Conditions: Pancreatic Cancer
Keywords: Pancreatic Cancer
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 4
Healthy volunteers: no

Brief summary:
This research study is evaluating a study drug to treat pancreatic exocrine insufficiency (PEI) during the first year after the diagnosis of pancreatic cancer while the participant is recovering from surgery and receiving adjuvant treatment.

The study drug involved in this study is:

-Zenpep

Detailed description:
The FDA (the U.S. Food and Drug Administration) has approved Zenpep as a treatment option for PEI. Zenpep is a combination of three enzymes (proteins). These enzymes are normally produced by the pancreas and are important in the digestion of fats, proteins, and sugars. Zenpep is used to replace these enzymes when the body does not have enough of its own as a result of surgery and/or pancreatic cancer.

In this research study, the investigators are studying whether Zenpep will improve the ability of patients to complete adjuvant treatment for their pancreatic cancer after surgery to remove their tumor. The investigators are also studying if Zenpep will have an effect on nutrition status and quality of life for pancreatic cancer patients after they have had surgery to remove their tumor.

Arms:
arm 1: * Pancrelipase (Zenpep) will be administered with every meal (breakfast, lunch, dinner) and snack(s), continuously.
* Participants will begin pancrelipase on the day of enrollment and continue therapy until 1 year after surgery per calendar date

Interventions: intervention 1: Pancrelipase
Intervention descriptions: intervention 1: Zenpep is a combination of three enzymes (proteins). These enzymes are normally produced by the pancreas and are important in the digestion of fats, proteins, and sugars. Zenpep is used to replace these enzymes when the body does not have enough of its own as a result of surgery and/or pancreatic cancer.

Protocol document:
Prot_SAP_000.pdf: 
 
 
Page 1 
 
DF/HCC Protocol #: 17-450 
 
TITLE:  A Phase II Study of Pancreatic Enzyme Replacement (Zenpep) on Completion Rates 
of Adjuvant Treatment among Subjects with Resected Pancreatic adenocarcinoma. 
 
Coordinating Center: 
 
 
Beth Israel Deaconess Medical Center 
 
*Principal Investigator (PI): 
A. James Moser, MD 
 
 
 
Department of Surgery 
 
 
 
Beth Israel Deaconess Medical Center 
 
 
 
330 Brookline Ave. 
 
 
 
Boston, MA 02215 
 
 
 
Tel: (617) 667-2792   
 
 
 
Email: ajmoser@bidmc.harvard.edu 
 
Co-Principal Investigator:         Bruno Bomfim da Silva Bockorny, MD 
 
 
 
Division of Hematology-Oncology  
 
 
 
Beth Israel Deaconess Medical Center 
 
 
 
330 Brookline Ave. 
 
 
 
Boston, MA 02215 
 
 
 
Tel: (617) 667-2100 
 
 
 
Fax: (617)667-4809  
 
 
 
Email: bbockorn@bidmc.harvard.edu 
 
 
Statistician: 
Hui Zheng, PhD  
 
                                             Massachusetts General Hospital 
 
 
                                             450 Brookline Ave, BP332A 
 
 
                                             Tel: (617)726-0687  
 
                                             Fax: (617) 632-4452 
 
 
                                             E-mail: hzheng1@partners.org  
 
 
 
 
 
Agents: Zenpep, supplied by Allergan PLC 
 
 
Study Exempt from IND Requirements per 21 CFR 312.2(b).   
 
 
 
Protocol Type / Version # / Version Date: 
Amendment 3 / March 4, 2019 
 
 


DF/HCC Protocol #:17-450 
Protocol Version Date: March 11, 2019 
2 
TABLE OF CONTENTS 
SCHEMA ..................................................................................................................................... 4 
1. 
OBJECTIVES .................................................................................................................. 5 
1.1. 
Study Design ........................................................................................................ 5 
1.2. 
Primary Objective ................................................................................................ 6 
1.3. 
Secondary Objectives........................................................................................... 6 
2. 
BACKGROUND ............................................................................................................. 6 
2.1. 
Study Disease(s)................................................................................................... 6 
2.2. 
Effect of Exocrine Pancreatic Insufficiency (EEPI) on Surgical Outcomes ........ 7 
2.3. 
Completion of Adjuvant Therapy ........................................................................ 7 
2.4. 
Pancrelipase (Zenpep) .......................................................................................... 7 
2.5. 
Rationale .............................................................................................................. 8 
3. 
TWO STAGE DESIGN ................................................................................................... 8 
3.1. 
PARTICIPANT SELECTION For Stage 1 ..................................................................... 8 
3.2. 
Stage 1 Enrollment Criteria ................................................................................. 9 
3.2. 
Stage 1 Exclusion Criteria ................................................................................... 9 
3.3. 
Stage 1 Replacement Criteria............................................................................. 11 
3.6. 
Inclusion of Women and Minorities .................................................................. 12 
4. 
REGISTRATION PROCEDURES ............................................................................... 12 
4.1. 
General Guidelines for DF/HCC Institutions .................................................... 12 
4.2. 
Registration Process for DF/HCC Institutions. .................................................. 13 
4.3. 
Study Procedures ............................................................................................... 13 
5. 
TREATMENT PLAN .................................................................................................... 13 
5.1. 
Treatment Regimen ............................................................................................ 13 
5.2. 
Agent Administration......................................................................................... 14 
5.3. 
General Concomitant Medication and Supportive Care Guidelines .................. 15 
5.4. 
Criteria for Taking a Participant Off Protocol Therapy ..................................... 15 
5.6. 
Duration of Follow Up ....................................................................................... 15 
5.7. 
Criteria for Taking a Participant Off Study ....................................................... 16 
6. 
DOSE MODIFICATIONS ............................................................................................ 16 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ........................ 19 
7.3. 
Adverse Event Characteristics ........................... Error! Bookmark not defined. 
Study medications may be interrupted for an AE at the discretion of the Investigator. 
Participants requiring toxicity management should be assessed and evaluated at 
least monthly as indicated by the severity of the event ..................................... 24 
7.3. 
Expedited Adverse Event Reporting .................................................................. 24 
7.4. 
Routine Adverse Event Reporting ..................................................................... 24 
7.5. 
Expedited Reporting to Hospital Risk Management ......................................... 25 


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Protocol Version Date: March 11, 2019 
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8. 
PHARMACEUTICAL  INFORMATION ..................................................................... 25 
8.1. 
Zenpep................................................................................................................ 25 
9. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES .................................... 27 
10. 
STUDY CALENDAR ..................................................................................................... 1 
11. 
MEASUREMENT OF EFFECT...................................................................................... 0 
11.1. Initiation and Completion of Adjuvant Therapy .................................................. 0 
11.2. Methods for Evaluation of Objective Response .................................................. 1 
11.3. Evaluation for progressive disease while on adjuvant therapy ............................ 2 
11.4. Initiation of adjuvant therapy ............................................................................... 4 
11.5. Evaluable for toxicity. .......................................................................................... 4 
11.6. Assessment of pancreatic enzyme insufficiency .................................................. 5 
11.7. Assessment of nutrition status ............................................................................. 5 
11.8. Quality of Life Assessments ................................................................................ 5 
11.9. Functional assessments ........................................................................................ 5 
12. 
DATA REPORTING / REGULATORY REQUIREMENTS ......................................... 5 
12.1. Data Reporting ..................................................................................................... 5 
12.2. Data Safety Monitoring........................................................................................ 6 
12.3. Multicenter Guidelines......................................................................................... 6 
13. 
STATISTICAL CONSIDERATIONS............................................................................. 6 
13.1. Study Design/Endpoints....................................................................................... 6 
13.2. Sample Size, Accrual Rate and Study Duration .................................................. 7 
13.3. Interim Monitoring Plan ...................................................................................... 7 
13.4. Analysis of Primary Endpoints .......................................................................... 78 
13.5. Analysis of Secondary Endpoints ........................................................................ 8 
13.6. Reporting and Exclusions .................................................................................... 9 
15. 
PUBLICATION PLAN ................................................................................................... 9 
APPENDIX A EQ-5D-5L Questionnaire ................................................................... 11 
APPENDIX B: PERFORMANCE STATUS CRITERIA ............................................. 13 
Appendix D – Clavien-Dindo Complication Index ....................................................... 16 
 


DF/HCC Protocol #:17-450 
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SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
STAGE 2 
Pre-Surgery 

Within 30 days prior to registration 
o
Assess Stage 1 Inclusion & Exclusion Criteria 
o
Initiate pancrelipase treatment if possible 
STAGE 1 

2 weeks after discharge, or per SOC (±7 days) 
o
Resume pancrelipase if not restarted at discharge 
o
Evaluate Stage 1 Replacement Criteria 
 

Subject Tolerance and drug toxicity: Enrollment through initiation of adjuvant 
treatment or postoperative week 12 (whichever comes first) 
o
Secondary Objectives: Assess drug-related adverse events, post-operative nutritional 
status, grip strength, EQ-5D, surgical complications  
POV #4 
POV #3 
Surgery 

Adjuvant therapy: Start date through end/cancellation of adjuvant therapy 
o
Primary Objective: Assess completion rate of adjuvant treatment 
o
Disease Progression Stopping Rule: >16 participants have disease progression while 
on adjuvant therapy 
o
Futility Stopping Rule: <12 participants complete adjuvant therapy within first 23 
POV #1 

Surgery through hospital discharge 
o
Hold pancrelipase throughout hospitalization (if already initiated) 
o
SAE monitoring suspended during SOC interventions 
POV #2 
Monitor treatment records and disease progression monthly 
Replenish study drug and monitor adherence 
Replacement for early disease progression  

POV#4 (12 weeks) after discharge, or per SOC (±7 days) 
o
Evaluate Stage 2 Replacement Criteria if proceeding to adjuvant 
treatment 

POV#3 (8 weeks) after discharge, or per SOC (±7 days) 
o
Evaluate Stage 2 Replacement Criteria (at POV 3 if proceeding to 
adjuvant before POV 4) 
Follow-Up 
 
POV #2 (4 weeks) after discharge, or per SOC (±7 days) 
o Evaluate Stage 1 Replacement Criteria  
EOT 
End of Treatment visit at week 52 or sooner due to progression 
Estimate primary endpoint 
Fecal elastase 1, Quality of life, nutrition, grip strength, adherence 


DF/HCC Protocol #:17-450 
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OBJECTIVES 
 
1.1. 
Study Design 
 
This is a single institution, single arm, open label, phase II clinical trial of pancrelipase 
(ZENPEP) among subjects undergoing standard of care pancreatic resection for early stage 
pancreatic adenocarcinoma. The study will have a 2 stage design.  
 
Stage 1: Tolerance to study drug during post-operative recovery following standard of 
care pancreatic resection 
Stage 1 takes place during the postoperative recovery following standard of care pancreatic 
resection among subjects with suspected pancreatic adenocarcinoma. Stage 1 will monitor the 
following secondary objectives between the date of hospital discharge and the start date of 
adjuvant treatment through postoperative week 12 (whichever comes first):  
 
 frequency of adverse events related to study drug 
 frequency of study-drug related dose modifications 
 study drug adherence 
 complications after pancreatic surgery (Calvien Dindo) 
 post-operative nutritional status (weight and albumin) 
 grip strength 
 ECOG status 
 quality of life (EQ-5D-5L) 
 Fecal pancreatic elastase 
 
Stage 2: Completion of adjuvant treatment and monitoring of disease progression in 
response to study drug. 
Stage 2 consists of evaluable subjects with resected, pathologically-confirmed pancreatic 
adenocarcinoma and initiate adjuvant therapy by week 12 after surgery.  Stage 2 begins with 
the start date of adjuvant treatment and ends 52 weeks after surgery.   
 
Stage 2 will estimate:  
 the primary objective (the completion rate of adjuvant treatment), 
 rate of early disease progression, defined as local recurrence or distant metastases 
during adjuvant treatment (a monitored toxicity).  
 Secondary outcomes 
o the initiation rate of adjuvant treatment 
o nutritional status (weight and albumin) 
o grip strength 
o ECOG status 
o quality of life (EQ-5D-5L) 
o Fecal pancreatic elastase 
o One year progression-free and one year overall survival 
 
 


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1.2. 
Primary Objective 
 
To assess the effect of pancreatic enzyme replacement (Zenpep) therapy on the completion rate 
of standard of care adjuvant therapy among participants with resected pancreatic 
adenocarcinoma (PDAC).  
 
1.3. 
Secondary Objectives 
 
 To assess the effect of pancreatic enzyme replacement (Zenpep) therapy on the 
initiation rate of standard of care adjuvant therapy 
 To assess subject adherence to pancreatic enzyme replacement therapy 
 To evaluate the frequency of study-drug related dose modifications and severity of drug 
related adverse events during stage 1 
 To evaluate the incidence and severity of postoperative complications during stage 1 
 To evaluate the effect of pancreatic enzyme replacement therapy on nutrition status 
during postoperative recovery and adjuvant treatment 
 To assess quality of life as measured by the EQ-5D-5L during postoperative recovery 
and adjuvant treatment 
 To evaluate grip strength, nutritional status and ECOG performance during 
postoperative recovery and adjuvant treatment 
 
2. BACKGROUND 
 
2.1. 
Study Disease(s) 
 
In 2015, the estimated number of new cases of pancreatic cancer in the US was 48,960 with 
nearly the same number of deaths1. Multimodal treatment of early stage pancreatic cancer, 
including surgical resection followed by adjuvant therapy, remains standard of care as the only 
potential treatment offering long-term survival. Supporting patients through surgery and 
subsequent adjuvant therapy remains a significant clinical challenge. Rapid early progression 
from undetected distant disease metastases is common, and delayed recovery from surgical 
resection frequently precludes adjuvant therapy.  Given these factors, median survival is 
limited to 23 months following surgical resection and adjuvant treatment in most published 
studies.1,2 
 


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2.2. 
Effect of Exocrine Pancreatic Insufficiency (EEPI) on Surgical Outcomes 
 
Although pancreatic enzyme replacement therapy (PERT) has been shown to improve quality 
of life (QOL) among participants with chronic pancreatitis9, there are no similar studies of 
pancreatic enzyme replacement among patients with PDAC that evaluate postoperative 
nutrition status and reductions in complication rates after surgical resection .  
 
The onset of exocrine pancreatic insufficiency (EPI) after resection of localized PDAC 
corresponds to the period of maximal nutritional and metabolic stress during surgical recovery 
(0-3 months) and subsequent adjuvant treatment (3-10 months). EPI causes malabsorption, 
steatorrhea, and weight loss and adversely impacts quality of life and survival, particularly 
among surgical patients with extremely low levels of fecal pancreatic elastase.6,7 EPI affects up 
to 68% of PDAC patients following potentially curative resection regardless of the type of 
surgical procedure, with 42% of those being severely affected.8 Poor post-operative nutrition is 
associated with increased risk of complications after surgery, and 40% of surgical patients with 
poor nutrition develop severe complications, including pancreatic fistula.10  
 
2.3. 
 Completion of Adjuvant Therapy 
 
Data from the prospective randomized ESPAC3 trial of 985 participants with resected PDAC 
shows a significant survival advantage among participants who completed adjuvant therapy 
regardless of the selected chemotherapy regimen, which in this trial was gemcitabine vs. 5-
fluorouracyl plus folinic acid.5 These data have recently been amplified by results of the as-yet-
unpublished PRODIGE trial comparing adjuvant FOLFIRINOX with gemcitabine-based 
regimens with postoperative median survival as long as 54 months among resected participants 
able to tolerate FOLFIRINOX and its significantly higher frequency of treatment-associated 
adverse events. 
 
Although level I evidence demonstrates the efficacy of adjuvant chemotherapy for resected 
PDAC, completion rates among these studies average approximately 50% when analyzed by 
intention to treat.1,2 Rates of initiating adjuvant therapy in current clinical practice remain low, 
with SEER data indicating standard adjuvant therapy rates below 50%.4 The observed rate at 
our Institution was 40% during a recent audit.4  
 
Causes for low rates of adjuvant therapy are multifactorial. Studies report delayed recovery 
from surgery and poor participant acceptance of adjuvant therapy as significant barriers to 
adherence with recommendations for adjuvant therapy 3.  
 
Despite ongoing development of new agents and chemotherapy combinations in the adjuvant 
setting, strategies are clearly needed to improve initiation and completion rates of adjuvant 
therapy to improve patient outcomes. This trial is designed to achieve that endpoint using a low 
risk adjunct to nutritional therapy. 
 
 
2.4. 
Pancrelipase (Zenpep) 
 


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Zenpep (pancrelipase) is an FDA approved drug for the treatment of exocrine pancreatic 
insufficiency. Post-marketing data has been available on pancrelipase since 2009. Pancrelipase 
is orally administered and excreted through the gastrointestinal (GI) tract. The pancreatic 
enzymes in pancrelipase catalyze the hydrolysis of fats to monoglycerides, glycerol, and free 
fatty acids, protein into peptides and amino acids, and starch into dextrins and short chain 
sugars such as maltose and maltriose in the duodenum and proximal small intestine, thereby 
mimicking digestive enzymes physiologically secreted by the pancreas. There have been two 
clinical trials confirming pancrelipase’s efficacy and safety in the treatment of pancreatic 
enzyme insufficiency11,12. Initial dosing is 75,000 IU with every meal, based on dosage for a 75 
kg individual derived from clinical trial data and the package insert. 
 
 The most common side effects are:  
o abdominal pain (18%),  
o flatulence (6%),  
o headache (15%),  
o confusion (6%),  
o weight loss (6%),  
o cough (6%),  
o and early satiety (6%).   
 Pancrelipase was generally safe and well-tolerated in both studies.  
 There were no deaths during either study and no serious adverse events (SAEs) related 
to pancrelipase11.   
 No drug interactions have been identified.  
 
2.5. 
Rationale 
 
The frequency and clinical severity of EPI among patients with pancreatic carcinoma is much 
higher than widely recognized. Up to sixty-eight (68%) percent of patients have EPI prior to 
surgical resection, with even higher rates are observed by one year after resection13.  
 
EPI causes significant physiological impact and nutritional stress during recovery from surgery 
and receipt of adjuvant treatment. EPI is associated with reduced survival, diminished QOL, 
and poor nutrition among PDAC patients14.  
 
Because PERT may improve nutrition status and QOL in the post-operative period, we 
hypothesize that PERT may increase rates of adjuvant therapy initiation and completion. 
 
3. TWO STAGE DESIGN 
 
3.1. 
PARTICIPANT SELECTION FOR STAGE 1 
 
Definition of stage 1: Stage 1 begins on the date that study drug is started and ends either at 
postoperative week 12 (± 5days) or the date that adjuvant treatment is started (whichever 
comes first).  
 
 


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Protocol Version Date: March 11, 2019 
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3.2. 
Stage 1 Enrollment Criteria prior to surgery 
 
3.2.1. Participant must be a candidate for standard of care surgical resection of a mass 
suspected or proven to be pancreatic adenocarcinoma (PDAC) and its WHO variants 
3.2.1.1. 
A signed surgical consent to perform elective pancreatic resection is sufficient 
documentation of eligibility for standard of care surgical resection 
3.2.1.2. 
All standard of care pancreatic resections are eligible, including potential 
concurrent vascular resection and reconstruction with or without vein grafting. 
3.2.1.3. 
Suspicious masses may be located anywhere within the pancreas.  
3.2.2. Pathological confirmation of pancreatic adenocarcinoma (PDAC) is NOT required prior 
to enrollment if the resection specimen is the planned source tissue for confirmatory 
pathology.  
3.2.2.1. 
Participants with prior biopsy or cytology confirmation of pancreatic 
adenocarcinoma are eligible. 
3.2.3. Participant must be a candidate for standard of care adjuvant treatment according to 
their treating oncologist.  
3.2.3.1. 
The anticipated treatment regimen and duration will be confirmed and recorded by 
study staff during the enrollment process. 
3.2.3.2. 
Participants receiving preoperative/neoadjuvant chemotherapy and/or radiation 
therapy for pancreatic cancer are eligible if additional chemotherapy and/or 
radiotherapy is planned in the adjuvant setting. 
3.2.3.2.1.Participants must not have completed more than half of the planned 
chemotherapy in the neoadjuant setting.  
3.2.3.3. 
Study staff shall confirm that potential participants are willing to consider adjuvant 
treatment after surgery. Participants who absolutely refuse to consider adjuvant 
treatment during the enrollment process are ineligible. 
3.2.4. ECOG performance status ≤2. 
 
3.2.5. Participant must tolerate oral intake as their sole source of nutrition.   
3.2.6. Age >18 years.  Participants <18 years old are excluded from this study because 
subsequent adjuvant therapy is based on therapy guidelines in the adult population. 
3.2.7. Pre-operative laboratory values adequate to undergo resection of pancreatic cancer, as 
defined below: 
 
 Hemoglobin > 7.0 g/dL; 
 Platelets ≥ 40,000/mL; 
 Creatinine < 2.5 mg/dL or; Creatinine clearance ≥ 20 mL/min/1.73m2 
for participants with creatinine levels above institutional normal. 
3.2.8. Ability to understand and willingness to provide written informed consent. 
 
3.2. 
Stage 1 Exclusion Criteria 
 


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Protocol Version Date: March 11, 2019 
10 
3.2.1. Any prior surgical resection, or attempted resection, of the pancreas for PDAC 
3.2.1.1. 
surgical biopsies of the pancreas are permitted 
3.2.2. Any prior treatment for local recurrence or metastasis due to pancreatic 
adenocarcinoma (i.e. salvage chemo- or radiotherapy or re-resection for recurrence are 
not permitted) 
3.2.3. Participant unable to tolerate oral nutrition as the sole source of caloric intake at the 
time of enrollment (i.e. no supplemental tube feeding or total parenteral nutrition) 
 
3.2.4. 
History of prior or concurrent malignancy requiring treatment ≤3 years prior to 
enrollment.  
3 
Exceptions: Curatively treated non-melanoma skin cancer, cervical cancer in situ, or 
prostatic intraepithelial neoplasia, or prostate cancer that do not 
require ongoing treatment 
3.2.5. History of allergic reactions or hypersensitivity attributed to compounds of similar 
chemical or biologic composition to pancrelipase 
3.2.6. 
Pregnant women are excluded because adjuvant therapy required by this study to assess 
the primary endpoint is teratogenic. Pancrelipase is category C. Animal reproduction 
studies have not been conducted on pancrelipase, and minimal data is available. 
3.2.7. Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive 
heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social 
situations that would limit compliance with study requirements. 
3.2.8. 
Participants receiving any other investigational agents. 
 
 


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Protocol Version Date: March 11, 2019 
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3.3. 
Stage 1 Re-screening Procedures after Surgery  
 
All study procedures will be suspended during hospitalization for standard of care surgical 
treatment. As a result, no adverse events resulting from standard of care surgical procedures 
will be attributed to study drug. The frequency and severity of adverse events occurring in the 
SOC setting will be recorded as secondary measures of the morbidity of surgery and correlated 
to nutritional and performance measures (i.e. grip strength and ECOG status) in the secondary 
analysis. 
 
Consequently, all study calendar references to postoperative visits during stage 1 will be timed 
according to the date of hospital discharge, rather than anchored to the date of surgery or 
enrollment, to simplify study calendar management for the following reasons: 
 Standard of care events may prolong hospitalization and delay or completely preclude 
interventions planned according to an absolute study calendar.  
 The intent of a flexible postoperative study calendar is to prevent unavoidable 
deviations related to the study calendar that have no effect on study safety or outcomes 
because study interventions are completely suspended during unplanned delays caused 
by prolonged hospitalization. 
 
Participants will be re-screened twice in the postoperative period to confirm continued 
eligibility:  
 
3.3.1. During postoperative visit #1 (POV#1; 2 weeks after hospital discharge ± 7 days), 
participants who did not undergo pancreatic resection for any reason shall be replaced. 
3.3.2. By POV#2 (4 weeks after hospital discharge ± 7 days), all participants must meet the 
following eligibility criteria: 
3.3.2.1. 
Pancreatic resection performed 
3.3.2.2. 
ECOG performance status ≤ 2 
3.3.2.3. 
Able to tolerate oral intake as their sole source of nutrition;  
3.3.2.4. 
Able to self-administer study drug.  
**Note: Subjects who reside in Skilled Nursing Facilities or rehabilitation centers 
after surgery are not barred from participation so long as they are tolerating oral 
nutrition and can self-administer study drug provided to them by the SNF/rehab 
staff. 
 
3.3.3. Stage 1 End of Treatment Visit 
The end of treatment (EOT) visit for ineligible participants will be conducted during POV#2; 
study drug will be retrieved at that time with no further issuance. If the EOT must be delayed 
so that study procedures do not interfere with SOC treatment (as late as postoperative week 
12), no further study drug will be issued, and ineligible participants will be instructed by study 
staff to stop taking study drug during/after POV#2 ± 7 days..  
 
3.4. 
Transition to Stage 2 


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12 
Stage 2 eligibility criteria shall be applied prior to initiation of adjuvant treatment at POV #3 or 
POV#4 depending on participant recovery, but not later than postoperative week 12. 
Participants who do not meet eligibility criteria prior to initiation of stage 2 shall be replaced. 
 
The purpose of stage 2 eligibility criteria is to maximize accrual of a uniform population of 
resected PDAC patients for estimation of the primary endpoint and its competing risk of early 
disease progression.  
 
Stage 2 Eligibility Criteria  
 
Final pathology must be pancreatic adenocarcinoma or WHO variants of PDAC or mixed 
histology if the predominant histology is adenocarcinoma.  
Participant unwilling to take study drug or receive adjuvant therapy following surgical 
resection of disease, which equates to withdrawal of study consent for stage 2.  
 
 
Monitoring of Disease Progression during Stage 2 
Disease progression will be monitored by imaging studies. Imaging studies will be ordered by 
the treating physician may be performed in the community or at DFHCC locations.  
 
All imaging studies will be retrieved by study staff and reviewed by TIMC. Radiographic 
findings will be recorded using RECIST criteria.  
 
Participants experiencing radiologic disease progression according to RECIST 1.1 during 
adjuvant treatment will be replaced but shall count toward the monitored safety metric of early 
disease progression in response to study drug. 
Participants must be replaced to maintain a strict definition of adjuvant treatment for evaluable 
subjects. Disease progression signifies local recurrence (stage 3) or distant metastases (stage 
IV) and defines failure of the current adjuvant regimen. Progression therefore makes 
participants unevaluable for the primary endpoint regarding completion of adjuvant treatment, 
as adjuvant treatment is cancelled by early recurrence.  
 
3.5. 
Inclusion of Women and Minorities 
 
Both men and women of all races and ethnic groups are eligible for this trial. 
 
4. REGISTRATION PROCEDURES 
 
4.1. 
General Guidelines for DF/HCC Institutions 
 
Institutions will register eligible participants in the Clinical Trials Management System 
(CTMS) OnCore. Registrations must occur prior to the initiation of protocol treatment. Any 
subject in screening that does not meet Stage 1 eligibility criteria will be logged as a screen fail 
in OnCore. 
 


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Protocol Version Date: March 11, 2019 
13 
An investigator will confirm eligibility criteria and a member of the study team will complete 
the protocol-specific eligibility checklist. 
 
Following registration, participants may begin protocol therapy. Issues that would cause 
treatment delays should be discussed with the Overall Principal Investigator (PI).  
 
4.2. 
Registration Process for DF/HCC Institutions. 
 
DF/HCC Standard Operating Procedure for Human Subject Research Titled Subject Protocol 
Registration (SOP #: REGIST-101) must be followed.   
 
 
4.3. 
Study Procedures 
 
4.3.1. Study Procedures Performed at BIDMC: 
 
Research staff will register eligible participants at BIDMC. All research related procedures will 
take place at BIDMC by research personnel. 
  
4.3.2. Administration of Standard of Care Adjuvant Treatment and related Imaging studies at 
non-DF/HCC Community Sites: 
Participants may receive standard of care adjuvant treatment and related imaging provided by a 
community medical oncologist per SOC at non-DFHCC sites.  
 
Participants receiving SOC adjuvant therapy in the community will be contacted by BIDMC 
research staff every 4 weeks (+/- 7 days) as detailed in Section 10.  
 
5. TREATMENT PLAN 
 
5.1. 
Treatment Regimen 
 
Pancrelipase (Zenpep) will be administered with every meal (breakfast, lunch, dinner) and 
snack(s), continuously. There is no limit to the number of snacks a participant can have per 
day. Treatment will be administered on an outpatient basis. The maximum number of capsules 
to be taken per day will be based on body weight and tolerance.  
 
Participants will be reassessed according to the Study Calendar (section 10). Adverse event 
reporting during Stage 1 and description of potential risks are described in Section 7. 
Appropriate dose modifications for Pancrelipase (Zenpep) are described in Section 6.  
 
No investigational, commercial agents or therapies intended to treat the participant’s pancreatic 
enzyme insufficiency may be administered other than Zenpep. Study participants should not be 
enrolled on any other therapeutic clinical trials.  
 
5.1.1. Initiation of Study Drug 


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14 
Participants may begin pancrelipase at any time after registration. Whenever possible, study 
drug should be initiated prior to surgery.  
 
If a given subject cannot begin pancrealipase prior to surgery for any reason, study drug will be 
started upon hospital discharge or during POV #1. 
 
5.1.2. Management of Study Drug during Standard of Care Surgery 
 
Study procedures and reporting will be suspended on the day of surgery and throughout the 
hospital stay after surgery. Pancrelipase will also be held. 
 
If the subject is tolerating oral intake as their sole source of nutrition and can take their 
medications orally, pancrelipase will resume on the day of hospital discharge (±7 days). If not,  
pancrelipase administration will be held and re-assessed during POV #1. 
 
5.1.3. Reconfirmation of eligibility at POV#1 
Stage 1 eligibility/inclusion and exclusion criteria shall be reconfirmed for all study 
participants per section 3. Subjects meeting Stage 1 eligibility criteria will receive up to 12 
weeks of pancrelipase treatment regardless of stage 2 eligibility criteria.  
 
5.1.4. Stage 2 Eligiblity Criteria 
Subjects who complete stage 1 will be assessed for Stage 2 eligibility during POV 4 or prior to 
starting adjuvant therapy, whichever comes first.  
 
Study medication shall be retrieved from participants who do not meet stage 2 eligibility 
criteria at their EOT visit.  
 
5.2. 
Agent Administration 
 
Participants must maintain a medication diary of each dose of study medication. The 
medication diary will be reviewed by study staff according to the study calendar until 
completion of adjuvant treatment.  
 
If study subjects are receiving adjuvant treatment at non-DFHCC sites during stage 2, study 
staff will retrieve the relevant medication diaries monthly using a pre-printed and stamped 
mailer and review those entries by telephone before refilling study drug. Subjects receiving 
adjuvant treatment at non-DFHCC sites shall return for in person study visits not less 
frequently than q 3 months, at which time medication diaries shall be reviewed in person with 
study staff. 
 
Participants must be able to swallow pancrelipase (Zenpep). If participant is not able to 
swallow Zenpep capsule whole, content may be sprinkled on small amounts of soft acidic food 
(e.g. applesauce or other commercially available preparations of bananas, or pears). The 
Zenpep-soft food mixture should be swallowed immediately without crushing or chewing, and 
followed with water or juice to ensure complete ingestion. Care should be taken to ensure that 
no drug is retained in the mouth. The initial Zenpep dose will be 75,000 lipase units per meal 


DF/HCC Protocol #:17-450 
Protocol Version Date: March 11, 2019 
15 
(3 pills) and 25,000 lipase units per snack (1 pill) orally as per package insert. Zenpep must be 
swallowed whole and taken with water or other liquid. Part of the dose of Zenpep should be 
taken in the middle of the meal and the remainder of the dose should be taken at the end of the 
meal. The maximum daily dose is 10,000 lipase units per kilogram of weight. If a dose is 
missed or vomited, it should not be made up. The next dose will be taken regularly with the 
next snack or meal. Storage of Zenpep must be in the same container, closed tightly between 
doses and stored at room temperature (i.e. subjects should not store Zenpep in a daily pill 
container with other medications).  
 
5.3. 
General Concomitant Medication and Supportive Care Guidelines 
 
No drug interactions have been identified. No formal interaction studies have been conducted. 
 
5.4. 
Criteria for Taking a Participant Off Protocol Therapy 
 
The duration of treatment with study drug will depend on individual tolerance and evidence of 
disease progression to a maximum of 52 weeks after surgery.  
 
Participants meeting the following criteria will be removed from the study: 
 
 Unacceptable adverse event(s) defined as: unexpected grade 3 events or higher during 
Stage 1 that are unresponsive to dose modifications and deemed possibly, probably or 
definitely related to study treatment. 
 Participant demonstrates an inability or unwillingness to comply with the oral 
medication regimen and/or documentation requirements. 
 Participant decides to withdraw. 
 Continuation not in the best interest of participant, or as otherwise determined by 
investigator. 
 Participant is replaced according to criteria (Section 3) 
 
When participants are removed from protocol therapy, the reason and date of removal from 
protocol therapy will be documented in the case report form (CRF). Alternative care options 
will be discussed with the participant.  
 
In the event of unusual or life-threatening complications, treating investigator must 
immediately notify the overall PI, A. James Moser at (617)-632-1032. 
 
5.6. 
Duration of Follow Up 
 
If no criteria from Section 5.4 are met, study participants will be followed for 52 weeks unless: 
 


DF/HCC Protocol #:17-450 
Protocol Version Date: March 11, 2019 
16 
 Participants removed from the study due to unacceptable adverse events attributed to 
study drug. Participants will be followed for 6-months or until resolution, stabilization 
or death even if this follow up would extend beyond 52 weeks after surgery.  
 
 Subjects who are replaced for any reason during stages 1 or 2 will complete an end of 
treatment (EOT) visit per section 10. Participants who are replaced shall be followed 
solely to determine their vital status one year after surgery (± 4 weeks).  
 
5.7. 
Criteria for Taking a Participant Off Study 
 
Participants will be removed from study when any of the following criteria apply: 
 Lost to follow-up defined as lack of subject response to three attempted contacts by the 
study team after the first missed visit specified in the study calendar 
 Withdrawal of consent for data submission 
 Death 
 
Participant will be replaced or removed from study according to criteria listed in Section 3 and 
section 5.7. 
 
The reason for taking a participant off study, and the date the participant was removed, must be 
documented in the case report form (CRF). 
 
For Decentralized Subject Registrations, the research team updates the relevant Off 
Treatment/Off Study information in OnCore.  
 
6. DOSE MODIFICATIONS 
 
Rationale for Dose Modifications 
The objective of Stage 1 is to distinguish adverse events associated with pancrelipase from 
toxicity caused by standard of care surgery or untreated pancreatic exocrine insufficiency. As a 
result, adverse events and toxicity will be assessed only during Stage 1. Dose modifications 
will only be made during Stage 1.  
 
Dose modifications may be made during Stage 2 only after discussion with a treating clinician 
delegated to do so by the principal investigator on the delegation of authority log. When 
adjuvant treatment is held, study drug may also be withheld at the discretion of the treating 
physician. The maximum permissible delay in completing adjuvant treatment is 30 days.  In 
parallel, the maximum duration of time that pancrelipase can be held during stage 2 is 30 
cumulative days.  
 
Adverse event toxicity during study drug administration may be indistinguishable from the 
symptoms of undertreated exocrine pancreatic insufficiency. For example, the side effects of 
weight loss, abdominal distension, diarrhea, flatulence, early satiety, and nausea may indicate 
undertreated EPI. Because there is no standard efficacious dose of Zenpep (pancrelipase), and 


DF/HCC Protocol #:17-450 
Protocol Version Date: March 11, 2019 
17 
because no standard tests allow Zenpep (pancrelipase) therapy to be monitored/tailored, we 
have developed a dose modification algorithm to adapt Zenpep (pancrelipase) dosing to 
symptoms of EPI while minimizing the risks of study-drug related toxicity.  
 
 
Dose Modification Algorithm 
The lowest dose permissible to stay on study is 25,000U of pancrelipase per meal or snack. 
 
Treatment modifications are based on specific safety criteria. Participants will delay or 
discontinue pancrelipase if they experience a Grade 3 adverse event, specified below, 
determined to be probably or definitely related to pancrelipase. We encourage early evaluation 
to identify if a dose reduction or a dose increase should be performed, as indicated in the 
following management tables and event specific guidelines. After a dose reduction, 
pancrelipase cannot be escalated.  
 
Please use these participant management tables and algorithms to determine dosing delay, 
restarting doses, dose increase or discontinuation: 
 
In the event that a participant experiences several adverse events, and there are conflicting 
recommendations, the investigator should use the recommended dose adjustment that reduces 
the dose to the lowest level.  
 
Table 1. Dose Modifications for Zenpep (pancrelipase) 
 
Gastrointestinal Disorders 
Flatulence 
Grade 1 
Maintain dose level 
Grade 2 
See Appendix C for algorithm 
Diarrhea 
Grade 1 
Maintain dose level 
Grade 2 
See Appendix C for algorithm 
Grade 3 
See Appendix C for algorithm 
Grade 4 
See Appendix C for algorithm 
 
Neurologic Disorders 
Headache  
Grade 1 
Maintain dose level 


DF/HCC Protocol #:17-450 
Protocol Version Date: March 11, 2019 
18 
Grade 2 
Decrease every meal dose by 25,000 unit #  
Grade 3 or higher 
Discontinue drug 
 
Respiratory Disorders 
Cough  
Grade 1 
Maintain dose level 
Grade 2 
Decrease every meal dose by 25,000 units # 
Grade 3 
Discontinue drug 
 
Skin Disorders 
Pruritus 
Grade 1 
Maintain dose level 
Grade 2 
Decrease every meal dose by 25,000 units # 
Grade 3  
Discontinue Drug 
Urticaria 
Grade 1 
Maintain dose level 
Grade 2 
Hold until Grade 1 or resolved 
Grade 3 
Discontinue Drug 
 
General System Disorder 
Weight loss  
Grade 1 
Maintain dose level 
Grade 2 
Assessment by study staff*.  If EPI, 
increase dose to 150,000 IU per meal. If 
AE, hold until < Grade 2 
Grade 3 
Hold Drug* 
 
* Recommended management: see General System Disorder AE management algorithm 
(Appendix C) 
# The snack dose will remain 25,000 units when the meal doses drop by 25,000 units 


DF/HCC Protocol #:17-450 
Protocol Version Date: March 11, 2019 
19 
 
          In the case of the dose increase to 150,000 units per meal, the snack dose should always 
be one third of the prescribed meal dose. 
 
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of reported and/or potential AEs (Section 7.1) and the characteristics of an 
observed AE (Section 7.2) will determine whether the event requires expedited reporting in 
addition to routine reporting. 
 
These AE (adverse event) management guidelines are intended to ensure the safety of each 
participant while attempting to characterize the safety and tolerability of Zenpep (pancrelipase) 
after surgery. In agreeing to the provisions of this protocol, the Investigators of this 
investigator-initiated trial accept all responsibilities for prompt notification of serious adverse 
events (SAEs) listed below to Allergan and the appropriate regulatory authorities as described 
below. 
 
Definitions: 
 
Adverse event: Any untoward medical occurrence associated with the use of the 
study   drug.  
 
Unexpected: the adverse event is not listed or the specificity or severity that has 
been observed is not listed.  
 
7.1. 
Expected Toxicities 
 
Suspension of Adverse Event Reporting after Standard of Care Surgery 
Adverse event reporting shall be suspended from the date of surgery until the date that study 
drug is restarted. All adverse events occurring between those dates shall be attributed to 
standard of care adverse events caused by surgery.  
 
Participants are observed during stage 1 to monitor their recovery until POV#2, at which time 
participants must either restart study drug or be replaced due to delayed postoperative 
recovery. Post-operative morbidity in this group of patients is frequent, reaching a rate as high 
as 40%. Some of the most frequent complications can be found below: 
 
Post Pancreatectomy Complications Overlapping with Possible Adverse Events  
 
 Abdominal Pain – Post Operative Pain  
 Flatulence –surgery-induced changes in gastrointestinal function or Clostridium 
difficile infection  
 Diarrhea –surgery-induced changes in gastrointestinal function or Clostridium 
difficile infection 
 Abdominal Distension - delayed gastric emptying and pancreatic leak 


DF/HCC Protocol #:17-450 
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20 
 Nausea – due to delayed gastric emptying and pancreatic leak 
 Early Satiety- due to delayed gastric emptying and pancreatic leak 
 Weight loss due to anorexia, prolonged delayed gastric emptying, untreated EPI, 
untreated diabetes resulting from pancreatic resection 
 Surgical site infections (deep and superficial) 
 
Resumption of Adverse Event Reporting During Stage 1 
Adverse event reporting will resume on the date that study drug is restarted and shall continue 
through completion of stage 1, which ends on the start date of adjuvant therapy or 
postoperative week 12, whichever comes first. 
 
The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential adverse events (AE) associated with an agent using a uniform 
presentation of events by body system. In addition to the comprehensive list, a subset, the 
(CAEPR), appears in a separate column and is identified with bold and italicized text. This 
subset of AEs (CAEPR) is a list of events that are protocol specific exception to expedited 
reporting. 
 
If an AE meets the reporting requirements of the protocol, and it is listed on the CAEPR, it 
should only be reported if the grade being reported exceeds the grade listed in the parentheses 
next to the event in the CAEPR. 
 
 
7.2. 
Adverse Events List 
 
7.2.1.1. 
Comprehensive Adverse Events and Potential Risks (CAEPR) List for Zenpep 
(pancrelipase) 
 
Table 7.1.1 Expected adverse effects 
Comprehensive Adverse Events and 
Potential Risks (CAEPR) 
Gastrointestinal Disorders* 
 
Abdominal Pain 
Abdominal Pain (Grade 2) 
Flatulence 
Flatulence (Grade 2) 
Diarrhea 
Diarrhea (Grade 2) 
Abdominal Distension 
Abdominal Distension (Grade 2) 
Nausea 
Nausea (Grade 2) 
Early Satiety 
Early Satiety (Grade 2) 
Weight loss 
Weight loss (Grade 2) 
Surgical site infection (deep and superficial) 
Infection (grade 3) 


DF/HCC Protocol #:17-450 
Protocol Version Date: March 11, 2019 
21 
Skin Disorders 
 
Pruritus 
Pruritis (Grade 2) 
Urticaria 
Urticaria (Grade 2) 
Rash 
Rash (Grade 2) 
Nervous System  
 
Headache  
Headache (Grade 2) 
Respiratory System 
 
Cough 
Cough (Grade 2) 
 
* Grade 3 or higher gastrointestinal expected adverse events will be reported after Standard of 
Care causes are excluded with algorithm. 
 
7.1.2 Unexpected adverse effects 
 


DF/HCC Protocol #:17-450 
Protocol Version Date: March 11, 2019 
22 
Fibrosing Colonopathy 
Fibrosing colonopathy has been reported following treatment with different pancreatic enzyme 
products. Fibrosing colonopathy is a rare serious adverse reaction initially described in association 
with high-dose pancreatic enzyme use, usually with use over a prolonged period of time and most 
commonly reported in pediatric patients with cystic fibrosis. The underlying mechanism of 
fibrosing colonopathy remains unknown. Patients with fibrosing colonopathy 
should be closely monitored because some patients may be at risk of progressing to stricture 
formation. It is uncertain whether regression of fibrosing colonopathy occurs.  
 
Potential for Irritation to Oral Mucosa 
Care should be taken to ensure that no drug is retained in the mouth. Zenpep should not be crushed 
or chewed or mixed in foods having a pH greater than 4.5. These actions can disrupt the protective 
enteric coating resulting in early release of enzymes, irritation of oral mucosa, and/or loss or 
enzyme activity. Recommendations about administration of Zenpep are detailed in Section 5.2. 
 
Potential for Risk of Hyperuricemia 
Caution should be exercised when prescribing Zenpep to patients with gout, renal impairment, or 
hyperuricemia. Porcine-derived pancreatic enzyme products contain purines that may increase 
blood uric acid levels. 
 
Allergic Reactions 
Caution should be exercised when administering pancrelipase to a patient with a known allergy to 
proteins of porcine origin. Rarely, severe allergic reactions including anaphylaxis, asthma, hives, 
and pruritus, have been reported with other pancreatic enzyme products with different formulations 
of the same active ingredient (pancrelipase). The risks and benefits of continued Zenpep treatment 
in patients with severe allergy should be taken into consideration with the overall clinical needs of 
the patient. 
 
 
7.3. 
Grading and Attribution of Adverse Events 
Adverse event reporting begins on the date that study drug is resumed during stage 1.  
 
 CTCAE term (AE description) and grade:  The descriptions and grading scales 
found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) 
version 4.0 will be utilized for AE reporting.    A copy of the CTCAE version 4.0 can 
be downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
 For expedited reporting purposes only:   
- 
AEs for the agent(s) that are listed above should be reported only if the adverse 
event varies in nature, intensity or frequency from the expected toxicity information 
which is provided. 


DF/HCC Protocol #:17-450 
Protocol Version Date: March 11, 2019 
23 
- 
Other AEs for the protocol that do not require expedited reporting are outlined in 
the next section (Expedited Adverse Event Reporting) under the sub-heading of 
Protocol-Specific Expedited Adverse Event Reporting Exclusions. 
 
 Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
Algorithm for Assigning Causality of Adverse Events during Stage 1 
 All AEs ≥Grade 3 will be reviewed with the surgeon/co-investigator to assess clinical 
significance and determine if the event is an expected toxicity from surgery. AE and 
SAE grading, attribution and reporting will be performed by the Investigators and 
discussed with the treating surgeon as this time period overlaps with the participant’s 
postoperative recovery process. SAEs occurring as a result of planned admissions for 
surgical resection and related standard of care interventions will not be considered or 
reported as an SAE. SAEs occurring in the process of readmissions after surgical 
resection and related standard of care interventions will not be considered or reported as 
an SAE unless attributed to study drug.  
 
 If the AE is not determined to be a standard surgical toxicity, surgeon/co-investigator 
will assess whether the AE is “possibly”, “probably” or “definitely” related to exocrine 
pancreatic insufficiency. If the AE is determined to be “possibly”, “probably” or 
“definitely” related to pancreatic insufficiency, the dose may be modified per table 1. If 
after two dose modifications, the AE does not resolve, it will be assumed that the AE is 
attributed to Zenpep, not pancreatic insufficiency. 
 
 If  AE is not “possibly”, “probably” or “definitely” related to pancreatic insufficiency, 
the AE will be attributed to Zenpep therapy and will be reported as per DF/HCC SAE 
reporting requirements.  
Adverse Event Monitoring during Stage 2 
Study drug toxicity and dose modifications are completed during stage 1. Adjuvant treatment is 
prescribed according to standard of care guidelines in stage 2. As a result, no AEs or SAEs will 
be collected or reported during adjuvant treatment.  Early disease recurrence is the only 
monitored toxicity. 
 
Participants will be evaluated monthly during stage 2 to monitor early disease progression. All 
participants will return to BIDMC every three months for re-evaluation and routine oncological 
care including re-staging imaging as delineated in the study calendar. 
 
For participants receiving their adjuvant treatment at BIDMC, monthly study visits to assess 
the progress of treatment and adherence/dispensing of study drug will occur in conjunction 
with routine SOC treatment. The study team will consult with the treating physician(s) and 


DF/HCC Protocol #:17-450 
Protocol Version Date: March 11, 2019 
24 
Electronic Medical Records to perform study-related activities and ascertain completion of 
adjuvant chemotherapy.  
 
For participants receiving adjuvant treatment outside of BIDMC, the study team will contact 
participants monthly to complete study calendar activities over the telephone. Monthly, 
participants will receive by mail a new drug diary, one month’s supply of study drug, and  
 
7.4. 
Reporting of an adverse event or serious adverse event:  
 
Zenpep (pancrelipase) is approved by the FDA for pancreatic enzyme insufficiency and its side 
effects are known. Only the following AEs will be reported: 
 known expected AEs that do not qualify as standard of care complications, and  
 unexpected grade 3 or higher AEs (section 7.3).  
Reporting of these AE/SAEs will be done per DF/HCC Adverse Event reporting policy.  
SAEs have to be reported up to 30 days post last dose of study medication. 
 
The Investigator should evaluate all expected and unexpected AEs (section 7.3) and make an 
immediate effort to determine their etiology. Participants continuing to experience toxicity at 
the end of stage 1 (start of adjuvant therapy or postoperative week 12, whichever comes first) 
may be contacted for additional assessment until the toxicity has resolved or is deemed 
irreversible.  
 
Adverse events and serious adverse event reporting is limited to stage 1 prior to participant 
initiation of adjuvant treatment.  
 
Study medications may be interrupted for an AE at the discretion of the Investigator. 
Participants requiring toxicity management should be assessed and evaluated at least monthly 
as indicated by the severity of the event 
 
7.3. 
Expedited Adverse Event Reporting  
 
7.3.1. Investigators must report to the Overall PI any serious adverse event (SAE) that occurs 
after the initial dose of study treatment, during treatment, or within 30 days of the last 
dose of treatment on the local institutional SAE form. An exception to this are AEs 
reported on the CAEPR list. SAEs will be reported per DF/HCC reporting policy. 
 
7.3.2. DF/HCC Expedited Reporting Guidelines 
 
BIDMC Investigators will report AEs directly to the DFCI Office for Human Research 
Studies (OHRS) per the DFCI IRB reporting policy.  
 
7.4. 
Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions to the Overall PI on the 
toxicity case report forms.  AEs reported through expedited processes (e.g., reported to the 
IRB, FDA, etc.) must also be reported in routine study data submissions. 


DF/HCC Protocol #:17-450 
Protocol Version Date: March 11, 2019 
25 
 
Non-serious (Grade 1-2) AEs will not be reported routinely. All unexpected Grade 3 or higher 
AEs that are classified as Possible, Probable or Definite will be reported. All unexpected Grade 
4 AEs will be reported. All Grade 5 AEs will be reported. An exception to this are AEs 
reported on the CAEPR list or those occurring during or as a result of standard of care 
hospitalizations.  However, AEs that are determined to be unlikely or unrelated to study drug, 
Zenpep (pancrelipase), will not be reported and do not require further evaluation.  
  
7.5. 
Expedited Reporting to Hospital Risk Management 
 
Participating investigators will report to their local Risk Management office any participant 
safety reports or sentinel events that require reporting according to institutional policy.  
 
8. PHARMACEUTICAL  INFORMATION 
 
A list of the adverse events and potential risks associated with Zenpep (pancrelipase) can be 
found in Section 7.1.  Pancrelipase is provided as investigational drug Zenpep by Allergan 
PLC. 
 
8.1. 
Zenpep 
 
8.1.1. Description 
 
Zenpep (pancrelipase) is a combination of porcine-derived lipases, proteases, and 
amylases. The pancreatic enzymes in Zenpep (pancrelipase) catalyze the hydrolysis of 
fats to monoglycerides, glycerol, and free fatty acids, protein into peptides and amino 
acids, and starch into dextrins and short chain sugars such as maltose and maltriose in 
the duodenum and proximal small intestine, thereby acting like digestive enzymes 
physiologically secreted by the pancreas. 
 
The pancreatic enzymes in Zenpep (pancrelipase) are enteric-coated to minimize 
destruction or inactivation in gastric acid. Zenpep (pancrelipase) is designed to release 
most of the enzymes in vivo at pH greater than 5.5. Pancreatic enzymes are not 
absorbed from the gastrointestinal tract in any appreciable amount. 
 
Zenpep (pancrelipase) will be provided in 25,000 units of lipase/pill capsules. 
Participants will use 3 capsules (75,000 units total) per meal and 1 capsule (25,000 
units) per snack initially. Dosing will be adjusted per symptoms as described in section 
6. Participants will be supplied with a sufficient supply on the initial visit to last 
through the second post op visit. Subjects will be supplied in one month increments on 
subsequent visits.  
 
8.1.2. Form 
 


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26 
Zenpep (pancrelipase) will be provided in 25,000 units of lipase/pill capsules. Each Zenpep 
(pancrelipase) capsule is available as a two piece hypromellose capsule with blue opaque cap 
and white body with a blue radial print. 
 
Zenpep is manufactured and will be provided by Allergan Inc.  
 
8.1.3. Storage and Stability 
 
Avoid excessive heat. Store at room temperature (68-77°F; 20-25°C), brief excursions 
permitted to 15-40°C (59-104°F). Protect from moisture. After opening, keep bottle tightly 
closed between uses to protect from moisture.  
 
8.1.4. Compatibility 
 
Zenpep (pancrelipase) should be taken with meals or snacks, with sufficient fluid (8oz). 
Pancrelipase capsules and capsule contents should not be crushed or chewed. Capsules should 
be swallowed whole. For participants who are unable to swallow intact capsules, the capsules 
may be carefully opened and the contents sprinkled on small amounts of acidic soft food of pH 
4.5 or less (e.g., commercially available preparations of bananas, pears and applesauce).  
 
The pancrelipase-soft food mixture should be swallowed immediately without crushing or 
chewing, and followed with water or juice to ensure complete ingestion. Care should be taken 
to ensure that no drug is retained in the mouth. 
 
8.1.5. Handling 
 
Keep out of reach of children. Do not crush Zenpep (pancrelipase) delayed release capsules. 
 
8.1.6. Availability 
 
Zenpep will be distributed by Allergan Inc and provided free of charge for this study. Zenpep 
is commercially available. 
 
8.1.7. Preparation 
 
Zenpep (pancrelipase) comes in capsules and should be swallowed whole with water or other 
liquid with a meal (breakfast, lunch, dinner and snack). For participants who are unable to 
swallow intact capsules, the capsules may be carefully opened and the contents sprinkled on 
small amounts of acidic soft food of pH 4.5 or less (e.g., commercially available preparations 
of bananas, pears and applesauce).  
 
8.1.8. Administration 
 
Zenpep (pancrelipase) dose will initially be 75,000 lipase units/meal (3 pills) and 25,000 lipase 
units/snack (1 pill). Pancrelipase must be swallowed whole and taken with water or any liquid; 
if participant is not able to swallow pancrelipase content may be sprinkled on small amounts of 


DF/HCC Protocol #:17-450 
Protocol Version Date: March 11, 2019 
27 
soft acidic food (e.g. applesauce). If a participant misses a dose, the next dose should be taken 
on schedule with the next snack or meal. In case of a vomited dose, participant should take 
next scheduled dose with next snack or meal. Recommendations about administration of 
Zenpep are detailed in Section 5.2. 
 
8.1.9. Ordering 
 
Zenpep will be ordered by qualified personnel at BIDMC directly from Allergan Inc. 
 
8.1.10. Accountability 
 
The investigator, or a responsible party designated by the investigator, should maintain a 
careful record of the inventory and disposition of the agent using the NCI Drug Accountability 
Record Form (DARF) or another comparable drug accountability form.  
 
8.1.11. Destruction and Return 
 
Unused or expired pancrelipase will be destroyed on site per pharmacy regulations. 
Investigators must maintain proper drug accountability records in the site master file. 
 
9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
No correlative studies will be performed.


 
 
Page 1 
STUDY CALENDAR 
Table 10.1.  Schedule of Assessments during Stage 1 
POV 3D 
POV 4D 
Week 8B 
Week 12B,D 
±
 
7
 
D
a
y
s
C
  
 
 
 
±
 
7
 
D
a
y
s
C 
 
 
 
 
 
 
 
 
 


DF/HCC Protocol #:17-450 
Protocol Version Date: September 25, 2018 
2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 


DF/HCC Protocol #:17-450 
Protocol Version Date: September 25, 2018 
3 
X 
X
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
XI 


DF/HCC Protocol #:17-450 
Protocol Version Date: September 25, 2018 
4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
XD 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
XD 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


DF/HCC Protocol #:17-450 
Protocol Version Date: September 25, 2018 
5 
 
 
A. 
Screening assessments must be completed within 30 days prior to registration. Ca19-9 and fecal elastase 
specimens will be obtained before pancrelipase is initiated. None of these results need to be available 
prior to registration or initiation of pancrelipase as the decision to perform surgery is made per SOC and 
the study drug is FDA approved. 
B. 
Timing of post-operative visit 1during stage 1 should occur 2 weeks after date of hospital discharge. If 
subject was not sufficiently recovered at two weeks post-surgery to be discharged, POV 2, which is to 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
XE 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
t 
  
Suspe
nd 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
ss study drug diary 
  
 Suspend 
X 
X 
X 
e 2 Replacement Criteria 
 
 
 
 
XD 


DF/HCC Protocol #:17-450 
Protocol Version Date: September 25, 2018 
6 
occur 4 weeks post-surgery may be omitted and the next study visit a subject will complete is POV 3 (8 
weeks ±7days post date of surgery).   
C. 
The postoperative visit schedule is determined per SOC. If a planned POV falls outside the scheduled 
study visit window by more than 7 days, study staff shall contact the surgeon and negotiate a follow-up 
visit within the prescribed visit window. However, it will not be considered a protocol deviation if the 
visit cannot be scheduled in the ±7 day window.   
D. 
Assessments prior to the initiation of adjuvant treatment may be performed at POV #3 or POV #4 (±7 
days) depending on the patient’s rate of recovery. If adjuvant treatment starts before POV#4, POV#4 
may be skipped from the stage 1 study calendar.  
E. 
EOT (End of Treatment)  during stage 1 applies to subjects meeting replacement criteria in Section 3.3.4. 
In addition to planned POV assessments, EOT requires collecting the study drug and drug diary.  
F. 
Study drug will be dispensed to subjects in person or by mail at any time after registration. Study drug 
will be held from the day of surgery until reassessment upon discharge (±7 days from discharge) or 
POV#1 if patient’s are not fit to restart pandrelipase at hospital discharge (Section 5).  
G. 
Imaging and Ca19-9 are ordered per SOC prior to surgery; visit windows do not apply. 
H. 
Pre-Operative Labs include: CBC, glucose, blood urea nitrogen (BUN), total bilirubin, alkaline 
phosphatase, AST (SGOT), ALT (SGPT), sodium, potassium, chloride, bicarbonate, creatinine. 
I. 
These tests must be performed once during stage 1 but may be done at any POV; POV#1 is preferred. 
 


 
 
Page 0 
Table 10.2  Stage 2 Study 
CalendarVisita 
Week
16c 
Week
20c 
Week
24b 
Week
28c 
Week
32c 
Week
36b 
Week
40c 
Week
44c 
Week
48c 
Week 52b or 
EOTD   
Follow 
Upd 
Visit Window 
±7 days 
Pancrelipase Therapy 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Stop 
 
Dispense Pancrelipase 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Retrieve Drug  
 
Interval History 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
   Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
   ECOG Status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
   Grip Strength 
  
  
X 
  
  
X 
  
  
  
X 
 
EQ-5D-5L 
  
  
X 
  
  
X 
  
  
  
X 
 
Imaginge 
  
  
X 
  
  
X 
  
  
  
X 
 
Ca19-9 
  
  
X 
  
  
X 
  
  
  
X 
 
Uric Acid 
  
  
  
  
  
  
  
  
  
 X 
 
Albumin 
  
  
X 
  
  
X 
  
  
  
X 
 
HbA1c 
  
  
X 
  
  
X 
  
  
  
X 
 
Fecal elastase 1 
  
  
  
  
  
  
  
  
  
X 
 
Review medication diary 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Monitor disease 
progressionf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Contact Treating 
Oncologistg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
a. Visit dates in Stage 2 are counted from the date of surgery.  
b. Study visit must occur at BIDMC regardless of the location at which SOC adjuvant therapy is being provided. 
c. Study visit conducted by telephone for participants receiving adjuvant treatment at non-DFHCC locations. The study team will retrieve medical records from 
the treating physician to determine symptoms, physical findings, weight data, treatment records, laboratory studies, and interval imaging which may indicate 
disease progression or alterations/delays/or cancellations of adjuvant therapy. Participants will receive a new medication diary and study drug via mail every 
month. A stamped, self-addressed envelope will be provided for returning unused study drug and the medication diary for review by study staff.  
d. EOT visit will be completed for all subjects completing the study or meeting stopping criteria in Section 5.4. EOT assessments will be done instead of 
scheduled assessments. EOT will be performed for all subjects completing treatment at week 52. 
e. Imaging prescribed per SOC; visit windows are not applicable to imaging. Available imaging studies will be reviewed by TIMC. 
f. Disease progression assessed per section 3  
g. The intended adjuvant therapy regimen, including duration and number of cycles, will be ascertained from the treating medical oncologist and recorded prior 
to the start of adjuvant therapy. Intended fractions of radiation therapy will also be obtained from the treating radiation oncologist prior to initiating radiation 
therapy.


 
 
Page 0 
10. MEASUREMENT OF EFFECT 
 
10.1. Initiation and Completion of Adjuvant Therapy  
 
The primary endpoint is completion of adjuvant therapy (a discrete binary variable). 
 
Completion of Adjuvant Treatment 
 
Definition of Evaluable 
In order to be evaluable for the primary endpoint, participants must begin adjuvant treatment 
by postoperative week 12. After receiving a single dose of adjuvant therapy, subjects are 
considered evaluable for the primary endpoint and will be assessed for completion of adjuvant 
therapy at each study visit. 
 
Definition of Completion of Adjuvant Treatment (Treatment Naïve) 
The completion rate is defined as the percentage of subjects who initiate adjuvant therapy by 
postoperative week 12 and complete all predefined adjuvant therapy course without 
radiographic evidence of disease progression satisfying RECIST 1.1 criteria. Tumor markers 
and clinical evidence of disease progression must be confirmed by imaging studies reviewed 
by TIMC. Disease progression cancels adjuvant treatment by definition and makes participants 
unevaluable for the primary endpoint. 
 
Participants must receive all intended cycles of standard of care chemotherapy as well as all 
intended fractions of radiation to satisfy the primary endpoint. Four weeks of treatment delays 
is permitted. When treatment is held, Zenpep may also be held. Treatment delays and 
omissions ordered by the treating physician are permissible as long as participant completes 
adjuvant treatment by the end of week 40 after surgery and delays do not exceed four weeks.   
 
Therefore: completion of fewer than 6 intended cycles of chemotherapy, or not completing 6 
cycles of adjuvant chemotherapy by week 40 after surgery, or not completing all intended 
fractions of radiation therapy will be considered failure to complete adjuvant treatment. 
 
Definition of Completion of Adjuvant Treatment (after Preoperative Treatment) 
Neoadjuvant patients are eligible so long as additional adjuvant treatment is planned before 
surgery is performed. Participants who have received all intended multimodality therapy in the 
preoperative setting shall be ineligible.  
 
The completion rate shall be defined as the percentage of subjects who initiate adjuvant 
therapy by postoperative week 12 and complete all predefined adjuvant therapy course without 
radiographic evidence of disease progression satisfying RECIST 1.1 criteria. Tumor markers 
and clinical evidence of disease progression must be confirmed by imaging studies reviewed 
by TIMC. Disease progression cancels adjuvant treatment by definition and makes participants 
unevaluable for the primary endpoint. 
 
The required completion date for adjuvant treatment among neoadjuvant participants shall not 
exceed the duration of intended cycles plus a 4 week delay. Adjuvant treatment must begin by 


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postoperative week 12. Among participants who received neoadjuvant treatment, completion 
of fewer than 6 intended cycles of chemotherapy, or not completing all 6 cycles of adjuvant 
chemotherapy by week 28 after surgery, or not completing all intended fractions of radiation 
therapy will be considered failure to complete adjuvant treatment.  
 
The calculation of week 28 follows: adjuvant treatment must start by week 12; if 3 cycles of 
treatment are planned after surgery (4 weeks each) plus a four week delay requires adjuvant 
therapy to conclude by week 28. 
 
10.2. Methods for Evaluation of Objective Response 
 
Evaluation of objective response will take place during Stage 2 of this trial: 
 
1. Monthly visits to the primary medical oncologist as part of standard of care 
during adjuvant therapy. 
2. Standard of care adjuvant chemotherapy may be administered by a community 
medical oncologist. In such cases, participants will be evaluated at BIDMC by 
research team every 4 weeks (+/- 7 days), either in person or by telephone 
according to the Stage 2 study calendar in section 10.2.  
3. If a DFHCC medical oncologist is the treating provider, participant will undergo 
standard of care visits in person, after which study interventions will be 
conducted strictly for research purposes (see Study Calendar). 
4. Research nurse will contact treating medical oncologist to establish intended 
treatment plan, set intended goals/cycles, and monitor progress with monthly 
contacts and medical record retrieval.  


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10.3. Evaluation for progressive disease while on adjuvant therapy  
 
Management of Imaging Performed at DFHCC and non-DFHCC Sites 
 
Imaging studies will be performed per standard of care and ordered at the discretion of 
the treating physician. Study staff shall retrieve all imaging studies performed per SOC 
regardless of facility participation in DFHCC.  
 
Provision of adjuvant therapy is a standard of care decision. If the treating medical 
oncologist cancels treatment as no longer in the participant’s interest for whatever 
reason prior to completion, the participant shall be taken off study and undergo an End 
of Treatment visit. If an imaging study performed per SOC indicates disease 
progression during adjuvant treatment, the participant shall be taken off study and 
undergo an End of Treatment visit provided that the TIMC central reading concurs with 
the treating radiologist. If there is discordance between the TIMC read and the official 
SOC radiology report, the research RN shall contact the treating physician within 48 
hours of the central TIMC reading to report these findings to the treating MD. The 
TIMC report shall be entered into the participant research file and communicated orally 
to the treating MD.  
 
All final decisions regarding the advisability, or not, of continued SOC adjuvant 
treatment shall be made solely by the treating physician without interference by the 
study team. Decisions of the treating physician are final.  TIMC readings shall not be 
entered into the participant’s medical record  or communicated to the participant by the 
study team. 
 
     Progressive Disease (PD): 
 
 
TIMC shall evaluate imaging studies from all facilities according to the following 
RECIST criteria for disease progression (CT or MRI): 
 
 
 At least a 20% increase in the sum of the diameters of target lesions, taking as 
reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study).  In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm since the adjuvant treatment 
started;  
 
 
 OR:  
 
 
 
 The appearance of one or more new lesions and/or unequivocal progression of 
existing non-target lesions. 
 
All measurements should be taken and recorded in metric notation using a ruler, calipers, or a 
digital measurement tool.  Disease progression will be evaluated in this study using the new 
international criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) 
guideline (version 1.1) and analyzed by Tumor Imaging Metrics Core (TIMC). Changes in the 


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largest diameter (unidimensional measurement) of the tumor lesions and the shortest diameter 
in the case of malignant lymph nodes are used in the RECIST criteria.   
 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam.  
 
Clinical lesions. Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes) and ≥10 mm in diameter as assessed using 
calipers (e.g., skin nodules).  In the case of skin lesions, documentation by color photography, 
including a ruler to estimate the size of the lesion, is recommended.  
 
Chest x-ray.  Lesions on chest x-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung; however, CT is preferable.  
 
Conventional CT and MRI. This guideline has defined measurability of lesions on CT scan 
based on the assumption that CT thickness is 5mm or less. If CT scans have slice thickness 
greater than 5 mm, the minimum size of a measurable lesion should be twice the slice 
thickness. MRI is also acceptable in certain situations (e.g. for body scans).   
 
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement.  Furthermore, the 
availability of MRI is variable globally.  As with CT, if an MRI is performed, the technical 
specifications of the scanning sequences used should be optimized for the evaluation of the 
type and site of disease.  Furthermore, as with CT, the modality used at follow-up should be 
the same as was used at baseline and the lesions should be measured/assessed on the same 
pulse sequence.  It is beyond the scope of the RECIST guidelines to prescribe specific MRI 
pulse sequence parameters for all scanners, body parts, and diseases.  Ideally, the same type of 
scanner should be used and the image acquisition protocol should be followed as closely as 
possible to prior scans.  Body scans should be performed with breath-hold scanning techniques, 
if possible. 
 
FDG-PET. While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease).  New lesions on the basis of 
FDG-PET imaging can be identified according to the following algorithm:  
(a) Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 
progressive disease (PD) based on a new lesion. 
(b)  No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive FDG-PET 
at follow-up corresponds to a new site of disease confirmed by CT, this is PD.  If the positive 
FDG-PET at follow-up is not confirmed as a new site of disease on CT, additional follow-up 
CT  scans are needed to determine if there is truly progression occurring at that site (if so, the 
date of PD will be the date of the initial abnormal FDG-PET scan).  If the positive FDG-PET at 


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follow-up corresponds to a pre-existing site of disease on CT that is not progressing on the 
basis of the anatomic images, this is not PD. 
 
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake greater 
than twice that of the surrounding tissue on the attenuation corrected image. 
 
PET-CT. At present, the low dose or attenuation correction CT portion of a combined PET-CT 
is not always of optimal diagnostic CT quality for use with RECIST measurements.  However, 
if the site can document that the CT performed as part of a PET-CT is of identical diagnostic 
quality to a diagnostic CT (with IV and oral contrast), then the CT portion of the PET-CT can 
be used for RECIST measurements and can be used interchangeably with conventional CT in 
accurately measuring cancer lesions over time.  Note, however, that the PET portion of the CT 
introduces additional data which may bias an investigator if it is not routinely or serially 
performed.   
Ultrasound. Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement. Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later data 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 from CT, MRI may be used 
instead of CT in selected instances.  
 
Endoscopy, Laparoscopy. The utilization of these techniques for objective tumor evaluation is 
not advised. However, such techniques may be useful to confirm progressive disease when 
biopsies are obtained or to determine recurrence following surgical resection. 
 
Tumor markers. Tumor markers alone cannot be used to assess recurrence of disease.  
 
10.4. Initiation of adjuvant therapy  
Participants will be assessed by their treating oncologist prior to initiating adjuvant 
therapy. The selection of the specific standard of care adjuvant therapy regimen will be 
at the discretion of the treating oncologist and may include systemic chemotherapy as 
well as radiation. Initiation of adjuvant treatment will be defined as date participant 
receives the first dose of standard of care adjuvant therapy. This will be determined by 
chart review of participant’s oncologic records and phone call by research nurse to 
treating medical oncologist. The intended adjuvant therapy regimen, which must begin 
by the end of week 12, will be specified in the CRF and will specify the intended 
chemotherapy regimen and number of intended cycles as well as the number of 
intended fractions of radiotherapy, if any. 
 
Patients who do not start adjuvant treatment by the end of week 12 will be considered 
as failure to initiate chemotherapy. 
 
10.5. Evaluable for toxicity.  
All participants are evaluable for toxicity from the time of their first treatment with 
pancrelipase until end of Stage 1. No toxicities of SOC adjuvant treatment will be 


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5 
monitored. The only monitored outcome is early disease progression, defined as 
radiographic evidence of progressive disease defined by RECIST 1.1 prior to 
completion of adjuvant treatment. 
 
10.6. Assessment of pancreatic enzyme insufficiency 
 
Fecal elastase 1 specimens will be obtained for analysis before initiation of 
pancrelipase at time of enrollment as well as at weeks 12 and 52. Note: the results of 
the fecal elastase testing do not need to be available prior to enrollment.  
 
10.7. Assessment of nutrition status 
 
 
 
This will be assessed via preoperative albumin and then with postoperative levels 
drawn once again as specified in the study calendars (10.1 and 10.2). Weight will also 
be documented as specified in the study calendar (10.1 and 10.2).  
 
10.8. Quality of Life Assessments 
 
Quality of life assessments will be done utilizing the EORTC EQ-5D-5L as specified in 
the time periods dictated in the study calendar (10.1 and 10.2). 
EORTC EQ-5D-5L Questionnaire:  Please see Appendix A  
 
10.9. Functional assessments 
 
Grip Strength: Evaluation of grip strength using a handgrip dynamometer will take place 
per the study calendar (10.1 and 10.2) and will be correlated with quality of life and 
functional assessments.   
 
ECOG performance scale:   Please see Appendix B 
 
11. DATA REPORTING / REGULATORY REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 
7.0 (Adverse Events: List and Reporting Requirements). 
 
The Office of Data Quality (ODQ) will collect, manage, and perform quality checks on the 
data for this study. 
 
11.1. Data Reporting 
 
11.1.1. Method 
 
Data will be collected, stored and managed using the secure electronic data capture application 
InForm supported by the Clinical Trials Research Informatics Office (CTRIO) at DFHCC and 
employing secure BIDMC network. 
   


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6 
11.2. Data Safety Monitoring 
 
The DF/HCC Data and Safety Monitoring Board (DSMB) will review and monitor study 
progress, toxicity, safety and other data from this study. The board is chaired by a medical 
oncologist from outside of DF/HCC and has external and internal representation. Information 
that raises any questions about participant safety or protocol performance will be addressed by 
the Overall PI, statistician and study team. Should any major concerns arise, the DSMB will 
offer recommendations regarding whether or not to suspend the study. 
 
The DSMB will meet twice a year to review accrual, toxicity, response and reporting 
information. Information to be provided to the DSMB may include: participant accrual; 
treatment regimen information; adverse events and serious adverse events reported by 
category; summary of any deaths on study; audit results; and a summary provided by the study 
team. Other information (e.g. scans, laboratory values) will be provided upon request. 
 
11.3. Multicenter Guidelines 
 
N/A 
 
12. STATISTICAL CONSIDERATIONS 
 
12.1. Study Design/Endpoints 
 
This is a single institution, single arm, open label, phase II clinical trial of pancrelipase 
(Zenpep) on subjects with resectable pancreatic cancer. Sixty-seven subjects will be enrolled 
prior to pancreatic resection in order to have 39 evaluable subjects to assess the primary 
endpoint.  
 
The primary endpoint is completion of adjuvant therapy (a discrete binary variable). 
 
The study will have a 2-stage design: 
 
Stage 1: Post-operative recovery and initiation of adjuvant therapy 
Starting at screening and lasting until POV 4 or initiation of adjuvant therapy, whichever 
comes first. This will encompass surgery and recovery time. This stage will evaluate the 
frequency of adverse events in response to study drug and the rate of initiation of adjuvant 
therapy. 
 
Stage 2: Progression monitoring and completion rate of adjuvant therapy 
Starting after POV 4 or start of adjuvant therapy, whichever comes first, and lasting until last 
follow up visit in week 52 after surgery. This stage will encompass completion of adjuvant 
therapy and monitoring for disease progression.  
 
Participants who meet stage 1 eligibility criteria (section 3) will be started on pancrelipase 
(Zenpep) as defined in section 5. Pancrelipase will start at the standard dose of 75,000 
units/meal and 25,000/snack. Participants will receive therapy for a maximum of 52 weeks 


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7 
after surgery, or until meeting criteria for discontinuation (section 5). Pancrelipase treatment 
will be held on the day of surgery and resumed during postoperative follow-up (POV #1). 
Stage 1 replacement criteria will be assessed at POV #1 and POV#2.  Subjects meeting stage 1 
replacement criteria shall discontinue study medication and will be replaced.   
 
Participants will be allowed to pursue adjuvant therapy at non-DFHCC sites.Subject stage 2 
replacement criteria will be assessed prior to initiating adjuvant treatment or at POV 4, 
whichever comes first. Subjects who meet develop early disease progression will be replaced.   
 
Adherence with study medication will be assessed by participant diary and pill counts by the 
study staff, conducted either in person for BIDMC or remotely via telephone for non-BIDMC 
patients to maximize participant convenience.  
 
Stopping Rule 
A Simon 2 stage design futility analysis will be conducted within the first 23 evaluable 
participants that have begun adjuvant therapy. If 12 participants complete adjuvant therapy, the 
study will continue. If only 11 complete adjuvant therapy, the trial will be stopped. If the study 
is not stopped for futility an additional 16 participants will be enrolled and evaluated.  At the 
end of the trial if 24 or more participants have completed adjuvant therapy the trial will be 
declared having met its primary endpoint objective.   
There is also a disease progression rule while on adjuvant therapy because theoretically 
improved nutrition can cause cancer cells to grow. If greater than 16 participants experience 
disease progression based on RECIST criteria while on adjuvant therapy, the trial will be 
stopped. This is based on a 40% historical rate of disease progression while on adjuvant 
therapy.5 
 
12.2. Sample Size, Accrual Rate and Study Duration 
 
The sample size is 39. This is based on detecting a 40% relative improvement in adjuvant 
therapy completion rate using a Simon’s minimax two-stage design. Proportion response under 
the null is 50%. Proportion response under the alternative is 70% (or greater).  Power is set to 
90% and alpha is 10% (one-sided). Having a target completion rate of 70%. 
 
Approximately 67 participants must be enrolled to meet the final needed 39 participants. This 
discrepancy is created by the need to have surgical pathology define tumor histology and allow 
subjects with inoperable tumors or prolonged surgical recovery to be replaced as they will be 
ineligible for the primary endpoint.  Additionally, tolerance of an oral diet requires some time 
period following surgical resection.  We anticipate accruing 3-4 participants/month. The 
anticipated time of accrual is approximately 2 years. 
 
12.3. Interim Monitoring Plan 
 
Interim monitoring plan specified above in Section 13.1. 
 
12.4. Analysis of Primary Endpoints 
 


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Primary Endpoint: Completion rate of adjuvant therapy. 
 
 
Completion of adjuvant therapy: Completion rate is defined as percentage of subjects who 
initiate adjuvant therapy by postoperative week 12 and complete all predefined adjuvant 
therapy course within the intended time frame allowing one month for treatment delays/holds.  
 
For example, subjects receiving 6 months’ adjuvant treatment are expected to complete all 
intended adjuvant treatment by week 40 (12 weeks during stage 1; 24 weeks for adjuvant 
treatment, with 4 weeks total treatment delay. 
 
For participants receiving neoadjuvant treatment lasting three months, the intended time frame 
for adjuvant treatment is shortened by 12 weeks and must be complete by week 28 (12 weeks 
stage 1; 12 weeks stage 2 plus 4 weeks total treatment delay). 
 
Subjects who experience disease progression during treatment are excluded from this 
assessment as disease progression cancels adjuvant treatment by definition and makes 
participants unevaluable for the primary endpoint. 
 
12.5. Analysis of Secondary Endpoints 
 
This study has several secondary endpoints: 
 
(1) Initiation rates of adjuvant therapy: Initiation of standard of care adjuvant treatment 
will be defined as subject receiving the first planned dose of adjuvant therapy by post-
operative week 12. This rate will be estimated with a 95% confidence interval.  A one-
sample binomial test will be performed to compare the initiation rates to historical 
control values of initiation rates of adjuvant therapy. 
(2) Measurement of subject adherence to pancreatic enzyme replacement therapy: 
This assessment will be conducted through participant diaries and pill counts. This will 
be conducted starting at the first post-operative visit (POV) and then every 28 days ±7 
days following that point. The rate of adherence to pancreatic enzyme replacement will 
be estimated and a 95% confidence interval provided. 
(3) Investigate whether pancreatic enzyme replacement therapy improves 
postoperative nutrition status: This will be assessed via pre-treatment albumin and 
albumin at 12, 24,36, and 52 weeks, weight gain/loss at monthly visits. Measurements 
of albumin and weight will be analyzed with descriptive statistics such as means (or 
medians) and 95% confidence intervals (or interquartile ranges) depending on the 
distribution of the measure. 
(4) Evaluate quality of life, measured via EQ-5D-5L Questionnaire (Appendix A) at 
weeks 2, 4, 8, 12, 24, 36 and 52 week following surgery. Questionnaire will be 
analyzed and descriptive statistics, means and 95% confidence intervals will be 
presented overall and by adjuvant therapy completion status.  Participants who 
complete adjuvant therapy versus those who do not complete adjuvant therapy will be 
compared using two-sample t-tests. 


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(5) Monitor the incidence and severity of postoperative complications: Postoperative 
complications will be graded via the Clavien-Dindo surgical complications grading 
system on day 90 after the date of surgery (Appendix E) and analyzed with descriptive 
statistics. 
(5) Grip strength measurement during initial visit to perform correlation with post-
operative nutrition and quality of life status. 
(6) For participants receiving neoadjuvant therapy, survival measures will commence 
on the day of their first dose of neoadjuvant treatment.  
(7) For patients undergoing surgery as their first cancer-directed therapy, survival 
measures begin on the day of surgery. 
 
12.6. Reporting and Exclusions 
 
12.6.1. Evaluation of Toxicity 
 
All participants will be evaluable for toxicity from the time of their first treatment with 
pancrelipase through Stage 1 of the study. 
 
15. PUBLICATION PLAN 
 
The results should be made public within 24 months of reaching the end of the study. The end 
of the study is the time point at which the last data items are to be reported, or after the 
outcome data are sufficiently mature for analysis, as defined in the section on Sample Size, 
Accrual Rate and Study Duration. If a report is planned to be published in a peer-review 
journal, then that initial release may be an abstract that meets the requirements of the 
International Committee of Medical Journal Editors. A full report of the outcome should be 
made public no later than three (3) years after the end of the study. 
 
 
 


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REFERENCES 
 
 
 
 
1. 
Neoptolemos JP, Moore MJ, Cox TF, et al: Effect of Adjuvant 
Chemotherapy with Fluorouracil Plus Folinic Acid or Gemcitabine vs. Observation on Survival 
in Patient with Resected Periampullary Adenocarcinoma: The ESPAC-3 Periampullaru Cancer 
Randomized Trial. JAMA 308:147-156, 2012 
 
2. 
Oettle H NP, Hochhaus A, Thomas-Hartmann J, Gellert K, Ridwelski K, 
NiedergethmannNm, Zulke C, Fahlke J, Arning MB, Sinn M, Hinke A, Riess H: Adjuvant 
Chemotherapy with Gemcitabine and Long-term Outcomes Among Patients with Resectable 
Pancreatic Cancer: The CONKO-001 Randomized Trial. JAMA 310:1473-81, 2013 
 
3. 
Davila JA CE, Hasche JC, Peterson NJ, McGlynn KA, Shaib YH: 
Utilization and determinants of adjuvant therapy among older patients who receive curative 
surgery for pancreatic cancer. Pancreas 38:e18-25, 2009 
 
4. 
McDade TP HJ, Simons JP, Piperdi B, Ng SC, Zhou Z, Kadish SP, 
Fitzgerald TJ, Tseng JF: A national propensity-adjusted analysis of adjuvant radiotherapy in 
the treatment of resected pancreatic adenocarcinoma Cancer 1:3256-66, 2010 
 
5. 
Valle JW, Palmer D, Jackson R, et al: Optimal duration and timing of 
adjuvant chemotherapy after definitive surgery for ductal adenocarcinoma of the pancreas: 
ongoing lessons from the ESPAC-3 study. J Clin Oncol 32:504-12, 2014 
 
6. 
Partelli S, Frulloni L MC, Bassi C, Barugola G, D'Onofrio M, Crippa S, 
Falconi M: Fecal elastase-1 is an independent predictor of survival in advanced pancreatic 
cancer. Dig Liver Dis 44:945-51, 2012 
 
7. 
Gooden HM, White KJ: Pancreatic cancer and supportive care—
pancreatic exocrine insufficiency negatively impacts on quality of life. Supportive Care in 
Cancer 21:1835-1841, 2013 
 
8. 
Matsumoto J, Traverso L: Exocrine function following the whipple 
operation as assessed by stool elastase. J Gastrointest Surg 10:1225-9, 2006 
 
9. 
de la Iglesia-García D, Huang W, Szatmary P, et al: Efficacy of 
pancreatic enzyme replacement therapy in chronic pancreatitis: systematic review and meta-
analysis. Gut, 2016 
 
10. 
Kanda M FT, Kodera Y, Nagai S, Takeda S, Nakao A: Nutritional 
predictors of postoperative outcome in pancreatic cancer. Br J Surg 98:268-74, 2011 
 
11. 
Wooldridge JL, Heubi JE, Amaro-Galvez R, et al: EUR-1008 pancreatic 
enzyme replacement is safe and effective in patients with cystic fibrosis and pancreatic 
insufficiency. J Cyst Fibros 8:405-17, 2009 
 
12. 
Stern RC, Eisenberg JD, Wagener JS, et al: A comparison of the efficacy 
and tolerance of pancrelipase and placebo in the treatment of steatorrhea in cystic fibrosis 
patients with clinical exocrine pancreatic insufficiency. Am J Gastroenterol 95:1932-8, 2000 
 
13. 
Sabater L, Ausania F, Bakker OJ, et al: Evidence-based Guidelines for 
the Management of Exocrine Pancreatic Insufficiency After Pancreatic Surgery. Ann Surg 
264:949-958, 2016 
 
14. 
Saito T, Hirano K, Isayama H, et al: The Role of Pancreatic Enzyme 
Replacement Therapy in Unresectable Pancreatic Cancer: A Prospective Cohort Study. 
Pancreas Publish Ahead of Print, 9000 


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APPENDIX A 
EQ-5D-5L Questionnaire  
Under each heading, please tick the ONE box that best describes your health TODAY. 
MOBILITY 
 I have no problems in walking about  
 I have slight problems in walking about 
 
 I have moderate problems in walking about  
 I have severe problems in walking about  
 I am unable to walk about  
 
SELF-CARE 
 I have no problems washing or dressing myself  
 I have slight problems washing or dressing 
myself  
 I have moderate problems washing or dressing 
myself 
 I have severe problems washing or dressing 
myself 
 I am unable to wash or dress myself 
 
USUAL ACTIVITIES (e.g. work, study, housework, 
family or leisure activities) 
 I have no problems doing my usual activities  
 I have slight problems doing my usual activities  
 I have moderate problems doing my usual activities  
 I have severe problems doing my usual activities  
 I am unable to do my usual activities  
 
PAIN / DISCOMFORT 
 I have no pain or discomfort 
 
 I have slight pain or discomfort 
 I have moderate pain or discomfort 
 


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 I have severe pain or discomfort 
 
 I have extreme pain or discomfort  
ANXIETY / DEPRESSION 
 I am not anxious or depressed  
 I am slightly anxious or depressed  
 I am moderately anxious or depressed  
 I am severely anxious or depressed  
 I am extremely anxious or depressed 
 
We would like to know how good or bad your health is TODAY. This scale is numbered 
from 0 to 100. 
 
100 means the best health you can imagine. 0 means the worst 
health you can imagine. 
 
Mark an X on the scale to indicate how your health is TODAY. 
 
Now, please write the number you marked on the scale in the box below. 
 


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APPENDIX B: PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to 
carry 
on 
all 
pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, 
but 
ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary 
nature 
(e.g., 
light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In 
bed 
<50% 
of 
the 
time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires 
considerable 
assistance 
and frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, 
fatal 
processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 
 
 


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APPENDIX C 
Algorithm for Weight Loss, Diarrhea and Flatulence Management 
 
 
 
 
 


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Appendix D – Clavien-Dindo Complication Index