Clinical trial NCT01845805
Conditions: Pancreatic Cancer
Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Start date: 2014-01-10; Completion date: 2021-04-09
Enrollment: 49 participants; Allocation: RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
To improve progression free survival in high risk patients with resected pancreatic adenocarcinoma who have node positive disease, margin positive disease, and/or elevation in CA 19-9 treated with CC-486 (oral azacitidine) as compared to observation after completion of adjuvant therapy.

Detailed description:
This trial is for patients with resected pancreatic adenocarcinoma who have concluded adjuvant therapy or were deemed unable to receive adjuvant therapy with an elevated CA19-9 or node positive or margin positive disease. CA 19-9 elevation is defined as two levels \> the institutional upper limit of normal (ULN) taken at least 2 weeks apart. These levels should be measured after adjuvant therapy has concluded or upon the decision that adjuvant therapy will not be offered. Patients will be randomized to one of two arms. Subjects enrolled due to node positive disease or R1 resection must be able to undergo randomization within 3 months of finishing adjuvant therapy or the decision that they are unable to take adjuvant therapy. Patients enrolling due to CA19-9 elevation can enroll any time after adjuvant therapy has completed. Arm A, the treatment arm, will be started on CC-486. Arm B, the control arm, will receive no additional therapy. In both arms, CA19-9 will be followed and CT scans (or MRI, if clinically indicated) will be done every three months. When patients have visible disease recurrence on imaging, CC-486 will be stopped and both groups will start first-line chemotherapy.

Arms: arm 1: CC-486 (oral azacitidine), 300 mg total, taken daily on days 1-21 (of a 28 day cycle) for up to 12 cycles. Upon disease recurrence, subjects will start on a first-line chemotherapy. arm 2: Observation until disease recurrence. Upon disease recurrence, subjects will start on a first-line chemotherapy.
Interventions: intervention 1: oral azacitidine intervention 2: Observation
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_SAP_000.pdf: 
Official Title: A Phase II trial to improve outcomes in patients with resected 
pancreatic adenocarcinoma at high risk for recurrence using epigenetic therapy 
Protocol Date: February 18, 2022 
ClinicalTrials.gov ID: NCT01845805 


 
 
SKCCC J12138 
IND 117362 
 
 
Title: A Phase II trial to improve outcomes in patients with resected pancreatic 
adenocarcinoma at high risk for recurrence using epigenetic therapy  
  
IND Sponsor:   
  
  
Nilofer Azad, MD  
 
Study drug provided by:     
Celgene Corporation  
  
  
 
  
Coordinating Center:   
 
Johns Hopkins Sidney Kimmel Comprehensive 
Cancer Center  
 
Principal Investigator:   
  
  
Nilofer Azad, MD  
Sidney Kimmel Comprehensive Cancer Center 
at Johns Hopkins 
 
 
 
 
 
Research Nurse:  
 
 
Sheila Linden, RN  
  
  
 
 
  
  
  
 
 
 
  
  
 
 
 
Statisticians:   
 
 
Elizabeth Sugar, PhD  
  
  
 
 
 
 
 
 


 
  
SKCCC J12138  
IND 117362  
  
Confidential   
  
2 
Version 11.0 / February 18, 2022  
Participating Sites  
Peter J. O’Dwyer, M.D.   
The Hospital of the University of  
Pennsylvania  
  
  
  
  
  
Dulabh K. Monga, M.D. 
Allegheny General Hospital 
 
 
 
 
 
 
  
  
CONFIDENTIAL  
The information contained in this document is regarded as confidential and, except to 
the extent necessary to obtain informed consent, may not be disclosed to another party 
unless law or regulations require such disclosure.  Persons to whom the information is 
disclosed must be informed that the information is confidential and may not be further 
disclosed by them.  
  
  
  
 
 
 


 
  
SKCCC J12138  
IND 117362  
  
Confidential   
  
3 
Version 11.0 / February 18, 2022  
PRINCIPAL INVESTIGATOR SIGNATURE PAGE  
Principal Investigator/Sponsor Approval:  
This clinical study protocol has been reviewed and approved by the study representative listed 
below:  
 Nilofer Azad, MD                                                                                                                 
  Print Name  
  Signature  
  
Associate Professor, Johns Hopkins 
                                                                                                                                                n 
 Title, Medical Institution 
 
           Date (DD MMM YYYY)  
  
 
Investigator’s Signature:  
I have fully discussed the objectives of this study and the contents of this protocol with the 
Sponsor’s representative.  
I understand that information contained in or pertaining to this protocol is confidential and 
should not be disclosed, other than to those directly involved in the execution or the ethical 
review of the study, without written authorization from the Sponsor. It is, however, 
permissible to provide information to a subject in order to obtain consent.  
I agree to conduct this study according to this protocol and to comply with its requirements, 
subject to ethical and safety considerations and guidelines, and to conduct the study in 
accordance with the Declaration of Helsinki, International Conference on Harmonization 
guidelines on Good Clinical Practice (ICH E6), and applicable regional regulatory 
requirements.  
I agree to make available to Sponsor personnel, their representatives and relevant regulatory 
authorities, my subjects’ study records in order to verify the data that I have entered into the 
case report forms. I am aware of my responsibilities as a Principal Investigator as provided 
by the Sponsor.  
I understand that the Sponsor may decide to suspend or prematurely terminate the study at 
any time for whatever reason; such a decision will be communicated to me in writing. 
Conversely, should I decide to withdraw from execution of the study, I will communicate 
my intention immediately in writing to the Sponsor.  
  


 
  
SKCCC J12138  
IND 117362  
  
Confidential   
  
4 
Version 11.0 / February 18, 2022  
----------------------------- 
 
 
----------------------------------------          
Print Name  
 Signature  
  
-------------------------  
 
 
------------------------------------------- 
  Title  
 Date (DD MMM YYYY)  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
  
SKCCC J12138  
IND 117362  
  
Confidential   
  
5 
Version 11.0 / February 18, 2022  
Table of Content  
1 Protocol Synopsis .................................................................................................................. 9 
1.1 Description ...................................................................................................................... 9 
1.2 Schema .......................................................................................................................... 12 
2 Schedule of Study Assessments .......................................................................................... 13 
2.1 Schedule during Initial Phase – Arm A & Arm B .................................................... 13 
2.2 Schedule during Follow Up – All Subjects* ............................................................... 17 
3 Background and Rationale ................................................................................................. 18 
3.1 Adenocarcinoma of the pancreas ................................................................................ 18 
3.2 Epigenetic modification in cancer .............................................................................. 20 
3.3 5-Azacitidine ................................................................................................................. 20 
3.3.1 Indication and Usage ............................................................................................... 23 
3.3.2 Adverse Events ........................................................................................................ 23 
3.4 Rationale for Treatment in this Setting ..................................................................... 24 
3.5 Correlative Studies ....................................................................................................... 25 
4 Study Objectives and Endpoints ........................................................................................ 26 
4.1 Objectives ...................................................................................................................... 26 
4.2 Endpoints ...................................................................................................................... 26 
5 Investigational Plan ............................................................................................................. 27 
5.1 Overall design ............................................................................................................... 27 
5.1.1 5-Azacitidine Description ....................................................................................... 27 
5.2 Screening and Eligibility ............................................................................................. 30 
5.2.1 Inclusion Criteria ..................................................................................................... 30 
5.2.2 Exclusion criteria .................................................................................................... 31 
5.2.3 Inclusion of Women and Minorities ....................................................................... 32 
5.2.4 Patient Recruitment ................................................................................................. 32 
5.2.5 Protocol and Drug Administration .......................................................................... 32 
5.2.6 Multicenter Guidelines ............................................................................................ 32 
5.2.7 Patient Registration ................................................................................................. 33 
5.2.8 Randomization ........................................................................................................ 34 


 
  
SKCCC J12138  
IND 117362  
  
Confidential   
  
6 
Version 11.0 / February 18, 2022  
5.2.9 Dosage Dispensing and Administration .................................................................. 34 
5.2.10 Record of administration ....................................................................................... 35 
5.3 Visit Schedule, Assessments, and Dose Modifications .............................................. 35 
5.3.1 Screening and Pre-Study Assessments .................................................................... 36 
5.3.2 Initial Phase: Assessments, Dose Modifications, and Termination ........................ 36 
5.4 Discontinuation of Treatment: Arm A ....................................................................... 39 
5.4.1 End of Treatment ..................................................................................................... 40 
5.5 Follow-up Phase Both Arms ........................................................................................ 40 
5.6 Concomitant Therapy .................................................................................................. 41 
5.6.1 Recommended Concomitant Therapy ..................................................................... 41 
5.6.2 Prohibited Concomitant Therapy ............................................................................ 42 
5.7 Treatment adherence ................................................................................................... 42 
6 Adverse events ..................................................................................................................... 42 
6.1 Definitions Adverse Event (AE) Definition ................................................................ 42 
6.1.1 Serious Adverse Event (SAE) Definition ............................................................... 42 
6.2 Adverse Event Reporting ............................................................................................ 43 
6.2.1 Pregnancies ............................................................................................................. 45 
6.2.2 Celgene Drug Safety Contact Information: ............................................................. 46 
6.3 Investigator Reporting Responsibilities ..................................................................... 46 
6.3.1 Expedited reporting by investigator to Celgene ...................................................... 46 
6.3.2 Report of Adverse Events to the Institutional Review Board ................................. 46 
6.3.3 Investigator Reporting to the FDA .......................................................................... 46 
6.4 Adverse event updates/IND safety reports ................................................................ 47 
7 Radiologic Evaluation ......................................................................................................... 47 
7.1 Baseline imaging assessments ..................................................................................... 47 
7.2 Definitions of Measurable and Non-Measurable Disease ......................................... 48 
7.3 Guidelines for Evaluation of Measurable Disease .................................................... 49 
7.3.1 Measurement Methods ............................................................................................ 49 
7.3.2 Acceptable Imaging Modalities for Measurable Disease ........................................ 49 


 
  
SKCCC J12138  
IND 117362  
  
Confidential   
  
7 
Version 11.0 / February 18, 2022  
7.3.4 Measurement of Effect ............................................................................................ 50 
7.3.5 Response Criteria during Follow-up Phase ............................................................. 50 
7.3.6 Overall Objective Status during Follow-up Phase .................................................. 51 
8 Correlative Studies .............................................................................................................. 53 
8.1 Plasma/Serum Samples ................................................................................................ 53 
8.2 Tumor Biopsies ............................................................................................................. 54 
8.2.1 Specimen Collection and Handling ......................................................................... 55 
9 Protocol Amendments/Deviations ...................................................................................... 56 
9.1 Protocol Amendments .................................................................................................. 56 
9.2 Protocol Deviations ...................................................................................................... 56 
10 Data Management ............................................................................................................. 56 
10.1 Data Collection ........................................................................................................... 56 
10.2 Analyses and Reporting ............................................................................................. 56 
10.3 Clinical Trial Monitoring .......................................................................................... 57 
10.4 Investigator Responsibilities ..................................................................................... 57 
10.5 Safety Meetings .......................................................................................................... 58 
11 Biostatistical Analysis ....................................................................................................... 58 
11.1 Study Design/Endpoints ............................................................................................ 58 
11.2 Study Populations ...................................................................................................... 58 
11.2.1 Efficacy Evaluable Population .............................................................................. 58 
11.2.2 Methylation Analysis Population .......................................................................... 58 
11.3 Statistical Methodology ............................................................................................. 59 
11.3.1 Efficacy Analyses .................................................................................................. 59 
11.3.2 Methylation Analyses ............................................................................................ 59 
11.3.3 Quality of life analysis .......................................................................................... 59 
11.3.4 Sample Size ........................................................................................................... 60 
11.3.5 Safety Monitoring ................................................................................................. 60 
11.3.6 Futility Analysis .................................................................................................... 61 
12 Regulatory Considerations ............................................................................................... 62 


 
  
SKCCC J12138  
IND 117362  
  
Confidential   
  
8 
Version 11.0 / February 18, 2022  
12.1 Institutional Review Board/Ethics Committee approval ....................................... 62 
12.2 Informed Consent ...................................................................................................... 63 
12.3 Subject Confidentiality .............................................................................................. 63 
12.4 Study Records Requirements .................................................................................... 63 
12.5 Premature Discontinuation of Study ........................................................................ 63 
13 References .......................................................................................................................... 64 
14 Appendices ......................................................................................................................... 68 
Appendix A: ECOG Performance Status Scale .............................................................. 68 
Appendix B: Medication Diary ......................................................................................... 69 
Appendix C: Recommendations for Management of Treatment-Induced Diarrhea (for 
CC-486) ............................................................................................................................ 71 
Appendix D: FACT – Hep (Version 4) ............................................................................. 72 
 
 
  
  
 


 
  
SKCCC J12138  
IND 117362  
  
Confidential   
  
9 
Version 11.0 / February 18, 2022  
1 Protocol Synopsis  
1.1 Description  
PROTOCOL TITLE: A phase II trial to improve outcomes in patients with resected
pancreatic adenocarcinoma at high risk for recurrence using epigenetic therapy  
DATE PROTOCOL FINAL:  
  
INDICATION:  
Cancer Therapy  
STUDY PHASE:  
Phase II  
BACKGROUND AND RATIONALE:    
DNA methylation is often abnormal in cancer cells and can lead to the inactivation of tumor 
suppressor genes.  Hypomethylating agents, such as 5-azacitidine, have been shown to 
reverse DNA hypermethylation and allow for reactivation of tumor suppressor genes and 
ultimately lead to cancer cell death.  These agents are currently the standard of care in 
myelodysplasia and have also shown some efficacy in early phase trials for solid tumors.  In 
pancreatic cancer cell lines, promoter regions of several tumor suppressor genes have been 
demonstrated to be abnormally hypermethylated.  The addition of hypomethylating agents 
has restored the expression of these genes and has decreased tumor growth.  While most of 
the trials have used the subcutaneous delivery of azacitidine, the oral formulation, CC-486, 
is currently being studied in a phase I trial for MDS/AML and has been shown to be 
bioavailable, well-tolerated, and produce similar clinical responses as the subcutaneous 
version.  
  
Pancreatic adenocarcinoma is a very deadly disease, with only 20% of patients being 
candidates for possible curative surgery at presentation.  However, the majority of these 
patients will recur.  Patients that are node positive or margin positive at the time of resection 
have a greater than 90% chance of recurrence and death from disease.  After surgery and 
adjuvant therapy, patients are monitored with CT scans and CA 19-9 levels.  In some 
patients, CA 19-9 levels rise before visible disease progression, suggesting micro-metastatic 
disease.  After completing adjuvant chemotherapy, further chemotherapy is typically not 
used before recurrent disease is visible even with an elevated biomarker; however a therapy 
that is well-tolerated would be ideal in this setting.  The goal of this trial is to demonstrate 
that CC-486 is well tolerated and effective when given after adjuvant therapy in patients 
with high risk disease (rising CA 19-9, node positive disease, or margin positive disease) by 
prolonging time to visible disease recurrence, increasing response rates to eventual 
chemotherapy, and increasing overall survival.  


 
  
SKCCC J12138  
IND 117362  
  
Confidential   
  
10 
Version 11.0 / February 18, 2022  
STUDY OBJECTIVES:  
Primary objective:  
To improve progression free survival in high risk patients with resected pancreatic 
adenocarcinoma who have node positive disease, margin positive disease, and/or elevation 
in CA 19-9 treated with CC-486 as compared to observation after completion of adjuvant 
therapy.  
 
Secondary objectives:  
1) 
To improve response rates to first-line chemotherapy (partial and complete response)
after recurrence in patients treated with CC-486 after completing adjuvant therapy.  
2) 
To improve overall survival in patients with resected pancreatic adenocarcinoma
treated with CC-486.  
3) 
To evaluate resected pancreatic cancer tissue and biopsies at time of recurrence for
epigenetic and genetic alterations to determine the pharmacodynamic effects of CC-
486.  
4) 
To evaluate resected pancreatic cancer tissue and blood samples to identify predictive
signatures of possible recurrence and the benefit of hypomethylating therapy.  
5) 
To evaluate quality of life during CC-486 using the FACIT-Hep questionnaire 
STUDY ENDPOINTS:  
Primary endpoint:  
The primary endpoint of the trial is to demonstrate an increase in the progression free survival,
PFS, in resected pancreatic cancer patients treated with CC-486.  
  
Secondary endpoints:  
1) 
Response rate (including partial and complete response) to first-line chemotherapy
when given after visible disease recurrence in patients primed with CC-486 compared
to observation.  
2) 
Overall survival  
3) 
Decreased methylation in candidate genes in the research biopsies as compared to the
original resected specimens in patients treated with CC-486.  
4) 
Change in quality of life as determined by FACIT-HEp scores  


 
  
SKCCC J12138  
IND 117362  
  
Confidential   
  
11 
Version 11.0 / February 18, 2022  
STUDY DESIGN:  
This trial is for patients with resected pancreatic adenocarcinoma who have concluded 
adjuvant therapy or were deemed unable to receive adjuvant therapy with an elevated CA 
19-9 or node positive or margin positive disease.  CA 19-9 elevation is defined as two levels 
> the institutional upper limit of normal (ULN) taken at least 2 weeks apart.  These levels 
should be measured after adjuvant therapy has concluded or upon the decision that adjuvant 
therapy will not be offered. Patients will be randomized to one of two arms.  Subjects 
enrolled due to node + disease or R1 resection must be able to undergo randomization within 
3 months of finishing adjuvant therapy or the decision that they are unable to take adjuvant 
therapy. Patients enrolling due to CA 19-9 elevation can enroll any time after adjuvant 
therapy has completed. Group A, the treatment arm, will be started on CC-486.  Group B, 
the control arm, will receive no additional therapy.  In both arms, CA 19-9 will be followed 
and CT scans (or MRI, if clinically indicated) will be done every three months. When 
patients have visible disease recurrence on imaging, CC-486 will be stopped and both groups 
will start first-line chemotherapy.  
  
STUDY DURATION:   
Assuming the maximum accrual with a goal 
of 2-3 subjects accrued per month, we 
estimate enrollment duration of 24 months 
with an additional 12 months for follow-up 
with concurrent data analysis and manuscript 
preparation.  
TOTAL SAMPLE SIZE:  
Maximum 60 patients, with 30 patients in each 
of the two arms.    
DRUG SUPPLIES:  
For study participants, Celgene Corporation will provide CC-486  
DOSING REGIMEN:  
Treatment 
Arm  
DRUG  
DOSE  
FREQUENCY # of CYCLES  
Route  
  
A  
  
CC-486  
300 mg  
total, three  
100 mg  
tablets  
Daily, Days 1-
21, Q28 Day 
cycles  
12 cycles and
then follow-up  Oral  
B  
Observation  N/A  
N/A  
12 cycles. 
Follow-up 1 
will be collected 
3 months after 
Cycle 10.  
N/A  


 
  
SKCCC J12138  
IND 117362  
  
Confidential   
  
12 
Version 11.0 / February 18, 2022  
1.2 Schema  
  
  
  
  
  
  
  
  
  


  
  
SKCCC J12138  
 
  
  
IND 117362 
 
  
Confidential  
 
13 
Version 10.0 / July 2, 2020 
 2 Schedule of Study Assessments  
2.1 Schedule during Initial Phase – Arm A & Arm B  
For Arm A ±3 day window for study assessments and ± 2 weeks for Tumor Assessments.   
For Arm B, schedule variations are permitted for Tumor Assessments and CA19-9 collection 
Procedure 
Screening 
Cycle 1 
Cycles 2, 3, 5, 6, 
8, 9, 11 and 12 
Cycles 4, 
7 and 10 
Safety 
Assessment 
Upon Visible 
Disease 
Progression 
≤28 days 
prior to C1D1 
(Day 1) 
(Day 1) 
(Day 1) 
28 days post 
d/c CC-486 
 
Arm A 
Arm B 
Arm A 
Arm A 
Arm B 
Arm A 
Arm A & B 
CC-486 dosing (D1-
21)20 
 
X 
 
X 
X 
 
 
 
Prior medications & 
anti-cancer Therapies  
X 
 
 
 
 
 
 
 
Physical examination 
X 
X1 
 
X 
X 
 
X 
X7 
Vital signs 
X 
X1 
 
X 
X 
 
X 
X7 
Weight 
X 
X1 
 
X 
X 
 
X 
X7 
ECOG performance 
status9 
X 
X1 
 
X 
X 
 
X 
X7 
Tumor assessment 
including CT or MRI 
chest/abd/pelvis10 
X 
 
 
 
X11 
X6, 11, 15 
 
X7 
CBC with differential 
X 
X1 
 
X 
X 
 
X 
X7 


  
  
SKCCC J12138  
 
  
  
IND 117362 
 
  
Confidential  
 
14 
Version 10.0 / July 2, 2020 
Procedure 
Screening 
Cycle 1 
Cycles 2, 3, 5, 6, 
8, 9, 11 and 12 
Cycles 4, 
7 and 10 
Safety 
Assessment 
Upon Visible 
Disease 
Progression 
≤28 days 
prior to C1D1 
(Day 1) 
(Day 1) 
(Day 1) 
28 days post 
d/c CC-486 
 
Arm A 
Arm B 
Arm A 
Arm A 
Arm B 
Arm A 
Arm A & B 
Serum chemistry and 
hepatic panel 
X 
X1 
 
X 
X 
 
X 
X7 
PT/PTT 
X 
 
 
 
 
 
 
X7 
CA 19-9 
X 
X1 
X1, 6 
 
X 
X6, 18 
 
X7 
Pregnancy Test12 
X 
X1 
 
 
 
 
 
 
Blood collection for 
correlative studies19 
X 
X1, 3 
X1, 2, 4 
X3 
X3 
X2, 4 
 
X8 
Tumor biopsy13, 19 
 
 
 
 
 
 
 
X 
Record adverse 
events/symptoms17 
X 
X1 
 
X 
X 
 
X 
X 
Collect remaining pills 
and diary21 
 
 
 
 
X 
X 
 
X 
X 
Record concomitant 
therapies/procedures 
X 
X1 
 
X 
X 
 
X 
X 
Archival Tissue16, 19 
X 
 
 
 
 
 
 
 
Quality of Life 
X 
X1 
X1, 5 
 
X 
X5 
X14 
X7 
 


  
  
SKCCC J12138  
 
  
  
IND 117362 
 
  
Confidential  
 
15 
Version 10.0 / July 2, 2020 
In order to minimize the need for research-only in-person visits, telemedicine visits may be substituted for in person clinical trial visits or portions of 
clinical trial visits where determined to be appropriate and where determined by the investigator not to increase the participants risks. Prior to initiating 
telemedicine for study visits the study team will explain to the participant, what a telemedicine visit entails and confirm that the study participant is in 
agreement and able to proceed with this method. Telemedicine acknowledgement will be obtained in accordance with the Guidance for Use of 
Telemedicine in Research. In the event telemedicine is not deemed feasible, the study visit will proceed as an in-person visit. Telemedicine visits will be 
conducted using HIPAA compliant method approved by the Health System and within licensing restrictions. 
 
1       If study assessment assessed within 7 days of Cycle 1, Day 1, they do not need to be repeated.  
2       Correlative blood sampling is optional for patients in Arm B except for at screening and at   time of visible disease progression.  
3 
For patients assigned to Arm A, research blood will be collected for tumor methylation analysis and other correlative studies on Day 1 of every 
cycle.  
4 
For patients assigned to Arm B, research blood will be collected for tumor methylation analysis and other correlative studies at screening and/or 
Cycle 1 Day 1 and Day 1 of every third cycle beginning with Cycle 4 (Cycle 4, 7, 10).  
5 
Patients on Arm B can provide this information to study team member over the phone.  
6 
Patients on Arm B who opt not to participate in correlative blood sampling may be assessed by their local oncologist for all clinical, laboratory 
and imaging parameters.  
7 
If study assessment was completed within 7 days of noting visible disease progression, they do not need to be repeated.  
8 
For Arm A patients, if research blood was collected within one month, it does not need to be repeated. For Arm B patients, if research blood was 
collected within 3 months, it does not need to be repeated. 
9 
Please refer to Appendix A for definition of ECOG performance status.  
10 
Radiologic imaging of chest/abdomen/pelvis (CT preferred, abdominal/pelvis MRI will be performed for patients with CT contrast allergy) and 
any other imaging required per RECIST for the particular subject are required at baseline must be obtained within 4 weeks of initiation of therapy. 
11 
Assessment for presence of visible disease will occur prior to every third cycle, beginning with Cycle 4 (Cycles 4, 7, 10). For each individual 
patient, the same imaging modality should be used at assessment as was used during screening.  
12 
Obtain a urine or serum pregnancy test at screening no more than 7 days prior to dosing on Day 1.  
13 
Tumor biopsies will be obtained at the time of visible disease recurrence for all subjects. Location of biopsy can be primary tumor or site of 
metastatic disease, as determined by the treating oncologist. Tumor biopsy may be obtained within 4 weeks of visible disease progression or 
before first dose of chemotherapy, whichever occurs latest.  
14 
Completed only if FACIT data not collected at time of visible disease progression  


  
  
SKCCC J12138  
 
  
  
IND 117362 
 
  
Confidential  
 
16 
Version 10.0 / July 2, 2020 
15 
Tumor assessments should ideally be performed within a +/- 2 week window every 3 months (Cycle, 4, 7, and 10). However, Tumor assessment 
may be completed at the patient’s oncologist’s discretion outside of the ideal window 
16 
May be obtained any time throughout the study for both Arm A and Arm B patients.  
17 
Assessment not required for Arm B patients 
18 
For Arm B patients CA19-9 may be collected outside of the recommended 3 month window at the patient’s local oncologist’s discretion. 
19  Research samples will be collected at the discretion of the PI based on availability of supplies and safety of patient and staff. 
20 
CC-486 dosing (D1-21) research drug may be shipped to patients to limit contact due to COVID-19 precautions. See Section 5.2.9.1 for more 
details. 
21 
Review of remaining pills and pill diary may be reviewed during a telemedicine visit when drug is unable to be returned to study staff due to 
COVID-19 precautions. Copies of the pill diary may be submitted to study staff by phone, email, fax, or mychart. 
 
 
 
 
 


  
  
SKCCC J12138  
 
  
  
IND 117362 
 
  
Confidential  
 
17 
Version 10.0 / July 2, 2020 
2.2 Schedule during Follow Up – All Subjects* 
Assessments are to be completed within 3 months of safety assessment/progression/previous follow-up 
Schedule variations for CA19-9 and Imaging assessments permitted 
Procedure * 
Follow Up 
 (Until 2nd disease 
progression) 
Survival  
Follow-Up** 
(<  3mo of previous follow up)
Information on new cancer therapies (records to be obtained)
X 
 
Subjective response to therapies (records to be obtained) 
X 
 
CA 19-9 (records to be obtained)  
X 
 
Imaging completed (records to be obtained)  
X 
 
Study team contact*** 
X 
X 
 
*  
For Arm B patients, follow up will be completed within 3 months of cycle 10 or within 3 months of disease progression. For Arm A patients, 
follow up will be completed within 3 months of safety assessment. If safety assessment was not completed, follow up will begin within 3 months 
of progression/discontinuation of drug. Follow Up assessments are ideally to be completed on a 3 month schedule, in which subsequent follow 
ups will be completed within 3 months of the previous follow-up. However, CA.19 and Imaging may be completed per the patient oncologist’s 
discretion. An attempt to contact patients and obtain information on new cancer therapies and subjective responses to such therapies will occur 
within 3 months of the previous follow up. 
 
** Survival Follow-Up will begin once the patient is deemed to have progressive disease for the second time. If the patient has not progressed and 
was put on Follow Up for reasons other than visible disease progression, patient must still have two instances of visible disease progression until 
being on the Survival Follow Up schedule. Patients will remain on the selected Follow-Up schedule for a combined total of up to 4 years, death 
or the subject withdraws consent (whichever occurs first). 
*** Study team will attempt to contact the patient in order to obtain information regarding his/her survival status, and any other comments/information 
per PI’s request. While it is preferred the study team contacts the patient for follow-up, this information may also be obtained through medical 
records and obituaries.  
 


SKCCC J12138 
IND 117362  
Confidential              
  
18 
Version 11.0 / February 18, 2022   
3 Background and Rationale  
3.1 Adenocarcinoma of the pancreas  
Pancreatic adenocarcinoma has one of the highest incidence-to-mortality ratios of any disease.  
Although it represents the 10th leading cause of cancer in the US, it is the 4th leading cause of 
cancer-related deaths.  In 2011, there was an estimated 44,030 new cases and 37,660 deaths from 
pancreatic cancer in the US alone1.  At diagnosis, at most 20% of patients are surgical candidates 
and thus potentially curable, however the majority will recur and eventually die of their disease.  
Their median survival is still under 2 years with a 20% 5-year survival2-4.  A standard adjuvant 
treatment approach for patients with resected disease has not yet been determined, although 
chemotherapy or chemoradiation therapy is most commonly used.  Patients that have positive 
lymph nodes (negative nodes is N0, positive nodes is N1) or positive margins (negative margin is 
R0, microscopic is R1) at the time of their resection have a very high risk of developing recurrence 
as their cancer has already spread beyond the pancreas itself.  In the event of tumor recurrence, 
defined as visible disease present on imaging, further chemotherapy is given.  However, an earlier 
sign of recurrence is sometimes a rising blood CA 19-9 level, a tumor marker indicative of 
presence of disease, without visible tumor seen on imaging.  Our goal is to give these patients 
who are high risk of recurrence (N1 disease, R1 margins, or elevated CA 19-9) a therapeutic 
option before their disease reveals itself on imaging.  Epigenetic agents are drugs that function by 
reactivating tumor suppressor genes to slow cancer progression.  This project aims to slow the 
recurrence of pancreatic cancer in these high risk patients by treatment with the epigenetic drug, 
azacitidine.  
 
Positive lymph nodes found at the time of resection have been consistently shown to be a poor 
prognostic factor for overall survival in resected pancreatic adenocarcinoma5.  As a result of this, 
lymph node status is incorporated into the AJCC staging classification.  Patients with positive 
nodes regardless of being T1, T2 or T3 disease are stage IIB6.  It is recommended that a minimum 
of 12-15 nodes should be removed during a pancreaticoduodenectomy procedure (Whipple) in 
order to accurately stage a patient as node positive or node negative.  This number was shown to 
be critical when 1150 patients who had undergone a Whipple procedure were examined from the 
SEER database.  Patients that had N0 disease when 15 or more lymph nodes were removed had 
an 8 month improved survival as compared to the patients who had N0 disease when less than 15 
nodes were removed7.  Similarly, patients who had N0 disease with fewer than 12 nodes removed 
had a similar survival to those with a few positive nodes in another retrospective review8. This 
implies that the patients with fewer than 12-15 removed lymph nodes may have occult positive 
nodal disease that is not found on pathologic review and could lead to a worse to a worse survival 
than expected based on stage.  However, examining more than 15 nodes does not improve the 
survival based on a prospective trial randomizing patients to standard Whipple versus extended 


SKCCC J12138 
IND 117362  
Confidential              
  
19 
Version 11.0 / February 18, 2022   
lymphadenectomy.  In both the standard and the extended group, the patients with node positive 
disease had about an 11-19% decrease in survival at 1 year and 21-44% decrease at 3 years when 
compared to the node negative patients and there was no difference in survival among the surgery 
groups9.  In a retrospective review of 1423 patients who underwent Whipple procedures from 
1970 to 2006 at The Johns Hopkins Hospital, 78% had positive lymph nodes.  On multivariate 
analysis, positive lymph node status was a predictor for shorter survival10. Nodal involvement 
was also shown to be an independent predictor of worse outcome in an analysis of a phase II 
Japanese trial of neoadjuvant therapy11, an MD Anderson retrospective review12, as well as in the 
RTOG 9704 trial where the hazard ratio for N0 disease was 0.63 when compared to patients with 
1-3 positive nodes13.  A large meta-analysis again showed that median survival across all studies 
of N0 patients was 25 months as compared to 13.6 months for all of the N1 patients14.  
The relationship between positive margins and worse survival has not been as conclusively 
determined.5 Both the Johns Hopkins Hospital10 and the MD Anderson12 reviews demonstrated 
that positive resection margins were independent predictors of decreased survival.  The large 
meta-analysis also demonstrated an increase in survival from 10.3 months for all patients with R1 
resections compared to 20.3 months for patients with R0 resections14. The benefit of an R0 
resection was proven to improve overall survival despite a larger surgery when a retrospective 
review compared patients who had pancreaticoduodenectomy with a positive pancreatic neck 
margin with patients who were converted to a total pancreatectomy and had negative margins.  
Median overall survival was 10 months in the R1 group versus 18 months in the R0 group15.  
However, margin status wasn’t a significant factor in a multivariate analysis in a retrospective 
study of 291 patients after taking into account size and stage of the tumor16. 
Serum biomarkers have been evaluated to aid in the early detection of pancreatic cancer and CA 
19-9 has shown the most promise to help differentiate carcinoma from non-malignancy2, 3.  It can 
also be used in the peri-resection state where higher levels are associated with increased tumor 
size, higher stage, and shorter survival17.  The RTOG 9704 trial evaluated patients who received 
adjuvant chemoradiation after resection and those with post-op CA 19-9 ≥ 180 had a median 
survival of 9 months compared to 21 months when CA 19-9 < 18018.  Patients who undergo 
resection and adjuvant therapy are monitored with imaging and CA 19-9 levels, but are not 
commonly offered more treatment until disease recurrence is evident on imaging given the 
cumulative toxicities of standard chemotherapy. However, rising CA 19-9 levels are likely an 
early sign of local recurrence or micro-metastatic disease and a treatment that can be easily 
tolerated would be beneficial in order to lengthen time to visible disease progression and survival. 
Although there is no published data, our experience is that it usually takes between 3 and 6 months 
for patients to develop visible disease after their CA 19-9 rises. We are currently performing a 
retrospective study of patients who have undergone surgery at Johns Hopkins and continue to be 
followed here to further clarify this observation.  
 


SKCCC J12138 
IND 117362  
Confidential              
  
20 
Version 11.0 / February 18, 2022   
 
 
 
  
3.2 Epigenetic modification in cancer  
 Epigenetic modification is the process by which gene expression is altered by mechanisms other 
than changes in the actual DNA sequence.  DNA methylation, a type of epigenetic modification, 
occurs when DNA methyltransferases transfer a methyl group onto the 5’ carbon of the cytosine 
pyrimidine ring of promoter regions of genes.  These promoter regions are characterized by a high 
number of cytosine-guanine dinucleotides, called CpG islands.  When the CpG islands are 
unmethylated, this leads to an open chromatin state that allows for the transcription of the gene 
that follows this promoter region. Conversely, when the CpG islands are hypermethylated, the 
chromatin is closed and transcription of the gene is suppressed.  Therefore, hypermethylated 
promoter regions silence the gene which follows.  In the normal cell, DNA methylation occurs in 
varying amounts throughout the genome in order to control gene expression.  This process is often 
abnormal in cancer cells19-21.    
Tumor suppressor genes are a large category of genes that control cell proliferation through 
various mechanisms like regulating the cell cycle, repairing damaged DNA, and encouraging 
apoptosis22.  They act as the stop signals for cells. However, when these genes are inactivated, 
cell growth is not properly controlled and damaged cells can accumulate and lead to tumorgenesis.  
In normal cells, the promoter regions for these tumor suppressor genes are unmethylated thereby 
allowing for transcription of the genes.  In cancer cells, however, some of these promoter regions 
are hypermethylated leading to inactivation and silencing of the tumor suppressor gene20, 23.  This 
mechanism is a very intriguing target for cancer therapy as DNA methylation, like other 
epigenetic modification, is reversible20, 23.  
3.3 5-Azacitidine  
5-Azacitidine (AZA) and 5-aza-2’-deoxycytidine (decitabine, DAC) are pyrimidine nucleoside 
analogs of cytidine, both with 5’ modifications of the ring.  These drugs were initially used at 
high doses in the 1970’s as cytotoxic agents, mainly in hematologic malignancies.  They have 
since been shown to promote DNA hypomethylation at lower doses by incorporating themselves 
in DNA and RNA, irreversibly binding to DNA methyltransferases, and causing decreased 
methylation in daughter cells.  This allows for reactivation of tumor suppressor genes leading to 
cessation of cancer cell growth, cancer cell damage and ultimately cancer cell death24.  In 
myelodysplastic syndrome and in elderly patients with acute myelogenous leukemia, AZA and 
DAC have demonstrated improved overall survival and time to leukemia progression25-27.  A 


SKCCC J12138 
IND 117362  
Confidential              
  
21 
Version 11.0 / February 18, 2022   
phase III trial randomized 358 patients with high-risk MDS to receive either AZA or best 
supportive care. Overall survival was 24.5 months in the AZA group compared to 15.0 months in 
the control group28.  AZA and DAC are now considered the standard of care for patients with 
intermediate or high-risk MDS and elderly patients with AML who cannot receive high intensity 
treatment29.  As these agents work best in cells as they are diving, optimal efficacy has been seen 
after several months as the drugs get incorporated into the cells24 and therefore are likely most 
effective in situations when time is available.    
While this phase III data was done using a subcutaneous administration of azacitidine, the oral 
formulation, CC-486, (typically given for 7-21 days and repeated every 28 day cycle) is currently 
being studied in early phase trials in this patient population.  It was first shown to be safe at a low 
dose in a pilot pharmacokinetic study in 200830.  In the phase I study supported by Celgene to 
determine the maximum tolerated dose of CC-486,  41 patients with MDS, CMML or AML 
refractory or inappropriate for conventional therapies received one cycle of subcutaneous 
azacitidine followed by cycles of CC-486 given days 1-7 of every 28 day cycle.  The maximum 
tolerated dose (MTD) was 480 mg.  The dose limiting toxicity was severe diarrhea, experienced 
in 2 of 3 of the patients at the 600 mg dose.  Nausea, vomiting, headache, fatigue, fever, cough 
and febrile neutropenia were the other grade 3 adverse events observed.  8 patients were still 
receiving the study drug at the time of the paper’s publication.  CC-486 was rapidly absorbed with 
a mean bioavailability at the MTD of 13%.  CC-486 did cause hypomethylated of a significant 
number of loci with peak effect at day 15 of each cycle, although not to the same extent as 
subcutaneous azacitidine.  Clinical responses were seen in 35% of patients with MDS and CMML 
who were previously treated and in 73% of patients who received this as first-line therapy.  
Therefore, CC-486 has proved to be bioavailable, well tolerated and produce similar clinical 
response as the subcutaneous version31.  This group also presented more detailed pharmacokinetic 
and pharmacodynamic data at the 11th International Symposium on Myelodysplastic Syndrome 
in Scotland in May 2011 of the above subcutaneous followed by oral dosing as well as oral dosing 
starting from the first cycle.  This poster demonstrated data from patients who in 28 day cycles 
took CC-486 200 mg days 1-14, 200 mg days 1-21, 300 mg days 1-14, and 300 mg days 1-21.  
The 300 mg given days 1-21 of a 28 day cycle demonstrated reduced DNA methylation, provided 
56% of the cumulative exposure to 5azacitidine as compared to 7 days of the subcutaneous 
version, and was well tolerated.  
 
The impact of methylation and use of hypomethylating agents has also been studied in solid 
tumors.  In lung cancer, there have been suggestions of efficacy, with some heavily pretreated 
metastatic patients showing tumor shrinkage or disappearance, and other patients that have lived 
longer than expected even without discrete tumor shrinkage.  Decitabine has been shown to act in 
nasopharyngeal carcinoma and gastric adenocarcinoma to allow for the re-expression of the tumor 
suppressor gene TSLC132 and ID433, respectively.  Epigenetic therapy is presently being tested in 


SKCCC J12138 
IND 117362  
Confidential              
  
22 
Version 11.0 / February 18, 2022   
colon and breast cancer as well. Most of the studies used subcutaneous azacitidine, however some 
recent phase I trials are investigating the use of the oral formulation, CC-486.  
 
 
 
 
 
 
 
 
 
 
 
    
 
In pancreatic cancer, hypermethylation of the promoter regions of mismatch repair genes 
(hMLHI)34, growth inhibitory genes (ARHI)35, cell cycle control genes (Cyclin D2)36, and 
proapoptotic genes (TNFRSF10c37, TMS138, and CRABP239) have been shown to lead to the loss 
of expression of those genes which contributes to tumor growth.  When DAC was added to 
pancreatic cancer cells that exhibited hypermethylation of the gene ARHI, ARHI was reexpressed, 
cell growth was inhibited by almost 50%, and apoptosis was increased by 10-fold.  Pancreatic 
cancer cells were then implanted into mouse xenografts, DAC was added to half of the cohort, 
and the mice were sacrificed after 3, 5, 7, or 9 days.  As compared to the control mice, those that 
were treated with DAC had a decrease in the volume of their tumor by 52% after 3 days of 
treatment and by 92% after 9 days, demonstrating that the addition of a hypomethylating agent 
can slow the growth of the tumor35.  Pancreatic cancer cell lines with hypermethylation of 
TNFRSF10c also showed an increase in gene expression by up to 8 times, a decrease in promoter 
region methylation by over 50%, as well as an increase in apoptosis with the addition of DAC37.  
When AZA was added to pancreatic cancer cells with hypermethylated TMS1, there was a 2.5 
fold increase in TMS1 expression. Furthermore, when gemcitabine or docetaxel were added to the 
cells, the ones that were pre-treated with AZA had a 25-30% increase in cell death after the 
chemotherapy as compared to the cells without pre-treatment38.  Lack of expression of CRABP2 
in pancreatic cell lines has been shown to make them resistant to treatment with retinoic acid.  The 
promoter regions were found to be hypermethylated in these resistant cell lines and expression of 
CRABP2 was increased with the treatment of DAC.  As CRABP2 over expression is known to 
cause apoptosis in other types of tumor cell lines, increasing its expression may make these cells 
more sensitive to treatment including retinoic acid39.  More recently, a putative tumor suppressor 
gene, myeloid/lymphoid or mixed-lineage leukemia 3 (MLL3) has been shown to have 
diminished expression in pancreatic tumor cell lines, tumor xenografts and archived patient 


SKCCC J12138 
IND 117362  
Confidential              
  
23 
Version 11.0 / February 18, 2022   
tumors.  Upon further lowering the MLL3 expression by RNAi, these cell lines demonstrated 
increased transformation and invasion under in vitro conditions.  Its CpG island promoter region 
was found to be hypermethylated.  Treatment with a DNA methyltransferase inhibitor caused 
hypomethylation and re-expression of the MLL3 gene in the cell lines.  Therefore, 
hypomethylating agents that allow for these genes to be re-activated can differentiate between 
cancerous and non-cancerous tissues and control tumor growth.  In addition, hypermethylation of 
these promoter regions may cause disruptions of the apoptotic pathway that contribute to the 
chemotherapy resistance seen in pancreatic cancers.  This data supports our hypothesis that 
pretreating patients with CC-486 will impair tumor growth and increase their sensitivity to 
chemotherapy.  
3.3.1 Indication and Usage  
5-Azacitidine is indicated for treatment of patients with both low and high-risk myelodysplastic 
syndrome (MDS) for the following French-American-British (FAB) subtypes: refractory anemia 
(RA) or refractory anemia with ringed sideroblasts (RARS) (if accompanied by neutropenia or 
thrombocytopenia or requiring transfusions), refractory anemia with excess blasts (RAEB), 
refractory anemia with excess blasts in transformation (RAEB-T), and chronic myelomonocytic 
leukemia (CMMoL).  It is also considered a category 2B recommendation per the NCCN 
guidelines (based on lower-level evidence with a non-uniform NCCN consensus but no major 
disagreement) for elderly patients with AML who cannot receive conventional high-intensity 
chemotherapy.  
3.3.2 Adverse Events  
The most common adverse reactions (>30%) for the subcutaneous route per the package insert 
are: nausea, anemia, thrombocytopenia, vomiting, pyrexia, leukopenia, diarrhea, injection site 
erythema, constipation, neutropenia and ecchymosis.  The most common adverse reactions by IV 
route also include petechiae, rigors, weakness and hypokalemia.   
 
The most common adverse reactions for the oral route (CC-486) per the phase I trial were: 
diarrhea, nausea, constipation, vomiting, abdominal pain, headache, fatigue, peripheral edema, 
fever, cough, confusion, dizziness and febrile neutropenia.  The DLT was diarrhea31.  
 
 
 
   
 
 
 


SKCCC J12138 
IND 117362  
Confidential              
  
24 
Version 11.0 / February 18, 2022   
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
Complete and updated adverse events are available in the Investigational Drug Brochure and the 
IND Safety Letters.  
3.4 Rationale for Treatment in this Setting  
Pancreatic cancer is a highly aggressive malignancy.  Increasing preclinical and clinical evidence 
has suggested that epigenetic therapy requires several months to achieve optimal efficacy, 
creating a great challenge in a rapidly progressing cancer.  High-risk pancreatic cancer patients 
with positive nodal disease, positive resection margins, and/or elevated CA 19-9, are a unique 
patient population to test this type of treatment.  The window of time until disease progression 
provides an ideal opportunity to employ epigenetic therapy.  Currently, there is no consensus as 
to how one should treat patients with pancreatic cancer who have undergone resection and 
adjuvant therapy but have an elevated CA 19-9.  Although CA 19-9 has a variable specificity for 
identifying pancreatic adenocarcinoma, its continual rise in a patient with previously known 
disease highly suggests microscopic recurrence, despite a lack of visible disease on scans.  
Physicians hesitate to give conventional cytotoxic chemotherapy in the absence of clear disease; 
however patients and physicians are left unsettled given the knowledge that the disease is 
recurring.  Similarly, patients who have N1 disease or R1 resections are not typically given any 
further treatment after completing their adjuvant therapy in the absence of disease; however 
virtually all of these patients will recur.  Azacitidine is a very well tolerated therapy that can be 
given to patients in this time period without significant toxicity.  Preclinical models demonstrate 
that multiple tumor suppressor genes have abnormally hypermethylated promoter regions in 
pancreatic cancer, therefore AZA would allow for these genes to be reactivated and to slow tumor 


SKCCC J12138 
IND 117362  
Confidential              
  
25 
Version 11.0 / February 18, 2022   
growth.  Furthermore, there is preclinical and clinical data in other solid tumors that suggests that 
AZA may prime the cancer to improve its response to chemotherapy – a hypothesis that our study 
will also test.    
3.5 Correlative Studies    
Correlative studies will be performed to determine if therapy with CC-486 results in 
demethylation which can be detected in tumor tissues, as well as plasma. These studies will also 
evaluate for an epigenetic signature that can help predict patients who will be responders versus 
non-responders and identify predictive signatures of possible recurrence and benefits of CC-486 
therapy.  
 
Blood for correlative studies will be drawn from both Arm A and Arm B patients at screening 
and/or on Day 1 of Cycle 1. Patients in Arm A will have research blood work done on Cycle 1 
Day 1 if Day 1 is not within 7 days of screening, and Day 1 of every subsequent cycle.  
 
For patients in Arm B, additional research blood work is optional, except for at visible disease 
progression. If patients in Arm B choose to provide research blood, it will be collected every third 
cycle beginning at Cycle 4. Research blood will be collected at recurrence if it was not collected 
within the last three months.  
 
These correlative studies are done in order to evaluate the methylation status of free tumor DNA 
circulating in the blood.  Quantitative analysis using real-time Methylation-specific PCR (MSP) 
will be used to detect the presence of methylated alleles for specific genes. Candidate genes found 
to be hypermethylated in pre-treatment samples will be monitored for changes in methylation 
during and after treatment using real-time MSP.  Methylation status analysis will also be done on 
pre-treatment and post-treatment samples using a novel nano-enabled methylation based 
technology, Methylation-on-Beads.  This assay has shown great promise as a tool for surveillance 
of responses to epigenetic therapy.  Blood will also be stored to use in the future if new biomarkers 
are developed that may better predict recurrence.  
 
All patients will also undergo a tumor biopsy at the time of their recurrence on scans that will be 
examined with their original resected pancreatic tumor.  All biopsy specimens will undergo tumor 
methylation analysis with MSP for select candidate genes (TMS1, ARH1, etc).   Where sufficient 
tissue is obtained, samples will also be studied using HumanMethylation 450K BeadChip 
(Illumina).  This technology examines over 450,000 CpGs and we will analyze the data and 
integrate the methylome data with mRNA or miRNA expression array studies.  


SKCCC J12138 
IND 117362  
Confidential              
  
26 
Version 11.0 / February 18, 2022   
4 Study Objectives and Endpoints  
4.1 Objectives  
Primary objective:  
To improve progression free survival in patients with resected pancreatic adenocarcinoma who 
have node positive disease, margin positive disease, and/or elevation in CA 19-9 treated with CC-
486 as compared to observation after completion of adjuvant therapy.  
  
Secondary objectives:  
1) To improve response rates to first line chemotherapy (partial and complete response) after 
recurrence in patients treated with CC-486 after completing adjuvant therapy   
2) To improve overall survival in patients with resected pancreatic adenocarcinoma treated with 
CC-486.  
3) To evaluate resected pancreatic cancer tissue and biopsies at time of recurrence for epigenetic 
and genetic alterations to determine the pharmacodynamic effects of CC-486.  
4) To evaluate resected pancreatic cancer tissue and blood samples to identify predictive 
signatures of possible recurrence and the benefit of hypomethylating therapy.  
5) To evaluate quality of life on CC-486 using the FACIT-Hep questionnaire  
4.2 Endpoints  
Primary endpoint 
The primary endpoint of the trial is to demonstrate an increase in the progression free survival, 
PFS, in resected pancreatic cancer patients treated with CC-486  
  
Secondary endpoints 
1) Response rate (including partial and complete response) to first line chemotherapy when given 
after visible disease recurrence in patients primed with CC-486 compared to observation  
2)  Overall survival  
3)  Decreased methylation in candidate genes in the research biopsies as compared to the original 
resected specimens in patients treated with CC-486.  
4) Change in quality of life scores as determined by FACIT-Hep  
 


SKCCC J12138 
IND 117362  
Confidential              
  
27 
Version 11.0 / February 18, 2022   
5 Investigational Plan  
5.1 Overall design  
This is a randomized, phase II study of CC-486 versus observation in patients with resected 
pancreatic adenocarcinoma who have finished adjuvant chemotherapy and/or chemoradiation (or 
were deemed unable to receive adjuvant therapy) with no evidence of visible disease on imaging 
and have high risk features.  High risk features are defined as an elevated CA 19-9 level > ULN 
drawn on 2 occasions at least 2 weeks apart; positive nodal disease; and/or positive resection 
margins. The study will be conducted at Johns Hopkins University, The University of 
Pennsylvania, Massachusetts General Hospital, and Beth Israel Deaconess Medical Center.  
Patients will be randomized to one of two arms to enable us to evaluate for effects of CC-486 in 
this population. Arm A will be started on CC-486 at 300 mg daily for 21 days, repeated every 28 
day cycle.  The maximum tolerated dose from the phase I trial in patients with MDS, CMML and 
AML was 480 mg given for 7 days every cycle31, however this lower dose given for a prolonged 
period of time appeared to be tolerated better and had good bioavailability. Arm B will receive 
observation only.  It will be recommended that patients obtain a CA 19-9 and tumor assessment 
every three months, however, schedule variations are permitted at the oncologist’s discretion. 
Patients on the observation arm who are unable to travel to study site may be followed by their 
local oncologist ideally adhering to the same schedule. When patients have visible disease 
recurrence on CT scan, Arm A will stop the CC-486 and may begin their preferred cancer 
treatment regime. Similarly, after visible recurrence on imaging, Arm B will begin their preferred 
cancer treatment regime. Both Arm A and Arm B patients will follow the Follow-up schedule 
after their first visible disease progression. Once patients have had a 2nd instance of visible disease 
progression, they will be moved to the survival follow-up schedule. We will power this study in 
order to see a 64% increase of the progression free survival between the two groups. This will 
require approximately 60 patients to be enrolled and randomized.    
5.1.1 5-Azacitidine Description  
5-Azacitidine is a pyrimidine nucleoside analog of cytidine.  5-Azacitidine is 4-amino-1-β-
Dribofuranosyl-s-triazin-2(1H)-one. The empirical formula is C8H12N4O5. The molecular weight 
is 244.   The structural formula is:  
  
Chemical Structure of 5-Azacitidine  
  


SKCCC J12138 
IND 117362  
Confidential              
  
28 
Version 11.0 / February 18, 2022   
  
5-Azacitidine is a white to off-white solid. It was found to be insoluble in acetone, ethanol, and 
methyl ethyl ketone; slightly soluble in ethanol/water (50/50), propylene glycol, and polyethylene 
glycol; sparingly soluble in water, water saturated octanol, 5% dextrose in water, N-methyl-2-
pyrrolidone, normal saline and 5% Tween 80 in water; and soluble in dimethylsulfoxide (DMSO).  
5.1.1.1 Clinical Pharmacology  
5-Azacitidine is a pyrimidine nucleoside analog of cytidine.  It 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 5-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 5-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 5-azacitidine.  
5.1.1.2 Pharmacokinetics  
The pharmacokinetics of 5-azacitidine were studied in 6 MDS patients following a single 75 
mg/m2 subcutaneous (SC) dose and a single 75 mg/m2 intravenous (IV) dose. 5-Azacitidine is 
rapidly absorbed after SC administration; the peak plasma 5-azacitidine concentration of 750 ± 
403 ng/ml occurred in 0.5 hour. The bioavailability of SC 5-azacitidine relative to IV 5azacitidine 
is approximately 89%, based on area under the curve. Mean volume of distribution following IV 
dosing is 76 ± 26 L. Mean apparent SC clearance is 167 ± 49 L/hour and mean half-life after SC 
administration is 41 ± 8 minutes.  
 
Published studies indicate that urinary excretion is the primary route of elimination of 5azacitidine 
and its metabolites. Following IV administration of radioactive 5-azacitidine to 5 cancer patients, 


SKCCC J12138 
IND 117362  
Confidential              
  
29 
Version 11.0 / February 18, 2022   
the cumulative urinary excretion was 85% of the radioactive dose. Fecal excretion accounted for 
<1% of administered radioactivity over 3 days. Mean excretion of radioactivity in urine following 
SC administration of 14C-5-azacitidine was 50%. The mean elimination half-lives of total 
radioactivity (5-azacitidine and its metabolites) were similar after IV and SC administrations, 
about 4 hours.  
 
The pharmacokinetics of CC-486 as a single agent were evaluated in the phase I/II trial in MDS, 
CMML and AML patients.  Plasma and urine studies were done on days 1 and 7 of cycle 1 (SQ 
dosing) and cycle 2 (oral dosing).  Rapid absorption was seen in both routes as the maximum 
observed plasma concentration (Cmax) was reached within 0.5 hours with SQ dosing and 1.0 hours 
with oral dosing.  The mean elimination half-life was 1.6 ± 0.7 hours for SC and 0.62 ± 0.25 hours 
for oral and the concentration decreased in a pseudobiphasic manner.  The MTD had a mean 
relative bioavailability of 13% ± 9%.  Apparent volume of distribution was greater than total body 
water and apparent total clearance was greater than hepatic blood flow, suggestive wide tissue 
distribution and extrahepatic metabolism, respectively.  Less than 2% of azacitidine was 
recovered in urine in both SQ and oral forms, implying the main elimination pathway is not renal.  
Tests after multiple doses suggest no azacitidine accumulation31.  
5.1.1.3 Handling, Storage, and Disposal of CC-486  
CC-486 is a cytotoxic drug and, as with other potentially toxic compounds, caution should be 
exercised when handling CC-486 tablets.  Procedures for proper handling and disposal of 
anticancer drugs should be applied.   
 
If CC-486 comes into contact with the skin, immediately and thoroughly wash with soap and 
water.  If it comes into contact with mucous membranes, flush thoroughly with water.  
 
CC-486 will be supplied as 100 mg tablets.  Each tablet is formulated using excipients that are 
generally regarded as safe and are used in marketed drug products.  Further details can be found 
in the CC-486 Investigator’s Brochure.  There is no need to protect CC-486 from exposure to 
light.  
 
Each tablet will be sealed in a blister package.  CC-486 tablets should be stored at 25oC (77oF), 
excursions permitted to 15oC to 30oC (59oF to 86oF), and free of environmental extremes.  The 
storage area should be secure and have limited access.  Shelf-life evaluations of the intact blister 
packages, pouches, and HDPE bottles are ongoing.  The CC-486 study drug will be monitored for 
stability for the duration of the study.   


SKCCC J12138 
IND 117362  
Confidential              
  
30 
Version 11.0 / February 18, 2022   
5.2 Screening and Eligibility  
The Investigator is responsible for keeping a record of all subjects who sign an Informed Consent 
Form for entry into the study.  All subjects will be screened for eligibility.  Screening procedures 
are outlined in Section 2, Schedule of Study Assessments and unless otherwise specified, must 
take place within 28 days prior to initiation of therapy.    
5.2.1 Inclusion Criteria  
Subjects must meet the following inclusion criteria to be eligible for the study:  
1. Understand and voluntarily sign an informed consent form.  
2. Age ≥18 years at the time of signing the informed consent form.  
3. Able to adhere to the study visit schedule and other protocol requirements.  
4. Subjects must have a histologically confirmed pancreatic adenocarcinoma that has had an 
R0 (negative margins) or R1 (microscopically positive margins) resection.  
5. Subjects must have finished adjuvant therapy, which can include chemotherapy and/or 
chemoradiation therapy or have been determined to be unable to take adjuvant therapy.  
Although patients will be expected to complete chemoradiation or chemotherapy per 
physician recommendations, patients who are unable to complete chemotherapy ± 
radiation therapy secondary to dose limiting toxicities will be eligible provided they meet 
study criteria.   
6. Subjects enrolled due to node + disease or R1 resection must be able to undergo 
randomization within 3 months of finishing adjuvant therapy or the decision that they are 
unable to take adjuvant therapy. Patients enrolling due to CA 19-9 elevations can enroll 
any time after adjuvant therapy has completed.  
7. All previous cancer therapy including radiation, chemotherapy, and surgery, must have 
been discontinued at least 4 weeks prior to treatment in this study  
8. Subjects must either have a CA 19-9 value > the institutional ULN on two separate checks 
at least 2 weeks apart OR have had an R1 resection margin OR N1 nodal disease regardless 
of CA 19-9 level  
9. Subjects must be free of visible disease on imaging (CT, PETCT or MRI) evaluating chest, 
abdomen, and pelvis within 28 days of enrollment on the study.  
10. Life expectancy of greater than 12 weeks  
11. ECOG performance status of ≥ 1 at study entry (see Appendix A).  
12. Subjects must have normal organ and marrow function as defined below:  


SKCCC J12138 
IND 117362  
Confidential              
  
31 
Version 11.0 / February 18, 2022   
• 
Absolute neutrophil count ≥ 1500/mm³   
• 
Leukocytes ≥ 3,000/mm3  
• 
Platelet count ≥ 100,000/mm³   
• 
Hemoglobin > 9.0 g/dL  
• 
Serum creatinine levels < 2 mg/dL  
• 
Serum bilirubin levels ≤1.5 mg/dL   
• 
AST (SGOT) and ALT (SGPT) ≤ 2.5 x ULN  
• 
Alkaline phosphatase ≤ 2.5 x ULN  
13. Free of prior malignancies for ≥ 5 years with exception of currently treated basal cell, 
squamous cell carcinoma of the skin, or carcinoma in situ of the cervix or breast.  
14. Women of childbearing potential should be advised to avoid becoming pregnant and men 
should be advised to not father a child while receiving treatment with CC-486 or nab-
paclitaxel.  All men and women of childbearing potential must use effective methods of 
birth control throughout the study and for three months after completing treatment.  
15. Women of childbearing potential must have a negative serum or urine β-hCG pregnancy 
test at screening.  
16. Subjects must have < Grade 2 pre-existing peripheral neuropathy (per CTCAE)  
5.2.2 Exclusion criteria   
Subjects who meet any of the following exclusion criteria are not eligible for the study:  
1. Any serious medical condition, laboratory abnormality, or psychiatric illness that would 
prevent the subject from signing the informed consent form.  
2. Pregnant or breastfeeding women.  
3. Use of any other chemotherapy, radiotherapy, or experimental drug or therapy within 4 
weeks (6 weeks for nitrosoureas or mitomycin C) prior to enrollment on study or those 
who have not recovered from adverse events ≥ grade 1 due to agents administered more 
than 4 weeks earlier except for stable grade 2 neuropathy.  
4. Subjects may not receive any other concomitant investigational agents.  
5. Known or suspected hypersensitivity to 5-azacitidine or mannitol  


SKCCC J12138 
IND 117362  
Confidential              
  
32 
Version 11.0 / February 18, 2022   
6. Known positive for HIV or infectious hepatitis, type B or C.  HIV patients are at increased 
risk of lethal infections when treated with marrow-suppressive therapy.  
7. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or 
psychiatric illness/social situations that would limit compliance with study requirements.  
8. Any known gastrointestinal disorders which would preclude oral administration of 
5azacitidine.  
5.2.3 Inclusion of Women and Minorities  
Both men and women and members of all races and ethnic groups are eligible for this trial.  
5.2.4 Patient Recruitment   
Patients will be contacted by phone via physician referrals and from investigator attendance at the 
weekly Pancreatic Multidisciplinary Conference.  In addition, the schedule of Whipple surgeries 
will be requested on a weekly basis from the operating room schedulers.  Patients eligible for the 
study will then be contacted by phone by the investigator.   
5.2.5 Protocol and Drug Administration  
This study will be conducted in accordance with the Sidney Kimmel Comprehensive Cancer 
Center’s Coordinating Center Protocol.  
5.2.6 Multicenter Guidelines  
 Protocol Chair  
  
The Protocol Chair is responsible for performing the following tasks:  
• 
Coordinating, developing, submitting, and obtaining approval for the protocol as well 
as its subsequent amendments.  
• 
Assuring that all participating institutions are using the correct version of the protocol.  
• 
Taking responsibility for the overall conduct of the study at all participating 
institutions and for monitoring the progress of the study.  
• 
Reviewing and ensuring reporting of Serious Adverse Events (SAE)  Reviewing 
data from all sites.  
  
Coordinating Center  
  
The Coordinating Center is responsible for performing the following tasks:  
• 
Ensuring that IRB approval has been obtained at each participating site prior to the 
first patient registration at that site, and maintaining copies of IRB approvals from 
each site.  


SKCCC J12138 
IND 117362  
Confidential              
  
33 
Version 11.0 / February 18, 2022   
• 
Managing central patient registration.  
• 
Collecting and compiling data from each site.  
• 
Establishing procedures for documentation, reporting, and submitting of AE’s and 
SAE’s to the Protocol Chair, and all applicable parties.  
• 
Facilitating audits by securing selected source documents and research records from 
participating sites for audit, or by auditing at participating sites.  
  
Participating Sites  
  
Participating sites are responsible for performing the following tasks:  
• 
Following the protocol as written, and the guidelines of Good Clinical Practice (GCP).  
• 
Submitting data to the Coordinating Center.  
• 
Registering all patients with the Coordinating Center by submitting patient registration 
form, and signed informed consent promptly.  
• 
Providing sufficient experienced clinical and administrative staff and adequate 
facilities and equipment to conduct a collaborative trial according to the protocol.  
• 
Maintaining regulatory binders on site and providing copies of all required documents 
to the Coordinating Center.  
• 
Collecting and submitting data according to the schedule specified by the protocol.  
  
5.2.7 Patient Registration  
Prior to protocol enrollment and initiation of treatment, subjects must sign and date an IRB 
approved consent form.  All patients must be registered centrally at the Sidney Kimmel 
Comprehensive Cancer Center.   
 
To register a patient, sites must send the following documents to Sheila Linden at the Coordinating 
Center by email at 
 
• 
Registration Form  
• 
HIPAA authorization form (if separate from consent)  
• 
Eligibility screening checklist  
• 
Copy of all required screening tests.  
  
The Coordinating Center will review the documents to confirm eligibility.  To complete the 
registration process, the Coordinating Center will:  
• 
assign a patient study number  
• 
register the patient on the study with the Sidney Kimmel Comprehensive  
Cancer Center’s Clinical Research Office  
• 
E-mail the patient study number to the participating site.  


SKCCC J12138 
IND 117362  
Confidential              
  
34 
Version 11.0 / February 18, 2022   
5.2.8 Randomization  
Subjects who are eligible to enroll in the study will be randomized in a 1:1 ratio to receive CC486 
or observation.  Subjects will be randomized through a computer program maintained by the study 
team.  
• 
CC-486 (three 100 mg tablets on Days 1-21 every 28 days)  
• 
Observation  
The randomization will be balanced by using randomly permuted blocks and will be stratified by 
the following criteria:   
• 
Positive lymph nodes at time of resection (N0 versus N1)   
Approximately 55-75% of patients are expected to be node positive.10, 13, 40-42  
CC-486 will be packaged and designated for a patient upon randomization to Arm A.  Subsequent 
bottles of study drug will be made available to patients as needed.  Patient will receive one bottle 
of study drug with no more than 63 tablets in the bottle.  
External sites will submit a patient enrollment log to the Coordinating Center monthly by email, 
at 
  
5.2.9 Dosage Dispensing and Administration  
Treatment will be administered on an outpatient basis. Reported adverse events and potential risks 
are described in Section 6.  Appropriate dose modifications are described in Section  
 
No investigational or commercial agents or therapies other than those described below may be 
administered with the intent to treat the patient’s malignancy.  
5.2.9.1 Dispensing and Administration of CC-486  
On Day 1 of each cycle, subjects in Arm A will be administered three tablets of 100 mg of CC486 
in clinic with approximately 8 ounces (240mL) of room temperature water.  CC-486 may be taken 
on an empty stomach or with food.  Dosing can occur at any time during the morning after 
completing the required pre-dose assessments.  Time of dose should be recorded in study 
documents.  Anti-emetics can be administered per discretion of the investigator (per Section 5.4.1) 
on an as needed basis.   
 
For each cycle, subjects in Arm A will take the three 100 mg tablets of CC-486 on days 1-21 of a 
28 day cycle.  On the first day of every cycle, subjects will be given a quantity of study drug for 
the dosing days at home.  Subjects should be instructed to inspect each CC-486 tablet and only 
take tablets that are totally intact.  Subjects should be instructed to return any doses not taken or 


SKCCC J12138 
IND 117362  
Confidential              
  
35 
Version 11.0 / February 18, 2022   
any tablet(s) found to be not totally intact to the study clinic on the first day of each cycle, 
beginning with Cycle 2.  Subjects should be instructed to open the study medication packaging as 
close as possible to when they are going to take the study drug and record the time of study drug 
administration on a diary card (Appendix B).  The diary card will be returned to clinic staff at the 
end of each cycle.  On days when study drug is taken at home, subjects should be encouraged to 
ingest CC-486 with approximately 8 ounces (240mL) of room temperature water.  CC-486 may 
be taken on an empty stomach or with food.  
 
If a dose of CC-486 is missed, it should be taken as soon as possible on the same day.  If it is 
missed for the entire day, it should not be made up.  If the patient vomits after a dose is taken, no 
more subsequent tablets should be administered.  
The cycle length is 4 weeks (28 days).  Treatment with protocol therapy will continue until 
unacceptable toxicities or subject has visible disease progression on imaging.  Further details per 
Sections 5 and 7.  
If CC-486 is shipped directly to patients for the safety of patients and staff as part of COVID-19 
precautions, a courier that monitors drug shipment conditions should be utilized. Study staff must 
call the patient to ensure that shipment was received in good condition at the patient’s home, and 
instruct patient to keep and return all empty, partially empty, or full bottles/blisters to the site at 
next visit for drug reconciliation. This call, including verbal confirmation of receipt by the patient, 
should be properly documented in the medical record. If COVID-19 precautions prevent the return 
of used/unused study drug supplies to the site, then study staff must review the remaining pills 
during a telemedicine visit. Undelivered supplies should be returned to the clinical site. 
5.2.10 Record of administration  
Accurate records will be kept in the source documents of all drug administration (including 
prescribing and dosing).  Subject diaries will be collected at the end of each cycle and at the 
discontinuation of treatment.  
Review of remaining pills and pill diary may be reviewed during a telemedicine visit when drug 
is unable to be returned to study staff due to COVID-19 precautions. Copies of the pill diary may 
be submitted to study staff by phone, fax, email, or mychart. 
5.3 Visit Schedule, Assessments, and Dose Modifications  
Screening assessments and all on-study scheduled visits and assessments are outlined in Section 
2 Table of Study Assessments and detailed below.  
 


SKCCC J12138 
IND 117362  
Confidential              
  
36 
Version 11.0 / February 18, 2022   
5.3.1 Screening and Pre-Study Assessments  
Screening for enrollment in this clinical trial should include a record of prior medications and 
anti-cancer treatments, a record of concomitant medications and procedures, medical history, a 
physical examination, vital signs, weight, ECOG performance status (per Appendix A), 
pregnancy test, labs (CBC with differential, serum chemistry and hepatic panel, CA 19-9, PT, 
PTT), research labs, quality of life measures and lesion assessment with CT (per Section 7).  All 
pre-study assessments should be done ≤ 28 days from Cycle 1 Day 1.  
5.3.2 Initial Phase: Assessments, Dose Modifications, and Termination  
5.3.2.1 Arm A for first cycle  
Prior to receiving Cycle 1 Day 1 of CC-486, patients must undergo a physical examination 
including vital signs, weight, and ECOG performance status assessments, and labs including CBC 
with differential, serum chemistry and hepatic panel, CA 19-9, PT/PTT, and research blood, a 
record of concomitant medications and procedures, quality of life, and an assessment of adverse 
events.  If screening assessments were done within 7 days of initiating Cycle 1 Day 1, these do 
not need to be repeated.  Cycle 1 of CC-486 in Arm A can then be administered on schedule if 
treatment criteria are met. 
  
5.3.2.2 Arm A for first 12 cycles  
Arm A patients will be evaluated on Day 1 of every cycle with a physical examination, ECOG 
performance status, vital signs, weight, CBC with differential, research blood and serum 
chemistry and hepatic panel. Arm A patients will also complete an assessment of adverse events 
and reporting of current medications/procedures on Day 1 of every cycle.   
 
Arm A patients will complete a CA 19-9, quality of life assessment and CT scan on Day 1 of 
every third cycle beginning at Cycle 4.   
 
Arm A subjects will be evaluated for adverse events on Day 1 of each cycle with the NCI CTCAE 
v4.0 (http://ctep.info.nih.gov) used as a guide for the grading of severity.  For Arm A patients, 
doses will be reduced for hematologic and other non-hematologic toxicities that can be attributed 
to the study drug.  Dose adjustments are to be made according to the system showing the greatest 
degree of toxicity.  When a dose reduction is required for Day 1 of any cycle, no dose re-escalation 
will be permitted for the duration of study treatment.  
 
NOTE: Arm B patients will not be evaluated for adverse events as they do not receive the study 
agent.  
   Criteria to Initiate Treatment 


SKCCC J12138 
IND 117362  
Confidential              
  
37 
Version 11.0 / February 18, 2022   
In Arm A, a new course of treatment may begin on the scheduled Day 1 of a new cycle if: 
• 
Absolute neutrophil count ≥ 1500/mm³ 
• 
Platelet count ≥ 100,000/mm³ 
• 
Serum creatinine levels < 2 mg/dL 
• 
Serum bilirubin levels ≤ 1.5 mg/dL. 
• 
AST (SGOT) and ALT (SGPT) ≤ 2.5 x the institutional upper limit (ULN) of the normal 
range 
• 
Any other drug-related adverse events that may have occurred must have resolved to  
˂ Grade 2 severity except grade 2 anorexia and any correctable metabolic abnormality. 
• 
No evidence of visible disease recurrence on imaging (if indicated per Study Schedule, 
Section 2, to be done prior to cycles 4, 7, and 10) 
 
If these conditions are not met on Day 1 of a new cycle, the subject will be evaluated weekly and 
a new cycle of treatment will not be initiated until the toxicity has resolved as described above 
utilizing the dose modifications as depicted below. If the study drug has to be held for > 
28 days, study treatment will be discontinued. 
 
5.3.2.3 Arm B for the first 12 cycles  
Arm B patients will ideally be evaluated (or at the very least contacted by the study team) on Day 
1 of every third cycle beginning with Cycle 4. 
Patients are permitted to see their local oncologist, and CA19-9 and lesion assessments may be 
completed outside of the recommended 3 month window (Cycles 4, 7, and 10) at their 
oncologist’s discretion. .  
Arm B patients will follow a similar schedule as patients in Follow-up, except for a Quality of 
Life assessment that will be performed.  
Correlative blood draw is optional for Arm B patients. If Arm B patients wish, they may have 
research bloods drawn for correlative studies.  
 
Arm B patients who opt to have research blood collected will have it collected on Day 1 of every 
third cycle (cycle 4, 7 and 10). 
 
Below is the list of information that must be obtained from Arm B patients. 
• 
Any further therapy received (records to be obtained)  
• 
Subjective response on therapy (records to be obtained)  
• 
Any CA 19-9 drawn (records to be obtained)  
• 
Any imaging (images to be obtained)  


SKCCC J12138 
IND 117362  
Confidential              
  
38 
Version 11.0 / February 18, 2022   
Arm B patients will complete a CA 19-9, quality of life assessment and CT scan (or alternate 
imaging, if clinically indicated) quarterly (ideally).  
Arm B patients who are not evaluated in person may have the Quality of Life assessment 
completed over the phone.  
5.3.2.4 Dose Modification  
Table 5.3.1: Arm A: Dose Modification Recommendations for CC-486 Phase  
Toxicity 
Grade 
CC-486 
Febrile Neutropenia 
Grade 3 or 4 
Hold until resolved and neutrophils ≥ 1500/mm3  
Restart study drug at 200 mg (two tablets, 33% dose 
reduction).  
If the same Grade 3 or 4 event recurs (i.e., third 
occurrence) despite CC-486 dose reduction to 200 mg, 
as described above, permanently discontinue study 
d
Leukopenia and/or Neutropenia 
Grade 2-3 
Hold dose until recovery to Grade ≤ 1 or baseline. 
Resume study drug at prior dose  
 
Grade 4 
Hold until resolved to ≤ Grade 1 
Restart study drug at 200 mg (two tablets,  33% dose 
reduction). 
If the same Grade 4 event recurs (i.e., third occurrence) 
despite CC-486 dose reduction to 200 mg, as described 
above, permanently discontinue study drug. 
Thrombocytopenia 
Grade 1* or 2
Hold treatment until resolution to normal values. 
Grade 3 or 4 
Hold until resolved and platelet count ≥100,000/mm³ 
Restart study drug at 200 mg (two tablets, 33% dose 
reduction).. 
Diarrhea (unresponsive to 
maximum medical 
management) 
Grade 1 or 2 
Consider administering symptomatic remedies and/or start 
prophylaxis.  
No dose/schedule changes 


SKCCC J12138 
IND 117362  
Confidential              
  
39 
Version 11.0 / February 18, 2022   
Toxicity 
Grade 
CC-486 
Grade 3 or 4 
Hold until resolved to ≤ Grade 1 
Restart study drug at 200 mg (two tablets,  33% dose 
reduction). 
Nausea/Vomiting 
(unresponsive to maximum 
medical management) 
Grade 1 or 2 
Consider changing/adding antiemetic medication 
treatment   
No dose/schedule changes 
Grade 3 or 4 
Hold until resolved and neutrophils ≥ 1000/mm3  
Restart study drug at 200 mg (two tablets, 33% dose 
reduction). 
 *Grade 1 thrombocytopenia: Platelet count < 100,000/mm³ 
 
Study drug should be stopped if grade 3 or 4 toxicity has occurred despite a dose reduction to 66% 
of original dose (200 mg of CC-486 in two 100 mg tablets).  
If grade 3 or 4 toxicities require patients to stop treatment mid cycle, they can resume their cycle 
at the recommended decreased dose if the toxicities resolve to ≤ Grade 1 within their 21 days of 
treatment (i.e. they would only continue treatment to complete their days 1-21 per the calendar, 
not to complete 21 days of taking the tablets).  If their toxicities recover after their 21 days has 
completed, they will not take more tablets until they begin their next cycle. 
5.3.2.5 Arm A: Missing doses 
 
Missed Doses Day 1 dose 
As Day 1 dose of CC-486 will be given in the office, this dose should not be missed.  If the patient 
does not meet the criteria to begin a new cycle, then the patient will be reassessed in a week and 
Cycle X Day 1 will start when the dose is actually given.   
Day X dose missed  
If the dose held or missed was to be given on any day other than Day 1, the cycle continues per 
protocol with one dose not given and that dose is just considered omitted.  
5.4 Discontinuation of Treatment: Arm A  
In the absence of treatment delays due to adverse events, treatment with CC-486 may continue 
until one of the following criteria applies:  
• 
Interruption of scheduled therapy for greater than four weeks,  


SKCCC J12138 
IND 117362  
Confidential              
  
40 
Version 11.0 / February 18, 2022   
• 
Intercurrent illness that prevents further administration of treatment,  
• 
Adverse event(s) that, in the judgment of the Investigator, may cause severe or permanent 
harm or which rule out continuation of the treatment regimen 
• 
For any grade 3 and 4 toxicity that recurs despite dose reduction 
• 
Discontinuation of CC-486 for any reason,  
• 
Treatment with other chemotherapeutic or investigational anti-neoplastic drugs,  
• 
Subject decides to withdraw from the study,  
• 
Suspected pregnancy or positive pregnancy, or  
• 
General or specific changes in the subject's condition render the subject unacceptable for 
further treatment in the judgment of the investigator, or  
• 
Disease recurrence on imaging, or  
• 
Patient has completed one year of therapy with CC-486.  
If the subject has visible disease recurrence on imaging or meets any of the aforementioned criteria 
for removal from study treatment, then the CC-486 or observation phase of this study will 
conclude and patient will enter the follow-up phase of the study, following the schedule of 
assessments as described in Section 5.4.2.9.    
Mandatory research bloods and tumor biopsies will be obtained at the time of recurrence for both  
Arm A and Arm B subjects, per the method determined best per the investigator as outlined on 
the Study Calendar and in Section. 
 
5.4.1 End of Treatment 
When coming off of CC-486 therapy, subjects in Arm A will undergo a physical examination, 
vital signs, weight, ECOG performance status, assessment of adverse events, labs including CBC 
with differential, serum chemistry and hepatic panel, CA 19-9, PT/PTT and research blood. If any 
of these were performed within 7 days, they do not need to be repeated. All remaining pills will 
be collected. 
 
  5.5 Follow-up Phase Both Arms 
No disease recurrence: 
Less than 10% of patients who have undergone surgery will not develop tumor recurrence after 
adjuvant therapy.  
Therefore, if patients have not recurred after one year of therapy with CC- 486 (Arm A) the drug 
will be discontinued.  


SKCCC J12138 
IND 117362  
Confidential              
  
41 
Version 11.0 / February 18, 2022   
Patients in Arm A will undergo a safety assessment 28 days (± 2 days) post the last dose of 
protocol therapy for resolution of toxicity.  
Because Arm B patients do not receive study drug, a safety assessment will not be performed. 
 
All patients (Arm A and B) will be then be contacted (ideally) every 3 months on to obtain the 
following information about recurrence, survival and anti-cancer treatment (2.2 Study 
Calendar):  
• 
Any further therapy received (records to be obtained)  
• 
Subjective response on therapy (records to be obtained)  
• 
Any CA 19-9 drawn (records to be obtained)  
 
• 
Any imaging (images to be obtained)  
 
Disease recurrence 
At the time of recurrence, Arm A and Arm B subjects will undergo biopsy of the recurrent lesion 
per the method determined best per the investigator. 
Post recurrence images will be also obtained (pre-recurrence images are optional) 
Thereafter, attempts to contact patients every 3 months in order to obtain lesion assessments/post 
recurrence images, CA19-9 and anticancer treatment and survival information as detailed in 
section 5.4.2. If study team is unable to make contact with patients, information may be obtained 
through medical and public records. This information will continue to be collected for patients 
until patients hit second disease progression.  
 
5.6 Concomitant Therapy    
5.6.1 Recommended Concomitant Therapy    
 Subjects should receive full supportive care, including transfusions of blood and blood products, 
antibiotics, antiemetics, and growth factor support when appropriate.   
1. It is recommended that all subjects must be pre-medicated for nausea and vomiting prior 
to the administration of CC-486.  Administration of a 5-HT3 serotonin receptor antagonist 
is recommended prior to CC-486.  Antiemetics should be administered at least 30 minutes 
prior to administration of CC-486.  Additional doses may be administered if required.  
Other antiemetic medications (prochlorperazine, lorazepam, etc.) may also be taken for 
delayed nausea as needed.  Specific anti-emetic regimens are up to the discretion of the 
investigator.  
2. Diarrhea: If diarrhea occurs during dosing, an antidiarrheal agent(s) may be used.  It is 
recommended that patients experiencing diarrhea associated with CC-486 be managed 
according to the guidelines provided in Appendix C, which are based on a publication in 


SKCCC J12138 
IND 117362  
Confidential              
  
42 
Version 11.0 / February 18, 2022   
the Journal of Clinical Oncology43.  A dose reduction of CC-486 may be appropriate based 
on the severity of diarrhea observed and the response to treatment intervention.  
3. Contraceptive Therapy: Sexually active men and women of child-bearing potential must 
agree to use effective contraception.  
5.6.2 Prohibited Concomitant Therapy  
1. Concomitant use of other anti-cancer therapies, including radiation, or other investigational 
agents is not permitted while subjects are receiving protocol therapy during the treatment 
phase of the study.    
5.7 Treatment adherence  
Research center personnel will review the dosing instructions with subjects. Subjects will be asked 
to maintain a diary to record CC-486 administration (see Appendix B). Subjects will be asked to 
bring any unused drug and empty drug containers to the research center at their next visit.  
Research personnel will count and record the number of used and unused drug at each visit and 
reconcile with the medication diary.  
  
6 Adverse events  
6.1 Definitions Adverse Event (AE) Definition  
An adverse event is the development of an undesirable medical condition or the deterioration of 
a pre-existing medical condition following or during exposure to a pharmaceutical product, 
whether or not considered causally related to the product.  An undesirable medical condition can 
be symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the abnormal 
results of an investigation (e.g., laboratory findings, electrocardiogram).  In clinical trials, from 
the time of signing an informed consent, an AE can include an undesirable medical condition 
occurring at any time, including run-in or washout periods, even if no trial treatment has been 
administered. For this trial, Adverse Events and Serious Adverse Events will be collected for Arm 
A patients only, as they are receiving study drug.  
6.1.1 Serious Adverse Event (SAE) Definition   
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  


SKCCC J12138 
IND 117362  
Confidential              
  
43 
Version 11.0 / February 18, 2022   
• 
Is an important medical event3  
• 
Pregnancy  
  
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 patient 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, or the development of drug dependency or drug abuse.  
A new diagnosis of cancer during the course of a treatment should be considered as 
medically important.   
 
6.2 Adverse Event Reporting  
Protocol Chair  
The Protocol Chair is ultimately responsible for the required reporting of all adverse events.  
  
Coordinating Center  
The Coordinating Center is the central location for the collection and maintenance of 
documentation of adverse events and is responsible for submitting adverse event reports to the 
Protocol Chair promptly.  The Coordinating Center will maintain documentation of all adverse 
event reports for each participating site. Adverse event reports submitted to the Coordinating 
Center must be signed and dated by the participating site’s Principal Investigator.  Participating 
sites must use the SKCCC template for reporting adverse events per SKCCC policy.  Information 
to be provided must include:  
• 
Subject ID number, and initials  
• 
Date of the event  
• 
Description of the event  
• 
Description of site's response to the event  
• 
Assessment of the subject's condition  
• 
Subject's status on the study (on study, off study, etc.)  
• 
Attribution of event to study drug  


SKCCC J12138 
IND 117362  
Confidential              
  
44 
Version 11.0 / February 18, 2022   
 
Participating Sites  
Participating sites are responsible for reporting adverse events to their IRB according to its 
specific requirements and to the Coordinating Center as follows:  
  
Fatal Events whether anticipated or unanticipated, and whether or not related to the study must 
be reported to the Coordinating Center within 24 hours of the participating site Principal 
Investigator's learning of the event.  
  
Serious and Unanticipated Adverse Events as defined above must be reported to the 
Coordinating Center within 24 hours of the participating site Principal Investigator's learning of 
the event.   
  
Other Serious Adverse Events which may result in a change to the protocol, informed consent, 
or risk to subjects as specified in the protocol must be reported within three (3) working days of 
the participating site Principal Investigator's learning of the event.   
  
Adverse Events which result in no change to protocol, informed consent, or risk to subjects must 
be reported to the Coordinating Center on a monthly basis.   
  
Adverse 
event 
reports 
are 
to 
be 
emailed 
to 
the 
Coordinating 
Center 
at 
. Follow-up reports are to be emailed to the Coordinating Center as 
necessary.  
  
The investigator must also report follow-up information about SAEs within the same time frames.  
  
If a non-serious AE becomes serious, this and other relevant follow-up information must also be 
provided within the same time frames described above.  
  
All SAEs for Arm A patients must be collected whether or not they are considered causally related 
to the investigational product.  Investigators and other site personnel are responsible for reporting 
all casually related SAEs to their IRB and the Protocol Chair.  
 
All 
SAE’s 
should 
be 
reported 
to 
the 
Coordinating 
Center 
by 
email 
at 
. 
 
Toxicity will be scored using CTCAE Version 4.0 for toxicity and adverse event reporting.  A 
copy of the CTCAE Version 4.0 can be downloaded from the CTEP homepage  


SKCCC J12138 
IND 117362  
Confidential              
  
45 
Version 11.0 / February 18, 2022   
(http://ctep.info.nih.gov).  All appropriate treatment areas should have access to a copy of the 
CTCAE Version 4.0.  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 test drug and about the subject’s outcome. Only 
clinically significant lab abnormalities will be recorded as adverse events. 
  
6.2.1 Pregnancies  
Pregnancy of a female subject or the female partner of a male subject occurring while the subject 
is on CC-486, or within 4 weeks after the subject’s last dose of CC-486, are considered expedited 
reportable events.  If the subject is on CC-486, it is to be discontinued immediately. The pregnancy 
must be reported to Celgene Drug Safety within 24 hours of the Investigator’s knowledge of the 
pregnancy by phone and facsimile using the SAE Form.  The female subject may be referred to 
an obstetrician-gynecologist (not necessarily one with reproductive toxicity experience) or 
another appropriate healthcare professional for further evaluation.  
 
The Investigator will follow the pregnant female until completion of the pregnancy, and must 
notify Celgene Drug Safety of the outcome of the pregnancy (either normal or abnormal outcome) 
as specified below.  The Investigator will provide this information as a follow-up to the initial 
SAE.  
 
If the outcome of the pregnancy meets the criteria for immediate classification as a SAE (i.e., 
spontaneous abortion [any congenital anomaly detected in an aborted fetus is to be documented], 
stillbirth, neonatal death, or congenital anomaly), the Investigator should follow the procedures 
for Expedited Reporting of SAEs to Celgene (i.e., report the event to Celgene Drug Safety by 
facsimile within 24 hours of the Investigator’s knowledge of the event).  
 
All neonatal deaths that occur within 30 days of birth should be reported, without regard to 
causality, as SAEs.  In addition, any infant death after 30 days that the Investigator suspects is 
related to the in utero exposure to CC-486 should also be reported.  In the case of a live “normal” 
birth, Celgene Drug Safety should be advised as soon as the information is available.  
  
If a female partner of a male subject taking CC-486 becomes pregnant, the male subject taking 
the project should notify the Investigator, and the pregnant partner should be advices to call their 
healthcare provider immediately.  


SKCCC J12138 
IND 117362  
Confidential              
  
46 
Version 11.0 / February 18, 2022   
6.2.2 Celgene Drug Safety Contact Information:  
Celgene Corporation  
 
  
  
  
   
  
   
   
 
6.3 Investigator Reporting Responsibilities  
The conduct of the study will comply with all FDA safety reporting requirements.    
6.3.1 Expedited reporting by investigator to Celgene  
Serious adverse events (SAE) are defined above.  The investigator must inform Celgene in writing 
using a Celgene SAE form or MEDWATCH 3500A form of any SAE within 24 hours of being 
aware of the event.  The written report must be completed and supplied to Celgene by facsimile 
within 24 hours/1 business day.  The initial report must be as complete as possible, including an 
assessment of the causal relationship between the event and the investigational product(s), if 
available.  Information not available at the time of the initial report (e.g., an end date for the 
adverse event or laboratory values received after the report) must be documented on a follow-up 
report.  A final report to document resolution of the SAE is required.  The Celgene tracking 
number (OA-PANC-PI-0294) and the institutional protocol number should be included on SAE 
reports (or on the fax cover letter) sent to Celgene.  A copy of the fax transmission confirmation 
of the SAE report to Celgene should be attached to the SAE and retained with the subject records.  
6.3.2 Report of Adverse Events to the Institutional Review Board  
The principal Investigator is required to notify his/her Institutional Review Board (IRB) of a 
serious adverse event according to institutional policy. 
    
6.3.3 Investigator Reporting to the FDA  
Serious adverse events (SAEs) that are unlisted/unexpected, and at least possibly associated 
to 5-azacitadine, and that have not previously been reported in the Investigator’s brochure, or 
reference safety information document should be reported promptly to the Food and Drug 
Administration (FDA) by telephone or by fax by the IND sponsor.  Fatal or life threatening SAEs 
that meet the criteria for reporting to the FDA must be reported to the FDA within 7 calendar days 
after awareness of the event.  All other SAEs that meet the criteria for reporting to the FDA must 
be reported to the FDA within 15 calendar days after awareness of the event by the IND sponsor.  


SKCCC J12138 
IND 117362  
Confidential              
  
47 
Version 11.0 / February 18, 2022   
A clear description of the suspected reaction should be provided along with an assessment as to 
whether the event is drug or disease related.     
 
In accordance with the regulation 21 CFR § 312.33, the IND Sponsor shall within 60 days of the 
anniversary date that the IND went into effect submit a brief report of the adverse events and 
progress of the investigation.  Please refer to Code of Federal Regulations, 21 CFR § 312.33 for 
a list of the elements required for the annual report.  All IND annual reports will be submitted to 
the FDA by the IND Sponsor.  
6.4 Adverse event updates/IND safety reports  
Celgene shall notify the Investigator via an IND Safety Report of the following information:  
• 
Any AE associated with the use of drug in this study or in other studies that is both serious 
and unexpected.  
• 
Any finding from tests in laboratory animals that suggests a significant risk for human 
subjects including reports of mutagenicity, teratogenicity, or carcinogenicity.  
The Investigator shall notify his/her IRB/EC promptly of these new serious and unexpected AE(s) 
or significant risks to subjects.  
 
The Investigator must keep copies of all AE information, including correspondence with Celgene 
and the IRB/EC, on file (see Section 12.4 for records retention information).  
7 Radiologic Evaluation  
7.1 Baseline imaging assessments  
Baseline imaging assessment must occur within ≤28 days of initiation of the CC-486 /observation 
phase to document lack of visible disease on imaging as indicated in Section 2, Schedule of Study 
Assessments.  Acceptable imaging modalities are described below and must include imaging of 
the chest, abdomen and pelvis.  To be declared free of visible disease, there can be no evidence 
of measurable disease, as defined below, or presence of malignant effusions.   
 
All effusions that can safely be diagnostically drained must be evaluated prior to enrolling to 
document lack of malignant cells via thoracentesis or paracentesis.  Fluid that is non-specific or 
too small to drain is considered no visible disease.  If there is a concern for bone metastasis or 
brain metastasis based on clinical symptoms, bone scan and/or brain MRI must be done to rule 
out metastatic disease prior to enrolling on this study.  These scans do not need to be done in the 
absence of concerning clinical symptoms.  


SKCCC J12138 
IND 117362  
Confidential              
  
48 
Version 11.0 / February 18, 2022   
Imaging will be performed every 3 cycles while on the CC-486. Ideally, imaging will be 
performed every 3 cycles for patients on the observation arm, but ultimately imaging/lesion 
assessments will be performed at the patient or his/her oncologist’s discretion. When patients have 
evidence of measurable disease, as defined below, they will then be classified as having “visible 
disease”.  If a lesion or effusion appears but is not confirmed to be disease until a later time point, 
the time noted for a patient to have “visible disease” should revert back to the time the lesion or 
effusion initially appeared.  They will stop the CC-486 /observation phase and enter the follow 
up phase.  Imaging assessment ideally should occur within < 28 days of initiation of first-line 
chemotherapy. If there is a delay between initial documentation of visible disease and starting 
treatment, imaging may be repeated as indicated in Section 2, Schedule of Study Assessments to 
get a true baseline.  
7.2 Definitions of Measurable and Non-Measurable Disease  
• 
Measurable disease is defined as at least one lesion whose longest diameter can be 
accurately measured as > 1.0 cm with CT scan, CT component of a PET/CT, or MRI. 
Clinical lesions will only be considered measurable if they meet the conditions of Section 
7.3.   
• 
Note:  Tumor lesions that are situated in a previously irradiated area might or might not 
be considered measurable.  
• 
Malignant lymph nodes. To be considered pathologically enlarged and measurable, a 
lymph node must be > 1.5 cm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm). At baseline and in follow-up, only 
the short axis will be measured and followed.  
• 
All other lesions (or sites of disease), including small lesions (longest diameter < 1 cm or 
pathological lymph nodes with ≥ 1 to <1.5 cm short axis) are considered nonmeasurable 
disease.  Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, 
lymphangitis cutis/pulmonis, inflammatory breast disease, and abdominal masses (not 
followed by CT or MRI), are considered non-measurable.  
• 
Note: Cystic lesions that meet the criteria for radiographically defined simple cysts should 
not be considered as malignant lesions (neither measurable nor non-measurable) since 
they are, by definition, simple cysts. ‘Cystic lesions’ thought to represent cystic metastases 
can be considered as measurable lesions, if they meet the definition of measurability 
described above. However, if non-cystic lesions are present in the same subject, these are 
preferred for selection as target lesions.  


SKCCC J12138 
IND 117362  
Confidential              
  
49 
Version 11.0 / February 18, 2022   
7.3 Guidelines for Evaluation of Measurable Disease  
7.3.1 Measurement Methods  
• 
All measurements should be recorded in metric notation (i.e., decimal fractions of 
centimeters) using a ruler or calipers.  
• 
The same method of assessment and the same technique must be used to characterize each 
identified and reported lesion at baseline and during follow-up.   
• 
Imaging-based evaluation is preferred to evaluation by clinical examination when both 
methods have been used at the same evaluation to assess the antitumor effect of a 
treatment.  
• 
All measurements will be made based on RECIST guideline version 1.144  
7.3.2 Acceptable Imaging Modalities for Measurable Disease  
• 
CT chest, abdomen and pelvis with IV contrast is the preferred modality to assess the 
presence of visible disease in study patients and then to follow their response to 
chemotherapy. When CT cannot be used, MRI chest, abdomen and pelvis is acceptable.  
If there is a lesion that is uncertain as to whether it is disease or not, PET-CT can be used 
to make this determination per the investigator’s discretion.  
• 
Conventional CT: This guideline has defined measurability of lesions on CT scan based 
on the assumption that CT slice thickness is 5 mm or less. If CT scans have slice thickness 
greater than 5 mm, the minimum size for a measurable lesion should be twice the slice 
thickness.  CT scans should be the default mode of assessing for visible disease in all 
patients.  
• 
Clinical Lesions: Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and >10 mm diameter as 
assessed using calipers (e.g., skin nodules). In the case of skin lesions, documentation by 
color photography, including a ruler to estimate the size of the lesion, is recommended.  
• 
Ultrasound (US): Ultrasound is not useful in assessment of lesion size and should not be 
used as a method of measurement. Ultrasound examinations cannot be reproduced in their 
entirety for independent review at a later date and, because they are operator dependent, 
it cannot be guaranteed that the same technique and measurements will be taken from one 
assessment to the next. If new lesions are identified by ultrasound in the course of the 
study, confirmation by CT or MRI is advised. If there is concern about radiation exposure 
at CT, MRI may be used instead of CT in selected instances.  


SKCCC J12138 
IND 117362  
Confidential              
  
50 
Version 11.0 / February 18, 2022   
7.3.4 Measurement of Effect  
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guidelines 
(version 1.1)44.  Radiologists are our institution will be interpreting the films and the principle 
investigator will be determining the type of response or progression using the RECIST criteria.  
7.3.4.1 Target Lesions  
• 
All measurable lesions (as defined in Section 7.2) up to a maximum of 2 lesions per organ 
and 5 lesions in total, representative of all involved organs, should be identified as target 
lesions and recorded and measured at baseline. If the protocol specified studies are 
performed, and there are fewer than 5 lesions identified (as there often will be), there is 
no reason to perform additional studies beyond those specified in the protocol to discover 
new lesions.  
• 
Target lesions should be selected on the basis of their size (lesions with the longest 
diameter), be representative of all involved organs, but in addition should be those that 
lend themselves to reproducible repeated measurements. It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement in which 
circumstance the next largest lesion which can be measured reproducibly should be 
selected.  
• 
Baseline sum of Diameters (BSD): A sum of the diameters (longest for non-nodal lesions, 
short axis for nodal lesions) for all target lesions will be calculated and reported as the 
baseline sum of diameters. If lymph nodes are to be included in the sum, then only the 
short axis is added into the sum. The BSD will be used as reference to further characterize 
any objective tumor response in the measurable dimension of the disease.  
7.3.4.2 Non-Target Lesions  
All other lesions (or sites of disease) should be identified as non-target lesions and should also be 
recorded at baseline. Measurements are not required, and these lesions should be followed in 
accord with Section 7.3.5.2.   
7.3.5 Response Criteria during Follow-up Phase  
All identified sites of disease must be followed on reevaluation. Specifically, a change in objective 
status to either a PR or CR cannot be done without rechecking all identified sites (i.e., target and 
non-target lesions) of pre-existing disease.    


SKCCC J12138 
IND 117362  
Confidential              
  
51 
Version 11.0 / February 18, 2022   
7.3.5.1 Evaluation of Target Lesions  
• 
Complete Response (CR): Disappearance of all target lesions and normalization of tumor 
biomarkers (CA 19-9). Any pathological lymph nodes (whether target or non-target) must 
have reduction in short axis to < 1 cm.  
• 
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions 
taking as reference the BSD.  
• 
Progression (PD): At least a 20% increase in the sum of diameters of target lesions taking 
as reference the smallest sum of diameters recorded on study (this includes the baseline 
sum if that is the smallest on study) or the appearance of one or more new lesions. In 
addition to the relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm.  
• 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase 
to qualify for PD taking as references the smallest sum of diameters while on study.  
7.3.5.2 Evaluation of Non-Target Lesions  
• 
Complete Response (CR): Disappearance of all non-target lesions and normalization of 
tumor biomarker level. All lymph nodes must be non-pathological in size (< 1 cm short 
axis)  
• 
Non-CR/Non-PD: Persistence of one or more non-target lesions and/or maintenance of 
tumor biomarker level above the normal limits.   
• 
Progression (PD): Appearance of one or more new lesions. Unequivocal progression of 
existing non-target lesions. Unequivocal progression should not normally trump target 
lesion status. It must be representative of overall disease status change, not a single lesion 
increase.  
• 
NOTE: Although a clear progression of “non-target” lesions only is exceptional, in such 
circumstances, the opinion of the treating physician will prevail, and the progression status 
will be confirmed at a later time by the study chair or a review panel.  
 
7.3.6 Overall Objective Status during Follow-up Phase  
The overall objective status for an evaluation is determined by combining the subject’s status on 
target lesions, non-target lesions, and new disease as defined in the following tables (Table 
7.3.6.1, 7.3.6.2)  
 
Table 7.3.6.1 For Subjects with Measurable Disease (i.e., Target Disease):   


SKCCC J12138 
IND 117362  
Confidential              
  
52 
Version 11.0 / February 18, 2022   
 
Target 
Lesions  
Non-Target 
Lesions*  
New 
Lesions  
CA 19-9  
Overall  
Objective  
Status  
CR  
CR  
No  
Normal (≤ 
ULN)  
CR  
CR  
Non-CR/Non-
PD/not evaluated  
No  
Normal  
PR  
PR  
Non-CR/Non-
PD/not evaluated  
No  
Any value  
PR  
SD  
Non-CR/Non-
PD/not evaluated  
No  
Any value  
SD  
PD  
Any  
Yes or No  
Any value  
PD  
Any  
PD  
Yes or No  
Any value  
PD  
Any  
Any  
Yes  
Any value  
PD  
  
* ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-
target disease since SD is increasingly used as an endpoint for 
assessment of efficacy in some trials so to assign this category 
when no lesions can be measured is not advised.  
  
Table 7.3.6.2 For Subjects with Non-Measurable Disease (i.e., Non-Target Disease):  
Non-Target 
Lesions  
New Lesions  
CA 19-9  
Overall 
Objective 
Status  
CR  
No  
Normal  
CR  
Non-CR/non-PD  
No  
Any value  
Non-CR/non-PD*  
Not all evaluated  
No  
Any value  
not evaluated  
Unequivocal PD  
Yes or No  
Any value  
PD  
Any  
Yes  
Any value  
PD  
  
* ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for 
non-target disease since SD is increasingly used as an 
endpoint for assessment of efficacy in some trials so to 
assign this category when no lesions can be measured is 
not advised.  
 


SKCCC J12138 
IND 117362  
Confidential              
  
53 
Version 11.0 / February 18, 2022   
7.3.6.1 Residual Disease  
In some circumstances it may be difficult to distinguish residual disease from normal tissue. When 
the evaluation of complete response depends upon this determination, it is recommended that the 
residual lesion be investigated (fine needle aspirate/biopsy) before confirming the complete 
response status.  
7.3.6.2 Symptomatic Deterioration  
Subjects with global deterioration of health status requiring discontinuation of treatment without 
objective evidence of disease progression at that time, and not either related to study treatment or 
other medical conditions, should be reported as PD due to “symptomatic deterioration.”  
Examples of symptomatic deterioration include:   
• 
Weight loss >10% of body weight.  
• 
Worsening of tumor-related symptoms.  
• 
Decline in performance status of >1 level on ECOG scale.  
Every effort should be made to document the objective progression even after discontinuation of 
treatment due to symptomatic deterioration.  
8 Correlative Studies  
Research samples will be collected at the discretion of the PI based on availability of supplies and 
safety of patient and staff.  
Two sources of tumor DNA, blood and tumor biopsies will be evaluated for DNA methylation 
status in each subject to determine if therapy with CC-486 results in demethylation.  These studies 
will also evaluate for an epigenetic signature that can help predict patients who will be responders 
versus non-responders and identify predictive signatures of possible recurrence and benefits of 
CC-486 therapy.  
8.1 Plasma/Serum Samples  
Blood for correlative studies will be drawn from all subjects in the study at screening and on Cycle 
1 Day 1 prior to starting treatment.  If screening assessments were done within 7 days of initiating 
Cycle 1 Day 1, these do not need to be repeated.  Arm B patients have optional research blood 
draws on Day 1 Cycle 1 and on Day 1 of every third cycle (Cycle 4, 7, 10, etc.) thereafter. Blood 
for correlative studies will also be drawn from all patients at disease progression during the initial 
CC-486/observation phase. The blood samples will be used to assess the methylation status of 
free tumor DNA circulating in the blood.  Both global and candidate gene methylation patterns 


SKCCC J12138 
IND 117362  
Confidential              
  
54 
Version 11.0 / February 18, 2022   
will be evaluated in plasma samples.  Some of the potential candidate genes include: TMS1, 
ARH1, hMLHI.    
 
Quantitative analysis using real-time Methylation-specific PCR (MSP) will be used to detect the 
presence of methylated alleles for specific genes.  Genes found to be methylated in pretreatment 
samples will be monitored for changes during and after treatment using real-time MSP.  DNA 
will first be extracted from plasma using standard phenol chloroform extraction.  The DNA will 
then be analyzed for changes in DNA methylation at specific gene promoters that include TMS1, 
ARH1, hMLHI.  PCR primers for these have been described and are in frequent use in the 
Azad/Yarchoan lab.  This strategy of real-time MSP has recently shown promising results in an 
ongoing trial in metastatic lung cancer with combination epigenetic therapy with subcutaneous 5-
azacitidine and the HDAC inhibitor, entinostat.  
 
We will also do methylation status analysis on samples using Methylation-on-Beads (MOB), a 
novel nano-enabled methylation based technology.  This assay has shown great promise as a tool 
for surveillance of responses to epigenetic therapy in preliminary studies in solid tumors.  The 
utility of the nano-enabled platform will also be explored in the ongoing correlative studies since 
this may provide a more sensitive assay for detection of response to epigenetic therapy than real 
time MSP.  
8.2 Tumor Biopsies  
Tumor biopsies will be attempted on all subjects at the time of visible disease recurrence.  We 
will also consent subjects to obtain paraffin-embedded blocks of their original resected pancreatic 
tumor.  Methylation status will be assessed on these samples to correlate with the data received 
from the plasma analysis.  All new biopsy specimens will be stored as fresh tissue at ≤ -70°C for 
extraction of DNA and RNA.  
 
All biopsy specimens will undergo tumor methylation analysis with MSP for select candidate 
genes (TMS1, ARH1, etc) as described above.  Evaluation of expression of genes that become 
demethylated post-treatment will be performed using quantitative real-time PCR, whenever 
possible.  Where sufficient tissue is obtained, samples will also be studied using an Infinium 
Methylation Assay that surveys genome-wide DNA methylation profiles (such as the Illumina  
HumanMethylation27 BeadChip or the newer Infinium HumanMethylation450 BeadChip).  This 
technology examines approximately 27,500 CpGs in 14,500 regions, including 12,833 well-
annotated genes described in the NCBI CCDS database, 144 methylation hotspots in cancer genes, 
982 cancer related targets, and 110 microRNA promoters.  Results are analyzed using BeadStudio 
software that allows for data analysis and integration of methylome data with mRNA or miRNA 
expression array studies.  In regions of cancer hotspots, there are 7 CpGs studied on average per 


SKCCC J12138 
IND 117362  
Confidential              
  
55 
Version 11.0 / February 18, 2022   
gene.  As little as 500ng of input DNA is required for the BeadChip, which allows for investigation 
of samples collected by laser capture microdissection.  We will investigate if the Illumina 
Infinium chip can be used to define epigenetic signatures between responders and non-responders 
to oral epigenetic therapy.  
8.2.1 Specimen Collection and Handling  
8.2.1.1 Blood  
Blood samples for methylation analysis will be collected from all participants in EDTA BD 
Vacutainer cell preparation tubes (purple tubes, Becton Dickinson, Franklin Lakes, NJ).  These 
tubes are designed to separate plasma and mononuclear cells from whole blood.  Forty to sixty 
mL of blood will be collected from each subject during each collection as per Section 2, Schedule 
of Study Assessment.  For samples drawn at Johns Hopkins, tubes will be transported on ice and 
processed within 30 minutes in Dr. Azad/ Yarchoan’s laboratory.  Blood collected at other sites 
will follow the process for shipping samples to Johns Hopkins Hospital as described in the 
Laboratory Manual for the study. All blood not used for correlative analyses will be stored for 
future use if new biomarkers are developed that may better predict recurrence. 
8.2.1.2 Archival Tissue  
Patients will be consented in order for us to obtain paraffin-embedded blocks and slides of their 
original resected tumor. This will enable us to perform methylation analysis on the primary tumor 
and compare this to the tumors at the time of recurrence to determine if treatment with CC-486 
led to any changes in methylation. The first slide should be stained for H&E (Hematoxylin and 
Eosin) for confirmation of the presence of tumor tissue; then, up to 20 serially cut slides should 
follow. Slides should be 10 microns in thickness and placed in tubes; alternatively, sections may 
be mounted on charged or silanted slides without coverslips. The H&E stained and all unstained 
slides will be submitted.   
8.2.1.3 Tumor Biopsies  
At the time of recurrence, there must be an attempt to obtain tumor samples by FNA or core biopsy 
from accessible tumor tissue.  A maximum of 8 core biopsies (or fine needle aspirates if cores are 
considered unsafe) will be obtained from each subject.  The aspirates will be used to prepare air 
dried cytologic smears and frozen samples.  The first pass will be used for on-site examination of 
the material, to determine presence and quality of lesional tissue.  The remaining biopsy 
specimens will be flash frozen in liquid nitrogen and then stored as fresh tissue at ≤ -70°C for 
extraction of DNA and RNA.  The biopsy specimens will be stored and evaluated in Dr. Azad/ 
Yarchoan’s laboratory.    
 


SKCCC J12138 
IND 117362  
Confidential              
  
56 
Version 11.0 / February 18, 2022   
8.2.1.4 Subject Anonymity  
A unique subject identifier will be assigned to each subject and will be used to identify tumor 
biopsies and blood samples.  The protocol scientific investigator(s) handling the samples will be 
blinded as to the subject identification, subject data and outcome.  
9 Protocol Amendments/Deviations  
9.1 Protocol Amendments  
Any amendment to this protocol must be agreed to by the Principal Investigator and reviewed by 
Celgene. Amendments should only be submitted to IRB/EC after consideration of Celgene 
review. Written verification of IRB/EC approval will be obtained before any amendment is 
implemented.    
9.2 Protocol Deviations  
When an emergency occurs that requires a deviation from the protocol for a subject, a deviation 
will be made only for that subject.  A decision will be made as soon as possible to determine 
whether or not the subject (for whom the deviation from protocol was effected) is to continue in 
the study.  The subject’s medical records will completely describe the deviation from the protocol 
and state the reasons for such deviation.  In addition, the Investigator will notify the IRB/EC in 
writing of such deviation from protocol. Non-emergency minor deviations from the protocol will 
be permitted with approval of the Principal Investigator.   
 
External sites will submit a master deviation log to the Coordinating Center monthly by email, at 
 
10 Data Management  
10.1 Data Collection  
Data will be collected and reported on either paper case report forms (CRF) or through an internal 
data monitoring system, which will be determined prior to the start of the study.  
10.2 Analyses and Reporting  
Data Submission  
Data and/or completed case report forms must be transmitted electronically using the study web 
based system provided by Johns Hopkins (CRMS). Data will be completed and submitted weekly 
for cycle 1 and monthly for each subsequent cycle. Case report forms will be provided to 
participating sites by the Coordinating Center.   
  


SKCCC J12138 
IND 117362  
Confidential              
  
57 
Version 11.0 / February 18, 2022   
Data will be analyzed and reported after the trial has completed accrual. All subsequent data 
collected will be analyzed and reported in a follow-up clinical report.   
  
10.3 Clinical Trial Monitoring  
The SKCCC Compliance Monitoring Program will provide external monitoring for JHU-
affiliated sites in accordance with SKCCC DSMP (Version 6.0, 02/21/2019). The SMC 
Subcommittee will determine the level of patient safety risk and level/frequency of monitoring. 
Eligibility for all sites will be monitored by the Protocol Chair. The IND Sponsor and PI at each 
site shall internally monitor the progress of the trial, including review and confirmation of all 
safety/treatment-related outcomes, response assessments, safety reports and/or any related source 
documentation. Additional data and safety monitoring oversight will also be performed by the 
SKCCC Safety Monitoring Committee (SMC - as defined in the DSMP). External monitoring 
will occur according to the following guidelines:  
  
Johns Hopkins SKCCC: The protocol will be monitored externally by the SKCCC CRO in 
accordance with SKCCC guidelines. Trial monitoring and reporting will be done through the 
Safety Monitoring Committee (SMC) at SKCCC.   
  
Participating site(s): The protocol will be monitored by the internal CRO at each site. A report of 
the reviews will be submitted to the Johns Hopkins principal investigator and SKCCC CRO.  
  
Authorized representatives of the Coordinating Center may visit the satellite sites to perform 
audits or inspections, including source data verification. The purpose of these audits or inspections 
is to systematically and independently examine all trial-related activities and documents to 
determine whether these activities were conducted and data were recorded, analyzed, and 
accurately reported according to the protocol, Good Clinical Practice (GCP), and any applicable 
regulatory requirements.  
  
Dr. Azad will be holding the IND for this study.  She will comply with all regulated reporting 
requirements to the FDA.  
10.4 Investigator Responsibilities  
Investigator responsibilities are set out in the ICH guideline for Good Clinical Practice (GCP) and 
in the US Code of Federal Regulations.  
 
Investigators must enter study data onto CRFs or other data collection system.  The Investigator 
will permit study-related audits by Celgene or its representatives, IRB/EC review, and regulatory 


SKCCC J12138 
IND 117362  
Confidential              
  
58 
Version 11.0 / February 18, 2022   
inspection(s) (e.g., FDA, EMEA, TPP), providing direct access to the facilities where the study 
took place, to source documents, to CRFs, and to all other study documents.  
 
The Investigator, or a designated member of the Investigator’s staff, must be available at some 
time during audits to review data and resolve any queries and to allow direct access to the subject’s 
records (e.g., medical records, office charts, hospital charts, and study related charts) for source 
data verification.  The data collection must be completed prior to each visit and be made available 
to the Celgene representative so that the accuracy and completeness may be checked.  
10.5 Safety Meetings  
Monthly teleconferences will be scheduled to include the PI/Sponsor, site Principal Investigators, 
Coordinating Center representatives, Site representatives and Celgene representatives (as 
appropriate). During these meetings, the Investigators shall provide the Coordinating Center with 
study progress updates.  The Investigators will provide a summary of key points from the weekly 
meetings with a focus on safety of the protocol participants, enrollment status, and progress of 
data for objectives.  In addition, Celgene will provide safety and applicable program updates to 
the Sponsor.  
 
11 Biostatistical Analysis  
11.1 Study Design/Endpoints  
This trial is a phase II trial with the primary endpoint to demonstrate an increase in progression 
free survival in the CC-486 arm (Arm A) as compared to the observational arm (Arm B).   
Secondary endpoints include determining the response rate to chemotherapy, overall survival, and 
hypomethylation seen in the CC-486 arm as compared to the observational arm.   
11.2 Study Populations  
11.2.1 Efficacy Evaluable Population  
The primary comparisons will include all randomized patients according to the assigned treatment 
groups (i.e. ‘as randomized’). Secondary sensitivity analyses will examine the subset of patients 
receiving at least 1 dose of study drug as well as the subset of patients receiving at least 1 dose of 
chemotherapy.  Comparisons of individuals based upon treatment received will also be examined 
as a sensitivity analysis.    
11.2.2 Methylation Analysis Population  
The methylation analysis population will consist of all subjects with any evaluable methylation 
results including plasma and/or tumor biopsies.  
 


SKCCC J12138 
IND 117362  
Confidential              
  
59 
Version 11.0 / February 18, 2022   
11.3 Statistical Methodology  
11.3.1 Efficacy Analyses  
Progression free survival is defined as the time from randomization until visible recurrence on 
any imaging modality, a confirmed biopsy, or death.  Individuals lost to follow-up prior to having 
an event will be censored at the time of the last scan or biopsy. In the case of an equivocal scan 
reading, the patient will be re-imaged on schedule, if clinically appropriate, and if subsequent re-
imaging confirms recurrence, the event will be considered to have occurred at the first time point 
when a related abnormality was noted.   Overall survival is defined as the time from enrollment 
until death.  Individuals lost to follow-up prior to death will be censored at the time of last 
physician contact.  
 
Time to event outcomes, including the primary endpoint progression free survival and overall 
survival, will be summarized using Kaplan-Meier estimates of the survival function.  From these 
estimates, median time to event and one-year survival proportions with 95% confidence intervals 
will be extracted.  Cox proportional hazards models will be used to compare the two treatment 
arms and to evaluate and adjust for potential prognostic factors (e.g. nodal status, microscopic 
margins, increase in CA19-9, therapy).  The number and type of responses to chemotherapy will 
be tabulated for each group.  Logistic regression will be used to compare the response rate between 
the groups and to identify risk factors associated with response. Results will be considered 
statistically significant for p-values < 0.05.  
11.3.2 Methylation Analyses  
The correlative secondary studies will not affect sample size and are exploratory in nature only 
and are meant for hypothesis generation for further studies.  Summary statistics (e.g. means, 
standard errors) and plots will be used to describe the pharmacodynamic endpoints at each time 
point (resection and relapse) as well as the change over time.  T-tests will be used to assess the 
differences in the change in pharmacodynamic outcomes between those with and without CC486 
exposure.  These changes may also be quantified as a binary variable (response vs. no response) 
in which case the comparisons will be made using Fisher’s exact test.  Modeling approaches, 
which allow for the assessment of multiple variables, will also be considered for both the 
continuous outcomes (linear regression) and binary outcomes (logistic regression).  A generalized 
estimating equation approach will also be considered to alleviate the impact of missing data on 
the inference.   
11.3.3 Quality of life analysis  
Quality of life will be assessed at screening and/or cycle 1 day 1 and then every 3 cycles thereafter 
(cycles 4, 7 and 10) using the Functional Assessment of Chronic Illness Therapy Hepatobiliary 
Cancer (FACIT-Hep) questionnaire.  The hepatobiliary, general function, and subscale scores will 


SKCCC J12138 
IND 117362  
Confidential              
  
60 
Version 11.0 / February 18, 2022   
be will be graded according to the guidelines provided at http://www.facit.org.  Summary statistics 
(e.g. means, medians, ranges) and graphical techniques (e.g. box-plots over time) will be used to 
summarize the patterns of scores over time and assess whether or not transformations are 
necessary.  Comparisons of the differences in the change in scores over time between treatment 
groups will be performed using generalize estimating equations (GEE).  Sensitivity analyses will 
be performed to assess the impact of missing data including best and worst case single imputation, 
multiple imputation.  One issue when assessing quality of life is how to handle scores for 
individuals who have died.  Some questionnaires (e.g. Stroke modified Rankin Score) include 
death as a value on the scale; however, this is not the case for the FACIT questionnaires.  We will 
assess the impact of missing data due to death by assessing the worst category score for those who 
have died.  
11.3.4 Sample Size   
The anecdotal time to progression without treatment is approximately 4 to 6 months.  A feasible 
goal of 60 patients (30 in each arm) will provide 80% power to identify a 64% improvement in 
the median PFS from the null rate of 6 months assuming a one-sided type 1 error rate of 0.20, 24 
months of accrual and a minimum of 12 months of follow-up while allowing for 10% loss to 
follow-up (protocol accruing for 6 months at the time of submission.  
    
1-sided Type I error rate  
Detectable HR (N = 60)  
0.05  
2.12  
0.10  
1.89  
0.15  
1.74  
0.20  
1.64  
  
11.3.5 Safety Monitoring  
Although the dose level is below the maximally tolerated dose, we will monitory the rates of grade 
3/4 toxicity for individuals treated with CC-486.  We would expect to observe grade 3/4 toxicities 
in 15% of patients.  The goal is to ensure that the percentage of grade 3/4 toxicities remains below 
30%.  A Bayesian stopping guideline has been developed.  The prior was chosen to be a Beta (1, 
4), representing a 20% toxicity rate, which is at the high end of our expected value.  The guidelines 
will recommend that the therapy be re-evaluated if the posterior probability of toxicity exceeding 
30% is greater than 65%.  Table 11.3.5.1 below summarizes the stopping guideline boundaries.   
 
Table 11.3.5.1 


SKCCC J12138 
IND 117362  
Confidential              
  
61 
Version 11.0 / February 18, 2022   
 
Cohort size 
Observed number 
of toxicities that 
trigger re-evaluation 
6-9  
4  
10-12  
5  
13-15  
6  
16-18  
7  
19-21  
8  
22-24  
9  
25-27  
10  
28-31  
11  
 
The probability of triggering the stopping guidelines was assessed for a range of underlying 
toxicity rates based upon simulations with 5000 replicates (Table 11.3.5.2 below).  In the expected 
range of toxicity, the probability of stopping early was less than 4.8%.  
Table 11.3.5.2 
 
True underlying  
toxicity rate 
Probability of triggering  
stopping guideline boundaries 
10%  
1.2% 
15%  
4.8% 
20%  
14.1% 
25%  
32.2% 
30%  
54.1% 
40%  
89.6% 
50%  
99.1% 
 
11.3.6 Futility Analysis  
An interim futility analysis will be performed once 50% of the expected progressions have 
occurred.   The conditional power will be calculated for the following three scenarios for the 
unobserved data: 
 Null hypothesis: Assumes no difference between the two treatment arms, i.e. the median 
PFS in both groups is 6 months. 


SKCCC J12138 
IND 117362  
Confidential              
  
62 
Version 11.0 / February 18, 2022   
 Alternative hypothesis: Assumes that the originally hypothesized rates (6 months vs 9.84 
months) will be observed. 
 Current pattern: Assumes that the PFS observed for each group in the initial cohort will 
be observed for the remaining patients. 
 
The decision to stop or continue will be based upon the currently observed pattern with the null 
and alternative hypothesis patterns providing an estimate of the range of possible values.  Since 
the cost of continuing (in terms of safety, resources and monetary cost) is low relative to the 
information to be gained, a low threshold for continuing was selected.  We will stop the trial and 
conclude futility if the conditional power is 30% or less.  Otherwise, the trial will continue.  No 
interim efficacy analysis is planned due to the high cost of type I error spending associated with 
an interim efficacy analysis. 
 
12 Regulatory Considerations  
12.1 Institutional Review Board/Ethics Committee approval  
The protocol for this study has been designed in accordance with the general ethical principles 
outlined in the Declaration of Helsinki.  The review of this protocol by the IRB/EC and the 
performance of all aspects of the study, including the methods used for obtaining informed 
consent, must also be in accordance with principles enunciated in the declaration, as well as ICH 
Guidelines, Title 21 of the Code of Federal Regulations (CFR), Part 50 Protection of Human 
Subjects and Part 56 Institutional Review Boards.  
 
The Investigator will be responsible for preparing documents for submission to the relevant 
IRB/EC and obtaining written approval for this study.  The approval will be obtained prior to the 
initiation of the study.  
 
The approval for both the protocol and informed consent must specify the date of approval, 
protocol number and version, or amendment number. Any amendments to the protocol after 
receipt of IRB/EC approval must be submitted by the Investigator to the IRB/EC for approval.  
The Investigator is also responsible for notifying the IRB/EC of any serious deviations from the 
protocol, or anything else that may involve added risk to subjects.  
 
Any advertisements used to recruit subjects for the study must be reviewed and approved by the 
IRB/EC prior to use.  


SKCCC J12138 
IND 117362  
Confidential              
  
63 
Version 11.0 / February 18, 2022   
12.2 Informed Consent  
The Investigator must obtain informed consent of a subject or his/her designee prior to any study 
related procedures as per GCPs as set forth in the CFR and ICH guidelines.  
 
Documentation that informed consent occurred prior to the subject’s entry into the study and the 
informed consent process should be recorded in the subject’s source documents.  The original 
consent form signed and dated by the subject and by the person consenting the subject prior to the 
subject’s entry into the study must be maintained in the Investigator’s study files.  
12.3 Subject Confidentiality  
Celgene affirms the subject’s right to protection against invasion of privacy.  In compliance with 
United States federal regulations, Celgene requires the Investigator to permit representatives of 
Celgene Corporation and, when necessary, representatives of the FDA or other regulatory 
authorities to review and/or copy any medical records relevant to the study in accordance with 
local laws.  
 
Should direct access to medical records require a waiver or authorization separate from the 
subject’s statement of informed consent, it is the responsibility of the Investigator to obtain such 
permission in writing from the appropriate individual.  
12.4 Study Records Requirements  
The Investigator must ensure that the records and documents pertaining to the conduct of the study 
and the distribution of the protocol therapy, that is copies of CRFs and source documents (original 
documents, data, and records [e.g., hospital records; clinical and office charts; laboratory notes; 
memoranda; subject’s diaries or evaluation checklists; SAE reports, pharmacy dispensing records; 
recorded data from automated instruments; copies or transcriptions certified after verification as 
being accurate copies; microfiches; photographic negatives, microfilm, or magnetic media; x-
rays; subject files; and records kept at the pharmacy, at the laboratories, and at medico-technical 
departments involved in the clinical study; documents regarding subject treatment and drug 
accountability; original signed informed consents, etc.]) be retained by the Investigator for as long 
as needed to comply with national and international regulations (generally 2 years after 
discontinuing clinical development or after the last marketing approval).  The Investigator agrees 
to adhere to the document/records retention procedures by signing the protocol.  
 
12.5 Premature Discontinuation of Study  
The Principal Investigator, institution and Celgene have the right to discontinue this study at any 
time for reasonable medical or administrative reasons.  Possible reasons for termination of the 
study could be but are not limited to:  


SKCCC J12138 
IND 117362  
Confidential              
  
64 
Version 11.0 / February 18, 2022   
• 
Unsatisfactory enrollment with respect to quantity or quality.  
• 
Inaccurate or incomplete data collection.  
• 
Falsification of records.  
• 
Failure to adhere to the study protocol.  
Any possible premature discontinuation would be documented adequately with reasons being 
stated, and information would have to be issued according to local requirements (e.g., IRB/EC, 
regulatory authorities, etc.).  
 
13 References  
1. 
Siegel R, Ward E, Brawley O, Jemal A. Cancer statistics, 2011: The impact of eliminating 
socioeconomic and racial disparities on premature cancer deaths. CA Cancer J Clin 2011; 
61(4): 212-36.  
2. 
Bunger S, Laubert T, Roblick UJ, Habermann JK. Serum biomarkers for improved 
diagnostic of pancreatic cancer: a current overview. J Cancer Res Clin Oncol 2011; 
137(3): 375-89.  
3. 
Sharma C, Eltawil KM, Renfrew PD, Walsh MJ, Molinari M. Advances in diagnosis, 
treatment and palliation of pancreatic carcinoma: 1990-2010. World J Gastroenterol 
2011; 17(7): 867-97.  
4. 
Van Laethem JL, Hammel P, Mornex F, et al. Adjuvant gemcitabine alone versus 
gemcitabine-based chemoradiotherapy after curative resection for pancreatic cancer: a 
randomized EORTC-40013-22012/FFCD-9203/GERCOR phase II study. J Clin Oncol 
2010; 28(29): 4450-6.  
5. 
Vincent A, Herman J, Schulick R, Hruban RH, Goggins M. Pancreatic cancer. Lancet 
2011; 378(9791): 607-20.  
6. 
Edge SB, Compton CC. The American Joint Committee on Cancer: the 7th edition of the 
AJCC cancer staging manual and the future of TNM. Ann Surg Oncol 2010; 17(6): 1471-
4.  
7. 
Tomlinson JS, Jain S, Bentrem DJ, et al. Accuracy of staging node-negative pancreas 
cancer: a potential quality measure. Arch Surg 2007; 142(8): 767-23; discussion 73-4.  
8. 
Pawlik TM, Gleisner AL, Cameron JL, et al. Prognostic relevance of lymph node ratio 
following pancreaticoduodenectomy for pancreatic cancer. Surgery 2007; 141(5): 610-8.  
9. 
Yeo CJ, Cameron JL, Lillemoe KD, et al. Pancreaticoduodenectomy with or without distal 
gastrectomy and extended retroperitoneal lymphadenectomy for periampullary 
adenocarcinoma, part 2: randomized controlled trial evaluating survival, morbidity, and 
mortality. Ann Surg 2002; 236(3): 355-66; discussion 66-8.  


SKCCC J12138 
IND 117362  
Confidential              
  
65 
Version 11.0 / February 18, 2022   
10. 
Winter JM, Cameron JL, Campbell KA, et al. 1423 pancreaticoduodenectomies for 
pancreatic cancer: A single-institution experience. J Gastrointest Surg 2006; 10(9): 1199-
210; discussion 210-1.  
11. 
Takahashi H, Ohigashi H, Ishikawa O, et al. Perineural invasion and lymph node 
involvement as indicators of surgical outcome and pattern of recurrence in the setting of 
preoperative gemcitabine-based chemoradiation therapy for resectable pancreatic cancer. 
Ann Surg 2012; 255(1): 95-102.  
12. 
Katz MH, Wang H, Fleming JB, et al. Long-term survival after multidisciplinary 
management of resected pancreatic adenocarcinoma. Ann Surg Oncol 2009; 16(4): 836-
47.  
13. 
Showalter TN, Winter KA, Berger AC, et al. The influence of total nodes examined, 
number of positive nodes, and lymph node ratio on survival after surgical resection and 
adjuvant chemoradiation for pancreatic cancer: a secondary analysis of RTOG 9704. Int J 
Radiat Oncol Biol Phys 2011; 81(5): 1328-35.  
14. 
Garcea G, Dennison AR, Pattenden CJ, Neal CP, Sutton CD, Berry DP. Survival following 
curative resection for pancreatic ductal adenocarcinoma. A systematic review of the 
literature. JOP 2008; 9(2): 99-132.  
15. 
Schmidt CM, Glant J, Winter JM, et al. Total pancreatectomy (R0 resection) improves  
survival over subtotal pancreatectomy in isolated neck margin positive pancreatic 
adenocarcinoma. Surgery 2007; 142(4): 572-8; discussion 8-80.  
16. 
Tseng JF, Raut CP, Lee JE, et al. Pancreaticoduodenectomy with vascular resection: 
margin status and survival duration. J Gastrointest Surg 2004; 8(8): 935-49; discussion 
49-50.  
17. 
Ferrone CR, Finkelstein DM, Thayer SP, Muzikansky A, Fernandez-delCastillo C, 
Warshaw AL. Perioperative CA19-9 levels can predict stage and survival in patients with 
resectable pancreatic adenocarcinoma. J Clin Oncol 2006; 24(18): 2897-902.  
18. 
Berger AC, Garcia M, Jr., Hoffman JP, et al. Postresection CA 19-9 predicts overall 
survival in patients with pancreatic cancer treated with adjuvant chemoradiation: a 
prospective validation by RTOG 9704. J Clin Oncol 2008; 26(36): 5918-22.  
19. 
Lomberk GA. Epigenetic silencing of tumor suppressor genes in pancreatic cancer. J 
Gastrointest Cancer 2011; 42(2): 93-9.  
20. 
McCabe MT, Brandes JC, Vertino PM. Cancer DNA methylation: molecular mechanisms 
and clinical implications. Clin Cancer Res 2009; 15(12): 3927-37.  
21. 
Grzenda A, Ordog T, Urrutia R. Polycomb and the emerging epigenetics of pancreatic 
cancer. J Gastrointest Cancer 2011; 42(2): 100-11.  
22. 
Sherr CJ. Principles of tumor suppression. Cell 2004; 116(2): 235-46.  
23. 
Koorstra JB, Hustinx SR, Offerhaus GJ, Maitra A. Pancreatic carcinogenesis. 
Pancreatology 2008; 8(2): 110-25.  


SKCCC J12138 
IND 117362  
Confidential              
  
66 
Version 11.0 / February 18, 2022   
24. 
Issa JP, Kantarjian HM. Targeting DNA methylation. Clin Cancer Res 2009; 15(12): 
3938-46.  
25. 
Silverman LR, Demakos EP, Peterson BL, et al. Randomized controlled trial of azacitidine 
in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group 
B. J Clin Oncol 2002; 20(10): 2429-40.  
26. 
Fenaux P, Mufti GJ, Hellstrom-Lindberg E, et al. Azacitidine prolongs overall survival 
compared with conventional care regimens in elderly patients with low bone marrow blast 
count acute myeloid leukemia. J Clin Oncol 2010; 28(4): 562-9.  
27. 
Lubbert M, Suciu S, Baila L, et al. Low-dose decitabine versus best supportive care in 
elderly patients with intermediate- or high-risk myelodysplastic syndrome (MDS) 
ineligible for intensive chemotherapy: final results of the randomized phase III study of 
the European Organisation for Research and Treatment of Cancer Leukemia Group and 
the German MDS Study Group. J Clin Oncol 2011; 29(15): 1987-96.  
28. 
Fenaux P, Mufti GJ, Hellstrom-Lindberg E, et al. Efficacy of azacitidine compared with 
that of conventional care regimens in the treatment of higher-risk myelodysplastic 
syndromes: a randomised, open-label, phase III study. Lancet Oncol 2009; 10(3): 223-32.  
29. 
Garcia-Manero 
G. 
Myelodysplastic 
syndromes: 
2011 
update 
on 
diagnosis, 
riskstratification, and management. Am J Hematol 2011; 86(6): 490-8.  
30. 
Garcia-Manero G, Stoltz ML, Ward MR, Kantarjian H, Sharma S. A pilot 
pharmacokinetic study of oral azacitidine. Leukemia 2008; 22(9): 1680-4.  
31. 
Garcia-Manero G, Gore SD, Cogle C, et al. Phase I study of oral azacitidine in 
myelodysplastic syndromes, chronic myelomonocytic leukemia, and acute myeloid 
leukemia. J Clin Oncol 2011; 29(18): 2521-7.  
32. 
Hui AB, Lo KW, Kwong J, et al. Epigenetic inactivation of TSLC1 gene in 
nasopharyngeal carcinoma. Mol Carcinog 2003; 38(4): 170-8.  
33. 
Chan AS, Tsui WY, Chen X, et al. Downregulation of ID4 by promoter hypermethylation 
in gastric adenocarcinoma. Oncogene 2003; 22(44): 6946-53.  
34. 
Li M, Zhao ZW. Clinical implications of mismatched repair gene promoter methylation 
in pancreatic cancer. Med Oncol 2011.  
35. 
Yang H, Lu X, Qian J, et al. Imprinted tumor suppressor gene ARHI induces apoptosis 
correlated with changes in DNA methylation in pancreatic cancer cells. Mol Med Report 
2010; 3(4): 581-7.  
36. 
Kuroki T, Tajima Y, Kanematsu T. Role of hypermethylation on carcinogenesis in the 
pancreas. Surg Today 2004; 34(12): 981-6.  
37. 
Cai HH, Sun YM, Miao Y, et al. Aberrant methylation frequency of TNFRSF10C 
promoter in pancreatic cancer cell lines. Hepatobiliary Pancreat Dis Int 2011; 10(1): 95-
100.  


SKCCC J12138 
IND 117362  
Confidential              
  
67 
Version 11.0 / February 18, 2022   
38. 
Ramachandran K, Miller H, Gordian E, Rocha-Lima C, Singal R. Methylation-mediated 
silencing of TMS1 in pancreatic cancer and its potential contribution to chemosensitivity. 
Anticancer Res 2010; 30(10): 3919-25.  
39. 
Gupta S, Pramanik D, Mukherjee R, et al. Molecular determinants of retinoic acid 
sensitivity in pancreatic cancer. Clin Cancer Res 2012; 18(1): 280-9.  
40. 
Oettle H, Post S, Neuhaus P, et al. Adjuvant chemotherapy with gemcitabine vs 
observation in patients undergoing curative-intent resection of pancreatic cancer: a 
randomized controlled trial. JAMA 2007; 297(3): 267-77.  
41. 
Neoptolemos JP, Stocken DD, Friess H, et al. A randomized trial of chemoradiotherapy 
and chemotherapy after resection of pancreatic cancer. N Engl J Med 2004; 350(12): 1200-
10.  
42. 
Neoptolemos JP, Stocken DD, Bassi C, et al. Adjuvant chemotherapy with fluorouracil 
plus folinic acid vs gemcitabine following pancreatic cancer resection: a randomized 
controlled trial. JAMA 2010; 304(10): 1073-81.  
43. 
Benson AB, 3rd, Ajani JA, Catalano RB, et al. Recommended guidelines for the treatment 
of cancer treatment-induced diarrhea. J Clin Oncol 2004; 22(14): 2918-26.  
44. 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009; 45(2): 228-47.  
  
  
  
  
 


SKCCC J12138 
IND 117362  
Confidential              
  
68 
Version 11.0 / February 18, 2022   
14 Appendices  
Appendix A: ECOG Performance Status Scale  
  
  
SCORE  
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 or sedentary nature, e.g., light house work, 
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 only 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.  
  
  
 
 
 
 
 
 
  
 
 


SKCCC J12138 
IND 117362  
Confidential              
  
69 
Version 11.0 / February 18, 2022   
Appendix B: Medication Diary 
J12138  
Medication Diary – CC-486  
Cycle Number __________  
Day 1 Date _____________  
Name_______________________(initials acceptable)               ID_____________________  
  
INSTRUCTIONS:  
1. Complete one form per cycle of therapy.  
2. Take your dose of the study drug days 1 through 21 of each 28 day cycle.  CC-486 may be taken 
on an empty stomach or with food.  The tablets should be taken with about 1 cup (240mL) of 
water.  You will take 3 tablets each day (or fewer if you have been dose reduced by your 
physician).  You should swallow the tablets whole.  Do not chew, crush, or break the tablets. If a 
dose of CC-486 is missed, it should be taken as soon as possible on the same day.  If it is missed 
for the entire day, it should not be made up.  If the patient vomits after a dose is taken, no more 
subsequent tablets should be administered.    
3. Record the date, the number of tablets of you took, and when you took them.  
4. If you have any comments or notice any side effects, please record them in the Comments section. 
5. Please return the forms to your physician/research nurse prior to the next cycle of therapy.  
6. On clinic days-please wait to take your medication until after you have been seen by the RN 
or Doctor  
Day  
Date  
What 
time 
was the dose 
taken?  
# of tablets   
Comments  
1  
  
  
  
  
2  
  
  
  
  
3  
  
  
  
  
4  
  
  
  
  
5  
  
  
  
  
6  
  
  
  
  
7  
  
  
  
  
8  
  
  
  
  
9  
  
  
  
  
10  
  
  
  
  
11  
  
  
  
  


SKCCC J12138 
IND 117362  
Confidential              
  
70 
Version 11.0 / February 18, 2022   
12  
  
  
  
  
13  
  
  
  
  
14  
  
  
  
  
15  
  
  
  
  
16  
  
  
  
  
17  
  
  
  
  
18  
  
  
  
  
19  
  
  
  
  
20  
  
  
  
  
21  
  
  
  
  
To be completed by research study staff:  
1. Date protocol treatment was started 
___________________________________________________________                                     
2. Date subject was removed from protocol 
___________________________________________________________  
3. Planned total daily dose 
___________________________________________________________  
4. Total number of pills taken this cycle 
___________________________________________________________  
5. Research Study Staff’s Signature: 
___________________________________________________________  
 
Participant’s signature ____________________________________ Date _______________  
 
 
 
 
 
 


SKCCC J12138 
IND 117362  
Confidential              
  
71 
Version 11.0 / February 18, 2022   
Appendix C: Recommendations for Management of Treatment-Induced Diarrhea (for 
CC-486)  
The following guidelines are based on a publication by Benson et al. in the Journal of Clinical 
Oncology43 .  
  
  
  
  
  


SKCCC J12138 
IND 117362  
Confidential              
  
72 
Version 11.0 / February 18, 2022   
Appendix D: FACT – Hep (Version 4)  


SKCCC J12138 
IND 117362  
Confidential              
  
73 
Version 11.0 / February 18, 2022   
  


SKCCC J12138 
IND 117362  
Confidential              
  
74 
Version 11.0 / February 18, 2022   
  


SKCCC J12138 
IND 117362  
Confidential              
  
75 
Version 11.0 / February 18, 2022