDTM 
Study Data Tabulation Model 
SOC 
system organ class 
t1/2 
elimination half-life  
TCR 
T cell receptor 
TEAE 
treatment-emergent adverse event 
Tmax 
time at which maximum plasma concentration was 
observed 
TSH 
thyroid stimulating hormone 
TTR 
time to response 
WHO 
World Health Organization 
λz 
terminal elimination rate constant 
 
 
 
 
 


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1 INTRODUCTION 
Clinical Trial SNDX-275-0601 is an open-label Phase 1b/2 evaluating the combination 
of entinostat with pembrolizumab in patients with advanced metastatic or recurrent 
NSCLC, melanoma, or mismatch repair-proficient colorectal cancer. The study has 
2 phases, a Dose Escalation/Confirmation Phase (Phase 1b) and an Expansion Phase 
(Phase 2), with the Expansion Phase utilizing a Simon 2-stage design (Simon 1989) for 
each cohort. An additional cohort (Entinostat Monotherapy Immune Correlate [EMIC] 
Cohort) evaluating single agent entinostat followed by the combination will also be 
evaluated in patients with NSCLC in the Phase 2 expansion phase. 
This SAP contains a detailed description of the data presentations and statistical 
analyses that will be included in the clinical study report for Protocol SNDX-275-0601. 
The statistical methods and analyses described here are based on those presented in the 
study protocol. Any changes made to the planned analyses after this document has been 
finalized will be noted in the clinical study report.  
This version of the SAP was written in accordance with the following protocol 
versions:  
Table 1-1                                        Protocol Versions 
Protocol 
Version Date 
Original 
08-April-2015 
Amendment #1 
05-June-2015 
Amendment #2 
04-April-2016 
Amendment #3 
23-February-2017 
Amendment #4 
25-August-2017 
Amendment #5 
12-April-2018 
 


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The first patient was enrolled under the original protocol dated 08-April-2015. Since 
then, study 601 has undergone 5 amendments (Table 1).   
For Amendment #1, significant changes include, addition of exploratory endpoint, the 
clarification of duration of therapy, clarification of the number of patients enrolled, 
modification of the language to include a definition of a DLT-evaluable patient, and 
the definition of DLT.  
Amendment #2 clarified the process of deciding on the Recommended Phase 2 Dose 
(RP2D), updated the Adverse Events terms of attribution/relatedness, updated the dose 
modification requirements for entinostat.  
Amendment #3 added an additional cohort of patients: Mismatch Repair-Proficient 
Colorectal Cancer and updated pembrolizumab background information 
 Amendment #4 increased the sample size for Cohorts 2 and 3 and modified the 
corresponding statistical considerations accordingly (Section 12 of the protocol), 
removed Proton Pump Inhibitors (PPIs) from the list of medications to be avoided, and 
modified Eligibility Criteria to clarify prior disease progression on immunotherapy.  
Amendment #5 increased the sample size for Cohort 4 and modified the corresponding 
statistical considerations accordingly (Section 12 of the protocol), updated the standard 
language regarding pembrolizumab, clarified the description of the irRECIST process 
for assessment of disease progression for imaging and treatment after first radiologic 
evidence of progressive disease.  
  
 


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2 STUDY SUMMARY 
2.1 STUDY OBJECTIVES 
 Primary Objectives 
 Phase 1b (Dose Escalation/Confirmation Cohorts):  To determine the dose-
limiting toxicities (DLT) and maximum tolerated dose (MTD) or recommended 
Phase 2 dose (RP2D) of entinostat (SNDX-275) given in combination with 
pembrolizumab. 
Phase 2 (Expansion Cohorts):  To evaluate the preliminary efficacy of 
entinostat at the RP2D in combination with pembrolizumab in patients with 
melanoma, non-small cell lung cancer (NSCLC), and mismatch repair-proficient 
colorectal cancer (CRC), as determined by overall response rate (ORR), per the 
Immune-related Response Evaluation Criteria in Solid Tumors (irRECIST) in 
each cohort evaluated. 
 Secondary Objectives 
Efficacy:  To evaluate the efficacy of entinostat in combination with pembrolizumab 
in patients with melanoma NSCLC, and mismatch repair-proficient colorectal cancer 
as determined by secondary measures of efficacy per the Response Evaluation Criteria 
in Solid Tumors version 1.1 (RECIST 1.1) and Immune-related Response Evaluation 
Criteria in Solid Tumors (irRECIST) including: 
• Clinical benefit rate (CBR) (complete response [CR]+partial response 
[PR]+stable disease [SD]) at 6 months 
• Progression-free survival (PFS) status at 6 months 
• PFS 
• Overall survival (OS) 
In patients who experience a response to treatment (i.e., CR or PR): 
• Duration of response (DOR) 
• Time to response (TTR) 


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Safety:  To evaluate safety and the tolerability of entinostat in combination with 
pembrolizumab, as measured by clinical adverse events (AEs) and laboratory 
parameter 
 Exploratory Objectives  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 


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2.2 STUDY ENDPOINTS 
 Primary Efficacy Endpoint 
•  ORR, as determined by irRECIST 
 Secondary Endpoints (analyzed for the same populations as the 
primary endpoint)  
An analysis of efficacy endpoints will be performed with response determined     using 
irRECIST, as well as RECIST version 1.1.  
• CBR (i.e., CR+PR+SD at 6 months)  
• PFS status at 6 months  
• PFS  
• OS 
In patients who experience a response to treatment (i.e., CR or PR): 
• DOR 
• TTR 
Safety:  
• Determination of DLTs, MTD, and RP2D (in Phase 1 only) 
• Incidence of treatment-emergent adverse events (TEAEs), serious adverse 
events (SAEs), AEs resulting in the permanent discontinuation of study 
drug, and deaths occurring within 90 days of the last dose of study drug 
• Changes from baseline in laboratory, vital signs, Eastern Cooperative 
Oncology Group (ECOG), physical examination, and electrocardiogram 
(ECG) values 
 Exploratory Endpoints  


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2.3 STUDY DESIGN 
Study SNDX-275-0601 is an open-label, Phase 1b/2 study evaluating the combination 
of entinostat plus pembrolizumab in patients with advanced metastatic or recurrent 
NSCLC, CRC, or melanoma. The study has 2 phases, a Dose Escalation/Confirmation 
Phase (Phase 1b) and an Expansion Phase (Phase 2), with the Expansion Phase utilizing 
a Simon 2-stage design (Simon 1989) for each cohort.  An additional cohort (Entinostat 
Monotherapy Immune Correlate Cohort (EMIC)) evaluating single agent entinostat 
followed by the combination in patients with NSCLC will also be evaluated in the 
Phase 2 Expansion Phase. The study schema is presented in Figure 2-1.  
 
 
 
 
 
 


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Figure 2-1:  
 
Regardless of phase, patients will be screened for study eligibility within 21 days before 
enrollment into the study. Patients who are determined to be eligible based on screening 
assessments, will be enrolled in the study within 3 days of starting study treatment on 
Cycle 1, Day 1 (C1D1) and will receive entinostat in combination with pembrolizumab.  
 
A cycle is 21 days in length. During treatment, patients will attend study center visits 
and have study evaluations performed on C1D1, C1D8, and C1D15; D1 and D15 of 
C2; and on D1 of each cycle thereafter. Patients will have radiological disease 
assessments performed during screening and every 6 weeks (+/-3 days) (Week 6, Week 
12, etc.) during treatment. The maximum duration of treatment for this study is planned 
to be 2 years. Disease will be assessed by computed tomography (CT), magnetic 
resonance imaging (MRI), and bone scans, as appropriate, and response will be 
assessed by the Investigator using irRECIST. Safety will be assessed during the study 
by documentation of AEs, clinical laboratory tests, physical examination, vital sign 
measurements, ECGs, and Eastern Cooperative Oncology Group (ECOG) performance 


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status. If a patient permanently discontinues 1 of the 2 study drugs (either entinostat or 
pembrolizumab), the patient may continue to receive monotherapy for up to 2 years, 
unless alternate therapy is started or another discontinuation criterion is met. After 
discontinuation of both study drugs, patients will complete an End of Treatment (EOT) 
visit within 7 days after the last study drug dose and Safety Follow-up visits 30 days 
and 90 days thereafter. After completion of the 30-day Safety Follow-up (F/U) visit, 
patients who have not experienced progressive disease (PD) are to be followed every 2 
months until PD and every 3 months thereafter until death or closure of the study by 
the Sponsor. Collection of fresh tumor tissue core biopsy (image-guided if applicable) 
and blood samples are outlined in Section 5.1 of the protocol.  
 Number of Patients and Sample Size Considerations 
Phase 1b/Safety Lead-in (Dose Determination Phase):  
Three to 6 patients will be enrolled in each dose cohort based on a standard Phase 1 
dose escalation scheme. Each patient will participate in only 1 dose cohort. The total 
number of patients to be enrolled in the Dose Escalation/Confirmation Phase is 
dependent upon the observed safety profile, which will determine the number of 
patients per dose cohort, as well as the number of dose escalations required to achieve 
the MTD or RP2D. 
A starting sample size of at least 3 patients per dose cohort, expanding to 6 patients in 
the event of a marginal DLT rate (33%) was deemed to be a safe and conventional 
approach in the dose escalation of a novel oncologic agent. Assuming a true DLT rate 
of 5% or less, there would be a 3% chance that dose escalation would be halted in a 
given cohort (i.e., observing 2 or more patients with DLT). If a true DLT rate of 50% 
is assumed, then there would be an 83% chance that dose escalation would be halted in 
a given cohort.  
A total of 9 additional patients will be enrolled in the Dose Confirmation Cohort to 
obtain additional AE, immune correlate, and anti-tumor activity data on entinostat at 
the MTD or RP2D in combination. 


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Phase 2/Expansion Phase:  
In the Expansion Phase of the study, the safety and preliminary antitumor activity of 
entinostat when administered at the RP2D with pembrolizumab will be explored in up 
to 4 cohorts of adult solid tumors as previously defined. Up to 252 patients are planned 
to be enrolled among the 4 cohorts. Patients will be enrolled in each cohort according 
to a single-arm study design with ORR, as determined by irRECIST, as the primary 
endpoint. The Expansion Phase will be carried out in 2 stages so that enrollment for 1 
or more of the cohorts evaluated can terminate early in the event the antitumor activity 
of the combination regimen is not sufficient. The decision to terminate or continue 
enrollment for each cohort will be made independently of the other. The number of 
patients evaluated in each stage and the minimum number of responders needed to 
continue to the next stage, as described for cohorts 1, 2 and 3, was determined based 
on the optimum version of Simon’s 2-stage design (Simon 1989), with 80% power and 
1-sided significance level of 10%. For cohort 4, the number of patients evaluated in 
each stage and the minimum number of responders needed to continue to the next stage 
was determined based on the optimum version of Simon’s 2-stage design, with 90% 
power and 1-sided significance level of 5%.  
Cohort 1 (NSCLC patients with squamous cell and adenocarcinoma histology who 
have not been previously treated with a PD-1 or PD-L1-blocking antibody) 
A maximum of 46 patients will be enrolled in Cohort 1. A true ORR of 35% is 
hypothesized. An ORR greater than 20% is considered a lower threshold for antitumor 
activity that would warrant continued development. Based on the design elements 
specified above, up to 13 patients may be enrolled for either tumor type during the first 
stage;  if 2 or fewer patients achieve an objective response (CR or PR), confirmed or 
unconfirmed, then enrollment will terminate; otherwise, 33 additional patients will be 
enrolled during the second stage. Upon completion of the second stage, if 13 or more 
patients out of the 46 enrolled achieve CR or PR, then the true ORR for the combination 
therapy likely exceeds 20%, the lower threshold of acceptable antitumor activity. 
Alternatively, if 12 or fewer patients achieve an objective response at the end of the 
second stage, then the true ORR is likely 20% or lower, and further evaluation of the 


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combination therapy may not be pursued for that tumor type. If the true ORR is 20% 
or less for a tumor type, then the expected sample size is 29.4, with probability of 
terminating enrollment at the end of the first stage equal to 50%. 
Cohort 2 (Patients with NSCLC (any histology) who have previously been treated 
and progressed on a PD-1 or PD-L1-blocking antibody)  
A maximum of 56 patients will be enrolled in Cohort 2. A true ORR of 15% is 
hypothesized. A response rate greater than 5% is considered the lower threshold for 
antitumor activity that would warrant continued development in this setting. Based on 
the design elements specified above, up to 20 patients may  be enrolled during the first 
stage: if 1 or no patients achieve a CR or PR, confirmed or unconfirmed then enrollment 
will terminate; otherwise 36 additional patients will be enrolled during the second 
stage. Upon completion of the second stage, if 5 or more patients out of 56 enrolled 
achieve CR or PR, then true ORR for the combination regimen likely exceeds 5%, the 
lower threshold of acceptable antitumor activity. Alternatively, if 4 or fewer patients 
achieve an objective response at the end of the second stage, then the true ORR is likely 
5% or lower and further evaluation of the combination therapy may not be pursued in 
this setting. If the true ORR is 5% or less, then the expected sample size is 29.5, with 
probability of terminating enrollment at the end of the first stage equal to 74%.  
However, with Amendment 5, the study design for this cohort is changed from Simon 
2-stage design to single proportional binomial test after moving in to 2nd stage. Based 
on single proportional binomial test, maximum of 70 patients are enrolled in Cohort 2.  
Ninety-six percent 1-sided confidence interval (or 92% 2-sided confidence interval) of 
the observed one sample proportion will be calculated. The trial will be considered a 
success if the lower limit of 96% confidence interval is greater than 5%.  
Syndax will conduct one administrative analysis when at least 60% (42 out of 70 
patients) of patient information has been accrued in cohort 2 for decision making for 
late phase development planning. This administrative look will not lead to stopping of 
the study. Nonetheless, 0.01 alpha is being allocated for the first administrative look, 
leaving 0.04 alpha for the final analysis. 
 


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Cohort 3 (Patients with melanoma who have previously been treated and progressed 
on a PD-1 or PD-L1-blocking antibody)  
A maximum of 34 patients will be enrolled in Cohort 3. A true ORR of 25% is 
hypothesized. A response rate greater than 10% is considered the lower threshold for 
antitumor activity that would warrant continued development in this setting. Based on 
the design elements specified above, up to 13 patients may  be enrolled during the first 
stage: if 1 or no patients achieve a CR or PR, confirmed or unconfirmed then enrollment 
will terminate; otherwise 21 additional patients will be enrolled during the second 
stage. Upon completion of the second stage, if 6 or more patients out of 34 enrolled 
achieve CR or PR, then true ORR for the combination regimen likely exceeds 10%, the 
lower threshold of acceptable antitumor activity. Alternatively, if 5 or fewer patients 
achieve an objective response at the end of the second stage, then the true ORR is likely 
5% or lower and further evaluation of the combination therapy may not be pursued in 
this setting. If the true ORR is 10% or less, then the expected sample size is 20.9, with 
probability of terminating enrollment at the end of the first stage equal to 62%.  
However, with Amendment 5, the study design for this cohort is changed from Simon 
2-stage design to single proportional binomial test after moving in to 2nd stage. Based 
on single proportional binomial test, maximum of 52 patients are enrolled in Cohort 3. 
Ninety-six percent 1-sided confidence interval (or 92% 2-sided confidence interval) of 
the observed one sample proportion will be calculated. The trial will be considered a 
success if the lower limit of 96% confidence interval is greater than 10%. Syndax will 
conduct one administrative analysis when at least 60% (31 out of 52 patients) of patient 
information has been accrued in cohort 3 for decision making for late phase 
development planning. This administrative look will not lead to stopping of the study. 
Nonetheless, 0.01 alpha is being allocated for the first administrative look, leaving 0.04 
alpha for the final analysis.  
Cohort 4 (Patients with CRC who have not previously been treated on a PD-1 or 
PD-L1-blocking antibody) 
A maximum of 84 patients will be enrolled in Cohort 4. A true ORR of 15% is 
hypothesized. An ORR greater than 5% is considered the lower threshold for antitumor 


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activity that would warrant continued development in this setting. Based on the 
optimum version of Simon’s 2-stage design, with 90% power and 1-sided significance 
level of 5%, up to 37 patients may be enrolled during the first stage:  if fewer than or 
equal to 2  patients achieve a CR or PR, confirmed or unconfirmed, then enrollment 
will terminate; otherwise, 47 additional patients will be enrolled during the second 
stage. Upon completion of the second stage, if 8 or more patients  of the 84 enrolled 
achieve CR or PR, then the true ORR for the combination regimen likely exceeds 5%, 
the lower threshold of acceptable antitumor activity. Alternatively, if 7 or fewer 
patients achieve an objective response at the end of the second stage, then the true ORR 
is likely 5% or lower and further evaluation of the combination therapy may not be 
pursued in this setting. If the true ORR is 5% or less, then the expected sample size is 
50.2, with probability of terminating enrollment at the end of the first stage equal to 
72%.  
 Estimated Treatment and Study Duration  
The maximum duration of treatment for this study is planned to be 35 cycles 
(approximately 2 years.)  
Patients who complete C1 may continue on study as long as, in the Investigator’s 
judgment, the patient is tolerating the study treatment, is not at an increased safety risk, 
and continues to meet protocol eligibility criteria. 
If a patient permanently discontinues 1 of the 2 study drugs (either entinostat or 
pembrolizumab), the patient may continue to receive monotherapy for up to 2 years, 
unless alternate therapy is started or another discontinuation criterion is met (Section 
10 of the protocol).   
Patients who discontinue both study drugs will receive standard of care outside the 
auspices of this study at the Investigator’s discretion.  
After discontinuation of both study drugs, patients will complete an EOT visit within 
7 days (+/- 3 days) after the last study drug dose and Safety Follow-up visits 30 days 
(+/- 3 days) and 90 days (+/- 3 days) thereafter. After completion of the 30-day Safety 
F/U visit, patients who have not experienced PD are to be followed every 2 months 
until PD and every 3 months thereafter until death or closure of the study by the 


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Sponsor. The purpose of the post-treatment follow-up is to ascertain the duration of 
PFS for all patients in the study. After development of PD, surviving patients are to be 
followed on an every 3-month basis for alternate therapy and survival until closure of 
the study. Up to approximately 40 study centers are planned to be recruited for 
participation in this study. 
 Study Drug Treatment  
Entinostat 
Patients will receive entinostat in an open-label fashion; the dose for an individual 
patient is dependent on the cohort/study phase in which the patient is enrolled (Section 
8.2.1.1 of the protocol). 
The dose of entinostat is dependent on the cohort / study phase in which the patient is 
enrolled. In the Dose Escalation Phase, the planned entinostat doses to be investigated 
are: 
• 3 mg weekly 
• 5 mg weekly 
In the Dose Confirmation Phase, 9 patients will receive entinostat at the prospective 
MTD/RP2D identified in the Dose Escalation Phase. 
All patients will self-administer entinostat at the assigned dose and regimen PO. On 
study days on which patients receive both entinostat and pembrolizumab, entinostat is 
to be taken prior to pembrolizumab. 
Pembrolizumab 
The pembrolizumab treatment to be used in this study is outlined in Table 2-1. 


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Table 2-1 
                                                 Study Treatment  
Drug 
Dose/Potency 
Dose 
Frequency 
Route of 
Administration 
Regimen 
Use 
Pembrolizumab 
200 mg 
Every three 
weeks 
(Q3W) 
Intravenous 
(IV) 
Day 1 of 
each cycle 
(3-week 
cycles) 
Experimental 
 
Pembrolizumab treatment will begin on C1D1. Pembrolizumab will be administered 
on D1 of each 3-week treatment cycle after all procedures and assessments have been 
completed as detailed on the Schedule of Study Assessments  ( Table 1-1 of the protocol 
or, for the EMIC cohort Table 1-2 of the protocol).  
Pembrolizumab will be administered as a dose of 200 mg using a 30-minute IV 
infusion. Sites should make every effort to target infusion timing to be as close to 30 
minutes as possible. However, given the variability of infusion pumps from site to site, 
a window between -5 minutes and +10 minutes is permitted (i.e., infusion time is 30 
minutes -5 min/+10 min). 
 Efficacy Assessments  
With the exception of OS, all efficacy endpoints in this trial (including the primary 
endpoint in Phase 2) are linked to the tumor response assessments. Therefore, the 
importance of timely and complete disease assessments in this study cannot be 
overstated. Failure to perform any of the required disease assessments will result in the 
inability to determine disease status for that time point. Frequent off schedule or 
incomplete disease assessments have the potential to weaken the conclusion of this 
clinical trial. 
The schedule of tumor burden assessments should be fixed according to the calendar, 
regardless of treatment interruptions. Tumor burden assessments will be performed 
until progressive disease as per irRECIST and RECIST 1.1, regardless of the 
discontinuation of study treatment or the start of a subsequent anticancer therapy. 
Patients with radiographic progression only, as defined by RECIST 1.1, should 


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continue on study treatment until unequivocal PD is determined at the discretion of the 
Investigator, as defined by irRECIST.  
The same method of assessment and technique (e.g., CT scan or MRI) used to 
characterize each lesion at study screening must be used at each subsequent 
post-screening assessment. Post-screening scans and the corresponding overall tumor 
assessment (according to RECIST and irRECIST) should be performed prior to 
initiating the subsequent cycle to rule out PD that would warrant study treatment 
discontinuation. 
2.3.4.1 Tumor Measurement and Disease Response Assessment 
Initial tumor imaging at screening must be performed within 28 days prior to C1D1. 
(Scans performed as part of routine clinical management are acceptable for use as initial 
tumor imaging if they are of diagnostic quality, have been performed within 28 days 
prior to C1D1, and can be assessed by the central imaging vendor). Patients will have 
radiological disease assessments performed every 6 weeks (+/-3 days) (Week 6, Week 
12, etc.) during study treatment until progressive disease. If a patient comes off study 
for reasons other than progressive disease, radiological assessments will continue on 
this same study schedule until progressive disease is unequivocally documented. 
Tumor assessments should be kept to the calendar schedule and not be delayed for 
delays in cycles or study drug administration. Disease response in target and non-target 
lesions will be assessed locally by the Investigator using irRECIST and RECIST 1.1. 
 
Measurable Disease 
To be eligible for study participation, all patients must have documented measurable 
disease per RECIST 1.1 that has been radiologically documented within 28 days prior 
to enrollment, defined as follows: 
At least 1 measurable lesion: 
• ≥ 10 mm in longest diameter on an axial image by CT scan or MRI with 
≤ 5 mm reconstruction interval 


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• If slice thickness is > 5 mm, longest diameter must be at least 2 times the 
thickness  
• ≥ 20 mm longest diameter by chest X-ray (if clearly defined and 
surrounded by aerated lung); CT is preferred, even without contrast  
• Lymph nodes ≥ 15 mm in short axis on CT scan (CT slice thickness of 
≤ 5 mm) 
If there is only 1 measurable lesion and it is located in a previously irradiated field, it 
must have demonstrated progression according to RECIST 1.1. 
Non-measurable Lesions 
Non-measurable lesions are defined per RECIST 1.1 as the following and should be 
captured and followed within the electronic case report form (eCRF) according to the 
eCRF guidelines.  
• Masses < 10 mm 
• Lymph nodes 10 to 14 mm in short axis 
• Leptomeningeal disease 
• Ascites, pleural or pericardial effusion 
• Lymphangitic involvement of skin or lung 
• Abdominal mases or organomegaly identified by physical examination 
which cannot be measured by reproducible imaging techniques  
• Blastic bone lesions 
• Both benign and equivocal (“cannot exclude”) findings should not be 
included  
Target versus non-target 
• Target: all measurable lesions up to a maximum of 2 lesions per organ and 
5 lesions in total, representative of all involved organs, are to be identified 
as target lesions and will be measured and recorded at screening. Target 
lesions are to be selected on the basis of their size (i.e., those with the 
longest diameter) and suitability for accurate, repeated measurement. The 
sum of the diameters for all target lesions is to be calculated and recorded 
on the eCRF as the sum of the longest diameters.  


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• Non-target: all other lesions not classified as target lesions (or sites of 
disease) are to be identified as non-target lesions and recorded on the eCRF. 
Measurement of non-target lesions is not required. 
2.3.4.2 Disease Response Assessment Criteria 
Patients will have radiological disease assessments performed every 6 weeks (± 3 days) 
(i.e., Week 6, Week 12, etc.) until unequivocal PD or closure of the study by the 
Sponsor. All scans will be submitted electronically to a central core radiologic 
laboratory. Scans from patients who were determined by the Investigator to have a 
response to treatment (CR or PR) will be reviewed by the core radiologic laboratory to 
confirm response. Scans from non-responders may also be reviewed by the core 
radiologic laboratory at the direction of the Sponsor. 
Disease response in target and non-target lesions will be assessed locally by the 
Investigator using immune response RECIST (irRECIST) and RECIST 1.1.  
Partial response or CR should be confirmed by a repeat tumor imaging assessment not 
less than 4 weeks from the date that the response was first documented. The tumor 
imaging for confirmation of response may be performed at the earliest 4 weeks after 
the first indication of response or at the next scheduled scan if on a 6-week schedule, 
whichever is clinically indicated. 
When clinically stable, participants should not be discontinued until progression is 
confirmed by the Investigator, working with local radiology, according to the rules 
outlined in Appendix 3 of the protocol. This allowance to continue treatment despite 
initial radiologic PD takes into account the observation that some participants can have 
a transient tumor flare in the first few months after the start of immunotherapy and then 
experience subsequent disease response. This data will be captured in the clinical 
database. 
For subjects who discontinue study therapy without documented, unequivocal PD, 
every effort should be made to continue monitoring their disease status by tumor 
imaging every 8 weeks until (1) unequivocal progressive disease; (2) death; or (3) the 
end of the study, whichever occurs first. 


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All scans will be submitted (electronically whenever possible) to a central core 
radiologic laboratory. Scans from patients who were determined by the Investigator to 
have a response to treatment (CR or PR) may be reviewed by the core radiologic 
laboratory. Scans from non-responders may also be reviewed by the core radiologic 
laboratory at the direction of the Sponsor. 
 Treatment After Initial Radiologic Progression 
Immune-related RECIST will be utilized to account for the unique tumor response 
characteristics seen with pembrolizumab treatment. Immunotherapeutic agents such as 
pembrolizumab may produce antitumor effects by potentiating endogenous cancer-
specific immune responses. The response patterns seen with such an approach may 
extend beyond the typical time course of responses seen with cytotoxic agents, and a 
clinical response may manifest after an initial increase in tumor burden or even the 
appearance of new lesions. Patients with radiographic progression only as defined by 
RECIST 1.1, should continue on study treatment until unequivocal PD is determined 
as defined by irRECIST. Therefore, the process that follows for assessing radiological 
PD will be used in this study: 
If radiologic imaging demonstrates initial evidence for PD, tumor assessment should 
be repeated 4 weeks at the earliest, or preferably on the study schedule of 6 weeks, to 
confirm PD. Treatment on-study may be continued while awaiting radiologic 
confirmation of progression. This clinical decision should be based on the patient’s 
overall clinical condition, including performance status, clinical symptoms, and 
laboratory data. Specifically, it is recommended that patients continue to receive both 
pembrolizumab and entinostat while waiting for confirmation of PD if they are 
clinically stable as defined by: 
• Absence of signs and symptoms indicating clinically significant 
progression of disease; 
• No decline in ECOG performance status; 
• No requirements for intensified management, including increased 
analgesia, radiation, or other palliative care 
If repeat imaging does not confirm PD per iRECIST, as assessed by the Investigator, 
and the participant continues to be clinically stable, study treatment may continue and 


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follow the regular imaging schedule. If PD is confirmed, participants will be 
discontinued from study treatment. 
If a participant has confirmed radiographic progression (iCPD) as defined in Appendix 
3 of the protocol, study treatment should be discontinued; however, if the participant is 
achieving a clinically meaningful benefit, an exception to continue study treatment may 
be considered following consultation with the Sponsor. In this case, if study treatment 
is continued, tumor imaging should continue to be performed following the intervals 
as outlined in Section 13 of the protocol and submitted to the central imaging vendor.  
A description of the adaptations and iRECIST process is provided in Appendix 3, with 
additional details in the iRECIST publication (Seymour 2017). A summary of imaging 
and treatment requirements after first radiologic evidence of progression is provided in 
Table 2-2 and illustrated as a flowchart in Figure 2-2. 


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Table 2-1 
Imaging and Treatment After 1st Radiologic Evidence of PD 
 
Clinically Stable 
Clinically Unstable 
Imaging 
Treatment 
Imaging 
Treatment 
First radiologic 
evidence of 
PD by 
RECIST 1.1 
Repeat 
imaging at 
4 to 8 weeks 
to confirm 
PD. 
May continue 
study treatment 
at the 
Investigator’s 
discretion while 
awaiting 
confirmatory 
tumor imaging 
by site by 
iRECIST. 
Repeat 
imaging at 
4 to 8 weeks 
to confirm PD 
per 
Investigator’s 
discretion 
only. 
Discontinue treatment 
Repeat tumor 
imaging 
confirms PD 
(iCPD) by 
iRECIST per 
Investigator 
assessment 
No additional 
imaging 
required. 
Discontinue 
treatment 
(exception is 
possible upon 
consultation with 
Sponsor). 
No additional 
imaging 
required. 
Not applicable 
Repeat tumor 
imaging shows 
iUPD by 
iRECIST per 
Investigator 
assessment 
Repeat 
imaging at 4 
to 8 weeks to 
confirm PD. 
May occur at 
next regularly 
scheduled 
imaging visit. 
Continue study 
treatment at the 
Investigator’s 
discretion. 
Repeat 
imaging at 4 
to 8 weeks to 
confirm PD 
per 
Investigator’s 
discretion 
only. 
Discontinue treatment 
Repeat tumor 
imaging shows 
iSD, iPR, or 
iCR by 
iRECIST per 
Investigator 
assessment. 
Continue 
regularly 
scheduled 
imaging 
assessments. 
Continue study 
treatment at the 
Investigator’s 
discretion. 
Continue 
regularly 
scheduled 
imaging 
assessments. 
May restart study 
treatment if condition 
has improved and/or 
clinically stable per 
Investigator’s 
discretion. Next 
tumor imaging should 
occur according to the 
regular imaging 
schedule. 
BICR = Blinded Independent Central Review; iCPD = iRECIST confirmed progressive disease; iCR = iRECIST 
complete response; iRECIST = modified Response Evaluation Criteria in Solid Tumors 1.1 for immune-based 
therapeutics; iSD = iRECIST stable disease; iUPD = iRECIST unconfirmed progressive disease; PD = progressive 
disease; RECIST 1.1 = Response Evaluation Criteria in Solid Tumors 1.1. 


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Figure 2-2: Imaging and Treatment for Clinically Stable Participants Treated 
with Pembrolizumab after First Radiologic Evidence of PD Assessed by the 
Investigator 
 
NOTE: If a patient has confirmed radiographic progression (i.e., 2 scans at least 4 
weeks apart demonstrating progressive disease), but the patient is achieving a clinically 
meaningful benefit, and there is no further increase in the tumor burden at the 
confirmatory tumor imaging, an exception to continue treatment may be considered 
following consultation with the Sponsor. In this case, if treatment is continued, tumor 
imaging should continue to be performed following the study intervals and be 
submitted to the central imaging vendor. 
When feasible, patients should not be discontinued until PD is confirmed. However, 
patients that are deemed clinically unstable are not required to have repeat imaging for 
confirmation of PD and should come off study treatment.


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 Protein Lysine Acetylation and Immune Correlates Assessments 
Blood  
Based on preclinical studies it is suggested that entinostat may specifically target a 
population of MDSCs and thus improve the response to PD-1 or PD-L1 antibody 
treatment. The Sponsor plans to evaluate populations of MDSC and other myeloid cells 
in peripheral blood and tumor tissues of the patients (if available) and also to evaluate 
the basic T-cell function in patients, with the expectation that if MDSC level is 
decreased the response to antigens would be improved. 
Blood for immune correlates and protein lysine acetylation is to be shipped on the same 
day of draw to the applicable laboratories with proper advanced notification according 
to the laboratory manual. 
Blood 
For patients in the EMIC Cohort, blood for immune correlates is to be collected pre-
dose on D-14, C1D1, C1D8, and C2D15. For patients in all other cohorts, blood for 
immune correlates is to be collected pre-dose on C1D1, C2D1, and C2D15. At these 
time points, 40 mL of heparinized peripheral blood is to be collected and shipped 
overnight to a central laboratory facility for analysis. 
For patients in the EMIC Cohort, blood for protein lysine acetylation is to be collected 
pre-dose on D-14, C1D1, C1D15, and C2D15. For patients in all other cohorts, blood 
for protein lysine acetylation is to be collected pre-dose on C1D1, C1D15 and C2D15. 
At these time points, approximately 16mL of blood is to be collected and shipped 
overnight to a central laboratory facility for analysis. 
The following immune correlate analyses will be performed on the collected samples: 
Cell Phenotype: 
• MDSC: Lin (CD3, CD14, CD19, CD56) negative, HLA-DR-, CD33+; 
• MDSC: CD11b+CD14-CD33+; 


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• PMN-MDSC: CD11b+CD14-CD33+CD15+; 
• M-MDSC: CD11b+CD14-CD33+CD15-; 
• M-MDSC: CD14+HLA-DR-/lo; 
• Monocytes: CD14+CD16+CD66b-HLA-DR+ including subsets of classical 
CD14hiCD16, intermediate CD14hiCD16+ and non-classical CD14+CD16hi; 
• Dendritic cells: Lin-HLA-DR+CD303+ (BDCA2) plasmacytoid; Lin-HLA-
DR+CD1c+ (BDCA1) myeloid; Lin-HLA-DR+CD141+ (BDCA3); 
• Neutrophils: CD11b+CD14-CD15+/CD66b+ cells in high density fraction; 
• T cells: CD3+CD4+; CD3+CD8+; Regulatory T cells: CD4+CD25+FoxP3+; 
• B cells: CD19. 
Cell Function: 
Mononuclear cells stimulated with CD3/CD28, ConA, and tetanus toxoid. Cell 
proliferation by 3H-thymidine uptake will be measured. Supernatant will be collected 
and interleukin-2, IFN-γ, and GM-CSF will be measure by enzyme-linked 
immunosorbent assay. 
Tumor Tissue 
Fresh tumor tissue samples will be collected during the study as follows: 
• During screening from all patients on a mandatory basis. 
• On C2D15 (+3 days) on an optional basis from patients in the Dose 
Escalation/Confirmation 
Phase. 
All 
patients 
in 
the 
Dose 
Escalation/Confirmation Phase will be strongly encouraged to provide an 
optional biopsy in order to help understand dose-immune correlate effects.  
• On C2D15 (+3 days) on a mandatory basis from the first 10 patients (in total, 
across cohorts) in Stage 1 in the Expansion Phase, the first 10 patients in 
the EMIC Cohort, and the first 10 patients in the CRC Cohort.    
• If, based on an interim review of tumor tissue data from the initial patients in 


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the Expansion Phase, such data are considered informative, then tumor tissue 
samples will be collected on a mandatory basis from all subsequent patients in 
the Expansion Phase on C2D15 (+ 3 days).  Alternatively, if such data are not 
considered informative, these samples will not be collected from subsequent 
patients.  
If patients whose only accessible lesion for biopsy is a solitary target lesion, it must be 
amenable to a core biopsy that will not compromise assessment of tumor 
measurements. If patients have only one measurable lesion per RECIST v1.1: 
1. the biopsy specimen should be obtained from a non-target lesion  
2. this lesion should not have been in a field of prior-irradiation unless confirmed 
progression of the lesion 
Should a patient opt out of a mandatory biopsy procedure, it will be considered a 
protocol deviation; however, the patient will be allowed to continue treatment on study. 
Tissue samples will be analyzed for changes in expression of checkpoint inhibitors 
(PD-1/PD-L1) Cohorts 1, 2, and 3 only) in tumor biopsies pre- and post-therapy as well 
as the following immune correlates:  
• MDSC: CD33+S100A9+; 
• Macrophages CD163+ or CD68+ cells; 
• Neutrophils – Neutrophil elastase+ cells; 
• Dendritic cells – DC-SIGN (CD209); 
• CD4, CD8, Granzyme B, and FoxP3 positive cells will be done as 
appropriate if the MDSC level in the tissues is decreased. 
 Pharmacokinetic Assessments 
Entinostat 
Blood samples will be collected to assess the PK of entinostat and will be quantified 
by a sensitive and specific validated bioanalytical method. One (1) blood samples will 


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be collected at the following time points: 
• Pre-dose C1D1 
• 2-4 hours post dose C1D1  
• C1D8 (anytime post dose) 
• C1D15 (anytime post dose) 
• Pre-dose C2D1 
On each PK sample collection day, the time and date of entinostat administration, the 
start and stop time of pembrolizumab administration, and the time and date of PK 
sample collection should be recorded in the eCRF. 
Pembrolizumab 
Samples for determination of trough pembrolizumab levels and anti-pembrolizumab 
antibodies will be collected at the following time points (all taken pre-dose): 
• C1D1 
• C2D1 
• C4D1 
• C6D1 
• C8D1 
• Every 4 cycles thereafter until last dose of pembrolizumab 
• 30 days after the last pembrolizumab dose (or until the patient starts new anti-
cancer therapy).  
All pre-dose trough samples should be collected within 24 hours before the 
pembrolizumab infusion. 
On each sample collection day, the time and date of entinostat administration, the start 
and stop time of pembrolizumab administration, and the time and date of sample 
collection should be recorded in the eCRF. 


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 Safety Assessments 
The following assessments will be performed to evaluate the safety profile of entinostat 
and pembrolizumab. The assessments will be performed during Screening, on Day 1 of 
each cycle, at the EOT visit (7 days post-last dose) and at the Safety Follow-up visits, 
as described in the Schedule of Study Assessments (Protocol Table 1-1, or Table 1-2 
for EMIC Cohort).  
• Vital signs: temperature, pulse rate, respiration rate, and blood pressure 
(systolic and diastolic) 
• Body height (at screening only) and weight 
• 12-lead Safety ECGs are recorded at the Screening Visit, and as clinically 
indicated throughout the study as outlined in the Schedule of Study 
Assessments  
• AE and SAE recording 
• Hematology: white blood cell (WBC) count with differential, red blood cell 
(RBC) count, platelet count, hemoglobin (HGB) and hematocrit (HCT), 
coagulation studies, including prothrombin time or international normalized 
ratio (PT/INR) and activated partial thromboplastin time (aPTT; at Screening 
only) 
• Chemistry: alanine transaminase (ALT), aspartate transaminase (AST), alkaline 
phosphatase (ALP), albumin, total bilirubin, blood urea nitrogen (BUN), 
calcium, creatinine, electrolytes (sodium, potassium, magnesium [Mg at 
Screening only; thereafter as clinically indicated], chloride, bicarbonate), 
glucose, lactate dehydrogenase (LDH), phosphorus, total protein, uric acid, 
thyroid-stimulating hormone (TSH), free thyroxine (FT4), and total or free 
triiodothyronine (T3 or FT3) 
• In the CRC cohort, blood tumor marker CEA should be drawn on day 1 of each 
cycle.  
 Other Assessments 
Other assessments include patient demographics, prior cancer history, prior systemic 


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anti-cancer therapy, prior surgery related to indicated cancer, prior radiation therapy, 
medical history, physical examinations, entinostat administration and accountability, 
pembrolizumab administration and accountability, concomitant medications and 
procedures, protocol deviations, post-treatment anti-cancer therapy, ECOG 
performance status score, and clinical disease assessment, collected per Schedule of 
Study Assessments (Protocol Table 1-1). 
3 STATISTICAL METHODS 
3.1 General Methods 
 Computing Environment 
The statistical analyses performed for this study will be presented by study phase. For 
the dose determination phase, tabulations will be provided by 3 mg dose cohort. For 
the expansion phase, tabulations will be provided by tumor type and overall. Data from 
dose determination phase for the patients who received 5 mg will be included in dose 
expansion phase.   
All statistical analyses will be performed using SAS® Version 9.2 or higher for 
Windows. Programming specifications will be prepared, which describe the datasets 
and variables created for this study. The datasets will be prepared using the most recent 
version of CDISC’s Study Data Tabulation Model (SDTM) and Analysis Dataset 
Model (ADaM).  
 Reporting of Numerical Values 
Descriptive statistics (n, mean, standard deviation, median, minimum, and maximum) 
will be calculated for continuous variables. Frequencies and percentages will be 
presented for categorical and ordinal variables. Percentages will be based on the 
number of patients with non-missing assessments. If there are missing values, the 
number missing will be presented, but without a percentage.  
Means and medians will be reported to one decimal place more than the data reported 
in the clinical data management system. Standard deviations will be reported to two 
decimal places more than the data reported. Minimum and maximum will be reported 


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to the same to the same number of decimal places displayed in the clinical data 
management system. 
 Baseline Value and Change from Baseline  
Baseline will be defined as the most recent, non-missing value obtained immediately 
prior to the first dose of any study drug (entinostat or pembrolizumab). Change from 
baseline will be calculated by subtracting the baseline value from the on-study 
assessment for each patient (i.e., post-dose – baseline).  
 Handling of Missing/Incomplete Values 
Unless otherwise specified, missing data will not be imputed. For AE start dates, the 
first algorithm described below will be used to determine treatment emergence. For 
incomplete dates of diagnosis, the second algorithm described below will be used to 
determine the incomplete date if the day and/or month is missing. 
Algorithm for Imputation of Incomplete/Missing Adverse Event Start Dates 
Case 1: 
if year portion of AE start date = missing then missing AE start date = dose date; 
Case 2: 
if year portion of AE start date = year portion of dose date 
then do; 
  if month portion of AE start date = missing 
  then missing AE start date = dose date; 
 
  else if month portion of AE start date = month portion of dose date 
  then missing AE start date = dose date; 
 
  else if month portion of AE start date ≠ month portion of dose date 
  then missing AE start date = mdy(AE start month, 1, AE start year); 


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end; 
Case 3: 
If year portion of AE start date > year portion of dose date, then AE is treatment-
emergent. 
Algorithm for Imputation of Incomplete/Missing Date of Diagnosis 
If the date of diagnosis is missing the day and/or month, the following algorithm will 
be used. 
Case 1:  
For cases where day and month are unknown or missing, the day and month will be set 
to June 30 with the known year, provided that the resulting date is before treatment 
start date. Otherwise, one day prior to treatment start date (treatment start date – 1) will 
be used.  
Case 2: 
For cases where only the day is unknown or missing, the day will be set to 15 with the 
non-missing month and year, provided the resulting date is before the treatment start 
date. Otherwise, one day prior to the treatment start date (treatment start date – 1) will 
be used.  
3.2 Analysis Sets  
 Full Analysis Set  
The Full Analysis Set (FAS) will serve as the primary population for the analysis of 
tumor response and other efficacy-related endpoints in the Phase 2 portion of the study. 
The FAS is a subset of all enrolled patients, with patients excluded for the following 
reasons:  


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• 
Failure to receive at least one dose of entinostat and pembrolizumab 
• 
Lack of baseline data for those analyses that require baseline data 
 Per-Protocol Analysis Set 
The Per-Protocol Analysis Set is a subset of the FAS. The Per-Protocol Analysis Set 
consists of all patients who do not violate the terms of the protocol in a way that would 
majorly impact the study outcome. All decisions to exclude patients for the 
Per-Protocol Analysis Set will be made prior to the data freeze for the primary analysis.  
 Evaluable Analysis Set 
The Evaluable Analysis Set is a subset of the FAS. The Evaluable Analysis Set is 
defined as patients who had week 6 assessment or were removed from study for 
progression of disease (or suspected progression) or for adverse event that was 
attributed to study drug. Patients who were excluded from Evaluable Analysis Set 
included those who discontinued due to adverse events that were not related to study 
drug or withdrew consent from treatment or study before the Week 6 scan assessment.  
 Safety Analysis Set 
Without otherwise specified, the Safety Analysis Set will be used for the analysis of 
safety data in both the Phase 1b and Phase 2 portions of the study. The Safety Analysis 
Set will include all patients who received at least one dose of either study drug, 
entinostat, or pembrolizumab. At least one laboratory or vital sign measurement 
obtained, subsequent to at least one dose of study treatment, is required for inclusion 
in the analysis of a safety specific parameter. To assess change from baseline, a baseline 
measurement is also required.  
 Pharmacokinetic Analysis Set  
Patients will be evaluable for the primary PK analysis if they receive the reference 
agent administered with and without the other agent. Additionally, patients must have 
sufficient plasma concentration-time data from each treatment period in order to 
provide for meaningful assessment of the PK parameters (e.g., AUC and Cmax). The PK 
Analysis Set will include all patients who have evaluable plasma concentration-time 


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data for each treatment period, and for whom one or more of the designated PK 
parameters can be determined.  
3.3 Analysis Variables 
 Efficacy Variables  
Efficacy variables include:  
• 
ORR (CR or PR) by irRECIST and RECIST 1.1 
• 
CBR (CR, PR, or SD for at least 24 weeks) by irRECIST and RECIST 1.1 
• 
PFS at 6 months by irRECIST and RECIST 1.1 
• 
PFS as determined by irRECIST and RECIST 1.1  
• 
OS  
• 
DOR and TTR (in patients who achieve a best overall response of CR or 
PR) 
 Pharmacokinetic Variables 
The following PK parameters for the plasma concentrations of entinostat or 
pembrolizumab will be calculated via non-compartmental methods and summarized, 
where applicable, using the WinNonlin™ software package (WinNonlin™ Phoenix, 
Version 6.3, Pharsight Corporation, Mountain View, CA). 
Pharmacokinetic variables include: 
• Cmax, maximum plasma concentration  
• Tmax, time at which maximum plasma concentration was observed  
• AUC0-t, area under the plasma concentration-time curve from time zero to the 
last measurable concentration  
• AUC0-inf, area under the plasma concentration-time curve from time zero 
extrapolated to infinity 
• t1/2, elimination half-life  
• λz, terminal elimination rate constant 
All measurable plasma concentrations will be used for the analysis. For concentration 
values reported as no Results/not Reportable (NR), values will be treated as missing. 


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Values below the quantifiable limit (BQL) that occur prior to the first measurable 
concentration will be treated as zero. All other BQL values will be treated as missing. 
The mean plasma concentration over time by treatment and the individual subject 
plasma concentration versus time data will be plotted. Nominal times will be used for 
plotting the mean plasma concentrations over time by treatment. Actual sampling times 
will be used for the individual figures and for the non-compartmental analysis.  
 Safety Variables 
Safety variables include: 
• Determination of DLT, MTD and RP2D 
• Incidence of TEAEs:  
TEAEs are defined as any AE occurring or worsening in severity after the 
administration of study drug. TEAEs will be categorized as: 
o 
Relationship to entinostat  
o 
Relationship to pembrolizumab 
o 
Severity/Grade according to National Cancer Institute Terminology 
Criteria for Adverse Events (NCI CTCAE) Version 4.03 
o 
Action with respect to entinostat 
o 
Action with respect to pembrolizumab  
o 
Seriousness and outcome 
• Change in chemistry and hematology parameters from baseline to minimum 
and maximum post-baseline values, average post-baseline value, and last 
post-baseline value  
• Shifts in chemistry and hematology parameters from baseline to worst 
post-baseline in CTCAE toxicity grade 
• Shifts in chemistry and hematology parameters outside the laboratory normal 
range from baseline to maximum increase and/or decrease, and last 
post-baseline value 
• Change from baseline in vital signs and weight at each post-baseline time point 
• Change from baseline in 12-lead ECG parameters at each post-baseline time 
point 
• Change from baseline in ECOG at each post-baseline time point 


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 Exploratory Variables 
 
 
 
 
 
 
 
  
 
 
  
 
 
  
 
 
 
  
 
 
 
 
 
  
 
 
 
 
  
 
 
  
  
3.4 Disposition and Evaluability 
 Disposition 
The number and percentage of patients who were enrolled, dosed, and withdrew prior 
to receiving a dose (including reasons for not completing dosing), the number of cycles 
on treatment, the reasons for discontinuation of each study treatment, the reason for 
discontinuation of the study, will be presented by dose cohort in Phase 1 and by tumor 
type and overall in Phase 2.  


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 Protocol Deviations 
Protocol deviations will be presented in a patient listing.  
3.5 Demographics and Baseline Characteristics 
 Demographics 
Demographics will be summarized by dose cohort for the Safety Analysis Set (Phase 1 
only) and will be summarized by tumor type for the Safety Analysis Set (Phase 2). 
Frequency statistics will be presented for sex, race, ethnicity, age group, and ECOG 
performance status at baseline. Summary statistics will be presented for age, weight 
(kg), height (cm), and body surface area (m2).  
Body surface area will be calculated using the Mosteller formula:  
 
Body surface area = ටheight (cm) × weight (kg) 
3600
 
 
All demographic data will be presented in patient listings. 
 Cancer Disease History  
The following baseline disease characteristics variables will be summarized (if 
available) for each cohort in Phase 2 and the Safety Analysis Set: 
• 
Time since initial diagnosis  
• 
Disease stage at initial diagnosis  
• 
Histopathological grade at initial diagnosis  
• 
Time since diagnosis of advanced or metastatic cancer  
• 
Metastatic sites  
Disease history, including prior anti-cancer therapies (e.g. PD-1/PD-L1), surgeries, and 
radiotherapy, will be summarized by dose cohort and by tumor type for the Safety 
Analysis Set (Phase 1 only) and for the Safety Analysis Set (Phase 2 only), 
respectively. Frequency statistics will be presented for ECOG performance status, 
primary tumor location, and disease status at enrollment. Summary statistics will be 


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presented for months since diagnosis.  
If the date of diagnosis is missing the day and/or month, the algorithm specified in 
Section 3.1.4 for incomplete dates will be used to determine the date and time since the 
study start.  
All cancer disease history data will be presented in patient listings. 
 Medical History, Prior Medications, and Physical Exam 
Data regarding medical history, prior medications, and clinically significant findings 
from the physical exam will be presented in patient listings for the Safety Analysis Set 
(Phase 1 only) and for the Safety Analysis Set (Phase 2). 
3.6 Concomitant Medications 
Any medication reported on the appropriate post treatment form (Concomitant 
Medications) will be considered concomitant.  
All medications will be coded using the World Health Organization (WHO) Drug 
Dictionary (September 2016). The number and percentage of patients taking each 
concomitant medication will be presented by dose cohort (Phase 1) and tumor type 
(Phase 2) for the Safety Analysis Set. All medication data will be listed individually 
and summarized by anatomical therapeutic class and generic name. 
3.7 Treatment Exposure 
The total number of cycles started and the total number of cycles started by category 
(≥1, ≥2, ≥3, so on) will be tabulated for each patient and summarized for each study 
phase. The cumulative dose of entinostat administered (in mg) will be calculated. These 
data will be further summarized by calculating the mean, standard deviation, median, 
and range of these values. The dose intensity = [total amount of actual dose of study 
drug / ( prescribed dose per cycle*# of cycles)] * 100 will be calculated for all patients. 
Similar analyses will be performed for pembrolizumab administration (in mg/kg). The 
number and proportion of patients with one or more dosage modification (i.e., reduction 
or delay) of each study drug will be tabulated along with the reasons for dosage 
modification. The primary reason for study drug discontinuation will be tabulated in a 


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similar manner. All treatment exposure data will be presented in patient listings for the 
Safety Analysis Set.  
3.8 Efficacy Analysis  
Efficacy analyses will be performed using the FAS and, where appropriate, the 
Per-Protocol Set. ORR will be estimated for each cohort evaluated in the Expansion 
Phase using irRECIST as the primary endpoint. Crude proportion of patients with best 
overall response of CR or PR, along with a 2-sided 95% CI, will be calculated for each 
cohort. The width of the CI will be adjusted to account for the multistage design 
(Atkinson, 1985).  Additionally, a 90% one-sided CI of the form (π, 1] will be reported 
for cohort 1 and a 95% one-sided CI will be reported for cohort 4 since the sample size 
for the Expansion Phases for cohorts 1 and 4 were determined using a one-sided 
significance level of 10%, 5%, respectively.  
Crude proportion of patients with best overall response of CR or PR, along with a 2-
sided 92% CI will be calculated for cohorts 2 and 3. ORR based on RECIST 1.1 will 
be analyzed in a similar manner.  
Clinical Benefit Rate 
Clinical benefit rate, as determined by irRECIST, will be estimated based on the crude 
proportion of patients in each cohort whose best overall response during the course of 
study treatment is a irCR, irPR, or irSD lasting for at least 6 months. Stable disease 
based on irRECIST will be measured from the start date of study treatment until the 
criteria for irPD is first met. Approximate 2-sided 95% CIs will be calculated for each 
cohort. Clinical benefit rate, as determined by RECIST 1.1, will be estimated based on 
the crude proportion of patients in each cohort whose best response during the course 
of study treatment is a CR, PR, or SD lasting for at least 6 months. Stable disease based 
on RECIST 1.1 will be measured from the start date of study treatment until the criteria 
for PD is first met. Approximate 2-sided 95% CIs will be calculated for each cohort. 
Progression-free Survival 
The PFS, defined as the number of months from first dose date to PD or death due to 
any cause, whichever occurs first. Disease assessments will continue until PD, even 


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after the originally assigned study treatment is discontinued. For purposes of analysis, 
1 month is considered 30.4375 days. The duration of PFS as determined by RECIST 
1.1 (Eisenhauer 2009) and irRECIST (Seymour 2017) will be summarized 
descriptively using the Kaplan-Meier method (Kaplan 1958). The PFS at 6 months by 
irRECIST and RECIST 1.1 will be analyzed in a similar manner.  
The date of progression or censoring for PFS will be determined according to the 
conventions listed in Table 3-1. 
All patients are to be followed for disease progression according to the 
protocol-specified schedule even after a non-protocol, anti-cancer therapy is started. 
For the primary analysis of PFS, documented disease progression (or death without 
prior disease progression) occurring after the start of such therapy will be considered 
as a PFS event.    
Table 3-1. Date of Progression or Censoring for Progression-free Survival 
Situation 
Date of Progression or Censoring 
Outcome 
Documented disease progression  
Date of disease assessment showing 
documented disease progression 
Progressed 
Death without documented 
progression 
Date of death 
Progressed 
No baseline disease assessments 
Date of enrollment 
Censored 
No post-baseline assessment and 
no death 
Date of enrollment 
Censored 
Alive and without documentation 
of disease progression 
Date of last disease assessment 
Censored 
Patient lost to follow-up (or 
withdrew consent from study 
participation) before documented 
progression or death 
Date of last disease assessment 
Censored 
Overall Survival  
Overall survival is defined as the number of months from first dose date to the date of 
death (due to any cause). Patients who are alive or lost to follow-up (as of the data 
analysis cutoff date) will be censored. The censoring date will be determined from the 
patients’ date of last contact or data analysis cutoff date, whichever date occurs first. 


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The analysis of OS will be based on the methods described above for PFS. The duration 
of OS will be summarized descriptively using the Kaplan-Meier method with 95% CIs, 
calculated using Greenwood’s formula.  
Duration of Response and Time to Response  
Duration of response will be calculated for patients who achieve CR or PR. For such 
patients, DOR is defined as the number of months from the start date of the PR or CR 
(whichever response occurs first and subsequently confirmed), to the first date that 
recurrent disease or PD is documented. The same analysis will be repeated for patients 
who achieve immune-related CR (irCR) or immune-related PR (irPR). The date of 
progression or censoring for DOR will be determined according to the conventions 
listed Table 3-2. These conventions are based on the May 2007 FDA Guidance for 
Industry, ‘Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics’. 
DOR will be summarized descriptively using the Kaplan-Meier method. 
Table 3-2. Date of Progression or Censoring for Duration of Response 
Situation 
Date of Progression or Censoring 
Outcome 
Documented disease 
progression  
Date of disease assessment showing 
documented disease progression 
Progressed 
Death without documented 
progression 
Date of death 
Progressed 
Alive and without 
documentation of disease 
progression 
Date of last disease assessment 
Censored 
Time to response will be calculated for patients who achieve a CR or PR. For such 
patients, TTR is defined as the number of months from the randomization date to the 
first date the patient achieved a PR or CR (whichever response occurs first and was 
subsequently confirmed). The same analysis will be repeated for patients who achieve 
irCR or irPR.  
To supplement the above analysis of OS, a summary of the anti-cancer therapies and 
interventions received following the discontinuation of study treatment, will be 
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up assessments. The therapies may be classified and summarized as chemotherapy, 
immunotherapy, radiation, surgery or other.  
3.9 Subgroup Analyses  
Supportive analyses will be performed to determine whether the estimated treatment 
effect that is observed for the ORR and PFS (based on irRECIST) is consistent across 
selected subgroups of patients. The HR (or odds ratio) for treatment effect will be 
estimated within each subgroup. If a subgroup consists of fewer than 10% of Phase 2 
randomized patients, analysis within that subgroup will be omitted. Forest plots will be 
used to display the ORs (or hazard ratios) and 95% CIs across subgroups.  
 Subgroup analyses:   
• PD-L1 expression (Yes, No, Missing)  
• Current Visceral Involvement (Yes, No, Missing)  
• Baseline LDH (%>ULN) (Yes, No, Missing)  
• Previously treated with ipilimumab and PD-1 (Melanoma cohort only) 
• Previously treated with BRAF/MEK Inhibitor (Melanoma cohort only)  
• Baseline classical monocytes  
• NLR = (ANC/ALC) 
• dNLR = (ANC/(WBC-ANC))  
• Smoking Status (Current Smoker, Former Smoker, Never a Smoker) (NSCLC 
Cohorts only) 
3.10 Safety Analysis  
Safety analyses will be performed on the Safety Analysis Set. 
 Adverse Events 
An AE is defined as any untoward medical occurrence in a patient or clinical 


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investigation patient administered a pharmaceutical product, and that does not 
necessarily have a causal relationship with this treatment. An AE can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, 
or disease, temporally associated with the use of a medicinal (investigational) product, 
whether or not the AE is related to the medicinal (investigational) product. The term 
also covers laboratory findings or results of other diagnostic procedures that are 
considered to be clinically relevant as determined by the Investigator. 
Analyses of AEs will be based on the principle of treatment emergence. Treatment-
emergent AEs are defined as having onset after study drug dosing or a sign, symptom, 
or diagnosis that worsens after study drug dosing. Henceforth, whenever an analysis or 
summary of AEs is mentioned, it is intended that this is in reference to TEAEs, unless 
it is stated otherwise.  
If AE start dates are completely missing or partially missing, the date imputation rules 
described previously in Section 3.1.4 will be applied for the determination of 
treatment-emergence. This algorithm will be used only if the end date of the AE (if 
reported) indicates the event was not resolved before the first administration of study 
drug. Imputed AE dates will not be used to calculate the duration of AE episodes. 
All AEs will be coded according to System Organ Class (SOC) and Preferred Term 
(PT) using the Medical Dictionary for Regulatory Activities (MedDRA) dictionary 
(Version 18.0 or later). 
For the escalation phase, the observed DLT rate in each dose cohort will be calculated 
by the crude proportion of patients who experienced DLT with a 2-sided, 95% exact 
binomial CI. 
For Phase 1, AE relatedness criteria is defined as “definitely not related”, “probably 
not related”, “probably related” and “definitely related”.  
A summary of AEs, including incidences of:  
• AEs  
• SAEs  
• AEs related to entinostat (“not related”, “unlikely related”, “possibly related” 


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or “related” for Phase 2) 
• AEs related to pembrolizumab (“not related”, “unlikely related”, “possibly 
related” or “related” for Phase 2)  
• AEs related to any study drug 
• SAEs related to entinostat, pembrolizumab, or both  
• AEs leading to dose modification of entinostat, pembrolizumab, or both  
• AEs leading to discontinuation of entinostat, pembrolizumab, or both  
• AEs with a fatal outcome 
• AEs with a CTCAE severity grade of Grade 3 or greater  
• AEs with CTCAE severity of Grade 3 or greater related to entinostat, 
pembrolizumab, or both  
will be presented by dose cohort in Phase 1 and by tumor type in Phase 2.  
Incidences of all AEs will be presented by SOC and PT by dose cohort in Phase 1 and 
by tumor type in Phase 2. SOCs will be sorted alphabetically. Within an SOC, PTs will 
be presented by decreasing incidence overall. Incidences of SAEs, and incidence of 
related SAEs by PT only, will be presented by decreasing incidence overall. 
Incidence of AEs will also be presented by PT and severity, and by PT and relationship 
to study drug. Incidence of AEs of Grade 3 or greater, and incidence of related AEs of 
Grade 3 or greater, will also be presented by PT. For patients experiencing the same 
PT at multiple severities, the occurrence of the AEs with the greatest severity will be 
used in the analysis of incidence by severity. For patients experiencing the same PT at 
multiple relationship levels, the occurrence of the AEs with the strongest relationship 
to study drug will be used in the analysis of incidence by relationship to study drug. 
All reported AEs, regardless of whether they were treatment-emergent, will be included 
in patient listings. Listings of all SAEs and AEs leading to discontinuation of entinostat, 
pembrolizumab, or both will also be provided. 
 Laboratory Evaluations 
Hematology and serum chemistries will be summarized using summary statistics for 
the following values by cohort and overall: baseline value, minimum and maximum 
post-baseline values, average post-baseline value, and last post-baseline value. Change 


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from baseline for each of these post-baseline values will also be summarized.  
Whenever available, laboratory values will be assigned toxicity grades using the 
NCI-CTCAE, version 4.03. Shifts in laboratory values to outside the local laboratory 
normal range will be evaluated for selected laboratory tests by assessing, relative to the 
baseline value, the maximum increase and/or decrease observed throughout the course 
of study treatment, and the last reported value. The number and proportion of patients 
with directional shifts above or below the normal range will be summarized for selected 
laboratory tests. Similar analyses will be performed for shifts in NCI CTCAE toxicity 
grades relative to the baseline toxicity grade. 
Percentages will be based on the total number of patients with a baseline assessment 
and at least one post-baseline assessment for the given laboratory parameter. 
Laboratory test groupings and standard normal ranges are described in Appendix 5.1, 
and CTCAE toxicity grades for hematology and chemistry parameters are described in 
Appendix 5.2 and Appendix 5.3, respectively.  
Listings of all clinical laboratory data for each patient will be provided. A separate 
listing of all out of normal range as well as all toxicity grade values will also be 
provided.  
 Vital Signs 
Change from baseline for vital signs (temperature, pulse, systolic/diastolic blood 
pressure, respiration rate, and weight) will be summarized over time by tumor type.  
A patient listing of all vital sign assessments will be provided.  
 ECG 
Electrocardiogram results will be listed and summarized in terms of the number and 
percentage of patients with abnormal and normal findings, as reported by the 
Investigator, at the time points where ECGs were assessed (screening and EOT).  
3.11 Pharmacokinetic Analysis  
A population PK analysis will be used to describe the PK of entinostat. The effects of 


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patient factors (e.g., demographics, clinical chemistries, and disease) on entinostat PK 
will be evaluated. In addition, the relationship between entinostat exposure parameters 
and indicators of safety will be assessed. Descriptive statistics will be used to 
summarize the PK of pembrolizumab and anti-pembrolizumab antibodies at each cycle 
and time point. 
Specific details for these analyses as well as analyses of trough pembrolizumab levels 
and anti-pembrolizumab antibodies will be provided in a separate analysis plan. 
3.12 Immune Correlate Analysis 
Immune correlate values will be summarized in a descriptive manner. For immune 
correlates measured on a continuous scale, the number of patients with non-missing 
data, mean, standard error or standard deviation, median, 25th percentile (first quartile), 
75th percentile (third quartile), minimum, and maximum values will be presented. For 
discrete data, the frequency and percent distribution will be presented. The Wilcoxon 
signed rank test (for within-treatment comparisons) and Wilcoxon rank sum test (for 
between-treatment comparisons) will be used to identify any systematic changes in 
biomarker levels from baseline. Additionally, the correlation among the various initial 
immune correlate values may be assessed by calculating Spearman’s correlation 
coefficient. Analysis of covariance models may be used to explore the relationship 
between changes in immune correlates and selected measures of antineoplastic activity 
(e.g., maximum change from baseline in the sum of product diameters in measurable 
lesions).  
 


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4 REFERENCES 
Cox DR. (1972), Regression models and life-tables. J Royal Stat Soc Ser B. 74(2):187-
220. 
Eisenhauer EA, Therasse P, Bogaert J, Schwartz LH, Sargent D, Ford R, Dancey J, 
Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, 
Lacombe D, Verweij J. New response evaluation criteria in solid tumours: revised 
RECIST guideline (version 1.1). (2007), Eur J Cancer. 2009;45(2) 228-247.Clinical 
Trial Endpoints for the Approval of Cancer Drugs and Biologics. Rockville, Md: US 
Dept of Health and Human Services, Food and Drug Administration. 
Kaplan EL, Meier P. (1958), Nonparametric estimation of incomplete observations. 
J Amer Stat Assoc., 53:457-481. 
O'Brien PC, Fleming TR. (1979). A multiple testing procedure for clinical trials, 
Biometrics. Sep;35(3):549-56. 
Seymour L, Bogaerts J, Perrone A, Ford R, Schwartz LH, Mandrekar S, Lin NU, Litière 
S, Dancey J, Chen A, Hodi S, Therasse P, Hoekstra OS, Shankar LK, Wolchok JD, 
Ballinger M, Caramella C, Vries EGE. (2017), iRECIST: guidelines for response 
criteria for use in trials testing immunotherapeutics, The Lancet Oncology, 18, No.3, 
143-152.  
Skolnik JM, Barrett JS, Jayaraman B, Patel D, Adamson PC. (2008). Shortening the 
timeline of pediatric phase I trials: the rolling six design, J Clin Oncol. 26(2):190-5.   
Therneau TM, Grambsch PM. (2000). Modeling Survival Data: Extending the Cox 
Model. 
 
 
 
 
 
 
 
 


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5 APPENDIX 
5.1 Laboratory Test Groupings and Standard Normal Range 
Analyte 
Standard 
Unit 
Significant 
Digits 
Directional 
Change of 
Interest 
Standard 
Normal Range† 
Lab group = Hematology, WBC with Differential 
WBC count‡ 
109 cells/L 
XX.X 
Decrease 
3.2 – 9.8 
Basophil count 
106 cells/L 
XX 
Decrease 
15 – 50 
Eosinophil count 
106 cells/L 
XXX 
Decrease 
50 – 250 
Lymphocyte count‡ 
106 cells/L 
XXXX 
Decrease 
1500 – 3000 
Monocyte count 
106 cells/L 
XXX 
Decrease 
285 – 500 
Neutrophil count‡ 
106 cells/L 
XXXX 
Decrease 
3000 – 5800 
Lab group = Hematology, Erythrocytes and Platelets 
Hematocrit 
Fraction of 1.00 
0.XX 
Decrease 
0.33 – 0.43 (female) 
0.39 – 0.49 (male) 
Hemoglobin‡ 
g/L 
XXX 
Decrease 
115 – 155 (female) 
140 – 180 (male) 
RBC count 
1012/L 
X.X 
Decrease 
3.5 – 5.0 
Platelet count‡ 
109/L 
XXX 
Decrease 
130 – 400 
Lab group = Hematology, Coagulation 
PT 
seconds 
XX 
Increase 
9 – 12 
PTT‡ 
seconds 
XX 
Increase 
22 – 37 
† Standard normal ranges are provided for reference and not will be used in analysis unless laboratory 
normal ranges are missing. Source: Laposta, M: SI Unit Conversion Guide, The New England Journal of 
Medicine Books, Boston, 1992. 
‡ If present, indicates CTCAE toxicity grade is defined for the analyte. 


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Laboratory Test Groupings and Standard Normal Range (continued) 
Analyte 
Standard 
Unit 
Significant 
Digits 
Directional 
Change of 
Interest 
Standard 
Normal Range† 
Lab group = Chemistry, Hepatic 
Albumin‡ 
g/L 
XX 
Decrease 
40 – 60 
Alk Phos‡ 
U/L 
XXX 
Increase 
30 – 120 
ALT‡ 
U/L 
XXX 
Increase 
0 – 35 
AST‡ 
U/L 
XXX 
Increase 
0 – 35 
Lactic dehydrogenase 
U/L 
XXX 
Increase 
50 – 150 
Total Bilirubin‡ 
micromol/L 
XX 
Increase 
2 – 18 
Total Protein 
g/L 
X.XX 
Decrease 
60 – 80 
Lab group = Chemistry, Renal 
BUN 
mmol/L of urea 
X.X 
Increase 
3.0 – 6.5 
Creatinine‡ 
micromol/L 
XXX 
Increase 
50 – 110 
Creatinine clearance 
mL/min 
XXX 
Decrease 
75 – 125 
† Standard normal ranges are provided for reference and not will be used in analysis unless laboratory 
normal ranges are missing.  
Source: Laposta, M: SI Unit Conversion Guide, The New England Journal of Medicine 
  Books, Boston, 1992. 
‡ If present, indicates CTCAE toxicity grade is defined for the analyte. 


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Laboratory Test Groupings and Standard Normal Range (continued) 
Analyte 
Standard 
Unit 
Significant 
Digits 
Directional 
Change of 
Interest 
Standard 
Normal Range† 
Lab group = Chemistry, Electrolytes 
Bicarbonate‡ 
mmol/L 
XX 
Both 
22 – 28 
Calcium‡ 
mmol/L 
X.XX 
Both 
2.20 – 2.56 
Chloride 
mmol/L 
XXX 
Both 
95 – 105 
Magnesium‡ 
mmol/L 
X.XX 
Both 
0.80 – 1.20 
Phosphorus 
mmol/L 
X.XX 
Both 
0.80 – 1.60 
Potassium‡ 
mmol/L 
X.X 
Both 
3.5 – 5.0 
Sodium‡ 
mmol/L 
XXX 
Both 
135 – 147 
Lab group = Chemistry, Metabolic 
Glucose‡ 
mmol/L 
XX.X 
Both 
3.9 – 6.1 
Uric Acid 
micromol/L 
XXX 
Increase 
120 – 420 
† Standard normal ranges are provided for reference and not will be used in analysis unless laboratory 
normal ranges are missing.  
Source: Laposta, M: SI Unit Conversion Guide, The New England Journal of Medicine 
  Books, Boston, 1992. 
‡ If present, indicates CTCAE toxicity grade is defined for the analyte. 
 


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5.2 CTCAE Toxicity Grades: Hematology  
Analyte 
Standard 
Unit 
Directional Change 
of Interest 
Toxicity Grades 
(CTCAE v4.03) 
WBC with Differential 
WBC count 
109/L 
Decrease 
Grade 0: ≥ LLN 
 
 
 
Grade 1: < LLN – 3.0 × 109/L 
 
 
 
Grade 2: < 3.0 – 2.0 × 109/L 
 
 
 
Grade 3: < 2.0 – 1.0 × 109/L 
 
 
 
Grade 4: < 1.0 × 109/L 
 
 
 
 
Lymphocyte count 
106 cells/L 
Decrease 
Grade 0: ≥ LLN 
 
 
 
Grade 1: < LLN – 0.8 × 106/L 
 
 
 
Grade 2: < 0.8 – 0.5 × 106/L 
 
 
 
Grade 3: < 0.5 – 0.2 × 106/L 
 
 
 
Grade 4: < 0.2 × 106/L 
 
 
 
 
Neutrophil count 
106 cells/L 
Decrease 
Grade 0: ≥ LLN 
 
 
 
Grade 1: < LLN – 1.5 × 106/L 
 
 
 
Grade 2: < 1.5 – 1.0 × 106/L 
 
 
 
Grade 3: < 1.0 – 0.5 × 106/L 
 
 
 
Grade 4: < 0.5 × 106/L 
LLN=lower limit of normal. ULN=upper limit of normal. The LLN and ULN for each analyte will be 
determined from the normal range of each local laboratory. 
 
 
 


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CTCAE Toxicity Grades: Hematology (continued) 
Analyte 
Standard 
Unit 
Directional Change 
of Interest 
Toxicity Grades 
(CTCAE v4.03) 
Erythrocytes and Platelets 
Hemoglobin 
g/L 
Decrease 
Grade 0: ≥ LLN 
 
 
 
Grade 1: < LLN – 100 g/L 
 
 
 
Grade 2: < 100 – 80 g/L 
 
 
 
Grade 3: < 80 g/L 
 
 
 
Grade 4: Not defined 
 
 
 
 
Platelet count 
109/L 
Decrease 
Grade 0: ≥ LLN 
 
 
 
Grade 1: < LLN – 75 × 109/L 
 
 
 
Grade 2: < 75 – 50 × 109/L 
 
 
 
Grade 3: < 50 – 25 × 109/L 
 
 
 
Grade 4: < 25 × 109/L 
Coagulation 
PTT 
seconds 
Increase 
Grade 0: ≤ ULN 
 
 
 
Grade 1: > ULN– 1.5 × ULN 
 
 
 
Grade 2: > 1.5 – 2.5 × ULN 
 
 
 
Grade 3: > 2.5 × ULN 
 
 
 
Grade 4: Not defined 
LLN=lower limit of normal. ULN=upper limit of normal. The LLN and ULN for each analyte will be 
determined from the normal range of each local laboratory. 
 


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5.3 CTCAE Toxicity Grades: Chemistry 
Analyte 
Standard 
Unit 
Directional Change of 
Interest 
Toxicity Grades 
(CTCAE v4.03) 
Hepatic 
Albumin 
g/L 
Decrease 
Grade 0: ≥ LLN 
 
 
 
Grade 1: < LLN – 30 g/L 
 
 
 
Grade 2: < 30 – 20 g/L 
 
 
 
Grade 3: < 20 g/L 
 
 
 
Grade 4: Not defined 
 
 
 
 
Alk Phos 
U/L 
Increase 
Grade 0: ≤ ULN 
 
 
 
Grade 1: > ULN – 2.5 × ULN 
 
 
 
Grade 2: > 2.5 – 5.0 × ULN 
 
 
 
Grade 3: > 5.0 – 20.0 × ULN 
 
 
 
Grade 4: > 20.0 × ULN 
 
 
 
 
ALT 
U/L 
Increase 
Grade 0: ≤ ULN 
 
 
 
Grade 1: > ULN – 3.0 × ULN 
 
 
 
Grade 2: > 3.0 – 5.0 × ULN 
 
 
 
Grade 3: > 5.0 – 20.0 × ULN 
 
 
 
Grade 4: > 20.0 × ULN 
LLN=lower limit of normal. ULN=upper limit of normal. The LLN and ULN for each analyte will be 
determined from the normal range of each local laboratory. 
 


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CTCAE Toxicity Grades: Chemistry (continued) 
Analyte 
Standard 
Unit 
Directional Change 
of Interest 
Toxicity Grades 
(CTCAE v4.03) 
Hepatic (continued) 
AST 
U/L 
Increase 
Grade 0: ≤ ULN 
 
 
 
Grade 1: > ULN – 3.0 × ULN 
 
 
 
Grade 2: > 3.0 – 5.0 × ULN 
 
 
 
Grade 3: > 5.0 – 20.0 × ULN 
 
 
 
Grade 4: > 20.0 × ULN 
 
 
 
 
Total Bilirubin 
micromol/L 
Increase 
Grade 0: ≤ ULN 
 
 
 
Grade 1: > ULN – 1.5 × ULN 
 
 
 
Grade 2: > 1.5 – 3.0 × ULN 
 
 
 
Grade 3: > 3.0 – 10.0 × ULN 
 
 
 
Grade 4: > 10.0 × ULN 
Renal 
Creatinine 
micromol/L 
Increase 
Grade 0: ≤ ULN 
 
 
 
Grade 1: > ULN – 1.5 × ULN 
 
 
 
Grade 2: > 1.5 – 3.0 × ULN 
 
 
 
Grade 3: > 3.0 – 6.0 × ULN 
 
 
 
Grade 4: > 6.0 × ULN 
LLN=lower limit of normal. ULN=upper limit of normal. The LLN and ULN for each analyte will be 
determined from the normal range of each local laboratory. 


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CTCAE Toxicity Grades: Chemistry (continued) 
Analyte 
Standard 
Unit 
Directional Change 
of Interest 
Toxicity Grades 
(CTCAE v4.03) 
Electrolytes 
Sodium 
mmol/L 
Increase 
Grade 0: ≤ ULN 
 
 
 
Grade 1: > ULN – 150 mmol/L 
 
 
 
Grade 2: > 150 – 155 mmol/L 
 
 
 
Grade 3: > 155 – 160 mmol/L 
 
 
 
Grade 4: > 160 mmol/L 
 
 
Decrease 
Grade 0: ≥ LLN 
 
 
 
Grade 1: < LLN – 130 mmol/L 
 
 
 
Grade 2: Not defined 
 
 
 
Grade 3: < 130 – 120 mmol/L 
 
 
 
Grade 4: < 120 mmol/L 
 
 
 
 
Potassium 
mmol/L 
Increase 
Grade 0: ≤ ULN 
 
 
 
Grade 1: > ULN – 5.5 mmol/L 
 
 
 
Grade 2: > 5.5 – 6.0 mmol/L 
 
 
 
Grade 3: > 6.0 – 7.0 mmol/L 
 
 
 
Grade 4: > 7.0 mmol/L 
 
 
Decrease 
Grade 0: ≥ LLN 
 
 
 
Grade 1: < LLN – 3.0 mmol/L 
 
 
 
Grade 2: Not defined 
 
 
 
Grade 3: < 3.0 – 2.5 mmol/L 
 
 
 
Grade 4: < 2.5 mmol/L 
LLN=lower limit of normal. ULN=upper limit of normal. The LLN and ULN for each analyte will be 
determined from the normal range of each local laboratory. 


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CTCAE Toxicity Grades: Chemistry (continued) 
Analyte 
Standard 
Unit 
Directional Change 
of Interest 
Toxicity Grades 
(CTCAE v4.03) 
Electrolytes (continued) 
Magnesium 
mmol/L 
Increase 
Grade 0: ≤ ULN 
 
 
 
Grade 1: > ULN – 1.23 mmol/L 
 
 
 
Grade 2: Not defined 
 
 
 
Grade 3: > 1.23 – 3.30 mmol/L 
 
 
 
Grade 4: > 3.30 mm/L 
 
 
Decrease 
Grade 0: ≥ LLN 
 
 
 
Grade 1: < LLN – 0.5 mmol/L 
 
 
 
Grade 2: < 0.5 – 0.4 mmol/L 
 
 
 
Grade 3: < 0.4 – 0.3 mmol/L 
 
 
 
Grade 4: < 0.3 mmol/L 
 
 
 
 
Calcium 
mmol/L 
Increase 
Grade 0: ≤ ULN 
 
 
 
Grade 1: > ULN – 2.9 mmol/L 
 
 
 
Grade 2: > 2.9 – 3.1 mmol/L 
 
 
 
Grade 3: > 3.1 – 3.4 mmol/L 
 
 
 
Grade 4: > 3.4 mmol/L 
 
 
Decrease 
Grade 0: ≥ LLN 
 
 
 
Grade 1: < LLN – 2.0 mmol/L 
 
 
 
Grade 2: < 2.0 – 1.75 mmol/L 
 
 
 
Grade 3: < 1.75 – 1.5 mmol/L 
 
 
 
Grade 4: < 1.5 mmol/L 
LLN=lower limit of normal. ULN=upper limit of normal. The LLN and ULN for each analyte will be 
determined from the normal range of each local laboratory. 


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CTCAE Toxicity Grades: Chemistry (continued) 
Analyte 
Standard 
Unit 
Directional Change 
of Interest 
Toxicity Grades 
(CTCAE v4.03) 
Electrolytes (continued) 
Bicarbonate* 
mmol/L 
Decrease 
Grade 0: ≥ LLN 
 
 
 
Grade 1: < LLN – 16.0 mmol/L 
 
 
 
Grade 2: < 16.0 – 11.0 mmol/L 
 
 
 
Grade 3: < 11.0 – 8.0 mmol/L 
 
 
 
Grade 4: < 8.0 mmol/L 
 
 
 
 
Phosphorus 
mmol/L 
Decrease 
Grade 0: ≥ LLN 
 
 
 
Grade 1: < LLN – 0.8 mmol/L 
 
 
 
Grade 2: < 0.8 – 0.6 mmol/L 
 
 
 
Grade 3: < 0.6 – 0.3 mmol/L 
 
 
 
Grade 4: < 0.3 mmol/L 
Metabolic 
Glucose 
mmol/L 
Increase 
Grade 0: ≤ ULN 
 
 
 
Grade 1: > ULN – 8.9 mmol/L 
 
 
 
Grade 2: > 8.9 – 13.9 mmol/L 
 
 
 
Grade 3: > 13.9 – 27.8 mmol/L 
 
 
 
Grade 4: > 27.8 mmol/L 
 
 
Decrease 
Grade 0: ≥ LLN 
 
 
 
Grade 1: < LLN – 3.0 mmol/L 
 
 
 
Grade 2: < 3.0 – 2.2 mmol/L 
 
 
 
Grade 3: < 2.2 – 1.7 mmol/L 
 
 
 
Grade 4: < 1.7 mmol/L 
LLN=lower limit of normal. ULN=upper limit of normal. The LLN and ULN for each analyte will be 
determined from the normal range of each local laboratory. 
*Bicarbonate toxicity grade are taken from CTCAE v3.0. 
 


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6 Tables, Listings, and Figures 
6.1 List of Tables 
Table Number 
Title 
Table 14.1.1 
Analysis Populations 
Table 14.1.2A 
Study Disposition – Phase 1b  
Table 14.1.2B 
Study Disposition – Phase 2  
Table 14.1.3A 
Demographics and Baseline Characteristics – Phase 1b 
Table 14.1.3B 
Demographics & Baseline Characteristics– Phase 2  
Table 14.1.4A 
NSCLC History – Phase 2– Cohort 1 
Table 14.1.4B 
NSCLC History – Phase 2– Cohort 2 
Table 14.1.4C 
Melanoma Cancer History – Phase 2– Cohort 3 
Table 14.1.4D 
Colorectal Cancer History – Phase 2– Cohort 4 
Table 14.1.5 
Prior Surgery – Phase 2  
Table 14.1.6 
Prior Chemotherapy – Phase 2  
Table 14.1.7 
Prior Radiation Therapy – Phase 2  
Table 14.1.8  
Prior PD-1/PD-L1 Therapy – Phase 2  
Table 14.1.9 
Concomitant Medications – Phase 2  
Table 14.2.1.1 
Summary Statistics for Entinostat Plasma Concentrations 
(PK) 


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Table 14.2.1.2 
Summary Statistics for Pembrolizumab Plasma 
Concentrations (PK) 
Table 14.2.2.1 
Summary Statistics for Pharmacokinetic Parameters of 
Entinostat (PK) 
Table 14.2.2.2 
Summary Statistics for Pharmacokinetic Parameters of 
Pembrolizumab (PK) 
Table 14.3.1.1 
Entinostat Dosing – Phase 2  
Table 14.3.1.2 
Pembrolizumab Dosing – Phase 2  
Table 14.3.2.1 
Entinostat Dosage Modifications – Phase 2  
Table 14.3.2.2 
Pembrolizumab Dosage Modifications – Phase 2  
Table 14.3.3A 
Objective Response Rate (irRECIST) – Phase 2 (FAS) 
Table 14.3.3B 
Objective Response Rate (irRECIST) – Phase 2 (PP) 
Table 14.3.3C 
Objective Response Rate (RECIST 1.1) – Phase 2 (FAS) 
Table 14.3.3D 
Objective Response Rate (RECIST 1.1) – Phase 2 (PP) 
Table 14.3.4A 
ORR by PD-L1 Expression (irRECIST) – Phase 2 (FAS) 
Table 14.3.4B  
ORR by visceral disease involvement (irRECIST) -Phase 2 
(FAS) 
Table 14.3.4C 
ORR by baseline LDH (%> ULN) -Phase 2 (FAS)  
Table 14.3.4D 
ORR by previously treated with ipilimumab and PD-1 
(Melanoma cohort only) (irRECIST) – Phase 2 (FAS) 
Table 14.3.4E 
ORR by previously treated with BRAF/MEK inhibitor 
(Melanoma cohort only) (irRECIST) – Phase 2 (FAS)  


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Table 14.3.4F 
ORR by baseline non-classical monocytes (cut-off median 
for NSCLC, but it might change for other cohorts) 
(irRECIST)  – Phase 2 (FAS)  
Table 14.3.4G 
ORR by NLR (irRECIST) – Phase 2 (FAS)  
Table 14.3.4H 
ORR by dNLR (irRECIST)– Phase 2 (FAS)  
Table 14.3.4I 
ORR by smoking status (current smoker, former smoker, 
never a smoker) (NSCLC cohorts only) (irRECIST) – Phase 
2 (FAS) 
Table 14.3.5A 
PFS by PD-L1 expression (irRECIST)– Phase 2 (FAS) 
Table 14.3.5B 
PFS by current visceral involvement (irRECIST)– Phase 2 
(FAS)  
Table 14.3.5C 
PFS by baseline LDH (%>ULN) (irRECIST)– Phase 2 
(FAS)  
Table 14.3.5D 
PFS by previously treated with ipilimumab and PD-1 
(Melanoma cohort only) (irRECIST)– Phase 2 (FAS) 
Table 14.3.5E 
PFS by Previously treated with BRAF/MEK inhibitor 
(Melanoma cohort only) (irRECIST) – Phase 2 (FAS)  
Table 14.3.5F 
PFS by baseline non-classical monocytes (cut-off median for 
NSCLC, but it might change for other cohorts) (irRECIST) – 
Phase 2 (FAS) 
Table 14.3.5G 
PFS by NLR (irRECIST) – Phase 2 (FAS) 
Table 14.3.5H 
PFS by dNLR (irRECIST) – Phase 2 (FAS) 
Table 14.3.5I 
PFS by smoking status (current smoker, former smoker, 
never a smoker) (NSCLC cohorts only) (irRECIST) – Phase 
2 (FAS) 
Table 14.3.6 
Clinical Benefit Rate (irRECIST) – Phase 2 (FAS) (RECIST 
1.1) – Phase 2 (FAS)  
Table 14.3.7A 
PFS status at 6 months (irRECIST) - Phase 2 (FAS) 


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Table 14.3.7B 
PFS status at 6 months – (RECIST 1.1) – Phase 2 (FAS) 
Table 14.3.8A 
PFS (irRECIST) - Phase 2 (FAS) 
Table 14.3.8B 
PFS (RECIST 1.1) – Phase 2 (FAS) 
Table 14.3.9 
Overall Survival – Phase 2 (FAS) 
Table 14.3.10 
Time to Response – Phase 2 (FAS) 
Table 14.3.11 
Duration of Response – Phase 2 (FAS) 
Table 14.4.1 
Overall Treatment-Emergent Adverse Event Information - 
Phase 2 (Safety) 
Table 14.4.1.1 
Dose Limiting Toxicities – Phase 1b (Safety) 
Table 14.4.1.2 
Treatment-Emergent Adverse Events by System Organ 
Class and Preferred Term -Phase 1b (Safety) 
Table 14.4.2 
Treatment-Emergent Adverse Events by System Organ 
Class and Preferred Term - Phase 2 (Safety)  
Table 14.4.3 
Treatment-Emergent Adverse Events by Preferred Term and 
Maximum Severity – Phase 2 (Safety) 
Table 14.4.4.1 
Treatment-Emergent Adverse Events by Preferred Term and 
Relationship to Any Study Drug – Phase 1b (Safety)  
Table 14.4.4.2 
Treatment-Emergent Adverse Events by Preferred Term and 
Relationship to Any Study Drug – Phase 2 (Safety) 
Table 14.4.4.3 
Treatment-Emergent Adverse Events by Preferred Term and 
Relationship to Entinostat Alone – Phase 2 (Safety) 


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Table 14.4.4.4 
Treatment-Emergent Adverse Events by Preferred Term and 
Relationship to Pembrolizumab Alone – Phase 2 (Safety) 
Table 14.4.5.1 
Treatment-Emergent Adverse Events with Severity of Grade 
3 or Greater – Phase 2 (Safety) 
Table 14.4.5.2A 
Treatment-Emergent Adverse Events with Severity of Grade 
3 or Greater and Judged Related to Any Study Drug – Phase 
2 (Safety) 
Table 14.4.5.2B  
Treatment-Emergent Adverse Events with Severity of Grade 
3 or Greater and Judged Related to Any Study Drug – Phase 
1b 
Table 14.4.5.3 
Treatment-Emergent Adverse Events with Severity of Grade 
3 or Greater and Judged Related to Entinostat – Phase 2 
(Safety) 
Table 14.4.5.4 
Treatment-Emergent Adverse Events with Severity of Grade 
3 or Greater and Judged Related to Pembrolizumab – Phase 
2 (Safety) 
Table 14.4.6.1A 
Treatment-Emergent Adverse Events Occasioning 
Treatment Modification of Any Study Drug – Phase 2 
(Safety) 
Table 14.4.6.1B 
Treatment-Emergent Adverse Events Occasioning 
Treatment Modification of Any Study Drug – Phase 1b 
(Safety) 
Table 14.4.6.2 
Treatment-Emergent Adverse Events Occasioning 
Treatment Modification of Entinostat Alone – Phase 2 
(Safety) 


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Table 14.4.6.3 
Treatment-Emergent Adverse Events Occasioning 
Treatment Modification of Pembrolizumab Alone – Phase 2 
(Safety) 
Table 14.4.7.1 
Serious Treatment-Emergent Adverse Events by Preferred 
Term – Phase 2 (Safety) 
Table 14.4.7.2 
Serious Treatment-Emergent Adverse Events by Preferred 
Term and Judged Related to Any Study Drug – Phase 2 
(Safety) 
Table 14.4.7.3 
Serious Treatment-Emergent Adverse Events by Preferred 
Term and Judged Related to Entinostat – Phase 2 (Safety) 
Table 14.4.7.4 
Serious Treatment-Emergent Adverse Events by Preferred 
Term and Judged Related to Pembrolizumab– Phase 2 
(Safety) 
Table 14.4.8.1 
Hematology Laboratory Values – Phase 2 (Safety) 
Table 14.4.8.2  
Chemistry Laboratory Values – Phase 2 (Safety) 
Table 14.4.9.1  
Abnormal Hematology Laboratory Values According to the 
Local Laboratory Normal Range – Phase 2 (Safety) 
Table 14.4.9.2 
Abnormal Chemistry Laboratory Values According to the 
Local Laboratory Normal Range – Phase 2 (Safety) 
Table 14.4.10.1 
Abnormal Hematology Laboratory Values by Cycle 
According to the CTCAE Toxicity Grade – Phase 2 (Safety) 
Table 14.4.10.2 
Abnormal Chemistry Laboratory Values by Cycle 
According to the CTCAE Toxicity Grade – Phase 2 (Safety) 


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Table 14.4.11.1 
Hematology Laboratory Value Shifts from Baseline 
According to the Local Laboratory Normal Range – Phase 2 
(Safety) 
Table 14.4.11.2 
Chemistry Laboratory Value Shifts from Baseline According 
to the Local Laboratory Normal Range – Phase 2 (Safety) 
Table 14.4.12.1 
Hematology Laboratory Value Shifts from Baseline 
According to the CTCAE Toxicity Grade – Phase 2 (Safety) 
Table 14.4.12.2 
Chemistry Laboratory Value Shifts from Baseline According 
to the CTCAE Toxicity Grade – Phase 2 (Safety) 
Table 14.3.15 
Vital Signs – Phase 2 (Safety) 
Table 14.3.16 
12-Lead Electrocardiogram Normality by Assessment –  
 
6.2 List of Figures 
Figure 14.3.1.1 
Swimmer Lane Plot (NSCLC) – Cohort 1  
Figure 14.3.1.2 
Swimmer Lane Plot (NSCLC) – Cohort 2  
Figure 14.3.1.3 
Swimmer Lane Plot (Melanoma) – Cohort 3 
Figure 14.3.1.4 
Swimmer Lane Plot (Colo-rectal) - Cohort 4 
Figure 14.3.2.1-4 
Waterfall Plots (Cohort 1-4) 
Figure 14.3.3.1-4 
Spider Lane Plots (Cohort 1-4) 
Figure 14.3.4.1 
Prior Therapy Swimmer Lane Plot for CR/PR Patients 
(Cohort 2)  


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Figure 14.3.4.2  
Prior Therapy Swimmer Lane Plot for CR/PR Patients 
(Cohort 3) 
 
 
 
6.3 List of Listings 
Number 
Title 
Listing 16.2.1.1 
Study Enrollment and Analysis Populations 
Listing 16.2.1.2 
Patients Not Evaluable for Efficacy or Safety Analysis 
Listing 16.2.2.2 
Study Disposition 
Listing 16.2.2.3 
Post-Treatment Follow-up 
Listing 16.2.2.4 
Post-Treatment Anti-Cancer Therapy 
Listing 16.2.3.1 
Exceptions to Protocol Eligibility Criteria 
Listing 16.2.4.1 
Demographic Characteristics 
Listing 16.2.1.6 
Cancer History (All cohorts) 
Listing 16.2.1.7 
Prior Systemic Anti-Cancer Therapy 
Listing 16.2.1.8 
Prior Surgery 
Listing 16.2.1.9 
Prior Radiation Therapy  
Listing 16.2.1.10 
Medical History 
Listing 16.2.1.11 
Entinostat Administration 


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Listing 16.2.1.12 
Pembrolizumab Administration 
Listing 16.2.1.13 
Concomitant Medications 
Listing 16.2.1.14 
Concomitant Procedures 
Listing 16.2.1.15 
Protocol Deviations 
Listing 16.2.2.1 
PK Plasma Concentrations for Entinostat 
Listing 16.2.2.2 
PK Plasma Concentrations for Pembrolizumab 
Listing 16.2.2.3 
PK Parameters for Entinostat 
Listing 16.2.2.4 
PK Parameters for Pembrolizumab 
Listing 16.2.3.1 
Adverse Events 
Listing 16.2.3.2 
Serious Adverse Events 
Listing 16.2.3.3 
Adverse Events with Action Taken of Dose of Either Drug 
Reduced, Held, or Discontinued Permanently 
Listing 16.2.3.4 
Deaths and Overall Survival 
Listing 16.2.3.5 
Clinical Laboratory Values – Hematology, WBC Count and 
Differential 
Listing 16.2.3.6 
Clinical Laboratory Values – Hematology, Erythrocytes and 
Platelets 
Listing 16.2.3.7 
Clinical Laboratory Values – Chemistry, Renal  
Listing 16.2.3.8 
Clinical Laboratory Values – Chemistry, Hepatic 
Listing 16.2.3.9 
Clinical Laboratory Values – Chemistry, Electrolytes 


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Listing 16.2.3.10 
Clinical Laboratory Values – Metabolic  
Listing 16.2.3.11 
Patients with Laboratory Values Out of Normal Range with 
CTCAE Toxicity Grade 
Listing 16.2.3.12 
Vital Signs 
Listing 16.2.3.13 
12-Lead Electrocardiograms 
Listing 16.2.3.14 
ECOG Performance Status 
Listing 16.2.3.15 
Clinical Disease Assessments 
Listing 16.2.4.1 
Imaging 
Listing 16.2.4.2 
Target Lesions 
Listing 16.2.4.3 
Non-Target Lesions 
Listing 16.2.4.4 
New Lesions  
Listing 16.2.4.5 
RECIST 1.1 Response 
Listing 16.2.4.6 
irRECIST Response