Clinical trial NCT01935947
Conditions: Recurrent Non-Small Cell Lung Carcinoma Stage IIIA Non-Small Cell Lung Cancer Stage IIIB Non-Small Cell Lung Cancer Stage IV Non-Small Cell Lung Cancer
Sponsor: National Cancer Institute (NCI)
Start date: 2013-05-01; Completion date: 2017-04-01
Enrollment: 17 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This randomized phase II trial studies how well azacitidine and entinostat before chemotherapy works in treating patients with non-small cell lung cancer that has spread to other places in the body. Drugs used in chemotherapy, such as azacitidine, irinotecan hydrochloride, gemcitabine hydrochloride, docetaxel, and pemetrexed disodium, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Entinostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving azacitidine and entinostat before chemotherapy may work better in treating patients with non-small cell lung cancer.

Detailed description:
PRIMARY OBJECTIVES:

I. Percentage of patients progression-free at 6 months from time of randomization.

SECONDARY OBJECTIVES:

I. Progression-free survival (PFS). II. Overall survival (OS).

OUTLINE: Patients are randomized to 1 of 3 treatment arms.

ARM A: Patients receive azacitidine subcutaneously (SC) on days 1-6 and 8-10 and entinostat orally (PO) on days 3 and 10. Treatment repeats every 28 days for 2 courses in the absence of disease progression or unacceptable toxicity. Patients with stable or progressive disease receive chemotherapy of the treating oncologist's choice comprising irinotecan hydrochloride intravenously (IV) on day 1, docetaxel IV on day 1, pemetrexed disodium IV on day 1, or gemcitabine hydrochloride IV on days 1 and 8. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity.

ARM B: Patients receive azacitidine PO on days 1-21 and entinostat PO on days 3 and 10. Treatment repeats every 28 days for 2 courses in the absence of disease progression or unacceptable toxicity. Patients with stable or progressive disease receive chemotherapy of the treating oncologist's choice as in Arm A.

ARM C: Patients receive chemotherapy of the treating oncologist's choice as in Arm A.

After completion of treatment, patients are followed up every 3-6 months for 24 months and then yearly thereafter.

Arms: arm 1: Patients receive azacitidine SC on days 1-6 and 8-10 and entinostat PO on days 3 and 10. Treatment repeats every 28 days for 2 courses in the absence of disease progression or unacceptable toxicity. Patients with stable or progressive disease receive chemotherapy of the treating oncologist's choice comprising irinotecan hydrochloride IV on day 1, docetaxel IV on day 1, pemetrexed disodium IV on day 1, or gemcitabine hydrochloride IV on days 1 and 8. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity. arm 2: Patients receive azacitidine PO on days 1-21 and entinostat PO on days 3 and 10. Treatment repeats every 28 days for 2 courses in the absence of disease progression or unacceptable toxicity. Patients with stable or progressive disease receive chemotherapy of the treating oncologist's choice as in Arm A. arm 3: Patients receive chemotherapy of the treating oncologist's choice as in Arm A.
Interventions: intervention 1: Azacitidine intervention 2: Azacitidine intervention 3: Docetaxel intervention 4: Entinostat intervention 5: Gemcitabine Hydrochloride intervention 6: Irinotecan Hydrochloride intervention 7: Laboratory Biomarker Analysis intervention 8: Pemetrexed Disodium
Intervention descriptions: intervention 1: Given SC intervention 2: Given PO intervention 3: Given IV intervention 4: Given PO intervention 5: Given IV intervention 6: Given IV intervention 7: Correlative studies intervention 8: Given IV

Protocol documents:
Prot_SAP_000.pdf: 
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TITLE:  A Randomized Phase II Trial of Cytotoxic Chemotherapy with or without 
Epigenetic Priming in Patients with Advanced Non-Small Cell Lung Cancer 
 
Coordinating Center: 
 
 
Johns Hopkins University School of Medicine 
 
*Principal Investigator: 
Julie Brahmer, MD 
 
Bunting Blaustein Cancer Research Building, G94 
 
1650 East Orleans Street  
 
Baltimore, MD 21287 
 
410-502-7159 
 
brahmju@jhmi.edu  
 
Johns Hopkins East Baltimore Campus (Coordinating Center) 
Co-Investigators (Consent): 
 
 
David Ettinger, MD 
 
Christine Hann, MD, PhD 
 
Ronan Kelly, MD 
 
Jarushka NaidooHyunseok Kang, MD 
 
Patrick Forde, MD 
 
Tammy Beckman, CRNP, MSN 
 
Sarah Bonerigo, PA-C 
 
 
Johns Hopkins East Baltimore Campus 
 
RECIST Radiology Co-Investigators (Do Not Consent):  
 
 
Karen Bleich, MD 
 
Karen Horton, MD 
 
Pamela Johnson, MD 
 
Atif Zaheer, MD 
 
Stefan Zimmerman, MD 
 
Siva Raman, MD 
 
Bayview Medical Center 
 
(Do Not Consent):                       
 
Serena McClam Liebengood, MD 
 
Franco Verde, MD 
 
Hazem Hawasli, MD 
 
Johns Hopkins East Baltimore Campus  
Pathologist (Do Not Consent): 
 
 
Peter Illei, MD 
 
Edward Gabrielson, MD 
 
Justin Bishop, MD 
 


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Johns Hopkins East Baltimore Campus 
Co-Investigators (Do not Consent): 
 
 
Malcolm Brock, MD 
 
Stephen Baylin, MD 
 
James Herman, MD 
 
 
 
Participating Institutions: 
Johns Hopkins Bayview Medical Center 
 
4940 Eastern Avenue 
 
Baltimore, MD 21224 
 
Michael Purtell, MD, PhD 
 
Danijela Jelovac, MD 
 
Margaret (Peggy) Lang, CRNP, MSN 
 
Clare Ferrigno, CRNP 
 
 
CA011/University of Southern California/ Norris 
Comprehensive Cancer Center  
Sub-Site Principal Investigator: Barbara Gitlitz, MD 323-865-3906 
 
1441 Eastlake Avenue,  
 
Los Angeles, CA 90089 
 
 
 
CA829/USC Norris Oncology/Hematology-Newport Beach 
Sub-Site Principal Investigator: George Semeniuk, MD 949-646-6441 
 
520 Superior Avenue, Suite 300 
 
Newport Beach, CA 92663 
 
 
      SC008/Medical University of South Carolina/Hollings Cancer    
 
      Center  
Sub-Site Principal Investigator: John Wrangle, MD 843-792-7789 
 
     173 Ashley Avenue 
 
     Charleston, SC 29425 
 
 
 
Statistician: 
 
Program Manager: 
 
Gary Rosner, ScD 
 
 
 
 
Jessica Wakefield 
 
410-955-4884 
 
 
 
 
443-287-9377 
 
grosner1@jhmi.edu 
 
 
 
 
jrober31@jhmi.edu 
 
Lead EB Campus Research Nurse: 
Responsible Data Manager: 
Joanne Riemer, RN 
 
 
 
 
Heather Schneider 
443-287-4114 
 
 
 
 
410-502-0984 
Fax 410-614-9334 
 
 
 
 
fax 410-502-9933 


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Jriemer3@jhmi.edu  
 
 
 
 
hschne12@jhmi.edu  
 
Lead Pharmacist: 
 
 
           Lead BV Campus Research Nurse: 
Jing Liu, Pharm D  
 
                 Barbara Coleman, RN 
410-614-6774 
 
 
          410-550-2705 
Fax: 410-502-0788 
 
 
 
    bcolema1@jhmi.edu 
Jliu69@jhmi.edu 
 
NCI Supplied Agent:   
Entinostat (IND #117931; NSC #706995) Syndax Pharmaceuticals, Inc.  
5-azacitidine for injection (IND #117931; NSC 102816) Celgene Corporation 
CC-486 (oral azacitidine) (IND #117931; NSC 102816) Celgene Corporation 
 
IND Sponsor:  NCI 
Protocol Type / Version # / Version Date: Amendment / 10.1 /03/11/2016 
 
 
 
SCHEMA 
 
 
 
Treating physician will choose the chemotherapy for each subject.  Patients will then be randomized, 
stratified by chosen chemotherapy, to receive chemotherapy alone (Arm C), chemotherapy preceded by 
azacitidine 40 mg/m2/day subcutaneous days 1-6 and 8-10 and entinostat 7mg PO days 3 and 10 on a 28 
day cycle (Arm A), or CC486 300 mg PO days 1-21 and entinostat 7 mg PO days 3 and 10 on a 28 day 
cycle (Arm B). 


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Chemotherapy will consist of the treating oncologist’s choice from 4 single agent regimens, including: 
- irinotecan 300mg/m2 IV once every 3 weeks 
- docetaxel 75mg/m2 IV once every 3 weeks 
- gemcitabine 1000g/m2 IV days 1 and 8 of a 3 week cycle 
- pemetrexed 500 mg/m2  IV once every 3 weeks (for non-squamous histology only) 
 
Patients randomized to no epigenetic priming (Arm C) will receive chemotherapy immediately.  Patients 
randomized to epigenetic priming (Arms A and B) who experience partial or complete response (PR or CR) 
after 2 cycles will be allowed continue epigenetic therapy until disease progression.  Patients randomized 
to epigenetic priming (Arms A and B) who experience stable or progressive disease (SD or PD) after 2 
cycles of induction, or progress before completing 2 cycles, will proceed to cytotoxic therapy.  All patients 
may continue on cytotoxic therapy until PD with the following exception: those with SD after 2 cycles of 
epigenetic priming and SD after the first 2 cycles of cytotoxic therapy will receive an additional 2 cycles 
of epigenetic priming, followed by re-initiation of cytotoxic therapy.  Patients receiving additional priming 
who experience PR or CR will continue azacitidine and entinostat until progression.  Patients receiving 
additional priming who experience SD or PD will proceed to cytotoxic therapy. 
 
 
 


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TABLE OF CONTENTS 
SCHEMA .........................................................................................................................................2 
1. 
OBJECTIVES ......................................................................................................................7 
1.1 
Primary Objectives ...................................................................................................7 
1.2 
Secondary Objectives ...............................................................................................7 
2. 
BACKGROUND .................................................................................................................7 
2.1 
Non-Small Cell Lung Cancer...................................................................................7 
2.2 
CTEP IND Agents ...................................................................................................7 
2.3 
Standard Cytotoxic Agents (No CTEP IND) .......................................................121 
2.4 
Rationale for Epigenetic Priming of Chemotherapy ............................................121 
2.5 
Correlative Studies Background ..........................................................................165 
3 
PATIENT SELECTION ..................................................................................................176 
3.1 
Eligibility Criteria ................................................................................................176 
3.2 
Exclusion Criteria ................................................................................................187 
3.3 
Inclusion of Women and Minorities ....................................................................198 
4 
REGISTRATION PROCEDURES ...................................................................................18 
4.1 
General Guidelines .................................................................................................18 
4.2 
Registration Process ...............................................................................................20 
5 
TREATMENT PLAN ........................................................................................................19 
5.1 
Agent Administration .............................................................................................19 
5.2 
General Concomitant Medication and Supportive Care Guidelines ....................243 
5.3 
Duration of Therapy .............................................................................................254 
5.4 
Duration of Follow Up .........................................................................................254 
5.5 
Criteria for Removal from Study .........................................................................255 
6 
DOSING DELAYS/DOSE MODIFICATIONS..............................................................265 
7 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ..........................288 
7.1 
Comprehensive Adverse Events and Potential Risks Lists (CAEPRs) .................28 
7.2 
Adverse Event Characteristics .............................................................................387 
7.3 
Expedited Adverse Event Reporting ......................................................................38 
7.4 
Routine Adverse Event Reporting .......................................................................411 
7.5 
Secondary Malignancy .........................................................................................411 
7.6 
Second Malignancy ..............................................................................................411 
8 
PHARMACEUTICAL INFORMATION ........................................................................411 
8.1 
CTEP IND Agent(s) .............................................................................................421 
8.2 
Commercial Agents .............................................................................................465 


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9 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ......................................477 
9.1 
Biomarker Studies ................................................................................................477 
10 
STUDY CALENDAR .......................................................................................................48 
11 
MEASUREMENT OF EFFECT......................................................................................511 
11.1 
Antitumor Effect – Solid Tumors ........................................................................511 
12 
DATA REPORTING / REGULATORY REQUIREMENTS .........................................588 
12.1 
Data Reporting .......................................................................................................58 
12.2 
CTEP Multicenter Guidelines ................................................................................59 
12.3 
Collaborative Agreements Language .....................................................................59 
13 
STATISTICAL CONSIDERATIONS.............................................................................611 
13.1 
Study Design/Endpoints.......................................................................................611 
13.2 
Sample Size/Accrual Rate ....................................................................................622 
13.3 
Stratification Factors ............................................................................................632 
13.4 
Interim Analyses ..................................................................................................632 
13.5 
Analysis of Secondary Endpoints ..........................................................................65 
13.6     Reporting and Exclusions ......................................................................................65 
REFERENCES ..............................................................................................................................66 
APPENDIX A: PERFORMANCE STATUS CRITERIA .............................................................69 
APPENDIX B: CTEP MULTICENTER GUIDELINES ..............................................................71 
APPENDIX C: PLASMA AND SERUM PROCESSING PROTOCOL ......................................73 
APPENDIX D:  PATIENT DIARY FOR ARM A PATIENTS ..................................................754 
APPENDIX E:  PATIENT DIARY FOR ARM B PATIENTS ....................................................765 
 
 
 
 
 
 
 
 
 
 
 


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1. OBJECTIVES 
 
1.1 Primary Objectives 
 
1) Percentage of patients progression-free at 6 months from time of 
randomization 
Disease status at six months will be compared to disease status at 
time of randomization, and response coded based on RECIST 1.1 
criteria.  (Note: interim scans between baseline and the 6 month 
assessment will be used for clinical decision making as defined in 
the protocol, but not for assessment of this primary endpoint.)  
 
1.2 Secondary Objectives 
 
1) Progression Free Survival 
Progression-free survival (PFS) will be measured from the time of 
randomization until progressive disease or death.  (Note: all scans 
will be used in assessment of this endpoint). 
 
2) Overall Survival 
Overall Survival (OS) will be measured from the time of enrollment 
to trial until death. 
 
 
2. BACKGROUND 
 
2.1 Non-Small Cell Lung Cancer 
Lung cancer is the most common cause of death from malignancy in both men and 
women. An estimated 157,300 people in the United States died from lung cancer in 
2010.1  Most non-small cell lung cancer patients present with advanced disease. 
Metastatic disease is typically treated with chemotherapy alone and is considered 
incurable with current therapy. There are many FDA-approved and compendia 
listed therapies for recurrent NSCLC, including all four of the chemotherapy 
options allowed in this protocol. Despite the variety of therapies, overall survival 
for NSCLC remains poor. New, effective therapies and strategies for lung cancer 
are a critical need. 
 
2.2 CTEP IND Agents 
 
2.2.1 Azacitidine 
 
DNA methyltransferase inhibitors have been under investigation for over 25 years.  
The most widely used DNA methyltransferase inhibitor is 5-azacitidine.2 This 
compound is a cytidine analogue that functions as a mechanism-dependent suicide 
inhibitor of DNA methyltransferases especially DNMT1.  The active metabolite of 


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5-azacitidine needs to be incorporated into DNA. DNA methyltransferases  
 
recognize 5-azacitidine as natural cytosine and initiate the methylation reaction. 
However, the 5-azacitidine prevents the completion of the methylation reaction.  
The DNMT1 enzyme becomes trapped and degraded.3 5-azacitidine has proven to 
be effective in a phase III clinical trial and has recently gained Food and Drug 
Administration approval for the treatment of myelodysplastic syndrome.4   
 
Azacitidine in Lung Cancer 
 
5-azacitidine has been studied in several phase I trials. Between 1973 and 1977, at 
least nine clinical studies of solid tumor patients (sample size between 8 and 177) 
treated with 5-azacitidine were performed that included a total of 78 lung cancer 
patients.5  A variety of doses and regimens (intravenously or subcutaneously) were 
studied, with overall modest or no benefit. In the largest of these, 1 of 24 lung 
cancer patients had a partial remission which was transient. In 1987, another 
demethylating azaribonucleoside, 5,6-dihydroxy-azacitidine (DHAC) was first 
investigated in a phase II study in patients with extensive, untreated NSCLC.6   It 
was given as a continuous infusion over five days and repeated every 21 days. Five 
out of 17 patients had disease stability of 2 or more months. Since 1984, at least six 
clinical phase I/II studies of solid tumor patients treated with decitabine were 
performed that included more than 50 lung cancer patients. Momparler et al. 
published their trial of decitabine in patients with metastatic lung cancer.7,8  Median 
survival was 6.7 months, with three patients surviving more than 15 months. Major 
toxicities were hematopoietic, requiring 5–6 weeks recovery before repeat of 
treatment.  
 
Oral Azacitidine (CC-486) 
 
Oral azacitidine entered clinical testing in 2006 in subjects with MDS, CMML, and 
AML. The AZA PH US 2007 CL 005 study has shown that oral azacitidine is 
bioavailable and produces cumulative exposures (area under the concentration 
curve [AUC]) that are 30 to 60% of the exposure achieved with the labeled dose 
and schedule of Vidaza®. A MTD of 480 mg daily for 7 days was defined based on 
dose-limiting diarrhea at 600 mg 36. The second part of the AZA PH US 2007 CL 
005 study went on to explore both daily and twice-daily extended dosing schedules 
of 14 and 21 out of 28 days in a non-crossover fashion. Daily doses of 300 mg have 
proven to be tolerated on both the 14 and 21 out of 28 day schedules with 
myelosuppression, GI symptoms, and fatigue being the most common toxicities.36 
Subjects treated with oral azacitidine for 21 days had DNA hypomethylation that 
persisted through the end of cycle. This contrasts with the lack of persistent 
hypomethylation at the end of cycle when treated with oral azacitidine for only 7 
days, thus providing mechanistic support for treating beyond 7 days. In summary, 
oral azacitidine is biologically active, reducing DNA methylation when 
administered at low doses on extended schedules. 


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In December, 2011, a Phase 1b study of CC-486 (AZA-ST-001) began enrolling 
subjects with relapsed or refractory solid tumors. In this safety study, patients are 
assigned at the investigator’s discretion to one of 3 arms: 
 Arm A: escalating doses of CC-486 days 1 to 14 out of 21 day schedule in 
combination with carboplatin (AUC = 4) on day 8 every 21 days. 
 Arm B: escalating doses of CC-486 days 1 to 14 out of 21 day schedule in 
combination with Abraxane® 100 mg/m2 days 8, 15 and 21 
 Arm C: escalating doses of CC-486 days 1 to 21 out of 21 day schedule 
 
Approximately 18 patients have completed at least on cycle of treatment on this 
study. There have been 4 Dose Limiting Toxicities (DLTs) to date at the 200 mg 
dose level of CC-486: 2 on Arm B and one each on Arms A and C. All 4 DLTs 
were neutropenia, 2 were febrile neutropenia (one on Arm B and one on Arm C) 
and 2 were delay to the start of Cycle 2 due to an Absolute Neutrophil Count < 1.5 
X 109/L (one on Arm B and one on Arm A). Arm B has since been amended to 
eliminate the day 21 dose of Abraxane®. The study is continuing to enroll and a 
MTD has not yet been defined. 
 
2.2.2 Entinostat 
 
Histone deacetylases (HDACs) are important in the regulation of gene expression 
and in the field of target-specific anticancer drug development.9-11 HDACs 
deacetylate histones which leads to repression of gene transcription. Eight HDACs 
have been identified in mammalian cells. Beside specific subcellular localization 
and distinct tissue expression patterns, different HDACs have been shown to 
associate with distinct transcription regulatory complexes.12-14 A number of HDAC 
inhibitors can induce differentiation, growth arrest, and/or apoptosis of tumor cells 
in vitro.11,15-24  Some have been shown to inhibit growth of cancer cells in animal 
models.11,25-28 A smaller number of these are apparently nontoxic to the host and 
possibly target tumors selectively.11,29 
 
Entinostat in Lung Cancer 
 
A phase I clinical trial has been conducted using entinostat in advanced solid 
tumors.  Of the 31 patients enrolled, four of them had NSCLC.30  One NSCLC 
patient required two dose reductions from the 10 mg/m2 dose cohort, but also had 
disease stabilization for 9 months.  Another NSCLC patient had stable disease after 
two cycles but during the fourth cycle opted to change to standard therapy before 
disease assessment could be made.  The main side effects included hematologic and 
gastrointestinal toxicities.   
 
2.2.3  Pre-clinical Use of DNMT and HDAC Inhibitor Combinations 
 
The use of DNMT and HDAC inhibitors as single agents in patients with solid 
tumors has been slowed by toxicity at doses required to achieve reversal of 


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methylation.  An observation by Cameron and colleagues may change the utility of 
these agents in solid tumors.31  This study showed that the methylation pattern of 
colon cancer cell lines was modulated in a synergistic fashion when treated with 
DNMT and HDAC inhibitors in combination.  
 
Further studies have been performed in lung cancer cell lines.  One study assessed 
the combination of decitabine with either depsipeptide or trichostatin A.  This study 
documented enhanced apoptosis in the cell lines treated with the combination as 
compared to an HDAC inhibitor alone.32  
 
The combination of DNA methyltransferase inhibitors has been assessed in a lung 
cancer animal model.  Decitabine and phenylbutyrate were studied in the 
preventative setting in mice.  Mice treated with decitabine had 30% fewer tobacco-
carcinogen induced lung cancers.  Mice treated with decitabine and phenylbutyrate 
had over 50% fewer tobacco-carcinogen induced lung cancers.  These data in pre-
clinical models are encouraging for the use of these classes of agents in patients.33 
 
2.2.4 Clinical Use of DNMT and HDAC Inhibitor Combinations in 
Hematologic Malignancies 
 
DNMT and HDAC inhibitors are currently being studied in combination in 
hematologic malignancies.  A phase I clinical trial assessing the use of 5-azacitidine 
and phenylbutyrate in myelodysplasia was recently published.34  In this study 11 of 
29 patients treated had clinical responses.  Response was highly correlated with 
reversal of previously aberrantly methylated genes in myelodysplasia.  The biggest 
drawback of this combination was the need for continuous infusion of 
phenylbutyrate.   
 
A phase I clinical trial recently completed at Johns Hopkins assessing the 
combination of entinostat and 5-azacitidine in myelodysplasia.  To date in this 
study, 14 of 19 evaluable patients have responded, including 2 complete remissions 
(Gore, unpublished data).  Several of the responses continue to improve over time 
(for example, hematologic improvement progressing to partial response). 
Responses have been seen across dose cohorts.   
 
2.2.5 Clinical Use of Azacitidine and Entinostat in Lung Cancer 
 
We have recently completed the first combination study of azacitidine and 
entinostat in patients with metastatic lung cancer.35  This study defined a regimen 
of azacitidine 40 mg/m2 days 1 – 6 and 8 – 10 and entinostat 7 mg PO on days 3 
and 10 on a 28-day schedule as safe and well-tolerated.  Remarkably, although this 
population was heavily pretreated (with progressive disease after a median of three 
prior regimens for metastatic disease), major objective responses were observed, 
including a complete response, a partial response with complete resolution of 
multiple liver metastases, and several patients with durable stable disease.  Median 


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overall survival in an intent-to-treat analysis (including all patients enrolled on 
study) was 6.4 months, comparing favorably with any available therapy for this 
patient population.   
 
 
2.3 Standard Cytotoxic Agents (No CTEP IND) 
 
2.3.1 Docetaxel 
Docetaxel is an FDA approved therapy for single agent treatment in the second line 
for NSCLC.   Docetaxel is an anti-mitotic chemotherapy.  The molecule reversibly 
binds and stabilizes microtubules and prevents depolymerization.  Docetaxel is 
administered intravenously as a bolus dosed at 75 mg/m2 every 3 weeks.  The drug 
is metabolized by cytochrome p450 CYP3A4 and CYP3A5 isoenzymes 
 
2.3.2 Gemcitabine 
Gemcitabine in combination with cisplatin is an FDA approved therapy for first 
line therapy in inoperable NSCLC.  It is frequently used as a single agent in the 
second line setting.  Gemcitabine is a nucleoside analog chemotherapy.  
Gemcitabine, when incorporated into DNA, blocks replication to exert its anti-
neoplastic activity.  Gemcitabine is administered intravenously as a bolus dosed at 
1000 mg/m2 on days 1, 8, and 15 of a 28 days cycle.  Gemcitabine has no indication 
for dose adjustments based on renal or hepatic impairment. 
 
2.3.3 Irinotecan 
Irinotecan is an NCCN compendia listed agent for single agent use in the second 
line for NSCLC.  Irinotecan is a topoisomerase I inhibitor which subsequently 
inhibits DNA replication and transcription.  Irinotecan is administered as an 
intravenous bolus on day one of a 21 day cycle at a dose of 300 mg/m2.  Major 
drug metabolism occurs through p450 CYP2B6 and CYP3A4, P-Glycoprotein, 
SLCO1b1, and UGT1A1 and dose reductions are recommended in the setting of 
hepatic impairment. 
 
2.3.4 Pemetrexed 
Pemetrexed carries an FDA approval for therapy as single agent treatment in the 
second line for NSCLC.  Pemetrexed is a folate analog that work by inhibiting 
purine and pyrimidine synthesis and prevents DNA and RNA formation.  
Pemetrexed is administered as an intravenous bolus on day one of a 21 day cycle 
at a dose of 500 mg/m2.  Use is not recommended in patient with creatinine 
clearance < 45 mL/minute.  Dose reductions are recommended in the setting of 
transaminitis.   
 
 
 
2.4 Rationale for Epigenetic Priming of Chemotherapy 
 


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Epigenetics in Cancer 
 
Both genetic and epigenetic alterations play central roles in tumorigenesis.37,38  
Aberrant DNA methylation and aberrant histone acetylation represent two of the 
critical mechanisms of tumor-specific epigenetic alterations. Through these 
epigenetic changes, tumor-suppressor genes can be aberrantly “silenced,” 
promoting dysregulated cell growth. Both of these critical mechanisms of 
epigenetic silencing can be reversed, using DNA methyltransferase inhibitors (such 
as azacitidine) and histone deacetylase inhibitors (such as entinostat).  Our group 
has led efforts to define the biology and therapeutic implications of epigenetic gene 
silencing in cancer, including demonstration of synergistic re-expression of 
silenced tumor suppressor genes using these classes of drugs.31,39 
 
Epigenetics and Chemotherapeutic Resistance in Lung Cancer 
 
Approximately 20 - 25% of advanced non-small cell lung cancer patients respond 
to initial therapy with platinum containing paclitaxel doublets.  However, response 
rates to subsequent single or double agent regimens for recurrent and progressive 
disease are poor, typically in the range of 9 - 10%.40 Erlotinib is the only agent 
approved for use after second-line therapy in lung cancer, with a demonstrated 
response rate of 8.9% in patients with one or two prior therapies.41  Mechanisms of 
resistance accounting for the progressively unresponsive nature of these tumors 
have not been fully defined. 
 
Recent data suggests that epigenetic mechanisms are essential to the maintenance 
of a subpopulation of drug-resistant tumor cells, even in tumors highly susceptible 
to targeted therapeutics.42 Using four different HDAC inhibitors, including 
entinostat, Sharma et al. were able to prevent persistence of a drug-tolerant 
population.  These data suggest that reversal of epigenetic gene silencing could 
represent a means of increasing the efficacy of treatments with known activity in 
lung cancer. 
 
Clinical observations from lung cancer patients treated with the combination 
of azacitidine and entinostat 
 
An intriguing observation from our completed study of the combination of 
azacitidine and entinostat in non-small cell lung cancer concerned the response to 
the immediate subsequent therapy following disease progression on study.  Given 
the advanced state of disease and the number of prior therapies given, the duration 
of survival post-epigenetic therapy in many patients on this study was surprising 
(Figure 3A).  Median survival among patients who completed at least one cycle of 
epigenetic therapy was 8.6 months (95% CI 5.5 – 12.2) and includes ongoing long-
term survivors of 44 and 52 months post-epigenetic therapy, both having received 
only one post-study treatment regimen. A total of 19 patients received at least one 
subsequent systemic treatment in the 6 months after going off study. Interestingly, 


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four of the patients who received subsequent chemotherapy (21%) had major 
objective responses to the immediate subsequent therapy (Figure 3B).  These data, 
while preliminary, support the hypothesis that combination epigenetic therapy may 
improve the responsiveness of lung cancer to subsequent cytotoxic therapies. 
Testing this concept, epigenetic priming as a strategy to sensitize tumors to 
cytotoxic therapy, is the primary goal of the current proposal. 
 
Several cases of major objective response observed here are of interest.  One is a 
man who had previously experienced disease progression on carboplatin, 
paclitaxel, and bevacizumab.  Following epigenetic therapy, he was given a similar 
regimen: cisplatin, docetaxel, and bevacizumab. Remarkably, he has experienced a 
rapid and durable response, with a 90% reduction in tumor by RECIST 1.1 criteria 
as well as normalization of elevated CEA.  Representative images are shown in 
Figure 4. 
 
Additional recent clinical data in support of epigenetic priming 
 
Emerging data from clinical studies in multiple tumor types supports the hypothesis 
that epigenetically targeted therapy may sensitize to subsequent cytotoxic therapy.  
A recent study in platinum-resistant ovarian cancer patients explored the 
demethylating agent decitabine days 1 – 5 followed by carboplatin on day 8.43  Of 
17 patients treated, 6 objective responses (1 CR, 5PR; RR = 35%) were observed.  
Overall clinical benefit rate was 70%, and median progression-free survival was 
over 300 days.  
 
 
 
 
 


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Figure 3: Survival, subsequent therapies, and response.  A.  Duration of survival on and after 
protocol therapy.  The height of the gray bar indicates duration of survival.  Light gray bars indicate 
patients who are still alive.  The colored portion of the bar represents the duration of therapy received on 
trial.  NE: non-evaluable for response, PD: progressive disease, SD: stable disease, PR: partial response, 
CR: complete response.  If a patient received subsequent chemotherapy within 6 months, it is listed above 
the patient’s survival bar.  Letters identify corresponding patients in panel B.  B. Waterfall plot of 
response to immediate subsequent therapy.  Best change in defined target lesions to subsequent 
systemic anti-cancer treatment following epigenetic therapy is shown.  Green: PR, blue: SD, red: PD. 
Three patients, indicated at right, died without follow-up imaging.  
 
A recent randomized phase II study in hormone-refractory ER-positive breast cancer 
evaluated exemestane with or without entinostat, seeking to restore hormonal 
sensitivity (unpublished data).  This study has met its predetermined statistical endpoint 
of progression free survival improvement, 4.28 vs. 2.27 months (Hazard Ratio= 0.73, 
p=0.06) and a phase III trial of the same concept is being planned. 
 
Finally, a clinical trial was recently reported using epigenetic priming prior to standard 
therapy in patients with AML.44  This study explored multiple schedules of decitabine 
prior to standard AC in less-than-favorable risk AML, demonstrating a 90% response 
rate including 57% CR.  Interestingly, of the 10 patients with PR, 8 achieved CR in 
response to their next therapy, raising the total CR rate to 83%. 
 
Together these studies offer strong preliminary data suggesting that epigenetic therapy, 
by reactivating silenced target genes in cancer, may enhance the efficacy of subsequent 
therapy.  We believe that it is time for this concept to be formally tested in a carefully 
designed randomized clinical study.  The clinical trial proposed in this concept will 
build on our initial CTEP-supported clinical trial data in metastatic lung cancer to 
rigorously test the idea that epigenetic therapy can augment the clinical utility of 


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cytotoxic therapy in patients with advanced disease. 
 
 
 
Figure 4.  Response after epigenetic priming.  A CT scans of a patient who received four cycles of 
epigenetic therapy, who had previously progressed on carboplatin, paclitaxel, and avastin.  Images on 
the left show multiple persistent lung masses after epigenetic therapy.  Images on the right show disease 
response after four cycles of cisplatin, docetaxel, and avastin. 
 
Summary 
 
We have demonstrated that azacitidine plus entinostat has remarkable activity in a 
small group of lung cancer patients.  Additionally, our data suggest an entirely different 
potential benefit from the same drug combination, namely increasing efficacy of more 
standard anticancer therapies.  Recent emerging data from other groups suggest that 
this mechanism may apply in multiple cancer types.  We will formally test the 
epigenetic priming concept in this study of patients with non-small cell lung cancer. 
 
2.5 Correlative Studies Background 
 
We had previously defined methylation status of 4 key genes (CDKN2a, CDH13, APC, 
and RASSF1a) in tumor and histologically normal mediastinal lymph nodes as a strong 
prognostic factor in patients with early stage non-small cell lung cancer.45  Patients 
with promoter methylation of at least 2 of these 4 genes in tumor and mediastinal lymph 
nodes had a markedly increased likelihood of early disease recurrence.  Our group had 
also demonstrated several years ago that tumor-specific methylation changes are 
detectable in circulating tumor DNA of lung cancer patients.46  Combining these lines 
of research, we quantitatively assessed methylation status of these 4 genes in circulating 
DNA from patients treated with azacitidine and entinostat.  We found that patients with 
detectable methylation of at least 2 of these 4 genes at baseline demonstrating 
demethylation in the first month of epigenetic therapy had significantly improved 
progression-free (p = 0.034) and overall survival (p = 0.035; Figure 2).  This represents 
a potential blood-based biomarker defining a subset of patients that may selectively 
benefit from combinatorial epigenetic therapy.  The proposed trial design offers an 
opportunity to validate this biomarker prospectively, by examination of this panel at 
baseline and after 1 month of therapy, both in patients receiving epigenetic therapy 


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AND, as an important control for the specificity of this biomarker, in patients receiving 
cytotoxic chemotherapy.  This is a key secondary goal of the proposed study. 
                 
 
Figure 2.  Kaplan-Meier analysis of survival by target gene demethylation. 
Promoter methylation of APC, CDH13, RASS1a, and CDKN2A were evaluated in 
circulating plasma DNA from patients, pre-treatment and on day 29. Red: patients 
with methylation of ≥2 of these 4 genes pre-treatment that demonstrate 
demethylation by day 29. Blue: all other patients with detectable circulating DNA 
(total N = 26).  
 
3 PATIENT SELECTION 
 
3.1 Eligibility Criteria  
 
3.1.1 Patients must have histologically or cytologically proven non-small cell 
lung cancer. Tumor tissue must be available from all patients prior to 
initiation of protocol therapy, either from original diagnostic biopsy, or 
biopsy performed prior to initiation of protocol therapy.   
3.1.2 Patients must have measurable disease, defined as at least one lesion that 
can be accurately measured in at least one dimension (longest diameter to 
be recorded for non-nodal lesions and short axis for nodal lesions) as >20 
mm with conventional techniques or as >10 mm with spiral CT scan, 
MRI, or calipers by clinical exam.  See Section 11 for the evaluation of 
measurable disease. 
3.1.3 Patients must have received 1 prior platinum containing doublet regardless 
of mutation status  
3.1.4 Patients with targetable mutation i.e. EGFR or ALK, must have been 
treated with at least 1 prior TKI. 
3.1.5 Prior immunotherapy is allowed. Do not feel tyrosine or targeted therapies 
have effects on immunotherapy; erlotenib is approved for patients without 
mutations in 3rd line setting.  We have tried to clarify this because we are 
testing this for patients with targetable mutations. We feel that with the 
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in near future we want to be able to allow more than 1 prior TKI. Prior 
Immunotherapy is allowed as we do not want to restrict patient eligibility 
regarding immunotherapy since not all patients are eligible to receive 
immune including those with hx of auto immune dx or those with 
interstitial lung disease. Maintenance chemo therapy does not count as line 
of chemo. 
3.1.6 Age >18 years.   
Because no dosing or adverse event data are currently available on 
the use of azacitidine or entinostat alone or in combination with 
irinotecan, gemcitabine, pemetrexed, or docetaxel in patients <18 
years of age, children are excluded from this study. 
3.1.7 ECOG performance status 0 or 1 (Karnofsky >70%, see Appendix A). 
3.1.8 Life expectancy of greater than 12 weeks. 
3.1.9 Patients must have normal organ and marrow function as defined below: 
 leukocytes  
 
 
 
 
>3,000/mcL 
 absolute neutrophil count 
 
>1,500/mcL 
 platelets  
 
 
 
 
 
>100,000/mcL 
 total bilirubin 
 
 
 
 
within normal institutional limits 
 AST(SGOT)/ALT(SGPT)  
<2.5 X institutional upper limit of normal 
 creatinine 
 
 
 
 
 
within normal institutional limits 
 
OR 
 creatinine clearance  
 
 
>60 mL/min/1.73 m2 for patients with 
creatinine levels above institutional normal. 
3.1.10 The effects of entinostat and azacitidine on the developing human fetus 
are unknown.  For this reason women of child-bearing potential and men 
must agree to use adequate contraception (hormonal or barrier method of 
birth control; abstinence) prior to study entry and for the duration of study 
participation.  Should a woman become pregnant or suspect she is 
pregnant while she or her partner is participating in this study, she should 
inform her treating physician immediately. 
3.1.11 Ability to understand and the willingness to sign a written informed 
consent document. 
 
3.2 Exclusion Criteria 
 
3.2.1 Patients who have had chemotherapy or radiotherapy within 4 weeks (6 
weeks for nitrosoureas or mitomycin C) prior to entering the study or 
those who have not recovered from adverse events due to agents 
administered more than 4 weeks earlier. 
3.2.2 Patients who are receiving any other investigational agents. 
3.2.3 Patients with uncontrolled brain metastases. Patients with brain metastases 
must have stable neurologic status following local therapy (surgery or 
radiation) for at least 4 weeks, and must be without neurologic dysfunction 
that would confound the evaluation of neurologic and other adverse 
events.  Patients may be treated with steroids as clinically indicated. 


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3.2.4 Patients with liver metastases that replace greater than 30% of the liver 
parenchyma. 
3.2.5 History of allergic reactions attributed to compounds of similar chemical 
or biologic composition to entinostat, azacitidine, mannitol, irinotecan, 
docetaxel, Pemetrexed, or gemcitabine, or other agents used in the study. 
3.2.6 Uncontrolled inter-current illness including, but not limited to, ongoing or 
active infection, NYHA class 3-4 congestive heart failure, unstable angina 
pectoris, cardiac arrhythmia, or psychiatric illness/social situations that 
would limit compliance with study requirements. 
3.2.7 Pregnant women are excluded from this study because entinostat, 
azacitidine, and irinotecan, docetaxel, Pemetrexed, or gemcitabine are 
agents with the potential for teratogenic or abortifacient effects. Because 
there is an unknown but potential risk for adverse events in nursing infants 
secondary to treatment of the mother with entinostat, azacitidine, or 
irinotecan, docetaxel, Pemetrexed, or gemcitabine breastfeeding should be 
discontinued if the mother is treated on this protocol. These potential risks 
may also apply to other agents used in this study.  
3.2.8 HIV-positive patients on combination antiretroviral therapy are ineligible 
because of the potential for pharmacokinetic interactions with entinostat, 
azacitidine, or irinotecan, docetaxel, Pemetrexed, or gemcitabine.  In 
addition, these patients are at increased risk of lethal infections when 
treated with marrow-suppressive therapy.  Appropriate studies will be 
undertaken in patients receiving combination antiretroviral therapy when 
indicated. 
 
3.3 Inclusion of Women and Minorities 
 
Both men and women of all races and ethnic groups are eligible for this trial. 
 
 
Table 1.  Accrual Targets 
Ethnic Category 
Sex/Gender
Females
Males
 
Total
Hispanic or Latino 
2 
+
3 
= 
5 
Not Hispanic or Latino 
63 
+
97 
= 
160 
Ethnic Category: Total of all subjects
               65 (A1) +
            100 (B1) = 
              165 (C1) 
Racial Category 
 
American Indian or Alaskan Native 
2 
+
0 
= 
2 
Asian 
6 
+
8 
= 
14 
Black or African American 
11 
+
15 
= 
26 
Native Hawaiian or other Pacific 
Islander 
0 
+
0 
= 
0 
White 
46 
+
77 
= 
123 
Racial Category: Total of all subjects
               65 (A2) +
            100 (B2) = 
              165 (C2) 
 
(A1 = A2) 
(B1 = B2) 
 
(C1 = C2) 
 


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4 REGISTRATION PROCEDURES 
 
4.1 General Guidelines 
 
Eligible patients will be entered on study centrally at the Johns Hopkins Sidney Kimmel 
Comprehensive Cancer Center by the Study Coordinator. The JHU Data Manager will 
notify The Johns Hopkins Oncology Center Central Registration Office (410-955-
8271) of each patient entered on study. All sites should call the JHU Data Manager at 
410-550-2751 to verify agent availability.  
Following registration, patients should begin protocol treatment within 72 hours. Issues 
that would cause treatment delays should be discussed with the Principal  
Investigator. If a patient does not receive protocol therapy following registration, the 
patient’s registration on the study may be canceled. The JHU Data Manager should be 
notified of cancellations as soon as possible.  
 
Except in very unusual circumstances, each participating institution will order DCTD-
supplied agents directly from CTEP. Agents may be ordered by a participating site only 
after the initial IRB approval for the site has been forwarded by the Coordinating Center 
to the CTEP PIO (PIO@ctep.nci.nih.gov) (except for Group studies).  
 
4.2 Registration Process  
 
To register a patient, the following documents should be completed by the research 
nurse or data manager and faxed 410-550-0675 or scanned and emailed 
jrober31@jhmi.edu(Appendix D):  
• Copy of required laboratory tests  
• Signed patient consent form  
• HIPAA authorization form  
 
The research nurse or data manager at the participating site will then call 410-550-2751 
to verify eligibility. To complete the registration process, the following will occur:  
• assignment of a patient study number  
• registration of the patient on the study  
• fax or e-mail of the patient study number and dose to the participating site  
• notification of the research nurse or data manager at the participating site to 
verbally confirm registration. 
 
5 TREATMENT PLAN 
 
5.1 Agent Administration 


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Treatment will be administered on an outpatient basis.  Reported adverse events and potential 
risks are described in Section 7.  Appropriate dose modifications are described in Section 6.  No 
investigational or commercial agents or therapies other than those described below may be 
administered with the intent to treat the patient's malignancy. 
 
 
Upon enrollment, the treating physician will choose an appropriate cytotoxic agent for the 
individual patient, and randomization will be stratified by the agent.  Patients will then be 
randomized to one of three study arms.   
 
The epigenetic priming phase of the study will proceed as follows.  On Arm A, patients will 
receive 2 cycles of azacitidine 40 mg/m2/day SC days 1-6 and 8-10 and entinostat 7mg PO days 
3 and 10 of a 28 day cycle. On Arm B, patients will receive 2 cycles of CC-486 300 mg PO days 
1-21 and entinostat 7mg PO days 3 and 10 of a 28 day cycle.  On Arm C, patients will not 
receive epigenetic priming, and instead will proceed directly to cytotoxic therapy.  If patients on 
Arms A or B have a PR or CR at the end of Cycle 2, they may continue epigenetic therapy until 
disease progression, at which time they will proceed to cytotoxic therapy.  All other patients will 
proceed to cytotoxic therapy after 2 cycles of epigenetic therapy (or fewer, if unable/unwilling to 
complete the full 2 cycles). 
 
In all 3 arms, in the cytotoxic therapy phase of the study, patients will receive the previously 
assigned cytotoxic agent.  In arms A and B, if the patient has SD after 2 cycles of epigenetic 
therapy and SD after 2 cycles of cytotoxic therapy, they will be re-primed with an additional 2 
cycles of epigenetic therapy, as described in the preceding paragraph, with the same rules for 
staying on epigenetic therapy or proceeding to cytotoxic therapy.  Only one “re-priming” will be 
allowed in any patient on study.  Patients may stay on cytotoxic therapy until PD, unacceptable 
toxicity, or a decision by the patient or the treating physician to stop therapy. 
 
 
 
 
 
 
 
 
 
 
 
 
Table 2.  Agents Used 
Agents 
Premedication 
Dose 
Route 
Schedule 
Cycle 
Length 
Epigenetic priming 


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Entinostat 
5HT3 inhibitor orally or IV 30 minutes prior to entinostat; 
take on am empty stomach, at least 1 hour before or 2 hours 
after a meal, avoid stomach acid-suppressing medications 
7mg 
PO 
Days 3 & 
10 
28 days 
Azacitidine 
5HT3 inhibitor orally or IV 30 minutes prior to injection with 
azacitidine; Rotate site of injection 
40 mg/m2 
SC 
Days 
1-6, 
8-10 
CC-486 
Subjects should drink 8 ounces (240 mL) of room 
temperature water with each dose. Oral azacitidine may be 
taken on an empty stomach or with food. 
300 mg 
PO 
Day 1-21 
Cytotoxic therapy 
Irinotecan 
Dexamethasone 12 mg orally or IV; 5HT3 orally or IV; both 
medications 30 minutes prior to irinotecan; Atropine 0.25 mg 
subcutaneously prn q2 hours for cholinergic reaction; 
loperamide 4 mg with first onset of diarrhea then 2 mg every 
2-4 hours around the clock until diarrhea free for at least 12 
hours; Dexamethasone 8 mg OR 5HT3 orally on days 2-4 
post chemotherapy. 
300 
mg/m2 
IV 
Day 1 
21 days 
Docetaxel 
Dexamethasone 8 mg orally every 8 hours for three doses the 
day prior to chemotherapy; Dexamethasone 8 mg orally 
every 8 hours for three doses starting the evening of 
chemotherapy administration. 
75 mg/m2 
IV 
Day 1 
Pemetrexed 
Dexamethasone 4 mg orally twice daily the day before, day 
of, and day after chemotherapy; Folate 1 mg orally for 7 days 
prior to first dose of chemo and continuing 21 days after 
chemo; B12 1gm IM 1 week prior to first dose of chemo and 
every 8-9 weeks while receiving chemo continuing until 3 
weeks after last dose of pemetrexed. 
500 
mg/m2 
IV 
Day 1 
Gemcitabine 
Dexamethasone 12 mg orally or IV days 1, 8, and 15 of each 
cycle;  Dexamethasone 12mg orally or IV 30 minutes prior 
to doses of gemcitabine. 
1000 
mg/m2 
IV 
Days 1 and 
8 
 
5.1.1 Epigenetic Modifying Agents 
 
5.1.1.1 Entinostat  
 
 
Entinostat is an oral agent. Entinostat should be taken on an empty stomach, at 
least 1 hour before or 2 hours after a meal. The tablets should be taken one at a 
time. Entinostat is known to cause nausea and vomiting. To reduce the 
incidence of nausea and vomiting associated with entinostat administration, 
patients will be instructed to take a 5-HT3 antagonist orally or IV 30-60 minutes 
prior to taking the dose of entinostat.   Entinostat tablets should not be split, 
crushed, or chewed. 
 
 
Entinostat absorption may be altered by drugs that reduce the acidity of the 
stomach. Proton-pump inhibitors should be avoided during the week on the 
study during which patients are receiving entinostat. H2-blockers and antacids 
should be avoided 24 hours prior to and following the time of entinostat 
administration.  
 
5.1.1.2 5-Azacitidine (subcutaneous) 


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Azacitidine is supplied as 100 mg of white, lyophilized powder with 100 mg of 
mannitol, USP in 30 ml flint vials. The contents of each vial should be dissolved 
in 4mL of sterile water or 0.9% sodium chloride to provide a 25 mg/ml slurry. 
Azacitidine does not go into solution but forms loose slurry when reconstituted 
in this fashion. Reconstituted solutions of azacitidine are unstable. Upon 
reconstitution, the material should be injected within 60 minutes. The slurry 
should be injected subcutaneously. The slurry SHOULD NOT be injected 
intravenously. Doses may be split into multiple injection sites if volume to be 
administered is too large. Injection sites should be rotated on a daily basis.  
 
5.1.1.3 CC-486 (oral azacitidine) 
 
CC-486 (oral azacitidine) is supplied as 100 mg tablets for oral administration. 
Oral azacitidine should be stored in an area free of environmental extremes and 
must be accessible only to study personnel. 
 
5.1.2 Cytotoxic Agents 
 
5.1.2.1 Irinotecan 
Irinotecan hydrochloride injection is supplied as a sterile, pale yellow, clear, 
aqueous solution. It is available in two single-dose sizes: 2 mL-fill vials 
containing 40 mg Irinotecan hydrochloride, and 5 mL-fill vials containing 
100 mg Irinotecan hydrochloride. Each milliliter of solution contains 20 mg 
of Irinotecan hydrochloride (on the basis of the trihydrate salt), 45 mg of 
sorbitol NF powder, and 0.9 mg of lactic acid, USP. The pH of the solution 
has been adjusted to 3.5 (range, 3.0 to 3.8) with sodium hydroxide or 
hydrochloric acid. Irinotecan hydrochloride injection is intended for dilution 
with 5% Dextrose Injection, USP (D5W), or 0.9% Sodium Chloride 
Injection, USP, prior to intravenous infusion. The preferred diluent is 5% 
Dextrose Injection, USP. 
 
5.1.2.2 Docetaxel 
Docetaxel is an antineoplastic agent belonging to the taxoid family. It is 
prepared by semisynthesis beginning with a precursor extracted from the 
renewable needle biomass of yew plants. The chemical name for docetaxel 
is (2R,3S)-N-carboxy-3-phenylisoserine,N- tert -butyl ester, 13-ester with 
5β-20-epoxy-1,2α,4,7β,10β,13α-hexahydroxytax-11-en-9-one 4-acetate 2-
benzoate, trihydrate. Docetaxel is a white to almost-white powder with an 
empirical formula of C43H53NO14• 3H2O, and a molecular weight of 861.9. 
It is highly lipophilic and practically insoluble in water. Docetaxel is 
available in multiple concentrations and vial configurations.  Consult 
specific product labels for preparation instructions and excipient 
information. 
 
5.1.2.3 Pemetrexed 


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Pemetrexed is supplied as a sterile lyophilized powder for intravenous 
infusion available in single-dose vials. The product is a white to either light 
yellow or green-yellow lyophilized solid. Each 100-mg or 500-mg vial of 
pemetrexed contains pemetrexed disodium equivalent to 100 mg pemetrexed 
and 106 mg mannitol or 500 mg pemetrexed and 500 mg mannitol, 
respectively. Hydrochloric acid and/or sodium hydroxide may have been 
added to adjust pH. 
 
 
 
5.1.2.4 Gemcitabine 
Gemcitabine HC1 is a white to off-white solid. It is soluble in water, slightly 
soluble in methanol, and practically insoluble in ethanol and polar organic 
solvents.  The clinical formulation is supplied in a sterile form for 
intravenous use only. Vials of gemcitabine contain either 200 mg or 1 g of 
gemcitabine HCl (expressed as free base) formulated with mannitol (200 mg 
or 1 g, respectively) and sodium acetate (12.5 mg or 62.5 mg, respectively) 
as a sterile lyophilized powder. Hydrochloric acid and/or sodium hydroxide 
may have been added for pH adjustment. 
 
5.2 General Concomitant Medication and Supportive Care Guidelines 
 
5.2.1 No investigational or commercial agents or therapies other than those 
described above may be administered with the intent to treat the malignancy.  
5.2.2 Contraceptive Therapy: Sexually active men and women of child-bearing 
potential must agree to use effective contraception.  
5.2.3 GI Medications: Drugs used to reduce the acidity (increase pH) of the 
stomach, i.e. H2 antagonists, proton-pump inhibitors, antacids, etc., could 
potentially interfere with entinostat absorption. Proton-pump inhibitors should 
be avoided during the week in which patients are receiving entinostat. H2-
blockers and antacids should be avoided 24 hours prior to and following the 
time of entinostat administration.  
5.2.4 Concomitant use of valproic acid is prohibited due to its known activity as a 
histone deacetylase inhibitor.  
5.2.5 Nausea and vomiting after entinostat administration are expected. 
Prophylactic 5-HT3 inhibitors will be administered at least 30 minutes prior to 
ingestion of entinostat as well as on an as needed basis. Delayed nausea and 
vomiting is associated with azacitidine 4-6 hours after treatment. Prophylactic 
5HT3 inhibitor will be administered 30 minutes prior to injection of 
azacitidine on days 1-2, 4-6, and 8-9.  5HT3 inhibitor may also be taken for 
delayed nausea as needed.  
5.2.6 Diarrhea: If diarrhea occurs during dosing, an anti-diarrheal agent(s) may be 
used. 
5.2.7 Neutropenia without fever: The clinical situation should be closely followed 
for fever, focal signs of infection, and neutrophil nadir.  


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5.2.8 Neutropenia with fever: Hospitalization and urgent broad-spectrum antibiotics 
are required for this potentially life-threatening complication. The occurrence 
of a temperature higher than 38.3°C (100.9°F) demands prompt evaluation of 
blood counts and examination for source of infection.  
5.2.9 Anemia: Red blood cell support should be given for any patient with 
symptomatic anemia and is recommended for patients with asymptomatic 
anemia when hemoglobin is below 8 g/dL. Erythropoietin or darbepoietin may 
be used at the discretion of the investigator.  
5.2.10 Thrombocytopenia: Platelet transfusion should be given for a platelet count 
below 10,000/mm3 in the absence of bleeding. If bleeding develops or 
invasive procedures are planned, platelet transfusion should be administered 
in accordance with standard practice.  
5.2.11 Constipation: Constipation has been a common side effect of this 
combination. Treatment with stool softeners and laxatives should be initiated 
early on to prevent symptoms from constipation.  
 
5.3 Duration of Therapy 
 
In the absence of treatment delays due to adverse event(s), treatment may continue until one of 
the following criteria applies: 
 
 
Disease progression, 
 
Intercurrent illness that prevents further administration of treatment, 
 
Unacceptable adverse event(s), 
 
Patient decides to withdraw from the study, or 
 
General or specific changes in the patient's condition render the patient unacceptable 
for further treatment in the judgment of the investigator. 
 
5.4 Duration of Follow Up 
 
Once treatment has been discontinued, patients will be followed  every 3 then 6 months, out 
to 24 months which is shown in the study calendar in section 10.  After the 24 month visit 
the patient will be followed by phone once a year for survival  or until death. We will 
routinely collect data on development of additional cancers, subsequent therapy 
(chemotherapy, radiation or surgery) for their cancer, and survival. Medical records 
including laboratory, pathology, operative, and radiology reports will be obtained at the 
discretion of the principal investigator with permission from the patient. Patients removed 
from study for unacceptable adverse events will be followed until resolution or stabilization 
of the adverse event.  Permission to obtain this data will be will be secured from the subject 
in the consent form. 
 
5.5 Criteria for Removal from Study 
 
A patient will be withdrawn from the study if any of the following events occur 
while on therapy:  


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5.5.1 Interruption of scheduled therapy for greater than two weeks. 
5.5.2 Intolerable adverse effects that are judged by the investigator to be either 
physically or psychologically detrimental to the patient.  
5.5.3 Patient decision to discontinue treatment.  
5.5.4 Pregnancy.  
5.5.5 Patient non-compliance.  
5.5.6 Unresolved or recurrent Grade 3 or 4 toxicity.  
5.5.7 Treatment with other chemotherapeutic or investigational anti-neoplastic drugs.  
5.5.8 Radiation therapy to any lesion. The need for palliative radiation therapy will be 
considered progressive disease.  
5.5.9 Disease progression. 
 
6 DOSING DELAYS/DOSE MODIFICATIONS 
 
Treatment will be modified based on toxicity as described below for all patients 
receiving entinostat and azacitidine.  
  
6.1.1 Neutropenia:  
 See Table 3 for dose adjustment criteria  
 Filgrastim or pegfilgrastim may be used in accordance with ASCO guidelines 
 If held, therapy should restart with appropriate dose adjustment in the following 
cycle if toxicity has resolved to ≤ Grade 2. 
 
6.1.2 Thrombocytopenia.  
 See Table 3 for dose adjustment criteria  
 If held, therapy should restart with appropriate dose adjustment in the following 
cycle if toxicity has resolved to ≤ Grade 2. 
 
6.1.3 Anemia.  
 Hold epigenetic therapy for Grade 3 or 4 anemia according to guidelines in table 3.  
 Erythropoietin or darbepoietin may be used to treat chemotherapy-induced anemia 
at the discretion of the treating physician. 
 If held, therapy should restart with appropriate dose adjustment in the following 
cycle if toxicity has resolved to ≤ Grade 2. 
 
6.1.4 Diarrhea  
 Patients will be instructed to begin taking loperamide at the earliest signs of:  
(1) a poorly formed or loose stool,  
(2) occurrence of 1 to 2 more bowel movements than usual in one day, or  
(3) unusually high volume of stool. 
 Loperamide should be taken in the following manner: 4 mg at the first onset of 
diarrhea, then 2 mg every two hours (4 mg every 4 hours while asleep) around the 
clock until diarrhea-free for at least 12 hours. Additional anti-diarrheal measures 


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may be used at the discretion of the treating physician.  
 If the measures above fail, the dose may be reduced as listed in Table 2.  
 
6.1.5 Nausea/Vomiting  
 Both entinostat and azacitidine use can lead to nausea and vomiting.  
 Prophylactic 5-HT3 inhibitors will be used on days when both entinostat and 
azacitidine will be administered  
 Prophylactic 5HT5 inhibitor will be used first-line on days when azacitidine is 
given alone or for delayed nausea and vomiting.  
 If nausea and vomiting persists despite these measures, more aggressive use of 5-
HT3 antagonists or other anti-emetics can be used at the discretion of the treating 
physician.  
 
6.1.6 Metabolic/electrolyte abnormalities  
 Entinostat is associated with multiple electrolyte abnormalities including 
hypermagnesemia, 
hyperglycemia, 
hypophosphatemia, 
hyponatremia, 
and 
hypocalcemia. Low values will be repleted as appropriate. Hyperglycemia will be 
corrected at the discretion of the treating physician.  
 Entinostat will only be dose-reduced for grade 4 toxicities refractory to appropriate 
treatment.  
 Hold epigenetic therapy for AST/ALT ൒ 3X upper limit of normal AND Bilirubin ≥ 2 
x upper limit of normal.   
 
6.1.7 Other non-hematologic toxicities  
 Dose adjustments will not be made for alopecia, fatigue, or loss of appetite of any 
grade.  
 For other grade 3 and 4 non-hematologic toxicities not described above, treatment 
should be withheld until the toxicity resolves to grade 1 or less.  
 If treatment is held or delayed for a non-hematologic toxicity not described above, 
both drugs should be dose-reduced (entinostat dose reduced to 4 mg, and azacitidine 
dose reduced by 10 mg/m2) unless the toxicity can be clearly attributed to entinostat 
or azacitidine specifically. 
 
6.1.8 Dose Delays and Modification for Commercially Available Chemotherapies 
 Dose delays and modifications for irinotecan, docetaxel, gemcitabine, and 
docetaxel will be made at the treating physician’s discretion.  
 
 
Table 3: Dose Reductions for azacitidine, CC-486, and entinostat 
Toxicity  
Grade  
Azacitidine (SC)
CC-486 (PO) 
Entinostat 
Neutropenia  
Grade 1 or 2  
 
Grade 3  
 
 
No change  
 
Hold and reduce next 
cycle by 10 mg/m2  
 
No change 
 
No change 
 
 
No change  
 
No change  
 
 


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Grade 4  
Hold and reduce next 
cycle by 10 mg/m2  
Hold and reduce next 
cycle to 200 mg 
Hold and reduce next 
cycle to 4 mg  
Thrombocytopenia  
Grade 1 (75-100)  
 
Grade 2 (50-75)  
 
Grade 3 or 4  
(25-50; < 25)  
No change  
 
No change  
 
Hold and reduce next 
cycle by 10 mg/m2  
No change 
 
No change 
 
Hold and reduce next 
cycle to 200 mg 
No change  
 
No change  
 
Hold and reduce next 
cycle to 4 mg  
Anemia 
Grade 1 or 2  
 
Grade 3  
 
 
Grade 4 
No change  
 
Hold and reduce next 
cycle by 10 mg/m2  
 
Hold and reduce next 
cycle by 10 mg/m2  
No change 
 
No change 
 
 
Hold and reduce next 
cycle to 200 mg 
No change  
 
No change  
 
 
Hold and reduce next 
cycle to 4 mg  
Diarrhea (Reduce dose 
only after optimal use 
of loperamide)  
Grade 1 or 2  
 
Grade 3  
 
 
Grade 4  
No change  
 
Hold and reduce next 
cycle by 10 mg/m2  
 
Hold and reduce next 
cycle by 10 mg/m2  
No change 
 
No change 
 
 
Hold and reduce next 
cycle to 200 mg 
No change  
 
No change  
 
 
Hold and reduce next 
cycle to 4 mg  
Nausea / Vomiting  
(Reduce 
dose 
only 
after optimal use of 
anti-emetics)  
Grade 1 or 2  
 
Grade 3 or 4  
No change  
 
Hold and reduce next 
cycle by 10 mg/m2  
No change 
 
Hold and reduce next 
cycle to 200 mg 
No change  
 
Hold and reduce next 
cycle to 4 mg  
 
7 ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of AEs (Section 7.1) and the characteristics of an observed AE (Section 7.2) will 
determine whether the event requires expedited reporting (via AdEERS) in addition to routine 
reporting. 
 
7.1 Comprehensive Adverse Events and Potential Risks Lists (CAEPRs) 
 
7.1.1 CAEPRs for CTEP IND Agent(s) 
 
7.1.1.1 CAEPR for 5-azacitidine and CC-486 
 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for 
Azacitidine (NSC 102816) 
The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a single list of reported 
and/or potential adverse events (AE) associated with an agent using a uniform presentation of events by 
body system. In addition to the comprehensive list, a subset, the Specific Protocol Exceptions to 
Expedited Reporting (SPEER), appears in a separate column and is identified with bold and italicized 
text. This subset of AEs (SPEER) is a list of events that are protocol specific exceptions to expedited 


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reporting to NCI (except as noted below).  Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting 
Requirements' http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf 
for further clarification.  Frequency is provided based on 1099 patients. Below is the CAEPR for 
azacitidine. 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to 
the AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple 
investigational agents and has an AE listed on different SPEERs, use the lower of the grades to 
determine if expedited reporting is required. 
 
 
 
 
 
 
Version 2.5, December 18, 20141 
 
 Adverse Events with Possible  
 Relationship to Azacitidine 
 (CTCAE 4.0 Term) 
[n= 1099] 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
 
Anemia 
 
 
Anemia (Gr 3) 
 
Febrile neutropenia 
 
Febrile neutropenia (Gr 3) 
CARDIAC DISORDERS 
 
 
Heart failure 
 
Heart failure (Gr 2) 
 
Pericardial effusion 
 
Pericardial effusion (Gr 2) 
 
Sinus tachycardia 
 
Sinus tachycardia (Gr 2) 
 
Supraventricular tachycardia 
 
Supraventricular tachycardia (Gr 2) 
EYE DISORDERS 
 
 
Conjunctivitis 
 
Conjunctivitis (Gr 2) 
GASTROINTESTINAL DISORDERS 
 
 
Abdominal pain 
 
Abdominal pain (Gr 2) 
 
Colitis 
 
Colitis (Gr 2) 
Constipation 
 
 
Constipation (Gr 2) 
Diarrhea 
 
 
Diarrhea (Gr 3) 
 
Dyspepsia 
 
 
 
Esophagitis 
 
Esophagitis (Gr 2) 
 
Gastrointestinal hemorrhage2 
 
 
 
Hemorrhoids 
 
 
 
Mucositis oral 
 
Mucositis oral (Gr 2) 
Nausea 
 
 
Nausea (Gr 3) 
Vomiting 
 
 
Vomiting (Gr 3) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
 
 
Chills 
 
Chills (Gr 2) 
 
Edema limbs 
 
Edema limbs (Gr 2) 
Fatigue 
 
 
Fatigue (Gr 3) 


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Fever 
 
 
Fever (Gr 3) 
Injection site reaction  
 
Injection site reaction (Gr 2) 
 
Malaise 
 
 
 
Non-cardiac chest pain 
 
 
 
Pain 
 
 
IMMUNE SYSTEM DISORDERS 
 
 
 
Allergic reaction 
Allergic reaction (Gr 2) 
 
 
Anaphylaxis 
 
INFECTIONS AND INFESTATIONS 
 
Infection3 
 
 
Infection3 (Gr 4) 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
 
 
Bruising 
 
Bruising (Gr 2) 
INVESTIGATIONS 
 
 
Alanine aminotransferase 
increased 
 
Alanine aminotransferase increased (Gr 
4) 
 
Alkaline phosphatase increased 
 
Alkaline phosphatase increased (Gr 2) 
 
Aspartate aminotransferase 
increased 
 
Aspartate aminotransferase increased 
(Gr 4) 
 
Blood bilirubin increased 
 
Blood bilirubin increased (Gr 2) 
 
GGT increased 
 
GGT increased (Gr 2) 
 
Lymphocyte count decreased 
 
Lymphocyte count decreased (Gr 4) 
Neutrophil count 
decreased 
 
 
Neutrophil count decreased (Gr 4) 
Platelet count 
decreased 
 
 
Platelet count decreased (Gr 4) 
 
Weight loss 
 
Weight loss (Gr 2) 
White blood cell 
decreased 
 
 
White blood cell decreased (Gr 4) 
METABOLISM AND NUTRITION DISORDERS 
 
 
Acidosis 
 
Acidosis (Gr 2) 
Anorexia 
 
 
Anorexia (Gr 2) 
 
Hypokalemia 
 
 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
 
 
Arthralgia 
 
Arthralgia (Gr 2)  
 
Back pain 
 
Back pain (Gr 2) 
 
Generalized muscle weakness 
 
Generalized muscle weakness (Gr 2) 
 
Myalgia 
 
Myalgia (Gr 2) 
 
Pain in extremity 
 
Pain in extremity (Gr 2) 
NERVOUS SYSTEM DISORDERS 
 
 
Dizziness 
 
Dizziness (Gr 2) 
 
Headache 
 
Headache (Gr 2) 
 
Lethargy 
 
 
 
Peripheral motor neuropathy 
 
Peripheral motor neuropathy (Gr 2) 
 
Somnolence 
 
Somnolence (Gr 2) 
PSYCHIATRIC DISORDERS 
 
 
Anxiety 
 
 
 
Confusion 
 
Confusion (Gr 2) 
 
Depression 
 
 
 
Insomnia 
 
 
RENAL AND URINARY DISORDERS 
 
 
 
Acute kidney injury 
 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
 


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Bronchopulmonary 
hemorrhage 
 
 
Cough 
 
Cough (Gr 2) 
Dyspnea 
 
 
Dyspnea (Gr 4) 
 
Epistaxis 
 
Epistaxis (Gr 2) 
 
Pharyngolaryngeal pain 
 
 
 
Postnasal drip 
 
Postnasal drip (Gr 2) 
 
Respiratory, thoracic and 
mediastinal disorders - Other 
(abnormal breath sounds)4 
 
Respiratory, thoracic and mediastinal 
disorders - Other (abnormal breath 
sounds)4 (Gr 2) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
 
 
Alopecia 
 
Alopecia (Gr 2) 
 
Hyperhidrosis 
 
 
 
Pruritus 
 
Pruritus (Gr 2) 
 
Purpura 
 
Purpura (Gr 2) 
Rash maculo-papular  
 
Rash maculo-papular (Gr 3) 
 
Skin and subcutaneous tissue 
disorders - Other (skin lesion) 
 
 
VASCULAR DISORDERS 
 
 
Hematoma 
 
Hematoma (Gr 2) 
 
Hypotension 
 
Hypotension (Gr 3) 
 
Vascular disorders - Other (pallor)  
 
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all 
Principal Investigators at the time of revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, the protocol and the agent should 
be included in the e-mail. 
 
2Gastrointestinal hemorrhage includes Anal hemorrhage, Cecal hemorrhage, Colonic hemorrhage, 
Duodenal hemorrhage, Esophageal hemorrhage, Esophageal varices hemorrhage, Gastric hemorrhage, 
Hemorrhoidal hemorrhage, Ileal hemorrhage, Intra-abdominal hemorrhage, Jejunal hemorrhage, Lower 
gastrointestinal hemorrhage, Oral hemorrhage, Pancreatic hemorrhage, Rectal hemorrhage, 
Retroperitoneal hemorrhage, and Upper gastrointestinal hemorrhage under the GASTROINTESTINAL 
DISORDERS SOC. 
 
3Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 
 
4Abnormal breath sounds includes rales and rhonchi. 
 
Adverse events reported on azacitidine trials, but for which there is insufficient evidence to 
suggest that there was a reasonable possibility that azacitidine caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system disorders - Other 
(agranulocytosis); Blood and lymphatic system disorders - Other (lymphadenopathy); Blood and lymphatic 
system disorders - Other (splenomegaly); Bone marrow hypocellular; Leukocytosis 
CARDIAC DISORDERS - Acute coronary syndrome; Atrial fibrillation; Atrial flutter; Atrioventricular block 
complete; Cardiac disorders - Other (cardiac valve vegetation); Chest pain - cardiac; Myocardial 
infarction; Palpitations; Pericarditis; Restrictive cardiomyopathy; Sinus bradycardia; Ventricular fibrillation 
EAR AND LABYRINTH DISORDERS - Hearing impaired; Tinnitus 
EYE DISORDERS - Eye disorders - Other (eye/conjunctival hemorrhage); Eye disorders- Other (retina 
hemorrhage); Papilledema; Uveitis 
GASTROINTESTINAL DISORDERS - Abdominal distension; Duodenal ulcer; Dysphagia; Enterocolitis; 
Esophageal pain; Esophageal ulcer; Flatulence; Gastritis; Gastrointestinal disorders - Other (diverticulitis); 
Gastrointestinal disorders - Other (inguinal hernia, obstructive); Gastrointestinal disorders - Other 


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(intestinal ischemia); Gastrointestinal disorders - Other (intussusception); Gastrointestinal disorders - 
Other (mouth/tongue/oral ulceration); Pancreatitis; Small intestinal obstruction 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Flu like symptoms; Gait 
disturbance; General disorders and administration site conditions - Other (general weakness);  General 
disorders and administration site conditions - Other (Sweet's Syndrome); General disorders and 
administration site conditions - Other (systemic inflammatory response syndrome); Multi-organ failure 
HEPATOBILIARY DISORDERS - Cholecystitis; Hepatic failure; Hepatobiliary disorders - Other (bile duct 
stone) 
IMMUNE SYSTEM DISORDERS - Autoimmune disorder 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Burn; Fall; Hip fracture; Injury, 
poisoning and procedural complications - Other (excoriation); Postoperative hemorrhage; Wound 
dehiscence 
INVESTIGATIONS - Activated partial thromboplastin time prolonged; Creatinine increased; 
Electrocardiogram QT corrected interval prolonged; INR increased; Investigations - Other (blood LDH 
increased); Investigations - Other (blood urea increased); Investigations - Other (cardiac murmur); 
Investigations - Other (protein total decreased); Lipase increased; Serum amylase increased 
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hyperglycemia; Hyperkalemia; 
Hyperuricemia; Hypoalbuminemia; Hypocalcemia; Hypomagnesemia; Hyponatremia; Hypophosphatemia; 
Metabolism and nutrition disorders - Other (fluid overload); Metabolism and nutrition disorders - Other 
(hypovolemia); Tumor lysis syndrome 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthritis; Bone pain; Chest wall pain; 
Flank pain; Muscle weakness lower limb; Musculoskeletal and connective tissue disorder - Other 
(chondritis); Musculoskeletal and connective tissue disorder -  Other (intervertebral disc protrusion); 
Musculoskeletal and connective tissue disorder -  Other (muscle cramps); Musculoskeletal and 
connective tissue disorder - Other (muscle spasms); Musculoskeletal and connective tissue disorder -  
Other (musculoskeletal stiffness); Neck pain 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - 
Myelodysplastic syndrome; Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other 
(colonic polyp, vaginal polyp); Treatment related secondary malignancy 
NERVOUS SYSTEM DISORDERS - Dysesthesia; Dysgeusia; Hydrocephalus; Intracranial hemorrhage; 
Memory impairment; Paresthesia; Peripheral sensory neuropathy; Seizure; Sinus pain; Syncope 
PSYCHIATRIC DISORDERS - Psychiatric disorders - Other (mental status changes) 
RENAL AND URINARY DISORDERS - Hematuria; Proteinuria; Renal and urinary disorders - Other 
(calculus urinary); Renal calculi; Urinary frequency; Urinary retention; Urinary tract pain 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Erectile dysfunction; Reproductive system and 
breast disorders - Other (benign prostatic hyperplasia); Uterine hemorrhage; Vaginal hemorrhage 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Atelectasis; Hypoxia; Nasal 
congestion; Pleural effusion; Pleuritic pain; Pneumonitis; Productive cough; Pulmonary edema; 
Respiratory failure; Respiratory, thoracic and mediastinal disorders - Other (Chronic Obstructive 
Pulmonary Disease); Respiratory, thoracic and mediastinal disorders - Other (oropharyngeal pain);  
Respiratory, thoracic and mediastinal disorders - Other (pharyngeal erythema); Respiratory, thoracic and 
mediastinal disorders - Other (pneumonia legionella); Wheezing 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Dry skin; Palmar-plantar erythrodysesthesia 
syndrome; Skin and subcutaneous tissue disorders - Other (ecthyma gangrenosum); Skin and 
subcutaneous tissue disorders - Other (skin laceration); Skin and subcutaneous tissue disorders - Other 
(skin nodule); Skin induration; Urticaria 
VASCULAR DISORDERS – Flushing; Hypertension; Thromboembolic event; Vasculitis; Visceral arterial 
ischemia 
 
Note: Azacitidine in combination with other agents could cause an exacerbation of any adverse event 
currently known to be caused by the other agent, or the combination may result in events never 
previously associated with either agent. 
 
7.1.1.2 CAEPR for Entinostat 


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Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for 
MS-275 (SNDX-275, entinostat, NSC 706995) 
The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential adverse events (AE) associated with an agent using a uniform 
presentation of events by body system. In addition to the comprehensive list, a subset, the 
Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column and 
is identified with bold and italicized text. This subset of AEs (SPEER) is a list of events that are 
protocol specific exceptions to expedited reporting to NCI via AdEERS (except as noted below).  
Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf for 
further clarification. Frequency is provided based on 215 patients. Below is the CAEPR for MS-
275 (SNDX-275, entinostat). 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses 
next to the AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple 
investigational agents and has an AE listed on different SPEERs, use the lower of the grades  
 
to determine if expedited reporting is required. 
 
Version 2.4, February 13, 20131 
 
 Adverse Events with Possible  
 Relationship to MS-275 (SNDX-275, entinostat) 
 (CTCAE 4.0 Term) 
[n= 215] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER) 
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious 
(<3%)
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
 
Anemia 
 
 
Anemia (Gr 3) 
 
Febrile neutropenia 
 
 
GASTROINTESTINAL DISORDERS 
 
 
Abdominal pain 
 
Abdominal pain (Gr 2) 
 
Constipation 
 
Constipation (Gr 2) 
Diarrhea 
 
 
Diarrhea (Gr 3) 
 
Dyspepsia 
 
Dyspepsia (Gr 2) 
 
Flatulence 
 
 
Nausea 
 
 
Nausea (Gr 3) 
Vomiting 
 
 
Vomiting (Gr 3) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
 
 
Edema limbs 
 
Edema limbs (Gr 2) 
Fatigue 
 
 
Fatigue (Gr 3) 
 
Fever 
 
Fever (Gr 2) 
 
Non-cardiac chest pain 
 
 
INFECTIONS AND INFESTATIONS 
 


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Infection2 
 
Infection2 (Gr 3) 
INVESTIGATIONS 
 
 
Alanine aminotransferase increased 
 
 
 
Alkaline phosphatase increased 
 
Alkaline phosphatase increased  
(Gr 2) 
 
Aspartate aminotransferase increased 
 
 
 
Blood bilirubin increased 
 
 
 
Creatinine increased 
 
 
 
Lymphocyte count decreased 
 
Lymphocyte count decreased (Gr 4)
Neutrophil count 
decreased 
 
 
Neutrophil count decreased (Gr 4) 
Platelet count 
decreased 
 
 
Platelet count decreased (Gr 4) 
 
Weight loss 
 
 
 
White blood cell decreased 
 
White blood cell decreased (Gr 3) 
METABOLISM AND NUTRITION DISORDERS 
 
Anorexia 
 
 
Anorexia (Gr 3) 
 
Dehydration 
 
Dehydration (Gr 2) 
 
Hyperglycemia 
 
Hyperglycemia (Gr 2) 
Hypoalbuminemia 
 
 
Hypoalbuminemia (Gr 2) 
 
Hypocalcemia 
 
Hypocalcemia (Gr 2) 
 
Hypokalemia 
 
Hypokalemia (Gr 2) 
 
Hypomagnesemia 
 
 
Hyponatremia 
 
 
Hyponatremia (Gr 3) 
Hypophosphatemia 
 
 
Hypophosphatemia (Gr 3) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
 
 
Arthralgia 
 
 
 
Back pain 
 
 
 
Generalized muscle weakness 
 
 
 
Myalgia 
 
Myalgia (Gr 2) 
 
Pain in extremity 
 
 
NERVOUS SYSTEM DISORDERS 
 
 
Dysgeusia 
 
Dysgeusia (Gr 2) 
Headache 
 
 
Headache (Gr 2) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
 
 
Cough 
 
Cough (Gr 2) 
Dyspnea 
 
 
Dyspnea (Gr 3) 
 
Epistaxis 
 
 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
 
 
 
Erythema multiforme 
 
SURGICAL AND MEDICAL PROCEDURES 
 
 
Surgical and medical procedures - Other 
(packed RBC transfusion) 
 
 
 
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be 
distributed to all Principal Investigators at the time of revision.  The current version can be 
obtained by contacting PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, 
the protocol and the agent should be included in the e-mail. 
 
2Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS 


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SOC. 
 
3Gastrointestinal hemorrhage includes Anal hemorrhage, Cecal hemorrhage, Colonic 
hemorrhage, Duodenal hemorrhage, Esophageal hemorrhage, Esophageal varices hemorrhage, 
Gastric hemorrhage, Hemorrhoidal hemorrhage, Ileal hemorrhage, Intra-abdominal hemorrhage, 
Jejunal hemorrhage, Lower gastrointestinal hemorrhage, Oral hemorrhage, Pancreatic 
hemorrhage, Rectal hemorrhage, Retroperitoneal hemorrhage, and Upper gastrointestinal 
hemorrhage under the GASTROINTESTINAL DISORDERS SOC. 
 
Also reported on MS-275 (SNDX-275, entinostat) trials but with the relationship to MS-275 
(SNDX-275, entinostat) still undetermined: 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Hemolysis; Leukocytosis 
CARDIAC DISORDERS - Atrial fibrillation; Atrioventricular block complete; Chest pain - 
cardiac; Conduction disorder; Heart failure; Left ventricular systolic dysfunction; Palpitations; 
Pericardial effusion; Pericarditis; Sinus tachycardia; Supraventricular tachycardia; Ventricular 
fibrillation 
EAR AND LABYRINTH DISORDERS - Hearing impaired 
EYE DISORDERS - Blurred vision 
GASTROINTESTINAL DISORDERS - Anal mucositis; Colitis; Dysphagia; Esophageal pain;  
 
Esophagitis; Gastrointestinal disorders - Other (hyperdefecation); Gastrointestinal hemorrhage3; 
Hemorrhoids; Mucositis oral; Pancreatitis; Periodontal disease; Rectal mucositis; Rectal pain; 
Small intestinal mucositis; Typhlitis 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS – Chills; Edema 
face; Injection site reaction; Multi-organ failure; Pain 
IMMUNE SYSTEM DISORDERS - Allergic reaction; Anaphylaxis; Autoimmune disorder 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Bruising 
INVESTIGATIONS - Activated partial thromboplastin time prolonged; CPK increased; GGT 
increased; INR increased; Investigations - Other (coagulopathy); Investigations - Other (vitamin 
D deficiency); Lipase increased; Serum amylase increased 
METABOLISM AND NUTRITION DISORDERS - Acidosis; Hypercalcemia; Hyperkalemia; 
Hypermagnesemia; Hypernatremia; Hypertriglyceridemia; Hyperuricemia; Hypoglycemia; 
Tumor lysis syndrome 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Bone pain; Chest 
wall pain; Musculoskeletal and connective tissue disorder - Other (muscle spasms); 
Musculoskeletal and connective tissue disorder - Other (thorax pain); Myositis 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND 
POLYPS) - Tumor pain 
NERVOUS SYSTEM DISORDERS - Ataxia; Depressed level of consciousness; Dizziness; 
Dysphasia; Intracranial hemorrhage; Neuralgia; Olfactory nerve disorder; Peripheral motor 
neuropathy; Peripheral sensory neuropathy; Syncope; Tremor 
PSYCHIATRIC DISORDERS - Anxiety; Confusion; Depression; Insomnia; Libido decreased 
RENAL AND URINARY DISORDERS - Acute kidney injury; Proteinuria; Renal and urinary 


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disorders - Other (bladder distension); Renal hemorrhage; Urinary frequency; Urinary retention 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Allergic rhinitis; 
Atelectasis; Hypoxia; Laryngeal mucositis; Pharyngeal mucositis; Pleural effusion; Pleuritic 
pain; Pulmonary edema; Respiratory failure; Tracheal mucositis 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Hyperhidrosis; Nail loss; 
Photosensitivity; Pruritus; Purpura; Rash maculo-papular; Skin and subcutaneous tissue 
disorders - Other (hyperkeratotic lesions/squamous cell carcinoma); Urticaria 
VASCULAR DISORDERS - Flushing; Hypertension; Hypotension; Thromboembolic event; 
Visceral arterial ischemia 
 
Note: MS-275 (SNDX-275, entinostat) in combination with other agents could cause an 
exacerbation of any adverse event currently known to be caused by the other agent, or the 
combination may result in events never previously associated with either agent. 
 
7.1.2 Adverse Event List(s) for Irinotecan, Docetaxel, Pemetrexed, or Gemcitabine  
Below are reported common side effects from these commercial agents.  For additional 
side effects and information, please refer to package insert for individual agents. 
 
Irinotecan 
 
Cardiovascular: Vasodilation (9% to 11%) 
Central nervous system: Cholinergic toxicity (47% - includes rhinitis, increased  
 
salivation, 
miosis, 
lacrimation, 
diaphoresis, 
flushing 
and 
intestinal 
hyperperistalsis); fever (44% to 45%), pain (23% to 24%), dizziness (15% to 
21%), insomnia (19%), headache (17%), chills (14%) 
Dermatologic: Alopecia (46% to 72%), rash (13% to 14%) 
Endocrine & metabolic: Dehydration (15%) 
Gastrointestinal: Diarrhea, late (83% to 88%; grade 3/4: 14% to 31%), diarrhea, early 
(43% to 51%; grade 3/4: 7% to 22%), nausea (70% to 86%), abdominal pain (57% 
to 68%), vomiting (62% to 67%), cramps (57%), anorexia (44% to 55%), 
constipation (30% to 32%), mucositis (30%), weight loss (30%), flatulence 
(12%), stomatitis (12%) 
Hematologic: Anemia (60% to 97%; grades 3/4: 5% to 7%), leukopenia (63% to 96%, 
grades 3/4: 14% to 28%), thrombocytopenia (96%, grades 3/4: 1% to 4%), 
neutropenia (30% to 96%; grades 3/4: 14% to 31%) 
Hepatic: Bilirubin increased (84%), alkaline phosphatase increased (13%) 
Neuromuscular & skeletal: Weakness (69% to 76%), back pain (14%) 
Respiratory: Dyspnea (22%), cough (17% to 20%), rhinitis (16%) 
Miscellaneous: Diaphoresis (16%), infection (14%) 
 
Docetaxel 
 
Cardiovascular: Fluid retention (13% to 60%; dose dependent) 
Central nervous system: Neurosensory events (20% to 58%; including neuropathy), 


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fever (31% to 35%), neuromotor events (16%) 
Dermatologic: Alopecia (56% to 76%), cutaneous events (20% to 48%), nail disorder 
(11% to 41%) 
Gastrointestinal: Stomatitis (19% to 53%; severe 1% to 8%), diarrhea (23% to 43%; 
severe: 5% to 6%), nausea (34% to 42%), vomiting (22% to 23%) 
Hematologic: Neutropenia (84% to 99%; grade 4: 75% to 86%; nadir (median): 7 days, 
duration (severe neutropenia): 7 days; dose dependent), leukopenia (84% to 99%; 
grade 4: 32% to 44%), anemia (65% to 94%; dose dependent; grades 3/4: 8% to 
9%), thrombocytopenia (8% to 14%; grade 4: 1%; dose dependent), febrile 
neutropenia (6% to 12%; dose dependent) 
Hepatic: Transaminases increased (4% to 19%) 
Neuromuscular & skeletal: Weakness (53% to 66%; severe 13% to 18%), myalgia (3% 
to 23%) 
 
Respiratory: Pulmonary events (41%) 
Miscellaneous: Infection (1% to 34%; dose dependent), hypersensitivity (1% to 21%; 
with premedication 15%) 
 
 
 
 
 
 
 
Gemcitabine 
 
Cardiovascular: Peripheral edema (20%), edema (13%) 
Central nervous system: Fever (38% to 41%), somnolence (11%) 
Dermatologic: Rash (28% to 30%), alopecia (15% to 16%), pruritus (13%) 
Gastrointestinal: Nausea/vomiting (69% to 71%; grade 3: 10% to 13%; grade 4: 1% to 
2%), diarrhea (19% to 30%), stomatitis (10% to 11%) 
Hematologic: Anemia (68% to 73%; grade 4: 1% to 2%), leukopenia (62% to 64%; 
grade 4: ≤1%), neutropenia (61% to 63%; grade 4: 6% to 7%), thrombocytopenia 
(24% to 36%; grade 4: ≤1%), hemorrhage (4% to 17%; grades 3: ≤2%; grade 4: 
<1%); myelosuppression is the dose-limiting toxicity 
Hepatic: AST increased (67% to 78%; grade 3: 6% to 12%; grade 4: 2% to 5%), 
alkaline phosphatase increased (55% to 77%; grade 3: 7% to 16%; grade 4: 2% 
to 4%), ALT increased (68% to 72%; grade 3: 8% to 10%; grade 4: 1% to 2%), 
bilirubin increased (13% to 26%; grade 3: 2% to 6%; grade 4: ≤2%) 
Renal: Proteinuria (32% to 45%; grades 3/4: <1%), hematuria (23% to 35%; grades 
3/4: <1%), BUN increased (15% to 16%) 
Respiratory: Dyspnea (10% to 23%) 
Miscellaneous: Flu-like syndrome (19%), infection (10% to 16%; grade 3: 1% to 2%; 
grade 4: <1%) 
 


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Pemetrexed 
 
Central nervous system: Fatigue (25% to 34%; dose-limiting) 
Dermatologic: Rash/desquamation (10% to 14%) 
Gastrointestinal: Nausea (19% to 31%), anorexia (19% to 22%), vomiting (9% to 
16%), stomatitis (7% to 15%), diarrhea (5% to 13%) 
Hematologic: Anemia (15% to 19%; grades 3/4: 3% to 4%), leukopenia (6% to 12%; 
grades 3/4: 2% to 4%), neutropenia (6% to 11%; grades 3/4: 3% to 5%; dose-
limiting; nadir: 8-10 days; recovery: 4-8 days after nadir) 
Respiratory: Pharyngitis (15%) 
 
7.2 Adverse Event Characteristics  
 
 CTCAE term (AE description) and grade:  The descriptions and grading 
scales found in the revised NCI Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.0 will be utilized for AE reporting.  All 
appropriate treatment areas should have access to a copy of the CTCAE 
version 4.0.  A copy of the CTCAE version 4.0 can be downloaded from the 
CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
 For expedited reporting purposes only:   
- 
AEs for the agent that are bold and italicized in the CAEPR (i.e., those 
listed in the SPEER column, Section 7.1.1) should be reported through 
AdEERS only if the grade is above the grade provided in the SPEER. 
- 
Other AEs for the protocol that do not require expedited reporting are 
outlined in section 7.3.4. 
 
 Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
7.3 Expedited Adverse Event Reporting 
 
7.3.1 Expedited AE reporting for this study must use AdEERS (Adverse Event 
Expedited Reporting System), accessed via the CTEP Web site 
(http://ctep.cancer.gov).  The reporting procedures to be followed are 
presented in the “NCI Guidelines for Investigators: Adverse Event 
Reporting Requirements for DCTD (CTEP and CIP) and DCP INDs and 
IDEs” which can be downloaded from the CTEP Web site 
(http://ctep.cancer.gov).  These requirements are briefly outlined in the 
tables below (Section 7.3.3). 


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In the rare occurrence when Internet connectivity is lost, a 24-hour 
notification is to be made to CTEP by telephone at 301-897-7497.  Once 
Internet connectivity is restored, the 24-hour notification phoned in must 
be entered electronically into AdEERS by the original submitter at the site. 
 
7.3.2 AdEERS is programmed for automatic electronic distribution of reports to 
the following individuals:  Study Coordinator of the Lead Organization, 
Principal Investigator, and the local treating physician.  AdEERS provides 
a copy feature for other e-mail recipients.  
 
7.3.3 Expedited Reporting Guidelines 
 
Use the NCI protocol number and the protocol-specific patient ID 
assigned during trial registration on all reports. 
 
Note:  A death on study requires both routine and expedited reporting 
regardless of causality, unless as noted below.  Attribution to 
treatment or other cause must be provided. 
 
Death due to progressive disease should be reported as Grade 5 
“Neoplasms benign, malignant and unspecified (incl cysts and polyps) 
- Other (Progressive Disease)” under the system organ class (SOC) of 
the same name.  Evidence that the death was a manifestation of underlying 
disease (e.g., radiological changes suggesting tumor growth or 
progression: clinical deterioration associated with a disease process) 
should be submitted.  
 
Table 6:  Late Phase 2 and Phase 3 Studies: Expedited Reporting Requirements for 
Adverse Events that Occur on Studies under an IND/IDE within 30 Days of the Last 
Administration of the Investigational Agent/Intervention1, 2 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or not they are 
considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
 An adverse event is considered serious if it results in ANY of the following outcomes:   
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization may be 
considered serious when, based upon medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. (FDA, 21 CFR 312.32; ICH 
E2A and ICH E6). 
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via AdEERS within 
the timeframes detailed in the table below. 


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Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 
Calendar Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
10 Calendar Days 
NOTE:  Protocol-specific exceptions to expedited reporting of serious adverse events are found in the Specific Protocol 
Exceptions to Expedited Reporting (SPEER) portion of the CAEPR 
Expedited AE reporting timelines are defined as: 
o 
“24-Hour; 5 Calendar Days” - The AE must initially be reported via AdEERS within 24 hours of learning of the 
AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour report. 
o 
“10 Calendar Days” - A complete expedited report on the AE must be submitted within 10 calendar days of 
learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational agent/intervention 
and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
 All Grade 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
 Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
 Grade 3 adverse events 
2 For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, rounded 
UP to the nearest whole day, after the agent/intervention was last administered.  Footnote “1” above applies after this 
reporting period. 
Effective Date:  May 5, 2011 
 
 
 
 
 
 
 
7.3.4 Protocol-Specific Expedited Adverse Event Reporting Exclusions 
 
 
For this protocol only, certain AEs/grades are exceptions to the Expedited 
Reporting Guidelines and do not require expedited reporting ( i.e., AdEERS).  
The following AEs must be reported through the routine reporting mechanism 
(Section 7.4): 
 
Table 7. 
AE 
Grade 
Grade 
Hospitalization/Prolongation of 
Hospitalization 
Comments 
Hemoglobin 
3 
4 
X 
Anemia 
Leukocytes (total WBC)  
3 
4 
X 
Leukopenia 
Neutrophils/granulocytes 
3 
4 
 
Neutropenia 
Platelets 
3 
4 
X 
Thrombocytopenia 
Transfusion pRBC  
3 
 
X 
 


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Fatigue (lethargy, maliaise, 
asthenia) 
3 
 
X 
 
Nausea 
3 
 
X 
 
Vomiting 
3 
 
X 
 
Diarrhea 
3 
 
X 
 
Infection with grade 3 or 4 
neutropenia 
3 
 
X 
 
Infection without neutropenia 
3 
 
X 
 
Infection with unknown ANC  
3 
 
X 
 
Febrile neutropenia  
3 
 
X 
 
 
7.4 Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions.  AEs reported through 
AdEERS must also be reported in routine study data submissions. 
 
7.5 Secondary Malignancy 
 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A secondary 
malignancy is not considered a metastasis of the initial neoplasm.  
CTEP requires all secondary malignancies that occur following treatment with an agent under an 
NCI IND/IDE be reported via AdEERS. Three options are available to describe the event:  
 
 
 
 Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia 
[AML])  
 Myelodysplastic syndrome (MDS)  
 Treatment-related secondary malignancy  
 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also be 
reported via the routine reporting mechanisms outlined in each protocol.  
 
7.6 Second Malignancy 
 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a 
metastasis from the initial malignancy).  Second malignancies require ONLY routine reporting 
via CDUS unless otherwise specified.  
 
8 PHARMACEUTICAL INFORMATION 


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A list of the adverse events and potential risks associated with the investigational or commercial 
agents administered in this study can be found in Section 7.1. 
 
8.1 CTEP IND Agent(s) 
 
8.1.1   5-Azacitidine (NSC 102816) 
 
8.1.1.1 Chemical Name: 4-Amino-1-ß-D-ribofuranosyl-1,3,5-triazin-2(1H)-one  
Other Names: 5-Azacitidine, 5-AZA, Mylosar7, Ladakamycin, Vidaza  
8.1.1.2 How supplied and preparation: Azacitidine will be supplied by Celgene 
and distributed by Cancer Therapy Evaluation Program of the Division of 
Cancer Treatment and Diagnosis in the National Cancer Institute. 
Azacitidine is supplied as 100 mg of white, lyophilized powder with 100 
mg of mannitol, USP in 30 ml flint vials. The contents of each vial should 
be dissolved in 4mL of sterile water or 0.9% sodium chloride to provide a 
25 mg/ml slurry. Azacitidine does not go into solution but forms a loose 
slurry when reconstituted in this fashion. Do not inject the slurry 
intravenously. Doses may be split into multiple injection sites if volume to 
be administered is too large. Injection sites should be rotated on a daily 
basis.  
8.1.1.3 Storage and Stability: The reconstituted product may be kept in the vial 
or drawn into a syringe. Doses greater than 4 mL should be divided 
equally into 2 syringes. The product must be refrigerated immediately, and 
may be held under refrigerated conditions (2°C - 8°C, 36°F - 46°F) for up 
to 8 hours. After removal from refrigerated conditions, the suspension may 
be allowed to equilibrate to room temperature for up to 30 minutes prior to 
administration.  Azacitidine is supplied as a lyophilized powder in 100 mg 
single-use vials. Store unreconstituted vials at 25° C (77° F); excursions 
permitted to 15°-30° C (59°-86° F). 
8.1.1.4 Route of administration: Subcutaneous injection. Patients will have their 
azacitidine injections administered in the outpatient clinic by a health care 
professional according to the standard chemotherapy administration 
protocol of the Cancer Center. 
8.1.1.5 Administration: To provide a homogeneous suspension, the contents of 
the dosing syringe must be re-suspended immediately prior to 
administration. To re-suspend, vigorously roll the syringe between the 
palms until a uniform, cloudy suspension is achieved. Azacitidine 
suspension is administered subcutaneously. Doses greater than 4 mL 
should be divided equally into 2 syringes and injected into 2 separate sites. 
Rotate sites for each injection (thigh, abdomen, or upper arm). New 
injections should be given at least one inch from an old site and never into 
areas where the site is tender, bruised, red, or hard. 
8.1.1.6 Toxicities: In clinical studies, the most commonly occurring adverse 
reactions were nausea (70.5%), anemia (69.5%), thrombocytopenia 


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(65.5%), vomiting (54.1%), pyrexia (51.8%), leukopenia (48.2%), 
diarrhea (36.4%), fatigue (35.9%), injection site erythema (35.0%), 
constipation (33.6%), neutropenia (32.3%) and ecchymosis (30.5%). Other 
adverse reactions included dizziness (18.6%), chest pain (16.4%), febrile 
neutropenia (16.4%), myalgia (15.9%), injection site reaction (13.6%), 
aggravated fatigue (12.7%) and malaise (10.9%).  
 
8.1.2 CC-486 (NSC 102816) 
 
8.1.2.1 
Chemical Name: 4-amino-1-[(2R,3R,4S,5R)-3,4-dihydroxy-5 
(hydroxymethyl)oxolan-2-yl]-1,3,5-triazin-2-one 
Other Names: 5-azacitidine, 5-aza, azacitidine, Vidaza® 
8.1.2.2 
Classification: antimetabolite, DNA hypomethylating agent 
8.1.2.4 
CAS Registry Number: 320-67-2 
Molecular Formula:  C8H12N4O5  M.W.:  244.2 
Approximate Solubility: 89 g/L at 25° C in water 
8.1.2.5 
Mode of Action: Azacitidine is a pyrimidine nucleoside analog of 
cytidine.  Azacitidine is incorporated into DNA and RNA at high doses 
and causes direct cytotoxicity as a result of inhibiting DNA and RNA 
functions. It also inhibits DNA methyltransferase at low doses, therefore 
causing DNA hypomethylation and subsequent alterations in gene 
expression. 
8.1.2.6 
How Supplied: Celgene supplies and DCTC, NCI distributes oral 
azacitidine as 100 mg tablets, packaged in 21-count blisterpacks. Each 
film-coated tablet contains the following excipients: mannitol, silicified 
microcrystalline cellulose, crospovidone, magnesium stearate and 
hydroxypropyl cellulose. 
8.1.2.7 
Storage: Store less than 25° C. 
 
 
Stability: Shelf life studies are ongoing. 
8.1.2.8 
Route of Administration: Take by mouth with 8 ounces of room 
temperature water on an empty stomach or with a light meal. 
8.1.2.9 
Potential Drug Interactions: Azacitidine is neither metabolized by 
CYP450 isoenzymes nor an inhibitor or inducer of any CYP enzymes. 
The data suggest that it will not produce clinically-relevant drug-drug 
interactions. It is also not a substrate for P-glycoprotein and has no 
inhibitory effect on this transport system.  
8.1.2.10 
Special Handling: Per the manufacturer’s instruction, do not use any 
tablets that are broken or damaged. Dispose of them using proper 
procedures for disposal of cytotoxic drugs. 
8.1.2.11 
Patient Care Implications: In the event of overdosage, the patient 
should be monitored with appropriate blood counts and should receive 
supportive treatment, as necessary. There is no known specific 
antidote for azacitidine overdosage. 
 
8.1.3 Entinostat (NSC 706995)  


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8.1.3.1 
Chemical name: 3-Pyridylmethyl N-{4-[(2-
aminophenyl)carbamoyl]benzyl}carbamate 
Other names: MS-27-275, MS-275, SNDX-275  
Molecular Formula: C21H20N4O3 M.W.: 376.41  
Classification: Antineoplastic; entinostat is an inhibitor of histone 
deacetylase  
8.1.3.2 
How Supplied: Entinostat is supplied by the Syndax Pharmaceuticals, 
Inc. and distributed by DCTD, NCI as 1 mg (pink to light red, in bottles of 
40), or 5 mg (yellow, in bottles of 40) film-coated tablets (round-biconvex). 
Each tablet also contains mannitol, sodium starch glycolate, hydroxypropyl 
cellulose, potassium bicarbonate, and magnesium stearate.  The film 
coating consists of hypromellose, talc, titanium dioxide, and ferric oxide 
pigments (red and yellow) as colorants.  
 
8.1.3.3 
Mechanism of Action:  Histone deacetylases (HDACs) are a family 
of enzymes that regulate chromatin remodeling and gene transcription 
via the dynamic process of acetylation and deacetylation of core 
histones.  Entinostat inhibits histone deacetylases, changes chromatin 
configuration, and induces differentiation and apoptosis of cancer 
cells through an epigenetic mechanism. 
 
 
 
 
8.1.3.4 
Route of Administration: Oral. Entinostat should be taken on an 
empty stomach, at least 1 hour before or 2 hours after a meal. 
Entinostat tablets should not be split, crushed, or chewed. 
8.1.3.5 
Storage and Stability: Store the bottles at controlled room 
temperature (15-25°C) and protect from light.  Entinostat is not to be 
exposed to extremes of temperature (greater than 30°C or less than 
5°C).  Shelf life stability studies of the intact bottles are on-going.  
8.1.3.6 
Potential Drug Interactions: Metabolism:  Data from in vitro 
metabolism experiments demonstrated that entinostat is not metabolized by 
CYP enzymes (Acharya 2006), but UGT 1A4 did metabolize entinostat to its 
M2 glucuronide metabolite.  No metabolites could be detected after 
incubation of entinostat in human liver micrsomes (Acharya 2006).  While 
inhibition of CYP enzymes 2B6 and 3A4 was seen, the data show that the 
degree of inhibition makes it unlikely that any in vivo systemic interactions 
would occur.  Intestional CYP3A4 may be inhibited by entinostat.  However, 
entinostat did not inhibit any UGT enzymes tested.  Entinostat was found to 
induce CYP 1A2, CYP 2C6, and CYP 2B8 as well as UGT 1A4.  Finally 
entinostat was found to be a substate for P-gp and BCRP transporters, but 
did not inhibit either of these transport proteins.  
8.1.3.7 
Toxicities: In the Phase I clinical trial of entinostat in patients with 
hematologic malignancies frequent toxicities included fatigue, 
anorexia, nausea, and electrolyte disturbances. Thrombocytopenia, 
leukopenia, granulocytopenia, abdominal pain, hypoalbumemia, 
hypophosphatemia, increased SGOT/SGPT, headache, fatigue 
(lethargy, malaise, asthenia), anorexia, nausea and vomiting. 
8.1.3.8 
Patient Care Implications:  Entinostat may cause fatigue or 


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malaises; advise patient to exercise cause while driving a vehicle or 
operating machinery.  Administation of entinostat is contraindicated 
in patients with a history of allergy to entinostat or other medicaitons 
that have a benzamide structure (eg tiapride, remoxipride, 
clebropride).  Careful monitoring of patients for signs of infection or 
reactivation of past infections is recommended, as reactivation of 
infection has been reported in patients treated with entinostat, in some 
cases without evidence of neutropenia.  The clinical significance of 
this finding and the potential association with entinostat is unknown.  
Entinostat must not be used during pregnancy or while breast feeding.  
Women and men participating in entinostat clinical studies must 
agree to use acceptable contraceptive methods, as indicated in the 
clinical study protocol, during treatment and for 3 months thereafter.    
 
8.1.4 Agent Ordering and Agent Accountability 
 
8.1.5 NCI-supplied agents may be requested by the Principal Investigator (or 
their authorized designee) at each participating institution.  Pharmaceutical 
Management Branch (PMB) policy requires that agent be shipped directly 
to the institution where the patient is to be treated.  PMB does not permit 
the transfer of agents between institutions (unless prior approval from 
PMB is obtained).  The CTEP-assigned protocol number must be used for 
ordering all CTEP-supplied investigational agents.  The responsible 
investigator at each participating institution must be registered with CTEP, 
DCTD through an annual submission of FDA Form 1572 (Statement of 
Investigator), Curriculum Vitae, Supplemental Investigator Data Form 
(IDF), and Financial Disclosure Form (FDF).  If there are several 
participating investigators at one institution, CTEP-supplied 
investigational agents for the study should be ordered under the name of 
one lead investigator at that institution. 
 
Active CTEP-registered investigators and investigator-designated shipping 
designees and ordering designees can submit agent requests through the 
PMB Online Agent Order Processing (OAOP) application (https://eapps-
ctep.nci.nih.gov/OAOP/pages/login.jspx).  Access to OAOP requires the 
establishment of a CTEP Identity and Access Management (IAM) account 
(https://eapps-ctep.nci.nih.gov/iam/) and the maintenance of an “active” 
account status and a “current” password.  For questions about drug orders, 
transfers, returns, or accountability, call (240) 276-6575 Monday through 
Friday between 8:30 am and 4:30 pm (ET) or email 
PMBAfterHours@mail.nih.gov anytime. 
 
8.1.6 Agent Inventory Records – The investigator, or a responsible party 
designated by the investigator, must maintain a careful record of the 
inventory and disposition of all agents received from DCTD using the NCI 


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Drug Accountability Record Form (DARF).  (See the NCI Investigator’s 
Handbook for Procedures for Drug Accountability and Storage.) 
 
8.2 Commercial Agents 
 
 
 
Irinotecan 
Chemical Name: (S)-4,11-diethyl-3,4,12,14-tetrahydro-4-hydroxy-3,14-
dioxo1Hpyrano[3',4':6,7]-indolizino[1,2-b]quinolin-9-yl-[1,4'bipiperidine]-1'-
carboxylate, monohydrochloride, trihydrate 
How Supplied: Supplied as a sterile, pale yellow, clear, aqueous solution. It is 
available in two single-dose sizes: 2 mL-fill vials contain 40 mg irinotecan 
hydrochloride and 5 mL-fill vials contain 100 mg irinotecan hydrochloride.  
Mechanism of Action: Topoisomerase I inhibitor 
Route of Administration: Intravenous 
Storage and Stability: Store at controlled room temperature 15° to 30°C (59° to 
86°F). Protect from light. It is recommended that the vial should remain in the 
carton until the time of use.   
 
Please refer to FDA-approved package insert for additional information about 
irinotecan. 
 
 
 
Gemcitabine 
 
 
Chemical Name: 2'-deoxy-2',2'-difluorocytidine monohydrochloride (β-isomer) 
 
 
How Supplied: Supplied in a sterile form for intravenous use only. Vials of 
gemcitabine HCl contain either 200 mg or 1 g of gemcitabine HCl (expressed as 
free base) formulated with mannitol (200 mg or 1 g, respectively) and sodium 
acetate (12.5 mg or 62.5 mg, respectively) as a sterile lyophilized powder.  
 
 
Mechanism of Action: Anti-metabolite nucleoside analog 
 
 
Route of Administration: Intravenous 
 
 
Storage and Stability: Store in glass vials, at 15 to 30°C. 
 
Please refer to FDA-approved package insert for additional information about 
gemcitabine. 
 
 
 
Docetaxel 
 
 
Chemical Name: (2R,3S)-N-carboxy-3-phenylisoserine,N-tert-butyl ester, 13-ester 
with 5β-20-epoxy-l,2α,4,7β,10β,13α-hexahydroxytax-ll-en-9-one 4-acetate 2-
benzoate, trihydrate 
 
 
How Supplied: Supplied as a sterile, non-pyrogenic, pale yellow to brownish-
yellow solution and is available as multiple concentrations and vial configurations.  
Consult specific product labels for preparation instructions and excipient 
information. 
 
 
Mechanism of Action: Binds microtubules irreversibly to inhibit mitotic cell 
division. 
 
 
Route of Administration: Intravenous 


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Storage and Stability: Store the unopened vials between 2°-25°C. Retain in the 
original package to protect from bright light 
 
Please refer to FDA-approved package insert for additional information about d 
 
docetaxel. 
 
 
 
Pemetrexed 
 
 
Chemical Name: L-Glutamic acid, N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-
pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-, disodium salt, heptahydrate 
 
 
How Supplied: Supplied as a sterile lyophilized powder for intravenous infusion 
available in single-dose vials 
 
 
Mechanism of Action: Folate analog antimetabolite 
 
 
Route of Administration: Intravenous 
 
 
Storage and Stability: Store between 2°C and 25°C (36°F and 77°F). Retain in the 
original package to protect from bright light. Freezing does not adversely affect 
the product. 
 
Please refer to FDA-approved package insert for additional information about 
pemetrexed. 
 
9 BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
9.1 Biomarker Studies 
 
9.1.1 Laboratory Correlative Studies 
 
9.1.1.1 Plasma 
9.1.1.2 Plasma samples will be obtained prior to initiation of therapy, one and two 
months after initiation of therapy (all arms), after completion of epigenetic 
therapy (arms A and B) and at time of progression. Some of these timepoints 
may be overlapping.  Samples obtained up to one week before or after the 
anticipated timepoints are acceptable. 
9.1.1.3 Quantitative candidate promoter methylation analysis will performed on 
APC, HCAD, p16, RASSF1A, GATA4, Actin 
9.1.1.4 For specific instructions on acquisition and handling of plasma samples 
please refer to APPENDIX C 
 
9.1.1.5 Biopsies 
9.1.1.6 Tumor tissue must be available from all patients prior to initiation of protocol 
therapy, either from original diagnostic biopsy, or biopsy performed prior to 
initiation of protocol therapy. If possible, patients randomized to receiving 
epigenetic therapy will be re-biopsied prior to starting chemotherapy.  As 
many of the following studies will be performed as tissue availability allows: 
A.  Quantitative candidate promoter methylation analysis: APC, HCAD, p16, 


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RASSF1A, GATA4, Actin 
B. Mutation and translocation analysis of known biologically relevant driver 
mutations in non-squamous NSCLC to include: EGFR, KRAS, EML4-
ALK, BRAF, PIK3CA, and ERBB2 overexpression 
C. Gene expression analysis using the Affymetrix gene expression array 
platform 
D. Promoter methylation analysis using the Illumina platform 
E. Ki67 by immunohistochemistry 
F. Expression of DNMT1, EZH2, BMI1, and SUZ12 
9.1.1.7 For specific instructions on acquisition and handling of fresh or frozen tissue 
samples please refer to LAB MANUAL 
 
10   STUDY CALENDAR 
 
Baseline evaluations are to be conducted within 1 week prior to start of protocol therapy.  Scans 
and x-rays must be done <4 weeks prior to the start of therapy.  In the event that the patient’s 
condition is deteriorating, laboratory evaluations should be repeated within 48 hours prior to 
initiation of the next cycle of therapy. 
 
Study Calendar for Arms A and B: Patients Randomized to Epigenetic Priming 
 
Prestudy 
Epigenetic therapy 
Chemotherapy 
Week 24 
from start 
of 
epigenetic 
therapy 
Off 
study 
4-week cycles 
3-week cycles 
Week 
1 
Week 
2 
Week 
3 
Week 
4 
 
Week 
8 
Odd-numbered cycles 
Even-numbered cycles 
Week 
1 
Week 
2 
Week 
3 
Week 
1 
Week 
2 
Week 
3 
Azacitidinea 
 
X 
X 
Xa 
 
 
 
 
 
 
 
 
 
 
Entinostatb 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Chemotherapy
c 
 
 
 
 
 
 
X 
Xd 
 
X 
Xd 
 
 
 
Informed 
Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
Medications 
X 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
Physical Exam 
X 
X 
 
X 
 
 
X 
 
 
 
 
 
 
 
Vital signs 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
Performance 
Status 
X 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
CBC w/diff., 
plts. 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
 
 
Serum 
chemistriese 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
 
 
Adverse Event 
Evaluation 
X 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
Tumor 
Measurements 
X 
 
 
 
Xf 
 
 
 
 
 
 
X 
X 
 
Radiologic 
Evaluation 
X 
 
 
 
Xf 
 
 
 
 
 
 
X 
X 
 
B-HCGg 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
EKG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Plasma 
X 
 
 
 
Xh 
 
 
 
 
 
 
 
 
X 


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Collection 
Tumor Biopsy 
X 
 
 
 
 
Xi 
 
 
 
 
 
 
 
 
a ArmA: Azacitidine  40mg/ m2 SC days 1-6 and 8-10 
 Arm B:  CC-486 200 mg PO days 1-21 
b Entinostat 7 mg PO days 3 and 10 
  
NOTE:  Epigenetic therapy is for 2 cycles only, except in patients with objective response 
c Chemotherapy regimens include: 
Docetaxel:  75mg/m2 IV Day 1 of a 21 day cycle OR  
         
  Gemcitabine:  1000 mg/ m2 IV Days 1 and 8 of a 21 day cycle OR  
         
  Irinotecan:  300mg/ m2 IV Day 1 of a 21 day cycle OR  
         
  Pemetrexed: 500 mg/ m2 IV Day 1 of a 21 day cycle 
NOTE:  Treatment on all chemotherapy regimens can continue until disease progression or other criteria as listed in 
section 5.5.  Patients with stable disease after 2 cycles of chemotherapy return to epigenetic therapy for 2 additional 
cycles.  See section 5.1 for details. 
d  Gemcitabine only 
e  Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, phosphorus, 
potassium, total protein, SGOT [AST], SGPT [ALT], sodium 
f Week 8 only 
g Serum pregnancy test (women of childbearing potential) 
h Weeks 4 and 8  
i Optional, in week 8 biopsy only for patients with fresh baseline biopsy and consenting to re-biopsy (can be  performed week 9 
pre-treatment) 
 
 
Study Calendar for Arm C: Patients Randomized to Chemotherapy Alone 
 
Prestudy 
3-week cycles 
Week 24 from 
start of therapy 
Off study 
Week 1 
Week 2 
Week 3  
 
 
Chemotherapya 
 
X 
Xb 
 
 
 
Informed 
Consent 
X 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
Concomitant 
Medications 
X 
X 
 
 
 
 
Physical Exam 
X 
X 
 
 
 
 
Vital signs 
X 
X 
 
 
 
 
Height 
X 
 
 
 
 
 
Weight 
X 
X 
 
 
 
 
Performance 
Status 
X 
X 
 
 
 
 
CBC w/diff., 
plts. 
X 
X 
 
 
 
 
Serum 
chemistriesc 
X 
X 
 
 
 
 
Adverse Event 
Evaluation 
 
X 
 
 
 
 
Tumor 
Measurements 
X 
 
 
Xe 
X 
 
Radiologic 
Evaluation 
X 
 
 
Xe 
X 
 
B-HCGd 
X 
 
 
 
 
 
Plasma 
Collection 
Xf 
Xf 
Xf 
 
 
Xf 
Tumor Biopsy 
X 
 
 
 
 
 
a Chemotherapy regimens include: 
Docetaxel:  75mg/m2 IV Day 1 of a 21 day cycle OR  
         
  Gemcitabine:  1000 mg/ m2 IV Days 1 and 8 of a 21 day cycle OR  
         
  Irinotecan:  300mg/ m2 IV Day 1 of a 21 day cycle OR  
         
  Pemetrexed: 500 mg/ m2 IV Day 1 of a 21 day cycle 


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NOTE:  Treatment on all regimens can continue until disease progression or other criteria as listed in section 5.5 
b  Gemcitabine only 
c  Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, phosphorus, 
potassium, total protein, SGOT [AST], SGPT [ALT], sodium 
d Serum pregnancy test (women of childbearing potential) 
e  Week 3 of even numbered cycles only  
f  Plasma collection pretreatment, week 4 from start of therapy, week 8 from start of therapy, and off study, +/- 7 days for all time  
   points. (time points for week 4 and week 8 do not necessarily correspond to a treatment day)


 
 
 
 
 
Tumor Measurement and Radiologic Evaluation Schema for 
Epigenetic Therapy Arm.  The guiding principal is that every patient 
on study, regardless of arm, receives tumor reevaluation every two 
cycles, regardless of therapy. 
 
 
11   MEASUREMENT OF EFFECT 
 
11.1 
Antitumor Effect – Solid Tumors 
 
The primary endpoint of this study will be based on comparison of the baseline tumor 
assessment, performed prior to randomization to study arm, and assessment 24 weeks after 
randomization, using the RECIST 1.1 criteria described below.  Scans performed up to 1 week 
prior to or after the planned time-points are acceptable.  Additional scans, performed as defined 
in the study calendar, and will be used to assess objective response to individual components of 


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the therapy administered on this study, as well as progression-free survival, but will not be 
considered in assessment of the primary endpoint. 
 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1) [Eur J Ca 45:228-247, 2009].  Changes in the largest diameter (unidimensional 
measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph 
nodes are used in the RECIST criteria. 
 
11.1.1 Definitions 
 
Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of their 
first treatment with azacitidine and entinostat. 
 
Evaluable for objective response.  Only those patients who have measurable disease 
present at baseline, have received at least one cycle of therapy, and have had their disease 
re-evaluated will be considered evaluable for response.  These patients will have their 
response classified according to the definitions stated below.  (Note:  Patients who exhibit 
objective disease progression prior to the end of cycle 1 will also be considered 
evaluable.) 
 
Evaluable Non-Target Disease Response.  Patients who have lesions present at baseline 
that are evaluable but do not meet the definitions of measurable disease, have received at 
least one cycle of therapy, and have had their disease re-evaluated will be considered 
evaluable for non-target disease.  The response assessment is based on the presence, 
absence, or unequivocal progression of the lesions.  
 
11.1.2 Disease Parameters 
 
Measurable disease.  Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as ≥20 mm by chest 
x-ray or as ≥10 mm with CT scan, MRI, or calipers by clinical exam.  All tumor 
measurements must be recorded in millimeters (or decimal fractions of centimeters). 
 
Note:  Tumor lesions that are situated in a previously irradiated area might or might not 
be considered measurable.  If the investigator thinks it appropriate to include them, the 
conditions under which such lesions should be considered must be defined in the 
protocol. 
 
Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a 
lymph node must be ≥15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm).  At baseline and in follow-up, only 
the short axis will be measured and followed. 
 
Non-measurable disease.  All other lesions (or sites of disease), including small lesions 


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(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 patient, these are preferred for selection as target 
lesions. 
 
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be identified as target 
lesions and recorded and measured at baseline.  Target lesions should be selected on the 
basis of their size (lesions with the longest diameter), be representative of all involved 
organs, but in addition should be those that lend themselves to reproducible repeated 
measurements.  It may be the case that, on occasion, the largest lesion does not lend itself 
to reproducible measurement in which circumstance the next largest lesion which can be 
measured reproducibly should be selected.  A sum of the diameters (longest for non-
nodal lesions, short axis for nodal lesions) for all target lesions will be calculated and 
reported as the baseline sum diameters.  If lymph nodes are to be included in the sum, 
then only the short axis is added into the sum.  The baseline sum diameters will be used 
as reference to further characterize any objective tumor regression in the measurable 
dimension of the disease. 
 
Non-target lesions.  All other lesions (or sites of disease) including any measurable 
lesions over and above the 5 target lesions should be identified as non-target lesions and 
should also be recorded at baseline.  Measurements of these lesions are not required, but 
the presence, absence, or in rare cases unequivocal progression of each should be noted 
throughout follow-up.  
 
11.1.3 Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or 
calipers.  All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the 
treatment. 
 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 
evaluation is preferred to evaluation by clinical examination unless the lesion(s) being 
followed cannot be imaged but are assessable by clinical exam. 


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Clinical lesions  Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and ≥10 mm diameter as 
assessed using calipers (e.g., skin nodules).  In the case of skin lesions, documentation by 
color photography, including a ruler to estimate the size of the lesion, is recommended.  
 
Chest x-ray  Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung.  However, CT is preferable.  
 
Conventional CT and MRI  This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT slice thickness is 5 mm or less.  If CT scans have 
slice thickness greater than 5 mm, the minimum size for a measurable lesion should be 
twice the slice thickness.  MRI is also acceptable in certain situations (e.g. for body 
scans).   
 
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement.  Furthermore, the 
availability of MRI is variable globally.  As with CT, if an MRI is performed, the 
technical specifications of the scanning sequences used should be optimized for the 
evaluation of the type and site of disease.  Furthermore, as with CT, the modality used at 
follow-up should be the same as was used at baseline and the lesions should be 
measured/assessed on the same pulse sequence.  It is beyond the scope of the RECIST 
guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body 
parts, and diseases.  Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior scans.  Body scans 
should be performed with breath-hold scanning techniques, if possible. 
 
PET-CT  At present, the low dose or attenuation correction CT portion of a combined 
PET-CT is not always of optimal diagnostic CT quality for use with RECIST 
measurements.  However, if the site can document that the CT performed as part of a 
PET-CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), 
then the CT portion of the PET-CT can be used for RECIST measurements and can be 
used interchangeably with conventional CT in accurately measuring cancer lesions over 
time.  Note, however, that the PET portion of the CT introduces additional data which 
may bias an investigator if it is not routinely or serially performed.   
 
Ultrasound  Ultrasound is not useful in assessment of lesion size and should not be used 
as a method of measurement.  Ultrasound examinations cannot be reproduced in their 
entirety for independent review at a later date and, because they are operator dependent, it 
cannot be guaranteed that the same technique and measurements will be taken from one 
assessment to the next.  If new lesions are identified by ultrasound in the course of the 
study, confirmation by CT or MRI is advised.  If there is concern about radiation 


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exposure at CT, MRI may be used instead of CT in selected instances. 
 
Endoscopy, Laparoscopy  The utilization of these techniques for objective tumor  
 
evaluation is not advised.  However, such techniques may be useful to confirm complete 
pathological response when biopsies are obtained or to determine relapse in trials where 
recurrence following complete response (CR) or surgical resection is an endpoint. 
 
Tumor markers  Tumor markers alone cannot be used to assess response.  If markers are 
initially above the upper normal limit, they must normalize for a patient to be considered 
in complete clinical response.  Specific guidelines for both CA-125 response (in recurrent 
ovarian cancer) and PSA response (in recurrent prostate cancer) have been published 
[JNCI 96:487-488, 2004; J Clin Oncol 17, 3461-3467, 1999; J Clin Oncol 26:1148-1159, 
2008].  In addition, the Gynecologic Cancer Intergroup has developed CA-125 
progression criteria which are to be integrated with objective tumor assessment for use in 
first-line trials in ovarian cancer [JNCI 92:1534-1535, 2000]. 
 
Cytology, Histology  These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor 
types, such as germ cell tumors, where known residual benign tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or 
stable disease is mandatory to differentiate between response or stable disease (an 
effusion may be a side effect of the treatment) and progressive disease. 
 
FDG-PET  While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease).  New lesions on the basis 
of FDG-PET imaging can be identified according to the following algorithm:  
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 
PD based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive FDG-
PET at follow-up corresponds to a new site of disease confirmed by CT, this is PD.  If 
the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT  scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal 
FDG-PET scan).  If the positive FDG-PET at follow-up corresponds to a pre-existing 
site of disease on CT that is not progressing on the basis of the anatomic images, this 
is not PD. 
c. FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy 
in cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring.  The use of FDG-PET in this circumstance should be prospectively 
described in the protocol and supported by disease-specific medical literature for the 
indication.  However, it must be acknowledged that both approaches may lead to false 


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positive CR due to limitations of FDG-PET and biopsy resolution/sensitivity. 
 
 
 
 
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake 
greater than twice that of the surrounding tissue on the attenuation corrected image. 
 
11.1.4 Response Criteria 
 
11.1.4.1 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. 
 
11.1.4.2 Evaluation of Non-Target Lesions 
 
Complete Response (CR):  Disappearance of all non-target lesions and normalization 
of tumor marker level.  All lymph nodes must be non-pathological in size (<10 mm 
short axis). 
 
Note:  If tumor markers are initially above the upper normal limit, they must 
normalize for a patient to be considered in complete clinical response. 
 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits. 
 
Progressive Disease (PD):  Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions.  Unequivocal progression 
should not normally trump target lesion status.  It must be representative of overall 
disease status change, not a single lesion increase.     


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Although a clear progression of “non-target” lesions only is exceptional, the opinion 
of the treating physician should prevail in such circumstances, and the progression 
status should be confirmed at a later time by the review panel (or Principal 
Investigator). 
 
11.1.4.3 Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started).  The patient's best 
response assignment will depend on the achievement of both measurement and 
confirmation criteria.  All patients on this study must have measurable disease. 
 
Table 8.   For Patients with Measurable Disease (i.e., Target Disease) 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non-CR/Non-
PD 
No 
PR 
>4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at least once >4 
wks. from baseline** 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**        Only for non-randomized trials with response as primary endpoint. 
***      In exceptional circumstances, unequivocal progression in non-target lesions may be 
            accepted as disease progression. 
 
Note:  Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration.”  Every effort should be made to document the 
objective progression even after discontinuation of treatment. 
 
 
 
 
 


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Table 9.  For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
 
‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign 
this category when no lesions can be measured is not advised 
 
11.1.5 Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first 
date that recurrent or progressive disease is objectively documented (taking as reference 
for progressive disease the smallest measurements recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first met 
for CR until the first date that progressive disease is objectively documented. 
 
 
Duration of stable disease:  Stable disease is measured from the start of the treatment 
until the criteria for progression are met, taking as reference the smallest measurements 
recorded since the treatment started, including the baseline measurements.  
 
11.1.6 Progression-Free Survival 
 
PFS is defined as the duration of time from start of treatment to time of progression or 
death, whichever occurs first. 
 
11.1.7 Response Review 
Baseline and 6 month scans of all patients will be reviewed by an attending radiologist to 
assign a response category. 
 
 
12   DATA REPORTING / REGULATORY REQUIREMENTS 
 


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Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements). 
 
 
 
 
 
 
12.1 
Data Reporting 
 
12.1.1 Method 
 
For phase 2 protocols: This study will be monitored by the Clinical Data Update System 
(CDUS) Version 3.0.  Cumulative protocol- and patient-specific CDUS data will be 
submitted electronically to CTEP on a quarterly basis, either by FTP burst of data or via 
the CDS web application.  Reports are due January 31, April 30, July 31, and October 31.  
Instructions for submitting data using the CDUS can be found on the CTEP Web site 
(http://ctep.cancer.gov/reporting/cdus.html).  
 
12.1.2 Responsibility for Data Submission 
Study participants are responsible for submitting CDUS data and/or data forms to either 
the Coordinating Center or to the Lead Organization on the study quarterly.  The date for 
submission to the Coordinating Center or to the Lead Organization will be set by them.  
CDUS does not accept data submissions from the participants on the study.  When setting 
the dates, allow time for Coordinating Center compilation, Principal Investigator review, 
and timely submission to CTEP by the quarterly deadlines (see Section 12.1.1).  For trials 
monitored by CTMS, a quarterly report of data will be provided by Theradex to the 
Coordinating Center. 
 
Either the Coordinating Center or the Lead Organization is responsible for compiling and 
submitting CDUS data to CTEP for all participants and for providing the data to the 
Principal Investigator for review.   
12.2 
CTEP Multicenter Guidelines 
 
This protocol will adhere to the policies and requirements of the CTEP Multicenter Guidelines.  
The specific responsibilities of the Principal Investigator and the Coordinating Center (Study 
Coordinator) and the procedures for auditing are presented in Appendix B. 
 The Principal Investigator/Coordinating Center is responsible for distributing all IND 
Action Letters or Safety Reports received from CTEP to all participating institutions for 
submission to their individual IRBs for action as required. 
 
 Except in very unusual circumstances, each participating institution will order DCTD-


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supplied agents directly from CTEP.  Agents may be ordered by a participating site only 
after the initial IRB approval for the site has been forwarded by the Coordinating Center 
to the CTEP PIO (PIO@ctep.nci.nih.gov) except for Group studies. 
 
 
 
 
 
 
12.3 
Collaborative Agreements Language 
 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI 
under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical 
Company(ies) (hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer 
Treatment and Diagnosis.  Therefore, the following obligations/guidelines, in addition to the 
provisions in the “Intellectual Property Option to Collaborator”  
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within the 
terms of award, apply to the use of the Agent(s) in this study: 
 
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 
Agent(s) be transferred or licensed to any party not participating in the clinical study.  
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and shall 
be maintained as such by the investigators.  The protocol documents for studies utilizing 
Agents contain confidential information and should not be shared or distributed without the 
permission of the NCI.  If a copy of this protocol is requested by a patient or patient’s family 
member participating on the study, the individual should sign a confidentiality agreement.  A 
suitable model agreement can be downloaded from: http://ctep.cancer.gov. 
 
2. For a clinical protocol where there is an investigational Agent used in combination with 
(an)other Agent(s), each the subject of different Collaborative Agreements, the access to and 
use of data by each Collaborator shall be as follows (data pertaining to such combination use 
shall hereinafter be referred to as "Multi-Party Data”): 
 
a. NCI will provide all Collaborators with prior written notice regarding the existence and 
nature of any agreements governing their collaboration with NCI, the design of the 
proposed combination protocol, and the existence of any obligations that would tend to 
restrict NCI's participation in the proposed combination protocol. 
 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical trial 
by any other Collaborator solely to the extent necessary to allow said other Collaborator 
to develop, obtain regulatory approval or commercialize its own Agent. 
 
c. Any Collaborator having the right to use the Multi-Party Data from these trials must 
agree in writing prior to the commencement of the trials that it will use the Multi-Party 
Data solely for development, regulatory approval, and commercialization of its own 


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Agent. 
 
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative 
Agreement will be made available to Collaborator(s), the NCI, and the FDA, as 
appropriate and unless additional disclosure is required by law or court order as described 
in the IP Option to Collaborator 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm).  Additionally, 
all Clinical Data and Results and Raw Data will be collected, used and disclosed 
consistent with all applicable federal statutes and regulations for the protection of human 
subjects, including, if applicable, the Standards for Privacy of Individually Identifiable 
Health Information set forth in 45 C.F.R. Part 164. 
 
4. When a Collaborator wishes to initiate a data request, the request should first be sent to the 
NCI, who will then notify the appropriate investigators (Group Chair for Cooperative Group 
studies, or PI for other studies) of Collaborator's wish to contact them. 
 
5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the 
guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is a 
DMC for this clinical trial. 
 
6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP by the 
Group office for Cooperative Group studies or by the principal investigator for non-
Cooperative Group studies for immediate delivery to Collaborator(s) for advisory review and 
comment prior to submission for publication.  Collaborator(s) will have 30 days from the 
date of receipt for review.  Collaborator shall have the right to request that publication be 
delayed for up to an additional 30 days in order to ensure that Collaborator’s confidential and 
proprietary data, in addition to Collaborator(s)’s intellectual property rights, are protected.  
Copies of abstracts must be provided to CTEP for forwarding to Collaborator(s) for courtesy 
review as soon as possible and preferably at least three (3) days prior to submission, but in 
any case, prior to presentation at the meeting or publication in the proceedings.  Press 
releases and other media presentations must also be forwarded to CTEP prior to release.  
Copies of any manuscript, abstract and/or press release/ media presentation should be sent to: 
 
Email: ncicteppubs@mail.nih.gov 
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No publication, 
manuscript or other form of public disclosure shall contain any of Collaborator’s confidential/ 
proprietary information. 
 
 
13   STATISTICAL CONSIDERATIONS 
 
13.1 
Study Design/Endpoints 
 
13.1.1 Study Design 


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The study will be a randomized phase II trial of single-agent chemotherapy alone or single-
agent chemotherapy preceded by epigenetic therapy consisting of entinostat combined with 
either oral or subcutaneous azacitidine until progression is noted. Chemotherapy may be 
chosen from among irinotecan, docetaxel, gemcitabine, or pemetrexed by the treating 
physician.  Patients will be stratified and randomized according to chemotherapy chosen.   
 
 
 
 
 
13.1.2 Arms/Regimens 
 
Patients will be randomized evenly to receive chemotherapy alone, chemotherapy primed 
by epigenetic therapy consisting of azacitidine 40 mg/m2/day subcutaneous days 1-6 and 
8-10 and entinostat 7 mg PO days 3 and 10 on a 28 day cycle, or chemotherapy primed by 
epigenetic therapy consisting of CC-486 300 mg PO days 1-21 and entinostat 7 mg PO 
days 3 and 10 on a 28 day cycle until disease progression. 
 
Chemotherapy will consist of one of the four following regimens chosen prior to 
randomization by the treating physician. 
- 
Irinotecan 300mg/m2 IV once every 3 weeks 
- 
Docetaxel 75mg/m2 IV once every 3 weeks 
- 
Gemcitabine 1000g/m2 IV days 1 and 8 of a 21 day cycle 
- 
Pemetrexed 500 mg/m2 IV once every 3 weeks (for non-squamous histology only) 
 
13.1.3   Endpoints 
 
13.1.3.1 
Primary Endpoint 
1) Percentage of patients progression-free at 6 months from the time of 
randomization. 
13.1.3.2 
Secondary Endpoint  
 1)  Progression-Free Survival 
Progression-free survival (PFS) will be measured from the time of 
randomization until radiologic or clinical progression is noted.   
2) Overall Survival 
Overall Survival (OS) will be measured from the time of enrollment to trial 
until death. 
 
13.2 
Sample Size/Accrual Rate 
 
The study will enroll up to 165 patients, 55 per treatment arm.  We will separately 
compare each treatment arm with epigenetic therapy (Arms A and B) to the single-
agent chemotherapy arm (Arm C).  The final analysis will be by Fisher’s Exact test, 
with percentage of patients who have no progressed as the outcome variable.  Using 


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Fisher’s Exact test for analysis with 55 patients per treatment group will provide 88% 
power to detect an increase from 40% (chemotherapy alone) to 65% (epigenetic 
therapy followed by chemotherapy) in the number of patients who are progression free 
at six months.  The power estimate is based on 1000 simulations of the 3-arm study 
with a one-sided 0.1-level of significance (see table below).  We will not adjust for 
multiple comparisons, because the simulations of the three-arm study with futility 
monitoring (see Section 13.4) show that the Type I error is below 0.1.  Allowing for 
up to 10% in-evaluable patients, we will enroll up to 61 patients per arm, or a total of 
183. Anticipated accrual rate is 5 patients per month. 
 
 
 
 
13.3 
Stratification Factors 
 
Treating physician will choose the chemotherapy for each subject.  Patients will then 
be randomized to one of three arms, stratified by chosen chemotherapy. 
 
13.4 
Interim Analyses 
 
The study design calls for separate interim futility analyses for each comparison of the 
chemotherapy alone arm to one of the arms with chemotherapy and epigenetic therapy.  
For each treatment pair, there will be two interim futility analyses. These analyses will 
occur after 20 patients and 40 patients per treatment group have been followed for 6 
months. The futility analysis will project the final test based on current and predicted 
PD information.  The Bayesian predictions are based on a Uniform(0,1) reference 
prior.  We will consider closing a treatment arm with epigenetic therapy for futility if 
either interim analysis suggests that the predictive probability is 5% or less that there 
will ultimately be a significant difference between it and the single-agent 
chemotherapy arm. We estimated via simulation the study’s operating characteristics 
(e.g., sample size, expected sample size, and error probabilities) considering these 
futility analyses.  The following table displays the operating characteristics of the 
design and is based on 1000 simulations for each scenario. 
 
 
 
 
 
 
 
 
 
 
 
 


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Response Probability 
Expected Sample Size 
Probability Stop 
Trt A at Interim 
Analysis 
Probability Stop 
Trt B at Interim 
Analysis 
Probability 
Reject 
Control 
A 
B 
Control 
A 
B 
#1 
#2 
#1 
#2 
A 
B 
0.40 
0.40 
0.40 
43.6 
38.4 
37.8 
33.0% 
33.7% 
34.4% 
34.6% 
7.8% 
8.0% 
0.40 
0.40 
0.45 
46.2 
38.3 
42.7 
33.0% 
34.4% 
23.3% 
27.4% 
8.4% 
17.6% 
0.40 
0.40 
0.50 
48.5 
38.1 
46.5 
34.1% 
32.8% 
15.8% 
19.5% 
7.0% 
31.1% 
0.40 
0.40 
0.55 
51.2 
38.3 
50.8 
32.9% 
34.3% 
7.2% 
11.5% 
6.5% 
53.9% 
0.40 
0.40 
0.60 
52.7 
37.9 
52.4 
34.1% 
34.6% 
4.7% 
6.3% 
6.3% 
74.0% 
0.40 
0.40 
0.65 
53.9 
38.3 
53.7 
34.1% 
32.0% 
3.0% 
1.6% 
8.6% 
88.1% 
0.40 
0.40 
0.70 
54.7 
38.2 
54.7 
33.4% 
34.2% 
0.8% 
0.4% 
7.0% 
95.9% 
0.40 
0.45 
0.45 
47.8 
42.7 
42.9 
23.3% 
27.8% 
22.8% 
27.4% 
17.1% 
18.4% 
0.40 
0.45 
0.50 
50.2 
43.1 
47.8 
23.6% 
24.0% 
13.6% 
16.2% 
18.0% 
36.1% 
0.40 
0.45 
0.55 
51.9 
42.7 
50.8 
23.9% 
26.2% 
7.6% 
10.3% 
18.2% 
54.5% 
0.40 
0.45 
0.60 
53.4 
42.7 
52.9 
23.0% 
28.6% 
3.6% 
5.7% 
15.9% 
75.1% 
0.40 
0.45 
0.65 
54.4 
42.7 
54.3 
22.8% 
28.5% 
1.3% 
1.8% 
15.7% 
88.9% 
0.40 
0.45 
0.70 
54.8 
43.5 
54.7 
20.9% 
28.2% 
0.4% 
1.0% 
16.4% 
96.9% 
0.40 
0.50 
0.50 
51.0 
46.8 
46.6 
15.1% 
19.5% 
15.5% 
19.8% 
34.2% 
35.8% 
0.40 
0.50 
0.55 
52.7 
47.2 
51.0 
14.2% 
18.9% 
6.7% 
11.3% 
34.5% 
54.4% 
0.40 
0.50 
0.60 
53.5 
47.6 
52.3 
13.2% 
18.7% 
4.6% 
7.0% 
32.7% 
72.2% 
0.40 
0.50 
0.65 
54.3 
46.6 
54.0 
16.4% 
17.5% 
1.7% 
2.5% 
36.2% 
87.7% 
0.40 
0.50 
0.70 
54.8 
47.3 
54.7 
13.7% 
19.5% 
0.6% 
0.4% 
34.5% 
95.5% 
0.40 
0.55 
0.55 
53.3 
50.2 
50.4 
9.0% 
10.9% 
8.2% 
11.2% 
53.4% 
54.4% 
0.40 
0.55 
0.60 
53.9 
50.6 
52.7 
8.6% 
9.6% 
4.4% 
5.3% 
55.1% 
74.5% 
0.40 
0.55 
0.65 
54.5 
51.3 
54.3 
7.3% 
7.9% 
1.4% 
1.5% 
55.3% 
90.3% 
0.40 
0.55 
0.70 
54.8 
50.6 
54.7 
8.4% 
9.6% 
0.7% 
0.6% 
55.5% 
95.8% 
0.40 
0.60 
0.60 
54.4 
53.1 
52.9 
3.4% 
4.6% 
4.0% 
4.8% 
74.7% 
74.7% 
0.40 
0.60 
0.65 
54.7 
52.5 
54.0 
5.0% 
4.7% 
2.4% 
1.4% 
74.1% 
87.9% 
0.40 
0.60 
0.70 
54.7 
52.0 
54.3 
5.7% 
6.5% 
1.7% 
0.4% 
72.2% 
95.2% 
0.40 
0.65 
0.65 
54.8 
53.9 
53.9 
2.4% 
2.0% 
2.2% 
2.4% 
88.4% 
88.9% 
0.40 
0.65 
0.70 
55.0 
54.3 
54.8 
1.4% 
1.4% 
0.3% 
0.6% 
88.5% 
97.1% 
0.40 
0.70 
0.70 
54.9 
54.7 
54.7 
0.7% 
0.4% 
0.7% 
0.2% 
96.6% 
96.2% 


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13.5 
Analysis of Secondary Endpoints 
 
While the trial is specifically powered for clinical endpoints we will report the 
outcome of laboratory studies performed on trial patient samples.  Each of the 
proposed laboratory correlates will be performed for each patient, to the extent 
possible.  Laboratory data will be used to identify patients likely to benefit from 
combination therapy and to refine therapy for future trials.  Because multiple 
endpoints will be employed in correlate analysis, these will be used to generate 
hypotheses to be further tested in future studies. 
 
i. The predictive and prognostic value of the previously defined epigenetic 
signature, comprised of promoter methylation analysis of 4 target genes, will 
be assessed 
ii. Response to therapy compared to genetic and epigenetic factors and tested for 
association 
iii. Genome-wide techniques will include expression array and methylation array 
will be compared to response. 
 
13.6     Reporting and Exclusions 
 
13.6.1  Evaluation of toxicity – All patients will be evaluable for toxicity from the time 
of their first treatment with any study therapy.   
 
13.6.2 Evaluation of response – All patients included in the study must be assessed for 
response to treatment, even if there are major protocol treatment deviations or if 
they are ineligible.  Each patient will be assigned one of the following categories:  
1) complete response, 2) partial response, 3) stable disease, 4) progressive 
disease, 5) early death from malignant disease, 6) early death from toxicity, 7) 
early death because of other cause, or 9) unknown (not assessable, insufficient 
data).  [Note:  By arbitrary convention, category 9 usually designates the 
“unknown” status of any type of data in a clinical database.] 
 
All of the patients who met the eligibility criteria (with the possible exception of 
those who received no study medication) should be included in the main analysis 
of the response rate.  Patients in response categories 4-9 should be considered to 
have a treatment failure (disease progression).  Thus, an incorrect treatment 
schedule or drug administration does not result in exclusion from the analysis of 
the response rate.  Precise definitions for categories 4-9 will be protocol specific.  
 
All conclusions should be based on all eligible patients.  Subanalyses may then 
be performed on the basis of a subset of patients, excluding those for whom major 
protocol deviations have been identified (e.g., early death due to other reasons, 
early discontinuation of treatment, major protocol violations, etc.).  However, 
these subanalyses may not serve as the basis for drawing conclusions concerning 


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treatment efficacy, and the reasons for excluding patients from the analysis should 
be clearly reported.  The 95% confidence intervals should also be provided.  
 
 
 
 
 
 
 
 
 
 
 
 
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Therapy Has Efficacy in Patients with Refractory Advanced Non–Small Cell Lung Cancer 
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 36. Garcia-Manero G, Gore SD, Cogle C, et al: Phase I study of oral azacitidine in 
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 37. Shi W, Nacev BA, Aftab BT, et al: Structure-activity relationship studies for inhibition of 
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 38. Baylin SB, Jones PA: A decade of exploring the cancer epigenome - biological and 
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 43. Ando S, Suzuki M, Yamamoto N, et al: The prognostic value of both neuron-specific enolase 
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 45. Brock MV, Hooker CM, Ota-Machida E, et al: DNA methylation markers and early 
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APPENDIX A: PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work.
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX B: CTEP MULTICENTER GUIDELINES 
 
If an institution wishes to collaborate with other participating institutions in performing a 
CTEP sponsored research protocol, then the following guidelines must be followed. 
 
Responsibility of the Protocol Chair  
 The Protocol Chair will be the single liaison with the CTEP Protocol and Information 
Office (PIO).  The Protocol Chair is responsible for the coordination, development, 
submission, and approval of the protocol as well as its subsequent amendments.  The 
protocol must not be rewritten or modified by anyone other than the Protocol Chair.  
There will be only one version of the protocol, and each participating institution will use 
that document.  The Protocol Chair is responsible for assuring that all participating 
institutions are using the correct version of the protocol. 
 The Protocol Chair is responsible for the overall conduct of the study at all participating 
institutions and for monitoring its progress.  All reporting requirements to CTEP are the 
responsibility of the Protocol Chair.  
 The Protocol Chair is responsible for the timely review of Adverse Events (AE) to assure 
safety of the patients. 
 The Protocol Chair will be responsible for the review of and timely submission of data 
for study analysis. 
 
Responsibilities of the Coordinating Center 
 Each participating institution will have an appropriate assurance on file with the Office 
for Human Research Protection (OHRP), NIH.  The Coordinating Center is responsible 
for assuring that each participating institution has an OHRP assurance and must maintain 
copies of IRB approvals from each participating site.  
 Prior to the activation of the protocol at each participating institution, an OHRP form 310 
(documentation of IRB approval) must be submitted to the CTEP PIO. 
 The Coordinating Center is responsible for central patient registration.  The Coordinating 
Center is responsible for assuring that IRB approval has been obtained at each 
participating site prior to the first patient registration from that site. 
 The Coordinating Center is responsible for the preparation of all submitted data for 
review by the Protocol Chair. 
 The Coordinating Center will maintain documentation of AE reports.  There are two 
options for AE reporting: (1) participating institutions may report directly to CTEP with a 
copy to the Coordinating Center, or (2) participating institutions report to the 
Coordinating Center who in turn report to CTEP.  The Coordinating Center will submit 
AE reports to the Protocol Chair for timely review. 
 Audits may be accomplished in one of two ways:  (1) source documents and research 
records for selected patients are brought from participating sites to the Coordinating 
Center for audit, or (2) selected patient records may be audited on-site at participating 
sites.  If the NCI chooses to have an audit at the Coordinating Center, then the 
Coordinating Center is responsible for having all source documents, research records, all 


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IRB approval documents, NCI Drug Accountability Record forms, patient registration  
 
lists, response assessments scans, x-rays, etc. available for the audit. 
 
Inclusion of Multicenter Guidelines in the Protocol 
 The protocol must include the following minimum information:  
 The title page must include the name and address of each participating institution and 
the name, telephone number and e-mail address of the responsible investigator at each 
participating institution. 
 The Coordinating Center must be designated on the title page. 
 Central registration of patients is required.  The procedures for registration must be 
stated in the protocol. 
 Data collection forms should be of a common format.  Sample forms should be 
submitted with the protocol.  The frequency and timing of data submission forms to 
the Coordinating Center should be stated. 
 Describe how AEs will be reported from the participating institutions, either directly 
to CTEP or through the Coordinating Center. 
 Describe how Safety Reports and Action Letters from CTEP will be distributed to 
participating institutions. 
 
Agent Ordering 
 Except in very unusual circumstances, each participating institution will order DCTD-
supplied investigational agents directly from CTEP.  Investigational agents may be 
ordered by a participating site only after the initial IRB approval for the site has been 
forwarded by the Coordinating Center to the CTEP PIO.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX C: PLASMA AND SERUM PROCESSING PROTOCOL 
 
Reagents: 
 Ficoll-Paque Plus Buffer  (must be stored at 4 degrees C ) 
 
Equipment: 
 
 15 mL conical tubes (1 for each tube of blood) 
 1.5 mL Eppendorf Tubes  
 Plastic non-graduated disposable pipetters 
 
Procedure: 
 
Preparation- 
1. First get the blood tubes (plasma and serum) 
2. Get 1- 15mL conical per tube of serum or plasma.  
3. Label each 15 mL conical with either plasma or serum, and the identification. This is only 
to be able to tell the samples apart if you are processing more than 1 patient at once 
4. Take the labeled conicals marked plasma, and fill each one with 3 to 4 mL Ficoll- Paque 
buffer.  
5. Take the plasma sample tubes (purple tops) and empty each one into the conicals 
containing the buffer. Pour very slowly as not to lyse the cells.   
*** The plasma samples will have buffer in them, the serum ones will not 
 
 
Spinning samples- 
6. Take all of the plasma and serum 15 mL conicals and spin them a refrigerated centrifuge 
set at 4 degrees C. Spin at a speed of 3000 rpm for 10 min.  
7. While the plasma and serum samples are spinning, set up and label your 1.5 mL Eppendorf 
tubes. You can start by labeling 4 tubes for serum and 4 for plasma. You might need more 
or less.  
8. Each tube should have the random number and sample type on the top (serum = S, plasma 
= P). The side of the tube should have the random number, sample type, and date.  
9. After the 10 min spin, take the plasma conicals out of the centrifuge and spin the serum 
conicals for another 10 minutes.  
10. Get 1 disposable transfer pipette per sample type. Put the pipettes in the hood before you 
start opening the conicals. 
11. Use the pipetter to carefully extract the plasma from the first conical, and transfer it into 
the pre-marked 1.5 mL Eppendorf tubes. Make sure you only take the yellowish fluid (the 
actual plasma). If you accidentally touch the red blood cells, don’t take the rest of the 
sample from that tube. **If the plasma appears to be pink or red when you get it from the 
centrifuge, the cells have lysed. Take some of the sample, but note that the sample lysed. 


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12. After harvesting the plasma, set conical aside for 1 min. After 1 minute, collect the white, 
buffy coat layer into its own eppendorf tube using a transfer pipetter.  
 
 
Storage: 
13. Once all of the samples have been taken, note what samples you have and record the 
necessary information in a spreadsheet or database.  (ex. How many vials are collected, 
blood processing times, etc.) 
14. Snap freeze all samples at -80 degrees Celsius.  
 
 
 


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APPENDIX D:  PATIENT DIARY FOR ARM A PATIENTS 
 
Patient initials________        Cycle___________ 
 
MRN_______________ 
 
Please take your anti-nausea medicine and entinostat 7 mg by mouth on days 3 and days 10 of 
each 28 day cycle.  Do not start cycle 2 until after 28 days.     
*** Entinostat should be taken on an empty stomach at least 1 hour before or 2 hours after a 
meal. If your dose requires more than one tablet, the tablets should be taken one at a time. 
***Your anti-nausea medicine should be taken at least 30 minutes prior to entinostat. 
 
 
 
Day/Date 
 
 
 
entinostat 
Check box and note time taken 
below:  Please note time next to the 
box. 
AM              OR             PM
 
Comments:  Please note any side-
effects you may be having or 
problems with compliance. 
Cycle 1 
Day 3 
  
  
 
Day 10 
  
  
 
Cycle 2 
Day 3 
  
  
 
Day 10 
  
  
 
 
 
 


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APPENDIX E:  PATIENT DIARY FOR ARM B PATIENTS 
 
Patient initials________        Cycle___________ 
 
MRN_______________ 
 
Please take CC-486 (oral azacitidine) 300 mg by mouth once daily, Days 1 through 21 of each 
28-day cycle.  Do not start cycle 2 until after 28 days.   
***You should drink 8 ounces (240 mL) of room temperature water with each dose. Oral 
azacitidine may be taken on an empty stomach or with food. 
 
Please also take entinostat 7 mg PO (by mouth) on days 3 and days 10 of each 28 day of cycle 1 
and cycle 2.  Do not start cycle 2 until after 28 days.     
*** Entinostat should be taken on an empty stomach. If your dose requires more than one tablet, 
the tablets should be taken one at a time. 
***Your anti-nausea medicine should be taken at least 30 minutes prior to entinostat. 
 
 
Day/Date 
 
 
 
CC-486 (oral 
azacitidine) 
Check box and note time 
taken below:  Please note 
time next to the box. 
  AM       OR      PM 
 
Entinostat 
 
Check box and note time 
taken below:  Please note 
time next to the box. 
AM       OR     PM
 
Comments:  Please 
note any side-effects 
you may be having or 
problems with 
compliance. 
Cycle 1 
Day 1 
  
  
 
 
Day 2 
  
  
 
Day 3 
  
  
  
  
 
Day 4 
  
  
 
 
Day 5 
  
  
 
Day 6 
  
  
 
Day 7 
  
  
 
Day 8 
  
  
 
Day 9 
  
  
 
Day 10 
  
  
  
  
 
Day 11 
  
  
 
 
Day 12 
  
  
 
Day 13 
  
  
 
Day 14 
  
  
 
Day 15 
  
  
 
Day 16 
  
  
 
Day 17 
  
  
 
Day 18 
  
  
 
Day 19 
  
  
 
Day 20 
  
  
 


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Day 21 
  
  
 
(wait until after Day 28 to start cycle 2) 
 
 
Day/Date 
 
 
 
CC-486 (oral 
azacitidine) 
Check box and note time 
taken below:  Please note 
time next to the box. 
  AM       OR      PM 
 
Entinostat 
 
Check box and note time 
taken below:  Please note 
time next to the box. 
AM       OR     PM 
 
Comments:  Please 
note any side-effects 
you may be having or 
problems with 
compliance. 
Cycle 2 
Day 1 
  
  
 
 
Day 2 
  
  
 
Day 3 
  
  
  
  
 
Day 4 
  
  
 
 
Day 5 
  
  
 
Day 6 
  
  
 
Day 7 
  
  
 
Day 8 
  
  
 
Day 9 
  
  
 
Day 10 
  
  
  
  
 
Day 11 
  
  
 
 
Day 12 
  
  
 
Day 13 
  
  
 
Day 14 
  
  
 
Day 15 
  
  
 
Day 16 
  
  
 
Day 17 
  
  
 
Day 18 
  
  
 
Day 19 
  
  
 
Day 20 
  
  
 
Day 21