Conditions: Metastatic Cholangiocarcinoma Cholangiocarcinoma Pancreatic Cancer Metastatic Pancreatic Cancer Unresectable Pancreatic Cancer Unresectable Cholangiocarcinoma
Keywords: Immunotherapy Nivolumab Entinostat Pancreatic Adenocarcinoma Cholangiocarcinoma Unresectable Metastatic PD-1 Antibody
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 44
Healthy volunteers: no

Brief summary:
The proposed study is an open-label, two-arm study of entinostat plus nivolumab in patients with unresectable or metastatic cholangiocarcinoma (CCA) or pancreatic ductal adenocarcinoma (PDAC).

Detailed description:

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: Entinostat intervention 2: Nivolumab intervention 3: Entinostat intervention 4: Nivolumab
Intervention descriptions: intervention 1: Entinostat (5mg) will be administered starting with 2 lead-in doses at 14 and 7 days before the first dose of nivolumab in combination with entinostat. After the lead-in dose, entinostat will be administered once a week (days 1, 8, 15, and 21 of each treatment cycle). intervention 2: After both lead-in doses of entinostat, nivolumab (240 mg) will be administered every 2 weeks (day 1 and day 15 of a cycle). intervention 3: Entinostat (5mg) will be administered starting with 2 lead-in doses at 14 and 7 days before the first dose of nivolumab in combination with entinostat. After the lead-in dose, entinostat will be administered once a week (days 1, 8, 15, and 21 of each treatment cycle). intervention 4: After both lead-in doses of entinostat, nivolumab (240 mg) will be administered every 2 weeks (day 1 and day 15 of a cycle).

Protocol document:
Prot_SAP_000.pdf: 
 
 
Cover Page for Protocol  
NCT Number:  
NCT03250273  
Official title of study:  
A Phase 2 Clinical Trial of Entinostat in  
Combination with Nivolumab for Patients with 
Previously Treated Unresectable or Metastatic  
Cholangiocarcinoma and Pancreatic  
Adenocarcinoma  
Document Date:  
May 21, 2020  
  


 
 


 
 
  
 
  
Version:   
Original/ Version 1/July 5, 2017  
Original/ Version 1.1/July 27, 2017  
Original/ Version 1.2/July 28, 2017  
Original/ Version 1.3/August 11, 2017  
Original/ Version 1.4/October 10, 2017  
Amendment 1/ Version 2.0/March 19, 2018  
Amendment 2/ Version 3.0/April 25, 2019  
Amendment 3/Version 4.0/October 10, 2019  
Amendment 3/Version 5.0/May 21, 2020  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Phase 2 Study Of Entinostat and Nivolumab in Unresectable or Metastatic Cholangiocarcinoma   
and Pancreatic Adenocarcinoma   
Principal Investigator:  Nilofer Azad, M.D.  


  
  
STUDY GLOSSARY  
Abbreviation/Acronym  
Definition  
2  
J1798/Version 5.0/May 21, 2020  
Phase 2 Study Of Entinostat and Nivolumab in Unresectable or Metastatic Cholangiocarcinoma   
and Pancreatic Adenocarcinoma   
Principal Investigator:  Nilofer Azad, M.D.  
J1798/Version 5.0/May 21, 2020  
  
AE  
Adverse event  
ALP  
Alkaline phosphatase  
ALT  
Alanine aminotransferase  
ANC  
Absolute neutrophil count  
aPTT  
Activated partial thromboplastin time  
AST  
Aspartate aminotransferase  
AZA  
5-Azacitadine  
BSA  
Body surface area  
BUN  
Blood urea nitrogen  
CBC  
Complete Blood Count  
CI  
Confidence interval  
CNS  
Central nervous system  
CpG  
Dinucleotides containing cytosine and guanine  
CR  
Complete response  
CrCl  
Creatinine clearance  
CT  
Computed tomography  
CTCAE  
Common Terminology Criteria for Adverse Events  
CTLA-4  
Cytotoxic T-lymphocyte-associated antigen-4  
DKA  
Diabetic ketoacidosis  
DNA  
Deoxyribonucleic acid  


  
  
STUDY GLOSSARY  
Abbreviation/Acronym  
Definition  
3  
J1798/Version 5.0/May 21, 2020  
Phase 2 Study Of Entinostat and Nivolumab in Unresectable or Metastatic Cholangiocarcinoma   
and Pancreatic Adenocarcinoma   
Principal Investigator:  Nilofer Azad, M.D.  
EC  
Ethics Committee  
ECG  
Electrocardiogram  
ECI  
Events of clinical interest  
ECOG  
Eastern Cooperative Oncology Group  
eCRF  
Electronic case report form  
EDC  
Electronic data capture  
EMA  
European Medicines Agency  
EOT  
End of Treatment  
FDG  
18F-deoxyglucose  
FGFR  
Fibroblast Growth Factor Receptor  
FoxP3  
Forkhead box P3  
G-CSF  
Granulocyte-colony stimulating factor  
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  
ICH  
International Conference on Harmonisation  
IFN-  
Interferon-gamma  
Ig  
Immunoglobulin  
IND  
Investigational New Drug Application  


  
  
STUDY GLOSSARY  
Abbreviation/Acronym  
Definition  
4  
J1798/Version 5.0/May 21, 2020  
Phase 2 Study Of Entinostat and Nivolumab in Unresectable or Metastatic Cholangiocarcinoma   
and Pancreatic Adenocarcinoma   
Principal Investigator:  Nilofer Azad, M.D.  
INR  
International normalized ratio  
irAE  
Immune-related adverse events  
IRB  
Institutional Review Board  
irRECIST  
Immune-related Response Evaluation Criteria in Solid Tumors  
IV  
Intravenous(ly)  
LDH  
Lactic dehydrogenase  
mAb  
Monoclonal antibody  
MDSC  
Myeloid-derived suppressor cells  
MRI  
Magnetic resonance imaging  
MTD  
Maximum tolerated dose  
NCI  
National Cancer Institute  
NSCLC  
Non-small cell lung cancer  
NYHA  
New York Heart Association  
ORR  
Overall response rate  
OS  
Overall survival  
PBMCs  
Peripheral Blood Mononuclear Cells  
PD  
Progressive disease  
PDAC  
Pancreatic Ductal Adenocarcinoma  
PD-1  
Programmed death receptor-1  
PD-L1  
Programmed death ligand-1  
PD-L2  
Programmed death ligand-2  
PET  
Positron emission tomography  


  
  
STUDY GLOSSARY  
Abbreviation/Acronym  
Definition  
5  
J1798/Version 5.0/May 21, 2020  
Phase 2 Study Of Entinostat and Nivolumab in Unresectable or Metastatic Cholangiocarcinoma   
and Pancreatic Adenocarcinoma   
Principal Investigator:  Nilofer Azad, M.D.  
PFS  
Progression-free survival  
PK  
Pharmacokinetic  
PO  
By mouth  
PR  
Partial response  
PT  
Prothrombin time  
RBC  
Red blood cell (count)  
RECIST  
Response Evaluation Criteria in Solid Tumors  
SAE  
Serious adverse event  
SC  
Subcutaneous(ly)  
SD  
  
  
Stable Disease  
SOC  
System organ class  
T1DM  
Type 1 diabetes mellitus  
T3  
Triiodothyronine  
T4  
Thyroxine  
TEAEs   
Treatment-emergent adverse events 
TGF  
Transforming growth factor  
TIL  
Tumor-infiltrating lymphocyte  
TKI  
Tyrosine kinase inhibitor  
TME  
Tumor microenvironment   
TSH  
Thyroid stimulating hormone  
ULN  
Upper limit of normal  
WBC  
White blood cell (count)  


  
  
STUDY GLOSSARY  
Abbreviation/Acronym  
Definition  
6  
J1798/Version 5.0/May 21, 2020  
Phase 2 Study Of Entinostat and Nivolumab in Unresectable or Metastatic Cholangiocarcinoma   
and Pancreatic Adenocarcinoma   
Principal Investigator:  Nilofer Azad, M.D.  
 WOCBP  
 
Women of child-bearing potential  
 
  


 
 


  
  
  
  
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Phase 2 Study Of Entinostat and Nivolumab in Unresectable or Metastatic Cholangiocarcinoma   
and Pancreatic Adenocarcinoma   
Principal Investigator:  Nilofer Azad, M.D.  
STUDY GLOSSARY .................................................................................................................... 
2 SCHEMA 
....................................................................................................................................... 6 1. 
OBJECTIVES ......................................................................................................................... 10  
1.1 Primary Objective ....................................................................................................... 10  
1.2 Secondary Objectives.................................................................................................. 10  
1.3 Exploratory Objectives ............................................................................................... 10  
1.4 Primary Endpoint ........................................................................................................ 11  
1.5 Secondary Endpoints .................................................................................................. 11  
1.6 Exploratory Endpoints ................................................................................................ 11  
2. BACKGROUND AND RATIONAL ..................................................................................... 
12  
2.1 Disease(s) Background ............................................................................................... 12  
2.2 Immunotherapy ........................................................................................................... 13  
2.3 Epigenetics Changes as a Target for New Therapy .................................................... 15  
2.4 Immunotherapy as an Anticancer Strategy in PDAC and CCA ................................. 18  
2.5 Investigational Agents ................................................................................................ 20  
2.6 Entinostat in Combination with PD-1 Checkpoint Inhibition: Rational of the Study 26  
3. PATIENT SELECTION ........................................................................................................ 33  
3.1 Eligibility Criteria ....................................................................................................... 33  
3.2 Exclusion Criteria ....................................................................................................... 34  
3.3 Inclusion of Women and Minorities ........................................................................... 37  
4. TREATMENT PLAN ............................................................................................................. 
38  
4.1 Agents Administration ................................................................................................ 38  
4.2 Overall Study Design .................................................................................................. 38  


  
  
  
  
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Phase 2 Study Of Entinostat and Nivolumab in Unresectable or Metastatic Cholangiocarcinoma   
and Pancreatic Adenocarcinoma   
Principal Investigator:  Nilofer Azad, M.D.  
4.3 Definition of Unacceptable Toxicities ........................................................................ 39  
4.4 Study Drugs ................................................................................................................ 40  
4.5 Supportive Care Guidelines and General Concomitant Medication ........................... 41  
4.6 Definition of an Overdose for this Protocol ................................................................ 45  
4.7 WOCBP, Contraception, Use in Pregnancy, Use in Nursing ..................................... 45  
4.8 Duration of Treatment and Criteria for Removal from Treatment ............................. 48  
4.9 Treatment Beyond Progression ................................................................................... 49  
4.10 Duration of Follow Up .............................................................................................. 50  
5. DOSING DELAYS/DOSE MODIFICATIONS ................................................................... 
51  
5.1 Dose Criteria ............................................................................................................... 51 
6. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................. 
62 
6.1 Study Drugs ................................................................................................................ 62  
6.2 Adverse Events Definition .......................................................................................... 63  
6.3 Reporting Procedures for All Adverse Events ............................................................ 65  
6.4 Serious Adverse Event Reporting Procedures ............................................................ 67  
6.5 Pregnancy and Lactation Reporting Procedures ......................................................... 68  
6.6 Reporting of Overdose to the Sponsor ........................................................................ 69  
6.7 Follow-Up of Adverse Events .................................................................................... 69  
  
6.8 Reconciliation of SAEs………………………………………………………………69  
6.9 Safety Reporting to Health Authorities, Ethics Committees/Institutional Review  
Boards and Investigators ................................................................................................... 70  
6.10 Food and Drug Administration (FDA) Reporting .................................................... 70  
6.11 Protocol Deviations Due to an Emergency or Adverse Event .................................. 71  
6.12 Safety Monitoring ..................................................................................................... 71  


  
  
  
  
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Phase 2 Study Of Entinostat and Nivolumab in Unresectable or Metastatic Cholangiocarcinoma   
and Pancreatic Adenocarcinoma   
Principal Investigator:  Nilofer Azad, M.D.  
7. PHARMACEUTICAL INFORMATION ............................................................................. 
72  
7.1 Entinostat (NSC #706995) .......................................................................................... 72  
7.2 Nivolumab (NSC #748726) ........................................................................................ 73  
8. MEASUREMENT OF EFFECT ........................................................................................... 
76  
8.1 Antitumor Effect – Solid Tumors (RECIST 1.1) ........................................................ 76  
8.2 Definitions................................................................................................................... 77  
8.3 Response Criteria ........................................................................................................ 80  
8.4 Safety/tolerability ........................................................................................................ 
84  
9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES .......................................... 
85  
9.1 Overview ..................................................................................................................... 
85  
9.2 Collection of Specimens ............................................................................................. 85  
9.3 Methods....................................................................................................................... 87  
10. STUDY CALENDAR ........................................................................................................... 89 
11. DATA REPORTING / REGULATORY REQUIREMENTS .......................................... 
95  
11.1 Data Management ..................................................................................................... 95  
11.2 Data Confidentiality and Subject Anonymity ........................................................... 95  
11.3 Protocol Compliance ................................................................................................. 95  
11.4 Safety meetings ......................................................................................................... 96 
11.5 Monitoring ................................................................................................................ 96 
12. STATISTICAL CONSIDERATIONS ................................................................................ 
97  
12.1 Overall Study Design ................................................................................................ 97  


  
  
  
  
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Phase 2 Study Of Entinostat and Nivolumab in Unresectable or Metastatic Cholangiocarcinoma   
and Pancreatic Adenocarcinoma   
Principal Investigator:  Nilofer Azad, M.D.  
12.2 Sample Size and Accrual Rate .................................................................................. 97  
12.3 Study Endpoints Analyses ........................................................................................ 98  
13. REFERENCES .................................................................................................................... 
101 14. APPENDICES 
..................................................................................................................... 111  
Appendix A: Eastern Cooperative Oncology Group Performance Status Scale, with  
Equivalent Karnofsky Performance Status Scores ......................................................... 111  
Appendix B:  Patient Drug Information Handout and Wallet Card ................................ 112  
Appendix C:  Entinostat Drug Diary .............................................................................. 114  
Appendix D: Management Algorithms for Nivolumab -Related Adverse Events ......... 115  
Appendix E: Concomitant Medications to be Avoided .................................................. 123  
Appendix F: Serious Adverse Event Reporting Form .................................................... 124  
Appendix G: Nivolumab Product Information Table ..................................................... 126  
  
  
  
  
  
  
  
  
  
1. OBJECTIVES  
  
1.1 Primary Objective  
  
1.1.1  To determine the objective response rate (ORR) of entinostat plus nivolumab in patients 
with unresectable or metastatic cholangiocarcinoma and unresectable or metastatic 
pancreatic adenocarcinoma, who have progressed after one more two lines of prior 
therapy.  


  
  
  
  
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J1798/Version 5.0/May 21, 2020  
Phase 2 Study Of Entinostat and Nivolumab in Unresectable or Metastatic Cholangiocarcinoma   
and Pancreatic Adenocarcinoma   
Principal Investigator:  Nilofer Azad, M.D.  
  
1.2 Secondary Objectives  
  
1.2.1 To assess the safety and tolerability of entinostat plus nivolumab in patients with 
unresectable or metastatic cholangiocarcinoma and unresectable or metastatic 
pancreatic adenocarcinoma.   
   
1.2.2 To assess the progression free survival (PFS) status of patients with unresectable or 
metastatic 
cholangiocarcinoma 
and 
unresectable 
or 
metastatic 
pancreatic 
adenocarcinoma treated with entinostat plus nivolumab at 6, 12 and 24 months.   
  
1.2.3 To determine the overall survival (OS) status of subjects with unresectable or metastatic 
cholangiocarcinoma and unresectable or metastatic pancreatic adenocarcinoma treated 
with entinostat plus nivolumab.  
  
1.2.4  To determine the overall survival (OS) status of subjects with unresectable or metastatic 
cholangiocarcinoma and unresectable or metastatic pancreatic adenocarcinoma treated 
with entinostat plus nivolumab at 6 months, at 1, 2 and 3 years.  
  
1.2.5 To assess the duration of response among subjects who demonstrate an objective 
response to treatment with entinostat in combination with nivolumab.  
  
1.3 Exploratory Objectives  
  
1.3.1 To measure the baseline levels of  immune markers including CD8+ T effector cells and 
CD4+FoxP3+ T regulatory cells, PD-L1 expression and tumor infiltrating lymphocytes 
(TILs), major histocompatibility complex (MHC) class I and II expression, and natural 
killer (NK) cell receptors and ligands expression and correlate these variables with 
treatment response and toxicity.  
  
1.3.2 To characterize changes in the immune markers described above after treatment  
  


  
  
  
  
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Phase 2 Study Of Entinostat and Nivolumab in Unresectable or Metastatic Cholangiocarcinoma   
and Pancreatic Adenocarcinoma   
Principal Investigator:  Nilofer Azad, M.D.  
1.3.3 To identify gene expression changes in malignant tissue after therapy, and complete gene 
set analysis to elucidate affected pathways  
  
1.3.4  To measure changes in circulating immune suppressor cells (myeloid derived 
suppressor cells (MDSC), Treg) in peripheral blood by flow cytometry and test for 
association with response to therapy.  
  
1.3.5 To assess the baseline characteristics of the subjects enrolled and to correlate these 
molecular and clinicopathologic criteria with treatment response and toxicity.   
  
1.4 Primary Endpoint  
  
1.4.1 ORR, defined as the proportion of patients achieving a complete response (CR) or partial 
response (PR) based on the Response Evaluation Criteria in Solid Tumors (RECIST 1.1) 
at any time during the study, of entinostat in combination with nivolumab in patients 
with unresectable or metastatic cholangiocarcinoma and unresectable or metastatic 
pancreatic adenocarcinoma.  
  
1.5 Secondary Endpoints     
  
1.5.1 Adverse events as graded by NCI CTCAE active version.  
  
1.5.2 Progression Free Survival (PFS) status at 6, 12 and 24 months.  
  
1.5.3 Duration of Response (DOR).  
  
1.5.4 Overall Survival (OS).  
  
1.5.5 OS at 6 months, at 1, 2 and 3 years  
  
1.6 Exploratory Endpoints  
  


  
  
  
  
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Phase 2 Study Of Entinostat and Nivolumab in Unresectable or Metastatic Cholangiocarcinoma   
and Pancreatic Adenocarcinoma   
Principal Investigator:  Nilofer Azad, M.D.  
1.6.1 Changes in immune-related biomarkers (e.g., expression of checkpoint receptors 
(PD1/PD-L1), the number of MDSCs, inflammatory T cell signature, in tumor biopsies 
and peripheral blood pre- and post-therapy and their correlation with response to 
therapy.  
1.6.2 Gene expression changes in circulating DNA and malignant tissue after therapy, and 
complete gene set analysis to elucidate affected pathways  
1.6.3 Changes in circulating immune suppressor cells (MDSC, Treg) in peripheral blood by 
flow cytometry and test for association with  response to therapy   
  
  
  
  
  
  
2. BACKGROUND AND RATIONAL  
  
2.1 Disease(s) Background  
  
2.1.1 Pancreatic Adenocarcinoma  
  
Pancreatic ductal adenocarcinoma (PDAC) constitutes one of the most aggressive malignancies 
with a 5-year survival rate of <7%, due to growing incidence, late diagnosis and insufficient 
treatment options [1]. Although intensified cytostatic combinations, particularly gemcitabine plus 
nabpaclitaxel and the folinic acid, fluorouracil, irinotecan, oxaliplatin  (FOLFIRINOX) protocol, 
provide some improvement in efficacy and survival compared with gemcitabine alone, a 
breakthrough in the treatment of metastatic pancreatic cancer remains out of sight [2, 3]. The 
nanoliposomal formulation of irinotecan, MM-398, in combinations with 5FU resulted in a two 
month improvement in median survival compared to 5FU and leucovorin [4]. Similarly the 
combination of weekly 5FU, leucovorin and oxaliplatin after gemcitabine failure resulted in a 
median overall survival of 5.9 months versus 3.3 months for weekly 5FU and leucovorin in the 
CONKO-003 trial [5]. However, a more recent trial showed no difference in outcome with 5FU 
versus 5FU and oxaliplatin in the same setting [6].  
  


  
  
  
  
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Phase 2 Study Of Entinostat and Nivolumab in Unresectable or Metastatic Cholangiocarcinoma   
and Pancreatic Adenocarcinoma   
Principal Investigator:  Nilofer Azad, M.D.  
Based on this, there is an urgent need for the development of more effective therapies in second 
line and beyond for advanced PDAC. One of the emerging interests in PDAC therapy is 
immunotherapy because these tumors generally escape immune surveillance through various 
mechanisms [7]. Unfortunately to date, monotherapy with immune checkpoint blockade that have 
being investigated, resulted ineffective in PDAC.   
  
Given the great promise of immune-based therapies in other malignancies, there is reason to hope 
that modulating the tumor microenvironment could also augment tumor control in this context (see 
Sections 2.4 and 2.5).  
  
 2.1.2 Cholangiocarcinoma  
  
Cholangiocarcinoma (CCA) is the most common biliary tract malignancy and the second most 
common primary hepatic malignancy. It is classified into intrahepatic (iCCA) and extrahepatic 
cholangiocarcinoma (eCCA) subtypes, the latter often further divided in perihilar (pCCA), and 
distal (dCCA).  The overall prognosis of CCA is dismal, with surgery as the only option for cure, 
but given the propensity for early metastasis and high recurrence, 5-year OS ranges from 14 to 40 
% after surgical resection [8, 9]. In the setting of metastatic disease we still have limited treatment 
options, and so far the combination of gemcitabine and cisplatin has been established as the 
standard of care first line systemic therapy option with a median survival of 11 months [10]. There 
are no established second line treatment options [9, 11].   
  
This huge unmet clinical need supports exploring novel therapies. Our understanding of the 
molecular tumor biology of CCA has been increased in the last years. For instance, Isocitrate 
Dehydrogenase 1 or 2 (IDH1/2), BAP1 mutations and FGFR fusions are more likely to occur in 
iCCA while KRAS, p53, and SMAD4 mutations are more common in eCCA. The mutational 
aberrations landscape vary with etiology, ethnicity and association with chronic liver disease too 
[9, 11]. Several clinical trials have demonstrated the potential role of monoclonal antibodies in 
improving patient outcomes via the targeting of interactions between immune regulatory 
checkpoint molecules and their ligands.  
  


  
  
  
  
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Phase 2 Study Of Entinostat and Nivolumab in Unresectable or Metastatic Cholangiocarcinoma   
and Pancreatic Adenocarcinoma   
Principal Investigator:  Nilofer Azad, M.D.  
Despite this growing body of evidence, it remains unknown whether this adaptive immune 
resistance pathway is relevant among patients with CCA and whether similar novel therapies might 
eventually be useful as adjunct therapies for these patients.  
Several data suggest that the Programmed Death-1 (PD-1) and its ligands (Programmed 
DeathLigand 1, PD-L1) pathway may be actively suppressing the host immune response in patients 
with ICC and can be a potential target for future therapies, providing a rationale for clinical trials 
to assess the efficacy and safety of anti-PD-1/PD-L1 therapies among patients with ICC (see 
Section  
2.4 and 2.5).  
  
2.2 Immunotherapy   
  
Immunotherapy is defined as the approach to treating cancer by generating or augmenting an 
immune response against it. Immunomodulation is based on the finding that stimulation of   
T‑cell function with antibodies that block or activate regulatory receptors, can cause the regression 
of some tumors. The generation of immunological memory is another unique feature of immune 
modulation as an effective cancer therapy [12].    
  
As far, antitumor immunotherapy has broad potential and could be used to treat many different 
types of advanced stage cancers owing to the durable and robust responses it elicits across a diverse 
spectrum of malignancies. Recent evidence highlights the pivotal role of the anti-cytotoxic T-cell 
lymphocyte-associated protein 4 (CTLA-4) receptor, and PD-1 T cell co-receptor and its ligands 
B7-H1/PD-L1 and B7-DC/PD-L2 in maintaining an immunosuppressive tumor microenvironment 
(TME), as part of the so called immune checkpoints family [13-15]. Immune-cell-targeted 
monoclonal antibodies (mAbs) therapy against these checkpoints inhibitors has emerged as 
particularly effective, having the potential to enhance and sustain endogenous immunity against 
tumor antigens and establishing durable tumor control.   
Clinical trials with anti–CTLA-4, anti–PD-1, and anti–PD-L1 mAbs, showed remarkable 
therapeutic responses [16-19], underscoring the idea that disruption of immune checkpoints can be 
therapeutically useful.   
  


  
  
  
  
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Phase 2 Study Of Entinostat and Nivolumab in Unresectable or Metastatic Cholangiocarcinoma   
and Pancreatic Adenocarcinoma   
Principal Investigator:  Nilofer Azad, M.D.  
Since, immunomodulatory mAbs target immune cells rather than cancer cells, we expect they are 
not necessarily specific to any cancer type.  However, despite the breakthroughs of the past decade, 
the successes to date do not fully capture the promise of immunotherapy: the objective responses 
are observed in a minority of the treated patients and tumor types, and the reasons why certain 
tumors respond and others do not are not fully understood [20].   
  
It has been hypothesized that some tumor types with a more “immunogenic profile” that naturally 
attract T cell infiltration, are more likely to respond to checkpoint blockade. Evidence for this 
hypothesis is supported by data from studies in which a subset of lung adenocarcinomas with 
higher levels of somatic mutations had increased levels of inflammation-related gene expression 
and immune-checkpoint effector molecules, including PD‑L1 and the evidence that the prevalence 
of neoantigens can be predictive of the response to checkpoint blockade with PD‑1‑targeted 
therapy in patients with non-small cell lung cancer (NSCLC), and with CTLA‑4‑targeted therapy 
in those with melanoma [21, 22].   
  
Conversely, tumors with low neoantigen-presenting capacity, such as those that have a reduced 
number of potentially immunogenic somatic mutations or that do not present neoantigens through 
downregulated antigen processing, presentation or HLA expression might be overlooked by 
endogenous T cells [12, 23]. In this situation, antigen presentation and tumor-infiltrating 
lymphocytes (TILs) burden will likely be low, and immune-modulating mAbs alone would be 
less likely to generate a robust antitumor response, unless it is administered in the proper 
therapeutic context.  
  
For instance, CCA and PDAC, has generally been considered a nonimmunogenic malignancy, 
insofar as tumor-infiltrating effector T lymphocytes do not represent a histopathologic hallmark of 
this disease. To date, studies of anti–CTLA-4 and anti–PD-1 mAbs have failed to demonstrate any 
objective responses in this setting, unless in the small fraction (about 3% of PDAC) of patients 
with hypermutated tumors and microsatellite instability [24].  
  
Strategies to sensitize these tumors to checkpoint inhibition are warranted and the epigenetic 
modulation seem to play a very important role in this framework.   
  


  
  
  
  
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Phase 2 Study Of Entinostat and Nivolumab in Unresectable or Metastatic Cholangiocarcinoma   
and Pancreatic Adenocarcinoma   
Principal Investigator:  Nilofer Azad, M.D.  
  
  
2.3 Epigenetics Changes as a Target for New Therapy   
  
The properties of a cell are determined both by its genetic information and by the pattern in which 
its genes are expressed. This pattern of expression must be heritable itself, and also highly 
adaptable. The non-genetic determinants that precisely control the patterns of gene expression in 
cells are commonly referred to as epigenetic mechanisms [25].   
Cancer cells represent a complex interplay between genetic and epigenetic abnormalities that, from 
beginning to end, drive the evolution of each patient’s malignancy. It has been demonstrated that 
virtually all tumors harbour mutations in genes that control the epigenome [26].   
  
Four major mechanisms are involved in the epigenetic regulation of gene expression patterns: 
covalent modification of DNA; covalent modification of histones; non-protein-coding RNAs  
(microRNAs –miRNAs-) and long non-coding RNAs (lncRNAs). Currently, the most studied and 
recognized cancer-specific epigenetic changes are alterations in DNA methylation and histone 
acetylation [27-29].  
  
Cancer-specific hypermethylation of hundreds of genes per tumor, typically involves normally 
unmethylated, dinucleotides containing cytosine and guanine (CpG) -enriched DNA sequences 
(so called the CpG islands) that reside in and around proximal gene promoters [27]. This 
hypermethylation can be associated with decreased gene expression, thus providing an alternative 
way to silence well known tumor suppressor genes. This mechanism is nowadays recognized as 
an early and central event in carcinogenesis [28, 29].   
  
Additionally, cancer-specific epigenetic chromatin events involve modifications of histone 
proteins, including histone deacetylation as well as decreases in methylation at lysine 4 of histone 
3 (H3K4an), that is known to be an active mark of gene transcription at promoters of DNA 
hypermethylated genes [30, 31]. These changes led to an important change in chromatin 
conformation, resulting in a close configuration and, indeed, in a decreased gene expression, even 
in the absence of DNA methylation.   
  


  
  
  
  
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These epigenetic changes contribute to tumorigenesis and to resistance to common therapies of 
many types of cancer, including PDAC and CCA. A number of elegantly conducted translational 
studies have provided significant evidence that dysregulation of chromatin organization strongly 
contributes to the aggressive behavior of PDAC and CCA, by promoting cellular plasticity and 
therapeutic resistance. In addition, whole genomic sequencing revealed pathogenic mutations and 
structural variants in several epigenetic regulator genes in these cancer types [32, 33].    
  
Consequently, several clinical trials have been initiated to determine the safety and efficiency of 
epigenetic drugs in patients with PDAC and CCA.DNA methyltransferase and HDAC inhibitors 
have been in clinical development as single agents for a number of years. Three HDAC inhibitors, 
vorinostat (Zolinza), romidepsin (Istodax) and panobinostat (Farydak) have reached approval by 
the US Food and Drug Administration (FDA) or by the European Medicines Agency (EMA) for 
the treatment of cutaneous T-cell lymphoma (vorinostat and romidepsin), peripheral T-cell 
lymphoma (romidepsin) and multiple myeloma (vorinostat and panobinostat). The presumptive 
mechanism of action of these drugs is the activation of tumor suppressor genes or 
immunityassociated genes silenced in tumor cells [34, 35].    
  
Study by Hopkins scientists discovered another important mechanism: the induction of a 
substantial reduction of the number of tumor-infiltrating myeloid derived suppressor cells  
(MDSCs) especially when combined with immune checkpoint blockade, as discussed below [36].    
  
2.3.1 HDAC Inhibitors  
  
Histone acetylation is controlled by a balance in activity between histone acetyltransferase (HAT) 
and HDAC. HDAC inhibitors are critically important in the regulation of gene expression and in 
the field of target-specific anticancer drug development [34, 35, 37, 38]. The HDACs exert their 
targeted action during post-translational acetylation of core nucleosomal histones, which affects 
chromatin structure, thereby regulating gene expression.   
  
DNA that is wrapped around condensed, non-acetylated histones is transcriptionally inactive, 
whereas acetylation of N-terminal histone lysine residues exposes DNA to important transcription 
factors that promote transcriptional activity.  The action of HDACs on nucleosomal histones leads 


  
  
  
  
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to tight coiling of chromatin and silencing of expression of various genes, including those 
implicated in the regulation of cell survival, proliferation, differentiation, and apoptosis [34, 35].   
  
The effects of HDACs are not limited to histone deacetylation. HDACs also act as members of a 
protein complex to recruit transcription factors to the promoter region of genes, including those of 
tumor suppressors, and they affect the acetylation status of specific cell cycle regulatory proteins. 
Because aberrant HDAC activity has been implicated in a variety of cancers, development of 
HDAC inhibitors is a rational approach to the design of targeted anticancer therapeutics [35]. 
Several HDAC inhibitors have been studied in phase 1 and 2 trials in hematological malignancies 
and solid tumors. A number of recent observations have led to the suggestion that the antitumor 
activity of HDACi may be in part due also to their immunomodulatory properties, by regulating 
cytokine production, altering activation and function of macrophage and dendritic cells, regulating 
the transcription of major histocompatibility class I and II, or the activation of costimulatory 
molecules, and increasing the function of Tregs and enhancing their immunosuppressive effect in 
vivo [28, 29, 35].   
  
Recent preclinical investigations highlight the Tregs-targeting and immune-promoting effect of a 
class I specific HDAC inhibitor, entinostat, in combination with either IL-2 in a murine renal cell 
carcinoma (RENCA) model or a surviving based vaccine therapy (SurVaxM) in a castration 
resistant prostate cancer (CR Myc-CaP) model [39].  
  
2.3.1.1 Rationale for use HDAC inhibitors in cholangiocarcinoma   
  
Expression of HDACs was studied in CCA cell lines (M213, M214 and KKU-100) and an 
immortal cholangiocyte (MMNK1) by semi-quantitative reverse transcription-PCR, demonstrating 
that HDACs were expressed in all studied cell types. HDAC inhibitors in this study inhibited cell 
proliferation in a dose-dependent manner. Interestingly, KKU-100 which was less sensitive to 
classical chemotherapeutic 5-FU was highly sensitive to HDAC inhibitors. Simultaneous 
combination of subtoxic doses of HDAC inhibitors and 5-FU significantly inhibited cell 
proliferation in CCA cell lines compared to single agent treatment, showing a synergistic antitumor 
potential of simultaneous combination of HDAC inhibitors and cytotoxic chemotherapy [40].   
  


  
  
  
  
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Another study investigate the antiproliferative effect of the HDAC inhibitor, entinostat, on CCA 
cells alone and in combination with conventional cytostatic drugs (gemcitabine or doxorubicin) or 
the novel anticancer agents sorafenib or bortezomib, using two human bile duct adenocarcinoma 
cell lines (EGI-1 and TFK-1). They demonstrated that entinostat treatment potently inhibited the 
proliferation of EGI-1 and TFK-1 CCA cells by inducing apoptosis and cell cycle arrest. 
Entinostat-induced apoptosis was characterized by activation of caspase-3, up-regulation of Bax 
and down-regulation of Bcl-2. Cell cycle was predominantly arrested at the G1/S checkpoint, 
which was associated with induction of the cyclin-dependent kinase inhibitor p21Waf/CIP1.   
Furthermore, additive anti-neoplastic effects were observed when entinostat treatment was 
combined with gemcitabine or doxorubicin, while combination with the multi-kinase inhibitor 
sorafenib or the proteasome inhibitor bortezomib resulted in overadditive anti-neoplastic effects 
[41].  
 2.3.1.2 Rational for Use HDAC Inhibitors in PDAC  
  
Whilst HDAC inhibitors have been investigated in numerous clinical trials with patients suffering 
from hematological cancers and other solid tumors, there are only few studies so far that tested 
them in PDAC patients.  
  
In two phase I studies testing the safety and activity of entinostat given alone and in combination 
with 13-cis-retinoic acid (13-cR), one PDAC patient either was enrolled, achieving stable disease 
in the first setting, while progressive disease was noted after combined treatment [42].   
In other phase I studies investigating the safety of oral treatment with mocetinostat and dacinostat 
respectively, PDAC patients had no objective tumor response.   
  
In a phase I study tested the safety of combined treatment with belinostat plus carboplatin and/or 
paclitaxel, one PDAC patient of three showed partial remission after receiving belinostat and 
carboplatin. The same result was obtained in another phase I study investigating the combination 
of valproic acid with epirubicin.   
  
A phase I study with 21 advanced PDAC patients investigated the maximally tolerated doses of 
concurrent vorinostat and capecitabine with radiation in neoadjuvant chemoradiation of 


  
  
  
  
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unresectable and borderline patients. The authors claimed potential activity of vorinostat in 
neoadjuvant chemoradiation to improve the intervention option in borderline patients.  
    
The combinations of vorinostat with proteasome inhibitors showed some potential for the 
treatment of certain advanced solid tumors, thus it has investigating in PDAC. So far, all the study 
revealed no favorable responses in PDAC patients [43, 44].  
  
Another phase I trial tested oral panobinostat combined with gemcitabine in  advanced solid 
tumor patients, including 3 PDAC patients, of which 1 had stable disease under treatment [45]. 
Likewise, in a phase I study combining 9 PDAC-patients were treated, and five of them obtain 
stable disease [46].   
A phase II study explored the activity of tacedinaline alone in 17 PDAC patients albeit well 
tolerated, no significant antitumoral activity was noted either in monotherapy or in combined 
treatment with gemcitabine [47].  
  
2.4 Immunotherapy as an Anticancer Strategy in PDAC and CCA  
  
Immunotherapeutic interventions have shown limited benefit to date in solid tumors that are not 
traditionally felt to be immunogenic (e.g., CCA and PDAC). This may relate to the presence of 
immunosuppressive factors which may be overcome through epigenetic modulation [48]. Indeed, 
the potential use of immune-based therapy to treat advanced CCA and PDAC has only recently 
been investigated.  
The tumor microenvironment in PDAC is remarkable for its profound desmoplasia, absence of 
effector T cells and its T helper 2 (Th2) cell immunophenotype, which contribute to its ability to 
avoid immune surveillance [49, 50].  Many strategies to modulate the tumor microenvironment to 
a Th1 cell immunophenotype are under study: vaccination to induce or reinforce pre-existing 
immune responses is being investigated with agents such as GVAX (autologous pancreatic cell 
lines transfected with granulocyte–macrophage colony-stimulating factor) or CRS‑207 (live 
attenuated Listeria monocytogenes-expressing mesothelin) alone or with a checkpoint inhibitor; 
directed cytolysis using T cells expressing chimeric antigen receptors; oncolytic virus therapy, to 
name but a few [51-54].    
  


  
  
  
  
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So far, treating PDAC with single-agent immune checkpoint inhibitors has not been effective [55, 
56]. In prior studies, it was shown that membranous PD-L1 expression is scarce in PDACs [57], 
and since PD-L1 expression is shown to be activated in either by oncogenic signaling or by 
inflammatory cytokines, particularly interferon gamma, as a result of adaptive immune response, 
this low expression can be secondary to the lack in PDAC of effective T cell infiltration, as stated 
above [58, 59].  
  
Evidence emerged recently that many genetic alterations in PDAC target epigenetic regulators [60, 
61, 62]. In PDAC recent whole genomic sequencing revealed pathogenic mutations, structural 
variants and aberrant expression in several epigenetic regulator genes including KDM6A, ARID1A, 
ARID1B, PBRM1, SMARCA2, SMARCA4, and MLL2 [31, 63].  Importantly, drug resistance in 
PDAC is mediated by pronounced plasticity enabling PDAC cells to switch between phenotypic 
states and to select for cellular clones that eventually evade therapy. The dynamic character of cell 
plasticity and drug resistance suggests the involvement of epigenetic regulation in controlling 
phenotypic heterogeneity in PDAC [64].  
Nevertheless, recent translational research activities propose that combining modulation of the 
immune response and pharmacological targeting of epigenetic modifications might open highly 
powerful therapeutic avenues in the treatment of PDAC [65].  
  
It has been demonstrated that PDL1 expression is present in a majority of CCA patients at baseline 
(49-94%), and is associated with poor survival, which suggests that CCA may be particularly 
sensitive to this strategy [66, 67]. In the study by Gani et al. the expression of PD-L1 within the 
tumor front was associated with an almost 60% worse survival [68]. These findings are very 
interesting insofar PD-L1 is an arguable biomarker for sensitivity to immune checkpoint inhibitors. 
Indeed, several clinical trials have investigated the potential role of immunotherapy in this 
malignance. Investigators at National Institute of Health (NIH) used a whole-exomic-
sequencingbased approach to demonstrate that TILs from a patient with metastatic CCA contained 
CD4+Th1 cells recognizing a mutation in erbb2 interacting protein (ERBB2IP). After adoptive 
transfer of TILs containing mutation-specific polyfunctional TH1 cells, the patient achieved 
prolonged partial response. Upon disease progression, the patient was retreated with mutation-
reactive TH1 cells and again experienced tumor regression [69].   
  


  
  
  
  
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Patients with MSI-H CCA who received pembrolizumab (an anti-PD-1) had a 71% objective 
response rate (ORR) and 67% progression free survival (PFS) [70]. Preliminary limited activity of 
immune checkpoint inhibitors in this disease is supported also by a phase 1B trial with 
pembrolizumab (Keynote 028), enrolling only patients with positive PD-L1 tumor expression, that 
reported a 17% ORR among CCA patients [71]. This result indicates that PD-1 inhibitors have 
modest but real activity in CCA and merit further investigation  
  
Interestingly, exome sequencing in iCCA showed frequent mutations in genes involved in 
chromatin remodeling such as BAP1, ARID1A, and PBRM1 [33]. Moreover, it has been established 
that IDH1/2 mutations in CCA impair the activity of TET family of DNA dioxygenases resulting 
in a decrease of cytosine hydroxymethylation with a concurrent increase of DNA methylation [72]. 
The epigenetic alterations caused by IDH1/2 mutations lead to a blockade of cellular 
differentiation, causing an increase in the progenitor cells [73].   
  
At the current time, there are no proven therapies for cancers having these mutations. In our 
opinion, HDAC inhibitors may offer therapeutic value and need further investigation.    
  
All together these findings have reinforced the potential role of immune therapy and epigenetic 
approach in this disease, and they paved the way forward for investigating their appropriate 
combination in improving patient outcomes.  
  
2.5 Investigational Agents  
  
2.5.1 Entinostat (SNDX 275)  
  
Entinostat belongs to the class of HDAC inhibitors which are critically important in the regulation 
of gene expression and in the field of target-specific anticancer drug development [34]. Entinostat 
is a member of the substituted pyridylcarbamate class of HDAC-inhibiting compounds with oral 
bioavailability [37, 38]. It selectively inhibits class I and IV HDACs, specifically, HDACs 1, 2, 3, 
and 11, thus promoting hyperacetylation of histones and allowing transcriptional activation of a 
distinct set of genes, ultimately inhibiting cell proliferation, terminal differentiation, and/or 


  
  
  
  
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apoptosis. This isoform selectivity may differentiate the safety and efficacy profiles from those of 
nonselective pan-HDAC inhibitors.  
  
In addition, entinostat has demonstrated immunomodulatory activity that may translate to direct 
effects on the TME and enhanced antitumor immune responses [35, 36, 39].   
  
 
  
 2.5.2 Nonclinical Development of Entinostat  
  
  
  
  
  
  
  
   
  
  
  
  
  
  
  
  
  
  
  
  
  


  
  
  
  
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2.5.3 Clinical Development of Entinostat  
  
  
  
  
  
  
  
  


  
  
  
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 Nivolumab (BMS-936558)  
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2.5.6 Nonclinical Development of Nivolumab  
2.5.7 Clinical Development of Nivolumab  
  
  
  
  
  
   
  
  


  
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2.6 Entinostat in Combination with PD-1 Checkpoint Inhibition: Rational of the Study   
  
One potential strategy for improving response to immune checkpoint inhibitors is to prime the 
tumor with an epigenetic therapy. Perhaps uniquely in the human body, the immune system is 
comprised of a complex network of interacting cells that is highly responsive and often stably 
adaptive to environmental cues.   
Understandably, therefore, acknowledgments about the precise relationships between epigenetic 
aberrations, immune system and the consequences for cancer cell phenotypes could have 
tremendously important translational implications [95, 96]. Importantly, epigenetic changes may 
be reversible and thus represent an active and attractive area of new drug investigation [13, 27, 
29].  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
   
  
  


 
 


 
 
  
 
  
  
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3. PATIENT SELECTION  
  
3.1 Eligibility Criteria  
  
3.1.1. Patients must have histologically or cytologically confirmed cholangiocarcinoma or 
pancreatic adenocarcinoma that is metastatic or unresectable and has progressed 
despite standard therapy or is intolerant of therapy; 1 or 2 prior chemotherapy regimens 
in the metastatic setting or progression < 6 months from the completion of adjuvant 
chemotherapy.  
  
3.1.2. Age ≥18 years.  
  
3.1.3. ECOG performance status of 0 or 1 (Karnofsky ≥70%, see Appendix A).  
  
3.1.4. Life expectancy of greater than 12 weeks.  
  
3.1.5. Patients must have normal organ and marrow function as defined below:  
• 
Hemoglobin (HgB)    
≥ 9.0 g/dL  
• 
Leukocytes  
  
≥ 3,000/mcL  
• 
Absolute neutrophil count 
≥ 1,500/mcL  
• 
Platelets  
  
≥ 100,000/mcL  
• 
Total bilirubin  ≤ 1.5 x institutional upper limit of normal (ULN);  an exception to 
this may be allowed for participants with Gilbert’s syndrome with documented 
approval by the Protocol Chair  
• 
AST(SGOT)/ALT (SGPT)  ≤ 3 × institutional ULN  
• 
Creatinine  
  
within normal institutional limits  
or  
• 
Creatinine clearance  ≥ 60 mL/min using the Modified Cockcroft-Gault, as the 
formula below:   
Female CrCl = (140 - age in years) x weight in kg x 0.85  
                              72 x serum creatinine in mg/dL  
  
Male CrCl = (140 - age in years) x weight in kg x 1.00   


  
  
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72 x serum creatinine in mg/dL  
  
3.1.6. Negative (serum or urine) pregnancy test, for women of childbearing potential.  NOTE: 
If a patient has a positive or indeterminate serum or urine pregnancy test, then an 
ultrasound must be done to rule out pregnancy to enroll on trial. A serum B-HCG value  
of <25 is considered a negative pregnancy test.  
  
3.1.7. Patients must have measurable disease per RECIST 1.1. (see Section 8.1)    
  
3.1.8. Patient must have an accessible non-bone tumor lesion from which serial core biopsy 
specimens can be obtained.   
NOTE: Patients with bone only disease are not eligible due to difficulties in obtaining 
serial bone biopsies for correlative analyses.      
  
3.1.9. Women of child-bearing potential (WOCBP) and men must agree to use adequate 
contraception (hormonal or barrier method of birth control; abstinence) prior to study 
entry and during all the period of study participation for at least 5 months following the 
last dose of nivolumab (see Section 4.7.2).  WOCBP must have a negative serum or 
urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) at 
baseline.  Women must not be breastfeeding.  Women who are not of childbearing 
potential (e.g., who are postmenopausal or surgically sterile as well as azoospermic men) 
do not require contraception. NOTE: If a patient has a positive or indeterminate serum 
or urine pregnancy test, then an ultrasound must be done to rule out pregnancy to enroll 
on trial. A serum B-HCG value of <25 is considered a negative pregnancy test.  
  
3.1.10. Willingness to provide tissue and blood samples for mandatory translational research.  
  
3.1.11. Ability to understand and the willingness to sign a written informed consent document.  
  
3.2 Exclusion Criteria  
  
3.2.1 Patients who have had chemotherapy or other systemic therapy or radiotherapy, or those 
who have not recovered from adverse events due to prior administered agents as follows:  


  
  
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• 
Chemotherapy < 3 weeks prior to registration  
• 
Targeted therapy (other than below) < 2 weeks prior to registration   
• 
Radiotherapy < 3 weeks prior to registration (NOTE:  A previously irradiated 
lesion may not be used as a target lesion unless there is evidence of post-radiation 
progression.)  
• 
Surgery < 3 weeks prior to registration  
• 
Other approved or investigational agents <3 weeks prior to registration unless 
otherwise noted by the Protocol Chair.  
• 
Patients who have received prior epigenetic therapy (e.g. HDAC inhibitors such as  
entinostat, panobinostat, vorinostat, romidepsin or demethylating agents such as 
5azacitidine or decitabine)   
• 
Those who have not recovered from acute adverse events to grade <2 or baseline 
due to agents administered, with exception of alopecia or stable neuropathy, unless 
approved by the Protocol Chair.  
  
3.2.2 Patients with a history of prior treatment with anti-PD-1, anti-PD-L1, anti-PD-L2, 
antiCTLA4 antibodies or any other antibody or drug specifically targeting T-cell 
costimulation or immune checkpoint pathways.  
  
3.2.3 Known sensitivity to or history of allergic reactions attributed to compounds of similar 
chemical or biologic composition of entinostat and/or nivolumab.  History of severe 
hypersensitivity reaction to any monoclonal antibody.  
  
3.2.4 Patients with active autoimmune disease or history of autoimmune disease that might 
recur, which may affect vital organ function or require immune suppressive treatment 
including systemic corticosteroids, should be excluded.  These include but are not limited 
to patients with a history of immune related neurologic disease,  multiple sclerosis, 
autoimmune (demyelinating)  neuropathy, Guillain-Barre syndrome, myasthenia gravis; 
systemic autoimmune disease such as SLE, connective tissue diseases, scleroderma, 
inflammatory bowel disease (IBD), Crohn’s, ulcerative colitis, autoimmune hepatitis; 
and patients with a history of toxic epidermal necrolysis (TEN), Stevens-Johnson 
syndrome, or phospholipid syndrome should be excluded because of the risk of 
recurrence or exacerbation of disease.  Patients with vitiligo, endocrine deficiencies 
including thyroiditis managed with replacement hormones including physiologic 


  
  
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corticosteroids are eligible.  Patients with rheumatoid arthritis and other arthropathies, 
Sjögren’s syndrome and psoriasis controlled with topical medication and patients with 
positive serology, such as antinuclear antibodies (ANA), anti-thyroid antibodies should 
be evaluated for the presence of target organ involvement and potential need for systemic 
treatment but should otherwise be eligible.   
  
NOTE:  Patients are permitted to enroll if they have vitiligo, type I diabetes mellitus, 
residual hypothyroidism due to autoimmune condition only requiring hormone 
replacement, psoriasis not requiring systemic treatment, or conditions not expected to 
recur in the absence of an external trigger (precipitating event).  
  
3.2.5 Subjects with interstitial lung disease that is symptomatic or may interfere with the 
detection or management of suspected drug-related pulmonary toxicity.   
  
3.2.6  Patient has a pulse oximetry of <92% on room air or is on supplemental home oxygen.  
  
3.2.7 Patients with active or untreated brain metastases or leptomeningeal metastases are 
excluded from this clinical trial because of their poor prognosis and because they often 
develop progressive neurologic dysfunction that would confound the evaluation of 
neurologic and other adverse events.    
  
NOTE: Patients with previously treated brain metastases must have stable neurologic 
status and imaging following local therapy (surgery or radiation) for at least 4 weeks, 
with no requirement for immunosuppressive doses of systemic corticosteroids (>10 
mg/day prednisone equivalents) for at least 2 weeks prior to study drug administration 
(stable low dose dexamethasone allowed at discretion of IND Sponsor).    
  
3.2.8 Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or 
psychiatric illness/social situations that in the judgment of the investigator would limit 
compliance with study requirements.  
  
3.2.9 Pregnant women are excluded from this study because the agents have the potential for 
teratogenic or abortifacient effects.  Because there is an unknown but potential risk for 


  
  
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adverse events in nursing infants secondary to treatment of the mother, breastfeeding 
should be discontinued.  
  
3.2.10 Known HIV-positive patients on combination antiretroviral therapy are ineligible.  
Patients who have a positive test for hepatitis B virus surface antigen (HBV sAg) or 
hepatitis C antibody (HCV Ab)/RNA (HCV RNA) indicating acute or chronic infection 
are also ineligible (baseline testing required).    
  
3.2.11 Patients should be excluded if they have a condition requiring systemic treatment with 
either corticosteroids (>10 mg daily prednisone equivalents) or other immunosuppressive 
medications within 14 days of study drug administration.  Inhaled or topical steroids and 
adrenal replacement doses <10 mg daily prednisone equivalents are permitted in the 
absence of active autoimmune disease.  Patients are permitted to use topical, ocular, 
intraarticular, intranasal, and inhalational corticosteroids (with minimal systemic 
absorption).  Physiologic replacement doses of systemic corticosteroids are permitted, 
even if <10 mg/day prednisone equivalents.  A brief course of corticosteroids for 
prophylaxis (e.g., contrast dye allergy) or for treatment of non-autoimmune conditions 
(e.g., delayed-type hypersensitivity reaction caused by contact allergen) is permitted.    
  
3.2.12 Patients requiring concurrent administration of valproic acid are also excluded.  
  
3.2.13 Patients who have had evidence of active or acute diverticulitis, intra-abdominal abscess, 
or GI obstruction which are known risk factors for bowel perforation should be evaluated 
for the potential need for additional treatment before coming on study.  
  
3.2.14 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.  
  
3.2.15 Another active malignancy ≤ 3 years prior to registration with the exception of 
nonmelanotic skin cancer or carcinoma-in-situ of any type.  NOTE:  If there is a history 
of prior malignancy, they must not be receiving other specific treatment for their cancer.  
Any malignancy considered to be indolent and that has never required therapy may 
allowed at the discretion of the IND Sponsor.  


  
  
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3.2.16 Patient is unwilling or unable to follow the study schedule for any reason.  
  
3.2.17 Patient is, at the time of signing informed consent, a regular user (including “recreational 
use”) of any illicit drugs or other substance abuse (including alcohol) that could 
potentially interfere with adherence to study procedures or requirements.  
  
3.2.18 Evidence of clinical or radiographic ascites. Trace or small amounts of radiographic 
ascites without prior concern for malignant ascites or not associated with peritoneal 
carcinomatosis may be approved by the protocol chair. NOTE: 3-D CT scans and 
RECIST reads will not be used to determine eligibility at baseline.  
  
3.3 Inclusion of Women and Minorities  
  
NIH policy requires that women and members of minority groups and their subpopulations be 
included in all NIH-supported biomedical and behavioral research projects involving NIH-defined 
clinical research unless a clear and compelling rationale and justification establishes to the 
satisfaction of the funding Institute & Center (IC) Director that inclusion is inappropriate with 
respect to the health of the subjects or the purpose of the research.  Exclusion under other 
circumstances must be designated by the Director, NIH, upon the recommendation of an IC 
Director based on a compelling rationale and justification.  Cost is not an acceptable reason for 
exclusion except when the study would duplicate data from other sources.  WOCBP should not be 
routinely excluded from participation in clinical research.   
  
4. TREATMENT PLAN  
  
4.1 Agents Administration  
  
Treatment will be administered on an outpatient basis.  Reported adverse events and potential risks 
are described in Section 6.  Appropriate dose modifications are described in Section 5.    
  
No investigational or commercial agents or therapies other than those described below may be 
administered with the intent to treat the patient's malignancy.    
  


  
  
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Principal Investigator:  Nilofer Azad, M.D.  
The cycle length is 28 days. Treatment will consist of the combination of entinostat and nivolumab. 
A lead-in of entinostat 2 weeks prior to combination therapy at the dose of 5 mg/weekly, will be 
incorporated to help determine the effect of entinostat on immune-related parameters in tumor 
biopsies.  
  
4.2 Overall Study Design  
  
The proposed study single institution, open-label, two-stage, phase 2 study evaluating the clinical 
activity and safety of entinostat plus nivolumab. We will enroll two cohorts of patients: 
unresectable or metastatic cholangiocarcinoma (Cohort 1) and unresectable or metastatic 
pancreatic adenocarcinoma (Cohort 2). The primary objective of the trial is to determine whether 
the combination of entinostat plus nivolumab yields a clinically compelling antitumor activity 
measured as objective response rate (ORR, assessed by RECIST 1.1).   
  
Secondary endpoints include safety, progression-free survival (PFS), overall survival (OS), and 
immunologic correlates.   
  
The study is planned with 27 evaluable subjects per histology based on a two-stage design that 
allows early termination for lack of efficacy.  
  
Patients will receive a biopsy at baseline and on approximately day 14 of entinostat therapy and 
approximately after 6 weeks from Cycle 1 Day 1. An optional biopsy will be performed at the time 
of disease progression. After a fourteen-day lead in with entinostat monotherapy, patients will 
begin to concurrently receive entinostat 5 mg oral once a week plus nivolumab 240 mg every two 
weeks for approximately four months. After 4 months, nivolumab will be given at a dose of 480 
mg fixed dose every 4 weeks (maintenance phase). Therapy may continue with entinostat 5 mg 
weekly plus nivolumab 480 mg every 4 weeks, until intolerance or progression. Nivolumab will 
be administered intravenously over a period of 30 minutes.  
  
4.3 Definition of Unacceptable Toxicities  
  
Unacceptable toxicities are defined as treatment-related:   
  
• 
Grade 3 or greater non-hematologic toxicities. Exceptions include:  


  
  
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- 
Grade 3 nausea/vomiting if improved to Grade 2 levels or better within 72 hours  
- 
Asymptomatic laboratory abnormalities  
- 
Grade 3 fatigue  
- 
Grade 3 dermatologic AEs that are considered mild in severity but only considered 
grade 3 because of >30% body surface involvement  
- 
Grade 3 pruritus  
- 
Grade 3-4 hyperglycemia or grade 3 endocrinopathies where symptoms are 
controlled on hormone replacement therapy  
• 
Febrile neutropenia Grade 3 or Grade 4:  
- 
Grade 3 is defined as ANC <1.0×109/L with a single temperature of >38.3°C 
(101°F) or a sustained temperature of ≥38°C (100.4°F) for more than 1 hour  
- 
Grade 4 is defined as ANC <1.0×109/L with a single temperature of >38.3°C 
(101°F) or a sustained temperature of ≥38°C (100.4°F) for more than 1 hour, with 
life-threatening consequences and urgent intervention indicated.  
• 
Grade 4 thrombocytopenia (i.e., platelet count <25×109/L)  
• 
Grade 3 thrombocytopenia with clinically significant bleeding  
• 
Any other toxicity resulting in a dose reduction in therapy (at the discretion of the IND 
Sponsor)  
• 
Failure to complete all protocol specified treatment doses (at the discretion of the IND 
Sponsor) • Concurrent elevation of transaminases and bilirubin consistent with Hy’s Law criteria  
Note: The original Hy's Law parameters for treated patients relative to comparator patients have 
been broadened over time (Kaplowitz and DeLeve 2003, Zimmerman 1999) to include additional 
parameters, but still require that these 3 criteria be met:  
i. injury: elevation of >3×ULN ALT or AST activity; and ii.function: >2×ULN total 
bilirubin (another clinical marker for function, such as >1.5×ULN INR may be acceptable 
if the change is clinically significant in the absence of obstruction) without >2×ULN 
alkaline phosphatase (ALP); and iii.clinical verification to ensure effect is health product-
induced and not induced by disease or another cause of injury.  
• 
Grade 5 toxicity  
  
4.4 Study Drugs  
  
NOTE:  Subjects will be given an information sheet and wallet card to remind them of serious 
risks and that may be shared with their other healthcare providers, including a reminder to notify 


  
  
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us of all new medications started during the course of the study due to the possibility for drug 
interactions (Appendix B).    
 
  
4.3.1 Nivolumab (OPDIVO ®, BMS-936558; MDX-1106)   
 
4.4.1 Entinostat (MS-275, SNDX-275)  
  
  
  
  
  
  
  
   
  
  
  
  
  
  
   
  
  
   
  
  
  
   
  
  
  
   
  
  
  


 
 


  
  
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Principal Investigator:  Nilofer Azad, M.D.  
Hypersensitivity reactions should be managed as per standard of care at the treating institution. 
Severe reactions, such as hypotension requiring treatment, dyspnea requiring bronchodilators, 
angioedema or generalized urticaria require immediate discontinuation of study drug 
administration and aggressive symptomatic therapy.   
Subjects who experience a severe hypersensitivity reaction to treatment should not be 
rechallenged.  
  
4.5.2.2 Nivolumab  
  
Nivolumab is a fully human monoclonal immunoglobulin (Ig) G4 antibodies. Subjects should be 
closely monitored for potential AEs during antibody infusion and potential AEs throughout the 
study.  
  
Since nivolumab contains only human immunoglobulin protein sequences, it is unlikely to be 
immunogenic and induce an infusion or hypersensitivity reaction. However, if such a reaction were 
to occur, it might manifest with fever, chills, rigors, headache, rash, pruritus, arthralgia, hypo- or 
hypertension, bronchospasm, or other symptoms. All grade 3 or 4 infusion reactions should be 
reported within 24 hours to the IND Sponsor and BMS and Syndax as an SAE if the criteria are 
met. Infusion reactions should be graded according to CTCAE (version 4.03) guidelines. 
Treatment recommendations are provided below and may be modified based on local treatment 
standards and guidelines as appropriate:  
  
• 
For Grade 1 symptoms: (Mild reaction; infusion interruption not indicated; intervention 
not indicated).  
Remain at bedside and monitor subject until recovery from symptoms. The following 
prophylactic premedications are recommended for future infusions: diphenhydramine 50 
mg (or equivalent) and/or paracetamol 325 to 1000 mg (acetaminophen) at least 30 minutes 
before additional nivolumab administrations.  
  
• 
For Grade 2 symptoms: (Moderate reaction requires therapy or infusion interruption but 
responds promptly to symptomatic treatment [e.g, antihistamines, non-steroidal 
antiinflammatory drugs, narcotics, corticosteroids, bronchodilators, IV fluids]; 
prophylactic medications indicated for 24 hours).  
  


  
  
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Principal Investigator:  Nilofer Azad, M.D.  
Stop the nivolumab infusion, begin an IV infusion of normal saline, and treat the subject 
with diphenhydramine 50 mg IV (or equivalent) and/or paracetamol 325 to 1000 mg 
(acetaminophen); remain at bedside and monitor subject until resolution of symptoms. 
Corticosteroid or bronchodilator therapy may also be administered as appropriate. If the 
infusion is interrupted, then restart the infusion at 50% of the original infusion rate when 
symptoms resolve; if no further complications ensue after 30 minutes, the rate may be 
increased to 100% of the original infusion rate. Monitor subject closely. If symptoms recur 
then no further nivolumab will be administered at that visit. Administer diphenhydramine 
50 mg IV, and remain at bedside and monitor the subject until resolution of symptoms. The 
amount of study drug infused must be recorded on the electronic case report form (eCRF). 
The following prophylactic premedications are recommended for future infusions: 
diphenhydramine 50 mg (or equivalent) and/or paracetamol 325 to 1000 mg 
(acetaminophen) should be administered at least 30 minutes before additional nivolumab 
administrations. If necessary, corticosteroids (recommended dose: up to 25 mg of IV 
hydrocortisone or equivalent) may be used.   
  
• 
For Grade 3 or Grade 4 symptoms: (Severe reaction, Grade 3: prolonged [e.g., not rapidly 
responsive to symptomatic medication and/or brief interruption of infusion]; recurrence of 
symptoms following initial improvement; hospitalization indicated for other clinical 
sequelae [eg, renal impairment, pulmonary infiltrates]). Grade 4: (life threatening; pressor 
or ventilatory support indicated).   
Immediately discontinue infusion of nivolumab. Begin an IV infusion of normal saline, 
and treat the subject as follows. Recommend bronchodilators, epinephrine 0.2 to 1 mg of a 
1:1,000 solution for subcutaneous administration or 0.1 to 0.25 mg of a 1:10,000 solution 
injected slowly for IV administration, and/or diphenhydramine 50 mg IV with 
methylprednisolone 100 mg IV (or equivalent), as needed. Subject should be monitored 
until the investigator is comfortable that the symptoms will not recur.   
Nivolumab will be permanently discontinued. Investigators should follow their 
institutional guidelines for the treatment of anaphylaxis. Remain at bedside and monitor 
subject until recovery from symptoms. In the case of late-occurring hypersensitivity 
symptoms (eg, appearance of a localized or generalized pruritus within 1 week after 
treatment), symptomatic treatment may be given (eg, oral antihistamine, or 
corticosteroids).   
  


  
  
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Principal Investigator:  Nilofer Azad, M.D.  
In the case of late-occurring hypersensitivity symptoms (e.g., appearance of a localized or 
generalized pruritus within 1 week after treatment), symptomatic treatment may be given (e.g., 
oral antihistamine, or corticosteroids). Additional treatment prior to next dose as per guidelines 
above.  
  
Please note that late occurring events including isolated fever and fatigue may represent the 
presentation of systemic inflammation.  Please evaluate accordingly.  
  
Nivolumab-related infusion reactions and adverse events must resolve prior to administration of 
entinostat.  
  
4.5.3 Prohibited and Restricted Therapies  
  
Patients may not use any of the following agents during the study:  
  
• 
Any non-study anticancer or immunotherapy agent (investigational or non-investigational). 
NOTE: With approval of the IND Sponsor subjects may receive palliative radiation therapy 
as long as a site(s) disease outside of the radiation field is available to follow for response. No 
study drug should be given during radiation therapy.  
  
• 
Concomitant use of valproic acid is prohibited due to its known activity as a HDAC inhibitor.  
  
• 
CD137 or other immunologic activation agonists.  
  
• 
Immunosuppressive agents.  
  
• 
Chronic systemic corticosteroids at supraphysiologic doses.   
  
NOTE: Subjects are permitted to use topical, ocular, intra-articular, intranasal, and 
inhalational corticosteroids (with minimal systemic absorption).    
Physiologic replacement doses of systemic corticosteroids are permitted, in the absence of 
active autoimmune disease.    
  
A brief course of corticosteroids for prophylaxis (e.g., contrast dye allergy), for treatment of 
non-autoimmune conditions (e.g., delayed-type hypersensitivity reaction caused by contact 


  
  
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allergen), and for treatment of infusion reactions and premedication (e.g., up to 25 mg IV 
hydrocortisone) is permitted.  
  
Otherwise, steroid treatment should be completed at least 14 days prior to resuming 
studyrelated treatments unless approval to resume sooner is obtained from the IND Sponsor.  
  
• 
Live vaccines (examples of live vaccines include, but are not limited to: measles, mumps, 
rubella, chicken pox, yellow fever, rabies, BCG, and typhoid [oral] vaccine). Seasonal 
influenza vaccines for injection are generally killed virus vaccines and are allowed. However, 
intranasal influenza vaccines (e.g. Flu-Mist®) are live attenuated vaccines, and are NOT 
allowed.  
  
• 
The use of anticoagulants is known to increase the risk of gastrointestinal hemorrhage. Since 
gastrointestinal hemorrhage is an adverse reaction with nivolumab, subjects who require 
concomitant anticoagulant therapy should be monitored closely.  
  
• 
Concomitant use of the drugs below with entinostat should be avoided during the study (also 
listed in Appendix E):  
• Sensitive substrates of CYP1A2, CYP2C8, CYP3A with a narrow therapeutic window  • 
Drugs that are known to inhibit or induce P-gp   
  
4.5.4 Precautions  
  
Combination therapy may result in unexpected toxicity especially in novel combinations with 
other immune modifying agents.  A striking example in macaques is presented in Vaccari, et al.  
2012 [120].  
  
4.6 Definition of an Overdose for this Protocol  
  
An overdose is defined as the accidental or intentional administration of any dose of a product that 
is considered both excessive and medically important. All occurrences of overdose must be 
reported as SAEs (see Section 6.6).  
  


  
  
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4.7 WOCBP, Contraception, Use in Pregnancy, Use in Nursing  
  
4.7.1 WOCBP  
  
A WOCBP is defined as any female who has experienced menarche and who has not undergone 
surgical sterilization (hysterectomy or bilateral oophorectomy) and is not postmenopausal. 
Menopause is defined as 12 months of amenorrhea in a woman over age 45 years in the absence 
of other biological or physiological causes. In addition, women under the age of 55 years must 
have a serum follicle stimulating hormone (FSH) level > 40mIU/mL to confirm menopause. 
Women treated with hormone replacement therapy (HRT) are likely to have artificially suppressed 
FSH levels and may require a washout period in order to obtain a physiologic FSH level. The 
duration of the washout period is a function of the type of HRT used. The duration of the washout 
periods below are suggested guidelines and the investigators should use their judgment in checking 
serum FSH levels. If the serum FSH level is >40 mIU/ml at any time during the washout period, 
the woman can be considered postmenopausal:  
  
• 
1 week minimum for vaginal hormonal products (rings, creams, gels)  
• 
4 week minimum for transdermal products  
• 
8 week minimum for oral products  
  
  
4.7.2 Contraception  
  
The investigational agents used in this protocol may have adverse effects on a fetus in utero. 
Furthermore, it is not known if the investigational agents have transient adverse effects on the 
composition of sperm.  Non-pregnant, non-breast-feeding women may be enrolled if they are 
considered highly unlikely to conceive. Highly unlikely to conceive is defined as 1) surgically 
sterilized, or 2) postmenopausal, or 3) amenorrheaic for <2 years without a hysterectomy and 
oophorectomy and with a documented FSH value in the postmenopausal range, or 4) not 
heterosexually active for the duration of the study, or 5) heterosexually active and willing to use 2 
methods of birth control (which is also required for the female partners of male subjects). The 2 
birth control methods can be 2 barrier methods or a barrier method plus a hormonal method to 
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dose of study medication.  Male subjects enrolled in this study must also agree to use an adequate 
method of contraception starting with Visit 1 through 7 months after the last dose of study drug.  
  
Investigators shall counsel WOCBP and male subjects who are sexually active with WOCBP on 
the importance of pregnancy prevention and the implications of an unexpected pregnancy.  
Investigators shall advise WOCBP and male subjects who are sexually active with WOCBP on the 
use of highly effective methods of contraception. Highly effective methods of contraception have 
a failure rate of < 1% per year when used consistently and correctly.  
  
4.7.2.1 Highly Effective Methods of Contraception  
  
• 
Male condoms with spermicide.  
  
• 
Hormonal methods of contraception including combined oral contraceptive pills, vaginal ring, 
injectables, implants, and intrauterine devices (IUDs) such as Mirena by WOCBP subject or 
male subject’s WOCBP partner.  
  
• 
Nonhormonal IUDs, such as ParaGard.  
  
• 
Tubal ligation.  
  
• 
Vasectomy.  
  
• 
Complete abstinence.  
  
Complete abstinence is defined as complete avoidance of heterosexual intercourse and is an 
acceptable form of contraception for all study drugs. Abstinence is only acceptable when this is in 
line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, 
ovulation, symptothermal, profession of abstinence for entry into a clinical trial, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception. Subjects who choose 
complete abstinence are not required to use a second method of contraception, but female subjects 
must continue to have pregnancy tests. Acceptable alternate methods of highly effective 
contraception must be discussed in the event that the subject chooses to forego complete 
abstinence. NOTE: If a patient has a positive or indeterminate serum or urine pregnancy test, then 


  
  
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an ultrasound must be done to rule out pregnancy to enroll on trial. A serum B-HCG value of <25 
is considered a negative pregnancy test.  
  
Subjects should be informed that taking the study medication 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.  If there is any question that a subject will not reliably comply with the requirements for 
contraception, that subject should not be entered into the study.  
  
4.7.3 Use in Pregnancy  
  
The investigational agents used in this protocol may have adverse effects on a fetus; therefore, 
women with a positive pregnancy test at screening will not be eligible for enrollment.  If a subject 
inadvertently becomes pregnant while on treatment, the subject will immediately be removed from 
the study treatment.  The study team will contact the subject at least monthly and document the 
subject’s status until the pregnancy has been completed or terminated.    
  
The investigator must immediately notify the Syndax Sponsor and BMS of any pregnancy using 
the Pregnancy Surveillance Form within 24 hours of notification and in accordance with the SAE 
reporting procedures described in Section 6.5. Any pregnancy that occurs in a female partner of a 
male study participant should also be reported to the Syndax and BMS.  
  
Protocol required procedures for study treatment discontinuation and follow-up must be performed 
on the subject unless contraindicated by pregnancy (e.g. x-ray studies). Other appropriate 
pregnancy follow-up procedures should be considered if indicated.   
  
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome and where applicable, offspring information must be reported on the Pregnancy 
Surveillance Form.   
4.7.4 Use in Nursing Women  
  
Since many drugs are excreted in human milk, and because of the potential for serious adverse 
reactions in the nursing infant, subjects who are breast-feeding are not eligible for enrollment.  
  


  
  
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4.8 Duration of Treatment and Criteria for Removal from Treatment  
  
In general, treatment will continue until one of the following criteria are met:  
  
• 
Disease progression. NOTE:  Treatment may continue under the guidelines discussed in 
Section 4.9, as per opinion of the Investigators.  
  
• 
The patient or legal representative (such as a parent or legal guardian) withdraws consent 
for treatment but not follow up.  
  
• 
Intercurrent illness that prevents further administration of treatment.  
  
• 
Unacceptable adverse events. If the study treatment has provided clinical benefit, the IND 
sponsor may approve trial continuation for patients experiencing entinostat-related 
toxicities that are not life threatening or of major clinical concern (such as pruritis or rash). 
NOTE: Assessment for discontinuation of entinostat may be made independently of 
nivolumab, continuation of entinostat may be considered with approval by the IND 
sponsor. There are instances where treatment with nivolumab may continue if entinostat 
has been discontinued. (Section 5.1)  
   
• 
If in the opinion of the Investigator, a change or temporal or permanent discontinuation of 
therapy would be in the best interest of the patient.  The Sponsor should be included in this 
decision.  
  
• 
Noncompliance with trial treatment or procedure requirements.  
  
• 
Patient becomes pregnant. All women of child bearing potential should be instructed to 
contact the investigator immediately if they suspect they might be pregnant (e.g., missed 
or late menstrual period) at any time during study participation. The investigator must 
immediately notify CTEP in the event of a confirmed pregnancy in a subject participating 
in the study.  
  
• 
Treatment required with other chemotherapeutic or investigational anti-neoplastic drugs.  
  


  
  
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• 
Patient is lost to follow-up.  
  
• 
In the case that a participant develops intolerance or side effect that is attributable to entinostat, 
the participant may, at his or her discretion, continue to receive only Nivolumab as otherwise 
indicated as long as they have received at least 1 full dose of both entinostat and nivolumab 
and nivolumab re-treatment criteria are met as outlined above.   
  
• 
If nivolumab has to be permanently discontinued because drug-related toxicity, the patient will 
be permanently discontinued from entinostat treatment too.   
  
The subject must be discontinued from the trial for any of the following reasons:  
  
• 
The patient or legal representative (such as a parent or legal guardian) withdraws consent 
for follow-up.  
  
• 
Termination of the study.  
  
• 
Patient is lost to follow up.  
  
The reason for study removal and the date the subject was removed must be documented in the 
Case Report Form.  
  
4.9 Treatment Beyond Progression  
  
A minority of subjects treated with immunotherapy may derive clinical benefit either delayed 
responses, stable disease, or increased overall survival despite initial evidence of progressive 
disease (PD) with nivolumab or combination treatment.    
  
Subjects may be permitted to continue treatment beyond initial RECIST 1.1-defined PD as long 
as the following criteria are met:  
  
• 
Patients must be clinically stable with no change in performance status due to disease 
progression.  
  


  
  
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• 
No indication for immediate alternative treatment  
  
• 
Patient [assessed by the investigator] is showing clinical benefit and tolerates study drug.  
The assessment of clinical benefit should take into account whether the subject is clinically 
stable or deteriorating and likely or unlikely to receive further benefit from continued 
treatment  
  
• 
The time of progression is noted from the first assessment that exceeds standard criteria 
All decisions to continue treatment beyond initial progression must be discussed with the 
PI in advance, including if for any exception to the criteria noted above.  
  
New lesions are considered measurable at the time of initial progression if the longest diameter is 
at least 10 mm (except for pathological lymph nodes, which must have a short axis of at least 15 
mm).  Any new lesion considered non-measurable at the time of initial progression may become 
measurable and therefore included in the tumor burden measurement if the longest diameter 
increases to at least 10 mm (except for pathological lymph nodes, which must have an increase in 
short axis to at least 15 mm).  
  
For statistical analyses that include the investigator-assessed progression date, subjects who 
continue treatment beyond initial investigator-assessed, RECIST 1.1-defined progression will be 
considered to have investigator-assessed progressive disease at the time of the initial progression 
event.  Subjects who have tumor shrinkage following RECIST-defined progression (e.g., irRC) 
will be also summarized separately.  
    
4.10 Duration of Follow Up  
  
The Follow-Up Phase begins when the decision to discontinue a subject from study therapy is 
made (no further treatment with study therapy).  
  
All subjects who discontinue investigational product should comply with protocol specified 
follow-up procedures as outlined in Section 10, Study Calendar.   
  
A mandatory End of treatment (EOT) visit (+/- 7 days) should be performed 28 days after the last 
dose of study drug(s).  


  
  
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After completion of the EOT visit, subjects will be followed every 3 months for survival.  
  
Subjects who are discontinued from the study treatment due to an unacceptable toxicity will be 
monitored for safety until the resolution of the AE to ≤ grade 1 or stabilization or until initiation 
of a new therapy for their cancer, whichever occurs first.  
  
SAEs will be collected and recorded throughout the study period, from the first dose of the 
investigational agent through 100 days (+ 14 days) after the last dose of study drug or end of the 
study (if thought to be related to study drug), or 30 days after the initiation of a new anticancer 
therapy, whichever is earlier.    
5. DOSING DELAYS/DOSE MODIFICATIONS   
  
In order to maintain dose-intensity and cumulative dose-delivery on this study, reasonable efforts 
will be made to minimize dose reduction and treatment delays as specified below.   
Although entinostat and immune checkpoint blockade have distinct toxicity profiles, they do share 
some adverse events such as fatigue, nausea and diarrhea. There is the theoretical possibility that 
one agent may potentiate the other and hence drug causality will not always be clear. In the event 
of uncertainty, dose reductions and/or delays will follow the most conservative approach.  
  
For any event which is apparent at baseline, the dose modifications will apply according to the 
corresponding shift in toxicity grade, if the investigator feels it is appropriate (e.g., if a subject has 
grade 1 asthenia at baseline which increases to grade 2 during treatment, this will be considered as 
a shift of 1 grade and treated as a grade 1 toxicity for dose modification purposes).   
  
All toxicity grades below are described using the NCI Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.03.  
  
All discontinuations, relationships to treatment, and treatment decisions must be clearly 
documented in the medical record.  Any questions should be discussed with the IND Sponsor.    
  
Dose reductions due to toxicity are permanent. Dose escalation is not allowed. Dose 
reduction is not allowed for Nivolumab treatment.   
  


  
  
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NOTE:  Tumor assessments should continue as per protocol even if dosing is delayed.  
  
5.1 Dose Criteria  
  
Entinostat  
  
Prior to administration of first dose of entinostat in each cycle, subject’s organ function and 
treatment-related toxicities must have recovered to the following values:   
  
• 
Absolute Neutrophil Count (ANC) ≥ 1,000 x 106/L   
  
• 
Platelets ≥ 75,000 x 106/L   
  
• 
Creatinine ≤ 1.5 x ULN OR > 60 mL/min for patient with creatinine levels >1.5× 
institutional ULN.  
  
• 
Non-hematologic toxicities ≤ Grade 2 as noted below for entinostat-related toxicity 
Nivolumab  
  
Dosing of nivolumab will be delayed for any of the criteria listed below:  
• 
Total bilirubin ≥ 1.5×ULN (for patients with diagnosed Gilbert’s Syndrome, direct 
bilirubin should be within normal institutional limits).  
  
• 
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) > 3 ×ULN OR ≥5 
×ULN for patients with liver metastases: NOTE - appropriate evaluation for autoimmune 
transaminitis must be conducted  
  
• 
Any ≥ Grade 2 non-skin, non-laboratory, drug-related adverse event, with the following 
exception:  
  
• 
Grade 2 drug-related fatigue does not require a treatment delay.  
  
• 
Grade 2 hypothyroidism or thyroiditis does not require a treatment delay  
  


  
  
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• 
Subjects with Grade 3 thyroiditis or hypopituitarism may be restarted with replacement 
hormones including thyroid hormone and physiologic doses of corticosteroids.    
NOTE: grading for hypophysitis with symptoms of headache, visual or neurologic 
changes or radiologic evidence of pituitary enlargement and other CNS events such 
as aseptic meningitis or encephalitis should be considered grade 3 events  
  
• 
Any ≥ Grade 3 skin, drug-related adverse event.  
  
• 
Any ≥ Grade 3 drug-related laboratory abnormality with the following exceptions:  
  
• 
Grade 3 lymphopenia does not require dose delay  
  
• 
Any Grade ≥ 3 drug-related amylase or lipase abnormality that is not associated with 
symptoms or clinical manifestations of pancreatitis does not require dose delay.   
  
• 
Isolated grade 3 or 4 electrolyte imbalances/abnormalities that are not associated  


 
 
 


 
 
 


 
 
 


 
 
 


 
 
 


 
 
 


 
 
 


 
 


  
  
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- Concurrent AST or ALT ≥ 3 × ULN and total bilirubin > 2 × ULN, irrespective of 
baseline levels  
  
• 
Any Grade 4 treatment-related AE or laboratory abnormality, except for the following 
events which DO NOT require discontinuation:  
  
- 
Grade 4 amylase or lipase abnormalities that are not associated with symptoms or 
clinical manifestations, or radiographic signs of pancreatitis.   
- 
Isolated grade 4 electrolyte imbalances/abnormalities that are not associated with 
clinical sequelae and are corrected with supplementation/appropriate management 
within 72 hours of their onset.  
- 
Grade 4 lymphopenia and leukopenia.   
- 
Grade 4 treatment-related endocrinopathy adverse events, such as ACTH deficiency, 
hyper- or hypothyroidism, or glucose intolerance, which resolve or are adequately 
controlled with physiologic hormone replacement (corticosteroids, thyroid 
hormones) or glucose-controlling agents, respectively, may not require 
discontinuation after discussion with and approval from the Sponsors.  
  
• 
Grade 3 and 4 adrenal insufficiency require discontinuation  
  
• 
Any dosing interruption lasting >6 weeks, with the following exceptions: NOTE: Dosing 
interruptions >6 weeks that occur for non-drug-related reasons as well as for treatment of 
related AEs and subsequently tapering of steroids may be allowed if approved by the IND 
Sponsor. Patients must have had no recurrence of symptoms or new symptoms during 
steroid taper.  
  
New immune related events or exacerbation of existing events during steroid treatment or taper 
suggest the presence of ongoing immune activation and should require permanent discontinuation.  
  
• 
Any subjects who require additional immune suppressive treatment beyond steroids should 
go off study treatment  
  
If nivolumab has to be permanently discontinued because drug-related toxicity, the patient will be 
permanently discontinued from entinostat treatment too.   
  


  
  
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In the case that a participant develops intolerance or side effect that is attributable to entinostat, 
the participant may, at his or her discretion, continue to receive only Nivolumab as otherwise 
indicated as long as they have received at least 1 full dose of both entinostat and nivolumab and 
nivolumab re-treatment criteria are met as outlined above.  
  
  
  
  
  
6. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS   
  
6.1 Study Drugs  
  
6.1.1 Entinostat  
  
Commonly encountered AEs across clinical studies of entinostat monotherapy in patients with 
solid tumors included hypoalbuminemia, fatigue, nausea, hypophosphatemia, anemia, and 
thrombocytopenia. Incidence and severity were dose- and schedule-dependent. In a Phase 2, 
randomized, placebo-controlled study in patients with lung cancer, in which patients received 
erlotinib+entinostat or erlotinib+placebo, treatment-emergent adverse events (TEAEs) occurring 
at a ≥10% higher incidence in entinostat-treated patients versus placebo-treated patients included 
nausea (49% versus 25%); anorexia (40% versus 16%); weight decreased (32% versus 18%); 
dyspnea (31% versus 18%); vomiting (31% versus 13%); peripheral edema (28% versus 13%); 
anemia (22% versus 11%); thrombocytopenia (15% versus 3%); hypotension (14% versus 2%); 
and stomatitis (12% versus 2%). In a Phase 2 study in patients with metastatic melanoma treated 
with entinostat monotherapy, the most common TEAEs were nausea (39%), hypophosphatemia 
(29%), pain in extremity (21%), and back pain and diarrhea (each 18%) [122].  Additional clinical 
experience is summarized in the entinostat IB.  
  
6.1.2 Nivolumab  
  
Blocking PD-1 function may permit the emergence of auto-reactive T cells and resultant clinical 
autoimmunity. Rash/pruritus, diarrhea/colitis, pneumonitis, hepatitis, and hypothyroidism were 
drug-related, presumptive autoimmune events noted in previous nivolumab studies.  
  


  
  
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For the purposes of this study, a nivolumab-related AE is defined as an AE of unknown etiology, 
associated with drug exposure and is consistent with an immune phenomenon. Efforts should be 
made to rule out neoplastic, infectious, metabolic, toxin or other etiologic causes. Serological, 
immunological, and histological (biopsy) data should be used to support the diagnosis of an 
immune-mediated toxicity. Suspected nivolumab-related AEs must be documented on an AE CRF. 
Identification and treatment of nivolumab-related AEs can be found in Section 4.4 as well as in 
Appendix D. Additional guidance can be found in the nivolumab IB.  
  
  
  
  
6.2 Adverse Events Definition  
  
6.2.1 Adverse Events   
  
An AE is defined in the International Conference on Harmonisation (ICH) Guideline for Good 
Clinical Practice as “any untoward medical occurrence in a patient or clinical investigation patient 
administered a pharmaceutical product and that does not necessarily have a causal relationship 
with this treatment” (ICH E6:1.2).  
  
Worsening of a pre-existing medical condition, (e.g., 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 (e.g., elective cosmetic surgery) or medical procedures 
that were planned before study enrollment are not considered AEs.  
  
Disease progression (PD) should not be recorded as an AE. If PD occurs, record the date first 
documented in the EOT visit eCRF. Also record all methods of assessment, e.g., 1 target/nontarget 
lesion, tumor response assessment, and/or clinical disease assessment. Indicate if the patient starts 
new treatment.  
  
In the case of death, only record “Fatal” for the event causing death. AEs that are ongoing at the 
end of the study or time of death are to be noted as “continuing.”   
  


  
  
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Classification of AEs is to be done by the Investigator is according to the NCI CTCAE, Version  
4.03. The Death eCRF must also be completed.  
  
The Investigator is responsible for reviewing laboratory test results and determining whether an 
abnormal value in an individual patient represents a significant change from baseline. In general, 
abnormal laboratory findings without clinical significance (based on the Investigator’s judgment) 
should not be recorded as AEs; however, laboratory value changes requiring therapy or adjustment 
in prior therapy are considered AEs.  
  
6.2.2 Suspected Adverse Reactions   
  
A suspected adverse reaction is any AE for which there is a reasonable possibility that the drug 
caused the adverse event. For the purposes of Investigational New Drug Application (IND) safety 
reporting, ‘reasonable possibility’ means there is evidence to suggest a causal relationship between 
the drug and the AE. A suspected adverse reaction implies a lesser degree of certainty about 
causality than adverse reaction, which means any AE caused by a drug.  
  
6.2.3 Expectedness  
  
Unexpected AE: An AE, which varies in nature, intensity or frequency from information on the 
investigational drug/agent provided in the product IB, package insert or safety reports. Any AE 
that is not included in the IB consent is considered “unexpected”.   
  
Expected (known) AE: An AE, which has been reported in the IB. An AE is considered “expected”, 
only if it is included in the IB document as a risk.  
  
6.2.4 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 (e.g., places the patient at immediate risk of death)  
• 
requires in-patient hospitalization or prolongation of existing hospitalization for >24 hours  
• 
results in persistent or significant disability/incapacity  


  
  
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• 
is a congenital anomaly/birth defect  
• 
is an important medical event that may not result in death, be life-threatening, or require 
hospitalization but may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, it may jeopardize the patient and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition. Examples of 
such medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse.  
• 
Potential drug induced liver injury (DILI) is also considered an important medical event.   
• 
Hemophagocytic lymphohistiocytosis is also considered an important medical event.  
• 
Suspected transmission of an infectious agent (eg, pathogenic or nonpathogenic) via the 
study drug is an SAE.  
• 
Is a new cancer (that is not a condition of the study)  
• 
Is associated with an overdose  
• 
Is a pregnancy or pregnancy outcome of spontaneous abortion, missed abortion, benign 
hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage, or stillbirth.  
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 (e.g., 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).  
  
6.3 Reporting Procedures for All Adverse Events  
  
The Investigator is responsible for ensuring that all AEs observed by the Investigator or reported 
by patients are properly captured in the patients’ medical records and reported on the eCRF. The 
evaluation time period for all adverse events is from the first dose of the investigational agent to at 
least 30 days after the last dose of entinostat or nivolumab, or until resolution of all acute toxicities 
associated with study drug administration, whichever is longer, with the exception of SAEs, which 
must be documented through 100 days following cessation of treatment, or 30 days after the 
initiation of a new anticancer therapy, whichever is earlier.  
  
The following AE attributes must be assigned by the Investigator:   
• 
event description (with detail appropriate to the event);   


  
  
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• 
seriousness;   
• 
dates of onset and resolution;   
• 
severity;  
• 
assessment of relatedness to entinostat and to nivolumab;    
the action taken.   
Laboratory abnormalities: Laboratory abnormalities present at the screening visit will be recorded 
as pre-treatment signs and symptoms. After study treatment administration, all grade 3 and 4 
clinical laboratory results that represent an increase in severity from baseline will be reported as 
AEs. A grade 1 or 2 clinical laboratory abnormality should be reported as an AE only if it is 
considered clinically significant by the investigator (induce clinical signs or symptoms or require 
therapy)  
  
The Investigator may be asked to provide follow-up information, discharge summaries, and 
extracts from medical records.  
  
If applicable, the study drug relationship will be assessed by means of the question: “Is there a 
reasonable possibility that the event may have been caused by one of the two drugs based on 
mechanism of action and/or toxicity profile, or by the combination of entinostat with nivolumab?”  
The relationship of an AE to the administration of the study drug is to be assessed by the 
investigator according to the following definitions:   
  
• 
No (unrelated, not related, no relation):  The time course between the administration of 
study drug and the occurrence or worsening of the adverse event rules out a causal 
relationship and another cause (concomitant drugs, therapies, complications, etc.) is 
suspected.   
  
• 
Yes (related): The time course between the administration of study drug and the occurrence 
or worsening of the adverse event is consistent with a causal relationship and no other cause 
(concomitant drugs, therapies, complications, etc.) can be identified.   
  
The following factors should also be considered:   
• 
The temporal sequence from study drug administration - The event should occur after the 
study drug is given. The length of time from study drug exposure to event should be 
evaluated in the clinical context of the event.   


  
  
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• 
Underlying, concomitant, intercurrent diseases - Each report should be evaluated in the 
context of the natural history and course of the disease being treated and any other disease 
the subject may have.   
• 
Concomitant medication - The other medications the subject is taking or the treatment the 
subject receives should be examined to determine whether any of them might be recognized 
to cause the event in question.   
• 
Known response pattern for this class of study drug - Clinical and/or preclinical data may 
indicate whether a particular response is likely to be a class effect.   
• 
Exposure to physical and/or mental stresses - The exposure to stress might induce adverse 
changes in the recipient and provide a logical and better explanation for the event.   
The pharmacology and pharmacokinetics of the study drug - The known pharmacologic properties 
(absorption, distribution, metabolism, and excretion) of the study drug should be considered.  
  
Whenever possible, the CTCAE, Version 4.03, should be used for assessing the severity of AEs 
(http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-4_QuickReference_8.5x11.pdf).   
For AEs that are not adequately addressed in the NCI CTCAE, the standard severity grading scale 
may be used (Table 6.3.1).  
  


  
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Table 6.3.1  
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.  
  
6.4 Serious Adverse Event Reporting Procedures  
  
: 


  
  
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SAEs will be collected and recorded throughout the study period, from the first dose of the 
investigational agent through 100 days after the last dose of study drug or end of the study (if 
thought to be related to study drug), or 30 days after the initiation of a new anticancer therapy, 
whichever is earlier.    
  
All SAEs, regardless of causality to study drug and/or administration device, will be 
reported  
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 and BMS or their representative. The SAE reporting 
procedure is provided in Appendix F. If this falls on a weekend or holiday, an email notification is 
acceptable but must be followed by an SAE reporting form on the next business day.  
  
After the initial SAE report, the investigator is required to proactively follow each subject and 
provide further information to the safety department in regards to the subject’s condition. All 
SAE(s) will be followed until:  
• 
Resolution  
• 
The condition stabilizes  
• 
The event is otherwise explained  
• 
The subject is lost to follow-up  
• 
Death  
  
As soon as relevant information is available, a follow-up SAE report will be submitted to the IND 
Sponsor, BMS, and Syndax.  
  
For all deaths, available autopsy reports and relevant medical reports should be provided to the 
IND Sponsor, Syndax and BMS or their representative. If a patient is permanently withdrawn from 
the study because of an SAE, this information must be included in the initial or follow-up Serious 
Adverse Event Report Form as well as the EOT eCRF.   
  
promptly  to  the  IND  sponsor  
  
  Syndax  
 and BMS  


  
  
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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 and BMS, in accordance with local procedures and statutes.  
  
6.5 Pregnancy and Lactation Reporting Procedures  
  
Although pregnancy and lactation are not considered AEs, it is the responsibility of Investigators 
or their designees to report any pregnancy or lactation in a patient (spontaneously reported to them) 
that occurs during the study or within 120 days of completing the study or 30 days following 
cessation of treatment if the patient initiates new anticancer therapy, whichever is earlier. All 
patients who become pregnant must be followed to the completion/termination of the pregnancy.   
  
Pregnancy outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, blighted 
ovum, fetal death, intrauterine death, miscarriage, and stillbirth must be reported as SAEs 
(Important Medical Events). If the pregnancy continues to term, the outcome (health of infant) must 
also be reported.  
  
Such events must be reported within 24 hours to the Sponsor either by electronic media or paper.   
  
6.6 Reporting of Overdose to the Sponsor  
  
6.6.1 Entinostat Overdose   
  
No information on the treatment of overdose of entinostat is currently available. Entinostat 
overdoses are defined as a single dose greater than 15 mg. This overdose will not be considered an 
SAE unless the outcome of the overdose meets seriousness criteria as defined in Section 6.2.4 In 
the event of an entinostat overdose, the Sponsor should be immediately notified. The patient should 
be carefully monitored for potential adverse reactions and symptomatic treatment instituted as per 
institutional standards of care.   
  
6.6.2 Nivolumab Overdose  
  
A nivolumab overdose is considered an SAE. No specific information is available on the treatment 
of overdose of nivolumab. In the event of overdose, the patient should be observed closely for signs 
of toxicity. Appropriate supportive treatment should be provided if clinically indicated.  


  
  
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6.7 Follow-Up of Adverse Events  
  
The Investigator must continue to follow all SAEs and non-serious AEs considered to be reasonably 
or possibly related to study drug either until resolution or the Investigator assesses them as chronic 
or stable. This follow-up may extend after the end of the study.  
  
6.8 Reconciliation of SAEs  
  
The Principal Investigator (or designee) will reconcile the clinical database SAE cases (case level 
only) transmitted to the IND sponsor and BMS Global Pharmacovigilance  
. Frequency of reconciliation should be approximately every 3  
months and prior to the database lock or final data summary. BMS GPVE will email, upon request 
from the Investigator, the reconciliation report. Requests for reconciliation should be sent to 
 and 
. The data elements listed on the BMS  
GPVE reconciliation report will be used for case identification purposes. If the sponsor determines 
a case was not transmitted to the IND sponsor and/or BMS GVPE, the case should be sent 
immediately to the IND sponsor and BMS.  
  
  
6.9 Safety Reporting to Health Authorities, Ethics Committees/Institutional Review Boards  
and Investigators  
  
The Sponsor will send appropriate safety notifications to Health Authorities in accordance with 
applicable laws and regulations.  
  
The Investigator must comply with any applicable site-specific institutional requirements related 
to the reporting of SAEs involving his/her patients to the EC/IRB that approved the trial.  
  
In accordance with local regulations, the IND Sponsor or designee will notify investigators of all 
SAEs that are unexpected (i.e., not previously described in the IB), and related to the study drugs. 
This notification will be in the form of an expedited safety report (ESR) that is to be faxed to the 
investigators and the study coordinators. Upon receiving such notices, the investigator must review 
and retain the notice with the IB and where required by local regulations, the investigator will 


  
  
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submit the ESR to the appropriate IRB. The investigator and IRB will determine if the informed 
consent requires revision. The investigator should also comply with the IRB procedures for 
reporting any other safety information.  
  
6.10 Food and Drug Administration (FDA) Reporting  
  
All reporting to the FDA will be completed by the IND Sponsor.  
  
7 Calendar-Day Telephone or Fax Report:  
  
The IND Sponsor is required to notify the FDA of any fatal or life-threatening adverse event that 
is unexpected and assessed by the investigator to be possibly related to the investigational agent.  
Such reports are to be telephoned or faxed (301-796-9849) to the FDA within 7 calendar days of 
first learning of the event. Follow-up information will be submitted to the FDA as soon as relevant 
information is available.   
  
10 Calendar-Day Written Report:    
  
The IND Sponsor is required to notify the FDA of any SAE that is unexpected and related to the 
investigational agent in a written IND Safety Report.    
  
Written IND Safety Reports should include an Analysis of Similar Events in accordance with 
regulation 21 CFR § 312.32.  All safety reports previously filed with the IND concerning similar 
events should be included in the analysis.  The new report should contain comments on the 
significance of the new event in light of the previous, similar reports.   
   
Follow-up information will be submitted to the FDA as soon as relevant information is available.  
  
IND Annual Reports:  
  
In accordance with the regulation 21 CFR § 312.33, the IND Sponsor shall within 60 days of the 
anniversary date that the IND went into effect submit a brief report of the adverse events and 
progress of the investigation.  Please refer to Code of Federal Regulations, 21 CFR § 312.33 for a 


  
  
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list of the elements required for the annual report.  All IND annual reports will be submitted to the 
FDA by the IND Sponsor.  
  
6.11 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 PI as soon as possible to discuss the circumstances of the emergency.  
  
The PI in conjunction with the Investigators, will decide whether the patient should continue to 
participate in the study. All protocol deviations and reasons for such deviations must be noted on 
the eCRF.  
  
6.12 Safety Monitoring  
  
The safety and tolerability of the investigational treatments will be monitored throughout the course 
of the study by the Investigators and the Sponsor Study Physicians(s).  
The safety and tolerability data that will be reviewed will include, but are not limited to: AEs, 
unacceptable toxicities, laboratory test results, and patient discontinuations. Additionally, the 
development of SAEs will be assessed by the IND Sponsor Study Physician(s) on a continuous 
basis. (NOTE: all SAEs must be reported to the IND Sponsor, Syndax and BMS or designee within 
24 hours of discovery or notification of the event [Section 6.4].)  
  
No formal safety stopping rules are specified in the protocol. However, if any significant safety 
issues arise, a decision to modify or terminate the study will be made by the Sponsor in 
collaboration with the Investigators.  
  
  
7. PHARMACEUTICAL INFORMATION  
  
A list of the adverse events and potential risks associated with the investigational agents 
administered in this study can be found in Section 6.1. Additional drug information can be found 
in the investigational agent’s Investigator Brochure.  


  
  
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7.2 Nivolumab (NSC #748726)  


 
 


  
  
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8.1 Antitumor Effect – Solid Tumors (RECIST 1.1)  
  
Although the clinical benefit of these drugs has not yet been established, the intent of offering this 
treatment is to provide a possible therapeutic benefit, and thus the subjects will be carefully 
monitored for tumor response and symptom relief in addition to safety and tolerability. Subjects 
will be assessed by standard criteria for response per the timelines noted in the Study Calendar 
(Section 10).    
  
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1) [123]. Changes in the largest diameter (unidimensional measurement) of the tumor 
lesions and the shortest diameter in the case of malignant lymph nodes are used in the RECIST 
criteria.  
  
In addition, if a formal reading for RECIST measurements is performed, but the results are not 
available prior to the scheduled start of the next cycle, treatment should continue based upon 
review of the routine/clinical radiologist report of the status of disease (e.g., response, stability or 
progression).  In the event that a RECIST re-read would have changed the treatment decision for 
the subject, if known prior, the IND Sponsor/designee should be consulted and course of action 
  
  
  
  
  
   
  
  
  
  
  
  
  
8 . MEASUREMENT OF EFFECT  


  
  
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clearly documented in the medical record.  If it is in the best interests of the subject to continue on 
study, this is permissible.  These cases will be reviewed in detail at the time of study analyses.  
  
  
8.2 Definitions  
  
Evaluable for toxicity: All patients will be included in the toxicity summaries, from the time of 
their first treatment with study drug.  
  
Evaluable for objective response:  All patients must be accounted for in the summary of objective 
response.  To formally classify a patient as RECIST-evaluable, only those patients who have 
measurable disease present at baseline (one of the eligibility criteria, Section 3.1) and start 
treatment (received at least one dose of entinostat) will be considered evaluable. These patients 
will have their response classified according to the definitions stated below (NOTE:  Subjects who 
exhibit objective disease progression prior to the end of cycle 1 will also be considered evaluable.)  
  
8.2.1 Disease Parameters  
  
Measurable disease:  Measurable lesions are defined as those that can be accurately measured in  
 
be recorded in millimeters (or decimal fractions of centimeters).  
  
NOTE: Tumor lesions that are situated in a previously irradiated area might or might not be 
considered measurable. In most cases, in the event of post-radiation disease progression, 
previously irradiated lesions may be considered measurable lesions. Otherwise, these lesions 
should be considered non-measurable.    
  
Malignant lymph nodes:  To be considered pathologically enlarged and measurable, a lymph node 
must be ≥15 mm (≥1.5 cm) in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm [0.5 cm]).  At baseline and in follow-up, only the short 
axis will be measured and followed.  
  
Non-measurable disease:  All other lesions (or sites of disease), including small lesions (longest  


  
  
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axis), are considered non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and 
abdominal masses (not followed by CT or MRI), are considered as non-measurable.  
  
NOTE:  Cystic lesions that meet the criteria for radiographically defined simple cysts should not 
be considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts.  
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions, if 
they meet the definition of measurability described above. However, if non-cystic lesions are 
present in the same subject, these are preferred for selection as target lesions.  
  
Target lesions:  All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in 
total, representative of all involved organs, should be identified as target lesions and recorded and 
measured at baseline.  Target lesions should be selected on the basis of their size (lesions with the 
longest diameter), be representative of all involved organs, but in addition should be those that 
lend themselves to reproducible repeated measurements.  It may be the case that, on occasion, the 
largest lesion does not lend itself to reproducible measurement in which circumstance the next 
largest lesion which can be measured reproducibly should be selected.  A sum of the diameters 
(longest for non-nodal lesions, short axis for nodal lesions) for all target lesions will be calculated 
and reported as the baseline sum diameters.  If lymph nodes are to be included in the sum, then 
only the short axis is added into the sum. A sum of the longest diameter (LD) for all target lesions 
will be calculated and reported as the baseline sum LD. The baseline sum LD will be used as 
reference by which to characterize the objective tumor response.  
  
Non-target lesions:  All other lesions (or sites of disease) including any measurable lesions over 
and above the 5 target lesions should be identified as non-target lesions and should also be recorded 
at baseline.  Measurements of these lesions are not required, but the presence, absence, or in rare 
cases unequivocal progression of each should be noted throughout follow-up.  
  
8.2.2 Methods for Evaluation of Measurable Disease  
  
All measurements should be taken and recorded in metric notation using a ruler or calipers.  All 
baseline evaluations should be performed as closely as possible to the beginning of treatment and 


  
  
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never more than 28 days before the beginning of the treatment. Tumor response will be assessed 
per RECIST 1.1 using radiographic scans every 8 weeks±7 days.  
  
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam.  
  
Clinical lesions:  Clinical lesions will only be considered measurable when they are superficial  
 
calipers (e.g., skin nodules).  In the case of skin lesions, documentation by color photography, 
including a ruler to estimate the size of the lesion, is recommended.   
Chest x-ray:  Lesions on chest x-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung.  However, CT is preferable.   
  
Conventional CT and MRI:  This guideline has defined measurability of lesions on CT scan based 
on the assumption that CT slice thickness is 5 mm (0.5 cm) or less.  If CT scans have slice thickness 
greater than 5 mm (0.5 cm), the minimum size for a measurable lesion should be twice the slice 
thickness.  MRI is also acceptable in certain situations (e.g., for body scans).    
  
MRI has excellent contrast, spatial, and temporal resolution; however, there are many image 
acquisition variables involved in MRI, which greatly impact image quality, lesion conspicuity, and 
measurement.  As with CT, if an MRI is performed, the technical specifications of the scanning 
sequences used should be optimized for the evaluation of the type and site of disease.  Furthermore, 
as with CT, the modality used at follow-up should be the same as was used at baseline and the 
lesions should be measured/assessed on the same pulse sequence.    
  
PET-CT:  At present, the low dose or attenuation correction CT portion of a combined PET-CT is 
not always of optimal diagnostic CT quality for use with RECIST measurements.  However, if the 
site can document that the CT performed as part of a PET-CT is of identical diagnostic quality to 
a diagnostic CT (with IV and oral contrast), then the CT portion of the PET-CT can be used for 
RECIST measurements and can be used interchangeably with conventional CT in accurately 
measuring cancer lesions over time.  Note, however, that the PET portion of the CT introduces 


  
  
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additional data which may bias an investigator if it is not routinely or serially performed.  Further, 
if the subject is allergic to contrast dye, the case should be discussed with the IND Sponsor.    
  
Ultrasound:  Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement.  If new lesions are identified by ultrasound in the course of the study, 
confirmation by CT or MRI is advised.  If there is concern about radiation exposure at CT, MRI 
may be used instead of CT in selected instances.  
  
Endoscopy, Laparoscopy:  The utilization of these techniques for objective tumor evaluation is not 
advised.    
  
Tumor markers (CA 19-9):  Tumor markers alone cannot be used to assess response.  If markers 
are initially above the upper normal limit, they must normalize for a subject to be considered in 
complete clinical response.    
  
Cytology: The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or stable disease 
is mandatory to differentiate between response or stable disease (an effusion may be a side effect 
of the treatment) and progressive disease.  
  
FDG-PET: While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in assessment 
of progression (particularly possible 'new' disease).  New lesions on the basis of FDG-PET imaging 
can be identified according to the following algorithm:   
• 
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based 
on a new lesion.  
• 
No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive FDG-PET at 
follow-up corresponds to a new site of disease confirmed by CT, this is PD.  If the positive 
FDG-PET at follow-up is not confirmed as a new site of disease on CT, additional follow-up 
CT  scans are needed to determine if there is truly progression occurring at that site (if so, the 
date of PD will be the date of the initial abnormal FDG-PET scan).  If the positive FDG-PET 
at follow-up corresponds to a pre-existing site of disease on CT that is not progressing on the 
basis of the anatomic images, this is not PD.  


  
  
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• 
FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in cases 
where a residual radiographic abnormality is thought to represent fibrosis or scarring.  The use 
of FDG-PET in this circumstance should be prospectively described in the protocol and 
supported by disease-specific medical literature for the indication.  However, it must be 
acknowledged that both approaches may lead to false positive CR due to limitations of 
FDGPET and biopsy resolution/sensitivity.  
  
NOTE: A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake greater 
than twice that of the surrounding tissue on the attenuation corrected image.  
  
8.3 Response Criteria  
  
8.3.1 Evaluation of Target Lesions  
  
Complete Response (CR): Disappearance of all target lesions determined by two separate 
observations conducted not less than 4 weeks apart. Any pathological lymph nodes (whether target 
or non-target) must have reduction in short axis to <10 mm (<1 cm). There can be no appearance 
of new lesions.  
  
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of target lesions, taking 
as reference the baseline sum diameters.  
  
Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest 
on study).  In addition to the relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm (0.5 cm).  (NOTE: the appearance of one or more new lesions is also 
considered progressions).  
  
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study.  
  
8.3.2 Evaluation of Non-Target Lesions  
  


  
  
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Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level.  All lymph nodes must be non-pathological in size (<10 mm [<1 cm] short axis). 
NOTE:  If tumor markers are initially above the upper normal limit, they must normalize for a 
subject to be considered in complete clinical response.  
  
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits.  
  
Progressive Disease (PD):  Appearance of one or more new lesions and/or unequivocal progression 
of existing non-target lesions. Unequivocal progression should not normally trump target lesion 
status.  It must be representative of overall disease status change, not a single lesion increase.  
  
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the treating 
physician should prevail in such circumstances, and the progression status should be confirmed at 
a later time by the review panel (or PI).  
  
8.3.3 Evaluation of Best Overall Response  
  
The best overall response is the best response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for progressive disease the smallest measurements 
recorded since the treatment started).    
  
The subject's best response assignment will depend on the achievement of both measurement and 
confirmation criteria (Table 8.3.1).  
  
  
  
  
Table 8.3.1 For Subjects with Measurable Disease (e.g., Target Disease)  
  
  
Target  
Lesions  
  
  
Non-Target  
Lesions  
  
New  
Lesions  
  
Overall  
Response  
Best  
Overall  
Response  
when 
Confirmation is Required1  
CR  
CR  
No  
CR  
>4 wks confirmation  


  
  
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CR  
Non-CR/Non-PD  
No  
PR  
>4 wks confirmation  
CR  
Not evaluated  
No  
PR  
PR  
Non-CR/Non- 
PD/not evaluated  
No  
PR  
SD  
Non-CR/Non- 
PD/not evaluated  
No  
SD  
Documented at least once >4 wks. from 
baseline  
PD  
Any  
Yes or No  
PD*  
no prior SD, PR or CR  
Any  
PD**  
Yes or No  
PD*  
Any  
Any  
Yes  
PD  
  
*A minority of subjects treated with immunotherapy may derive clinical benefit either delayed 
responses, stable disease, or increased overall survival despite initial evidence PD with nivolumab 
or combination treatment.    
  
Subjects may be permitted to continue treatment beyond initial RECIST 1.1-defined PD (see 
Section 4.9). In these cases, a radiological assessment will be repeated 4 weeks later to confirm or 
not the progression disease, as defined by RECIST criteria.   
  
** In exceptional circumstances, unequivocal progression in non-target lesions may be accepted 
as disease progression.  
  
NOTE: Subjects with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as “symptomatic 
deterioration;” (e.g., weight loss >10% of baseline body weight; worsening of tumor-related 
symptoms, decline in performance status >1 left on ECOG scale) after discussion with IND 
Sponsor. .Every effort should be made to document the objective progression even after 
discontinuation of Treatment.  
  
8.3.4 Confirmation of Response  
  
Confirmation of response is required per RECIST 1.1.  
  
8.3.5 Duration of Response  
  


 
 
 


 
 


  
  
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9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES  
  
9.1 Overview  
  
The major hypothesis of our correlative studies are that:  
1) Treatment with entinostat will result in changes in TME enhancing T cell effectors and/or 
reducing suppressive ability of CD4+FoxP3+ T regulatory cells and MDCSs in the tumors.  
2) Immunologic changes in biopsy specimens will correlate with subsequent clinical response 
to anti-PD-1/PD-L1 therapy.  
  
Explorative correlative studies will be performed on biopsy specimens (pre - and post- entinostat 
treatment and approximately after 6 weeks from Cycle 1 day 1) and blood samples.   
  
Mandatory research bloods and tumor biopsies will be obtained at baseline (day -14), after two 
weeks of entinostat lead in period (on approximately day 14 from the first entinostat 
administration), and approximately after 6 weeks from Cycle 1 day 1 visit. (see Study Calendar, 
Section 10). Biopsies at progression are optional.    
  
These three mandatory biopsies will provide valuable information regarding the mechanism of 
action of entinostat and the impact on the TME when PD1 inhibition is added in, as well as primary 
resistance mechanisms to the strategy.  
  
NOTE: All samples will be collected as outlined below, initially processed, and stored/bank until 
future analysis.    
  
9.2 Collection of Specimens  
  
9.2.1 Tissue Samples  
  
Mandatory and optional tumor biopsies will be obtained at the time points as outlined above and 
on the Study Calendar.    
  
Subjects will undergo a direct or image-guided research biopsy procedure. FNA and on-site 
cytopathologic evaluation, where appropriate, will be done for sample/site adequacy followed by 


  
  
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core biopsies for collection of tissue for the research correlates outlined.  The biopsy site will be 
clearly documented in the records; baseline and each follow-up biopsy will preferentially be done 
in the same organ site.    
  
Approximately six (6) core biopsy specimens will be obtained with each biopsy as outlined; the 
cytopathology slide will also be retained and submitted, if performed. Up to three cores will be 
placed in formalin solution and paraffin embedded. The remaining biopsy specimens will be flash 
frozen in liquid nitrogen and then stored as fresh tissue at ≤ -70°C for extraction of DNA and RNA. 
The biopsy specimens will be stored and batch shipped at the latest at the conclusion of study 
enrollment.  
  
The study staff will be notified when a biopsy is taking place. If core biopsy is not possible, other 
methods may be approved in advance by the IND Sponsor/designee.  
  
If a subject discontinues the study prior to a planned follow-up biopsy, an attempt should be made 
to collect the next scheduled biopsy when the decision is made to discontinue and prior to initiation 
of additional treatment, if possible.  
  
In the event that a subject cannot undergo a second biopsy for any reason, including refusal, or the 
baseline biopsy was unsuccessful or invaluable, the second and the third biopsies, as well as the 
optional biopsy at the time of progression, will not be required and the subject will continue to be 
treated per study protocol.  
  
NOTE: Archival tumor specimens from previously collected samples will be obtained for 
correlative analysis, if available.  
Biopsy Instructions  
  
Acceptable biopsy sites are:  
• 
Percutaneous biopsy of deep sites with local anesthetic and/or sedation (with an expected risk 
of severe complications < 2%)  
• 
Cutaneous biopsy of palpable sites with local anesthetic and/or sedation with an expected risk 
of severe complications < 2%  
• 
No open surgical or laparoscopic procedures will be performed solely to obtain a biopsy for 
this protocol.  


  
  
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Such biopsies can be safely performed as evidenced by literature reports [122, 123], as well as, in 
the prior experience of our PI at the NIH Clinical Center [124], where, among 244 research tumor 
biopsies (18G needle) in liver (126), subcutaneous/chest wall/abdominal wall (36), intramuscular 
(18), lung and lymph nodes, there were 8 minor cases of bleeding, and one pneumothorax requiring 
48h hospitalization (21). This evidence support that serial percutaneous core-needle biopsies can 
be obtained safely yielding material applicable for multiple translational applications.  
  
Considering the tumor histologies to be enrolled in this study are pancreatic cancer and 
cholangiocarcinoma, biopsies will probably be of liver. In our institution, the expected 
complication rate of percutaneous liver biopsy similar to those that will be done for this trial is less 
than 1 %. Risks of the procedure include, but are not limited to, bleeding, infection, pain, and 
scarring.  
  
9.2.2 Blood Samples  
  
Whole blood for PBMCs (up to 180cc) will be collected at the specified timepoints (See Section 
10). Detailed instructions for blood collection, processing, and storage are provided in the 
Laboratory Manual.   
  
Sera (up to 10 cc) and plasma (up to 20cc) will be collected at the specified timepoints (See Section 
10). Detailed instructions for blood collection, processing, and storage are provided in the 
Laboratory Manual.  
  
In the event that a subject cannot have all blood samples or volume needed at a single visit, the 
samples and/or remaining samples should be collected at the next possible visit.   
  
9.2.3 Handling and Shipping of Specimens  
  
A unique subject identifier will be assigned to each subject by the coordinating center and will be 
used to label the samples. The protocol scientific investigator(s) analyzing the samples will be 
blinded as to the direct subject identifiers.    
  


  
  
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A Laboratory Manual will be provided for specific handling and processing instructions; this 
document will be disseminated with the clinical protocol and is also available to investigators on 
request from the Coordinating Center.  
  
After shipping, samples, and associated data, will be stored at Johns Hopkins unless the subject 
withdraws consent.  
  
9.3 Methods  
  
9.3.1 Immunohistochemistry (IHC) and Gene Array Analyses  
  
The density of CD8+ Teffs, PD-1+, FoxP3+ Tregs, and the number of MDSCs will be evaluated by 
IHC in tumor specimens. Human PD-L1 IHC staining of paraffin embedded tumor specimens will 
be done using the Dako Catalyzed Signal Amplification system [126]. The density of cells will be 
determined at the junction between tumor tissue and non-tumor tissue (invasive front) and within 
the tumor (TILs). The densities will be reported as positive cells / mm2 of tissue using digital 
analysis. Each slide will be digitally scanned at 20X magnification and areas to be analyzed will 
be indicated using Aperio software.  PD-L1 expression is considered positive if membranous 
staining is present in more than 5% of the neoplastic cells [127]. In addition, immune aggregates 
will be microdissected and evaluated for immune signatures using gene array analyses.  These 
studies will be conducted as previously described [128].  
  
9.3.2 Next Generation Sequencing (NGS)  
  
Tumor specific somatic mutations will be identified by whole-exome sequencing (WES)  using  
DNA isolated from tumor tissue, along with subject-matched normal lymphocytes. Genomic DNA 
from tissue and lymphocyte sample will be sonicated to a modal size of 200 bp and ligated to 
Illumina TruSeq adaptors with barcodes, and subjected to minimal amplification. The resulting 
libraries will be subjected to selection of all exonic sequences in the genome via hybrid-capture 
with 120 bp biotinylated RNA-baits using the Agilent SureSelect platform. Enriched exonic 
sequences will be further amplified and subject to massively parallel sequence-by-synthesis 
100x100 bp paired end sequencing on an Illumina HiSeq 2000 at a minimal depth of 75x average 
coverage. The resulting reads will be aligned to the genome using bowtie2 and variants will be 
called on each sample compared to the human reference using the GATK software. Somatic 
variants will be identified using the strelka software.  


  
  
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The T cell repertoire in TILs will be evaluated in tumor specimens using Adaptive 
Biotechnologies’ next-generation sequencing-based approach.   
  
9.3.3 HLA-Binding Prediction Algorithms and Elispot Assays  
  
Quantification of tumor neoantigen-specific CD8+ T cell levels in PBL:  Each of the somatic 
missense mutations identified by WES will be screened for potential HLA class I-binding 
neoepitopes using the predictive algorithm NetMHC.  19mer peptides will be synthesized spanning 
each mutation predicted to generate a neoeptiope; and used in IFN ELISPOT assays to measure 
neoepitope-specific CD8+ T cell levels in PBL.  
  
9.3.4 MDSC Analysis  
  
Levels of granulocytic and monocytic MDSCs in peripheral blood will be evaluated by 6-color 
fluorescence-activated cell sorting (FACS) using monoclonal antibodies specific to CD11b, CD14, 
CD15, CD33, HLA-DR and the IL-4 receptor.  
  
10. STUDY CALENDAR  
  
Notations/reminders for all calendars:    
• Baselines assessments are to be conducted within 28 days of registration unless otherwise noted. 
 Correlative blood and tissue sample participation is mandatory.   
• Additional tests may be performed at the discretion of the treating investigator as per routine 
practice, or as otherwise clinically indicated.  
The schedule should be followed as closely as is realistically possible; the schedule may be 
modified due to problems such as scheduling delays or conflicts (e.g., clinic closure, vacations, 
etc.) with the guidance of the IND Sponsor/designee, as appropriate, and will not be reportable as 
a deviation unless the endpoints of the study are affected.  
  
*     
Required ≤ 7 days prior to the first dose of entinostat   
**   Required assessment windows during combination treatment for each cycle as noted (e.g.,  
Days 1 and 15 is 3 days, weekly is ±1 day).  Assessments on Days 1 and 15 should be  
completed/reviewed prior to planned nivolumab administration.  


  
  
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***  After 4 months, nivolumab will be given at a dose of 480 mg fixed dose every 4 weeks  
(maintenance phase). Therapy may continue with entinostat 5 mg weekly plus nivolumab  480 
mg every 4 weeks, until intolerance or progression.  
 Patients will be assessed in clinic on D1 of every cycle, and will be contacted by phone weekly, 
on the weeks entinostat alone is self-administered at home.   
  
# Required ≤ 14 days prior to the first dose of entinostat  
  
NOTE: All timeframes noted after the lead-in phase refer to duration on combination treatment 
(e.g., first-restaging should occur after 8 weeks of initiation of combination treatment of entinostat 
and nivolumab.)  
  
  
  
  


 
 
 


 
 
 


 
 


 
 
  
 
  
9. Thyroid function will be assessed by TSH (Thyroid Stimulating Hormone) at baseline and prior to each dose of nivolumab.  If 
abnormal, Free T3 (triiodothyronine) and T4 (thyroxine) should be assessed.  
10. The following should be assessed at baseline: Hepatitis B surface antigen (HBV sAg) and Hepatitis C antibody (HCV Ab) or 
Hepatitis C RNA (HCV RNA).  
11. An ECG is required during screening (prior to starting study treatment), as well as at any other time point when clinically indicated. 
All 12-lead ECGs should be recorded while the subject is in the supine position. The same method of assessment should be used 
throughout the study. Twelve-lead ECGs will be obtained after the subject has been resting in a supine position for at least 5 minutes.   
12. Bilirubin, blood, glucose, ketones, pH, protein, specific gravity, color and appearance.  Microscopy should be used as appropriate 
to investigate white blood cells and use the high power field for red blood cells  
13. For WOCBP (women of childbearing potential) only.  A serum or urine pregnancy testing is required prior to study 
enrollment/registration, ≤7 days prior to the first dose of entinostat and <24 hours prior to the first dose of nivolumab. After the first 
dose of nivolumab, an interim history to evaluate any risk of exposure to a fetus must be done prior to each dose in lieu of routine 
HCG testing, if appropriate.    
Female subject of childbearing potential should have a negative urine or serum pregnancy test within 72 hours prior to receiving 
retreatment with study medication. NOTE: If a patient has a positive or indeterminate serum or urine pregnancy test, then an 
ultrasound must be done to rule out pregnancy to enroll on trial. A serum B-HCG value of <25 is considered a negative pregnancy 
test.  
14. Radiologic imaging of chest/abdomen/pelvis (CT preferred, abdominal/pelvis MRI will be performed for patients with CT contrast 
allergy) and any other imaging required per RECIST for the particular subject are required at baseline. A baseline bone scan or 
PET/CT could be required to assess bone disease in patients with suspected or known bone metastases.  A baseline brain CT scan 
or MRI is requested in patients with suspected or known brain metastases.   Repeat same modality(ies) in follow-up to follow known 
site(s) of disease, with other assessments as clinically indicated if one has not been done within the past 6 weeks.  .  
15. Entinostat is to be self-administered by the patient weekly.   
16. Patients will receive entinostat 5 mg oral once a week plus nivolumab 240 mg every two weeks for approximately four months. 
After 4 months (16 weeks), nivolumab will be given at a dose of 480 mg fixed dose every 4 weeks. Therapy may continue with 
entinostat 5 mg weekly plus nivolumab 480 mg every 4 weeks, until intolerance or progression.  
Phase 2 Study Of Entinostat and Nivolumab in Unresectable or Me tastatic Cholangiocarcinoma   
and Pancreatic Adenocarcinoma   
Principal Investigator :  Nilofer Azad, M.D.  


 
 
17. Blood for serum and plasma samples will be collected at baseline (D -14), after entinostat lead in (on approximately day 14 (D-1) 
of entinostat therapy), on week 6, prior to dosing on C2D15, and at the time of the EOT visit. Detailed instructions for blood 
collection, processing, and storage are provided in the Laboratory Manual.  
18. Mandatory fresh tissue samples will be collected at D-14 and after entinostat lead-in (on approximately day 14 (D-1) of entinostat 
therapy prior to dosing on C1D1) and on week 6, prior to dosing on C2D15. A ±3 day window applies to both time points. All  
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samples are collected pre-dose on treatment days). Approximately six (6) core biopsy specimens will be obtained with each biopsy  
as outlined; the cytopathology slide will also be retained and submitted, if performed (See Section 9.2.1) All 
correlative blood/tissue studies should be performed on the same day.    
NOTE: If applicable, the daily dose of entinostat may occur prior to hematology/chemistry tests and these laboratory tests may be 
drawn at the same time as the correlative blood samples.  
19. A third mandatory biopsy will be performed at week 6 from Cycle 1, Day1. A window of +14 days applies to this time point  
20. An optional biopsy will be performed at the time of disease progression.  
21. Archival tumor specimens from previously collected samples will be obtained for correlative analysis, if available.  
22. Weekly assessments for toxicity/adverse events may occur by phone on days when entinostat alone is administered. Additionally, 
assessments are to continue for 30 days after the last dose of nivolumab (at intervals <21 days) or to resolution of drug-related AEs 
to ≤ Grade 1, whichever occurs later. SAEs that occur within 100 days of the last treatment or before initiation of a new antineoplastic 
treatment should also be followed and recorded.  These may occur by phone for subjects no longer being seen at the institution; 
however, an in-person clinic visit may be needed to confirm event resolution and/or to effectively evaluate possible immune-related 
events.  Subjects must be told of follow-up requirements at study entry.   
23. Subjects who complete or discontinue from treatment because of progression disease will be followed (by phone or email) every 
three months (+/- 2 weeks) after completion of the EOT visit for up to 2 years or study closure to monitor overall survival. 
Information of other cancer therapies after discontinuation from the study treatment will also be collected.   
For subjects who discontinue treatment for reasons other than tumor progression, will be contacted (by phone or email) every three 
months (+/- 2 weeks) after completion of the EOT for up to 2 years or study closure to monitor overall survival, and information 
Phase 2 Study Of Entinostat and Nivolumab in Unresectable or Me tastatic Cholangiocarcinoma   
and Pancreatic Adenocarcinoma   
Principal Investigator :  Nilofer Azad, M.D.  


 
 
about disease status will be also collected if possible (i.e. radiological imaging and/or tumor markers) until documented tumor 
progression.  
  
NOTE: For evaluation of PFS, all subjects who discontinue study drug administration prior to 6 months must have restaging 
scans/imaging within a 7 day window of the 6 month time point from the date of initiation of combination treatment 
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11. DATA REPORTING / REGULATORY REQUIREMENTS  
  
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 6 
(Adverse Events: List and Reporting Requirements).  
  
11.1 Data Management  
  
All information will be collected on study-specific case report forms (CRFs) by study staff. These 
data will be reviewed for completeness and accuracy by the PI.   
  
CRFs will be used to capture study results and data. The study coordinator or other authorized 
study personnel will transcribe data from source documents onto eCRFs. Before or between visits, 
the IND Sponsor,, Syndax and BMS or designee may request copies of the CRFs for preliminary 
medical review. Once the CRFs are complete and source-verified, the investigator must sign and 
date all required pages, verifying the accuracy of all data contained within the CRF. Training will 
be provided on proper completion of CRFs.  
  
11.2 Data Confidentiality and Subject Anonymity  
  
All information about the nature of the proposed investigation (with the exception of information 
required by law or regulations to be disclosed to the IRB, the subject or the appropriate regulatory 
authority) must be kept in confidence by the entire study personnel.  
  
The anonymity of participating subjects must be maintained. Subjects will be identified by their 
initials and an assigned subject number on CRFs and other documents retrieved from the site or 
sent to the IND Sponsor, Syndax and BMS, study monitor, regulatory agencies, or central 
laboratories/reviewers. Documents that identify the subject (e.g., the signed ICF) must be 
maintained in strict confidence by the investigator, except to the extent necessary to allow auditing 
by the appropriate regulatory authority, the study monitor, IND Sponsor or their representative.  
  
11.3 Protocol Compliance  
  


  
  
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Substantive changes in the protocol include changes that affect the safety of subjects or changes 
that alter the scope of the investigation, the scientific quality of the study, the experimental design, 
dosages, assessment variable(s), the number of subjects treated or the subject selection criteria.   
  
A protocol amendment must receive IRB approval before implementation. In parallel with the IRB 
approval process, the protocol amendment will be submitted to the appropriate regulatory authority 
as an amendment to the regulatory submission under which the study is being conducted. If a 
protocol amendment requires changes in the ICF, the revised ICF and protocol prepared by the 
investigator must also be approved by the IND Sponsor, Syndax/BMS, and the IRB before 
implementation.  
  
Emergency departures from the protocol that eliminate an apparent immediate hazard to a 
particular subject and that are deemed crucial for the safety and well-being of that subject may be 
instituted for that subject only. The investigator or the attending physician also will contact the 
IND Sponsor and/or designee as soon as possible in the case of such a departure. These departures 
do not require preapproval by the IRB; however, the IRB and the IND Sponsor and/ or designee 
must be notified in writing as soon as possible after the departure has been made. In addition, the 
investigator will document in the subject’s CRF the reasons for the protocol deviation and the 
ensuing events.  
  
11.4 Safety meetings  
  
Scheduled meetings will take place weekly and will include the protocol PI, study coordinator(s), 
research nurse (s), and sub-investigators (as appropriate). During these meetings matters related to 
the following will be discussed: safety of protocol participants, validity and integrity of the data, 
enrollment rate relative to expectation, characteristics of participants, retention of participants, 
adherence to protocol (potential or real protocol violations), data completeness, and progress of 
data for objectives.  
  
  
Quarterly teleconferences will be scheduled to include the Investigator and Syndax and BMS 
representatives. During these meetings, the Investigator shall provide Syndax and BMS with study 
progress updates. The Investigator will provide a summary of key points from the weekly meetings 
with a focus on safety of the protocol participants, enrollment status, and progress of data for 
objectives. In addition, both Syndax and BMS will provide safety and applicable program updates 
to the Sponsor.  


  
  
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11.5 Monitoring  
  
The SKCCC Compliance Monitoring Program will provide external monitoring for JHU-affiliated 
sites in accordance with SKCCC DSMP (Version 6.0, 02/21/2019).  The SMC Subcommittee will 
determine the level of patient safety risk and level/frequency of monitoring.   
  
Dr. Nilofer Saba Azad will be holding the IND for this study. She will comply with all regulated 
reporting requirements to the FDA.  
  
12. STATISTICAL CONSIDERATIONS  
  
12.1 Overall Study Design  
  
This is an open-label, two-stage, phase 2 study evaluating the clinical activity and safety of 
entinostat plus nivolumab. We will enroll two cohorts of patients: unresectable or metastatic 
cholangiocarcinoma (Cohort 1) and unresectable or metastatic pancreatic adenocarcinoma (Cohort 
2). Patients must have progressed (or were intolerant) to 1 or 2 prior chemotherapy regimens in the 
metastatic setting, or progression < 6 months from the completion of adjuvant chemotherapy.  
  
The primary objective of the trial is to determine whether the combination of entinostat plus 
nivolumab yields a clinically compelling antitumor activity measured as objective response rate 
(ORR, assessed by RECIST 1.1). Secondary endpoints include safety, progression-free survival 
(PFS), overall survival (OS), and immunologic correlates.   
  
The study is planned with 27 evaluable subjects per histology, based on a two-stage design that 
allows early termination for lack of efficacy.   
  
12.2 Sample Size and Accrual Rate   
  
Approximately 27 patients with unresectable or metastatic CCA and 27 patients with locally 
advanced or metastatic PDAC will be enrolled, with ORR as the primary endpoint. Enrollment 
will be carried out in 2 stages so that the study can terminate early if the combination of entinostat 
plus nivolumab is not sufficiently effective.   


  
  
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Simon’s two-stage, minimax, design will be employed in each cohort to test the null hypothesis 
that the true ORR is 5% or less (not considered clinically compelling for this combination). In the 
first stage, 13 subjects will be accrued.   
  
If there are no responders among the first 13 subjects, the study will be terminated for futility. 
Otherwise, 14 additional subjects will be accrued to target a total of 27 treated and response 
evaluable subjects. The null hypothesis will be rejected if 4 or more responses are observed in 27 
subjects per each cohort.   
The probability of stopping the trial early for futility is 51% if the true ORR is 5% or less. This 
design yields 80% power at a one-sided type I error rate of 5% when the true response rate is 20% 
The study may enroll 33 subjects per cohort to ensure 27 would be evaluable for the primary 
efficacy endpoint. We expect to enroll 4-6 patients per month. We estimate that we could reach 
the accrual goal within 1 year.  
  
Any patient who comes off of study due to toxicity before completing the first cycle of treatment, 
without evidence of disease progression may be replaced.   
  
12.3 Study Endpoints Analyses  
  
12.3.1 Analysis of Primary Endpoints  
  
The objective response rate defined as the proportion of response evaluable subjects who have a 
CR or PR using RECIST 1.1 at any time during the study.   
  
The evaluable population includes all subjects who have completed at least one dose of entinostat..   
  
An exact binomial test will be used to evaluate the primary question of whether the response rate 
for combination therapy exceeds the historic rate for the single agent. Response rate will be 
reported with exact confidence interval.  
  
12.3.2 Analysis of Secondary Endpoints  
  


  
  
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• 
OS is defined as the duration of time from start of study treatment to time of death. For 
subjects lost to follow-up or whose vital status is unknown, every effort will be made to 
determine the date such subjects were last known to be alive. Such efforts may include phone 
calls, certified mail, and the checking of public records. Subjects who are alive or lost to 
follow-up as of the data analysis cutoff date will be right-censored. The censoring date will 
be determined from the date the subject was last known to be alive.  
  
• 
PFS is defined as the time from cycle 1, day 1 of immunotherapy until first documented local 
progression or death due to any cause. Disease progression will be assessed using RECIST 
(version 1.1). Due to the expectation that some patients may experience delayed clinical 
responses to therapy, patients with disease progression by radiographic imaging or laboratory 
parameters during a 12-week evaluation period but without rapid clinical deterioration or 
significant change in performance status that requires additional immediate therapy may 
continue to receive treatment on study.   
  
Subjects that meet the above criteria and continue on study therapy must discontinue treatment 
upon documentation of disease progression on the second scan. The date of progression will 
be backdated to the time of first RECIST criteria progression. Tumor assessments will be 
made using RECIST 1.1 and immune-related response criteria (irRC). Individuals will be 
censored at the date of the last scan for PFS if no event occurs.  
  
Median time to event will be calculated and reported with confidence intervals.   
  
Analysis of PFS will be restricted to evaluable individuals who complete at least one dose of 
entinostat, while the analysis of OS will be performed on all evaluable patients.   
  
OS curves, OS medians with 95% CIs, and OS rates at 6, 12, 24 and 36 months with 95% CIs 
will be estimated using Kaplan-Meier methodology  
  
PFS curves, PFS medians with 95% CIs, and PFS rates at 6, 12 and 24 months with 95% CIs 
will be estimated using Kaplan-Meier methodology.  
  
• 
Duration of response (DOR) will be calculated for subjects who achieve a best overall 
response of CR or PR with entinostat in combination with nivolumab. For such subjects, 


  
  
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duration of response is defined as the number of weeks from the start date of PR or CR 
(whichever response is recorded first) and subsequently confirmed to the first date that 
recurrent or progressive disease or death is documented. In such cases, recurrent or 
progressive disease will be assessed relative to the smallest tumor measurements recorded 
since the start of study treatment. The primary analysis of duration of response will be based 
on the time point responses, best overall response, and PD status that are determined by the 
review of the investigator  
DOR will be summarized descriptively using the Kaplan-Meier method with 95% confidence 
intervals (CIs)  
  
• 
The safety analysis will be performed in all subjects who receive any amount of study drug. 
A baseline measurement and at least 1 laboratory or other safety-related measurement 
obtained after at least 1 dose of study treatment may be required for inclusion in the analysis 
of a specific safety parameter (e.g., lab shifts from baseline).   
  
A complete list of all AE data will be provided along with an assessment of NCI CTCAE 
grade and relationship to study drug. The incidence of AEs will be tabulated by subgroups 
of interest (e.g. grade 3 or higher, organ class, relationship to study drug).   
  
For analyses at the individual level, the highest grade and relationship to study drug will be 
assumed if multiple events have occurred.   
  
Toxicity will be tabulated by type and grade and will be summarized with descriptive statistics. 
Other safety data will be assessed in terms of physical examination, clinical chemistry, 
hematology, vital signs, and ECGs. Negative binomial regression and Cox proportional hazards 
models will be used to assess the rate of AE and time to first toxicity, respectively.  
  
12.3.3 Data & Safety Monitoring  
  
The PI and the study statistician will review the study as needed based upon rate of accrual for 
toxicity monitoring to identify accrual, and any endpoint problems that might be developing. The 
Sidney Kimmel Comprehensive Cancer Center Clinical Research Review Committee and Safety 
Monitoring Committee are responsible for reviewing accrual and safety data for this trial at least 
twice a year.  


  
  
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12.3.4 Analysis of Exploratory Endpoints  
  
Exploratory correlative studies will be performed to investigate:  
▪ To measure the baseline levels of  immune markers including CD8+ T effector cells and 
CD4+FoxP3+ T regulatory cells, PD-L1 expression and tumor infiltrating lymphocytes 
(TILs), major histocompatibility complex (MHC) class I and II expression, and natural killer 
(NK) cell receptors and ligands expression and correlate these variables with treatment 
response and toxicity.  
▪ To characterize changes in the immune markers described above after treatment  
▪ To identify gene expression changes in malignant tissue after therapy, and complete gene set 
analysis to elucidate affected pathways  
▪ To measure changes in circulating immune suppressor cells (MDSC, Treg) in peripheral 
blood by flow cytometry and test for association with response to therapy.  
  
The overarching aim of these exploratory studies is to establish baseline levels and measure 
changes in immunological pathways after treatment. Little is known about baseline levels for these 
variables in Cholangiocarcinoma and Pancreatic Adenocarcinoma, let alone changes after 
treatment, and if the primary and secondary aims are successful, these investigations will establish 
a biological foundation on which to build in follow-up studies.   
  
Immunological variables will be examined in plots and summary statistics, to characterize 
distributions, identify outliers and other potential problems in the data.   Joint exploratory analysis 
will identify associations and potential interactions.   Variables may be transformed on the basis 
of these investigations, to reduce skewness, minimize the influence of outliers and/or to regularize 
relationships between predictors and response for better model fit. Exploratory analysis of the 
molecular markers, including visualizations and statistical summaries such as hierarchical cluster 
analysis, heat maps, multidimensional scaling, and principle component analysis will offer 
important views of the structural characteristics of the expression data.    
  
Response will be described categorically, and associations between response and immunological 
variables will be characterized, in each cohort, using multivariate logistic regression models, with 
adjustment for clinical and pathological co-variates that may be associated with response. 
Estimated effects will be reported with standard errors and confidence intervals.    


  
  
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We will fit empirical Bayes linear models [129] to identify genes for which expression is associated 
with response to treatment, controlling type I error at an FDR of <10%. Gene set enrichment 
analysis [130, 131] will be applied to the results to identify immune pathways that are significantly 
altered after treatment.   
  
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14. APPENDICES   
  
Appendix A: Eastern Cooperative Oncology Group Performance Status Scale, with  
Equivalent Karnofsky Performance Status Scores  
  
ECOG1  
Karnofsky2  
Score  
Criterion  
%  
Criterion  
0  
Normal activity  
100  
Normal; no complaints; no evidence of 
disease  
  
 
90  
Able to carry on normal activity; minor 
signs or symptoms of disease  
1  
Symptoms but ambulatory  
80  
Normal activity with effort; some signs or 
symptoms of disease  
  
 
70  
Cares for self; unable to carry on normal 
activity or do active work  
2  
In bed <50% of time  
60  
Requires occasional assistance but is able 
to care for most of his/her needs  
  
 
50  
Requires considerable assistance and 
frequent medical care  
3  
In bed >50% of time  
40  
Disabled, requires special care and 
assistance  
  
 
30  
Severely 
disabled; 
hospitalization 
is 
indicated though death is not imminent  
4  
100% bedridden  
20  
Very sick; hospitalization is necessary  
  
 
10  
Moribund; fatal processes progressing 
rapidly  
5  
Dead  
0  
Dead  
1Oken 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.  
  
  
  
  
  


  
  
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Appendix B:  Patient Drug Information Handout and Wallet Card  
  
Information for Patients, Their Caregivers, and Non-Study Healthcare Team on Possible 
Interactions with Other Drugs and Herbal Supplements   
  
[Note to site:  This appendix consists of an “information sheet” to be handed to the patient at the 
time of enrollment.  Update the “patient name” and study doctor’s/team’s contact information 
prior to giving to the patient.]  
  
The patient, ____________________________, is enrolled on a clinical trial using the 
experimental study drugs:  entinostat and nivolumab.  This clinical trial is sponsored by the 
National Cancer Institute.  This form is addressed to the patient, but includes important information 
for others who care for this patient.   
  
These are the things that you as a healthcare provider need to know:  
  
Entinostat and nivolumab are not known or expected to interact with certain enzymes in the body, 
the heart’s electrical activity, or with other medications; however, there is the possibility of 
interactions.  For instance, entinostat may interact with other drugs that are processed by your liver.    
  
To the patient: Take this paper with you to your medical appointments and keep the 
attached information card in your wallet.    
  
Entinostat and nivolumab may interact with other drugs which can cause side effects. For this 
reason, it is very important to tell your study doctors of any medicines you are taking before you 
enroll onto this clinical trial.  It is also very important to tell your doctors if you stop taking any 
regular medicines, or if you start taking a new medicine while you take part in this study.  When 
you talk about your current medications with your doctors, include medicine you buy without a 
prescription (over-the-counter remedy), or any herbal supplements such as St. John’s Wort.  It is 
helpful to bring your medication bottles or an updated medication list with you.  
  


  
  
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Many health care providers can write prescriptions.  You must tell all of your health care providers 
(doctors, physician assistants, nurse practitioners, pharmacists) you are taking part in a clinical 
trial.    
These are the things that you and they need to know:   
  
Before you enroll onto the clinical trial, your study doctor will work with you and your regular 
health care providers, as needed, to review any medicines and herbal supplements that you are 
taking or may start during the study.  
  
• 
Please be very careful!  Over-the-counter drugs (including herbal supplements) may 
contain ingredients that could interact with your study drug.  Speak to your doctors or 
pharmacist to determine if there could be any side effects.   
• 
Your regular health care provider should check a frequently updated medical reference or 
call your study doctor before prescribing any new medicine or discontinuing any medicine.  
Your study doctor’s name is…_____________________________________   
  
and he or she can be contacted at …___________________________________.  
  
  
  
  
  
  
 STUDY DRUG INFORMATION WALLET CARD    
You are enrolled on a clinical trial using the experimental study  drugs 
entinostat and nivolumab . This clinical trial is sponsored by the  NCI.  
Entinostat and nivolumab may interact with other drugs.   
Because of this, it is very important to:   
➢ 
Tell your doctors if you stop taking any medicines or if you 
start  taking any new medicines.   
➢ 
Tell all of your health care providers (doctors, physician 
assistants,  nurse practitioners, or pharmacists) that you are taking part 
in a clinical trial.   
➢ 
Check with your doctor or pharmacist whenever you need to 
use an  over‐the‐counter medicine or herbal supplement.   
  
  
   
  
Entinostat and nivolumab must be used very carefully with other 
medicines.   
➢ Before you enroll onto the clinical trial, your study doctor will work 
with you and your regular health care providers, as needed, to review 
any medicines  and herbal supplements that you are taking or may 
start during the study.   
➢ Before prescribing new medicines, your regular health care 
providers should go to a frequently‐updated medical reference for 
a list of drugs to avoid, or contact your study doctor.    
➢ Your study doctor’s name is _____________________________ 
and can be contacted at _________________________________.   


  
  
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and Pancreatic Adenocarcinoma   
Principal Investigator:  Nilofer Azad, M.D.  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  


 
 


 
 
  
 
  
Appendix D: Management Algorithms for Nivolumab -Related Adverse Events   
  
Adverse Event Management Algorithms:    
GI   
Renal  
Pulmonary  
Hepatic   
Endocrinopathy   
Skin  
Neurological  
  
  
  
  
  
  
  
  
Phase 2 Study Of Entinostat and Nivolumab in Unresectable or Metastatic Cholangiocarcinoma   
and Pancreatic Adenocarcinoma   
Principal Investigator:  Nilofer Azad, M.D.  


 
 
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Appendix E: Concomitant Medications to be Avoided  
Examples of sensitive in vivo CYP substrates and CYP substrates with narrow therapeutic range 
are summarized in Table 14.1  
  
Table 14.1 Examples of substrates that may be affected by entinostat  
 
relationship indicates that small increases in their exposure levels by the concomitant use of 
CYP inhibitors may lead to serious safety concerns (e.g., Torsades de Pointes).  
2 Because a number of CYP3A substrates (e.g., darunavir, maraviroc) are also substrates of P-
gp, the observed increase in exposure could be due to inhibition of both CYP3A and P-gp.  
3 Withdrawn from the United States market because of safety reasons.  
  
Refer to Table 14.2 for examples of transporter inhibitors and inducers.  
Table 14.2 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  
  
Phase 2 Study Of Entinostat and Nivolumab in Unresectable or Metastatic Cholangiocarcinoma   
and Pancreatic Adenocarcinoma   
Principal Investigator:  Nilofer Azad, M.D.  
CYP Enzymes  
Substrates with narrow therapeutic range 1  
CYP1A2  
Theophylline, tizanidine  
CYP2C8  
Paclitaxel  
CYP3A 2  
Alfentanil,  
astemizole 3,  
cisapride 4
cyclosporine,  
,  
ihydroergotamine, ergotamine, fentanyl, pimozide, quinidine,  
sirolimus, tacrolimus, terfenadine 4  
1 CYP substrates with narrow therapeutic range refers to drugs whose exposure-response  


 
 
  
  
  
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