Conditions: Renal Cell Carcinoma
Allocation: NA | Intervention model: SEQUENTIAL
Enrollment: 12
Healthy volunteers: no

Brief summary:
This is a Phase II, open-label, safety, pharmacodynamic and efficacy study of entinostat in combination with nivolumab and ipilimumab in subjects with metastatic renal cell carcinoma (RCC) who have progressed on ipilimumab + nivolumab regimen. Prior to Phase II, a safety lead-in will be conducted to establish the RP2D of entinostat when used in combination with ipilimumab + nivolumab. Subjects will initially be treated with the combination of oral entinostat and intravenous (IV) nivolumab plus ipilimumab. Entinostat will be dosed weekly, and nivolumab and ipilimumab will be dosed every 3 weeks, for a total of four, 3-week cycles. Following these first four cycles, entinostat will continue to be administered weekly in combination with nivolumab every 4 weeks or every 2 weeks based on subject tolerance (ipilimumab will be discontinued), with treatment continued until disease progression or prohibitive toxicity. Anti-tumor activity will be assessed by radiological tumor assessments conducted at baseline and every 6 weeks thereafter using RECIST version 1.1.

Detailed description:

Arms:
arm 1: Entinostat: 5mg, 3mg, or 2mg orally (PO) on D1, 8, 15 plus Nivolumab: 3 mg/kg IV D1 and Ipilimumab 1 mg/kg IV D1

Each cycle is 21 days

Interventions: intervention 1: Entinostat intervention 2: Nivolumab intervention 3: Ipilimumab
Intervention descriptions: intervention 1: RP2D will be determined with a 6 patient safety lead-in. Entinostat will continue until disease progression or prohibitive toxicity. Cycles 1-4 are 21 day cycles. Cycles 5 and subsequent are 28 day cycles. intervention 2: Nivolumab will continue until disease progression or prohibitive toxicity. Cycles 1-4 are 21 day cycles. Cycles 5 and subsequent are 28 day cycles. intervention 3: Ipilimumab will be administered in combination with entinostat and nivolumab for Cycles 1-4 only.

Protocol document:
Prot_SAP_001.pdf: 
Clinical Study Protocol 
HCRN GU17-326 
 
A Phase II Study to Evaluate the Safety, Pharmacodynamics, and Efficacy of Entinostat in 
Combination with Nivolumab plus Ipilimumab in Patients with Renal Cell Carcinoma Previously 
Treated with Nivolumab plus Ipilimumab or Nivolumab Alone 
 
 
Sponsor Investigator 
Roberto Pili, MD 
 
 
Co-Investigators 
Nabil Adra, MD 
Theodore Logan, MD 
Abhishek Tripathi, MD 
Michael B. Atkins, MD 
 
Statistician 
Hao Liu, PhD 
 
 
Trial Management Provided by  
Hoosier Cancer Research Network, Inc. 
7676 Interactive Way Suite 120 
Indianapolis, IN 46278 
 
 
Trial Supported by  
Bristol-Myers Squibb (CA209-9HU) 
Syndax Pharmaceuticals, Inc. 
 
 
Investigational New Drug (IND) Number: 139024 
 
 
 
Initial Protocol Version Date: 25MAY2018 
Protocol Amendment Version Date:  
10OCT2019 
05NOV2019 
18DEC2020 
07JUL2021 
 
 
 


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PROTOCOL SIGNATURE PAGE 
 
A Phase II Study to Evaluate the Safety, Pharmacodynamics, and Efficacy of  
Entinostat in Combination with Nivolumab plus Ipilimumab in Patients with Renal Cell 
Carcinoma Previously Treated with Nivolumab plus Ipilimumab or Nivolumab Alone 
 
 
VERSION DATE:  07JUL2021 
I confirm I have read this protocol, I understand it, and I will work according to this protocol and 
to the ethical principles stated in the latest version of the Declaration of Helsinki, the applicable 
guidelines for good clinical practices, whichever provides the greater protection of the 
individual. I will accept the monitor’s overseeing of the study. I will promptly submit the 
protocol to applicable institutional review board(s). 
 
 
 
 
 
 PLEASE COMPLETE AND EMAIL A COPY TO HCRN 
 
 
 
 
____________________________________ 
________________________ 
Signature of Site Investigator  
 
 
  
Date 
 
 
____________________________________ 
Site Investigator Name (printed) 
 
 
____________________________________ 
Site Investigator Title 
 
 
Name of Facility 
 
 
Location of Facility (City and State) 
____________________________________
____________________________________


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SYNOPSIS 
TITLE 
A Phase II Study to Evaluate the Safety, Pharmacodynamics, and 
Efficacy of Entinostat in Combination with Nivolumab plus 
Ipilimumab in Patients with Renal Cell Carcinoma Previously 
Treated with Nivolumab plus Ipilimumab or Nivolumab Alone
PHASE  
II 
OBJECTIVES 
Primary Objective  
 Establish the recommended Phase II dose (RP2D) during the 
Safety Lead-In and to assess efficacy via objective response 
rate (ORR) via RECIST 1.1 during the Phase II study of 
entinostat in combination with nivolumab and ipilimumab in 
patients with advanced renal cell carcinoma who have 
progressed on nivolumab + ipilimumab regimen or 
nivolumab alone. 
 
Secondary Objectives 
 Characterize safety of entinostat in combination with 
nivolumab and ipilimumab or nivolumab alone 
 Estimate ORR via Immune Related Response Criteria (irRC) 
 Estimate progression free survival (PFS) by RECIST 1.1 and 
irRC 
 Estimate overall survival (OS) 
 
Exploratory Objectives 
Characterize PD-L1/2, immune cell subsets, and miRs in tumor 
and/or blood and correlation with response. 
STUDY DESIGN 
Originally this study was intended as a Phase II, open-label, 
safety, pharmacodynamics and efficacy study of entinostat in 
combination with nivolumab and ipilimumab in subjects with 
advanced renal cell carcinoma (RCC) who have progressed on 
ipilimumab + nivolumab regimen or nivolumab alone. The 
clinical study was composed of a two-stage Phase II portion. The 
Safety Lead-in was to establish the Recommended Phase II Dose 
(RP2D) in subjects with metastatic RCC. Subjects will be treated 
with oral entinostat every 7 days continuously, and with 
nivolumab at a dose of 3 mg/kg mg IV every three weeks in 
combination with ipilimumab at a dose of 1 mg/kg every 3 
weeks  4 doses. Then, nivolumab 480 mg will be continued 
every 4 weeks. Subjects that do not tolerate this dosing strategy 
may receive nivolumab 240 mg IV every 2 weeks. Therefore, 
each cycle is every 21 days  4 cycles and then every 28 days 
thereafter. One dose level of entinostat will be tested in 6-patient 
cohorts with a dose de-escalation design (5 mg, 3 mg and 2 mg). 
The 5 mg dose represents 50% of the recommended entinostat 


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dose as single agent. The starting dose level of entinostat will be 
5 mg PO every 7 days. The first dose level will have a minimum 
of 6 patients treated. If ≤ 1 dose limiting toxicity (DLT) is 
observed the study was to move to the Phase II portion and the 6 
patients be included in Stage 1 of the Phase II portion.  If >1 
DLT is observed 6 additional patients will be treated at the lower 
dose level, etc. DLTs are defined in Section 5.2.1. Due to Funder 
decision, accrual will halt after enrollment of the safety lead in. 
This decision is a result of a shift in priorities at the Funder and 
not due to safety issues. Subjects currently on treatment will 
continue until criteria as defined in Section 6.2 is met.
KEY ELIGIBILITY 
CRITERIA  
See Section 3 for full 
eligibility criteria 
 Metastatic renal cell carcinoma with progressive disease on 
nivolumab + ipilimumab regimen or nivolumab alone.  
 Adequate hematologic, hepatic, and renal function is 
required. 
 ECOG performance status of 0-1.  
 Life expectancy of at least 6 months.
STATISTICAL 
CONSIDERATIONS 
For the Safety Lead-in, up to 18 subjects could be enrolled. 
Entinostat will be tested in 3 dose level cohorts (5 mg, 3 mg, or 
2 mg). The highest of 3 dose levels of entinostat (either 5mg, 3 
mg or 2mg) that results in ≤ 1 out of 6 subject rate of DLT will 
be the RP2D.  For Phase II, assuming a type I error rate of 5% 
and a power of 90% to compare an uninteresting objective 
response rate per RECIST 1.1 of 5% while declaring efficacy at 
20%, Simon's optimal two stage design enrolls 21 patients in the 
first stage (with 6 of the 21 from the Safety Lead-in RP2D 
cohort). If at most one response is seen, then the trial is 
terminated for futility. Otherwise, accrual continues to a total of 
41 patients. If at most 4 patients respond among the 41 patients, 
the combination would not warrant further investigation. If at 
least 5 patients respond, this therapy would warrant further 
investigation. The average sample size is 26.66 and the early 
termination probability is 71.70% for a drug with a response rate 
of 5%. All the calculations are based on the R function 
ph2simon from the package clinfun.  
TOTAL  
NUMBER OF 
SUBJECTS 
N = Due to Funder decision, accrual will halt after 
enrollment of the safety lead in. This decision is a result of a 
shift in priorities at the Funder and not due to safety issues. 
Subjects currently on treatment will continue until criteria as 
defined in Section 6.7 is met. 
ESTIMATED 
ENROLLMENT 
PERIOD 
12 months 


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ESTIMATED 
STUDY DURATION  
24 months 
 
 


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TABLE OF CONTENTS 
 
Schema ............................................................................................................................... 7 
1. 
Background and Rationale ..................................................................................... 8 
2. 
Study Objectives and Endpoints........................................................................... 11 
3. 
Eligibility Criteria .................................................................................................. 12 
4. 
Subject Registration............................................................................................... 15 
5. 
Treatment Plan....................................................................................................... 15 
6. 
Toxicities and Dose Delays/Dose Modifications .................................................. 24 
7. 
Study Calendar & Evaluations ............................................................................. 30 
8. 
Biospecimen Studies and Procedures ................................................................... 33 
9. 
Criteria for Disease Evaluation ............................................................................ 35 
10. Drug Information ................................................................................................... 41 
11. Adverse Events ....................................................................................................... 50 
12. Statistical Methods ................................................................................................. 54 
13. Trial Management ................................................................................................. 56 
14. Data Handling and Record Keeping .................................................................... 58 
15 
Ethics ....................................................................................................................... 59 
16 
References ............................................................................................................... 60 
11. APPENDICES ........................................................................................................ 61 
 
 
 
 
 


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SCHEMA 
Due to Funder decision, enrollment will halt after completion of accrual to the safety lead in 
group. This decision is a result of a shift in priorities at the Funder level and not due to safety 
issues. Subjects currently on treatment will continue until criteria for discontinuation is met. 
 
 
 
 
 
 
 
 
Stage II (n= 20) 
Metastatic renal cell carcinoma progressing on  
ipilimumab plus nivolumab or nivolumab alone (n=53) 
Cycles 1-4 (cycle =21 days) 

Entinostat PO at RP2D on D 1, 8, 15 

Nivolumab 3 mg/kg on Day 1 

Ipilimumab 1 mg/kg on Day 1 
≥ 2 responses observed 
≤ 1 response observed 
Terminate Study 
Treat until disease progression or 
unacceptable toxicity 
Cycle 5+ (cycle =28 days) 

Entinostat PO at RP2D on Day 1, 8, 15 and 22 

Nivolumab 480 mg on Day 1; subjects that do not 
tolerate every 4 week dosing of nivolumab may 
receive nivolumab 240 mg on Day 1 and Day 15 
Stage I (n= 21) 
Cycles 1-4 (cycle =21 days) 

Entinostat PO at RP2D on D 1, 8, 15 

Nivolumab 3 mg/kg on Day 1 

Ipilimumab 1 mg/kg on Day 1 
Cycle 5+ (cycle =28 days) 

Entinostat PO at RP2D on Day 1, 8, 15 and 22 

Nivolumab 480 mg on Day 1; subjects that do not 
tolerate every 4 week dosing of nivolumab may 
receive nivolumab 240 mg on Day 1 and Day 15
Safety lead-in (n= up to 18) 
Entinostat will be tested in 6-patient cohorts with a dose de-escalation design (5, 3, or 2 mg) 
Cycles 1-4 (cycle =21 days) 

Entinostat PO Day 1, 8, 15 

Nivolumab 3 mg/kg on Day 1 

Ipilimumab 1 mg/kg on Day 1 
Cycle 5+ (cycle =28 days) 

Entinostat PO Day 1, 8, 15 and 22 

Nivolumab 480 mg on Day 1; subjects that do not 
tolerate every 4 week dosing of nivolumab may 
receive nivolumab 240 mg on Day 1 and Day 15 


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1. 
BACKGROUND AND RATIONALE 
 
1.1 
Renal Cell Carcinoma 
Incidence of renal cell carcinoma (RCC) is reported 338,000 cases worldwide. RCC has a high 
mortality rate, causing an estimated 144,000 death each year.1 Approximately 30% of patients 
are known to have metastatic disease at the time of diagnosis and another one third develop 
metastatic disease throughout their disease course.2 
 
1.2 
Background on RCC Treatment 
VEGF receptor tyrosine kinase inhibitors represent the standard of care treatment for renal cell 
carcinoma (RCC). Blocking the PD-1/PD-L1 interaction is a novel immunotherapeutic approach 
for the treatment of solid tumors including RCC. PD-1 inhibition has shown single-agent activity 
in clear cell RCC patients whose disease has progressed following VEGF pathway inhibitor 
therapy and nivolumab is now approved in RCC previously treated with tyrosine kinase 
inhibitors.3 The combination of nivolumab with the CTLA inhibitor ipilimumab also has shown 
promising activity in RCC.4 The results from a phase III clinical trial are pending. Though this 
new class of agents represents a very promising therapeutic strategy only a fraction of patients 
seems to achieve durable responses. 
 
HDAC inhibitors induce acetylation of several histone and non-histone proteins, which 
contributes to a wide spectrum of anti-tumor and immunomodulatory activities of this class of 
agents. Pan HDAC inhibitors have shown either immunosuppressive or immunopromoting 
properties through modulating cytokine expression, affecting macrophage and dendritic cells, or 
regulating costimulation 
molecules. HDAC inhibitors 
have been also shown to induce 
activation of major 
histocompatibility complex 
(MHC) class I and class II 
proteins, and co-stimulatory 
molecules CD40, CD80 and 
CD86 (Figure 1).  
 
The results from the clinical 
trials with HDAC inhibitors in 
cutaneous T-cell lymphoma 
and large cell lymphoma 
patients that had led to the 
approval of vorinostat and 
romidepsin suggest that the 
antitumor activity these agents 
may be in part due to the 
modulation of the immune 
response. Our group has reported that the class I HDAC inhibitor entinostat suppresses 
regulatory T (Treg) cell function, enhances anti-tumor immune response and facilitates cytokine 
and vaccine immunotherapy in murine renal cell carcinoma and prostate cancer models, 
Figure 1: Class I HDAC inhibition decreases Treg function and may enhance 
immune response. Class I HDAC inhibitors induce acetylation of STAT3 by 
inhibiting HDAC3 or HDAC1, down regulates Foxp3 gene expression and 
suppresses Treg function. Class II HDAC inhibitor treatment induces Foxp3 
hyper acetylation by targeting HDAC7 and HDAC 9, which leads to 
stabilization of Foxp3 protein and enhanced Treg function. A pan inhibitor may 
target Class I HDACs at a low dose and impair Treg function. At a higher dose, 
the pan inhibitor may target also Class II HDAC and show a dominant Treg 
promoting effect (Shen L and Pili R Oncoimmunology 2013). 


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respectively.5,6 This Treg suppression action does not seem to occur through a depletion 
mechanism. On further analysis, we observed that entinostat suppresses Foxp3 gene expression 
in Treg cells and inhibits suppressive function of Treg cells. Entinostat acetylates STAT 3 
leading to down regulation of Foxp3. Our preclinical data have shown the synergistic effect of 
entinostat in combination with high dose interleukin 2 in the RENCA model. Our data also 
suggest that inhibitors able to modify class I HDACs (class I specific and pan) decrease Foxp3 
levels in Tregs in a dose- dependent manner, whereas class II specific HDAC inhibitors did not 
affect Foxp3 levels. This observation suggests that only class I HDAC inhibition results in Treg 
suppression.7,8  
 
Based on these results, we have completed a CTEP-sponsored phase I/II clinical trial with 
entinostat in combination with high dose interleukin 2 in patients with RCC (NCT01038778). 
The phase II results have been recently reported and suggest a biological and clinical activity of 
this combination.9 The primary objectives were to evaluate the safety, tolerability and efficacy of 
this combination strategy. The main eligibility criteria were clear cell histology, no prior 
treatments, and being fit to receive high dose IL-2. The phase I portion consisted of two dose 
levels of entinostat (3 and 5 mg, PO every14 days) and a fixed standard dose of IL-2 (600,000 
units/kg every 8 hrs). To test our hypothesis, the fixed sample size at the phase II dose level was 
36 with a type I/II error of 10%. 
If 11 or more of the pts have a 
response, the hypothesis that the 
response rate is ≤ 20% is 
rejected. Dose levels 1 and 2 
were completed without DLTs 
and 5 mg was the phase II 
recommended dose for 
entinostat. The most common 
transient grade 3/4 toxicities 
were hypophosphatemia (16%). 
lymphopenia (15%), and 
hypocalcemia (7%) We have 
enrolled 47 pts (44 at dose level 
2), and 37 have completed one 
cycle (84 days) treatment. Four 
patients were not evaluable. 13 
patients have achieved objective 
response (35%; 10 PR, 3 CR). 
To date the median PFS is 16.1 
months. Decreased Tregs have 
been observed following 
treatment. Preliminary data 
suggest an association of higher 
activated antigen presenting 
cells and monocityc myeloid suppressive cells (MDSCs) with objective responses. The 
preliminary results from this phase I/II suggest that entinostat may increase the therapeutic effect 
of high dose IL-2 by modulating immunosuppressive cells. 
Figure 2: Entinostat enhances the anti-tumor effect of PD1 inhibition in the 
RENCA model. Murine renal cell carcinoma cells (RENCA) expressing 
luciferase were orthotopically implanted. Bioluminescence was assessed at 
regular intervals (see schema). Tumor bearing animals were randomized to 
either vehicle, anti-PD1, entinostat or combination. Endpoint tumor weights 


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Based on these data we have tested the effect of entinostat in combination with PD1 inhibition in 
a murine model of renal cell carcinoma (RENCA). As shown in figure 2, entinostat enhanced the 
antitumor effect of anti PD1 antibody treatment. Preliminary data also show that entinostat may 
inhibit the immunosuppressive activity of MDSC. These data suggest that HDAC inhibition may 
synergize with immune checkpoint inhibitors.  
 
1.3 
Investigational Treatment 
 
1.3.1 Entinostat 
Entinostat (SNDX-275, also known as MS-275, ZK244894 and KHK2375) is a novel, potent, 
orally bioavailable, class I selective histone deacetylase inhibitor (HDACi) that was licensed by 
Syndax from Bayer Schering Pharma. Entinostat is a substituted pyridylcarbamate with a 
molecular weight of 376.4 and is classified as an antineoplastic agent. 
 
Entinostat increases the acetylation of histones and other nuclear and cytoplasmic proteins. 
Although the mechanisms of action are not entirely elucidated, ample evidence has demonstrated 
that entinostat alters chromatin structure of genes (epigenetic modulation) involved in 
malignancy to allow for re-expression of tumor suppressor genes, up-regulation of pro-apoptotic 
genes, down-regulation of cell-survival genes, and down-regulation of oncogenic signaling 
pathways. These events restore the ability of cells to undergo cell-cycle arrest, differentiation, 
and apoptosis, restore sensitivity to antineoplastic agents, and reverse malignant characteristics. 
 
1.3.2 Ipilimumab 
Ipilimumab is a fully human monoclonal IgG1κ that binds to the CTLA-4 antigen expressed on a 
subset of T cells from human and nonhuman primates. CTLA-4 is a negative regulator of T-cell 
activity. Ipilimumab is a mAb that binds to CTLA-4 and blocks the interaction of CTLA-4 with 
its ligands, CD80/CD86. Blockade of CTLA-4 has been shown to augment T-cell activation and 
proliferation, including the activation and proliferation of tumor-infiltrating T-effector cells. 
Inhibition of CTLA-4 signaling can also reduce Treg function, which may contribute to a general 
increase in T-cell responsiveness, including the anti-tumor response. Ipilimumab is currently 
FDA approved in the treatment of unresectable or metastatic melanoma. Ipilimumab is also 
under investigation for the treatment of subjects with other types of cancer. Studies are being 
sponsored by Bristol-Myers Squibb, with the US National Cancer Institute (NCI) and Mayo 
Clinic as additional sponsors.  
 
1.3.3 Nivolumab 
Nivolumab (also referred to as BMS-936558 or MDX1106) is a human monoclonal antibody 
(HuMAb; immunoglobulin G4 [IgG4]-S228P) that targets the programmed death-1 (PD-1) 
cluster of differentiation 279 (CD279) cell surface membrane receptor. PD-1 is a negative 
regulatory molecule expressed by activated T and B lymphocytes.* Binding of PD-1 to its 
ligands, programmed death–ligands 1 (PD-L1) and 2 (PD-L2), results in the down-regulation of 
lymphocyte activation. Inhibition of the interaction between PD-1 and its ligands promotes 
immune responses and antigen-specific T-cell responses to both foreign antigens as well as self-
antigens. Nivolumab is expressed in Chinese hamster ovary (CHO) cells and is produced using 
standard mammalian cell cultivation and chromatographic purification technologies. The clinical 
study product is a sterile solution for parenteral administration. 


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OPDIVO™ (nivolumab) is approved for use in multiple countries including the United States 
(US, Dec-2014), the European Union (EU, Jun-2015), and Japan (Jul-2014). 
 
*Clinical Study Report: Study No. CA209017. An Open-label Randomized Phase III Trial of BMS-936558 
(Nivolumab) versus Docetaxel in Previously Treated Advanced or Metastatic Squamous Cell Non-small Cell Lung 
Cancer (NSCLC). Bristol-Myers Squibb Company; 2015. Document Control No. 930086504. 
 
1.4 
Rationale 
Novel strategies to enhance the antitumor activity of immune-checkpoint inhibitors are under 
development. This study will assess the immunomodulatory activity of entinostat in patients who 
have progressed while receiving the immune-checkpoint inhibitors nivolumab and ipilimumab or 
nivolumab alone. The overall hypothesis is that entinostat will restore the immune response and 
antitumor effect induced by the PD1/CTLA inhibition by suppressing Treg and MDSC function. 
The schedule of entinostat is based on our previous experience with this agent. Based on our 
working hypothesis that low dose HDAC inhibitors will have a suppressive function on Tregs 
and MDSC but not on T effector cells, the starting dose of entinostat will be 5 mg weekly. 
 
2. 
STUDY OBJECTIVES AND ENDPOINTS 
 
2.1 
Objectives 
 
2.1.1 Primary Objectives 
Establish the recommended Phase II dose (RP2D) during the Safety Lead-In and to assess 
efficacy via objective response rate (ORR) via RECIST 1.1 during the Phase II study of 
entinostat in combination with nivolumab and ipilimumab in subjects with metastatic RCC who 
have progressed on nivolumab + ipilimumab regimen. 
 
2.1.2 Secondary Objectives 
 Characterize safety of entinostat in combination with nivolumab and ipilimumab  
 Estimate ORR via Immune Related Response Criteria (irRC) 
 Estimate progression free survival (PFS) via RECIST 1.1 and irRC 
 Estimate overall survival (OS) 
 
2.1.3 Correlative Objectives 
Characterize PD-L1/2, immune cell subsets, and miRNAs in tumor and/or blood and correlate 
with response. 
 
2.2 
Endpoints 
 
2.2.1 Primary Endpoint 
 ORR (rate of complete response (CR) + partial response (PR)) per RECIST v1.1  
 
2.2.2 Secondary Endpoints 
 Toxicity will be graded according to the National Cancer Institute’s Common 
Terminology Criteria for Adverse Events (NCI-CTCAE) version 4 
 ORR (rate of irCR + irPR) per irRC 


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 PFS per RECIST 1.1 is defined from day 1 of treatment until disease progression or death 
as a result of any cause, with progression defined per RECIST 1.1 
 PFS per irRC is defined from Day 1 of treatment until disease progression or death as a 
result of any cause, with progression defined per irRC 
 OS is defined from Day 1 of treatment until death as a result of any cause 
 
2.2.3 Correlative Endpoints 
 PD-L1/2 
 Immune cell subsets 
 miRNAs 
 
3. 
ELIGIBILITY CRITERIA 
 
3.1 
Inclusion Criteria 
Subject must meet all of the following applicable inclusion criteria to participate in this study: 
 
1. Written informed consent and HIPAA authorization for release of personal health 
information. NOTE:  HIPAA authorization may be included in the informed consent or 
obtained separately. 
 
2. Age ≥ 18 years at the time of consent. 
 
3. ECOG Performance Status of 0-1 within 28 days prior to registration. 
 
4. Histological or cytological evidence of renal cell carcinoma (initial diagnosis).  
 
5. Metastatic disease. 
 
6. Progressive disease on nivolumab + ipilimumab regimen or nivolumab alone. NOTE: 
Patients who have completed at least one dose of ipilimumab + nivolumab and progress 
or have completed the 4 doses of ipilimumab + nivolumab and progress during 
nivolumab monotherapy maintenance are eligible. Patients who have completed at least 
one dose of nivolumab monotherapy and have progressed are also eligible. Patients who 
discontinue prior ipilimumab + nivolumab or nivolumab monotherapy for toxicity are 
excluded.  
 
7. Target lesions according to RECIST v1.1 or non-target bone lesions assessed by bone 
scan or PET scan. 
 
8. A subject with prior brain metastasis may be considered if they have completed their 
treatment for brain metastasis at least 4 weeks prior to study registration, have been off 
corticosteroids for ≥ 4 weeks, and are asymptomatic. 
 
9. Prior cancer treatment (excluding nivolumab + ipilimumab or nivolumab alone) must be 
completed at least 28 days prior to start treatment and the subject must have recovered 
from all reversible acute toxic effects of the regimen (other than alopecia or neuropathy) 


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to ≤ Grade 1 or baseline. If subject underwent major surgery or radiation therapy of >30 
Gy, they must have recovered from the toxicity and/or complications from the 
intervention. 
 
10. Demonstrate adequate organ function as defined in the table below; all screening labs to 
be obtained within 28 days prior to registration. 
 
System 
Laboratory Value 
Hematological
Platelets
≥100 x 109/L
Absolute Neutrophil Count (ANC)
≥1.5 x 109/L
Hemoglobin (Hgb)
≥9 g/dL or ≥5.6 mmol/L
Renal
Creatinine OR 
Measured or calculated1 creatinine clearance 
(CrCl) (glomerular filtration rate [GFR] can 
also be used in place of CrCl) 
1 Creatinine clearance should be calculated 
per institutional standard
≤1.5 x the upper limit of normal (ULN) OR 
≥60 mL/min for subject with creatinine 
levels >1.5 x institutional ULN 
Hepatic
Bilirubin 
≤1.5 x ULN OR 
Direct bilirubin ≤ ULN for subjects with 
total bilirubin levels > 1.5 x ULN
Aspartate aminotransferase (AST) 
≤3 x ULN 
Alanine aminotransferase (ALT) 
≤3 x ULN  
Coagulation
International Normalized Ratio (INR) or 
Prothrombin Time (PT) 
Activated Partial Thromboplastin Time 
(aPTT)
≤ 1.5 × ULN unless subject is receiving 
anticoagulant therapy as long as 
PT/INR/PTT is within therapeutic range of 
intended use of anticoagulants
 
11. Women of childbearing potential (WOCBP) must have a negative serum pregnancy test 
during screening and a negative urine pregnancy test within 3 days prior to first dose of 
study drug. If the screening serum test is done within 3 days prior to receiving the first 
dose of study drug, a urine test is not required.  
 
12. Women of childbearing potential must be willing to abstain from heterosexual 
intercourse or to use an effective method of contraception from the time of informed 
consent until 5 months after the last dose of study drug.  
 
13. Men who are sexually active with WOCBP must use any contraceptive method with a 
failure rate of less than 1% per year. Men receiving study drugs and who are sexually 
active with WOCBP will be instructed to adhere to contraception for a period of 3 
months after the last dose of entinostat.  
 
14. As determined by the enrolling physician or protocol designee, ability of the subject to 
understand and comply with study procedures for the entire length of the study. 


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15. Life expectancy of at least 6 months per investigator discretion. 
 
3.2 
Exclusion Criteria 
Subjects meeting any of the criteria below may not participate in the study: 
1. History or current evidence of any condition, therapy, or laboratory abnormality that 
might confound the results of the study, interfere with the subject’s participation for the 
full duration of the study, or is not in the best interest of the subject to participate, in the 
opinion of the treating investigator, including, but not limited to: 
 Myocardial infarction or arterial thromboembolic events within 6 months prior to 
screening or severe or unstable angina, New York Heart Association (NYHA) 
Class III or IV disease, or a QTc interval > 470 msec. 
 Uncontrolled hypertension or diabetes mellitus. 
 Another known malignancy that is progressing or requires active treatment.  
 Any prior history of other cancer within the prior 5 years with the exception of 
adequately treated basal cell carcinoma or cervical intraepithelial neoplasia 
[CIN]/cervical carcinoma in situ or melanoma in situ). 
 Active infection requiring systemic therapy. 
 Known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis. 
 
2. Pregnant or breastfeeding. NOTE: breast milk cannot be stored for future use while the 
mother is being treated on study. 
 
3. Any contraindication to oral agents or significant nausea and vomiting, malabsorption, or 
significant small bowel resection that, in the opinion of the investigator, would preclude 
adequate absorption. 
 
4. Allergy to benzamide or inactive components of entinostat. 
 
5. Hypersensitivity to nivolumab, ipilimumab, or any of their excipients. 
 
6. Treatment with any investigational drug or device within 4 weeks prior to registration.  
 
7. Treatment with systemic steroids within 4 weeks prior to registration. NOTE: adrenal 
replacement doses of steroids (equivalent of prednisone 10mg daily) are permitted. 
 
8. Evidence of active autoimmune disease requiring systemic treatment within the past 90 
days or a documented history of clinically severe autoimmune disease, or a syndrome that 
requires systemic steroids or immunosuppressive agents. Subjects with vitiligo or 
resolved childhood asthma/atopy would be an exception to this rule. Subjects that require 
intermittent use of bronchodilators or local steroid injections would not be excluded from 
the study. Subjects with hypothyroidism stable on hormone replacement or Sjogren’s 
syndrome will not be excluded from the study. 
 
9. Interstitial lung disease or history of pneumonitis requiring treatment with 
corticosteroids. 


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10. Diagnosis of immunodeficiency; or is receiving chronic systemic corticosteroid therapy 
or other immunosuppressive therapy (excludes inhaled corticosteroids) within 4 weeks 
prior to registration. 
 
11. Known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies). Testing 
during screening is not required. 
 
12. Known active hepatitis B (e.g., hepatitis B surface antigen-reactive) or hepatitis C (e.g., 
hepatitis C virus ribonucleic acid [qualitative]). Subjects with past hepatitis B virus 
(HBV) infection or resolved HBV infection (defined as the presence of hepatitis B core 
antibody [HBc Ab] and absence of HBsAg) are eligible. HBV DNA test must be 
performed in these subjects prior to study treatment, and results must be negative to be 
eligible. Subjects with a history of hepatitis C must be tested for presence of hepatitis C 
virus (HCV) antibody. If HCV antibody positive, subjects will only be eligible if 
polymerase chain reaction is negative for HCV RNA. 
 
13. Has received a live vaccine within 30 days prior to planned start of study therapy. Note: 
Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are 
allowed; however, intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated 
vaccines, and are not allowed. 
 
4. 
SUBJECT REGISTRATION 
All subjects must be registered through HCRN’s electronic data capture (EDC) system. A subject 
is considered registered when an “On Study” date is entered into the EDC system. Subjects must 
be registered prior to starting protocol therapy.  
 
5. 
TREATMENT PLAN 
This is a Phase II, open-label, safety, pharmacodynamic and efficacy study of entinostat in 
combination with nivolumab and ipilimumab in subjects with metastatic RCC who have 
progressed on ipilimumab + nivolumab regimen or nivolumab alone. Prior to Phase II, a safety 
lead-in will be conducted to establish the RP2D of entinostat when used in combination with 
ipilimumab + nivolumab (see Section 5.1). Subjects will initially be treated with the combination 
of oral entinostat and intravenous (IV) nivolumab plus ipilimumab. Entinostat will be dosed 
weekly, and nivolumab and ipilimumab will be dosed every 3 weeks, for a total of four, 3-week 
cycles. Following these first four cycles, entinostat will continue to be administered weekly in 
combination with nivolumab every 4 weeks or every 2 weeks based on subject tolerance. 
Ipilimumab will be discontinued. Treatment continued until disease progression or prohibitive 
toxicity. Anti-tumor activity will be assessed by radiological tumor assessments conducted at 
baseline and every 6-8 weeks thereafter using RECIST version 1.1. 
 
Due to Funder decision, enrollment will halt after completion of accrual to the safety lead in 
group. This decision is a result of a shift in priorities at the Funder level and not due to safety 
issues. Subjects currently on treatment will continue until the criteria for treatment continuation 
as defined above is met.  
 
 
 


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5.1 
Study Treatment Administration 
 
5.1.1 Cycles 1-4 (cycle =21 days) 
Drug 
Dose 
Route 
Schedule1 
Cycle Length 
Entinostat 
5mg, 3mg, or 2mg 2
PO 
Days  
1, 8, 15
21 days 
Nivolumab 
3 mg/kg  
IV over 30 minutes 
Day 1 
Ipilimumab 
1 mg/kg 3 
IV over 30 minutes 
Day 1 
1 A window of ± 3 days may be applied to all study visits to accommodate observed holidays, 
inclement weather, scheduling conflicts etc. Date and time of each drug administration should be 
clearly documented in subject’s chart or on drug diary and in the electronic case report forms (eCRFs). 
2See Section 5.2 on the Safety Lead-In for determining the RP2D of entinostat 
3Use the subject’s actual (not ideal) body weight for dosing as per the American Society of Clinical 
Oncology (ASCO) guidelines on dosing of obese adult subjects. If a subject’s weight changes by more 
than 10% from Cycle 1 Day 1 the dose of nivolumab and ipilimumab should be recalculated.
 
5.1.2 Cycles 5+ (cycle = 28 days) 
Drug 
Route 
Dose 
Schedule1 
Cycle 
Length 
Entinostat 
PO 
RP2D 2 
Days 1, 8, 15 and 22 
28 days 
Nivolumab 3 
IV over 30 
minutes 
480 mg 
Day 1 
Subjects that do not tolerate every 4 week dosing 
240 mg 
Day 1 and 15 
1 A window of ± 3 days may be applied to all study visits to accommodate observed holidays, 
inclement weather, scheduling conflicts etc. Date and time of each drug administration should be 
clearly documented in subject’s chart or on drug diary and in the eCRFs. 
2 See Section 5.2 on the Safety Lead-In for determining the RP2D of entinostat 
3 See Section 5.4.2 for additional details regarding nivolumab administration during the maintenance 
period. Subjects will receive 480 mg on Day 1 of each cycle. Subjects that do not tolerate an every 4 
week dosing regimen may receive nivolumab 240 mg on Day 1 and Day 15 of each cycle.
 
5.2 
Safety Lead-In 
Entinostat in combination with fixed dose nivolumab and ipilimumab will be tested using a 3+3 
dose de-escalation design (5 mg, 3 mg and 2 mg). The starting dose level of entinostat will be 5 
mg PO every 7 days, which is 50% of the recommended entinostat dose when used as single 
agent. Dose limiting toxicities (DLTs) will be evaluated during the first two cycles (6 weeks) of 
treatment. Each dose level will have up to 6 patients treated.  
 
The trial will proceed in a 3+3 fashion. The study will recruit the first 3 patients starting at the 
highest dose level (5 mg). If there is 0 or 1 DLT, then the study will recruit additional 3 patients 
treated at that dose level. If ≤ 1 DLT is observed after 6 patients at this dose, that will be the 


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RP2D. If any time at this dose level, more than 1 DLT is observed, then the accrual to this dose 
level will be stopped, and the study will be de-escalated to the next dose level (3mg).   
 
This procedure is repeated at the second dose level cohort (3 mg).  At this dose level, the study 
will study 3 patients first. If there is 0 or 1 DLT, then the study will recruit additional 3 patients 
treated at that dose level. If ≤ 1 DLT is observed after 6 patients at this dose, that will be the 
RP2D. If any time at this dose level, more than 1 DLT is observed, then the accrual to this dose 
level will be stopped, and the study will be de-escalated to the next dose level (2 mg).   
 
Up to 6 patients will be enrolled and treated at the last dose level cohort (2 mg). At this dose 
level, the study will study 3 patients first. If there is 0 or 1 DLT, then the study will recruit 
additional 3 patients treated at that dose level. If ≤ 1 DLT is observed after 6 patients at this dose, 
that will be the RP2D. If any time at this dose level, more than 1 DLT is observed, then the 
accrual to this dose level will be stopped, and the study will be terminated and no RP2D can be 
reached.  
 
For the Safety Lead-in, up to 18 patients could be enrolled. The RP2D will be the highest of 
these 3 dose levels of entinostat that results in ≤ 1 out of 6 subjects experience a DLT. The 6 
subjects in the RP2D cohort will be included in Stage 1 of the Simon’s optimal two-stage Phase 
II study. 
  
5.2.1 Dose Limiting Toxicity (DLT) 
DLTs are defined as: 
 Prolonged (>1 week) Grade ≥ 3 anemia attributable to entinostat and/or nivolumab plus 
ipilimumab during the first 2 cycles (6 weeks) of the combination treatment. 
 Grade 3-4 febrile neutropenia  
 Grade 4 thrombocytopenia 
Grade 3 thrombocytopenia with hemorrhage 
 Grade 3-4 nonhematological toxicities attributable to entinostat and/or nivolumab plus 
ipilimumab during the first 2 cycles (6 weeks) of the combination treatment. Exceptions 
include: 
o Grade 3 fatigue < 7 days 
o Grade 3 nausea lasting < 72 hrs in patients who have not received adequate anti-
emetic therapy 
o Grade 3-4 vomiting lasting < 72 hrs in patients who have not received adequate 
anti-emetic therapy 
o Grade 3-4 diarrhea lasting < 72 hrs in patients who have not received adequate 
anti-diarrheal therapy 
o Asymptomatic laboratory abnormalities lasting < 72 hrs 
o Asymptomatic elevations in AST or ALT lasting < 7 days. 
 AST or ALT > 3 x ULN in patients in whom these abnormalities cannot be attributed to 
another, non-drug related cause 
 Total bilirubin > 2 x ULN in patients whom this abnormality cannot be attributed to 
another, non-drug related cause 
 


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5.3 
Phase II 
Due to Funder decision, enrollment will halt after completion of accrual to the safety lead in 
group and not proceed to Phase II. This decision is a result of a shift in priorities at the Funder 
level and not due to safety issues. Subjects currently on treatment will continue until the criteria 
for treatment continuation as defined above is met. 
 
The six subjects treated at the RP2D of entinostat from the Safety Lead-in would have been 
rolled over into Stage 1 of the Phase II portion of the study, and an additional 15 subjects would 
have been enrolled. If at most one response is seen within Stage 1, then the trial would have been 
terminated for futility. Otherwise, accrual would have continued to a total of 41 subjects treated 
at the RP2D. Pre-medication Subjects do not require routine pre-medication prior to each 
treatment. However, local institutional standards may be followed, at the discretion of the 
investigator.  
 
See Section 5.6.1 for recommended premedication in subjects who experience infusion related 
reaction (IRR), allergic reaction or bronchospasm associated with nivolumab and/or ipilimumab. 
 
5.4 
Study Drug(s) Administration 
 
5.4.1 Entinostat 
Entinostat (5mg, 3mg, or 2 mg) will be administered orally every 7 days. Treatment will 
continue until disease progression in the absence of prohibitive toxicities. 
 
Entinostat is to be taken on an empty stomach, at least 2 hours after a meal and at least 1 hour 
before the next meal. Entinostat tablets should not be split, crushed, or chewed. If entinostat is 
vomited, dosing should not be re-administered but instead the dose should be skipped. Subjects 
should record the emesis and the skipped dose in their drug diary. If an entinostat dose is missed, 
it may be taken up to 48 hours after the scheduled dosing time. If it is not taken within the 48 
hour window, the dose should not be taken and should be counted as a missed dose. The subject 
should take the next scheduled dose per protocol and record the missed dose in their drug diary.  
 
5.4.1.1 Entinostat Compliance 
Subjects will complete a diary to document their drug compliance. They will be instructed to 
return all unused drugs (partially used and empty containers) and their diary at each clinic visit. 
Site staff will perform accountability of the returned drug, assess subject compliance, and 
educate the subject on the directions for self-medication. 
 
5.4.2 Nivolumab 
Nivolumab 3mg/kg will be administered as a 30 minute IV infusion on Day 1 of each 21 day 
cycle for 4 cycles. During maintenance, nivolumab will be administered at 480 mg IV on Day 1 
of each 28 day cycle. Subjects that do not tolerate an every 4 week dosing regimen may receive 
nivolumab 240 mg IV on Day 1 and Day 15 of each 28 day cycle. The decision to change the 
dosing regimen is at the site investigator’s discretion. If a subject transitions to an every 2 week 
dosing regimen that subject will remain on that dosing regimen for the remainder of their 
treatment. See Section 5.6.1 for management of any infusion reaction that occurs with 
nivolumab. Sites should make every effort to target infusion timing as close to 30 minutes as 


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possible. However, given the variability of infusion pumps from site to site, a window of + 10/-5 
minutes is acceptable. Treatment will continue in the absence of prohibitive toxicities or disease 
progression. 
 
5.4.3 Ipilimumab 
Ipilimumab 1mg/kg will be administered as a 30 minute IV infusion on Day 1 of each 21 day 
cycle for 4 cycles. See Section 5.6.1 for management of any infusion reaction that occurs with 
ipilimumab. 
 
Sites should make every effort to target infusion timing as close to 30 minutes as possible. 
However, given the variability of infusion pumps from site to site, a window of ± 10/-5 minutes 
is acceptable. Treatment will continue for up to 4 cycles, in the absence of prohibitive toxicities 
or disease progression. 
 
Nivolumab will be given first, followed by 30 minutes of monitoring, and then ipilimumab given 
second, followed by 30 minutes of monitoring. If the subject does not have an infusion reaction 
during the first cycle, the post-ipilimumab monitoring may be discontinued for subsequent cycles 
at the discretion of the treating physician. However, monitoring between the nivolumab/ 
ipilimumab infusions will continue throughout all 4 cycles.  
 
5.5 
Concomitant Medications 
All concomitant medications received within 28 days before the first dose of trial treatment and 
30 days after the last dose of trial treatment should be recorded. Subjects who are still being 
followed for a serious adverse events (SAE) will have SAE-specific concomitant medications 
recorded until resolution of the SAE. 
 
5.5.1 Allowed Concomitant Medications 
All treatments that the site investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the site investigator in keeping with the community standards of 
medical care. All concomitant medications will be recorded on the eCRF including all 
prescription, over-the-counter (OTC), herbal supplements, and IV medications and fluids. If 
changes occur during the trial period, documentation of drug dosage, frequency, route, and date 
may also be included on the eCRF. Use of bisphosphonates during study treatment is at site 
investigator’s discretion. 
 
5.5.2 Prohibited Concomitant Medications 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial. If there is a clinical indication for one of these or other medications or 
vaccinations specifically prohibited during the trial, discontinuation from trial therapy or 
vaccination may be required. The site investigator should discuss any questions regarding this 
with the sponsor-investigator via the HCRN project manager. The final decision on any 
supportive therapy or vaccination rests with the site investigator and/or the subject's primary 
physician. There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
The following medications are excluded while the subject is receiving study drugs: 
 Any other HDAC inhibitor, including valproic acid 
 DNA methyltransferase inhibitors 


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 Any additional anticancer agents, such as chemotherapy, immunotherapy, targeted 
therapy, biological response modifiers, or endocrine therapy, will not be allowed, even if 
utilized as treatment of non-cancer indications. 
 Any therapeutic investigational agents 
 Radiation therapy 
Note: Radiation therapy to a symptomatic solitary lesion or to the brain may be 
considered on an exceptional case-by-case basis after consultation with Sponsor 
Investigator. The subject must have clear measurable disease outside the radiated field. 
Administration of palliative radiation therapy will be considered clinical progression. 
 Traditional herbal medicines; these therapies are not fully studied and their use may 
result in unanticipated drug-drug interactions that may cause or confound the assessment 
of toxicity  
 Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial. Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, varicella/zoster, chicken pox, yellow fever, rabies, 
BCG, and typhoid (oral) vaccine. Seasonal influenza vaccines for injection are generally 
killed virus vaccines and are allowed; however intranasal influenza vaccines (e.g. Flu-
Mist®) are live attenuated vaccines, and are not allowed. 
 Systemic glucocorticoids (>10 mg prednisone equivalent) for any purpose other than to 
modulate symptoms from an event of clinical interest of suspected immunologic etiology. 
Brief, limited use of systemic corticosteroids (≤7 days) are permitted where such use is 
considered standard of care (e.g. as premedication for contrast allergy or for COPD 
exacerbation). Inhaled or topical steroids, and adrenal replacement doses of steroids (for 
example prednisone 10mg daily) are permitted while on study. 
 
5.5.3 Recommendations for Medications to be Avoided 
 Sensitive substrates of CYP1A2, CYP2C8, CYP3A with a narrow therapeutic window 
(see Appendix 1) 
 Drugs that are known to inhibit or induce P-gp (see Appendix 1) 
 
5.6 
Supportive Care 
Subjects should receive appropriate supportive care measures as deemed necessary by the site 
investigator.  
 
Suggested supportive care measures for the management of adverse events (AEs) with potential 
immunologic etiology are outlined below. Where appropriate, these guidelines include the use of 
oral or intravenous treatment with corticosteroids as well as additional anti-inflammatory agents 
if symptoms do not improve with administration of corticosteroids. Note that several courses of 
steroid tapering may be necessary as symptoms may worsen when the steroid dose is decreased. 
For each disorder, attempts should be made to rule out other causes such as metastatic disease or 
bacterial or viral infection, which might require additional supportive care. The treatment 
guidelines are intended to be applied when the investigator determines the events to be related to 
nivolumab or ipilimumab.  
 


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5.6.1 Suggested supportive care measures for the management of AEs that are related to 
nivolumab or ipilimumab 
Immuno-oncology (I-O) agents are associated with AEs that can differ in severity and duration 
than AEs caused by other therapeutic classes. Nivolumab and ipilimumab are considered 
immuno-oncology agents in this protocol. Early recognition and management of AEs associated 
with immuno-oncology agents may mitigate severe toxicity. Management algorithms have been 
developed to assist investigators in assessing and managing the following groups of AEs: 
Gastrointestinal, Renal, Pulmonary, Hepatic, Endocrinopathies, Skin, Neurological. 
 
For subjects expected to require more than 4 weeks of corticosteroids or other 
immunosuppressants to manage an AE, consider recommendations provided in the algorithms. 
These algorithms are found in Appendix 2. The guidance provided in these algorithms should not 
replace the site Investigator’s medical judgment but should complement it. 
 
Subjects on IV steroids may be switched to an equivalent dose of oral corticosteroids (e.g. 
prednisone) at start of tapering or earlier, once sustained clinical improvement is observed. 
Lower bioavailability of oral corticosteroids should be taken into account when switching to the 
equivalent dose of oral corticosteroids.  
 
Subjects who are started on steroids for management of an immune-related event should not 
resume immunotherapy until steroids have been tapered to ≤ prednisone 10mg daily or an 
equivalent dose of an alternative corticosteroid.  
 
Management of Infusion Reactions:  Acute infusion reactions (which can include cytokine 
release syndrome, angioedema, or anaphylaxis) are different from allergic/hypersensitive 
reactions, although some of the manifestations are common to both AEs. The table below shows 
treatment guidelines for subjects who experience an infusion reaction associated with 
administration of nivolumab or ipilimumab. 
 
Management of Infusion Related Reaction (IRR), Allergic Reaction, Hypersensitivity 
reaction or Bronchospasm from Nivolumab or Ipilimumab 
Description 
Action 
CTCAE Grade 1 IRR, 
allergic reaction or 
bronchospasm  
Remain at bedside and monitor subject until recovery from symptoms. 
For subsequent infusions, it is recommended that diphenhydramine 50 
mg (or equivalent) and/or paracetamol (acetaminophen) 325 to 1000 mg 
should be administered at least 30 minutes prior to subsequent infusions 
of nivolumab or ipilimumab. If necessary, corticosteroids (recommended 
dose: up to 25 mg of IV hydrocortisone or equivalent) may be used.
CTCAE Grade 2 IRR, 
allergic reaction or 
bronchospasm  
Stop the infusion, begin an IV infusion of normal saline, and treat the 
subject with diphenhydramine 50 mg IV (or equivalent) and/or 
paracetamol 325 to 1000 mg (acetaminophen); remain at bedside and 
monitor subject until resolution of symptoms. Corticosteroid or 
bronchodilator therapy may also be administered as appropriate. If the 
infusion is interrupted, then restart the infusion at 50% of the original 
infusion rate when symptoms resolve; if no further complications ensue 
after 30 minutes, the rate may be increased to 100% of the original 
infusion rate. Monitor subject closely. If symptoms recur, then no further 


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nivolumab will be administered at that visit. Administer 
diphenhydramine 50 mg IV, and remain at bedside and monitor the 
subject until resolution of symptoms. The amount of study drug infused 
must be recorded on the eCRF. For subsequent infusions, it is 
recommended that diphenhydramine 50 mg (or equivalent) and/or 
paracetamol (acetaminophen) 325 to 1000 mg should be administered at 
least 30 minutes prior to subsequent infusions of nivolumab or 
ipilimumab. If necessary, corticosteroids (recommended dose: up to 25 
mg of IV hydrocortisone or equivalent) may be used.
CTCAE Grade 3 or 4 
IRR, allergic reaction, 
bronchospasm or 
hypersensitivity reaction1  
Immediately discontinue infusion of nivolumab. Begin an IV infusion of 
normal saline, and treat the subject as follows. Recommend 
bronchodilators, epinephrine 0.2 to 1 mg of a 1:1,000 solution for 
subcutaneous administration or 0.1 to 0.25 mg of a 1:10,000 solution 
injected slowly for IV administration, and/or diphenhydramine 50 mg IV 
with methylprednisolone 100 mg IV (or equivalent), as needed. Subject 
should be monitored until the investigator is comfortable that the 
symptoms will not recur. Nivolumab or ipilimumab will be permanently 
discontinued. Investigators should follow their institutional guidelines 
for the treatment of anaphylaxis. Remain at bedside and monitor subject 
until recovery from symptoms. In the case of late-occurring 
hypersensitivity symptoms (eg, appearance of a localized or generalized 
pruritis within 1 week after treatment), symptomatic treatment may be 
given (eg, oral antihistamine, or corticosteroids).
1Hypersensitivity reactions included in CTCAEv4 include anaphylaxis, Stevens-Johnson syndrome and 
toxic epidermal necrolysis; in the case of late-occurring hypersensitivity symptoms (e.g., appearance of 
a localized or generalized pruritis within 1 week after treatment), symptomatic treatment may be given 
(e.g., oral antihistamine, or corticosteroids).
 
5.7 
Contraception 
Women of childbearing potential are defined as any female who has experienced menarche and 
who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or who is 
not postmenopausal. Menopause is defined clinically as 12 months of amenorrhea in a woman 
over 45 in the absence of other biological or physiological causes. In addition, women under the 
age of 62 must have a documented serum follicle stimulating hormone (FSH) level less than 40 
mIU/mL. Women of childbearing potential must be willing to abstain from heterosexual 
intercourse or to use an effective method of contraception from the time of informed consent 
until 5 months after the last dose of study drug. This timeframe is applicable to breast-feeding as 
well.  
 
Men who are sexually active with WOCBP must use any contraceptive method with a failure 
rate of less than 1% per year (i.e., a highly effective contraceptive method). Men receiving study 
drug and who are sexually active with WOCBP will be instructed to adhere to contraception for a 
period of 3 months after the last dose of entinostat. This timeframe is applicable to sperm 
donation. 
 
Subjects should be informed that taking the study medication may involve unknown risks to the 
fetus (unborn baby) if pregnancy were to occur during the study. In order to participate in the 
study they must adhere to the contraception requirements for the duration of the study and during 


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the follow-up period. If there is any question that a subject will not reliably comply with the 
requirements for contraception, that subject should not be entered into the study. 
 
5.7.1 Highly Effective Methods of Contraception 
 Male condoms with spermicide 
 Hormonal methods of contraception including combined oral contraceptive pills, vaginal 
ring, injectables, implants and intrauterine devices (IUDs) such as Mirena by WOCBP 
subject or male subject’s WOCBP partner. Female partners of male subjects participating 
in the study may use hormone based contraceptives as one of the acceptable methods of 
contraception since they will not be receiving study drug 
 Nonhormonal IUDs, such as ParaGard 
 Tubal ligation  
 Vasectomy 
 Complete Abstinence: Complete abstinence is defined as complete avoidance of 
heterosexual intercourse and is an acceptable form of contraception for all study drugs. 
Subjects who choose complete abstinence are not required to use a second method of 
contraception. Acceptable alternate methods of highly effective contraception must be 
discussed in the event that the subject chooses to forego complete abstinence. 
 
5.7.2 Less Effective Methods of Contraception 
 Diaphragm with spermicide 
 Cervical cap with spermicide 
 Vaginal sponge 
 Male Condom* without spermicide  
 Progestin only pills by WOCBP subject or male subject’s WOCBP partner  
 Female Condom*. 
* A male and female condom must not be used together 
 
5.8 
Use in Pregnancy 
If a subject becomes pregnant while on treatment, the subject will immediately be removed from 
the study. The site will contact the subject at least monthly and document the subject’s status 
until the pregnancy has been completed or terminated. The outcome of the pregnancy will be 
reported to HCRN within 24 hours of discovery of event and HCRN will notify the sponsor-
investigator, Bristol-Myers Squibb (BMS) and Syndax within 24 hours if the outcome is a 
serious adverse experience (e.g., death, abortion, congenital anomaly, or other disabling or life-
threatening complication to the mother or newborn). The site investigator will make every effort 
to obtain permission to follow the outcome of the pregnancy and report the condition of the fetus 
or newborn to HCRN who will report to BMS and Syndax.  If a male subject impregnates his 
female partner the study personnel at the site must be informed immediately and the pregnancy 
reported to HCRN who will report the event to BMS and Syndax and follow as described above. 
 
 
 


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6. 
TOXICITIES AND DOSE DELAYS/DOSE MODIFICATIONS 
The NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4 will be used to 
grade AEs.  
 
Subjects enrolled in this study will be evaluated clinically and with standard laboratory tests 
before and at regular intervals during their participation in this study as specified in Study 
Calendar & Evaluations. 
 
Subjects will be evaluated for AEs (all grades), SAEs, and AEs requiring study drug interruption 
or discontinuation as specified in Study Calendar & Evaluations.  
  
6.1 
Dose Delays/Dose Modifications 
All dose modifications should be based on the AE requiring the greatest modification and should 
be properly documented in source documents. Investigators may take a more conservative 
approach than the guidelines outlined below based on clinical judgment that is in the best interest 
of the subject. NOTE: if one or more study drugs are permanently discontinued, subjects may 
continue with the remaining drugs per protocol at the discretion of the treating physician if the 
subject is receiving clinical benefit. 
 
For subjects with immune-related adverse events (irAEs), if the management guidelines suggest 
delay or discontinuation, both nivolumab and ipilimumab should be held or discontinued. In the 
event that ipilimumab must be permanently discontinued due to an AE which can be directly 
attributed to ipilimumab (e.g. an infusion reaction), nivolumab may be continued per protocol at 
the discretion of the treating physician.  
 
6.1.1 Entinostat 
The dose levels used for dose modifications of entinostat will be 5, 3 or 2 mg PO QW, with the 
chosen dose based on the starting dose. If a dose below 2mg PO QW is required for entinostat, 
entinostat must be permanently discontinued, and the subject followed-up per protocol. If a dose 
of entinostat is held for toxicity and cannot be resumed within 48 hours, the dose will not be 
made up, and the subject will continue to follow the standard dosing schedule. If the dose of 
entinostat is held for toxicity and can be resumed within 48 hours, the dose will be given, and the 
subject will continue to follow the standard dosing schedule (i.e., the next dose will be given on 
time). 
 
 
 


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Management of toxicities that are at least possibly related to entinostat will be managed as 
follows: 
 
Non-hematologic Toxicity 
Toxicity 
Entinostat Dose Modifications 
Grade 4 
Administer symptomatic remedies/start prophylaxis. Permanently discontinue 
drug
Grade 3 
Administer symptomatic remedies/ start prophylaxis. Hold dose until recovery to 
Grade 1 or baseline under the following directions:  
1. If recovered within 1 week, resume study drug at prior dose. If not recovered 
within 1 week, continue to hold dose.  
2. If recovered within 2-4 weeks, resume study drug as follows:  
a. If receiving 5 mg, restart study drug at 3 mg  
b. If receiving 3 mg, restart study drug at 2 mg  
c. If receiving 2 mg, permanently discontinue study drug  
If not recovered within 4 weeks, permanently discontinue study drug. 
Recurrence of the 
same ≥ Grade 3 
toxicity despite 
dose reduction 
If the same ≥Grade 3 event recurs: 
1. Administer symptomatic remedies/ start prophylaxis. Hold1 dose until 
recovery to Grade 1 or baseline. 
2. If recovered within 2 weeks, resume study drug as follows: 
a. If receiving 5 mg, restart study drug at 3 mg 
b. If receiving 3 mg, restart study drug at 2 mg 
c. If receiving 2 mg, permanently discontinue study drug 
3. If the same ≥Grade 3 event recurs (i.e., third occurrence) despite entinostat 
dose reduction to 2 mg, as described above, permanently discontinue study 
drug. 
≤ Grade 2 
Administer symptomatic remedies / start prophylaxis. 
Dosing of study drug may be interrupted (held) 1 at the Investigator’s discretion. 
1. If dose is held for 4 consecutive weeks, permanently discontinue study drug. 
2. If toxicity resolves, resume entinostat at the original dose. 
1If greater than 50% of doses are missed during any 6 week period, discontinue from study drug 
treatment.
 
 


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Hematologic Toxicity 
Toxicity 
Entinostat Dose Modifications 
≥Grade 3 
neutropenia, ≥Grade 
3 febrile 
neutropenia, ≥Grade 
3 uncomplicated 
thrombocytopenia, 
or Grade 2 
complicated 
thrombocytopenia 
Administer symptomatic remedies/start prophylaxis. 
Hold dose1 until recovery to Grade 1 or study baseline under the following 
direction:  
1. If not recovered by next scheduled dose, skip the dose. If recovered by 
next scheduled dose, resume study drug at prior dose. 
2. If receiving 2 mg dose, and not recovered by either of the next 2 scheduled 
doses, permanently discontinue study treatment. Otherwise, skip each 
dose. If recovered for either of these doses, resume study drug as follows: 
a. If receiving 5 mg, restart study drug at 3 mg. 
b. If receiving 3 mg, restart study drug at 2 mg. 
3. If not recovered within 4 weeks, permanently discontinue study drug. 
Recurrence of the 
same hematologic 
toxicity 
If the same hematologic toxicity recurs:  
1. Administer symptomatic remedies/ start prophylaxis. Hold1 dose until 
recovery to Grade 1 or baseline.  
2. If recovered within 2 weeks, resume study drug as follows:  
a. If receiving 5 mg, restart study drug at 3 mg  
b. If receiving 3 mg, restart study drug at 2 mg  
c. If receiving 2 mg, permanently discontinue study drug  
3. If the same ≥ Grade 3 event recurs (i.e., third occurrence) despite entinostat 
dose reduction to 2 mg, as described above, permanently discontinue study 
drug. 
1If greater than 50% of doses are missed during any 6 week period, discontinue from study drug 
treatment.
 
 
6.1.2 Ipilimumab 
There are no dose reductions for ipilimumab. For toxicity as outlined in this protocol, study 
therapy should be delayed until the AE improves to the stated level or should be discontinued 
permanently depending on severity (see table below). If a dose of ipilimumab is held for toxicity 
and cannot be resumed within 48 hours, the dose will not be made up, and the subject will 
continue to follow the standard dosing schedule. If the dose of ipilimumab is held for toxicity 
and can be resumed within 48 hours, the dose will be given, and the subject will continue to 
follow the standard dosing schedule (i.e., the next dose will be given on time). 
 
6.1.3 Nivolumab 
There are no dose reductions for nivolumab. For toxicity as outlined in this protocol, study 
therapy should be delayed until the AE improves to the stated level or should be discontinued 
permanently depending on severity (see table below). If a dose of nivolumab is held for toxicity 
and cannot be resumed within 48 hours, the dose will not be made up, and the subject will 
continue to follow the standard dosing schedule. If the dose of nivolumab is held for toxicity and 
can be resumed within 48 hours, the dose will be given, and the subject will continue to follow 
the standard dosing schedule (i.e., the next dose will be given on time). 
 
 
 


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Dose delay guidelines for nivolumab related adverse events 
Recommendations for nivolumab modifications are below. When nivolumab is administered 
with ipilimumab, if nivolumab is held then ipilimumab should also be held. 
 
 
 


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Dose delay guidelines for ipilimumab related adverse events 
Recommendations for nivolumab modifications are below. When nivolumab is administered 
with ipilimumab, if nivolumab is held then ipilimumab should also be held. 
 
 
 


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6.2 
Protocol Therapy Discontinuation 
In addition to discontinuation from therapy related to toxicities as outlined in section 6.1, a 
subject will also be discontinued from protocol therapy and followed up per protocol under the 
circumstances outlined below. The reason for discontinuation of protocol therapy will be 
documented on the eCRF. 
 
Documented disease progression per RECIST 1.1. 
 
The treating physician thinks a change of therapy would be in the best interest of the 
subject 
 
The subject requests to discontinue protocol therapy, whether due to unacceptable 
toxicity or for other reasons 
o If a subject decides to prematurely discontinue protocol therapy (“refuses 
treatment”), the subject should be asked if he or she may still be contacted for 
further scheduled study assessments. The outcome of that discussion should be 
documented in both the medical records and in the eCRF. 
 
A female subject becomes pregnant  
 
6.3 
Protocol Discontinuation 
If a subject decides to withdraw from the study (and not just from protocol therapy) all efforts 
should be made to complete the final study assessments. The site study team should contact the 
subject by telephone or through a clinic visit to determine the reason for the study withdrawal. If 
the reason for withdrawal is an adverse event, it will be recorded on the eCRF. 
 
 


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7. 
STUDY CALENDAR & EVALUATIONS 
 
Screen 
Cycle= 21 days 
Cycle= 28 days 
Safety 
follow up13 
Long-term 
Follow up14
-28 
days1 
Cycle 1
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5+ 
30/100 
days 
(±7)
Q 6 months 
(±30) 
D1 ±3 
D1 ±3 
D1 ±3 
D1 ±3 
D1 ±3 
D15 ±312 
REQUIRED ASSESSMENTS 
Informed Consent
X
Medical history; Diagnosis1
X
Physical exam
X
X
X
X
X
X
D30
Vital signs, ECOG Performance status2
X
X
X
X
X
X
D30
AEs & concomitant medications
X
X
X
X
X
X
X12
X
Drug compliance review (entinostat)
X
X
X
X
X12
D30
LABORATORY ASSESSMENTS 
Complete Blood Cell Count w/ diff (CBC)
X
X11
X
X
X
X
X12
D30
Comprehensive Metabolic Profile (CMP)
X
X11
X
X
X
X
X12
D30
Magnesium, Phosphate, Uric Acid, Lactate 
Dehydrogenase
X 
X11 
X 
X 
X 
X 
X12 
D30 
 
PT/INR and aPTT 
X 
 
 
 
 
 
 
 
 
Thyroid Function (TSH, T4, free T3)3
X
X
X
Q3cycles
Pregnancy test WOCBP4
X
X
DISEASE ASSESSMENT 
CT of chest, abdomen and pelvis5
X
X
X5
D305
Per SOC
Bone scan5
X
X
X5
D305
Per SOC
MRI of brain5
X
TREATMENT EXPOSURE 
Entinostat
D1,8,15 
D1,8,15 
D1,8,15 
D1,8,15 
D1, 8, 15, 22
Nivolumab
X
X
X
X
X
X12
Ipilimumab
X
X
X
X
CORRELATIVE STUDIES
Archival Tissue (required if available)6
X
Optional fresh biopsy6
X
X
Blood samples7
X
X
X
Q2 cycle7
 
 


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Screen 
Cycle= 21 days 
Cycle= 28 days 
Safety 
follow up13 
Long-term 
Follow up14
-28 
days1 
Cycle 1
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5+ 
30/100 
days (±7) 
Q 6 months 
(±30) 
D1 ±3 
D1 ±3 
D1 ±3 
D1 ±3 
D1 ±3 
D15 ±312 
BANKING SAMPLES 
Whole Blood8
X
Unstained Slides (if available)9
X
Serum and Plasma10
X
D30
FOLLOW-UP 
Survival status, subsequent therapy 
X
 
CBC with differential and platelet to include: WBC, ANC, Hgb, Hct, PLT. CMP to include sodium, potassium, chloride, creatinine, blood urea 
nitrogen; liver function tests (LFTs) to include AST, ALT, total bilirubin, alkaline phosphatase  
 
Key to Footnotes  
 
1: Medical History; other data to obtained during this assessment includes: diagnosis and staging to include pathology report and staging 
documentation.  a smoking history questionnaire and trial awareness question.  In addition, prior anti-cancer treatment should be documented. 
 
2: Vital signs to include blood pressure, weight, and height (screening only) and ECOG performance status.   
 
3: Thyroid function to be checked at screening, Cycle 2 Day 1, Cycle 4 Day 1, then every 3rd cycle thereafter starting with Cycle 6. More frequent 
testing is at the discretion of the site investigator. TSH will be obtained. T4 and T3 including free versus total testing is at the discretion of the site 
investigator. 
 
4: For women of childbearing potential (WOCBP): serum pregnancy test during screening and a urine pregnancy test within 3 days prior to first 
dose of study drugs. If the screening serum test was done within 3 days prior to receiving the first dose of study drugs, a urine test is not required.  
 
5: Tumor response assessment will be performed at screening, prior to Cycle 3 Day 1 then prior to Cycle 5 (±7); Tumor imaging to be performed 
every 8-12 weeks after Cycle 5 based on investigator discretion. Tumor imaging to be done at treatment discontinuation at discretion of 
investigator. Baseline bone scan will be obtained if there is any suspicion of metastatic bone involvement.  If bone scan is positive at baseline, it 
will be included with subsequent tumor response assessments as noted above at the discretion of the treating physician. MRI of brain should be 
performed at screening only to evaluate for the presence of brain metastases. Additional imaging of the brain will be at the discretion of the 
treating physician. Tumor imaging modality used should be consistent throughout trial. 
 


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6: Archival tissue from a metastatic lesion or nephrectomy (metastatic lesion preferred) is required if available and will be obtained at screening. If 
archival tissue is unavailable, patients will be given the option to consent to a biopsy during the screening phase prior to Cycle 1 Day 1 treatment. 
All subjects with accessible tumor will be given the option to consent to a second optional biopsy on Cycle 2 Day 1. The Cycle 2 Day 1 samples 
will be collected ~2 hours following the most recent dose of entinostat.  To ensure that these samples are obtained at the correct time, patients are 
urged to take their entinostat dose in the clinic on the day of on-treatment sample collection. The time of the entinostat dose and the time of sample 
collection must be recorded. 
 
7: Serial blood samples for PBMCs and plasma, serum will be collected prior to treatment Cycle 1 Day 1, Cycle 2 Day 1, Cycle 4 Day 1, and then 
every 2nd cycle thereafter starting with Cycle 6. 
 
8: Whole blood for banking is to be collected at Pre-Treatment Cycle 1 Day 1. See CLM for collection, processing, labeling and shipping 
instructions. 
 
9: Submission of unstained slides for banking from an archived FFPE tumor block (if available). See CLM for collection, labeling, and shipping 
instructions. 
 
10: Serum and plasma for banking are to be collected at Pre-Treatment Cycle 1 Day 1 and at the 30-Day Safety Follow up visit. See CLM for 
collection, labeling, processing, and shipping instructions. 
 
11: If screening (baseline) CBC and CMP (including Mg, Phos, uric acid and LDH) were performed within 7 days of Day 1 of treatment, these do 
not need to be repeated.  All laboratory assessments should be done prior to treatment. 
 
12: During maintenance, subjects will receive nivolumab IV over 30 minutes at 480 mg on Day 1 of each cycle. Subjects that do not tolerate every 
4 week dosing regimen may receive nivolumab 240 mg IV over 30 minutes on Day 1 and Day 15 of each cycle. Those subjects receiving 
nivolumab on Day 15 will have laboratory testing as well as AE and conmed assessment. These subjects will continue every 2 week dosing for the 
remainder of study treatment. 
 
13: A safety follow-up visit will occur 30 days (±7 days) after the last dose of treatment. AEs will be collected for 100 days after the end of 
treatment. This may be accomplished via phone call, email or medical records. 
 
14: Subjects who discontinue treatment for any reason will be followed every 6 months until death, withdrawal of consent, or the end of the study, 
whichever occurs first. Follow up may be accomplished via clinic visit, phone call, or other avenues as appropriate. 
 
 
 
 


 
 
 
 
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8. 
BIOSPECIMEN STUDIES AND PROCEDURES 
Correlative blood and fresh tissue studies will be analyzed at Indiana University. Please refer to the 
Correlative Laboratory Manual (CLM) for all sample collection, processing, labeling, and shipping 
instructions.  
 
8.1 
Tissue 
Missed biopsies will not be considered protocol deviations for the purposes of this study. 
 
8.1.1 Tissue at Screening 
Archival tissue from a metastatic lesion or nephrectomy (metastatic lesion preferred) is required if 
available and will be obtained at screening after eligibility is reviewed. If archival tissue is unavailable, 
patients will be given the option to consent to a biopsy during the screening phase prior to treatment. 
Representative formalin-fixed paraffin-embedded (FFPE) tumor specimens in paraffin blocks (blocks 
are preferred) or at least 4 unstained slides, with an associated pathology report, for central testing of 
tumor PD-L1 expression.  
 Tumor tissue suitable for PD-L1 expression testing should be of good quality based on total and 
viable tumor content. Fine needle aspiration, brushing, cell pellet from pleural effusion, bone 
metastases, and lavage samples are not acceptable. Tumor tissue from bone metastases is not 
evaluable for PD-L1 expression and is therefore not acceptable. For core-needle biopsy 
specimens, at least three cores should be submitted for evaluation. 
 Acceptable samples include core needle biopsies for deep tumor tissue (minimum of three cores) 
or excisional, incisional, punch, or forceps biopsies for cutaneous, subcutaneous, or mucosal 
lesions. 
 
8.1.2 Fresh Tissue Cycle 2 Day 1 
All subjects with accessible tumor will be given the option to consent to a second, optional biopsy 
during Cycle 2 on Day 1 (±7 days). Screening and Cycle 2 Day 1 tumor biopsy samples for gene 
expression analysis will be collected from patients who consent and who have accessible tumor per 
institutional procedures. The biopsy sample will be split into two portions: one (1) portion will be placed 
in RNAlaterTM and one (1) portion will be placed in 10% formalin solution.   
 
The Cycle 2 Day 1 samples will be collected ~2 hours following the most recent dose of entinostat.  To 
ensure that these samples are obtained at the correct time, patients are urged to take their entinostat dose 
in the clinic on the day of on-treatment sample collection. The time of the entinostat dose and the time of 
sample collection must be recorded. 
 
Biomarker assays will be done by IHC to examine: 
 
PDL-1/2 
 
T effector cells 
 
Tregs 
 
MDSCs 
 
M1/M2 macrophages 
 
 
 
 


 
 
 
 
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8.2 
Peripheral Blood Samples 
 
8.2.1 Whole Blood 
Serial blood samples for PBMCs and plasma, serum will be collected during prior to treatment C1D1, 
Cycle 2 Day 1, Cycle 4 Day 1, and then every 2nd cycle thereafter starting with Cycle 6. Blood samples 
should be collected prior to treatment administration whenever possible. Biomarker assays will be done 
to examine: 
 CD45 cells 
 Effector CD4 T cells 
 Effector CD8 T cells 
 FoxP3+ CD4+ Regulatory T cells (Tregs) 
 CD11b+ CD14+ HLA-DR low/neg MDSCs 
 Circulating microRNAs 
 
8.3 
Samples for future studies 
Subject consent will be obtained for additional samples collected for future unspecified cancer related 
research. Hoosier Cancer Research Network will manage the banked samples. Samples will be banked 
indefinitely in the Hoosier Cancer Research Network Biorepository.  
 
This includes: 
 Whole blood: Whole blood will be collected prior to treatment on Cycle 1 Day 1.  
 Pre- and Post-treatment plasma: Whole blood for plasma will be collected prior to treatment on 
Cycle 1 Day 1 and at the 30-day Safety Follow-up visit.  
 Pre- and Post-treatment serum: Whole blood for serum will be collected prior to treatment on 
Cycle 1 Day 1 and at the 30-day Safety Follow-up visit. 
 Unstained slides: Unstained slides will be obtained from the subject’s archived formalin fixed 
paraffin embedded tumor sample.  
 
Please refer to the Correlative Laboratory Manual (CLM) for all sample collection, processing, labeling, 
and shipping instructions. 
 
8.4 
Storage of Biospecimens 
Any specimens remaining (leftover) once protocol described biospecimen-based studies are complete 
will be stored for future unspecified cancer related research. Permission for storage of leftover samples 
will be obtained from subjects during informed consent. 
 
8.5 
Confidentiality of Biospecimens 
Samples that are collected will be identified by a subject’s sequence ID assigned at the time of 
registration to the trial. Any material issued to collaborating researchers will be anonymized and only 
identified by the subject’s study number. 
 
 
 


 
 
 
 
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9. 
CRITERIA FOR DISEASE EVALUATION 
Response assessments will be made both using the Immune Related Response Criteria (irRC) and using 
RECIST v1.1, allowing additional comparisons among these criteria for disease response assessment. 
The same measurable and non-measurable lesions will be followed by both RECIST v1.1 & irRC. 
Disease progression will be determined using RECIST 1.1 criteria. 
 
9.1 
Measurable Disease 
Measurable disease is defined as the presence of at least one measurable lesion. 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, as >10 mm with CT scan, or >10 mm with calipers by clinical 
exam. All tumor measurements must be recorded in millimeters (or decimal fractions of centimeters). 
 
9.1.1 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. 
 
9.2 
Non-measurable Lesions 
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, lymphangitis cutis/pulmonitis, 
inflammatory breast disease, and abdominal masses (not followed by CT or MRI), are considered as 
non-measurable. 
 
NOTE:  Cystic lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, by definition, 
simple cysts. ‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-cystic lesions are 
present in the same subject, these are preferred for selection as target lesions. 
 
9.3 
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. 
 
 
 


 
 
 
 
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9.4 
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. 
 
9.5 
Evaluation of Target Lesions 
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
 
9.6 
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 size (<10 mm short axis) 
 
Note:  If tumor markers are initially above the upper 
normal limit, they must normalize for a subject to be 
considered in complete clinical response.
Non-CR/ Non-PD 
Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal 
limits
Progressive Disease (PD) 
Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target 
lesions. Unequivocal progression should not normally 
trump target lesion status. It must be representative of 
overall disease status change, not a single lesion 
increase.
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the site 
investigator should prevail in such circumstances, and the progression status should be confirmed at a 
later time by the sponsor investigator. 
 
 
 


 
 
 
 
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9.7 
Evaluation of Best Overall Response 
 
Target Lesions 
Non-Target Lesions 
New Lesions
Overall 
Response 
CR
CR
No
CR
CR
Non-CR/ Non-PD
No
PR
CR
Not evaluated
No
PR
PR 
Non-PD/ or not all 
evaluated
No 
PR 
SD
Non-PD or not all evaluated
No
SD
Not all evaluated
Non-PD
No
Non-evaluable
PD
Any
Yes or No
PD
Any
PD*
Yes or No
PD
Any
Any
Yes
PD
*In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression.
 
Subjects with a global deterioration of health status requiring discontinuation of treatment without 
objective evidence of disease progression at that time should be classified as having “symptomatic 
deterioration.” Every effort should be made to document the objective progression even after 
discontinuation of treatment. 
 
In some circumstances, it may be difficult to distinguish residual disease from normal tissue. When the 
evaluation of complete response depends on this determination, it is recommended that the residual 
lesion be investigated (fine needle aspirate/biopsy) to confirm the complete response status. 
 
9.8 
Definitions for Response Evaluation – RECIST 1.1 
 
9.8.1 First Documentation of Response 
The time between initiation of therapy and first documentation of PR or CR. 
 
9.8.2 Confirmation of Response 
To be assigned a status of complete or partial response, changes in tumor measurements must be 
confirmed by repeat assessments performed no less than four weeks after the criteria for response are 
first met. 
 
9.8.3 Objective Response Rate  
The objective response rate is the proportion of all subjects with confirmed PR or CR according to 
RECIST 1.1, from the start of treatment until disease progression/recurrence (taking as reference for 
progressive disease the smallest measurements recorded since the start of treatment). 
 
9.8.4 Progression Free Survival 
A measurement from the date of treatment start until the criteria for disease progression is met as 
defined by RECIST 1.1 or death occurs. Subjects who have not progressed will be right-censored at the 
date of the last disease evaluation. 
 


 
 
 
 
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9.8.5 Overall Survival 
Overall survival is defined by the date of treatment start to date of death from any cause. 
 
9.9 
Immune Related Response Criteria (irRC) 
This study will evaluate concordance of the Immune Related Response Criteria (irRC) with RECIST 
1.1. These response criteria were developed to overcome the variable and unusual patterns of response 
to immunotherapeutic agents, in particular, ipilimumab. The development of the guidelines was 
prompted by observations, mostly in subjects with metastatic melanoma, of initial disease progression 
followed by later response, late responses, and mixed responses with an overall decrease in tumor 
burden. See article in Clin Cancer Res 2009;15(23) December 1, 2009. 
 
9.9.1 Antitumor response based on total measurable tumor burden 
For the irRC, only index and measurable new lesions are taken into account (in contrast to conventional 
WHO criteria, which do not require the measurement of new lesions, nor do they include new lesion 
measurements in the characterization of evolving tumor burden). At the baseline tumor assessment, the 
sum of the products of the two largest perpendicular diameters (SPD) of all index lesions (5 lesions per 
organ, up to 10 visceral lesions) is calculated. At each subsequent tumor assessment, the SPD of the 
index lesions and of new, measurable lesions (up to 5 new lesions per organ; 10 visceral lesions) are 
added together to provide the total tumor burden: 
 
Tumor Burden = SPDindex lesions + SPDnew, measurable lesions 
 
Table: Comparison of WHO and irRC criteria 
 
WHO 
irRC 
New, measurable lesions
Always represent PD
Incorporated into tumor burden
New, non measurable 
lesions
Always represent PD 
Do not define progression (but 
preclude irCR)
Non-index lesions 
Changes contribute to defining BOR 
of CR, PR, SD, and PD 
Contribute to defining irCR 
(complete disappearance 
required)
CR 
Disappearance of all lesions in two 
consecutive observations not less than 
4 wk apart
Disappearance of all lesions in 
two consecutive observations 
not less than 4 wk apart
PR 
≥50% decrease in SPD of all index 
lesions compared with baseline in two 
observations at least 4 wk apart, in 
absence of new lesions or unequivocal 
progression of non-index lesions
≥50% decrease in tumor burden 
compared with baseline in two 
observations at least 4 wk apart 
SD 
50% decrease in SPD compared with 
baseline cannot be established nor 
25% increase compared with nadir, in 
absence of new lesions or unequivocal 
progression of non-index lesions
50% decrease in tumor burden 
compared with baseline cannot 
be established nor 25% increase 
compared with nadir 
PD 
At least 25% increase in SPD 
compared with nadir and/or 
unequivocal progression of non-index 
lesions and/or appearance of new 
lesions (at any single time point)
At least 25% increase in tumor 
burden compared with nadir (at 
any single time point) in two 
consecutive observations at least 
4 wk apart


 
 
 
 
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9.9.2 Time-point response assessment using irRC 
Percentage changes in tumor burden per assessment time point describe the size and growth kinetics of 
both conventional and new, measurable lesions as they appear. At each tumor assessment, the response 
in index and new, measurable lesions is defined based on the change in tumor burden (after ruling out 
irPD). Decreases in tumor burden must be assessed relative to baseline measurements (i.e., the SPD of 
all index lesions at screening). The irRC were derived from WHO criteria and, therefore, the thresholds 
of response remain the same. However, the irRC response categories have been modified from those of 
WHO criteria as detailed in the above table. 
 
9.9.3 Overall response using the irRC 
The sum of the products of diameters at tumor assessment using the immune-related response criteria 
(irRC) for progressive disease incorporates the contribution of new measurable lesions. Each net 
Percentage Change in Tumor Burden per assessment using irRC criteria accounts for the size and 
growth kinetics of both old and new lesions as they appear. 
 
Definition of Index Lesions Response Using irRC 
 irComplete Response (irCR): Complete disappearance of all index lesions. This category 
encompasses exactly the same subjects as “CR” by the mWHO criteria. 
 irPartial Response (irPR): Decrease, relative to baseline, of 50% or greater in the sum of the 
products of the 2 largest perpendicular diameters of all index and all new measurable lesions 
(i.e., Percentage Change in Tumor Burden). Note: the appearance of new measurable 
 Disease (irSD): Does not meet criteria for irCR or irPR, in the absence of progressive disease. 
 irProgressive Disease (irPD): At least 25% increase Percentage Change in Tumor Burden (i.e., 
taking sum of the products of all index lesions and any new lesions) when compared to SPD at 
nadir. 
 
Definition of Non-Index Lesions Response Using irRC 
 irComplete Response (irCR): Complete disappearance of all non-index lesions. This category 
encompasses exactly the same subjects as “CR” by the mWHO criteria. 
 irPartial Response (irPR) or irStable Disease (irSD): non-index lesion(s) are not considered in 
the definition of PR, these terms do not apply. 
 irProgressive Disease (irPD): Increases in number or size of non-index lesion(s) does not 
constitute progressive disease unless/until the Percentage Change in Tumor Burden increases by 
25% (i.e., the SPD at nadir of the index lesions increases by the required amount). 
 
Impact of New Lesions on irRC New lesions in and by themselves do not qualify as progressive 
disease. However, their contribution to total tumor burden is included in the SPD, which in turn feeds 
into the irRC criteria for tumor response. Therefore, new non-measurable lesions will not discontinue 
any subject from the study. 
 
9.9.4 Definition of Overall Response Using irRC 
Overall response using irRC will be based on these criteria (see Table below): 
 Immune-Related Complete Response (irCR): Complete disappearance of all tumor lesions 
(index and non-index together with no new measurable/unmeasurable lesions) for at least 4 
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 Immune-Related Partial Response (irPR): The sum of the products of the two largest 
perpendicular diameters of all index lesions is measured and captured as the SPD baseline. At 
each subsequent tumor assessment, the sum of the products of the two largest perpendicular 
diameters of all index lesions and of new measurable lesions are added together to provide the 
Immune Response Sum of Product Diameters (irSPD). A decrease, relative to baseline of the 
irSPD compared to the previous SPD baseline, of 50% or greater is considered an immune 
Partial Response (irPR). 
 Immune-Related Stable Disease (irSD): irSD is defined as the failure to meet criteria for 
immune complete response or immune partial response, in the absence of progressive disease. 
 Immune-Related Progressive Disease (irPD): It is recommended in difficult cases to confirm 
PD by serial imaging. Any of the following will constitute progressive disease: 
o At least 25% increase in the sum of the products of all index lesions over nadir SPD 
calculated for the index lesions.  
o At least a 25% increase in the sum of the products of all index lesions and new 
measurable lesions (irSPD) over the baseline SPD calculated for the index lesions. 
 Immune-Related Best Overall Response Using irRC (irBOR) irBOR is the best confirmed 
irRC overall response over the study as a whole, recorded between the date of first dose until the 
last tumor assessment before subsequent therapy (except for local palliative radiotherapy for 
painful bone lesions) for the individual subject in the study. For the assessment of irBOR, all 
available assessments per subject are considered. irCR or irPR determinations included in the 
irBOR assessment must be confirmed by a second (confirmatory) evaluation meeting the criteria 
for response and performed no less than 4 weeks after the criteria for response are first met. 
 
Derivation of irRC overall responses 
 
Measurable Response
Nonmeasurable Response
Overall Response
Index and new, measurable 
lesions (tumor burden),*% 
Non-index lesions 
New, 
Nonmeasurable 
lesions
Using irRC 
↓100
Absent
Absent
irCR†
↓100
Stable
Any
irPR†
↓100 
Unequivocal 
Progression
Any 
irPR† 
↓≥50
Any/Stable
Any
irPR†
↓≥50 
Unequivocal 
Progression
Any 
irPR† 
↓<50 to <25↑
Any/Stable
Any
irSD
↓<50 to <25↑ 
Unequivocal 
Progression
Any 
irSD 
≥25
Any
Any
irPD†
*Decreases assessed relative to baseline (scan prior to start of any protocol therapy), including 
measurable lesions only. 
†Assuming response (irCR) and progression (irPD) are confirmed by a second, consecutive 
assessment at least 4 wk apart.
 


 
 
 
 
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10. 
DRUG INFORMATION 
Please refer to the current versions of the Investigator’s Brochures (IBs) for additional information 
regarding these drugs. 
 
10.1 
Entinostat 
Entinostat is a synthetic orally available HDACi that belongs to the class of substituted 
pyridylcarbamates. Entinostat is in the pharmacologic class of antineoplastic agents. 
 
10.1.1 Supplier/How Supplied 
Syndax will supply entinostat at no charge to subjects participating in this clinical trial.  
 
The investigator shall take responsibility for and shall take all steps to maintain appropriate records and 
ensure appropriate supply, storage, handling, distribution, and usage of investigational product in 
accordance with the protocol and any applicable laws and regulations. 
 
10.1.2 Storage and Stability 
Entinostat is an oral drug supplied by Syndax as pink to light red (1 mg) or yellow (5 mg) as polymorph 
B coated tablets. Each tablet contains mannitol, sodium starch glycolate, hydroxypropyl cellulose, 
potassium bicarbonate, and magnesium stearate as inert fillers. The film coating consists of 
hypromellose, talc, titanium dioxide, and ferric oxide pigments (red and yellow) as colorants. Entinostat 
is to be stored at controlled room temperature (15ºC to 25ºC) in a secure, locked storage area to which 
access is limited.  Entinostat is to be protected from light and not to be exposed to extremes of 
temperature (greater than 30ºC or less than 5ºC). The pharmacist should dispense the investigational 
material to the patient at appropriate intervals throughout the study in childproof containers. 
 
10.1.3 Dispensing 
Entinostat must be dispensed only from official study sites and to eligible subjects under the supervision 
of the site investigator. Entinostat should be stored in a secure area according to local regulations.  It is 
the responsibility of the site investigator to ensure that study drug is only dispensed to subjects.   
 
10.1.4 Adverse Events 
Please refer to the entinostat Investigator’s Brochure for a complete list of adverse events. Entinostat has 
been evaluated as monotherapy and in combination with other agents in greater than 1055 cancer 
patients in 31 clinical studies sponsored by Syndax or predecessors, the United States NCI and KHK, of 
which 8 are active. 
Across indications and regimens, the AEs reported most commonly in entinostat-treated patients 
include: 
 Fatigue (63%) 
 GI disturbances, primarily nausea (55%), vomiting (32%), anorexia (31%), and diarrhea (32%) 
 Hematologic abnormalities, including anemia (47%), thrombocytopenia (41%), neutropenia 
(33%), and leukopenia (31%) 
 
Fatigue is the most common AE associated with entinostat. In placebo-controlled study SNDX-275-
0301, the incidence of fatigue of any grade was 48% versus 26% for entinostat versus placebo, with the 
incidence of Grade 3 or 4 fatigue being 13% vs 3%. Fatigue tended to occur early and to be variable in 
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over several months. Fatigue was often, but not always accompanied by anemia, which also was more 
prevalent in the entinostat group relative to placebo. Overall, fatigue was tolerable. 
 
Neutropenia has been associated commonly with entinostat. In placebo-controlled study SNDX-275-
0301, the incidence of neutropenia of any grade was 30% vs 0% for entinostat vs placebo, and 
approximately half of the events were Grade 3. Neutropenia tended to occur later in treatment and in 
patients with disease in the bone, but was not complicated by fever or infection in this study. 
 
The incidence of thrombocytopenia (all severities) varied markedly across entinostat studies, with 
incidences as high as 79% in the combination study with AZA in hematologic malignancies and as low 
as 15% in the combination study with the EGFR inhibitor erlotinib in solid tumors. The incidence of 
Grade 3 or 4 thrombocytopenia was even more disparate, with incidences of 78% in the former study 
and 3% in the latter. The incidence of Grade 3 or 4 thrombocytopenia was 1% in patients with solid 
tumors who received entinostat in combination with AZA. In monotherapy studies, the incidence of 
thrombocytopenia of any grade was moderately higher in hematologic malignancies relative to solid 
tumors (52% vs 41%, respectively), but the incidence of Grade 3 or 4 thrombocytopenia was markedly 
higher (46% vs 5%). Although thrombocytopenia tended to be higher in the monotherapy studies in 
general, this may have been due to the Phase 1 nature of these studies, which tended to enroll more 
heavily pretreated patients than the later-phase combination studies and which enrolled patients at doses 
higher than the MTD. In summary, thrombocytopenia tended to be more common and more severe in 
patients with hematologic malignancies (who typically have compromised bone marrow and/or 
preexisting thrombocytopenia) compared to patients with solid tumors and was higher with certain drug 
combinations (i.e., AZA). Thrombocytopenia is considered a class effect of HDACi and appears to be 
due to an effect on platelet maturation and release as opposed to myelosuppression, a cytotoxic effect on 
megakaryocytes, or a decrease in the half-life of circulating platelets (Bishton 2011). 
 
Entinostat Combination Therapy 
Overall, the AE profile of entinostat when given in combination was similar to that seen when given as 
monotherapy, with the most commonly reported AEs (regardless of tumor type) being fatigue (68%), 
nausea (59%), anemia (49%), thrombocytopenia (40%), leukopenia (35%), diarrhea (35%), neutropenia 
(34%), and vomiting (34%). 
 
As would be expected, the AE profiles of entinostat when given in combination varied somewhat based 
on the combination agent and the corresponding patient population. Higher rates of AEs overall and of 
individual AEs were seen when entinostat was given with AZA than when given in combination with an 
AI. Consistent with the overall AE profile of entinostat, nausea, vomiting, fatigue, and anemia were 
common regardless of the combination agent. 
 
When given in combination with AIs in patients with breast cancer, the individual AEs and Grade 3 or 4 
AEs occurred less frequently compared to other patient populations and regimens. Overall, the AEs 
reported most frequently in this setting were fatigue (50%), nausea (45%), diarrhea (27%), peripheral 
edema (25%), neutropenia (24%), and vomiting and weight decreased (each 23%). The overall incidence 
of Grade 3 or 4 AEs was 55%; however, the incidence of individual Grade 3 or 4 AEs was relatively 
low, with the only events occurring at an incidence >5% being neutropenia (13%) and fatigue (9%). In 
the placebo-controlled study SNDX-275-0301, in which entinostat was given in combination with the AI 
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was variable, with some patients experiencing multiple short episodes, and others prolonged fatigue that 
persisted for several months. For some patients, dose modification was helpful in ameliorating fatigue. 
Fatigue was accompanied in some cases by anemia, which also was more prevalent in the entinostat 
group compared with placebo. Only 1 patient treated with entinostat permanently discontinued treatment 
due to fatigue. In the same study, neutropenia was also a notable treatment-emergent AE, tending to 
occur later in treatment and in patients with disease involvement in the bone. Approximately half of the 
patients with neutropenia required a dose modification; treatment was discontinued due to neutropenia 
in only 1 entinostat-treated patient. Importantly, the neutropenia was not associated with fever or 
infection. 
 
Overall, among the 535 patients with solid tumors receiving entinostat in combination, the AEs reported 
most frequently were: fatigue (66%), nausea (58%), anemia (44%), vomiting and diarrhea (each 34%), 
thrombocytopenia and anorexia (each 30%), leukopenia (25%), dyspnea (22%) and injection site 
reaction (20%). 
 
Overall, among the 205 patients with hematologic malignancies receiving entinostat in combination, the 
SAEs reported  most  frequently were: fatigue (70%), thrombocytopenia (67%), anemia (65%), 
neutropenia (62%), leukopenia (60%), nausea (58%), anorexia (41%), diarrhea (29%), 
hypoalbuminaemia (36%), injection site reaction (35%), febrile neutropenia (34%), vomiting (33%), 
constipation (32%), hyperglycaemia, hypocalcaemia and hyponatraemia (each 31%), oedema peripheral 
and dyspnea (each 30%), and headache and hypophosphataemia (each 20%). 
 
10.2 
Ipilimumab 
Ipilimumab (BMS-734016, MDX-010) is a recombinant, human monoclonal antibody that binds to the 
CTLA-4. Ipilimumab is an IgG1 kappa immunoglobulin with an approximate molecular weight of 148 
kDa. Ipilimumab is produced in mammalian (Chinese hamster ovary) cell culture. 
 
10.2.1 Supplier/How Supplied 
Bristol-Meyers Squibb will supply ipilimumab at no charge to subjects participating in this clinical trial. 
 
The site investigator shall take responsibility for and shall take all steps to maintain appropriate records 
and ensure appropriate supply, storage, handling, distribution, and usage of investigational product in 
accordance with the protocol and any applicable laws and regulations. 
 
A copy of the drug destruction certificate should be maintained for provision to BMS at the end of the 
study. 
 
10.2.2 Product Description and Dosage Form 
Ipilimumab injection, or 200 mg/40 mL (5 mg/mL), is formulated as a clear to slightly opalescent, 
colorless to pale yellow, sterile, nonpyrogenic, single-use, isotonic aqueous solution that may contain 
particles. Ipilimumab injection, 200 mg/40 mL, is supplied in 50-cc Type I flint glass vials, respectively, 
stoppered with gray butyl stoppers and sealed with aluminum seals. The drug product is formulated at a 
concentration of 5 mg/mL at a pH of 7.0. 
 


 
 
 
 
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Ipilimumab injection must not be administered as an IV push or bolus injection. Care must be taken 
to assure sterility of the prepared solutions since the drug product does not contain any antimicrobial 
preservatives or bacteriostatic agents. 
 
10.2.3 Storage and Stability 
Ipilimumab injection, 200 mg/40 mL (5 mg/mL), must be stored refrigerated (2°C to 8°C) and 
protected from light. Ipilimumab injection must not be frozen. Partially used vials or empty vials 
of ipilimumab injection should be discarded at the site according to appropriate drug disposal 
procedures. 
 
Ipilimumab injection may be stored undiluted (5 mg/mL) or following dilution in 0.9% Sodium 
Chloride Injection, USP or 5% Dextrose Injection, USP in PVC, non-PVC/non-DEHP, or glass 
containers for up to 24 hours at 2°C to 8°C or room temperature/room light. 
 
Recommended safety measures for preparation and handling include protective clothing, gloves, and 
safety cabinets. 
 
After opening: 
Solution for infusion: From a microbiological point of view, once opened, the medicinal product should 
be infused or diluted and infused immediately. The chemical and physical in-use stability of the 
undiluted or diluted concentrate (between 1 and 4 mg/ml) has been demonstrated for 24 hrs at 25°C and 
2 to 8°C. If not used immediately, the infusion solution (undiluted or diluted) may be stored for up to 24 
hours in a refrigerator (2°C to 8°C) or at room temperature (20°C to 25°C). 
 
10.2.4 Handling and Disposal 
Preparation should be performed by trained personnel in accordance with good practices rules, 
especially with respect to asepsis. 
 
After final drug reconciliation, unused ipilimumab vials should be disposed at the site following 
procedures for the disposal of anticancer drugs. 
 
10.2.5 Dispensing 
Ipilimumab must be dispensed only from official study sites and to eligible subjects under the 
supervision of the site investigator. Ipilimumab should be stored in a secure area according to local 
regulations.  It is the responsibility of the site investigator to ensure that study drug is only dispensed to 
subjects.   
 
10.2.6 Administration 
Ipilimumab injection (5 mg/mL) can be used for intravenous (IV) administration without dilution after 
transferring to a polyvinyl chloride (PVC), non-PVC/non-di-(2-ethylhexyl)phthalate (DEHP), or glass 
container and is stable for 24 hours at 2°C to 8°C or room temperature/room light. Ipilimumab injection 
may be diluted in 0.9% Sodium Chloride Injection, United States Pharmacopeia (USP) or 5% Dextrose 
Injection, USP to concentrations between 1 and 4 mg/mL and stored in PVC, non-PVC/non-DEHP, or 
glass containers for up to 24 hours at 2°C to 8°C or room temperature/room light. The product may be 
infused using a volumetric pump at the protocol-specific dose(s) and rate(s) through a PVC IV solution 
infusion set with an in-line, sterile, nonpyrogenic, low-protein-binding filter (pore size of 0.2 to 1.2 μm). 
Ipilimumab injection must not be administered as an IV push or bolus injection. Care must be taken to 


 
 
 
 
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assure sterility of the prepared solutions since the drug product does not contain any antimicrobial 
preservatives or bacteriostatic agents. 
 
10.2.7 Adverse Events 
Please refer to the ipilimumab Investigator’s Brochure for a complete list of adverse events.  
 
Blockade of CTLA-4 by ipilimumab leads to T-cell activation, with the potential for clinical 
inflammatory AEs primarily involving the skin (dermatitis/pruritus), GI tract (diarrhea/colitis), liver 
(hepatitis), endocrine glands (eg, hypophysitis and adrenal or thyroid abnormalities), and other less 
frequent organs (eg, uveitis/episcleritis). The majority of these inflammatory AEs initially manifested 
during treatment; however, a minority occurred weeks to months after discontinuation of ipilimumab. 
The majority of the inflammatory AEs is reversible with the guidance issued below and in Appendix 2. 
In rare cases, these inflammatory AEs may be fatal. 
 
Gastrointestinal Toxicities 
The most common site for ipilimumab-induced GI toxicity was the lower GI tract, and the most 
common presentation was mild to severe diarrhea or colitis with occasional bloody stools. In some 
cases, diarrhea began as mild and then worsened. Constipation was rarely associated with ipilimumab 
administration. 
 
Liver Toxicities 
Subjects receiving ipilimumab may develop elevations in LFTs in the absence of clinical symptoms. 
Occasionally, patients may present with symptoms, including right upper quadrant abdominal pain or 
unexplained vomiting. 
 
Endocrine Toxicities 
The most common inflammatory endocrine toxicities occurring in ipilimumab-treated subjects are 
hypophysitis and hypopituitarism. Secondary cortisol deficiency (hypoadrenalism), hypothyroidism or 
thyroiditis, and, less commonly, other endocrinopathies may occur concomitantly with hypophysitis; 
however, these may also present as the only or as primary endocrinopathy. Most patients with 
hypopituitarism presented with nonspecific complaints such as fatigue, visual field defects, confusion, or 
impotence. Some patients have had headache as the predominant presentation. The majority of subjects 
with hypopituitarism demonstrated enlarged pituitary glands based on brain magnetic resonance imaging 
(MRI). Low ACTH and cortisol were the most common biochemical abnormality; abnormal (mostly 
low) thyroid-stimulating hormone (TSH), free thyroxine (fT4), triiodothyronine (T3), testosterone, or 
prolactin have also been reported in some subjects.  
 
Skin Toxicities 
The most common inflammatory skin toxicities occurring in ipilimumab-treated subjects are rash and 
pruritus, mostly mild to moderate in severity. Two cases of fatal treatment-related toxic epidermal 
necrolysis have been reported in clinical trials. Postmarketing surveillance identified a fatal toxic 
epidermal necrolysis event in 1 subject who received ipilimumab after experiencing a severe or life-
threatening skin adverse reaction on a prior cancer immune-stimulating therapy. Caution should be used 
when considering the use of ipilimumab in patients who have previously experienced a severe or life-
threatening skin adverse reaction on a prior cancer immune-stimulating therapy.  
 


 
 
 
 
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Neurological Toxicities 
Neurological manifestations in subjects treated with ipilimumab may include motor and/or sensory 
neuropathy. Given the difficulty in definitely establishing an inflammatory etiology, alternative 
etiologies (eg, tumor progression) should be excluded. Fatal Guillain-Barre syndrome and cases of 
myasthenia gravis have been reported in clinical trials of ipilimumab. Unexplained motor neuropathy, 
muscle weakness, or sensory neuropathy should be evaluated, and noninflammatory causes such as 
disease progression, infections, metabolic disorders, and medications should be excluded. 
 
Other Toxicities 
Ocular inflammation, manifested as Grade 2 or 3 episcleritis or uveitis, was associated with concomitant 
diarrhea in a few subjects (< 1%) and occasionally occurred in the absence of clinically apparent GI 
symptoms. 
 
Other presumed inflammatory events reported include, but were not limited to, the following 
(individually reported for < 1% of subjects unless noted otherwise): arthritis/arthralgias, pneumonitis, 
pancreatitis, autoimmune (aseptic) meningitis, autoimmune nephritis, pure red cell aplasia, noninfective 
myocarditis, polymyositis, eosinophilia, pericarditis, urticaria (2%), large intestinal ulcer, esophagitis, 
acute respiratory distress syndrome, renal failure, infusion reactions, and MG. 
 
10.3 
Nivolumab 
Nivolumab (ONO-4538, MDX-1106, BMS-936558-01 or BMS-936558) is an anti-PD-1, anti-
programmed cell death-1 monoclonal antibody. 
 
10.3.1 Supplier/How Supplied 
Bristol-Meyers Squibb will supply nivolumab at no charge to subjects participating in this clinical trial. 
 
The site investigator shall take responsibility for and shall take all steps to maintain appropriate records 
and ensure appropriate supply, storage, handling, distribution, and usage of investigational product in 
accordance with the protocol and any applicable laws and regulations. 
 
A copy of the drug destruction certificate should be maintained for provision to BMS at the end of the 
study 
 
10.3.2 Product Description and Dosage Form 
Nivolumab Injection, 100mg/10 mL (10mg/mL) is a clear to opalescent, colorless to pale yellow liquid, 
which may contain light (few) particulates. The drug product is a sterile, non-pyrogenic, single-use, 
isotonic aqueous solution formulated at 10 mg/mL in sodium citrate, sodium chloride, mannitol, 
diethylenetriaminepentaacetic acid (pentetic acid), and polysorbate 80 (Tween™ 80), pH 6.0 and 
includes an overfill to account for vial, needle, and syringe holdup. It is supplied in 10-cc Type I flint 
glass vials, stoppered with butyl rubber stoppers and sealed with aluminum seals. The only difference 
between the two drug product presentations is the vial fill volume. 
 
10.3.3 Storage and Stability 
Clinical supplies must be stored in a secure, limited-access location under the storage conditions 
specified on the label. Store nivolumab under refrigeration at 2°C to 8°C (36°F to 46°F). Protect 
nivolumab from light by storing in the original package until time of use. Do not freeze or shake. For 


 
 
 
 
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additional details on prepared drug storage and use time of nivolumab under room temperature/light and 
refrigeration, please refer to the BMS-936558 (nivolumab) Investigator Brochure section for 
“Recommended Storage and Use Conditions.” 
 
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 (20C to 25C, 68F to 77F) and room light. The maximum 8-hour period under room 
temperature and room light conditions includes the product administration period. 
 
10.3.4 Dispensing 
Nivolumab must be dispensed only from official study sites and to eligible subjects under the 
supervision of the site investigator. Nivolumab should be stored in a secure area according to local 
regulations. It is the responsibility of the site investigator to ensure that study drug is only dispensed to 
subjects.  
 
10.3.5 Administration 
Nivolumab is to be administered as an IV infusion through a 0.2-micron to 1.2-micron pore size, low-
protein binding (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. Nivolumab injection can be infused 
undiluted (10 mg/mL) or diluted with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, 
USP to protein concentrations as low as 0.35 mg/mL. During drug product preparation and handling, 
vigorous mixing or shaking is to be avoided. Care must be taken to assure sterility of the prepared 
solution as the product does not contain any antimicrobial preservative or bacteriostatic agent. No 
incompatibilities between nivolumab and polyvinyl chloride (PVC) and non-PVC/non-DEHP (di(2-
ethylhexyl)phthalate) containers/IV components or glass bottles have been observed. 
 
10.3.6 Adverse Events 
Please refer to the nivolumab Investigator’s Brochure for a complete list of adverse events.  
 
Potential safety concerns and recommended management guidelines regarding pulmonary toxicities, GI 
toxicities, hepatotoxicities, endocrinopathies, dermatologic toxicities, and other toxicities of concern are 
summarized below. Management algorithms are found in Appendix 2.  
 
The overall safety experience with nivolumab is based on experience in approximately 12,300 subjects 
as either monotherapy or in combination with other therapeutics. In general, for monotherapy, the safety 
profile is similar across tumor types. The only exception is pulmonary inflammation AEs, which may be 
numerically greater in subjects with NSCLC, possibly because in some cases, it can be difficult to 
distinguish between nivolumab-related and unrelated causes of pulmonary symptoms and radiographic 
changes. The most frequently reported treatment-related AE is fatigue, which is almost always of low 
grade. 
 
Most related AEs are thought to be due to the effects of inflammatory cells on specific tissues. A variety 
of preferred terms (PTs) have been used to describe similar kinds of organ-related AEs, with the result 
being that AE frequency tables organized by PTs can lead to underestimation of the frequency of similar 
kinds of organ-related AEs. Select AE categories group together the most common and impactful PTs by 


 
 
 
 
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organ category. These categories include the following: pulmonary, GI, hepatic, skin, endocrine, 
hypersensitivity/infusion reaction, and renal AEs.  
 
Pulmonary Adverse Events 
Pulmonary AEs have been observed following treatment with nivolumab. The frequency of pulmonary 
AEs may be greater with nivolumab combination therapies than with nivolumab monotherapy. The 
majority of cases reported were Grade 1 or 2, and subjects presented with either asymptomatic 
radiographic changes (e.g., focal ground glass opacities and patchy infiltrates) or with symptoms of 
dyspnea, cough, or fever. Subjects with reported Grade 3 or 4 pulmonary AEs were noted to have more 
severe symptoms, more extensive radiographic findings, and hypoxia. Pulmonary AEs have been 
reported in subjects with a variety of tumor types; however, there have been numerically more cases in 
subjects with NSCLC. It is not clear whether the underlying NSCLC is a distinct risk factor, or if 
subjects with NSCLC are more likely to develop radiographic changes and symptoms for which it is 
difficult to distinguish between nivolumab-related and unrelated causes. At this time, no other 
underlying risk factor, including prior radiotherapy, presence of lung metastases, or underlying 
pulmonary medical history, has yet to be identified. 
 
Gastrointestinal Adverse Events 
Gastrointestinal AEs have been observed following treatment with nivolumab. Most cases of diarrhea 
were of low grade (Grade 1-2). Colitis occurred less frequently than diarrhea. High-grade cases of 
diarrhea and colitis were managed with corticosteroids and, in all cases, the events resolved. 
 
Diverticular Perforation 
The prevalence of diverticulosis in the general population is common and increases with age from 10% 
under 40 years of age to approximately 50% over 60 years of age. Approximately 10% to 25% of 
subjects with diverticulosis develop diverticulitis. Perforation occurs in 50% to 70% of instances of 
complicated diverticulitis [36, 37]. Corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs), 
and opioid analgesics are known risk factors for diverticular perforation [38]. Given the high prevalence 
of diverticulosis and diverticulitis in the general population, it is expected that some nivolumab-treated 
subjects will have these conditions concurrently with their malignancy. Cases of diverticular perforation 
while on concomitant corticosteroids (6 cases) or NSAID (1 case) were observed in nivolumab program. 
While there is insufficient evidence to suggest that diverticulosis or diverticulitis is a predisposing factor 
for GI perforation following nivolumab administration, clinical caution should be exercised, as 
appropriate, for subjects on concomitant medications of corticosteroids, NSAID, or opioid analgesics. In 
addition, be vigilant for signs and symptoms of potential perforation, especially in subjects with known 
diverticular disease. 
 
Hepatic Adverse Events 
Hepatic AEs, including elevated liver function tests (LFTs) and, infrequently, drug-induced liver injury 
(DILI) have been observed following treatment with nivolumab and nivolumab in combination with 
ipilimumab. Most cases were of low or moderate grade. Higher-grade hepatic AEs, including DILI, were 
managed with corticosteroids (with or without mycophenolate mofetil) and, in almost all cases, the 
events resolved. 
 
 
 


 
 
 
 
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Endocrinopathies 
Endocrinopathies have been observed following treatment with nivolumab. Most cases were of low or 
moderate grade. The events have typically been identified through either routine periodic monitoring of 
specific laboratories (e.g., TSH) or as part of a work-up for associated symptoms (e.g., fatigue). Events 
may occur within weeks of beginning treatment, but also have been noted to occur after many months 
(while still on treatment). More than 1 endocrine organ may be involved (e.g., hypophysitis [pituitary 
inflammation] may need to be evaluated at the time adrenal insufficiency or thyroid disorder is 
suspected). Moderate- to high-grade cases were managed with hormone replacement therapy and, in 
some cases, with the addition of corticosteroids. In some cases, nivolumab treatment was held until 
adequate hormone replacement was provided. 
 
Skin Adverse Events 
Rash and pruritus were the most common skin AEs observed following treatment with nivolumab. The 
rash was typically focal with a maculopapular appearance occurring on the trunk, back, or extremities. 
Most cases have been of low or moderate grade. In some cases, rash and pruritus resolved without 
intervention. Topical corticosteroids have been used for some cases of rash. Anti-histamines have been 
used for some cases of pruritus. More severe cases responded to systemic corticosteroids. 
 
Renal Adverse Events 
Elevated creatinine and biopsy-confirmed tubulointerstitial nephritis and allergic nephritis have been 
infrequently observed following treatment with nivolumab. The frequency of renal AEs may be greater 
with nivolumab combination therapies than with nivolumab monotherapy. Most cases were Grade 2 or 3 
and based on creatinine elevation. Subjects with a history of renal cell carcinoma or prior nephrectomy 
did not appear to be at higher risk. Events were managed with corticosteroids and, in all cases, renal 
function partially or fully improved. 
 
Neurologic Adverse Events 
Neurologic AEs have been uncommonly observed following treatment with nivolumab. The frequency 
of neurologic AEs may be greater with nivolumab + ipilimumab combination therapies than with 
nivolumab monotherapy or other nivolumab combinations. Neurologic AEs can manifest as central 
abnormalities (e.g., aseptic meningitis, encephalopathy, or encephalitis) or peripheral sensory/motor 
neuropathies (e.g., Guillain-Barre Syndrome, myasthenia gravis complicated with sepsis and fatality). 
The onset has been observed as early as after a single treatment with the nivolumab + ipilimumab 
combination. 
 
Infusion Reactions 
Infusion reactions, including high-grade hypersensitivity reactions, following administration of 
nivolumab are uncommon. Investigators are advised to monitor for fever, chills, shakes, itching, rash, 
hypertension or hypotension, or difficulty in breathing during and immediately after administration of 
nivolumab. 
 
Lipase/Amylase Elevations 
Asymptomatic elevations in lipase and amylase have been reported. In monotherapy studies, lipase and 
amylase levels were not systematically monitored, so an estimate of the frequency of asymptomatic 
lipase/amylase elevations is unknown. In studies evaluating the safety of the nivolumab + ipilimumab 
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elevations in any grade of lipase/amylase were consistently noted in approximately 10% to 30% of 
subjects. Very few subjects reported associated symptoms (e.g., abdominal pain) or radiographic 
findings (e.g., stranding) consistent with pancreatitis. Thus, there does not seem to be clinical 
significance to the elevated laboratory values. 
 
Uveitis and Visual Complaints 
Immune therapies have been uncommonly associated with visual complaints. Inflammation of 
components within the eye (e.g., uveitis) is an uncommon, but clinically important, event. Uveitis may 
occur more frequently with nivolumab + ipilimumab combination therapy than with nivolumab 
monotherapy or nivolumab in combination with other therapies. An ophthalmologist should evaluate 
visual complaints with examination of the conjunctiva, anterior and posterior chambers, and retina. 
Topical corticosteroids may be used to manage low-grade events. Low-grade events that do not resolve 
and high-grade events should be managed with systemic corticosteroids. Consultation with the sponsor-
investigator should be sought for all cases of ocular inflammatory events. Complaints of double vision 
should also prompt medical evaluation. In addition to ocular inflammatory events, a work-up should also 
consider pituitary inflammation as a cause. 
 
Other Immune-mediated Adverse Events 
For suspected immune-related adverse reactions, adequate evaluation should be performed to confirm 
etiology or exclude other causes. Based on the severity of the adverse reaction, nivolumab or nivolumab 
in combination with ipilimumab should be withheld and corticosteroids administered. Upon 
improvement, nivolumab or nivolumab in combination with ipilimumab may be resumed after 
corticosteroid taper. Nivolumab or nivolumab in combination with ipilimumab must be permanently 
discontinued for any severe immune-related adverse reaction that recurs and for any life-threatening 
immune-related adverse reaction. 
 
11. 
ADVERSE EVENTS 
The descriptions and grading scales found in the NCI CTCAE v4 will be utilized for AE assessment. A 
copy of the CTCAE v4 can be downloaded from the CTEP website at http://ctep.cancer.gov. All forms 
for AE/SAE recording and reporting can be found in the EDC system (Documents and Information 
Tab). 
 
11.1 
Definitions 
 
11.1.1 Adverse Event (AE) 
An AE is any untoward medical occurrence whether or not considered related to the study drug that 
appears to change in intensity during the course of the study. The following are examples of AEs:  
 Unintended or unfavorable sign or symptom 
 A disease temporally associated with participation in the protocol 
 An intercurrent illness or injury that impairs the well-being of the subject 
 
Hospitalization for elective surgery or routine clinical procedures that are not the result of an AE (e.g., 
surgical insertion of central line) should not be recorded as an AE.  
 
Disease progression should not be recorded as an AE, unless it is attributable to the study regimen by the 
site investigator. 


 
 
 
 
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11.1.2 Serious Adverse Event (SAE) 
A SAE is an adverse event that: 
 Results in death. NOTE: Death due to disease progression should not be reported as a SAE, 
unless it is attributable by the site investigator to the study drug(s) 
 Is life-threatening (defined as an event in which the subject was at risk of death at the time of the 
event; it does not refer to an event which hypothetically might have caused death if it were more 
severe) 
 Requires inpatient hospitalization for >24 hours or prolongation of existing hospitalization. 
NOTE: Hospitalization for anticipated or protocol specified procedures such as administration 
of chemotherapy, central line insertion, metastasis interventional therapy, resection of primary 
tumor, or elective surgery, will not be considered serious adverse events. 
 Results in persistent or significant disability/incapacity 
 Is a congenital anomaly or birth defect 
 Is an important medical event (defined as a medical event(s) that may not be immediately life-
threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the subject or may require intervention (e.g., medical, 
surgical) to prevent one of the other serious outcomes listed in the definition above). Examples 
of such events include, but are not limited to, intensive treatment in an emergency room or at 
home for allergic bronchospasm; blood dyscrasias or convulsions not resulting in hospitalization; 
or the development of drug dependency or drug abuse. 
 
11.1.3 Unexpected Adverse Event 
For this study, an AE is considered unexpected when it varies in nature, intensity or frequency from 
information provided in the current IB, prescribing information or when it is not included in the 
informed consent document as a potential risk. Unexpected also refers to AEs that are mentioned in the 
IB as occurring with a class of drugs or are anticipated from the pharmacological properties of the drug, 
but are not specifically mentioned as occurring with the particular drug under investigation.   
 
11.1.4 Relatedness 
AEs will be categorized according to the likelihood that they are related to the study drug(s). 
Specifically, they will be categorized using the following terms:  
 
Unrelated 
Adverse Event is not related to the study drug(s)  
Unlikely 
Adverse Event is doubtfully related to the study drug(s)  
Possible 
Adverse Event may be related to the study drug(s)  
Probable 
Adverse Event is likely related to the study drug(s)  
Definite 
Adverse Event is clearly related to the study drug(s)  
 
 
 


 
 
 
 
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11.2 
Reporting 
 
11.2.1 Adverse Events  
 AEs will be recorded from time of signed informed consent until 100 days after discontinuation 
of study drug(s) or until a new anti-cancer treatment starts, whichever occurs first.  
 AEs will be recorded regardless of whether or not they are considered related to the study 
drug(s).   
 All AEs will be recorded in the subject’s medical record and on the appropriate study specific 
eCRF form within the EDC system. 
 AEs considered related to study drug(s) will be followed until resolution to        
 ≤ Grade 1 or baseline, deemed clinically insignificant, and/or until a new anti-cancer treatment 
starts, whichever occurs first. 
 
11.2.2 Serious Adverse Events (SAEs) 
 
11.2.2.1 Site Requirements for Reporting SAEs to HCRN 
 SAEs will be reported from time of signed informed consent until 100 days after discontinuation 
of study drug(s) or until a new anti-cancer treatment starts, whichever occurs first.  
 SAEs will be reported on the SAE Submission Form within 1 business day of discovery of the 
event.   
 SAEs include events related and unrelated to the study drug(s).  
 All SAEs will be recorded in the subject’s medical record and on the appropriate study specific 
eCRF form within the EDC system.   
 All SAEs regardless of relation to study drug will be followed until resolution to ≤ Grade 1 or 
baseline and/or deemed clinically insignificant and/or until a new anti-cancer treatment starts, 
whichever occurs first. 
 
The site will submit the completed SAE Submission Form to HCRN within 1 business day of discovery 
of the event. The form may be submitted to HCRN electronically to safety@hoosiercancer.org. The site 
investigator is responsible for informing the IRB and/or other local regulatory bodies as per local 
requirements.   
 
The original copy of the SAE Submission Form and the email correspondence must be kept within the 
study file at the study site. 
 
Once the SAE has resolved (see resolution guidelines listed above), sites must submit a follow-up SAE 
Submission Form within a reasonable timeframe to HCRN electronically to safety@hoosiercancer.org.   
 
11.2.2.2 HCRN Requirements for Reporting SAEs to BMS  
HCRN will report all SAEs to BMS within 1 business day of receipt of the SAE Submission Form 
from a site. Follow-up information will be provided to BMS as it is received from site.    
 
Contact information for sending SAE information to BMS: 
SAE Email Address:  Worldwide.Safety@BMS.com 
SAE Facsimile Number:  609-818-3804 
 


 
 
 
 
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Reconciliation with the BMS safety database should occur every 3 months and prior to the database lock 
or final data summary. To complete the reconciliation, the sponsor-investigator or designee will request 
from BMS GPV&E (aepbusinessprocess@bms.com) the SAE reconciliation report. The request will 
include a reference to the study specific BMS protocol number. BMS GPV&E will send the sponsor-
investigator or designee the SAE reconciliation report to verify and confirm that all SAEs have been 
transmitted to BMS GPV&E. If the sponsor-investigator or designee determines a SAE was not 
submitted to BMS, the case should be sent immediately to BMS Worldwide Safety 
(worldwide.safety@bms.com).  The data elements listed on the GPV&E SAE reconciliation report will 
be used for case identification purposes. 
 
11.2.2.3 
HCRN Requirements for Reporting SAEs to Syndax 
HCRN will report SAEs to Syndax within 1 business day of receipt of the SAE Reporting Form from a 
site. Follow-up information will be provided to Syndax as it is received from a site.  
 
Contact information for sending SAE information to Syndax:  
Email Address:  SyndaxSAEReporting@syndax.com 
Facsimile Number:  1-888-529-3580 
 
11.3 
Sponsor-Investigator Responsibilities  
HCRN will send a SAE summary to the sponsor-investigator within 1 business day of receipt of SAE 
Submission Form from a site.  The sponsor-investigator will promptly review the SAE summary and 
assess for expectedness and relatedness.   
 
11.4 
HCRN Responsibilities to FDA 
HCRN will manage the Investigational New Drug Application (IND) associated with this protocol on 
behalf of the sponsor-investigator. HCRN will cross-reference this submission to the BMS and Syndax’s 
parent IND at the time of submission. Additionally, HCRN will submit a copy of these documents to 
BMS and Syndax at the time of submission to FDA. 
 
For protocols conducted under an IND, HCRN will be responsible for all communication with the FDA 
in accordance with 21CFR312 including but not limited to the 7 and 15 Day Reports, as well as an 
Annual Progress Report. Additionally, HCRN will submit a copy of these reports to BMS and Syndax at 
the time of submission to FDA. 
 
11.5 
IND Safety Reports Unrelated to this Trial 
BMS and Syndax will provide to HCRN IND safety reports from external studies that involve the study 
drug(s) per their guidelines.  HCRN will forward safety reports to the sponsor-investigator who will 
review these reports and determine if revisions are needed to the protocol or consent. HCRN will 
forward these reports to participating sites within 1 business day of receiving the sponsor-investigator’s 
review.  Based on the sponsor-investigator’s review, applicable changes will be made to the protocol 
and informed consent document (if required).  All IND safety reports will also be made available to sites 
via the EDC system.    
 
Upon receipt from HCRN, site investigators (or designees) are responsible for submitting these safety 
reports to their respective IRBs, as per their IRB policies. 
 


 
 
 
 
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12. 
STATISTICAL METHODS 
Statistical analysis of this study will be the responsibility of the Department of Biostatistics at Indiana 
University School of Medicine. Parameter estimates and relevant summary statistics will be reported for 
both efficacy and safety outcomes. Continuous variables will be summarized by means, medians, 
minima, maxima and standard deviations. Categorical variables will be summarized by frequencies and 
percentages. Missing data will not be imputed. Additional exploratory analysis will be conducted when 
appropriate. Changes from the analysis plan will not require an amendment to the protocol unless it 
changes a significant feature in the protocol; however, all changes from the original analysis plan will be 
documented in the final study report. The statistical analysis methods are outline below.   
 
12.1 
Study Design 
This is an open-label Phase II clinical trial with a safety lead-in. No randomization or blinding is 
involved. 
 
12.2 
Endpoints 
 
12.2.1 Definition of Primary Endpoint 
Overall Response rate (ORR) per RECIST is defined as CR plus PR by RECIST 1.1. 
 
12.2.2 Definition of Secondary Endpoints 
Overall Response rate per irRC is defined as irCR plus irPR as per irRC. PFS per RECIST is defined as 
the time from treatment start until the criteria for disease progression is met as defined by RECIST 1.1 
or death as a result of any cause. PFS per irRC is defined as the time from treatment start until the 
criteria for disease progression is met as defined by irRC or death as a result of any cause. Censoring 
will occur at date of last disease evaluation. Overall survival will be defined as the time from treatment 
start until death from any cause. Censoring will occur at last known date alive. 
 
Adverse events will be defined by the NCI Common Terminology Criteria for Adverse Events (NCI 
CTCAE) v4. 
 
12.3 
Sample Size and Accrual 
For the safety Lead-In, up to 18 subjects may be enrolled.  For Phase II, assuming a type I error rate of 
5% and a power of 90% to compare an uninteresting overall response rate (per RECIST 1.1) of 5% 
while declaring efficacy at 20%, Simon's optimal two stage design enrolls 21 patients in the first stage 
(with 6 of the 21 from the Safety Lead-in RP2D cohort). If at most one response is seen, then the trial is 
terminated for futility. Otherwise, stage 2 accrual continues to a total of 41 patients. If at most 4 patients 
respond among the 41 patients, the combination would not warrant further investigation. If at least 5 
patients respond, this therapy would warrant further investigation. The average sample size is 26.66 and 
the early termination probability is 71.70% for a drug with a response rate of 5%. All the calculations 
are based on the R function ph2simon from the package clinfun. 
 
Due to Funder decision, enrollment will halt after completion of accrual to the safety lead in group and 
not move on to Phase II. This decision is a result of a shift in priorities at the Funder level and not due to 
safety issues. Subjects currently on treatment will continue until the criteria for treatment 
discontinuation as defined above is met. 
 


 
 
 
 
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12.4 
Population for Analysis 
 
Population
Definition
Enrolled 
This will comprise all subjects who meet the 
eligibility criteria and are registered onto the study. 
Evaluable 
This will comprise all subjects who receive at least 
one dose of trial drug and either undergo at least 
one post-baseline assessment or die before any 
evaluation.
Safety 
This will comprise of all subjects that take a least 
one dose of study drug.
 
 
12.5 
Assessment of Safety 
Toxicities will be defined by the NCI Common Terminology Criteria for Adverse Events (NCI CTCAE) 
v4. 
 
12.6 
Assessment of Efficacy 
ORR and PFS will be assessed with RECIST 1.1 and irRC. 
 
12.7 
Data Analysis Plans 
 
12.7.1 Analysis Plans for Primary Objective 
For the Phase II study, the primary endpoint of objective response rate (per RECIST) in all evaluable 
and eligible patients will be summarized with the point estimate and corresponding 95% confidence 
interval that accounts the nature of two-stage design (Jung SH and Kim KM. On the estimation of the 
binomial probability in multistage clinical trials. Statistics in Medicine 23, 881-896. 2004). As an 
exploratory analysis, this will be also done separately for the patient cohort defined by their previous 
treatment, either nivolumab plus ipilimumab or nivolumab alone, respectively.  
 
12.7.2 Analysis Plans for Secondary Objectives 
Safety will be assessed in the Safety population.  Separate frequency tables will be generated for the 
safety run-in (by cohort) and the Phase II study.  ORR by irRC will be analyzed similarly to the primary 
endpoint.  Progression free (by both RECIST and irRC) and overall survival will be estimated using 
standard Kaplan-Meier curves. The median time-to-event for survival endpoint will be estimated along 
with the corresponding 95% confidence interval. Similar to Section 12.7.1, the analysis will be first done 
for all evaluable and eligible patients, and then done separately for the nivolumab plus ipilimumab 
cohort and the nivolumab alone cohort. 
 
12.7.3 Analysis Plans for Exploratory Objectives 
Quantitative analysis of correlative endpoints will be characterized by their mean and corresponding 
95% confidence interval by time point. Changes over time in PD-L1/L2 expression levels in tumor and 
blood, microRNA, and immune markers (see Section 8 for details) will be analyzed with paired t-tests.  
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to Section 12.7.1, the analysis will be first done for all evaluable and eligible patients, and then stratified 
for their previous treatment (nivolumab plus ipilimumab vs nivolumab alone) in the analysis using the 
logistic and Cox regression models. 
 
12.8 
Interim Analysis/Criteria for Stopping Study 
The formal interim analysis for efficacy is described in Section 12.3.   
 
13. 
TRIAL MANAGEMENT 
 
13.1 
Data and Safety Monitoring Plan (DSMP) 
The study will be conducted in accordance with the Indiana University Melvin and Bren Simon Cancer 
Center’s (IUSCC) DSMP for High Risk Safety Lead-In/Phase II Trials. 
 
HCRN facilitated oversight activities for High Risk Safety Lead-In/Phase II Trials include: 
 Review and processing of all AEs requiring expedited reporting as defined in the protocol 
 Provide trial accrual progress, safety information, and data summary reports to the sponsor-
investigator, including a weekly update of aggregate AE data. 
 Investigators will conduct continuous review of data and patient safety. For any increase in 
frequency of grade 3 or above adverse events (above the rate reported in the Investigator 
Brochure or package insert), the sponsor investigator will notify HCRN who will notify the 
DSMC Chair and Compliance Officer immediately. The notification will include the incidence 
of study adverse events, grades, and attributions, as well as investigator statements regarding 
comparison with risks per the IB/ package insert.    
 Notify participating sites of adverse events potentially requiring expedited reporting and 
subsequent DSMC recommendations for study modifications. 
 Investigators will conduct continuous review of data and patient safety.  
 Coordinate, during safety lead-in, weekly (Phase I) meetings (Safety Calls),and subsequently, 
during the phase II portion, monthly (Phase II) meetings which will include representation from 
each accruing site. 
o These meetings should include review of data, the number of subjects and significant 
toxicities as described in the protocol. HCRN should maintain meeting minutes and 
attendance for submission to the DSMC upon request. 
 Conduct the trial across all participating sites in accordance with the requirements set forth in the 
IUSCC DSMP. 
 
13.2 
IUSCC Data Safety Monitoring Committee Oversight 
The IUSCC Data and Safety Monitoring Committee (DSMC) is responsible for oversight of subject 
safety, regulatory compliance, and data integrity for this trial. The DSMC will review this study to 
assess toxicity, compliance, data integrity, and accrual per the Institutional DSMP. Trials managed by 
HCRN are not routinely audited or monitored by IUSCC; however, the IUSCC DSMC retains the right 
to audit HCRN trials on a for cause basis.  
 
The IUSCC DSMC will review study data semi-annually during the active treatment and safety follow-
up portion of the trial per the IUSCC DSMP.  
 
 
 


 
 
 
 
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In preparation for the IUSCC DSMC review, HCRN will provide the following: 
 Monthly Summary Reports 
 Reports of the following, if not already included in the Monthly Summary Report: 
o Adverse event summary report (including serious adverse events) 
o Study accrual patterns  
o Protocol deviations 
 Audit and/or monitoring results, if applicable 
 Data related to stopping/decision rules described in study design 
 HCRN weekly (Phase I) or monthly (Phase II) study update meeting minutes/ attendance  
 
Documentation of DSMC reviews will be provided to sponsor-investigator (SI) and HCRN.  The IUSCC 
DSMC will notify the sponsor-investigator and other regulatory bodies, as appropriate, for issues of 
immediate concern. The sponsor-investigator will work with HCRN to address the DSMC’s concerns as 
appropriate. 
 
At any time during the conduct of the trial, if it is the opinion of the sponsor-investigator that the 
risks (or benefits) to the patient warrant early closure of the study, this recommendation should be 
made in writing to the DSMC Chair and Compliance Officer. Alternatively, the DSMC may initiate 
suspension or early closure of the study at any time based on its review of the study reports.   
 
13.2.1 DSMC DLT Review  
Prior to making dose escalation/expansion/de-escalation decisions, the SI and the study team will 
officially review all toxicity events for each subject for confirming treatment-related DLT. The study 
statistician will assist the determination of DLT and the interpretation of the statistical rule for dose 
escalation. Once a decision has been reached by the investigator, the official decision and toxicity data 
will be submitted to the DSMC via email (IUSCC-DLT-Review-L@list.iupui.edu). Treating additional 
subjects may not proceed until official DSMC correspondence confirms approval of dosing decisions for 
the next stage. 
 
13.2.2 IND Annual Reports 
For trials with an IND held locally by the IU principal investigator or university, the IND Annual Report 
will be prepared and submitted to the Compliance Team. This report will be reviewed by the DSMC at 
the time of FDA submission.  
 
13.4 
Data Quality Oversight Activities 
Remote validation of the EDC system data will be completed on a continual basis throughout the life 
cycle of the study. Automated edit check listings will be used to generate queries in the EDC system and 
transmitted to the site to address in a timely fashion. Corrections will be made by the study site 
personnel.  
 
13.4.1 Onsite Monitoring 
Monitoring visits to the trial sites may be made periodically during the trial to ensure key aspects of the 
protocol are followed. During onsite monitoring visits, source documents will be reviewed for 
verification of agreement with data entered into the EDC system. It is important for the site investigator 
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or audit, if applicable. The site investigator and institution guarantee access to source documents by 
HCRN or its designee. 
 
The trial sites may also be subject to quality assurance audit by BMS, Syndax or its designee as well as 
inspection by appropriate regulatory agencies. 
 
13.5 
Compliance with Trial Registration and Results Posting Requirements 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the Food and 
Drug Administration Amendments Act (FDAAA), the sponsor-investigator of the trial is solely 
responsible for determining whether the trial and its results are subject to the requirements for 
submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov. All results of primary and 
secondary objectives must be posted to CT.gov within a year of completion.  The sponsor-investigator 
has delegated responsibility to HCRN for registering the trial and posting the results on 
clinicaltrials.gov. Information posted will allow subjects to identify potentially appropriate trials for 
their disease conditions and pursue participation by calling a central contact number for further 
information on appropriate trial locations and study site contact information.   
 
14. 
DATA HANDLING AND RECORD KEEPING 
 
14.1 
Data Management 
HCRN will serve as the Clinical Research Organization for this trial. Data will be collected through a 
web based clinical research platform (EDC system), a system compliant with Good Clinical Practices 
and Federal Rules and Regulations.  HCRN personnel will coordinate and manage data for quality 
control assurance and integrity. Select data will be collected and entered into the EDC system  by study 
site personnel from participating institutions.   
 
14.2 
Case Report Forms and Submission 
Generally, clinical data will be electronically captured in the EDC system and correlative results will be 
captured in EDC system or other secure database(s). If procedures on the study calendar are performed 
for standard of care, at minimum, that data will be captured in the source document. Select standard of 
care data will also be captured in the EDC system, according to study-specific objectives.  
 
The completed dataset is the sole property of the sponsor-investigator’s institution and should not be 
exported to third parties, except for authorized representatives of appropriate Health/Regulatory 
Authorities, without permission from the sponsor-investigator and HCRN. 
 
14.3 
Record Retention 
To enable evaluations and/or audits from Health Authorities/HCRN, the site investigator agrees to keep 
records, including the identity of all subjects (sufficient information to link records; e.g., hospital 
records), all original signed informed consent forms, copies of all source documents, and detailed 
records of drug disposition. All source documents are to remain in the subject’s file and retained by the 
site investigator in compliance with the site contract with HCRN.  No records will be destroyed until 
HCRN confirms destruction is permitted. 
 


 
 
 
 
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14.4 
Confidentiality 
There is a slight risk of loss of confidentiality of subject information. All records identifying the subjects 
will be kept confidential and, to the extent permitted by the applicable laws and/or regulations, will not 
be made publicly available. Information collected will be maintained on secure, password protected 
electronic systems. Paper files that contain personal information will be kept in locked and secure 
locations only accessible to the study site personnel.  
 
Subjects will be informed in writing that some organizations including the sponsor-investigator and 
his/her research associates, HCRN, BMS, Syndax, IRB, or government agencies, like the FDA, may 
inspect their medical records to verify the information collected, and that all personal information made 
available for inspection will be handled in strictest confidence and in accordance with local data 
protection laws. 
 
If the results of the study are published, the subject’s identity will remain confidential. 
 
15 
ETHICS 
 
15.1 
Institutional Review Board (IRB) Approval 
The final study protocol and the final version of the informed consent form must be approved in writing 
by an IRB. The site investigator must submit written approval by the IRB to HCRN before he or she can 
enroll subjects into the study.   
 
The site investigator is responsible for informing the IRB of any amendment to the protocol in 
accordance with local requirements. In addition, the IRB must approve all advertising used to recruit 
subjects for the study. The protocol must be re-approved by the IRB, as local regulations require.  
 
Progress reports and notifications of serious and unexpected adverse events will be provided to the IRB 
according to local regulations and guidelines. 
 
15.2 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles originating from the Declaration of 
Helsinki.  Conduct of the study will be in compliance with ICH Good Clinical Practice, and with all 
applicable federal (including 21 CFR parts 56 & 50), state, or local laws. 
 
15.3 
Informed Consent Process 
The site investigator will ensure the subject is given full and adequate oral and written information about 
the nature, purpose, possible risks and benefits of the study. Subjects must also be notified they are free 
to discontinue from the study at any time. The subject should be given the opportunity to ask questions 
and allowed time to consider the information provided. 
 
The subject’s signed and dated informed consent must be obtained before conducting any procedure 
specifically for the study. The site investigator must store the original, signed informed consent form. A 
copy of the signed informed consent form must be given to the subject.  
 
 
 


 
 
 
 
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16 REFERENCES 
 
1. Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F. 
Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 
2012. International journal of cancer. 2015 Mar 1;136(5):E359-86. 
2. Fisher R, Gore M, Larkin J. Current and future systemic treatments for renal cell carcinoma. 
InSeminars in cancer biology 2013 Feb 28 (Vol. 23, No. 1, pp. 38-45). Academic Press. 
3. Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, Tykodi SS, Sosman JA, 
Procopio G, Plimack ER, Castellano D. Nivolumab versus everolimus in advanced renal-cell 
carcinoma. New England Journal of Medicine. 2015 Nov 5;373(19):1803-13. 
4. Hammers H, Plimack ER, Infante JR, Ernstoff M, Rini BI, McDermott DF, Razak A, Pal SK, Voss 
M, Sharma P, Kollmannsberger CK. 1050OPhase I study of nivolumab in combination with 
ipilimumab in metastatic renal cell carcinoma (MRCC). Annals of Oncology. 2014 Sep 1;25(suppl 
4):iv361-2. 
5. Kato Y, Yoshimura K, Shin T, Verheul H, Hammers H, Sanni TB, Salumbides BC, Van Erp K, 
Schulick R, Pili R. Synergistic in vivo antitumor effect of the histone deacetylase inhibitor MS-275 
in combination with interleukin 2 in a murine model of renal cell carcinoma. Clinical Cancer 
Research. 2007 Aug 1;13(15):4538-46.  
6. Shen L, Ciesielski M, Ramakrishnan S, Miles KM, Ellis L, Sotomayor P, Shrikant P, Fenstermaker 
R, Pili R. Class I histone deacetylase inhibitor entinostat suppresses regulatory T cells and enhances 
immunotherapies in renal and prostate cancer models. PLoS One. 2012 Jan 27;7(1):e30815. 
7. Shen L, Pili R. Class I histone deacetylase inhibition is a novel mechanism to target regulatory T 
cells in immunotherapy. Oncoimmunology. 2012 Sep 1;1(6):948-50. 
8. Shen L, Orillion A, Pili R. Histone deacetylase inhibitors as immunomodulators in cancer 
therapeutics. Epigenomics. 2016 Mar;8(3):415-28. 
9. Pili R, Shen L, George S, Hammers H, Sandecki A, Collins C, Espinoza-Delgado I, Carducci MA. 
Phase I/II study of high-dose interleukin 2, aldesleukin, in combination with the histone deacetylase 
inhibitor entinostat in patients with metastatic renal cell carcinoma. ASCO 2016. 
 
 


 
 
 
 
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11. 
APPENDICES 
11.1 
Appendix 1. Concomitant Medications to Avoid 
Examples of sensitive in vivo CYP substrates and CYP substrates with narrow therapeutic range are 
summarized below.  
 
Examples of substrates that may be affected by entinostat 
CYP Enzymes 
Substrates with narrow therapeutic range1 
CYP1A2  
Theophylline, tizanidine  
CYP2C8
Paclitaxel
CYP3A2  
Alfentanil, astemizole3, cisapride3, cyclosporine, dihydroergotamine, ergotamine, fentanyl, 
pimozide, quinidine, sirolimus, tacrolimus, terfenadine3 
1 
CYP substrates with narrow therapeutic range refers to drugs whose exposure-response relationship 
indicates that small increases in their exposure levels by the concomitant use of CYP inhibitors may lead to 
serious safety concerns (e.g., Torsades de Pointes). 
2 
Because a number of CYP3A substrates (e.g., darunavir, maraviroc) are also substrates of P-gp, the 
observed increase in exposure could be due to inhibition of both CYP3A and P-gp. 
3 
Withdrawn from the United States market because of safety reasons.
 
P-gp Inhibitors and Inducers 
Inhibitors 
Inducers 
Amiodarone, azithromycin, captopril, carvedilol, clarithromycin, 
conivaptan, diltiazem, dronedarone, felodipine, lopinavir, quercetin, 
ranolazine, ticagrelor, ritonavir, cyclosporine, verapamil 
erythromycin, ketoconazole, itraconazole, quinidine 
Avasimibe, carbamazepine, phenytoin, rifampin, 
St John’s Wort, tipranavir/ritonavir  
 
Gastric Acid Reducing Drugs 
Proton Pump Inhibitors 
 
Omeprazole (Prilosec, Zegerid)  
 
Lansoprazole (Prevacid)  
 
Rabeprazole (AcipHex)  
 
Pantoprazole (Protonix)  
 
Esomeprazole (Nexium)  
H2 Inhibitors 
 
Cimetidine (Tagamet) 
 
Ranitidine (Zantac) 
 
Famotidine (Pepcid) 
 
Nizatidine (Axid) 
Antacids 
 
Alka-Seltzer 
 
Alka-2, Surpass Gum, Titralac, Tums 
 
Milk of Magnesia 
 
Alternagel, Amphojel 
 
Gaviscon, Gelusil, Maalox, Mylanta, Rolaids 
 
Pepto-Bismol 
 
Information obtained from the following website: Gastric acid reducing drugs: http://www.everydayhealth.com/ulcer/ulcer-
treatment.aspx  
 


 
 
 
 
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11.2 
Appendix 2. Nivolumab and Ipilimumab Adverse Event Management Algorithms 
These general guidelines constitute guidance to the site Investigator and may be supplemented through 
discussions with the Sponsor-Investigator by contacting the BTCRC project manager. The guidance 
applies to all immuno-oncology agents and regimens. 
 
As general principle, differential diagnoses should be diligently evaluated according to standard medical 
practice. Non-inflammatory etiologies should be considered and appropriately treated. 
 
Corticosteroids are a primary therapy for immuno-oncology drug-related adverse events. The oral 
equivalent of the recommended IV doses may be considered for ambulatory patients with low-grade 
toxicity. The lower bioavailability of oral corticosteroids should be taken into account when switching to 
the equivalent dose of oral corticosteroids. 
 
Consultation with a medical or surgical specialist, especially prior to an invasive diagnostic or 
therapeutic procedure, is recommended. 
 
The frequency and severity of the related adverse events covered by these algorithms will depend on the 
immuno-oncology agent or regimen being used. 


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