Conditions: Breast Cancer
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 89
Healthy volunteers: no

Brief summary:
The purpose of this study is to determine the safety and tolerability of entinostat used in combination with atezolizumab in participants with Advanced Triple Negative Breast Cancer (aTNBC). Additionally, the purpose of the study is to assess how effective entinostat and atezolizumab are in combination in participants with aTNBC.

Detailed description:
SNDX-275-0602 is a Phase 1b/2 study evaluating the combination of entinostat plus atezolizumab in participants with aTNBC. The study has 2 phases: an open-label Dose Determination Phase (Phase 1b) followed by an Expansion Phase (Phase 2). The Expansion Phase will evaluate the efficacy and safety of entinostat when administered at the RP2D with atezolizumab in participants with aTNBC in a randomized, double-blind, placebo-controlled setting.

Safety will be assessed during the study by documentation of AEs, clinical laboratory tests, physical examinations, vital sign measurements, electrocardiograms (ECGs), and Eastern Cooperative Oncology Group (ECOG) performance status. Adverse events of special interest (AESI) will be collected and reviewed in a manner consistent with serious adverse event reporting procedures.

Arms:
arm 1: Participants in this arm will receive entinostat in combination with atezolizumab.

Phase 1b Dose Determination: The initial 3 to 6 participants will receive entinostat at a starting dose of 5 milligrams (mg) (Dose Group 1) on Days 1, 8, and 15 along with atezolizumab 1200 mg via intravenous (IV) infusion on Day 1 of each 21-day cycle. If the 5 mg dose exceeds the maximum tolerated dose (MTD), then a 3 mg dose of entinostat (Dose Group -1) will be evaluated in the same manner. If the -1 dose level exceeds the MTD, then a 2 mg dose of entinostat (Dose Group -2) will be evaluated.

Phase 2 Dose Expansion: Participants will receive the RP2D identified in the Dose Determination Phase. arm 2: Participants in this arm will receive placebo in combination with atezolizumab 1200 mg.

Interventions: intervention 1: Entinostat intervention 2: Atezolizumab intervention 3: Placebo
Intervention descriptions: intervention 1: An orally available histone deacetylases inhibitor (HDAC). intervention 2: A humanized, engineered monoclonal antibody of IgG1 isotype against the protein programmed cell death ligand 1 (PD-L1). intervention 3: A pill containing no active drug ingredient

Protocol document:
Prot_000.pdf: 
Product: Entinostat 
Protocol Number: SNDX-275-0602 (TRIO025) 
Date: 11 Sep 2018 
Page 1 of 141 
CONFIDENTIAL 
SYNDAX PHARMACEUTICALS 
A Randomized, Placebo-controlled, Double-blind, Multicenter Phase 2 Study of 
Atezolizumab With or Without Entinostat in Patients with Advanced Triple Negative 
Breast Cancer, with a Phase 1b Lead in Phase [SNDX-275-0602] 
Syndax Protocol SNDX-275-0602 
TRIO Study Number: TRIO025 
Clinical Study Sponsor: 
Syndax Pharmaceuticals, Inc. 
35 Gatehouse Drive, 
Building D, Floor 3 
Waltham, MA 02451 
Key Sponsor Contacts: 
 
 
Telephone: 
 
 
Telephone: 
 
Contract Research 
Organization 
Translational Research in Oncology (TRIO) 
Suite 1100 
9925 – 109th Street 
Edmonton, Alberta T5K 2J8 
Canada 
Date, Version: 
11 Sep 2018, Version 3.0 
Amendment: 
IND Number: 
2 
64,722 
Confidentiality Notice 
This document contains confidential information of Syndax Pharmaceuticals, 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. 
NCT #NCT02708680


Product: Entinostat 
Protocol Number: SNDX-275-0602 (TRIO025) 
Date: 11 Sep 2018 
Page 2 of 141 
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SYNDAX PHARMACEUTICALS 
 
 
 
 
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. 


Product: Entinostat 
Protocol Number: SNDX-275-0602 (TRIO025) 
Date: 11 Sep 2018 
Page 3 of 141 
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SYNDAX PHARMACEUTICALS 
 
 
Investigator’s Agreement 
 
I have read the attached protocol entitled “A Randomized, Placebo-controlled, Double-blind, 
Multicenter Phase 2 Study of Atezolizumab With or Without Entinostat in Patients with 
Advanced Triple Negative Breast Cancer, with a Phase 1b Lead in Phase [SNDX-275- 
0602]”, dated 11 Sep 2018 and agree to abide by all provisions set forth therein. 
I agree to comply with the International Conference on Harmonisation Tripartite Guideline on 
Good Clinical Practice applicable regulations of the Food and Drug Administration and other 
applicable regulations. 
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-275-0602 (TRIO025) 
Date: 11 Sep 2018 
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Table of Contents 
1. 
PROTOCOL SYNOPSIS SNDX-275-0602 (TRIO-025) .................................................. 9 
2. 
STUDY GLOSSARY ......................................................................................................... 23 
3. 
OBJECTIVES ..................................................................................................................... 28 
3.1 
Primary ................................................................................................................... 28 
3.2 
Secondary .............................................................................................................. 28 
3.3 
Exploratory ............................................................................................................. 29 
4. 
ENDPOINTS ....................................................................................................................... 30 
4.1 
Efficacy ................................................................................................................... 30 
4.2 
Safety ...................................................................................................................... 30 
4.3 
Exploratory ............................................................................................................. 30 
5. 
BACKGROUND AND RATIONALE ................................................................................ 31 
5.1 
Study Treatment .................................................................................................... 36 
5.1.1 
Entinostat (SNDX-275) ....................................................................... 36 
5.1.2 
Atezolizumab ....................................................................................... 38 
5.2 
Study Rationale ..................................................................................................... 41 
5.3 
Rationale for the Dose Selection ......................................................................... 41 
5.3.1 
Entinostat ............................................................................................. 41 
5.3.2 
Atezolizumab ....................................................................................... 42 
5.4 
Hypothesis ............................................................................................................. 43 
6. 
EXPERIMENTAL PLAN .................................................................................................... 45 
6.1 
Study Design ......................................................................................................... 45 
6.2 
Number of Centers ................................................................................................ 49 
6.3 
Number of Patients ................................................................................................ 49 
6.4 
Estimated Study Duration .................................................................................... 50 
7. 
PATIENT ELIGIBILITY ...................................................................................................... 51 
7.1 
Inclusion Criteria ................................................................................................... 51 
7.2 
Exclusion Criteria .................................................................................................. 53 
8. 
PATIENT ENROLLMENT ................................................................................................. 55 
9. 
TREATMENT PROCEDURES ......................................................................................... 56 
9.1 
Study Drugs ........................................................................................................... 56 
9.2 
Entinostat ............................................................................................................... 56 
9.2.1 
Supply and Storage ............................................................................ 56 
9.2.2 
Dosing and Administration ................................................................. 57 
9.3 
Atezolizumab ......................................................................................................... 58 
9.3.1 
Supply and Storage ............................................................................ 58 


Product: Entinostat 
Protocol Number: SNDX-275-0602 (TRIO025) 
Date: 11 Sep 2018 
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9.3.2 
Dosing and Administration ................................................................. 58 
9.4 
Study Drug(s) Accountability ............................................................................... 59 
9.5 
Entinostat Compliance ......................................................................................... 59 
9.6 
Dose-limiting Toxicity............................................................................................ 59 
9.7 
Maximum Tolerated Dose .................................................................................... 61 
9.8 
Recommended Phase 2 Dose ............................................................................ 61 
9.9 
Treatment Duration ............................................................................................... 62 
9.10 
Dose Interruptions and Modifications ................................................................. 62 
9.10.1 
Entinostat ............................................................................................. 63 
9.10.2 
Atezolizumab ....................................................................................... 65 
9.11 
Concomitant Therapy ........................................................................................... 66 
9.12 
Prohibited Medication ........................................................................................... 67 
9.13 
Medications to be Avoided During the Study .................................................... 68 
9.14 
Management for Atezolizumab-Specific Adverse Events ............................... 68 
9.14.1 
Pulmonary Events ............................................................................... 69 
9.14.2 
Hepatic Events .................................................................................... 71 
9.14.3 
Gastrointestinal Events ...................................................................... 72 
9.14.4 
.Endocrine Events ............................................................................... 75 
9.14.5 
Ocular Events ...................................................................................... 77 
9.14.6 
Immune-Related Myocarditis .............................................................. 78 
9.14.7 
Pancreatic Events ............................................................................... 81 
9.14.8 
Infusion-Related Events...................................................................... 84 
9.14.9 
Dermatologic Events .......................................................................... 86 
9.14.10 
Neurological Disorders ....................................................................... 86 
9.14.11 
Immune-Related Meningoencephalitis ............................................... 88 
9.14.12 
Systemic Immune Activation ............................................................. 89 
9.15 
Diet/Activity/Other Considerations ...................................................................... 90 
9.15.1 
Diet ........................................................................................................ 90 
9.15.2 
Contraception ...................................................................................... 90 
9.15.3 
Study Drug Use in Pregnancy ........................................................... 90 
9.15.4 
Study Drug Use in Nursing Women ................................................. 91 
10. 
STUDY TESTS AND OBSERVATIONS ......................................................................... 92 
10.1 
Screening Assessments ...................................................................................... 93 
10.1.1 
Demographics ..................................................................................... 93 
10.1.2 
Medical History .................................................................................... 93 
10.1.3 
Pregnancy Testing .............................................................................. 93 
10.2 
Safety Assessments ............................................................................................. 93 
10.2.1 
Physical Examination ......................................................................... 93 
10.2.2 
Electrocardiograms ............................................................................. 94 
10.2.3 
Vital Signs ............................................................................................ 94 


Product: Entinostat 
Protocol Number: SNDX-275-0602 (TRIO025) 
Date: 11 Sep 2018 
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10.2.4 
Weight................................................................................................... 94 
10.2.5 
ECOG Performance Status ............................................................... 94 
10.2.6 
Clinical Laboratory Tests ................................................................... 95 
10.2.7 
Adverse Events ................................................................................... 96 
10.3 
Efficacy Assessments .......................................................................................... 97 
10.3.1 
Tumor Measurements and Disease Response Assessment ........ 97 
10.3.2 
Treatment after Initial Radiologic Progression ............................. 102 
10.4 
Protein Lysine Acetylation and Immune Correlates ...................................... 103 
10.4.1 
Blood ...................................................................................................103 
10.4.2 
Tumor Tissue .....................................................................................104 
10.5 
Pharmacokinetics ................................................................................................105 
10.5.1 
Entinostat ...........................................................................................105 
10.5.2 
Atezolizumab .....................................................................................106 
10.6 
TRegs and Ki67 .................................................................................................. 106 
10.7 
Atezolizumab Plasma Biomarker ......................................................................106 
10.8 
Atezolizumab Serum Biomarker .......................................................................106 
11. 
DISCONTINUATION AND REPLACEMENT OF PATIENTS ....................................107 
12. 
ADVERSE EVENTS, DATA REPORTING, AND RECORDING .............................. 108 
12.1 
Study Drugs .........................................................................................................108 
12.1.1 
Entinostat ...........................................................................................108 
12.1.2 
Atezolizumab .....................................................................................108 
12.2 
Adverse Event Definitions ..................................................................................108 
12.2.1 
Adverse Events ................................................................................ 108 
12.2.2 
Suspected Adverse Reaction ......................................................... 109 
12.2.3 
Unexpected Adverse Event ............................................................ 109 
12.2.4 
Serious Adverse Events .................................................................. 110 
12.3 
Reporting Procedures for All Adverse Events ............................................... 110 
12.4 
Serious Adverse Event Reporting Procedures .............................................. 112 
12.4.1 
Pregnancy and Lactation Reporting Procedures ......................... 113 
12.4.2 
Definition of an Overdose and Reporting of Overdose to the 
Sponsor ..............................................................................................113 
12.4.3 
Adverse Events of Special Interest with Atezolizumab ............... 113 
12.4.4 
Follow-Up of Adverse Events ......................................................... 115 
12.4.5 
Reporting Safety Information .......................................................... 116 
12.4.6 
Protocol Deviations Due to an Emergency or Adverse Event ... 116 
12.5 
Safety Monitoring ................................................................................................117 
13. 
STATISTICAL CONSIDERATIONS ............................................................................. 118 
13.1 
Sample Size Estimation .....................................................................................118 
13.1.1 
Dose Determination Phase ............................................................. 118 


Product: Entinostat 
Protocol Number: SNDX-275-0602 (TRIO025) 
Date: 11 Sep 2018 
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13.1.2 
Expansion Phase ............................................................................. 118 
13.2 
Phase 2 Interim Efficacy Analyses ...................................................................119 
13.3 
Populations for Analysis .....................................................................................120 
13.4 
Study Endpoints ..................................................................................................120 
13.5 
Statistical Methods ..............................................................................................121 
13.5.1 
General ...............................................................................................121 
13.5.2 
Patient Disposition ........................................................................... 122 
13.5.3 
Demographics and Characteristics ................................................ 122 
13.5.4 
Extent of Exposure .......................................................................... 122 
13.5.5 
Efficacy Analyses ............................................................................. 122 
13.5.6 
Safety Analyses................................................................................ 124 
13.5.7 
Pharmacokinetic and Antidrug Antibody Analyses ...................... 126 
13.5.8 
Correlative Analyses ........................................................................ 126 
14. 
REGULATORY OBLIGATIONS .....................................................................................127 
14.1 
Informed Consent ...............................................................................................127 
14.2 
Institutional Review Board (IRB)/Ethics Committee (EC) ............................. 127 
14.3 
Pre-study Documentation Requirements ........................................................ 128 
14.4 
Patient Confidentiality .........................................................................................128 
15. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS ...................................................... 130 
15.1 
Protocol Amendments and Study Termination .............................................. 130 
15.2 
Study Documentation and Archive .................................................................. 130 
15.3 
Study Monitoring and Data Collection ............................................................. 131 
16. 
REFERENCES .................................................................................................................132 
17. 
APPENDICES ..................................................................................................................132 
17.1 
Appendix 1 New York Heart Association (NYHA) Classification of Heart 
Failure ...................................................................................................................137 
17.2 
Appendix 2 Concomitant Medications to be Avoided ................................... 138 
17.3 
Appendix 3: Pre-existing Autoimmune Diseases ......................................... 139 
17.4 
Appendix 4: Immune-related Response Criteria Derived from RECIST 
1.1 (irRECIST) .....................................................................................................140 
Table 1-1 
Schedule of Study Assessments ..................................................................... 19 
Table 9-1 
Non-hematologic Toxicity: Dose Modifications for Entinostat ..................... 64 
Table 9-2 
Hematologic Toxicity: Dose Modification for Entinostat .............................. 65 
Table 9-3 
Management Guidelines for Pulmonary Events, Including Pneumonitis ... 70 
Table 9-4 
Management Guidelines for Hepatic Events .................................................. 72 
Table 9-5 
Management Guidelines for Gastrointestinal Events (Diarrhea/Colitis) ..... 74 
Table 9-6 
Management Guidelines for Endocrine Events ............................................. 76 


Product: Entinostat 
Protocol Number: SNDX-275-0602 (TRIO025) 
Date: 11 Sep 2018 
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Table 9-7 
Management Guidelines for Ocular Events ................................................... 78 
Table 9-8 
Management Guidelines for Immune-Related Myocarditis .......................... 80 
Table 9-9 
Management Guidelines for Pancreatitis ........................................................ 82 
Table 9-10 
Management Guidelines for Infusion-Related Reactions ............................. 84 
Table 9-11 
Management Guidelines for Pancreatitis ........................................................ 84 
Table 9-12 
Management Guidelines for Immune-Mediated Dermatologic Events ....... 86 
Table 9-13 
Management Guidelines for Neurologic Disorders ....................................... 87 
Table 9-14 
Management Guidelines for Immune-Related Meningoencephalitis .......... 89 
Table 10-1 
Eastern Cooperative Oncology Group Performance Status Scale, with 
Equivalent Karnofsky Performance Status Scores ....................................... 95 
Table 10-2 
Imaging and Treatment After 1st Radiologic Evidence of PD ................... 103 
Table 12-1 
Standard Severity Grading Scale .................................................................. 112 
Table 17-1: 
Examples of substrates that may be affected by entinostat ...................... 138 
Table 17-2 
P-gp Inhibitors and Inducers .......................................................................... 138 


Product: Entinostat 
Protocol Number: SNDX-275-0602 (TRIO025) 
Date: 11 Sep 2018 
Page 9 of 141 
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SYNDAX PHARMACEUTICALS 
 
 
 
1.PROTOCOL SYNOPSIS SNDX-275-0602 (TRIO-025) 
 
Title: A Randomized, Placebo-controlled, Double-blind, Multicenter Phase 2 Study of Atezolizumab With 
or Without Entinostat in Patients with Advanced Triple Negative Breast Cancer, with a Phase 1b Lead in 
Phase [SNDX-275-0602 (TRIO025)] 
Study Phase: Phase 1b/2 
Indication: Advanced Triple Negative Breast Cancer (aTNBC) 
Primary Objective: 
Phase 1b: (Dose Determination Cohort): 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 atezolizumab. 
Phase 2 (Expansion Cohort): To perform an evaluation of the efficacy of entinostat at the RP2D in 
combination with atezolizumab in patients with aTNBC, as determined by the duration of progression-free 
survival (PFS) based on the local investigator’s assessment of progressive disease Response Evaluation 
Criteria in Solid Tumors version 1.1 (RECIST 1.1). 
Secondary Objectives: 
Efficacy: To evaluate the efficacy of entinostat in combination with atezolizumab in patients with aTNBC, 
as determined by: 
• 
PFS based on immune response RECIST (irRECIST) 
• 
Overall response rate (ORR) (i.e., complete response [CR] or partial response [PR]) based on 
RECIST 1.1 
• 
Overall response rate (ORR) (i.e., complete response [CR] or partial response [PR]) based on 
irRECIST 
• 
Clinical benefit rate (CBR) (i.e. CR or PR or stable disease [SD] for at least 24 weeks) based on 
RECIST 1.1 and irRECIST 
• 
Overall survival (OS) 
In patients with best overall response of CR or PR: 
• 
Duration of response (DOR) 
• 
Time to response (TTR) 
Safety: To evaluate safety and the tolerability of entinostat in combination with atezolizumab, as 
measured by clinical adverse events (AEs) and laboratory parameters. 
Exploratory Objectives: 
• 
 
 
• 
 
• 
 
 
• 
 
• 
 


Product: Entinostat 
Protocol Number: SNDX-275-0602 (TRIO025) 
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SYNDAX PHARMACEUTICALS 
 
 
Exploratory Objectives cont’d 
• 
 
 
• 
 
• 
 
• 
 
• 
 
• 
 
Hypothesis: 
Phase 1b: The combination of atezolizumab and entinostat at a biologically active dose will be sufficiently 
safe and well tolerated to warrant further investigation. 
Phase 2: Entinostat at the dose determined in Phase 1b combined with atezolizumab will result in an 
improved progression free survival compared to atezolizumab alone. 
Study Design: 
This is a Phase 1b/2 study evaluating the combination of entinostat plus atezolizumab in patients with 
aTNBC. The study has 2 phases: an open-label Dose Determination Phase (Phase 1b) followed by an 
Expansion Phase (Phase 2). The Expansion Phase will evaluate the efficacy and safety of entinostat 
when administered at the RP2D with atezolizumab in patients with aTNBC in a randomized, double-blind, 
placebo-controlled setting. Following the enrollment and completion of Cycle 1 of the first 20 patients in 
the Expansion Phase, cumulative study safety data will be reviewed by an independent safety review 
board. Up to 88 evaluable patients are anticipated if the study completes all phases of evaluation (up to 
18 patients for Phase 1b, up to 70 patients for Phase 2). Up to 50 international study centers may 
participate. 
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 business days of starting study treatment Cycle 1, Day 1 (C1D1). 
A treatment cycle is 3 weeks (21 days) in length. The dose of atezolizumab will be fixed at 1200 mg IV 
q 3 weeks (day 1 of each cycle) for all patients. Entinostat (during the Phase 1b Dose Determination 
Phase) and entinostat / placebo (during Phase 2, Expansion Phase) will be administered orally on days 1, 
8 and 15 of each 21 day cycle. The Dose Determination Phase will begin with a starting dose (dose level 
1) of entinostat 5 mg po weekly. If dose level 1 exceeds the MTD, then entinostat 3 mg po weekly (dose 
level -1) will be investigated. If dose level -1 exceeds the MTD, then entinostat 2 mg po weekly (dose 
level -2) will be investigated. Dosing is planned to be continuous unless interrupted for management of an 
adverse event. The entinostat dose determined appropriate for combination with atezolizumab will then 
be taken forward into the Phase 2 Expansion Phase of the study as the RP2D. 
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 within 28 days prior to the first dose of study drug, and then every 6 
weeks (+/-3 days) through week 36 (Weeks 6, 12, 18, 24, 30, 36) until unequivocal progressive disease. 
Patients remaining on study after week 36 will undergo radiological disease assessments every 9 weeks 
(+/- 3 days) until unequivocal progressive disease occurs. Disease will be assessed by computed 
tomography (CT), magnetic resonance imaging (MRI), and bone scans, as appropriate using the same 
method as used for the screening evaluation, and response will be assessed by the Investigator using 
RECIST 1.1. 


Product: Entinostat 
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Safety will be assessed during the study by documentation of AEs using United States (US) National 
Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.03, clinical 
laboratory tests, physical examinations, vital sign measurements, electrocardiograms (ECGs), and 
Eastern Cooperative Oncology Group (ECOG) performance status. Adverse events of special interest 
(AESI) will be collected and reviewed in a manner consistent with serious adverse event reporting 
procedures. 
Fresh tumor tissue core biopsy samples will be collected during the study as follows: 
• 
During screening from all patients on a mandatory basis. Archival biopsies when available will 
also be collected for comparison. 
• 
On C2D15 (+3 days) on an optional basis from patients in the Dose Determination Phase. All 
patients will be encouraged to provide an optional biopsy in order to help understand dose- 
immune correlate effects. 
• 
On C2D15 (+3 days) on a mandatory basis until 20 samples are obtained in the Phase 2 portion 
and on an optional basis for subsequent patients in this phase 2 expansion. 
• 
At the end of study treatment prior to the start of another systemic therapy, on an optional basis. 
• 
At the time of disease progression on an optional basis. 
• 
If, based on an interim review of tumor tissue data from the initial patients in the Phase 2 portion 
such data are considered informative, then tumor tissue samples may be collected on a 
mandatory basis from all subsequent patients on C2D15 (+3 days). Alternatively, if such data are 
not considered informative, these samples will not be collected from subsequent patients. 
Blood for immune correlates is to be collected pre-dose on C1D1, C2D1, C2D15 and C3D1 and at the 
end of treatment visit. Blood for protein lysine acetylation testing will be collected pre-dose on C1D1 and 
C1D15. 
Blood samples for determination of entinostat levels will be collected pre-dose on C1D1 and 2-4 hours 
post dose; anytime post dose on C1D8 and D15, and pre-dose on C2D1. 
Blood samples for determination of atezolizumab levels and anti-atezolizumab antibodies will be collected 
pre-dose on C1D1 and again 30 minutes (+/- 10 minutes) following infusion completion (this sample is for 
PK only), and pre-dose on C2D1, C4D1 and at the end of treatment visit. A PK sample will also be 
collected from any patient who continues to be followed per protocol for PFS, 120 days after the end of 
treatment visit. 
Patients will remain on study treatment until unequivocal progression of disease (PD), intolerable toxicity, 
or one of the other study withdrawal criteria is met (Protocol Section 11). 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. After 
study treatment discontinuation, patients will complete an End of Treatment (EOT) visit within 7 days after 
the last study drug dose and a Safety Follow-up (F/U) visit 30 days (+/-3 days) later. After completion of 
the 30-day (+/- 3 days) Safety F/U visit, patients who have not experienced PD, are to be followed every 6 
weeks for a clinic visit and radiological imaging until unequivocal progressive disease or until study week 
36, whichever occurs first. If PD has not been documented at that time, patients will be followed every 9 
weeks for radiological imaging until unequivocal progressive disease, death or end of the study whichever 
occurs first. Patients who discontinue study treatment for PD will be contacted every 3 months for survival 
status and post study therapies until death or closure of the study by the Sponsor. 
Phase 1b / Dose Determination Phase: Up to 18 patients are expected to be enrolled in the Dose 
Determination Phase of the study which employs a classical 3+3 design, with the determination of DLT 
and the MTD and/or RP2D based on entinostat in combination with atezolizumab in C1. All dose cohorts 
will receive entinostat orally at the assigned dose on Days 1, 8 and 15 along with atezolizumab 1200 mg 
on Day 1 of a 21 day cycle. Dose group 1 will include 3-6 patients who will receive entinostat at a starting 
dose of 5 mg. If the entinostat 5 mg dose exceeds the MTD, then a 3 mg dose of entinostat (Dose Group 


Product: Entinostat 
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-1) will be evaluated in the same manner. If the entinostat 3 mg dose exceeds the MTD, then a 2 mg dose 
of entinostat (Dose Group -2) will be evaluated in the same manner. All patients within a cohort are to 
complete C1, have safety assessments performed through C2D1, and be assessed for DLT before 
enrollment of additional patients may commence. If <33% patients within a cohort have a DLT (i.e., <2 of 
6), then enrollment of the Phase 2 Expansion cohort may commence with approval from the Syndax 
Study Physician. 
If the -2 dose level exceeds the MTD, then the study will discontinue or additional doses or dosing 
schedules may be investigated via a protocol amendment. Also, based on evaluation of the safety and 
tolerability data gathered during the dose determination phase together with data from other clinical trials, 
it may also be decided that accrual will take place at an alternate dose level or dosing schedule via a 
protocol amendment. 
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. Although decisions 
regarding subsequent patient dosing will be made 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 Syndax Study Physician 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. 
Phase 2 / Expansion: In the Expansion Phase, the efficacy and safety of entinostat (compared to 
placebo) in combination with atezolizumab will be evaluated using the RP2D identified in the Dose 
Determination Phase. Following the enrollment and completion through Cycle 1 of the first 20 patients in 
the Expansion Phase, cumulative study safety data will be reviewed by a Data Safety Monitoring Board. 
Up to 70 patients with aTNBC will be randomized to receive atezolizumab + entinostat or atezolizumab + 
placebo in a 1:1 ratio. 
Sample Size Considerations 
Dose Determination Phase 
Three to 6 patients will be enrolled in each dose cohort based on a standard Phase 1 dose scheme. Each 
patient will be counted in only 1 dose cohort. Six patients will need to be treated in a dose level for it to be 
considered MTD or the RP2D. The total number of patients to be enrolled in the Dose Determination 
Phase will be determined by the number of necessary dose cohorts 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 confirmation 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. 
Note: Patients who discontinued the study for reasons other than study drug related toxicities before 
completing C1 may be replaced. 
Expansion Phase: Phase 2 aTNBC Cohort 
The Expansion Phase will evaluate the efficacy and safety of entinostat (compared to placebo) when 
administered at the RP2D with atezolizumab in a randomized, double-blind, placebo-controlled setting. 
PFS will be the primary measure of efficacy; secondary measures of efficacy include ORR, CBR, DOR, 
TTR, and OS. Up to 70 eligible patients with aTNBC will be randomized to receive atezolizumab with 
entinostat or placebo in a 1:1 allocation. The sample size was determined based on the following 
considerations: True median PFS for patients with a TNBC receiving atezolizumab monotherapy is 
expected to be approximately 4 months when measured from randomization. It is hypothesized the 
combination of entinostat and atezolizumab will improve true median PFS by 3 months (i.e., median PFS 
of 4 vs. 7 months). Under the exponential distribution, such an improvement in median PFS represents a 
reduction of 43% for the true PFS failure hazard rate or equivalently, a hazard ratio of 0.57. The primary 


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analysis of PFS will be performed using a stratified log-rank test, stratifying on the randomization 
stratification factor of geographic location. Total information of 60 PFS failures, defined as documented 
progressive disease by RECIST 1.1 or death due to any cause without documented progressive disease 
beforehand, is estimated to provide 80% power to detect the aforementioned 43% reduction in the PFS 
failure hazard rate with one-sided significance level of 0.1. Assuming approximately 9 months of accrual 
and an additional 9 months of follow-up, total accrual of 70 patients (approximately 35 per treatment arm) 
is projected to result in 60 PFS failures within approximately 18 months of the date the first patient is 
randomized. Patients who discontinue study treatment for reasons not due to documented progressive 
disease by RECIST 1.1 will continue to undergo disease assessments until the earlier of documented 
progressive disease, death, or withdrawal of consent/lost to follow-up. It is anticipated that the number of 
patients who will drop out of the study without PFS failure beforehand will be low (expected to not exceed 
2–3%). Depending on the actual number of such dropouts, the number of patients accrued may be 
increased by 6–10 additional patients to accommodate for a higher-than-expected number of dropouts. 
The sample size and number of PFS failures was adjusted using the O’Brien-Fleming group sequential 
procedure to account for one planned interim analysis of PFS after 45 events (75% information). It is 
projected 75% and 100% of total information will be reported at approximately 12 and 18 months, 
respectively. The interim analysis will be performed to support the Sponsor’s product development plans 
and ongoing resourcing activities. Although there are no plans to terminate the study early because of 
early evidence of superior efficacy for the combination treatment, the significance levels at the interim 
analysis and final analysis will be adjusted to maintain control of the overall type I error rate for multiple 
testing of PFS (O’Brien 1979). 
Endpoints 
Primary Efficacy Endpoint: 
• 
PFS, as determined by the local investigator using RECIST 1.1 
Secondary Endpoints: (analyzed in the same populations as the primary endpoint): 
• 
PFS by immune response RECIST (irRECIST) 
• 
ORR (CR or PR) by RECIST 1.1 and irRECIST 
• 
CBR (CR, PR, or SD for at least 24 weeks) 
• 
OS 
In patients who experience best overall response of CR or PR: 
• 
DOR 
• 
TTR 
Safety: 
• 
Determination of DLT, MTD and RP2D 
• 
AEs 
• 
Clinical laboratory parameters, vital signs, physical exam 
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: 
1. Females aged 18 years or older on the day written informed consent is given. 
2. Has histologically or cytologically confirmed triple negative breast adenocarcinomathat is either 
metastatic (stage IV of the TNM classification) or locally recurrent and not amenable to local curative 
treatment. TNBC diagnosis should be based on local ER/PgR/HER-2 laboratory results and will be 
defined as HER2 negativity (IHC 0-1 and/or ISH non-amplification) and ER and PgR negativity (<1%). 
Disease must also be amenable to a core biopsy (image-guided if applicable) at screening and for 
certain cohorts as described in the protocol, at least once during study treatment. 
3. Evidence of measurable (according to RECIST version 1.1) locally recurrent or metastatic disease 
based on imaging studies (e.g., CT, MRI) within 28 days before the first dose of study drug. 
4. Has received at least 1, but no more than 2, prior lines of systemic therapy for locally recurrent and/or 
metastatic disease. 
5. If patient has a history of treated asymptomatic CNS metastases they are eligible, provided they meet 
all of the following criteria: 
• 
Patient has measurable disease outside CNS; 
• 
Patient does not have metastases to midbrain, pons, medulla or spinal cord; 
• 
Patient is not on corticosteroids as therapy for CNS disease (anticonvulsants at a 
stable dose are allowed); 
• 
Patient has not had whole-brain radiation within 6 weeks prior to study enrollment; 
• 
Patient has stable CNS disease as demonstrated by at least 4 weeks of stability 
between the last intervention scan and the study screening scan 
6. ECOG performance status of 0 or 1. 
7. Has the following laboratory parameters within 21 days before enrollment 
 
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 


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System 
Laboratory Value 
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 
≤1.5×ULN OR 
Total bilirubin 
Direct bilirubin ≤ULN for patients with total bilirubin 
levels >1.5×ULN 
Aspartate aminotransferase (AST) and alanine 
≤2.5×ULN OR 
aminotransferase (ALT) 
≤5×ULN for patients with liver metastases 
Coagulation 
International Normalized Ratio (INR) or Prothrombin 
≤1.5×ULN unless patient is receiving anticoagulant 
Time (PT) 
therapy as long as PT or PTT is within therapeutic range 
of intended use of anticoagulants 
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 
Creatinine clearance should be calculated per institutional standard. 
 
8. If a female of childbearing potential, has a negative serum blood pregnancy test during screening and 
a negative urine pregnancy test within 3 days prior to receiving the first dose of study drug. If the 
screening serum test is done within 3 days prior to receiving the first dose of study drug, a urine test 
is not required. Note: Women of childbearing potential (WoCP) are any women between menarche 
and menopause who have not been permanently or surgically sterilized and are capable of 
procreation. Menopause is defined as at least 12 consecutive months since date of last menstruation, 
FSH and estradiol in postmenopausal ranges. Permanent sterilization includes hysterectomy and/or 
bilateral oophorectomy and/or bilateral salpingectomy but excludes bilateral tubal occlusion. WoCP 
include women who have experienced menopause onset < 12 months prior to enrollment. 
9. If a female of childbearing potential, willing to use 2 methods of birth control or willing to abstain from 
heterosexual activity for the course of the study through 120 days after the last dose of study drug. 
10. Experienced resolution of toxic effect(s) of the most recent prior anti-cancer therapy to Grade <1 
(except alopecia or neuropathy). If patient underwent major surgery or radiation therapy of >30 Gy, 
they must have recovered from the toxicity and/or complications from the intervention. 
11. 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 receiving systemic steroid therapy or any other form of 
immunosuppressive therapy within 7 days prior to the first dose of study drug. The use of physiologic 
doses of corticosteroids may be approved after consultation with the Medical Monitor. 
2. Active autoimmune disease including active diverticulitis, symptomatic peptic ulcer disease, colitis, or 
inflammatory bowel 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. Previously treated with a PD-1/PD-L1-blocking antibody (e.g., atezolizumab, nivolumab, 
pembrolizumab) or a histone deacetylase inhibitor (e.g.., vorinostat, belinostat, romidepsin, 
panobinostat) 


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4. 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: 
• 
History of immune deficiencies or autoimmune disease (refer to Appendix 3 for complete list) 
• 
Myocardial infarction or arterial thromboembolic events within 6 months prior to screening or 
severe or unstable angina, New York Heart Association (NYHA) Class III or IV disease, or a QTc 
interval > 470 msec. 
• 
Uncontrolled hypertension or diabetes mellitus. 
• 
Another known malignancy that is progressing or requires active treatment (excluding adequately 
treated basal cell carcinoma or cervical intraepithelial neoplasia [CIN]/cervical carcinoma in situ or 
melanoma in situ). Prior history of other cancer is allowed, as long as there is no active disease 
within the prior 5 years. 
• 
Active infection requiring systemic therapy. 
• 
Known active central nervous system (CNS) metastases and/or carcinomatous meningitis. (see 
inclusion criterion 5) 
5. Any contraindication to oral agents or significant nausea and vomiting, malabsorption, or significant 
small bowel resection that, in the opinion of the investigator, would preclude adequate absorption. 
6. Received a live vaccine within 30 days of the first dose of treatment. (Inactivated forms of influenza 
vaccinations can be given during influenza season only (approximately October to March in the 
Northern hemisphere and April to September in the Southern Hemisphere)). 
7. Prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to enrollment or who has not 
recovered (i.e., ≤Grade 1 at enrollment) from AEs due to mAb agents administered more than 4 
weeks earlier. 
8. Prior chemotherapy within 3 weeks, targeted small molecule therapy or radiation therapy within 
2 weeks prior to enrollment, or who has not recovered (i.e., ≤Grade 1 at enrollment) 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. 
9. 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. 
10. 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 
study drug. 
11. Currently receiving treatment with any other agent listed on the prohibited medication list (protocol 
section 9.12 
12. If female, is pregnant, breastfeeding, or expecting to conceive starting with the screening visit through 
120 days after the last dose of study drug. 
13. Known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies). 
14. Known active hepatitis B (e.g., hepatitis B surface antigen-reactive) or hepatitis C (e.g., hepatitis C 
virus ribonucleic acid [qualitative]). Patients with past hepatitis B virus (HBV) infection or resolved 
HBV infection (defined as the presence of hepatitis B core antibody [HBc Ab] and absence of HBsAg) 
are eligible. HBV DNA test must be performed in these patients prior to randomization. Patients 


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positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction is negative 
for HCV RNA. 
15. Allergy to benzamide or inactive components of entinostat. 
16. History of allergies to any active or inactive ingredients of atezolizumab. 
17. Known psychiatric or substance abuse disorders that would interfere with cooperation with the 
requirements of the study. 
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 by promoting 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 given orally and is supplied in two strengths of film-coated 
tablets containing 1.0 mg (pink to light red) or 5.0 mg (yellow). 
Entinostat should be stored at a controlled room temperature of 15°C–25°C (59°F–77°F). 
Atezolizumab 
Atezolizumab is a humanized monoclonal antibody designed to target PD-L1 expressed on tumor cells 
and tumor-infiltrating immune cells, and prevent binding to PD-1 and B7.1 on the surface of T cells. This 
may enable the activation of effector T cells as well as recruitment of other T cells to attack the tumor, 
thus empowering the body's own immune system to fight multiple types of cancer. 
Atezolizumab drug product is provided in a single-use, 20-mL USP/PH. Eur. Type 1 glass vial as a 
colorless-to-slightly-yellow, sterile, preservative-free clear liquid solution intended for IV administration. 
The vial is designed to deliver 20 mL (1200 mg) of atezolizumab solution but may contain more than the 
stated volume to enable delivery of the entire 20-mL volume. The atezolizumab drug product is 
formulated as 60 mg/mL of atezolizumab in 20 mM histidine acetate, 120 mM sucrose, 0.04% polysorbate 
20, pH 5.8. 
Atezolizumab must be refrigerated at 2°C−8°C (36°F−46°F) upon receipt until use. Atezolizumab vials 
should not be used beyond the expiration date provided by the manufacturer. No preservative is used in 
the atezolizumab drug product; therefore, each vial is intended for single use only. Vial contents should 
not be frozen or shaken and should be protected from direct sunlight. 
Statistical Considerations: 
The safety and efficacy analyses will be presented by study phase. For the Dose Determination Phase, 
tabulations will be provided by dose cohort and overall. Some analyses may be performed based on the 
Dose Determination and Expansion Phases combined. 
Safety Analyses 
Safety analyses will be conducted using the Safety Analysis Set. 
An interim safety analysis is planned following the completion of Cycle 1 for the first 20 patients enrolled 
in the Phase 2 expansion phase and will utilize a Data Safety Monitoring Board. 
Treatment-emergent AEs reported during the study will be tabulated and listed by Medical Dictionary for 
Regulatory Activities (MedDRA) 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 treatment; AEs by severity; DLTs; AEs occasioning treatment delay, reduction 
or discontinuation; and serious adverse events (SAEs). For the Dose Determination 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). 


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Hematology and serum chemistries will be summarized using conventional summary statistics (mean, 
standard deviation, median, and range) for the following: enrollment value, minimum and maximum post 
enrollment values, average post enrollment value, and last post enrollment value. Standard shift tables 
will also be prepared presenting worst post enrollment toxicity grade versus enrollment. 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. 
Efficacy Analyses 
Efficacy analyses will be conducted using the Full Analysis Set and, where appropriate, the Per-protocol 
Set. An interim efficacy analysis is planned after 45 PFS events have occurred in the Phase 2 study 
portion. 
PFS is the primary endpoint for the Expansion Phase of this study. PFS is defined in the conventional 
manner as the number of months from the randomization date to the earlier of documented progressive 
disease or death due to any cause. Progressive disease will be assessed by the local investigator using 
RECIST 1.1. The disease progression date and censoring date will be based on published conventions ( 
FDA 2007). Sensitivity analyses will be performed to identify asymmetry between treatment arms for the 
frequency of missed disease assessments, deviations of the actual disease assessment times from the 
planned assessment times. Alternative censoring conventions will also be used to assess among other 
concerns, dropouts with undocumented progressive disease. PFS will be summarized descriptively using 
the Kaplan-Meier method. The primary inferential comparison between treatment arms will be performed 
using the log-rank test stratified by the randomization stratification factor of geographic location. 
Estimation of the hazard ratio for treatment arm will be determined using a stratified Cox proportional 
hazards model, without any other covariate. The corresponding results from the log-rank test and Cox 
model without stratification will be reported as supplemental analyses. 
The statistical methods to be used for the analysis and reporting of the secondary efficacy endpoints are 
described in Section 13.5 of the protocol. 
Procedures: The Schedule of Study Assessments is included in Table 1-1 below. 


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Table 1-1 
Schedule of Study Assessments 
 
Procedure 
Screening 
(D -21 to -1) 
Combination Therapy 
EOT 
(≤7 days of 
last 
study 
drug dose) 
Safety 
F/U 
(≤30 days of 
EOT) 
Post- 
Study 
F/U 1 
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 
Medical and disease history 
X 
X 
Complete physical examination 
X2 
X2 
X 
X 
Symptom-directed physical examination 
X 
X 
X 
X 
X 
X 
ECG 
X 
X3 
X 
Vital signs, weight (height at screening only) 
X 
X 
X 
X 
X 
X 
ECOG performance status4 
X 
X 
X 
X 
X 
X 
Radiological Imaging, Disease assessment 
X5 
X6 
X7 
X7 
Pregnancy testing 
X 
X8 
Hematology, coagulation studies9, and 
clinical chemistries10, 11 
X 
X11 
X 
X 
X 
X 
X 
X 
Blood sample for immune correlates12 
X12 
X12 
X12 
X12 
X12 
Blood sample for TRegs/KI67 
X13 
X13 
X13 
X13 
Blood sample for atezolizumab serum 
biomarker 
X13 
X13 
X13 
X13 
X13 
Blood sample for atezolizumab plasma 
biomarker 
X13 
X13 
X13 
X13 
X13 
Blood sample for protein lysine acetylation13 
X14 
X14 
Tissue sample biopsy for immune correlates 
(also archival tissue when available) 
X15 
X15 
X15 
Entinostat self-administration 
Self-administered weekly starting on C1D1; C1D1 ≤3 business days of 


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Procedure 
Screening 
(D -21 to -1) 
Combination Therapy 
EOT 
(≤7 days of 
last 
study 
drug dose) 
Safety 
F/U 
(≤30 days of 
EOT) 
Post- 
Study 
F/U 1 
C1 
C2 
≥C3 
D1 
D8 
D15 
D1 
D15 
Day 1 
Visit Window 
- 
- 
±1D 
±1D 
±3D 
±3D 
±3D 
±3D 
±3D 
±5D 
enrollment 
Atezolizumab administration16 
X 
X 
X 
Blood sample for entinostat 
pharmacokinetics17 
X17 
X17 
X17 
X17 
Blood sample for atezolizumab 
pharmacokinetics and anti-therapeutic 
antibodies18 
X18 
X18 
X18 
X18 
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 
X 
X 
X 
1 After the Safety F/U visit, patients who have not experienced PD are followed (including radiological assessments) q6 weeks (+/- 3 d) through study week 36 and 
then every 9 weeks (+/- 3 d) thereafter until unequivocal PD. Thereafter, they are contacted q3 months until death or study closure for information on PD, alternate 
treatments and survival status. 
2 If the screening complete PE was performed within 7 days before C1D1, then a symptom-directed examination may be performed at enrollment. 
3 An ECG is to be performed pre-dose on C3D1 (- 3d) and then every 3 cycles (- 3d) thereafter. An ECG may be repeated anytime, as clinically indicated. 
4 Also performed if fluid retention occurs 
5 Performed only if last scan was performed >28 days before C1D1 
6Patients will have radiological disease assessments performed every 6 weeks (+/-3 d) through week 36 (Week 6, 12, 18, etc.) and then q9 weeks (+/- 3 d) hereafter 
during treatment and for patients who have not yet progressed when discontinuing study treatment, until progression based on this schedule. 
- 
 Partial or complete response should be confirmed by a repeat tumor imaging assessment 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. 
- 
If radiologic imaging demonstrates initial evidence for PD, tumor assessment should be repeated at the earliest of 4 weeks, or preferably on the study 
schedule of 6 weeks, in order to confirm PD. 
7 Performed only if radiological progression was not previously observed on study. 
8 For female patients of child-bearing potential, a required serum pregnancy test is to be performed during screening and a urine test within 3 days before the first 
study drug dose. Pregnancy testing is to be repeated during the study any time pregnancy is suspected. 
9 Analytes tested: RBC, WBC with absolute counts of individual cell types, platelet count, HGB and HCT. Screening only also includes: prothrombin time (PT) or 
international normalized ratio (INR) and activated partial thromboplastin time (aPTT). 10Analytes tested: ALT, AST, albumin, alkaline phosphatase, total bilirubin, 
BUN, calcium, creatinine, sodium, potassium, chloride, bicarbonate, glucose, LDH, phosphorus, total protein and uric acid. Magnesium and TSH at enrollment only, 
unless clinically indicated. 


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11 Performed only if screening laboratory tests performed >7 days prior to enrollment; screening laboratory results remain as the baseline entry criteria and 
abnormalities thereafter are to be noted as, and treated as, adverse events 
12 Samples collected pre-dose; not collected after C3 D1 except at EOT. 
13 Samples collected pre-dose. 
14 Sample taken before any study drug administration. 
15 Fresh tumor core biopsy during screening from all patients on a mandatory basis; required on C2D15 (+/-3 days) funtil 20 samples are obtained in the Phase 2, but 
optional for everyone else; optional for all patients at disease progression and end of study treatment. Archival tissue is collected at screening when available. 
16The initial dose of atezolizumab will be delivered over 60 (± 15) minutes. If tolerated without infusion-associated adverse events, the second infusion may be 
delivered over 30 (± 10) minutes and if well tolerated, all subsequent infusions as well. Vital signs should be determined up to 60 minutes before each infusion 
as well as during and after infusion if clinically indicated. 
17C1D1 samples are taken pre-dose and 2-4 h post entinostat dosing; C1D8 and C1D15 taken any time after entinostat dosing; C2D1 taken pre-dose 
18C1D1 samples for PK and ADA are taken pre-dose and again 30 minutes (+/- 10 minutes) post infusion (PK only); C2D1, C4D1 are taken pre-dose; EOT and, if 
patient is still being following per protocol on day 120 after coming off study treatment, a PK sample should be collected 


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Page Intentionally Left Blank 


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2.STUDY GLOSSARY 
Abbreviation/Acronym 
Definition 
ADaM 
Analysis Dataset Model 
AE 
Adverse event 
AESI 
Adverse Event of Special Interest 
ALK 
Anaplastic lymphoma kinase 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
aPTT 
Activated partial thromboplastin time 
ATA 
Anti-tumor activity 
aTNBC 
Advanced Triple Negative Breast Cancer 
AZA 
5-Azacitadine 
BSA 
Body surface area 
BUN 
Blood urea nitrogen 
C 
Cycle 
CBC 
Complete blood count 
CBR 
Clinical benefit rate 
CI 
Confidence interval 
CIN 
Cervical intraepithelial neoplasia 
CNS 
Central nervous system 
CR 
Complete response 
CrCl 
Creatinine clearance 
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 
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 
IB 
Investigator’s Brochure 


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Abbreviation/Acronym 
Definition 
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 
Inevaluable 
NSCLC 
Non-small cell lung cancer 
NYHA 
New York Heart Association 
ORR 
Overall response rate 
OS 
Overall survival 


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Abbreviation/Acronym 
Definition 
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 
RP2D 
Recommend Phase 2 Dose 
SAE 
Serious adverse event 
SC 
Subcutaneous(ly) 
SD 
Stable Disease 
SDTM 
Study Data Tabulation Model 
SIA 
Systemic immune activation 
SOC 
System organ class 
SOD 
Sum of Diameters 
T1DM 
Type 1 diabetes mellitus 
T3 
Triiodothyronine 


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Abbreviation/Acronym 
Definition 
T4 
Thyroxine 
TEAE 
Treatment-emergent adverse event 
TGF 
Transforming growth factor 
TIL 
Tumor-infiltrating lymphocyte 
TKI 
Tyrosine kinase inhibitor 
TMTB 
Total Measured Tumor Burden 
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) 
WoCBP 
Women of Child Bearing Potential 


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3.OBJECTIVES 
 
3.1 Primary 
The primary study objectives are: 
 
Phase 1b (Dose Determination Cohort): 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 atezolizumab. 
Phase 2 (Expansion Cohort): To perform an evaluation of the efficacy of entinostat at the 
RP2D in combination with atezolizumab in patients with aTNBC, as determined by the duration 
of progression-free survival (PFS) based on the local investigator’s assessment of progressive 
disease using Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) . 
3.2 Secondary 
Secondary study objectives are: 
 
Efficacy: In Phase 2, to evaluate the efficacy of entinostat in combination with atezolizumab in 
patients with aTNBC, as determined by: 
• 
PFS based on immune-related RECIST (irRECIST) 
• 
Overall response rate (ORR) (i.e., complete response [CR] or partial response [PR]) 
based on RECIST 1.1 and irRECIST 
• 
Clinical benefit rate (CBR) (i.e. CR or PR or stable disease [SD] for at least 24 weeks) 
based on RECIST 1.1 and irRECIST 
• 
Overall survival (OS) 
In patients with best overall response of CR or PR: 
 
• 
Duration of response (DOR) 
• 
Time to response (TTR) 
Safety: To evaluate safety and tolerability of entinostat in combination with atezolizumab, as 
measured by clinical adverse events (AEs) and laboratory parameters. 


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3.3 Exploratory 
The exploratory study objectives are to: 
 
• 
 
 
 
• 
 
 
• 
 
 
• 
 
• 
 
 
• 
 
 
• 
 
 
• 
 
 
• 
 
• 
 
 
• 
 
 


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4. ENDPOINTS 
 
4.1 Efficacy 
The primary efficacy endpoint is: 
• 
PFS, as determined by the local investigator using RECIST 1.1 
Secondary endpoints: 
• 
PFS determined by the local investigator using irRECIST 
• 
ORR (CR or PR) by RECIST 1.1 and irRECIST 
• 
CBR (CR, PR, or SD for at least 24 weeks) by RECIST 1.1 and irRECIST 
• 
OS 
In patients who experience a response to treatment (i.e., CR or PR): 
• 
DOR 
• 
TTR 
4.2 Safety 
Safety endpoints are: 
 
• 
Determination of DLT, MTD and RP2D 
• 
AEs 
• 
Clinical laboratory parameters, Vital Signs, Physical Exam 
4.3 Exploratory 
Exploratory endpoints include: 
• 
 
• 
 
• 
 
• 
 
• 
 
• 
 
 
• 
 
• 
 
• 
 
• 
 
• 
 


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5. BACKGROUND AND RATIONALE 
 
Triple negative breast cancer (TNBC) represents 15-20% of newly diagnosed breast cancer 
cases, and is associated with a younger age and advanced stage at diagnosis, increased risk of 
visceral metastasis and poorer outcome. The five-year survival rate for women diagnosed with 
Stage IV TNBC is only 22% with limited treatment options. Development of novel approaches to 
improve the treatment outcome for TNBC patients remains a significant unmet challenge. 
Immuno-oncology is an emerging field of cancer medicine that has focused on the development 
of therapeutic approaches designed to activate the immune system to find and destroy cancer 
cells. The immune system consists of two parts, the innate immune system and the adaptive 
immune system and both play a role in an immune mediated effective anti-tumor immune 
response. The innate immune system, composed of key cells such as natural killer (NK) and 
neutrophils, is non-specific and is designed to rapidly identify and eliminate immediate threats to 
the body, such as infections and other pathogens. The adaptive immune system, composed of 
B cells, T cells and other immune regulatory cells, targets specific antigens and provides a long- 
term response, known as immunologic memory, to antigens it recognizes as foreign. 
Many tumors have the ability to evade both the innate and adaptive immune system through 
direct cellular interactions and recruitment of immune-suppressive cells to the area surrounding 
the tumor (Wu 2015). Cancer cells can express proteins on their cell surface known as check 
point proteins, such as PD-L1 and programmed cell death protein ligand 2, or PD-L2, that block 
the ability of immune cells known as cytotoxic T cells to kill cancer cells (Mahoney 2015; 
Sharma 2015). Antibodies that block PD-L1 or PD-L2 restore the ability of cytotoxic T cells to kill 
cancer cells and have shown great clinical promise. Positive results notwithstanding, durable 
responses have been observed in only a relatively small population of patients, with overall 
response rates below 30% depending on tumor type; this suggests that additional strategies 
enhancing the anti-tumor immune response are needed to improve the survival of cancer 
patients (Mahoney 2015; Sharma 2015). 


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Research to identify the basis for the limited efficacy of recently developed immune therapies 
has provided investigators with an appreciation for the role that specific immune regulatory cells, 
such as MDSCs and Tregs, have in dampening the cytotoxic T cell response (Joyce 2015; 
Mahoney 2015; Sharma 2015). MDSCs and Tregs localize in the area surrounding the tumor 
and, together with the immune checkpoints, play a significant role in helping a tumor evade 
detection and elimination by the immune system (Marvel 2015; Adeegbe). 
MDSCs are immature myeloid cells that are activated by disease or injury and are generally 
increased in cancer patients. The primary function of MDSCs is to suppress an activated T cell 
immune response through the production and secretion of enzymes that deplete key amino 
acids required for the growth and function of cytotoxic T cells (Marvel 2015). High 
concentrations of circulating MDSCs in various cancers, including breast, lung, head and neck, 
correspond with a poor prognosis and limited response to cancer therapy (Liu 2010; Najjar 
2013; Solito 2011; Weed 2014). Recent data further indicate that high concentrations of 
circulating MDSCs in melanoma patients are inversely correlated with clinical response to 
immune checkpoint inhibitors suggesting that targeting MDSCs may offer new therapeutic 
opportunities for enhancing the anti-tumor response to immune checkpoint inhibitors (Weber 
2015). 
Tregs are a second type of immune suppressor cell and are recruited to sites of active immune 
response in order to shut down the cytotoxic T cell response (Adeegbe 2013; Zhang 2015). 
Unlike MDSCs, which are found in activated states in circulating blood, Tregs are recruited to 
the tumor microenvironment and activated by local signals from the cancer cell (Adeegbe 2013; 
Zhang 2015). As with MDSCs, an increase in the concentration of activated Tregs correlates 
with poor prognosis in a number of tumor types including breast, colorectal, and ovarian cancers 
(Freiser 2013; Zhang 2015). Tregs suppress cytotoxic T cell responses through the secretion of 
cytokines that inhibit the growth of cytotoxic T cells. In addition Tregs can cause other immune 
regulatory cells in the tumor microenvironment to secrete immune suppressive enzymes 
(Freiser 2013; Zhang 2015). Inhibiting Tregs may therefore relieve immune suppression in a 
way similar and potentially complementary to that of other immune-targeted approaches. 


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Separate preclinical studies have demonstrated that entinostat is a dual inhibitor of immune 
suppressor cells and targets both MDSCs and Tregs. Figure 5-1 below shows that entinostat 
reduces the growth of MDSCs at concentrations that spare the growth of cytotoxic T cells. 
Approximately half of the MDSCs are stopped from growing at 200 nM of entinostat, which is 35 
times less than the concentration of entinostat that stops half of the cytotoxic T cells from 
growing (Kim 2014). 
Investigators have previously demonstrated FOXP3, a protein involved in Treg function, is an 
indicator of Treg immune suppressor activity. Figure 5-2 below shows that entinostat reduces 
the expression of FOXP3 protein in Tregs, when administered in an animal cancer model, thus 
demonstrating entinostat’s ability to inhibit Treg immune suppressor activity (Shen 2012). 
 
 
 
 
Figure 5-1 (Kim 2014) 
Figure 5-2 (Shen 2012) 
 
 
In order to determine whether the effects observed in preclinical research studies can also be 
observed in cancer patients treated with entinostat, an analysis was conducted on immune cells 
in blood samples collected from a subset of patients treated in ENCORE 301, a Phase 2b 
clinical trial in advanced HR+ breast cancer patients. As shown in Figure 5-3 below, in these 
peripheral blood samples, a statistically significant reduction in the concentration of circulating 
MDSCs was observed in patients treated with the combination of entinostat and exemestane, a 
hormone therapy, but not in patients treated with the combination of placebo and exemestane. 


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Data on file 
 
 
Data Supporting Entinostat in Combination with Immune Checkpoint Inhibitors. 
 
 
Preclinical. In order to determine whether entinostat could be combined effectively with immune 
checkpoint inhibitors, entinostat was tested in combination with anti-PD-1 and anti-cytotoxic T- 
lymphocyte-associated protein 4, or CTLA4, directed antibodies in immune-resistant animal 
models. As shown in Figure 5-4 below, the elimination of both primary and metastatic tumors 
was observed in a 4T1 mouse triple negative metastatic breast cancer model that was treated 
with entinostat together with dual PD-1/CTLA4 checkpoint inhibition. In this experiment, it was 
observed that entinostat reduced the number and activity of MDSCs, rather than attacking and 
destroying replicating cells like standard chemotherapy drugs. The significant anti-tumor effect 
of entinostat combine with immune checkpoint blockade in the 4T1 TNBC mouse model 
supports the clinical testing of entinostat combined with atezolizumab in TNBC. 


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Source: (Kim 2014) 
 
Clinical. In patients who were treated in two unrelated clinical trials, physicians at JHU observed 
preliminary evidence for the potential beneficial effects of combining entinostat with a PD-1 or 
PDL-1 inhibitor. In a heavily pre-treated metastatic NSCLC population, patients given the 
combination of entinostat and azacitidine, an approved agent, achieved few objective responses 
and only a modest 3% overall response rate (Juergens 2011). However, investigators observed 
that patients who received the combination of entinostat and azacitidine and subsequently 
received immune checkpoint therapy demonstrated a higher response rate than expected for 
this patient population. Figure 5-5 below illustrates that all five patients who received either 
nivolumab, an approved anti-PD-1, or an investigational PDL-1 inhibitor as their next therapy 
derived durable clinical benefit. Three of the patients had durable responses and two had 
durable stable disease. This enhanced response rate was better than the 15% response to 
nivolumab alone observed in a similar advanced NSCLC population and led investigators to 
hypothesize that the prior effect of the combination of entinostat and azacitidine therapy was 
“priming” the tumors to the subsequent immune therapy (Wrangle 2013). To confirm these 
findings and further explore the ability of the combination of azacitidine and entinostat to 
enhance the response of NSCLC patients to nivolumab, the investigators at JHU have initiated 
a follow-on randomized Phase 2 clinical trial, J1353. 


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Data on file 
 
 
Based on these findings it is hypothesized that entinostat combined with a PD-1/PD-L1-blocking 
antibody, atezolizumab, will result in an improvement in PFS for the combination compared to 
atezolizumab alone. 
5.1 Study Treatment 
 
5.1.1 Entinostat (SNDX-275) 
 
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 deacetylated 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. 
Entinostat (SNDX-275), an orally available synthetic pyridylcarbamate licensed from Bayer 
Schering AG by Syndax Pharmaceuticals and previously named MS-275, inhibits histone 


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deacetylases (HDACs). Entinostat 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). 
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 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 xenograft model, including 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, leading to a reduction in 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). 
5.1.1.1 Entinostat in Patients with Solid Tumors, including breast cancer 
To date, entinostat has been investigated alone or in combination in >1000 patients with cancer 
in clinical studies. In breast cancer, entinostat has been studied in a randomized phase 2 
clinical trial sponsored by Syndax, ENCORE 301, in patients with ER+ metastatic breast cancer. 
ENCORE-301 was a placebo-controlled, double-blind trial of exemestane in combination with 
entinostat (EE) versus exemestane plus placebo (EP). The primary endpoint of PFS was met, 
with EE resulting in a median of 4.3 months and EP a median of 2.3 months. Overall survival, 
an exploratory endpoint, showed a survival benefit of approximately 8 months in favor of EE 
(28.1 months) versus EP (19.8 months), In 2014 the FDA granted Breakthrough Therapy 
designation for entinostat combined with exemestane in metastatic hormone receptor-positive 
breast cancer in post-menopausal women whose disease has progressed following non- 
steroidal aromatase inhibitor (AI) therapy based on these results. A phase 3 registration study, 


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E2112, has been designed to confirm the ENCORE 301 results and is currently being 
conducted by ECOG-ACRIN under sponsorship from the NCI under a Special Protocol 
Assessment. 
In clinical trials to date, entinostat has been well tolerated at the doses and schedules 
investigated. The AEs reported most frequently included gastrointestinal (GI) disturbances, 
primarily nausea with or without vomiting and diarrhea; fatigue; and hematologic abnormalities, 
primarily anemia, thrombocytopenia, neutropenia, and leukopenia. Most of these events were 
Grade 1 or 2 in severity and non-serious. Grade 3 and 4 hematologic abnormalities are more 
commonly seen in patients with hematologic malignancies and are less common in patients with 
solid tumors. 
Additional information on the chemistry, pharmacology, toxicology, preclinical findings, and 
clinical experience to date may be found in the Investigator’s Brochure (IB). 
 
5.1.2 Atezolizumab 
 
5.1.2.1 Background 
Atezolizumab (MPDL3280A) is a humanized immunoglobulin (Ig) G1 monoclonal antibody 
consisting of two heavy chains (448 amino acids) and two light chains (214 amino acids) and is 
produced in Chinese hamster ovary cells. Atezolizumab was engineered to eliminate Fc- 
effector function via a single amino acid substitution (asparagine to alanine) at position 298 in 
the heavy chain, which results in a non-glycosylated antibody that has minimal binding to 
Fc receptors and, consequently, eliminates detectable Fc-effector function and depletion of cells 
expressing PD-L1. Atezolizumab targets human PD-L1 and inhibits its interaction with its 
receptor, PD-1. Atezolizumab also blocks the binding of PD-L1 to B7.1, an interaction that is 
reported to provide additional inhibitory signals to T cells. 
Atezolizumab is being investigated as a potential therapy for solid tumors and hematologic 
malignancies in humans. 
Refer to the current atezolizumab IB for detailed background information on this drug product. 
 
5.1.2.2 Pharmaceutical and Therapeutic Background 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control (Pedoeem 2014). 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 


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responses, including autoimmune reactions. PD-1 (encoded by the gene Pdcd1) is an 
immunoglobulin (Ig) superfamily member related to CD28 and CTLA-4, which has been shown 
to negatively regulate antigen receptor signaling upon engagement of its ligands (PD-L1 and/or 
programmed death ligand-2 [PD-L2]). The structures of murine PD-1 alone (Zhang 2004) and in 
complex with its ligands have been resolved (Lazar-Molnar 2008; Lin 2008), and more recently 
the nuclear magnetic resonance-based structure of the human PD-1 extracellular region and 
analyses of its interactions with its ligands were also reported (Cheng 2013). PD-1 and family 
members are type I transmembrane glycoproteins containing an Ig Variable-type (V-type) 
domain responsible for ligand binding and a cytoplasmic tail which is 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 CD3ζ, PKCθ and ZAP70, which are involved in the CD3 T cell 
signaling cascade (Sheppard 2004). The mechanism by which PD-1 down-modulates T cell 
responses is similar to, but distinct from that of CTLA-4 (Ott 2013). PD-1 was shown to be 
expressed on activated lymphocytes, including peripheral CD4+ and CD8+ T cells, B cells, T 
regs and natural killer cells (Yao 2014). Expression has also been shown during thymic 
development on CD4-CD8- (i.e., double-negative) T cells (Nishimura 1996), as well as subsets 
of macrophages (Huang 2009) and dendritic cells (Pena-Cruz 2010). The ligands for PD-1 
(PD-L1 and PD-L2) are constitutively expressed or can be induced in a variety of cell types (Keir 
 
 
2008). PD-L1 is expressed at low levels on various non-hematopoietic tissues, most notably on 
vascular endothelium, whereas PD-L2 protein is only detectably expressed on antigen- 
presenting cells found in lymphoid tissue or chronic inflammatory environments (Keir 2008). 
Both ligands are type I transmembrane receptors containing both Ig variable- and Ig constant- 
like domains in the extracellular region and short cytoplasmic regions with no known signaling 
motifs. Binding of either PD-1 ligand to PD-1 inhibits T cell activation triggered through the T cell 
receptor. PD-L2 is thought to control immune T cell activation in lymphoid organs, whereas 
PD-L1 serves to dampen unwarranted T cell function in peripheral tissues. Although healthy 
organs express little (if any) PD-L1, a variety of cancers were demonstrated to express 
abundant levels of this T cell inhibitor (Karim 2009; Taube 2012), which, via its interaction with 
the PD-1 receptor on tumor-specific T cells, plays a critical role in immune evasion by tumors 


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(Sanmamed 2014). As a consequence, the PD-1/PD-L1 pathway is an attractive target for 
therapeutic intervention in cancer (Topalian 2012). 
5.1.2.3 Atezolizumab Non-Clinical Studies Summary 
The nonclinical strategy of the atezolizumab program was to demonstrate in vitro and in vivo 
activity, to determine in vivo pharmacokinetic (PK) behavior, to demonstrate an acceptable 
safety profile, and to identify a Phase I starting dose. Comprehensive pharmacology, PK, and 
toxicology evaluations were performed with atezolizumab. 
The safety, pharmacokinetics, and toxicokinetics of atezolizumab were investigated in mice and 
cynomolgus monkeys to support intravenous (IV) administration and to aid in projecting the 
appropriate starting dose in humans. Given the similar binding of atezolizumab for cynomolgus 
monkey and human PD-L1, the cynomolgus monkey was selected as the primary and relevant 
nonclinical model for understanding the safety, pharmacokinetics, and toxicokinetics of 
atezolizumab. 
Overall, the nonclinical pharmacokinetics and toxicokinetics observed for atezolizumab 
supported entry into clinical studies, including providing adequate safety factors for the 
proposed Phase I starting doses. The results of the toxicology program were consistent with the 
anticipated pharmacologic activity of downmodulating the PD-L1/PD-1 pathway; heightened 
immune responses and the potential to increase immune-associated inflammatory lesions were 
identified as possible safety risks in patients. 
Refer to the Atezolizumab Investigator’s Brochure (IB) for details on the nonclinical studies. 
 
5.1.2.4 Atezolizumab Clinical Studies Summary 
Atezolizumab is currently being tested in multiple Phase I, II, and III studies, both as 
monotherapy and in combination with several anti-cancer therapies (see the Atezolizumab 
Investigator’s Brochure for study descriptions). The single-agent safety and efficacy data 
available to date are from the following studies: one Phase Ia (Study PCD4989g) and two 
Phase II studies (Studies GO28625 [FIR] and GO28753 [POPLAR]). 
Clinical benefit from atezolizumab monotherapy was observed in a broad range of malignancies 
including non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), melanoma, urothelial 
bladder cancer (UBC), head and neck cancer, gastric cancer, breast cancer and sarcoma. 
Results suggest that PD-L1 expression in the tumor microenvironment is associated with an 
increased probability of clinical benefit with atezolizumab. 


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Across all these patients, fatigue was the most frequently reported adverse event. Given the 
mechanism of action of atezolizumab, events associated with inflammation and/or immune- 
mediated adverse events have been monitored closely during the clinical program. These 
include potential dermatologic, hepatic, endocrine, gastrointestinal and respiratory events. 
In trials investigating atezolizumab both as a single agent and in combination with 
chemotherapy, the incidence of adverse events in the treatment arms with combined use was 
consistent with the known safety profiles of the individual study drugs. Currently, no maximum 
tolerated dose, no dose-limiting toxicities and no clear dose-related trends in the incidence of 
adverse events have been determined. 
Refer to the Atezolizumab Investigator’s Brochure for additional details on clinical studies. 
 
5.2 Study Rationale 
Treatment of TNBC represents a significant challenge due to the lack of clinically validated 
targets that are available for the other breast cancer subtypes. Preliminary data has indicated 
that treatment with immune checkpoint inhibitors targeting PD-1 such as pembrolizumab and 
PD-L1 such as atezolizumab results in approximately an 18-19% response rate in women with 
TNBC who also test positive for PD-L1 expression. While these data are promising, the benefit 
appears to be restricted to a relatively small fraction of the total TNBC patient population. 
Combination strategies to increase the clinical benefit of PD-1 / PD-L1 inhibitors in TNBC are 
the focus of intense research efforts. Preclinical testing in the 4T1 mouse model of TNBC 
indicate that entinostat combined with immune checkpoint blockade results in complete 
inhibition of primary tumors and metastases. The mechanism for this combined anti-tumor effect 
was determined to be entinostat’s ability to inhibit the growth and function of MDSCs, an 
immune suppressor cell shown to block the anti-tumor T cell immune response. These data 
provide the basis for clinical testing of entinostat combined with atezolizumab in TNBC patients. 
5.3 Rationale for the Dose Selection 
 
5.3.1 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/m2 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 


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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/m2. 
The MTD for single agent entinostat in non-hematologic indications was established as 4 mg/m2 
weekly x 3 followed by a 1 week rest, or 10 mg/m2 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. In a 
linear regression analysis on factors that may contribute to this variability, 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 patients with locally advanced or metastatic breast cancer or 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. The 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). 
Based on the clinical experience with entinostat, fixed dose of 5 mg given weekly has been 
selected as the starting dose for this study, with dose initial de-escalation to 3 mg and secondly 
to 2 mg, if toxicity occurs with the combination treatment. 
 
5.3.2 Atezolizumab 
 
The fixed dose of 1200 mg (equivalent to an average body weight−based dose of 15 mg/kg) 
was selected on the basis of both nonclinical studies and available clinical data from Study 
PCD4989g as described below. 
The target exposure for atezolizumab was projected on the basis of nonclinical tissue 
distribution data in tumor-bearing mice, target-receptor occupancy in the tumor, the observed 
atezolizumab interim pharmacokinetics in humans, and other factors. The target trough 
concentration (Ctrough) was projected to be 6 µg/mL on the basis of several assumptions, 
including: 1) 95% tumor-receptor saturation is needed for efficacy and 2) the tumor-interstitial 
concentration to plasma ratio is 0.30 based on tissue distribution data in tumor-bearing mice. 


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The atezolizumab dose is also informed by available clinical activity, safety, PK, and 
immunogenicity data. Anti-tumor activity (ATA) has been observed across doses from 1 mg/kg 
to 20 mg/kg administered q3w. The MTD of atezolizumab was not reached, and no DLTs have 
been observed at any dose in Study PCD4989g. Available preliminary PK data (0.03−20 
mg/kg) from Study PCD4989g suggest that for doses ≥ 1 mg/kg q3w, overall atezolizumab 
exhibits pharmacokinetics that are both linear and consistent with typical IgG1 antibodies. 
Detectable ATAs were observed in patients at all dose levels but were associated with changes 
in pharmacokinetics for some patients in only the lower dose cohorts (0.3, 1, and 3 mg/kg). It is 
unclear from currently available data in these lower dose cohorts whether administration of 
higher doses to patients with both detectable ATAs and reduced exposure would necessarily 
restore exposure to expected levels. No clear relationship between the development of 
measurable ATAs and safety or efficacy has been observed. Available data suggest that the 
development of detectable ATAs does not appear to have a significant impact on 
pharmacokinetics for doses from 10 to 20 mg/kg administered q3w in most 
patients. Correspondingly, patients dosed at the 10-, 15-, and 20-mg/kg q3w dose levels have 
maintained target trough concentrations of drug despite the detection of ATAs. 
Currently available PK and anti-treatment antibody data suggest that the 15-mg/kg 
atezolizumab q3w regimen (or fixed-dose equivalent) would be sufficient to both maintain 
Ctrough ≥ 6 µg/mL and further safeguard against both interpatient variability and potential effect of 
ATAs that could lead to sub-therapeutic levels of atezolizumab relative to the 10-mg/kg q3w 
regimen (or fixed-dose equivalent). From inspection of available observed Ctrough data, a 
20 mg/kg atezolizumab q3w regimen does not appear to be warranted to maintain targeted 
Ctrough levels relative to the proposed 15-mg/kg q3w level. 
Simulations (Bai et al. 2012) do not suggest any clinically meaningful differences in exposure 
following fixed dose or dose adjusted for weight. On the basis of this analysis, a fixed dose of 
1200 mg q3w is selected (equivalent to a body weight−based dose of 15 mg/kg q3w). 
Selection of an every-21-day dosing interval is supported by this preliminary pharmacokinetics 
evaluation and allows for a convenient integration with common therapeutic regimens. 
5.4 Hypothesis 
Phase 1b: The combination of atezolizumab and entinostat at a biologically active dose will be 
sufficiently safe and well tolerated to warrant further investigation. 


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Phase 2: Entinostat at the dose determined in Phase 1b combined with atezolizumab will result 
in an improved Progression-Free Survival compared to atezolizumab alone. 


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6. EXPERIMENTAL PLAN 
 
6.1 Study Design 
Study SNDX-275-0602 (TRIO025) is a randomized, placebo-controlled, double-blind, 
multicenter phase 2 study evaluating the combination of atezolizumab with or without entinostat 
in patients with aTNBC with a Phase 1b lead-in phase to determine the recommend phase 2 
dose of entinostat. 
 
 
Figure 6-1 
Flowchart of Dose Determination Advancement 
 
Entinostat 
Dose 
DLT in: 
Action 
DLT in: 
Outcome 
 
 
 
0 or 1 of 6 
 
0 or 1 of 3 
Add 3 
 
5 mg 
≥ 2 of 6 
 
≥ 2 of 3 
 
 
 
0 or 1 of 6 
 
0 or 1 of 3 
Add 3 
 
3 mg 
≥ 2 of 6 
 
≥ 2 of 3 
 
 
 
 
 
0 or 1 of 6 
 
0 or 1 of 3 
Add 3 
 
2 mg 
≥ 2 of 6 
 
≥ 2 of 3 
Amend protocol to 
study alternative 
dosing regimen 
Recommended 
Phase 2 Dose 
Enroll at 2 mg 
Recommended 
Phase 2 Dose 
Enroll at 3 mg 
Recommended 
Phase 2 Dose 


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Phase 2: a TNBC 
Randomized, double-blind 
Dose Determination 
N = 6-18 
Entinostat + 
Atezolizumab 
N = 35 
Placebo + 
Atezolizumab 
N = 35 
 
 
Figure 6-2 Study Schema 
 
 
 
Phase 1b sites will be notified by TRIO regarding the availability of slots in a given cohort, 
observation of DLTs and entinostat dose levels, to assist with screening activity. 
Regardless of phase, patients will be screened for study eligibility within 21 days before 
enrollment. Patients who are determined to be eligible, based on screening assessments, will 
be enrolled in the study within 3 business days of starting study treatment on Cycle 1, Day 1 
(C1D1). 
A cycle is 21 days in length. During treatment, patients will attend study center visits and study 
evaluations will be performed on C1D1, C1D8, and C1D15; D1 and D15 of C2; and on D1 of 
each cycle thereafter. 
Phase 1b: aTNBC 
open label 


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Fresh tumor tissue core biopsy (image-guided if applicable) will be collected during the study as 
follows.: 
• 
During screening from all patients on a mandatory basis. Archival tumor tissue will also 
be collected when available. 
• 
On C2D15 (+/-3 days) on an optional basis from patients in the Phase 1b Dose 
Determination Phase. All patients in the Dose Determination Phase will be strongly 
encouraged to undergo an optional biopsy in order to help understand dose-immune 
correlate effects. 
• 
On C2D15 (+/-3 days) on a mandatory basis until 20 samples are obtained in the 
Phase 2 Expansion Phase and on an optional basis for subsequent patients in this 
phase. 
• 
At the end of study treatment prior to the start of another systemic therapy, on an 
optional basis for all patients. 
• 
At disease progression on an optional basis for all patients. 
If, based on an interim review of tumor tissue data from the initial patients in the Expansion 
Phase, such data are considered informative, tumor tissue samples will be collected on a 
mandatory basis from all subsequent patients on C2D15 (+/-3 days). Alternatively, if such data 
are not considered informative, subsequent samples will not be collected. 
Blood for immune correlates is to be collected pre-dose on each of C1D1, C2D1, C2D15, C3D1 
and at the end of treatment. Blood for protein lysine acetylation is to be collected pre-dose on 
C1D1 and C1D15. Patients will have radiological disease assessments performed every 
6 weeks (+/-3 days) (Week 6, Week 12, etc.) beginning at C1D1, during study treatment through 
week 36 or until progressive disease. If progressive disease has not occurred by week 36, 
radiological assessments will then be done every 9 weeks (+/-3 days) until progressive disease. 
If a patient comes off study for reasons other than progressive disease, radiological 
assessments will continue at 6 week intervals until what would have been study week 36 and 
then switch to a 9 week interval, until progressive disease is radiologically documented. 
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. The same imaging modality should be employed for all follow-up scans as was used 
at baseline. 


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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. 
Within 7 days of the last dose of study treatment, all patients will complete an End of Treatment 
(EOT) visit, and a Safety Follow-up (F/U) visit will be required 30 days (+/- 3 days) thereafter. 
After completion of the 30-day F/U visit, patients who have experienced progressive disease are 
to be contacted every 3 months thereafter for survival status and information regarding 
treatment regimens, until death or closure of the study by the Sponsor. Those patients who 
have not experienced progressive disease, will continue radiological disease assessments as 
noted above. 
Phase 1b (Dose Determination): This study phase employs a classical 3+3 design, with the 
determination of DLT and the MTD or RP2D based on the combination of entinostat with 
atezolizumab in C1. Six patients will need to be treated in a dose level for it to be considered 
MTD or the RP2D.The recommended dose for Phase 2 investigation will be the higher of either 
2, 3 or 5 mg weekly PO that results in less than a 33% incidence of DLT. The final 
determination of the optimal dose for further use 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. 
The initial 3-6 patients will receive entinostat at a starting dose of 5 mg (Dose Group 1) on D1, 
D8, and D15 along with atezolizumab 1200 mg via intravenous (IV) infusion on D1 of each 21- 
day cycle. 
If the 5 mg dose exceeds the MTD, then a 3 mg dose of entinostat (Dose Group -1) will be 
evaluated in the same manner. If the -1 dose level exceeds the MTD, then a 2 mg dose of 
entinostat (Dose Group -2) will be evaluated. Based on evaluation of the safety and tolerability 
data gathered during the dose determination phase together with data from other clinical trials, it 
may also be decided that accrual will take place at an alternate dose level or dosing schedule 
via a protocol amendment. 
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 9.10). 


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Phase 2 (Expansion): The efficacy and safety of entinostat in combination with atezolizumab 
will be evaluated using the RP2D identified in the Dose Determination Phase. In this 
randomized, placebo-controlled, double-blind study phase, 70 patients will be randomized in a 
1:1 fashion to atezolizumab + entinostat versus atezolizumab + placebo. The randomization will 
be stratified by geographic location (US vs. rest of world). 
Patients will follow the same schedule of study visits and assessments as specified in the Dose 
Determination phase. The exception is the C2D15 tumor tissue core biopsy. While this was 
optional in the Dose Determination phase, it is mandatory in the Expansion Phase until 20 
samples are obtained. If the data learned from those first 20 samples is deemed informative, 
this procedure may become mandatory for the remainder of the patients enrolled in this phase. 
Following the enrollment and completion of Cycle 1 of the first 20 patients in this study phase, 
cumulative study safety data for all study patients will be reviewed by a Data Safety Monitoring 
Board (DSMB). The development of serious adverse events will be assessed by the Medical 
Monitor and DSMB on a continuous basis. At the first DSMB meeting, the DSMB members will 
confirm which SAEs they need to see real time or at time of DSMB meetings only. Unless the 
DSMB wishes to suspend enrollment during the review of the safety data for the first 20 
patients, enrollment will continue during the data review process. 
6.2 Number of Centers 
Up to approximately 50 international 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 in consultation with the Sponsor. 
6.3 Number of Patients 
Phase 1b Dose Determination Phase: Up to 18 patients may be enrolled. In this phase, up to 3 
doses of entinostat will be explored in a standard “3+3” Phase 1 dose finding scheme. Six 
patients will need to be treated in a dose level for it to be considered MTD or the RP2D. 
Entinostat dosing will start at 5 mg po weekly and then decrease to 3 mg weekly in the case that 
the 5 mg weekly dose leads to ≥ 2 DLTs. It will again be de-escalated to 2 mg weekly should the 
3 mg weekly dose lead to ≥ 2 DLTs. Each patient will be counted in only 1 dose cohort. Thus, 
the total number of patients to be enrolled in the Dose Determination 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 de-escalations required to achieve the MTD. 


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Note: The patients who discontinued the study for reasons other than study drug related 
toxicities before completing Cycle 1 may be replaced. 
In the Phase 2 Expansion Phase, a total of 70 TNBC patients are planned to be enrolled for 
evaluation (35 patients per arm). Note: It is anticipated that the number of patients who will 
drop out of the study without PFS failure beforehand will be low (expected to not exceed 2–3%). 
Depending on the actual number of such dropouts, the number of patients accrued may be 
increased by 6–10 additional patients to accommodate for a higher-than-expected number of 
dropouts. 
6.4 Estimated Study Duration 
The estimated duration of study enrollment is approximately 15 months; 6 months for the Phase 
1b and 9 months for the Phase 2. Patients may continue study treatment until unequivocal 
progressive disease, intolerable toxicity or meets one of the study withdrawal criteria (Protocol 
Section 11). Patients will be followed for overall survival until the Sponsor terminates the trial. 


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7. PATIENT ELIGIBILITY 
 
7.1 Inclusion Criteria 
Patients meeting all of the following criteria are considered eligible to participate in the study: 
 
1. Females aged 18 years or older on the day written informed consent is given. 
2. Has histologically or cytologically confirmed triple negative breast adenocarcinoma that is 
either metastatic (stage IV of the TNM classification) or locally recurrent and not amenable 
to local curative treatment. TNBC diagnosis should be based on local laboratory 
ER/PgR/HER-2 tests and will be defined as HER2 negativity (IHC 0-1 and/or ISH non- 
amplification) and ER and PgR negativity (<1%). Disease must also be amenable to core 
biopsy (image-guided if applicable) at enrollment and for certain cohorts as described in the 
protocol, at least once during study treatment. 
3. Evidence of measurable (according to RECIST version 1.1) locally recurrent or metastatic 
disease based on imaging studies (e.g., CT, MRI) within 28 days before 
enrollment/randomization. 
4. Has received at least 1, but no more than 2, prior lines of systemic therapy for locally 
recurrent and/or metastatic disease 
5. If patient has a history of treated asymptomatic CNS metastases they are eligible, provided 
they meet all of the following criteria: 
• 
Patient has measurable disease outside CNS; 
• 
Patient does not have metastases to midbrain, pons, medulla or spinal cord; 
• 
Patient is not on corticosteroids as therapy for CNS disease (anticonvulsants 
at a stable dose are allowed); 
• 
Patient has not had whole-brain radiation within 6 weeks prior to study 
enrollment; 
• 
Patient has stable CNS disease as demonstrated by at least 4 weeks of 
stability between the last intervention scan and the study screening scan 
6. ECOG performance status of 0 or 1. 
7. Has the following laboratory parameters within 21 days of enrollment: 
 
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 


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System 
Laboratory Value 
Hepatic 
≤1.5×ULN OR 
Total bilirubin 
Direct bilirubin ≤ULN for patients with total bilirubin 
levels >1.5×ULN 
Aspartate aminotransferase (AST) and alanine 
≤2.5×ULN OR 
aminotransferase (ALT) 
≤5×ULN for patients with liver metastases 
Coagulation 
International Normalized Ratio (INR) or Prothrombin 
≤1.5×ULN unless patient is receiving anticoagulant 
Time (PT) 
therapy as long as PT or PTT is within therapeutic range 
of intended use of anticoagulants 
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 
Creatinine clearance should be calculated per institutional standard. 
 
8. If a female of childbearing potential, has a negative serum blood pregnancy test during 
screening and a negative pregnancy test (urine or serum) within 3 days prior to receiving the 
first dose of study drug. If the screening serum test is done within 3 days prior to receiving 
the first dose of study drug, a second test is not required. Note: Women of childbearing 
potential (WoCP) are any women between menarche and menopause who have not been 
permanently or surgically sterilized and are capable of procreation. Menopause is defined as 
any of the following: 
• 
Bilateral oophorectomy, 
• 
Age ≥ 60, 
• 
Age <60 and amenorrheic for ≥ 12 months in the absence of an alternative 
medical cause and FSH and estradiol in postmenopausal ranges. . 
Permanent sterilization includes hysterectomy and/or bilateral oophorectomy and/or bilateral 
salpingectomy but excludes bilateral tubal occlusion. WoCP include women who have 
experienced menopause onset < 12 months prior to enrollment. 
9. If a female of childbearing potential, willing to use 2 methods of birth control or willing to 
abstain from heterosexual activity for the course of the study through 120 days after the last 
dose of study drug. 
10. Experienced resolution of toxic effect(s) of the most recent prior anti-cancer therapy to 
≤Grade 1 (except alopecia or neuropathy). If patient underwent major surgery or radiation 
therapy of >30 Gy, they must have recovered from the toxicity and/or complications from the 
intervention. 
11. Able to understand and give written informed consent and comply with study procedures. 


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7.2 Exclusion Criteria 
Patients meeting any of the following criteria are not eligible for study participation: 
 
1. Diagnosis of immunodeficiency or receiving systemic steroid therapy or any other form of 
immunosuppressive therapy within 7 days prior to the first dose of study drug. The use of 
physiologic doses of corticosteroids may be approved after consultation with the Medical 
Monitor. 
2. Active autoimmune disease including active diverticulitis, symptomatic peptic ulcer disease, 
colitis, or inflammatory bowel 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. Previously treated with a PD-1/PD-L1-blocking antibody (i.e., atezolizumab, nivolumab, 
pembrolizumab) or a histone deacetylase inhibitor (i.e., vorinostat, belinostat, romidepsin, 
panobinostat) 
4. 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: 
• 
History of immune deficiencies or autoimmune disease (see Appendix 3 for complete 
list) 
• 
Myocardial infarction or arterial thromboembolic events within 6 months prior to 
enrollment or severe or unstable angina, New York Heart Association (NYHA) Class III 
(see Appendix I) or IV disease, or a QTc interval > 470 msec. 
• 
Uncontrolled hypertension or diabetes mellitus. 
• 
Another known malignancy that is progressing or requires active treatment (excluding 
adequately treated basal cell carcinoma or cervical intraepithelial neoplasia 
[CIN]/cervical carcinoma in situ or melanoma in situ). Prior history of other cancer is 
allowed, as long as there is no active disease within the prior 5 years. 
• 
Active infection requiring systemic therapy. 
• 
Known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis. (see inclusion criterion 5) 
5. Any contraindication to oral agents or significant nausea and vomiting, malabsorption, or 
significant small bowel resection that, in the opinion of the investigator, would preclude 
adequate absorption. 
6. Received a live vaccine within 30 days of the first dose of treatment (inactivated forms of 
influenza vaccinations can be given during influenza season only (approximately October to 
March in the Northern hemisphere and April to September in the Southern Hemisphere). 
7. Prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study enrollment or who 
has not recovered (i.e., ≤Grade 1 at enrollment) from AEs due to mAb agents administered 
more than 4 weeks earlier. 


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8. Prior chemotherapy within 3 weeks, targeted small molecule therapy or radiation therapy 
within 2 weeks prior to study enrollment or who has not recovered (i.e., ≤Grade 1 at 
enrollment) 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. 
9. 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. 
10. 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 study drug. 
11. Currently receiving treatment with any other agent listed on the prohibited medication list 
(protocol section 9.12) 
12. If female, is pregnant, breastfeeding, or expecting to conceive starting with the screening 
visit through 120 days after the last dose of study drug. 
13. Known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies). 
14. Known active hepatitis B (e.g., hepatitis B surface antigen-reactive) or hepatitis C (e.g., 
hepatitis C virus ribonucleic acid [qualitative]). Patients with past hepatitis B virus (HBV) 
infection or resolved HBV infection (defined as the presence of hepatitis B core antibody 
[HBc Ab] and absence of HBsAg) are eligible. HBV DNA test must be performed in these 
patients prior to randomization. Patients positive for hepatitis C virus (HCV) antibody are 
eligible only if polymerase chain reaction is negative for HCV RNA. 
15. Allergy to benzamide or inactive components of entinostat. 
16. History of allergies to any active or inactive ingredients of atezolizumab. 
17. Known psychiatric or substance abuse disorders that would interfere with cooperation with 
the requirements of the study. 


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8. PATIENT ENROLLMENT 
 
Section 15.3 describes documentation required prior to the commencement of study enrollment. 
 
The screening period for a particular patient commences on the date on which the patient signs 
the informed consent form. The consent form must be signed before any study-specific tests are 
performed. 
In Phase 1b, after a patient has been screened and successfully fulfills all eligibility criteria, a 
site representative will send a registration/enrollment form to the appropriate TRIO 
representative. A patient identification (ID) number will be provided to the site and the patient 
will be created in the electronic data capture (EDC) system. The site will then enter complete 
screening data. Once the screening data have been manually reviewed by TRIO, and the 
eligibility confirmed, the site will be informed via form, that the patient is eligible to be enrolled 
into the study at a determined Entinostat dose. If the patient is not eligible, the site will again be 
informed, via form and asked to indicate screen failure into the EDC system. This patient ID 
must be used on all study documentation related to that patient. 
In the Phase 2 portion of the study, an automated system will randomize the patient to one of 
the blinded study arms. Refer to the Study Manual for details on this procedure. 


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9. TREATMENT PROCEDURES 
 
9.1 Study Drugs 
The study drugs being studied in combination during this clinical trial are atezolizumab and 
entinostat. First Study treatment is to be administered within 3 business days of 
enrollment/randomization into the study. 
The Investigator shall take responsibility for maintaining appropriate records and ensuring 
appropriate supply, storage, handling, distribution, and usage of study drug, in accordance with 
the protocol and any applicable laws and regulations. 
9.2 Entinostat 
 
9.2.1 Supply and Storage 
 
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 that 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/placebo is an oral drug supplied by Syndax to the sites as pink to light red (1 mg) or 
yellow (5 mg) as polymorph B coated tablets. 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. 
Entinostat/placebo is to be stored at controlled room temperature (15ºC to 25ºC / 59ºF to 77ºF ) 
in a secure, locked storage area to which access is limited. 
Entinostat/placebo is to be protected from light. Entinostat/placebo is not to be exposed to 
extremes of temperature (greater than 30ºC / 86°F or less than 5ºC / 41°F). The pharmacist will 
dispense the investigational material to the patient at appropriate intervals throughout the study 
in childproof containers. 
Entinostat/placebo will be supplied to patients in bottles containing enough pills for a 3-week 
cycle, plus an additional dose in case tablets are lost. 


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Please refer to the Pharmacy Manual for complete details regarding supply, storage 
accountability and destruction Entinostat. 
 
9.2.2 Dosing and Administration 
 
All patients will self-administer entinostat/placebo PO once weekly on study days 1, 8 and 15 of 
each 21 day cycle. A new bottle of entinostat/placebo will be dispensed on day 1 of each cycle, 
regardless of the number of pills remaining in the bottle from the previous cycle. 
On study days on which patients receive both entinostat/placebo and atezolizumab, 
entinostat/placebo is to be taken prior to atezolizumab. 
Entinostat/placebo is to be taken on an empty stomach, at least 2 hours after a meal and at 
least 1 hour before the next meal. 
If an entinostat/placebo dose is missed, it may be taken up to 48 hours after the scheduled 
dosing time. If it is not taken within the 48 hour window, the dose should not be taken and will 
be counted as a missed dose. The patient should take the next scheduled dose per protocol. 
Missed doses should be noted as such on the patient drug diary and in the eCRF. 
If entinostat/placebo is vomited, dosing should not be re-administered but instead the dose 
should be skipped. 
9.2.2.1 Phase 1b 
During the Phase 1b Dose Determination Phase, all patients will receive atezolizumab 1200 mg 
IV on D1 of each 21 day cycle. They will also receive entinostat orally weekly on days 1, 8 and 
15 of each cycle at either 5 mg, 3 mg or 2 mg. Both drugs will be given in an open-label fashion. 
Patients who discontinue from the study treatment for reasons other than study drug-related 
toxicity before completing C1 may be replaced (refer to section 9.4). 
9.2.2.2 Phase 2 
During the Phase 2 Dose Expansion Phase, all patients will receive atezolizumab 1200 mg IV 
on D1 of each 21 day cycle. They will also receive the RP2D of entinostat or matched placebo 
weekly on days 1, 8 and 15 or each cycle. Entinostat/placebo will be given in double blind 
fashion. 
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. 


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9.3 Atezolizumab 
 
9.3.1 Supply and Storage 
 
Atezolizumab is a humanized monoclonal antibody that blocks the interaction between PD-1 
and its ligands, PD-L1 and PD-L2. Atezolizumab is an IgG4 kappa immunoglobulin with an 
approximate molecular weight of 149 kDa. 
Atezolizumab drug product is provided in a single-use, 20-mL USP/PH. Eur. Type 1 glass vial 
as a colorless-to-slightly-yellow, sterile, preservative-free clear liquid solution intended for IV 
administration. The vial is designed to deliver 20 mL (1200 mg) of atezolizumab solution but 
may contain more than the stated volume to enable delivery of the entire 20-mL volume. The 
atezolizumab drug product is formulated as 60 mg/mL of atezolizumab in 20 mM histidine 
acetate, 120 mM sucrose, 0.04% polysorbate 20, pH 5.8. 
Atezolizumab must be refrigerated at 2°C−8°C (36°F−46°F) upon receipt until use. 
Atezolizumab vials should not be used beyond the expiration date provided by the 
manufacturer. No preservative is used in the atezolizumab drug product; therefore, each vial is 
intended for single use only. Vial contents should not be frozen or shaken and should be 
protected from direct sunlight. 
Atezolizumab is supplied by Syndax to the sites and is given intravenously. 
 
9.3.2 Dosing and Administration 
 
The dose level of atezolizumab in this study is 1200 mg administered by IV infusion q3w. 
 
Administration of atezolizumab will be performed in a setting with emergency medical facilities 
and staff who are trained to monitor for and respond to medical emergencies. 
The initial dose of atezolizumab will be delivered over 60 (± 15) minutes. If the first infusion is 
tolerated without infusion-associated adverse events, the second infusion may be delivered over 
30 (± 10) minutes. If the 30-minute infusion is well tolerated, all subsequent infusions may be 
delivered over 30 (± 10) minutes, otherwise it should be delivered over 60 (±15) minutes. The 
patient’s vital signs (heart rate, respiratory rate, blood pressure, and temperature) should be 
determined no more than 60 minutes before each atezolizumab infusion. Vital signs should also 
be obtained during or after the atezolizumab infusion if clinically indicated. 


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No premedication will be allowed for the first dose of atezolizumab. Premedication may be 
administered for subsequent infusions at the discretion of the treating physician after 
consultation with the Medical Monitor. 
Any overdose or incorrect administration of study drug should be noted on the Study Drug 
Administration electronic eCRF. Adverse events associated with an overdose or incorrect 
administration of study drug should be recorded on the Adverse Event eCRF. 
Refer to the Pharmacy Manual for complete details regarding supply, storage, accountability, 
and destruction of Atezolizumab. 
9.4 Study Drug(s) Accountability 
The lot number(s) of the study drugs (entinostat and atezolizumab) received at the site are to be 
recorded on the Drug Accountability Log 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/placebo self-administration. 
9.5 Entinostat Compliance 
Treatment compliance to entinostat will be assessed at the end of each cycle. Patients will 
complete a diary to document their weekly intakes. They will be instructed to return all unused 
drugs (partially used and empty containers) and their diary at each visit. Site staff will perform 
accountability of the returned drug and will assess patient compliance. Site staff must ensure 
that the patient clearly understands the directions for self-medication and follows the schedule. 
9.6 Dose-limiting Toxicity 
In the Dose-Determination Phase, DLTs will be assessed during the DLT assessment window, 
which is defined as the first cycle of treatment. The DLT assessment window (Cycle 1) is the 
time period between C1D1 until C2D1 (expected to be 21 days after C1D1). 
In addition, the total dose of entinostat received over the first two cycles has to be evaluated as 
it corresponds to one of the DLT criteria. 
A patient will be considered DLT evaluable if she: 
 
• 
Incurs an adverse event meeting DLT criteria during Cycle 1 
Or 


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• 
Completes Cycle 1 and receives the full dose of atezolizumab and all doses of entinostat 
during this cycle, without incurring a DLT. In case a patient would not begin Cycle 2 for 
reasons other than a DLT, she would be considered DLT evaluable if she receives all 
planned doses of entinostat and atezolizumab during cycle 1 and completes 7 days after 
C1D15 without incurring a DLT. 
Patients who are not considered DLT evaluable may be replaced to complete a cohort. 
 
DLT is defined as the occurrence of any of the following events within the DLT Assessment 
window that are considered by the Investigator to be at least possibly related to study drug: 
• 
Grade 5 events 
• 
Grade ≥ 4 neutropenia (ANC < 500/µL) lasting ≥ 7 days 
• 
Grade ≥ 3 febrile neutropenia 
• 
Grade ≥ 4 thrombocytopenia lasting > 48 hours 
• 
Grade ≥ 4 anemia 
• 
Grade ≥ 4 rash (cont’d on next page) 
• 
Grade ≥ 3 symptomatic hepatic toxicities that do not resolve to Grade ≤ 2 within 
48 hours or Grade ≥ 3 asymptomatic hepatic toxicities that do not resolve to Grade ≤ 1 
within 3 weeks of onset with the following exception: 
o For patients with Grade 2 AST, ALT, and/or alkaline phosphatase abnormality at 
enrollment, an increase to > 10 × the upper limit of normal (ULN) that does not 
resolve to Grade ≤ 2 within 48 hours (if symptomatic) or that does not resolve to 
Grade ≤ 1 within 3 weeks of onset (if asymptomatic) will be considered a DLT. 
• 
Grade ≥ 3 non-hematologic, non-hepatic organ toxicity, with the following exceptions: 


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o Grade 3 immune-related adverse event that resolves to Grade ≤ 1 within 3 weeks 
of its onset 
o Grade 3 nausea or vomiting that resolves to Grade ≤ 1 within 72 hours of 
appropriate supportive therapy 
o Grade ≥ 3 fatigue that resolves to Grade ≤ 2 within 7 days 
o Grade 3 arthralgia that can be adequately managed with supportive care or that 
resolves to Grade ≤ 2 within 7 days 
o Grade 3 fever (in the absence of any clinically significant source of fever) that 
resolves to Grade ≤ 2 within 7 days with supportive care 
o Grade ≥ 3 laboratory abnormality that is asymptomatic and deemed by the 
investigator not to be clinically significant 
o Grade 3 autoimmune thyroiditis or other endocrine abnormality that can be 
managed by endocrine therapy or hormonal replacement 
o Grade 3 tumor flare defined as local pain, irritation, or rash localized at sites of 
known or suspected tumor 
o Grade 3 infusion reaction that resolves within 6 hours to Grade ≤ 1 
• 
Inability to receive all 3 doses of entinostat during the first cycle 
In addition, the inability to receive greater than 60% of the planned entinostat dose during the 
first 2 cycles, will also be considered a DLT. 
All DLTs will be reported on the AE eCRF in the EDC system within 24 hours. All DLTs will be 
considered adverse events of special interest for this protocol and will be reported to TRIO in an 
expedited manner. Please see Protocol Section 12.4 and also refer to the Adverse Event 
Reporting Procedures in the Study Manual. 
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 9.10). 
9.7 Maximum Tolerated Dose 
MTD is defined as the highest dose level at which <33% of 6 patients experience DLT. 
 
9.8 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 Dose Determination Phase Investigators. 
Additionally, observations related to immune correlates, and any cumulative toxicity observed 
after multiple cycles may be included in the rationale supporting the RP2D. 


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9.9 Treatment Duration 
The duration of treatment for this study is expected to be 1 year. Patients may remain on study 
until unequivocal progressive disease, unacceptable toxicity, or another treatment withdrawal 
criteria is met per Protocol Section 11. Study patients with evidence of radiological progressive 
disease who meet the criteria set forth in Protocol Section 10.3.2 for “Treatment After Initial 
Radiological Progression”, should continue treatment and be followed according to irRECIST as 
described in section 10.3.2. Any questions should be directed to the Medical Monitor. 
If a patient permanently discontinues either study drug (entinostat/placebo or atezolizumab), the 
patient will be taken off study treatment and followed for progressive disease per protocol 
guidelines, or overall survival should progressive disease have been previously determined on 
study. Patients will receive standard of care outside the auspices of this study at the 
Investigator’s discretion. 
After discontinuation of study treatment, patients will complete an EOT visit within 7 days (+/- 3 
days) after the last study drug dose and a Safety F/U visit 30 days (+/- 3 days) thereafter. 
After completion of the 30-day Safety F/U visit, patients who have not experienced PD are to 
continue to undergo radiological assessments every 6 weeks until study week 36, and then 
every 9 weeks thereafter until progressive disease. The purpose of the post-treatment follow-up 
is to ascertain the duration of PFS for all patients in the study. 
After they experience PD, surviving patients are to be contacted every 3-months for 
documentation of subsequent therapies and survival until closure of the study or patient death, 
whichever should occur first. 
9.10 Dose Interruptions and Modifications 
Although entinostat and atezolizumab have distinct toxicity profiles, they do share some AEs 
such as fatigue and nausea. There is also the possibility that 1 agent may potentiate the other 
and hence drug causality will not always be clear. In the event of uncertainty, dose reductions or 
delays will follow the most conservative approach (i.e., delays and/or dose reductions for both 
drugs) until resolution of the event, or the patient is taken off study. However, if the toxicity is 
clearly associated with only one of the study drugs, then the other study drug may be continued 
at the discretion of the study investigator in consultation with the Medical Monitor, until 
resolution of the event or the patient is taken off study. 


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Note: If a patient permanently discontinues either study drug (entinostat/placebo or 
atezolizumab), the patient will be taken off study treatment 
No dose reductions will be performed for atezolizumab. 
 
Guidance for entinostat delays and or dose reductions can be found in Protocol Section 9.10.1 . 
All dose modifications should be based on the AE requiring the greatest modification and should 
be properly documented in source documents. Investigators may take a more conservative 
approach than the guidelines outlined in the protocol on the basis of clinical judgment that is in 
the best interest of the subject. Such instances should be reported to the Medical Monitor. 
Expected AEs for each agent are summarized in Section 12. 
 
9.10.1 Entinostat 
 
In Phase 1b, dose delays, but not dose reductions will be allowed for entinostat during Cycle 1. 
If a dose reduction is required during Cycle 1, the patient will be taken off study. Dose delays for 
reasons other than toxicities definitely or possibly related to entinostat should be avoided as 
much as possible during Cycle 1. 
In Phase 2, both dose delays and dose reductions will be allowed as described below. Once the 
entinostat dose is reduced, it cannot be re-escalated. 
9.10.1.1 Non-hematologic Toxicity at Least Possibly Related to Entinostat 
The rules outlined in Table 9-1 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. Note: No dose reduction is allowed 
during the first study treatment cycle in phase 1b. 


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1
 
Table 9-1 
Non-hematologic Toxicity: Dose Modifications for Entinostat 
 
Toxicity 
Dose modifications 
 
Grade 4 
Administer symptomatic remedies/ start prophylaxis. 
Hold1 dose P until recovery to Grade 1 or baseline under the following directions. 
1. If recovered within 4 weeks of onset (ie: ≤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, discontinue study treatment 
2. If dose is held for 4 consecutive weeks, permanently discontinue study 
drug. 
Grade 3 
Administer symptomatic remedies/ start prophylaxis. 
Hold1 dose P until recovery to Grade 1 or baseline under the following directions: 
1 
If recovered by next scheduled dose, resume study drug at prior dose. If 
not recovered by next scheduled dose, continue to hold the dose. 
2 
If recovered within 2-4 weeks (i.e. missed 3 or less 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, discontinue study treatment. 
If dose is held for 4 consecutive weeks, permanently discontinue study 
drug. 
Recurrence of the 
same Grade 3 toxicity 
despite dose 
reduction 
Administer symptomatic remedies / start prophylaxis. 
If receiving 2 mg, permanently discontinue study drug. Otherwise, hold1 dose 
until recovery to Grade 1 or baseline. 
1. If recovered within the next 2 scheduled 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 
2. If the same ≥Grade 3 event recurs (i.e., 3 occurrence) despite entinostat 
dose reduction to 2 mg, as described above, discontinue study drug. 
 
 
≤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.1 
• 
If toxicity resolves, resume entinostat at the original dose. 
P 
P 
 If greater than 50% of doses are missed during any 6 week period, discontinue from study drug treatment. 


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9.10.1.2 Hematologic Toxicity at Least Possibly Related to Entinostat 
The guidelines in Table 9-2 will be followed for determining the timing of cycles based on 
hematologic status at the time of planned dosing. Note: No dose reduction is allowed during the 
first study treatment cycle during phase 1b. 
Table 9-2 
Hematologic Toxicity: Dose Modification for Entinostat 
 
ToxicityP 
Dose modifications 
 
≥Grade 3 neutropenia, 
≥Grade 3 uncomplicated 
thrombocytopenia, or 
Grade 2 complicated 
thrombocytopenia 
 
 
 
 
 
 
 
 
Recurrence of the same 
hematologic toxicity 
Administer symptomatic remedies/ start prophylaxis. 
Hold dose1 until recovery to Grade 1 or study baseline using the following 
directions: 
1. If recovered by next scheduled dose, resume study drug at prior dose. If 
not recovered by next scheduled dose, hold the dose. 
2. If recovered within the next 2-4 weeks (i.e. missed 3 or less 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. 
3. If not recovered within 4 weeks (i.e. 4 doses missed), permanently 
discontinue study drug. 
Administer symptomatic remedies/ start prophylaxis. If receiving 2 mg, 
permanently discontinue study drug. Otherwise, hold1 dose until recovery to 
Grade 1 or baseline. 
1. If recovered within the next 2 scheduled 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 
2. If the same ≥Grade 3 event recurs (i.e., third occurrence) despite 
entinostat dose reduction to 2 mg, as described above, discontinue study 
drug. 
 
 
 
1 
If greater than 50% of doses are missed during any 6 week period, discontinue from study drug treatment. 
 
9.10.2 Atezolizumab 
 
There will be no dose reduction for atezolizumab in this study. 
 
Patients may temporarily suspend study treatment for up to 84 days beyond the last dose if they 
experience adverse events that require atezolizumab to be withheld. If atezolizumab is 
withheld because of atezolizumab related adverse events for > 84 days beyond the last dose, 
then the patient will be discontinued from study treatment and will be followed up for safety 
and efficacy per protocol. 


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If, in the judgment of the investigator, the patient is likely to derive clinical benefit from 
atezolizumab after a hold of > 84 days, and entinostat has been administered per protocol 
during this time, study drug may be restarted only with the approval of the Medical Monitor. 
As discussed in Protocol Section 9.12, systemic corticosteroids should be used to treat immune 
mediated toxicities related to atezolizumab. If a patient must be tapered off steroids used to 
treat adverse events, atezolizumab may be held for additional time beyond 84 days from the 
last dose until steroids are discontinued or reduced to prednisone dose (or dose equivalent) 
≤ 10 mg/day. The acceptable length of interruption will depend on an agreement between the 
investigator and the Medical Monitor. 
Dose interruptions for reason(s) other than toxicity, such as surgical procedures, may be 
allowed with Medical Monitor approval. The acceptable length of interruption will depend on 
agreement between the investigator and the Medical Monitor . 
9.11 
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 should 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 9.12. 
No premedication will be allowed for the first dose of atezolizumab. Premedication may be 
administered for subsequent infusions at the discretion of the treating physician after 
consultation with the Medical Monitor. Patients must notify the Investigator of all concomitant 
medications taken through completion of the study (30 day follow-up safety visit). 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing study (Section 9.12). If there is a clinical indication for any medication or 
vaccination specifically prohibited during the study, discontinuation from study drug will be 
required. The Investigator should discuss any questions regarding this with the Medical Monitor. 


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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 patient on study drug requires 
the mutual agreement of the investigator, the Medical Monitor and the patient. 
9.12 Prohibited Medication 
The following medications are excluded while the patient is receiving study treatment: 
• 
Any other HDAC inhibitor, including valproic acid 
• 
DNA methyltransferase inhibitors 
• 
Any additional investigational or commercial anticancer agents, such as chemotherapy, 
immunotherapy, targeted therapy, biological response modifiers, or endocrine therapy, will 
not be allowed, even if utilized as treatment of non-cancer indications. 
• 
Prophylactic use of hematopoietic colony stimulating factors are not allowed during the 
Phase 1b, but can be used per investigator discretion during other parts of the study. 
• 
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 the Medical Monitor. The 
radiation field cannot encompass a target lesion. Radiation to a target lesion is considered 
progressive disease and the subject should be removed from study treatment. The patient 
must have clear measurable disease outside the radiated field. Administration of palliative 
radiation therapy will be considered clinical progression. 
• 
Traditional herbal medicines; these therapies are not fully studied and their use may result in 
unanticipated drug-drug interactions that may cause or confound the assessment of toxicity 
• 
RANKL inhibitor (denosumab): patients who are receiving denosumab prior to 
randomization must be willing and eligible to receive a bisphosphonate instead while on 
study 
• 
Immunomodulatory agents, including but not limited to interferons or IL-2, during the entire 
study; these agents could potentially increase the risk for autoimmune conditions when 
received in combination with atezolizumab 
• 
Immunosuppressive medications, including but not limited to cyclophosphamide, 
azathioprine, methotrexate, and thalidomide; these agents could potentially alter the activity 
and the safety of atezolizumab 
• 
Use of steroids to premedicate patients for whom CT scans with contrast are contraindicated 
(i.e., patients with contrast allergy or impaired renal clearance); in such patients, MRIs of the 
chest, abdomen, and pelvis with a non-contrast CT scan of the chest must be performed 
• 
Any live, attenuated vaccine (e.g., FluMist) while the patient is receiving atezolizumab and 
for a period of 90 days after the discontinuation of atezolizumab 


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Influenza vaccinations (inactivated forms only) should be given during influenza season only 
(approximately October to March in the Northern hemisphere and April to September in the 
Southern Hemisphere). 
Systemic corticosteroids and anti−TNF-α agents may attenuate potential beneficial immunologic 
effects of treatment with atezolizumab. If feasible, alternatives to these agents should be 
considered. Systemic corticosteroids may be administered at the discretion of the treating 
physician in consultation with the Medical Monitor at doses no greater than 10 mg prednisone or 
for no longer than 7 consecutive days if at higher doses, to treat acute conditions other than 
immune-mediated toxicity related to study drug. The use of physiologic doses of corticosteroids 
for prolonged periods may be approved in consultation with the Medical Monitor. Inhaled 
steroids are allowed for management of asthma or other chronic disorders, as prescribed. 
Patients should not receive other immunomodulatory agents for 10 weeks after the last dose of 
atezolizumab. 
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, unless 
as otherwise noted. Patients may receive other medications that the Investigator deems to be 
medically necessary. 
The exclusion criteria (Section 7.2) describe other medications that are prohibited in this study. 
 
9.13 Medications to be Avoided During the Study 
Concomitant use of the drugs below with entinostat should be avoided during the study: 
• 
Sensitive substrates of CYP enzymes listed in Appendix 2 
• 
Drugs that are known to inhibit or induce P-gp (see Appendix 2) 
Should the use of these medications be required, the Medical Monitor must be consulted for 
guidance. 
9.14 Management for Atezolizumab-Specific Adverse Events 
Toxicities associated with, or possibly associated with atezolizumab treatment, should be 
managed according to standard medical practice. Additional tests, such as autoimmune 
serology or biopsies, should be used to determine a possible immunogenic etiology. 
Although most immune-mediated adverse events observed with immunomodulatory agents 
have been mild and self-limiting, such events should be recognized early and treated promptly 


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to avoid potential major complications. Discontinuation of atezolizumab may not have an 
immediate therapeutic effect and, in severe cases, immune-mediated toxicities may require 
acute management with topical corticosteroids, systemic corticosteroids, mycophenolate, or 
TNF-α inhibitors. 
The investigator should consider the benefit-risk balance for a given patient prior to further 
administration of atezolizumab. Atezolizumab should be permanently discontinued in patients 
with life-threatening immune-mediated adverse events. 
For the management of other adverse events associated with the atezolizumab not provided 
below, refer to the Atezolizumab IB. 
 
9.14.1 Pulmonary Events 
 
Dyspnea, cough, fatigue, hypoxia, pneumonitis, and pulmonary infiltrates have been associated 
with the administration of atezolizumab.. Patients will be assessed for pulmonary signs and 
symptoms throughout the study and will also have CT scans of the chest performed at every 
tumor assessment. 


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Continue atezolizumab with close monitoring 
Re-evaluate on serial imaging 
Consider pulmonary consultation 
Withhold atezolizumab for up to 12 weeks after event onset.ª 
Pulmonary and infectious disease specialists consultation and consider 
bronchoscopy or bronchoscopic alveolar lavage (BAL) 
Start treatment with 1−2 mg/kg/day oral prednisone or equivalent 
When improves to Grade 0 or Grade 1, then taper steroids over ≥ 1 
month.Atezolizumab may be resumed if the event improves to Grade 0 or Grade 1 b 
If event does not resolve to Grade 1 or better while withholding atezolizumab, 
permanently discontinue atezolizumab and contact Medical Monitor c 
Treat as Grades 3−4 for recurrent events 
Permanently discontinue atezolizumab and contact Medical Monitor c 
Bronchoscopy/BAL is recommended 
Start treatment with 1-2 mg/kg/day oral prednisone or equivalent 
Taper steroids over ≥ 1 month after symptoms improve to Grade 0 or Grade 1 
If not improving within 48 hoursafter initiating corticosteroids, consider adding an 
immunosuppressive agent 
• 
Grades 3−4 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
Grade 1 
Grade 2 
Management 
Severity 
 
All pulmonary events should be evaluated thoroughly for other commonly reported etiologies 
such as pneumonia/infection, lymphangitic carcinomatosis, pulmonary embolism, heart failure, 
chronic obstructive pulmonary disease, or pulmonary hypertension. by the following means: 
Measurement of oxygen saturation (i.e., arterial blood gas) 
Bronchoscopy with bronchoalveolar lavage and biopsy 
Pulmonary function tests (diffusion capacity of the lung for carbon monoxide [DLCO]) 
Pulmonary function testing with a pulmonary embolism protocol 
Table 9-3 
Management Guidelines for Pulmonary Events, Including Pneumonitis 
 
 
a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event onset) to allow 
for corticosteroids (if started) to be reduced to ≤ 10 mg/day oral prednisone or equivalent. The 
acceptable length of the extended period of time must be agreed upon by the investigator and the 
Medical Monitor. 
b If corticosteroids have been started, they must be tapered over ≥ 1 month to ≤ 10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully 
recovered from the immune-related event. Patients can be re-challenged with atezolizumab only 
after approval has been documented by both the investigator (or an appropriate delegate) and the 
Medical Monitor. 


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9.14.2 Hepatic Events 
 
Immune-mediated hepatitis has been associated with the administration of atezolizumab. 
Eligible patients must have adequate liver function, as manifested by measurements of total 
bilirubin and hepatic transaminases, and liver function will be monitored throughout study 
treatment. 
While in this study, patients who present with right upper-quadrant abdominal pain and/or 
unexplained nausea or vomiting should have liver function tests (LFTs) performed immediately 
and reviewed before administration of the next dose of study drug. 
If LFTs increase, concurrent medications, viral hepatitis, and toxic or neoplastic etiologies 
should be considered and addressed, as appropriateImaging of the liver, gall bladder, and 
biliary tree should be performed to rule out neoplastic or other causes for increased LFTs. 
Anti-nuclear antibody, perinuclear anti-neutrophil cytoplasmic antibody, anti-liver kidney 
microsomal antibodies, and anti−smooth muscle antibody tests should be performed if an 
autoimmune etiology is considered. 


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Table 9-4 
Management Guidelines for Hepatic Events 
Severity 
Management 
Grade 1 
•  Continue atezolizumab 
• Continue LFT monitoring until values resolve to within normal limits 
Grade 2 
All Events: 
• 
Monitor LFTs at least twice a week until return to baseline values 
Events of > 5 days’ duration: 
• 
Withhold atezolizumab for up to 12 weeks after event onset. a 
• 
Initiate treatment with 1−2 mg/kg/day oral prednisone or equivalent. 
• 
If event resolves to Grade 0 or Grade 1, resume atezolizumab b 
• 
If corticosteroids have been started, they must be tapered over ≥ 1 month to 
≤ 10 mg/day oral prednisone or equivalent before atezolizumab can be 
resumed. 
• 
If event does not resolve to Grade 0 or Grade 1 while withholding 
atezolizumab, permanently discontinue atezolizumab and contact Medical 
Monitor c 
• 
If persists > 5−7 days: withhold therapy and start 60 mg prednisone or 
equivalent per day; when LFTs are ≤ Grade 1, taper steroids over ≥ 1 month, 
resume therapy if the event improves to Grade 0 or Grade 1 within 12 weeks 
and systemic steroid dose is ≤ 10mg oral prednisone equivalent per day. 
Grades 3−4 
•  Permanently discontinue atezolizumab and contact Medical Monitor. c 
• Consider gastrointestinal (GI) specialist consult and liver biopsy to establish 
etiology of hepatic injury 
• Start 1-2 mg/kg/day oral prednisone or equivalent 
• If event does not improve within 48 hours after initiation of corticosteroids, 
consider adding an immunosuppressive agent 
• Taper steroids over ≥ 1 month, when symptoms improve to Grade 0 or Grade 1 
a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event onset) to 
allow for corticosteroids (if started) to be reduced to ≤ 10 mg/day oral prednisone or equivalent. 
The acceptable length of the extended period of time must be agreed upon by the investigator 
and the Medical Monitor. 
b If corticosteroids have been started, they must be tapered over ≥ 1 month to ≤ 10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-related event. Patients can be rechallenged with atezolizumab 
only after approval has been documented by both the investigator (or an appropriate delegate) 
and the Medical Monitor. 
 
 
9.14.3 Gastrointestinal Events 
 
Immune-mediated colitis has been associated with the administration of atezolizumab. 


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All events of diarrhea or colitis should be thoroughly evaluated for other more common 
etiologies. If the event is of significant duration or magnitude or is associated with signs of 
systemic inflammation or acute phase reactants (e.g., increased C-reactive protein, platelet 
count, or bandemia), perform sigmoidoscopy (or colonoscopy, if appropriate) with colonic biopsy 
with three to five specimens for standard paraffin block to check for inflammation and 
lymphocytic infiltrates for confirmation of the diagnosis of colitis. 
Perform laboratory tests to rule out alternate etiology (i.e., WBCs and stool calprotectin). 


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Table 9-5 
Management Guidelines for Gastrointestinal Events (Diarrhea/Colitis) 
Severity 
Management 
Grade 1 
•  Continue atezolizumab 
• Symptomatic treatment 
• Endoscopy is recommended if symptoms persist for greater than 7 days 
• Close monitoring 
Grade 2 
• 
Withhold atezolizumab for up to 12 weeks after event onset a 
• Symptomatic treatment 
• GI consultation recommended 
• If persists > 5 days or recurs start oral prednisone 1-2 mg/kg/day or equivalent 
• Taper steroids over ≥ 1 month when symptoms improve to Grade 0 or Grade 1 
• 
may be resumed if the event improves to Grade 0 or Grade 1b 
• If event does not resolve to Grade 0 or Grade 1 while withholding 
atezolizumab, permanently discontinue atezolizumab and contact Medical 
Monitor c 
Grade 3 
• 
Withhold atezolizumab for up to 12 weeks after event onset a 
• GI referral and confirmation biopsy 
• Start treatment with IV steroids 1−2 mg/kg/day methylprednisolone or 
equivalent and convert to 1-2 mg/kg/day oral prednisone or equivalent after 
improvement 
• When improves to Grade 0 or Grade 1, then taper steroids over ≥ 1 month. 
• 
may be resumed if event improves to Grade 0 or Grade 1b 
• If event does not resolve to Grade 1 or better while withholding atezolizumab, 
permanently discontinue atezolizumab and contact Medical Monitor c 
Grade 4 
•  Permanently discontinue atezolizumab and contact Medical Monitor c 
• GI referral and confirmation biopsy 
• Start treatment with IV steroids 1−2 mg/kg/day methylprednisolone or 
equivalent and convert to 1-2 mg/kg/day oral prednisone or equivalent after 
improvement 
• When patient’s diarrhea or colitis improves to Grade 0 or Grade 1, then taper 
steroids over ≥ 1 month 
• If not improving within 48 hours of initiating corticosteroids, consider adding an 
a immunosuppressive agent 
IV = intravenous 
a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event onset) to allow 
for corticosteroids (if initiated) to be reduced to ≤ 10 mg/day oral prednisone or equivalent. The 
acceptable length of the extended period of time must be agreed upon by the investigator and the 
Medical Monitor. 
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to ≤ 10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed.Resumption of atezolizumab may be 
considered in patients who are deriving benefit and have fully 
recovered from the immune-related 
event. Patients can be rechallenged with atezolizumab only after approval has been documented by 
both the investigator (or an appropriate delegate) and the Medical Monitor 


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9.14.4 .Endocrine Events 
 
Thyroid disorders, adrenal insufficiency, diabetes mellitus and pituitary disorders have been 
associated with the administration of atezolizumab. 
Patients with unexplained symptoms such as headache, fatigue, myalgias, impotence, mental 
status changes, or constipation should be investigated for the presence of thyroid, pituitary, or 
adrenal endocrinopathies. An endocrinologist should be consulted if an endocrinopathy is 
suspected. Thyroid-stimulating hormone (TSH) and free triiodothyronine (T3) and thyroxine 
(T4) levels should be obtained to determine whether thyroid abnormalities are present. Pituitary 
hormone levels and function tests (e.g. TSH, growth hormone, luteinizing hormone, follicle- 
stimulating hormone, testosterone, prolactin, adrenocorticotropic hormone [ACTH] levels and 
ACTH stimulation test) and magnetic resonance imaging (MRI) of the brain (with detailed 
pituitary sections) may help to differentiate primary adrenal insufficiency from primary pituitary 
insufficiency. 


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Table 9-6 
Management Guidelines for Endocrine Events 
Severity/Event 
Management 
Asymptomatic 
hypothyroidism 
• 
Continue atezolizumab 
• 
Start thyroid replacement hormone 
• 
Monitor TSH weekly 
• 
Withhold atezolizumab. 
• 
Start thyroid replacement hormone 
• 
Monitor TSH weekly 
• 
Consider referral to an endocrinologist. 
• 
Restart atezolizumab when symptoms are controlled andthyroid function is 
improving 
If serum TSH ≥ 0.1 mU/L and < 0.5mU/L: 
• 
Continue atezolizumab. 
• 
Monitor TSH every 4 weeks 
TSH < 0.1 mU/L: 
Follow guidelines for symptomatic hyperthyroidism 
• 
Withhold atezolizumab 
• 
Initiate treatment with anti-thyroid drug such as methimazole or carbimazole as 
needed 
• 
Consider referral to an endocrinologist 
• 
Restart atezolizumab when symptoms are controlled by thyroid replacement and 
thyroid function is improving 
• 
Permanently discontinue atezolizumab and contact Medical Monitor for 
life-threatening immune-related hyperthyroidism c 
Symptomatic 
hypothyroidism 
Asymptomatic 
hyperthyroidism 
Symptomatic 
hyperthyroidism 
Symptomatic 
• 
Withhold atezolizumab for up to 12 weeks after event onset a 
• 
Refer patient to endocrinologist 
• 
Perform appropriate imaging 
• 
Initiate treatment with 1−2 mg/kg/day IV methylprednisolone or equivalent and 
convert to 1−2 mg/kg/day oral prednisone or equivalent upon improvement 
• 
If event resolves to Grade 0 or Grade 1 and patient is stable on replacement 
therapy, resume atezolizumab b 
• 
If event does not resolve to Grade 0 or Grade 1 or patient is not stable on 
replacement therapy while withholding atezolizumab, permanently discontinue 
atezolizumab and contact Medical Monitor c 
adrenal 
insufficiency, 
Grade 2−4 
Hyperglycemia 
Grade 1 or 2 
• 
Continue atezolizumab 
• 
Start treatment with insulin if needed 
• 
Monitor for glucose control 


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Table 9-6 
Management Guidelines for Endocrine Events 
Hyperglycemia, 
• 
Withhold atezolizumab 
Grade 3 or 4 
• 
Start treatment with insulin 
• 
Monitor for glucose control 
• 
Resume atezolizumab when symptoms resolve and glucose levels are stable 
Hypophysitis 
• 
Withhold atezolizumab for up to 12 weeks after event onset a 
pan- 
• 
Refer patient to endocrinologist 
hypopituitarism), 
• 
Perform brain MRI (pituitary protocol) 
Grade 2-3 
• 
Start treatment with 1−2 mg/kg/day IV methylprednisolone or equivalent and 
convert to 1−2 mg/kg/day oral prednisone or equivalent upon improvement a 
• 
Initiate hormone replacement therapy if clinically indicated 
• 
If event resolves to Grade 0 or Grade 1, resume atezolizumab b 
• 
If event does not resolve to Grade 0 or Grade 1 while withholding 
atezolizumab, permanently discontinue atezolizumab and contact Medical 
Monitor c 
• 
For recurrent hypophysitis, treat as a Grade 4 event 
Hypophysitis 
• 
Permanently discontinue atezolizumab and contact Medical Monitor c 
(pan- 
• 
Refer patient to endocrinologist. 
hypopituitarism), 
Grade 4 
• 
Perform brain MRI (pituitary protocol) 
• 
Start treatment with 1−2 mg/kg/day IV methylprednisolone or equivalent and 
convert to 1−2 mg/kg/day oral prednisone or equivalent upon improvement a 
• 
Initiate hormone replacement therapy if clinically indicated 
IV = intravenous; TSH = thyroid stimulating hormone; MRI = magnetic resonance imaging; 
a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event onset) to allow 
for corticosteroids (if initiated) to be reduced to ≤ 10 mg/day oral prednisone or equivalent. The 
acceptable length of the extended period of time must be agreed upon by the investigator and the 
Medical Monitor. 
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to ≤ 10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed. 
C Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully 
recovered from the immune-related event. Patients can be rechallenged with atezolizumab only after 
approval has been documented by both the investigator (or an appropriate delegate) and the Medical 
Monitor. 
 
 
9.14.5 Ocular Events 
 
An ophthalmologist should evaluate visual complaints (e.g., uveitis, retinal events). 


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• 
Permanently discontinue atezolizumab and contact Medical Monitor c 
• 
Refer patient to ophthalmologist 
• 
Initiate treatment with 1−2 mg/kg/day oral prednisone or equivalent 
• 
If event resolves to Grade 0 or Grade 1, taper corticosteroids over ≥ 1 month 
Grade 3 or 
4 
Continue atezolizumab 
Evaluation by an ophthalmologist is strongly recommended 
Treat with topical corticosteroid eye drops and topical immunosuppressive 
therapy 
If symptoms persist, treat as a Grade 2 event 
Withhold atezolizumab for up to 12 weeks after event onset a 
Patient referral to ophthalmologist is strongly recommended 
Start treatment with topical corticosteroid eye drops and topical 
immunosuppressive therapy 
• 
If event resolves to Grade 0 or Grade 1, resume atezolizumab b 
• 
If event does not resolve to Grade 0 or Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact Medical 
Monitor c 
• 
• 
• 
• 
Grade 2 
• 
• 
• 
Grade 1 
Management 
Severity 
 
Table 9-7 
Management Guidelines for Ocular Events 
 
a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event onset) to allow 
for corticosteroids (if initiated) to be reduced to ≤ 10 mg/day oral prednisone or equivalent. The 
acceptable length of the extended period of time must be agreed upon by the investigator and the 
Medical Monitor. 
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to ≤ 10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully 
recovered from the immune-related event. Patients can be rechallenged with atezolizumab only after 
approval has been documented by both the investigator (or an appropriate delegate) and the Medical 
Monitor. 
 
9.14.6 
Immune-Related Myocarditis 
Immune-related myocarditis has been associated with the administration of atezolizumab. 
Immune-related myocarditis should be suspected in any patient presenting with signs or 
symptoms suggestive of myocarditis, including, but not limited to, dyspnea, chest pain, 
palpitations, fatigue, decreased exercise tolerance, or syncope. Immune-related myocarditis 
needs to be distinguished from myocarditis resulting from infection (commonly viral, e.g. in a 
patient who reports a recent history of gastrointestinal illness), ischemic events, underlying 
arrhythmias, exacerbation of pre-existing cardiac conditions, or progression of malignancy. 


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All patients with possible myocarditis should be urgently evaluated by performing cardiac 
enzyme assessment, an ECG, a chest X-ray, an echocardiogram, and a cardiac MRI as 
appropriate per institutional guidelines. A cardiologist should be consulted. An endomyocardial 
biopsy may be considered to enable a definitive diagnosis and appropriate treatment, if clinically 
indicated. 


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Table 9-8 
Management Guidelines for Immune-Related Myocarditis 
 
Severity 
Management 
Grade 1 
• 
Refer patient to cardiologist 
• 
Start treatment as per institutional guidelines 
Grade 2 
• 
Withhold atezolizumab for up to 12 weeks after event onset a 
and contact Medical Monitor 
• 
Refer patient to cardiologist 
• 
Initiate treatment as per institutional guidelines and consider 
antiarrhythmic drugs, temporary pacemaker, ECMO, or VAD as 
appropriate 
• 
Consider treatment with 1−2 mg/kg/day IV methylprednisolone 
or equivalent and convert to 1−2 mg/kg/day oral prednisone or 
equivalent upon improvement a 
• 
If event resolves to Grade 0 or Grade 1, resume atezolizumab b 
• 
If event does not resolve to Grade 0 or Grade 1 while 
withholding atezolizumab, permanently discontinue 
atezolizumab and contact Medical Monitor c 
Grade 3-4 
• 
Permanently discontinue atezolizumab and contact Medical 
Monitor c 
• 
Refer patient to cardiologist 
• 
Initiate treatment as per institutional guidelines and consider 
antiarrhythmic drugs, temporary pacemaker, ECMO, or VAD as 
appropriate 
• 
Initiate treatment with 1−2 mg/kg/day IV methylprednisolone or 
equivalent and convert to 1−2 mg/kg/day oral prednisone or 
equivalent upon improvement a,b 
• 
If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent 
• 
If event resolves to Grade 0 or Grade 1, taper corticosteroids 
over ≥ 1 month 
ECMO = extracorporeal membrane oxygenation; VAD = ventricular assist device; 
IV = intravenous. 
a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event onset) to 
allow for corticosteroids (if initiated) to be reduced to ≤ 10 mg/day oral prednisone or equivalent. 
The acceptable length of the extended period of time must be agreed upon by the investigator 
and the Medical Monitor. 
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to ≤ 10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-related event. Patients can be rechallenged with atezolizumab 
only after approval has been documented by both the investigator (or an appropriate delegate) 
and the Medical Monitor. 


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9.14.7 Pancreatic Events 
 
Symptoms of abdominal pain associated with elevations of amylase and lipase, suggestive of 
pancreatitis, have been associated with the administration of other immuno-modulatory agents. 
The differential diagnosis of acute abdominal pain should include pancreatitis. Appropriate 
work-up should include an evaluation for ductal obstruction, as well as serum amylase and 
lipase tests. 


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Table 9-9 
Management Guidelines for Pancreatitis 
 
Pancreatic 
Event 
Severity 
Management 
Amylase and 
/or lipase 
elevation 
Grade 2 
Grades 3 and 4 
Grade 2 or 3 
• 
Continue atezolizumab 
• 
Monitor amylase/lipase weekly 
• 
Consider oral prednisone 10 mg daily or equivalent for prolonged 
elevation (e.g., more than 3 weeks) 
• 
Withhold atezolizumab for up to 12 weeks after event onset a 
• 
Consult a gastroenterologist 
• 
Monitor amylase/lipase every other day 
• 
Consider oral prednisone 1-2 mg/kg/day or equivalent if no 
improvement 
• 
Atezolizumab may be resumed if the event resolves to Grade 0 or 
Grade 1 b 
• 
If event does not resolve to Grade 0 or Grade 1 while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor c 
• 
Permanently discontinue atezolizumab for recurrent events and 
notify the Medical Monitor c 
• 
Withhold atezolizumab for up to 12 weeks after event onset a 
• 
Consult a gastroenterologist 
• 
Start treatment with 1-2 mg/kg/day IV methylprednisone or 
equivalent and convert to 1-2 mg/kg/day oral prednisone or 
equivalent when symptoms improve 
• 
Atezolizumab may be resumed if the event improves to Grade 0 or 
Grade 1 If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue atezolizumab 
and contact Medical Monitor c 
• 
Permanently discontinue atezolizumab for recurrent events and 
notify the Medical Monitor c 
Amylase and 
/or lipase 
elevation 
Immune- 
related 
pancreatitis 
Immune- 
related 
pancreatitis 
Grade 4 
• 
Permanently discontinue atezolizumab and contact Medical 
Monitor c 
• 
Refer patient to gastrointestinal specialist 
• 
Start treatment with 1−2 mg/kg/day IV methylprednisolone or 
equivalent and convert to 1−2 mg/kg/day oral prednisone or 
equivalent upon improvement 
• 
If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent 
• 
If event resolves to Grade 0 or Grade 1, taper corticosteroids 
over ≥ 1 month. 
IV = intravenous; 
a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to ≤ 10 mg/day oral 
prednisone or equivalent. The acceptable length of the extended period of time must 
be agreed upon by the investigator and the Medical Monitor. 


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b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to ≤ 10 
mg/day oral prednisone or equivalent before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-related event. Patients can be rechallenged 
with atezolizumab only after approval has been documented by both the investigator (or 
an appropriate delegate) and the Medical Monitor. 


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Reduce infusion rate to half the rate being given at the time of event onset 
After the event has resolved, the investigator should wait for 30 minutes while 
delivering the infusion at the reduced rate 
If tolerated, the infusion rate may then be increased to the original rate 
Interrupt atezolizumab infusion 
Administer aggressive symptomatic treatment (e.g., oral or IV antihistamine, 
anti-pyretic, glucocorticoids, epinephrine, bronchodilators, oxygen) 
After symptoms have resolved to baseline, resume infusion at half the rate 
being given at the time of event onset 
o For subsequent infusions, consider administration of oral 
premedication with antihistamine, anti-pyretics, and/or analgesics 
and monitor closely for IRRs 
Stop infusion 
Administer aggressive symptomatic treatment (e.g., oral or IV antihistamine, 
anti-pyretic, glucocorticoids, epinephrine, bronchodilators, oxygen) 
• 
Permanently discontinue atezolizumab and contact Medical Monitor a 
Grades 3−4 
• 
• 
• 
• 
• 
• 
Grade 2 
• 
• 
Grade 1 
Management 
Severity 
 
9.14.8 Infusion-Related Events 
 
No premedication is indicated for the administration of atezolizumab in Cycle 1. Patients who 
experience an infusion-related reaction with Cycle 1 of atezolizumab may receive premedication 
with antihistamines or antipyretics/analgesics (e.g., acetaminophen) for subsequent infusions. 
Metamizole (dipyrone) is prohibited in treating atezolizumab associated infusion-related 
reactions, due to its potential for causing agranulocytosis. 
 
 
Table 9-10 
Management Guidelines for Infusion-Related Reactions 
 
IRR = infusion-related reactions; IV = intravenous. 
a Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully 
recovered from the immune-related event. Patients can be rechallenged with atezolizumab only after 
approval has been documented by both the investigator (or an appropriate delegate) and the Medical 
Monitor. 
Table 9-11 
Management Guidelines for Pancreatitis 
 
Pancreatic 
Event 
Severity 
Management 
Amylase and 
/or lipase 
elevation 
Grade 2 
• 
Continue atezolizumab 
• 
Monitor amylase/lipase weekly 
• 
Consider oral prednisone 10 mg daily or equivalent for prolonged 
elevation (e.g., more than 3 weeks) 


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Amylase and 
Grades 3 and 4 
Grade 2 or 3 
• 
Withhold atezolizumab for up to 12 weeks after event onset a 
• 
Consult a gastroenterologist 
• 
Monitor amylase/lipase every other day 
• 
Consider oral prednisone 1-2 mg/kg/day or equivalent if no 
improvement 
• 
When lab abnormalities return to Grade 0 or Grade 1, then taper 
steroids over ≥ 1 monthAtezolizumab may be resumed if the event 
resolves to Grade 0 or Grade 1 b 
• 
If event does not resolve to Grade 0 or Grade 1 while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor c 
• 
Permanently discontinue atezolizumab for recurrent events and 
notify the Medical Monitor c 
• 
Withhold atezolizumab for up to 12 weeks after event onset a 
• 
Consult a gastroenterologist 
• 
Start treatment with 1-2 mg/kg/day IV methylprednisone or 
equivalent and convert to 1-2 mg/kg/day oral prednisone or 
equivalent when symptoms improve 
• 
Atezolizumab may be resumed if the event improves to Grade 0 or 
Grade 1 If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue atezolizumab 
and contact Medical Monitor c 
• 
Permanently discontinue atezolizumab for recurrent events and 
notify the Medical Monitor c 
/or lipase 
elevation 
Immune- 
related 
pancreatitis 
Immune- 
related 
pancreatitis 
Grade 4 
• 
Permanently discontinue atezolizumab and contact Medical 
Monitor c 
• 
Refer patient to gastrointestinal specialist 
• 
Start treatment with 1−2 mg/kg/day IV methylprednisolone or 
equivalent and convert to 1−2 mg/kg/day oral prednisone or 
equivalent upon improvement 
• 
If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent 
• 
If event resolves to Grade 0 or Grade 1, taper corticosteroids 
over ≥ 1 month. 
IV = intravenous; 
a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to ≤ 10 mg/day oral 
prednisone or equivalent. The acceptable length of the extended period of time must 
be agreed upon by the investigator and the Medical Monitor. 
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to ≤ 10 
mg/day oral prednisone or equivalent before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-related event. Patients can be rechallenged 
with atezolizumab only after approval has been documented by both the investigator (or 
an appropriate delegate) and the Medical Monitor. 


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Continue atezolizumab 
Consider topical corticosteroids and/or other symptomatic therapy (e.g., 
antihistamines) 
Continue atezolizumab 
Consider dermatologist referral 
Administer topical corticosteroids 
Consider higher potency topical corticosteroids if event does not improve 
Withhold atezolizumab for up to 12 weeks after event onset a 
Consult a dermatologist 
Start treatment with oral prednisone 10 mg/day or equivalent. If event 
unresolved after 48−72 hours, administer oral prednisone 1-2 mg/kg/day or 
equivalent 
Restart atezolizumab if event resolves to Grade 0 or Grade 1 b 
If event does not resolve to Grade 0 or Grade 1 while withholding atezolizumab, 
permanently discontinue atezolizumab and contact Medical Monitor c 
Grade 4 
• 
Permanently discontinue atezolizumab and contact Medical Monitor c 
• 
• 
• 
• 
• 
• 
• 
• 
• 
Grade 3 
Grade 1 
• 
• 
Grade 2 
Management 
Severity 
 
 
9.14.9 Dermatologic Events 
 
Treatment-emergent rash has been associated with atezolizumab. The majority of cases of 
rash were mild in severity and self-limited, with or without pruritus. A dermatologist should 
evaluate persistent and/or severe rash or pruritus. A biopsy should be considered unless 
contraindicated. 
Table 9-12 
Management Guidelines for Immune-Mediated Dermatologic Events 
 
a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event onset) to allow 
for corticosteroids (if initiated) to be reduced to ≤ 10 mg/day oral prednisone or equivalent. The 
acceptable length of the extended period of time must be agreed upon by the investigator and the 
Medical Monitor. 
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to ≤ 10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed. 
C Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully 
recovered from the immune-related event. Patients can be rechallenged with atezolizumab only after 
approval has been documented by both the investigator (or an appropriate delegate) and the Medical 
Monitor. 
 
9.14.10 Neurological Disorders 
 
Myasthenia gravis and Guillain-Barré syndrome have been observed with single agent 
atezolizumab. Patients may present with signs and symptoms of sensory and/or motor 


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neuropathy. Diagnostic work-up is essential for an accurate characterization to differentiate 
between alternate etiologies. 
Table 9-13 
Management Guidelines for Neurologic Disorders 
 
Neurologic 
Disorder 
Severity 
Management 
Myasthenia 
Gravis and 
Guillain-Barré 
syndrome 
All grades 
• 
Permanently discontinue atezolizumab and contact the 
Medical Monitor c 
• 
Refer patient to a neurologist 
• 
Start treatment as per institutional guidelines 
Consider initiation of 1-2 mg/kg/day oral of IV prednisone or 
equivalent 
Immune- 
Grade 1 
• 
Continue atezolizumab. 
• 
Investigate etiology 
• 
Withhold atezolizumab for up to 12 weeks after event 
onset a 
• 
Investigate etiology 
• 
Treatment should be as per institutional guidelines 
• 
If event resolves to Grade 0 or Grade 1, resume 
atezolizumab b 
• 
If event does not resolve to Grade 0 or Grade 1 while 
withholding atezolizumab, permanently discontinue 
atezolizumab and contact Medical Monitor c 
• 
Permanently discontinue atezolizumab and contact the 
Medical Monitor c 
• 
Start treatment as per institutional guidelines 
• 
related 
neuropathy 
Immune- 
related 
neuropathy 
Grade 2 
Immune- 
related 
neuropathy 
Grades 3−4 
IV = intravenous 


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a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event onset) to allow 
for corticosteroids (if initiated) to be reduced to ≤ 10 mg/day oral prednisone or equivalent. The 
acceptable length of the extended period of time must be agreed upon by the investigator and the 
Medical Monitor. 
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to ≤ 10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully 
recovered from the immune-related event. Patients can be rechallenged with atezolizumab only after 
approval has been documented by both the investigator (or an appropriate delegate) and the Medical 
Monitor. 
9.14.11 
Immune-Related Meningoencephalitis 
Immune-related meningoencephalitis is an identified risk associated with the administration of 
atezolizumab. Immune-related meningoencephalitis should be suspected in any patient 
presenting with signs or symptoms suggestive of meningitis or encephalitis, including, but not 
limited to, headache, neck pain, confusion, seizure, motor or sensory dysfunction, and altered or 
depressed level of consciousness. Encephalopathy from metabolic or electrolyte imbalances 
needs to be distinguished from potential meningoencephalitis resulting from infection (bacterial, 
viral, or fungal) or progression of malignancy, or secondary to a paraneoplastic process. 
All patients being considered for meningoencephalitis should be urgently evaluated with a CT 
scan and/or MRI scan of the brain to evaluate for metastasis, inflammation, or edema. If 
deemed safe by the treating physician, a lumbar puncture should be performed and a 
neurologist should be consulted. Patients with signs and symptoms of meningoencephalitis, in 
the absence of an identified alternate etiology, should be treated according to the guidelines in 
Table 9-13. 


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Table 9-14 
Management Guidelines for Immune-Related Meningoencephalitis 
 
Event 
Management 
Immune-related 
meningoencephalitis, 
all grades 
• 
Permanently discontinue atezolizumab and contact 
Medical Monitor a 
• 
Refer patient to neurologist 
• 
Initiate treatment with 1−2 mg/kg/day IV 
methylprednisolone or equivalent and convert to 
1−2 mg/kg/day oral prednisone or equivalent upon 
improvement 
• 
If event does not improve within 48 hours after 
initiating corticosteroids, consider adding an 
immunosuppressive agent 
• 
If event resolves to Grade 1 or better, taper 
corticosteroids over ≥ 1 month 
IV = intravenous. 
a Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-related event. Patients can be 
rechallenged with atezolizumab only after approval has been documented by both 
the investigator (or an appropriate delegate) and the Medical Monitor. 
 
 
 
9.14.12 Systemic Immune Activation 
 
Systemic immune activation (SIA) is a rare condition characterized by an excessive immune 
response. Given the mechanism of action of atezolizumab, SIA is considered a potential 
risk when given in combination with other immunomodulating agents. SIA should be included in 
the differential diagnosis for patients who, in the absence of an alternative etiology, develop a 
sepsis-like syndrome after administration of atezolizumab, and the initial evaluation should 
include the following: 
• 
CBC with peripheral smear 
• 
PT, PTT, fibrinogen, and D-dimer 
• 
Ferritin 
• 
Triglycerides 
• 
AST, ALT, and total bilirubin 
• 
LDH 
• 
Complete neurologic and abdominal examination (assess for 
hepatosplenomegaly) 


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9.15 Diet/Activity/Other Considerations 
 
9.15.1 Diet 
 
Patients should maintain a normal diet unless modifications are required to manage an AE such 
as diarrhea, nausea, or vomiting. 
 
9.15.2 Contraception 
 
Women of childbearing potential must agreement to remain abstinent (refrain from heterosexual 
intercourse) or use 2 contraceptive methods that result in a failure rate of < 1% per year during 
the treatment period and for at least 120 days after the last dose of study treatment. 
A woman is considered to be of childbearing potential if she is between menarche and 
menopause and has not been permanently or surgically sterilized and is capable of procreation. 
Permanent sterilization includes hysterectomy and/or bilateral oophorectomy and/or bilateral 
salpingectomy but excludes bilateral tubal occlusion. This definition also includes women who 
have experienced menopause onset < 12 months prior to enrollment. 
Examples of single contraceptive methods with a failure rate of < 1% per year include bilateral 
tubal ligation, male sterilization, and copper intrauterine devices. 
The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical 
trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, 
ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable 
methods of contraception. 
Patients should be informed that taking the study dug may involve unknown risks to the fetus 
(unborn baby) if pregnancy were to occur during the study. In order to participate in the study 
they must adhere to the contraception requirement (described above) for the duration of the 
study and for at least 120 days after the last dose of study treatment. 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. 
 
9.15.3 Study Drug Use in Pregnancy 
 
If a patient inadvertently becomes pregnant while on study drug, the patient will immediately be 
removed from study treatment. The site will contact the patient at least monthly and document 


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the patient’s status until the pregnancy has been completed or terminated. The outcome of the 
pregnancy will be reported to TRIO 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. See Section 12.4.1 for information regarding reporting a pregnancy. 
 
9.15.4 Study Drug Use in Nursing Women 
 
It is unknown whether study drug is excreted in human milk. Since many drugs are secreted 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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10. STUDY TESTS AND OBSERVATIONS 
 
After provision of written informed consent, patients will be screened for study eligibility within 
21 days before study enrollment. Patients who are determined to be eligible based on screening 
assessments and who are enrolled, must begin treatment (C1D1) with entinostat/placebo in 
combination with atezolizumab within 3 business days of the date of 
enrollment/randomization. 
A cycle is 21 days in length. Patients will attend study center visits and undergo study 
evaluations on C1D1, C1D8, and C1D15; D1 and D15 of C2; and on D1 of each cycle 
thereafter. 
Patients will have radiological disease assessments during screening and then during treatment 
and follow-up every 6 weeks (+/-3 days) (Week 6, Week 12, etc.) through week 36 and then 
every 9 weeks (+/- 3 days) thereafter until unequivocal progressive disease. This schedule is to 
be followed both during study treatment and following discontinuation of study treatment in the 
absence of progressive disease. 
After discontinuation of study treatment, patients will complete an EOT visit within 7 days (+/- 3 
days) after the last study drug dose and a Safety Follow-up visit 30 days (+/- 3 days) thereafter. 
After completion of the 30-day Safety F/U visit, patients who have not experienced PD are to 
continue to undergo radiological assessments every 6 weeks through week 36 and then every 9 
weeks thereafter until unequivocal progressive disease. The purpose of the post-treatment 
follow-up is to ascertain the duration of PFS for all patients in the study. After progressive 
disease, surviving patients are to be followed every 3-months for documentation of subsequent 
therapy and survival until closure of the study or death. 
Protocol-required tests, observations, and procedures are summarized in Table 1-1. 


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10.1 Screening Assessments 
All patients must provide written informed consent before the performance of any study-related 
procedures. 
 
10.1.1 Demographics 
 
Patient demographics, including age, race, and ethnicity, are to be documented during 
screening. 
 
10.1.2 Medical History 
 
A complete medical history is to be documented during screening and updated prior to 
administration of the first study drug dose. 
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. It should also include any medical condition that might complicate the patient’s 
disease or affect the treatment outcome. 
 
10.1.3 Pregnancy Testing 
 
For females of child-bearing potential, a serum pregnancy test is required and must be 
performed during screening and a urine test within 3 days before the first study drug dose if the 
serum test is performed more than 3 days before 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. 
10.2 Safety Assessments 
 
10.2.1 Physical Examination 
 
A complete physical examination will be conducted for all patients during screening; at 
enrollment; and at the EOT (within 7 days post-last dose) and Safety F/U (30 days (+/-3 days) 
thereafter) visits. If the screening complete physical examination was performed within 7 days of 
enrollment, then a symptom-directed physical examination may be performed at C1D1. 
Symptom-directed physical examinations will be performed for all patients on D1, D8, and D15 
of C1; D1 and D15 of C2; and on D1 of each subsequent cycle. 


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10.2.2 Electrocardiograms 
 
All patients will undergo a 12-lead ECG during screening; pre-dose (i.e., before entinostat and 
atezolizumab) on C3D1, and then every 3 cycles thereafter. A 12-lead ECG also is to be 
repeated as clinically indicated during treatment and again at the EOT visit (within 7 days post- 
last dose). 
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. 
 
10.2.3 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, 
on D1 of each treatment cycle, at the EOT (7 days post-last dose) and the Safety F/U 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. Height will be collected at the screening visit only. 
 
10.2.4 Weight 
 
Weight is to be measured during screening, on D1 of each treatment cycle, at the EOT and the 
Safety F/U visits. 
 
10.2.5 ECOG Performance Status 
 
ECOG performance status is to be assessed during screening, on D1 of each treatment cycle, 
and at the EOT and Safety F/U visits. It should also be measured if there is any indication of 
fluid retention. 
The ECOG performance status scale, with corresponding Karnofsky performance status score 
equivalents, is presented in Table 10-1. 


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Table 10-1 
Eastern Cooperative Oncology Group Performance Status Scale, with 
Equivalent Karnofsky Performance Status Scores 
 
ECOG1 
Karnofsky2 
Score 
Criterion 
% 
Criterion 
0 
Normal activity 
100 
90 
80 
70 
60 
50 
40 
30 
20 
10 
0 
Normal; no complaints; no evidence of 
disease 
Able to carry on normal activity; minor 
signs or symptoms of disease 
Normal activity with effort; some signs 
or symptoms of disease 
Cares for self; unable to carry on 
normal activity or do active work 
Requires occasional assistance but is 
able to care for most of his/her needs 
Requires considerable assistance and 
frequent medical care 
Disabled, requires special care and 
assistance 
Severely disabled; hospitalization is 
indicated though death is not 
imminent 
Very sick; hospitalization is necessary 
Moribund; fatal processes progressing 
rapidly 
Dead 
1 
Symptoms but ambulatory 
2 
In bed <50% of time 
3 
In bed >50% of time 
4 
100% bedridden 
5 
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. 
 
10.2.6 Clinical Laboratory Tests 
 
Blood samples for hematology and clinical chemistries are to be collected during screening, 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. If screening hematology and clinical chemistry tests are performed within 7 days 
of enrollment, they need not be repeated at C1D1 unless clinically indicated. 


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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 
Coagulation studies, including PT or INR and 
aPTT (screening only) 
 
Clinical Chemistries 
 
ALT 
AST 
 
Alkaline phosphatase 
Albumin 
 
Total bilirubin 
Blood urea nitrogen (BUN) 
 
Calcium 
Creatinine 
 
Sodium 
Potassium 
 
Chloride 
Bicarbonate 
 
Glucose 
Lactic dehydrogenase 
 
Phosphorus 
Total Protein 
 
Uric acid 
Magnesium and TSH (screening only, unless 
clinically indicated) 
 
In addition to the scheduled assessments, 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. 
 
10.2.7 Adverse Events 
 
AEs, as defined in Section 12.2.1, are to be documented from the time of informed consent 
through 30 days post-last dose, with the exception of AESIs with atezolizumab, which must be 


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documented through 90 days following cessation of treatment, or 30 days after the initiation of a 
new anticancer therapy, whichever is earlier. 
10.3 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 RECIST 1.1 and irRECIST 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. 
Post-screening scans and the corresponding overall tumor assessment (according to RECIST 
and irRECIST) should be done at the next visit after the scans are performed and prior to 
indicating the subsequent cycle, to rule out progressive disease that would warrant study 
treatment discontinuation. 
 
10.3.1 Tumor Measurements and Disease Response Assessment 
 
10.3.1.1 Tumor Measurement and Assessment 
Initial tumor imaging at screening must be performed within 28 days prior to initial study drug 
dosing (C1D1). (Scans performed as part of routine clinical management are acceptable for use 
as initial tumor imaging if they are of diagnostic quality and 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 through week 36 or until progressive disease. If progressive disease has not 


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occurred by week 36, radiological assessments will be then be done every 9 weeks (+/-3 days) 
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 RECIST 1.1 and irRECIST. 
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 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 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 Lesions 
 
Non-measurable lesions are defined per RECIST 1.1 as the following and should be captured 
and followed accordingly and within the eCRF according the eCRF guidelines. 
• 
Masses < 10 mm 
• 
Lymph nodes ≥10 to <15 mm in short axis 
• 
Leptomeningeal disease 
• 
Ascites, pleural or pericardial effusion 
• 
Inflammatory breast disease (cont’d on next page) 
• 
Lymphangitic involvement of skin or lung 


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• 
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 sum of the longest 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. 
10.3.1.2 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. The imaging 
modality used at screening should continue for all images during study participation, unless 
clinically contra-indicated. 
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. 
10.3.1.3 Disease Response Assessment Criteria 
Patients will have radiological disease assessments performed every 6 weeks (+/-3 days) 
(Week 6, Week 12, etc.) during study treatment through week 36 or until unequivocal 
progressive disease. If progressive disease has not occurred by week 36, radiological 
assessments will be then be done every 9 weeks (+/-3 days) until unequivocal progressive 
disease. Images should be kept to the calendar schedule and not be delayed for missed study 
drug administration. 
Partial or complete response should be confirmed by a repeat tumor imaging assessment not 
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 if on a 6 week schedule, whichever is clinically 
indicated. 
In subjects who discontinue study therapy without documented unequivocal progressive 
disease, every effort should be made to continue monitoring their disease status by tumor 
imaging every 6 weeks until (1) unequivocal progressive disease (2) death, or (3) the end of the 
study, whichever occurs first. All scans will be submitted (electronically whenever possible) to a 
central core radiologic laboratory within 3 days of being performed, where they will immediately 
be reviewed for readability. The lab will contact the site should any issues or questions arise. 
Disease progression is determined locally, not by the central core radiologic lab. 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 The lab will collect and 
hold all scans should the sponsor decide to have them read to confirm PFS outcomes. 
Scans from non-responders may also be reviewed by the core radiologic laboratory at the 
direction of the Sponsor. 


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10.3.2 Treatment after Initial Radiologic Progression 
 
Immune related RECIST (irRECIST) (Appendix 4) will be utilized to account for the unique 
tumor response characteristics seen with atezolizumab treatment. Immunotherapeutic agents 
such as atezolizumab 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 a first radiological evidence of progressive disease, should continue on study 
treatment, at the discretion of the investigator, until confirmed progressive disease is 
determined per irRECIST in a subsequent scan. Therefore, the following process for assessing 
radiological progressive disease will be used in this study: 
1. If radiologic imaging demonstrates initial evidence for PD, tumor assessment should be 
repeated at the earliest of 4 weeks, or preferably on the study schedule of 6 weeks, in 
order 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. 
2. Specifically, it is recommended that patients continue to receive study drug while waiting 
for confirmation of PD if they are clinically stable as defined by: 
• 
Absence of signs and symptoms indicating PD. 
• 
No decline in ECOG performance status. 
• 
Absence of rapid PD. 
• 
Absence of progressive tumor at critical anatomical sites (e.g., cord compression) 
requiring urgent alternative medical intervention. 
As per irRECIST, if repeat imaging does not show irPD, then PD by irRECIST will not have 
been confirmed and treatment may be continued. If repeat imaging confirms irPD, PD will have 
been confirmed and the patient will be discontinued from study treatment. 


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Table 10-2 
Imaging and Treatment After 1st Radiologic Evidence of PD 
 
Clinically Stable 
Clinically Unstable 
Imaging 
Treatment 
Imaging 
Treatment 
1st radiologic 
Repeat imaging at 
May continue 
Repeat imaging at 
Discontinue 
evidence of PD 
next scheduled 
study drug at the 
next scheduled 
treatment 
time point to 
Investigator’s 
time point to 
confirm PD 
discretion while 
confirm PD per 
awaiting 
physician 
confirmatory scan 
discretion only 
by site 
Repeat scan 
confirms irPD 
No additional 
imaging required 
Discontinue 
treatment 
No additional 
imaging required 
N/A 
Repeat scan 
Continue regularly 
Continue study 
Continue regularly 
May restart study 
shows SD, PR or 
scheduled 
drug at the 
scheduled 
drug if condition 
CR (per 
imaging 
Investigator’s 
imaging 
has improved 
irRECIST) 
assessments 
discretion 
assessments 
and/or clinically 
stable per 
Investigator’s 
discretion 
NOTE: If a subject has confirmed radiographic progression (i.e. 2 scans at least 4 weeks apart 
demonstrating progressive disease), but the subject 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 Medical 
Monitor. In this case, if treatment is continued, tumor imaging should continue to be performed 
following the study required intervals per Table 1-1. 
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. 
 
 
10.4 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 PD1 or PDL1 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. 
 
10.4.1 Blood 
 
Thirty (30) mL of blood for immune correlates is to be collected pre-dose on C1D1, C2D1, 
C2D15, C3D1 and at EOT for analysis at the Wistar Institute. Five (5) mL of blood will be 
collected pre-dose on C1D1, C2D1, C2D15 and at EOT for immune correlate analysis at 


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Serametrix Laboratory. Blood is to be collected and prepared according to the instructions 
provided in the Laboratory Study Manual. 
Sixteen (16) mL of blood for protein lysine acetylation is to be collected pre-dose on C1D1 and 
C1D15, for analysis at the National Cancer Institute in the United States. 
The following are immune correlate analyses that may be performed on the collected samples: 
 
• 
MDSCs, PNM-MDSCs, Monocytes, DCs, Neutrophils, B cells 
• 
Protein lysine acetylation in PBMCs 
• 
Peripheral T-cell activation and Treg panels, Proliferation (Ki-67) 
• 
Functional/proliferation assay with PBMCs using CD3/CD28, ConA and tetanus toxoid 
• 
Plasma analysis for chemokine/cytokines (IL18, CXCL10, CXCL9, IL6, CRP) 
• 
Antibody to tumor Antigen using peptide array 
• 
Whole exome sequencing for Germline identification 
Refer to the Study Laboratory Manuals for Covance and Serametix for instructions on sample 
collection and shipment. 
 
10.4.2 Tumor Tissue 
 
Fresh tumor tissue core biopsy 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 Determination 
Phase. Patients will be encouraged to provide an optional biopsy in order to help 
understand dose-immune correlate effects. 
• 
On C2D15 (+/-3 days) on a mandatory basis until 20 samples are obtained in the 
Phase 2 portion of the study and on an optional basis for subsequent patients in this 
Phase 2 Expansion. 
• 
At the time of progressive disease on an optional basis for all patients 
• 
At the end of study treatment prior to the start of another systemic therapy, on an 
optional basis for all patients 
Note: Archival tissue should also be collected at time of screening when available. 
If, based on an interim review of tumor tissue data from the initial patients in Phase 2, such data 
are considered informative, then tumor tissue samples will be collected on a mandatory basis 
from all subsequent patients in the study. Alternatively, if such data are not considered 
informative, these samples will not be collected from subsequent patients. 


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Tissue samples will be sent to a central laboratory facility for preparation and distribution to 
other central laboratories for analysis. In addition to protein lysine acetylation testing, pre and 
post treatment tissue samples will also be analyzed for the following: 
• 
PD-L1 expression level 
• 
MDSCs – CD33+, S100A9+ 
• 
Macrophage – CD163+ or CD68+ 
• 
Neutrophil – Neutrophil elastase+ 
• 
CD8/Ki-76 
• 
Dendritic cells – DC-SIGN (CD209) 
• 
MHC class I 
• 
FoxP3, CD4, CD8, granzyme B positive cells 
• 
Gene expression – nanostring 
• 
Whole exome sequencing and RNAseq 
Refer to the Study Laboratory Manual for instructions on sample collection and shipment. 
 
 
10.5 Pharmacokinetics 
 
10.5.1 Entinostat 
 
Blood samples for determination of entinostat levels will be collected at the following time points: 
 
• 
Pre-dose C1D1 
• 
2-4 hours post dose C1D1 (1 sample) 
• 
C1D8 (1 sample, anytime post dose) 
• 
C1D15 (1 sample, anytime post dose) 
• 
Pre-dose C2D1 
On each sample collection day, the time and date of entinostat administration, the start and stop 
time of atezolizumab administration, and the time and date of PK sample collection should be 
recorded in the eCRF. 
Refer to the Study Laboratory Manual for instructions on sample collection and shipment. 


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10.5.2 Atezolizumab 
 
Blood samples for determination of atezolizumab levels and anti-atezolizumab antibodies will be 
collected at the following time points: 
• 
Pre-dose on C1D1 
• 
C1D1 30 minutes (+/- 10 minutes) post infusion (for atezolizumab level only) 
• 
Pre-dose on C2D1 
• 
Pre-dose on C4D1. 
• 
End of Treatment 
• 
Day 120 after coming off study treatment if patient is still being followed as per the 
protocol. 
On each sample collection day, the time and date of entinostat administration, the start and stop 
time of atezolizumab administration, and the time and date of sample collection should be 
recorded in the eCRF. 
Refer to the Study Laboratory Manual for instructions on sample collection and shipment. 
 
10.6 TRegs and Ki67 
Six (6) mL of blood will be collected from all study patients in the United States for analysis of T 
regulatory cells and cell proliferation pre-dose on C1D1, C2D1, C3D1 and EOT. 
 
Refer to the Study Laboratory Manual for instructions on sample collection and shipment. 
 
10.7 Atezolizumab Plasma Biomarker 
Six (6) mL of blood will be collected from all study patients for analysis of plasma biomarkers 
pre-dose on C1D1, C2D1, C2D15, C3D1 and EOT. 
Refer to the Study Laboratory Manual for instructions on sample collection and shipment. 
 
10.8 Atezolizumab Serum Biomarker 
Three and one-half (3.5) mL of blood will be collected from all study patients for the analysis of 
serum biomarkers pre-dose on C1D1, C2D1, C2D15, C3D1 and EOT. 
 
Refer to the Study Laboratory Manual for instructions on sample collection and shipment. 


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11. 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 or follow-up 
contact). Any patient may withdraw full or partial consent to participate in the study at any time 
during the study. The level of study withdrawal is to be noted in the source documentation. 
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. 
During the Phase 1b Dose Determination Phase, patients who discontinue the study for reasons 
other than study drug-related toxicity before completing C1 may be replaced. 
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 progressive disease 
• 
the investigator believes it is no longer in the patient’s best interest to continue study 
therapy 
During the Phase 2, the number of patients may be increased by 6-10 additional patients to 
accommodate for a higher than expected number of drop outs without PFS. 


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12. 
ADVERSE EVENTS, DATA REPORTING, AND RECORDING 
 
12.1 Study Drugs 
 
12.1.1 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 breast cancer, in which patients received 
exemestane+entinostat or exemestane+placebo, treatment-emergent adverse events (TEAEs) 
occurring at a ≥10% higher incidence in entinostat-treated patients versus placebo-treated 
patients included fatigue (48% vs 26%), nausea (40% vs 15%), neutropenia (30% vs 0%), 
peripheral edema and vomiting (both 21% vs 5%), thrombocytopenia (19% vs 6%), pain (16% 
vs 6%), and dyspepsia and leukopenia (both 14% vs 3%). The only Grade 3 or 4 AE occurring 
at a >10% incidence for entinostat vs placebo was neutropenia (14% vs 0%). 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 atezolizumab. 
 
12.1.2 Atezolizumab 
 
Please refer to the current Informed Consent and the Investigator’s Brochure for the current 
safety profile and information regarding atezolizumab. 
12.2 
Adverse Event Definitions 
 
12.2.1 Adverse Events 
 
An AE is defined in the International Council for Harmonisation (ICH) Guideline for Good 
Clinical Practice as “any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product and which 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. 
PD should not be recorded as an AE. 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, record “Fatal” for only the event causing death. AEs that are ongoing at the 
end of the study or time of death are to be noted as “not recovered/not resolved.” Classification 
of AEs is to be done by the Investigator in accordance with 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. 
 
12.2.2 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 regulatory 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. 
 
12.2.3 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 


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described in the General Investigational Plan or elsewhere in the current application, as 
amended. 
 
12.2.4 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 a significant medical hazard, such as new malignancy 
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). 
12.3 Reporting Procedures for All Adverse Events 
 
The Investigator is responsible for ensuring that all AEs (as defined in Section 12.2) observed 
by the Investigator or reported by patients are properly captured in the patients’ medical records 
and reported in the Adverse Event eCRF. 
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 atezolizumab; 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 the combination of entinostat 


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with atezolizumab?” 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 drugs 
 
• 
Possibly related: event may be explained by administration of the study drugs, 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 
(https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03/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 12-1). 


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Table 12-1 
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. 
12.4 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 after the end of 
the study if thought to be related to entinostat or the combination. 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 EOS eCRF. 


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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. 
 
12.4.1 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 last dose of study drugor 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). 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. 
If the pregnancy continues to term, the outcome (health of infant) must also be reported. 
 
Please refer to the Study Manual for further details on the pregnancy reporting procedure and 
associated report form. 
12.4.2 Definition of an Overdose and Reporting of Overdose to the Sponsor 
 
For this study, a study drug overdose will be defined as any amount over the specified dose of 
1,200 mg dose for atezolizumab and >15 mg for entinostat. No specific information is available 
on the treatment of overdose of Atezolizumab or entinostat. If such an event occurs, TRIO 
should be immediately notified and the patient observed closely for signs of toxicity. Any toxicity 
that occurs as a result of the overdose will be captured on the AE eCRF within 24 hours of site 
awareness. Appropriate supportive treatment should be provided if clinically indicated. An 
overdose will not be considered an SAE unless the outcome of the SAE meets seriousness 
criteria as defined in Section 12.2.4 Serious Adverse Events. 
 
12.4.3 Adverse Events of Special Interest with Atezolizumab 
 
Selected non-serious and SAEs are also known as AESI, Adverse Events of Special Interest. 
As noted in Section 9.6, DLTs will also be captured as AESI. AESI must be recorded as such in 


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the AE eCRF, completing the same fields as for Serious Adverse Events, and reported within 24 
hours to the Sponsor. Such events must be documented through 90 days following cessation of 
treatment, or 30 days after the initiation of a new anticancer therapy, whichever is earlier. 
Sponsor Contact information can be found in the Study Manual. 
 
Toxicities associated or possibly associated with atezolizumab treatment should be managed 
according to standard medical practice. Additional tests, such as autoimmune serology or 
biopsies, should be used to determine a possible immunogenic etiology. 
Although most immune-mediated adverse events observed with immunomodulatory agents 
have been mild and self-limiting, such events should be recognized early and treated promptly 
to avoid potential major complications. Discontinuation of atezolizumab may not have an 
immediate therapeutic effect and, in severe cases, immune-mediated toxicities may require 
acute management with topical corticosteroids, systemic corticosteroids, mycophenolate, or 
TNF-α inhibitors. 
The investigator should consider the benefit-risk balance for a given patient prior to further 
administration of atezolizumab. Atezolizumab should be permanently discontinued in patients 
with life-threatening immune-mediated adverse events. 
For the management of other adverse events associated with the atezolizumab not 
provided below, refer to the Atezolizumab IB. Patients should be assessed for possible 
AESIs prior to each dose of study medication. Laboratory results should be evaluated and 
patients should be asked for signs and symptoms suggestive of an immune-related event. 
Patients who develop an AESI thought to be immune-related should have additional testing to 
rule out other causes. If laboratory results or symptoms indicate a possible immune-related 
AESI, then additional testing should be performed to rule out other causes. If no other cause is 
found, then it is assumed to be immune-related. 
The following conditions may be suggestive of an autoimmune disorder and are considered 
AESI for this study: 
 
Pneumonitis 
 
Colitis 
 
Endocrinopathies: Diabetes mellitus, Pancreatitis, Adrenal Insufficiency, 
Hyperthyroidism, and Hypophysitis 
 
Vasculitis 


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 
Cases of potential drug-induced liver injury that include AST or ALT >3x 
ULN in combination with bilirubin >2x ULN 
 
Hepatitis Transaminitis: including AST/ALT >10x ULN 
 
Systemic Lupus Erythematosus 
 
Neurologic Disorders: Guillain Barre Syndrome, myasthenic syndrome or 
Myasthenia Gravis, and meningoencephalitis 
 
Grade ≥2 Cardiac Disorders (e.g., Atrial fibrillation, Myocarditis, 
Pericarditis) 
 
Events suggestive of hypersensitivity, infusion related reactions, cytokine 
release syndrome, influenza like illness, SIRS, and systemic immune 
activation 
 
Nephritis 
 
Ocular toxicities (e.g., uveitis, retinitis, and optic neuritis) 
 
Myositis 
 
Myopathies, including rhabdomyolysis 
 
Autoimmune hemolytic anemiaSevere cutaneous reactions (e.g., 
Stevens-Johnson syndrome, dermatitis bullous, toxic epidermal 
necrolysis) 
 
Suspected transmission of an infectious agent by the study treatment, as 
defined below: 
• 
Any organism, virus, or infectious particle (e.g., prion protein 
transmitting transmissible spongiform encephalopathy), 
pathogenic or non-pathogenic, is considered an infectious 
agent. A transmission of an infectious agent may be suspected 
from clinical symptoms or laboratory findings that indicate an 
infection in a patient exposed to a medicinal product. This term 
applies only when a contamination of study treatment is 
suspected. 
 
 
12.4.4 Follow-Up of Adverse Events 
 
The Investigator must continue to follow all SAEs and non-serious AEs considered to be 
possibly related or related to study drug (as defined in section 12.3) until resolution or the 
Investigator assesses them as chronic or stable. This follow-up may extend after the end of the 
study. 


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12.4.5 Reporting Safety Information 
 
The Investigator must promptly report to his or her IRB/EC all unanticipated problems involving 
risks to patients. This includes death from any cause and all serious adverse events reasonably 
or possibly associated with the use of study drug according to IRB/EC procedures. 
 
12.4.6 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 corresponding 
remediation plan will be tracked in the TRIO Clinical Trial Management System. 
Period of Observation: 
 
The table below summarizes the different periods of observation of AE, SAE, AESI with 
Atezolizumab and Pregnancy/Lactation. 
 
 
 
Type of 
Event 
AE 
SAE 
AESI with 
Atezolizumab 
Pregnancy/Lactation 
Reporting 
period 
From consent 
until 30 days 
after the end 
of the 
treatment 
From consent 
until 90 days 
after the last 
dose of study 
treatment for all 
SAEs, and any 
time after the 
end of study for 
SAEs believed 
related to 
entinostat or the 
combination 
From consent 
until 90 days 
after the last 
dose of study 
treatment, or 
30 days after 
the initiation of 
a new 
anticancer 
therapy, 
whichever is 
earlier 
From consent until 
120 days after the 
last dose of study 
treatment or 30 days 
following the 
discontinuation of the 
study treatment in 
case of the start of a 
new anticancer 
therapy 
Note: all patients 
becoming pregnant 
must be followed up 


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to the completion / 
termination of the 
pregnancy. 
Reporting 
Timelines to 
the Sponsor 
Entered into 
the clinical 
database on 
an ongoing 
basis 
Within 24 hours 
Within 24 
hours 
Within 24 hours 
 
12.5 Safety Monitoring 
The safety and tolerability of the investigational treatments will be monitored throughout the 
course of the study by the Investigator and the Medical Monitor. Additionally, an independent 
data safety monitoring board (DSMB) will be established for the Phase 2 portion of this study to 
act in an advisory capacity to the Sponsor with respect to safeguarding the interests of trial 
patients and assessing the safety of the interventions administered during the trial. 
 
The safety and tolerability data that will be reviewed by the Medical Monitor and DSMB will 
include, but are not limited to, adverse events, laboratory test results, and patient 
discontinuations. Additionally, the development of serious adverse events will be assessed by 
the Medical Monitor and DSMB on a continuous basis. Note: All serious 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 DSMB and the study’s Steering Committee. 


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13. STATISTICAL CONSIDERATIONS 
 
13.1 Sample Size Estimation 
 
13.1.1 Dose Determination Phase 
 
Three to 6 patients will be enrolled in each dose cohort based on a standard Phase 1 dose- 
finding scheme. The total number of patients to be enrolled in the dose determination 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 adjustments required to achieve either the MTD or 
the recommended Phase 2 dose. Therefore between 6 and 18 patients will be included in the 
Dose Determination Phase 1 part. Note: patients who discontinued the study for reasons other 
than study drug related toxicities before completing cycle 1 may be replaced. 
A starting sample size of 3 evaluable patients per dose cohort, expanding to 6 in the event of a 
marginal DLT rate (33%) was deemed to be a safe and conventional approach in dose-finding. 
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. 
 
13.1.2 Expansion Phase 
 
The Expansion Phase will evaluate the efficacy and safety of entinostat when administered at 
the recommended Phase 2 dose with atezolizumab in a randomized, double-blind, placebo- 
controlled setting. Up to 70 eligible patients with metastatic TNBC will be randomized to receive 
atezolizumab with entinostat or placebo in a 1:1 allocation. 
The true median PFS for patients with aTNBC receiving atezolizumab monotherapy is expected 
to be approximately 4 months from the initiation of such treatment. It is hypothesized that the 
combination of entinostat and atezolizumab will improve true median PFS by 3 months (i.e., 
from 4 to 7 months). Under the exponential distribution, such an improvement in median PFS 
represents a reduction of 43% for the true PFS failure hazard rate or equivalently, a hazard ratio 
of 0.57. Inferential comparisons will be performed using a stratified log-rank test, stratifying on 
the randomization stratification factor of geographic location. Total information of 60 PFS 
failures, defined as documented progressive disease by RECIST 1.1 or death due to any cause 


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without documented progressive disease beforehand, is estimated to provide 80% power to 
detect a 43% reduction in the PFS failure hazard rate with 1-sided significance level of 0.1 
(SEQDESIGN procedure, SAS version 9.2). 
Assuming approximately 9 months of accrual and an additional 9 months of follow-up, total 
accrual of 70 patients (approximately 35 per treatment arm) is projected to result in 60 PFS 
failures within approximately 18 months of the first patient randomization. Patients who 
discontinue study treatment for reasons not due to documented progressive disease by RECIST 
1.1 will continue to undergo disease assessments until the earlier of documented progressive 
disease, death, or withdrawal of consent/lost to follow-up. It is anticipated that the number of 
patients who will drop out of the study without PFS failure beforehand will be low (2–3%). 
Depending on the actual number of such dropouts, the number of patients accrued may be 
increased by 6–10 additional patients to accommodate for a higher-than-expected number of 
dropouts. 
13.2 Phase 2 Interim Efficacy Analyses 
The sample size and number of PFS failures were adjusted using the O’Brien 
 
-Fleming group sequential procedure to account for 1 planned interim analysis of PFS after 45 
events (75% information). It is projected that 75% and 100% of total information will be reported 
at approximately 12 and 18 months, respectively. 
The interim analysis will be performed to support the Sponsor’s product development plans and 
ongoing resourcing activities. Although there are no plans to terminate the study early because 
of early evidence of superior efficacy for the combination treatment, the significance levels at 
the interim analysis and final analysis will be adjusted to maintain control of the overall type I 
error rate for multiple testing of PFS (O’Brien 1979). 


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13.3 Populations for Analysis 
The Full Analysis Set (FAS) will serve as the primary population for the analysis of PFS and 
other efficacy-related endpoints in the Phase 2 portion of the study. The FAS will include all 
patients who undergo randomization, irrespective of the actual receipt of study treatment. 
Patients will be grouped for analysis according to the treatment arm to which they were 
randomized. 
The Per-protocol Analysis Set is for various supportive analyses that may be performed; this 
excludes patients with important deviations that may substantially affect the results of the 
primary efficacy analyses. The final determination on protocol violations, and thereby the 
composition of the per-protocol set, will be made prior to locking the clinical database will be 
documented in a separate memo. 
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 population will consist of all patients who receive at 
least 1 dose of either entinostat or atezolizumab. At least 1 laboratory or other safety-related 
assessment subsequent to at least 1 dose of entinostat and atezolizumab 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 AE meeting DLT criteria during Cycle 1 or who receives the full 
dose of atezolizumab and all doses of entinostat during Cycle 1 without experiencing a DLT, is 
considered a DLT-evaluable patient. 
13.4 Study Endpoints 
The primary endpoint of the Phase 1b Dose Determination portion of the study is the 
recommended Phase 2 dose as assessed by incidence of DLT and overall tolerance. 
The endpoints of the randomized Phase 2 Expansion portion of the study are as follows: 
 
Primary Efficacy 
 
• 
PFS, as determined by the local investigator using RECIST 1.1 
Secondary Efficacy 
 
• 
PFS as determined by irRECIST 
• 
ORR (CR or PR), by RECIST 1.1 and irRECIST 


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• 
CBR (CR, PR, or SD for at least 24 weeks) 
• 
OS 
• 
TTR and DOR (in patients who experience a best overall response of CR or PR) 
Safety 
 
• 
AEs, clinical laboratory parameters, vital signs, physical exams 
Exploratory: 
 
• 
 
• 
 
 
• 
 
• 
 
• 
 
• 
 
• 
 
 
• 
 
• 
 
• 
 
• 
 
 
13.5 Statistical Methods 
 
13.5.1 General 
 
The statistical analyses performed for this study will be presented by study phase. For the Dose 
Determination phase, tabulations will be provided by dose cohort and overall. For the 
expansion phase, tabulations will be provided by treatment arm. Some analyses may be 
performed based on both phases combined. 
The statistical analyses 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 


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source SDTM and ADaM datasets from which a statistical analysis is performed (including 
interim reviews) will be archived with the Sponsor. 
 
13.5.2 Patient Disposition 
 
The number of patients included in each analysis set will be summarized, along with the reason 
for any exclusions. Patients discontinuing from study treatment and/or withdrawing from study 
participation the primary reason for discontinuation will be summarized. 
 
13.5.3 Demographics and Characteristics 
 
Descriptive summaries of demographic and screening characteristics will be tabulated for each 
study phase. 
 
13.5.4 Extent of Exposure 
 
The overall duration of study treatment administration and number of cycles initiated will be 
tabulated for each patient and summarized for each study phase. For each patient, the 
cumulative doses administered (in mg) of both entinostat and atezolizumab will be calculated. 
These data will be further summarized for each dose cohort (or treatment arm) by calculating 
the mean, standard deviation, median, and range of these values. The number and proportion 
of patients with one or more dose modifications (i.e., reduction or delay) will be tabulated along 
with the reason for modification. 
 
13.5.5 Efficacy Analyses 
 
Efficacy analyses will be conducted using the Full Analysis Set and, where appropriate, the Per- 
protocol Set. With the exception of PFS, all hypothesis testing will be assessed using a one- 
sided significance level of 0.1. The Lan-DeMets alpha spending function with an O’Brien- 
Fleming type boundary will be used to control the overall type I error for multiple testing of PFS. 
The boundary will be derived based on the actual number of PFS failures reported for each 
analysis. 
The primary efficacy endpoint is duration of PFS, defined as the number of months from 
randomization to the earlier of progressive disease or death due to any cause. Disease 
assessments will continue until progressive disease, even after the originally assigned study 
treatment is discontinued. For purposes of analysis, one month is considered 30.4375 days. 


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The duration of PFS will be summarized descriptively using the Kaplan-Meier method with 95% 
confidence intervals calculated using Greenwood’s formula. Inferential comparisons between 
treatment arms will be made using the stratified log rank test, stratifying on the randomization 
stratification factor of geographic location. Estimation of the hazard ratio for treatment effect 
and its corresponding 95% confidence interval will be determined using a stratified Cox 
proportional hazards model, without any other covariate. Homogeneity in the hazard ratios 
between randomization strata will be examined by Wald’s test. The corresponding results 
without stratification will be reported as supplemental analyses. The adequacy of the Cox 
model will be evaluated, including an assessment of the proportional hazards assumption 
(Therneau 2000). 
 
For the interim and primary analyses, PFS will be right-censored for patients who meet one or 
more of the following conditions: 
• 
Patients with no screening or post-screening disease assessments unless death 
occurred prior to the first planned assessment (in which case the death will be 
considered a PFS event) 
• 
Patients who initiate subsequent anticancer therapy in the absence of documented 
progression 
• 
Patients who die or have progressive disease after missing 2 or more consecutively 
scheduled disease assessment visits 
• 
Patients who are last known to be alive and progression-free on or before the data cut- 
off date 
 
For such patients, the progression or censoring date will be determined based on described 
conventions (FDA 2007). Sensitivity analyses will be performed to assess the impact of the 
different censoring mechanisms and deviations from the planned schedule of disease 
assessments (Bhattacharya 2009; Stone 2011). 
ORR will be estimated based on the crude proportion of patients in each treatment arm whose 
best overall response during the course of study treatment is CR or PR. Tumor response will be 
assessed using irRECIST. Approximate 95% confidence intervals will be calculated by 
treatment arm for the true ORR. The inferential comparison of the observed ORRs will be made 
using the Cochran-Mantel-Haenszel chi-square test, stratified by the randomization stratification 
factors. The corresponding results without stratification will be reported as supplemental 
analyses. 


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DOR 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 PR or CR (whichever response occurs first) and 
subsequently confirmed, to the first date that recurrent or progressive disease is documented. 
The date of progression or censoring for DOR will be determined using the conventions 
described for PFS. DOR will be summarized descriptively for each treatment arm using the 
Kaplan-Meier method. Inferential comparisons between treatment arms for DOR are not 
planned. 
CBR will be estimated based on the crude proportion of patients in each treatment arm whose 
best overall response during the course of study treatment is CR, PR, or stable disease lasting 
for at least 24 weeks. Stable disease will be measured from the start date of study treatment 
until the criteria for progressive disease is first met. The analysis of CBR and its duration will be 
based on the methods described above for ORR and DOR, respectively. 
OS is defined as the number of months from randomization to the date of death (due to any 
cause). Patients who are alive or lost to follow-up as of a data analysis cutoff date will be right- 
censored. The censoring date will be determined from the patients’ date of last contact or data 
analysis cutoff date, whichever date occurs first. The analysis of OS will be based on the 
methods described above for PFS. 
 
13.5.6 Safety Analyses 
 
Safety will be assessed by clinical review of all relevant parameters including AEs, SAEs, 
laboratory values, vital signs, physical exam and ECG results. Unless specified otherwise, the 
safety analyses will be conducted for the safety population. An interim safety analysis is planned 
following the completion of Cycle 1 for the first 20 patients enrolled in the Phase 2 expansion 
phase and will utilize a Data Safety Monitoring Board. 
Summary tables and listings will be provided for all reported Treatment Emergent Adverse 
Events (TEAEs), defined as AEs that start on or after the first administration of study treatment. 
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 system organ class (SOC) and preferred term (PT). In the event a patient 


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experiences repeat episodes of the same AE, then the event with the highest severity grade and 
strongest causal relationship to study treatment will be used for purposes of incidence 
tabulations. 
Tabular summaries will be provided for: 
 
• 
all TEAEs 
• 
TEAEs by relationship to study treatment and maximum severity grade 
• 
TEAEs with action of study treatment delayed/interrupted or dose reduced 
• 
TEAEs with action of study treatment 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 30 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 and serum chemistries 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 
• 
last post baseline value 
 
Laboratory values will be assigned toxicity grades when available using the NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.03. 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. 


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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. 
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). 
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. 
 
13.5.7 Pharmacokinetic and Antidrug 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 atezolizumab levels and anti- 
atezolizumab antibodies will be provided in a separate analysis plan. 
 
13.5.8 Correlative Analyses 
 
Immune correlate values will be summarized in a descriptive manner. For immune correlates 
measured on a continuous scale, the number of patients with no 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. 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). The 
association among the various immune correlates and clinical outcomes (data permitting) may 
be explored using heat map and other data visualization techniques. 


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14. REGULATORY OBLIGATIONS 
 
This clinical study was designed and shall be implemented and reported in accordance with the 
protocol, the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable 
local regulations (including European Directives 2001/20/EC and 2005/28/EC and the US Code 
of Federal Regulations Title 21), and with the ethical principles laid down in the Declaration of 
Helsinki. 
14.1 Informed Consent 
A template 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 acceptable representative after adequate 
explanation of the aims, methods, anticipated benefits, and potential hazards of the study and 
before any protocol-specific screening procedures are conducted 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. 


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When required, 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. 
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. 
• 
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 or its representative and the 
authorized representative at the institution, or investigator if applicable. 
• 
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. In the eCRFs or 
other study documentation submitted to Syndax or its representative, patients should be 
identified only by their initials (unless prohibited by local regulatory guidelines) 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. 


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In compliance with federal guidelines and applicable local regulations, 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 Health Authority 
(where required) and 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 and audit 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 (Section14.3), and all correspondence to and from the 
IRB/EC and Syndax. 
• 
Investigational Product Accountability Records and all drug-related correspondence. 


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In addition, all original source documents supporting entries on the eCRFs must be maintained 
and be readily available. Source documents should be retained by the investigator according to 
ICH-E6 and local regulations or as indicated in the clinical study agreement, whichever is 
longer. 
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 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, the ICH GCP and applicable local regulatory requirements, the study site may be 
selected for audit by a designee of Syndax or its representative and/or regulatory inspection by 
appropriate regulatory authorities. Inspection and audit of site facilities (i.e., pharmacy, drug 
storage areas, laboratories) and review of study-related records may occur to evaluate the study 
conduct and compliance with the protocol and applicable regulatory requirements. 
Agreements between Syndax, the Institution and/or Principal Investigator regarding study 
payments, insurance coverages and publication policy are covered in the clinical trial agreement 
and not in this protocol. 


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Peña-Cruz V, McDonough SM, Diaz-Griffero F, Crum CP, Carrasco RD, Freeman GJ. PD-1 on 
immature and PD-1 ligands on migratory human Langerhans cells regulate antigen-presenting 
cell activity. J Invest Dermatol 2010;130(9):2222-30. 
Sanmamed MF, Chen L. Inducible expression of B7-H1 (PD-L1) and its selective role in tumor 
site immune modulation. Cancer J 2014;20(4):256-61. 
Shah P, Gau Y, Sabnis G. Histone deacetylase inhibitor entinostat reverses epithelial to 
mesenchymal transition of breast cancer cells by reversing the repression of E-cadherin. Breast 
Cancer Res Treat 2014;143(1):99-111. 


Product: Entinostat 
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Sharma P, Allison JP. The future of immune checkpoint therapy. Science 2015;348(6230):56- 
61. 
Shen Li, Ciesielski M, Ramakrishnan S, Miles KM, Ellis L, Sotomayor P, et al. Class I histone 
deacetylase inhibitor entinostat suppresses regulatory T cells and enhances immunotherapies 
in renal and prostate cancer models. PLoS One 2012;7(1):e30815. 
Sheppard KA, Fitz LJ, Lee JM, Benander C, George JA, Wooters J, et al. PD-1 inhibits T-cell 
receptor induced phosphorylation of the ZAP70/CD3zeta signalosome and downstream 
signaling to PKCtheta. FEBS Lett, 2004;574(1-3):37-41. 
Solito S, Falisi E, Diaz Montero CM, Doni A, Pinton L, Rosato A, et al. A human promyelocytic- 
like population is responsible for the immune suppression mediated by myeloid-derived 
suppressor cells. Blood 2011;118(8):2254-65. 
Stone AM, Bushnell W, Denne J, Sargent DJ, Amit O, Chen C, et al. Research outcomes and 
recommendations for the assessment of progression in cancer trials from a PhRMA working 
group. European Journal of Cancer. 2011;47:1763–1771. 
Taube JM, Anders RA, Young GD, Xu H, Sharma R, McMiller TL, et al. Colocalization of 
inflammatory response with B7-h1 expression in human melanocytic lesions supports an 
adaptive resistance mechanism of immune escape. Sci Transl Med 2012;4(127):127ra37. 
Therneau TM, Grambsch PM. Modeling survival data: extending the Cox model. New York: 
Springer Science & Business Media; 2000. 
Topalian SL, Drake CG, Pardoll DM. Targeting the PD-1/B7-H1(PD-L1) pathway to activate anti- 
tumor immunity. Curr Opin Immunol 2012;24(2):207-12. 
Uppaluri R, Dunn GP, Lewis, JS, Jr. Focus on TILs: prognostic significance of tumor infiltrating 
lymphocytes in head and neck cancers. Cancer Immun 2008;8:16. 
Weber JS, Gibney GT, Yu B, Cheng PY, Martinez AJ, Kroeger J, et al. Survival, biomarker, and 
toxicity analysis of nivolumab (NIVO) in patients that progressed on ipilimumab (IPI). Journal of 
Clinical Oncology 2015;33:(suppl; abstr 9055). 


Product: Entinostat 
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Weed DT, Vella JL, Reis IM, De la Fuente AC, Gomez C, Sargi Z, et al. Tadalafil reduces 
myeloid-derived suppressor cells and regulatory T cells and promotes tumor immunity in 
patients with head and neck squamous cell carcinoma. Clinical cancer research 2015;21(1):39- 
48. 
Wrangle J, Wang W, Koch A, Easwaran H, Mohammad HP, Vendetti F, et al. Alterations of 
immune response of Non-Small Cell Lung Cancer with Azacytidine. Oncotarget 
2013;4(11):2067-79. 
Wu A, Drake V, Huang H, Chiu S, Zheng L. Reprogramming the tumor microenvironment: 
tumor-induced immunosuppressive factors paralyze T cells. Oncoimmunology 
2015;4(7):e1016700. 
Yao S, Chen L. PD-1 as an immune modulatory receptor. Cancer J 2014;20(4):262-4. 
 
Zhang X, Kelaria S, Kerstetter J, Wang J. The functional and prognostic implications of 
regulatory T cells in colorectal carcinoma. Journal of Gastrointestinal Oncology 2015;6(3):307- 
13. 
Zhang X, Schwartz JC, Guo X, Bhatia S, Cao E, Lorenz M, et al. Structural and functional 
analysis of the costimulatory receptor programmed death-1. Immunity 2004;20(3):337-47. 


Product: Entinostat 
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17. APPENDICES 
 
 
17.1 Appendix 1 
New York Heart Association (NYHA) 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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17.2 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, 
cisapride, cyclosporine, 
dihydroergotamine, 
ergotamine, fentanyl, 
pimozide, quinidine, 
sirolimus, tacrolimus, 
terfenadine 
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. 
 
 
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 


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17.3 Appendix 3: Pre-existing Autoimmune Diseases 
Subjects should be carefully questioned regarding their history of acquired or congenital 
immune deficiencies or autoimmune disease. Subjects with any history of immune deficiencies 
or autoimmune disease listed in the table below are excluded from participating in the study. 
Possible exceptions to this exclusion could be subjects with a medical history of such entities as 
atopic disease or childhood arthralgias where the clinical suspicion of autoimmune disease is 
low. Patients with a history of autoimmune-related hypothyroidism on a stable dose of thyroid 
replacement hormone may be eligible for this study. In addition, transient autoimmune 
manifestations of an acute infectious disease that resolved upon treatment of the infectious 
agent are not excluded (e.g., acute Lyme arthritis). Contact the Medical Monitor regarding any 
uncertainty over autoimmune exclusions. 
 
Acute disseminated 
Dermatomyositis 
Neuromyotonia 
encephalomyelitis 
Dysautonomia 
Opsoclonus myoclonus 
Addison’s disease 
Epidermolysis bullosa acquista 
syndrome 
Ankylosing spondylitis 
Gestational pemphigoid 
Optic neuritis 
Antiphospholipid antibody 
Giant cell arteritis 
Ord’s thyroiditis 
syndrome 
Goodpasture’s syndrome 
Pemphigus 
Aplastic anemia 
Graves’ disease 
Pernicious anemia 
Autoimmune hemolytic anemia 
Guillain-Barré syndrome 
Polyarteritis nodusa 
Autoimmune hepatitis 
Hashimoto’s disease 
Polyarthritis 
Autoimmune 
IgA nephropathy 
Polyglandular autoimmune 
hypoparathyroidism 
Inflammatory bowel disease 
syndrome 
Autoimmune hypophysitis 
Interstitial cystitis 
Primary biliary cirrhosis 
Autoimmune myocarditis 
Kawasaki’s disease 
Psoriasis 
Autoimmune oophoritis 
Lambert-Eaton myasthenia 
Reiter’s syndrome 
Autoimmune orchitis 
syndrome 
Rheumatoid arthritis 
Autoimmune 
Lupus erythematosus 
Sarcoidosis 
thrombocytopenic 
Lyme disease - chronic 
Scleroderma 
purpura 
Meniere’s syndrome 
Sjögren’s syndrome 
Behcet’s disease 
Mooren’s ulcer 
Stiff-Person syndrome 
Bullous pemphigold 
Morphea 
Takayasu’s arteritis 
Chronic inflammatory 
Multiple sclerosis 
Ulcerative colitis 
demyelinating 
Myasthenia gravis 
Vogt-Kovanagi-Harada 
polyneuropathy 
disease 
Chung-Strauss syndrome 
Wegener’s granulomatosis 
Crohn’s disease 


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17.4 Appendix 4: Immune-related Response Criteria Derived from RECIST 1.1 (irRECIST) 
 
Increasing clinical experience indicates that traditional response criteria may not be sufficient to 
fully characterize activity in this new era of targeted therapies and/or biologics. This is 
particularly true for immunotherapeutic agents such as anti-CTLA-4 and anti-PD1\anti PDL1 
which exert the antitumor activity by augmenting activation and proliferation of T cells, thus 
leading to tumor infiltration by T cells and tumor regression rather than direct cytotoxic effects 
(Hoos 2010; Hodi 2008). Clinical observations of patients with advanced melanoma treated 
with ipilimumab, for example, suggested that conventional response assessment criteria such 
as RECIST and WHO criteria are not sufficient to fully characterize pattercccns of tumor 
response to immunotherapy because tumors treated with immunotherapeutic agents may show 
additional response patterns that are not described in these conventional criteria (Hoos 2010; 
Nishino 2014). 
 
Furthermore, the conventional tumor assessment criteria (RECIST and WHO criteria) have 
been reported as not capturing the existence of a subset of patients who have an OS similar to 
those who have experienced CR or PR but were flagged as PD by WHO criteria (Hoos 2010; 
Nishino 2012). 
 
On these grounds, a tumor assessment system has been developed that incorporates these 
delayed or flare-type responses into the RECIST 1.1 criteria (irRECIST; Nishino 2014). . 
 
Lesion measurability and baseline selection of lesions: 
 
The RECIST 1.1 definitions for measurable and non-measurable lesions apply. At baseline, all 
tumor lesions/lymph nodes will be categorized as measurable or non-measurable. For target 
lesions, a Total Measured Tumor Burden (TMTB) for all target lesions will be calculated and 
reported as the baseline TMTB (similarly to the Sum of Diameters in RECIST 1.1). The baseline 
TMTB will be used as reference to further characterize any objective tumor response in the 
measurable dimension of the disease. 
 
New lesions: 
 
irRECIST do not necessarily score the appearance of new lesions as progressive disease. Also, 
new lesions should be categorized as measurable or non-measurable (same measurability rules 
as RECIST 1.1. apply). 
 
In order to be selected as new measurable lesions (≤ 2 lesions per organ, ≤ 5 lesions total, per 
timepoint), new lesions must meet criteria as defined for baseline target lesion selection and 
meet the same minimum size requirements of 10 mm in long diameter and minimum 15 mm in 
short axis for new measurable lymph nodes. New measurable lesions shall be prioritized 
according to size, and the largest lesions shall be selected as new measured lesions. 
 
All new lesions not selected as New Measurable lesions are considered New Non-measurable 
lesions and are followed qualitatively. 


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Post baseline tumor assessments: 
- 
TMTB: At each post-baseline assessment the TMTB is defined as the sum of: 
o Longest diameters of all non-nodal target lesions 
o Longest diameters of all NEW non-nodal measurable lesions 
o Short axis of all nodal target lesions 
o Short axis of all NEW nodal measurable lesions 
- 
Non-target lesions/New Non-measurable lesions: the RECIST 1.1 definitions for the 
assessment of non-target lesions apply (irCR; irNN, irPD). 
 
Overall response at each time point: 
 
- 
Immune-related complete response (irCR): Complete disappearance of all lesions 
(whether measurable or not) and no new lesions. All measurable lymph nodes also 
must have a reduction in short axis to <10 mm. 
- 
Immune-related partial response (irPR): Decrease of ≥ 30% in TMTB relative to 
baseline, non-target lesions are irNN, and no unequivocal progression of new non- 
measurable lesions 
- 
Immune-related stable disease (irSD): Failure to meet criteria for irCR or irPR in the 
absence of irPD. 
- 
Immune-related progressive disease (irPD): Minimum 20% increase and minimum 5 mm 
absolute increase in TMTB compared to nadir, or irPD for non-target or new non- 
measurable lesions. 
- 
irNE (Not evaluable): used in exceptional cases where insufficient data exists. 

SAP_001.pdf: 
Statistical Analysis Plan 
SDNX- 275-0602 (TRIO025) 
DM-025-037 
Document owner(s): 
 
Document ID: DM-025-037 Version: 1.0 – Final – 08-Jun-2017 
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Statistical Analysis Plan 
SDNX-275-0602 (TRIO025) 
Title 
A Randomized, Placebo-controlled, Double-blind, Multicenter 
Phase 2 Study of Atezolizumab With or Without Entinostat in 
Patients with Advanced Triple Negative Breast Cancer, with a 
Phase 1b Lead in Phase 
Study Number 
SNDX-275-0602 (TRIO025) 
Document Number 
DM-025-037 
Version Number 
1.0 
Product Name 
Entinostat (SNDX-275) 
Indication 
Advanced Triple Negative Breast Cancer (aTNBC) 
Study Phase 
1b / 2 
Sponsor 
Syndax Pharmaceuticals, Inc. 
400 Totten Pond Road, Suite 110 
Waltham, MA 02154 
Version Date 
08-Jun-2017 
Confidentiality Statement 
The information contained herein is confidential and proprietary and may not be disclosed, reproduced, or 
circulated without the prior written consent of TRIO. 
NCT #NCT02708680


Statistical Analysis Plan 
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DM-025-037 
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STATISTICAL ANALYSIS PLAN APPROVAL SHEET 
Protocol Number: 
SNDX-275-0602 (TRIO025) 
Product: 
Entinostat (SNDX-275) 
Protocol Title: 
A Randomized, Placebo-controlled, Double-blind, Multicenter Phase 2 Study of Atezolizumab 
With or Without Entinostat in Patients with Advanced Triple Negative Breast Cancer, with a 
Phase 1b Lead in Phase. 
Author: 
 
Version Number: 
1.0 
Version Date: 
08-Jun-2017 
The undersigned have reviewed this plan and find it to be consistent with the requirements of the 
protocol as it applies to their respective areas. 
Date 
Signature 
 
, TRIO 
 
, TRIO 
 
, TRIO 
 
, TRIO 
 
, TRIO 


Statistical Analysis Plan 
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DM-025-037 
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STATISTICAL ANALYSIS PLAN APPROVAL SHEET 
SNDX-275-0602 (TRIO025) 
Product: 
Entinostat (SNDX-275) 
Protocol Title: 
A Randomized, Placebo-controlled, Double-blind, Multicenter Phase 2 Study of Atezolizumab With 
or Without Entinostat in Patients with Advanced Triple Negative Breast Cancer, with a Phase 1b 
Lead in Phase. 
Author: 
 
Version Number: 
1.0 
Version Date: 
08-Jun-2017 
The undersigned have reviewed this plan and find it to be consistent with the requirements of the 
protocol as it applies to their respective areas. 
Date 
Signature 
 
 
Scott Cruickshank & Associates 
 
, 
Syndax Pharmaceuticals, Inc. 
 
 
Syndax Pharmacueticals, Inc. 


Statistical Analysis Plan 
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DM-025-037 
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TABLE OF CONTENTS 
1. 
Introduction ................................................................................................................................ 10 
2. 
Study Objectives ........................................................................................................................ 10 
2.1 
Primary Objective ..............................................................................................................10 
2.2 
Secondary Objectives .........................................................................................................10 
2.2.1 
Efficacy ....................................................................................................................... 10 
2.2.2 
Safety .......................................................................................................................... 11 
2.3 
Exploratory Objectives .......................................................................................................11 
3. 
Study Design .............................................................................................................................. 11 
3.1 
Phase 1b Dose Determination Phase ..................................................................................12 
3.2 
Phase 2 Expansion Phase ...................................................................................................12 
4. 
Study Endpoints .......................................................................................................................... 13 
4.1 
Phase 1b Dose Determination Phase ..................................................................................13 
4.2 
Phase 2 Expansion Phase ...................................................................................................13 
4.2.1 
Primary Efficacy Endpoint .......................................................................................... 13 
4.2.2 
Secondary Efficacy Endpoints .................................................................................... 13 
4.2.3 
Safety .......................................................................................................................... 14 
4.2.4 
Exploratory.................................................................................................................. 14 
5. 
Statistical Considerations ............................................................................................................. 14 
5.1 
Hypothesis for Phase 2 .......................................................................................................14 
5.2 
Sample Size ........................................................................................................................14 
5.2.1 
Phase 1b Dose Determination Phase ........................................................................... 14 
5.2.2 
Phase 2 Expansion Phase ............................................................................................ 15 
5.3 
Randomization and Stratification .......................................................................................15 
5.4 
Timing of Analyses ............................................................................................................16 
5.4.1 
Phase 1b Dose Determination Phase ........................................................................... 16 
5.4.2 
Phase 2 Expansion Phase ............................................................................................ 16 
6. 
Definitions .................................................................................................................................. 16 
6.1 
Progression-Free Survival (PFS) ........................................................................................16 
6.2 
Objective Response Rate (ORR) ........................................................................................18 
6.3 
Clinical Benefit Rate (CBR) ...............................................................................................20 
6.4 
Overall Survival (OS) .........................................................................................................20 
6.5 
Duration of Response (DOR) ..............................................................................................20 
6.6 
Time to Response (TTR) ....................................................................................................21 
6.7 
Dose-limiting Toxicity (DLT) ............................................................................................21 
6.8 
Maximum Tolerated Dose (MTD) .....................................................................................21 
6.9 
Recommended Phase 2 Dose (RP2D) ................................................................................21 
6.10 
Treatment Emergent Adverse Events (TEAEs) ..................................................................21 
6.11 
Other Definitions ................................................................................................................22 
6.11.1 Baseline ....................................................................................................................... 22 
6.11.2 Date of First Dose ....................................................................................................... 22 
6.11.3 Date of Last Dose ........................................................................................................ 22 
6.11.4 Last Contact Date ........................................................................................................ 22 
7. 
Study Population ........................................................................................................................ 22 
7.1 
Full Analysis Set (FAS) .....................................................................................................22 
7.2 
Per-protocol Analysis Set ...................................................................................................23 


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7.3 
Safety Analysis Set .............................................................................................................23 
8. 
Interim Analysis and Early Stopping Rule ................................................................................. 23 
9. 
Data Screening and Acceptance ................................................................................................. 23 
9.1 
General Principles ...............................................................................................................24 
9.2 
Unblinding Plan ..................................................................................................................24 
9.3 
Data Handling and Electronic Data Transfer......................................................................24 
9.4 
Handling of Incomplete and Missing Data .........................................................................25 
9.5 
Outliers ...............................................................................................................................26 
9.6 
Validation Plan ...................................................................................................................26 
10. Statistical Methods of Analysis .................................................................................................. 26 
10.1 
Patient Disposition .............................................................................................................26 
10.2 
Demographics and Disease Characteristics ........................................................................27 
10.3 
Prior Surgery for Breast Cancer ..........................................................................................28 
10.4 
Prior Systemic Anti-Cancer Therapy .................................................................................28 
10.5 
Prior Radiation Therapy .....................................................................................................28 
10.6 
Medical History ..................................................................................................................28 
10.7 
Extent of Exposure .............................................................................................................28 
10.8 
Efficacy Analyses ...............................................................................................................29 
10.8.1 PFS .............................................................................................................................. 29 
10.8.2 ORR ............................................................................................................................ 31 
10.8.3 CBR ............................................................................................................................ 31 
10.8.4 OS ................................................................................................................................ 31 
10.8.5 DOR and TTR ............................................................................................................. 31 
10.8.6 Anticancer therapy after end of study treatment ......................................................... 31 
10.9 
Safety Analyses ..................................................................................................................31 
10.9.1 Physical Examinations ................................................................................................. 32 
10.9.2 Adverse Events ........................................................................................................... 32 
10.9.3 Death ........................................................................................................................... 32 
10.9.4 Laboratory Values ....................................................................................................... 33 
10.9.5 ECOG Performance Status .......................................................................................... 33 
10.9.6 Vital Signs ................................................................................................................... 33 
10.9.7 Electrocardiogram (ECG) ............................................................................................ 34 
10.9.8 Concomitant Medication ............................................................................................. 34 
10.10 Subgroup Analysis .............................................................................................................34 
10.11 Pharmacokinetic and Antidrug Antibody Analyses............................................................35 
10.12 Correlative Analyses ..........................................................................................................35 
11. List of Planned Tables, Figures, Listings ................................................................................... 35 
11.1 
Planned Tables ...................................................................................................................35 
11.2 
Planned Listings .................................................................................................................40 
11.3 
Planned Figures ..................................................................................................................42 


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List of Abbreviations 
 
ADaM 
Analysis Data Model 
ADSL 
Subject-level Analysis Dataset 
AEs 
Adverse Events 
aTNBC 
Advanced Triple Negative Breast Cancer 
CBR 
Clinical Benefit Rate 
CI 
Confidence Interval 
CMH 
Cochran-Mantel-Haenszel 
CR 
Complete Response 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
Dose-limiting Toxicity 
DOR 
Duration of Response 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic Case Report Form 
FAS 
Full Analysis Set 
FASFL 
Full Analysis Set Population Flag 
HER2 
Human Epidermal Growth Factor Receptor 2 
irRECIST 
Immune-related RECIST 
IDDI 
International Drug Development Institute 
IV 
Intravenous 
IWRS 
Interactive Web Response System 


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KM 
Kaplan-Meier 
MedDRA 
Medical Dictionary for Regulatory Activities 
MTD 
Maximum Tolerated Dose 
NCI 
National Cancer Institute 
NE 
Not evaluable 
ORR 
Objective Response Rate 
OS 
Overall Survival 
PD 
Progressive Disease 
PFS 
Progression Free Survival 
PO 
per os (Oral Administration) 
PPROTFL 
Per-protocol Population Flag 
PR 
Partial Response 
PT 
Preferred Term 
Q1 
First Quartile (25th percentile) 
Q3 
Third Quartile (75th percentile) 
RDI 
Relative Dose Intensity 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP2D 
Recommended Phase 2 Dose 
SAEs 
Serious Adverse Events 
SAFFL 
Safety Population Flag 
SAP 
Statistical Analysis Plan 
SD 
Stable Disease 
SOC 
System Organ Class 


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TEAEs 
Treatment Emergent Adverse Events 
TLF 
Tables, Listings, and Figures 
TRIO 
Translational Research in Oncology 
TTR 
Time To Response 
WHODD 
World Health Organization Drug Dictionary 


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Revision History 
 
Not applicable; this is the initial version of Statistical Analysis Plan. 


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1. 
INTRODUCTION 
 
This Statistical Analysis Plan (SAP) describes the detailed statistical methodology for executing the 
statistical analyses to assess the antitumor activity and safety profile of atezolizumab in 
combination with entinostat versus atezolizumab alone in treatment of advanced triple negative 
breast cancer (aTNBC) according to SNDX-275-0602 (TRIO025) protocol version 1.0. 
Statistical analysis will be performed by TRIO using SAS® software Version 9.3 which meets the 
requirement as stated in the protocol. 
2. 
STUDY OBJECTIVES 
 
2.1 
Primary Objective 
 
The primary objective for each phase of the study is as follows: 
Phase 1b (Dose Determination Cohort): 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 atezolizumab. 
Phase 2 (Expansion Cohort): To perform an evaluation of the efficacy of entinostat at the RP2D in 
combination with atezolizumab in patients with aTNBC, as determined by the duration of 
progression-free survival (PFS) based on the local investigator’s assessment of progressive disease 
Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). 
2.2 
Secondary Objectives 
 
2.2.1 
Efficacy 
To evaluate the efficacy of entinostat in combination with atezolizumab in patients with aTNBC, as 
determined by: 
• 
PFS based on immune-related RECIST (irRECIST) 
• 
Overall response rate (ORR) (complete response [CR] or partial response [PR]) based on 
RECIST 1.1 
• 
ORR (irCR or irPR) based on irRECIST 
• 
Clinical benefit rate (CBR) (CR or PR or stable disease [SD] for at least 24 weeks) based 
on RECIST 1.1 
• 
CBR (irCR, irPR or irSD for at least 24 weeks) based on irRECIST 
• 
Overall survival (OS) 
In patients with best overall response of CR or PR based on RECIST 1.1 and irCR or irPR based on 
irRECIST: 


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• 
Duration of response (DOR) 
• 
Time to response (TTR) 
2.2.2 
Safety 
To evaluate safety and the tolerability of entinostat in combination with atezolizumab, as measured 
by clinical adverse events (AEs) and laboratory parameters. 
2.3 
Exploratory Objectives 
 
The exploratory study objectives are to: 
 
• 
 
 
. 
• 
 
 
• 
 
. 
• 
 
• 
 
 
• 
 
 
• 
 
 
• 
 
 
• 
 
• 
 
• 
 
. 
The exploratory objectives will be performed afterwards and detailed in a separate document(s). 
 
3. 
STUDY DESIGN 


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This is a Phase 1b/2 study evaluating the combination of entinostat plus atezolizumab in patients 
with aTNBC. The study has 2 phases: an open-label Dose Determination Phase (Phase 1b) followed 
by an Expansion Phase (Phase 2). 
The Expansion Phase will evaluate the efficacy and safety of entinostat when administered at the 
RP2D with atezolizumab in patients with aTNBC in a randomized, double-blind, placebo- 
controlled setting. 
3.1 
Phase 1b Dose Determination Phase 
 
This study phase employs a classical 3+3 design, with the determination of DLT and the MTD or 
RP2D at cycle 1 based on the combination of entinostat (at the dose of 5mg, 3mg or 2mg weekly) 
with atezolizumab at a fixed dose of 1200 mg iv. Six patients will need to be treated in a dose level 
for it to be considered MTD or the RP2D. The recommended dose for Phase 2 investigation will be 
the higher of either 2, 3, or 5mg weekly PO that results in less than a 33% incidence of DLT. 
Note: Based on evaluation of the safety and tolerability data gathered during the dose determination 
phase together with data from other clinical trials, it may also be decided that accrual will take 
place at an alternate dose level or dosing schedule via a protocol amendment. 
Up to 18 patients are expected to be enrolled in the Dose Determination Phase of the study. 
 
3.2 
Phase 2 Expansion Phase 
 
The phase 2 expansion phase is a randomized, multicenter, double-blind, placebo-controlled study 
phase. Randomization for this portion of the study is stratified by geographic location (US vs. rest 
of world). 
70 eligible patients are randomly assigned in a 1:1 ratio to either: 
 
• 
Entinostat per os (p.o.) weekly at the RP2D combined with atezolizumab at a fixed 
dose of 1200 mg iv every 3 weeks 
OR 
 
• 
Placebo combined with atezolizumab at a fixed dose of 1200 mg iv every 3 weeks 
 
Patients will follow the same schedule of study visits and assessments as specified in the Dose 
Determination Phase (with the exception of the tumor tissue biopsy at C2D15).  Patients may 


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continue study treatment until documented progressive disease, intolerable toxicity or meets one of 
the study withdrawal criteria (Protocol Section 11). 
Patients will be followed for overall survival (OS) until death (due to any cause) or the Sponsor 
terminates the trial. 
4. 
STUDY ENDPOINTS 
 
4.1 
Phase 1b Dose Determination Phase 
 
The primary endpoint of the Phase 1b Dose Determination portion of the study is the determination 
of the DLT, MTD or RP2D of entinostat in combination with atezolizumab at the dose of 1200mg . 
The following safety endpoints will also be assessed: 
• 
AEs 
• 
Clinical laboratory parameters, vital signs, physical examinations, and ECGs 
 
Exploratory endpoints will also be assessed 
 and are discussed in a separate 
SAP. 
4.2 
Phase 2 Expansion Phase 
 
4.2.1 
Primary Efficacy Endpoint 
 
The primary efficacy endpoint is PFS as determined by the local investigator using RECIST 1.1. 
 
4.2.2 
Secondary Efficacy Endpoints 
 
• 
PFS determined by the local investigator using irRECIST 
• 
ORR (CR or PR) by RECIST 1.1 
• 
ORR (irCR or irPR) by irRECIST 
• 
CBR (CR, PR or SD for at least 24 weeks) by RECIST 1.1 
• 
CBR (irCR, irPR, or irSD for at least 24 weeks) by irRECIST 
• 
OS 
 
In patients who experience a response to treatment based on RECIST 1.1 (CR or PR) or on 
irRECIST (irCR or irPR): 
• 
DOR 
• 
TTR 


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4.2.3 
Safety 
Safety endpoints are: 
• 
AEs 
• 
Clinical laboratory parameters, vital signs, physical examinations, and ECGs 
 
4.2.4 
Exploratory 
 
The exploratory endpoints will be discussed in separate SAP(s). 
 
5. 
STATISTICAL CONSIDERATIONS 
 
5.1 
Hypothesis for Phase 2 
 
The primary efficacy analysis will be the comparison of the distribution of PFS between the two 
treatment groups using a stratified logrank test at one-sided 10 % level of significance, i.e.: 
Ho: 
PFS in experimental arm (entinostat + atezolizumab) = PFS in control arm (placebo + 
atezolizumab) 
vs. 
Ha: PFS in experimental arm (entinostat + atezolizumab) > PFS in control arm (placebo + 
atezolizumab) 
 
 
5.2 
Sample Size 
 
5.2.1 
Phase 1b Dose Determination Phase 
 
Three to six patients will be enrolled in each dose cohort based on a standard Phase 1 dose-finding 
scheme. 
A starting sample size of 3 evaluable patients per dose cohort, expanding to 6 in the event of a 
marginal DLT rate (33%) was deemed to be a safe and conventional approach in dose-finding. 
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. 
6 patients will need to be treated in a dose level for it to be considered as MTD or RP2D. 


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Patients who discontinued the study for reasons other than study drug related toxicities before 
completing Cycle 1 will be replaced. 
Therefore, between 6 and 18 patients will be included in the Dose Determination Phase. 
 
5.2.2 
Phase 2 Expansion Phase 
The following assumptions are made: 
• 
Patients in the control arm have true median PFS of 4 months 
• 
Patients in the experimental arm have true median PFS of 7 months (under exponential 
distribution, true PFS hazard ratio of 0.57) 
• 
Expected accrual duration will be 9 months and an additional 9 months of follow-upThe α 
type I error rate is set to 10% (1-sided) 
• 
The β type II error rate is set to 20% (i.e. the power of the trial will be 80%) 
 
Under these assumptions, 70 patients (35 per arm) will be enrolled in the trial, which is projected to 
result in 60 PFS failures, defined as documented disease progression by RECIST 1.1 or death due 
to any cause without documented disease progression beforehand, within approximately 18 months 
of the first patient randomized. 
It is anticipated that the number of patients that drop out without PFS failure will be low (2-3%). 
Depending on the actual number of such dropouts, the number of patients accrued maybe increased 
by 6-10 patients to accommodate for a higher-than-expected number of dropouts. 
5.3 
Randomization and Stratification 
 
The randomization technique used for the study is a stochastic minimization, using 
minimization probability parameter of 0.80. The randomization is performed via ID-net 
(which is the IWRS from IDDI). 
Prior to dosing, eligible patients are randomized in a 1:1 ratio into 2 treatment arms, 
stratified by geographic location. 
5.4 
Timing of Analyses 
 
5.4.1 
Phase 1b Dose Determination Phase 
 
A safety analysis will be performed at the completion of the dose determination phase. 


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5.4.2 
Phase 2 Expansion Phase 
The following analyses are planned: 
• 
An interim safety analysis will be performed following the completion of Cycle 1 for the 
first 20 patients enrolled in the Phase 2 expansion phase, and will utilize a Data Safety 
Monitoring Board (DSMB). 
• 
An interim efficacy analysis will be performed when 45 PFS events have observed. Data 
cut-off for the analysis will be based on the calendar date of the 45th PFS event (per 
RECSIT 1.1). Safety and secondary endpoints will also be evaluated. The same data cut-off 
used for the PFS analysis is also used for the corresponding analysis of safety and 
secondary endpoints. 
• 
Primary efficacy analysis will be performed when 60 PFS events are observed. Similarly, 
the data cut-off for the primary analysis will be based on the calendar date of the 60th PFS 
event. Safety and secondary endpoints will coincide with the primary PFS analysis. 
• 
End of study analysis for safety and OS analysis will be performed when the last patient 
terminates study treatment. 
6. 
DEFINITIONS 
 
6.1 
Progression-Free Survival (PFS) 
 
The duration of PFS, defined as the number of months from randomization to the earlier of 
progressive disease or death due to any cause. One month is considered 30.4375 days. 
PFS (months) = (Date of Progression or Censoring – Date of Randomization + 1) ÷ 30.4375 
Patients who meet one or more of the following conditions at the time of primary analysis will be 
censored: 
• 
No screening or post-screening disease assessments unless death occurred prior to the first 
planned assessment. 
• 
Initiation of a new anticancer therapy in the absence of documented progression. 
• 
Death or progressive disease after missing 2 or more consecutively scheduled disease 
assessment visits 
• 
Last known to be alive and progression-free on or before the data cut-off date 


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The following table, adopted from FDA guidance “Guidance for Industry Clinical Trial Endpoints 
for the Approval of Cancer Drugs and Biologics” (May 2007) illustrates how the cases will be 
handled for primary analysis. If a patient is censored satisfying more than one criteria, the situation 
with the earliest date will be considered. 
Table 1 – Primary Rules for Determining Date of Progression or Censor for Primary Progression-Free 
Survival 
 
Situation 
Date  of  Progression  or 
Censoring 
Outcome 
1 
Death before first PD assessment 
Date of death 
Progressed 
2 
Death 
or 
disease 
progression 
between 
planned 
disease 
assessments 
Date of death or first 
disease assessment showing 
disease 
progression, 
whichever occurs first 
Progressed 
3 
No baseline tumor assessments 
Date of randomization 
Censored 
4 
New anticancer treatment started 
(in 
absence 
of 
documented 
progression) 
Date of last radiological 
assessment 
of 
measured 
lesions prior to the start of 
the   new   anticancer 
treatment 
Censored 
5 
Death or progression after more 
than 2 or more consecutive visits 
Date of last radiological 
assessment 
of 
measured 
lesions without documented 
disease progression that is 
before the first missed visit 
Censored 
6 
Last 
known to be alive and 
progression-free on or before the 
data cut-off date 
Date of last radiological 
assessment 
of 
measured 
lesions 
Censored 
 
The following sensitivity analyses will also be provided: 
 
Table 2 – Progression-Free Survival Sensitivity Analysis 


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Analysis # 
Definition and/or changes from primary analysis; unless otherwise stated, the 
same PFS censoring rules will be applied 
1 
Per-protocol analysis set, instead of full analysis set 
2 
PFS events occurring immediately after two or more missing visits will not be 
censored 
3 
Patients who discontinue treatment due to any reason other than disease 
progression or death are censored at the date of last tumor assessment prior to (or 
at) treatment discontinuation 
4 
Patients who received new anticancer treatment without documented progression 
will not be censored 
5 
Worst case analysis: A patient who is lost to follow-up (or withdrew consent from 
study participation) before documented progression will be considered progressed 
at first scheduled radiological assessment date after lost to follow-up (or withdrew 
consent) (i.e. last radiological assessment + 42 days) 
 
All analyses described above will use the same methodologies as the primary analysis, except 
changes as noted in the second column. Each analysis will modify only the rule as stated in the 
specific row; i.e. rows will not be combined unless otherwise specified. 
6.2 
Objective Response Rate (ORR) 
 
ORR is defined as the crude proportion of patients achieving a best overall response of CR or PR 
assessed using RECIST 1.1. The best overall response assessed using irRECIST will also be 
analyzed separately and the corresponding ORR will be calculated. The overall response will be 
determined locally by the investigator at each scheduled assessment. 
Per protocol (Section 10.3.1.3), partial or complete response should be confirmed by a repeat 
tumor imaging assessment not less than 4 weeks from the date the response was first documented. 
The following table will be followed to assign a best overall response based on the achievement and 
confirmation of two consecutive assessments according to RECIST 1.1: 
Overall response 
First time point 
Overall response Subsequent 
time point 
(at Least 4 Weeks Later) 
Best Overall Response 
CR 
CR 
CR 


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Overall response 
First time point 
Overall response Subsequent 
time point 
(at Least 4 Weeks Later) 
Best Overall Response 
CR 
PR 
PR 
CR 
SD 
SD 
CR 
PD 
PD 
CR 
NE 
SD 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
PD 
PR 
NE 
SD 
 
 
𝑂𝑂𝑂𝑂𝑂𝑂𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅1.1 = # 𝑜𝑜𝑜𝑜 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝 𝑤𝑤𝑤𝑤𝑤𝑤ℎ 𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏 𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜 𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟 𝑎𝑎𝑎𝑎 𝐶𝐶𝐶𝐶 𝑜𝑜𝑜𝑜 𝑃𝑃𝑃𝑃 
𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇 𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛 𝑜𝑜𝑜𝑜 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝 
 
 
Similarly, irCR or irPR based on irRECIST will also be confirmed. 
The following table is therefore used for best overall response based on irRECIST: 
 
Overall response 
First time point 
Overall response Subsequent 
time point 
(at Least 4 Weeks Later) 
Best Overall Response 
irCR 
irCR 
irCR 
irCR 
irPR 
irPR 
irCR 
irSD 
irSD 
irCR 
irPD 
irPD 
irCR 
irNE 
irSD 
irPR 
irCR 
irPR 
irPR 
irPR 
irPR 
irPR 
irSD 
irSD 
irPR 
irPD 
irPD 
irPR 
irNE 
irSD 
 
And ORR based on irRECIST is calculated as follows: 
 
𝑂𝑂𝑂𝑂𝑂𝑂𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖 = # 𝑜𝑜𝑜𝑜 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝 𝑤𝑤𝑤𝑤𝑤𝑤ℎ 𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏 𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜 𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟 𝑎𝑎𝑎𝑎 𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖 𝑜𝑜𝑜𝑜 𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖 
𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇 𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛 𝑜𝑜𝑜𝑜 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝 


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6.3 
Clinical Benefit Rate (CBR) 
 
CBR is estimated based on the crude proportion of patients in each treatment arm whose best 
overall response during the course of study treatment is CR, PR or SD lasting for at least 24 weeks 
(measured from the date of randomization to the last date where SD is reported). 
 
 
𝐶𝐶𝐶𝐶𝐶𝐶𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅 1.1 = # 𝑜𝑜𝑜𝑜 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝 𝑤𝑤𝑤𝑤𝑤𝑤ℎ 𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐 𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜 𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟 𝑎𝑎𝑎𝑎 𝐶𝐶𝐶𝐶/𝑃𝑃𝑃𝑃/ 𝑆𝑆𝑆𝑆𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙 𝑓𝑓𝑓𝑓𝑓𝑓≥24 𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤  
𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇 𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛 𝑜𝑜𝑜𝑜 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝 
 
 
Similarly, CBR is calculated based on irRECIST as below: 
 
 
𝐶𝐶𝐶𝐶𝐶𝐶𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖 = # 𝑜𝑜𝑜𝑜 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝 𝑤𝑤𝑤𝑤𝑤𝑤ℎ 𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐 𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜 𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟 𝑎𝑎𝑎𝑎 𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖/𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖/𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙 𝑓𝑓𝑓𝑓𝑓𝑓≥24 𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤 
𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇 𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛 𝑜𝑜𝑜𝑜 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝 
 
 
6.4 
Overall Survival (OS) 
 
OS is defined as the number of months from randomization to date of death from any cause. 
Patients who are alive or lost to follow-up as of a data analysis cutoff date will be right-censored. 
OS (months) = (Date of Death/Censoring – Date of Randomization + 1) ÷ 30.4375 
 
6.5 
Duration of Response (DOR) 
 
DOR is defined as the number of months from the date where a CR / PR (based on RECIST 1.1) or 
irCR / irPR (based on irRECIST) was firstly observed, to the first date that recurrent or progressive 
disease is documented. DOR will be calculated for patients who achieved a confirmed CR / PR or 
irCR / irPR. The same censoring rules for primary analysis will also apply here for patients who 
achieved a confirmed CR / PR or irCR / irPR. Patients with no baseline or post-baseline 
assessments will not be analyzed. 
DORRECIST 1.1 (months) = (Date of Progressive Disease – Date of CR/PR + 1) ÷ 30.4375 
DORirRECIST (months) = (Date of Progressive Disease – Date of irCR/irPR + 1) ÷ 30.4375 
6.6 
Time to Response (TTR) 
 
TTR is defined for the subset of patients that achieve best overall response of confirmed CR/PR or 
confirmed irCR/irPR as the number of months from date of randomization to date of the initial 
documented response of CR/PR (based on RECIST 1.1) or irCR/irPR (based on irRECIST). 


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TTRRECIST 1.1 (months) = (Date of CR/PR – Date of Randomization + 1) ÷ 30.4375 
TTR irRECIST (months) = (Date of irCR/irPR – Date of Randomization + 1) ÷ 30.4375 
6.7 
Dose-limiting Toxicity (DLT) 
 
DLT is defined as the occurrence of specific events defined in Section 9.6 of the protocol within the 
first cycle of treatment (i.e. between Day 1 to Day 21 of Cycle 1) of entinostat in combination with 
atezolizumab that are considered by the investigator to be at least possibly related to study drug 
using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.03. 
6.8 
Maximum Tolerated Dose (MTD) 
 
MTD is defined as the highest dose level at which < 33% of 6 patients experience DLT. 
 
6.9 
Recommended Phase 2 Dose (RP2D) 
 
RP2D will be equal to or less than the preliminary MTD. This will be determined in discussion with 
the sponsor, the study medical monitor and dose determination phase investigators. 
6.10 Treatment Emergent Adverse Events (TEAEs) 
 
TEAEs is defined as AEs that start on or after the first administration of study treatment or AEs that 
start before the first administration of study treatment but worsened after study treatment is 
initiated. 
6.11 Other Definitions 
 
6.11.1 Baseline 
 
The last available assessment done on or before the date of first dose of study treatment. 
If patients have no value as defined above, the baseline value will be missing. 
6.11.2 Date of First Dose 
 
The date of first dose (of study drug) is derived as the first date when a nonzero and nonmissing 
dose of study drug is administered. This can also be referred to as the start of the study treatment. 


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6.11.3 Date of Last Dose 
 
The date of last dose (of study drug) is derived as the last date when a nonzero and nonmissing dose 
of study drug is administered. 
6.11.4 Last Contact Date 
 
The last contact date will be derived for patients not known to have died at the analysis cut-off 
using the latest complete date among the following dates which precede the cut-off date: 
• 
All assessment dates (e.g. vital signs assessment, performance status assessment, tumor 
assessments, etc.) 
• 
Date patient was last known alive 
• 
Start and stop dates of concomitant medications 
• 
Start and stop dates of adverse events 
• 
Date of last dose 
• 
Date of registration (Phase 1b)/randomization (Phase 2) 
 
7. 
STUDY POPULATION 
 
7.1 
Full Analysis Set (FAS) 
 
The Full Analysis Set (FAS) includes all patients who were enrolled (for Phase 1b) or randomized 
(for Phase 2) to study treatment, regardless of whether they actually received study medication. All 
efficacy analyses will be evaluated based on data from this population set according to the 
treatment group they were assigned to at registration/randomization and based on the strata they 
were originally assigned to at the time of randomization. This population set will be identified using 
the FASFL (Full Analysis Set Population Flag) as defined in Subject-Level Analysis Dataset 
(ADSL) according to Analysis Data Model (ADaM). 
7.2 
Per-protocol Analysis Set 
 
The Per-protocol Analysis Set consists of all patients who were enrolled/randomized and did not 
have any important deviations (i.e. excludes patients with important deviations from FAS). The list 
of patients who are identified with important deviations will be provided to biostatistician(s) by 
TRIO Project Management. This population set will be identified using the PPROTFL (Per- 
Protocol Population Flag) as defined in ADSL according to ADaM. 


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7.3 
Safety Analysis Set 
 
The Safety Analysis Set consists of all patients who receive any study treatment, and will be used 
for the analysis of safety data in both Phase 1b and Phase 2 portions of the study. This population 
will be based on the first dose received at cycle 1, if this differs from that to which the subject was 
randomized and will be used for the analysis of safety data. This population set will be identified 
using the SAFFL (Safety Population Flag) as defined in ADSL according to ADaM. 
8. 
INTERIM ANALYSIS AND EARLY STOPPING RULE 
 
One interim safety analysis is planned during the Phase 2 of the study after the first 20 patients are 
treated for one cycle. As mentioned in section 5.3.2, the result of this analysis will be reviewed by 
DSMB who will act in an advisory capacity to the Sponsor with respect to safeguarding the 
interests of trial patients and assessing the safety of the interventions administered during the trial. 
As per Section 13.2 of the protocol, an interim efficacy analysis is performed when 45 PFS events 
are observed to support the Sponsor’s product development plans and ongoing resourcing activities. 
Although there are no plans to terminate the study early, the DSMB will review the results and 
decision will be made in collaboration with the Sponsor as well as the Steering Committee should 
the study needs to be terminated. 
9. 
DATA SCREENING AND ACCEPTANCE 
 
9.1 
General Principles 
 
For the planned analyses, data acceptance will be based on the creation and review of the tables, 
listings, and figures (TLF) in collaboration with Data Management and Project Management 
according to TRIO Standard Guideline SG8.1 “Validation of Statistical Analysis”. In general, TLF 
programs will be created prior to a database snapshot or database lock. Dry run(s) of TLF programs 
will be done in order to review for extreme, unusual, and missing values. Such cases will be 
identified to Data Management and Project Management for further investigation and potential 
resolution prior to a snapshot or lock of the database. As data issues are detected, additional 
procedures might be needed in order to ensure resolution in subsequent data transfer(s). 
For the final analysis, all procedures will be run to ensure previously identified data issues have 
been resolved. The TLF programs will also be run and the outputs will be reviewed to ensure no 
further data issues are found. 


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9.2 
Unblinding Plan 
 
For the Phase 2 Expansion Phase of this study, all TRIO personnel will be blinded. At the time of 
statistical analysis, only the Independent Statistician, who does not work on the study directly, will 
be unblinded. He/she will obtain the unblinded randomization file as well as unblinded medication 
list in order to unblind the data and perform the analysis accordingly. All relevant unblinded files 
will be stored separately on the network and access to the unblinded data will be restricted to the 
Independent Statistician only. Refer to TRIO Standard Operating Procedure SOP 5.7 “Blinding and 
Unblinding”. 
9.3 
Data Handling and Electronic Data Transfer 
 
All clinical data will be entered directly by the designated users at the site into the database using 
Oracle Clinical Remote Data Capture (OCRDC) according to electronic Case Report Form (eCRF) 
and will be extracted in the form of raw SAS® datasets by Data Management. Data extracts will be 
provided to biostatistician(s) on a regular basis. Once the final data queries have been generated and 
resolved, the database will be deemed “locked” and final database extract will be performed after 
official data snapshots are completed. The data used for all the analyses will be archived. 
9.4 
Handling of Incomplete and Missing Data 
 
Missing and incomplete data will be identified for investigation, and possible resolution, by Data 
Management and Project Management prior to an official database snapshot or database lock 
through review of TLF. 
Missing Data: All analyses and descriptive summaries will be based on the reported data. Unless 
otherwise specified, missing data will not be imputed or “carried forward.” 
Partial or Missing Date for Adverse Events and Concomitant Medications: 
Imputation Rules for Partial or Missing Stop Dates: 
If the month and year are present, impute the last day of that month. 
If only the year is present, impute December 31 of that year. 
If the stop date is entirely missing, assume the event or medication is ongoing. 
If a partial or complete stop date is present and the ‘ongoing’ box is checked, then it will be 
assumed that the adverse event or concomitant medication stopped and the stop date will be 
imputed if partial. 


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Imputation Rules for Partial or Missing Start Dates 
 
Start Date 
Stop Date 
Complete: 
yyyymmdd 
Partial: yyyymm 
Partial: yyyy 
Missing 
< 1st 
dose 
≥ 1st 
dose 
< 1st dose 
yyyymm 
≥ 1st dose 
yyyymm 
< 1st dose 
yyyy 
≥ 1st 
dose 
yyyy 
Partial: 
yyyymm 
= 1st dose 
yyyymm 
2 
1 
2 
1 
n/a 
1 
1 
≠ 1st dose 
yyyymm 
2 
2 
2 
2 
2 
Partial: 
yyyy 
= 1st dose 
yyyy 
3 
1 
3 
1 
n/a 
1 
1 
≠ 1st dose 
yyyy 
3 
3 
3 
3 
3 
Missing 
4 
1 
4 
1 
4 
1 
1 
 
1 = Impute the date of first dose 
2 = Impute the first of the month 
3 = Impute January 1 of the year 
4 = Impute January 1 of the stop year 
 
9.5 
Outliers 
 
Outliers will be identified through a review of TLF for investigation by Data Management and 
Project Management. All outlier data will be included in the analyses presented in this SAP. Any 
unconfirmed outlier data will be followed up by Project Management. 
9.6 
Validation Plan 
 
SAS® version 9.3 on the Windows system will be used for all TLF creation. The verification of the 
outputs, the analysis datasets as well as the review of all programs and macros created specifically 
for this study, will be conducted as outlined in TRIO Standard Operating Procedures SOP 8.3 
“Conduct of Statistical Analysis”, SOP 8.4 “Preparation of Statistical Analysis” and Standard 
Guidelines SG 8.1 “Validation of Statistical Analysis”. 


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10. STATISTICAL METHODS OF ANALYSIS 
 
Categorical variables will be summarized in frequency tables, with the counts and percentage of 
patients in each category. Percentages given in the summary tables will be rounded and thus may 
not always add up to exactly 100 percent. For continuous variables, summary statistics will include 
number of patients, mean, standard deviation, first quartile (Q1), median, third quartile (Q3), 
minimum and maximum values (range). 
10.1 Patient Disposition 
 
The patient disposition will be tabulated using the FAS. Frequency count and respective 
percentages of patients who were in each analysis set (i.e. FAS, Per-protocol, and Safety), and 
discontinued from treatment and/or study will be summarized by treatment group. The reason for 
discontinuation (from treatment and/or from study participation where applicable) will be 
summarized considering the categories specified in the case report forms. Listings of disposition 
information and analysis population will be provided as well. 
Protocol Deviation including eligibility deviations of the inclusion/exclusion criteria will be 
summarized and listed for FAS, by treatment group. 
The stratifications factor (for Phase 2 portion) will also be tabulated by treatment group. 
 
10.2 Demographics and Disease Characteristics 
 
The following demographics and baseline characteristics will be summarized and listed for the FAS 
by treatment group: 
Demographics: 
 
• 
Age, INT (Date of enrollment/randomization – Date of birth) / 365.25) 
o 
INT = integer part 
o 
Since only the year of birth is collected (YYYY), we assume the full date to be 31-Dec-YYYY 
• 
Race 
• 
Ethnicity 
• 
Menopausal Status 
• 
Weight at Baseline 
• 
Height at Baseline 
• 
ECOG Status at Baseline 
 
Disease Characteristics: 


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• 
Time from Initial Diagnosis to Randomization 
• 
Primary Tumor Location 
• 
Staging at Initial Diagnosis 
• 
Histopathological Type at Initial Diagnosis 
• 
Histopathological Grade at Initial Diagnosis 
• 
Disease Status at Registration 
• 
Time from Metastatic / Locally Recurrent Disease to Randomization 
• 
Local Estrogen Receptor Status 
• 
Local Progesterone Receptor Status 
• 
Local HER2 Status 
 
10.3 Prior Surgery for Breast Cancer 
 
Number of patients who underwent prior surgeries will be summarized by type and location of 
surgery. A listing will also be provided. 
10.4 Prior Systemic Anti-Cancer Therapy 
 
Number of regimens of prior systemic anti-cancer therapies will be summarized by type and 
indication. A listing will be provided to show the specifics of the therapies. 
10.5 Prior Radiation Therapy 
 
Number of radiation therapies will be summarized by site and indication. A listing will be provided 
to show the specifics of all reported radiation therapies. 
10.6 Medical History 
 
The medical history is coded by the most current version of Medical Dictionary for Regulatory 
Activities (MedDRA), and will be summarized for FAS by System Organ Class (SOC) and 
Preferred Term (PT) by treatment group. 
10.7 Extent of Exposure 
 
Number of Cycles, Duration of Treatment, Cumulative Dose and Relative Dose Intensity (RDI) will 
be summarized by treatment for the safety analysis set. 
Atezolizumab: 


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• 
Number of Cycles: number of cycles having total dose > 0 mg reported 
• 
Duration of Treatment (weeks) = [(Date of last dose - date of first dose) + 21] ÷ 7 
• 
Cumulative Dose (mg) = sum of total dose administered as reported 
• 
Weekly Dose Intensity (mg/week) = (Cumulative Dose) ÷ (Duration of Treatment) 
• 
Planned Weekly Dose Intensity (mg/week) = 1200mg ÷ 3 weeks = 400 
• 
RDI (%) = (Weekly Dose Intensity ÷ Planned Weekly Dose Intensity) × 100 
 
Entinostat: 
 
• 
Number of Cycles: number of cycles having total dose > 0 mg reported 
• 
Duration of Treatment (weeks) = [(Date of last dose - date of first dose) + 21] ÷ 7 
• 
Cumulative Dose (mg) = sum of total dose administered as reported 
• 
Weekly Dose Intensity (mg/week) = (Cumulative Dose) ÷ (Duration of Treatment) 
• 
Planned Weekly Dose Intensity (mg/week) = (Dose Cohort as assigned in Phase 1b or 
RP2D in Phase 2) ÷ 3 weeks 
• 
RDI (%) = (Weekly Dose Intensity ÷ Planned Weekly Dose Intensity) × 100 
 
The RDI will be additionally presented categorized (i.e., number and percentage of patients with 
RDI of < 60%, 60 - < 80%, 80 - < 90%, 90 - < 110%, ≥ 110%). 
The number and percentage of patients with dose interruptions/discontinuations or reduced 
(entinostat/placebo at Phase 2 only), along with their respective reasons will be summarized. 
For entinostat/placebo, the compliance will be summarized by visit using the following calculation: 
𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶 (%) = 𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁 𝑜𝑜𝑜𝑜 𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇 𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡 + 𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁 𝑜𝑜𝑜𝑜 𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇 𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅 × 100 
𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁 𝑜𝑜𝑜𝑜 𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇 𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷 
 
10.8 Efficacy Analyses 
 
Efficacy data for the primary endpoint and the secondary endpoints will be analyzed for the FAS 
and, where appropriate, the Per-protocol Set. Sensitivity analyses and subgroup analyses will be 
conducted as appropriate; refer to Table 2 and Table 3. Summaries and figures of the efficacy 
endpoints will be generated by treatment group as per randomization. 
10.8.1 PFS 
 
The duration of PFS will be summarized descriptively using Kaplan-Meier (KM) curves. Inferential 
comparisons between treatment arms will be made using stratified log-rank test, stratifying on 


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geographic location (US vs. Rest of World). The KM estimate of the PFS survival distribution 
function will be computed for each treatment group using PROC LIFETEST with method=KM 
option in SAS. For each treatment group, the KM estimates for the median PFS time, the first and 
third quartiles will be presented, along with approximate 95% confidence intervals (CI) calculated 
using Greenwood’s formula. Example of PROC LIFETEST code with and without stratification is 
presented below: 
* Unstratified; 
proc lifetest data=<PFS> method=km; 
time <pfsmonth>*<pfscens>(1); 
strata <trt>; 
run; 
 
* Stratified; 
proc lifetest data=<PFS> method=km; 
time <pfsmonth>*<pfscens>(1); 
strata <geographical region> / group= <trt>; 
run; 
 
 
The effect of treatment on PFS will also be compared using a stratified Cox proportional hazards 
model. The hazard ratio with two-sided 95% CI will be derived from the stratified Cox proportional 
hazards model using PROC PHREG with ties=EXACT option in the model. Homogeneity in the 
hazard ratios between randomization strata will be examined by Wald’s test. The corresponding 
results without stratification will be reported as supplemental analyses. 
Example of PROC PHREG code with and without stratification is presented below: 
* Unstratified; 
proc phreg data=PFS; 
class trt(ref='1'); 
model dfsmonth*dfscens(1)=trt / risklimits ties=exact; 
run; 
 
 
* Stratified; 
proc phreg data=PFS; 
class trt(ref='1'); 
model dfsmonth*dfscens(1)=trt / risklimits ties=exact; 
strata <geographical region>; 
run; 
 
Testing of Proportional Hazard assumption will also be done using the following stratified model: 
proc phreg data=pfs; 
model <pfsmonths>*<pfscens>(1)= <trt> / risklimits Ties=exact; 
assess var=(<trt>) ph / crpanel resample seed=199; 
strata <geographical region>; 
run; 


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In addition, Hazard Ratio for treatment effect will be estimated using a multivariate Cox 
proportional hazards model to be constructed by selecting variables among all the potential 
variables listed in the subgroup analysis (see Section 10.10) using stepwise selection method with 
entry p-value 0.05 and exit p-value 0.1. The treatment factor will be kept out of the model 
throughout the covariate selection process and only added into the final model. HR for treatment 
effect and corresponding 95% confidence interval (CI) will be estimated from the final model. 
Note that a covariate may be removed from the analysis if the number of patients/events 
representing one level of that variable is insufficient or data collected on that variable are 
insufficient. 
 
A sensitivity analysis will be performed to assess the impact of the different censoring mechanisms 
and deviations from the planned schedule of disease assessments; refer to Table 2. 
10.8.2 ORR 
 
The ORR observed in the treatment groups will be compared adjusting for the stratification 
variables using the Cochran-Mantel-Haenszel (CMH) test using PROC FREQ in SAS. A 95% CI 
will be calculated by treatment arm for the true ORR. 
Example of PROC FREQ for testing ORR is provided below: 
proc freq data=<ORR>; 
tables <trt> * <Response> / relrisk cmh; 
weight Count; 
run; 
 
 
The best overall response outcome (CR/PR/SD/PD/NE) will be summarized and tabulated for the 
FAS by treatment group. 
10.8.3 CBR 
 
The analysis of CBR will be based on the methods described above for ORR. 
 
10.8.4 OS 
 
The analysis of OS will be based on methods described above for PFS. 
 
10.8.5 DOR and TTR 
 
DOR and TTR will be summarized descriptively for each treatment arm using the KM method. 
Inferential comparisons between treatment arms for DOR and TTR are not planned. 


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10.8.6 Anticancer therapy after end of study treatment 
 
A summary of number of patients received anticancer therapy after end of study treatment will be 
tabulated by the type of therapy according to treatment group. 
10.9 Safety Analyses 
 
Safety analyses will be performed on the safety analysis set. 
 
10.9.1 Physical Examinations 
 
The number of patients who had done complete and/or symptom-directed physical examinations at 
each visit will be tabulated by treatment group. 
10.9.2 Adverse Events 
 
The reported AE term will be coded using the current version of the MedDRA. The severity of AE 
will be presented as reported by the investigator based on NCI CTCAE version 4.03. 
Incidence of TEAE will be tabulated by SOC, PT for: 
 
• 
All TEAEs 
• 
TEAEs by relationship to study treatment and maximum severity grade 
• 
TEAEs with action of study treatment delayed/interrupted or dose reduced 
• 
TEAEs with action of study treatment discontinued 
• 
Serious Adverse Events (SAE) (not Serious TEAEs) 
 
In the event a patient experiences repeat episodes of the same AE, the event with the highest 
severity grade and strongest causal relationship to study treatment will be used for purposes of 
incidence tabulations. 
All AEs leading to deaths will be summarized (not TEAEs). An AE will be considered as leading to 
death if it has a grade 5. 
Detailed listings for all AEs will be provided. A flag will be used to identify which AE is 
considered as treatment emergent. 
For the Phase 1b dose determination 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. 


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10.9.3 Death 
 
All deaths will be reported in a patient listing, which will include the primary cause of death, and 
the number of days between the date of last dose to study drug and death. 
10.9.4 Laboratory Values 
 
Hematology and serum blood chemistry will be summarized in descriptive statistics by calculating 
the mean, standard deviation, median, and range for the following: 
• 
Baseline value 
• 
Minimum post baseline value 
• 
Maximum post baseline value 
• 
Average post baseline value 
• 
Last post baseline value 
 
Laboratory values will be assigned toxicity grade when available using NCI CTCAE version 4.03. 
Shift tables 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 laboratory tests 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. 
10.9.5 ECOG Performance Status 
 
Tabulation of ECOG Performance Status results will be done for the following: 
 
• 
Baseline value 
• 
Minimum post baseline value 
• 
Maximum post baseline value 
• 
Last post baseline value 
 
A shift table will be provided as well from baseline status to the worst status of post-baseline time 
points. 


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10.9.6 Vital Signs 
 
Vital sign measurements will be summarized by descriptive statistics in the same manner described 
for laboratory values. 
10.9.7 Electrocardiogram (ECG) 
 
ECG results will be tabulated in terms of frequency and percentage of patients according to findings 
reported by investigators at the assessed time points. 
10.9.8 Concomitant Medication 
 
Prior and concomitant medications are coded to the current version of World Health Organization 
Drug Dictionary (WHODD). The generic term will be tabulated and listed by patient. 
10.10 Subgroup Analysis 
 
Subgroup analyses will be done for PFS and OS to assess internal consistency of study results and 
whether there is significant treatment heterogeneity across any of the subgroups. Tests within each 
subgroup and tests for subgroup-by-treatment-interaction terms will use an unstratified test from an 
unstratified Cox proportional hazards model. Additionally, these subgroup analyses will also be 
performed using a stratified test/model. 
The following subgroup analyses are planned: 
 
Table 3 – Planned Subgroup Analyses 
 
Subgroup 
Reason 
Geographical region (US vs. Rest of World) 
IWRS stratification factor 
Prior endocrine therapy 
Baseline demographic or prognostic factor 
Prior chemotherapy 
Baseline demographic or prognostic factor 
Prior adjuvant/neoadjuvant systemic anticancer 
therapy 
Baseline demographic or prognostic factor 
ECOG 0 vs. ECOG 1 
Baseline demographic or prognostic factor 
Disease stage at study entry: unresectable 
locally recurrent vs. metastatic 
Baseline demographic or prognostic factor 
Number of metastatic sites: ≥ 3 vs. < 3 (based 
on the location/organ; i.e. 3 liver lesions count 
Baseline demographic or prognostic factor 


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as 1 metastatic site) 
Disease-free interval: none, < 24 months, vs. > 
24months (based on the first surgery expected to 
be curative, to the first relapse/progression date) 
Baseline demographic or prognostic factor 
 
 
10.11 Pharmacokinetic and Antidrug Antibody Analyses – 
 
It will be done in a separate document. 
 
10.12 Correlative Analyses 
 
It will be done in a separate document. 
 
11. LIST OF PLANNED TABLES, FIGURES, LISTINGS 
 
11.1 Planned Tables 
 
Title 
Population 
Description 
Patient Disposition 
FAS 
Tabulates the disposition of all patients by treatment 
group, including the number of patients in each 
population set as well as the number of patients 
discontinued from study treatment, and the number of 
patients discontinued from study. The reason for drug 
discontinuation and study discontinuation will also be 
summarized. 
Stratification Factors 
FAS 
Tabulates 
the 
stratification 
factor 
(Geographic 
Location – US vs. Rest of World) by treatment group. 
(Phase 2 only.) 
Protocol Deviations 
FAS 
Tabulate the number of patients who reported protocol 
deviations by deviation category for each treatment 
group. 
Eligibility Deviations 
FAS 
Tabulates  the  number  of  patients  who  violates 
inclusion/exclusion  criteria  by  criterion  for  each 


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Title 
Population 
Description 
treatment group 
Baseline Demographics 
FAS 
Tabulates summary statistics of the demographics 
(age, race, ethnicity, menopausal status, weight, height 
and ECOG status at baseline). 
Disease Characteristics 
FAS 
and 
Safety 
Tabulates summary statistics for time from initial 
diagnosis to randomization, primary tumor location, 
staging at initial diagnosis, histopathological type at 
initial diagnosis, histopathological grade at initial 
diagnosis, disease status at registration, time from 
metastatic/locally recurrent disease to randomization, 
hormonal receptor status, and HER2 status. 
Prior Surgery for Breast 
Cancer 
FAS 
Tabulates the number of patients with type and 
location of surgery for each treatment group. 
Prior 
Systemic 
Anti- 
Cancer Therapy 
FAS 
Tabulates the number of patients by type and 
indication of the systemic cancer therapy for each 
treatment group. 
Prior Radiation Therapy 
FAS 
Tabulates the number of patients by site and indication 
of prior radiation therapy for each treatment group. 
Medical History 
FAS 
Summarizes medical history by SOC and PT for each 
treatment group. 
Study Drug Exposure 
Safety 
Summarizes the number of cycles, the duration of 
treatment, cumulative dose, and RDI by treatment 
group. 
The 
number 
of 
dose 
interruptions/discontinuation or reduction will also be 
summarized. 
Compliance 
Safety 
Compliance assessment will be summarized by each 
visit. 
Dose Limiting Toxicity 
Safety 
Tabulates the number of patients experienced DLT 


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Title 
Population 
Description 
and the corresponding DLT at cycle 1 and 2 for each 
treatment group. 
For Phase 1b only. 
Progression-Free 
Survival 
FAS1 
Summary 
of 
PFS 
results 
including 
treatment 
comparison results. Separate tables will be done for 
PFS based on RECIST 1.1 and irRECIST. 
Progression-Free 
Survival 
FAS1 
Summary 
of 
PFS 
results 
including 
treatment 
comparison results (sensitivity analysis). Separate 
tables will be done for PFS based on RECIST 1.1 and 
irRECIST. 
Objective Response 
Rate 
FAS1 
Summary of ORR results including treatment 
comparison results. Separate tables will be done for 
ORR based on RECIST 1.1 and irRECIST. 
Clinical Benefit Rate 
FAS1 
Summary of CBR results including treatment 
comparison results. Separate tables will be done for 
CBR done based on RECIST 1.1 and irRECIST. 
Overall Survival 
FAS1 
Summary of OS results by treatment group. 
Duration of Response ( 
those with CR/PR or 
irCR/irPR 
FAS1 
Summary of DOR results by treatment group. 
Time to Response (same 
comment as above) 
FAS1 
Summary of TTR results by treatment group. 
TEAEs Overview 
Safety 
Tabulates the number of patients with TEAEs, Related 
TEAEs, Grade 3 / 4 TEAEs, TEAEs with action taken 
as dose reduced or drug interrupted, TEAEs leading to 
drug withdrawn, SAE, Fatal AE. 
For Phase1b, the DLT rate will be presented. 


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Title 
Population 
Description 
TEAEs 
Safety 
Summary by SOC and PT for each treatment group. 
TEAEs 
Safety 
Summary by PT for each treatment group ordered by 
frequency. 
TEAEs per Maximum 
Grade 
Safety 
Summary by SOC and PT for each treatment group. 
TEAEs 
Related 
to 
Entinostat 
Safety 
Summary by SOC and PT for each treatment group. 
TEAEs 
Related 
to 
Entinostat 
per 
Maximum Grade 
Safety 
Summary by SOC and PT for each treatment group. 
Grade 3 / 4 TEAEs 
Safety 
Summary by SOC and PT for each treatment group. 
Grade 3 / 4 TEAEs 
Safety 
Summary by PT for each treatment group ordered by 
frequency. 
TEAEs 
Related 
to 
Atezolizumab 
Safety 
Summary by SOC and PT for each treatment group. 
TEAEs 
Related 
to 
Atezolizumab 
per 
Maximum Grade 
Safety 
Summary by SOC and PT for each treatment group. 
TEAEs 
Related 
to 
Entinostat 
and/or 
Atezolizumab 
Safety 
Summary by SOC and PT for each treatment group. 
TEAEs 
Related 
to 
Entinostat 
and/or 
Atezolizumab 
 
per 
Maximum Grade 
Safety 
Summary by SOC and PT for each treatment group. 
TEAEs 
with 
Action 
Taken 
as 
Treatment 
delayed/interrupted for 
Entinostat 
Safety 
Summary by SOC and PT for each treatment group. 
TEAEs 
with 
Action 
Taken 
as 
Treatment 
delayed/interrupted for 
Atezolizumab 
Safety 
Summary by SOC and PT for each treatment group. 
TEAEs 
with 
Action 
Taken as Dose Reduced 
Safety 
Summary by SOC and PT for each treatment group. 
(For Phase 2 only) 


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Title 
Population 
Description 
for Entinostat 
TEAEs 
Leading 
to 
Treatment 
Discontinuation 
Safety 
Summary by SOC and PT for each treatment group. 
TEAEs 
Leading 
to 
Treatment 
Discontinuation 
Safety 
Summary by PT for each treatment group ordered by 
frequency. 
SAE 
Safety 
Summary by SOC and PT for each treatment group. 
AEs Leading to Death 
Safety 
Summary by SOC and PT for each treatment group. 
Laboratory Values 
Safety 
Summary of each laboratory parameter at baseline, 
minimum post baseline value, maximum post baseline 
value, average post baseline value and last post 
baseline value for each treatment group. In addition, 
shift tables will be presented. 
ECOG 
Performance 
Status 
Safety 
Summary of ECOG performance status at each 
baseline, minimum post baseline value, maximum 
post baseline value, last post baseline value for each 
treatment group. In addition, a shift table will be 
presented. 
Vital Signs 
Safety 
Summary of descriptive statistics for each vital sign 
measurements will be done for baseline value, 
minimum post baseline value, maximum post baseline 
value, average post baseline value, and last post 
baseline value for each treatment group. 
ECG 
Safety 
Tabulate the frequency and percentage of patients 
according to findings reported at each time point for 
each treatment group. 
Prior and Concomitant 
Medications 
Safety 
Tabulate the frequency and percentage of patients 
according to 
generic name. 
Summary will  be 
presented separately for prior medications and 


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Title 
Population 
Description 
concomitant medications. 
Anticancer 
Therapy 
Received after end of 
study treatment 
FAS 
Tabulate the frequency and percentage of patients 
according to type of anticancer therapy received after 
end of study treatment. 
1 Separate tables to be produced based on per-protocol analysis set if needed. 
 
11.2 Planned Listings 
 
Title 
Population 
Description 
Screen Failures 
N/A 
Listing of screen failures and the corresponding 
reason(s) of failures. 
Patient Accountability 
FAS 
Listing of all patients and with population indicators, 
treatment groups. For patients who discontinued from 
treatment and/or study, include the reason of 
respective discontinuations. 
Demographics 
FAS 
Listing of demographics. 
Disease Characteristics 
FAS 
Listing of disease characteristics. 
Prior Surgery 
FAS 
Listing of prior surgery. 
Prior 
Systemic 
Anti- 
Cancer Therapy 
FAS 
Listing of prior systemic anti-cancer therapy. 
Prior Radiation Therapy 
FAS 
Listing of prior radiation therapy. 
Study Drug Exposure 
Safety 
Listing of patients for extent of exposure by visit. 
Study Drug Exposure 
Summary 
Safety 
Listing of patients for summary of exposure (e.g. 
number of cycles, duration of treatment, cumulative 
dose, weekly dose intensity, RDI). 
Efficacy Parameters 
FAS 
Listing of all efficacy parameters for each patient, 
including PFS, OS, best overall response, duration of 
response, and time to response. 
Tumor Assessment 
FAS 
Listing of tumor assessment including lesion number, 
date of assessment, lesion measurement/response, and 
time-point overall response assessed by RECIST 1.1 
and irRECIST. 
Anticancer 
Treatment 
Received after End of 
Study Treatment 
FAS 
Listing of anticancer therapies received after end of 
study treatment; the listing includes the type of 
therapy, start date, end date (or ongoing) 
AEs 
Safety 
Listing of all AE for each patient; the listing includes 
the verbatim term, PT, SOC, seriousness, worst grade, 
start date, outcome, stop date, relationship to study 
drug, action taken for study drug, and treatment 


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Title 
Population 
Description 
emergent flag. 
TEAEs 
Related 
to 
Entinostat 
Safety 
Listing of TEAEs in this category using the same 
structure as the AEs listing with the omission of 
treatment emergent flag. 
TEAEs 
Related 
to 
Atezolizumab 
Safety 
Listing of TEAEs in this category using the same 
structure as the AEs listing with the omission of 
treatment emergent flag. 
TEAEs 
Related 
to 
Entinostat 
and/or 
Atezolizumab 
Safety 
Listing of TEAEs in this category using the same 
structure as the AEs listing with the omission of 
treatment emergent flag. 
TEAEs 
with 
Action 
Taken 
 for 
 Drug 
Interrupted 
for 
Entinostat 
Safety 
Listing of TEAEs in this category using the same 
structure as the AEs listing with the omission of 
treatment emergent flag. 
TEAEs 
with 
Action 
Taken for Dose Reduced 
for Entinostat 
Safety 
Listing of TEAEs in this category using the same 
structure as the AEs listing with the omission of 
treatment emergent flag. 
TEAEs 
with 
Action 
Taken 
 of 
 Drug 
Interrupted 
for 
Atezolizumab 
Safety 
Listing of TEAEs in this category using the same 
structure as the AEs listing with the omission of 
treatment emergent flag. 
TEAEs Leading to Study 
Treatment 
Discontinuation 
Safety 
Listing of TEAEs in this category using the same 
structure as the AEs listing with the omission of 
treatment emergent flag. 
SAEs 
Safety 
Listing of TEAEs in this category using the same 
structure as the AEs listing . 
AEs Leading to Death 
Safety 
Listing of TEAEs in this category using the same 
structure as the AEs listing. 
Deaths 
Safety 
Listing of patients who died, including primary cause 
of death, date of death, date of last dose, and the 
number of days from date of last dose to death. 
Laboratory Values 
Safety 
Listing of all laboratory values and their assigned 
toxicity grade (where applicable). 
ECOG 
Performance 
Status 
Safety 
Listing of ECOG at each assessment. 
Vital Signs 
Safety 
Listing of all vital signs results at each assessment. 
Prior and Concomitant 
Medications 
Safety 
Listing of all prior and concomitant medications; the 
listing includes verbatim product name, generic name, 
start date, end date (or ongoing) and indication. 
Post Study Follow-up 
Safety 
Listing of patients who are being followed in post 


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Title 
Population 
Description 
study follow-up visits. 
11.3 Planned Figures 
 
Title 
Population 
Description 
PFS 
FAS 
KM plot of PFS by treatment group. 
Forest plots are done for subgroup analyses. 
OS 
FAS 
KM plot and Forest plots of OS by treatment group. 
DOR 
FAS 
KM plot of DOR by treatment group. 
TTR 
FAS 
Swimmer plot of TTR by treatment group. 
BOR 
FAS 
Waterfall plot and Spider plot of BOR for RECIST 
and irRECIST by treatment group.