Clinical trial NCT01928576
Conditions: Non-Small Cell Lung Cancer Epigenetic Therapy
Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Start date: 2013-11-06; Completion date: 2023-04-04
Enrollment: 143 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Response Rate

Detailed description:
Objective response rate to Nivolumab preceded by epigenetic priming. Response will be assessed by RECIST 1.1 criteria, baseline scans for this assessment will be the baseline scans done within 4 weeks of enrollment.

Arms: arm 1: Nivolumab 3mg/kg every 2 weeks until progression arm 2: Anti-PD-1/PD-L1 treatment naïve patients only

Every 28 days for 6 cycles Azacitidine 40mg/m2 days 1-5 and 8-10 Entinostat 5mg Days 3 and 10 Nivolumab 3mg/kg Days 1 and 15

Followed by:

Nivolumab 3mg/kg every 2 weeks until progression

After a patient has completed 6 months of nivolumab, they can receive nivolumab every 4 weeks instead of every 2 weeks. The dose for Nivolumab every 4 weeks is 480mg. arm 3: Patients must have had refractory (Arm E=less than 24 weeks from first dose of anti-PD-1/PD-L1) disease during or after anti-PD-1 or anti-PD-L1 therapy and, in the opinion of the investigator, must be unlikely to benefit from nivolumab monotherapy.

Every 28 days for 6 cycles Azacitidine 40mg/m2 days 1-5 and 8-10 Entinostat 5mg Days 3 and 10 Nivolumab 3mg/kg Days 1 and 15

Followed by:

Nivolumab 3mg/kg every 2 weeks until progression

After a patient has completed 6 months of nivolumab, they can receive nivolumab every 4 weeks instead of every 2 weeks. The dose for Nivolumab every 4 weeks is 480mg. arm 4: Patients must have had recurrent (Arm F=more than 24 weeks from first dose of anti-PD1/PD-L1) disease during or after anti-PD-1 or anti-PD-L1 therapy and, in the opinion of the investigator, must be unlikely to benefit from nivolumab monotherapy.

Every 28 days for 6 cycles Azacitidine 40mg/m2 days 1-5 and 8-10 Entinostat 5mg Days 3 and 10 Nivolumab 3mg/kg Days 1 and 15

Followed by:

Nivolumab 3mg/kg every 2 weeks until progression

After a patient has completed 6 months of nivolumab, they can receive nivolumab every 4 weeks instead of every 2 weeks. The dose for Nivolumab every 4 weeks is 480mg. arm 5: Anti-PD-1/PD-L1 treatment naïve patients only Every 28 days for 2 cycles Azacitidine 40mg/m2 subcutaneous days 1-6 and 8-10 Entinostat 7mg by mouth Days 3 and 10

Followed by:

Nivolumab 3mg/kg every 2 weeks until progression After a patient has completed 6 months of nivolumab, they can receive nivolumab every 4 weeks instead of every 2 weeks. The dose for Nivolumab every 4 weeks is 480mg arm 6: Every 28 days for 2 cycles CC-486 300 mg by mouth days 1 - 21

Followed by:

Nivolumab 3mg/kg every 2 weeks until progression After a patient has completed 6 months of nivolumab, they can receive nivolumab every 4 weeks instead of every 2 weeks. The dose for Nivolumab every 4 weeks is 480mg.
Interventions: intervention 1: Azacitidine intervention 2: Entinostat intervention 3: Nivolumab intervention 4: CC-486 300
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None intervention 4: None

Protocol documents:
Prot_SAP_000.pdf: 
Protocol Version 15, Date: August 9, 2022 
Johns Hopkins Protocol #: J1353/ NA_00084192; NCT01928576
TITLE: A Phase II Study of Epigenetic Therapy with Azacitidine and Entinostat with 
Concurrent Nivolumab in Subjects with Metastatic Non-Small Cell Lung Cancer. 
Center: 
Johns Hopkins University School of Medicine, Sidney Kimmel 
Comprehensive Cancer Center 
Principal Investigator: 
Name 
Julie Brahmer, MD 
Telephone  
410-502-7159
Fax 
410-614-9334
e-mail
brahmju@jhmi.edu
Participating Institutions: 
Norris Comprehensive Cancer Center, University of Southern 
California; University of Pittsburgh Medical Center 
USC Principal Investigator: 
 Jorge Nieva, MD, Jorge.Nieva@med.usc.edu 
1441 Eastlake Avenue, Room 3440 
      Los Angeles, CA 90089-2211 
  LAC+USC Medical Center 
USC Sub-Site Principal Investigator 
Jorge Nieva, MD 
328-865-0421
1200 N. State St.
Los Angeles, CA 90033
 
Keck Medical Center of USC Pasadena 
USC Sub-Site Principal Investigator 
Jorge Nieva, MD  
328-865-0421
625 S. Fair Oaks Ave, #400,
Pasadena, CA 91105
 
USC Norris Oncology/Hematology-Newport Beach 
USC Sub-Site Principal Investigator 
Jorge Nieva, MD  
323-865-0241
520 Superior Avenue, Suite 300
Newport Beach, CA 92663
Johns Hopkins Bayview Medical Center 
BV Lead Site Co-Investigator: Julie Brahmer, MD 
4940 Eastern Avenue 
Baltimore, MD 21224 
Sibley Memorial Hospital (Johns Hopkins) 
Sibley Lead Site Co-Principal Investigator:  Benjamin Levy, MD 
Sibley Memorial Hospital 
5255 Loughborough Rd. NW 
Washington DC 20016 


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University of Pittsburgh Medical Center Lung Cancer Center of Excellence 
UPMC Principal Investigator: James G. Herman, MD 
 
hermanj3@upmc.edu  
 
Cancer Pavilion 
 
5150 Centre Avenue 
 
Pittsburgh, PA 15232 
 
 
Coordinating Center: 
 
 
Lead Study Coordinator:  
Name  
 
Amber Michalik 
 
 
Telephone  
410-502-0756 
 
 
e-mail  
 
amichal2@jhmi.edu 
 
 
 
Protocol Version Date, Number: 
 
August 9, 2022, Version 15 
 
 
 
 
 
Supported by: 
SU2C 
Rising Tide Foundation 
Jim Toth 
 
Supplied Agents:  
Entinostat (IND #118,458) Syndax Pharmaceuticals, Inc.  
5-azacitidine for injection (IND #118,458) Celgene Corporation  
Nivolumab (BMS-936558) (IND#118,458) BMS Inc. 
 
IND 118,458 Sponsor: Julie Brahmer, M 
 
 
 


Protocol Version 15, Date: August 9, 2022 
 
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iii
SCHEMA 
          
 
 
 
 
 
 
After a subject has completed 6 months of nivolumab (regardless of arm assignment), they 
can receive nivolumab every 4 weeks instead of every 2 weeks.  
 
The goal of this study is to assess whether 6 cycles of concurrent epigenetic therapy consisting 
of azacitidine and entinostat in combination with nivolumab can increase response compared to 
nivolumab single agent in patients who are immunotherapy naïve (Arm D), or in patients whose 
disease has progressed on immunotherapy when compared to historical single agent docetaxel 
(Arms E & F).  
 
Primary endpoint is the response rate by treatment Arm.  Response will be assessed from first 
dose of trial therapy.    
   
Patients experiencing significant toxicities on Arm D during cycles 1-6 of combination therapy of 
azacitidine, entinostat and Nivolumab may proceed to Nivolumab only.  Otherwise, patients 
whose disease is responding, progressing, or stable on combination therapy with Nivolumab, 
azacitadine and entinostat will proceed to Nivolumab monotherapy after 6 cycles.  Patients 
experiencing significant toxicities due to nivolumab or documented disease progression (see 
Section 9) on Arm E or Arm F during cycles 1-6 of combination therapy of azacitidine, entinostat 
and Nivolumab must come off study treatment.  Patients whose disease is responding or stable 
on combination therapy with Nivolumab, azacitadine and entinostat will proceed to Nivolumab 
monotherapy after 6 cycles on Arms E and F.   
 
 


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We plan to enroll up to 20 patients each on Arms D, E and F (N=60). Allowing for up to 10% 
unevaluable patients, we will enroll up to 22 patients on each Arm (D-F), or a total of 66.


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TABLE OF CONTENTS 
SCHEMA ................................................................................................................................... iiiiii 
TABLE OF CONTENTS ............................................................................................................vv 
1. 
OBJECTIVES ..................................................................................................................11 
2. 
BACKGROUND ..............................................................................................................11 
3. 
PATIENT SELECTION ..................................................................................................99 
4. 
TREATMENT PLAN ...................................................................................................1212 
4.1 
Agent Administration .......................................................................................1212 
4.1.1     Entinostat ...........................................................................................1313 
4.1.2     Azacitidine ..........................................................................................1313 
4.1.3     Nivolumab ..........................................................................................1313 
4.2 
General concomitant medication and supportive care guidelines ...........1414 
4.3 
Management of Nivolumab-related infusion reactions ..............................1616 
4.4 
Duration of Therapy ........................................................................................1717 
4.4.1     Treatment Beyond Disease Progression ......................................1818 
4.5 
Duration of Follow Up ..................................................................................1919 
4.6 
Criteria for Removal from Study Treatment ................................................2020 
5. 
DOSING DELAYS/DOSE MODIFICATIONS .........................................................2020 
5.1 
Dose Modifications/Treatment Delays for Azacitidine and 
Entinostat Only ..............................................................................................2020 
5.2 
Nivolumab dose delay criteria .......................................................................2424 
6. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ...................2525 
6.1 
Adverse effects of azacitidine ...................................................................2525 
6.2 
 Adverse effects of entinostat....................................................................2525 
6.3 
 Adverse effects of Nivolumab ..................................................................2626 
6.4 
 Adverse Event Characteristics .....................................................................2727 
6.5 
 Adverse Event Reporting ...........................................................................2727 
Expedited Reporting by Investigator to Celgene ........................................2828 
Celgene Drug Safety Contact Information: .................................................2929 
Expedited Reporting by Investigator to Syndax .........................................2929 
Syndax Drug Safety Contact Information: ...................................................2929 
6.6 
 Data Handling and Record Keeping .......................................................3030 
6.7 
Ethical Considerations ................................................................................3232 
7. 
PHARMACEUTICAL INFORMATION ....................................................................3232 
7.1 
 Azacitidine .......................................................................................................3232 
7.2 
 Entinostat .........................................................................................................3333 
7.3 
 Nivolumab........................................................................................................3433 
8. 
STUDY CALENDARS ................................................................................................3535 
9. 
MEASUREMENT OF EFFECT .................................................................................3736 
9.1 
 Antitumor Effect – Solid Tumors ..................................................................3737 


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10. 
STATISTICAL CONSIDERATIONS ........................................................................4544 
10.1 
Study Design/Endpoints .............................................................................4545 
10.1.1 Study Design ........................................................................................4545 
10.1.2 Endpoints ..............................................................................................4545 
10.2 
Sample size, Analysis, and Accrual Rate ....................................................4646 
10.3 
Stratification Factors .......................................................................................4746 
10.5 
Feasibility monitoring ......................................................................................4848 
10.6  Analysis of secondary endpoints ....................................................................5050 
10.7 
Data Safety, Monitoring and Between Site Communication .........................5050 
11. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES – Please see 
lab manual for full details. ......................................................................................5050 
11.1 
Plasma..............................................................................................................5050 
11.2 
Tumor ................................................................................................................5050 
11.3 
Peripheral Blood Mononuclear Cells (PBMCs) ..........................................5151 
11.4     Analysis ...........................................................................................................5151 
REFERENCES ........................................................................................................................5252 
  


 
 
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1. OBJECTIVES 
 
1.1 
Primary Endpoint 
 
1) 
Objective response rate  
Objective response to combination Nivolumab and epigenetic therapy will be assessed 
by Arm.  Response will be assessed by RECIST 1.1 criteria, baseline scans for this 
assessment will be done within 4 weeks of enrollment. 
 
1.2 
Secondary Endpoints 
 
    
2) 
Progression free survival 
Progression-free survival will be measured from the time of study enrollment until   
radiologic, clinical progression or death.   
3) 
Time to Progression 
Time to progression will be measured from the time treatment begins until radiologic or 
clinical progression is noted. 
4) 
Overall survival 
Overall survival will be measured from the time of enrollment until death. 
5) 
Safety and tolerability 
Toxicities observed in the study will be assessed by CTCAE 4.0 criteria. 
 
1.3 
Exploratory Endpoints 
 
Assessment of tumor baseline PD-L1 expression will be performed.  Serial assessment 
of genomic and immunologic parameters will be undertaken.  Genomic analyses will 
include target gene DNA methylation status in circulating DNA and in pre- and post-tumor 
biopsies, DNA exome sequencing to assess mutational burden and status of driver gene 
mutations, genome wide and target gene DNA methylation levels, and RNA-seq analyses 
of genome wide gene expression for detection of drug induced changes in endogenous 
retroviral (ERV) transcripts. Assessment of immunologic parameters in pretreatment, on 
treatment and post-treatment (when feasible) biopsies, will also be performed and 
compared. 
 
2. BACKGROUND 
 
2.1 
Lung cancer 
 
Lung cancer is the most common cause of death from malignancy in both men and women1. 
Most non-small cell lung cancer patients present with advanced disease. Metastatic disease 
was typically treated with chemotherapy alone and is considered incurable with this therapy. 
Recently, immunotherapy has been approved in a variety of ways for the treatment of 
advanced lung cancer; however, many patients who receive this therapy either don’t respond 
or develop resistance. Immunotherapy either alone or in combination with chemotherapy in 
the front-line treatment setting is now dominating the treatment landscape for advanced 
disease.  Fewer and fewer patients are now receiving single agent immunotherapy in the 
second-line treatment setting due to the rapidly evolving treatment landscape.  New, effective 


 
 
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therapies and strategies for lung cancer are a critical need in the immunotherapy era 
particularly after disease progression on first-line immunotherapy containing treatment.  
 
2.2  
Agents used 
 
2.2.1 Azacitidine 
 
DNA methyltransferase inhibitors have been under investigation for over 25 years.  
The most widely used DNA methyltransferase inhibitor is azacitidine 2. Azacitidine is a 
cytidine analogue that functions as a mechanism-dependent suicide inhibitor of the 
DNA methyltransferase DNMT1.  DNA methyltransferases recognize azacitidine as a 
natural cytosine. However, the azacitidine prevents the completion of the methylation 
reaction, leading to trapping and degradation of the DNMT1 enzyme 3. Azacitidine is 
approved by the US Food and Drug Administration for the treatment of myelodysplastic 
syndrome4.   
 
 
2.2.2 Entinostat 
 
Histone deacetylases (HDACs), like DNA methyltransferases, are important negative 
regulators of gene expression5-7. Several HDAC inhibitors are in active clinical 
development, including entinostat. In a phase I clinical trial of entinostat in 31 patients 
with advanced solid tumors8, major side effects included hematologic and 
gastrointestinal toxicities. 
 
2.2.3 Nivolumab 
 
Nivolumab (BMS-936558 (MDX-1106)) is a fully human IgG4: monoclonal antibody 
that blocks PD-1, an inhibitory receptor expressed on activated T and B cells.  PD-L1 
or PD-L2 expressed on tumors or nontransformed cells in the tumor microenvironment 
can bind to PD-1 on the surface of CD4 helper and CD8 cytotoxic T cells, suppressing 
anti-tumor cytolytic responses9.  Phase I testing of Nivolumab has been associated 
with objective responses in multiple solid tumors including non-small cell lung cancer10-
12.  BMS-936558 was generally well tolerated, with a grade 3-4 AEs in 14% of patients 
treated biweekly. Based on two Phase III trials showing improved overall survival when 
compared to single agent chemotherapy, Nivolumab has been FDA approved in the 
second line treatment setting of metastatic squamous and non-squamous NSCLC 
patients18,19. Trials combining Nivolumab with cytotoxic therapies, ipilimumab, and 
other targeted therapies in NSCLC are ongoing. 
 
 
2.3  
Rationale for epigenetic priming of immunotherapy 
 
2.3.1 
Azacitidine and entinostat in non-small cell lung cancer patients: the priming 
 
 
hypothesis 
 
We have completed a combination study of azacitidine and entinostat in patients with 
extensively pretreated metastatic lung cancer13. This study defined a regimen of 


 
 
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azacitidine 40 mg/m2 days 1-6 and 8-10 and entinostat 7 mg PO on days 3 and 10 on 
a 28-day schedule as safe and well-tolerated. Major objective responses were 
observed in 2 patients.  
 
 
More surprising than the responses 
observed was that several patients 
treated on this protocol experienced 
major 
objective 
responses 
to 
the 
subsequent line of therapy, despite 
being heavily pretreated.  Of 28 patients 
who received a subsequent line of 
therapy, the response rate was 29%, 
higher than for any agent for recurrent 
lung cancer (reported response rates to 
erlotinib, docetaxel, or pemetrexed are 
approximately 9%). Although the extent 
of data are limited, most notable of all 
has been the response to subsequent 
immunotherapy targeting the PD-1/PD-
L1 pathway.  Of five patients with 
progressive lung cancer after multiple 
prior therapies who were treated with 
azacitidine and entinostat, and who 
received Nivolumab or a similarly targeted anti-PD-L1 antibody(BMS-936559) as the 
immediate subsequent therapy, three have experienced major objective responses, a 
fourth has had disease stabilization beyond 6 months after initiation of Nivolumab, and 
the fifth has stable disease beyond 6 months but required palliative radiation to a mass 
eroding into the chest wall from the right lung.  Of the 5 patients, two had prior radiation 
with concurrent chemotherapy followed by one platinum doublet, one had one prior 
platinum doublet, and one had two prior therapies for metastatic disease.  The last 
patient had 4 prior therapies as well as radiation.  These responses and stable disease 
at 24 weeks compare favorably to the 18% NSCLC response rate and a 7% stable 
disease rate at 24 weeks reported in the multi-dose Phase I trial of Nivolumab and 
10% NSCLC response rate and 12% stable disease rate at 24 weeks reported in the 
multi-dose Phase I trial of BMS-93655914,15. 
 
These responses have been quite impressive, and are ongoing; one example is shown 
in the figure to the right.  Only one of the 5 patients was a responder to epigenetic 
therapy, and in fact 3 progressed at the very first time point assessed.  Such major 
objective responses in rapidly progressing non-small cell lung cancer after multiple 
prior therapies are rarely observed. 
 
 
2.3.2 Biological rationale 
 
Aberrant DNA methylation and histone deacetylation represent two of the critical 
mechanisms of tumor-specific gene silencing.  Both of these critical mechanisms of 
        Pre-treatment           12mo on Nivolumab 
 
 
 
Epigenetic priming?  Serial CT scans of a 
patient with advanced NSCLC, progressive on 
azacitidine and entinostat, with major objective 
response to subsequent Nivolumab. 


 
 
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epigenetic silencing can be reversed, using DNA methyltransferase inhibitors (such as 
azacitidine) and histone deacetylase inhibitors (such as entinostat).  Our group has 
led efforts to define the biology and therapeutic implications of epigenetic gene 
silencing in cancer, including demonstration of synergistic re-expression of silenced 
tumor suppressor genes using these classes of drugs 16,17. 
 
Beyond cell-autonomous effects, a combination of published and unpublished data 
offers three non-mutually exclusive mechanisms by which epigenetic modulation of 
tumors can enhance anti-tumor immunity. First, epigenetic modulation induces a vast 
array of new antigens by the tumors that are potential targets for T cell and antibody 
responses. Second, re-expression is induced at silenced promoters of key cytokine 
genes in T cells, such as interferon-gamma and IL-2 – critical effector cytokines in anti-
tumor responses. Third, global demethylation of DNA in tumor cells induces a 
“pathogen response” pattern of gene expression, characterized in part by a type I 
interferon response.  Specifically, in cultured NSCLC and other human cells, low doses 
of the DNA demethylating agent 5-azacitidine (5-Aza-CR) up-regulated pro-
inflammatory, viral defense, and tumor antigen presentation pathways while increasing 
PD-L1 
expression18. 
Colon 
cancer 
cells 
genetically 
disrupted 
for 
DNA 
methyltransferases (DNMT’s), 5-Aza-CR targets, have a similar signature18. 
Importantly, pathways up-regulated by 5-Aza-CR, including PD-L1 expression,  were 
found to be basally decreased in hundreds of primary SC and AC samples, including 
low expression and  increased promoter methylation of immune -related transcription 
factors, prominently, IRF7 in SC. Thus, combining epigenetic therapy with immune 
checkpoint blockade could significantly alter management of NSCLC19, 20.  
 
The very latest pre-clinical data from our group, in mouse model studies of NSCLC 
and serous ovarian cancer, identify that the epigenetic therapy agents  generate anti-
tumor responses and these, importantly are associated with immune cell infiltration, 
and notably activated CD8 T-cells into tumors20, 21.  This is all associated, as outlined 
in the correlative science section, with an upregulation of ERV transcripts and the viral 
defense gene stimulation of Type 1 interferon signaling including for levels of the 
immune inhibitory ligand, PD-L1. These drug effects also contribute to, in tumor 
associated CD8 T-cells, reversion of a transcriptional profile for immune exhaustion20. 
All of these epigenetic therapy effects will predictably sensitize tumors for response to  
antibodies that block the PD-1 inhibitory pathway and unleash the anti-tumor immune 
response. Therefore, a scientific rationale underpins the combination proposed herein.  
 
2.4 Rationale for combining epigenetic therapy with immunotherapy 
 
2.4.1 Clinical Rationale for combination epigenetic and immunotherapies 
Due to 2015 FDA-approval of nivolumab in the 2nd line treatment setting of advanced or  
metastatic NSCLC22,23, this protocol was previously amended to update nivolumab 
 
administration to be given concurrently starting at the initiation of combination study 
 
treatment. Therefore, for those patients randomized to combination therapy, nivolumab 
 
will be given in combination with epigenetic therapy for 6 cycles, followed by nivolumab 
 
monotherapy until disease progression. This will provide patients treated with maximal 
 
exposure to both epigenetic therapy and the immune checkpoint inhibitor, in keeping 
 
with standard of care practice.  In this manner, patients will have longer exposure to the 


 
 
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potential benefits of both epigenetic therapy and immune checkpoint inhibition. This 
 
update in therapy is further supported by data indicating that 58.3% (14/24) patients 
 
were unable to receive two months of epigenetic therapy alone ("priming") prior to 
 
initiation of nivolumab in an earlier therapeutic intervention in this trial (Arm A), due to 
 
both symptoms (nausea, vomiting, fatigue, pain) and subsequent rapid disease 
 
progression on epigenetic therapy alone. 
 
Importantly, the concurrent administration of epigenetic therapy and immune checkpoint 
 
inhibition is hypothesized to quickly combine the immune attraction signals from 
 
epigenetic therapy with the initial immune-tolerance inhibiting activity of immune 
 
checkpoint blockade, and allow the patient's tumor to be exposed to this interaction for a 
 
longer and perhaps more significant length of time than in the previous treatment arm. 
 
This is supported by pre-clinical data for the combination of these agents’ mechanisms 
 
of action on efficacy and overall tolerability as detailed below. 
 
 
2.4.2 Biological rationale 
The question of whether epigenetic therapy may be able to increase the efficacy of  
immune checkpoint therapy by priming or sensitizing patients remains an area of active  
clinical and pre-clinical investigation across a variety of tumor types. The early clinical  
data for the value of an epigenetic priming paradigm (combination epigenetic therapy  
followed by immune checkpoint inhibition monotherapy), and which guided the initial 
 
design of this trial for advanced NSCLC, suggested priming could be operative – and it 
 
may be. However, for those patients with advanced NSCLC treated on the original 
 
epigenetic priming arm of this study, it is clear that any long priming phase will not be 
 
clinically tolerated by the majority of patients with advanced NSCLC because of the 
 
aggressiveness of the disease, and dictates a need to move the epigenetic therapy 
 
concurrent with immune checkpoint therapy. We have found success in treating 
 
aggressive malignant mouse models concurrently with epigenetic therapy and 
 
checkpoint inhibitors at the initiation of therapy.  
 
Pre-clinical data from the Baylin and Zahnow laboratories at JHH, summarized below, 
 
shows that this is a potentially relevant area of clinical therapy across multiple tumor 
 
types and is an area of ongoing active investigation.  To date, numerous mouse models 
 
in their laboratories have been treated with concurrent Azacitidine and checkpoint 
 
inhibitors without significant adverse events being noted. On the contrary, overall 
 
survival was optimized when using combination therapy consisting of epigenetic agents 
 
and immune checkpoint inhibitors. 
 
Data in a mouse B6 melanoma model treated with Azacitidine and anti-CTLA-4 at the 
 
initiation of therapy18 is presented in Figure 1. Significant anti-tumor effects were seen 
 
only with the combination of AZA and anti-CTLA-4 when compared to each drug alone. 
 
This difference was also seen in multiple decreasing doses of AZA in the combination 
 
treatment arm. 


 
 
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Fig. 1  Tumor responses of mice injected with B16-F10 cells and 
treated with either PBS, anti-CTLA-4, Aza, or both anti-CTLA-4 
and Aza. Data represent results from one of two independent 
experiments with identical results, each with n = 10 per arm. Y axis = 
mean tumor surface, error bars ± SEM.  C57BL/6J mice were 
subcutaneously injected with 1 3 105 B16-F10 tumor cells. On days 4, 
8, 11, 14, and 18, mice were treated intraperitoneally with 100 mg anti-
ctla-4. Mice received two cycles of intraperitoneal injection of 0.1 to 
0.75 mg/kg Aza in PBS for 5 consecutive days followed by 7 days off 
treatment, starting at day 8 after developing palpable tumors, with 
control groups receiving corresponding doses of non-specific isotype 
antibody control and PBS intraperitoneally.  
 
 
 
 
The Baylin lab has treated mouse models of NSCLC with a regimen of low dose 
 
Azacitidine + low dose HDAC inhibitor (ITF) and anti-PD1 (Figure 2A)20. The anti-PD-1 
 
agent was administered at the end of the first 2 week first cycle with the first two drugs, 
 
and this cycle was repeated every two weeks for three months.  The mice showed no 
 
toxicity and efficacy with respect to tumor reduction at 3 months is shown in Figure 2B. 
 
B 
   
Fig. 2  Mock and combination regimen therapy in a mouse model of NSCLC. A.  Schema for dosing mock and combo 
regimens. B. In-vivo NSCLC mouse response to anti-PD1 alone versus anti-PD1 + Epigenetic combination therapy.  
The Zahnow lab has also treated a mouse model of serous ovarian carcinoma with this 
 
novel therapeutic combination21. In this therapeutic paradigm epigenetic agents were 
 
given in the first 2 weeks, and anti-PD1 was given concurrently with the epigenetic 
 
therapy for 2 weeks thereafter. The animals did not manifest toxicity and the efficacy is 
 
seen in the mouse survival curves (Figure 3) wherein the triplet therapy was most 
 
efficacious versus each agent alone or the combination of epigenetic drugs alone 
 
without anti-PD1.   


 
 
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C 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 3: Combining epigenetic therapy and immunotherapy in an intact mouse model of ovarian cancer decreases 
tumor burden and increases survival. 2.5x105 cells were injected i.p. into 8-10 week old female C57/Bl6 mice.  3 days after 
injection, 0.5mg/kg AZA or saline was given i.p., for 5 days a week.  The following week, 2mg/kg ITF2357 or MS275 or 1% 
DMSO in saline was injected i.p. for 5 days.  For the rest of the experiment, the treatment alternated between AZA and HDACi 
every other week.   Anti-PD-1 (200ug/mouse) was given on days 17, 20, 24, and 27 after injection.  Tumor burden was measured 
by the weight gain and amount of ascites drained from the mice. A) Treatment schematic. B) mL of ascites fluid drained at week 
6. C) Survival of the mice.   
 
 
This preclinical data consistently demonstrates across numerous animal models that 
 
tumor burden is decreased, overall survival is increased, and minimal toxicity is 
 
observed in mice receiving epigenetic therapy concurrent with checkpoint inhibitors.  By 
 
giving the anti-PD-1 up front with epigenetic therapy, this novel combinatorial approach 
 
may be able to slow rapid tumor progression and thus give the epigenetic therapy more 
 
time to effectively increase TILs and sensitize the tumor microenvironment to immune 
 
checkpoint inhibition. This concurrent treatment paradigm also affords the ability to 
 
expose the tumor to epigenetic therapy for a longer period of time, thus maximizing it’s 
 
potential effects as well.   
 
 
2.5 Rationale for combining epigenetic therapy with immunotherapy following progression on 
anti-PD-1 
 
2.5.1 Clinical Rationale for combination epigenetic and immunotherapy in PD-1   
 
 
refractory or resistant disease 
 
 
This amendment addresses the increasing complexity of standard of care NSCLC  
 
treatment with immunotherapy. The anti-PD-1 agent, pembrolizumab, is now approved  


 
 
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for the first line setting as monotherapy in advanced or metastatic PD-L1 positive (tumor  
 
 
proportion score (TPS)>50%) NSCLC24. Also, due to recent results of  
 
 
 
 
KEYNOTE189, as well as previous results of KEYNOTE021 cohort G, the combination  
 
 
of pembrolizumab with carboplatin and pemetrexed chemotherapies is now considered  
 
 
standard of care for first line treatment of advanced or metastatic non-squamous NSCLC 
 
 
patients with good performance status, regardless of PD-L1 status25,26. While the   
 
 
response rates and overall survival are significantly better than chemotherapy alone, the  
 
 
majority of patients will either not respond or eventually develop PD-1 resistance.  
 
 
Therefore, further evaluation for therapeutic options that will reignite the ability for  
 
 
PD-1 to initiate a robust anti-tumor immune response are needed.   This is especially  
 
 
true in KRAS mutated NSCLC, as many have co-inactivated tumor suppressor  
 
 
 
STK11/LKB1 genes, which have been shown to generate a proinflammatory, T-cell  
 
 
suppressive tumor microenvironment27. 
 
 
 
 
 
Recent data was released from Syndax regarding the ENCORE 601 trial, whose NSCLC 
 
 
patient cohort that enrolled patients with disease progression on or after anti-PD1/L1  
 
 
therapy. The company reported that they had met their pre-specified objective response  
 
 
threshold to advance into the second stage of the Phase 2 trial28. This trial evaluates the 
 
 
combination of entinostat plus pembrolizumab in two NSCLC patient cohorts: those who  
 
 
had previously progressed on PD1/L1 therapy, and those patients that are anti-PD-1/L1  
 
 
 
 
naïve.  
 
 
 
 
 
Although trial data is not yet published, Mirati’s class I HDACi mocetinostat has been  
 
 
combined with the anti-PD-L1 agent durvalumab in NSCLC, after it was shown to induce 
 
 
PD-L1 expression, improve tumor antigen presentation and facilitate efficient anti-tumor  
 
 
immune response by altering cellular subsets29.  
 
 
 
 
 
There is currently another trial in progress using guadecitabine (DNMTi) with durvalumab 
 
 
(anti-PD-L1) in advanced renal cell carcinoma, in both the immunotherapy naive and  
 
 
resistant patient populations. This is based on preclinical data showing that   
 
 
 
hypermethylation of CXCL9/10, important tumor microenvironment chemoattractants for  
 
 
activated Th1 and NK cells, is a significant immune evasion mechanism used in these  
 
 
tumors30. 
 
2.5.2 Pre-Clinical Rationale for combination epigenetic and immunotherapy in PD-1  
 
 
refractory or resistant disease 
 
 
The application of epigenetic therapy to PD-1 refractory or resistant disease represents  
 
 
an emerging area of inquiry with some preclinical data indicating efficacy. A recent  
 
 
publication by Youngblood and colleagues suggests that CD8 tumor infiltrating  
 
 
 
lymphocytes can become PD-1 refractory in the presence of continuous antigen   
 
 
exposure through the development of a fully exhausted population31. Therapeutic  
 
 
intervention with a demethylating agent prevented the emergence of this fully exhausted  
 
 
CD8 T cell population and thus enabled response to PD-1 in the Tramp-C2 murine  
 
 
model, which is endogenously refractory to immunotherapy. Additionally, a study by  
 
 
Baylin and colleagues demonstrated that combination epigenetic therapy   
 
 
 
(DNMTi+HDACi) can alter the CD8 T cell transcriptome, skewing from an exhausted to  
 
 
an effector/memory like population in a Kras driven murine NSCLC model20. These  


 
 
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studies suggest that epigenetic therapy can both modulate the T cell exhausted state  
 
 
and drive responses to immunotherapy in the setting of PD-1 refractory disease.  
  
 
3. PATIENT SELECTION 
 
3.1 
Eligibility Criteria  
 
 
 
 
3.1.1 Patients must have histologically proven stage IIIB, IV or recurrent non-small cell lung 
cancer. Patients must be willing to undergo a pre-treatment tumor biopsy, either core 
needle biopsy or equivalent amount or via excisional specimen (cytology specimen 
not acceptable for this purpose).  
 
3.1.2 Patients must have measurable disease, defined as at least one lesion that can be 
accurately measured in at least one dimension (longest diameter to be recorded for 
non-nodal lesions and short axis for nodal lesions) as >20 mm with conventional 
techniques or as >10 mm with spiral CT scan, MRI, or calipers by clinical exam.  See 
Section 11 for the evaluation of measurable disease. A CT scan of the abdomen and 
pelvis is not required for patients with no disease in these areas.   
 
3.1.3 Age >18 years.   
Because no dosing or adverse event data are currently available on the use of 
azacitidine with entinostat, or of Nivolumab, in patients <18 years of age, children are 
excluded from this study. 
 
3.1.4 Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1. 
 
3.1.5 Life expectancy of greater than 12 weeks. 
 
3.1.6 Patients must have normal organ and marrow function as defined below: 
 leukocytes  
 
 
 
 
>2,000/mcL 
 absolute neutrophil count 
 
>1,500/mcL 
 platelets  
 
 
 
 
 
>100,000/mcL 
 total bilirubin  
 
 
 
 
within normal institutional limits 
 AST(SGOT)/ALT(SGPT) 
 
<3 X institutional upper limit of normal 
 creatinine 
 
 
 
 
 
within normal institutional limits 
 
OR 
 creatinine clearance 
 
 
>40 mL/min for patients with creatinine levels above 
institutional normal. 
 Resting and walking O2 saturation must remain above 90% at the time of screening 
 
3.1.7 The effects of entinostat, azacitidine, and Nivolumab, on the developing human fetus 
are unknown.  For this reason women of child-bearing potential and men must agree 
to use adequate contraception (hormonal or barrier method of birth control; 
abstinence) prior to study entry and for the duration of study participation and for up 
to 23 weeks after the last dose of nivolumab.  Should a woman become pregnant or 
suspect she is pregnant while she or her partner is participating in this study, she 
should inform her treating physician immediately.   Men who are sexually active with 


 
 
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10
women of childbearing potential must also use an adequate contraceptive method for 
up to 31 weeks after the last dose of nivolumab. 
 
3.1.8 Ability to understand and the willingness to sign a written informed consent document. 
 
3.1.9 All adenocarcinoma patients must be tested for ALK rearrangements and EGFR 
(Exon 19 Deletion and Exon 21 L8585R Substitution) mutations and must have been 
treated with EGFR or ALK TKI therapy if found to have an actionable alteration. If 
patients are KRAS positive, testing for ALK rearrangements and EGFR mutations is 
not applicable.  
 
3.1.10 All patients should have been offered a platinum-based chemotherapy. For EGFR/ALK 
wild type patients, no more than two prior chemotherapy-based lines of therapy for 
advanced or metastatic NSCLC is permitted. For EGFR mutated or ALK translocated 
patients, no more than three prior lines of therapy for advanced or metastatic NSCLC 
is permitted. Patients who refuse platinum based chemotherapy, may be allowed to 
enroll if they meet all other criteria. 
 
 
3.1.10.1 Patients 
who 
received 
adjuvant 
or 
neoadjuvant 
platinum-doublet 
chemotherapy (after surgery and/or radiation therapy) and developed 
recurrent or metastatic disease within 6 months of completing therapy are 
eligible and the adjuvant or neoadjuvant chemotherapy will count as a line of 
therapy as above.   
 
3.1.10.2 Subjects with recurrent disease > 6 months after adjuvant or neoadjuvant 
platinum-based chemotherapy, who also subsequently progressed during or 
after a platinum-doublet regimen given to treat the recurrences, are eligible 
and do not count as another  line of therapy for advanced disease.   
 
3.1.10.3 Subjects who received pemetrexed, bevacizumab, or erlotinib as 
maintenance therapy (nonprogressors with platinum-based doublet 
chemotherapy) and subsequently progressed after maintenance therapy, are 
eligible and do not count as a line of therapy.  However, subject who received 
a tyrosine kinase inhibitor after failure of a prior platinum-based therapy, that 
tyrosine kinase inhibitor therapy would count as an additional line of therapy. 
3.1.10.4 Patients who have been treated with prior standard of care PD-1/L1                  
agents, alone or in combination with chemotherapy, are eligible. Patients 
previously treated on clinical trials with non PD-1/PD-L1 immunotherapy 
agents are eligible. Patients who have been treated with a PD-1/L1 agent in 
more than 1 line of therapy (as standard of care or in clinical trial) are not 
eligible. 
 
3.1.11 Arm-specific eligibility criteria 
 
 
 
3.1.11.1 Arm D: Anti-PD-1/PD-L1 treatment naïve patients only 
 
 
 
3.1.11.2 Arm E & F: Anti-PD-1/PD-L1 treatment experienced patients: Patients must  
 
 
 
 
have had refractory (Arm E=less than 24 weeks from first dose of anti-PD- 


 
 
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11
 
 
1/PD-L1) or recurrent (Arm F=more than 24 weeks from first dose of anti-PD-
 
 
1/PD-L1) disease during or after anti-PD-1 or anti-PD-L1 therapy and, in the  
 
 
opinion of the investigator, must be unlikely to benefit from nivolumab  
 
 
monotherapy. 
 
3.1.13  Patients must have disease amenable to biopsy at the time of enrollment as biopsies  
are required for study participation (see Study Calendar Section 8, for biopsy 
schedule by Arm).   
 
3.2  
Exclusion Criteria 
 
3.2.1 Any active history of a known autoimmune disease.  Subjects with vitiligo, type 1 
diabetes mellitus, residual hypothyroidism requiring hormone replacement, or 
conditions not expected to recur in the absence of an external trigger are permitted to 
enroll. 
 
3.2.2 Subjects with a history of interstitial lung disease or lung disease that has required 
intubation in the past (i.e. such as Asthma or COPD)..  
 
3.2.3 Patients who have had chemotherapy within 2 weeks (6 weeks for nitrosoureas or 
mitomycin C) prior to entering the study or those who have not recovered from adverse 
events due to agents administered more than 2 weeks earlier. 
 
3.2.4 Patients who have had radiation therapy within 1 week prior to entering the study.  
 
3.2.5 Patients who are receiving any other anticancer therapy. 
 
3.2.6 Patients with uncontrolled brain metastases. Patients with brain metastases must have 
stable neurologic status following local therapy (surgery or radiation) for at least 2 
weeks without the use of steroids or on stable or decreasing dose of < 10mg daily 
prednisone (or equivalent), and must be without neurologic dysfunction that would 
confound the evaluation of neurologic and other adverse events.  Patients with a 
history of carcinomatous meningitis are not eligible.  
 
3.2.7 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to entinostat, azacitidine, or Nivolumab. 
 
                  3.2.8    Known or suspected hypersensitivity to azacitidine or mannitol 
 
3.2.9 Uncontrolled inter-current illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, uncontrolled 
cardiac arrhythmia, myocardial infarction or new onset angina within six months of 
enrollment, or psychiatric illness/social situations that would limit compliance with 
study requirements. 
 
3.2.10 Pregnant women are excluded from this study because entinostat, azacitidine, and 
Nivolumab are agents with the potential for teratogenic or abortifacient effects. 
Because there is an unknown but potential risk for adverse events in nursing infants 


 
 
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secondary to treatment of the mother with entinostat, azacitidine, or Nivolumab 
breastfeeding should be discontinued if the mother is treated on this protocol. 
 
3.2.11 HIV-positive patients are excluded. (Patients cannot have known history of HIV. 
Testing for it at baseline is not required unless it is suspected they may have it).  
 
3.2.12 Patients with active hepatitis B or hepatitis C are excluded. (Patients cannot have 
known history of hepatitis B or hepatitis C. Testing for it at baseline is not required 
unless it is suspected they may have it).  
 
3.2.13 Patients with a condition requiring systemic treatment with either corticosteroids (>10 
mg daily prednisone equivalent) or other immunosuppressive medications within 14 
days of randomization.  Inhaled or topical steroids and adrenal replacement steroid 
doses < 10 mg daily prednisone equivalent, are permitted in the absence of active 
autoimmune disease. 
 
3.2.14 Patients with malabsorption in the small intestine or other conditions that would 
preclude administration of oral medication. 
 
3.2.15 Prior therapy with DNA methyltransferase therapy or HDAC inhibitor therapy. 
 
Patients must meet all inclusion criteria and none of the exclusion criteria.  Eligibility Waivers will 
not be granted. 
 
 
3.3  
Inclusion of Women and Minorities 
 
Both men and women of all races and ethnic groups are eligible for this trial. 
 
4. TREATMENT PLAN 
 
 
 
 
4.1 Agent Administration 
 
Patients will be treated by Arm according to disease status. Treatment will be administered 
on an outpatient basis.  Reported adverse events and potential risks are described in Section 
7.  Appropriate dose modifications are described in Section 6.  No investigational or 
commercial agents or therapies other than those described below may be administered with 
the intent to treat the patient's malignancy. 
 
Regimen description 
 
Agents 
Premedications/instructions 
Dose 
Route 
calendar 
Cycle 
length 
# of Cycles 
Epigenetic component 
 
Arm D-F 
Azacitidine 
5HT3 inhibitor PO or IV 30 min 
prior; rotate site of injection 
40 
mg/m2 
SC 
Days 1-
5, 8-10 
28 days 
 
         6 
     Cycles 
        
Arm D-F 
Entinostat 
5HT3 inhibitor PO or IV 30 min 
prior; on an empty stomach 
5 mg 
PO 
Days 3 
and 10 


 
 
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13
Immunotherapy component 
 
Arm C-F 
Nivolumab 
Optional: acetaminophen 650 
mg PO and diphenhydramine 
50 mg PO/IV 30 min prior. 
240 mg 
 
480 mg  
(after 
Cycle 6) 
IV 
Days 1, 
15 
 
Day 1 
28 days 
 
 
28 days 
 
 
Until PD^ 
 
^Patients are allowed to remain on nivolumab monotherapy treatment after the first documented PD if 
clinically stable. (See Section 4.4.1) 
 
˄After a patient has completed 6 months of nivolumab (regardless of arm assignment), they can 
receive nivolumab every 4 weeks instead of every 2 weeks. 
 
 
4.1.1     Entinostat  
 
 
Entinostat is an oral agent. Entinostat should be taken on an empty stomach (fasting) 
either at least 1 hour prior to a meal or at least 2 hours after a meal. The tablets should 
be taken one at a time. The tablets should not be split, crushed or chewed.  Entinostat 
is known to cause nausea and vomiting. To reduce the incidence of nausea and 
vomiting associated with entinostat administration, patients will be instructed to take a 
5-HT3 antagonist orally or IV 30-60 minutes prior to taking the dose of entinostat.  
 
 
 
 
4.1.2     Azacitidine 
  
Azacitidine is supplied as 100 mg of white, lyophilized powder with 100 mg of mannitol, 
USP in 30 ml flint vials. The contents of each vial should be dissolved in 4mL of sterile 
water or 0.9% sodium chloride to provide a 25 mg/ml slurry.  Azacitidine does not go 
into solution but forms a loose slurry when reconstituted in this fashion. Reconstituted 
solutions of azacitidine are unstable. Upon reconstitution, the material should be 
injected within 60 minutes. The slurry should be injected subcutaneously. The slurry 
SHOULD NOT be injected intravenously. Doses may be split into multiple injection 
sites if volume to be administered is too large. Injection sites should be rotated on a 
daily basis.  
 
 
 
4.1.3     Nivolumab 
  
Nivolumab vials are to be stored at a temperature of 2°C to 8°C and should be 
protected from light. If stored in a glass front refrigerator, vials should be stored in the 
carton. Recommended safety measures for preparation and handling of BMS-
936558 include laboratory coats and gloves. After Nivolumab been prepared for 
administration, the total storage time (combination of refrigeration and room 
temperature) is not to exceed 24 hours.  Stability data for Nivolumab following 
dilution and transfer to the IV bag supports either: 24 hours at 2°C to 8°C in the 


 
 
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14
refrigerator, or 4 hours at room temperature/under room light and 18 hours at 2°C to 
8°C in the refrigerator. Care must be taken to assure sterility of the prepared solution 
as the product does not contain any anti-microbial preservative or bacteriostatic 
agent. No incompatibilities between Nivolumab and polyolefin bags have been 
observed. 
 
Nivolumab will be administered as an IV infusion as close to 30 minutes as possible, 
using a volumetric pump with a 0.2 micron in-line filter, followed by a saline flush.  
Nivolumab will be administered as a flat 240 mg dose or 480 mg every 4 weeks once 
the completion of cycle 6 has occurred. There will be no dose escalations or 
reductions of nivolumab allowed.  Subjects may be dosed no less than 12 days from 
the previous dose.  There are no premedications recommended for Nivolumab on 
the first cycle. If an allergic reaction is noted, then acetaminophen 650 mg PO and 
diphenyhydramine 50 mg PO/IV may be administered prior to Nivolumab infusion. 
 
 
 
4.2 General concomitant medication and supportive care guidelines 
 
4.2.1  No investigational or commercial agents or therapies other than those described 
above may be administered with the intent to treat the malignancy.  
 
4.2.2  Contraceptive therapy: Sexually active men and women of child-bearing potential must 
agree to use effective contraception.  
 
 
4.2.3  Concomitant use of valproic acid is prohibited due to its known activity as a histone 
deacetylase inhibitor.  
 
4.2.4  Nausea and vomiting after entinostat administration are expected. Prophylactic 5-HT3 
inhibitors will be administered at least 30 minutes prior to ingestion of entinostat as 
well as on an as needed basis. Delayed nausea and vomiting is associated with 
azacitidine 4-6 hours after treatment. Prophylactic 5HT3 inhibitor will be administered 
30 minutes prior to injection of azacitidine on days 1-5, and 8-10. Prochlorperazine 
and/or 5HT3 inhibitor may also be taken for delayed nausea as needed.  
 
4.2.5 Diarrhea: If diarrhea occurs during Nivolumab treatment, workup and treatment 
should follow the Nivolumab diarrhea toxicity treatment algorithm located in the 
appendix of the Nivolumab investigators brochure. 
 
4.2.6 Neutropenia without fever: The clinical situation should be closely followed for fever, 
focal signs of infection, and neutrophil nadir.  
 
4.2.7 Neutropenia with fever: Hospitalization and urgent broad-spectrum antibiotics are 
required for this potentially life-threatening complication. The occurrence of a 
temperature higher than 38.3°C (100.9°F) demands prompt evaluation of blood counts 
and examination for source of infection.  
 
4.2.8  Anemia: Red blood cell support should be given for any patient with symptomatic 


 
 
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15
anemia and is recommended for patients with asymptomatic anemia when hemoglobin 
is below 8 g/dL. Erythropoietin or darbepoietin may be used at the discretion of the 
investigator.  
 
4.2.9 Thrombocytopenia: Platelet transfusion should be given for a platelet count below 
10,000/mm3 in the absence of bleeding. If bleeding develops or invasive procedures 
are planned, platelet transfusion should be administered in accordance with standard 
practice.  
 
 
4.2.10 Constipation: Constipation has been a common side effect of azacitidine and 
 
entinostat. Treatment with stool softeners and laxatives should be initiated early on to 
prevent symptoms from constipation.  
 
4.2.11 The following medications are prohibited during the study (unless utilized to treat a 
drug-related adverse event): immunosuppressive agents, immunosuppressive doses 
of systemic corticosteroids (except as noted in inclusion/exclusion section), Subjects 
are permitted to use topical, ocular, intra-articular, intranasal, and inhaled 
corticosteroids (with minimal systemic absorption).  Physiologic replacement doses of 
systemic corticosteroids (eg prednisone < 10 mg/day) are permitted.  A brief (less than 
3 weeks) course of corticosteroids for prophylaxis (eg, contrast dye allergy) or for 
treatment of non-autoimmune conditions (eg, delayed-type hypersensitivity reaction 
caused by a contact allergen) is permitted. Sensitive substrates of CYP1A2, CYP2C8, 
CYP3A with a narrow therapeutic window are prohibited (including: Theophylline, 
tizanidine, 
paclitaxel, 
alfentanil, 
astemizole, 
cisapride, 
cyclosporine, 
dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus 
and terfenadine). Drugs that are known to inhibit or induce P-gp are prohibited 
(including: amiodarone, azithromycin, captopril, carvedilol, clarithromycin, conivaptan, 
diltiazem, dronedarone, felodipine, lopinavir, quercetin, ranolazine, ticagrelor, 
ritonavir, 
cyclosporine, 
verapamil, 
erthyromycin, 
ketoconazole, 
itraconazole, 
quinidine, avasimibe, carbamazepine, phenytoin, rifampin, St. John’s Wort, and 
tipranavir/ritonavir)   
 
4.2.12 Non-palliative radiation therapy is not allowed.  Palliative radiation therapy is only  
allowed during Nivolumab monotherapy, not during concurrent epigenetic therapy, if 
deemed necessary for the patient by the investigator. Palliative radiation therapy to 
the lung is not recommended.  
 
If palliative radiotherapy is required, and the patient is currently receiving concurrent 
epigenetic therapy, the epigenetic therapy must be held. Upon completion of the 
palliative XRT, the patient may be allowed to resume study treatment with epigenetic 
therapy and nivolumab following the 1 week washout period.  
 
If the patient is on single agent Nivolumab therapy when they require palliative 
radiation therapy, then Nivolumab should be withheld for at least 1 week before, during 
and 1 week after radiation.  Patients should be closely monitored for any potential 
toxicity during and after receiving radiotherapy, and AEs should resolve to grade < 1 
prior to resuming Nivolumab.   


 
 
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16
 
 
4.3 Management of Nivolumab-related infusion reactions 
 
Since Nivolumab contains only human immunoglobulin protein sequences, it has a low 
incidence of infusion or hypersensitivity reactions. However, if such a reaction were to occur, 
it might manifest with fever, chills, rigors, headache, rash, pruritus, arthralgias, hypotension, 
hypertension, bronchospasm, or other allergic-like reactions. All Grade 3 or 4 infusion 
reactions must be reported as an SAE if it meets the criteria. Infusion reactions must be 
graded according to NCI CTCAE (Version 4.0) guidelines. 
 
Treatment recommendations are provided below: 
 
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 acetaminophen/paracetamol 325 to 1000 mg 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 [eg, antihistamines, non-steroidal anti-
inflammatory drugs, narcotics, corticosteroids, IV fluids]; prophylactic medications indicated 
for ≤ 24 hours). 
 
•  Stop the Nivolumab infusion, begin an IV infusion of normal saline, and treat the subject 
with diphenhydramine 50 mg IV (or equivalent) and/or acetaminophen/paracetamol 325 
to 1000 mg; remain at bedside and monitor subject until resolution of symptoms. 
Corticosteroid 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. 
• 
For future infusions, the following prophylactic premedications are recommended: 
diphenhydramine 50 mg (or equivalent) and/or acetaminophen 325 to 1000 mg should be 
administered at least 30 minutes before Nivolumab infusions. If necessary, corticosteroids 
(up to 25 mg of SoluCortef or equivalent) may be used. 
 
For Grade 3 or 4 symptoms: (Severe reaction, Grade 3: prolonged [ie, 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 1:1000 solution for subcutaneous administration or 0.1 to 0.25 mg of a 1:10,000 solution 


 
 
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17
injected slowly for IV administration, and/or diphenhydramine 50 mg IV with 
methylprednisolone 100 mg IV or equivalent), as needed. Subject must be monitored until 
the Investigator is comfortable that the symptoms will not recur. Nivolumab will be 
permanently discontinued. Investigators must follow their institutional guidelines for the 
treatment of anaphylaxis. Remain at bedside and monitor subject until recovery of the 
symptoms. 
 
In 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). 
 
4.4 Duration of Therapy 
 
Arm D:  Epigenetic therapy (azacitidine and entinostat) in combination with nivolumab will be 
given for six 28-day cycles on this protocol.  Patients experiencing adverse event(s) that in 
the view of the treating physician or principal investigator make six cycles undesirable, may 
continue with Nivolumab as a single agent after only 2 cycles of concurrent epigenetic therapy 
with Nivolumab.  Please see section 4.4.1 regarding treatment at time of progressive disease 
(PD).   
 
Arm E and Arm F: Epigenetic therapy (azacitidine and entinostat) in combination with 
nivolumab will be given for six 28-day cycles on this protocol.  Patients experiencing adverse 
event(s) that in the view of the treating physician or principal investigator make six cycles 
undesirable, may continue with Nivolumab as a single agent after only 2 cycles of concurrent 
epigenetic therapy with Nivolumab. Please see section 4.4.1 regarding treatment at time of 
progressive disease (PD).   
 
 
Nivolumab monotherapy on all Arms may continue until one of the following criteria applies 
and at that time, nivolumab treatment will be permanently discontinued: 
 
 
 
Any Grade > 2 drug-related uveitis, eye pain or blurred vision that does not respond to 
topical therapy and does not improve to Grade 1 severity within the re-treatment period 
OR requires systemic treatment 
 
Any Grade 3 non-skin, drug-related adverse event lasting > 7 days, with the following 
exceptions for laboratory abnormalities, drug-related bronchospasm, hypersensitivity 
reactions, and infusion reaction: 
 
 
Grade 3 drug-related bronchospasm, hypersensitivity reaction, or infusion reaction of 
any duration requires discontinuation 
 
Grade 3 drug-related laboratory abnormalities do not require treatment discontinuation 
except: 
 
o Grade 3 drug-related thrombocytopenia > 7 days or associated with bleeding 
requires discontinuation 
 
o Any drug-related liver function test (LFT) abnormality that meets the following 


 
 
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18
 
criteria require discontinuation: 
 
 
AST or ALT > 5-10x ULN for > 2 weeks 
 
AST or ALT > 10x ULN 
 
Total bilirubin > 5x ULN 
 
Concurrent AST or ALT > 3x ULN and total bilirubin > 2x ULN 
 
 
Any Grade 4 drug-related adverse event or laboratory abnormality, except for the 
 
following events which do not require discontinuation: 
 
 
Grade 4 neutropenia < 7 days 
 
Grade 4 lymphopenia or leucopenia 
 
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 
 
 
Any dosing interruption lasting > 6 weeks with the following exceptions: 
 
Dosing interruptions to allow for prolonged steroid tapers to manage drug-related 
adverse events are allowed after discussion with study PI.   
 
Dosing interruptions > 6 weeks that occur for non-drug-related reasons may be 
allowed.  
 
Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment 
of the investigator, presents a substantial clinical risk to the subject with continued 
nivolumab dosing 
 
 
Confirmed disease progression at time points after first cycle of nivolumab monotherapy.  
This allows for patients to remain on treatment with nivolumab after disease progression 
if clinically stable.  However, once the next disease assessment confirms progression or 
if clinically unstable, patients must stop treatment. (See section 4.4.1) 
 
 
Intercurrent illness that prevents further administration of treatment, 
 
 
Unacceptable adverse event(s), not able to be managed by steroid/or other 
immunosuppressive therapy (such as infliximab or IVIG) administration. 
 
 
Patient decides to withdraw from the study, or 
 
 
General or specific changes in the patient's condition render the patient unacceptable for 
further treatment in the judgment of the investigator. 
 
4.4.1     Treatment Beyond Disease Progression 
 
Treatment beyond disease progression is allowed for patients receiving concurrent 
azacitidine, entinostat and nivolumab on Arm D, Arm E and Arm F.  If disease progression 
(PD) is noted during the 6 cycles of concurrent therapy per RECIST 1.1, the patient may 
continue study treatment until disease progression is confirmed. If at that time disease 
progression (PD) is confirmed, the patient will come off study treatment. After 6 concurrent 
cycles, patients will continue nivolumab monotherapy treatment irrespective of disease 


 
 
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progression status, and will follow the decision to treat beyond disease progression (PD) 
as per below. If the noted PD requires palliative radiation therapy, please see Section 
4.2.12 regarding subsequent study treatment.  
 
Subjects being currently treated with nivolumab monotherapy on any study Arm will be 
permitted to continue treatment beyond initial RECIST 1.1 defined PD as long as they 
meet the following criteria: 
 
1. Investigator-assessed clinical benefit, and do not have rapid disease progression 
2. Continue to meet all other study protocol eligibility criteria 
3. Tolerance of the study drug 
4. Stable performance status 
5. Treatment beyond progression will not delay an imminent intervention to prevent 
 
serious complications of disease progression (e.g. CNS metastasis) 
 
The decision to continue treatment beyond initial progression must be documented in the 
study records. 
 
A radiographic assessment/scan will be performed at the end of the cycle following the 
original PD to determine whether there has been a decrease in the tumor size or continued 
PD.  The assessment of clinical benefit should be balanced by clinical judgment as to 
whether the subject is clinically deteriorating and unlikely to receive any benefit from 
continued treatment with nivolumab. 
 
If the investigator feels that the patient receiving nivolumab monotherapy continues to 
achieve clinical benefit by continuing treatment, the subject may remain on the trial and 
continue to receive monitoring according to the Study calendar.  
 
New lesions are considered measurable at the time of initial progression if the longest 
diameter is at least 10mm (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 volume 
if the longest diameter increases to at least 10 mm (except for pathological lymph nodes 
which must have a short axis of at least 15 mm). 
 
For subject in either treatment arm, global deterioration of health status requiring 
discontinuation of treatment without objective evidence of disease progression at that time 
should be reported as symptomatic deterioration.  Every effort should be made to 
document objective progression (i.e. radiographic confirmation) even after discontinuation 
of treatment. 
 
4.5 Duration of Follow Up 
 
Once treatment has been discontinued, patients will be followed with phone calls every 3 
months until death or for 5 years, whichever occurs first. We will collect data on development 
of additional cancers, subsequent therapy (chemotherapy, radiation or surgery) for their 
cancer, and survival. Medical records including laboratory, pathology, operative, and radiology 
reports will be obtained at the discretion of the principal investigator with permission from the 


 
 
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20
patient. Patients removed from study for unacceptable adverse events will be followed until 
resolution or stabilization of the adverse event.  
 
4.6 Criteria for Removal from Study Treatment 
 
A patient will be withdrawn from the study treatment if any of the following events occur while 
on therapy:  
 
Interruption of scheduled therapy for greater than 6 weeks except as noted above in 
section 4.4. 
 
Intolerable adverse effects, laboratory abnormality or intercurrent illness that is judged by 
the investigator to be either physically or psychologically detrimental to the patient.  
 
Pregnancy.  
 
Patient non-compliance.  
 
Unresolved or recurrent Grade 3 or 4 toxicities except as noted above in section 4.4.  
 
Treatment with other anti-cancer drugs.  
 
Confirmed disease progression on therapy as outlined in Section 4.4 and Section 4.4.1. 
 
Withdrawal of informed consent (subject’s decision to withdraw for any reason).  
 
Loss of ability to freely provide consent through imprisonment or involuntary incarceration 
for treatment of either a psychiatric or physical (e.g., infectious disease) illness. 
 
All subjects who discontinue study treatment should comply with protocol specified follow-
up and survival procedures as outlined in Section 4.5.  The ONLY exception to this 
requirement is when a subject withdraws consent for all study procedures or loses the 
ability to consent freely (i.e., is imprisoned or involuntarily incarcerated for the treatment 
of either a psychiatric or physical illness); in this case they will be deemed off study and 
no further follow up will be performed.  
 
5. DOSING DELAYS/DOSE MODIFICATIONS 
 
Dosing delays and dose modifications on this study will be made at the discretion of the treating 
physician.  No dose modifications will be allowed for nivolumab.  Adverse symptoms prompting 
dose delay of greater than 6 weeks in any phase of the study will result in study discontinuation 
except as noted in section 4.4. 
 
5.1 Dose Modifications/Treatment Delays for Azacitidine and Entinostat Only 
 
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. In 
case of toxicity, appropriate medical treatment should be used (including anti-emetics for 
nausea/vomiting, etc.) No dose escalation is planned for this study. 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 patient has a 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). Where 
several toxicities with different grades or severity occur at the same time, the dose 
modifications applied should be the greatest reduction applicable.  
 
Treatment will be modified based on treatment-related toxicity as described below for all 
patients receiving azacitidine and entinostat on Arm D, Arm E and Arm F.  Dose omits due 


 
 
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to toxicity will not be made-up; patients may resume treatment once toxicity resolves as per 
the regular schedule.  
 
5.1.1 White blood cell decreased/Neutrophil count decreased. 
 
See Table for dose adjustment criteria. 
 
Filgrastim or pegfilgrastim should not be given during nivolumab treatment. 
 
5.1.2 Platelet Count Decreased. 
 
See table for the dose adjustment criteria. 
 
5.1.3 Anemia 
 
There are no specific recommendations regarding management of anemia. 
 
Blood transfusions or erythropoietin stimulating agents may be used to treat 
 
chemotherapy-induced anemia at the discretion of the treating physician per  
 
current ASCO Guidelines. These state that “for patients with chemotherapy- 
 
associated anemia, initiating an erythropoiesis-stimulating agent (ESA) as 
 
hemoglobin (Hb) approaches, or falls below, 10 g/dL, to increase Hb and  
 
decrease transfusions”. 
 
5.1.4 Diarrhea 
If diarrhea develops, patient must be evaluated for potential signs or symptoms of 
infectious causes or nivolumab-related colitis. If these etiologies are excluded, 
patients will be instructed to begin taking loperamide at the earliest signs of: 
 
A loose stool. 
 
Occurrence of 1 to 2 more bowel movements than usual in one day, or 
Unusually high volume of stool, 
 
Loperamide should be taken in the following manner: 4 mg at the first onset of 
diarrhea, then 2 mg every two hours (4mg every 4 hours while asleep) around 
the clock until diarrhea-free for at least  12 hours. Additional antidiarrheal 
measures may be used at the discretion of the treating physician. 
 
If the measures above fail, the dose may be reduced as listed below. 
 
5.1.5 Nausea/Vomiting 
 
Both entinostat and azacitidine use can lead to nausea and vomiting. 
 
Prophylactic 5-HT3 antagonist will be used on days when either entinostat 
orazacitidine will be administered.If nausea and vomiting persists despite these 
measures, more aggressive use of5-HT3 antagonists or other anti-emetics can be 
used at the discretion of the treating physician.  
 
See table below for the dose adjustment criteria. 
 
5.1.6 Metabolic/electrolyte abnormalities 
 
Entinostat is associated with multiple electrolyte abnormalities including 
 
hypermagnesemia, hyperglycemia, hypophosphatemia, hyponatremia, and 
 
hypocalcemia. Low values will be repeated as appropriate per institutional 
 
standard. Hyperglycemia will be corrected at the discretion of the treating 
 
physician. 
 
See table for the dose adjustment criteria. 


 
 
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5.1.7 Other non-hematologic toxicities 
 
Dose adjustments will not be made for alopecia, fatigue, or loss of appetite of any 
 
 
grade. 
 
For other grade 3 and 4 non-hematologic toxicities not described above, see 
 
  Table for dose adjustment criteria.  
 
 
CTCAE 
System Organ 
Class (SOC) 
Adverse Event 
Grade 
Azacitidine 
Dose 
Change 
Entinostat 
Dose 
Change 
 
 
 
 
 
 
 
 
 
Investigations  
Neutrophil Count 
decreased  
Grade 1 
or 2 
No Change  
 
No Change  
 
Grade 3 
or 4 
Omit for 2 
weeks and 
reduce next 
cycle by 10 
mg/m2
Omit for 2 
weeks and 
reduce next 
cycle to 3 
mg
Platelet count 
decreased  
Grade 1 
or 2 
 
No change 
 
No change 
 
Grade 3 
or 4 
Omit for 2 
weeks and 
reduce next 
cycle by 10 
mg/m2
Omit for 2 
weeks and 
reduce next 
cycle to 3 
mg
White blood cell 
decreased
Grade 1 
or 2
No change 
No change 
 
 
Grade 3 
or 4 
Omit for 2 
weeks and  
reduce next  
cycle by 10 
mg/m2
Omit for 2 
weeks and 
reduce next 
cycle to 3 
mg
 
 
 
 
 
 
 
 
Gastrointestinal
disorders 
Diarrhea 
(Reduce dose only 
after optimal use of 
loperamide) 
 
Grade 1 
or 2 
No change 
No change  
Grade 3 
or 4 
 
 
 
 
Omit for 2  
Weeks and  
reduce next 
cycle by 10 
mg/m2 
 
Omit for 2 
weeks 
and reduce 
next 
cycle to 3 
mg 
 
Nausea / Vomiting 
(reduce dose only 
after optimal use of 
Grade 1 
or 2 
No change 
 
No change 


 
 
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23
anti-emetics) 
Grade 3 
or 4 
Omit for 2 
weeks and 
reduce next  
cycle by 10 
mg/m2 
Omit for 2 
weeks 
And reduce 
next 
cycle to 3 
mg 
 
 
 
 
Metabolism 
nutrition 
disorders 
 
 
-Hyperglycemia 
-Hypoglycemia 
-
Hypophosphatemia
-Hyponatremia 
 
-Hypocalcemia 
-Hypercalcemia  
Grade 1 
or 2 
No change 
 
No Change 
 
Grade 3 
 
 
 
 
 
 
No change 
 
 
 
 
 
 
Omit for 2 
weeks and 
reduce next 
Cycle  to 3 
mg if 
refractory to 
appropriate 
treatment  
 
Grade 4 
No Change 
Omit for 2 
weeks  
and reduce 
next cycle to 
3 mg
Other  
non-hematologic adverse events 
not mentioned above² 
Grade 1 
or 2 
No change 
No change 
 
Grade 3 
or 4 
Omit 
treatment 
until toxicity 
Resolves to 
Grade 1 
then 
Dose reduce 
by 
10mg/m2
Omit 
treatment  
Until toxicity 
Resolves to 
Grade 
1 then dose 
reduce to 3 
mg 
¹If adverse events are noted on day 1 of any cycle of therapy then both agents should be held until treatment 
is deemed safe to administer. Unless otherwise specified, grade 3 or 4 toxicity should improve to grade 2 or 
better prior to resuming treatment.  
²If treatment is omitted for non-hematologic adverse events not described above both drugs should be dose-
reduced unless the toxicity can be clearly attributed to entinostat or azacitidine specifically. 
 
5.1.8 Hypersensitivity Reactions 
 
Hypersensitivity reactions to azacitidine or entinostat 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 re-challenged.  


 
 
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5.1.9 Special Considerations 
 
Up to 2 dose reductions are allowed for azacitidine and one dose reduction for 
entinostat.  For any grade 4 toxicity that recurs despite prophylaxis or dose 
reduction, study treatment should be discontinued. 
 
 
5.2 Nivolumab dose delay criteria 
 
      
Nivolumab administration should be only delayed for the following immunologic toxicity: 
      
  
 
Any Grade > 2 non-skin, drug-related adverse event, with the following exceptions: 
 
Grade 2 drug-related fatigue or laboratory abnormalities do not require a treatment 
 
delay. 
 
Any Grade 3 skin, drug-related adverse event 
 
Any Grade 3 drug-related laboratory abnormality, with the following exceptions for 
 
lymphopenia, leucopenia, AST, ALT, or total bilirubin: 
 
Grade 3 lymphopenia or leucopenia does not require dose delay. 
 
If a subject has baseline AST, ALT, or total bilirubin within the Grade 1 toxicity range, 
 
delay dosing for drug-related Grade > 3 toxicity. 
 
Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment 
 
of the investigator, warrants delaying the dose of study medication. 
 
5.2.1 Criteria to Resume Treatment with Nivolumab 
 
Subjects may resume treatment with nivolumab when the drug-related AE(s) 
resolve(s) to Grade < or baseline, with the following exceptions: 
 
 
Subjects may resume treatment in the presence of Grade 2 fatigue 
 
Subjects who have not experienced a Grade 3 drug-related skin AE may resume 
 
treatment in the presence of Grade 2 skin toxicity. 
 
Subjects with baseline AST/ALT or total bilirubin in the Grade 1 toxicity range 
who require dose delays for reasons other than a 2-grade shift in AST/ALT or 
total bilirubin may resume treatment in the presence of Grade 2 AST/ALT OR 
total bilirubin. 
 
Subjects with combined Grade 2 AST/ALT AND total bilirubin values meeting 
discontinuation parameters (section 4.4) should have treatment permanently 
discontinued. 
 
Drug-related pulmonary toxicity, diarrhea, or colitis must have resolved to 
Baselin before treatment is resumed.  Drug-related endocrinopathies adequately 
controlled with only physiologic hormone replacement may resume treatment 
 
If treatment is delayed > 6 weeks, the subject must be permanently discontinued 
from study therapy, except as specified in section 4.4. 
 
 
 
 


 
 
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6. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial. The following list 
of AEs (Section 6.1) and the characteristics of an observed AE (Section 6.2) will determine whether 
the event requires expedited reporting in addition to routine reporting. 
 
6.1 Adverse effects of azacitidine  
 
Very common adverse effects of azacitidine (≥10%) include anemia which may require 
blood transfusion, febrile neutropenia, neutropenia, leukopenia, thrombocytopenia, 
abdominal pain (including abdominal discomfort and upper abdominal pain), constipation, 
diarrhea, nausea, vomiting, asthenia, chest pain, fatigue, injection site erythema, injection 
site pain, injection site reaction, pyrexia, nasopharyngitis, pneumonia (including bacterial, 
fungal and viral), weight loss, decreased appetite, hypokalemia, arthralgia, musculoskeletal 
pain (includes back pain, bone pain and pain in extremity), myalgia, dizziness, headache, 
insomnia, dyspnea, epistaxis, ecchymosis, petechiae, pruritus (includes pruritus 
generalized) and rash.   
 
Common adverse effects of azacitidine (≥1%-≤10%) include bone marrow failure, 
pancytopenia, conjunctival hemorrhage, eye hemorrhage, dyspepsia, gastrointestinal 
hemorrhage (includes mouth hemorrhage), gingival bleeding, hemorrhoidal bleeding, 
stomatitis, catheter site hemorrhage, chills, injection site bruising, injection site discoloration, 
injection site hematoma, injection site hemorrhage, injection site induration, injection site 
inflammation, injection site nodule, injection site pruritus, injection site rash, malaise, 
cellulitis, diverticulitis, neutropenic sepsis, oral fungal infection, pharyngitis, respiratory tract 
infection (including bronchitis and upper respiratory tract infection), rhinitis, sepsis (including 
bacterial, fungal and viral), sinusitis, skin infection, urinary tract infection, blood creatinine 
increased, dehydration, muscle spasms, intracranial hemorrhage, lethargy, somnolence, 
syncope, anxiety, hematuria, renal failure, shortness of breath on exertion (Dyspnea 
exertional), laryngeal pain, pleural effusion, alopecia, erythema, skin lesion, urticarial, 
hematoma, hypertension and orthostatic hypertension.   
 
Uncommon adverse effects of azacitidine (≥0.1%- <1%) include hypersensitivity.  
 
 
 
6.2  
Adverse effects of entinostat 
 
Common adverse effects of entinostat occurring in over 20% of patients, include anemia, 
diarrhea, nausea, vomiting, fatigue, anorexia, neutropenia, thrombocytopenia, 
hypoalbuminemia, hyponatremia, hypophosphatemia, leukopenia and headache. 
 
 
Less common adverse effects include neutropenic fever, abdominal pain, constipation, 
pyrosis, peripheral edema, fever, chest pain, infection, hepatitis and liver dysfunction, renal 
insufficiency, 
lymphopenia, 
leucopenia, 
dehydration, 
hypocalcemia, 
hypokalemia, 
hypomagnesemia, myalgias, arthralgias, dysgeusia, cough, and dyspnea. 


 
 
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26
 
Rare but serious adverse effects have included erythema multiforme.  
 
6.3  
Adverse effects of Nivolumab 
 
Very Common adverse effects of Nivolumab, occurring in >10% of patients, include fatigue, 
rash, diarrhea, and pruritus.      
 
Common adverse effects (>1-9%) Include abdominal pain, alkaline phosphatase increased: 
lab test result associated with liver or bone abnormalities, allergic reaction/hypersensitivity, 
ALT increased: lab test result associated with abnormal liver function, Amylase increased: 
lab test result associated with pancreas inflammation, AST increased: lab test result 
associated with abnormal liver function, bilirubin (liver function blood test) increased, chills, 
constipation, cough, creatinine increased: lab test result associated with decreased kidney 
function, decreased appetite, dizziness or vertigo (feeling off balance which can lead to 
dizziness), dry mouth, dry skin, fever, headache, increased blood sugar, inflammation of the 
colon, inflammation of the mouth, infusion related reaction, lipase increased: lab test result 
associated with pancreas inflammation, loss of color (pigment) from areas of skin, lung 
inflammation (pneumonitis - see details below), musculoskeletal pain, nausea, redness (of 
the skin), shortness of breath, sodium levels in the blood low, swelling (including face, arms, 
and legs), thyroid gland function decreased, thyroid gland function increased, thyroid 
stimulating hormone increased (lab test associated with abnormal thyroid function), tingling, 
burning, numbness or weakness, possibly in arms, legs, hands and feet, and vomiting.  
 
Uncommon adverse effects (>0.1%-1%) include adrenal gland function decreased, bronchitis, 
dehydration, diabetes, double Vision, dry eye, erythema multiforme, hair loss, heart rate 
increased, heart rhythm abnormal, high blood pressure, hives, inflammation of the eye, 
inflammation of the kidney, inflammation of the pancreas, inflammation of the pituitary gland, 
inflammation of the stomach, inflammation of the thyroid gland, joint pain or stiffness, liver 
inflammation, low blood pressure, muscle inflammation, pemphigoid: blistering of the skin or 
mouth caused by the immune system attacking healthy tissue, pituitary gland function 
decreased, psoriasis: characterized by patches of abnormal, scaly skin, renal (kidney) failure 
or kidney injury, respiratory failure, upper respiratory tract infection, and vision blurred.  
 
Rare, but serious adverse effects (<1%) have included pneumonitis resulting in hypoxia and 
death, anaphylactic reaction (severe allergic reaction), cranial nerve disorder, damage to the 
protective covering of the nerves in the brain and spinal cord, diabetes complications 
resulting in excess blood acids, disease caused by the body’s immune system attacking 
healthy organs, drug induced liver injury, Guillain-Barre syndrome (an autoimmune disorder 
associated with progressive muscle weakness or paralysis) inflammation of blood vessels, 
inflammation of the brain, potentially life-threatening or fatal, inflammation of the lining of the 
brain and spinal cord, inflammation of the heart, lung infiltrates (associated with infection or 
inflammation), Myasthenic syndrome (neurologic syndrome characterized by muscle 
weakness including myasthenia gravis, a nerve disease that may cause weakness of eye, 
face, breathing, and swallowing muscles) Polymyalgia rheumatic, Rhabdomyolysis: muscle 
fiber released into the blood stream which could damage your kidneys, Rosacea: acne-like 
skin condition resulting in redness of face, rupture of the intestine/hole in the intestine, 
Sarcoidosis (a disease involving abnormal collections of inflammatory cells (granulomas) in 


 
 
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organs such as lungs, skin, and lymph nodes), Stevens Johnson syndrome: inflammatory 
disorder of skin and mucous membranes, resulting in blistering and shedding of skin, 
syndrome associated with fever, white blood cell activation and abnormal function (including 
destruction of other blood cells by certain white blood cells), low blood cell counts, rash, and 
enlargement of the spleen, toxic epidermal necrolysis: a potentially fatal disease 
characterized by blistering and peeling of the top layer of skin resembling a severe burn, 
Histiocytic necrotizing lymphadenitis or Kikuchi lymphadenitis (disorder of the lymph nodes 
which causes the lymph nodes to become enlarged, inflamed and painful, commonly 
affecting lymph nodes of the neck and possibly associated with fever or muscle and joint 
pains) and Vogt Koyangi Harada syndrome (a disease that affects the pigmented tissue; this 
may affect the eye leading to swelling, pain and/or blurred vision, the ear leading to hearing 
loss, ringing in the ears and/or the skin leading to loss of skin color), Fulminant type 1 
diabetes mellitus, hepatic enzyme increased, immune-mediated nephritis and immune-
mediated pneumonitis. 
 
Of particular concern is pneumonitis, reported in approximately 3% of patients, including 3 
fatalities. 
 
6.4  
Adverse Event Characteristics  
 
CTCAE term (AE description) and grade:  The descriptions and grading scales found in the 
revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be 
utilized for AE reporting.   
 
Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
 
6.5  
Adverse Event Reporting 
 
The principal investigator will notify the appropriate regulatory agencies of any serious 
adverse event due to any cause during the course of this investigation. These include the 
Johns Hopkins Cancer Center Data and Safety Monitoring Committee, and the Johns Hopkins 
Medical Institutional Review Board (JHM-IRB) of The Johns Hopkins Medical Institutions. The 
required reporting time period is 3 days for fatal events, and 10 days for all other events.  
 
Adverse event information will be collected for the duration of the study. Patients will be 
instructed to notify investigators of any symptoms, and investigators will assess patients for 
adverse events at each visit. All toxicity and adverse events will be recorded on Case Report 
Forms, graded as to the severity and relationship to the study drug, and reported within the 
required time frame.  
 
6.5.1 Adverse event reporting period  


 
 
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All SAEs, whether related or unrelated to nivolumab, azacitidine, and / or entinostat and all 
pregnancies must be reported to the Coordinating Center within 24 hours for reporting to  
BMS, Syndax, and Celgene (by the investigator or designee) within 24 hours of knowledge of 
the event. 
For studies conducted under an Investigator IND, any event that is both serious and 
unexpected must be reported to the Food and Drug Administration (FDA) as soon as 
possible and no later than 7 days (for a death or life-threatening event) or 15 days (for all 
other SAEs) after the investigator’s or institution’s initial receipt of the information. 
BMS will be provided with a simultaneous copy of all adverse events filed with the FDA.  
 
Any investigational safety event that meets the requirements for 15-day reporting or follow-
up reporting should not be sent via email, fax, or other rapid communication, but instead 
should be formally submitted to the IND directly, unless FDA has requested specific 
information on an event that requires rapid communication (such as an information request 
response).  
SAEs should be reported on MedWatch Form 3500A or similar form. It MUST include the 
institutional AND BMSstudy ID [per study Agreement] 
 
MedWatch SAE forms meeting the expedtided reporting requirments should be sent 
to the FDA at: 
 
MEDWATCH 
5600 Fishers Lane 
Rockville, MD 20852-9787 
Fax: 301-796-9849 (DOP2 Fax number) 
Meredith.libeg@FDA.HHS.Gov (emails may be sent by the Study PI or an 
authorized party only) 
http://www.accessdata.fda.gov/scripts/medwatch/ 
 
All SAEs should simultaneously be faxed or e-mailed to BMS at: 
Global Pharmacovigilance & Epidemiology 
Bristol-Myers Squibb Company 
Fax Number: 609-818-3804 
SAE Email Address: Worldwide.Safety@BMS.com 
 
Expedited Reporting by Investigator to Celgene 
Serious adverse events (SAE) are defined above.  The Coordinating Center must inform 
Celgene in writing using a Celgene SAE form or MEDWATCH 3500A form of any SAE within 
24 hours of being aware of the event.  The written report must be completed and supplied to 
Celgene by facsimile within 24 hours/1 business day.  The initial report must be as complete 
as possible, including an assessment of the causal relationship between the event and the 
investigational product(s), if available.  Information not available at the time of the initial 
report (e.g., an end date for the adverse event or laboratory values received after the report) 
must be documented on a follow-up report.  A final report to document resolution of the SAE 
is required.  The Celgene tracking number (VZ-CL-NSCLC-PI-003404) and the institutional 


 
 
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29
protocol number should be included on SAE reports (or on the fax cover letter) sent to 
Celgene.  A copy of the fax transmission confirmation of the SAE report to Celgene should 
be attached to the SAE and retained with the patient records. 
Celgene Drug Safety Contact Information: 
Celgene Corporation 
Global Drug Safety and Risk Management 
Connell Corporate Park 
300 Connell Dr.  Suite 6000 
Berkeley Heights, NJ  07922 
Fax:  (908) 673-9115 
E-mail:  drugsafety@celgene.com 
 
The study period during which adverse events will be reported is from the initiation of study 
procedures to the end of the study treatment follow-up, defined as 100 days following the 
last administration of nivolumab treatment. 
 
Expedited Reporting by Investigator to Syndax 
Serious adverse events (SAE) are defined above.  The Coordinating Center must inform 
Syndax in writing using a Syndax SAE form or MEDWATCH 3500A form of any SAE within 
24 hours of being aware of the event.  The written report must be completed and supplied to 
Syndax by facsimile within 24 hours/1 business day.  The initial report must be as complete 
as possible, including an assessment of the causal relationship between the event and the 
investigational product(s), if available.  Information not available at the time of the initial 
report (e.g., an end date for the adverse event or laboratory values received after the report) 
must be documented on a follow-up report.  A final report to document resolution of the SAE 
is required.  The Syndax tracking number and the institutional protocol number should be 
included on SAE reports (or on the fax cover letter) sent to Syndax.  A copy of the fax 
transmission confirmation of the SAE report to Syndax should be attached to the SAE and 
retained with the patient records. 
Syndax Drug Safety Contact Information: 
Syndax Pharmaceuticals, Inc. 
Drug Safety and Regulatory 
Attn:  Miranda Rees    
400 Totten Pond Road, Suite 110 
Waltham, MA    
Main:  781-419-1400 
Direct:  781-419-1417 
E-mail:  aereporting@syndax.com; syndaxprogram@parexel.com; 
jnunes@syndax.com 
 
The study period during which adverse events will be reported is from the initiation of study 
procedures to the end of the study treatment follow-up, defined as 100 days following the 
last administration of nivolumab treatment. 
If only limited information is initially available, follow-up reports are required. (Note: Follow-up 
SAE reports should include the same investigator term(s) initially reported.) If an ongoing SAE 
changes in its intensity or relationship to study drug or if new information becomes available, 


 
 
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a follow-up SAE report should be sent to BMS, Celgene, and Syndax using the same 
procedure used for transmitting the initial SAE report. 
In accordance with local regulations, BMS, Celgene and Syndax will notify investigators of 
all SAEs that are suspected (related to their respective investigational product) and 
unexpected (ie, not previously described in the Investigator Brochure). In the European 
Union (EU), an event meeting these criteria is termed a Suspected, Unexpected Serious 
Adverse Reaction (SUSAR). Investigator notification of these events will be in the form of an 
expedited safety report (ESR). 
 
6.5.2 Adverse event definition  
 
An adverse event (AE) is any symptom, sign, illness or experience that develops or worsens 
in severity during the course of the study. Intercurrent illnesses or injuries are regarded as 
adverse events. Abnormal results of diagnostic procedures are considered to be adverse 
events if the abnormality:  
 
•  Results in study withdrawal  
•  Is associated with a serious adverse event  
•  Is associated with clinical signs or symptoms  
•  Leads to additional treatment or to further diagnostic tests  
•  Is considered by the investigator to be of clinical significance  
 
6.5.3 Serious adverse event definition  
 
A serious adverse event is any AE that is:  
• 
Fatal  
•  Life-threatening 
•  Requires or prolongs hospital stay  
•  Results in persistent or significant disability or incapacity  
•  A congenital anomaly or birth defect  
•  An important medical event  
 
 
6.5.4 Important medical event definition  
 
Important medical events are those that may not be immediately life threatening, but 
are judged by the study investigator to be of major clinical significance. They may 
jeopardize the subject, and may require intervention to prevent one of the other serious 
outcomes noted above.  
 
6.6  
Data Handling and Record Keeping  
 
6.6.1 Confidentiality  
 
Information about study subjects will be kept confidential and managed according to 
the requirements of the Health Insurance Portability and Accountability Act of 1996 
(HIPAA).  


 
 
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6.6.2 Source Documents  
 
Source data include all information, original records of clinical findings, observations, 
or other activities in a clinical trial necessary for the reconstruction and evaluation of 
the trial.  
 
6.6.3 Case Report Forms  
 
The study case report forms (CRFs) are the primary data collection instrument for the 
study. All data requested on the CRF will be recorded for each subject. If a procedure 
was not done or a question was not asked, this will be recorded as “N/D”. If the item 
is not applicable to the individual case, this will be recorded as “N/A”. CRFs will be 
built electronically in CRMS.  All data will be entered electronically onto the electronic 
CRF through CRMS by the Study Coordinator and/ or Data Manager from each site. 
RedCap will be used for Data Analysis purposes by the Johns Hopkins Biostats team, 
but it will not contain CRFs.  
 
6.6.4     Auditing and Monitoring  
 
The investigator will permit study-related monitoring, audits, and inspections by the 
IRB, government regulatory bodies, University compliance and quality assurance 
groups and the Coordinating Center of all study related documents. The investigator 
will ensure the capability for inspections of applicable study-related facilities (e.g. 
pharmacy, diagnostic laboratory, etc.).  
 
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.  
  
The protocol will be monitored internally at SKCCC by the Principal Investigator and 
externally by the SKCCC CRO in accordance with SKCCC guidelines.  Trial 
monitoring and reporting will be done through the Safety Monitoring Committee 
(SMC) at SKCCC. 
 
 
      6.6.5    Treatment Arm Assignment 
 
There will be no randomization for treatment in Arm D, Arm E and Arm F. Arm 
assignment will be based on previous immune-oncology (IO) treatment status, as well 
as time from last IO treatment.  
 
Arm D (naïve): previously treated recurrent or metastatic NSCLC, IO treatment naïve.  
Arm E (refractory): previously treated recurrent or metastatic NSCLC, previous IO 
treatment with progression of disease within (<) 24 weeks of first IO dose. 


 
 
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32
Arm F (resistant): previously treated recurrent or metastatic NSCLC, previously 
treated with IO therapy, with initial clinical benefit defined by disease progression 
seen after > 24 weeks since first dose of IO therapy.    
 
 
 
6.7 
Ethical Considerations  
 
This study is to be conducted according to US and international standards of Good 
Clinical Practice (FDA Title 21 part 312 and International Conference on 
Harmonization guidelines), applicable government regulations and Institutional 
research policies and procedures. 
 
This protocol and any amendments will be submitted to a properly constituted 
independent Ethics Committee (EC) or Institutional Review Board (IRB), in agreement 
with local legal prescriptions, for formal approval of the study conduct. The decision of 
the EC/IRB concerning the conduct of the study will be made to the investigator before 
commencement of this study. 
 
All subjects for this study will be provided a consent form describing this study and 
providing sufficient information for subjects to make an informed decision about their 
participation in this study. The consent form will be submitted with the protocol for 
review and approval by the EC/IRB for the study. The formal consent of a subject, 
using the EC/IRB-approved consent form, must be obtained before that subject is 
submitted to any study procedure. This consent form must be signed by the subject or 
legally acceptable surrogate, and the investigator-designated research professional 
obtaining the consent.  
 
Patients will also be required to reconsent for treatment beyond disease progression 
while on nivolumab. 
 
 
7. PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the agents administered in this study 
can be found in Section 6.1. 
 
7.1  
Azacitidine 
 
7.1.1 Chemical Name: 4-Amino-1-ß-D-ribofuranosyl-1,3,5-triazin-2(1H)-one  
  
Other Names: 5-Azacitidine, 5-AZA, Mylosar7, Ladakamycin, Vidaza  
7.1.2  Azacitidine will be supplied by Celgene Corporation.  It will be supplied as 100 mg of 
white, lyophilized powder with 100 mg of mannitol, USP in 30 ml flint vials. The 
contents of each vial should be dissolved in 4mL of sterile water or 0.9% sodium 
chloride to provide a 25 mg/ml slurry. Azacitidine does not go into solution but forms a 
loose slurry when reconstituted in this fashion. Do not inject the slurry intravenously. 
Doses may be split into multiple injection sites if volume to be administered is too large. 
Injection sites should be rotated on a daily basis.  


 
 
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7.1.3  Storage and Stability: Store the intact vials at refrigeration temperature (2- 8 degree 
centigrade). The intact vials are stable for at least 4 years at refrigeration temperature. 
The constituted solutions hydrolyze at room temperature and should be used within 
60 minutes for delivery of maximum potency.  
7.1.4  Route of Administration: Subcutaneous injection. Patients will have their azacitidine 
injections administered in the outpatient clinic by a health care professional according 
to the standard chemotherapy administration protocol of the Cancer Center. 
Reconstituted solutions of azacitidine are unstable. Upon reconstitution, the material 
should be injected within 60 minutes.  
7.1.5  Azacitidine will be supplied by Celgene Corporation.  The IDS Pharmacy will be 
responsible for ordering study drug directly from Celgene Corporation.  
 
7.2  
Entinostat 
 
7.2.1  Chemical name: 3-Pyridylmethyl N-{4-[(2-aminophenyl)carbamoyl]benzyl}carbamate  
 
Other names: MS-27-275, MS-275, SNDX-275 
 
Molecular Formula: C21H20N4O3 M.W.: 376.41  
 
Classification: Antineoplastic; entinostat is an inhibitor of histone deacetylase  
7.2.2  How Supplied: entinostat is supplied by Syndax as a 1 mg (pink to light red, in bottles 
of 40), or 5 mg (yellow, in bottles of 40) film-coated tablets (round-biconvex). Each 
tablet also contains mannitol, sodium starch glycolate, hydroxypropyl cellulose, 
potassium bicarbonate, and magnesium stearate.  The film coating consists of 
hypromellose, talc, titanium dioxide and ferric oxide pgments (red and yellow) as 
colorants.  
7.2.3  Mechanism of Action: entinostat is a histone deacetylases (HDACs) which is a family 
of enzymes that regulates chromating remodeling and gene transcription via the 
dynamic process of acetylation and deacetylation of core histones.  Entinostat inhibits 
histone deacetylases, changes chromatin configuration, and induces differentiation 
and apoptosis of cancer cells through an epigenetic mechanism.  Among the genes 
whose expression is induced by entinostat is p21WAF-1/CIP-1, independent of p53 
activity. The induction of p21, in turn, is thought to be responsible for the cell cycle 
arrest (at least in part through reduction of retinoblastoma protein phosphorylation) 
and antiproliferative activities of entinostat seen in multiple malignant cell types. In 
addition to its ability to bypass p53-dependent pathways, entinostat also appears to 
be independent of the presence and magnitude of multidrug resistance–1 (MDR) 
gene/protein expression.  
7.2.4  Route of Administration: Oral. Entinostat should be taken fasting either at least 1 hour 
prior to or at least 2 hours after a meal. If the patient’s dose requires more than one 
tablet, the tablets should be taken one at a time.  Entinostat tablets should not be split, 
crushed or chewed.  
7.2.5  Storage and Stability: Store the bottles at room temperature (15-25°C) and protect 
from light.  Entinostat is not to be exposed to extremes of temperature (greater than 
30ºC or less than 5ºC).  Shelf life stability studies of the intact bottles are on-going.  
7.2.6  Potential Drug Interactions: Studies examining interactions between entinostat and 
other agents have not been conducted.  
7.2.7   Entinostat will be supplied by Syndax Pharmaceuticals Inc.  The IDS Pharmacy will be 
responsible for ordering study drug directly from Syndax Pharmaceuticals Inc. 
 


 
 
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7.3  
Nivolumab 
 
7.3.1  Fully human anti-PD-1 IgG4: monoclonal antibody 
 
 
Other names: BMS-936558, MDX-1106  
 
 
Classification: Monoclonal antibody; impedes PD-1/PD-L1 interaction  
7.3.2  How Supplied: Nivolumab is provided as a sterile liquid in vials each containing 
100mg/10ml of the monoclonal antibody. 
 
7.3.3  Mechanism of Action: Nivolumab is a monoclonal antibody that binds to the cell 
surface protein PD-1, a key regulator of cytotoxic T lymphocyte activation.  Nivolumab 
inhibits PD-1/PD-L1 and PD-1/PD-L2 interaction, facilitating CTL reactivity and 
promoting an anticancer cytolytic response.  
7.3.4 Route of Administration: Nivolumab is to be administered as an intravenous infusion, 
using a volumetric pump with a 0.2 micron in-line filter at the protocol-specified doses. 
It is not to be administered as an intravenous push or bolus injection. At the end of the 
infusion, the line should be flushed with a sufficient quantity of normal saline.  A 30 
minute infusion, can be diluted with 0.9% NS for delivery but the total drug 
concentration of the solution cannot be below 0.35mg/ml. 
7.3.5  Storage and Stability: Nivolumab Injection: Vials of nivolumab injection must be 
stored at 2C to 8C (36F to 46F) and protected from light and freezing. The 
unopened vials can be stored at room temperature (up to 25C, 77F) and room light 
for up to 48 hours. 
 
Undiluted Nivolumab Injection and Diluted Nivolumab Injection in the IV Container: 
The administration of nivolumab infusion must be completed within 24 hours of 
preparation. If not used immediately, the infusion solution may be stored under 
refrigeration conditions (2°C to 8°C, 36°F to 46°F) for up to 24 hours, and a 
maximum of 8 hours of the total 24 hours can be at room temperature (up to 25C, 
77F) and room light. The maximum of 8 hours under room temperature and room 
light conditions includes the product administration period. 
 
 
7.3.6  Potential Drug Interactions: Studies examining interactions between Nivolumab and 
other agents are ongoing. 
7.3.7  Nivolumab will be supplied directly from BMS Inc..  The IDS Pharmacy will be 
responsible for ordering the study drug directly from BMS Inc. 
7.3.8   Pharmacy:  Nivolumab injection is to be administered as an IV infusion through a 
0.2-micron to 1.2-micron pore size, low-protein binding (eg, polyethersulfone 
membrane) in-line filter at the protocol-specified doses and infusion times. It is not to 
be administered as an IV push or bolus injection. When the dose is based on patient 
weight (ie, mg/kg), nivolumab injection can be infused undiluted (10 mg/mL) or 
diluted with 0.9% sodium chloride injection or 5% dextrose injection to protein 
concentrations as low as 0.35 mg/mL. When the dose is fixed (eg, 240 mg, 360 mg, 
or 480 mg flat dose), nivolumab injection can be infused undiluted or diluted so as 
not to exceed a total infusion volume of 160 mL. For patients weighing less than 40 
kg, the total volume of infusion must not exceed 4 mL per kg of patient weight.  
 
During drug product preparation and handling, vigorous mixing or shaking is to be 


 
 
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35
avoided. Instructions for dilution and infusion of nivolumab injection will be provided 
to the clinical site. Care must be taken to ensure sterility of the prepared solution as 
the product does not contain any antimicrobial preservative or bacteriostatic agent. 
Nivolumab infusions are compatible with polyvinyl chloride or polyolefin containers 
and infusion sets, and glass bottles.  
 
The placebo for nivolumab injection is administered in a similar manner as described 
above for the active drug product. 
  
 
 
8. 
STUDY CALENDARS 
Pre-study laboratory and exam evaluations are to be conducted within 2 weeks prior to start of 
protocol therapy. Pre-study scans and x-rays must be done <4 weeks +/- 1 week prior to the 
start of therapy. In the event that the patient’s condition is deteriorating, laboratory evaluations 
should be repeated within 48 hours prior to initiation of the next cycle of therapy.  All time 
points on study have leeway of plus or minus 3 days unless otherwise noted. 
 
NOTE: In order to minimize the need for research-only in-person visits, telemedicine visits may 
be substituted for in-person clinical trial visits or portions of clinical trial visits where determined 
to be appropriate and where determined by the investigator not to increase the participants 
risks. Prior to initiating telemedicine for study visits the study team will explain to the participant, 
what a telemedicine visit entails and confirm that the study participant is in agreement and able 
to proceed with this method. Telemedicine acknowledgement will be obtained in accordance 
with the Guidance for Use of Telemedicine in Research. In the event telemedicine is not 
deemed feasible, the study visit will proceed as an in-person visit. Telemedicine visits will be 
conducted using HIPAA compliant method approved by the Health System and within licensing 
restrictions. 
 
ARM C: Nivolumab control arm (Will not continue enrollment) 
 
 
Pre-Study 
 
28 day cycles (repeat) 
Week 1 
Week 2 
Week 3 
Week 4 
Week 
32
Follow up 
Nivolumab 1 
 
X 
 
X 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
History & Physical2 
X 
X 
 
X 
 
 
 
Concurrent  Meds 
X 
X 
 
X 
 
 
 
CBC and  Chemistry3 
X 
X 
 
X 
 
 
 
Research Bloods 4 
X 
X4 
 
 
 
 
 
β-HCG 
X 
 
 
 
 
 
 
AE assessment 
X 
X 
 
X 
 
 
 
MRI or CT Scan of 
Brain
X 
 
 
 
 
 
 
CT or MRI for Tumor 
Assessment 5 
X5* 
 
 
 
X5* 
X5* 
 
Tumor Biopsy6 
X 
 
 
 
 
 
 
Review of medical 
records, telephone 
 
 
 
 
 
 
Every 3 
months up 


 
 
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contact for recurrence-
free and overall 
survival
to 5 years 
 
1. 
240 mg IV; After a subject has completed 6 months of nivolumab, they can receive nivolumab 480 mg every 4 weeks instead 
of every 2 weeks. 
2. History and physical, includes interval history, oncologic driver mutation, smoking history, vital signs, oxygenation at rest and 
walking, height, weight, and performance status 
3. Complete blood count and differential, and comprehensive metabolic panel, NOTE -TSH, Free T4 once every 28 days. 
4. Plasma for assessment of methylation, peripheral blood lymphocytes for assessment of gene expression WILL BE 
COLLECTED PRIOR TO NIVOLUMAB ADMINISTRATION at baseline or day 1,  week 5, week 9, week 17, week 25 and at 
progression (please see lab manual). 
5. Tumor assessment includes radiologic assessment for RECISTv1.1 evaluation. Repeat radiologic assessment at week 8-9 
and every 8 weeks thereafter while patient continues to receive Nivolumab.  *During week 24, whenever that falls, tumor 
radiologic assessment for RECISTv1.1 evaluation for the primary endpoint will occur no matter where that falls during 
the cycle or treatment with nivolumab. 
6. Tumor biopsy is required prior to INITIATION OF NIVOLUMAB, and at the time of progression. Biopsy at the time of 
progression should be conducted as soon as possible following imaging-confirmed disease progression.  
 
Arm D, E and F: Epigenetic and Nivolumab Combination Therapy 
 
Pre-
study 
Cycle 1-6 
Nivolumab monotherapy  
 
 
 
 
 
Week 1 
 
 
 
 
 
 
 
 
 
 
Week 2 
 
 
 
 
Week 3 
 
 
 
 
 
Week 4 
 
 
 
 
 
Week 1 
 
 
 
 
 
Week 2 
 
 
 
 
Week 3 
 
 
 
 
 
Week 4 
 
Follow 
up 
Azacytidine 1 
 
d 1 - 5 
d 8 - 10 
 
 
 
 
 
 
 
Entinostat 2 
 
d 3 
d 10 
 
 
 
 
 
 
 
Nivolumab10 
 
D1 
 
D15 
 
D1 
 
D1510 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
History & Physical 3 
X 
X 
 
X 
 
X 
 
X10 
 
 
Concurrent  Meds 
X 
X 
X 
 
 
X 
X 
 
 
 
CBC and Chemistry 4 
X 
X 
X 
X 
 
X 
 
X10 
 
 
Research Bloods 5 
X 
X5 
 
 
 
X5 
 
 
 
 
β-HCG 
X 
 
 
 
 
 
 
 
 
 
AE assessment 
X 
X 
X 
X 
 
X 
 
X10 
 
 
CT or MRI for Tumor 
Assessment6 
X 
 
 
 
X 
 
 
 
X 
 
MRI or CT with 
contrast of Brain
X 
 
 
 
 
 
 
 
 
 
Tumor Biopsy 
X7 
 
X8,9 
X8 
X9 
 
 
 
X9 
 
Review of medical 
records, telephone 
contact for 
recurrence-free and 
overall survival 
 
 
 
 
 
 
 
 
 
Every 3 
months 
up to 5 
years 
 
1. 
40 mg/m2 s.c. days 1 – 5 and 8 – 10 
2. 5 mg PO days 3 and 10 
3. History and physical, includes interval history, oncologic driver mutation, smoking history, vital signs, oxygenation at rest and 
walking, height, weight, and performance status 
4. Complete blood count and differential, comprehensive metabolic panel, serum magnesium and serum phosphate. Note-TSH, 
Free T4 once every 4 weeks. 


 
 
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5. Plasma for assessment of methylation, peripheral blood lymphocytes for assessment of gene expression WILL BE 
COLLECTED PRIOR TO TREATMENT ADMINISTRATION at baseline or day 1, week 5, week 9, week 17 and week 25 and 
at progression (please see lab manual).  
6. Tumor assessment at all later time points include radiology scans to be performed every 8 weeks. The window is +/- 1 week.   
7. Tumor biopsy required prior to treatment initiation.   
8. Required on treatment biopsy should be performed during Cycle 2 Week 2 or 3 FOLLOWING completion of epigenetics for 
that cycle; must be completed prior to Cycle 3 dosing.  
9. Required biopsy at time of disease progression while on combination therapy or nivolumab monotherapy per patient course. 
Biopsy at the time of progression should be conducted as soon as possible following imaging-confirmed disease progression. 
10. After a subject has completed 6 months of nivolumab, they can receive nivolumab 480 mg every 4 weeks instead of every 2 
weeks. Day 15 lab assessments, history and physical and AE assessments are not required for patients receiving nivolumab 
every 4 weeks. These assessments will be captured on day 1 of every cycle for subjects on Nivolumab every 4 weeks. 
 
 
9. MEASUREMENT OF EFFECT 
 
9.1  
Antitumor Effect – Solid Tumors 
 
On this study, planned radiologic evaluations will be performed at baseline (within 4 weeks 
prior to starting study therapy) and then every 8 weeks.  For all Arms, confirmatory scans 
should be obtained not less than 4 weeks following initial documentation of objective 
response, and will typically be obtained at the time of the next planned evaluation (i.e. 8 weeks 
following).  
 
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) [Eur J Ca 45:228-247, 2009], Changes in the longest diameter (unidimensional 
measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph 
nodes are used in the RECISTv1.1 criteria. RECIST readers will be blinded to the treatment 
assignment of all subjects.  
 
Accumulating evidence indicates that the emergence of objective responses to agents that 
activate anti-tumor immune responses may follow delayed kinetics of weeks or months, and 
can be preceded by initial apparent radiological progression, or the appearance of new lesions 
or some enlarging lesions while certain target lesions are regressing (“mixed response”). It is 
thus reasonable, in the absence of clinical deterioration, to continue to treat these subjects 
until radiologic progression is both confirmed and found to have worsened at a subsequent 
imaging evaluation. Evidence of PD will be based on a comparison with baseline (or nadir) 
scans, in which there is either an increase of 20% or more in the sum of the longest diameters 
(SLD) of target lesions taking as reference the smallest sum of the longest diameters (nadir) 
recorded since starting nivolumab treatment, and/or unequivocal progression of non-target 
lesions, with or without the development of 1 or more new lesions.  PD should be confirmed 
by repeat scans at the next scheduled imaging evaluation 8 weeks later (but no sooner than 
4 weeks). 
 
Subjects with PD should be managed in the study as per Section 4.4.1.  
 
9.1.1 Definitions 
 
Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of their 
first treatment on protocol. 


 
 
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Evaluable for objective response.  Response to azacitidine/entinostat and to 
Nivolumab, will be assessed separately.  For each, only those patients who have 
measurable disease present at baseline, have received at least one cycle of therapy, 
and have had their disease re-evaluated will be considered evaluable for response.  
These patients will have their response classified according to the definitions stated 
below.  (Note:  Patients who exhibit objective disease progression prior to the end of 
the first cycle of either therapy will also be considered evaluable.) 
 
Evaluable Non-Target Disease Response.  Patients who have lesions present at 
baseline that are evaluable but do not meet the definitions of measurable disease, 
have received at least one cycle of therapy, and have had their disease re-evaluated 
will be considered evaluable for non-target disease.  The response assessment is 
based on the presence, absence, or unequivocal progression of the lesions.  
 
9.1.2       Disease Parameters 
 
To assess objective response or future progression, it is necessary to estimate the 
overall tumor burden at baseline and use this as a comparator for subsequent 
measurements.  Measurable disease is defined by the presence of at least one 
measurable lesion. 
 
Measurable disease.  Measurable lesions are defined as those that can be 
accurately measured in at least one dimension (longest diameter to be recorded) as 
>20 mm by chest x-ray or as >10 mm with CT scan, MRI, or calipers by clinical 
exam.  All tumor measurements must be recorded in millimeters (or decimal fractions 
of centimeters). 
 
Note:  Tumor lesions that are situated in a previously irradiated area are not 
considered measurable unless there has been demonstrated progression in the 
lesion. 
 
Malignant lymph nodes.  To be considered pathologically enlarged and measurable, 
a lymph node must be >15 mm in short axis when assessed by CT scan (CT scan 
slice thickness recommended to be no greater than 5 mm).  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 diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm 
short axis), are considered non-measurable disease.  Bone lesions, leptomeningeal 
disease, ascites, pleural/pericardial effusions, lymphangitic involvement of the skin or 
lung, inflammatory breast disease, and abdominal masses/abdominal organomegaly 
(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. 
 


 
 
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‘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 patient, 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.  
The baseline sum diameters will be used as reference to further characterize any 
objective tumor regression in the measurable dimension of the disease. 
 
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.  
 
9.1.3       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 never more than 4 weeks before the beginning of the 
treatment. 
 
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 (e.g., skin nodules and palpable lymph nodes) and 10 mm diameter as 
assessed using 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 


 
 
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40
scan based on the assumption that CT slice thickness is 5 mm or less.  If CT scans 
have slice thickness greater than 5 mm, 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).   
 
Use of MRI remains a complex issue.  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.  
Furthermore, the availability of MRI is variable globally.  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.  It is beyond 
the scope of the RECISTv1.1 guidelines to prescribe specific MRI pulse sequence 
parameters for all scanners, body parts, and diseases.  Ideally, the same type of 
scanner should be used and the image acquisition protocol should be followed as 
closely as possible to prior scans.  Body scans should be performed with breath-hold 
scanning techniques, if possible. 
 
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 v1.1 
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 v1.1 
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 additional data which may bias an investigator if it is not routinely or 
serially performed.   
 
Ultrasound  Ultrasound is not useful in assessment of lesion size and should not be 
used as a method of measurement.  Ultrasound examinations cannot be reproduced 
in their entirety for independent review at a later date and, because they are operator 
dependent, it cannot be guaranteed that the same technique and measurements will 
be taken from one assessment to the next.  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.  However, such techniques may be useful to confirm 
complete pathological response when biopsies are obtained or to determine relapse 
in trials where recurrence following complete response (CR) or surgical resection is 
an endpoint. 
 
Tumor markers  Tumor markers alone cannot be used to assess response.  If 
markers are initially above the upper normal limit, they must normalize for a patient 
to be considered in complete clinical response.  Specific guidelines for both CA-125 
response (in recurrent ovarian cancer) and PSA response (in recurrent prostate 


 
 
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41
cancer) have been published [JNCI 96:487-488, 2004; J Clin Oncol 17, 3461-3467, 
1999; J Clin Oncol 26:1148-1159, 2008].  In addition, the Gynecologic Cancer 
Intergroup has developed CA-125 progression criteria which are to be integrated with 
objective tumor assessment for use in first-line trials in ovarian cancer [JNCI 
92:1534-1535, 2000]. 
 
Cytology, Histology  These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in 
tumor types, such as germ cell tumors, where known residual benign tumors can 
remain). 
 
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 related to NSCLC management 
and to immunotherapy need additional study, it is sometimes reasonable to 
incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of tumor progression (particularly possible 'new' disease) or regression 
(evaluation of potential CR).  Lesions can be assessed on FDG-PET imaging 
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. 
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.  However, it must be acknowledged that both approaches may 
lead to false positive CR due to limitations of FDG-PET 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. 
 
 
 
9.1.4 Response Criteria 
 
9.1.4.1 Evaluation of Target Lesions 
 


 
 
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42
Complete Response (CR): 
Disappearance of all target lesions.  Any 
pathological lymph nodes (whether target or non-target) must have reduction in short 
axis to <10 mm. 
 
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.  (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. 
 
Special notes on the assessment of target lesions: 
Lymph nodes:  Lymph nodes identified as target lesions should always have the 
actual short axis measurement recorded and should be measured in the same 
anatomical plane as the baseline examination, even if the nodes regress to below 
10mm on study.  This means that when lymph nodes are included as target lesions, 
the ‘sum’ of lesions may not be zero even if complete response criteria are met, 
since a normal lymph node is defined as having a short axis of < 10 mm. 
Target lesions that become ‘too small to measure’:  All lesions (nodal and non-
nodal) recorded at baseline should have their actual measurements recorded at each 
subsequent evaluation, even when very small (eg, 2mm).  If the radiologist is able to 
provide an actual measure, that should be recorded, even if it is below 5mm.  When 
such a lesion becomes difficult to assign an exact measurement, it is recommended 
to:  If it is in the opinion of the radiologist that the lesion has likely disappeared, the 
measurement should be recorded as 0 mm.  If the lesion is believed to be present 
and is faintly seen but too small to measure, a default value of 5 mm should be 
assigned (note: in case of a lymph node believed to be present and faintly seen but 
too small to measure, a default value of 5 mm should be assigned in this 
circumstance as well).  This default value is derived from the 5 mm CT slice 
thickness (but should not be changed with varying CT slice thickness). 
Lesions that split or coalesce on treatment:  When non-nodal lesions ‘fragment’, 
the longest diameters of the fragmented portions should be added together to 
calculate the target lesion sum.  Similarly, as lesions coalesce, a plane between 
them may be maintained that would aid in obtaining maximal diameter 
measurements of each individual lesion.  If the lesions have coalesced such that 
they are no longer separable, the vector of the longest diameter in this instance 
should be the maximal longest diameter for the ‘coalesced lesion’. 
 
9.1.4.2 Evaluation of Non-Target Lesions 
 
Complete Response (CR): 
Disappearance of all non-target lesions and 
normalization of tumor marker level.  All lymph nodes must be non-pathological in 


 
 
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size (<10 mm short axis). 
 
Note:  If tumor markers are initially above the upper normal limit, they must normalize 
for a patient 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 Principal 
Investigator).  When the patient also has measurable disease:  To achieve 
‘unequivocal progression’ on the basis of the non-target disease, there must be an 
overall level of substantial worsening in non-target disease such that, even in 
presence of SD or PR in target disease, the overall tumor burden has increased 
sufficiently to merit discontinuation of therapy.  A modest ‘increase’ in size of one or 
more non-target lesions is usually not sufficient to qualify for unequivocal progression 
status.  When the patients has only non-measurable disease:  To achieve 
‘unequivocal progression’ on the basis of the non-target disease, there must be an 
overall level of substantial worsening such that the overall tumor burden has 
increased sufficiently to merit discontinuation of therapy.  A modest ‘increase’ in the 
size of one or more non-target lesions is usually not sufficient to qualify for 
unequivocal progression status.  Because worsening in non-target disease cannot be 
easily quantified (by definition: if all lesions are non-measurable) a useful test that 
can be applied when assessing patients for unequivocal progression is to consider if 
the increase in overall disease burden based on the change in non-measurable 
disease is comparable in magnitude to the increase that would be required to declare 
PD for measurable disease: i.e., an increase in tumor burden representing an 
additional 73% increase in ‘volume’ (which is equivalent to a 20% increase diameter 
in a measurable lesion).  Examples include an increase in a pleural effusion from 
‘trace’ to ‘large’, an increase in lymphangitic disease from localized to widespread, or 
may be described in protocols as ‘sufficient to require a change in therapy’.  If 
‘unequivocal progression’ is seen, the patient should be considered to have had 
overall PD at that point. 
 
9.1.4.3 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 
patient's best response assignment will depend on the achievement of both 
measurement and confirmation criteria. 
    


 
 
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44
 
Target 
Lesions
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response
Best Overall 
Response when 
Confirmation is 
Required*
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
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 
* 
See RECIST 1.1 manuscript for further details on what is 
evidence of a new lesion. 
** 
Only for non-randomized trials with response as primary 
endpoint. 
*** 
In exceptional circumstances, unequivocal progression in non-
target lesions may be accepted as disease progression. 
 
Note: Patients 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.”  Every effort should be made to document the objective 
progression even after discontinuation of treatment.
 
 
 
9.1.5 Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from the 
time measurement criteria are met for CR or PR (whichever is first recorded) until the 
first date that recurrent or progressive disease is objectively documented (taking as 
reference for progressive disease the smallest measurements recorded since the 
treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first met 
for CR until the first date that progressive disease is objectively documented. 
 


 
 
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45
 
Duration of stable disease:  Stable disease is measured from the start of the treatment 
until the criteria for progression are met, taking as reference the smallest measurements 
recorded since the treatment started, including the baseline measurements.  
 
9.1.6 Progression-Free Survival 
 
PFS is defined as the duration of time from start of treatment to time of progression or 
death, whichever occurs first. 
 
 
10. STATISTICAL CONSIDERATIONS 
 
10.1 
Study Design/Endpoints 
 
10.1.1 Study Design 
 
The study is a non-randomized phase II study of nivolumab with concurrent epigenetic 
therapy (consisting of azacitidine and entinostat) for 6 cycles, followed by nivolumab 
monotherapy until confirmed disease progression is noted.  We are evaluating the strategy 
of combination epigenetic therapy with Nivolumab in three distinct patient populations: PD-
1/PD-L1 naïve, PD-1/PD-L1 refractory (previously treated with disease progression < 6 
months from first dose) and PD-1/PD-L1 resistant (previously treated with disease 
progression > 6 months from first dose). This study is intended to identify response to this 
regimen in the three patient groups.  
 
 
10.1.1.1 Arms/Regimens 
 
All patients on each of the three arms will receive the same treatment of epigenetic 
therapy. The treatment consists of azacitidine 40 mg/m2/day subcutaneously days 1-
5 and 8-10 and entinostat 5 mg PO days 3 and 10 on a 28 day cycle concurrently with 
nivolumab for 6 cycles, followed by nivolumab until confirmed disease progression. 
 
The arms are as follows:  
 
Arm D: PD-1/PD-L1 naïve  
 
Arm E: PD-1/PD-L1 refractory (i.e., previously treated with disease progression < 
 
 
24 weeks from first dose)  
 
Arm F: PD-1/PD-L1 resistant (i.e., previously treated with disease progression >  
 
 
24 weeks from first dose).  
 
 
10.1.2 Endpoints 
 
      Primary Endpoint 
 
Overall response rate (ORR) 
Response, by Arm, will be measured per RECIST 1.1, as described in Section 9.   
   


 
 
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46
Secondary Endpoints  
 
Progression free survival 
Progression-free survival (overall) will be measured from the time of first dose of 
therapy until radiologic or clinical progression is noted or death from any cause.   
 
Time to Progression 
Time to progression will be measured from the time treatment begins until radiologic 
or clinical progression is noted.  
 
Overall survival (OS) 
Overall survival will be measured from the time of randomization until death from any 
cause.  
 
Safety and tolerability 
Toxicities observed in the study will be assessed by CTCAE 4.0 criteria. We will 
tabulate toxicities and compare the two treatment groups via methods appropriate for 
categorical data. 
 
Feasibility 
Feasibility for the purposes of this study means the ability for a patient to take the full 
course of their assigned treatment (minimum of six cycles) through 24 weeks, except 
for progression or death. 
 
Exploratory Endpoints  
 
Laboratory correlates of response 
See section 11.  These analyses are considered exploratory. 
 
10.2 
Sample size, Analysis, and Accrual Rate 
 
The study will enroll up to 20 patients on Arm D, 20 patients on Arm E and 20 patients on Arm 
F. With this amendment, there will be no further enrollment for treatment on Arm C, although 
these patients will be allowed to cross over to Arms E or F if they progress and are otherwise 
eligible. The sample size is driven by what we think is feasible for enrollment over a 
reasonable period of time (e.g., a few years). We are including futility analyses within each 
Arm to allow us to stop a treatment arm if it appears not to have enough activity to warrant 
further investigation. Additionally, we have interim analyses to assess the feasibility of 
continuing an arm, with feasibility defined in the previous subsection. 
 
The final analysis for each arm will be descriptive, consisting of summary statistics and 
confidence intervals. We will use survival analysis methods (e.g., the Kaplan-Meier survival 
estimation) for time-to-event data. We will not adjust for multiple comparisons; the futility 
analyses do not inflate the type I error, as seen in the simulation results (see section 10.4).  
Allowing for up to 10% inevaluable patients, we will enroll up to 22 patients on each Arm, or a 
total of 66.  Anticipated accrual rate is 5 patients per month.  
 


 
 
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47
10.3     Stratification Factors 
There are no stratification factors in this study. Patients will be assigned treatment Arm 
based on prior therapeutic regimen and disease response to that regimen.  
 
 
10.4   Interim Analyses 
The study design calls for interim futility analysis by arm.  These analyses will occur 
separately by arm once 10 patients are on an arm and have either received at least 6 cycles 
of therapy or experienced a PFS event. Subsequent analyses will occur after 15 patients 
have either received at least 6 cycles of therapy or experienced a PFS event. The final 
analysis will occur after 20 patients have entered and received full therapy (6 cycles). The 
futility analysis is based on Bayesian hypothesis testing32.  
 
For Arm D, we take the expected ORR to be 20% if epigenetic therapy does not increase 
the clinical effectiveness of nivolumab alone. This estimate is based on results of the 
Checkmate studies (CheckMate 057 (non-squamous NSCLC) ORR  = 19%; CheckMate017 
(squamous cell NSCLC) ORR = 20%). We would consider the addition of epigenetic therapy 
encouraging if the ORR is 35% or higher. The study will stop for futility if we see 0 
responses among the first 10 patients or no more than 1 response in the first 15 patients. 
We will not consider this Arm promising if we see 3 or fewer responders out of 20 patients. 
The following table provides the operating characteristics for Arm D based on 5000 
simulations. 
 
Simulation Results for Arm D 
Scenario 
Assumed true 
response rate 
Pr(Stop for inferiority) 
Average # patients treated 
(10%, 25%, 50%, 75%, 90%)  
1 
0.1 
0.876 
15.4 (10, 10, 15, 20, 20 ) 
2 
0.15 
0.662 
17.3 (10, 15, 20, 20, 20 ) 
3 
0.2 
0.434 
18.51 (10, 20, 20, 20, 20 ) 
4 
0.25 
0.243 
19.25 (20, 20, 20, 20, 20 ) 
5 
0.3 
0.119 
19.61 (20, 20, 20, 20, 20 ) 
6 
0.35 
0.047 
19.86 (20, 20, 20, 20, 20 ) 
7 
0.4 
0.021 
19.92 (20, 20, 20, 20, 20 ) 
8 
0.45 
0.008 
19.96 (20, 20, 20, 20, 20 ) 
9 
0.5 
0.002 
19.99 (20, 20, 20, 20, 20 ) 
 
For Arms E and F, respectively, we take the expected ORR to be virtually 0% if epigenetic 
therapy does not increase the clinical effectiveness of nivolumab alone. We would consider 
the addition of epigenetic therapy encouraging if the ORR is at least 10%. The study will 
stop for futility if we see 0 responses among the first 15 patients. We will not consider an 


 
 
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48
Arm promising if none of the 20 patients on that Arm responds. The following table provides 
the operating characteristics for Arms E and F, respectively, based on 5000 simulations. 
 
Simulation Results for Arm E and for Arm F 
Scenario
Assumed true 
response rate 
Pr(Stop for inferiority) 
Average # patients treated 
(10%, 25%, 50%, 75%, 90%)  
1 
0.025 
0.683 
16.58 (15, 15, 15, 20, 20 ) 
2 
0.05 
0.462 
17.69 (15, 15, 20, 20, 20 ) 
3 
0.1 
0.206 
18.97 (15, 20, 20, 20, 20 ) 
4 
0.15 
0.085 
19.58 (20, 20, 20, 20, 20 ) 
5 
0.2 
0.037 
19.82 (20, 20, 20, 20, 20 ) 
6 
0.25 
0.013 
19.93 (20, 20, 20, 20, 20 ) 
7 
0.3 
0.006 
19.97 (20, 20, 20, 20, 20 ) 
8 
0.35 
0.002 
19.99 (20, 20, 20, 20, 20 ) 
9 
0.4 
0 
20 (20, 20, 20, 20, 20 ) 
 
 
 
10.5 Feasibility monitoring 
 
We will use separate Bayesian calculations to monitor the feasibility of each treatment. We 
define feasibility as the ability for a patient to take their full course of their assigned treatment 
(minimum of six cycles) through 24 weeks, except for progression or death. If there is 
considerable probability (≥ 67%) that the regimen is feasible for less than half of the patients, 
we will consider stopping the study.  We will base the decision on the posterior probability that 
the treatment is not feasible (> 50% of patients who do not progress or die before 24 weeks 
do not make it to 24 weeks). The prior distribution for this calculation is Uniform (0,1). We will 
apply the monitoring rule separately by treatment group, and the analysis will occur at the time 
of each interim analysis.  For each treatment Arm, though, we will apply the rules to all patients 
pooled together, rather than separately within each subtype, since we do not expect one group 
to be at greater risk of toxicity than the other.  We will consider stopping the study if the data 
indicate that the treatment regimen is feasible for less than half of all patients, where we 
quantify certainty as two thirds or greater (i.e., 2:1 odds it is not feasible). 
 
Rule: Stop if there is two-thirds (2:1 odds) or greater probability that 50% or more patients 
cannot complete at least 6 cycles of therapy (24 weeks), unless the patient’s disease 
progressed or the patient died. The following table shows the stopping boundaries for 
monitoring that starts at the fifth patient. 
 


 
 
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49
Stop if not feasible for 
Probability that feasibility > 50% = 
4 out of 5 patients. 
0.891 
4 out of 6 patients. 
0.773 
5 out of 7 patients. 
0.855 
5 out of 8 patients. 
0.746 
6 out of 9 patients. 
0.828 
6 out of 10 patients. 
0.726 
7 out of 11 patients. 
0.806 
7 out of 12 patients. 
0.709 
8 out of 13 patients. 
0.788 
8 out of 14 patients. 
0.696 
9 out of 15 patients. 
0.773 
9 out of 16 patients. 
0.685 
10 out of 17 patients. 
0.760 
10 out of 18 patients. 
0.676 
11 out of 19 patients. 
0.748 
11 out of 20 patients. 
0.668 
 
 
The table below shows the operating characteristics of this monitoring rule for the study. The 
results are based on 5000 simulated studies for each scenario. 
 
Assumed true risk 
not feasible
Percent of times the study 
stops for lack of feasibility 
Average sample size 
0.05
0.1% 
20.0 
0.10
0.8% 
19.9 
0.15
2.6% 
19.6 
0.20
6.3% 
19.1 
0.25
12.2% 
18.2 
0.30
18.0% 
17.4 
0.35
28.8% 
16.0 
0.40
40.7% 
14.6 
0.45
54.1% 
12.9 
0.50
67.5% 
11.2 
0.55
79.5% 
9.6
0.60
88.3% 
8.3
0.65
94.3% 
7.1
0.70
98.2% 
6.2
0.75
99.6% 
5.7
 
 


 
 
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10.6  Analysis of secondary endpoints 
 
We will analyze progression-free survival by comparing the treatments via the logrank test.  
We will also estimate progression-free and overall survival probabilities using the Kaplan-
Meier method.  Toxicities will be categorized for azacitidine/entinostat and for Nivolumab, by 
frequency and type, and reported in tabular form. All patients will be evaluable for toxicity 
from the time of their first treatment with any study therapy.   
 
 
10.7 
Data Safety, Monitoring and Between Site Communication 
 
 
 
As this is a multi-institutional study, there will be ongoing communications between sites. 
This includes site initiation visits, weekly telephone conferences and encrypted electronic 
communications. All data will be stored electronically on CRMS. All biologic samples will be 
held in a central location and overseen by study staff.  
 
11. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES – Please see lab manual for full 
details. 
 
Serial assessment for a series of correlative science parameters will be performed. These reflect, from 
pre-clinical studies including use of the epigenetic therapy agents in mouse models of NSCLC, our latest 
appreciation of epigenetic therapy induced changes that are predicted to potentially improve the efficacy 
of nivolumab20. These include target gene DNA methylation status in circulating DNA and in pre- and 
post-tumor biopsies, DNA exome sequencing to assess mutational burden and status of deriver gene 
mutations, genome wide and target gene DNA methylation levels, RNA-seq analyses of genome wide 
gene expression for detection of drug induced changes in endogenous retroviral (ERV) transcripts,  
transcripts for genes in a viral defense signaling pathway which drives Type 1 interferon responses 
which in turn increase PD-L1 expression, antigen presentation, and cytokine production. These 
expression studies also assess levels of CMYC, and key target genes which have a direct, positive 
relationship to tumor proliferation and immune evasion status. The biopsy expression studies also allow 
for detection of a transcriptional profile for immune exhaustion in subsets of immune cells and 
especially CD8 cells in the tumor microenvironment. Serial samples of blood mononuclear cells, will be 
assessed for immune exhaustion versus activation status with many of the above assays and serial 
plasma samples are collected to assay levels of key cytokines. 
 
11.1 Plasma 
 
Plasma samples will be obtained at timepoints indicated in the study calendar.  Quantitative 
candidate promoter methylation analysis will performed on APC, HCAD, p16, RASSF1A, 
GATA4, as well as Actin. 
 
Pre- and post-epigenetic therapy plasma will be tested by chemokine array which will analyze 
circulating chemokine ligands and receptors, specific interleukins and associated gene 
products such as TNF and MMP, as well as other immunomodulatory effects. 
 
11.2 Tumor 
 


 
 
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Baseline tumor biopsy is required and will be analyzed in all subjects. Tumor biopsy while 
on epigenetic therapy and at progression are required for all Arms. These are detailed in the 
patient calendars found in Section 8.  
 
As many of the following studies will be performed as tissue availability allows: 
 
Immunohistochemical (IHC) staining of tumor samples for PD-L1 infiltrating immune 
 
cell subsets (CD3, 4, 8, 20, 68), as well as other immune markers using both IHC or 
 
ISH. 
 
Laser capture microdissection, or macrodissection, followed by qRT-PCR and whole- 
 
genome microarray for pre- and post-treatment gene expression profiles related to 
 
immunological pathways. 
 
Quantitative candidate promoter methylation analysis: APC, HCAD, p16, RASSF1A, 
 
GATA4, Actin 
 
RNA Sequencing for human endogenous retrovirus (ERV) pathways known to be related  
 
to epigenetic therapies.  
 
Mutation, translocation, and amplification analysis of known biologically relevant driver 
 
mutations in non-squamous NSCLC to include: EGFR, KRAS, EML4-ALK, BRAF, 
 
PIK3CA, and ERBB2 overexpression 
 
 
 
11.3 
Peripheral Blood Mononuclear Cells (PBMCs) 
 
        
Baseline PBMCs will be analyzed as well as PBMCs following two cycles of therapy, 
prior to the third cycle (ie/between week 4 of Cycle 2 and week 1 of cycle 3). 
 
 
Pre- and post-epigenetic therapy PBMCs will be evaluated for Cytokine expression,  
 
epigenetic status of cytokine promoters, and induction of responses to tumor antigens as 
 
well as other immunologic evaluations. 
 
11.4     Analysis 
 
To assess pharmacodynamic effects in samples obtained from subjects on each 
treatment arm, summary statistics for biomarkers of immunoregulatory activity and their 
corresponding changes (or percent changes) from baseline will be tabulated.  Possible 
associations between changes in biomarker measures of interest and exposure to drug 
will be explored graphically.  The frequency of significant demethylation and acetylation 
will be summarized in both treatment arms.  The difference between the methylation 
indices post- and pre-treatment will be compared using paired Student’s t-test.  Similar 
analyses will be performed for other biomarker parameters.  Relationships between 
changes in gene re-expression and other correlates with clinical response will be 
assessed using the Mantel-Haenszel test.  In addition, estimates of the variance in the 
biological correlative parameters will be made in this group to be used in planning the 
integration of these studies in future trials. 
 
 
 


 
 
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Langer CJ, Gadgeel SM, Borghaei H, et al. Carboplatin and pemetrexed with or without 
pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort 
of the open-label KEYNOTE-021 study. Lancet Oncol 2016;17:1497-508. 
27.  
Koyama S, Akbay EA, Li YY, et al. STK11/LKB1 Deficiency Promotes Neutrophil Recruitment and 
Proinflammatory Cytokine Production to Suppress T-cell Activity in the Lung Tumor Microenvironment. 
Cancer Res 2016;76:999-1008. 
28. 
Pharmaceuticals S. Syndax Pharmaceuticals Announces Presentation of Data from Immuno-
oncology Clinical Trials at the Society for Immunotherapy of Cancer 32nd Annual Scientific Meeting.  
ENCORE 601 data continue to support increased immune responsiveness in both PD-(L)1 refractory and 
PD-(L)1 naïve NSCLC patients treated with entinostat and KEYTRUDA® (pembrolizumab)2018. 
29. 
Briere D, Sudhakar N, Woods DM, et al. The class I/IV HDAC inhibitor mocetinostat increases 
tumor antigen presentation, decreases immune suppressive cell types and augments checkpoint inhibitor 
therapy. Cancer Immunol Immunother 2018;67:381-92. 
30. 
Yentz SE, Reimers MA, Joshi M, et al. Single-arm phase ib/II study of durvalumab and 
guadecitabine in advanced kidney cancer (NCT03308396). Journal of Clinical Oncology 
2018;36:TPS711-TPS 
31.  
Ghoneim HE, Fan Y, Moustaki A, et al. De Novo Epigenetic Programs Inhibit PD-1 Blockade-
Mediated T Cell Rejuvenation. Cell 2017;170:142-57 e19. 
32. 
Johnson VE, Cook JD. Bayesian design of single-arm phase II clinical trials with continuous 
monitoring. Clin Trials 2009;6:217-26. 

ICF_001.pdf: 
Phase II Anti-PD1 Epigenetic Therapy Study in NSCLC
NCT01928576
4/14/2021


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Combined Informed Consent/Authorization June 2015 Version 15 
RESEARCH PARTICIPANT INFORMED CONSENT AND PRIVACY 
AUTHORIZATION FORM 
Protocol Title:
A Phase II Study of Epigenetic Therapy with Azacitidine and 
Entinostat with Concurrent Nivolumab in Subjects with 
Metastatic Non-Small Cell Lung Cancer. (Protocol Version 13; 
September 17, 2020)
Application No.:
NA_00084192
Sponsor: 
Stand Up To Cancer; Rising Tide Foundation; Jim Toth 
Principal Investigator: Julie Brahmer, MD. 
Skip Viragh Building  
201 N Broadway, 8121 
Baltimore, MD 21287 
Phone:  410-502-7159 
Fax:  410-614-9334 
1.
What you should know about this study:

You are being asked to join a research study. This consent form explains the research study and your
part in it. Please read it carefully and take as much time as you need. Ask your study doctor or the
study team to explain any words or information that you do not understand.

You are a volunteer.  If you join the study, you can change your mind later.  There will be no penalty
or loss of benefits if you decide to quit the study.

During the study, we will tell you if we learn any new information that might affect whether you
wish to continue to participate.

If we think your participation in this study may affect your clinical care, information about your
study participation will be included in your medical record, which is used throughout Johns Hopkins.
Doctors outside of Johns Hopkins may not have access to this information.  You can ask the research
team to send this information to any of your doctors.

When Johns Hopkins is used in this consent form, it includes The Johns Hopkins University, The
Johns Hopkins Hospital, Johns Hopkins Bayview Medical Center, Howard County General Hospital,
Johns Hopkins Community Physicians, Suburban Hospital, Sibley Memorial Hospital and All
Children’s Hospital.

Biospecimens will be collected in this study.  Biospecimens may include any of the following:
blood, tissue, saliva, urine, bone marrow, cells, etc.  Most biospecimens contain DNA, which is the
genetic code for each person.
If appropriate for this study, a scanned copy of 
the signed consent form should be uploaded to 
the participant’s Epic/EMR record.
Patient I.D. plate 


 
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 A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by 
U.S. Law.  This Web site will not include information that can identify you. At most, the Web site 
will include a summary of the results. You can search this Web site at any time.  
 If you would like to review the information for this study, or a summary of the results, ask the study 
team doctor for the ClinicalTrials.gov study registration number. 
 During this study, you will not have access to certain medical information and test results collected 
for study purposes.  If an emergency occurs while you are in the study, medical information needed 
for your treatment can be made available to your study physician and other physicians who treat you.  
When the study is completed, all the information in your medical record will be available to you. 
 
2. 
Why is this research being done? 
This research is being done to see if the investigational two-drug combination when given at the same 
time as another investigational drug called nivolumab (also known as BMS-936558) improves the 
effectiveness of nivolumab in preventing cancer growth compared to nivolumab by itself.  
 
You are being asked to join a study combining two drugs used before anti-cancer therapy with 
nivolumab (BMS-936558). These drugs are oral entinostat in combination with subcutaneous (under the 
skin) azacitidine.  
 
Entinostat is not approved by the U. S. Food and Drug Administration (FDA) and is still being tested in 
research studies and is consider “Investigational”.  Azacitidine given subcutaneously is approved by the 
FDA for treatment of a blood cancer (myelodysplastic syndrome), but is not approved for the treatment 
of lung cancer.  However, the FDA is allowing the combination use of Entinostat and subcutaneous 
azacitidine with the use of nivolumab (BMS-936558) in this study.  The combination of entinostat with 
subcutaneous azacitidine with nivolumab is also investigational.   
 
Nivolumab alone is approved for the treatment of: 
 
unresectable (can't be removed by surgery) or advanced melanoma, alone or in combination with 
ipilimumab 
 
previously treated metastatic non-small cell lung cancer 
 
previously treated advanced renal cell carcinoma 
 
previously treated progressive classical Hodgkin lymphoma  
 
previously treated recurrent or metastatic squamous cell carcinoma of the head and neck 
 
previously treated locally advanced or metastatic urothelial carcinoma (type of bladder cancer) 
 
How do these drugs work? 
Cancers can grow because they have mutations in genes, but they can also grow because the way a gene 
is controlled is abnormal even though gene has no mutations.  Azacitidine and entinostat work trying to 
restore the way genes in a cancer are controlled to normal.   
 
Epigenetic priming refers to the idea that using epigenetic therapy before chemotherapy might improve 
the way chemotherapy works.  Certain genes, when turned off, allow the cancer to escape tumor shrinkage 
that might be caused by chemotherapy.  Epigenetic priming may turn genes on that allow cancers to shrink 
more in response to chemotherapy. 
 
Nivolumab is an antibody (a type of human protein) that is being tested to see if it will allow the body’s 
immune system to work against tumor cells.   
 
People with non-small cell lung cancer may join.  


 
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The goal of this study is to assess whether 6 cycles of concurrent (at the same time) epigenetic therapy 
consisting of azacitidine and entinostat with nivolumab can increase response compared to nivolumab 
alone in patients who are immunotherapy naïve (Arm D), or in patients whose disease has progressed on 
immunotherapy when compared to histological single agent docetaxel (Arms E & F).  
 
Subjects will be assigned to one of three study arms according to previous cancer treatments.  
 
How many people will be in this study? 
About 120 people will take part in this multi-center study.  About 75people will be enrolled at Johns 
Hopkins Hospital.  The other participating sites are Norris Comprehensive Cancer Center at the 
University of Southern California, University of Pittsburgh.  
 
3. 
What will happen if you join this study? 
If you agree to be in this study, we will ask you to do the following things: 
 
Screening Visit: 
You will need to have the following exams, tests or procedures to find out if you can be in the study.  
These exams, tests or procedures are part of regular cancer care and may be done even if you do not join 
the study.  If you have had some of them recently, they may not need to be repeated.  This will be up to 
your study doctor. 
 
 Medical history 
 Past and current medication information will be collected 
 A physical exam 
 Your ability to do everyday activities will be determined 
 Vital signs (blood pressure, heart rate, oxygenation and body temperature) will be collected 
 Weight and height 
 Routine blood tests (4 teaspoons) to assess your blood counts, liver, and kidney function 
 A pregnancy test will also be done for women capable of becoming pregnant. The test will be 
done by collecting a urine sample or a blood sample (less than 1 teaspoon). 
 MRI scan or CT scan of the brain 
 
Study Procedures: 
If the results of the “screening procedures” show that you are eligible for the study, the following 
procedures will be done before starting the study drugs: 
 
 CT and/or MRI scans will be done to measure the extent of your tumor. 
 
If the exams, tests and procedures show that you can be in the study, and you choose to take part, then 
you will need the following tests and procedures.  They are part of regular cancer care.  
 
 Routine blood work  
 Periodic CT scans to assess cancer growth 
 Tumor biopsy, if no tissue is available, is required to participate in this study 
 Tumor biopsy prior to starting Nivolumab treatment and at the time of tumor progression is also 
required to participate in this study. 
 


 
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You will be enrolled on the study and assigned to one of three study arms according to previous cancer 
treatments.  
When you are finished taking the drugs as part of the study, you will continue to be followed by the 
study team until your cancer has progressed, if this has not already occurred.  Additionally, the study 
team may want to follow you for longer to observe how you respond to other therapies. 
 
Arm D, E and F: Epigenetic and Nivolumab Combination Therapy 
 
Pre-
study 
Cycle 1-6 
Nivolumab monotherapy  
 
 
 
 
 
Week 
1 
 
 
 
 
 
 
 
 
 
 
Week 2 
 
 
 
 
 
Week 
3 
 
 
 
 
 
Week 
4 
 
 
 
 
 
Week 
1 
 
 
 
 
 
Week 
2 
 
 
 
 
Week 
3 
 
 
 
 
 
Week 4 
 
Follow 
up 
Azacytidine 1 
 
d 1 - 5 
d 8 - 10 
 
 
 
 
 
 
 
Entinostat 2 
 
d 3 
d 10 
 
 
 
 
 
 
 
Nivolumab11 
 
D1 
 
D15 
 
D1 
 
D15 
 
 
Informed 
Consent 
X 
 
 
 
 
 
 
 
 
 
History & 
Physical 3 
X 
X 
 
 
 
X 
 
 
 
 
Concurrent  
Meds 
X 
X 
X 
 
 
X 
X 
 
 
 
CBC and 
Chemistry 4 
X 
X 
X 
X 
 
X 
 
X 
 
 
Research 
Bloods 5 
X 
 
 
 
 
X 
 
 
 
 
β-HCG 
X 
 
 
 
 
 
 
 
 
 
AE assessment 
X 
X 
X 
 
 
X 
 
X 
 
 
CT or MRI for 
Tumor 
Assessment6 
X 
 
 
 
X7 
 
 
 
X7 
 
MRI or CT 
with contrast 
of Brain 
X 
 
 
 
 
 
 
 
 
 
Tumor Biopsy 
X8 
 
X8,9 
X8 
X9 
 
 
 
X9 
 
Review of 
medical 
records, 
telephone 
contact for 
recurrence-free 
and overall 
survival 
 
 
 
 
 
 
 
 
 
Every 3 
months 
for up to 
5 years 
1. 
40 mg/m2 s.c. days 1 – 5 and 8 – 10 
2. 
5 mg PO days 3 and 10 
3. 
History and physical, includes interval history, oncologic driver mutation, smoking history, vital signs, height, weight, and performance 
status 
4. 
Complete blood count and differential, comprehensive metabolic panel, serum magnesium and serum phosphate. Note-TSH, Free T4 once 
every 4 weeks. 
5. 
Plasma for assessment of methylation, peripheral blood lymphocytes for assessment of gene expression WILL BE COLLECTED PRIOR TO 
TREATMENT ADMINISTRATION, at end of last cycle of combination therapy and then at the time of progression or study discontinuation 


 
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whichever occurs first. (see lab manual) 
6. 
Tumor assessment at all later time points should include radiology scans to be performed every 8 weeks. The window is +/- 1 week.  
7. 
Tumor biopsy required prior to treatment initiation 
8. 
Required on treatment biopsy should be performed during Cycle 2 Week 2 or 3 FOLLOWING completion of epigenetics for that cycle; must 
be completed prior to Cycle 3 dosing.  
9. 
Required biopsy at time of disease progression while on combination therapy or nivolumab monotherapy per patient course.  
10. 
After a subject has completed 6 months of nivolumab, they can receive nivolumab 480 mg every 4 weeks instead of every 2 weeks. Day 15 
lab assessments, history and physical and AE assessments are not required for patients receiving nivolumab every 4 weeks. These assessments 
will be captured on day 1 of every cycle for subjects on Nivolumab every 4 weeks.  
 
Study Plan: 
Another way to find out what will happen to you during the study is to read the chart below.  Start 
reading at the top and read down the list, following the lines and arrows.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
As part of this study, we will study genes measured in blood samples taken before the start of the study 
regimen, after completion of the study regimen with entinostat and azacitidine, and when your cancer 
grows.  These blood samples will be about 8 tablespoons each.  We will also study genes from the tumor 
biopsies on this study.  We will study all subjects’ tumors biopsied before a study regimen begins (your 
original tumor sample used for diagnosis may be used for this test).  Research tumor biopsies on study 
are required to be a part of this study, then these samples will also be used for genetic testing.  The blood 
samples and initial tumor tissue and a second biopsy are required for the study.  These blood samples 
and these biopsies are for research purposes only.  The reason to study genes in these samples is to look 
for genes that may predict who benefits from this drug regimen and who does not. 
 
The Genetic Information Nondiscrimination Act (GINA) may help protect you from health insurance or 
employment discrimination based on genetic information.   
 
The law provides that health insurance companies and group health plans  
 may not ask for genetic information from this research and  
 may not use genetic information when making decision about eligibility or premiums 
 
Enrolled: determined by prior treatment    
       Start Here 
Check your eligibility for this trial 
Group D 
SC azacitidine, entinostat and 
Nivolumab 28 day cycle X6  
and then nivolumab every 2 weeks 
until PD 
Group E 
SC azacitidine, entinostat and 
Nivolumab 28 day cycle X6  
and then nivolumab every 2 weeks 
until PD 
Group F 
SC azacitidine, entinostat and 
Nivolumab 28 day cycle X6  
and then nivolumab every 2 weeks 
until PD


 
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The law will not stop health insurance companies from using genetic information to decide whether to 
pay claims. The law also will not help you get other types of insurance (such as: life, disability, or long-
term care).  
 
How long will you be in the study? 
You will be in the study until the lung cancer has progressed. After you are finished with the study 
regimen, the study doctor will ask you to visit the office for follow-up exams for at least 3 months, and 
to continue to monitor your health by office visits or by telephone every 12 weeks for 5 years.  Keeping 
in touch with you and checking on your condition helps us look at the long-term effects of the study. 
 
CONSENT/AUTHORIZATION TO OBTAIN MEDICAL RECORDS AFTER STUDY 
REGIMEN DISCONTINUATION:  
(Mark choice with an “X”) 
 
  I agree to allow my medical records to be obtained for this study after study regimen 
discontinuation. 
 
  I do not agree to allow my medical records to be obtained for this study after study regimen 
discontinuation. 
 
Subject Initials: _________________ 
 
Date of Initials:  ____________________ 
 
CONSENT/AUTHORIZATION FOR USE OF YOUR TISSUE FOR FUTURE RESEARCH:  
(Mark choice with an “X”) 
 
  I agree to allow my tissue (specimen) to be kept for use in research to learn about, prevent, or treat 
cancer. 
 
  I do not agree to allow my tissue (specimen) to be kept for use in research to learn about, prevent, or 
treat cancer. 
 
Subject Initials: _________________ 
 
Date of Initials:  ____________________ 
 
  I agree to allow my tissue (specimen) to be kept for use in research to learn about, prevent, or treat 
other health problems (for example: diabetes, Alzheimer's disease, or heart disease). 
 
  I do not agree to allow my tissue (specimen) to be kept for use in research to learn about, prevent, or 
treat other health problems (for example: diabetes, Alzheimer's disease, or heart disease). 
 
Subject Initials: _________________ 
 
Date of Initials:  ____________________ 
 
 


 
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Future Contact 
We would like your permission to contact you about other studies that you may be eligible for in the 
future. 
 
Please check box and sign to indicate your choice below: 
 
YES     ________________________   
 
 
 
Signature of Participant 
 
 
 
 
 
 
NO     __________________  
 
 
 
Signature of Participant 
 
4. 
What are the risks or discomforts of the study? 
Risks to Azacitidine 
You may have side effects while you are in the study, but you will be carefully checked by the study 
doctor for any problems.  There may be risks or side effects of the study drug that are unknown at this 
time.  You should tell the study doctor/staff about anything that is bothering you or any side-effects you 
may have, even if you do not think they are related to the study drug.  
 
The most commonly reported side-effects with azacitidine treatment were the following: 
 
anemia (decrease in cells that carry oxygen) 
 
low number of white blood cells with or without fever  
 
Infection especially when white blood cell count is low 
 
Shortness of breath 
 
injection site reactions (inflammation in or damage to the tissue surrounding where an injection 
was given)   
 
Low blood counts may result in significant anemia, infection, bleeding, and feeling tired and weak. The 
dosage and treatment schedule of azacitidine will be adjusted if certain levels of toxicity are found in 
your laboratory results. The following is a list of the most medically significant or most common side 
effects reported in completed and ongoing studies considered to be related to azacitidine. In some cases, 
side effects can be serious, long-lasting, may never go away, or can cause death.  This is not a complete 
list of all side effects that may occur.  Other side effects not listed here may occur.  For more 
information about risks and side effects, please ask the study doctor.  The study doctor may give you 
medicines to help lessen the side effects.   
 
Very Common (≥10%)  
 Anemia which may require blood transfusion 
 Febrile neutropenia 
 Neutropenia  
 Low white bloods cell count (Leukopenia)  
 Low platelets in the blood (Thrombocytopenia) 
 Abdominal pain (including abdominal discomfort and upper abdominal pain) 
 Constipation 
 Diarrhea 
 Nausea  
 Vomiting  


 
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 Decreased muscle strength (Asthenia)  
 Chest pain 
 Fatigue  
 Injection site erythema  
 Injection site pain 
 Injection site reaction  
 Fever (Pyrexia) 
 Common cold (Nasopharyngitis)  
 Pneumonia (including bacterial, fungal and viral)  
 Weight loss 
 Decreased appetite  
 Low potassium (Hypokalemia)  
 Arthralgia  
 Musculoskeletal pain (includes back pain, bone pain and pain in extremity)  
 Muscle pain (Myalgia) 
 Dizziness 
 Headache 
 Insomnia  
 Shortness of breath (Dyspnea)  
 Nosebleed (Epistaxis)    
 Bruising (Ecchymosis)  
 Tiny round brown-purple spots due to bleeding under the skin (Petechiae) 
 Itching/Pruritus (includes pruritus generalized) 
 Rash  
 
Common (≥1%-≤10%)  
 Bone marrow failure  
 Low counts for red blood cell, white blood cell and platelets (Pancytopenia)  
 Red patch appearing in the white of the eye beneath the clear lining of the eye (Conjunctival 
hemorrhage)  
 Eye hemorrhage 
 Indigestion (Dyspepsia)   
 Gastrointestinal hemorrhage (includes mouth hemorrhage)  
 Bleeding gums/Gingival bleeding  
 Hemorrhoidal bleeding  
 Mouth sores (Stomatitis)   
 Catheter site hemorrhage 
 Chills  
 Injection site bruising, discoloration, hematoma, hemorrhage, induration, inflammation, nodule, 
pruritus, and rash  
 Malaise  
 Bacterial skin infection (Cellulitis)   
 Inflammation or infection of one or more small pouches in the digestive tract (Diverticulitis)   
 Serious infection (Neutropenic sepsis)  
 Oral fungal infection 
 Pain or irritation in the throat (Pharyngitis)   
 Respiratory tract infection (including bronchitis and upper respiratory tract infection)  


 
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 Stuffy nose (Rhinitis)   
 Sepsis (including bacterial, fungal and viral) 
 Sinus infection (Sinusitis)   
 Skin infection  
 Urinary tract infection  
 Blood creatinine increased 
 Dehydration 
 Muscle spasms  
 Stroke (Intracranial hemorrhage)   
 Lack of energy (Lethargy)   
 Excess sleepiness (Somnolence)   
 Loss of consciousness, fainting (Syncope)   
 Anxiety  
 Blood in urine (Hematuria)   
 Renal failure  
 Shortness of breath on exertion (Dyspnea exertional)  
 Laryngeal pain  
 Fluid buildup between the lungs and chest (Pleural effusion)   
 Hair loss (alopecia)  
 Reddening of the skin (Erythema)  
 Skin lesion  
 Hives (Urticaria)  
 Bruise (Hematoma)  
 Hypertension  
 Hypotension  
 Orthostatic hypotension  
 
Uncommon (≥0.1%- <1%) 
 Hypersensitivity  
 
Additional events not otherwise noted above include: Rapid death of cancer cells where the 
accumulating contents of dying cancer cells cause an imbalance in the chemistry of the body which can 
lead to kidney damage. 
 
Risks of Entinostat 
Common, Some May be Serious  
In 100 people receiving MS-275 (SNDX-275, entinostat), more than 20 may have: 
 Fatigue (tiredness) 
 Nausea 
 Decreased number of platelets in the blood that may cause you to bruise easily and for your blood 
to clot slowly after bleeding  
 Decrease in the number of blood cells that carry oxygen which may cause you to feel tired or short 
of breath  
 Vomiting 
 Decreased number of a type of white blood cell called neutrophils in the blood which may increase 
your risk of infection 
 Diarrhea 
 Decreased number of a type of white blood cell called leukocytes in the blood 


 
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 Feeling not hungry (decreased appetite) 
 Decreased level of phosphate in the blood which may cause muscle weakness or confusion  
 Low level of salt in blood that may cause you to feel tired, confused, or have headache, muscle 
cramps or upset stomach  
 Decreased level of a form of protein called albumin in the blood  
 Headache 
 anorexia 
 
Occasional, Some May be Serious 
In 100 people receiving MS-275 (SNDX-275, entinostat), from 10 to 20 may have: 
 Shortness of breath or difficulty breathing 
 Constipation 
 Increased level of glucose in the blood  
 Decreased level of calcium in the blood, which may cause you to feel, tired, or have muscle 
weakness or muscle cramps. 
 Decreased level of potassium in the blood, which may cause you to feel tired, weak, have 
constipation, or muscle cramps.  
 Swelling in the legs, feet and/or ankles  
 Increase in the level of alkaline phosphatase in your blood 
 Decreased number of lymphocytes in the blood, which may cause enlarged lymph nodes, cold 
like symptoms, painful joints or rash.  
 Pain in your abdomen 
 Fever 
 Cough  
 Muscle pain 
 Salty, metallic taste sensation  
 Indigestion 
 Dehydration 
 
Rare, and Serious 
In 100 people receiving MS-275 (SNDX-275, entinostat), 3 or fewer may have: 
 Fatigue (tiredness) 
 Shortness of breath or difficulty breathing 
 Feeling not hungry (decreased appetite) 
 Decreased number of a type of white blood cell called neutrophils in the blood which may 
increase your risk of infection 
 Dehydration 
 Decrease in the number of blood cells that carry oxygen which may cause you to feel tired or 
short of breath  
 Fever 
 Nausea 
 Pain in your abdomen 
 Diarrhea 
 Infection 
 Decreased number of platelets in the blood that may cause you to bruise easily and for your 
blood to clot slowly after bleeding 
 
 


 
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Risks of Nivolumab:  
Cancer regimens often have side effects, including some that are life-threatening.  There is the 
possibility of death occurring as a result of this study regimen and its side effects.  There may be 
additional unknown risks. 
 
If you experience side effects associated with the study drug, please contact your study doctor right 
away.  Your doctor may prescribe medications to treat the side effect(s), future dosing of the study drug 
may be delayed, or may be stopped permanently. Any significant new findings that develop during the 
course of the research and may relate to your willingness to continue participation will be provided to 
you. 
 
Nivolumab may cause the side effects listed below.  This information is based on data from subjects in 
other clinical trials with nivolumab.  In addition, there may be side effects that are not yet known that 
may occur.  You should tell your doctor or nurse about any side effects you experience. 
 
Most common side effects (≥ 10%) of nivolumab are: 
 Diarrhea  
 Fatigue  
 Itching  
 Rash 
 
Common side effects of Nivolumab may include (> 1% - < 10%): 
 Abdominal pain 
 Alkaline phosphatase increased: lab test result associated with liver or bone abnormalities 
 Allergic reaction/hypersensitivity 
 ALT increased: lab test result associated with abnormal liver function 
 Amylase increased: lab test result associated with pancreas inflammation 
 AST increased: lab test result associated with abnormal liver function 
 Bilirubin (liver function blood test) increased 
 Chills 
 Constipation 
 Cough 
 Creatinine increased: lab test result associated with decreased kidney function 
 Decreased appetite 
 Dizziness or vertigo (feeling off balance which can lead to dizziness) 
 Dry mouth 
 Dry skin 
 Fever 
 Headache 
 Increased blood sugar 
 Inflammation of the colon 
 Inflammation of the mouth 
 Infusion related reaction 
 Lipase increased: lab test result associated with pancreas inflammation 
 Loss of color (pigment) from areas of skin 
 Lung inflammation (pneumonitis - see details below) 
 Musculoskeletal pain 
 Nausea 


 
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 Redness (of the skin) 
 Shortness of breath 
 Sodium levels in the blood low 
 Swelling, including face, arms, and legs 
 Thyroid gland function decreased 
 Thyroid gland function increased 
 Thyroid stimulating hormone increased (lab test associated with abnormal thyroid function 
 Tingling, burning, numbness or weakness, possibly in arms, legs, hands and feet 
 Vomiting 
 
When additional side effects are noted, we will contact your study doctor to make sure these are being 
followed carefully. 
 
Uncommon side effects of nivolumab include (> 0.1% to < 1%): 
 Adrenal gland function decreased 
 Bronchitis 
 Dehydration 
 Diabetes 
 Double Vision 
 Dry eye 
 Erythema multiforme 
 Hair loss 
 Heart rate increased 
 Heart rhythm abnormal 
 High blood pressure 
 Hives 
 Inflammation of the eye 
 Inflammation of the kidney 
 Inflammation of the pancreas 
 Inflammation of the pituitary gland 
 Inflammation of the stomach 
 Inflammation of the thyroid gland 
 Joint pain or stiffness 
 Liver inflammation 
 Low blood pressure 
 Muscle inflammation 
 Pemphigoid: blistering of the skin or mouth caused by the immune system attacking healthy 
tissue  
 Pituitary gland function decreased 
 Psoriasis: characterized by patches of abnormal, scaly skin 
 Renal (kidney) failure or kidney injury 
 Respiratory failure 
 Upper respiratory tract infection 
 Vision blurred 
 
Rare side effects of nivolumab include: [≥ 1/10,000 to < 1/1,000 or > 0.01% to < 0.1%] 
 Anaphylactic reaction (severe allergic reaction) 


 
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 Cranial nerve disorder 
 Damage to the protective covering of the nerves in the brain and spinal cord 
 Diabetes complications resulting in excess blood acids 
 Disease caused by the body’s immune system attacking healthy organs 
 Drug induced liver injury 
 Guillain-Barre syndrome, an autoimmune disorder associated with progressive muscle 
weakness or paralysis  
 Inflammation of blood vessels 
 Inflammation of the brain, potentially life-threatening or fatal 
 Inflammation of the lining of the brain and spinal cord 
 Inflammation of the heart 
 Lung infiltrates, associated with infection or inflammation 
 Myasthenic syndrome (neurologic syndrome characterized by muscle weakness) including 
myasthenia gravis, a nerve disease that may cause weakness of eye, face, breathing, and 
swallowing muscles. 
 Polymyalgia rheumatica 
 Rhabdomyolysis: muscle fiber released into the blood stream which could damage your 
kidneys 
 Rosacea: acne-like skin condition resulting in redness of face 
 Rupture of the intestine/hole in the intestine 
 Sarcoidosis, a disease involving abnormal collections of inflammatory cells (granulomas) in 
organs such as lungs, skin, and lymph nodes 
 Stevens Johnson syndrome: inflammatory disorder of skin and mucous membranes, resulting 
in blistering and shedding of skin 
 Syndrome associated with fever, white blood cell activation and abnormal function 
(including destruction of other blood cells by certain white blood cells), low blood cell 
counts, rash, and enlargement of the spleen 
 Toxic epidermal necrolysis: a potentially fatal disease characterized by blistering and peeling 
of the top layer of skin resembling a severe burn 
 Histiocytic necrotizing lymphadenitis or Kikuchi lymphadenitis: disorder of the lymph nodes 
which causes the lymph nodes to become enlarged, inflamed and painful, commonly 
affecting lymph nodes of the neck and possibly associated with fever or muscle and joint 
pains. 
 Vogt Koyangi Harada syndrome: a disease that affects the pigmented tissue; this may affect 
the eye leading to swelling, pain and/or blurred vision, the ear leading to hearing loss, ringing 
in the ears and/or the skin leading to loss of skin color  
 Fulminant type 1 diabetes mellitus 
 Hepatic enzyme increased 
 Immune-mediated nephritis 
 Immune-mediated pneumonitis 
 
Lung Inflammation (pneumonitis):  It is possible that nivolumab may cause inflammation of the 
tissues of the lung.  This adverse effect has been reported in about 3% of people given nivolumab.  
While many people with x-ray or CT abnormalities have not developed any symptoms some people 
have developed mild to severe symptoms and 2 people have died as a result of their lung inflammation.  
Symptoms of lung inflammation may include difficulty breathing, pain or discomfort while breathing, 
chest pain, cough, shortness of breath, increased rate of breathing, fever, or fatigue.   
 


 
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Your study doctor and nurse will watch you closely for changes in your ability to breathe and for other 
signs or symptoms that might show you are developing this type of lung inflammation and will perform 
regular tests including physical exams, measurement of oxygen levels through non-invasive testing (i.e., 
pulse oximeter), blood tests, chest x-rays and/or CT scans. 
 
Please inform your study doctor or nurse AT ONCE if you experience any of the following: 
 Any new or increased shortness of breath; 
 Any new or increased chest pain; 
 Any new or increased pain/difficulty while breathing; 
 Any new or increased cough or any significant change in your type of cough; for 
example, any new or increased mucous or blood in your cough;  
 Any change in the amount of oxygen you require  
 Any fever, fatigue, or other symptoms that occur at the same time as any changes to 
your breathing or other lung symptoms.  
 Any new-onset rash 
 
If you start to develop symptoms, your study doctor will ask you to return to the clinic for additional 
tests, which could include a physical exam, measurement of oxygen levels, blood tests, chest x-rays, 
and/or CT scans.  You will be monitored very closely for changes to your overall lung symptoms, 
monitoring may require hospitalization.  You may also be seen by a doctor called a pulmonologist, who 
is an expert in how your lungs work. 
 
Kidney failure: It is possible that nivolumab can cause kidney damage due to inflammation to the 
structures within the kidney called nephrons.  This adverse event is very rare.  You should let your study 
doctor know if you notice any decreased amount of urine, difficulty urinating, sudden weight gain, 
increased tiredness, increased thirst or inability to tolerate liquids.  This may require treatment with 
steroids and holding the nivolumab. 
 
Opportunistic Infections due to Immunosuppression:  Some subjects may require prolonged 
treatment with high dose corticosteroids or alternative immunosuppressants for the treatment of 
nivolumab related adverse events.  If you start to develop symptoms, your study doctor will ask you to 
return to the clinic for additional tests, which could include a physical exam, measurement of oxygen 
levels, blood tests, chest x-rays, and/or CT scans. You will be monitored very closely for changes in 
your overall lung symptoms, monitoring may require hospitalization. You may require specific 
treatment in order to control infections. You may also be seen by a special doctor called a 
pulmonologist, who has special training to be an expert in how your lungs work. 
 
Solid Organ and Tissue Transplant 
Solid organ and tissue transplant rejection has been reported in patients who have previously undergone 
transplantation. Treatment with Nivolumab may increase the risk of rejection in solid organ or tissue 
transplant recipients. 
 
Rapid-onset and serve Graft Versus Host Disease (GVHD), some with fatal outcome, has been reported 
in patients who had undergone prior allogeneic hematopoietic stem cell transplantation (HSCT). 
 
Complications of allogeneic HSCT after treatment administered before allogeneic HSCT may be 
associated with an increased risk of transplant-related complications, including GVHD. Fatal cases have 
been reported in clinical studies. 
 


 
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Potential Risks - Study Procedures 
 
Blood Drawing 
Taking blood may cause discomfort, bleeding or bruising where the needle enters the body; in rare 
cases, it may result in fainting. There is a small risk of infection. If you feel dizzy, you should lie down 
for a few minutes to avoid hurting yourself if you fall.  
 
Confidentiality Loss  
There is the risk that information about you may become known to people outside this study. To protect 
against this, all study records will be identified with code numbers instead of your name. 
 
Despite the GINA protections and the best efforts of the research team, there may still be a risk if 
information about you were to become known to people outside of this study. 
 
CT Scans When you receive a CT scan, you will be exposed to radiation and you may be allergic to the 
contrast dye used during the study. The radiation exposure you will receive from participating in this 
study is equivalent to an exposure of 1.5 rems to your whole body (for each CT scan).  The scans may 
also need to be repeated every 8 weeks.  Naturally occurring radiation (cosmic radiation, radon, etc.) 
produces whole body radiation exposures of about 0.3 rem per year. Occupationally exposed individuals 
are permitted to receive whole body exposures of 5 rems per year. 
 
Other risks of the study: 
If you agree to have a biopsy as part of this study, there are risks associated with any biopsy.  The risks 
of the biopsy will depend on the site of the biopsy.  All biopsies will be done by physicians who 
specialize in collecting biopsies.  The risks of biopsy can include soreness and discomfort.  You may 
feel a stinging sensation each time the biopsy needle pierces the tumor. Serious bleeding and infection 
are very rare, but minor bleeding is common.  Tell you study doctor immediately if the bleeding is heavy 
or lasts a long time. Signs of infection include pain, swelling, redness, or fever.  Infection is the 
bloodstream (sepsis), causing high fever, is rare but serious.   If your lung is biopsied, there is a risk of 
collapsed lung. 
 
There may be side effects and discomforts that are not yet known. 
 
5. 
Are there risks related to pregnancy? 
Females:  Azacitidine can cause harm to an embryo or fetus if given to a pregnant woman.  You cannot 
take part in this study if you are pregnant or breast-feeding.  Because of the possible risks to an embryo 
or fetus, if you are a female who can become pregnant, you will be asked to take a pregnancy test within 
2 weeks prior to starting the study drug regimen and prior to each study drug cycle. 
 
If you decide to take part in this study, you must agree to use medical doctor-approved contraception 
(such as, oral, injectable, or implantable hormonal contraceptive; tubal ligation; intra-uterine device; 
barrier contraceptive with spermicide; or vasectomized partner) throughout the study, and for 3 months 
after your last dose of study drug.  If you become pregnant during the study you must tell the study 
doctor right away.  If this happens, your participation in this study will be discontinued.  If you become 
pregnant within 3 months after taking your last dose of study drug you must tell the study doctor right 
away.  The study sponsor will follow you and your pregnancy to birth and then for some time after birth.   
 
Males:  If you have a partner who is able to become pregnant, you must agree to use a medical doctor-
approved form of contraception throughout the study, and should avoid fathering a child for 3 months 


 
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after your last dose of study drug.  If your partner becomes pregnant during the study or within 3 months 
after you took your last dose of study drug, you must tell the study doctor right away. 
 
Reproductive Risks to nivolumab (BMS-936558) General Statement:  
You must not be pregnant or breastfeeding, and you should not become pregnant or breastfeed while 
you are taking the study drug. You must use an adequate method to avoid pregnancy for the duration of 
this study and for up to 23 weeks after the last dose of nivolumab (BMS-936558). Male subjects who are 
sexually active with a  woman who is able to become pregnant should also use an adequate method of 
birth control to avoid pregnancy  of their partner for up to 31 weeks after the last dose of study drug.  
You should immediately contact your study doctor if there is a change in your method to avoid 
pregnancy or if you start any prescription drug or other medication (including over-the-counter drugs 
and herbal supplements) not prescribed by the study doctor. 
 
Unforeseeable Risks 
There may be unknown risks to you, your embryo or fetus, or nursing infant if you are or become 
pregnant during this study or are breastfeeding during this study.  
 
MRI imaging is not known to cause risk to the developing fetus though there may be risks that are not 
known at this time. MRI contrast is known to cross the placenta and subsequent risks to the developing 
fetus are not known. 
 
Laboratory and Animal Reproductive Toxicology Findings 
While laboratory and animal studies have been conducted to determine possible risks, the results do not 
necessarily show what will happen when the drug is used in humans. 
 
No studies have been conducted to determine if nivolumab (BMS-936558) causes damage to genetic 
material (DNA). Because nivolumab (BMS-936558) is an antibody, the risk of damage to DNA is 
believed to be low. 
 
Laboratory and animal studies have not been conducted using nivolumab (BMS-936558) to determine if 
nivolumab (BMS-936558) may cause cancer, or to determine possible risks to reproduction or to an 
embryo or fetus. 
 
Human Pregnancy Outcomes 
No pregnancy outcomes have been documented in women or partners of subjects during administration 
of nivolumab (BMS-936558). 
 
Findings with Similar Drugs in the Class 
There is no data/information for similar drugs in this class that may be under evaluation in other clinical 
trials.   
 
6. 
Are there benefits to being in the study? 
You may or may not benefit from being in this study. We do not know whether you will benefit from 
being in the study.  Taking part in this study may help others in the future. 
 
7. 
What are your options if you do not want to be in the study? 
You do not have to join this study. If you do not join, your care at Johns Hopkins will not be affected.  
Alternative options may include other chemotherapy, radiation therapy, other investigational research 
studies, no treatment, or comfort care (palliative care, which is designed to reduce suffering). 


 
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Please ask any questions you may have and take as much time as you need to make your decision. 
 
8. 
Will it cost you anything to be in this study? 
The Study Drugs (azacitidine, entinostat, and nivolumab) will be provided at no charge to the Study 
subjects. 
 
You will receive a separate Insurance and Research Participant Financial Responsibility Information 
Sheet (Sheet). This Sheet will give you the following information: 
 The procedures, tests, drugs or devices that are part of this research and that will be paid for by 
the study (no cost to you).   
 The procedures, tests, drugs or devices that will be billed to you and/or your health insurer.  If 
you have health insurance, you will be responsible for any co-pays or deductibles not covered by 
your insurance.  
 
9. 
Will you be paid if you join this study? 
No.   
 
10. 
Can you leave the study early? 
 You can agree to be in the study now and change your mind later.  
 If you wish to stop the study at any time, please notify us right away.  
 Leaving this study early will not stop you from getting regular medical care.  
 If you leave the study early, Johns Hopkins may use or give out your health information that it 
already has if the information is needed for this study or any follow-up activities. 
 
11. 
Why might we take you out of the study early?  
You may be taken out of the study if: 
 Staying in the study would be harmful. 
 You need treatment not allowed in the study. 
 You fail to follow instructions. 
 You become pregnant. 
 The study is cancelled. 
 There may be other reasons to take you out of the study that we do not know at this time.  
 
If you are taken out of the study early, Johns Hopkins may use or give out your health information that it 
already has if the information is needed for this study or any follow-up activities. 
 
12. 
How will your privacy be protected? 
We have rules to protect information about you.  Federal and state laws and the federal medical Privacy 
Rule also protect your privacy.  By signing this form you provide your permission, called your 
“authorization,” for the use and disclosure of information protected by the Privacy Rule. 
 
The research team working on the study will collect information about you.  This includes things learned 
from the procedures described in this consent form.  They may also collect other information including 
your name, address, date of birth, and information from your medical records (which may include 
information about HIV status, drug, alcohol, or STD treatment, genetic test results, or mental health 
treatment). 
 


 
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The research team who may be a part of Johns Hopkins Health System, Johns Hopkins University or the 
Johns Hopkins Applied Physics Laboratory will know your identity and that you are in the research 
study.  Other people at Johns Hopkins, including your doctors, may also see or give out your 
information. We make this information available to your doctors for your safety.    
 
People outside of Johns Hopkins may need to see or receive your information for this study.  Examples 
include government agencies (such as the Food and Drug Administration), safety monitors, other sites in 
the study and companies that sponsor the study.  
 
If you are in a cancer study that receives federal funding, the National Cancer Institute (NCI) now 
requires that we report identifiable information (such as, zip code) about your participation.  You may 
contact the NCI if you have questions about how this information is used.  
 
We cannot do this study without your authorization to use and give out your information.  You do not 
have to give us this authorization.  If you do not, then you may not join this study. 
 
We will use and disclose your information only as described in this form and in our Notice of Privacy 
Practices; however, people outside Johns Hopkins who receive your information may not be covered by 
this promise or by the federal Privacy Rule.  We try to make sure that everyone who needs to see your 
information keeps it confidential – but we cannot guarantee that your information will not be re-
disclosed. 
 
The use and disclosure of your information has no time limit. You may revoke (cancel) your permission 
to use and disclose your information at any time by notifying the Principal Investigator of this study by 
phone or in writing.  If you contact the Principal Investigator by phone, you must follow-up with a 
written request that includes the study number and your contact information.  The Principal 
Investigator’s name, address, phone and fax information are on page one of this consent form.  
 
If you do cancel your authorization to use and disclose your information, your part in this study will end 
and no further information about you will be collected. Your revocation (cancellation) would not affect 
information already collected in the study, or information we disclosed before you wrote to the Principal 
Investigator to cancel your authorization. 
 
13. 
What is a Certificate of Confidentiality? 
Your study information is protected by a Certificate of Confidentiality. This Certificate allows us, in 
some cases, to refuse to give out your information even if requested using legal means. 
 
It does not protect information that we have to report by law, such as child abuse or some infectious 
diseases. The Certificate does not prevent us from disclosing your information if we learn of possible 
harm to yourself or others, or if you need medical help. 
 
Disclosures that you consent to in this document are not protected. This includes putting research data in 
the medical record or sharing research data for this study or future research. Disclosures that you make 
yourself are also not protected. 
 
14. 
What does a conflict of interest mean to you as a participant in this study?  
A researcher has a financial or other interest in this study, which may affect the researcher’s judgment 
when conducting the study.  
 


 
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In some situations, the results of the study may lead to a financial gain for the researcher(s) and/or Johns 
Hopkins.  This interest has been reviewed in accordance with Johns Hopkins' policies and approved with 
certain conditions 
 
If you have any questions about this financial interest, please talk to Dr. Julie Brahmer at 410-502-7159. 
This person is a member of the study team, but does not have a financial interest related to the study. 
You may also call the Office of Policy Coordination (410-361-8667) for more information. The Office 
of Policy Coordination reviews financial interests of investigators and/or Johns Hopkins. 
 
15. 
What treatment costs will be paid if you are injured in this study?  
Johns Hopkins does not have a program to pay you if you are hurt or have other bad results from being 
in the study.  However, medical care at Johns Hopkins is open to you as it is to all sick or injured people. 
 
 If you have health insurance:  The costs for any treatment or hospital care you receive as the result of 
a study-related injury will be billed to your health insurer. Any costs that are not paid for by your 
health insurer will be billed to you.  
 
 If you do not have health insurance:  You will be billed for the costs of any treatment or hospital care 
you receive as the result of a study-related injury. 
 
By signing this form you will not give up any rights you have to seek compensation for injury. 
 
16. 
What other things should you know about this research study? 
a. What is the Institutional Review Board (IRB) and how does it protect you? 
The Johns Hopkins Medicine IRB is made up of: 
 Doctors 
 Nurses 
 Ethicists 
 Non-scientists 
 and people from the local community.  
 
The IRB reviews human research studies. It protects the rights and welfare of the people taking part 
in those studies.  You may contact the IRB if you have questions about your rights as a participant or 
if you think you have not been treated fairly.  The IRB office number is 410-955-3008. You may 
also call this number for other questions, concerns or complaints about the research.  
 
When the Johns Hopkins School of Medicine Institutional Review Board (IRB) reviews a study at 
another site, that site (institution) is solely responsible for the safe conduct of the study and for 
following the protocol approved by the Johns Hopkins IRB. 
 
b. What do you do if you have questions about the study?    
Call the principal investigator, Dr. Brahmer at 410-502-7159.  If you wish, you may contact the 
principal investigator by letter or by fax.  The address and fax number are on page one of this 
consent form. If you cannot reach the principal investigator or wish to talk to someone else, call the 
IRB office at 410-955-3008.  
 
If you are taking part at Sibley Memorial Hospital call Dr. Benjamin Levy at 202-660-6500. 
 
 
 


 
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c. What should you do if you are injured or ill as a result of being in this study?  
If you have an urgent medical problem related to your participation in this study, call either Dr. 
Brahmer at 410-502-7159 or the medical oncologist on call at 410-955-4331. 
 
If you think you are injured or ill as a result of being in this study, call the principal investigator, Dr. 
Brahmer at 410-502-7159. 
 
If you are taking part at the Bayview Medical Center and you have an urgent medical problem 
related to your taking part in this study, call Dr. Julie Brahmer at 410-502-7159. You can also call 
the Doctor “On Call” from Bayview at 410-550-1711 if you have an urgent medical problem related 
to you taking part in this study. 
 
If you are taking part at Sibley Memorial Hospital and you have a medical problem related to 
your taking part in this study, call Dr. Benjamin Levy at 202-660-6500. If this doctor is not available, 
the operator will page the “on call physician.”  
 
d. What happens to Data and Biospecimens that are collected in the study?  
Johns Hopkins and our research partners work to understand and cure diseases. The biospecimens 
and/or data you provide are important to this effort. 
 
If you join this study, you should understand that you will not own your biospecimens or data, and 
should researchers use them to create a new product or idea, you will not benefit financially. 
 
With appropriate protections for privacy, Johns Hopkins may share your biospecimens and 
information with our research sponsors and partners.    
 
17. 
What is Genomic Data Sharing? 
Genomic studies, including genome-wide association studies (GWAS), examine genetic differences in 
the entire human genome (the complete set of human genes) and the association between these genetic 
differences and health conditions.   
 
As part of this study, we will collect information about your health and your individual genes.  
This information may be sent to a National Institutes of Health (NIH) designated data repository or other 
controlled access repositories (such as the European Genome Phenome Archive).  These repositories 
collect all kinds of genomic data from studies funded by the NIH or other funding mechanisms. .  
 
The aim of collecting this information is to look for genetic connections that: 
 May increase the likelihood of getting a certain disease (such as asthma, cancer, diabetes, heart 
disease or mental illness) or a condition (such as high blood pressure or obesity) 
 May affect the progress of a certain disease or condition 
 May affect treatments (medicines, etc.) that work for certain diseases in some people, but not in 
others.  
 
We will remove direct identifiers (such as your name) and instead code your information before sending 
it to the repository. NIH or other controlled access repositories will never get this code or the identifiers 
we have removed.  
 
The repository is a controlled-access repository.  Controlled-access data is only available to researchers 
and companies who apply to the repository. The NIH or other controlled access repositories will review 


 
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data requests for scientific merit and for methods to protect data and methods to ensure data will be used 
for the approved purpose.  We will not know what types of health-related research will be done with the 
data that are sent to the repository.  
 
18. 
Continuing Treatment beyond Disease Progression 
Accumulating evidence indicates a small number of subjects treated with the study drug, nivolumab, 
may derive clinical benefit despite initial growth of their tumor(s). 
 
You will be permitted to continue treatment with nivolumab beyond your initial tumor growth as long 
as: 
 You continue to meet all other study protocol eligibility criteria. 
 Your doctor has assessed the potential clinical benefit of continuing treatment. 
 You do not have rapid tumor growth or clinical deterioration. 
 The symptoms you are having from your disease are stable. 
 You can tolerate nivolumab. 
 Your treatment will not delay an immediate intervention of side effects due to tumor growth (e.g. 
Brain Metastases). 
 
If you continue treatment with nivolumab, all foreseeable risks or discomforts and other alternative 
treatment options as described in the main informed consent form are applicable. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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19. 
What does your signature on this consent form mean?   
Your signature on this form means that: You understand the information given to you in this form, you 
accept the provisions in the form and you agree to join the study. You will not give up any legal rights 
by signing this consent form.  
 
WE WILL GIVE YOU A COPY OF THIS SIGNED AND DATED CONSENT FORM 
 
 
________________________________________________________________________________________________________________________ 
Signature of Participant                                                                           (Print Name)                                                 
 
Date/Time  
 
 
 
________________________________________________________________________________________________________________________ 
Signature of Person Obtaining Consent                                                  (Print Name)                                               
 
Date/Time 
 
 
 
________________________________________________________________________________________________________________________ 
Signature of Witness to Consent Procedures                                         (Print Name) 
 
Date/Time 
 
(optional unless IRB or Sponsor required) 
 
 
I have received the separate Insurance and Research Participant Financial Responsibility Information Sheet.   
 
 
 
________________________________________________________________________________________________________________________ 
Signature of Participant, LAR or Parent/Guardian                               (Print Name)                                                         
 
Date/Time 
 
 
NOTE: A COPY OF THE SIGNED, DATED CONSENT FORM MUST BE KEPT BY THE PRINCIPAL INVESTIGATOR AND A COPY 
MUST BE GIVEN TO THE PARTICIPANT.  IF APPROPRIATE FOR THIS STUDY, A SCANNED COPY OF THE SIGNED CONSENT 
FORM SHOULD BE UPLOADED TO THE PARTICIPANT’S EPIC/EMR RECORD (UNLESS NO MEDICAL RECORD EXISTS OR 
WILL BE CREATED).  


 
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DOCUMENTATION OF PHYSICIAN/MID-LEVEL PROVIDER CONSENT PROCESS 
 
My signature below indicates that I have discussed the risks, benefits, and alternatives, answered any 
questions, and believe the participant is able to make an informed choice to join the study. 
 
 
 
________________________________________________________________________________________________________________________ 
Signature of Physician/Mid-Level Provider                     (Print Name)                                                                     
 
Date/Time   
 
 
 
 
________________________________________________________________________________________________________________________ 
Signature of Participant                                                    (Print Name)                                                                    
 
Date/Time     
 
 
 
________________________________________________________________________________________________________________________ 
Signature of Witness to Consent Procedures                   (Print Name) 
 
Date/Time 
 
(optional unless IRB or Sponsor required) 
 
 
NOTE: A COPY OF THE SIGNED, DATED CONSENT FORM MUST BE KEPT BY THE PRINCIPAL INVESTIGATOR AND A COPY 
MUST BE GIVEN TO THE PARTICIPANT.  IF APPROPRIATE FOR THIS STUDY, A SCANNED COPY OF THE SIGNED CONSENT 
FORM SHOULD BE UPLOADED TO THE PARTICIPANT’S EPIC/EMR RECORD (UNLESS NO MEDICAL RECORD EXISTS OR 
WILL BE CREATED).