Clinical trial NCT02900560
Conditions: Epithelial Ovarian Cancer
Sponsor: Translational Research in Oncology
Start date: 2016-12-20; Completion date: 2021-05-27
Enrollment: 34 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of the study is to determine the optimal dose of CC-486 (oral azacitidine) in combination with pembrolizumab for the treatment of platinum-resistant/refractory Epithelial Ovarian Cancer (EOC).

Detailed description:
This is an open-label, non-randomized, four-cohort study, in which intravenous pembrolizumab will be combined with 4 different schedules of administration of CC-486 (oral azacitidine), for the treatment of platinum-resistant/refractory (EOC). This is also a futility trial for the strategy to combine pembrolizumab and CC-486 in EOC. Eligible subjects will be treated in one of four cohorts of combined oral CC-486 and intravenous pembrolizumab (200 mg intravenous (IV) every 3 weeks in all cohorts) to evaluate the safety of each combination schedule and to have preliminary data on their efficacy. The primary objective is to establish the optimal dosing schedule for comparison with pembrolizumab alone.

Subjects will be assigned to a treatment cohort in the order they are enrolled in the study. In all subjects, tumor tissue will be obtained via image-guided core biopsy at study entry and 6 weeks after commencing treatment with CC-486. A cohort will remain open to accrual until five subjects treated on that cohort have completed two CC-486 cycles and have had the first post-baseline tumor burden assessment and both tumor biopsies performed and adequate paired tissue obtained. At least 5 evaluable subjects per cohort will be accrued over an estimated period of approximately 24 months.

Subjects will be treated in the assigned cohort until progressive disease based on Immune-Related Response Evaluation Criteria In Solid Tumors (irRECIST), unacceptable toxicity, consent withdrawal or the Investigator concludes that it is in the subject´s best interest to discontinue. Once 5 subjects in each cohort are considered evaluable for response, toxicity and treatment responses will be analyzed for each of the four cohorts and an optimal schedule will be selected.

This study includes mandatory tumor core biopsies for biomarkers research and mandatory whole blood sampling for deoxyribonucleic acid (DNA) methylation analyses.

Arms: arm 1: CC-486 100 mg once a day, 21 days on, 7 days off combined with Pembrolizumab 200 mg IV every 21 days arm 2: CC-486 100 mg twice a day, 21 days on, 7 days off combined with Pembrolizumab 200 mg IV every 21 days arm 3: CC-486 300 mg once a day, 14 days on and 14 days off combined with Pembrolizumab 200 mg IV every 21 days arm 4: CC-486 300 mg once a day, 21 days on, 7 days off combined with Pembrolizumab 200 mg IV every 21 days
Interventions: intervention 1: CC-486 intervention 2: Pembrolizumab
Intervention descriptions: intervention 1: CC-486 Intervention will depend on cohort enrolled in. 100 mg tablet intervention 2: Pembrolizumab 200 mg IV every 21 days

Protocol documents:
Prot_000.pdf: 
Phase II randomized study of pembrolizumab with or without epigenetic 
modulation with CC-486 in patients with platinum-resistant epithelial ovarian, 
fallopian tube or primary peritoneal cancer 
CLINICAL TRIAL PROTOCOL TRIO026 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
  
Protocol version / Date 
 3.0 / 14 September 2018 
 
 
 
 
 
 
 
 
 
 
 
 
NCT02900560 


TRIO026 Protocol  
Version 3.0 – 14 September 2018 
 TRIO026 Protocol v. 3.0 – Rationale for Amendment 
Version 3.0 of the protocol is an amendment applicable to all sites and triggered by safety findings in patients 
receiving investigational CC-486 in another trial. 
On February 28, 2018 the Data Monitoring Committee (DMC) for the AZA-MDS-003 study released 
recommendations after some CC-486 related toxicities in patients, with International Prognostic Scoring 
System Lower-risk Myelodysplastic Syndromes, participating in that trial.  
Based on these recommendations the TRIO026 Study Steering Committee (SSC) reviewed the TRIO026 safety 
data available in the clinical database as of 24-Apr-2018. Due to the hematologic and gastrointestinal 
treatment-emergent toxicities observed in the patients analyzed, the SSC decided to amend the protocol to 
require more frequent hematology assessments, dose modifications in case of neutropenia, and to make 
recommendations on the prevention and management of gastrointestinal toxicities.  
The TRIO026 protocol was amended as follows: 
Document 
Version Date 
Summary of changes 
Protocol version 3.0 
14 September 2018 • PROTOCOL SYNOPSIS: new requirement for hematology on 
day 8, day 15 and day 22 of each cycle added. Revision of 
exclusion criteria #15 and #16 to exclude patients with known 
history of hepatitis B and active infectious pneumonitis 
respectively. 
• Section 4.2 Exclusion criteria: Revision of exclusion criteria
#15 and #16 to exclude patients with known history of
hepatitis B and active infectious pneumonitis respectively.
• Section 5.3.1 Premedication: modification of the
recommended antiemetic medication.
• Section 5.7.2.3 Supportive care measures for pembrolizumab
toxicity: specification that immune-mediated adverse
reactions in patients receiving pembrolizumab could be
severe and fatal. Also it is specified that immune-mediated
adverse reactions can occur after discontinuation of
treatment.
• Table 4 CC-486 dose modifications for hematologic toxicity:
separated updated recommendations for treatment
emergent neutropenia.
• Table 5: addition of recommendation for proactive
management of diarrhea.
• Tables 6 and 7: addition of hematology test requirement was
separated from the one from blood chemistry. Additionally,
hematology test requirement on day 8, day 15 and day 22
were added.
• Section 6.3.2.1 Part A: addition of hematology test
requirement on day 8, day 15 and day 22.
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TRIO026 Protocol  
Version 3.0 – 14 September 2018 
Protocol version 2.0 
05 January 2018 
• DOCUMENT HISTORY section added.
• Update to the TRIO Project Team.
• PROTOCOL SYNOPSIS, Study Duration: accrual has been
extended from 6 to 24 months .
• Section 1.3.2, Pembrolizumab: inclusion of new approved
indications for pembrolizumab.
• Section 5.1, CC-486: reference to CC-486 150 mg tablets
removed as only 100 mg tablets are used.
• Section 5.3.1, Pre-medication: recommendation for the use
of pre-medication based on anti-emetics for CC-486, added as
per recommendation by Celgene.
• Table 1: Treatment schedule adjustments for pembrolizumab:
table revision, specific guidance for myocarditis added
• Table 6 and Table 7: clarification added for CA-125 that does
not need to be repeated prior to 1st dose of study treatment
if done at screening within 7 days of enrollment.
• Section 6.4.7.2, Formalin-Fixed Paraffin-Embedded (FFPE)
block/partial block from the debulking surgery: possibility to
provide 15 FFPE tumor unstained slides instead of a
block/partial block added.
• Section 9.6, Recording, Processing and Retention of Data:
clarification on the study documentation retention which
must be done according to ICH-GCP, local regulations or as
indicated in the contractual agreement whichever is longer.
• Section 9.7, Data Protection: addition of wording specifying
that the anonymity of the subjects will be respected with
strict adherence to professional standards of confidentiality
and the Health Insurance Portability and Accountability Act
(HIPPA) Privacy Rule has been added.
 Protocol version 1.1 
27 July 2016 
• Changes in some sections where the protocol was referring to
Arm instead of cohort in Part A .
• Changes to the wording to improve clarity .
• Wrong cross-references corrected .
 Protocol version 1.0 
13 Jun 2016 
Initial version 
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TRIO026 Protocol  
Version 3.0 – 14 September 2018 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ..................................................................................................................................... 12 
PROTOCOL SYNOPSIS .......................................................................................................................................... 14 
1.
BACKGROUND AND RATIONALE ................................................................................................................. 28
1.1 
Disease Overview ................................................................................................................................ 28 
1.2 
Overview of Current Treatment for Platinum-Resistant EOC ............................................................. 28 
1.3 
Investigational Medicinal Product Overview ...................................................................................... 29 
1.3.1 
CC-486 ......................................................................................................................................... 29 
1.3.2 
Pembrolizumab ........................................................................................................................... 30 
1.4 
Study Rationale ................................................................................................................................... 31 
1.4.1 
Rationale for Conducting the Study ............................................................................................ 31 
1.4.2 
Rationale for Regimen and Dose Selection ................................................................................. 33 
2.
OBJECTIVES ................................................................................................................................................. 34
2.1 
Part A .................................................................................................................................................. 34 
2.1.1 
Primary Objective ....................................................................................................................... 34 
2.1.2 
Secondary Objective ................................................................................................................... 34 
2.1.3 
Exploratory Objectives ................................................................................................................ 34 
2.2 
Part B ................................................................................................................................................... 34 
2.2.1 
Primary Objective ....................................................................................................................... 34 
2.2.2 
Secondary Objectives .................................................................................................................. 35 
2.2.3 
Exploratory Objectives ................................................................................................................ 35 
3.
STUDY DESIGN ............................................................................................................................................ 35
3.1 
Part A .................................................................................................................................................. 35 
3.2 
Part B ................................................................................................................................................... 36 
3.3 
Part A: Determination of the Optimal Schedule for Part B ................................................................. 37 
3.4 
Number of Subjects and Investigational Sites .................................................................................... 38 
3.5 
Study End ............................................................................................................................................ 38 
4.
SUBJECT SELECTION .................................................................................................................................... 38
4.1 
Inclusion Criteria ................................................................................................................................. 38 
4.2 
Exclusion Criteria ................................................................................................................................ 40 
5.
TREATMENT ................................................................................................................................................ 42
5.1 
CC-486 ................................................................................................................................................. 42 
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TRIO026 Protocol  
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5.2 
Pembrolizumab ................................................................................................................................... 42 
5.3 
Dosage and Administration ................................................................................................................ 43 
5.3.1 
Pre-medications .......................................................................................................................... 43 
5.3.1.1 
Antiemetics for Prevention and Treatment of Emesis............................................................ 43 
5.3.1.2 
Antidiarrheals .......................................................................................................................... 43 
5.3.1.3 
Pembrolizumab Premedication .............................................................................................. 43 
5.3.2 
Preparation ................................................................................................................................. 43 
5.3.2.1 
CC-486 ..................................................................................................................................... 43 
5.3.2.2 
Pembrolizumab ....................................................................................................................... 43 
5.3.3 
Study Treatment Administration in Part A ................................................................................. 43 
5.3.3.1 
CC-486 intake instructions ...................................................................................................... 44 
5.3.3.2 
CC-486 Intake: Specificities on Day 1 of the First CC-486 cycle (all schedules) ...................... 44 
5.3.3.3 
Treatment Regimen for Schedule 1 ........................................................................................ 44 
5.3.3.4 
Treatment Regimen for Schedule 2 ........................................................................................ 45 
5.3.3.5 
Treatment Regimen for Schedule 3 ........................................................................................ 46 
5.3.3.6 
Treatment Regimen for Schedule 4 ........................................................................................ 46 
5.3.4 
Study Treatment Administration in Part B .................................................................................. 47 
5.3.4.1 
Treatment Regimen in Arm A ................................................................................................. 48 
5.3.4.2 
Treatment Regimen in Arm B ................................................................................................. 48 
5.3.5 
Treatment Compliance ............................................................................................................... 48 
5.4 
Study Treatments Management ......................................................................................................... 48 
5.4.1 
Packaging and Labeling ............................................................................................................... 48 
5.4.2 
Storage and Handling .................................................................................................................. 48 
5.4.2.1 
CC-486 ..................................................................................................................................... 48 
5.4.2.2 
Pembrolizumab ....................................................................................................................... 48 
5.4.3 
Accountability, Drug Return/Destruction ................................................................................... 48 
5.4.3.1 
CC-486 ..................................................................................................................................... 49 
5.4.3.2 
Pembrolizumab ....................................................................................................................... 49 
5.5 
Study Treatment Discontinuation ....................................................................................................... 49 
5.6 
Concomitant Treatment and Procedures ........................................................................................... 50 
5.6.1 
Contraception ............................................................................................................................. 50 
5.6.2 
Prohibited Treatments ................................................................................................................ 51 
5.6.3 
Palliative Radiotherapy ............................................................................................................... 51 
5.7 
Treatment Schedule Adjustments and Adverse Events Management ............................................... 51 
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TRIO026 Protocol  
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5.7.1 
General Rules .............................................................................................................................. 51 
5.7.2 
Pembrolizumab ........................................................................................................................... 52 
5.7.2.1 
Dose Reductions ..................................................................................................................... 52 
5.7.2.2 
Treatment Schedule Adjustments .......................................................................................... 52 
5.7.2.3 
Supportive Care Measures for Pembrolizumab Toxicities ...................................................... 56 
5.7.3 
CC-486 ......................................................................................................................................... 59 
5.7.3.1 
Dose Levels.............................................................................................................................. 59 
5.7.3.2 
Treatment Schedule Adjustments and Management of CC-486 Toxicities ............................ 60 
5.7.3.3 
Criteria for CC-486 Discontinuation ........................................................................................ 64 
6.
STUDY VISITS AND ASSESSMENTS .............................................................................................................. 64
6.1 
Subject Inclusion ................................................................................................................................. 64 
6.1.1 
Informed Consent ....................................................................................................................... 64 
6.1.2 
Registration, Enrollment/Randomization and Treatment Assignment ...................................... 65 
6.1.2.1 
Part A....................................................................................................................................... 65 
6.1.2.2 
Part B ....................................................................................................................................... 66 
6.2 
Schedule or Visits and Assessments ................................................................................................... 66 
6.2.1 
Part A........................................................................................................................................... 67 
6.2.2 
Part B ........................................................................................................................................... 70 
6.3 
Study Visits and Assessments/Investigations ..................................................................................... 73 
6.3.1 
Baseline/Screening Period .......................................................................................................... 73 
6.3.2 
Treatment Period Visits .............................................................................................................. 73 
6.3.2.1 
Part A....................................................................................................................................... 74 
6.3.2.2 
Part B ....................................................................................................................................... 74 
6.3.3 
End of Treatment Visit ................................................................................................................ 75 
6.3.4 
Follow-up Visits ........................................................................................................................... 76 
6.3.4.1 
Part A....................................................................................................................................... 76 
6.3.4.2 
Part B ....................................................................................................................................... 76 
6.4 
Description of Study Assessments/Investigations .............................................................................. 76 
6.4.1 
Demographics and Medical History ............................................................................................ 76 
6.4.2 
Physical Examination and Vital Signs .......................................................................................... 76 
6.4.3 
ECOG Performance Status .......................................................................................................... 77 
6.4.4 
Adverse Events Assessment and Concomitant Treatments Review ........................................... 77 
6.4.5 
Laboratory Safety Assessments .................................................................................................. 77 
6.4.6 
Efficacy Assessments .................................................................................................................. 77 
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TRIO026 Protocol  
Version 3.0 – 14 September 2018 
6.4.6.1 
Schedule/Details of Tumor Burden Assessments ................................................................... 77 
6.4.6.2 
CA-125 Measurements ........................................................................................................... 79 
6.4.7 
Biological Sampling Procedures .................................................................................................. 79 
6.4.7.1 
Tumor core biopsies: Fresh-frozen tissue (FFT) and Formalin-fixed paraffin-embedded (FFPE) 
samples  ................................................................................................................................................ 80 
6.4.7.2 
Formalin-Fixed Paraffin-Embedded (FFPE) block/partial block from the debulking surgery . 80 
6.4.7.3 
Whole-blood samples for DNA methylation analysis ............................................................. 81 
6.5 
Subject Discontinuation ...................................................................................................................... 81 
6.5.1 
Discontinuation from Study Treatment ...................................................................................... 81 
6.5.2 
Discontinuation from Study Participation .................................................................................. 81 
7.
SAFETY MONITORING ................................................................................................................................. 81
7.1 
Definitions ........................................................................................................................................... 81 
7.1.1 
Period of Observation ................................................................................................................. 82 
7.1.2 
Adverse Event ............................................................................................................................. 82 
7.1.3 
Serious Adverse Event ................................................................................................................ 83 
7.1.3.1 
Disease-related events ............................................................................................................ 83 
7.1.3.2 
Planned or administrative hospitalization .............................................................................. 83 
7.1.3.3 
Unexpected Adverse Event ..................................................................................................... 83 
7.1.4 
Events of Clinical Interest (ECI) with Pembrolizumab ................................................................. 84 
7.2 
Performing Adverse Event Assessment .............................................................................................. 84 
7.2.1 
Collection of Adverse Event Information .................................................................................... 84 
7.2.2 
Assessment of Causality .............................................................................................................. 84 
7.3 
Reporting of Serious Adverse Events, Events of Clinical Interest and Pregnancies ............................ 85 
7.3.1 
Reporting of SAEs/ECIs/Pregnancies from the sites to TRIO ...................................................... 85 
7.3.2 
SAE/ECI/Pregnancies Information Provided by TRIO to Celgene and Merck ............................. 85 
7.4 
Management of Specific Cases ........................................................................................................... 85 
7.4.1 
Overdoses ................................................................................................................................... 86 
7.4.2 
Pregnancy.................................................................................................................................... 86 
7.5 
Reporting to Ethics Committees, Regulatory Authorities and other Investigators ............................ 87 
8.
STATISTICAL CONSIDERATIONS ................................................................................................................... 87
8.1 
Populations for Analyses ..................................................................................................................... 87 
8.2 
Demographics and Baseline Characteristics ....................................................................................... 87 
8.3 
Protocol Treatment ............................................................................................................................. 87 
8.4 
Primary Efficacy Endpoints ................................................................................................................. 87 
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TRIO026 Protocol  
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8.5 
Secondary Efficacy Endpoints ............................................................................................................. 88 
8.6 
Safety Endpoints ................................................................................................................................. 88 
8.7 
Hypotheses and Sample Size .............................................................................................................. 88 
8.8 
Timing of Analysis ............................................................................................................................... 89 
9.
ADMINISTRATIVE, ETHICAL AND REGULATORY STANDARDS ..................................................................... 89
9.1 
Steering Committee ............................................................................................................................ 89 
9.2 
Ethical Conduct of the Study ............................................................................................................... 89 
9.3 
Institutional Review Board/Independent Ethics Committee (IRB/IEC) .............................................. 90 
9.4 
Compliance with the Protocol and Protocol Amendments ................................................................ 90 
9.5 
Monitoring, Auditing and Inspecting .................................................................................................. 91 
9.6 
Recording, Processing and Retention of Data .................................................................................... 91 
9.7 
Data Protection ................................................................................................................................... 91 
9.8 
Confidentiality and Data Protection ................................................................................................... 92 
9.9 
Withdrawal of Informed Consent for Submitted Biological Samples ................................................. 92 
9.10 
Insurance of Liabilities ........................................................................................................................ 92 
9.11 
Use of Information and Publication .................................................................................................... 92 
10.
REFERENCES ............................................................................................................................................ 93
11.
APPENDICES ............................................................................................................................................ 95
APPENDIX 1: Eastern Cooperative Oncology Group Performance Status Scale ................................................. 95 
APPENDIX 2: Immune-related Response Evaluation Criteria in Solid Tumors (irRECIST) ................................... 96 
LIST OF FIGURES 
Figure 1: DNA demethylating agents: proposed mechanism of action .............................................................. 32 
Figure 2: Viral defense gene signature and CC-486 preclinical activity .............................................................. 33 
Figure 3: Study schema ....................................................................................................................................... 37 
Figure 5: Treatment regimen for Schedule 2 ...................................................................................................... 45 
Figure 6: Treatment regimen for Schedule 3 ...................................................................................................... 46 
Figure 7: Treatment regimen for Schedule 4 ...................................................................................................... 47 
LIST OF TABLES 
Table 1: Treatment schedule adjustments for pembrolizumab ......................................................................... 53 
Table 2: Pembrolizumab infusion reaction treatment guidelines ...................................................................... 58 
Table 3: CC-486 dose levels ................................................................................................................................ 59 
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Table 4: CC-486 dose modifications for hematologic toxicity ............................................................................ 60 
Table 5: CC-486 dose delays/adjustments for non-hematologic toxicity ........................................................... 63 
Table 6: Schedule of visits and assessments in Part A ........................................................................................ 67 
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TRIO026 Protocol  
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STUDY STEERING COMMITTEE 
List of members is available in the Steering Committee Charter 
 
 
INVESTIGATORS 
A total of 4 sites from the USA will participate in Part A of the trial. An additional, of approximately, 20 sites 
(from USA and Germany) will participate in Part B. The list of Investigators participating in the study will be 
maintained in TRIO’s Clinical Trial Management System.  
 
 
 
 
 
 
 
 
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TRIO026 Protocol  
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TRIO026 Protocol  
Version 3.0 – 14 September 2018 
LIST OF ABBREVIATIONS 
5-HT3 
Three 5-hydroxytryptamine 
°C 
Degrees Celsius 
AE 
Adverse Event 
ALK 
Anaplastic Lymphoma Kinase 
ALT 
Alanine Aminotransferase / GPT 
AML 
Acute myeloid leukemia 
ANC 
Absolute Neutrophil Count 
aPTT/PTT 
(activated) Partial thromboplastin time 
ASCO 
American Society of Clinical Oncology 
AST 
Aspartate Transaminase / GOT 
BCG 
Bacillus Calmette–Guérin 
BID 
Twice a Day 
CAP 
Chest, Abdomen, and Pelvis 
CIOMS 
Council for International Organizations of Medical Sciences 
CSR 
Clinical Study Report 
CT 
Computed tomography 
CTLA-4 
Cytotoxic T-Lymphocyte-Associated Protein 4 
DNA 
Deoxyribonucleic Acid 
ECOG 
Eastern Cooperative Oncology Group 
ECI 
Event of clinical interest 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EGFR 
Epidermal Growth Factor Receptor 
EMA CHMP 
European Medicine Agency Committee for Medicinal Products for Human Use 
EOC 
Epithelial Ovarian Cancer (throughout the protocol EOC may be used interchangeably with EOC/FTC/PPC) 
ERV’s 
Endogenous retroviral transcripts 
ESMO 
European Society of Medical Oncology 
EU 
European Union 
FDA 
Food and Drug Administration 
FFPE 
Formalin-Fixed Paraffin-Embedded  
FFT 
Fresh-frozen tissue 
FTC 
Fallopian Tube Cancer 
GCIG 
Gynecologic Cancer Intergroup 
GCP 
Good Clinical Practices 
G-CSF 
Granulocyte colony stimulating factor 
HBsAg 
Hepatitis B surface Antigen 
HCV 
Hepatitis C Virus 
HDAC 
Histone deacetylase 
HIV 
Human Immunodeficiency Virus 
IB 
Investigator’s Brochure 
ICH 
International Council for Harmonization 
IEC 
Independent Ethics Committee 
IgG4 
Immunoglobulin G4 
IMP 
Investigational Medicinal Product 
INR/PT 
International Normalized Ratio / Prothrombin time 
irCR/PR/PD 
Immune-related Complete Response/Partial Response/Progressive Disease 
irDCR/PFS 
Immune-related Disease Control Rate/Progression Free Survival 
irORR 
Immune-related Objective Response Rate 
irPFS 
Immune-related Progression Free Survival 
irRECIST 
Immune-Related Response Evaluation Criteria In Solid Tumors 
IRB 
Institutional Review Board 
IRR 
Infusion-related reaction 
ITT 
Intent-To-Treat 
IV 
Intravenous 
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TRIO026 Protocol  
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IWRS 
Interactive Web Response System 
kg 
kilogram 
mAb 
monoclonal Antibody 
MDS 
Myelodysplastic Syndromes 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
mL 
Milliliter 
MRI 
Magnetic Resonance image 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NSCLC 
Non Small Cell Lung Cancer 
NTL 
Non Target Lesion 
OS 
Overall Survival 
PD-1 
Programmed (cell)Death protein 1 
PD-L1 
Programmed (cell) Death-Ligand 1 
PD-L2 
Programmed (cell) Death-Ligand 2 
PEM 
Pembrolizumab 
PICF 
Patient Informed Consent Form 
PPC 
Primary Peritoneal Cancer 
PS 
Performance status 
Q3W 
Every 3 weeks 
q.d. 
Once a Day 
RNA 
Ribonucleic Acid 
SAE 
Serious Adverse Event 
SmPC 
Summary of Product Characteristics 
SoC 
Standard of Care 
SOP 
Standard Operating Procedures 
SSC 
Study Steering Committee 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
T1DM 
Type 1 Diabetes Mellitus 
TL 
Target Lesion 
TORL 
Translational Oncology Research Labs 
TRIO 
Translational Research In Oncology 
TSH 
Thyroid-stimulating hormone 
UCLA 
University of California, Los Angeles 
UNL 
Upper Normal Limit 
US 
United States 
WBC 
White Blood Cells 
WoCBP 
Women of Childbearing Potential 
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TRIO026 Protocol  
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PROTOCOL SYNOPSIS 
Protocol Title 
Phase II randomized study of pembrolizumab with or without epigenetic 
modulation with CC-486 in patients with platinum-resistant epithelial 
ovarian, fallopian tube or primary peritoneal cancer 
Protocol # 
TRIO026 
Indication 
Platinum-resistant epithelial ovarian cancer (EOC), fallopian tube 
carcinoma (FTC) or primary peritoneal carcinomas (PPC) 
Study Duration 
Part A: 

Accrual: 24 months

Treatment phase: 6 months

Follow-up: According to subject´s status at End of Treatment
Part B: 

Accrual: 24 months

Treatment phase: 6 months

Follow-up: 12 months
Sponsor / Participating 
Investigator 
This is a TRIO-sponsored study, led by Dr. John Glaspy (Professor of 
Medicine, Jonsson Comprehensive Cancer Center, UCLA, USA) as Study 
Chair. The study is financially supported by Celgene Corporation. 
Participating Investigator 
Sites 
Part A: 4 sites in 1 country (USA) 
Part B: approximately 25 sites in 2 countries (USA and Germany; includes 
sites participating in Part A) 
Target Population 
The target study population consists of adult patients with platinum-
resistant/refractory EOC/FTC/PPC who have received a maximum of 2 
prior treatment regimens for the platinum-resistant/refractory relapse 
(definition of platinum resistant/refractory disease will be based on the 
platinum-free interval following frontline chemotherapy). Subjects must 
have previously received platinum-based chemotherapy (intravenous 
and/or intraperitoneal) following and/or preceding debulking surgery. 
They will be required to have measurable disease according to irRECIST 
(Immune-related Response Evaluation Criteria in Solid Tumors) for Part A. 
For Part B, subjects will be required to have either measurable and/or 
non-measurable disease. They will also be required to have a life 
expectancy of at least 6 months, Eastern Cooperative Oncology Group 
(ECOG) Performance Status (PS) of 0-1, adequate liver, renal and bone 
marrow functions; absence of known autoimmune diseases, of certain 
bone marrow conditions and of serious diseases which could affect 
protocol compliance or the interpretation of study results. 
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Background and Rationale 
There are approximately 200,000 new cases of EOC diagnosed each year 
in the world and this is the leading cause of death from gynecologic 
cancer in the United States and in many other countries.  
More than 75% of patients present with advanced disease at primary 
diagnosis. The current standard initial therapy is debulking surgery 
followed by platinum-based doublet chemotherapy administered either 
intravenously and/or intraperitoneally. Neoadjuvant chemotherapy is 
being increasingly used.  
Despite aggressive surgery and frontline chemotherapy, most patients 
with advanced disease experience a relapse. Patients with a platinum-
free interval of less than 6 months are considered to have platinum-
resistant disease and those that recur/progress while receiving frontline 
chemotherapy are considered to have platinum-refractory disease. At 
first 
relapse, 
approximately 
25% 
of 
patients 
have 
platinum-
resistant/refractory ovarian cancer and their prognosis is poor, with a 
median overall survival of approximately 12 months. All current 
treatment options have a response rate of < 15-20%. There is a clear, 
unmet medical need for effective treatments for patients with platinum-
resistant/refractory relapsed EOC. 
Recent advances in immunotherapy have led to the development and 
rapid introduction into clinical practice of monoclonal antibodies 
directed against two immune checkpoints, CTLA-4 (Cytotoxic T-
lymphocyte-associated antigen-4) and PD-1 (Programmed death protein 
1) (or PD-L1, Programmed death-ligand 1). All of these agents, and in 
particular the anti-PD-1 antibodies, have shown clear benefit in the 
treatment of metastatic melanoma and non-small cell lung cancer 
(NSCLC). Moreover, responses have been of long duration, suggesting 
that the immune system may be adaptive and to some extent being able 
to counteract the development of treatment resistance. Immune 
checkpoint inhibitors have recently demonstrated encouraging signs of 
antitumor activity for patients with pretreated advanced ovarian cancer. 
It is known that epigenetic modifications in gene expression associated 
with methylation and de-acetylation of DNA and histones occurs in 
human malignancies and can be associated with disease progression and 
resistance 
to 
treatment. 
Epigenetic 
therapies 
with 
either 
hypomethylating agents, such as azacitidine, or histone deacetylase 
(HDAC) inhibitors have been shown to be of benefit in the treatment of 
some malignancies. More recently, exciting data have emerged 
indicating that treatment with azacitidine may increase the response to 
anti-PD-1 
therapy 
in 
patients 
with 
NSCLC, 
suggesting 
that 
hypermethylation may in part explain failure to respond to immune 
checkpoint inhibition. 
Pre-clinical research investigating the effects of epigenetic therapy 
(azacitidine and/or HDAC inhibitors) on gene expression in human cancer 
cell lines has identified a group of relevant genes whose expression 
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increases in response to epigenetic therapy. In general, these genes are 
involved in immune response, supporting a hypothesis that anti-PD-1 
therapy may be more effective when combined with epigenetic therapy. 
This “immune signature” that is seen following epigenetic therapy may 
also be a useful biomarker to predict a benefit from epigenetic priming 
during immune checkpoint therapy. In a broad screen across cell lines of 
multiple tumor types, the strongest “immune signature” that is seen 
following epigenetic therapy was observed in ovarian cancer cell lines. 
However, the optimal clinical dosing and scheduling of epigenetic 
therapy aimed at enhancing response to anti-PD-1 has and the efficacy of 
combined epigenetic therapy and immune checkpoint inhibition has not 
been studied yet in EOC. 
CC-486 is a new, oral formulation of azacitidine. This drug is well 
tolerated and produces evidence of induced hypomethylation at doses of 
100 to 300 mg daily. The primary toxicity of this agent is hematologic; 
however doses of 300 mg per day are well tolerated in patients with 
myelodysplastic syndromes, a setting where marrow tolerance is known 
to be reduced. We expect doses of 300 mg daily to be well tolerated in 
patients with EOC, who do not have intrinsic bone marrow disease. 
This study will enroll subjects with platinum-resistant/refractory 
EOC/FTC/PPC into a phase II clinical trial to be conducted in two 
sequential parts. Part A aims to explore the optimal combination of the 
monoclonal anti-PD-1 antibody pembrolizumab (given at a dose of 200 
mg every 3 weeks) with CC-486 (given at four different dosing 
schedules). Part B will then further evaluate the efficacy and safety of the 
optimal schedule of CC-486 and pembrolizumab selected in Part A, and 
compare the combination therapy with pembrolizumab as a single agent 
in a randomized controlled trial setting. Part B will test whether adding 
epigenetic therapy to pembrolizumab can improve the progression free 
survival to pembrolizumab monotherapy in relapsed EOC. 
Part A Objectives / 
Endpoints  
Primary Objectives: 

To establish an optimal schedule of CC-486 combined with
pembrolizumab in subjects with platinum-resistant/refractory
EOC.
The primary endpoint will be based on the safety profile, futility
evaluation as well as on the irORR/irDCR per irRECIST criteria
(also, data from the correlative analyses to be done in the biologic
samples may be taken into consideration for determining the
optimal schedule).
Secondary Objective: 

To assess the CA-125 response based on the Gynecologic Cancer
Intergroup (GCIG) criteria.
Exploratory objectives: 
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 
Tumor samples will be used to assess potential prognostic or 
predictive biomarkers, improve understanding of ovarian cancer 
biology and identify candidate biomarkers that may correlate with 
treatment benefit and/or safety signals. 
 
Whole blood samples will be used to analyze changes in DNA 
methylation during treatment with CC-486. 
Part B 
Objectives/Endpoints 
Primary Objective: 
 
To evaluate whether the addition of CC-486 to pembrolizumab 
(optimal schedule selected in Part A) improves the Investigator-
assessed immune-related Progression free survival (irPFS) 
compared to pembrolizumab alone, in subjects with platinum-
resistant/refractory EOC.  
The primary endpoint will be assessed according to the Immune-
Related Response Evaluation Criteria in Solid Tumors (irRECIST). 
Secondary Objective: 
 
To assess secondary measures of efficacy for CC-486 combined 
with pembrolizumab (optimal schedule selected in Part A) relative 
to pembrolizumab alone. 
Efficacy endpoints:  
o Immune-related Overall Response Rate (irORR) 
o Immune-related Disease Control Rate (irDCR) 
o Immune-related Duration of Response (irDoR)  
o CA-125 response based on GCIG criteria 
o Overall Survival (OS) 
 
To assess the safety and tolerability of CC-486 combined with 
pembrolizumab 
Exploratory objectives: 
 
Tumor samples will be used to assess potential prognostic or 
predictive markers, improve understanding of ovarian cancer 
biology and identify candidate biomarkers that may correlate with 
treatment benefit and/or safety signals. 
Study Design 
This is an open-label, multicenter, multinational trial that will be carried 
out in two sequential parts.  
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Part A: Part A is an open-label, non-randomized, four-cohort, lead-in 
selection phase in which intravenous pembrolizumab will be combined 
with 4 different schedules of administration of oral CC-486, for the 
treatment of platinum-resistant/refractory EOC. Part A is also a futility 
trial for the strategy to combine pembrolizumab and CC-486 in EOC. 
Eligible subjects will be treated in one of four cohorts of combined oral 
CC-486 and intravenous pembrolizumab (200 mg IV q 3 weeks in all 
cohorts) to evaluate the safety of each combination schedule and to have 
preliminary data on their efficacy. The primary objective of Part A is to 
establish 
the 
optimal 
dosing 
schedule 
for 
comparison 
with 
pembrolizumab alone in Part B of the study. 
Subjects will be assigned to a treatment cohort in the order they are 
enrolled in the study. In all subjects, tumor tissue will be obtained via 
image-guided core biopsy at study entry and 6 weeks after commencing 
treatment with CC-486 (provided that the tumor lesion is amenable to a 
second biopsy). A cohort will remain open to accrual until five subjects 
treated on that cohort have completed two CC-486 cycles and have had 
the first post-baseline tumor burden assessment and both tumor biopsies 
performed and adequate paired tissue obtained. At least 5 evaluable 
subjects per cohort will be accrued to Part A over an estimated period of 
approximately 24 months. 
Subjects will be treated in the assigned cohort until progressive disease 
based on irRECIST, unacceptable toxicity, consent withdrawal or the 
Investigator concludes that it is in the subject´s best interest to 
discontinue. Once 5 subjects in each cohort are considered evaluable for 
response, toxicity and treatment responses will be analyzed for each of 
the four cohorts and an optimal schedule to be taken forward into Part B 
will be selected.  
Part A includes mandatory tumor core biopsies for biomarkers research 
and mandatory whole blood sampling for DNA methylation analyses. 
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Part B: This will be an open-label, randomized phase II study that will 
compare the safety and efficacy of CC-486 and pembrolizumab (using the 
schedule that was established as optimal in Part A) with pembrolizumab 
alone, for the treatment of platinum-resistant/refractory EOC.  
Eligible subjects will be randomly assigned in a 1:1 ratio to either: 
Arm A: Pembrolizumab (200 mg IV every 21 days) in combination with
CC-486 (dosing schedule established in Part A)
or 
Arm B: Pembrolizumab (200 mg IV every 21 days) as a single agent
A total of 150 subjects, 75 per arm, will be randomized over an estimated 
period of 24 months. To ensure equal distribution of prognostic factors in 
the two study arms, subjects will be stratified according to the following 
parameters:  
Platinum-refractory vs. platinum-resistant
Number 
of 
prior 
treatment 
regimens 
for 
the 
platinum-
refractory/resistant EOC: none vs. 1 or 2.
Subjects with tumor lesions amenable to core biopsy will be proposed 
(although not mandated) to undergo an image-guided core biopsy at 
study entry and 6 weeks (± 1 week) after first dose of study treatment, 
provided that the tumor lesion is amenable to a second biopsy.  
Subjects will be treated until progressive disease based on irRECIST, 
unacceptable toxicity, consent withdrawal or the Investigator concludes 
that it is in the subject´s best interest to discontinue. Once the subject has 
discontinued from study treatment and has undergone the End of 
Treatment visit, she will enter into the follow-up phase.  
Part B includes an optional exploratory research component. 
Population 
Inclusion Criteria 
1.
Signed and dated informed consent document obtained prior to
initiation of any study-specific procedure and treatment (by the
subject or a legally acceptable representative as per the local
regulations).
2.
Women ≥ 18 years old.
3.
Histologically confirmed EOC, FTC or PPC.
4.
Received 
debulking 
surgery 
and 
preoperative 
and/or
postoperative 
platinum-based 
frontline 
chemotherapy
(intravenous and/or intraperitoneal) for the treatment of
EOC/FTC/PPC.
5.
Documented platinum-resistant or platinum-refractory disease.
Platinum-resistant disease is defined as progression within < 6
months from completion of a minimum of 4 platinum frontline
therapy cycles in the pre or postoperative setting (the date should
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be calculated from the last administered dose of platinum agent). 
Platinum-refractory 
is 
defined 
as 
disease 
that 
has 
recurred/progressed while receiving platinum-based frontline 
therapy. 
6. Measurable disease according to irRECIST for Part A. For Part B, 
subjects must have either measurable and/or non-measurable 
disease according to irRECIST (Appendix 2).  
7. Indication of systemic treatment for the relapsed EOC, FTC or 
PPC. 
8. For Part A, subjects must have a tumor lesion that is amenable to 
an image-guided core biopsy and willingness to undergo two 
biopsies (baseline and 6 weeks after first dose of study 
treatment). For Part B, subjects will be eligible even if their 
disease is not amenable to biopsy and/or the subject does not 
consent to the optional biopsies. 
9. Eastern Cooperative Oncology Group (ECOG) Performance Status 
(PS) 0 or 1.  
10. Expected survival of more than 6 months. 
11. Adequate organ function within 7 days prior to enrollment in Part 
A or randomization in Part B, as defined by the following criteria: 
• 
Absolute neutrophils count (ANC) ≥ 1.5 x 109/L, platelets ≥ 
100 x 109/L, hemoglobin > 9 g/dL (without transfusion or 
erythropoiesis stimulating agents’ dependency).  
• 
Serum creatinine ≤ 1.5 x upper limit of normal (ULN). 
• 
Total serum bilirubin ≤ 1.5 x ULN regardless of liver 
involvement secondary to tumor. Higher levels are 
acceptable if these can be attributed to active hemolysis or 
ineffective erythropoiesis. 
• 
Serum aspartate transaminase (AST) and serum alanine 
transaminase (ALT) < 2.0 x ULN or ≤ 5 x ULN for subjects with 
liver metastases. 
• 
International Normalized Ratio (INR) or Prothrombin Time 
(PT) ≤ 1.5 x ULN unless subject is receiving anticoagulant 
therapy as long as PT or PTT is within therapeutic range of 
intended use of anticoagulants 
• 
Partial Thromboplastin Time (PTT) or Activated Partial 
Thromboplastin Time (aPTT) ≤ 40 seconds unless subject is 
receiving anticoagulant therapy as long as PT or PTT is within 
therapeutic range of intended use of anticoagulants. 
12. For women of childbearing potential, negative serum pregnancy 
test within 7 days of enrollment in Part A or randomization in Part 
B. 
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13. Women of childbearing potential must agree to use acceptable 
methods of birth control starting with the screening visit and up 
to 120 days after the last dose of study treatment. 
Recommendation is for 2 effective contraceptive methods during 
the study. Adequate forms of contraception are double-barrier 
methods (condoms with spermicidal jelly or foam and diaphragm 
with spermicidal jelly or foam), oral depo-provera, or injectable 
contraceptives, intrauterine devices, and tubal ligation. 
14. Willingness and ability to comply with scheduled visits, treatment 
plan, laboratory tests, and other trial procedures. 
Exclusion Criteria 
1. Non-epithelial ovarian cancers, including malignant mixed 
Müllerian tumors. 
2. Ovarian tumors with low malignant potential (i.e. borderline 
tumors). 
3. Relapse/progression based solely on elevation of CA-125, in 
absence of measurable disease (for Part A) or in the absence of 
measurable/non-measurable disease (for Part B), according to 
irRECIST criteria. 
4. More than 2 prior treatment regimens for the platinum-
resistant/refractory relapsed EOC, FTC, or PTC, defined as 
investigational, chemotherapy, hormonal, biologic, or targeted 
therapy. 
5. Any concurrent or previous malignancy within 5 years prior to 
enrollment in Part A or randomization in Part B, except for 
adequately and radically treated basal or squamous skin cancer, 
or carcinoma in situ of the cervix, or other non-invasive/in-situ 
neoplasm. A subject with previous history of invasive malignancy 
(other than adequately and radically treated basal or squamous 
skin cancer or carcinomas in situ) is eligible provided that she has 
been disease free for more than 5 years. 
6. Brain metastases (even if treated and/or stable), spinal cord 
compression, carcinomatous meningitis, or leptomeningeal 
disease. 
7. Prior systemic anticancer therapy within 4 weeks prior to 
enrollment in Part A or randomization in Part B; or who has not 
recovered (i.e. ≤ Grade 1 or baseline grade) from adverse events 
due to a previously administered agent  
Notes: subjects with ≤ Grade 2 neuropathy are an exception to this 
criterion and may qualify for the study. If subject received major 
surgery, they must have recovered adequately from the toxicity 
and/or complications from the intervention prior to starting 
therapy. Subjects with toxicity that has not recovered to ≤ Grade 1 
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or baseline grade are allowed if meeting all inclusion criteria.  
8. Prior treatment with a monoclonal antibody within 4 weeks prior 
to enrollment in Part A or randomization in Part B; or who has not 
recovered (i.e. ≤ Grade 1 or baseline grade) from adverse events 
due to agents administered more than 4 weeks earlier. 
Notes: subjects with ≤ Grade 2 neuropathy are an exception to this 
criterion and may qualify for the study.  
9. Diagnosis of immunosuppression or receiving systemic steroid 
therapy or any other form of immunosuppressive therapy within 
7 days prior to enrollment in Part A or randomization in Part B. 
The use of physiologic doses of corticosteroids may be approved 
after consultation with the sponsor.  
10. Active autoimmune disease or history of autoimmune disease or 
syndrome that has required systemic treatment in the past 2 
years (i.e. with use of disease modifying agents, corticosteroids or 
immunosuppressive drugs). Replacement therapy (e.g. thyroxine, 
insulin, or physiologic corticosteroid replacement therapy for 
adrenal or pituitary insufficiency, etc.) is not considered a form of 
systemic treatment. Subjects with vitiligo or resolved childhood 
asthma/atopy will not be excluded. 
11. Received live vaccines within 30 days prior to enrollment in Part A 
or randomization in Part B. 
12. Current or prior history of myelodysplastic syndrome, leukemia or 
clinically significant (as per Investigator judgment) bone marrow 
failure. 
13. Uncontrolled systemic fungal, bacterial or viral infection at time 
of enrollment in Part A or randomization in Part B (defined as 
ongoing 
signs/symptoms 
related 
the 
infection 
without 
improvement despite appropriate antibiotics, antiviral therapy 
and/or other treatment). 
14. Known history of active TB (Bacillus Tuberculosis). 
15. Known HIV infection or known history of Hepatitis B or known 
positivity for active Hepatitis B (HBsAg reactive) or Hepatitis C 
(HCV RNA [qualitative] is detected). 
16. Known history of non-infectious pneumonitis that required 
steroids or has current pneumonitis (infectious or non-infectious). 
17. Significant active cardiac disease within 6 months prior to 
enrollment in Part A or randomization in Part B , including but not 
limited to New York Heart Association class 4 cardiac heart 
failure, unstable angina, myocardial infarction  
18. History or current evidence of any condition, therapy, or 
laboratory abnormality that might confound the results of the 
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trial, interfere with the subject’s participation for the full duration 
of the trial, or is not in the best interest of the subject to 
participate, in the opinion of the treating Investigator. Is or has an 
immediate family member (e.g. spouse, parent/legal guardian, 
sibling or child) who is investigational site or sponsor staff directly 
involved with this trial, unless prospective IRB approval (by chair 
or designee) is given allowing exception to this criterion for a 
specific subject. 
19. Any contraindication to oral agents or significant nausea and 
vomiting, malabsorption, or significant small bowel resection that, 
in the opinion of the Investigator, would preclude adequate 
absorption. 
20. Known psychiatric or substance abuse disorders that would 
interfere with cooperation with the requirements of the trial. 
21. Prior treatment with any anti-PD-1, or PD-L1 or PD-L2 agent; or 
with azacitidine (any formulation) or any other hypomethylating 
agent; or with anti-CD137, or anti-CTLA-4 antibody (including 
ipilimumab) or any other antibody or drug specifically targeting T-
cell co-stimulation or checkpoint pathways. 
22. Known 
or 
suspected 
hypersensitivity 
to 
azacitidine, 
pembrolizumab or the excipients of any of the study drugs 
(including mannitol). Known or suspected hypersensitivity to 
monoclonal antibodies. 
23. Currently participating and receiving study therapy or has 
participated in a study of an investigational agent and received 
study therapy or used an investigation device within 4 weeks 
prior to enrollment in Part A or randomization in Part B. 
24. Pregnant or lactating women or is expecting to conceive children 
or breastfeed within the projected duration of the trial, starting 
with the screening visit through 120 days after the last dose of 
trial treatment. 
Study Treatment 
In this study, CC-486 and pembrolizumab are both considered 
Investigational Medicinal Products (IMP) given their intended use and 
the objectives of the study. Collectively they are referred as “study 
treatments”. 
Part A:  
Pembrolizumab 200 mg IV every 21 days combined with one of the 
below four schedules of CC-486: 
• Cohort 1: CC-486 100 mg q.d. 21 days on, 7 days off.  
• Cohort 2: CC-486 100 mg BID, 21 days on, 7 days off.  
• Cohort 3: CC-486 300 mg q.d. 14 days on and 14 days off.  
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• Cohort 4: CC-486 300 mg q.d. 21 days on, 7 days off.  
Part B: 
Subjects will be randomized (1:1) to receive: 
• Arm A: pembrolizumab 200 mg IV every 21 days combined with 
CC-486 (optimal schedule selected in Part A)  
or 
• Arm B: pembrolizumab 200 mg IV every 21 days 
Efficacy Assessments 
Assessment of irORR, irPFS, irDoR, irDCR will be based on tumor 
assessments (according to irRECIST criteria) using CT/MRI of chest, 
abdomen and pelvis. Contrast-enhanced CT scan is the preferred 
method. The same assessment technique must be used throughout the 
study to evaluate a particular lesion. 
Tumor burden assessments will be performed: 
• At baseline: within 28 days prior to enrollment in Part A or 
randomization in Part B. Lesions must be clearly identified and 
documented as Target or Non-Target lesions per irRECIST. 
• After baseline: 
• In Part A: 
o 6 weeks (± 1 week) after first CC-486 intake (first post-
baseline tumor assessment). 
o Thereafter, every 12 weeks (± 1 week), always taking as a 
reference the date of the first post-baseline tumor 
assessment (not the date of the immediately previous 
tumor assessment). 
o Whenever disease progression is suspected based on 
signs, symptoms, performance status deterioration, CA-
125, etc. 
o Confirmation of progression (irPD) is recommended 
minimum 4 weeks after the first irPD assessment and is 
required during the flare time-window of the first 12 
weeks of treatment. 
• In Part B: 
o Every 12 weeks (± 1 week), always taking as a reference 
the date of randomization in the study (not the date of 
the previous tumor assessment). 
o Whenever disease progression is suspected based on 
signs, symptoms, performance status deterioration, CA-
125, etc. 
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o Confirmation of progression (irPD) is recommended 
minimum 4 weeks after the first irPD assessment and is 
required during the flare time-window of the first 12 
weeks of treatment. 
Assessment of response will also be based on GCIG CA-125 criteria in 
subjects with CA-125 evaluable disease at baseline. However, 
progression cannot be declared on the basis of CA-125 alone.  
Disease assessments with imaging and CA-125 will be performed until 
progressive disease based on irRECIST, regardless of the end of study 
treatment and start of a subsequent anticancer therapy. After 
progressive disease, subjects in Part B will be followed every 6 months 
(visit or phone contact) until death or for at least 1 year after the End of 
Treatment visit, to assess the survival status. 
Safety Assessments 
Safety assessments will be done at baseline, at each visit during the study 
treatment phase and at the End of treatment visit. Additionally, 
hematology testing will be done weekly. All assessments will be 
scheduled as indicated in the Schedule of Visits and Assessments and 
include:  
• Physical examination and vital signs 
• Hematology: hemoglobin, absolute neutrophils count (ANC), 
platelets 
• Blood chemistries: creatinine, AST, ALT, alkaline phosphatase, 
bilirubin, glucose, TSH 
• Coagulation tests (at baseline and then only if clinically indicated) 
Recording of adverse events will be done according to NCI-CTC AE 
version 4.03. 
Biomarker Studies 
Tumor core biopsies: Fresh-frozen tissue (FFT) and Formalin-fixed 
paraffin-embedded (FFPE) samples (and ascites samples if feasible): will 
be collected on a mandatory basis at baseline and 6 weeks after study 
treatment start in all subjects participating in Part A. In Part B, tumor will 
be collected in subjects consenting to participate in the optional tissue 
acquisition study, provided they have lesion(s) amenable to biopsy. 
These samples will be transported to the Translational Oncology 
Research Laboratory at the University of California Los Angeles (TORL-
UCLA). 
Formalin-Fixed Paraffin-Embedded (FFPE) block/partial block from the 
debulking surgery: for subjects consenting to the optional tissue 
acquisition part of the study, a FFPE block/partial block from the ovarian 
cancer debulking surgery (or a minimum of 15 unstained slides if FFPE 
tissue block cannot be provided) will be obtained and submitted to the 
TORL-UCLA.  
Whole-blood samples for DNA methylation analysis: these samples are 
mandatory in Part A and will be used to analyze changes in DNA 
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methylation during treatment with CC-486. Peripheral whole blood 
samples will be obtained on Day 1 of the 1st CC-486 cycle (prior to the 
first CC-486 intake) and on the pre-treatment visit prior to the 2nd CC-486 
cycle. 
Procedures for sample collection, labeling, storage and shipment will be 
described in the study lab manual. 
Statistical Methods  
Analysis populations: 
For each of the 2 parts of the study, there will be 2 analysis sets : 
• Intent-to-Treat Population (ITT): defined as all enrolled subjects 
• Safety Population: defined as all subjects who received at least 
one dose of study treatment (CC-486 and/or pembrolizumab) 
Sample size justification: 
Part A 
Part A is an exploratory pilot study of various possible schedules for the 
combination of CC-486 and pembrolizumab. Part A is also a futility trial 
for the strategy to combine pembrolizumab and CC-486 in EOC. Criteria 
for Part B Go/No-Go decision and the determination of an optimal dosing 
schedule can be found in section 3.3 of the protocol. There is no formal 
sample size calculation for lead-in safety and efficacy selection phase of 
the trial. 
Part B 
Part 
B 
is 
designed 
to 
test 
the 
hypothesis 
that 
combined 
epigenetic/immune checkpoint inhibition is superior to checkpoint 
inhibition alone in the treatment of EOC. The study will be powered to 
detect a difference in the log rank tests of the irPFS curves reflecting a 
hazard ratio of 0.625 favoring the combination. Assumptions are based 
on (a) an anticipated median irPFS in the pembrolizumab monotherapy 
arm to be 4 months and 6.4 months in the combination arm, (b) that the 
accrual time will be 24 months and the total study time will be 46 
months and (c) a power of 80% and an alpha error at 0.05 for a two-sided 
test. Based on these assumptions 75 evaluable subjects need to be 
enrolled in each arm (n=73 subjects exactly) resulting in a total planned 
enrollment of 150 subjects. 
Statistical Methods: 
Part A 
The immune-related Overall response rate (irORR) is defined as the 
proportion of subjects who achieve a best overall response of immune-
related Complete response (irCR) or an immune-related Partial response 
(irPR) based on irRECIST criteria, as per Investigator assessment. 
The immune-related Disease Control Rate (irDCR) is defined as the 
proportion of subjects who achieve a best overall response of irCR, irPR 
or irSD, as per Investigator assessment. 
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The CA-125 response rate is defined as the proportion of subjects having 
a CA-125 response according to the GCIG criteria. 
Part B 
The immune-related Progression-Free Survival (irPFS) is defined as the 
time from the date of randomization until the date of progression 
(assessed by irRECIST) or death due to any cause, whichever occurs first, 
as per Investigator assessment. Progression will be based on tumor 
assessment made by the Investigators according to the irRECIST criteria. 
Progression will not be declared on the basis of CA-125 alone. 
The immune-related Duration of Response (irDoR) is defined as the time 
(in months) from the date when irPR or irCR is first met (whichever status 
comes first) and the date of irPD or death, whichever occurs first (as per 
Investigator assessment). 
irORR, irDCR and CA-125 response rate as described above. 
Overall Survival (OS) defined as the time (in months) from randomization 
to death from any cause. 
 
 
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1. BACKGROUND AND RATIONALE 
1.1 Disease Overview 
Comprehensive global cancer statistics indicate that there are approximately 200,000 new cases of 
epithelial ovarian cancer (EOC) diagnosed each year in the world and over 125,000 deaths attributed to 
the disease.1 Although the death rate for ovarian cancer has been stable for the last 10 years it remains 
the cause of more cancer deaths of the female reproductive system than any other. Fallopian tube 
cancer (FTC) and primary peritoneal carcinoma (PPC) are grouped with EOC because of their similar 
prognostic, therapeutic, histologic and biologic features as EOC.2,3  
In more than 75% of the newly identified cases, the disease has already reached an advanced state 
(stage III or IV) at the time of initial diagnosis.4 Patients with newly diagnosed EOC are typically primarily 
treated with a major and extensive surgical procedure with the intent to remove all intra-abdominally 
visible tumors.5 After the initial surgery, most patients undergo six cycles of combination chemotherapy 
with two cytotoxic agents, most commonly a platinum salt (cisplatin or carboplatin) and a taxane 
(paclitaxel or less frequently docetaxel), administered intravenously or intra-peritoneally.4–6 
Neoadjuvant chemotherapy is also increasingly used.6 The systemic therapy is administered in hopes of 
effectively treating any residual or micro-metastatic disease remaining in the abdomen. Despite this 
rigorous treatment, more than 75% of patients experience a recurrence of their disease within the first 
20 months of completing their frontline therapy.7 Almost all of these recurrences are intra-abdominal 
and many are treated with further surgical resections (when indicated) and almost all are treated with 
multiple cycles of “salvage” chemotherapy with the same or other cytotoxic agents as the ones used in 
the pre/postoperative setting.8,9 If the disease recurrence has occurred more than 6 months after 
completion of the initial chemotherapy, usually a platinum/taxane-based regimen is used again and 
these patients have good probabilities of response to treatment. 
Patients whose recurrence occurs within 6 months of initial chemotherapy are considered to have 
platinum-resistant disease. At first relapse, approximately 25% of patients have platinum-resistant EOC 
and their prognosis is poor, with relapses occurring within few months after completing salvage therapy 
and a median overall survival of approximately 12 months.10,11  
1.2 Overview of Current Treatment for Platinum-Resistant EOC 
There are a number of treatment options available for women with platinum-resistant EOC, and the 
ideal treatment is not known. Due to the added toxicity and lack of high-quality evidence showing 
improvement in survival for combination chemotherapy, most oncologists choose to treat these patients 
with sequential single-agent therapy.12,13  
Agents such as topotecan, paclitaxel, docetaxel, oral etoposide, gemcitabine or pegylated liposomal 
doxorubicin are associated with response rates typically < 20% and a median PFS of 3-4 months.14 The 
addition of bevacizumab to single-agent chemotherapy have shown to improve PFS and ORR and is an 
acceptable alternative treatment.14 The choice among these strategies depends upon the clinician's 
experience, the side effect profile, and prior therapy. 
Treatment for platinum-resistant ovarian cancer is far from being curative. Because palliation is the goal 
of treatment, choosing the proper agent for use in this setting involves balancing the perceived need to 
obtain an objective response against the importance of maintaining quality of life.  
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Given the low response rates and short PFS, there is a clear, unmet medical need for more effective 
treatments for patients with platinum-resistant/refractory relapsed EOC. Since chemotherapeutic 
approaches have not been able to demonstrate a significant improvement in disease outcomes, these 
improvements depend upon the optimal integration of novel approaches into clinical trials. 
1.3 Investigational Medicinal Product Overview 
1.3.1 CC-486 
Azacitidine is an analog of the pyrimidine nucleoside cytidine that has effects on cell differentiation, 
gene expression, and DNA synthesis and metabolism. Azacitidine is believed to exert its antineoplastic 
effects by causing hypomethylation of DNA and direct cytotoxicity on abnormal hematopoietic cells in 
the bone marrow. The concentration of azacitidine required for maximum inhibition of DNA methylation 
in vitro does not cause major suppression of DNA synthesis. Hypomethylation may restore normal 
function to genes that are critical for differentiation and proliferation. The cytotoxic effects of 
azacitidine cause the death of rapidly dividing cells, including cancer cells that are no longer responsive 
to normal growth control mechanisms. Non-proliferating cells are relatively insensitive to azacitidine. 
Since the early 1970s, azacitidine has been investigated in the United States (US) for the treatment of 
acute leukemia. These investigations indicated azacitidine has activity in the treatment of acute myeloid 
leukemia (AML). Clinical trials subsequently have been conducted to evaluate the effects of azacitidine 
in a variety of other malignant and hematologic disorders, including solid tumors, hemoglobinopathies 
(thalassemia and sickle cell anemia), and myelodysplastic syndromes (MDS). Vidaza® (azacitidine for 
injection) is approved by the US Food and Drug Administration (FDA) for the following 5 subtypes of the 
French-American-British classification system of MDS: refractory anemia or refractory anemia with 
ringed sideroblasts (if accompanied by neutropenia or thrombocytopenia or requiring transfusions), 
refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and 
chronic myelomonocytic leukemia. Vidaza® is also approved by the European Commission (EU) for the 
treatment of adult patients who are not eligible for hematopoietic stem cell transplantation (HSCT) with 
the following: intermediate-2 and high-risk MDS according to the International Prognostic Scoring 
System, chronic myelomonocytic leukemia with 10% to 29% marrow blasts without myeloproliferative 
disorder, and AML with 20% to 30% blasts and multilineage dysplasia. For these indications, Vidaza® can 
be administered by the intravenous or subcutaneous routes as designated by country approval. 
Currently Vidaza® has received marketing authorization in over 80 countries worldwide including US and 
EU. 
CC-486 is an oral formulation of azacitidine that is currently being evaluated in clinical trials, either as a 
single agent or in combination with other drugs, for the treatment of hematological and solid 
malignancies. CC-486 is under development and is not approved by any regulatory agency worldwide for 
any indication.  
The safety profile of azacitidine has been well characterized and is based on an extensive amount of 
patient exposure across a wide range of doses and indications, as well as routes of administration (SC, 
IV, oral). The vast majority of safety data for azacitidine comes from patients with myelodysplastic 
syndromes, a setting where marrow tolerance is known to be reduced. Most common adverse reactions 
(≥ 30%) by SC route are nausea, anemia, thrombocytopenia, vomiting, pyrexia, leukopenia, diarrhea, 
injection site erythema, constipation, neutropenia and ecchymosis. The most common adverse reactions 
by IV route also included petechiae, rigors, weakness and hypokalemia.  
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For oral azacitidine, the most frequently reported adverse reactions (≥ 30%) are: diarrhea, nausea, 
constipation, vomiting, fatigue and decreased appetite. Overall, about 50% of patients receiving CC-486 
reported at least one treatment-emergent AE of myelosuppression (neutropenia, thrombocytopenia, 
anemia, and/or general myelosuppression). 
The reporting frequencies for the common hematological and non-hematological events were generally 
highest during Cycles 1 and 2, after which time the frequencies decreased over subsequent treatment 
cycles. This and other similar findings suggest a lack of cumulative toxicity and that AEs of azacitidine 
attenuate over time. 
1.3.2 Pembrolizumab 
The programmed death protein 1 (PD-1) receptor-ligand interaction is a major pathway hijacked by 
tumors to suppress immune control. The normal function of PD-1, expressed on the cell surface of 
activated T-cells under healthy conditions, is to down-modulate unwanted or excessive immune 
responses, including autoimmune reactions. Binding of PD-1 ligands to PD-1 inhibits T-cell activation 
triggered through the T-cell receptor. Pembrolizumab (Keytruda®) is a potent and highly selective 
humanized monoclonal antibody (mAb) of the immunoglobulin G4 (IgG4)/kappa isotype designed to 
directly block the interaction between PD-1 and its ligands, programmed cell death ligand 1 (PD-L1) and 
programmed cell death ligand 2 (PD-L2). This blockade enhances functional activity of the target 
lymphocytes to facilitate tumor regression and ultimately immune rejection. 
Pembrolizumab is approved in various jurisdictions for various indications: 
• 
For the treatment of patients with unresectable or metastatic melanoma and disease 
progression following treatment with ipilimumab and, if BRAF V600 mutation positive, a BRAF 
inhibitor (US, EU, Japan) 
• 
As first-line treatment of patients with metastatic non-small cell lung carcinoma (NSCLC) whose 
tumors with PD-L1 positive, with no epidermal growth factor receptor (EGFR) or anaplastic 
lymphoma kinase (ALK) genomic tumor aberrations.  
• 
As first-line treatment of patients with metastatic non-squamous NSCLC in combination with 
platinum chemotherapy and pemetrexed (US) 
• 
For the treatment of PD-L1 positive metastatic NSCLC with disease progression on/after 
platinum-containing chemotherapy (US) 
• 
For the treatment of patients with refractory classical Hodgkin Lymphoma or who have relapsed 
after greater than or equal to 3 prior lines of therapy (US, EU) 
• 
For the treatment of patients with recurrent or metastatic head and neck squamous cell 
carcinoma with disease progression on or after platinum-containing chemotherapy (US) 
• 
For the treatment of patients with locally advanced or metastatic urothelial carcinoma (UC) who 
are not eligible for cisplatin-containing chemotherapy or patients with locally advanced or 
metastatic UC who have received platinum-containing chemotherapy (US) 
• 
For the treatment of adult and pediatric patients with unresectable or metastatic, microsatellite 
instability-high or mismatch repair deficient solid tumors who have progressed following prior 
treatment and who have no satisfactory alternative treatment options, or colorectal cancer that 
has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. 
• 
Patients with recurrent locally advanced or metastatic gastric or GEJ adenocarcinoma whose 
tumors express PD-L1, with disease progression on or after two or more prior lines of therapy 
including fluoropyrimidine and platinum-containing chemotherapy and if appropriate, 
HER2/neu-targeted therapy. 
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Pembrolizumab is currently being evaluated in clinical trials in several hematologic malignancies and 
solid tumors.  
Pembrolizumab is generally well tolerated and has demonstrated a favorable safety profile in 
comparison to chemotherapy. The most common treatment related adverse events observed with 
pembrolizumab are mostly grade 1-2 and include fatigue, diarrhea, decreased appetite, nausea, and 
anemia. Pembrolizumab is an immunomodulatory agent, and based on this mechanism of action, 
immune mediated adverse events are of primary concern. Important identified risks for pembrolizumab 
are 
of 
an 
immune 
mediate 
nature, 
including 
pneumonitis, 
colitis, 
thyroid 
disorders 
(hypothyroidism/hyperthyroidism), hepatitis, hypophysitis, Type I diabetes mellitus, uveitis, and 
nephritis. The majority of immune-mediated adverse events are mild to moderate in severity, are 
manageable with appropriate care, and rarely require discontinuation of therapy.  
Refer to the pembrolizumab Investigator´s Brochure (IB) for additional information on the drug. 
1.4 Study Rationale 
1.4.1 Rationale for Conducting the Study 
Recent advances in immunotherapy have led to the development and rapid clinical introduction of 
monoclonal antibodies directed against two immune checkpoints, CTLA-4 (Cytotoxic T-lymphocyte-
associated antigen-4) and PD-1 or PD-L1. All of these agents, and in particular the anti-PD-1 antibodies, 
have shown clear benefit in the treatment of metastatic melanoma and NSCLC.15–17 Moreover, 
responses have been of long duration, suggesting that the immune system may be adaptive and to 
some extent being able to counteract the development of treatment resistance.  
Immune checkpoint inhibitors have recently demonstrated encouraging signs of antitumor activity for 
patients with pretreated advanced ovarian cancer. A phase Ib trial with the PD-L1 inhibitor avelumab 
demonstrated clinical activity (ORR 10.7% (95% CI, 4.7-19.9) and DCR 54.7%) and a low toxicity profile 
in treatment-refractory unselected patients with EOC.18 Additionally, a phase Ib study with 
pembrolizumab demonstrated activity (ORR 11.5% (95% CI, 2.4-30.2) and DCR 34.6%) and a favorable 
safety profile in heavily pretreated PD-1-positive patients.19 The observed response and disease control 
rates in pre-treated patients with relapsed EOC clearly indicate that immune checkpoint inhibition is a 
strategy that warrants further research in the treatment of EOC. 
It is known that epigenetic modifications in gene expression associated with methylation and de-
acetylation of DNA and histones occurs in human malignancies and can be associated with disease 
progression and resistance to treatment. Epigenetic therapies with either hypomethylating agents, such 
as azacitidine, or histone deacetylase (HDAC) inhibitors have been shown to be of benefit in the 
treatment of some malignancies. More recently, exciting data have emerged indicating that treatment 
with azacitidine may increase the response to anti-PD-1 therapy in patients with NSCLC, suggesting that 
hypermethylation may in part explain failure to respond to immune checkpoint inhibition.20,21 However, 
the optimal clinical dosing and scheduling of epigenetic therapy aimed at enhancing response to anti-
PD-1 has and the efficacy of combined epigenetic therapy and immune checkpoint inhibition has not 
been studied yet in EOC. 
Preclinical research investigating the effects of epigenetic therapy (azacitidine and/or HDAC inhibitors) 
on gene expression in human cancer cell lines has identified a group of relevant genes whose 
expression increases in response to epigenetic therapy. In general, these genes are involved in immune 
response, supporting a hypothesis that anti-PD-1 therapy may be more effective when combined with 
epigenetic therapy. In a broad screen across cell lines of multiple tumor types, the strongest “immune 
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signature” that is seen following epigenetic therapy was observed in ovarian cancer cell lines. There is, 
thus, a robust concordance for induced increases in genes, highest in ovarian cancer cells, which can 
trigger increased interferon signaling and concordant upregulation of surface antigens and their 
assembly proteins and viral defense pathways in 77 epithelial cancer cell lines treated with 
azacitidine.22 These upregulated genes include transcript and surface protein levels of PD-L1, the tumor 
ligand for immune cell PD-1 and high versus low expression in tumor cells of this ligand appears to 
correlate with good response to anti-PD-1 therapy.16,22 Most recently, work from two groups indicates a 
key way in which azacitidine upregulates immune signaling and interferon signaling in cancer cells, 
including ovarian cancer, is through activation of a double strand RNA (dsRNA) viral defense pathway 
(Chiappinelli KB, et al, Cell in press, 2015). 
All of these above data lead to the hypothesis, inherent to this trial, that through coordinated 
upregulation of tumor antigens and MHC proteins, interferon pathway induction by dsRNA transcripts 
including endogenous retroviral transcripts (ERV’s), and upregulation of tumor–associated tolerance 
ligands, DNA demethylating agents may induce T-cell attraction (Figure 1). Immune checkpoint efficacy 
in this setting may be enhanced when tolerance inducing ligand and receptor interactions are 
interrupted. 
 
Figure 1: DNA demethylating agents: proposed mechanism of action 
Model for how the findings outlined above suggest DNA demethylating agents (DNMTis) may 
sensitize to immune checkpoint therapies. The DNMTis activate tumor antigens, MHC proteins 
and their assembly, and the interferon driving viral defense pathway with down stream up-
regulation of PD-L1. This concordant signature would attract T-cells and tolerance would then be 
broken with anti-PD1 therapy.   
 
The levels of the above, ~ 20 gene, viral defense “immune signature” that is upregulated following 
epigenetic therapy also appears to be a useful biomarker to predict benefit from epigenetic priming 
during immune checkpoint therapy. This will be tested in tumor biopsy samples, pre- and post-therapy 
in this trial. In a recent study, high basal levels of the azacitidine-induced viral defense gene signature 
expression in tumor samples correlated with long-term benefit (Chiappinelli et al., Cell, in press) in 
patients with advanced melanoma treated with the immune checkpoint inhibitor, anti-CTLA-4.23 
Importantly, for virtually all of these melanoma patients, treatment benefit, high tumor mutational 
burden and basal viral defense signature are all significantly associated (Chiappinelli et al., Cell, in press) 
(Figure 2 A). Moreover, low dose azacitidine plus anti-CTLA-4 are significantly more effective at 
controlling tumor growth compared to each agent alone in the B16 mouse model of melanoma 
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(Chiappinelli et al., Cell, in press) (Figure 2 B). The hypothesis in the trial is that patients with a low level 
of the above gene panel will be benefitted by having azacitidine induce a higher level to help sensitize 
to anti-PD-1.   
 
Figure 2: Viral defense gene signature and CC-486 preclinical activity 
(From Chiappinelli et al., Cell, in press): A: Viral defense gene signature is upregulated in tumors 
from anti-CTLA-4 treated metastatic melanoma patients who derived durable clinical benefit 
(complete response, partial response, or progression free-survival > 6 months as previously 
described23) compared to those without benefit. Tumors collected pre-CTLA-4 treatment and 
shortly post-treatment are shown. B: Tumor responses of mice injected with B16-F10 cells and 
treated with either phosphate-buffered saline, anti-CTLA-4, azacitidine, or both anti-CTLA-4 and 
azacitidine. Data represent results from one of two independent experiments with identical 
results, each with n = 10 per arm. 
 
This study will enroll subjects with platinum-resistant/refractory EOC into a phase II clinical trial to be 
conducted in two sequential parts. Part A aims to explore the optimal combination of the monoclonal 
anti-PD-1 antibody pembrolizumab (given at a dose of 200 mg every 3 weeks) with CC-486 (given at 
four different dosing schedules). Part B will then further evaluate the efficacy and safety of the optimal 
schedule of CC-486 and pembrolizumab selected in Part A, and compare the combination therapy with 
pembrolizumab as a single agent in a randomized controlled trial setting. Part B will test whether 
adding epigenetic therapy to pembrolizumab can improve the progression free survival to 
pembrolizumab when given as a single agent in relapsed EOC. 
1.4.2 Rationale for Regimen and Dose Selection 
CC-486 is well tolerated and produces evidence of induced hypomethylation at doses of 100 to 300 mg 
daily. Doses of 300 mg per day are well tolerated in patients with myelodysplastic syndromes, a setting 
where bone marrow tolerance is known to be reduced. We expect doses up to 300 mg daily to be well 
tolerated in patients with EOC, who do not have intrinsic bone marrow disease. 
Pembrolizumab will be used at a fixed dose of 200 mg every 3 weeks. The choice of the 200 mg Q3W as 
an appropriate dose for the switch to fixed dosing is based on simulations performed using the 
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population PK model of pembrolizumab showing that the fixed dose of 200 mg every 3 weeks will 
provide exposures that: (1) are optimally consistent with those obtained with the 2 mg/kg dose every 3 
weeks, (2) will maintain individual patient exposures in the exposure range established in melanoma as 
associated with maximal efficacy response and (3) will maintain individual patients exposure in the 
exposure range established in melanoma that are well tolerated and safe. A fixed dose regimen will 
simplify the dosing regimen to be more convenient for physicians and to reduce potential for dosing 
errors. A fixed dosing scheme will also reduce complexity in the logistical chain at treatment facilities 
and reduce wastage. 
In all treatment schedules in the study, CC-486 will be given for 7 days before the first pembrolizumab 
administration with the intent of hypomethylation being induced at time of first pembrolizumab 
exposure. 
This is not the first study that is assessing the combination of pembrolizumab and azacitidine. A phase II 
study in colorectal cancer patients is currently recruiting patients and evaluating the combination of 
pembrolizumab (200 mg every 21 days) and IV azacitidine. Another phase II study is assessing the safety 
and efficacy of CC-486 (at a dose of 300 mg daily for 14 days) and pembrolizumab in advanced NSCLC. 
No safety or efficacy results are publicly available at time of release of this protocol.  
2. OBJECTIVES 
2.1 Part A 
2.1.1 Primary Objective 
 To establish an optimal schedule of CC-486 combined with pembrolizumab in subjects with 
platinum-resistant/refractory EOC. 
2.1.2 Secondary Objective 
 To assess the CA-125 response based on the Gynecological Cancer Intergroup (GCIG) criteria24. 
2.1.3 Exploratory Objectives 
 Tumor samples will be used to assess potential prognostic or predictive biomarkers, improve 
understanding of ovarian cancer biology and identify candidate biomarkers that may correlate with 
treatment benefit and/or safety signals. 
 Whole blood samples will be used to analyze changes in DNA methylation during treatment with CC-
486. 
2.2 Part B  
2.2.1 Primary Objective 
 To evaluate whether the addition of CC-486 to pembrolizumab (optimal schedule selected in Part A) 
improves the Investigator-assessed immune-related Progression free survival (irPFS)* compared to 
pembrolizumab alone, in subjects with platinum-resistant/refractory EOC.  
*The primary endpoint will be assessed according to the Immune-Related Response Evaluation Criteria in 
Solid Tumors (irRECIST). irRECIST is a modification of RECIST v1.1 guidelines, to account for the unique 
response patterns observed with immunotherapy.25,26 (refer to Appendix 2). 
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2.2.2 Secondary Objectives 
 To assess secondary measures of efficacy for CC-486 combined with pembrolizumab (optimal 
schedule selected in Part A) relative to pembrolizumab alone. 
Efficacy endpoints:  
o Immune-related Overall Response Rate (irORR) 
o Immune-related Disease Control Rate (irDCR) 
o Immune-related Duration of Response (irDoR)  
o CA-125 response based on GCIG criteria 
o Overall Survival (OS) 
 To assess the safety and tolerability of CC-486 combined with pembrolizumab. 
2.2.3 Exploratory Objectives 
 Tumor samples will be used to assess potential prognostic or predictive markers, improve 
understanding of ovarian cancer biology and identify candidate biomarkers that may correlate with 
treatment benefit and/or safety signals. 
3. STUDY DESIGN 
This is an open-label, multicenter, multinational trial that will be carried out in two sequential parts 
(Figure 3).  
3.1 Part A 
Part A is an open-label, four-cohort, non-randomized, lead-in selection phase in which intravenous (IV) 
pembrolizumab will be combined with 4 different schedules of administration of oral CC-486, for the 
treatment of platinum-resistant/refractory EOC. Part A is also a futility trial for the strategy to combine 
pembrolizumab and CC-486 in EOC. 
Eligible subjects will be treated in one of four cohorts of combined oral CC-486 and pembrolizumab (200 
mg IV q3 weeks in all cohorts) (refer to section 5.3.3 for details on study treatments administration) to 
evaluate the safety of each combination schedule and to have preliminary data on their efficacy. The 
primary objective of Part A is to establish the optimal dosing schedule for comparison with 
pembrolizumab alone in Part B of the study. 
Subjects will be assigned to a treatment cohort in the order they are enrolled in the study (e.g. first 
subject in cohort 1, second subject in cohort 2, etc.). In all subjects, tumor tissue will be obtained via 
image-guided core biopsy at study entry and 6 weeks after commencing treatment with CC-486, 
provided that the tumor lesion is amenable to a second biopsy. A cohort will remain open to accrual 
until five subjects treated on that cohort have completed two CC-486 cycles and have had the first post-
baseline tumor burden assessment and both tumor biopsies performed and adequate paired tissue 
obtained. If a subject assigned to a given cohort is not evaluable (i.e. have not completed two CC-486 
cycles and/or have not had the first post-baseline tumor assessment and/or both tumor biopsies) then 
these subjects will be replaced. At least 5 evaluable subjects per cohort will be accrued to Part A over an 
estimated period of approximately 24 months. 
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Subjects will be treated in the assigned cohort until progressive disease based on irRECIST, unacceptable 
toxicity, consent withdrawal or the Investigator concludes that it is in the subject´s best interest to 
discontinue (or any other withdrawal criteria is met according to section 5.5). Subjects who discontinue 
treatment for reasons different than irPD will enter the follow-up phase and will continue to be followed 
with tumor assessment every 12 weeks until irPD. After irPD, and provided that subject has undergone 
the End of Treatment visit, all subjects will be taken off the study unless presence of serious adverse 
events (SAEs) or study treatment-related adverse events. In such case these events will be monitored as 
clinically indicated until the events have resolved (or return to baseline) or in the Investigator’s opinion, 
are unlikely to resolve due to the nature of the condition and/or the subject’s underlying disease.  
Once 5 subjects in each cohort are considered evaluable, enrollment will be stopped and data from each 
cohort will be analyzed and the optimal schedule to be taken forward into Part B will be selected 
according to section 3.3. 
Part A includes mandatory tumor core biopsies for biomarkers research and mandatory whole blood 
sampling for DNA methylation analyses (see section 6.4.7). 
3.2 Part B 
This will be an open-label, randomized phase II study that will compare the safety and efficacy of CC-486 
and pembrolizumab (using the schedule that was established as optimal in Part A) with pembrolizumab 
alone, for the treatment of platinum-resistant/refractory EOC.  
If necessary, a protocol amendment may be released to further define the eligibility criteria, treatment 
schema, etc. for Part B, based on the analysis of Part A. If there are no changes in the study design, 
conduct, treatments, safety consideration, etc., this same protocol version will be used for both Part A 
and Part B. 
Eligible subjects will be randomly assigned in a 1:1 ratio to either: 
 Arm A: Pembrolizumab (200 mg IV every 21 days) in combination with CC-486 (dosing schedule 
established in Part A)  
or 
 Arm B: Pembrolizumab (200 mg IV every 21 days) as a single agent  
A total of 150 subjects, 75 per arm, will be randomized over an estimated period of 24 months. To 
ensure equal distribution of prognostic factors in the two study arms, subjects will be stratified 
according to the following parameters:  
 Type of relapsed disease: platinum-refractory vs. platinum-resistant (refer to the corresponding 
definitions in section 4.1) 
 Prior treatment regimens for the platinum-refractory/resistant EOC: none vs. 1 or 2 
Subjects with tumor lesions amenable to core biopsy will be proposed (although not mandated) to 
undergo image-guided core biopsy at study entry and 6 weeks (± 1 week) after first dose of study 
treatment, provided that the tumor lesion is amenable to a second biopsy.  
Subjects will be treated until progressive disease based on irRECIST, unacceptable toxicity, consent 
withdrawal or the Investigator concludes that it is in the subject´s best interest to discontinue (or any 
other withdrawal criteria is met according to section 5.5). Once the subject is discontinued from study 
treatment and has undergone the End of Treatment visit, she will enter into the follow-up phase. 
Subjects who discontinue treatment for reasons different than progressive disease will continue to be 
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followed with tumor assessment every 12 weeks until irPD. After progressive disease, subjects will be 
followed for assessment of survival status every 6 months (visit or phone contact) until death or for at 
least 1 year after the End of Treatment visit.  
Part B also includes an optional exploratory research component (see section 6.4.7). 
Figure 3: Study schema  
 
3.3 Part A: Determination of the Optimal Schedule for Part B 
The optimal schedule to be used in Part B will be selected after analysis of the accumulated safety and 
efficacy data from Part A by the Steering Committee. The analyses will be conducted once 5 subjects in 
each cohort are considered evaluable. Subjects will be considered evaluable once they have: 
 Completed at least two CC-486 cycles 
 Undergone the 1st post-baseline tumor burden assessment 
 Undergone the 2nd tumor biopsy and adequate paired tissue obtained  
Full details of the criteria to be used to guide the Steering Committee in their selection of the optimal 
regimen will be described in the Steering Committee Charter. In general, however, the following 
decision criteria will be applied: 
 Step 1: Safety and Futility evaluation:  
A cohort will be rejected due to toxicity if any of the below criteria is met: 
R One grade 5 AE related to study drugs 
R More than one subject experiencing a grade 4 AE related to study drugs (other than 
hypothyroidism)  
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o More than 2 subjects experiencing a grade 3 AE related to study drugs (other than 
hypothyroidism) 
A cohort will be rejected due to futility if at least one response or stable disease (irPR, irCR or irSD) is 
not observed in that schedule. 
 Step 2: Determination of the optimal schedule: In the cohort(s) not rejected due to toxicity or due to 
futility, the selection by the Steering Committee of the optimal schedule will be based on the 
toxicity profile and the irORR of each cohort (irDCR may also be considered for the determination of 
the optimal schedule). For example, if one cohort has higher irORR and similar toxicity profile 
compared to another cohort, the first one will be selected as optimal. If two or more cohorts have 
the same irORR, the optimal schedule will be established based primarily on the more favorable 
toxicity profile. Additionally, data from the correlative analyses to be done in the biologic samples 
described in section 6.4.7, may be taken into consideration for determining the optimal schedule. 
3.4 Number of Subjects and Investigational Sites 
In Part A, at least 5 evaluable subjects per cohort will be included in the study, from 4 participating sites 
from the USA. 
In Part B, 150 subjects will be included, from approximately 25 participating sites from the USA and 
Germany. The sites participating in Part A will also be participating in Part B. 
3.5 Study End  
The study will end once the last subject undergoes the last visit and all events required for the final 
analyses have been observed and collected.  
The trial may be prematurely terminated by the sponsor. In this case, subjects deriving clinical benefit 
from the study treatment at time of trial termination will continue to be provided with study drug by the 
sponsor/manufacturer. 
4. SUBJECT SELECTION 
This study can fulfill its objectives only if appropriate subjects are enrolled. The following eligibility 
criteria are applicable both for Part A and B of the study.  
Subjects who fail to meet all inclusion criteria or fulfill at least one exclusion criteria cannot be enrolled 
in the study. The sponsor will not grant any eligibility waivers. If a subject that does not meet the 
eligibility criteria is incorrectly enrolled in Part A or randomized in Part B, the Investigator should 
immediately inform the Medical Monitor. The decision about the continuation or discontinuation of 
these subjects on the study will be based on medical judgment, treatment benefit and safety risks for 
the subject. 
4.1 Inclusion Criteria 
1. Signed and dated informed consent document obtained prior to initiation of any study-
specific procedure and treatment (by the subject or a legally acceptable representative as 
per the local regulations). 
2. Women ≥ 18 years old. 
3. Histologically confirmed EOC, FTC or PPC. 
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4. Received debulking surgery and preoperative and/or postoperative platinum-based 
frontline chemotherapy (intravenous and/or intraperitoneal) for the treatment of 
EOC/FTC/PPC. 
5. Documented platinum-resistant or platinum-refractory disease. Platinum-resistant disease is 
defined as progression within < 6 months from completion of a minimum of 4 platinum 
frontline therapy cycles in the pre or postoperative setting (the date should be calculated 
from the last administered dose of platinum agent). Platinum-refractory is defined as 
disease that has recurred/progressed while receiving platinum-based frontline therapy. 
6. Measurable disease according to irRECIST for Part A. For Part B, subjects must have either 
measurable and/or non-measurable disease according to irRECIST (Appendix 2).  
7. Indication of systemic treatment for the relapsed EOC, FTC or PPC. 
8. For Part A, subjects must have a tumor lesion that is amenable to an image-guided core 
biopsy and willingness to undergo two biopsies (baseline and 6 weeks after first dose of 
study treatment). For Part B, subjects will be eligible even if their disease is not amenable to 
biopsy and/or the subject does not consent to the optional biopsies. 
9. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 or 1 (Appendix 1).  
10. Expected survival of more than 6 months. 
11. Adequate organ function within 7 days prior to enrollment in Part A or randomization in Part 
B, as defined by the following criteria: 
 
Absolute neutrophils count (ANC) ≥ 1.5 x 109/L, platelets ≥ 100 x 109/L, hemoglobin > 9 
g/dL (without transfusion or erythropoiesis stimulating agents’ dependency).  
 
Serum creatinine ≤ 1.5 x upper limit of normal (ULN). 
 
Total serum bilirubin ≤ 1.5 x ULN regardless of liver involvement secondary to tumor. 
Higher levels are acceptable if these can be attributed to active hemolysis or ineffective 
erythropoiesis. 
 
Serum aspartate transaminase (AST) and serum alanine transaminase (ALT) < 2.0 x ULN 
or ≤ 5 X ULN for subjects with liver metastases. 
 
International Normalized Ratio (INR) or Prothrombin Time (PT) ≤ 1.5 X ULN unless 
subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic 
range of intended use of anticoagulants 
 
Partial Thromboplastin Time (PTT) or Activated Partial Thromboplastin Time (aPTT) ≤40 
seconds unless subject is receiving anticoagulant therapy as long as PT or PTT is within 
therapeutic range of intended use of anticoagulants 
12. For women of childbearing potential*, negative serum pregnancy test within 7 days of 
enrollment in Part A or randomization in Part B. 
13. Women of childbearing potential* must agree to use acceptable methods of birth control 
starting with the screening visit and up to 120 days after the last dose of study treatment. 
Recommendation is for 2 effective contraceptive methods during the study. Adequate forms 
of contraception are double-barrier methods (condoms with spermicidal jelly or foam and 
diaphragm with spermicidal jelly or foam), oral depo-provera, or injectable contraceptives, 
intrauterine devices, and tubal ligation. 
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14. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and 
other trial procedures. 
 
* Note: Given the patient population in the trial, it is highly unlikely that women of childbearing potential (WoCBP) 
are enrolled. WoCBP are any women between menarche and menopause who have not been permanently or 
surgically sterilized and are capable of procreation. Permanent sterilization includes hysterectomy and/or bilateral 
oophorectomy and/or bilateral salpingectomy but excludes bilateral tubal ligation/occlusion. Non-sterile women 
will be considered of WoCBP if they did not have at least 12 months with no menses without an alternative medical 
cause.  
4.2 Exclusion Criteria 
1. Non-epithelial ovarian cancers, including malignant mixed Müllerian tumors. 
2. Ovarian tumors with low malignant potential (i.e. borderline tumors). 
3. Relapse/progression based solely on elevation of CA-125, in absence of measurable disease 
(for Part A) or in the absence of measurable/non-measurable disease (for Part B), according 
to irRECIST criteria. 
4. More than 2 prior treatment regimens for the platinum-resistant/refractory relapsed EOC, 
FTC, or PTC, defined as investigational, chemotherapy, hormonal, biologic, or targeted 
therapy. 
5. Any concurrent or previous malignancy within 5 years prior to enrollment in Part A or 
randomization in Part B, except for adequately and radically treated basal or squamous skin 
cancer, or carcinoma in situ of the cervix, or other non-invasive/in-situ neoplasm. A subject 
with previous history of invasive malignancy (other than adequately and radically treated 
basal or squamous skin cancer or carcinomas in situ) is eligible provided that she has been 
disease free for more than 5 years. 
6. Brain metastases (even if treated and/or stable), spinal cord compression, carcinomatous 
meningitis, or leptomeningeal disease. 
7. Prior systemic anticancer therapy within 4 weeks prior to enrollment in Part A or 
randomization in Part B; or who has not recovered (i.e. ≤ Grade 1 or baseline grade) from 
adverse events due to a previously administered agent  
- Notes: subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for 
the study. If subject received major surgery, they must have recovered adequately from the 
toxicity and/or complications from the intervention prior to starting therapy. Subjects with 
toxicity that has not recovered to ≤ Grade 1 or baseline grade are allowed if meeting all 
inclusion criteria.  
8. Prior treatment with a monoclonal antibody within 4 weeks prior to enrollment in Part A or 
randomization in Part B; or who has not recovered (i.e. ≤ Grade 1 or baseline grade) from 
adverse events due to agents administered more than 4 weeks earlier. 
- Notes: subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for 
the study. 
9. Diagnosis of immunosuppression or receiving systemic steroid therapy or any other form of 
immunosuppressive therapy within 7 days prior to enrollment in Part A or randomization in 
Part B. The use of physiologic doses of corticosteroids may be approved after consultation 
with the sponsor. 
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10. Active autoimmune disease or history of autoimmune disease or syndrome that has 
required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, 
corticosteroids or immunosuppressive drugs). Replacement therapy (e.g. thyroxine, insulin, 
or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) 
is not considered a form of systemic treatment. Subjects with vitiligo or resolved childhood 
asthma/atopy will not be excluded. 
11. Received live vaccines within 30 days prior to enrollment in Part A or randomization in Part 
B. 
12. Current or prior history of myelodysplastic syndrome, leukemia or clinically significant (as 
per Investigator judgment) bone marrow failure.  
13. Uncontrolled systemic fungal, bacterial or viral infection at time of enrollment in Part A or 
randomization in Part B (defined as ongoing signs/symptoms related the infection without 
improvement despite appropriate antibiotics, antiviral therapy and/or other treatment). 
14. Known history of active TB (Bacillus Tuberculosis). 
15. Known HIV infection or known history of Hepatitis B or known positivity for active Hepatitis 
B (HBsAg reactive) or Hepatitis C (HCV RNA [qualitative] is detected). 
16. Known history of non-infectious pneumonitis that required steroids or has current 
pneumonitis (infectious or non-infectious). 
17. Significant active cardiac disease within 6 months prior to enrollment in Part A or 
randomization in Part B , including but not limited to New York Heart Association class 4 
cardiac heart failure, unstable angina, myocardial infarction  
18. History or current evidence of any condition, therapy, or laboratory abnormality that might 
confound the results of the trial, interfere with the subject’s participation for the full 
duration of the trial, or is not in the best interest of the subject to participate, in the opinion 
of the treating Investigator. Is or has an immediate family member (e.g. spouse, parent/legal 
guardian, sibling or child) who is investigational site or sponsor staff directly involved with 
this trial, unless prospective IRB approval (by chair or designee) is given allowing exception 
to this criterion for a specific subject. 
19. Any contraindication to oral agents or significant nausea and vomiting, malabsorption, or 
significant small bowel resection that, in the opinion of the Investigator, would preclude 
adequate absorption. 
20. Known psychiatric or substance abuse disorders that would interfere with cooperation with 
the requirements of the trial. 
21. Prior treatment with any anti-PD-1, or PD-L1 or PD-L2 agent; or with azacitidine (any 
formulation) or any other hypomethylating agent; or with anti-CD137, or anti-CTLA-4 
antibody (including ipilimumab) or any other antibody or drug specifically targeting T-cell co-
stimulation or checkpoint pathways. 
22. Known or suspected hypersensitivity to azacitidine, pembrolizumab or the excipients of any 
of the study drugs (including mannitol). Known or suspected hypersensitivity to monoclonal 
antibodies. 
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23. Currently participating and receiving study therapy or has participated in a study of an 
investigational agent and received study therapy or used an investigation device within 4 
weeks prior to enrollment in Part A or randomization in Part B.  
24. Pregnant or lactating women or is expecting to conceive children or breastfeed within the 
projected duration of the trial, starting with the screening visit through 120 days after the 
last dose of trial treatment. 
5. TREATMENT 
In the TRIO026 study, CC-486 and pembrolizumab are both considered Investigational Medicinal 
Products (IMP) given their intended use and the objectives of the study. Collectively they are referred as 
“study treatments”. 
In both parts (A and B), subjects will remain on their assigned study treatment until progressive disease 
based on irRECIST, unacceptable toxicity, consent withdrawal, Investigator’s decision that it is in the 
subject´s best interest to discontinue or other treatment withdrawal criteria is met (section 5.5).  
5.1  CC-486 
All subjects in Part A and subjects randomized to Arm A of Part B will receive oral CC-486 at the dosing 
described in sections 5.3.3 and 5.3.4. 
At each visit during the treatment phase, subjects should be given container(s) with enough 100 mg 
tablets for one full CC-486 treatment cycle (defined as 21 or 14 days on-treatment followed by 7 or 14 
days off-treatment (depending on the cohort)) of the corresponding schedule/arm (refer to section 5.3). 
In Part A, the following number of 100 mg tablets would be needed for a subject to complete one CC-
486 cycle of treatment, assuming no dose delays or interruptions or dose reductions from the starting 
dose level: 
 Schedule 1: 21 tablets of 100 mg 
 Schedule 2: 42 tablets of 100 mg 
 Schedule 3: 42 tablets of 100 mg 
 Schedule 4: 63 tablets of 100 mg 
The number of tablets may need to be adjusted in case of dose modifications. 
For the purpose of this trial, the Single Reference Document to be used for CC-486 is the azacitidine IB. 
5.2 Pembrolizumab 
Pembrolizumab will be administered in all cohorts in Part A and in both arms in Part B at a fixed dose of 
200 mg as a 30 minute IV infusion. Sites should make every effort to target infusion timing to be as close 
to 30 minutes as possible.  
In all cohorts in Part A and in Arm A of Part B, the first pembrolizumab infusion will be administered 7 
days (± 3 days) after commencing treatment with CC-486 and thereafter all subsequent infusions will be 
administered every 21 days (± 3 days). 
For the purpose of this trial, the Single Reference Document to be used is the pembrolizumab IB. 
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5.3 Dosage and Administration 
5.3.1 Pre-medications 
5.3.1.1 Antiemetics for Prevention and Treatment of Emesis 
Drugs with the highest therapeutic index for the management of treatment induced nausea and 
vomiting are the type three 5-hydroxytryptamine (5-HT3) receptor antagonists and the neurokinin-1 
receptor (NK1R) antagonists. Additionally, recent data has demonstrated substantial antiemetic activity 
for the antipsychotic medication olanzapine when used in combination with other antiemetics.  
The following antiemetic medication is recommended for CC-486: 
 Prophylactic 5-HT3 antagonist should be considered on days when CC-486 is administered. 
 Prochlorperazine and/or 5-HT3 inhibitor could also be considered for delayed nausea as needed.  
 If subjects experience nausea sub-optimally controlled with prochlorperazine on the days of CC-486 
administration, prophylactic 5-HT3 inhibitors may be used. 
 If nausea and vomiting persists despite the above measures, more aggressive use of 5-HT3 
antagonists or other anti-emetics could be used at the discretion of the treating physician. In cases 
of nausea and/or vomiting insufficiently controlled by prophylactic treatment with a 5-HT3 receptor 
antagonist, antiemetic therapy with a combination of an NK1R antagonist and a 5-HT3 receptor 
antagonist and consideration of olanzapine is recommended. 
5.3.1.2 Antidiarrheals 
Although premedication for diarrhea prophylaxis is not required, proactive management of first signs of 
diarrhea is strongly recommended according to section 5.7.3.2. Prophylaxis can be considered as per 
investigator’s best clinical judgement and local practice.  
5.3.1.3 Pembrolizumab Premedication 
No specific pre-medication is required upfront for pembrolizumab. However pre-medications may be 
given as per the institutional standard of care. 
5.3.2 Preparation  
5.3.2.1 CC-486 
Not applicable. 
5.3.2.2 Pembrolizumab 
Preparation should be done in accordance with the Single Reference Document for pembrolizumab and 
with site´s standard procedures for preparing pembrolizumab.  
5.3.3 Study Treatment Administration in Part A 
Eligible subjects will receive pembrolizumab 200 mg IV every 21 days (± 3 days) combined with one of 
the below four schedules of CC-486: 
 Schedule 1: CC-486 100 mg q.d. 21 days on, followed by 7 days off-treatment.  
 Schedule 2: CC-486 100 mg BID 21 days on, followed by 7 days off-treatment.  
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 Schedule 3: CC-486 300 mg q.d. 14 days on, followed by 14 days off-treatment.  
 Schedule 4: CC-486 300 mg q.d. 21 days on, followed by 7 days off-treatment.  
For each subject, the corresponding study treatment schedule will be assigned according the process 
described in section 6.1.2.1.  
On the first CC-486 cycle, after 7 days (± 3 days) of CC-486 monotherapy, the first pembrolizumab 
administration will be done and thereafter subsequent pembrolizumab infusions will be given every 21 
days (± 3 days). CC-486 will continue according to the applicable schedule. 
Treatment duration with CC-486 is fixed to 21 consecutive days for schedules 1, 2 & 4, and to 14 
consecutive days for schedule 3, regardless of treatment interruptions for any reason. The treatment 
period with CC-486 must always be followed by the ‘off treatment period’ defined for each of the 
treatment schedules. 
Subjects will remain on their assigned treatment until progressive disease based on irRECIST, 
unacceptable toxicity, consent withdrawal, the Investigator concludes that it is in the subject´s best 
interest to discontinue, or other treatment withdrawal criteria is met (section 5.5).  
If a subject is enrolled in Part A but does not receive any study treatment, the reason must be 
documented in the electronic case report form (eCRF). Baseline data will be collected and subject will 
undergo the End of Treatment visit (even if no treatment administered) and will be taken off the study. 
5.3.3.1 CC-486 intake instructions 
CC-486 should be taken at the same time each day (± 2 hours). When taken twice a day, CC-486 should 
be taken approximately every 12 hours, in the morning and at night. CC-486 may be taken on an empty 
stomach or with food (a light breakfast or meal of up to approximately 600 calories). Subjects will ingest 
CC-486 whole tablets with approximately 240 mL (8 ounces) of room temperature water. No tablet 
should be ingested if it is broken, cracked, or otherwise not intact. 
If the subject misses a dose of CC-486, she should take the dose as soon as possible, but not more than 6 
hours after the missed scheduled dose. If greater than 6 hours, the missed dose should be skipped and 
the subject should take the next dose when scheduled. No “make-up dose” or increased dosing should 
occur. 
If vomiting occurs following CC-486 administration, subjects should not take additional drug on that 
same day. It is recommended that the subject receives an antiemetic (e.g. ondansetron) 30 minutes 
prior to all subsequent CC-486 doses. 
5.3.3.2 CC-486 Intake: Specificities on Day 1 of the First CC-486 cycle (all schedules) 
In all schedules, the first CC-486 intake in the study (i.e. on the first CC-486 cycle) should be taken by the 
subject during the clinic visit and after the whole blood sample for DNA methylation was drawn.  
Subject must arrive to the clinic in the fasting state (i.e. no food or drink [except water] for 
approximately 8 - 10 hours) for the required pre-dose assessments (DNA methylation blood sample and 
safety evaluations as per section 6.4 if applicable). Once these assessments are completed, subjects will 
ingest CC-486 with 240 mL of room temperature water in the clinic. 
5.3.3.3 Treatment Regimen for Schedule 1 
The treatment to be used in the trial is outlined below in Figure 4.  
 
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Figure 4: Treatment regimen for Schedule 1
Notes:  

Within 3 days of enrollment, study treatment will begin with CC-486 monotherapy. After 7 days (± 3 days) 
of CC-486 treatment, the first pembrolizumab administration will be done. 

Pembrolizumab will be administered at a dose of 200 mg as a 30-minutes IV infusion every 21 days (± 3 
days). Sites should make every effort to target infusion timing to be as close to 30 minutes as possible. 

CC-486 is administered 100 mg orally once daily, 21 days on treatment followed by 7 days off. CC-486 may 
be taken on an empty stomach or with food (a light breakfast or meal of up to approximately 600 
calories). Whole tablets of CC-486 must be taken with approximately 240 mL (8 ounces) of room 
temperature water. 

On days when both CC-486 and pembrolizumab are administered, pembrolizumab will be infused after 
CC-486 intake. 

Refer to section 5.7 for treatment schedule adjustments. 
5.3.3.4 Treatment Regimen for Schedule 2 
The treatment to be used in the trial is outlined below in Figure 5. 
 
Figure 5: Treatment regimen for Schedule 2 
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Notes:  

Within 3 days after enrollment, study treatment will begin with CC-486 monotherapy. After 7 days (± 3 
days) of CC-486 treatment, the first pembrolizumab administration will be done. 

Pembrolizumab will be administered at a dose of 200 mg as a 30-minutes IV infusion every 21 days (± 3 
days). Sites should make every effort to target infusion timing to be as close to 30 minutes as possible. 

CC-486 is administered 100 mg orally twice a day (approximately every 12 hours, in the morning and at 
night), 21 days on treatment followed by 7 days off. CC-486 may be taken on an empty stomach or with 
food (a light breakfast or meal of up to approximately 600 calories). Whole tablets of CC-486 must be 
taken with approximately 240 mL (8 ounces) of room temperature water. 

On days when both CC-486 and pembrolizumab are administered, pembrolizumab will be infused after 
the first CC-486 intake on that day. 

Refer to section 5.7 for treatment schedule adjustments. 
5.3.3.5 Treatment Regimen for Schedule 3 
The treatment to be used in the trial is outlined below in Figure 6: Treatment regimen for Schedule 3 
 
Figure 6: Treatment regimen for Schedule 3 
Notes:  

Within 3 days of enrollment, study treatment will begin with CC-486 monotherapy. After 7 days (± 3 days) 
of CC-486 treatment, the first pembrolizumab administration will be done. 

Pembrolizumab will be administered at a dose of 200 mg as a 30-minutes IV infusion every 21 days (± 3 
days). Sites should make every effort to target infusion timing to be as close to 30 minutes as possible. 

CC-486 is administered 300 mg orally once daily, 14 days on treatment followed by 14 days off. CC-486 
may be taken on an empty stomach or with food (a light breakfast or meal of up to approximately 600 
calories). Whole tablets of CC-486 must be taken with approximately 240 mL (8 ounces) of room 
temperature water. 

On days when both CC-486 and pembrolizumab are administered, pembrolizumab will be infused after 
CC-486 intake. 

Refer to section 5.7 for treatment schedule adjustments. 
5.3.3.6 Treatment Regimen for Schedule 4 
The treatment to be used in the trial is outlined below in Figure 7: Treatment regimen for Schedule 4  
 
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Figure 7: Treatment regimen for Schedule 4 
Notes:  

Within 3 days of enrollment, study treatment will begin with CC-486 monotherapy. After 7 days (± 3 days) 
of CC-486 treatment, the first pembrolizumab administration will be done. 

Pembrolizumab will be administered at a dose of 200 mg as a 30-minutes IV infusion every 21 days (± 3 
days). Sites should make every effort to target infusion timing to be as close to 30 minutes as possible.  

CC-486 is administered 300 mg orally once daily, 21 days on treatment followed by 7 days off. CC-486 may 
be taken on an empty stomach or with food (a light breakfast or meal of up to approximately 600 
calories). Whole tablets of CC-486 must be taken with approximately 240 mL (8 ounces) of room 
temperature water. 

On days when both CC-486 and pembrolizumab are administered, pembrolizumab will be infused after 
CC-486 intake. 

Refer to section 5.7 for treatment schedule adjustments. 
5.3.4 Study Treatment Administration in Part B 
Subjects will be randomized (1:1) to receive: 
 Arm A: Pembrolizumab 200 mg IV every 21 days (± 3 days) combined with CC-486 (optimal 
schedule selected based on Part A)  
OR 
 Arm B: Pembrolizumab 200 mg IV every 21 days (± 3 days) 
The optimal schedule after the analysis of Part A will be communicated to the participating sites through 
a protocol amendment (if required; refer to section 3.2) or through a letter if an amendment is not 
required. 
Subjects will remain on their assigned treatment until progressive disease based on irRECIST, 
unacceptable toxicity, consent withdrawal, Investigator’s decision that it is in the subject´s best interest 
to discontinue or other treatment withdrawal criteria is met (section 5.5).  
If a subject is randomized into Part B but does not receive any study treatment, the reason must be 
documented in the eCRF. Subjects will remain on study, baseline data will be collected and follow-up will 
continue as described in the Schedule of Visits and Assessments in section 6.2, unless subject completely 
withdraws from the study or other criteria for discontinuation from study participation is met according 
to section 6.5.2. 
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5.3.4.1 Treatment Regimen in Arm A 
Study treatments will be administered to subjects randomized to Arm A according to the applicable 
schedule and guidance in section 5.3.3. 
5.3.4.2 Treatment Regimen in Arm B 
Subjects will receive pembrolizumab at a dose of 200 mg as a 30-minutes IV infusion, every 21 days (± 3 
days). Sites should make every effort to target infusion timing to be as close to 30 minutes as possible. 
5.3.5 Treatment Compliance 
The administration of all study treatments should be recorded in the appropriate sections of the eCRF. 
Additionally, for CC-486, treatment compliance will be assessed at each visit during treatment phase. 
Subjects will complete a diary to document their daily intake. They will be instructed to return all unused 
drugs (partially used and empty containers) and their diary at each visit. Site staff will perform 
accountability of the returned drug and will assess compliance of the subject. Site staff must ensure that 
the subject clearly understands the directions for self-medication and follows the schedule adequately. 
5.4 Study Treatments Management 
5.4.1 Packaging and Labeling 
Clinical supplies will be affixed with a clinical label in accordance with applicable regulatory 
requirements, and will include a statement regarding it’s limitation to investigational use only.  
5.4.2 Storage and Handling 
Study drugs must be stored in a secure, limited-access location under the storage conditions specified 
on the label/package insert. Receipt and dispensing of trial medication must be recorded by an 
authorized person at the site. Clinical supplies may not be used for any purpose other than that stated in 
the protocol. 
5.4.2.1 CC-486  
Store as directed on the label. 
CC-486 is a cytotoxic drug and, as with other potentially toxic compounds, caution should be exercised 
when handling CC-486.  
Procedures for proper handling of CC-486 should be applied according to standards established at each 
site for cytotoxic drugs. If a tablet is broken or damaged, dispose of the drug product and do not use. 
5.4.2.2 Pembrolizumab 
Storage of pembrolizumab vials and of reconstituted and diluted solutions should be done according to 
the instructions detailed in the local package insert.  
5.4.3 Accountability, Drug Return/Destruction 
The Investigator is responsible for keeping accurate records of the clinical supplies received from the 
sponsor or designee, the amount administered or dispensed to and returned by the subjects, and the 
amount remaining at the conclusion of the trial. 
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TRIO will provide appropriate documents (e.g. drug inventory log or similar) that must be completed for 
drug accountability and return. 
5.4.3.1 CC-486 
Subjects must return all unused medication and empty containers to the site staff at each visit. 
Unused/expired CC-486 should be destroyed locally once accountability is performed and drug supplies 
are reconciled. Procedures for proper disposal of CC-486 should be applied according to standards 
established at each site for cytotoxic drugs. 
5.4.3.2 Pembrolizumab 
Unused/expired pembrolizumab will be managed by the sites according to their local requirements.  
5.5 Study Treatment Discontinuation 
By default, subjects are treated until progressive disease as per irRECIST (Appendix 2) when study 
treatment must be discontinued. CA-125 increases should not be used to declare disease progression 
and/or study treatment discontinuation (refer to section 6.4.6.2). 
In Part A and in Arm A of Part B, in case there is a need to permanently discontinue one of the study 
drugs (whichever the reason), the other one will also be discontinued (i.e. monotherapy with CC-486 or 
with pembrolizumab is not allowed in Part A and in Arm A of Part B). 
The Investigator will also discontinue study treatments if any of the following conditions is met: 
 Intercurrent illness or a change in subject´s condition or unacceptable toxicity (see section 5.7) that 
warrants study treatment discontinuation according to Investigator judgment 
 Any event, condition, criterion which would warrant discontinuation of pembrolizumab or CC-486 as 
per section 5.7. 
 Any event, condition, reason which would warrant pembrolizumab or CC-486 to be held for more 
than the maximum acceptable delay as per section 5.7.1. 
 Subject completed 24 months of uninterrupted treatment with pembrolizumab or 35 
administrations of pembrolizumab, whichever is later (Note: 24 months is calculated from the date 
of first pembrolizumab dose).  
 Need for additional local and/or systemic non-protocol anticancer therapy or subject receives non-
protocol anticancer therapy at any time during the study treatment 
 Subject’s decision to withdraw study treatments 
 Lost to follow up 
 Death 
 Pregnancy  
 Investigator’s decision 
 Discontinuation of the study by the sponsor 
 
 
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5.6 Concomitant Treatment and Procedures 
Concomitant treatment includes any medication or therapeutic procedure (e.g. prescription drugs, over-
the-counter drugs, herbal/homeopathic remedies, nutritional supplements, blood transfusions, etc.) 
used by a subject from the date the Patient Informed Consent Form (PICF) is signed until the End of 
Treatment visit. After the End of Treatment visit, collection of concomitant therapies will be done 
according to section 6.4.4. 
Concomitant therapies will be assessed at all clinic visits and must be recorded on the appropriate eCRF. 
Not all concomitant medications need to be recorded in the eCRF. Refer to the CRF Completion 
Guidelines for guidance on how to report concomitant medications in the TRIO026 study. If the use of 
any medication during the study is due to an AE, the AE must be recorded on the eCRF and in the 
subject’s source documents.  
Any concomitant treatment not listed in section 5.6.2 is considered permitted in the study.  
Refer to section 5.6.3 for guidance on the use of radiotherapy during the study. 
5.6.1 Contraception 
Given the patient population in the trial, it is highly unlikely that WoCBP are enrolled in the TRIO026 
study (refer to section 4.1 for the definition of WoCBP).  
WoCBP may be included only if they agree to acceptable contraception starting with the screening visit 
and up to 120 days after the last dose of study treatment. 
WoCBP must agree to avoid becoming pregnant by complying with one of the following:  
(1) practice abstinence† from heterosexual activity;  
OR  
(2) use (or have their partner use) acceptable contraception during heterosexual activity.  
Acceptable methods of contraception are‡: 
 Single method (one of the following is acceptable): 
• intrauterine device (IUD) 
• vasectomy of a subject’s male partner  
• contraceptive rod implanted into the skin 
 Combination method (requires use of two of the following): 
• diaphragm with spermicide (cannot be used in conjunction with cervical 
cap/spermicide) 
• cervical cap with spermicide (nulliparous women only)  
• contraceptive sponge (nulliparous women only)  
• male condom or female condom (cannot be used together) 
• hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or progestin-
only pill), contraceptive skin patch, vaginal contraceptive ring, or subcutaneous 
contraceptive injection 
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†Abstinence (relative to heterosexual activity) can be used as the sole method of contraception if it is consistently 
employed as the subject’s preferred and usual lifestyle and if considered acceptable by local regulatory agencies 
and ERCs/IRBs. Periodic abstinence (e.g. calendar, ovulation, symptom-thermal, post-ovulation methods, etc.) and 
withdrawal are not acceptable methods of contraception.  
‡If a contraceptive method listed above is restricted by local regulations/guidelines, then it does not qualify as an 
acceptable method of contraception for subjects participating at sites in this country/region. 
5.6.2 Prohibited Treatments 
Subjects are prohibited from receiving the following therapies since PICF signature until the End of 
Treatment visit: 
 Investigational agents other than the study treatments. 
 Any additional investigational or commercial anticancer agents, such as chemotherapy, 
immunotherapy, targeted therapy, biological response modifiers, or endocrine therapy, will not be 
allowed, even if utilized as treatment of non-cancer indications.  
 Immunotherapy, including steroids, except for the treatment of potential immune-related AEs 
during the study.  
 Live vaccines. Also, subjects who have received live vaccines within 30 days prior to enrollment in 
Part A or randomization in Part B are not eligible in the study. Examples of live vaccines include, but 
are not limited to, the following: measles, mumps, rubella, chicken pox, yellow fever, seasonal flu, 
H1N1 flu, rabies, BCG, and typhoid vaccine. 
5.6.3 Palliative Radiotherapy 
Subjects may receive palliative radiotherapy before discontinuing study treatment only for local pain 
control and only if in the opinion of the treating Investigator, the subject does not have progressive 
disease. The radiation field cannot encompass a target lesion. Radiation to a target lesion is considered 
progressive disease and the subject should be removed from study treatment. 
5.7 Treatment Schedule Adjustments and Adverse Events Management 
5.7.1 General Rules 
Regular assessment and monitoring of AEs is required throughout study treatment period and at least 
up until the End of Treatment visit (refer to section 7.1.1).  
Toxicity will be assessed utilizing the National Cancer Institute Common Terminology Criteria for Adverse 
Events (NCI CTCAE) v4.03. For toxicities not specifically listed in the NCI CTCAE, the following grading will 
apply for assessing severity: 
• 
Grade 1: Mild 
• 
Grade 2: Moderate  
• 
Grade 3: Severe 
• 
Grade 4: Life-threatening  
• 
Grade 5: Death related to AE 
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Subjects will be instructed to notify their physician immediately for any and all toxicities. Assessment of 
causality (chronology, confounding factors, concomitant medications, diagnostic tests, and previous 
experience with the study treatment) should be conducted by the Investigator prior to dose 
modification and/or delay whenever possible. As a general approach, it is suggested that all AEs be 
managed with supportive care at the earliest signs of toxicity and before delaying/reducing study drugs, 
when possible and if clinically appropriate.  
All dose modifications should be based on the AE requiring the greatest modification and should be 
properly documented in source documents. Investigators may take a more conservative approach than 
the guidelines outlined in the protocol on the basis of clinical judgment that this is in the best interest of 
the subject.  
In case a delay/withhold of one study drug is required, treatment with the other drug may continue 
according to the protocol schedule if clinically appropriate (applicable for Part A and Arm A of Part B).  
Maximum acceptable delays due to adverse events related to study drug(s) are: 
 For pembrolizumab: 12 weeks after prior dose of pembrolizumab 
 For CC-486: the maximum number of days that dose may be withheld due to toxicity before a 
subject is permanently discontinued from CC-486 is 14 days (not comprising treatment off-period) 
If due to an adverse event related to study drug(s) it is required to delay study treatment for more than 
the maximum acceptable period, then study treatment should be permanently discontinued and subject 
should undergo the End of Treatment visit.  
Dosing interruptions/delays of one or both study drugs with a maximum duration of 21 days are 
permitted in the case of medical/surgical events or logistical reasons unrelated to study treatments (e.g. 
elective surgery, unrelated medical events, subject vacation and/or holidays). Subjects should be placed 
back on study therapy within 21 days of the scheduled interruption, unless otherwise discussed with the 
Medical Monitor. 
In Part A and in Arm A of Part B, in case there is a need to permanently discontinue one of the study 
drugs (whichever the reason), the other one will also be discontinued (i.e. monotherapy with CC-486 or 
with pembrolizumab is not allowed in part A and in Arm A of Part B). 
General guidelines on dose delay and modifications for each of the study drugs are detailed in the 
following subsections. 
5.7.2 Pembrolizumab 
5.7.2.1 Dose Reductions 
No dose reductions are allowed for pembrolizumab. 
5.7.2.2 Treatment Schedule Adjustments 
Adverse events (both non-serious and serious) associated with pembrolizumab exposure may represent 
an immunologic etiology. For assessment and management of irAEs, investigators should refer to the 
last version of pembrolizumab IB. These adverse events may occur shortly after the first dose or several 
months after the last dose of treatment. Pembrolizumab must be withheld for drug-related toxicities 
and severe or life-threatening AEs as per Table 1. 
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Table 1: Treatment schedule adjustments for pembrolizumab 
General instructions: 
1. Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks. 
2. For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to Grade 1 or 0 and 
corticosteroid has been tapered. Pembrolizumab should be permanently discontinued if AE does not resolve within 12 weeks of last dose or 
corticosteroids cannot be reduced to ≤10 mg prednisone or equivalent per day within 12 weeks.  
3. For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other immunosuppressive treatment 
should be initiated if irAEs cannot be controlled by corticosteroids. 
 
Immune-related 
AEs 
Toxicity grade or 
conditions 
(CTCAEv4.0) 
Action taken to 
pembrolizumab 
irAE management with 
corticosteroid and/or other 
therapies  
Monitor and follow-up  
Pneumonitis  
Grade 2 
Withhold  
Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper 
• 
Monitor participants for signs and symptoms of 
pneumonitis 
• 
Evaluate participants with suspected 
pneumonitis with radiographic imaging and 
initiate corticosteroid treatment 
• 
Add prophylactic antibiotics for opportunistic 
infections 
Grade 3 or 4, or 
recurrent Grade 2 
Permanently 
discontinue 
Diarrhea / Colitis  
Grade 2 or 3 
Withhold 
Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper 
 
• 
Monitor participants for signs and symptoms of 
enterocolitis (i.e., diarrhea, abdominal pain, 
blood or mucus in stool with or without fever) 
and of bowel perforation (i.e., peritoneal signs 
and ileus). 
• 
Participants with ≥ Grade 2 diarrhea suspecting 
colitis should consider GI consultation and 
performing endoscopy to rule out colitis.  
• 
Participants with diarrhea/colitis should be 
advised to drink liberal quantities of clear fluids. 
If sufficient oral fluid intake is not feasible, fluid 
and electrolytes should be substituted via IV 
infusion. 
Grade 4 
Permanently 
discontinue 
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Immune-related 
AEs 
Toxicity grade or 
conditions 
(CTCAEv4.0) 
Action taken to 
pembrolizumab 
irAE management with 
corticosteroid and/or other 
therapies  
Monitor and follow-up  
AST / ALT 
elevation or 
Increased 
bilirubin 
suggestive of 
hepatitis 
Grade 2 
Withhold 
Administer corticosteroids (initial 
dose of 0.5- 1 mg/kg prednisone or 
equivalent) followed by taper 
Monitor with liver function tests (consider weekly or 
more frequently until liver enzyme value returned to 
baseline or is stable 
Grade 3 or 4  
Permanently 
discontinue 
Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper 
Type 1 diabetes 
mellitus (T1DM) 
or 
Hyperglycemia 
 
Newly onset T1DM 
or  
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of β-cell 
failure 
Withhold 
• Initiate insulin replacement 
therapy for participants with 
T1DM  
• Administer anti-hyperglycemic in 
participants with hyperglycemia  
 
Monitor participants for hyperglycemia or other signs 
and symptoms of diabetes. 
Hypophysitis 
Grade 2 
Withhold 
Administer corticosteroids and 
initiate hormonal replacements as 
clinically indicated.  
 
Monitor for signs and symptoms of hypophysitis 
(including hypopituitarism and adrenal insufficiency)  
Grade 3 or 4  
Withhold or 
permanently 
discontinue1  
Hyperthyroidism  
Grade 2 
Continue  
Treat with non-selective beta-
blockers (e.g., propranolol) or 
thionamides as appropriate  
Monitor for signs and symptoms of thyroid disorders.  
 
Grade 3 or 4  
Withhold or  
permanently 
discontinue1 
Hypothyroidism 
Grade 2-4 
Continue  
Initiate thyroid replacement 
hormones (e.g., levothyroxine or 
liothyroinine) per standard of care 
Monitor for signs and symptoms of thyroid disorders.  
 
Nephritis and 
Renal 
dysfunction 
Grade 2 
Withhold  
Administer corticosteroids 
(prednisone 1-2 mg/kg or 
equivalent) followed by taper. 
Monitor changes of renal function 
Grade 3 or 4 
Permanently 
discontinue 
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Immune-related 
AEs 
Toxicity grade or 
conditions 
(CTCAEv4.0) 
Action taken to 
pembrolizumab 
irAE management with 
corticosteroid and/or other 
therapies  
Monitor and follow-up  
Myocarditis 
Grade 1 or 2 
Withhold 
Based on severity of AE administer 
corticosteroids 
Ensure adequate evaluation to confirm etiology 
and/or exclude other causes 
 
Grade 3 or 4 
Permanently 
discontinue 
Stevens Johnson 
Syndrome 
Any grade 
Permanently 
discontinue 
Refer the patient for specialized care 
for assessment and treatment. 
Refer the patient for specialized care for assessment 
and treatment. 
Toxic Epidermal 
Necrolysis 
Any grade 
Permanently 
discontinue 
Refer the patient for specialized care 
for assessment and treatment. 
Refer the patient for specialized care for assessment 
and treatment. 
All other 
immune-related 
AEs 
Intolerable/ 
persistent Grade 2 
Withhold 
Based on type and severity of AE 
administer corticosteroids  
Ensure adequate evaluation to confirm etiology 
and/or exclude other causes 
 
Grade 3 
Withhold or 
discontinue based 
on the type of 
event. Events that 
require 
discontinuation 
include and not 
limited to: 
Guillain-Barre 
Syndrome, 
encephalitis 
Grade 4 or 
recurrent Grade 3  
Permanently 
discontinue 
1. Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician.  
NOTE:  
For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, pembrolizumab may be resumed 
when AE resolves to ≤ Grade 2 and is controlled with hormonal replacement therapy or achieved metabolic control (in case of T1DM).  
 
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5.7.2.3 Supportive Care Measures for Pembrolizumab Toxicities 
Immune-mediated adverse reactions, including severe and fatal cases, have occurred in patients 
receiving pembrolizumab. Immune-mediated adverse reactions can occur after discontinuation of 
treatment. Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating Investigator. Suggested supportive care measures for the management of adverse events with 
potential immunologic etiology are outlined below in this section. Where appropriate, these guidelines 
include the use of oral or intravenous treatment with corticosteroids as well as additional anti-
inflammatory agents if symptoms do not improve with administration of corticosteroids.  Note that 
several courses of steroid tapering may be necessary as symptoms may worsen when the steroid dose is 
decreased. For each disorder, attempts should be made to rule out other causes such as metastatic 
disease or bacterial or viral infection, which might require additional supportive care. The treatment 
guidelines are intended to be applied when the Investigator determines the events to be related to 
pembrolizumab.  
Note: if after the evaluation the event is determined not to be related, the Investigator does not need to 
follow the treatment guidance (as outlined below). Refer to section 5.7.2.2 for dose modification.  
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or skin 
photography as part of evaluation of the event.  
• 
Pneumonitis:  
o For Grade 2 events, treat with systemic corticosteroids. When symptoms improve to 
Grade 1 or less, steroid taper should be started and continued over no less than 4 
weeks. 
o For Grade 3-4 events, immediately treat with intravenous steroids. Administer 
additional anti-inflammatory measures, as needed. 
o Add prophylactic antibiotics for opportunistic infections in the case of prolonged steroid 
administration. 
• 
Diarrhea/Colitis:  
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such as 
diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of bowel 
perforation (such as peritoneal signs and ileus).  
o All subjects who experience diarrhea/colitis should be advised to drink liberal quantities 
of clear fluids. If sufficient oral fluid intake is not feasible, fluid and electrolytes should 
be substituted via IV infusion. For Grade 2 or higher diarrhea, consider GI consultation 
and endoscopy to confirm or rule out colitis. 
o For Grade 2 diarrhea/colitis, administer oral corticosteroids.  
o For Grade 3 or 4 diarrhea/colitis, treat with intravenous steroids followed by high dose 
oral steroids.  
o When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 
• 
Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis [DKA]) or ≥ Grade 3 
Hyperglycemia, if associated with ketosis (ketonuria) or metabolic acidosis (DKA) 
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o For T1DM or Grade 3-4 Hyperglycemia 
 
Insulin replacement therapy is recommended for Type I diabetes mellitus and 
for Grade 3-4 hyperglycemia associated with metabolic acidosis or ketonuria.  
 
Evaluate subjects with serum glucose and a metabolic panel, urine ketones, 
glycosylated hemoglobin, and C-peptide.  
• 
Hypophysitis: 
o For Grade 2 events, treat with corticosteroids. When symptoms improve to Grade 1 or 
less, steroid taper should be started and continued over no less than 4 weeks. 
Replacement of appropriate hormones may be required as the steroid dose is tapered. 
o For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, steroid taper should be 
started and continued over no less than 4 weeks. Replacement of appropriate hormones 
may be required as the steroid dose is tapered. 
• 
Hyperthyroidism or Hypothyroidism:  
Thyroid disorders can occur at any time during treatment. Monitor subjects for changes in 
thyroid function (at the start of treatment, periodically during treatment, and as indicated based 
on clinical evaluation) and for clinical signs and symptoms of thyroid disorders. 
o Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism): 
 
In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are suggested 
as initial therapy. 
 
In hypothyroidism, thyroid hormone replacement therapy, with levothyroxine 
or liothyroinine, is indicated per standard of care. 
o Grade 3-4 hyperthyroidism  
 
Treat with an initial dose of IV corticosteroid followed by oral corticosteroids. 
When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. Replacement of appropriate hormones 
may be required as the steroid dose is tapered. 
• 
Hepatic: 
o For Grade 2 events, monitor liver function tests more frequently until returned to 
baseline values (consider weekly). 
 
Treat with IV or oral corticosteroids 
o For Grade 3-4 events, treat with IV corticosteroids for 24 to 48 hours.  
o When symptoms improve to Grade 1 or less, a steroid taper should be started and 
continued over no less than 4 weeks. 
• 
Renal Failure or Nephritis: 
o For Grade 2 events, treat with corticosteroids. 
o For Grade 3-4 events, treat with systemic corticosteroids. 
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o When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks.  
• 
Management of Infusion Reactions: Signs and symptoms usually develop during or shortly after 
drug infusion and generally resolve completely within 24 hours of completion of infusion. Table 
2 below shows treatment guidelines for subjects who experience an infusion reaction associated 
with administration of pembrolizumab. 
Table 2: Pembrolizumab infusion reaction treatment guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
Grade 1 
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of 
the Investigator. 
None 
Grade 2 
Requires infusion interruption 
but responds promptly to 
symptomatic treatment (e.g. 
antihistamines, NSAIDS, 
narcotics, IV fluids); 
prophylactic medications 
indicated for < =24 hrs. 
Stop Infusion and monitor symptoms. 
Additional appropriate medical therapy 
may include but is not limited to: 
- 
IV fluids 
- 
Antihistamines 
- 
NSAIDS 
- 
Acetaminophen 
- 
Narcotics 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of 
the Investigator. 
If symptoms resolve within one hour of 
stopping drug infusion, the infusion may 
be restarted at 50% of the original 
infusion rate (e.g. from 100 mL/hr. to 50 
mL/hr.). Otherwise dosing will be held 
until symptoms resolve and the subject 
should be premedicated for the next 
scheduled dose. 
Subjects who develop Grade 2 toxicity 
despite adequate premedication should 
be permanently discontinued from 
further trial treatment administration. 
Subject may be premedicated 
1.5h (± 30 minutes) prior to 
infusion of pembrolizumab with: 
 
Diphenhydramine 50 mg p.o. (or 
equivalent dose of antihistamine). 
 
Acetaminophen 500-1000 mg p.o. 
(or equivalent dose of 
antipyretic). 
Grades 3 or 4 
 
Grade 3: 
Prolonged (i.e. not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
Stop Infusion. 
Additional appropriate medical therapy 
may include but is not limited to: 
- 
IV fluids 
- 
Antihistamines 
- 
NSAIDS 
- 
Acetaminophen 
No subsequent dosing 
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NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
recurrence of symptoms 
following initial improvement; 
hospitalization indicated for 
other clinical sequelae (e.g. 
renal impairment, pulmonary 
infiltrates) 
 
Grade 4: 
Life-threatening; pressor or 
ventilatory support indicated 
- 
Narcotics 
- 
Oxygen 
- 
Pressors 
- 
Corticosteroids 
- 
Epinephrine 
 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of 
the Investigator. 
Hospitalization may be indicated. 
Subject is permanently discontinued 
from further trial treatment 
administration. 
Appropriate resuscitation equipment should be available in the room and a physician readily available during 
the period of drug administration. 
5.7.3 CC-486 
5.7.3.1 Dose Levels 
Refer to Table 3: CC-486 dose levels for guidance on dose reduction levels for each schedule. Dose 
reductions will be allowed from the original start dose except in Schedule 1 where no dose reductions 
are allowed.  
Re-escalation to the higher dose level is not permitted once dose has been reduced due to toxicity with 
the only exception of cases considered in Table 4. 
Table 3: CC-486 dose levels 
Dose levels 
Schedule 1 
Schedule 2 
Schedule 3 
Schedule 4 
Dose level 0 
(Starting dose) 
100 mg q.d. D1-21 
100 mg BID D1-21 
300 mg q.d D1-14 
300 mg q.d D1-21 
Dose level -1 
No dose reduction 
allowed. Discontinue.
100 mg q.d 
200 mg q.d. 
200 mg q.d. 
Dose level -2 
Not applicable 
Discontinue 
100 mg q.d 
100 mg q.d 
Need for 
additional dose 
reduction 
Not applicable 
Not applicable 
Discontinue 
Discontinue 
q.d.: once a day; BID: twice a day  
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5.7.3.2 Treatment Schedule Adjustments and Management of CC-486 Toxicities 
During CC-486 treatment subjects should receive appropriate supportive care measures as deemed 
necessary by the Investigator considering the recommendations provided in this section.  
Table 4: CC-486 dose modifications for hematologic toxicity 
Toxicity 
Recommendation 
Grade 2-3 neutropenia on any testing* 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
* If grade ≥ 3 associated with fever at any 
time, the dose adjustment guidelines for 
grade 4 neutropenia should be enacted. 
For Schedule 1, withhold CC-486 until recovery to ≤ Grade 1.  
After recovery , resume CC-486 at the same dose. If no 
recovery from neutropenia to ≤ Grade 1 is observed after 14 
days of neutropenia diagnosis, permanently discontinue CC-
486. 
 
For Schedules 2, 3 and 4, temporarily reduce CC-486 one dose 
level as per Table 3 until cycle completion. If no further 
reduction is allowed as per Table 3, temporarily withhold CC-
486 until next cycle.  
At next CC-486 cycle: 
• If recovery to ≤ Grade 1, re-escalate CC-486 to the 
previous dose (i.e. dose administered prior to the 
temporary reduction/interruption). 
• If no recovery from neutropenia to ≤ Grade 1 is observed 
after 14 days of neutropenia diagnosis, permanently 
discontinue CC-486. 
 
Note: In cases of recurrent neutropenia (grade 3/4) after two 
temporary dose reductions/interruptions, CC-486 will be 
permanently discontinued. 
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Toxicity 
Recommendation 
Grade 4 neutropenia on a pre CC-486 
hematology testing or during CC-486 
treatment 
All schedules: Withhold CC-486 until next cycle and monitor 
ANC until recovery to ≤ Grade 1. 
• If recovery ≤ 7 days: at next cycle, resume CC-486 at the 
same dose (i.e. dose administered prior to the 
interruption). 
• If no recovery > 7 days: permanently discontinue CC-486 
Initiation of G-CSF should be considered by the Investigator. If 
initiated, administer G-CSF per institutional practice or 
package insert and continue until ANC recovers to ≥ 2.0 x 
109/L. 
 
Note: In cases of recurrent neutropenia (grade 3/4) after two 
temporary dose reductions/interruptions, CC-486 will be 
permanently discontinued. In cases where as a consequence of 
previous toxicity no additional dose reductions are allowed as 
per Table 3, CC-486 could be temporarily interrupted until next 
cycle. 
Grade 2 thrombocytopenia on any 
testing 
Hold CC-486 until Platelets recover to ≤ Grade 1. Hematology 
to be tested periodically until recovery. 
If delay: 
• ≤ 7 days: resume CC-486 at same dose 
• 8-14 days: reduce CC-486 one dose level (if allowed per 
Table 3) except in Schedule 1 where treatment can be 
resumed at same dose, unless in the opinion of the 
Investigator it is in the best subject´s interest to 
discontinue treatment with CC-486.  
If dose was previously reduced and no further dose 
reduction is allowed per Table 3 then CC-486 should be 
permanently discontinued 
• > 14 days: permanently discontinue 
Grade 3 thrombocytopenia on any 
testing * 
 
 
 
 
* If grade 3 thrombocytopenia with 
clinically significant bleeding occurs at any 
time, the dose adjustment guidelines for 
grade 4 thrombocytopenia should be 
enacted. 
Hold CC-486 until Platelets recover to ≤ Grade 1. Hematology 
to be tested periodically until recovery. 
If delay: 
• ≤ 7 days: resume CC-486 at same dose 
• 8-14 days: reduce CC-486 one dose level (if allowed per 
Table 3) except in Schedule 1 where CC-486 should be 
permanently discontinued. 
If dose was previously reduced and no further dose 
reduction is allowed per Table 3 then CC-486 should be 
permanently discontinued 
• > 14 days: permanently discontinue 
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Toxicity 
Recommendation 
Grade 4 thrombocytopenia 
on a pre-CC-486 hematology testing or 
during CC-486 treatment 
Hold CC-486 until Platelets recover to ≤ Grade 1. Hematology 
to be tested periodically until recovery.  
If delay: 
• ≤ 7 days: reduce CC-486 one dose level (if allowed per 
Table 3) except in Schedule 1 where CC-486 should be 
permanently discontinued. 
If dose was previously reduced and no further dose 
reduction is allowed per Table 3 then CC-486 should be 
permanently discontinued 
• No recovery by day 7: permanently discontinue 
Notes:  
• 
When neutropenia is concomitantly observed with other toxicity/ies that require a more conservative 
approach, guidance on dose modifications for other AEs than neutropenia should be followed. 
• 
The initiation of G-CSF is left at the Investigator´s discretion and should only be utilized in accordance to 
ASCO or ESMO recommendations. In case of G-CSF use, concurrent use (on same days) with CC-486 
should be avoided: at least a two day wash-out period should be respected from CC-486 discontinuation 
and G-CSF initiation. 
• 
In cases of neutropenia without any evidence of infection, prophylactic antibiotic use is left under 
investigator’s discretion. 
• 
If neutropenia is associated with fever and severe diarrhea, subject should be managed appropriately 
according to the local practice. In case of recurrence of the diarrhea with neutropenia and fever, the 
continuation of the subject in the study should be discussed on a case-by-case basis with the sponsor’s 
medical monitor 
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Table 5: CC-486 dose delays/adjustments for non-hematologic toxicity 
Toxicity 
Recommendation 
Grade 3 or 4 Nausea or Vomiting 
 
Grade 3 or 4 Diarrhea 
 
Grade 3 or 4 Fatigue/Asthenia 
 
 
 
Hold until resolution to ≤ Grade 1 and provide optimal 
medical management according the type and severity of 
toxicity (also refer to section 5.3.1). 
If response ≤ 72 hours (3 days) and recovery ≤ 7 days:  
• Reduce CC-486 one dose level (if allowed per Table 3) 
except in Schedule 1 where CC-486 should be 
permanently discontinued.  
• If dose was previously reduced and no further dose 
reduction is allowed per Table 3 then CC-486 should be 
permanently discontinued  
• If event recurs with same/greater severity after re-
challenge at a lower dose level: discontinue CC-486 
If no recovery within 7 days: discontinue CC-486/placebo 
 
Note: Emesis and diarrhea should be proactively managed in 
all cases regardless of the grade. Anti-diarrheic treatment 
(including anti-diarrheic diet and use of loperamide) is 
recommended for the management of treatment emergent 
diarrhea in all cases. 
Grade 3 or 4 any other clinically 
significant non-hematologic toxicity 
Hold until resolution to ≤ Grade 1 and provide optimal 
medical management according the type and severity of 
toxicity. 
If recovery ≤ 7 days:  
• Reduce CC-486 one dose level (if allowed per Table 3) 
except in Schedule 1 where CC-486 should be 
permanently discontinued.  
• If dose was previously reduced and no further dose 
reduction is allowed per Table 3 then CC-486 should be 
permanently discontinued  
• If event recurs with same/greater severity after re-
challenge at a lower dose level: discontinue CC-486 
If no recovery within 7 days: discontinue CC-486/placebo 
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Toxicity 
Recommendation 
Renal dysfunction - For any 
unexplained reductions in serum 
bicarbonate levels to < 20 mEq/L or 
unexplained elevations of serum 
creatinine (or urea) > 20% from 
baseline 
Hold until resolution to baseline level (+/- 20%) and provide 
optimal medical management. 
Reduce CC-486 dose in the next cycle of treatment to the 
next lower dose level except in Schedule 1 where CC-486 
should be permanently discontinued.  
If dose was previously reduced and no further dose reduction 
is allowed per Table 3 then CC-486 should be permanently 
discontinued  
 If similar unexplained renal and/or electrolyte disturbances 
subsequently persist or recur, discontinue CC-486 
5.7.3.3 Criteria for CC-486 Discontinuation 
CC-486 needs to be permanently discontinued for any of the following: 
 Any life-threatening adverse reaction 
 Anaphylactic-like reaction related to CC-486 administration 
 Necrotising fasciitis 
 Any criteria/event listed in section 5.5 or 5.7.3 
6. STUDY VISITS AND ASSESSMENTS 
6.1 Subject Inclusion  
6.1.1 Informed Consent 
Prior to any study-specific screening evaluation, the subject or legally acceptable representative (if 
applicable per local regulation) will be informed of the nature of the study and will be given pertinent 
information as to the intended purpose, possible benefits, and possible adverse experiences. The 
procedures and possible hazards to which the subject will be exposed will be explained. A legally 
acceptable representative is an individual or other body authorized under applicable law to consent, on 
behalf of a prospective subject, to the subject’s participation in the study. 
An approved PICF will then be read and signed by the subject (or legally acceptable representative if 
applicable) and, when required, a witness, and the Investigator or a person designated by the 
Investigator, as per local regulations. The subject will be provided with an original copy of the signed 
PICF. 
The subject may partially or completely withdraw from the study at anytime without prejudicing future 
medical treatment. In any case, the type and extent of withdrawal should be documented on the initial 
informed consent form, and must be dated and signed by the subject and by the Investigator. 
If a potential subject or legally acceptable representative is illiterate or visually impaired, the 
Investigator must provide an impartial witness to read the PICF to the subject and must allow for 
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questions. Thereafter, both the subject or legally acceptable representative and the witness must sign 
the PICF to attest that informed consent was freely given and understood.  
The PICF will include a statement by which the subject allows the sponsor’s duly authorized personnel, 
the Ethics Committee (IRB/IEC), and the regulatory authorities to have direct access to its data that will 
be processed according to the confidentiality regulations.  
If important new information becomes available that may be relevant to the subject’s consent and 
willingness to continue participation in the study, the PICF will be revised and submitted to IRB/IEC for 
approval/favorable opinion. The new information will be then discussed with the subject in a timely 
manner and if she agrees to continue participation in the study, the revised PICF will be signed and 
dated and the subject will receive an original copy. 
In line with each country’s applicable regulations, the source should also support the documentation of 
the consent process, for each subject. 
Both parts of this study have an optional component described in the PICF, with a consent section 
dedicated to this optional component. If a subject opts not to participate in the optional portion, this in 
no way affects the subject’s ability to participate in the main research study. 
6.1.2 Registration, Enrollment/Randomization and Treatment Assignment 
6.1.2.1 Part A 
The following steps for registering and enrolling a subject are chronologically performed: 
1. The subject must provide written informed consent prior to performing any study specific 
procedure not considered standard practice by the institution. 
2. The site will ask TRIO for subject’s registration immediately after signature of PICF. A unique 
registration number will be assigned to each subject in the study. 
3. The site will proceed to perform the screening procedures according to the Schedule of 
Assessments and section 6.4. Upon completion of screening procedures, the Investigator or 
his/her delegate will check if the subject meets all eligibility criteria:  
 Subjects who do not meet all eligibility criteria: sites will have the screen failure form 
completed in the eCRF with corresponding reason for screen failure captured. 
 Subjects who meet all eligibility criteria: sites will enter the screening data in the eCRF 
which will be reviewed centrally by TRIO. After the review of the eligibility criteria, TRIO 
may address, if necessary, some discrepancies that will have to be answered by the site. 
Once the eligibility central review is completed and discrepancies have been resolved (if 
applicable) TRIO will provide the confirmation that the subject is eligible and the site will 
be able to move forward with the subject’s enrollment in the eCRF. The site will receive a 
confirmation of enrollment. If the subject is deemed not eligible following the central 
eligibility review, the site will be asked to report the screen failure reason in the eCRF. 
4. Subjects will be assigned to a cohort in the order they are enrolled in the study. Subjects 
enrolled in Part A must start study treatment within 3 days of enrollment. 
A cohort will remain open to accrual until five subjects treated on that schedule are considered 
evaluable as per the definition in section 3.3 (subject completed at least 2 CC-486 cycles and have 
undergone the 1st post-baseline tumor burden assessment and the 2nd tumor biopsy). It is critical that 
data about the tumor biopsies and 1st tumor burden assessment is entered by the sites in the eCRF in a 
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timely manner since this is required to close accrual for the corresponding cohort also in a timely 
manner. TRIO will also review the tumor collection and tumor assessments data and closely follow-up 
the performance of these procedures. 
Details regarding the Registration and Enrollment processes are provided in a specific Instruction 
Manual related to the Registration and Enrollment. 
6.1.2.2 Part B 
The following steps for registering and randomizing a subject are chronologically performed: 
1. The subject must provide written informed consent prior to performing any study specific 
procedure not considered standard practice by the institution. 
2. The site will register the subject in the IWRS system. The registration needs to be done as soon 
as the subject signs the PICF. The system will uniquely attribute a registration number to each 
subject in the study and the site will receive an automated registration confirmation. 
3. The site will proceed to perform the screening procedures according to the Schedule of 
Assessments and to sections 6.3 and 6.4. Upon completion of screening procedures the 
Investigator or his/her delegate will check if the subject meets all eligibility criteria:  
 Subjects who do not meet the eligibility criteria will be moved to a screen failure category 
in the IWRS.  
 Subjects who meet all eligibility criteria: the sites will enter the screening data in the eCRF 
which will be reviewed centrally by TRIO. After the review of the eligibility criteria, TRIO 
may address, if necessary, some discrepancies that will have to be answered by the site. 
Once the eligibility central review is completed and discrepancies have been resolved (if 
applicable) TRIO will provide the confirmation that the subject is eligible and the site will 
be able to move forward with the subject’s randomization in IWRS. Treatment assignment 
will be done by the system and the site will receive an automated randomization 
confirmation.  
Subjects will be randomized to treatment arms in a 1:1 ratio. To ensure the equal distribution of 
prognostic factors in the two study arms, subjects will be stratified according to the following 
parameters:  
 Type of relapsed disease: platinum-refractory vs. platinum-resistant (refer to the corresponding 
definitions in section 4.1) 
 Prior treatment regimens for the platinum-refractory/resistant EOC: none vs. 1 or 2 
Details regarding the Registration and Randomization processes are provided in a specific Instruction 
Manual related to the Registration and Randomization processes. 
Subjects randomized in Part B must start study treatment within 3 days of randomization. 
6.2 Schedule or Visits and Assessments 
For both parts of the trial, all study visits and procedures are detailed in the Schedule of Visits and 
Assessments tables presented in this section. The detailed description of the study visits and 
assessments is in sections 6.3 and 6.4. Adherence to the schedule of visits and assessments is required 
and visits should be planned accordingly.  
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6.2.1 Part A 
Table 6: Schedule of visits and assessments in Part A 
Protocol Activities 
Screening1 
Treatment Period2 
End of 
treatment3 
Follow-
up4 
Days  
-28 to -1 
Days  
-7 to -1 
Days 8, 15 
and 22 
 
 
 
Informed consent/ Registration5 
X 
 
 
 
 
 
Demographics, medical history 
X 
 
 
 
 
 
Physical examination (incl. vital 
signs) 
 
X 
 
At each visit prior to each CC-486 cycle. Vital signs will 
be assessed as per site´s standard practice 
X 
According 
to SoC 
ECOG PS 
 
X 
 
At each visit prior to each CC-486 cycle 
X 
 
Serum pregnancy test6 
 
X 
 
As clinically indicated 
 
 
Hematology7 
 
X 
X 
Within 3 days of every visit prior to each CC-486 cycle 
and at day 8, day 15 and day 22 of each cycle (± 1 day) 
X 
 
Blood chemistry7 
 
X 
 
Within 3 days of every visit prior to each CC-486 cycle 
X 
 
INR or PT AND aPTT/PTT 
 
X 
 
As clinically indicated 
 
 
CA-1258 
 
X 
 
Within 3 days of every visit prior to each CC-486 cycle 
X 
X 
AEs assessments 
 
X 
 
At each visit prior to each CC-486 cycle 
X 
X9 
Concomitant treatments 
X10 
 
 
At each visit prior to each CC-486 cycle 
X 
X11 
Tumor burden assessments12 
X 
 
 
1st assessment: 6 weeks (± 1 week) after first CC-486 
intake. Then every 12 weeks (± 1 week) 
 
X 
FFPE block from debulking surgery 
(optional)13 
X 
 
 
 
 
 
Tumor biopsy (mandatory)14 
X 
 
 
6 weeks (± 1 week) after first CC-486 intake 
 
 
Whole blood for DNA methylation 
analysis15 
 
 
 
On Day 1 of the 1st CC-486 cycle and on the pre-
treatment visit prior to the 2nd CC-486 cycle 
 
 
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Notes:  
 All assessments should be performed within 3 days of the scheduled visit, unless otherwise specified.  
 All pre-treatment tests/procedures should be performed and assessed by the Investigator prior to dosing. 
Footnotes: 
1: Day -1 is the day before subject enrollment (see footnote 5) 
2: Study treatment with CC-486 should start within 3 days of enrollment. The first on-treatment visit should occur on Day 1 of the 1st CC-486 cycle (subject 
should receive the first CC-486 dose during the visit and after the whole blood sample for DNA methylation was drawn). Afterwards, study visits are 
scheduled every 4 weeks ± 3 days and should be done during the CC-486 off period as close as possible to restarting the next CC-486 cycle. Additionally, 
every 21 days (± 3 days) subjects will visit the site to receive pembrolizumab. Refer to section 5.3.3 for details on the administration of each schedule. 
Study treatment will continue until progressive disease according to irRECIST criteria, unacceptable toxicity, consent withdrawal or the Investigator 
concludes that is in the subject´s best interest to discontinue (or any other withdrawal criteria is met according to section 5.5). Progression and study 
treatment discontinuation should not be declared on the basis of CA-125 alone. 
In case there is a need to permanently discontinue one of the study drugs, the other one will also be discontinued and the subjects will undergo the End of 
treatment visit (and begin the Follow-up phase if applicable as per footnote 4). 
3: End of Treatment visit must be scheduled 30 days (± 7 days) after the last administration of any study drug. The End of Treatment will be the last study 
visit for all subjects except those requiring follow-up according to footnote #4.  
4: The subjects that will enter the follow-up phase are those who:  
• Discontinue treatment for reasons different than irPD. These subjects will continue to be followed up to assess response/progression (with tumor 
burden assessments and CA-125) every 12 weeks (± 1 week) until irPD. After irPD, and provided that subject has undergone the End of Treatment 
visit, all subjects will be taken off the study unless requiring AE/SAE follow-up according to the next bullet.  
•  Discontinue treatment for any reason and have ongoing SAEs (regardless of relationship with study drugs) or study treatment-related AEs at time 
of the End of Treatment visit. Monitoring of these events will continue as clinically indicated until the events have resolved (or return to baseline) 
or in the Investigator’s opinion, are unlikely to resolve due to the nature of the condition and/or the subject’s underlying disease. Frequency of 
visits will be according to Investigator judgment. 
5: There is no window to obtain the signed and dated PICF. Study specific screening assessments not considered standard practice by the institution must 
start only once the PICF has been signed. Registration takes place as soon as the subject signs the PICF. After screening procedures and if subject meets all 
eligibility criteria, enrollment will be done according to the process described in section 6.1.2.1.  
6: Only in women of childbearing potential. Refer to section 4.1 for definition of women of childbearing potential. 
7: Hematology: Hemoglobin, Absolute Neutrophils Count (ANC), Platelets. Blood chemistry: creatinine, AST, ALT, alkaline phosphatase, total bilirubin, 
glucose, TSH. There is no need to repeat hematology and blood chemistry prior to first dose of study treatment provided that they were done at screening 
within 7 days of enrollment, unless deemed clinically required by the Investigator. During treatment period hematology will be done within 3 days of every 
visit prior to each CC-486 cycle and on Days 8, 15 and 22 (± 1 day). Blood chemistry will be done within 3 days of every visit prior to each CC-486 cycle. 
There is no need to repeat them prior to pembrolizumab administration unless clinically indicated and/or required according to the standard of care at the 
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institution. 
8: There is no need to repeat CA-125 prior to first dose of study treatment provided that it was done at screening within 7 days of enrollment. Whenever 
possible, CA-125 should be tested at the same laboratory and with the same technique throughout the study. At the End of Treatment visit and during the 
follow-up, CA-125 will only be tested in subjects without irPD at time of study treatment discontinuation. 
9: During the follow-up phase, only SAEs (regardless of the relationship to study drugs) and non-serious AEs related to study treatments are to be reported 
and/or followed up (refer to section 6.3.4).  
10: Concomitant treatments to be collected from date the PICF is signed 
11: Only concomitant treatments to treat AEs related to study treatment and SAEs (regardless of their relationship) will be recorded after the End of 
Treatment visit 
12: CT/MRI of chest abdomen and pelvis to be done at each tumor assessment. The schedule of assessments should be fixed according to the calendar, 
regardless of treatment interruptions. The first post-baseline assessment will be done 6 weeks (± 1 week) after first CC-486 intake. Subsequent 
assessments should be done thereafter every 12 weeks (± 1 week) taking as a reference the date of the first post-baseline tumor assessment. Tumor 
burden assessments will be done according to irRECIST criteria until documentation of irPD regardless of the end of study treatment and start of 
subsequent anticancer therapy or CA-125 values. Confirmation of progression (irPD) is recommended minimum 4 weeks after the first irPD assessment 
and is required during the flare time-window of the first 12 weeks of treatment. If there is suspicion of disease progression based on clinical or laboratory 
findings before the next scheduled assessment, an unscheduled assessment should be performed at the Investigator´s discretion. During the follow-up, 
tumor assessments will only be required in subjects without irPD at time of End of treatment visit.  
13: For subjects consenting to this optional tissue acquisition part of the study, a FFPE block/partial block from the EOC debulking surgery will be obtained 
(or a minimum of 15 unstained slides in case FFPE tissue block cannot be provided). 
14: Image-guided core tumor biopsy is mandatory at baseline (within 28 days of study treatment start) and 6 weeks (± 1 week) after first CC-486 intake. 
The second biopsy must be done during the on-treatment period of the 2nd CC-486 cycle. As much as possible and if clinically indicated, the second biopsy 
should be scheduled to coincide with the 1st post-baseline tumor burden assessment (both 6 weeks ± 1 week after first CC-486 intake) so the image-guided 
biopsy is done at the same time the subject undergoes the scans to assess response/progression. If feasible, a fresh-frozen ascites sample will also be 
collected in subjects with ascites, during the same procedure as the biopsy. Refer to section 6.4.7.1 and the Study Laboratory Manual for additional 
details. 
15: Whole blood for DNA methylation analysis will be obtained via venipuncture. On day 1 of the 1st CC-486 cycle, sample should be obtained prior to the 
first CC-486 intake. 
 
 
 
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6.2.2 Part B 
Table 7: Schedule of visits and assessments in Part B 
Protocol Activities 
Screening1 
Treatment Period2 
End of 
treatment3 
Follow-up4 
Days  
-28 to -1 
Days  
-7 to -1 
 
 
 
Informed consent5 
X 
 
 
 
 
Demographics, medical history 
X 
 
 
 
 
Physical examination (incl. Vital 
signs) 
 
X 
At each visit prior to each CC-486 cycle (Arm A) or each 
PEM infusion (Arm B). Vital signs will be assessed as per 
site´s standard practice 
X 
According to 
SoC 
ECOG PS 
 
X 
At each visit prior to each CC-486 cycle 
X 
 
Serum pregnancy test6 
 
X 
As clinically indicated 
 
 
Hematology7 
 
X 
Within 3 days of every visit prior to each CC-486 cycle and 
at day 8, day 15 and day 22 of each cycle (± 1 day) (Arm A) 
or each PEM infusion (Arm B)  
X 
 
Blood chemistry7 
 
X 
Within 3 days of every visit prior to each CC-486 cycle (Arm 
A) or each PEM infusion (Arm B) 
X 
 
INR or PT AND aPTT/PTT 
 
X 
As clinically indicated 
 
 
CA-1258 
 
X 
Within 3 days of every visit prior to each CC-486 cycle (Arm 
A) or each PEM infusion (Arm B) 
X 
X 
AEs assessments 
 
X 
At each visit prior to each CC-486 cycle (Arm A) or each 
PEM infusion (Arm B) 
X 
X9 
Concomitant treatments 
X10 
 
At each visit prior to each CC-486 cycle (Arm A) or each 
PEM infusion (Arm B) 
X 
X11 
Tumor burden assessments12 
X 
 
Every 12 weeks (± 1 week) 
 
X 
FFPE block from debulking surgery 
(optional)13 
X 
 
 
 
 
Tumor biopsy (optional)14 
X 
 
6 weeks (± 1 week) after first dose of study treatment 
 
 
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Notes:  
 All assessments should be performed within 3 days of the scheduled visit, unless otherwise specified.  
 All pre-treatment tests/procedures should be performed and assessed by the Investigator prior to dosing. 
Footnotes: 
1: Day -1 is the day before randomization. 
2: Study treatment should start within 3 days of randomization. In Arm A, the first on-treatment visit should occur on Day 1 of the 1st CC-486 cycle 
(when subject should receive the first CC-486 dose during the visit). Afterwards, study visits are scheduled every 4 weeks ± 3 days and should be done 
during the CC-486 off period as close as possible to restarting the next CC-486 cycle. Additionally, every 21 days (± 3 days) subjects will visit the site to 
receive pembrolizumab. In Arm B, study visits are scheduled every 21 days ± 3 days, prior to each pembrolizumab infusion. Study treatment will 
continue until progressive disease according to irRECIST criteria, unacceptable toxicity, consent withdrawal or the Investigator concludes that is in the 
subject´s best interest to discontinue (or any other withdrawal criteria is met according to section 5.5). Progression and study treatment 
discontinuation should not be declared on the basis of CA-125 alone. 
In Arm A (CC-486 and pembrolizumab), in case there is a need to permanently discontinue one of the study drugs, the other one will also be 
discontinued and the subjects will undergo the End of treatment visit and begin the Follow-up phase. 
3: End of Treatment visit must be scheduled 30 days (± 7 days) after the last administration of any study drug.  
4: Once the subject is discontinued from study treatment and has undergone the End of Treatment visit, she will enter in the follow-up phase. 
Subjects discontinued from study treatment for reasons different than progressive disease per irRECIST (e.g. unacceptable toxicity, physician´s 
decision) will be followed up (with tumor burden assessments and CA-125) every 12 weeks (± 1 week) until irPD. Once irPD is declared, all subjects will 
be followed for survival every 6 months (visit or phone contact) until death or for at least 1 year after the End of Treatment visit, to assess the survival 
status. 
5: There is no window to obtain the signed and dated PICF. Study specific screening assessments not considered standard practice by the institution 
must start only once the PICF has been obtained. Subject will be registered in the study immediately after PICF signature. 
6: Only in women of childbearing potential. Refer to section 4.1 for definition of women of childbearing potential. 
7: Hematology: Hemoglobin, Absolute Neutrophils Count (ANC), Platelets. Blood chemistry: creatinine, AST, ALT, alkaline phosphatase, total bilirubin, 
glucose, TSH. There is no need to repeat hematology and blood chemistry prior to the first dose of study treatment, provided that they were done at 
screening within 7 days prior to randomization, unless deemed clinically required by the Investigator. During treatment period: In Arm A, hematology 
will be done within 3 days of every visit prior to each CC-486 cycle and on Days 8, 15 and 22 (± 1 day). Blood chemistry will be done within 3 days of 
every visit prior to each CC-486 cycle. There is no need to repeat them prior to pembrolizumab administration unless clinically indicated and/or 
required according to the standard of care at the institution. In Arm B, hematology and blood chemistry will be done within 3 days of every visit prior 
to each pembrolizumab infusion. 
8: There is no need to repeat CA-125 prior to first dose of study treatment provided that it was done at screening within 7 days of enrollment. 
Whenever possible, CA-125 should be tested at the same laboratory and with the same technique throughout the study. At the End of Treatment visit 
and during the follow-up, CA-125 will only be tested in subjects without irPD at time of study treatment discontinuation. 
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9: During the follow-up phase, only AEs and SAEs related to study treatments that are ongoing by the End of Treatment visit are to be reported and/or 
followed up (refer to section 6.3.4).  
10: Concomitant treatments to be collected from date the PICF is signed 
11: Only concomitant treatments to treat AEs/SAEs related to study treatment will be recorded after the End of Treatment visit 
12: CT/MRI of chest abdomen and pelvis to be done at each tumor burden assessment. The schedule of assessments should be fixed according to the 
calendar, regardless of treatment interruptions and taking as a reference the randomization date. Tumor burden assessments will be done according 
to irRECIST criteria until documentation of irPD regardless of the end of study treatment and start of subsequent anticancer therapy or CA-125 values. 
Confirmation of progression (irPD) is recommended minimum 4 weeks after the first irPD assessment and is required during the flare time-window of 
the first 12 weeks of treatment. If there is suspicion of disease progression based on clinical or laboratory findings before the next scheduled 
assessment, an unscheduled assessment should be performed at the Investigator´s discretion. During the follow-up, tumor assessments will only be 
required in subjects without irPD at time of End of treatment visit and only until irPD. 
13: For subjects consenting to this optional tissue acquisition part of the study, a FFPE block/partial block from the EOC debulking surgery will be 
obtained (or a minimum of 15 unstained slides in case FFPE tissue block cannot be provided). 
14: Image-guided core tumor biopsy is an optional procedure and will be collected in consenting subjects with lesion amenable to biopsy, at baseline 
(within 28 days of study treatment start) and 6 weeks (± 1 week) after first dose of study treatment. If feasible, a fresh-frozen ascites sample will also 
be collected in subjects with ascites, during the same procedure as the biopsy. Refer to section 6.4.7.1 and the Study Laboratory Manual for additional 
details. 
 
 
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6.3 Study Visits and Assessments/Investigations 
During all visits below, assessments should be done according to the Schedule of Visits and Assessments 
(section 6.2). The description/details of the different assessments are found in section 6.4. 
6.3.1 Baseline/Screening Period 
The baseline/screening period starts with the signature of the PICF and ends when the subject is 
enrolled in Part A, randomized in Part B or screen failed.  
During the screening period the following assessments will be done: 
 Demographics, Medical History 
 Complete physical examination (including weight) 
 Vital signs (according to standard of care) 
 ECOG PS  
 Laboratory assessments: 
o Hematology: Hemoglobin, Absolute Neutrophils Count (ANC) and Platelets 
o Blood chemistry: creatinine, AST, ALT, alkaline phosphatase, total bilirubin, glucose, TSH 
o Coagulation tests: INR or PT and aPTT/PTT 
o Serum pregnancy test: only in women of childbearing potential (within 7 days of 
registration) 
o CA-125 
Notes: If for some reason laboratory tests are repeated between these tests done at screening and 
treatment start, the most recent measurement obtained prior to treatment start must be within the 
required values according to the inclusion criteria, to begin study treatment. 
 Adverse events assessment 
 Concomitant medication 
 Tumor burden assessments 
 Tumor biopsy 
 Collection of FFPE block from debulking surgery (optional) 
6.3.2 Treatment Period Visits 
Study treatment should begin within 3 days of enrollment in Part A or randomization in Part B. All 
assessments should be performed within 3 days of the scheduled visit, unless otherwise specified. All 
pre-treatment tests/procedures should be performed and assessed by the Investigator prior to dosing. 
During the treatment period, visits will be done as follows: 
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6.3.2.1 Part A  
The first on-treatment visit should occur on Day 1 of the 1st CC-486 cycle (subject should receive the first 
CC-486 dose during the visit and after the whole blood sample for DNA methylation was drawn as per 
section 5.3.3.2). Afterwards, visits will be done every 4 weeks ± 3 days, during the CC-486 off period as 
close as possible to restarting the subsequent CC-486 cycle.  
During the treatment period visits the following assessments will be done: 
 Physical examination (symptom-oriented) 
 ECOG PS 
 Adverse events assessment 
 Concomitant medication 
 Laboratory assessments: 
o Hematology: Hemoglobin, Absolute Neutrophils Count (ANC) and Platelets 
o Blood chemistry: creatinine, AST, ALT, alkaline phosphatase, total bilirubin, glucose, TSH 
o Coagulation tests and pregnancy test: only if clinically indicated 
o CA-125 
 Tumor burden assessments: if applicable according to sections 6.2 and 6.4.6.1 
 Tumor biopsy: if applicable according to sections 6.2 and 6.4.7.1. 
 Whole blood sample for DNA methylation analysis: if applicable according to sections 6.2 and 6.4.7.3 
Prior to the first CC-486 cycle, there is no need to repeat hematology, blood chemistry and CA-125 tests 
provided they were done at screening within 7 days of enrollment, unless deemed clinically required by 
the Investigator. 
In addition to these visits, the subject will visit the clinic at time of each pembrolizumab infusion. There 
is no need to repeat laboratory tests prior to pembrolizumab administration unless clinically indicated 
and/or required according to the standard of care at the institution. 
Hematology (at least hemoglobin, Absolute Neutrophils Count (ANC) and platelets) will be repeated at 
day 8, day 15 and day 22 (± 1 day) of each cycle. No clinical visit is required on these days. CC-486 dose 
adjustments, treatment withhold or treatment discontinuation based on hematology test results will be 
performed as per section 5.7.3. 
6.3.2.2 Part B 
In Arm A: The first on-treatment visit should occur on Day 1 of the 1st CC-486 cycle (subject should 
receive the first CC-486 dose during the visit). Afterwards, visits will be done every 4 weeks ± 3 days, 
during the CC-486 off period as close as possible to restarting the subsequent CC-486 cycle. 
Additionally the subject will visit the clinic at time of each pembrolizumab infusion. 
In Arm B: every 21 days ± 3 days, prior to each pembrolizumab infusion 
During the treatment period visits the following assessments will be done in both arms: 
 Physical examination (symptom-oriented) 
 ECOG PS 
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 Adverse events assessment 
 Concomitant medication 
 Laboratory assessments: 
o Hematology: Hemoglobin, Absolute Neutrophils Count (ANC) and Platelets 
o Blood chemistry: creatinine, AST, ALT, alkaline phosphatase, total bilirubin, glucose, TSH 
o Coagulation tests and pregnancy test: only if clinically indicated 
o CA-125 
 Tumor burden assessments: if applicable according to sections 6.2 and 6.4.6.1 
 Tumor biopsy (optional): if applicable according to sections 6.2 and 6.4.7.1. 
Prior to the first dose of study treatment, there is no need to repeat hematology, blood chemistry and 
CA-125 tests provided they were done at screening within 7 days of randomization, unless deemed 
clinically required by the Investigator. 
In Arm A, prior to each pembrolizumab infusion, there is no need to repeat laboratory tests unless 
clinically indicated and/or required according to the standard of care at the institution. 
In Arm A only, hematology (hemoglobin, Absolute Neutrophils Count (ANC) and platelets) will be 
repeated at day 8, day 15 and day 22 (± 1 day) of each cycle. No clinical visit is required per protocol on 
these days. CC-486 dose adjustments, treatment withhold or treatment discontinuation based on 
hematology test results will be performed as per section 5.7.3. 
6.3.3 End of Treatment Visit 
End of Treatment visit must be scheduled 30 days (± 7 days) after the last administration of the last 
study drug.  
The primary purpose of this visit is to follow-up any AEs ongoing at the time of discontinuation and to 
assess any new AEs that may have occurred since discontinuation.  
During the End of Treatment visit the following assessments will be done: 
 Physical examination (symptom-oriented) 
 ECOG PS 
 Hematology and Blood chemistry 
 CA-125 ( only in subjects without irPD at time of study treatment discontinuation) 
 Adverse events assessment 
 Concomitant medication 
In Part A only, the End of Treatment will be the last study visit for all subjects except those who: 
 Discontinue treatment for reasons different than irPD 
 Discontinue treatment for any reason and have ongoing SAEs (regardless of relationship with study 
treatment) or study treatment-related AEs at time of the End of Treatment visit 
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6.3.4 Follow-up Visits 
6.3.4.1 Part A 
The subjects that will enter the follow-up phase are those who:  
a) 
Discontinue treatment for reasons different than irPD: These subjects will enter the follow-up 
phase and will be followed up to assess response/progression (with tumor burden assessments and 
CA-125) every 12 weeks (± 1 week) until irPD. After irPD, and provided that subject has undergone 
the End of Treatment visit, all subjects will be taken off the study unless requiring AE/SAE follow-up 
according to the paragraph (b) below. 
b) 
Discontinue treatment for any reason and have ongoing SAEs (regardless of relationship with study 
treatment) or study treatment-related AEs at time of the End of Treatment visit: Monitoring of 
these events will continue as clinically indicated until the events have resolved (or return to 
baseline) or in the Investigator’s opinion, are unlikely to resolve due to the nature of the condition 
and/or the subject’s underlying disease. Frequency of visits will be according to Investigator 
judgment. 
6.3.4.2 Part B 
All subjects will be followed-up.  
Subjects discontinued from study treatment for reasons different than progressive disease per irRECIST 
(e.g. unacceptable toxicity, Investigator´s decision, etc.) will be followed up to assess 
response/progression (with tumor burden assessments and CA-125) every 12 weeks (± 1 week) until 
irPD.  
Once irPD is declared, all subjects will be followed for survival every 6 months (through visit or phone 
contact) until death or for at least 1 year after the End of Treatment visit, to assess the survival status.  
Any AE or SAE related to study treatments that is ongoing by the End of Treatment visit, must be 
followed up to resolution or until the events have resolved (or return to baseline) or in the Investigator’s 
opinion, are unlikely to resolve due to the nature of the condition and/or the subject’s underlying 
disease. 
6.4 Description of Study Assessments/Investigations 
6.4.1 Demographics and Medical History 
The Investigator will collect and report in the eCRF demographics and complete history of malignant and 
clinically-significant non-malignant diseases including known hypersensitivity reactions. 
6.4.2 Physical Examination and Vital Signs 
At screening physical examinations will include a complete assessment of body systems (i.e. general 
appearance, head, eyes, ears, nose, mouth, skin, heart, lungs, lymph nodes, gastrointestinal, 
genitourinary, skeletal, and neurologic) per standard of care at the study site or as clinically indicated by 
symptoms. Weight will also be measured at screening. 
During treatment period visits and at the End of Treatment visit, a symptom-directed physical 
examination will be done. 
Vital signs will be assessed as per site´s standard practice. 
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6.4.3 ECOG Performance Status 
Assessment of ECOG PS (Appendix 1) is required to assess subject´s functional status for study eligibility 
purposes and will be performed throughout the study according to the Schedule of Visits and 
Assessments (section 6.2). 
6.4.4 Adverse Events Assessment and Concomitant Treatments Review 
• 
Adverse events assessment: For information on the assessment and collection of AEs refer to 
section 7 and to the Schedule of Visits and Assessments in section 6.2. 
• 
Concomitant Treatments: Concomitant treatment includes any medication or therapeutic 
procedure (e.g. prescription drugs, over-the-counter drugs, herbal/homeopathic remedies, 
nutritional supplements, blood transfusions, etc.) used by a subject from the date the PICF is 
signed until the End of Treatment visit. After the End of Treatment visit, in Part A, only 
concomitant therapies to treat AEs related to study treatment and any SAE (regardless of the 
relationship) will be recorded. In Part B only concomitant treatments to treat AEs/SAEs related 
to study treatment will be collected after the End of Treatment visit. 
6.4.5 Laboratory Safety Assessments 
The following laboratory safety assessments will be done according to the Schedule of Visits and 
Assessments in section 6.2.  
 Hematology: hemoglobin, Absolute Neutrophils Count (ANC) and platelets 
 Blood chemistry: AST, ALT, Alkaline Phosphatase, Total Bilirubin, Creatinine, Glucose, TSH 
 Coagulation tests: INR or PT and aPTT/PTT  
 Serum pregnancy test: only in women of childbearing potential  
6.4.6 Efficacy Assessments 
Efficacy assessments include: 
 Evaluation of tumor burden according to the irRECIST to assess irPFS, irORR, irDOR and irDCR 
 Serial measurement of CA-125 to monitor for response according to the GCIG criteria in subjects 
with CA-125 evaluable disease at baseline 
6.4.6.1 Schedule/Details of Tumor Burden Assessments  
All efficacy endpoints (including the primary and secondary objectives in both Part A and B) are linked to 
the tumor burden response assessments and therefore the importance of timely and complete disease 
assessments in this study cannot be understated. Failure to perform any of the required disease 
assessments will result in the inability to determine disease status for that time point. Frequent off 
schedule or incomplete disease assessments have the potential to weaken the conclusion of this clinical 
trial. 
The schedule of tumor burden assessments should be fixed according to the calendar, regardless of 
treatment interruptions. Tumor burden assessments will be performed until progressive disease as per 
irRECIST regardless of the discontinuation of study treatment, the start of a subsequent anticancer 
therapy or CA-125 values.  
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The same method of assessment and the same technique used at baseline (CT scan or MRI) to 
characterize each lesion must be used at each subsequent post-baseline assessment. Review of post-
baseline scans and assessment of overall response (according to irRECIST) should be done at the next 
visit after the scans are performed and prior to indicating subsequent study therapy, to rule out 
progressive disease that would warrant study treatment discontinuation.  
The irRECIST guidelines for measurable, non-measurable, target and non-target and the tumor response 
criteria are presented in Appendix 2. 
6.4.6.1.1 Baseline assessments 
Baseline disease assessments should be performed as close as possible to the treatment start and never 
more than 28 days before enrollment in Part A or randomization in Part B. Disease assessment at 
screening will be used to determine the measurability of the disease (measurable versus non-
measurable) and to document lesions as Target or Non- Target lesions as per irRECIST. Subjects without 
measurable lesions are not eligible in Part A. Subjects who have no measurable and no non-measurable 
lesions are not eligible in Part B (i.e. subjects categorized as “No Disease” (irND) according to irRECIST). 
Baseline assessment will include at least: 
 CT or MRI scan of the chest, abdomen, and pelvis (CAP) 
 Any additional imaging as deemed appropriate 
 If applicable, clinical assessment of superficial lesions 
6.4.6.1.2 Post-baseline assessments 
Post-baseline assessments will be done: 
 In Part A: 
o 6 weeks (± 1 week) after first CC-486 intake (first post-baseline tumor assessment). 
o Thereafter, every 12 weeks (± 1 week), always taking as a reference the date of the first 
post-baseline tumor assessment (not the date of the immediately previous tumor 
assessment). 
o Whenever disease progression is suspected based on signs, symptoms, performance 
status deterioration, CA-125, etc. 
o Confirmation of progression (irPD) is recommended minimum 4 weeks after the first 
irPD assessment and is required during the flare time-window of the first 12 weeks of 
treatment. 
 In Part B: 
o Every 12 weeks (± 1 week), always taking as a reference the date of randomization in 
the study (not the date of the immediately previous tumor assessment) 
o Whenever disease progression is suspected based on signs, symptoms, performance 
status deterioration, CA-125, etc. 
o Confirmation of progression (irPD) is recommended minimum 4 weeks after the first 
irPD assessment and is required during the flare time-window of the first 12 weeks of 
treatment. 
Post baseline assessments will include at least: 
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 CT or MRI scan of the chest, abdomen, and pelvis (CAP) 
 Any other imaging that revealed lesions at baseline 
 Any additional imaging as deemed appropriate 
6.4.6.2 CA-125 Measurements 
CA-125 will be measured in all subjects at baseline, at each pre-treatment visit during the study 
treatment phase and at the End of Treatment visit. During follow-up, CA-125 will be tested only in 
subjects without irPD at time of treatment discontinuation and until irPD is declared. CA-125 
measurement is not required following irPD. Whenever possible, CA-125 should be tested at the same 
laboratory and with the same technique throughout the study.  
CA-125 will be used to assess tumor response based on the GCIG criteria but will not be used to declare 
disease progression and/or study treatment discontinuation. Any elevation in CA-125 suggestive of 
disease progression needs to be confirmed through tumor burden disease assessments as an irPD to 
declare progression and to warrant study treatment discontinuation. CA-125 elevation alone is not 
defined as disease progression. If the elevation of CA-125 is not radiographically confirmed as an irPD, 
study treatment should continue until progression based on irRECIST, unless the Investigator concludes 
that it is in the best interest of the subjects to discontinue protocol therapy. 
6.4.6.2.1 Evaluation of Response according to CA-125 
The GCIG has developed criteria for defining response and progression of ovarian carcinoma based on 
CA-125.24 The GCIG recommends that for trials of relapsed ovarian cancer the following definition for 
response according to CA-125 be used. 
Definition of response: A response according to CA-125 has occurred if there is at least a 50% reduction 
in CA-125 levels from a pre-treatment sample. The response must be confirmed and maintained for at 
least 28 days. Subjects can be evaluated according to CA-125 only if they have a pre-treatment sample 
that is at least twice the upper limit of normal and within 2 weeks prior to starting treatment (TRIO026 
study requires that baseline CA-125 is tested within 7 days prior to enrollment in Part A or 
randomization in Part B). 
To calculate CA-125 responses accurately, the following rules apply: 
 Intervening samples and the 28-day confirmatory sample must be less than or equal to (within an 
assay variability of 10%) the previous sample. 
 Variations within the normal range of CA-125 levels will not interfere with the response definition. 
 For each subject, it is preferred that the same assay method be used, and the assay must be tested 
in a quality-control scheme. 
 Subjects are not evaluable by CA-125 if they have received mouse antibodies (unless the assay used 
has been shown not to be influenced by Human anti-mouse antibody) or if there has been medical 
and/or surgical interference with their peritoneum or pleura during the previous 28 days.  
The date when the CA-125 level is first reduced by 50% is the date of the CA-125 response.  
6.4.7 Biological Sampling Procedures 
The area of research into the identification of tumor markers and biological processes / targets to aid in 
the identification of clinical benefit in certain subsets of populations or even in the identification of 
anticancer therapies to target the marker, is rapidly growing. Tumor samples will be used to assess 
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potential prognostic or predictive markers, improve understanding of ovarian cancer biology and 
identify candidate biomarkers that may correlate with treatment benefit and/or safety signals. 
As more development and information is revealed in the future, TRIO would like to use these tumor 
samples for measurement of the new markers. The tumor samples will be stored in the TRIO central 
laboratory until future use is required. TRIO may collaborate in the future with experts in the field, and 
the tumor material may be shared with other researchers. 
Details on the analyses to be performed on the biologic samples and procedures for sample collection, 
labeling, storage and shipment/return of biological samples will be described in separate document(s) 
(e.g. Samples Manual, Samples Plan). 
All samples will be submitted to central laboratories (located in the USA) and will be stored for and 
indefinite time period unless otherwise required by the subject, Investigator, ethics committee and/or 
regulations.  
Refer to the Schedule of Visits and Assessments in section 6.2 for the samples collection time points. 
6.4.7.1 Tumor core biopsies: Fresh-frozen tissue (FFT) and Formalin-fixed paraffin-embedded (FFPE) 
samples  
These samples are mandatory in Part A and optional in Part B. 
In all subjects participating in Part A, tumor samples will be collected through image-guided core biopsy 
at baseline and 6 weeks (± 1 week) after first CC-486 intake (provided that the tumor lesion is amenable 
to a second biopsy). The second biopsy must be done during the on-treatment period of the second CC-
486 cycle. As much as possible and if clinically indicated, the second biopsy should be scheduled to 
coincide with the 1st post-baseline tumor burden assessment (both 6 weeks ± 1 week after first CC-486 
intake) so the image-guided biopsy is done at the same time the subject undergoes the scans to assess 
response/progression.  
In Part B, tumor will be collected in the same time points and with the same procedure as in Part A, in 
subjects consenting to participate in this optional tissue acquisition study, provided they have lesion(s) 
amenable to biopsy.  
A minimum of three cores at each time point is required to perform the molecular analyses. If three 
cores are taken, two of them will be formalin-fixed paraffin-embedded and one will be fresh-frozen. If a 
different number of cores is taken, (approximately) half of them will be fresh-frozen and the other half 
formalin-fixed paraffin-embedded. If only one core can be obtained, this only core will be fresh-frozen. 
Once the cores have been removed, the applicable number of cores must be immediately snap-frozen 
(procedure described in the study Laboratory Manual), while the remaining ones will be formalin-fixed 
according to site´s procedures. 
Both in Parts A and B, if feasible, a fresh-frozen ascites sample will also be collected in subjects with 
ascites, during the same procedure as the biopsy. 
All these samples will be transported to the Translational Oncology Research Labs at the University of 
California, Los Angeles (TORL-UCLA).  
6.4.7.2 Formalin-Fixed Paraffin-Embedded (FFPE) block/partial block from the debulking surgery 
For Part A and Part B subjects consenting to this optional tissue acquisition part of the study, a FFPE 
block/partial block from the EOC debulking surgery will be obtained and submitted to the TORL-UCLA. 
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FFPE tumor tissue will be used for biomarker research. In case FFPE tissue block cannot be provided, a 
minimum of 15 unstained slides would be required to be submitted to the TORL-UCLA. 
6.4.7.3 Whole-blood samples for DNA methylation analysis 
These samples are mandatory in Part A and will be used to analyze changes in DNA methylation during 
treatment with CC-486. Peripheral whole blood samples will be obtained on Day 1 of the 1st CC-486 cycle 
(prior to the first CC-486 intake) and on the pre-treatment visit prior to the 2nd CC-486 cycle. 
6.5 Subject Discontinuation 
The Investigator has the right to discontinue a subject from study treatment or withdraw a subject from 
the study at any time. In addition, subjects have the right to voluntarily discontinue study treatment or 
withdraw from the study at any time for any reason.  
6.5.1 Discontinuation from Study Treatment 
Refer to section 5.5. 
6.5.2 Discontinuation from Study Participation 
The primary reason for study participation discontinuation should be documented on the eCRF. Reasons 
for subject´s discontinuation from the study include: 
 Death 
 Consent withdrawal from entire study participation 
 Subject completes the follow-up period as per protocol sections 6.3.3 and 6.3.4  
 Subject non-compliance 
 Lost to follow-up 
Should a subject decide to withdraw consent, all efforts will be made to complete and report the 
observations as thoroughly as possible. The Investigator should contact the subject by telephone or 
through a personal visit to establish as completely as possible the reason for the withdrawal. A complete 
final evaluation at the time of the subject’s withdrawal should be made with an explanation of why the 
subject is withdrawing from the study. After complete withdrawal of consent, no further study 
procedure will be performed and no further data will be collected after the date of the subject’s 
withdrawal from study.  
Partial withdrawal occurs when the subject withdraws consent but agrees to be contacted for further 
information on survival. It should be documented in both the medical records and the eCRF that the 
subject agreed to be contacted for information on survival despite the subject’s withdrawal of informed 
consent. Partial consent withdrawal is not considered a discontinuation from study participation. 
In the case a subject does not show up for study visits, site staff should make reasonable contact 
attempts before declaring the subject as lost to follow-up. These attempts need to be documented in 
the medical records.  
7. SAFETY MONITORING 
7.1 Definitions 
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7.1.1 Period of Observation 
At each visit and any contact during the study and follow-up period, the Investigator or designee will 
inquire about the occurrence of AEs and will document them in the subject file. 
The Investigator or designee will report the AEs in the eCRF and to TRIO Drug Safety and 
Pharmacovigilance Department when required as per the table below: 
Table 8: Reporting period of AEs/SAEs 
Study period 
AEs (non-serious) 
Serious Adverse 
Events/Pembrolizumab Events of 
Clinical Interest (ECI) 
Part A 
Part B 
Part A 
Part B 
From PICF to first 
dose 
Not required to 
report 
Only if related to 
study participation 
Only if related to 
study participation 
Only if related to 
study participation 
Study treatment 
period until End of 
Treatment visit 
All (regardless of 
relationship) 
All (regardless of 
relationship) 
All (regardless of 
relationship) 
All (regardless of 
relationship) 
From End of 
Treatment visit until 
End of subject 
participation1  
Only if related to 
study treatment 
Only if related to 
study treatment) 
All (regardless of 
relationship) 
Only if related to 
study treatment 
1 The applicable events as per the table that are ongoing at time of the End of Treatment visit should be 
followed up to resolution or until the event becomes stable (or returns to baseline) or is unlikely to 
resolve further in the opinion of the Investigator. Regarding SAEs, in Part A all should be 
reported/followed after the End of Treatment visit, regardless of the relationship with the study drugs. In 
Part B, only study-drug related SAEs should be followed/reported. 
7.1.2 Adverse Event 
An AE is defined as any untoward medical occurrence, including an exacerbation of a pre-existing 
condition, in a subject in a clinical investigation who received a pharmaceutical product. The event does 
not necessarily have to have a causal relationship with this treatment. 
Worsening of pre-existing conditions: A pre-existing condition present at baseline, which remains 
unchanged during the trial, does not need to be recorded as AE. 
Any worsening of any pre-existing baseline condition should be reported as an AE in the eCRF. Examples 
of worsening of a pre-existing condition that should be recorded as an AE are given below:   
 Worsening of condition meets the criteria for an AE or SAE 
 Action is taken with the investigational drug (e.g. Dose is reduced or treatment is discontinued) 
 Treatment is required (concomitant medication is added or changed) 
 The Investigator believes a subject has shown a clear deterioration from baseline symptoms 
Expected fluctuations or expected deterioration of the EOC (symptoms of disease progression) should 
not be recorded as an AE. 
Changes in vital signs, physical examination and laboratory test results: will only be recorded as an AE 
in the eCRF if they are judged clinically relevant by the Investigator. 
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Overdoses: refer to section 7.4.1.  
7.1.3 Serious Adverse Event 
A serious adverse event is one that at any dose (including overdose): 
 Results in death 
 Is life-threatening1 
 Requires inpatient hospitalization or prolongation of existing hospitalization 
 Results in persistent or significant disability or incapacity2 
 Is a congenital anomaly or birth defect 
 Is an important medical event3 
1 “Life-threatening” means that the subject was at immediate risk of death at the time of the serious adverse 
event; it does not refer to a serious adverse event that hypothetically might have caused death if it were 
more severe. 
2 “Persistent or significant disability or incapacity” means that there is a substantial disruption of a person’s 
ability to carry out normal life functions. 
3 Medical and scientific judgment should be exercised in deciding whether expedited reporting is appropriate 
in situations where none of the outcomes listed above occurred. Important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the subject or may 
require intervention to prevent one of the other outcomes listed in the definition above should also usually 
be considered serious. Examples of such events include allergic bronchospasm requiring intensive treatment 
in an emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, the development of drug dependency or drug abuse, etc. 
7.1.3.1 Disease-related events 
An event that is part of the natural course of the disease under study (i.e. disease progression) does not 
need to be reported as an SAE. Progression of the subject’s EOC will be recorded in the appropriate 
pages of the eCRF. Death due to progressive disease is to be recorded on Death Report Form of the eCRF 
and not as an SAE. 
However, if the Investigator considers that there was a causal relationship between treatment with 
investigational product or protocol design/procedures and the disease progression, then this must be 
reported as an SAE. Any new primary cancer must be reported as an SAE. 
7.1.3.2 Planned or administrative hospitalization 
Subjects may be hospitalized for administrative or social reasons during the trial (e.g. days on which 
infusion takes place, long distance from home to site…). These and other hospitalizations planned at the 
beginning of or before the trial do not need to be reported as an SAE in case they have been reported at 
screening visit in the source data and have been performed as planned. 
7.1.3.3 Unexpected Adverse Event 
Azacitidine and pembrolizumab IBs provide an overview of the adverse events reported across each 
drug´s clinical trials in monotherapy and in combination.  
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Any Serious Adverse Event assessed as related to azacitidine or pembrolizumab but not reported in the 
listed adverse events’ section of the corresponding IB will be documented as a suspected unexpected 
serious adverse reaction (SUSAR) and will be submitted according to applicable local regulations. 
7.1.4 Events of Clinical Interest (ECI) with Pembrolizumab 
Selected non-serious and serious pembrolizumab adverse events are also known as ECI and must be 
reported within 24 hours to the sponsor according to section 7.3.1 during the collection period specified 
in section 7.1.1.  
Any ECI, or follow up to an ECI, that occurs to any subject must be reported immediately to the sponsor 
if it causes the subject to be excluded from the trial, or is the result of a protocol-specified intervention, 
including but not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure. 
ECIs for this trial include: 
 A pembrolizumab overdose (as defined in section 7.4.1) that is not associated with clinical 
symptoms or abnormal laboratory results.  
 An elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of normal and an 
elevated total bilirubin lab value that is greater than or equal to 2X the upper limit of normal and, at 
the same time, an alkaline phosphatase lab value that is less than 2X the upper limit of normal, as 
determined by way of protocol-specified laboratory testing or unscheduled laboratory testing.* 
*Note: These criteria are based upon available regulatory guidance documents. The purpose of 
the criteria is to specify a threshold of abnormal hepatic tests that may require an additional 
evaluation for an underlying etiology.  
7.2 Performing Adverse Event Assessment 
7.2.1 Collection of Adverse Event Information 
The following information will be collected in the eCRF: Description of event, start/stop date, worst 
grade experienced (severity), seriousness, action taken on study treatments and relationship to study 
treatments. 
Intensity of adverse event: The intensity of adverse events will be classified and recorded according to 
the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 in the eCRF or according to 
the grading defined in section 5.7.1 if the adverse event is not specifically listed in NCI CTCAE. 
All adverse clinical experiences, whether observed by the Investigator or reported by the subject, must 
be recorded, with details about the duration and intensity of each episode, the action taken with 
respect to the test drug, and the subject’s outcome. The Investigator must evaluate each adverse 
experience for its relationship to the test drug and for its seriousness. 
The Investigator must appraise all abnormal laboratory results for their clinical significance. If any 
abnormal laboratory result is considered clinically significant, the Investigator must provide details 
about the action taken with respect to the study treatments and about the subject’s outcome. 
7.2.2 Assessment of Causality 
The Investigator will determine the relationship of the study treatments to all AEs as defined in Single 
Reference Documents for CC-486 and pembrolizumab (see sections 5.1 and 5.2). 
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Medical judgment should be used to determine the relationship, considering all relevant factors, 
including pattern of reaction, temporal relationship, de-challenge or re-challenge, confounding factors 
such as concomitant medication, concomitant diseases and relevant history. Assessment of causal 
relationship must be recorded for each adverse event. 
Relationship to study drugs will be reported as either “Yes” or “No”. 
 Yes: There is a reasonable causal relationship between the investigational product administered and 
the AE. 
 No: There is no reasonable causal relationship between the investigational product administered 
and the AE. 
7.3 Reporting of Serious Adverse Events, Events of Clinical Interest and Pregnancies 
7.3.1 Reporting of SAEs/ECIs/Pregnancies from the sites to TRIO 
SAEs and ECIs will be reported via the Serious Adverse Event Reporting Form. Pregnancies will be 
reported via the Pregnancy Reporting Form (refer to section 7.4.2 for more information on reporting 
pregnancies). The initial report must be as complete as possible, including an assessment of the causal 
relationship between the event and the investigational product(s). Information not available at the time 
of the initial report (e.g. an end date for the adverse event or laboratory values received after the 
report) must be documented on a follow-up report. A final report to document resolution of the SAE is 
required. 
These forms will be faxed or emailed to TRIO Drug Safety and Pharmacovigilance Department to: 
 Email: safety@trioncology.org 
 Fax number: North America: + 1 780-702-2273 / Rest of the World: +33. 1.58.10.09.05 
Table 9: SAE/ECIs and Pregnancies reporting timelines 
 
Initial Reports 
Follow-up Information 
Type of Event 
Time Frame 
Documents 
Time Frame 
Documents 
All SAEs/ECIs 
Immediate 
SAE Reporting 
Form 
Immediate 
SAE Reporting Form 
Pregnancy 
Immediate 
Pregnancy 
Reporting 
Form 
Immediate 
Pregnancy 
Reporting Form 
 
7.3.2 SAE/ECI/Pregnancies Information Provided by TRIO to Celgene and Merck 
TRIO will report all SAEs and pregnancies to Celgene and Merck by forwarding the SAE Reporting Form 
or Pregnancy Reporting Form via email or other secure method within 24 hours of site awareness. 
Additionally, any ECI will be provided by TRIO to Merck also within 24 hours of site awareness. The 
SAEs/ECIs/Pregnancies will be a copy of the SAE or Pregnancy Reporting Form.  
7.4 Management of Specific Cases 
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7.4.1 Overdoses 
CC-486 overdose is defined as the accidental or intentional use of CC-486 in a daily dose ≥ 2 times the 
indicated dose.  
Pembrolizumab overdose will be defined as any dose of 1,000 mg or greater (≥ 5 times the indicated 
dose).  
In the event of overdose, the subject should be observed closely for signs of toxicity. Appropriate 
supportive treatment should be provided if clinically indicated. There is no known specific antidote for 
pembrolizumab and/or CC-486 overdose.  
If an adverse event(s) is associated with (“results from”) the overdose of a study drug, the adverse 
event(s) is reported as SAE, even if no other seriousness criteria are met. 
If a dose of CC-486 meeting the protocol definition of overdose is taken without any associated adverse 
event, the overdose should be reported as a non-serious adverse event, using the terminology 
“accidental or intentional overdose without adverse effect”.  
If a dose of pembrolizumab meeting the protocol definition of overdose is taken without any associated 
clinical symptoms or abnormal laboratory results, the overdose should be reported as a non-serious ECI, 
using the terminology “accidental or intentional overdose without adverse effect”. 
All reports of overdoses associated with SAEs or that are considered ECI must be reported to the 
sponsor immediately (i.e. no more than 24 hours after learning of the event; section 7.3) 
7.4.2 Pregnancy 
Given the patient population in the trial, it is extremely unlikely that WoCBP are enrolled and therefore 
that pregnancies occur in study subjects. 
Pregnancies and suspected pregnancies (including elevated βhCG or positive pregnancy test in a female 
subject of reproductive potential, regardless of disease state) occurring while the subject is on study 
treatment up to and including 30 days after the subject’s last dose, are considered immediately 
reportable events. The study treatment is to be discontinued immediately.  
The pregnancy, suspected pregnancy, or positive pregnancy test must be reported to TRIO on a 
Pregnancy Reporting Form (see section 7.3.1). The female subject should be referred to an obstetrician-
gynecologist (preferably one with reproductive toxicity experience) or another appropriate healthcare 
professional for further evaluation. 
The Investigator will follow the subject until completion of the pregnancy outcome and a follow up 
Pregnancy Reporting Form must be submitted at that point with the outcome of the pregnancy (either 
normal or abnormal outcome). If the outcome of the pregnancy was abnormal (e.g. spontaneous or 
therapeutic abortion, stillbirth, neonatal death or congenital anomaly) the Investigator should report 
the abnormal outcome as an AE. If the abnormal outcome meets any of the serious criteria, it must be 
reported as an SAE to TRIO Drug Safety and Pharmacovigilance Department immediately, within 24 
hours of the Investigator’s knowledge of the event using the SAE Reporting Form.  
All neonatal deaths that occur within 28 days of birth should be reported, without regard to causality, as 
SAEs. In addition, any infant death after 28 days that the Investigator suspects is related to the in utero 
exposure to the IMP should also be reported to TRIO immediately by facsimile, or other appropriate 
method, within 24 hours of the Investigator’s knowledge of the event using the SAE Report Form, or 
approved equivalent form. 
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The investigator will be responsible to follow-up on all information regarding a reported drug exposure 
during pregnancy.  
7.5 Reporting to Ethics Committees, Regulatory Authorities and other Investigators 
Prompt notification of SAEs by the Investigator to the sponsor is essential so that legal obligations and 
ethical responsibilities towards the safety of subjects are met. 
TRIO will comply with country specific regulatory requirements relating to safety reporting to the 
regulatory authority, Institutional Review Board (IRB)/Independent Ethics Committee (IEC) and 
Investigators. 
Investigator safety reports are prepared for suspected unexpected serious adverse reactions according 
to local regulatory requirements and are forwarded to Investigators as necessary. 
An Investigator who receives an Investigator safety report describing a SAE(s) or other specific safety 
information (e.g. summary or listing of SAEs) from TRIO will file it with the IB and will notify the IRB/IEC, 
if appropriate according to local requirements. 
8. STATISTICAL CONSIDERATIONS 
8.1 Populations for Analyses 
The Intent-to-treat (ITT) will consist of all subjects who were enrolled (Part A)/randomized (Part B) to 
study treatment, regardless of whether they actually received study medication. All efficacy analyses will 
be evaluated based on data from this population according to the treatment group they were assigned 
to at enrollment (Part A)/randomization (Part B) and based on the strata they were originally assigned to 
at the time of enrollment/randomization. 
The Safety population will be used to assess clinical safety and tolerability and will consist of all subjects 
who were enrolled (Part A)/randomized (Part B) and received at least one dose of study medication. This 
population will be based on the actual treatment received, if this differs from that to which the subject 
was enrolled/randomized and will be used for the analysis of safety data. 
8.2 Demographics and Baseline Characteristics 
Demographics and baseline characteristics data will be listed and summarized by treatment group using 
the ITT population. 
8.3 Protocol Treatment 
Duration of treatment, duration of exposure, cumulative dose and relative dose intensity will be 
summarized by treatment group using the Safety population. The subjects with dose modifications will 
be presented by treatment group, along with reasons for the dose change. 
8.4 Primary Efficacy Endpoints 
The efficacy evaluations will be made on the ITT population. 
The primary objective of Part A of the trial is to establish an optimal schedule of CC-486 combined with 
pembrolizumab. Therefore, the primary endpoint will be based on the safety profile as well as on futility 
evaluation and the irORR/irDCR per irRECIST criteria (refer to section 3.3).  
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The primary objective of Part B of the trial is to evaluate whether the addition of CC-486 to 
pembrolizumab (optimal schedule selected in Part A) improves the immune-related Progression free 
survival (irPFS) compared to pembrolizumab alone.  
The primary efficacy endpoints will be analyzed according to the assessment made by the Investigators. 
8.5 Secondary Efficacy Endpoints 
The efficacy evaluations will be made on the ITT population. 
The following secondary endpoint will be assessed for Part A of the trial: 
 The CA-125 response based on GCIG criteria  
The following secondary endpoints will be assessed for Part B of the trial:  
 The Immune-related Overall Response Rate (irORR) 
 The Immune-related Disease Control Rate (irDCR) 
 The Immune-related Duration of Response (irDoR)  
 The CA-125 response based on GCIG criteria (in subjects with CA-125 evaluable disease) 
 The Overall survival (OS) 
The secondary efficacy endpoints will be analyzed according to the assessment made by the 
Investigators. 
8.6 Safety Endpoints 
The assessment of safety will be made on the safety population and will be based mainly on the 
frequency of adverse events. The latest version of the Medical Dictionary for Regulatory Activities 
(MedDRA) will be used to code all adverse events to a preferred term and system organ class. Adverse 
events will be graded using the Common Terminology Criteria for Adverse Events (NCI CTCAE v4.03) or 
according to the grading defined in section 5.7.1 if the adverse event is not specifically listed in NCI 
CTCAE. Subject’s incidence of adverse events will be tabulated by system organ class, preferred term 
and toxicity grade by treatment arm. Adverse events leading to death or drug discontinuation, drug 
related and serious adverse events will also be summarized by treatment arm. 
Detailed listings for all adverse events will also be provided. 
Laboratory parameters: Laboratory parameters, graded according to the NCI CTCAE v4.03, will be 
summarized at baseline, along visits and at the end of study treatment by treatment arm. Tables of 
shifts in toxicity will also be provided. 
Other Safety Data: Weight and ECOG will be summarized at baseline, along visits and at the end of study 
treatment by treatment arm. Tables of shifts in toxicity will also be provided when applicable. 
8.7 Hypotheses and Sample Size  
Part A is an exploratory pilot study of various possible schedules for the combination of CC-486 and 
pembrolizumab. Part A is also a futility trial of the combination strategy in EOC. Criteria for Part B 
Go/No-Go decision and the determination of the optimal schedule can be found in section 3.3. There 
was no formal sample size calculation for lead-in safety and efficacy selection phase of the trial. 
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Part B is designed to test the hypothesis that combined epigenetic/checkpoint inhibitor therapy is 
superior to checkpoint inhibitor therapy alone in the treatment of EOC. The study will be powered to 
detect a difference in the log rank tests of the irPFS curves reflecting a hazard ratio of 0.625 favoring the 
combination. Assumptions are based on (a) an anticipated median irPFS in the pembrolizumab 
monotherapy arm to be 4 months and 6.4 months in the combination arm, (b) that the accrual time will 
be 24 months and the total study time will be 46 months and (c) a power of 80% and an alpha error at 
0.05 for a two-sided test. Based on these assumptions 75 evaluable subjects need to be enrolled in each 
arm (n=73 subjects exactly) resulting in a total planned enrollment of 150 subjects. 
The other efficacy or safety study endpoints will be secondary ones, and thus there will be no multiple 
testing adjustments required.  
8.8 Timing of Analysis 
The primary analysis in Part A will be conducted once 5 subjects in each cohort are considered evaluable 
for response. Subjects will be considered evaluable once they have completed at least 2 CC-486 cycles, 
have undergone the 1st post-baseline tumor burden assessment and both tumor biopsies performed and 
adequate paired tissue obtained. 
The primary analysis in Part B will be performed once at least 142 events of disease progression or death 
have been observed, or at the end of study whichever occurs first. The trial may be prematurely 
terminated by the sponsor. An interim analysis is planned when 50% of expected events are observed 
(i.e., 71 events); safety analysis will also be performed at this time. There are no plans to terminate the 
study early; the interim analysis is performed to support ongoing resourcing activities. 
In Part B, a follow-up analysis will be performed one year after the primary analysis. Both efficacy and 
safety analysis will be performed.  
9. ADMINISTRATIVE, ETHICAL AND REGULATORY STANDARDS 
This is a TRIO-sponsored study, led by Dr. John Glaspy (Professor of Medicine, Jonsson Comprehensive 
Cancer Center, UCLA, CA, USA) as Study Chair. The study is financially supported by Celgene 
Corporation. 
9.1 Steering Committee 
A Study Steering Committee (SSC) will be set-up and operate as per TRIO Standard Operational 
Procedures (SOPs) which are consistent with the FDA guidance for Clinical Trial Sponsors: Establishment 
and Operation of Clinical Trial Data Monitoring Committees, as well as with the EMA CHMP guideline on 
Data Monitoring Committees. The SSC will have the sole responsibility for the scientific conduct and 
integrity of the trial. Responsibilities include development and approval of the protocol document, 
monitoring of accrual, compliance and safety during the conduct of the trial. The SSC will be solely 
responsible for the analysis, interpretation and public disclosure of the results of the trial in accordance 
with the statistical plan. The SSC should endeavor to ensure that the study is conducted at all times to 
the standards set out in Guidelines for Good Clinical Practice (GCP). In all of the deliberations of the SSC, 
the rights, safety and well being of the study participants are the most important considerations. 
9.2 Ethical Conduct of the Study 
This clinical study was designed and shall be implemented and reported in accordance with the protocol, 
the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, applicable local regulations, the 
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Council for International Organizations of Medical Sciences (CIOMS), and the ethical principles laid down 
in the Declaration of Helsinki. This study will be conducted under ethical, scientific and medical 
standards that protect the rights of participants which include informed consent, independent review, 
and post-study medical care.  
9.3 Institutional Review Board/Independent Ethics Committee (IRB/IEC)  
Each participating institution must provide for the review and approval of this protocol and the 
associated informed consent documents and recruitment material by an appropriate Institutional 
Review Board (IRB) or an Independent Ethics Committee (IEC) or. The IRB/IEC decision concerning the 
conduct of the study will be made in writing and kept with the Investigator study file. A copy of this 
decision will also be provided to TRIO. 
Particular attention is drawn to the FDA's requirements for IRBs under 21 CFR Part 56. By signing the 
"Statement of Investigator" form (Form FDA 1572), the Investigator provides TRIO with the necessary 
assurance that an IRB is responsible for the initial/continuing review and subsequent approval of the 
proposed clinical study in accordance with these regulations when applicable. 
In compliance with the applicable country regulations, the Investigator is responsible for keeping the 
IRB/IEC informed of the progress with study renewal at least once a year, or more frequently, as 
required by the IRB/IEC. The Investigator must also report any serious adverse events, life-threatening 
problems or deaths to the IRB/IEC as per institutional guidelines and inform the sponsor according to 
GCP and applicable local regulations. The IRB/IEC must be informed by the Investigator of the 
termination of the study. 
9.4 Compliance with the Protocol and Protocol Amendments 
Investigators ascertain they will apply due diligence to avoid protocol deviations. Under no 
circumstances should the Investigator contact TRIO or its agents, if any, to request approval of a 
protocol deviation, as no such authorized deviations are permitted.  
When a deviation occurs in an emergency situation, such as when a departure from the protocol is 
required to protect the life or physical well being of a participant, TRIO and the reviewing IRB/IEC must 
be notified as soon as possible after the emergency situation occurred (ICH GCP 4.5.2).  
A planned deviation from the protocol that is non-emergent and represents a major change in the 
protocol as approved by the IRB/IEC must be considered an amendment and treated as such. Even if the 
Investigator feels a protocol deviation would improve the conduct of the study this must be considered 
a protocol amendment, and unless such an amendment is agreed upon by TRIO and subsequently 
approved by the Health Authorities and IRB/IEC, it cannot be implemented. All significant protocol 
deviations will be recorded and reported in the Clinical Study Report (CSR). This includes any 
modifications to the protocol which may have an impact on the conduct of the study, potential benefit 
of the subject or may affect subject safety, including changes of study objectives, study design, subject 
population, sample sizes, study procedures, or significant administrative aspects will require a formal 
amendment to the protocol. As previously stated, only amendments that are required to eliminate an 
immediate hazard to subjects for subject safety can be implemented prior to IRB/IEC approval. 
Notwithstanding the need for approval of formal protocol amendments, the Investigator is expected to 
take any immediate action required for the safety of any subjects included in this study, even if this 
action represents a deviation from the protocol. 
 
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9.5 Monitoring, Auditing and Inspecting 
To ensure compliance with current local regulations and the ICH guidelines, data generated by this study 
must be available for monitoring, audit or inspection upon request by representatives of the national 
and local health authorities, TRIO and duly authorized representatives of any entity providing support 
for this trial. On site, they will notably review adverse events, study records and directly compare them 
with source documents, review regulatory documents, discuss the conduct of the study with the 
Investigator, verify study drug accountability, and confirm that the facilities remain acceptable. 
9.6 Recording, Processing and Retention of Data 
The Investigator is responsible for the preparation and maintenance of adequate case histories designed 
to record all observations and other relevant data. All subject data reported on the eCRF must be 
derived from source documents and as such be consistent with the source documents, or the 
discrepancies must be explained. 
Data will be entered and collected via an electronic data capture system (EDC) using eCRFs. EDC is a 
validated system designed for entry of data in a way that is attributable, secure, and accurate, in 
compliance with U.S. Food and Drug Administration (FDA) regulations for electronic records (21 CFR Part 
11). Study site staff will receive training and have access to a manual for appropriate eCRF completion. 
All eCRFs should be completed by designated, trained site staff. eCRFs should be reviewed and 
electronically signed and dated by the Investigator or authorized designee. Only identified and trained 
users may view the data as their actions become part of the audit trail. 
While study sites will be responsible for data entry, TRIO will be responsible for data management of 
this study, including quality checks. 
The eCRF must be completed shortly after the subject’s visit. All requested information must be entered 
on the eCRF. If an item is not available or is not applicable, it must be documented as such. The 
completed eCRF must be promptly reviewed and approved by the Investigator or authorized designee. 
In the event of discrepant data, TRIO will request data clarification from the sites. The sites will resolve 
the discrepancy electronically in the EDC system. eCRF and data clarification documentation will be 
maintained in the EDC system’s audit trail. 
At the end of the study, the Investigator will receive subject data, for their site, in a readable format on 
CD, DVD, or other similar storage format that must be kept with the study records. Acknowledgement of 
receipt of the storage disc or similar is required. 
The investigator should retain the study documentation according to ICH-GCP, local regulations or as 
indicated in the contractual agreement whichever is longer. 
9.7 Data Protection 
Subject confidentiality is strictly held in trust by the participating Investigators, their staff, TRIO or 
affiliates. This confidentiality is extended to cover testing of biological samples and genetic tests in 
addition to the clinical information relating to participating subjects. 
Subject and Investigator personal data which may be included in the study database shall be treated in 
compliance with all applicable laws and regulations. When archiving or processing personal data, TRIO 
shall take all appropriate measures to safeguard and prevent access to this data by any unauthorized 
third party. The anonymity of the subjects will be respected with strict adherence to professional 
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standards of confidentiality and the Health Insurance Portability and Accountability Act (HIPPA) Privacy 
Rule. 
The study protocol, documentation, data and all other information generated will be held in strict 
confidence. No information concerning the study or the data will be released to any unauthorized third 
party without prior written approval by TRIO. 
The study monitor or TRIO’s other authorized representatives will review all documents and records 
required to be maintained by the Investigator, including but not limited to, medical records (office, clinic 
or hospital) and pharmacy records for the subjects in this study. The clinical study site will permit access 
to such records. 
9.8 Confidentiality and Data Protection 
All information concerning the study supplied by TRIO, in connection with this study and/or by any other 
party collaborating with TRIO, and not previously published, is considered confidential and proprietary 
information. This information includes but is not limited to the IB, clinical protocol, workbooks (if 
applicable), case report forms, assay methods, TRIO technical methodology, and other technical and 
scientific data. This confidential information shall remain the sole property of TRIO and shall not be 
disclosed to others without prior written consent from TRIO. Information shall not be used except in the 
performance of this study. 
9.9 Withdrawal of Informed Consent for Submitted Biological Samples 
If a subject withdraws consent to the use of optional donated biological samples, then the samples will 
be returned, disposed of/destroyed, and the action documented. In the event that analysis/research has 
already been performed, TRIO or its representatives, in strict compliance with the applicable country’s 
regulations, should retain the results and associated data for regulatory reasons but these will not be 
used in any subsequent analyses. 
If a subject withdraws this consent, the Investigator has the responsibility to notify TRIO immediately. 
TRIO will ensure that the laboratory(ies) holding the samples is/are informed about the withdrawn 
consent immediately and that samples are disposed/destroyed/repatriated and the action documented 
and returned to the study site. 
9.10 Insurance of Liabilities 
If required, the Investigator may forward to the IRB/IEC a copy of the insurance document required by 
TRIO, in order to cover his/her liabilities, and those of any other participating parties. 
9.11 Use of Information and Publication 
All information concerning the study drug or in connection with this study, supplied by TRIO and/or by 
any other party collaborating with TRIO within this study, and not previously published, is considered 
confidential and proprietary information. This information includes, but is not limited to, the IB, clinical 
protocol, workbooks (if applicable), case report forms, assay methods, TRIO technical methodology, and 
basic scientific data. This confidential information shall remain the sole property of TRIO, the respective 
collaborating party, and shall not be disclosed to others without prior written consent from TRIO. 
Information shall not be used except in the performance of this study. 
To allow for the use of the information derived from this clinical study and to ensure compliance to 
current regulations, the Investigator is obliged to provide TRIO with complete test results and all data 
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developed in this study. No publication, abstract or presentation of the study will be made without the 
approval of the SSC. The SSC will review the manuscript to prevent forfeiture of patent rights to data not 
in the public domain. Prior to publication, the authorship list will be agreed upon by the SSC. For the 
purpose of the efficacy and safety analyses, the names on the author list will be given according to the 
participation in the concept of the study design as well as accrual input (number of eligible subjects 
accrued) by the Investigators at each center. The maximum number of authors will be determined by 
the publication policy established by the targeted journal. Abstracts and publications will be submitted 
to the authors and to the SSC at least 30 days prior to the expected date of submission to the intended 
publisher. 
10. REFERENCES 
1 
Sankaranarayanan R, Ferlay J. Worldwide burden of gynaecological cancer: the size of the problem. Best 
Pract Res Clin Obstet Gynaecol 2006;20:207–225. 
2 
Bloss JD, Brady MF, Liao SY, et al. Extraovarian peritoneal serous papillary carcinoma: a phase II trial of 
cisplatin and cyclophosphamide with comparison to a cohort with papillary serous ovarian carcinoma-a 
Gynecologic Oncology Group Study. Gynecol Oncol 2003;89:148–154. 
3 
Schneider C, Wight E, Perucchini D, et al. Primary carcinoma of the fallopian tube. A report of 19 cases 
with literature review. Eur J Gynaecol Oncol 2000;21:578–582. 
4 
Heintz APM, Odicino F, Maisonneuve P, et al. Carcinoma of the ovary. FIGO 26th Annual Report on the 
Results of Treatment in Gynecological Cancer. Int J Gynaecol Obstet Off Organ Int Fed Gynaecol Obstet 2006;95 
Suppl 1:S161-192. 
5 
Hoskins WJ. Epithelial Ovarian Carcinoma: Principles of Primary Surgery. Gynecol Oncol 1994;55:S91–S96. 
6 
Morrison J, Haldar K, Kehoe S, et al. Chemotherapy versus surgery for initial treatment in advanced 
ovarian epithelial cancer. Cochrane Database Syst Rev 2012;8:CD005343. 
7 
du Bois A, Quinn M, Thigpen T, et al. 2004 consensus statements on the management of ovarian cancer: 
final document of the 3rd International Gynecologic Cancer Intergroup Ovarian Cancer Consensus Conference 
(GCIG OCCC 2004). Ann Oncol Off J Eur Soc Med Oncol ESMO 2005;16 Suppl 8:viii7-viii12. 
8 
du Bois A. Treatment of advanced ovarian cancer. Eur J Cancer Oxf Engl 1990 2001;37 Suppl 9:S1-7. 
9 
Aletti GD, Gallenberg MM, Cliby WA, et al. Current management strategies for ovarian cancer. Mayo Clin 
Proc 2007;82:751–770. 
10 
Ozols RF. Treatment goals in ovarian cancer. Int J Gynecol Cancer Off J Int Gynecol Cancer Soc 2005;15 
Suppl 1:3–11. 
11 
Naumann RW, Coleman RL. Management strategies for recurrent platinum-resistant ovarian cancer. 
Drugs 2011;71:1397–1412. 
12 
Lortholary A, Largillier R, Weber B, et al. Weekly paclitaxel as a single agent or in combination with 
carboplatin or weekly topotecan in patients with resistant ovarian cancer: the CARTAXHY randomized phase II trial 
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from Groupe d’Investigateurs Nationaux pour l’Etude des Cancers Ovariens (GINECO). Ann Oncol Off J Eur Soc Med 
Oncol ESMO 2012;23:346–352. 
13 
Brewer CA, Blessing JA, Nagourney RA, et al. Cisplatin plus gemcitabine in platinum-refractory ovarian or 
primary peritoneal cancer: a phase II study of the Gynecologic Oncology Group. Gynecol Oncol 2006;103:446–450. 
14 
National Comprehensive Cancer Network. Ovarian Cancer Including Fallopian Tube Cancer and Primary 
Peritoneal Cancer. Version 2.2015. Available at http://www.nccn.org/professionals/physician_gls/pdf/ovarian.pdf. 
Accessed July 21, 2015. 
15 
Robert C, Schachter J, Long GV, et al. Pembrolizumab versus Ipilimumab in Advanced Melanoma. N Engl J 
Med 2015;372:2521–2532. 
16 
Garon EB, Rizvi NA, Hui R, et al. Pembrolizumab for the Treatment of Non–Small-Cell Lung Cancer. N Engl J 
Med 2015;372:2018–2028. 
17 
Efficacy and safety of the anti-PD-1 monoclonal antibody MK-3475 in 411 patients (pts) with melanoma 
(MEL). J Clin OncolAvailable at http://meetinglibrary.asco.org/content/133842-144. Accessed July 22, 2015. 
18 
Avelumab (MSB0010718C), an anti-PD-L1 antibody, in patients with previously treated, recurrent or 
refractory ovarian cancer: A phase Ib, open-label expansion trial. J Clin OncolAvailable at 
http://meetinglibrary.asco.org/content/147268-156. Accessed July 22, 2015. 
19 
Antitumor activity and safety of pembrolizumab in patients (pts) with PD-L1 positive advanced ovarian 
cancer: Interim results from a phase Ib study. J Clin OncolAvailable at 
http://meetinglibrary.asco.org/content/147724-156. Accessed July 22, 2015. 
20 
Wrangle J, Wang W, Koch A, et al. Alterations of immune response of non-small cell lung cancer with 
Azacytidine. Oncotarget 2013;4:2067–2079. 
21 
Juergens RA, Wrangle J, Vendetti FP, et al. Combination epigenetic therapy has efficacy in patients with 
refractory advanced non-small cell lung cancer. Cancer Discov 2011;1:598–607. 
22 
Li H, Chiappinelli KB, Guzzetta AA, et al. Immune regulation by low doses of the DNA methyltransferase 
inhibitor 5-azacitidine in common human epithelial cancers. Oncotarget 2014;5:587–598. 
23 
Snyder A, Makarov V, Merghoub T, et al. Genetic Basis for Clinical Response to CTLA-4 Blockade in 
Melanoma. N Engl J Med 2014;371:2189–2199. 
24 
Rustin GJS, Quinn M, Thigpen T, et al. Re: New Guidelines to Evaluate the Response to Treatment in Solid 
Tumors (Ovarian Cancer). J Natl Cancer Inst 2004;96:487–488. 
25 
Bohnsack O, Hoos A, Ludajic K. Adaptation of the Immune Related Response Criteria: IrRECIST. Ann Oncol 
2014;25:iv369-iv369. 
26 
Adaptation and modification of the immune related response criteria (IRRC): IrRECIST. J Clin 
OncolAvailable at http://meetinglibrary.asco.org/content/130631-144. Accessed June 26, 2015. 
 
 
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11. APPENDICES 
APPENDIX 1: Eastern Cooperative Oncology Group Performance Status Scale 
 
 
 
Grade 
Description 
 
0 
Fully active, able to carry on all pre-disease performance without restriction. 
 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light and sedentary nature, e.g. light housework, office work. 
 
2 
Ambulatory and capable of all self-care, but unable to carry out any work 
activities. Up and about more than 50% of waking hours. 
 
3 
Capable of limited self-care, confined to bed or chair more than 50% of waking hours. 
 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 
 
5 
Dead 
 
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APPENDIX 2: Immune-related Response Evaluation Criteria in Solid Tumors (irRECIST) 
Conventional response assessment criteria such as RECIST criteria are not ideal to fully characterize 
patterns of tumor response to immunotherapy, since patients treated immune-checkpoint inhibitors 
may present response patterns that are not accurately categorized by these conventional criteria. Often 
response to immunotherapy is noted to occur after an initial increase in tumor burden. Furthermore, 
regression of initial lesions may occur despite development of new lesions. Using the RECIST criteria, 
patients can be classified as having progressive disease when in fact there has been a positive response 
to the immunotherapy. 
Immune-related Response Evaluation Criteria in Solid Tumors (irRECIST) is a recently established and 
published measurement guideline that intends to provide better assessment and more reliable and 
reproducible study data for targeted immunotherapeutic agents in oncology studies.  
1. DEFINITIONS OF MEASURABLE/NON MEASURABLE DISEASE 
The RECIST 1.1 definitions for measurable and non-measurable lesions apply. At baseline, all tumor 
lesions/lymph nodes will be categorized at baseline as measurable or non-measurable.  
Measurable Tumor lesions: Must be accurately measured in at least one dimension with a size of: 
 
≥ 10mm in the longest diameter by CT/MRI scan (or no less than double the slice thickness) 
for non-nodal lesions 
 
≥ 15mm in the short diameter by CT/MRI for nodal lesions 
 
≥ 10mm caliper measurement by clinical exam (lesions which cannot be accurately 
measured with calipers should be recorded as non-measurable) 
Non-measurable Tumor lesions: include all other lesions as follows: 
 
Small non-nodal lesions (longest diameter < 10mm or < twice the reconstruction interval) 
 
Pathological lymph nodes with short axis ≥ 10 but < 15mm 
 
Lesions considered truly non-measurable: leptomeningeal disease, ascites, pleural or 
pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, 
abdominal masses/abdominal organomegaly identified by physical exam that is not 
measurable by reproducible imaging techniques. 
Special considerations: 
Lymph nodes: Lymph nodes merit special mention since they are normal anatomical structures 
which may be visible by imaging even if not involved by tumor. Pathological nodes which are 
defined as measurable and may be identified as target lesions must meet the criterion of a short axis 
of ≥ 15mm by CT/MRI scan. Only the short axis of these nodes will contribute to the baseline Total 
Measured Tumor Burden (TMTB). The short axis of the node is the diameter normally used by 
radiologists to judge if a node is involved by solid tumor. Nodal size is normally reported as two 
dimensions in the plane in which the image is obtained (for CT scan this is almost always the axial 
plane; for MRI the plane of acquisition may be axial, sagittal or coronal). The smaller of these 
measures is the short axis. For example, an abdominal node which is reported as being 20mm x 
30mm has a short axis of 20mm and qualifies as a malignant, measurable node. In this example, 
20mm should be recorded as the node measurement. All other pathological nodes (those with short 
axis ≥ 10mm but < 15 mm) should be considered non-target lesions. Nodes that have a short axis < 
10mm are considered non-pathological and should not be recorded or followed. 
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Bone lesions: Bone scan, PET scan or plain films are not considered adequate imaging techniques to 
measure bone lesions. However, these techniques can be used to confirm the presence or 
disappearance of bone lesions. Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft 
tissue components, that can be evaluated by cross sectional imaging techniques such as CT or MRI 
can be considered as measurable lesions if the soft tissue component meets the definition of 
measurability described above. Blastic bone lesions are always non-measurable. 
Cystic lesions: 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. 
Lesions with prior local treatment: Tumor lesions situated in a previously irradiated area, or in an 
area subjected to other loco-regional therapy, are usually not considered measurable unless there 
has been demonstrated progression in the lesion. 
2. BASELINE DOCUMENTATION OF TARGET AND NON-TARGET LESIONS 
2.1. TARGET LESIONS 
All measurable lesions up to a maximum of five lesions total (and a maximum of two lesions per 
organ) representative of all involved organs should be identified as Target lesions and will be 
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. 
A Total Measured Tumor Burden (TMTB) for all target lesions will be calculated and reported as 
the baseline TMTB. The TMTB results from adding: 
 
the longest diameters of all non-nodal target lesions, and 
 
the short axis for all nodal lesions  
The baseline TMTB will be used as reference to further characterize any objective tumor 
regression/progression in the measurable dimension of the disease. 
2.2. NON-TARGET LESIONS 
All other lesions (or sites of disease) not selected as Target lesions should be identified as Non-
Target lesions and should also be recorded at baseline. There is no limit to the number of Non-
Target lesions that can be recorded at baseline. In addition, it is possible to record multiple non-
target lesions involving the same organ as a single item on the CRF (e.g. “multiple enlarged pelvic 
lymph nodes” or “multiple liver metastases”). 
Measurements are not required and these lesions should be followed as “present”, “absent”, or in 
rare cases “unequivocal progression”. 
Baseline selected Non-target lesions can never convert to measurable lesions, not even if they 
increase in size at subsequent timepoints and become “measurable”. Only true New lesions can be 
measured and can contribute to the TMTB if measurable. 
 
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3. METHODS OF ASSESSMENT 
The same method of assessment and the same technique used at baseline to characterize each 
lesion must be used at each subsequent post-baseline assessment. All measurements should be 
recorded in metric notation, using calipers if clinically assessed.  
3.1. CT AND MRI 
CT is the best currently available and reproducible method to measure lesions selected for response 
assessment. In the TRIO026 study it is recommended that CT examinations of the chest, abdomen, 
and pelvis will be used to assess tumor burden at baseline and follow-up visits. CT examination with 
intravenous (i.v.) contrast media administration is the preferred method. Measurability threshold of 
lesions on CT scan is based on the assumption that CT slice thickness is 5mm or less. When CT scans 
have slice thickness greater than 5 mm, the minimum size for a measurable lesion should be twice 
the slice thickness.  
MRI should be used where CT is not feasible or it is medically contra-indicated. MRI has excellent 
contrast, spatial and temporal resolution; however, there are many image acquisition variables 
involved in MRI, which greatly impact image quality and lesion measurement. For these reasons, CT 
is the imaging modality of choice. 
3.2. CLINICAL LESIONS 
In TRIO026, clinical examination will not be used for assessment of TL. Clinically detected lesions can 
be selected as target lesions only in case they are assessed by CT or MRI scans. In this case, 
measurement will be based on the CT/MRI and not on clinical examination. Clinical examination can 
be used to assess NTL and to identify the presence of new lesions.  
3.3. CHEST X-RAY  
In TRIO026, chest x-ray will not be used for assessment of TL/NTL as they will be assessed by 
CT/MRI.  
3.4. ULTRASOUND 
In TRIO026, ultrasound will not be used for assessment of TL/NTL as it is not a reproducible method, 
does not provide an accurate assessment of tumor size and is operator dependent. Ultrasound 
examination can be used to identify the presence of new lesions if new lesions are identified by 
ultrasound in the course of the study, confirmation by CT or MRI is advised. 
3.5. ENDOSCOPY AND LAPAROSCOPY 
The utilization of these techniques for objective tumor evaluation is not advised. 
3.6. CYTOLOGY AND HISTOLOGY 
In TRIO026 histology will not be used as part of the tumor response assessment as per irRECIST. 
Cytological confirmation of the neoplastic origin of any effusion that appears or worsens during 
treatment is required when the measurable disease has met criteria for response or stable disease. 
In such circumstances, the cytology is necessary to differentiate between response / stable disease 
(an effusion may be a side effect of the treatment) and progressive disease (if the neoplastic origin 
of the fluid is confirmed). Where cytology findings are not available, any effusion that significantly 
worsens (from trace to large) or appearance of clinically significant effusion (requiring change in 
drug therapy) during the study treatment will be considered to be progression of NTL, or disease 
progression due to new lesions. 
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3.7. BONE SCAN 
Bone lesions identified on a bone scan at baseline and confirmed as tumor lesions by CT/MRI at 
baseline should be recorded as NTL and followed by the same method as per baseline assessment. 
In TRIO026 bone scans may be used as a method of assessment to identify the presence of new 
bone lesions at follow-up visits. New lesions will be recorded where a positive hot-spot that was not 
present on the baseline bone scan assessment (if available) is identified on a bone scan performed 
at any time during the study. Confirmation by CT, MRI and x-ray is recommended where bone scan 
findings are equivocal. 
3.8. FDG-PET SCAN AND PET-CT 
In TRIO026, PET scans may be used as a method for identifying new lesions, according with the 
following algorithm:  
 
New lesions will be recorded where there is positive FDG uptake not present on baseline 
FDG-PET scan (if available) or in a location corresponding to a new lesion on CT/MRI at the 
same follow-up visit.  
 
If there is no baseline FDG-PET scan available, and no evidence of new lesions on CT/MRI 
scans then follow-up CT/MRI assessments should be continued, scheduled as per protocol 
or clinical indicated, in order to confirm new lesions in subsequent tumor assessments 
Low dose or attenuation correction CT portions of a combined PET–CT are of limited use in efficacy 
assessments in clinical trials and therefore they should not substitute dedicated diagnostic contrast 
enhanced CT scans. In exceptional situations, if a 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 irRECIST measurements. However, this is not recommended 
because the PET portion of the CT introduces additional data that may bias an Investigator if it is not 
routinely or serially performed. 
4. POST-BASELINE: TMTB 
At each post-baseline assessment the TMTB is defined as the sum of: 
 
Longest diameters of all non-nodal target lesions 
 
Longest diameters of all NEW non-nodal measurable lesions  
 
Short axis of all nodal target lesions 
 
Short axis of all NEW nodal measurable lesions 
Definition of New Measurable Lesion 
In order to be selected as new measurable lesions (≤ 2 lesions per organ, ≤ 5 lesions total, per 
timepoint), new lesions must meet criteria as defined for baseline target lesion selection and meet 
the same minimum size requirements of 10 mm in long diameter and minimum 15 mm in short axis 
for new measurable lymph nodes. New measurable lesions shall be prioritized according to size, and 
the largest lesions shall be selected as new measured lesions.  
5. POST-BASELINE: NON-TARGET LESIONS ASSESSMENT 
Non-Target lesions assessment 
The RECIST 1.1 definitions for the assessment of non-target lesions apply: 
CONFIDENTIAL 
 
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Version 3.0 – 14 September 2018 
 
Complete Response (CR): Disappearance of all non-target lesions. All lymph nodes must be 
non-pathological in size (< 10mm short axis). 
 
Non-CR/Non-PD (irNN): Persistence of one or more non-target lesion(s). 
 
Progressive Disease (PD): Unequivocal progression of existing non-target lesions (note: the 
appearance of unequivocal new lesions is also considered progression). 
The response of non-target lesions primarily contributes to the overall response assessments of irCR 
and irNon-CR/Non-PD (irNN). Non-target lesions do not affect irPR and irSD assessments. Only a 
massive and unequivocal worsening of non-target lesions alone, even without progress in the TMTB 
is indicative of irPD. 
Definition of New Non-Measurable lesions 
All new lesions not selected as New Measurable lesions are considered New Non-measurable lesions 
and are followed qualitatively. Only a massive and unequivocal progression of New Non-measurable 
lesions leads to an overall assessment or irPD for the given timepoint. Persisting new Non-
measurable lesions prevent irCR. 
6. IMMUNE-RELATED OVERALL TUMOR ASSESSMENT AT EACH TIMEPOINT 
Immune-related Complete Response (irCR): complete disappearance of all measurable and non-
measurable lesions. Lymph nodes must decrease to < 10 mm in short axis.  
Immune-related Partial Response (irPR): decrease of ≥ 30% in TMTB relative to baseline, non-target 
lesions are irNN, and no unequivocal progression of new non-measurable lesions.  
Immune-related Stable Disease (irSD): failure to meet criteria for irCR or irPR in the absence of irPD.  
irNN: no target disease was identified at baseline and at follow-up the patient fails to meet criteria 
for irCR or irPD.  
Immune-related Progressive Disease (irPD): minimum 20% increase and minimum 5 mm absolute 
increase in TMTB compared to nadir, or irPD for non-target or new non-measurable lesions.  
irNE (Not evaluable): used in exceptional cases where insufficient data exists. 
7. CONFIRMATION OF RESPONSE AND PROGRESSION 
In TRIO026, imaging for confirmation of response (irCR or irPR) is not required. 
On the other side, confirmation of progression (irPD) is recommended minimum 4 weeks after the 
first irPD assessment and is required during the flare time-window of the first 12 weeks of 
treatment.  
8. OTHER CONSIDERATIONS 
irPR if no Target Lesions: If new measurable lesions appear in patients with no target lesions at 
baseline, irPD will be assessed. That irPD timepoint will be considered a new baseline, and all 
subsequent timepoints will be compared to it for response assessment. irPR is possible if the TMTB 
of new measurable lesions decreases by ≥ 30% compared to the first irPD documentation. 
Symptomatic deterioration: this is not a descriptor of a progressive disease. It may be reason for 
discontinuation from study treatment but overall response should be based on the objective tumor 
response according to irRECIST criteria. Subjects with ‘symptomatic deterioration’ requiring 
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Version 3.0 – 14 September 2018 
discontinuation of treatment without objective evidence of disease progression at that time should 
continue to undergo tumor until objective disease progression is observed. 
Doubtful progression: If the Investigator is in doubt as to whether progression has occurred, 
particularly with regard to non-target lesions or the appearance of a new lesion, it is advisable to 
continue treatment until the next scheduled assessment or sooner if clinically indicated, and 
reassess the subject’s status. If repeat scans confirm progression, then the date of the initial scan 
should be declared as the date of progression. 
CONFIDENTIAL 
 
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SAP_001.pdf: 
 
 
 
 
 
 
 
 
 
 
 
 
Title:  
TRIO026 (Part A) – Statistical Analysis Plan 
Translational Research In Oncology - Confidential and Proprietary 
Page 1 of 32 
Statistical Analysis Plan 
Protocol Title 
Phase II randomized study of pembrolizumab with or without 
epigenetic modulation with CC-486 in patients with platinum-
resistant epithelial ovarian, fallopian tube or primary peritoneal 
cancer 
Protocol Number 
TRIO026 (Part A) 
 
 
Revision 
01 
Product Name 
CC-486 
Indication 
Platinum-resistant epithelial ovarian cancer (EOC), fallopian 
tube carcinoma (FTC) or primary peritoneal carcinomas (PPC) 
Study Phase 
II 
Sponsor 
TRIO 
Version Date 
10-Apr-2018 
Confidentiality Statement 
The information contained herein is confidential and proprietary and may not be disclosed, reproduced, or 
circulated without the prior written consent of TRIO. 
 / NCT02900560 


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


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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List of Abbreviations  
AE 
Adverse Event 
CI 
Confidence Interval 
CM 
Concomitant Medications 
EOC 
Epithelial Ovarian Cancer 
FTC 
Fallopian Tube Carcinoma 
GCIG 
Gynecologic Cancer Intergroup 
irCR 
Immune-related Complete Response 
irDCR 
Immune-related Disease Control Rate 
irNE 
Immune-related Unevaluable 
irORR 
Immune-related Overall Response Rate 
irPD 
Immune-related Progressive Disease 
irPR 
Immune-related Partial Response 
irRECIST 
Immune-related Response Evaluation Criteria in Solid Tumors 
irSD 
Immune-related Stable Disease 
ITT 
Intent-to-treat 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
PEM 
Pembrolizumab 
PPC 
Primary Peritoneal Carcinomas 
PT 
Preferred Term 
RDI 
Relative Dose Intensity 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SOC 
System Organ Class 
SSC 
Study Steering Committee 
TRIO 
Translational Research in Oncology 
WHODD 
World Health Organization Drug Dictionary 
ULN 
Upper Limit of Normal 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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TRIO026 (Part A) – Statistical Analysis Plan 
 
 
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Title:  
TRIO026 (Part A) – Statistical Analysis Plan 
 
 
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Page 5 of 32 
 
1. Introduction 
This Statistical Analysis Plan (SAP) describes the detailed statistical methodology for executing 
the statistical analyses to assess the safety profile of CC-486, futility evaluation as well as CA-
125 response according to TRIO026 protocol version 2.0 for patients enrolled in Part A of the trial. 
Separate document(s) will be prepared to describe statistical analysis perform on Part B of this 
trial. 
Statistical analysis will be performed by TRIO using SAS® software Version 9.4 or higher. 
2. Study Design and Objectives 
2.1. Study Design 
The protocol synopsis is provided in Appendix 6.1. Refer to protocol for additional details. 
2.2. Study Objectives 
2.2.1. Primary Objectives 
The primary objective for Part A of this study is to establish an optimal schedule of CC-486 
combined with pembrolizumab (PEM) in patients with platinum-resistant/refractory EOC. This will 
be determined based on safety profile, futility evaluation as well as immune-related Overall 
Response Rate (irORR)/ immune-related Disease Control Rate (irDCR) per irRECIST criteria. 
2.2.2. Secondary Objectives 
To assess the CA-125 response based on the Gynecologic Cancer Intergroup (GCIG) criteria. 
2.2.3. Exploratory Objectives 
• 
Tumor samples will be used to assess potential prognostic or predictive biomarkers, 
improve understanding of ovarian cancer biology and identify candidate biomarkers that 
may correlate with treatment benefit and/or safety signals 
• 
Whole blood samples will be used to analyze changes in DNA methylation during 
treatment with CC-486 
Details of methodologies used to assess exploratory objectives will be described in a separate 
SAP. 
2.3. Sample Size 
At least 20 patients will be enrolled to TRIO026 Part A. Patients are assigned to one of the 
following four treatment schedule cohorts in the order they are enrolled in the study (minimum of 
five patients per cohort): 
• 
Cohort 1: CC-486 100 mg/d, 21 d on, 7 d off + PEM 200 mg iv q3 weeks 
• 
Cohort 2: CC-486 100 mg BID, 21 d on, 7 d off + PEM 200 mg iv q3 weeks 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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• 
Cohort 3: CC-486 300 mg/d, 14 d on, 14 d off + PEM 200mg iv q3 weeks 
• 
Cohort 4: CC-486 300 mg/d, 21 d on, 7 d off + PEM 200 mg iv q3 weeks 
2.4. Timing of Analyses 
The analysis for TRIO026 Part A is conducted when five patients in each cohort are considered 
evaluable. The criteria for evaluability is described under Section 3.1.3. 
3. Statistical Methods 
3.1. Analysis Population 
3.1.1. Intent-to-Treat Population 
The Intent-to-Treat (ITT) Population includes all patients who were enrolled in the study, 
regardless of whether they actually received study medication. All efficacy analyses will be 
evaluated based on data from this population according to the cohort they were assigned to at 
enrollment. 
3.1.2. Safety Population 
The Safety Population consists of all patients who receive any study treatment, and will be used 
for the analysis of safety data of the study. This population will assign patients to the cohort based 
on the treatment schedule observed in Cycle 1. If this differs from that to which the patient was 
enrolled, the actual observed treatment schedule will be used for the analysis of safety data. 
3.1.3. Evaluable Population 
As per protocol version 2.0, the Evaluable Population consists of patients in ITT population who 
also meet the following criteria: 
• 
Completed at least two CC-486 cycles 
• 
Undergone 1st post-baseline tumor burden assessment 
• 
Undergone 2nd tumor biopsy with adequate paired tissue obtained 
3.2. Data Handling 
3.2.1. Baseline Assessment/Measurement 
The last available assessment/measurement of a particular data point on or prior to the latter of 
the date of enrollment and the date of first dose of study treatment. If patients have no value as 
defined above, the baseline value will be missing. 
3.2.2. Date of First Dose 
The date of first dose (of study drug) is derived as the first date when a non-zero and non-missing 
dose of study drug is administered. This is also referred as the start of the study treatment. 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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3.2.3. Date of Last Dose 
The date of last dose (of study drug) is derived as the last date when a non-zero and non-missing 
dose of study drug is administered. 
3.2.4. Duration 
Duration, except for duration of treatment, is calculated as: 
• 
Duration (days): (End Date – Start Date + 1). 
• 
Duration (weeks): (End Date – Start Date + 1) / 7 
• 
Duration (months): (End Date – Start Date + 1) / 30.4375 
• 
Duration (years): (End Date – Start Date + 1) / 365.25 
3.2.5. Missing Data 
All analyses and descriptive summaries will be based on the observed data. Unless otherwise 
specified, missing data will not be imputed or “carried forward.” 
3.2.6. Partial Dates 
Only partial or missing date for Adverse Events (AE) and Concomitant Medications (CM) 
(including prior and on study systemic anti-cancer therapies) will be imputed according to the 
following: 
3.2.6.1. Imputation Rules for Partial or Missing Stop Dates: 
If the month and year are present, impute the last day of that month. 
If only the year is present, impute December 31 of that year. 
If the stop date is entirely missing, assume the event or medication is ongoing. 
If a partial or complete stop date is present and the ‘ongoing’ box is checked, then it will be 
assumed that the AE or CM stopped and the stop date will be imputed if partial. 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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3.2.6.2. Imputation Rules for Partial or Missing Start Dates 
Start Date 
Stop Date 
Complete: 
yyyymmdd 
Partial: yyyymm 
Partial: yyyy 
Missing 
< 1st 
dose 
≥ 1st 
dose 
< 1st 
dose 
yyyymm 
≥ 1st 
dose 
yyyymm 
< 1st 
dose 
yyyy 
≥ 1st 
dose 
yyyy 
Partial: 
yyyymm 
= 
1st 
dose 
yyyymm 
2 
1 
2 
1 
n/a 
1 
1 
≠ 1st dose 
yyyymm 
2 
2 
2 
2 
2 
Partial: 
yyyy 
= 
1st 
dose 
yyyy 
3 
1 
3 
1 
n/a 
1 
1 
≠ 1st dose 
yyyy 
3 
3 
3 
3 
3 
Missing 
4 
1 
4 
1 
4 
1 
1 
• 
1 = Impute the date of first dose 
• 
2 = Impute the first of the month 
• 
3 = Impute January 1 of the year 
• 
4 = Impute January 1 of the stop year 
3.3. Statistical Analysis 
Categorical variables will be summarized in frequency tables, with the counts and percentage of 
patients in each category. Percentages given in the summary tables will be rounded and thus 
may not always add up to exactly 100 percent. For continuous variables, summary statistics will 
include number of patients, mean, standard deviation, first quartile (Q1), median, third quartile 
(Q3), and minimum and maximum values (range). 
3.3.1. Patient Disposition 
The patient disposition will be tabulated using the ITT. Frequency count and respective 
percentages of patients who were in each population (i.e. ITT, Safety, and Evaluable), and 
discontinued from treatment and/or study will be summarized by cohort. The reason for 
discontinuation (from treatment and/or from study participation where applicable) will be 
summarized considering the categories specified in the case report forms. Listings of disposition 
information and analysis population will be provided as well. 
Protocol Deviations including eligibility deviations of the inclusion/exclusion criteria will be 
summarized and listed for ITT, by cohort. 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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3.3.2. Demographics and Disease Characteristics 
The following patient demographics and disease characteristics will be summarized and listed for 
the ITT and Safety Population (where applicable) by cohort: 
Patient Demographics: 
• 
Age, INT (Date of enrollment – Date of birth) / 365.25) 
o INT = integer part 
o Since only the year of birth is collected (YYYY), we assume the full date to be 31-
Dec-YYYY 
• 
Race 
• 
Ethnicity 
• 
Weight at Baseline 
• 
ECOG Status at Baseline 
Disease Characteristics: 
• 
Time from Initial Diagnosis to Enrollment 
• 
Primary Tumor Location 
• 
Staging at Initial Diagnosis 
• 
Histopathological Type at Initial Diagnosis 
• 
Histopathological Grade at Initial Diagnosis 
• 
Disease Status at Enrollment 
• 
Time from First Progression/Relapse to Enrollment 
Prior Surgery for Ovarian Cancer: 
Number of patients who underwent prior surgeries will be summarized by type of procedures. A 
listing will also be done. 
Prior Systemic Anti-Cancer Therapy: 
Number of regimens of prior systemic anti-cancer therapies will be summarized by type and 
setting. A listing will be provided to show the specifics of the therapies. 
Medical History: 
The medical history is coded by the most current version of Medical Dictionary for Regulatory 
Activities (MedDRA), and will be summarized for ITT by System Organ Class (SOC) and Preferred 
Term (PT) by cohort. 
3.4. Efficacy Analyses 
Efficacy data for the primary objective and the secondary objectives will be analyzed for the ITT. 
Summaries and figures of the efficacy endpoints will be generated by cohort as per enrollment. 
3.4.1. Primary Efficacy Objective 
Immune-related Overall Response Rate (irORR): 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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irORR is defined as the proportion of patients achieving a best overall response of immune-related 
Complete Response (irCR) or immune-related Partial Response (irPR) assessed as per 
investigator assessment. 
irORR = # of patients with best overall response as irCR or irPR
Total number of patients
 
The best overall response outcome (irCR/irPR/irSD/irPD/irNE) will be summarized and tabulated 
for ITT by cohort. 
Immune-related Disease Control Rate (irDCR): 
irDCR is estimated based on the proportion of patients in each cohort whose best overall response 
during the course of study treatment is irCR, irPR or irSD as per investigator assessment.  
irDCR = # of patients with best confirmed overall response as irCR/irPR/irSD
Total number of patients
 
3.4.2. Secondary Efficacy Endpoints 
CA-125 Response Rate: 
The CA-125 response rate is defined as the proportion of patients having a CA-125 response 
according to the GCIG criteria:  
• 
A response according to CA-125 is observed when there is at least a 50% reduction in 
CA-125 level from baseline. The response must be confirmed and maintained for at least 
28 days. 
• 
Patients can be evaluated according to CA-125 if they have a pre-treatment sample that 
is at least twice the upper limit of normal (ULN) and within 2 weeks prior to starting 
treatment 
3.5. Safety Analyses 
Safety analyses will be performed on the Safety Population. 
3.5.1. Extent of Exposure 
Number of Cycles, Duration of Treatment, Cumulative Dose and Relative Dose Intensity (RDI) 
will be summarized by treatment for the safety population. 
CC-486: 
Number of Cycles: number of cycles having total dose > 0 mg reported 
Duration of Exposure (day) = sum of [(Date of last dose - Date of first dose + 1) of cycle] 
Duration of Treatment (day) of each administration sequence = (Date of last dose – Date 
of first dose + 1) 
Cumulative Dose (mg) = sum of (Duration of Treatment of each administration sequence 
× daily dose) 
Dose Intensity (mg/day) = (Cumulative Dose) ÷ (Duration of Exposure) 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Planned Dose Intensity (mg/day) = Planned Daily Dose as per cohort 
RDI (%) = (Dose Intensity ÷ Planned Dose Intensity) × 100 
The compliance of CC-486 will be summarized by cycle using the following calculation: 
Compliance (%) = Number of Tabs taken + Number of Tabs Returned
Number of Tabs Dispensed
 × 100 
Pembrolizumab: 
Number of Cycles: number of cycles having total dose > 0 mg reported 
Duration of Treatment (weeks) = [(Date of last dose - date of first dose) + 21] ÷ 7 
Cumulative Dose (mg) = sum of total dose administered as reported 
Weekly Dose Intensity (mg/week) = (Cumulative Dose) ÷ (Duration of Treatment) 
Planned Weekly Dose Intensity (mg/week) = 200mg ÷ 3 weeks 
RDI (%) = (Weekly Dose Intensity ÷ Planned Weekly Dose Intensity) × 100  
The RDI will be additionally presented categorized (i.e., number and percentage of patients with 
RDI of < 60%, 60 - < 80%, 80 - < 90%, 90 - < 110%, ≥ 110%). 
The number and percentage of patients with dose modifications will be summarized. The 
respective reasons of dose modification will be listed. 
3.5.2. Adverse Events (AEs) 
AE information will be collected from treatment initiation and continues throughout the study until 
end of participation (refer to Section 7.1.1 of the protocol).  
The reported AE term will be coded using the current version of the MedDRA. The severity of AE 
will be presented as reported by the investigator based on National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE) grades version 4.03. 
Incidence of AEs will be tabulated by SOC and PT for: 
• 
All AEs 
• 
AEs by relationship to study treatment and maximum severity grade 
• 
AEs with action taken drug interrupted 
• 
AEs with action taken dose reduced 
• 
AEs with action taken drug withdrawn 
• 
Serious Adverse Events (SAE) 
• 
AEs leading to deaths – An AE is considered as leading to death if CTCAE Grade 5 is 
reported. 
In the event a patient experiences repeated episodes of the same AE according to PT, the event 
with the highest severity grade to study treatment will be used for purposes of incidence 
tabulations. 
Detailed listings for all AEs will be provided. 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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3.5.3. Laboratory Values 
Lab values will be converted to standard units and categorized according to NCI CTCAE version 
4.03. Laboratory results not corresponding to NCI CTCAE terms will not be graded. 
Hematology and serum blood chemistry will be summarized in descriptive statistics by calculating 
the mean, standard deviation, median, and range for the following: 
• 
Baseline value 
• 
Minimum post baseline value 
• 
Maximum post baseline value 
Shift tables in laboratory toxicity grades (comparing baseline grade with worst post-baseline 
grade) will be analyzed using standard shift tables, presenting number and proportion of patients 
and their maximum grade shift.  
For laboratory tests without a toxicity grading scale, the shift table will present directional shifts 
from baseline to above or below the laboratory standard normal range using the maximum 
increase and/or decrease observed throughout the course of treatment/observation. 
3.5.4. ECOG Performance Status 
Descriptive statistics of ECOG Performance Status results will be done for the following: 
• 
Baseline value 
• 
Minimum post baseline value 
• 
Maximum post baseline value 
A shift table will be provided as well from baseline status to the worst status of post-baseline time 
points. 
3.5.5. Concomitant Medications 
CM and on study systemic anti-cancer therapies are coded to the current version of World Health 
Organization Drug Dictionary (WHODD). The preferred name will be tabulated and listed by 
patient. 
3.5.6. Death 
All deaths will be reported in a patient listing, which will include date of death, date of last dose, 
the primary cause of death, and the number of days between the date of last dose to study drug 
and death. 
4. Study Steering Committee (SSC) 
The result of statistical analysis will be reviewed by SSC who is responsible for the scientific 
conduct and integrity of the trial. SSC will review the results and act in correspondence to the 
SSC Charter. 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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5. List of Planned Statistical Outputs 
5.1. Planned Tables 
Title 
Population 
Description 
Patient Disposition  
ITT 
Tabulates the disposition of all patients by cohort, 
including the number of patients in each population 
set, discontinued from study treatment, and 
discontinued from study. The reason for drug 
discontinuation and study discontinuation will also 
be summarized. 
Protocol Deviations 
ITT 
Tabulate the number of patients who reported 
protocol deviations by deviation category for each 
cohort. 
Eligibility Deviations 
ITT 
Tabulates the number of patients who violates 
inclusion/exclusion criteria by criterion for each 
cohort 
Patient Demographics  
ITT 
Safety 
Tabulates summary statistics of patient 
demographics (age, race, ethnicity, weight and 
ECOG status at baseline) for each cohort. 
Disease Characteristics  
ITT 
Tabulates summary statistics for time from initial 
diagnosis to enrollment, primary tumor location, 
staging at initial diagnosis, histopathological type at 
initial diagnosis, histopathological grade at initial 
diagnosis, disease status at enrollment, time from 
first progression/relapse to enrollment for each 
cohort. 
Prior Surgery for Ovarian 
Cancer 
ITT 
Tabulates the number of patients with type of 
procedures for each cohort. 
Prior Systemic Anti-
Cancer Therapy 
ITT 
Tabulates the number of regimens received by 
patient according to type and indication of the 
systemic cancer therapy for each cohort. 
Medical History 
ITT 
Summarizes medical history by SOC and PT for 
each cohort. 
Study Drug Exposure  
Safety 
Summarizes the number of cycles, the duration of 
treatment, cumulative dose, and RDI by cohort. The 
number of dose modification will also be 
summarized by study drug. 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Title 
Population 
Description 
Compliance 
Safety 
CC-486 Compliance assessment will be 
summarized by each cycle. 
Best Overall 
Response/irORR and 
irDCR 
ITT 
Summary of Best Overall Response as per 
irRECIST will be tabulated by cohort 
irORR and irDCR will also be reported 
CA-125 
ITT 
Summary of CA-125 Response Rate will be 
tabulated by cohort. 
AEs Overview 
Safety 
Tabulates the number of patients with AEs, Related 
AEs, Grade 3 / 4 AEs, AEs with action taken dose 
reduced, AEs with action taken drug interrupted, 
AEs leading to drug withdrawn, SAEs, Fatal AEs. 
AEs 
Safety 
Summary by SOC and PT of number of patients and 
events for each cohort. 
Related AEs – CC-486 
Safety 
Summary by SOC and PT of number of patients and 
events for each cohort. 
Related AEs – 
Pembrolizumab 
Safety 
Summary by SOC and PT of number of patients and 
events for each cohort. 
SAE 
Safety 
Summary by SOC and PT of number of patients and 
events for each cohort. 
Grade 3 / 4 AEs 
Safety 
Summary by SOC and PT of number of patients and 
events for each cohort. 
Grade 5 AE 
Safety 
Summary by SOC and PT of number of patients and 
events for each cohort. 
AEs with Action Taken as 
Dose Reduced – CC-486 
Safety 
Summary by SOC and PT of number of patients and 
events for each cohort.  
AEs with Action Taken as 
Drug interrupted – CC-
486 
Safety 
Summary by SOC and PT of number of patients and 
events for each cohort. 
AEs with Action Taken as 
Drug interrupted – 
Pembrolizumab 
Safety 
Summary by SOC and PT of number of patients and 
events for each cohort. 
AEs Leading to Drug 
Withdrawn – CC-486 
Safety 
Summary by SOC and PT of number of patients and 
events for each cohort. 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Title 
Population 
Description 
AEs Leading to Drug 
Withdrawn – 
Pembrolizumab 
Safety 
Summary by SOC and PT of number of patients and 
events for each cohort. 
Laboratory Values 
Safety 
Summary of each laboratory parameter at baseline, 
minimum post baseline value, and maximum post 
baseline value for each cohort. 
In addition, shift tables will be presented. 
ECOG Performance 
Status  
Safety 
Summary of ECOG performance status at baseline, 
minimum post baseline value, and maximum post 
baseline value for each cohort.  
In addition, a shift table will be presented. 
Concomitant Medications  Safety 
Tabulate the frequency and percentage of patients 
according to preferred name.  
Summary will be presented separately for 
concomitant medications and on study systemic 
anti-cancer therapies. 
5.2. Planned Listings 
Title 
Population 
Description 
Patient Accountability 
ITT 
Listing of all patients and with population indicators. 
For patients who discontinued from treatment and/or 
study, include the reason of respective 
discontinuations. 
Deaths 
ITT 
Listing of patients who died, including primary cause 
of death, date of death, date of last dose, and the 
number of days from date of last dose to death.  
Patient Demographics 
ITT 
Listing of patient demographics. 
Disease Characteristics 
ITT 
Listing of disease characteristics. 
Prior Surgery for Ovarian 
Cancer 
ITT 
Listing of prior surgery for ovarian cancer. 
Prior Systemic Anti-
Cancer Therapy 
ITT 
Listing of prior systemic anti-cancer therapy. 
Study Drug Exposure 
Safety 
Listing of patients for extent of exposure by cycle. 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Title 
Population 
Description 
Study Drug Exposure 
Summary 
Safety 
Listing of patients for summary of exposure (e.g. 
number of cycles, duration of treatment, cumulative 
dose, dose intensity, RDI). 
Efficacy Parameters 
ITT 
Listing of best overall response for each patient 
Tumor Assessment 
ITT 
Listing of tumor assessment including lesion 
number, date of assessment, lesion 
measurement/response, and time-point overall 
response. 
CA-125 
ITT 
Listing of CA-125 reported for each patient. 
AEs 
Safety 
Listing of all AEs for each patient; the listing 
includes the verbatim term, PT, SOC, seriousness, 
worst grade, start date, outcome, stop date, 
relationship to study drug, and action taken for study 
drug.  
Related AE – CC-486 
Safety 
Listing of AEs in this category using the same 
structure as the AEs listing. 
Related AE – 
Pembrolizumab 
Safety 
Listing of AEs in this category using the same 
structure as the AEs listing. 
SAEs 
Safety 
Listing of AEs in this category using the same 
structure as the AEs listing.  
Grade 3 / 4 AE 
Safety 
Listing of AEs in this category using the same 
structure as the AEs listing.  
AEs Leading to Death 
Safety 
Listing of AEs in this category using the same 
structure as the AEs listing. 
AEs with Action Taken 
for Dose Reduced – CC-
486 
Safety 
Listing of AEs in this category using the same 
structure as the AEs listing. 
AEs with Action Taken 
for Drug Interrupted – 
CC-486 
Safety 
Listing of AEs in this category using the same 
structure as the AEs listing. 
AEs with Action Taken 
for Drug Interrupted – 
Pembrolizumab 
Safety 
Listing of AEs in this category using the same 
structure as the AEs listing. 
AEs Leading to Drug 
Withdrwan – CC-486 
Safety 
Listing of AEs in this category using the same 
structure as the AEs listing  


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Title 
Population 
Description 
AEs Leading to Drug 
Withdrwan – 
Pembrolizumab 
Safety 
Listing of AEs in this category using the same 
structure as the AEs listing  
Laboratory Values 
Safety 
Listing of all laboratory values and their assigned 
toxicity grade (where applicable). 
ECOG Performance 
Status 
Safety 
Listing of ECOG at each assessment. 
Concomitant Medications 
Safety 
Listing of verbatim product name, preferred name, 
start date, end date (or ongoing) and indication. 
On Study Systemic Anti-
Cancer Therapies 
Safety 
Listing of regiment number, verbatim product name, 
preferred name, type of therapy, start date, end date 
(or ongoing)  
5.3. Planned Graphs 
Not Applicable. 
6. Appendix 
6.1. Protocol Synopsis 
Protocol Title  
Phase II randomized study of pembrolizumab with or without epigenetic 
modulation with CC-486 in patients with platinum-resistant epithelial ovarian, 
fallopian tube or primary peritoneal cancer 
Protocol #  
TRIO026 
Indication  
Platinum-resistant epithelial ovarian cancer (EOC), fallopian tube carcinoma 
(FTC) or primary peritoneal carcinomas (PPC) 
Study Duration  
Part A:  
 
Accrual: 24 months  
 
Treatment phase: 6 months  
 
Follow-up: According to subject´s status at End of Treatment  
Part B:  
 
Accrual: 24 months  
 
Treatment phase: 6 months  
 
Follow-up: 12 months 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Sponsor / 
Participating 
Investigator  
This is a TRIO-sponsored study, led by Dr. John Glaspy (Professor of Medicine, 
Jonsson Comprehensive Cancer Center, UCLA, USA) as Study Chair. The study is 
financially supported by Celgene Corporation. 
Participating 
Investigator Sites  
Part A: 4 sites in 1 country (USA) 
Part B: approximately 25 sites in 2 countries (USA and Germany; includes sites 
participating in Part A)  
Target Population  
The target study population consists of adult patients with platinum-
resistant/refractory EOC/FTC/PPC who have received a maximum of 2 prior 
treatment regimens for the platinum-resistant/refractory relapse (definition of 
platinum resistant/refractory disease will be based on the platinum-free interval 
following frontline chemotherapy). Subjects must have previously received 
platinum-based chemotherapy (intravenous and/or intraperitoneal) following 
and/or preceding debulking surgery. They will be required to have measurable 
disease according to irRECIST (Immune-related Response Evaluation Criteria in 
Solid Tumors) for Part A. For Part B, subjects will be required to have either 
measurable and/or non-measurable disease. They will also be required to have 
a life expectancy of at least 6 months, Eastern Cooperative Oncology Group 
(ECOG) Performance Status (PS) of 0-1, adequate liver, renal and bone marrow 
functions; absence of known autoimmune diseases, of certain bone marrow 
conditions and of serious diseases which could affect protocol compliance or the 
interpretation of study results. 
Background and 
Rationale 
There are approximately 200,000 new cases of EOC diagnosed each year in the 
world and this is the leading cause of death from gynecologic cancer in the United 
States and in many other countries. 
More than 75% of patients present with advanced disease at primary diagnosis. 
The current standard initial therapy is debulking surgery followed by platinum-
based doublet chemotherapy administered either intravenously and/or 
intraperitoneally. Neoadjuvant chemotherapy is being increasingly used. 
Despite aggressive surgery and frontline chemotherapy, most patients with 
advanced disease experience a relapse. Patients with a platinum-free interval of 
less than 6 months are considered to have platinum-resistant disease and those 
that recur/progress while receiving frontline chemotherapy are considered to 
have platinum-refractory disease. At first relapse, approximately 25% of patients 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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have platinum-resistant/refractory ovarian cancer and their prognosis is poor, 
with a median overall survival of approximately 12 months. All current treatment 
options have a response rate of < 15-20%. There is a clear, unmet medical need 
for effective treatments for patients with platinum-resistant/refractory relapsed 
EOC. 
Recent advances in immunotherapy have led to the development and rapid 
introduction into clinical practice of monoclonal antibodies directed against two 
immune checkpoints, CTLA-4 (Cytotoxic T-lymphocyte-associated antigen-4) and 
PD-1 (Programmed death protein 1) (or PD-L1, Programmed death-ligand 1). All 
of these agents, and in particular the anti-PD-1 antibodies, have shown clear 
benefit in the treatment of metastatic melanoma and non-small cell lung cancer 
(NSCLC). Moreover, responses have been of long duration, suggesting that the 
immune system may be adaptive and to some extent being able to counteract 
the development of treatment resistance. Immune checkpoint inhibitors have 
recently demonstrated encouraging signs of antitumor activity for patients with 
pretreated advanced ovarian cancer.  
It is known that epigenetic modifications in gene expression associated with 
methylation and de-acetylation of DNA and histones occurs in human 
malignancies and can be associated with disease progression and resistance to 
treatment. Epigenetic therapies with either hypomethylating agents, such as 
azacitidine, or histone deacetylase (HDAC) inhibitors have been shown to be of 
benefit in the treatment of some malignancies. More recently, exciting data have 
emerged indicating that treatment with azacitidine may increase the response to 
anti-PD-1 therapy in patients with NSCLC, suggesting that hypermethylation may 
in part explain failure to respond to immune checkpoint inhibition.  
Pre-clinical research investigating the effects of epigenetic therapy (azacitidine 
and/or HDAC inhibitors) on gene expression in human cancer cell lines has 
identified a group of relevant genes whose expression increases in response to 
epigenetic therapy. In general, these genes are involved in immune response, 
supporting a hypothesis that anti-PD-1 therapy may be more effective when 
combined with epigenetic therapy. This “immune signature” that is seen 
following epigenetic therapy may also be a useful biomarker to predict a benefit 
from epigenetic priming during immune checkpoint therapy. In a broad screen 
across cell lines of multiple tumor types, the strongest “immune signature” that 
is seen following epigenetic therapy was observed in ovarian cancer cell lines. 
However, the optimal clinical dosing and scheduling of epigenetic therapy aimed 
at enhancing response to anti-PD-1 has and the efficacy of combined epigenetic 
therapy and immune checkpoint inhibition has not been studied yet in EOC.  


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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CC-486 is a new, oral formulation of azacitidine. This drug is well tolerated and 
produces evidence of induced hypomethylation at doses of 100 to 300 mg daily. 
The primary toxicity of this agent is hematologic; however doses of 300 mg per 
day are well tolerated in patients with myelodysplastic syndromes, a setting 
where marrow tolerance is known to be reduced. We expect doses of 300 mg 
daily to be well tolerated in patients with EOC, who do not have intrinsic bone 
marrow disease.  
This study will enroll subjects with platinum-resistant/refractory EOC/FTC/PPC 
into a phase II clinical trial to be conducted in two sequential parts. Part A aims 
to explore the optimal combination of the monoclonal anti-PD-1 antibody 
pembrolizumab (given at a dose of 200 mg every 3 weeks) with CC-486 (given at 
four different dosing schedules). Part B will then further evaluate the efficacy and 
safety of the optimal schedule of CC-486 and pembrolizumab selected in Part A, 
and compare the combination therapy with pembrolizumab as a single agent in 
a randomized controlled trial setting. Part B will test whether adding epigenetic 
therapy to pembrolizumab can improve the progression free survival to 
pembrolizumab monotherapy in relapsed EOC. 
Part A Objectives / 
Endpoints 
Primary Objectives:  
 
To establish an optimal schedule of CC-486 combined with 
pembrolizumab in subjects with platinum-resistant/refractory EOC.  
The primary endpoint will be based on the safety profile, futility 
evaluation as well as on the irORR/irDCR per irRECIST criteria (also, data 
from the correlative analyses to be done in the biologic samples may be 
taken into consideration for determining the optimal schedule).  
Secondary Objective:  
 
To assess the CA-125 response based on the Gynecologic Cancer 
Intergroup (GCIG) criteria.  
Exploratory objectives: 
 
Tumor samples will be used to assess potential prognostic or predictive 
biomarkers, improve understanding of ovarian cancer biology and 
identify candidate biomarkers that may correlate with treatment benefit 
and/or safety signals.  
 
Whole blood samples will be used to analyze changes in DNA 
methylation during treatment with CC-486. 
Part B 
Objectives/Endpoints 
Primary Objective:  


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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 
To evaluate whether the addition of CC-486 to pembrolizumab (optimal 
schedule selected in Part A) improves the Investigator-assessed immune-
related Progression free survival (irPFS) compared to pembrolizumab 
alone, in subjects with platinum-resistant/refractory EOC.  
The primary endpoint will be assessed according to the Immune-Related 
Response Evaluation Criteria in Solid Tumors (irRECIST).  
Secondary Objective:  
 
To assess secondary measures of efficacy for CC-486 combined with 
pembrolizumab (optimal schedule selected in Part A) relative to 
pembrolizumab alone.  
Efficacy endpoints:  
o Immune-related Overall Response Rate (irORR)  
o Immune-related Disease Control Rate (irDCR)  
o Immune-related Duration of Response (irDoR)  
o CA-125 response based on GCIG criteria  
o Overall Survival (OS)  
 
To assess the safety and tolerability of CC-486 combined with 
pembrolizumab  
Exploratory objectives:  
 
Tumor samples will be used to assess potential prognostic or predictive 
markers, improve understanding of ovarian cancer biology and identify 
candidate biomarkers that may correlate with treatment benefit and/or 
safety signals. 
Study Design 
This is an open-label, multicenter, multinational trial that will be carried out in 
two sequential parts. 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Part A: Part A is an open-label, non-randomized, four-cohort, lead-in selection 
phase in which intravenous pembrolizumab will be combined with 4 different 
schedules of administration of oral CC-486, for the treatment of platinum-
resistant/refractory EOC. Part A is also a futility trial for the strategy to combine 
pembrolizumab and CC-486 in EOC.  
Eligible subjects will be treated in one of four cohorts of combined oral CC-486 
and intravenous pembrolizumab (200 mg IV q 3 weeks in all cohorts) to evaluate 
the safety of each combination schedule and to have preliminary data on their 
efficacy. The primary objective of Part A is to establish the optimal dosing 
schedule for comparison with pembrolizumab alone in Part B of the study.  
Subjects will be assigned to a treatment cohort in the order they are enrolled in 
the study. In all subjects, tumor tissue will be obtained via image-guided core 
biopsy at study entry and 6 weeks after commencing treatment with CC-486 
(provided that the tumor lesion is amenable to a second biopsy). A cohort will 
remain open to accrual until five subjects treated on that cohort have completed 
two CC-486 cycles and have had the first post-baseline tumor burden assessment 
and both tumor biopsies performed and adequate paired tissue obtained. At 
least 5 evaluable subjects per cohort will be accrued to Part A over an estimated 
period of approximately 24 months.  
Subjects will be treated in the assigned cohort until progressive disease based on 
irRECIST, unacceptable toxicity, consent withdrawal or the Investigator 
concludes that it is in the subject´s best interest to discontinue. Once 5 subjects 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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in each cohort are considered evaluable for response, toxicity and treatment 
responses will be analyzed for each of the four cohorts and an optimal schedule 
to be taken forward into Part B will be selected.  
Part A includes mandatory tumor core biopsies for biomarkers research and 
mandatory whole blood sampling for DNA methylation analyses.  
Part B: This will be an open-label, randomized phase II study that will compare 
the safety and efficacy of CC-486 and pembrolizumab (using the schedule that 
was established as optimal in Part A) with pembrolizumab alone, for the 
treatment of platinum-resistant/refractory EOC.  
Eligible subjects will be randomly assigned in a 1:1 ratio to either:  
 
Arm A: Pembrolizumab (200 mg IV every 21 days) in combination with 
CC-486 (dosing schedule established in Part A)  
or 
 
Arm B: Pembrolizumab (200 mg IV every 21 days) as a single agent  
A total of 150 subjects, 75 per arm, will be randomized over an estimated period 
of 24 months. To ensure equal distribution of prognostic factors in the two study 
arms, subjects will be stratified according to the following parameters:  
 
Platinum-refractory vs. platinum-resistant  
 
Number 
of 
prior 
treatment 
regimens 
for 
the 
platinum-
refractory/resistant EOC: none vs. 1 or 2. 
Subjects with tumor lesions amenable to core biopsy will be proposed (although 
not mandated) to undergo an image-guided core biopsy at study entry and 6 
weeks (± 1 week) after first dose of study treatment, provided that the tumor 
lesion is amenable to a second biopsy.  
Subjects will be treated until progressive disease based on irRECIST, 
unacceptable toxicity, consent withdrawal or the Investigator concludes that it is 
in the subject´s best interest to discontinue. Once the subject has discontinued 
from study treatment and has undergone the End of Treatment visit, she will 
enter into the follow-up phase.  
Part B includes an optional exploratory research component. 
Population 
Inclusion Criteria  
1. Signed and dated informed consent document obtained prior to 
initiation of any study-specific procedure and treatment (by the subject 
or a legally acceptable representative as per the local regulations).  


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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2. Women ≥ 18 years old.  
3. Histologically confirmed EOC, FTC or PPC.  
4. Received debulking surgery and preoperative and/or postoperative 
platinum-based 
frontline 
chemotherapy 
(intravenous 
and/or 
intraperitoneal) for the treatment of EOC/FTC/PPC.  
5. Documented 
platinum-resistant 
or 
platinum-refractory 
disease. 
Platinum-resistant disease is defined as progression within < 6 months 
from completion of a minimum of 4 platinum frontline therapy cycles in 
the pre or postoperative setting (the date should be calculated from the 
last administered dose of platinum agent). Platinum-refractory is defined 
as disease that has recurred/progressed while receiving platinum-based 
frontline therapy.  
6. Measurable disease according to irRECIST for Part A. For Part B, subjects 
must have either measurable and/or non-measurable disease according 
to irRECIST (Appendix 2).  
7. Indication of systemic treatment for the relapsed EOC, FTC or PPC.  
8. For Part A, subjects must have a tumor lesion that is amenable to an 
image-guided core biopsy and willingness to undergo two biopsies 
(baseline and 6 weeks after first dose of study treatment). For Part B, 
subjects will be eligible even if their disease is not amenable to biopsy 
and/or the subject does not consent to the optional biopsies.  
9. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 
or 1.  
10. Expected survival of more than 6 months.  
11. Adequate organ function within 7 days prior to enrollment in Part A or 
randomization in Part B, as defined by the following criteria:  
• 
Absolute neutrophils count (ANC) ≥ 1.5 x 109/L, platelets ≥ 100 x 
109/L, hemoglobin > 9 g/dL (without transfusion or erythropoiesis 
stimulating agents’ dependency).  
• 
Serum creatinine ≤ 1.5 x upper limit of normal (ULN).  
• 
Total serum bilirubin ≤ 1.5 x ULN regardless of liver involvement 
secondary to tumor. Higher levels are acceptable if these can be 
attributed to active hemolysis or ineffective erythropoiesis.  


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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• 
Serum aspartate transaminase (AST) and serum alanine 
transaminase (ALT) < 2.0 x ULN or ≤ 5 x ULN for subjects with liver 
metastases.  
• 
International Normalized Ratio (INR) or Prothrombin Time (PT) ≤ 1.5 
x ULN unless subject is receiving anticoagulant therapy as long as PT 
or PTT is within therapeutic range of intended use of anticoagulants  
• 
Partial 
Thromboplastin 
Time 
(PTT) 
or 
Activated 
Partial 
Thromboplastin Time (aPTT) ≤ 40 seconds unless subject is receiving 
anticoagulant therapy as long as PT or PTT is within therapeutic 
range of intended use of anticoagulants.  
12. For women of childbearing potential, negative serum pregnancy test 
within 7 days of enrollment in Part A or randomization in Part B.  
13. Women of childbearing potential must agree to use acceptable methods 
of birth control starting with the screening visit and up to 120 days after 
the last dose of study treatment. Recommendation is for 2 effective 
contraceptive methods during the study. Adequate forms of 
contraception are double-barrier methods (condoms with spermicidal 
jelly or foam and diaphragm with spermicidal jelly or foam), oral depo 
provera, or injectable contraceptives, intrauterine devices, and tubal 
ligation.  
14. Willingness and ability to comply with scheduled visits, treatment plan, 
laboratory tests, and other trial procedures.  
Exclusion Criteria  
1. Non-epithelial ovarian cancers, including malignant mixed Müllerian 
tumors.  
2. Ovarian tumors with low malignant potential (i.e. borderline tumors).  
3. Relapse/progression based solely on elevation of CA-125, in absence of 
measurable disease (for Part A) or in the absence of measurable/non-
measurable disease (for Part B), according to irRECIST criteria.  
4. More 
than 2 
prior 
treatment 
regimens 
for 
the 
platinum-
resistant/refractory 
relapsed 
EOC, 
FTC, 
or 
PTC, 
defined 
as 
investigational, chemotherapy, hormonal, biologic, or targeted therapy.  
5. Any concurrent or previous malignancy within 5 years prior to 
enrollment in Part A or randomization in Part B, except for adequately 
and radically treated basal or squamous skin cancer, or carcinoma in situ 
of the cervix, or other non-invasive/in-situ neoplasm. A subject with 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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previous history of invasive malignancy (other than adequately and 
radically treated basal or squamous skin cancer or carcinomas in situ) is 
eligible provided that she has been disease free for more than 5 years.  
6. Brain metastases (even if treated and/or stable), spinal cord 
compression, carcinomatous meningitis, or leptomeningeal disease.  
7. Prior systemic anticancer therapy within 4 weeks prior to enrollment in 
Part A or randomization in Part B; or who has not recovered (i.e. ≤ Grade 
1 or baseline grade) from adverse events due to a previously 
administered agent  
Notes: subjects with ≤ Grade 2 neuropathy are an exception to this criterion 
and may qualify for the study. If subject received major surgery, they must 
have recovered adequately from the toxicity and/or complications from the 
intervention prior to starting therapy. Subjects with toxicity that has not 
recovered to ≤ Grade 1 or baseline grade are allowed if meeting all inclusion 
criteria.  
8. Prior treatment with a monoclonal antibody within 4 weeks prior to 
enrollment in Part A or randomization in Part B; or who has not 
recovered (i.e. ≤ Grade 1 or baseline grade) from adverse events due to 
agents administered more than 4 weeks earlier.  
Notes: subjects with ≤ Grade 2 neuropathy are an exception to this criterion 
and may qualify for the study.  
9. Diagnosis of immunosuppression or receiving systemic steroid therapy 
or any other form of immunosuppressive therapy within 7 days prior to 
enrollment in Part A or randomization in Part B. The use of physiologic 
doses of corticosteroids may be approved after consultation with the 
sponsor.  
10. Active autoimmune disease or history of autoimmune disease or 
syndrome that has required systemic treatment in the past 2 years (i.e. 
with 
use 
of 
disease 
modifying 
agents, 
corticosteroids 
or 
immunosuppressive drugs). Replacement therapy (e.g. thyroxine, 
insulin, or physiologic corticosteroid replacement therapy for adrenal or 
pituitary insufficiency, etc.) is not considered a form of systemic 
treatment. Subjects with vitiligo or resolved childhood asthma/atopy will 
not be excluded.  
11. Received live vaccines within 30 days prior to enrollment in Part A or 
randomization in Part B.  
12. Current or prior history of myelodysplastic syndrome, leukemia or 
clinically significant (as per Investigator judgment) bone marrow failure.  


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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13. Uncontrolled systemic fungal, bacterial or viral infection at time of 
enrollment in Part A or randomization in Part B (defined as ongoing 
signs/symptoms related the infection without improvement despite 
appropriate antibiotics, antiviral therapy and/or other treatment).  
14. Known history of active TB (Bacillus Tuberculosis).  
15. Known HIV infection or known history of Hepatitis B or known positivity 
for active Hepatitis B (HBsAg reactive) or Hepatitis C (HCV RNA 
[qualitative] is detected).  
16. Known history of non-infectious pneumonitis that required steroids or 
has current pneumonitis (infectious or non-infectious).  
17. Significant active cardiac disease within 6 months prior to enrollment in 
Part A or randomization in Part B , including but not limited to New York 
Heart Association class 4 cardiac heart failure, unstable angina, 
myocardial infarction  
18. History or current evidence of any condition, therapy, or laboratory 
abnormality that might confound the results of the trial, interfere with 
the subject’s participation for the full duration of the trial, or is not in the 
best interest of the subject to participate, in the opinion of the treating 
Investigator. Is or has an immediate family member (e.g. spouse, 
parent/legal guardian, sibling or child) who is investigational site or 
sponsor staff directly involved with this trial, unless prospective IRB 
approval (by chair or designee) is given allowing exception to this 
criterion for a specific subject. 
19. Any contraindication to oral agents or significant nausea and vomiting, 
malabsorption, or significant small bowel resection that, in the opinion 
of the Investigator, would preclude adequate absorption. 
20. Known psychiatric or substance abuse disorders that would interfere 
with cooperation with the requirements of the trial. 
21. Prior treatment with any anti-PD-1, or PD-L1 or PD-L2 agent; or with 
azacitidine (any formulation) or any other hypomethylating agent; or 
with anti-CD137, or anti-CTLA-4 antibody (including ipilimumab) or any 
other antibody or drug specifically targeting T-cell co-stimulation or 
checkpoint pathways. 
22. Known or suspected hypersensitivity to azacitidine, pembrolizumab or 
the excipients of any of the study drugs (including mannitol). Known or 
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23. Currently participating and receiving study therapy or has participated in 
a study of an investigational agent and received study therapy or used 
an investigation device within 4 weeks prior to enrollment in Part A or 
randomization in Part B. 
24. Pregnant or lactating women or is expecting to conceive children or 
breastfeed within the projected duration of the trial, starting with the 
screening visit through 120 days after the last dose of trial treatment. 
Study Treatment 
In this study, CC-486 and pembrolizumab are both considered Investigational 
Medicinal Products (IMP) given their intended use and the objectives of the 
study. Collectively they are referred as “study treatments”.  
Part A:  
Pembrolizumab 200 mg IV every 21 days combined with one of the below four 
schedules of CC-486:  
• 
Cohort 1: CC-486 100 mg q.d. 21 days on, 7 days off.  
• 
Cohort 2: CC-486 100 mg BID, 21 days on, 7 days off.  
• 
Cohort 3: CC-486 300 mg q.d. 14 days on and 14 days off.  
• 
Cohort 4: CC-486 300 mg q.d. 21 days on, 7 days off.  
Part B:  
Subjects will be randomized (1:1) to receive:  
• 
Arm A: pembrolizumab 200 mg IV every 21 days combined with CC-486 
(optimal schedule selected in Part A)  
or 
• 
Arm B: pembrolizumab 200 mg IV every 21 days 
Efficacy Assessments 
Assessment of irORR, irPFS, irDoR, irDCR will be based on tumor assessments 
(according to irRECIST criteria) using CT/MRI of chest, abdomen and pelvis. 
Contrast-enhanced CT scan is the preferred method. The same assessment 
technique must be used throughout the study to evaluate a particular lesion.  
Tumor burden assessments will be performed:  
• 
At baseline: within 28 days prior to enrollment in Part A or 
randomization in Part B. Lesions must be clearly identified and 
documented as Target or Non-Target lesions per irRECIST.  
• 
After baseline:  


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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• 
In Part A: 
o 6 weeks (± 1 week) after first CC-486 intake (first post-
baseline tumor assessment).  
o Thereafter, every 12 weeks (± 1 week), always taking as a 
reference the date of the first post-baseline tumor 
assessment (not the date of the immediately previous tumor 
assessment).  
o Whenever disease progression is suspected based on signs, 
symptoms, performance status deterioration, CA-125, etc.  
o Confirmation of progression (irPD) is recommended 
minimum 4 weeks after the first irPD assessment and is 
required during the flare time-window of the first 12 weeks 
of treatment.  
• 
In Part B:  
o Every 12 weeks (± 1 week), always taking as a reference the 
date of randomization in the study (not the date of the 
previous tumor assessment).  
o Whenever disease progression is suspected based on signs, 
symptoms, performance status deterioration, CA-125, etc.  
o Confirmation of progression (irPD) is recommended 
minimum 4 weeks after the first irPD assessment and is 
required during the flare time-window of the first 12 weeks 
of treatment. 
Assessment of response will also be based on GCIG CA-125 criteria in subjects 
with CA-125 evaluable disease at baseline. However, progression cannot be 
declared on the basis of CA-125 alone.  
Disease assessments with imaging and CA-125 will be performed until 
progressive disease based on irRECIST, regardless of the end of study treatment 
and start of a subsequent anticancer therapy. After progressive disease, subjects 
in Part B will be followed every 6 months (visit or phone contact) until death or 
for at least 1 year after the End of Treatment visit, to assess the survival status.  
Safety Assessments  
Safety assessments will be done at baseline, at each visit during the study 
treatment phase and at the End of treatment visit. Additionally, hematology 
testing will be done weekly. All assessments will be scheduled as indicated in the 
Schedule of Visits and Assessments and include:  


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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• 
Physical examination and vital signs  
• 
Hematology: hemoglobin, absolute neutrophils count (ANC), platelets 
• 
Blood chemistries: creatinine, AST, ALT, alkaline phosphatase, bilirubin, 
glucose, TSH  
• 
Coagulation tests (at baseline and then only if clinically indicated)  
Recording of adverse events will be done according to NCI-CTC AE version 4.03.  
Biomarker Studies  
Tumor core biopsies: Fresh-frozen tissue (FFT) and Formalin-fixed paraffin-
embedded (FFPE) samples (and ascites samples if feasible): will be collected on 
a mandatory basis at baseline and 6 weeks after study treatment start in all 
subjects participating in Part A. In Part B, tumor will be collected in subjects 
consenting to participate in the optional tissue acquisition study, provided they 
have lesion(s) amenable to biopsy. These samples will be transported to the 
Translational Oncology Research Laboratory at the University of California Los 
Angeles (TORL-UCLA). 
Formalin-Fixed Paraffin-Embedded (FFPE) block/partial block from the 
debulking surgery: for subjects consenting to the optional tissue acquisition part 
of the study, a FFPE block/partial block from the ovarian cancer debulking 
surgery (or a minimum of 15 unstained slides if FFPE tissue block cannot be 
provided) will be obtained and submitted to the TORL-UCLA.  
Whole-blood samples for DNA methylation analysis: these samples are 
mandatory in Part A and will be used to analyze changes in DNA methylation 
during treatment with CC-486. Peripheral whole blood samples will be obtained 
on Day 1 of the 1st CC-486 cycle (prior to the first CC-486 intake) and on the pre-
treatment visit prior to the 2nd CC-486 cycle. 
Procedures for sample collection, labeling, storage and shipment will be 
described in the study lab manual. 
Statistical Methods  
Analysis populations: 
For each of the 2 parts of the study, there will be 2 analysis sets :  
• 
Intent-to-Treat Population (ITT): defined as all enrolled subjects  
• 
Safety Population: defined as all subjects who received at least one dose 
of study treatment (CC-486 and/or pembrolizumab)  
Sample size justification:  
Part A  


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Title:  
TRIO026 (Part A) – Statistical Analysis Plan 
 
 
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Part A is an exploratory pilot study of various possible schedules for the 
combination of CC-486 and pembrolizumab. Part A is also a futility trial for the 
strategy to combine pembrolizumab and CC-486 in EOC. Criteria for Part B 
Go/No-Go decision and the determination of an optimal dosing schedule can be 
found in section 3.3 of the protocol. There is no formal sample size calculation 
for lead-in safety and efficacy selection phase of the trial.  
Part B  
Part B is designed to test the hypothesis that combined epigenetic/immune 
checkpoint inhibition is superior to checkpoint inhibition alone in the treatment 
of EOC. The study will be powered to detect a difference in the log rank tests of 
the irPFS curves reflecting a hazard ratio of 0.625 favoring the combination. 
Assumptions are based on (a) an anticipated median irPFS in the pembrolizumab 
monotherapy arm to be 4 months and 6.4 months in the combination arm, (b) 
that the accrual time will be 24 months and the total study time will be 46 months 
and (c) a power of 80% and an alpha error at 0.05 for a two-sided test. Based on 
these assumptions 75 evaluable subjects need to be enrolled in each arm (n=73 
subjects exactly) resulting in a total planned enrollment of 150 subjects.  
Statistical Methods:  
Part A  
The immune-related Overall response rate (irORR) is defined as the proportion 
of subjects who achieve a best overall response of immune-related Complete 
response (irCR) or an immune-related Partial response (irPR) based on irRECIST 
criteria, as per Investigator assessment.  
The immune-related Disease Control Rate (irDCR) is defined as the proportion of 
subjects who achieve a best overall response of irCR, irPR or irSD, as per 
Investigator assessment.  
The CA-125 response rate is defined as the proportion of subjects having a CA-
125 response according to the GCIG criteria.  
Part B  
The immune-related Progression-Free Survival (irPFS) is defined as the time from 
the date of randomization until the date of progression (assessed by irRECIST) or 
death due to any cause, whichever occurs first, as per Investigator assessment. 
Progression will be based on tumor assessment made by the Investigators 
according to the irRECIST criteria. Progression will not be declared on the basis 
of CA-125 alone.  
The immune-related Duration of Response (irDoR) is defined as the time (in 
months) from the date when irPR or irCR is first met (whichever status comes 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Title:  
TRIO026 (Part A) – Statistical Analysis Plan 
 
 
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first) and the date of irPD or death, whichever occurs first (as per Investigator 
assessment).  
irORR, irDCR and CA-125 response rate as described above.  
Overall Survival (OS) defined as the time (in months) from randomization to 
death from any cause.