Pancreatic-enzyme Replacement Therapy With Pancreaze (Pancrelipase) Delayed-release in Addition to Standard of Care for Borderline Resectable, Locally Advanced, and Advanced Pancreatic Adenocarcinoma Patients (PANCAX-3) With Cachexia and Exocrine Pancreatic Insufficiency
Phase: PHASE2
Conditions: Pancreatic Adenocarcinoma
Sponsor: Andrew Hendifar, MD

 
CONFIDENTIAL 
This material is the property of Cedars-Sinai Medical Center. Do not disclose or use except as authorized in writing by the study sponsor. 
 
 
 
 
IIT2018-29-HENDIFAR-PNCX3 
 
 
PANCREATIC-ENZYME REPLACEMENT THERAPY WITH PANCREAZE (PANCRELIPASE) DELAYED-RELEASE IN 
ADDITION TO STANDARD OF CARE FOR BORDERLINE RESECTABLE, LOCALLY ADVANCED AND ADVANCED 
PANCREATIC ADENOCARCINOMA PATIENTS (PANCAX-3) WITH CACHEXIA AND EXOCRINE PANCREATIC 
INSUFFICIENCY 
 
 
Principal Investigators: 
Andrew Hendifar, MD 
 
 
 
 
Cedars-Sinai Medical Center 
 
 
 
 
8700 Beverly Blvd, Los Angeles, CA 90048 
 
 
 
 
T:  310-423-2217 
 
 
 
 
F:  310-659-3928 
 
 
 
 
E:  Andrew.Hendifar@cshs.org 
 
 
 
 
 
 
 
 
 
 
 
 
Sub-investigators 
Department/Division 
Meghan Laszlo, RD 
Hematology/Oncology 
Jun Gong, MD 
Hematology/Oncology 
Arsen Osipov, MD 
Hematology/Oncology  
Gillian Gresham, PhD 
Hematology/Oncology 
Kamya Sankar, MD 
Hematology/Oncology 
 
  
 
 
 
 
Biostatistician: 
Márcio Augusto Diniz, PhD 
 
Funding Source:  
Vivus 
 
NCT Number:   
 
NCT04098237 
 
Initial version:  
 
Protocol Version 1 dated 12 SEP 2019 
 
Current version: 
 
Protocol Version 7 dated  18MAY2023 
 
Prior version:  
 
Protocol Version 6 dated 14OCT2022 
 
 
 
 
Protocol Version 5 dated 17JAN2022 
 
 
 
 
Protocol Version 4 dated 13 SEP 2021 
 
 
 
 
Protocol Version 3 dated 04 JAN 2021 
 
 
 
 
Protocol Version 2 dated 28 MAY 2020 
 
 
 
 
Protocol Version 2.1 dated 02 SEP 2020 
 
 

 
CONFIDENTIAL 
This material is the property of Cedars-Sinai Medical Center. Do not disclose or use except as authorized in writing by the study sponsor. 
 
 
 
 
 
Protocol v7 dated 18MAY2023 
 
Signature Page 
 
The signature below constitutes the approval of this protocol and the attachments, and provides the 
necessary assurances that this trial will be conducted according to all stipulations of the protocol, including 
all statements regarding confidentiality, and according to local legal and regulatory requirements and 
applicable U.S. federal regulations and ICH guidelines. 
 
 
 
Principal Investigator (PI) Name: _____________________________ 
 
 
 
Signature: _____________________________  Date: ____________________ 
 
 

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TABLE OF CONTENTS  
 
LIST OF ABBREVIATIONS............................................................................................................. 1 
STUDY SCHEMA ............................................................................................................................ 2 
STUDY SUMMARY ......................................................................................................................... 2 
1.0 
BACKGROUND AND RATIONALE .................................................................................... 4 
2.0 
STUDY OBJECTIVES ......................................................................................................... 7 
3.0 
PATIENT ELIGIBILITY   .................................................................................................... 11 
4.0 
TREATMENT PLAN .......................................................................................................... 13 
5.0 
STUDY PROCEDURES ..................................................................................................... 14 
6.0 
ADVERSE EVENTS .......................................................................................................... 22 
7.0 
CORRELATIVES/SPECIAL STUDIES .............................................................................. 26 
8.0 
STATISTICAL CONSIDERATIONS .............................................................................. 29 
9.0 
STUDY MANAGEMENT ................................................................................................ 30 
10.0 
REFERENCES ............................................................................................................... 35 
11.0 
APPENDICES ................................................................................................................ 38 

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LIST OF ABBREVIATIONS 
 
 
5FU 
5- fluorouracil 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
ALC 
Absolute Lymphocyte Count 
AST 
Aspartate Aminotransferase 
CA19-9 
Carbohydrate antigen 19-9  
CACS 
Cancer anorexia cachexia syndrome 
CBC 
Complete Blood Count 
CCK 
Cholecystokinin 
CMP 
Comprehensive Metabolic Panel 
CR 
Complete Response 
CRP 
C Reactive Protein 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DSMB 
Data and Safety Monitoring Board 
ECOG 
Eastern Cooperative Oncology Group 
EPI 
EOT 
Exocrine Pancreatic Insufficiency 
End-of-Treatment 
FA 
Folinic Acid (Leucovorin) 
GLP-1 
Glucagon-like peptide-1 
H&P 
History & Physical Exam 
HRPP 
Human Research Protections Program 
IL1a 
Interleukin 1-alpha 
IV (or iv) 
Intravenously 
MTD 
Maximum Tolerated Dose 
LMF 
Lipid Mobilizing Factors 
LBM 
Lean Body Mass 
NCI 
National Cancer Institute 
ORR 
Overall Response Rate 
OS 
Overall Survival 
PAWL 
Pancreatic Cancer-Associated Weight Loss 
PBMCs 
Peripheral Blood Mononuclear Cells 
PD 
Progression of Disease 
PFS 
Progression Free Survival 
PR 
Partial Response 
PYY 
Peptide YY 
 
 
 

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STUDY SCHEMA   
 
 
 
 
 
 
 
 
 
 
 
 
End of 
Study 
Screening  
Cycles 1-6 
Q6 
months 
Screening Phase 
1. Informed consent 
2. Screening  
3. Eligibility review 
4. Measure stool 
fecal elastase 
5.  Measure fat-
soluble vitamins
Treatment Phase 
 Cycle = 28 days 
1. Measure weight stability 
2. Assess 24-hour caloric 
intake 
3. Assess stool frequency and 
consistency 
4. Evaluate microbiome 
5. Assess activity levels 
6. Measure quality of life 
7. Assess inflammatory 
biomarkers 
8. Assess the presence of 
frailty phenotype 
9. Assess body composition 
 
End-of-Treatment 
After C6D28: 
1. Return pill bottles 
2. Transition to Soc enzymes 
 
 
 
Follow-up Phase 
Safety evaluation 
Measure fat-soluble vitamins 
Survival 
Optional sub-study: Follow-
up activity tracking
End of 
Treatment 

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STUDY SUMMARY 
 
Title 
Pancreatic-enzyme replacement therapy with pancreaze (pancrelipase) delayed-
release in addition to standard of care for borderline resectable, locally advanced 
and advanced pancreatic adenocarcinoma patients (PANCAX-3) with cachexia 
and exocrine pancreatic insufficiency. 
Short Title 
PANCAX-3 
Protocol Number 
IIT2018-29-Hendifar-PNCX3 
Phase 
Phase 2 
Methodology 
Single arm, Single center 
Accrual Duration 
18 months 
Study Duration 
Approximately 6 months from screening to end of treatment assessment. 
Subjects will continue to be followed for survival for 36 months. 
Study Center(s) 
Single-center, Cedars-Sinai Medical Center 
Objectives 
1. Feasibility to complete pancreatic enzyme replacement therapy at 8 weeks 
2. Measure weight stability at baseline and day 1 of every cycle for 6 months 
3. 24-hour caloric intake at baseline, C3D1, and end-of-study 
4. Stool frequency at baseline and C3D1 
5. Quality of life assessment baseline and day 1 of every other cycle for 6 
months 
6. Fitness tracking will be assessed with a wrist-worn wearable activity monitor 
(e.g., Fitbit Charge HR) continuously from day 1 of cycle 1 until the end of study 
visit. 
Number of Subjects 
Up to 40 patients (30 evaluable patients) 
Diagnosis and Main Inclusion 
Criteria 
1.  Age ≥ 18 years of age 
2.  Biopsy proven pancreatic cancer  
3.  Borderline resectable, locally advanced or advanced disease 
4. Clinical diagnosis of exocrine pancreatic insufficiency 
5.  Cachexia defined as 5% weight loss in last 6 months 
Study Product(s), Dose, 
Route, Regimen 
Subjects meeting enrollment criteria will be given Pancrelipase (84,000 lipase 
units per main meal and 42,000 lipase units per snack). This will be in addition to 
standard of care procedures including consult with a dietitian and systemic 
chemotherapy. Subjects will undergo treatment with pancreatic enzymes 
indefinitely as per standard therapy for patients with EPI. 
Duration of administration 
Daily for 24 weeks 
Statistical Methodology 
A single institution, phase 2 clinical trial. 
 
 

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1.0 
BACKGROUND AND RATIONALE 
1.1 
Disease Background 
 
Pancreatic-enzyme replacement therapy (PERT) is the standard of care to prevent maldigestion, 
malnutrition, and excessive weight loss in patients with exocrine pancreatic insufficiency (EPI) due 
to chronic pancreatitis (CP) or  pancreatic surgery (PS). The utility of this therapy for patients with 
EPI in the setting of pancreatic cancer is unclear.  
Pancreatic cancer is the fourth leading cause of cancer related deaths in the United States and 
associated with poor prognosis. EPI is a common complication of pancreatic cancer. There are 
several mechanisms for this, which includes tumor induced pancreatic duct obstruction, pancreatic 
fibrosis and atrophy. Under normal circumstances, digestive enzymes secreted from the pancreas 
are essential for digestion of proteins and fats. Impairment in enzyme secretion can lead to 
malabsorption of these compounds producing symptoms of delayed gastric emptying, increased 
bloating, abdominal fullness/discomfort, nausea, and early satiety in addition to potential nutrient 
deficiencies. Studies have shown a prevalence varying from 50-89% demonstrated by low fecal 
elastase [1-3]. Studies have shown that cachexia worsens the prognosis of patients with 
pancreatic cancer [4, 5]. Weight loss has also been associated with a poorer quality of life in 
patients with pancreatic cancer and those with stabilization of weight reported a greater global 
quality of life score[5]. Studies have shown small peak or no peak in the release of pancreatic 
enzymes in patients with pancreatic cancer[6] . DiMagno showed lower trypsin, lipase and 
bicarbonate secretion in patients with non-resectable pancreatic cancer and pancreatic duct 
obstruction [7]  
Pancreatic enzyme supplementation has demonstrated benefit for patients with EPI due to chronic 
pancreatitis. Two previous randomized-controlled trials have evaluated the impact of enzyme 
supplementation among patients with chronic pancreatitis. Both studies demonstrated 
improvement in measures of fat absorption (coefficient of fat absorption, fecal fat excretion) among 
patients treated with enzyme supplements [8, 9]. In addition, the study reported by Safdi et al also 
noted that the enzyme treatment group experienced reduced stool frequency, improved stool 
consistency and greater physician-assessed global symptom improvement [10]. No serious 
adverse events related to study medication occurred in either trial.  
However, the evidence for the use of pancreatic enzymes in pancreatic cancer is limited. Despite 
this, according to the guidelines published in Gut in 2005 for the management of patients with 
pancreatic cancer, pancreatic enzymes supplementation should be used to maintain weight and 
increase quality of life [11]. A double blinded randomized controlled trial looking at 21 patients with 
unresectable cancer in the head of the pancreas with obstructive jaundice and suspected 
pancreatic duct obstruction were randomized to placebo or enteric coated pancreatin enzyme 
supplementation. Patients were given 25000 units of lipase with snacks and 50,000 units with 
meals. The investigators found that patients on the enzyme supplementation gained 1.2% body 
weight compared to placebo who lost 3.7% body weight over 4-week follow-up. Fat absorption 
coefficient improved by 12% in those receiving enzymes [12]. Dominguez Munoz et al presented 
an abstract at the APA in 2013 of a retrospective non-randomized case series of 76 patients with 
nonresectable pancreatic cancer who were receiving Creon replacement with nutritional 
counseling and palliative care or standard palliative care without enzyme therapy. They found that 
the median survival of patients who were receiving pancreatic enzyme therapy was longer than 
those with standard palliative care (301 days versus 89 days). This study was limited by the lack of 
measurement of EPI [13].  
 
 

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Our objective is to assess weight stability, functional changes, and quality of life when pancreaze 
(pancrelipase) delayed-release 84,000-lipase unit capsules, for main meals, and 42,000-lipase unit 
capsules, for snacks, are added to standard of care in patients with EPI due to pancreatic 
adenocarcinoma. This will be the first prospective study of this particular formulation in addition to 
standard of care in advanced pancreatic cancer patients. We will treat 30 consecutive patients with 
borderline resectable, locally advanced and advanced pancreatic cancer who present with weight 
loss and exocrine pancreatic insufficiency with this advanced formulation of pancreaze.  
Standard of Care Nutrition Screening and Clinical Assessment:  
A full nutrition assessment involves the following elements: obtaining a food history, evaluation of 
anthropometric measurements, review of medical history, biochemical data, medical tests and 
procedures, and completion of a nutrition-focused physical assessment [14]. Routine assessment 
of food intake should include patient estimate of overall food intake and 24-h food recall [15]. An 
oncology focused assessment also involves reviewing the oncologic treatment plan with the goal 
to determine current and anticipated nutrition issues [16-18]. This information is all assimilated and 
used to formulate a plan to address existing and potential influences on malnutrition.  
Dietitians play a central role in the successful management of pancreatic cancer-associated weight 
loss (PAWL). Nutrition interventions for PAWL have improved weight [19], quality of life, and 
outcomes [14, 20, 21]. Dietitians can provide essential dietary suggestions, identify pancreatic 
exocrine insufficiency, and provide recommendations for oral nutritional supplementation and 
specialized nutrition support [22]. Dietitians may also provide more detailed advice on diet and 
pancreatic enzyme supplementation for management of symptoms of EPI [23-26]. 
1.2 
Study Agent(s) Background and Associated Known Toxicities 
Pancreaze (pancrelipase) Delayed-Release Capsules is a combination of porcine-derived lipases, 
proteases, and amylases indicated for the treatment of exocrine pancreatic insufficiency due to 
cystic fibrosis, or other conditions. 
Pancreatic-enzyme replacement therapy (PERT) is the standard of care to prevent maldigestion, 
malnutrition, and excessive weight loss in patients with exocrine pancreatic insufficiency (EPI) due 
to chronic pancreatitis (CP) or pancreatic surgery (PS).  Pancreaze is available in dosages of 
2,600, 4,200, 10,500, 16,800, and 21,000-lipase units per capsule.  
1.3 
Rationale 
 
Pancrelipase has been approved for the use in patients with exocrine pancreatic insufficiency due 
to cystic fibrosis or other conditions.  In randomized studies it has improved fat absorption and 
decreased the stool frequency in these patients.  However, its utility in advanced pancreatic 
cancer patients has not been evaluated to date. 
 
Advanced pancreatic adenocarcinoma is characterized by progressive weight loss and nutritional 
deterioration [27].  It is estimated that up to 80% of these patients present with cachexia [28].  This 
wasting has been linked not only to survival, but also to alterations in host defenses, functional 
ability, and quality of life [29]. There have been few studies of whether nutritional support improves 
outcomes for these patients and the results have been inconsistent [30, 31].  This is despite 
evidence that artificial nutrition can improve performance status and other outcomes in terminal 
cancer patients [32].  
Exocrine pancreatic insufficiency (EPI), which results from tumor-induced damage to the 
pancreatic parenchyma, obstruction of the pancreatic duct, and surgical removal of pancreatic 
tissue, is considered a major cause of this syndrome[33]. This deficiency impairs the body’s ability 
to absorb fat, carbohydrates, and proteins, which results in steatorrhea, abdominal cramps, weight 
loss, and malnutrition[34].  Associated symptoms include foul-smelling flatulence, diarrhea, greasy 
stools, abdominal discomfort following meals, pain, bloating, and belching[34]. EPI is estimated to 

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affect 68% to 92% of patients with pancreatic cancer prior to surgery and as many as 94% of 
those following surgery[35]. 
There are few effective therapies for pancreatic cancer and none for its associated cachexia. 
Megesterol and Marinol are routinely prescribed for appetite stimulation but not effective[36].  
Therapies attempting diet modifications and supplements have also failed to improve 
outcomes[37].   
One study randomized patients with pancreatic cancer to either 6 capsules of a high-dose 
pancreatic enzyme supplement per day or placebo for 8 weeks, with both groups receiving dietary 
counseling. Patients taking PERT gained 1.2% of their body weight compared with a 3.7% weight 
loss in the placebo group, with a mean difference in percentage of body weight change of 4.9% (P 
=.02; 95% confidence interval [CI] for the difference, 0.9%-8.9%). In addition, the fat absorption 
coefficient improved by 12% among those treated with PERT, while declining 8% for patients 
taking placebo (P =.13)[33]. 
Patients with borderline resectable, locally advanced, and advanced disease have distinct 
treatment paradigms and clinical outcomes. It is known that malabsorption is present in 68-92% of 
patients at diagnosis and most patients have associated symptoms [3, 6, 35, 38, 39]. In patients 
who had surgical resections, PERT was shown to improve the digestion of fat and associated 
symptoms of malabsorption [40]. As the cancer advances and the disease has spread to more 
area within the pancreas, the reliance on PERT is often increasingly recommended as the 
pancreas becomes less able to perform normal functions to aid in digestion of food. Previous 
studies have shown that lower trypsin, lipase and bicarbonate secretion are present in patients 
with non-resectable pancreatic cancer and pancreatic ductal obstruction [7]. As the utility of PERT 
varies with respect to each of the three cohorts of patients, it will be important to understand if 
there are some patient cohorts with an increased need for PERT.  
1.4 
Correlative Studies 
In this prospective study, we will evaluate stool frequency and quality associated with the use of 
pancreatic enzyme replacement therapy. Recent evidence also suggests that gut microbial 
metabolites regulate the release of the gut hormones, which is associated with changes in gut 
microflora and its metabolic products [38, 39][38, 39].  In the last few years, several studies have 
presented substantial data suggesting a role for the oral and gut microbiota in pancreatic cancer 
[40]. In this context, the generation of germ-free mice has been extremely valuable to better 
understand the influence of the microbiome in carcinogenesis. In most models, these animals are 
less inclined to carcinogenesis, probably due to decreased tumor-associated inflammation [41]. 
The same profile is observed in antibiotic-treated mice that reduces the microbial load of the gut 
[42] Remarkably, bowel sterilization with broad-spectrum antibiotics appears to be protective in 
acute pancreatitis as well.  
It would be important to better understand the microbiome associated with exocrine pancreatic 
insufficiency. We would also measure the changes in the microbiome as a response to the 
enzyme therapy.   
We will also further explore the impact of this therapy on quality life, pain and patient reported 
outcomes in pancreatic cancer.  We will utilize the PROMIS-29, and FACT-Hepatobiliary survey 
tools [43-45].  They are both validated in patients with pancreatic cancer and will help us 
understand the benefit of this therapy in our patient population.  
Currently, the majority of information upon which oncologists base their treatment decisions is 
obtained at the time of the patient clinic visit. This data includes the patient’s recall of symptoms 
and physical functioning, in addition to laboratory, imaging and physical exam information. Patient 
reported data (PRD) can be affected by recall bias [46, 47]. Furthermore, PRD can be influenced 
by a patient’s desire to affect the physician’s understanding of their clinical condition. For example, 

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patients may want their oncologist to believe that they are doing well, so that they may be a 
candidate for further cancer-directed therapies. Patients may de-emphasize physical symptoms 
and tolerance to therapy in an attempt to convince themselves that they are doing well. 
Oncologists rely on the PRD to make their own clinical judgments regarding changes in a patient’s 
clinical condition and therapy choices.  
The utilization of wearable biometric sensors may allow an inexpensive method of acquiring 
objective clinical data. Currently, off-the-shelf technology is being used commercially to track 
fitness. These wrist-worn devices can provide real-time data relating to movement, altitude, heart 
rate, body composition, temperature, and sleep quality. We will use the wearable activity monitor 
(e.g., Fitbit Charge HR) to assess activity in patients with pancreatic cancer and determine 
whether that activity correlates with changes in cachexia, functional status and PROs 
(i.e.PROMIS-29 and FAACT) around functional domains of quality of life [48-50]. Data collected 
may support the efficacy of this therapeutic intervention and influence the development of 
additional patient-centric, meaningful endpoints for future therapeutic trials around exocrine 
pancreatic insufficiency.  
 
2.0 
STUDY OBJECTIVES 
2.1 
Primary Objectives 
2.1.1  Feasibility to complete pancreatic enzyme replacement therapy during the first 8 
weeks of the study 
2.2 
Secondary Objectives  
2.2.1 
Measure weight stability at baseline and day 1 of every cycle for 6 months 
2.2.2 
Record 24-hour caloric intake at C1D1, C3D1, and end-of-study 
2.2.3 
Assess stool frequency at C1D1 and C3D1 
2.2.4 
Stool consistency at C1D1 and C3D1 
2.2.5 
Measurement of fat-soluble vitamins at baseline and end-of-study 
2.2.6 
Evaluate microbiome at C1D1 and C3D1 
2.2.7 
Determine if pancreatic enzyme replacement therapy is associated with increased 
daily activity (steps, counts, stairs, sleep, heart rate, active minutes) using a wrist-
worn fitness tracker (e.g., Fitbit) 
 

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2.3 
Patient-Reported Outcomes / Exploratory Objectives 
2.3.1 
To assess quality of life including pain assessment using PROMIS-29 at baseline 
and day 1 of every cycle for 6 months 
2.3.2 
To assess patient-reported response to therapy using FAACT (Functional 
Assessment of Anorexia/Cachexia Therapy) baseline and day 1 of every cycle for 
6 months 
2.3.3 
Measure fecal elastase at baseline  
2.3.4 
Assess overall survival  
2.3.5 
Assess adverse events for safety and tolerability 
2.3.6 
Assess inflammatory biomarkers in research blood 
2.3.7 
Assess the presence of frailty phenotype 
2.3.8 
Assess body composition using computed tomography collected as standard of 
care every 8 weeks 
 
2.4 
Study Hypotheses 
2.4.1 
Primary Hypothesis 
Pancreatic enzyme supplementation in addition to standard of care treatment is 
feasible for patients to follow for at least 8 weeks.    
2.4.2 
Secondary Hypotheses 
Pancreatic enzyme supplementation in addition to standard of care treatment will 
stabilize weight loss in patients with borderline resectable, locally advanced, and 
advanced pancreatic cancer patients with exocrine pancreatic insufficiency. 
Pancreatic enzyme supplementation, in addition to standard of care 
chemotherapy and dietitian consultation, will:  
 
Increase caloric intake 
 
Make stool frequency more consistent 
 
Improve stool consistency 
 
Improve levels of fat-soluble vitamins 
 
Alter the microbiome favorably 
 
Increase daily activity 
2.4.3 
Exploratory Hypotheses 
 
Improve quality of life and symptoms of pain from baseline  
 
Patient-reported response the therapy will improve 

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 
Fecal elastase may correlate with response to pancreatic enzyme 
supplementation 
 
Survival and response rate may benefit from a comprehensive     
approach to nutritional support 
 
Pancreatic enzyme supplementation will be safe and tolerable 
 
Weight loss and cachexia may be associated with genomic and stromal 
alterations in the tumor. 
 
Inflammatory biomarkers may be improved  
 
The frailty phenotype may be improved 
 
Lean body mass may be maintained throughout treatment course 
2.5 
Endpoints 
2.5.1 
Primary endpoint 
 
Measure patient compliance to take pancreatic enzyme replacement 
therapy using a patient reported Pancreaze daily accountability log. 
Patient compliance will be defined as patients taking ≥ 50 % of the 
needed total lipase units. The primary endpoint will be met if at least 50% 
of the subjects in each cohort take at least 50% of the total needed lipase 
units within the first 8 weeks of treatment. 
2.5.2 
Secondary endpoints 
 
Measure weight stability at baseline and day 1 of every cycle for 6 months 
 
Food intake will be assessed by study staff at C1D1, C3D1, and end-of-
study. A validated 24-hour recall questionnaire will be analyzed using the 
automated self-administered 24-hour Dietary Assessment tool (ASA-24)  
 
Assess stool frequency at C1D1 and C3D1 using a stool survey 
 
Stool consistency at C1D1 and C3D1 
 
Measurement fat-soluble vitamins (including Vitamins A, D, E, and K) at 
baseline and end-of-study 
 
Evaluate microbiome at C1D1 and C3D1 
 
Activity (steps taken, stairs climbed, sleep duration and disturbances, 
heart rate and intensity) will be collected using the wearable activity 
monitor (e.g., Fitbit Charge HR) daily for the duration of the study. 
2.5.3 
Exploratory endpoints 
 
Quality of life and symptoms of pain will be measured using the PROMIS-
29 at baseline and day 1 of every cycle for 6 months 
 
Patient-reported response the therapy will be measured using FAACT at 
baseline and day 1 of every cycle for 6 months 

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 
Measure fecal elastase at baseline 
 
Survival will be evaluated at every visit and every 6 months during 36-
month follow-up 
 
Safety and tolerability will be assessed by collecting adverse events 
throughout the study 
 
Research blood will be assessed for inflammatory biomarkers including: 
IL-6, interferon 1-alpha, TNF-alpha, Interleukin-1β, neuropeptide y, ZAG, 
ghrelin, CCK, GLP-1, PYY, glucagon and insulin at baseline and day 1 of 
every other cycle for 6 months and at the end-of-study visit. We will use 
standardized ranges for normal levels of the following assays. 
 
Presence of frailty phenotype using Fried’s definition [50] will be evaluated 
at baseline and day 1 of every other cycle for 6 months by measuring 
patient grip strength, using a dynamometer during physical exam, a 15 
foot walk test, question about energy levels and activity (APPENDIX E) 
 
Assess body composition using computed tomography collected as 
standard of care every 8 weeks 
 
 
 
 

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3.0 
PATIENT ELIGIBILITY  
 
Subjects must meet all of the inclusion and exclusion criteria to be registered to the study. Study 
treatment may not begin until a subject is registered. 
 
3.1 
Inclusion Criteria 
3.1.1 
Borderline resectable, locally advanced, and advanced pancreatic cancer patients 
(can include new or recurrent diagnosis) referred to SOCCI-CSMC 
3.1.2 
Age ≥ 18 years. 
3.1.3 
ECOG performance status 0-1 or Karnofsky PS >60% (Appendix A)  
3.1.4 
Clinical diagnosis of exocrine pancreatic insufficiency 
3.1.5 
Cachexia defined as ≥5% weight loss in the presence of chronic illness, within any 
6-month period prior to screening OR as documented by the medical physician 
based on standard diagnosis of cachexia  
3.1.6 
Life expectancy of greater than 3 months, in the opinion of the investigator. 
3.1.7 
Patients must have normal organ and marrow function as defined below: 
 
Absolute Neutrophil Count (ANC) 
>500/mcL 
Platelets 
>50,000/mcL 
Total bilirubin 
≤ 5X upper limit of normal 
(ULN)  
 
 
 
 
 
 
 
AST(SGOT)/ALT(SGPT) 
≤ 5 X ULN 
Creatinine OR creatinine 
clearance 
≤ 3 times the upper limit of 
normal OR > 30 mL/min/1.73 
m2 for patients with creatinine 
levels above normal. 
 
 Note:  Patients with biliary stents are eligible provided that all other inclusion criteria are met. 
  
 
3.1.8 
Woman of child-bearing potential (WOCBP) and men must agree to use adequate 
contraception (hormonal or barrier method of birth control; abstinence) from the 
time of signing the informed consent form, for the duration of study participation, 
and for at least 30 days after discontinuing from study treatment.  
3.1.9 
Ability to understand and the willingness to sign a written informed consent 
document 
 
 
 
 

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3.2 
Exclusion Criteria 
3.2.1 
Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, or psychiatric illness/social situations that would limit compliance with 
study requirements. 
3.2.2 
Women who are pregnant or are breastfeeding 
3.2.3 
Dementia or altered mental status that would prohibit the understanding or 
rendering of informed consent 
3.2.4 
Unable to swallow intact capsules  
3.2.5 
Fibrosing colonopathy: Patients with history of fibrosing colonopathy have been 
reported to experience advancement to colonic strictures with doses of 
lipase>6000 units/kg/meal over prolonged periods of time. 
3.2.6 
History of chronic illness associated with malabsorption or nutrient deficiency        
including but not limited to chronic pancreatitis, cystic fibrosis, celiac disease, 
Crohn’s disease, pernicious anemia and/or prior intestinal resection. 
3.2.7 
Pregnancy, breastfeeding, or of childbearing potential and not willing to use       
methods of birth control during the study 
3.2.8 
Active drug abuse or intoxication with any substance including alcohol (blood 
alcohol content >0.08%, legal driving limit) 
3.2.9 
Known allergy to any of the active ingredients in pancreatic enzyme    
supplementation 
3.2.10 Concurrent use of pancreatic enzyme supplementation or over the counter 
supplements which contain lipase, protease, and amylase as active ingredients 
 
 
 

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4.0 
TREATMENT PLAN 
4.1 
Treatment Dosage and Administration 
4.1.1 
Agent Administration 
Treatment will be administered on an outpatient basis. The investigational 
treatment cycle is every 4 weeks. Patients removed from study for unacceptable 
adverse events will be followed until resolution or stabilization of the adverse 
event.  
 
Subjects meeting enrollment criteria will be given Pancreaze (84,000 lipase units 
per main meal and 42,000 lipase units per snack). Subjects will undergo treatment 
with pancreatic enzymes indefinitely as per standard therapy for patients with EPI.  
If symptoms and signs of steatorrhea persist, the dosage may be increased by the 
healthcare professional. 
 
If doses are to exceed 2,500 lipase units/kg of body weight per meal, further 
investigation is warranted. Doses greater than 2,500 lipase units/kg of body 
weight per meal (or greater than 10,000 lipase units/kg of body weight per day) 
should be used with caution and only if they are documented to be effective by 3-
day fecal fat measures that indicate a significantly improved coefficient of fat 
absorption. Doses greater than 6,000 lipase units/kg of body weight per meal 
have been associated with colonic stricture, indicative of fibrosing colonopathy, in 
children less than 12 years of age. Patients currently receiving higher doses than 
6,000 lipase units/kg of body weight per meal should be examined and the dosage 
either immediately decreased or titrated downward to a lower range. 
 
Subjects will be instructed to take 84,000 units (4 capsules) per main meal and 
42,000 units (2 capsules) per snack. Should dose reductions be required per 
treating investigator, the guidelines in Section 4.1.3 will be followed. 
 
4.1.2 
Drug Interactions 
No drug interactions have been identified. No formal interaction studies have been 
conducted.  
 
Patients taking fat-soluble vitamin supplements will be advised to discontinue use 
while on this trial as it is likely to interfere with the proposed study assessments. 
4.1.3 
Dosing Delays / Modifications 
Treatment is administered according to the Time & Events Table (Section 5.6).  
Treatment will be delivered over 4-week cycles (1 cycle=28 days). Data will also 
be collected for patients that receive titrated dosing per investigator’s discretion 
and following Table 1. 
 
Toxicity will be evaluated using the NCI Common Terminology Criteria for Adverse 
Events, Version 4.0. The frequency of toxicities per organ system will be tabulated 
using descriptive statistics. All patients who receive any amount of the study drug 
will be evaluable for toxicity. 
 
Subjects will be instructed to take 84,000 units (4 capsules) per main meal and 
42,000 units (2 capsules) per snack. Should dose reductions be required per 
treating investigator, the following guidelines will be followed: 
 
Table 1. Dose modifications 

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Per meal
Per snack
Starting dose 
84,000 USP units of 
lipase (4 capsules) 
42,000 USP units of 
lipase (2 capsules) 
Dose modification 1 
63,000 USP units of 
lipase (3 capsules) 
21,000 USP units of 
lipase (1 capsule) 
Dose modification 2 
42,000 USP units of 
lipase (2 capsules) 
21,000 USP units of 
lipase (1 capsule) 
 
Any dose modifications will be recorded in the research record, including dates. 
Compliance will be calculated based on the recommended dose. 
 
4.1.4 Duration of Therapy 
The patients will be followed on treatment for the 24-week study treatment period. 
Treatment may continue per SOC until death or until any of the following occur: 
 
Inter-current illness that prevents further administration of treatment 
 
Unacceptable adverse event(s) 
 
Patient decides to withdraw from the study, OR 
 
General or specific changes in the patient’s condition render the patient 
unacceptable for further treatment in the judgment of the investigator. 
 
In the absence of the above criteria, subjects may continue to receive study 
treatment at the investigator’s discretion. 
4.2 
Concomitant Medications 
Concurrent use of other pancreatic enzyme supplementation, fat-soluble vitamin 
supplements, or over the counter supplements which contain lipase, protease, and 
amylase as active ingredients is not permitted. 
 
Only conmeds that are used to treat an adverse event deemed at least possibly related to 
Pancreaze need to be recorded in the REDCap database. 
4.3 
Duration of Follow-up 
Patients will undergo an End of Study assessment 30 days after completion of the 24-
week study treatment period.  Patients removed from treatment for unacceptable adverse 
events will then be followed until resolution or stabilization of the adverse event and will 
continue to be followed for the duration of the study as per protocol.  After the End of 
Study Assessment, follow-up will involve every 6-month phone calls to collect survival data 
for 36 months. 
4.4 
Removal of Patients from Protocol Therapy 
Patients will be removed from therapy when any of the criteria listed in Section 5.7 apply. 
4.5 
Subject Replacement 
Subjects who withdraw from the study treatment will be replaced.  
 
5.0 
STUDY PROCEDURES 

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5.1 
List of Study Procedures 
5.1.1 Informed Consent – must be obtained within 6 weeks of Day 1 
5.1.2 Review subject eligibility criteria 
5.1.3 Pregnancy test 
 
Pregnancy test for women of child-bearing potential as per standard of care. 
5.1.4 Demographics 
Age, gender, race, and ethnicity  
5.1.5 Medical/surgical history 
Complete medical and surgical history, history of infections 
5.1.6 Physical exam including vital signs, height and weight 
Vital signs (temperature, pulse, respirations, blood pressure), height (at 
screening/baseline only), weight  
5.1.7 Performance status  
Performance status evaluated prior to study entry according to Eastern 
Cooperative Oncology Group (ECOG) or Karnofsky performance status criteria 
(Appendix A) 
5.1.8 Standard of care CT imaging 
As indicated per standard of care, approximately every 8 weeks  
5.1.9 Adverse event assessment 
Signs/symptoms present at baseline prior to treatment initiation will be recorded as 
medical history. Adverse events will be assessed from time of treatment initiation 
for the duration of the study treatment period until the end-of-study visit. See 
Section 6 for Adverse Event monitoring and reporting.  
5.1.10 Review previous and concomitant medications  
5.1.11 Blood collection for general health assessment  
CBC with differential, CMP, Phosphorus, Magnesium. Phosphorus and Magnesium 
will be assessed at C1D1 only.  
5.1.12 Blood draw for tumor assessment  
CA-19-9, C-reactive protein (CRP). CRP will be assessed at C1D1 only. 
5.1.13 Blood draw for fat soluble vitamin levels 
           Serum levels of Vitamins A (serum retinol), D (25-Hydroxy), E (serum alpha-
tocopherol), and K (PIVKA-II and prothrombin time). 
5.1.14 Research blood draw 
See Section 7.0 for details. 8 hour fast is required. Morning blood draw is 
required. 
5.1.15 Stool sample 
A stool collection kit will be given to the patient during physical exam, where patient 
will be advised to follow instructions on kit and bring their sample into laboratory as 

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instructed (see Sections 5.2 and 5.3.2).  Microbiome analysis and fecal elastase 
will be measured from collection of stool sample (Section 8). Fecal elastase will be 
measured at baseline only.  
5.1.16 Hand grip and 15 ft walk test 
Hand grip using the hand-held dynanometer. Three assessments for each hand 
will be completed and recorded. A timed walk-test from first foot fall to last foot fall 
over 15 feet will be performed twice per assessment. 
5.1.17 Bionutrition assessment 
ASA-24 (24-hour food recall) and taste and smell alteration. ASA-24 is completed 
electronically and may be completed within 7 days of the study visit. 
5.1.18 Patient reported outcomes 
Patient reported outcomes (Quality-of-life questionnaire: PROMIS-29; FAACT) 
5.1.19 Self-reported daily Pancreaze accountability log and compliance calculation 
Subjects will record usage of Pancreaze in a daily log. Subjects will return log to 
study staff at study visits for compliance calculation. 
5.1.20 Activity Monitoring 
Wearable activity monitor (e.g., Fitbit Charge HR) activity monitoring to measure 
step count, heart rate, activity intensity, stairs climbed and sleep. Provide 
wearable activity monitor with charger and instructions for activity monitoring. 
Wearable activity monitor will be paired to the subject’s personal smartphone. 
Subject may keep or return the wearable activity monitor at the end-of-study visit. 
Continued collection of activity monitor data during follow-up will be optional. 
5.1.21 Survival follow-up 
 
 Per Section 5.5. 
 
5.2 
Screening/Baseline Procedures 
Assessments performed exclusively to determine eligibility for this study will be done 
only after obtaining informed consent. Assessments performed for clinical indications 
(not exclusively to determine study eligibility) may be used for baseline values even if 
the studies were done before informed consent was obtained.  
 
All screening procedures used for eligibility verification must be performed within 4 
weeks of Day 1 unless otherwise stated.  Baseline procedures not required for 
eligibility verification can occur on Cycle 1, Day 1 of treatment (See section 5.3).  
The screening and baseline procedures include: 
 
Informed consent 
 
Eligibility review, including: 
o 
Pregnancy test 
 
Demographics 
 
Medical/Surgical history 
 
Complete physical exam 
 
Standard of care CT imaging 
 
Height, weight, vital signs 
 
Performance status (ECOG or Karnofsky) 
 
AE (baseline symptom) assessment 

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 
Concomitant medications review 
 
Labs: CBC/diff, CMP 
 
Blood draw for fat soluble vitamin levels 
 
Fecal elastase 
o Note: for maximum flexibility for the patients, the fecal elastase stool 
sample may be collected during screening or until C1D1 (+ 7 days). 
Patients will be encouraged to provide the fecal elastase stool sample 
prior to starting treatment, if possible.   
5.3 
Procedures During Treatment 
These visits can occur within a window of -/+ 7 business days of the anticipated 
visit date to account for clinic closures or holidays and to align with the standard of 
care chemotherapy administration schedule. 
 
5.3.1 
Day 1 of Every Cycle (each 4 weeks/28 days)  
 
Treatment as per dosing schedule 
 
Completion of study dosing diary - for the first two cycles only 
 
Safety evaluation (As per CTCAE grading) 
 
Physical Exam 
 
Weight 
 
Vital signs 
 
ECOG or Karnofsky performance status (Appendix A) 
 
Concomitant medications 
 
Blood collection (CBC with differential, CMP) 
 
CMP add-ons (Phos, Mag) (C1D1 only) 
 
Tumor markers (CA 19-9) 
 
CRP (C1D1 only) 
 
Assess wearable activity monitor functionality 
5.3.2 
Day 1 of Every Other Cycle (every 8 weeks)  
 
Research blood (See Section 7). 8 hour fast is required. Morning blood 
draw is required. 
 
Self-administered QOL surveys: PROMIS-29, FAACT (APPENDICES C, 
D) 
 
Frailty status (hand grip; 15 ft walk-test – Appendix E) 
 
Bionutrition assessment (ASA-24 +taste and smell alteration) conducted 
by study staff (Appendix B) (C1D1, C3D1 only) 
 
Stool sample for microbiome analysis (Section 8) (C1D1 and C3D1 only) 
o 
Note: for maximum flexibility for the patients, the C1D1 
microbiome stool sample may be collected during screening or 
until C1D1 (+ 7 days). Patients will be encouraged to provide the 
microbiome stool sample prior to starting treatment if possible. If 
collected during screening, the microbiome sample will be stored 
until eligibility is confirmed; if the patient results in a screen fail, 
the sample will be destroyed unless consent is granted for its use 
on another IRB-approved protocol, e.g., GI-Bank protocol (IRB# 
Pro00054363). 
o 
Note: for maximum flexibility for the patients, the C3D1 
microbiome stool sample may be collected +/- 7 days of C3D1. 
 
Stool survey (C1D1 and C3D1 only) 
 

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5.3.3 
End-of-Treatment Visit (EOT), +7 days.  
Subjects will continue to take the study drug until the Cycle 6 Day 28 time point. 
Subjects should be reminded to discontinue study supply of Pancreaze following 
Cycle 6 Day 28. Up to seven days following the last dose, there will be an EOT 
visit for subjects to return pill bottles and to transition to SoC enzymes, if 
applicable.  
 
 
Safety evaluation (As per CTCAE grading) 
 
Return pill bottles 
 
Transition to SoC enzymes (if applicable) 
5.3.4 Standard of care CT imaging 
As indicated per standard of care, approximately every 8 weeks 
 
5.4 
End-of-Study Visit  
 
The End-of-Study visit is to occur 30 days following last dose of study 
treatment, +/- 7 days. 
 
Research blood (See Section 7). 8 hour fast is required. Morning blood 
draw is required. 
 
Safety evaluation (As per CTCAE grading) 
 
Physical Exam 
 
Weight 
 
Vital signs 
 
ECOG or Karnofsky performance status (Appendix A) 
 
Concomitant medications 
 
Blood collection (CBC with differential, CMP) 
 
Tumor markers (CA 19-9) 
 
Fat soluble vitamin levels 
 
Frailty status (hand grip; 15 ft walk-test – Appendix E) 
 
Bionutrition assessment (ASA-24 +taste and smell alteration) conducted 
by study staff (Appendix B)  
 
Self-administered QOL surveys: PROMIS-29, FAACT (APPENDICES C, 
D) 
 
Assess wearable activity monitor functionality 
 
5.5 
Follow-up Procedures 
Patients will be followed every 6 months for 36 months after completion of (or early 
withdrawal from) study treatment or until death.  
 
If there is no record of patient survival in medical chart by review, a phone call will be 
made to assess survival. Physical exam, weight, vital signs, and ECOG or Karnofsky 
performance status will also be collected from the medical record if available per standard 
of care.  
 
 

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5.6 
Time and Events Table 
 
 
 
Procedures 
 
 
 
Screening
/ 
Baseline 
Treatment 
Follow-up Phase 
Within 4 
weeks of 
Day 1 
Every Cycle  
(Every 4 weeks) 
End of 
Treatment9 
End-of-
Study Visit 
Survival 
Follow-up 
Every 6 months 
for 36 months 
(+/7 days)  
Cycles 1, 2, 3, 4, 5, 6 
(Weeks 0, 4, 8, 12, 16, 20)
End of Week 
24   
 
(+ 7 days)     
 
30 days after 
treatment 
termination 
(+/- 7 days) 
 
Day 1         (+/- 7 days)     
 
 
Informed Consent 
X 
  
  
 
  
  
Eligibility review 
X 
  
  
 
  
  
Pregnancy test 
X 
  
  
 
  
  
Demographics 
X 
  
  
 
  
  
Medical / Surgical History 
X 
  
  
 
  
  
Complete Physical Exam 
X 
X  
 
X 
X 
Standard of Care CT 
imaging 
 
As per standard of care, approximately every 8 weeks 
 
Height 
X 
  
  
 
  
  
Weight 
X 
X 
 
X 
X 
Vital Signs 
X 
X 
 
X 
X 
Performance Status (ECOG 
or Karnofsky) 
X 
X  
 
X 
X 
Adverse Event Assessment 
X 
X  
X 
X 
 
Concomitant Medications 
X 
X  
 
X 
 
Blood collection (CBC, 
CMP) 
X 
X  
 
X 
 
CMP add-ons (Phos, Mag) 
 
X (C1D1 only) 
 
 
 

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Procedures 
 
 
 
Screening
/ 
Baseline 
Treatment 
Follow-up Phase 
Within 4 
weeks of 
Day 1 
Every Cycle  
(Every 4 weeks) 
End of 
Treatment9 
End-of-
Study Visit 
Survival 
Follow-up 
Every 6 months 
for 36 months 
(+/7 days)  
Cycles 1, 2, 3, 4, 5, 6 
(Weeks 0, 4, 8, 12, 16, 20)
End of Week 
24   
 
(+ 7 days)     
 
30 days after 
treatment 
termination 
(+/- 7 days) 
 
Day 1         (+/- 7 days)     
 
 
CA 19-9 (biomarker) 
 
X 
  
 
X 
  
C-reactive protein (CRP) 
 
X (C1D1 only) 
  
 
 
  
Fat soluble vitamin levels5  
X 
 
 
X 
 
Research Blood Tests 
 
X1  
  
 
X  
  
Stool Sample 
Microbiome and Stool 
Survey 
 
X (C1D17 and C3D18 only)
 
  
  
Fecal elastase 
X7 
 
 
  
  
Hand grip and 15 ft walk test 
  
 X1  
  
 
X 
  
Bionutrition assessment: 
ASA-24 (24-hour food 
recall)3; taste and smell 
alteration 
 
X (C1D1 and C3D1 only)  
  
 
 X 
  
Self-administered QOL 
survey: PROMIS-29; FAACT 
  
X1  
  
 
X 
  
Pancreaze treatment 
 
X (daily)6 
 
 
 
Self-reported daily 
Pancreaze accountability log 
and compliance calculation4 
 
X 
 
 
 
Physical Activity: Assess 
wearable activity monitor 
functionality 
 
X 
  
 
X 
  
Wearable activity monitoring 
 
 
Continuous 
X2 
Return research pill 
bottles/transition to SOC 
enzymes 
 
 
X 
 
 

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Procedures 
 
 
 
Screening
/ 
Baseline 
Treatment 
Follow-up Phase 
Within 4 
weeks of 
Day 1 
Every Cycle  
(Every 4 weeks) 
End of 
Treatment9 
End-of-
Study Visit 
Survival 
Follow-up 
Every 6 months 
for 36 months 
(+/7 days)  
Cycles 1, 2, 3, 4, 5, 6 
(Weeks 0, 4, 8, 12, 16, 20)
End of Week 
24   
 
(+ 7 days)     
 
30 days after 
treatment 
termination 
(+/- 7 days) 
 
Day 1         (+/- 7 days)     
 
 
Survival Follow-up 
  
  
  
 
  
X 
 
1To be completed at baseline and day 1 of every other cycle for 6 months. 8 hour fast is required for all 
research blood draws, blood draws must be scheduled in the morning, and deviations must be recorded. 
2Fitness tracking with the wrist-worn wearable activity monitor is optional during follow-up. 
 
3ASA-24 is completed electronically and may be completed within 7 days of the visit. 
4Subjects will complete a daily compliance diary for the first two cycles only. Diary will be given to patients 
on Day 1 of the first two cycles. Subjects will return diary to study staff for compliance calculation on 
completion of each of the first two cycles.  
5Fat-soluble vitamin labs to be drawn include: Vitamin A: serum retinol; Vitamin D:25-Hydroxy; Vitamin E: 
serum alpha-tocopherol; Vitamin K: PIVKA-II and prothrombin time. 
6The patients will be followed on treatment for the 24-week study treatment period. Treatment may 
continue beyond the study treatment period, at the physician’s discretion, per standard of care. 
Pancreaze will be dispensed at C1D1 and C4D1, and subjects will return remaining supply at C4D1 and 
the end-of-treatment visit for drug accountability by Research Pharmacy.  
7Stool sample may be collected during screening or until C1D1 + 7 days. 
8 Window for C3D1 sample is +/- 7 days. 
9Subjects will continue to take the study drug until the Cycle 6 Day 28 time point. Subjects should be 
reminded to discontinue study supply of Pancreaze following Cycle 6 Day 28.  
 
 
 
5.7 
Removal of Subjects from Study 
Patients can be taken off the study treatment and/or study at any time at their own 
request, or they may be withdrawn at the discretion of the investigator for safety, 
behavioral or administrative reasons. The reason(s) for discontinuation will be 
documented and may include: 

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5.7.1 
Patient voluntarily withdraws (follow-up permitted);  
5.7.2 
Patient withdraws consent (termination of treatment and follow-up); 
5.7.3 
Patient is unable to comply with protocol requirements; 
5.7.4 
Patient experiences toxicity that makes continuation in the protocol unsafe; 
5.7.5 
Treating physician judges continuation on the study would not be in the patient’s 
best interest; 
5.7.6 
Patient becomes pregnant (pregnancy to be reported along same timelines as a 
serious adverse event); 
5.7.7 
Lost to follow-up. If a research subject cannot be located to document survival 
after a period of 2 years, the subject may be considered “lost to follow-up.” All 
reasonable efforts must be made to locate subjects to determine and report their 
ongoing status. Lost to follow-up is defined by the inability to reach the subject 
after a minimum of three documented phone calls, faxes, or emails as well as lack 
of response by subject to one registered mail letter. 
 
All attempts should be documented in the subject’s medical records. If it is 
determined that the subject has died, the site will use permissible local methods to 
obtain the date and cause of death. If after all attempts, the subject remains lost to 
follow-up, then the last known alive date as determined by the investigator should 
be reported and documented in the subject’s medical records. 
 
6.0 
ADVERSE EVENTS 
6.1 
Adverse Event Monitoring 
The investigator or designee is responsible for ensuring that adverse events (both serious 
and non-serious) observed by the clinical team or reported by the subject which occur 
after the subject has initiated treatment and until the 30-day end-of-study visit, are fully 
recorded in the subject’s medical records. Source documentation must be available to 
support all adverse events.  
A laboratory test abnormality considered clinically relevant (e.g., causing the subject to 
withdraw from the study, requiring treatment or causing apparent clinical manifestations, 
result in a delay or dose modification of study treatment, or judged relevant by the 
investigator), should be reported as an adverse event.   
 
The investigator or sub-investigator (treating physician if applicable) will provide the 
following for all adverse events (both serious and non-serious): 
 
Event term (as per CTCAE) - Descriptions and grading scales found in the NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 5 will be 
utilized for AE reporting.  
 
Description of the event 
 
Date of onset and resolution 
 
Expectedness of the toxicity 
 
Grade of toxicity  
 
Attribution of relatedness to the investigational agent- (this must be assigned by 
an Investigator, sub-investigator, or treating physician) 

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 
Action taken as a result of the event, including but not limited to; no changes, 
dose interrupted, reduced, discontinued, etc. or action taken with regard to the 
event, i.e. no action, received conmed or other intervention, etc. 
 
Outcome of event 
 
All patients experiencing an adverse event, regardless of its relationship to study drug, will 
be monitored until:  
 
the adverse event resolves or the symptoms or signs that constitute the adverse  
 
event return to baseline 
 
any abnormal laboratory values have returned to baseline 
 
there is a satisfactory explanation other than the study drug for the changes  
 
observed, or 
 
death 
 
6.2 
Protocol-specific Adverse Event Monitoring Guidelines 
Since this supplement is FDA approved as part of standard of care in the patient population under 
study, only AEs of interest, as outlined below, will be collected and recorded in the EDC:  
• Any event deemed serious and expected OR unexpected, regardless of cause.  
AND 
 
AEs of interest included below: 
 
Expected toxicities to Pancreaze
Abdominal pain 
Abdominal pain upper 
Flatulence 
Diarrhea 
Abnormal feces 
Fatigue 
 
 
Note; All expected toxicities from chemotherapy can be found in the FDA approved Package 
Insert. 
 
6.3 
Definitions 
6.3.1 Adverse Event 
Any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug related. Therefore, an AE can be ANY 
unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not considered related to the medicinal 
(investigational) product (attribution of unrelated, unlikely, possible, probable, or 
definite).  AE’s will be collected once the consent is signed and treatment is 
initiated.  
6.3.2 Serious Adverse Events 
A “serious” adverse event is defined in regulatory terminology as any untoward 
medical occurrence that: 

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6.3.2.1 
Results in death. 
If death results from (progression of) the disease, the disease should 
be reported as event (SAE) itself. 
6.3.2.2 
Is life-threatening. 
The patient was at risk of death at the time of the event; it does not 
refer to an event that hypothetically might have caused death if it were 
more severe. 
6.3.2.3 
Requires in-patient hospitalization or prolongation of existing 
hospitalization for ≥ 24 hours. 
6.3.2.4 
Results in persistent or significant disability or incapacity. 
6.3.2.5 
Is a congenital anomaly/birth defect 
6.3.2.6 
Is an important medical event 
Any event that does not meet the above criteria, but that in the 
judgment of the investigator jeopardizes the patient, may be 
considered for reporting as a serious adverse event. The event may 
require medical or surgical intervention to prevent one of the outcomes 
listed in the definition of “Serious Adverse Event.“  
Medical events may include, but are not limited to: allergic 
bronchospasm requiring intensive treatment in an emergency room or 
at home; convulsions that may not result in hospitalization; 
development of drug abuse or drug dependency. 
6.3.3 
Unanticipated Problem (UP) 
Unanticipated problems include any incident, experience, or outcome that meets 
all of the following criteria: 
• 
Unexpected (in terms of nature, severity, frequency) given (a) the 
research procedures that are described in the protocol-related 
documents, such as the IRB-approved research protocol and informed 
consent document; and (b) the characteristics of the subject population 
being studied; 
• 
Related or possibly related to participation in the research (possibly 
related means there is a reasonable possibility that the incident, 
experience, or outcome may have been caused by the procedures 
involved in the research); and 
• 
Suggests that the research places subjects or others at a greater risk of 
harm (including physical, psychological, economic, or social harm) than 
was previously known to an individual or group of individuals (including 
research subjects, research staff, or others not directly involved in the 
research). 
6.3.4 Evaluable for toxicity  
Any patient who receives at least one dose of study drug is evaluable for toxicity 
and will be included in the safety analysis. 
6.4 
Severity of Adverse Events 
All non-hematologic adverse events will be graded according to the NCI Common 

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Terminology Criteria for Adverse Events (CTCAE) version 5.0. The CTCAE v5 is 
available at http://ctep.cancer.gov/reporting/ctc.html. 
 
If no CTCAE grading is available, the severity of an AE is graded as follows: 
Mild (grade 1): the event causes discomfort without disruption of normal daily 
activities. 
Moderate (grade 2): the event causes discomfort that affects normal daily 
activities. 
Severe (grade 3): the event makes the patient unable to perform normal daily 
activities or significantly affects his/her clinical status. 
Life-threatening (grade 4): the patient was at risk of death at the time of the event. 
Fatal (grade 5): the event caused death. 
6.5 
Reporting Requirements for Adverse Events 
6.6 
Steps to Determine If an Adverse Event Requires Expedited Reporting 
 
Step 1: Identify the type of adverse event using the NCI Common Terminology Criteria for 
Adverse Events (CTCAE v5).  
 
Step 2:  Grade the adverse event using the NCI CTCAE v5. 
 
Step 3:  Determine whether the adverse event is related to the protocol therapy  
Attribution categories are as follows: 
- 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. 
- Unrelated – The AE is clearly NOT related to the study treatment. 
Note: This includes all events that occur within 30 days of the last dose of protocol-defined 
treatment. Any event that occurs more than 30 days after the last dose of protocol-defined 
treatment and is attributed (possibly, probably, or definitely) to the agent(s) must also be 
reported accordingly. 
 
Step 4: Determine the prior experience of the adverse event.  
Expected events are those that have been previously identified as resulting from 
administration of the agent. An adverse event is considered unexpected when either the 
type of event or the severity of the event is not listed in the current known adverse events 
listed in the package insert. 
 
6.6.1 
Expedited Reporting  
6.6.1.1 Reporting to the Principal Investigator 
The Principal Investigator must be notified within 24 hours of learning of any 
serious adverse events, regardless of attribution, occurring during the study or 
within 30 days of the last protocol-defined administration of the study drug.  
 
PI Phone Number for Expedited Reporting: 
Andrew Hendifar, MD (310) 423-2217 

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Alternate Phone Number for Expedited Reporting: 
Jun Gong (310) 423-5776 
 
6.6.1.2 Reporting to the DSMC 
Serious Adverse Events deemed to be related to the protocol and on-study 
deaths, including death of a research subject unless the death is expected (e.g. 
due to disease progression) to be reported to the DSMC within 24 hours of 
awareness for medical monitor ad hoc review between meetings to determine if 
immediate action is required. Reports to be emailed to the DSMC team at 
GroupSOCCICCTODSMCAdmin@cshs.org.  
6.6.1.3  Reporting to the Institutional Review Board (IRB) 
 
The IRB must be notified within 10 business days of “any unanticipated problems 
involving risk to subjects or others.” 
1. Any serious event (injuries, side effects, deaths or other problems), which in 
the opinion of the Principal Investigator was unanticipated, involved risk to 
subjects or others, and was possibly related to the research procedures. 
2. Any serious accidental or unintentional change to the IRB-approved protocol 
that alters the level of risk. 
3. Any deviation from the protocol taken without prior IRB review to eliminate 
apparent immediate hazard to a research subject. 
4. Any new information (e.g., publication, safety monitoring report, updated 
sponsor safety report), interim result or other finding that indicates an 
unexpected change to the risk/benefit ratio for the research. 
5. Any breach in confidentiality that may involve risk to the subject or others. 
6. Any complaint of a subject that indicates an unanticipated risk or that cannot 
be resolved by the Principal Investigator. 
6.6.1.4 Reporting to the External Funding Source (Vivus) 
All SAEs to be forwarded to Vivus within 24 hours of awareness. This will allow 
Vivus to cross report to other clinical trials/investigators in a timely manner. Vivus 
may request additional or supportive information to clarify details in a follow-up 
report and will submit request to the site in writing.    
 
Reports should be submitted to: GPV@vivus.com 
 
7.0 
 CORRELATIVES/SPECIAL STUDIES 
7.1 
Research Blood Collection Kit and Instructions 
Patients will be instructed to fast for at least 8 hours prior to research blood draws and 
blood draws must be scheduled in the morning. Deviations from this must be recorded.  
This Kit is for collection, processing, storage and/or shipping of serum, plasma, or whole 
blood (as specified by the protocol): 
 
Kit contents: 
 One (1) 5 – 10 cc Red Top tube for serum (A) 

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 One (1) 5 – 10 cc Lavender Top EDTA preserved with anticoagulant tube for 
plasma (B) 
 One (1) 5 – 10 cc Lavender Top EDTA preserved with anticoagulant tube for 
Whole Blood (C) 
 Fifteen (15) to thirty (30) 1 ml cryovials 
 Pipettes 
 Two (2) patient-specific cryovial storage boxes   
 Biohazard bags (3) and Absorbent shipping material (3) 
 Styrofoam container (inner) and Cardboard shipping (outer) box 
 UN1845 DRY Ice Sticker and UN3373 Biological Substance Category B Stickers 
 Lab Requisition Form and Kit Instructions 
7.1.1 Preparation and processing of serum, plasma, and whole blood 
7.1.2 Serum: Red Top Tube 
 
Label as many 1ml cryovials (up to 5-10) as necessary for the serum collected. 
Label them with: 
- 
Study name: PanCax3 
- 
Subject ID 
- 
Patient initials (First, Middle, Last) 
- 
Collection date (Month, Day, Year) 
- 
Serum cryovial number (e.g., S1, S2, S3, S4, S5, etc…) 
7.1.2.1 
Process 
 
 
Transport Red Top Tube for processing at room temperature 
 
Allow the blood to clot by leaving it undisturbed at room temperature (15-30 
minutes) 
 
Centrifuge at 1,000 x g for 10 minutes in a refrigerated centrifuge (4°C). If 
unable to process samples at 4°C then spinning at room temperature is 
acceptable if done within 2 hours of draw but must be noted on the Lab 
Requisition Form. 
 
Aliquot 0.5 ml serum into as many 1 ml cryovials (up to 5-10) as are 
necessary for the serum collected and stored at -80°C. Ensure the patient 
initials, collection date and serum cryovial number (e.g., S1, S2, S3, S4, S5, 
etc…) are marked on the cryovials. 
 
Place cryovials into the patient-specific cryovial storage box and immediately 
freeze at -70 to -90° C, and store frozen until ready to ship/transfer. See 
below for storage conditions. 
7.1.3 Plasma: Lavender Top EDTA tube #1 
 Label as many 1ml cryovials (up to 5-10) as necessary for the plasma 
collected. Label them with: 
- Study name: PanCax3 
- Subject ID 
- Patient initials (First, Middle, Last) 
- Collection date (Month, Day, Year) 
- Plasma cryovial number (e.g., P1, P2, P3, P4, P5, etc…) 

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7.1.3.1 
Process 
 
 
After collection, invert tube(s) twice to ensure adequate mixing of EDTA. 
 
Centrifuge specimen(s) within one hour of collection at 2,000 x g for 15 
minutes in a refrigerated centrifuge (4°C).  If unable to process samples at 
4°C then spinning at room temperature is acceptable if done within 2 hours of 
draw but must be noted on the Lab Requisition Form. 
 
If the interval between specimen collection and processing is anticipated to 
be more than one hour, keep specimen on ice until centrifuging is performed. 
 
Aliquot 0.5 ml plasma into as many 1 ml cryovials (up to 5-10) as are 
necessary for the plasma collected and stored at -80°C. Ensure the patient 
initials, collection date and plasma cryovial number (e.g., P1, P2, P3, P4, P5, 
etc…) are marked on the cryovials. 
 
Place cryovials into the patient-specific cryovial storage box and immediately 
freeze at -70 to -90° C, and store frozen until ready to ship/transfer. See 
below for storage conditions. 
 
 
 
7.1.4 Whole Blood: Lavender Top EDTA tub #2 
Label as many 1ml cryovials (up to 5-10) as necessary for the whole blood 
collected. Label them with: 
 
Study name: PanCax3 
 
Subject ID 
 
Patient initials (First, Middle, Last) 
 
Collection date (Month, Day, Year) 
 
Whole blood cryovial number (e.g., WB1, WB2, WB3, WB4, WB5, etc…) 
7.1.4.1 
Process 
 
After collection, invert tube(s) twice to ensure adequate mixing of EDTA. 
 
Blood can also be mixed for 5 minutes on a mixer at room temperature. 
 
Aliquot 0.5 ml blood into as many 1 ml cryovials (up to 5-10) as are 
necessary for the whole blood collected and stored at -80°C. Ensure the 

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patient initials, collection date and whole blood cryovial number (e.g., WB1, 
WB2, WB3, WB4, WB5, etc…) are marked on the cryovials. 
 
Place cryovials into biohazard bag and immediately freeze at -70 to -90° C, 
and store frozen until ready to ship/transfer. See below for storage 
conditions. 
7.1.5 All Blood Samples – Freezing and Storage 
 
Freeze all blood samples in a -80°C Freezer or on Dry Ice or snap freeze in 
liquid nitrogen. 
 
Store at –80°C (-70°C to -90°C) until ready to transfer. 
 
If a -80°C Freezer is not available, 
 
Samples can be stored short term in a -20°C freezer (non-frost free 
preferred) for up to one week; OR 
 
Samples can be stored in plenty of dry ice for up to one week, replenishing 
daily; OR 
 
Samples can be stored in liquid nitrogen vapor phase 
 
Please indicate on Lab Requisition the storage conditions used and time 
stored. 
 
 
8.0 
FECAL SPECIMEN COLLECTION 
8.1 
Materials 
 
Toilet hat 
 
Collection bucket 
 
Gloves 
 
Sterile container with scooper attached to cap 
 
Biohazard laboratory bags (2) 
 
Post-it to record collection date and time 
 
Styrofoam ice box 
 
Ice packs 
 
8.2 
Home Instructions (see Appendix H) 
8.3 
Storage of stool sample 
The sample should be frozen until transport to the visit. The specimen should be 
transported frozen and kept frozen upon delivering specimen. Upon receipt of the sample 
at the investigator site – site personnel should verify that the collection date and subject 
ID is written on the paper. Stool specimens will be submitted to the CCTO laboratory for 
documentation and temporary storage in -20oC or -80oC.   
9.0 
STATISTICAL CONSIDERATIONS 
9.1 
Power Assessment 
The primary hypothesis to be tested is whether the percentage of patients who complete 
the course of pancreatic enzyme replacement therapy at 8 weeks is at least 50% for each 
of the three cancer stage subgroups: borderline resectable, locally advanced and 
advanced pancreatic cancer. We assumed a sample size equal to 10 patients for each 
group. The minimum detectable difference from the proportion 0.5 is 0.417 using a 
Binomial Exact test with Bonferroni correction. Thus, we will declare the sustainability of 
the therapy if 9 or more patients complete the treatment for each subgroup. 

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9.2 
Data Analysis Plan 
The primary hypothesis to be tested is whether is the percentage of patients who complete 
the pancreatic enzyme replacement therapy at 8 weeks is at least 50% for each of the 
three cancer stage subgroups: borderline resectable, locally advanced and advanced 
pancreatic cancer. A 95% confidence interval [1] for the proportion of treatment 
completeness will be calculated for each cancer stage. The statistical analysis will be 
performed in three steps for all secondary endpoints: 1) Descriptive analysis: Measures of 
central tendency (mean, median and mode), measures of variability (standard deviation, 
range and quantiles). Standard distribution plots such as profiles-plots for repeated 
measures and box-plots will be constructed to examine the distribution of the data. 2) 
Univariable Analysis and 3) Multivariable analysis: The linear regression model will be 
applied to explain the secondary endpoints as a function of the patient's baseline 
variables. Assumptions of the linear regression model will be examined. If the 
assumptions are not met, Generalized Additive models for Location, Scale and Shape 
(GAMLSS) which provide a general framework for extending a standard linear model will 
be applied [2]. The goodness of fit for each model will be accessed through a residual 
analysis using Worm-plots [51] and variable selection will be performed as outlined by 
Harrell [4]. Random effects will be added to describe the repeated measures. In addition, 
overall survival curve will be estimated using the Kaplan-Meier method with 95% 
confidence interval. All tests of hypotheses will be two-sided and a significance level of 
0.05 and calculations will be performed using R, version 3.2.3 [5].         
 
10.0 
STUDY MANAGEMENT 
10.1 
Conflict of Interest 
Any reportable conflict of interest will be disclosed to the local IRB and will be outlined in 
the Informed Consent Form. 
10.2 
Institutional Review Board (IRB) Approval and Consent  
It is expected that the IRB will have the proper representation and function in accordance 
with federally mandated regulations. The IRB should approve the consent form and 
protocol. 
 
In obtaining and documenting informed consent, the investigator should comply with the 
applicable regulatory requirement(s), and should adhere to Good Clinical Practice (GCP) 
and to ethical principles that have their origin in the Declaration of Helsinki. 
 
 
Before recruitment and enrollment onto this study, the patient will be given a full 
explanation of the study and will be given the opportunity to review the consent form. 
Each consent form must include all the relevant elements currently required by the FDA 
Regulations and local or state regulations. Once this essential information has been 
provided to the patient and the investigator is assured that the patient understands the 
implications of participating in the study, the patient will be asked to give consent to 
participate in the study by signing an IRB-approved consent form. 
 
Prior to a patient’s participation in the trial, the written informed consent form should be 
signed and personally dated by the patient and by the person who conducted the 
informed consent discussion. 
10.3 Registration Procedures 
 
All subjects that sign informed consent will be assigned a subject number sequentially by 
their date of consent.  Those subjects that do not pass the screening phase will be listed 
as screen failures on the master list of consented subjects.  Eligible subjects, as 

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determined by screening procedures and verified by a treating investigator, will be 
registered on study at Cedars Sinai Medical Center by the Study Coordinator.   
 
Issues that would cause treatment delays after registration should be discussed with the 
Principal Investigator (PI). If a patient does not receive protocol therapy following 
registration, the patient’s registration on the study may be canceled.  The Study 
Coordinator should be notified of cancellations as soon as possible. 
 
Assignment of Subject ID: The study team will track all subjects who sign consent using 
OnCore. Subjects found to be ineligible will be recorded as screen failures. Subjects 
found to be eligible will be registered using a three-digit numeric ID that follows the 
standard SOCCI format (001, 002, etc.). 
 
A) 
Eligibility Verification 
 
Prior to registration, all subjects must undergo eligibility verification by SOCCI Cancer 
Clinical Trials Office (CCTO) Quality Management Core (QMC). The following documents 
will be organized into an eligibility packet, scanned as a pdf, and emailed to 
GroupSOCCICROQMC@cshs.org for review: 
 
 
Registration form (or equivalent), if applicable 
 
Copy of applicable source documents 
 
QMC-approved eligibility checklist (signed by investigator and 2 members of the 
study team) 
 
Signed patient consent form with Subject’s Bill of Rights, HIPAA authorization 
form, consent progress note, and any optional consent forms, as applicable 
 
B) 
Registration 
 
After eligibility is verified, registration is completed as follows: 
 
 
Assign a patient study number 
 
Enter the patient in OnCore 
 
Notify the investigational pharmacy and treating physicians that a subject has 
gone on study and anticipated treatment start date 
 
Oversight by the principal investigator is required throughout the entire 
registration process 
 
10.4 Data and Safety Monitoring 
 
10.4.1 Data Monitoring and Quality Assurance 
Adherence to the protocol, Good Clinical Practices (GCP), and institutional policy will be 
monitored by the PI during the course of the study through routine Disease Research 
Group (DRG) meetings or equivalent. In addition, the SOCCI Cancer Clinical Trials Office 
(CCTO) Quality Management Core (QMC) will conduct internal monitoring visits and 
audits for data quality and protocol adherence. QMC reports will be forwarded to the 
SOCCI Data and Safety Monitoring (DSMC). Refer to the DSMC Charter for more details. 
For any protocol, QMC has the authority to request more frequent reviews or focused 
safety monitoring if it is deemed appropriate for any reason. 
 
QMC will also conduct the following:  

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1. Central eligibility verification for all subjects enrolled as described in protocol 
section 10.3.   
2. Central review by the SOCCI CCTO Medical Director or designee of all eligibility 
exception requests and waiver requests to assess appropriateness to ensure 
quality data and subject safety protections for investigator-initiated research 
 
 
10.4.2 Safety Monitoring 
Oversight of the progress and safety of the study will be provided by the PI. The PI will 
maintain continuous safety monitoring for the duration of the study by reviewing 
subject/study data. Adverse events and unanticipated problems are not expected, but if 
they occur they will be documented and reported according to CS-IRB policies and 
procedures. If the PI becomes aware of any new safety information that may place 
subjects at increased risk than what was previously known the IRB will be promptly 
notified and if warranted, enrollment may be held until the PI determines whether a 
modification to the study is necessary and/or the informed consent documents are 
updated accordingly. It is the responsibility of the principal investigator to adhere to the 
Data Safety Monitoring Plan throughout the life of the study. 
 
In addition, this protocol will utilize the SOCCI Data and Safety Monitoring Committee will 
provide another layer of data and safety oversight. DSMC membership and 
responsibilities are governed by the committee charter. Every six (6) months the DSMC 
findings and recommendations will be reported in writing to the Principal Investigator as a 
summary letter which will be forwarded by the Principal Investigator or designee to the 
CS-IRB. The DSMC may increase or decrease the frequency of study review, at their 
discretion. Refer to the DSMC Charter for details of the DSMC review.  
10.5 
Record Retention 
Study documentation includes all Case Report Forms, data correction forms or queries, 
source documents, monitoring/auditing logs/letters, and regulatory documents (e.g., 
protocol and amendments, IRB correspondence and approval, signed patient consent 
forms). 
 
Source documents include all recordings of observations or notations of clinical activities 
and all reports and records necessary for the evaluation and reconstruction of the clinical 
research study. Government agency regulations and directives require that the study 
investigator must retain all study documentation pertaining to the conduct of a clinical 
trial. Study documents should be kept on file per institutional guidelines. 
10.6 
Adherence to Protocol 
Except for an emergency situation in which proper care for the protection, safety, and 
well-being of the study patient requires alternative treatment, or a protocol exception 
request approved by the SOCCI Medical Director and CSMC IRB, the study shall be 
conducted exactly as described in the approved protocol. 
10.6.1 Emergency Modifications 
Investigators may implement a deviation from, or a change of, the protocol to eliminate 
an immediate hazard(s) to trial subjects without prior IRB approval. For any such 
emergency modification implemented, the IRB must be notified as soon as possible, but 
no more than 10 days from the investigator’s awareness of the event. 
 

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10.6.2 Protocol Exceptions and Eligibility Waivers  
 
A protocol exception is an anticipated or planned deviation from the IRB-approved 
research protocol, as described in the IRB Policy, Reporting Possible Unanticipated 
Problems Involving Risks to Subject or Others (UPIRSO) Policy: Institutional Review 
Board/Research Compliance and Quality Improvement. A protocol exception most often 
involves a single subject and is not a permanent revision to the research protocol. 
Protocol exceptions that extend beyond a single subject should result in a protocol 
amendment to avoid serial violations.  
Planned exceptions to the protocol that are more than logistical in nature and/or impact 
an eligibility criterion, affect timing of study drug administration, or the investigator 
assesses the event may impact subject safety and/or study integrity, may not be 
implemented without prior approval from the SOCCI (CCTO) Medical Director and the 
IRB. The PI or her/his designee is responsible for submitting a protocol exception and its 
supporting documents to the SOCCI CCTO Medical Director for review and further 
instructions on IRB reporting.   
 
Study team should refer to the IRB Reporting Possible Unanticipated Problems Involving 
Risks to Subject or Others (UPIRSO) Policy: Institutional Review Board/Research 
Compliance and Quality Improvement guidelines to determine which deviations and 
exception requests meet reporting guidelines. Once approved by the medical director, the 
deviation or exception request must be submitted to the IRB for review and approval prior 
to implementation.   
 
Special considerations for Eligibility Waivers (EW) 
In general, subjects who do not meet the eligibility requirements should not be enrolled. 
In the rare event that it is appropriate for subject inclusion, the rationale/justification and 
subject case history should be forwarded to the SOCCI CCTO Medical Director for 
assessment prior to submission to the IRB for approval.  
 
The CCTO Medical Director will review the case and contact the investigator if additional 
information is needed or further discussion is warranted. The CCTO Medical Director will 
provide a written assessment/recommended course of action. The CCTO Medical 
Director’s assessment must be uploaded into CS-IRB with the waiver request for IRB 
review and consideration. The CCTO Medical Director may recommend future protocol 
changes.  
 
Eligibility Waiver and Exception Request Submission Process  
The PI and/or treating physician will provide a written request for an eligibility waiver 
including case history and justification for prospective deviation from the study design, to 
the SOCCI CCTO Medical Director. The “IIT Monitoring – Eligibility Waivers and 
Exception Requests (EW/ER) Form” must be completed then submitted, along with any 
applicable supporting documents, by email to QMC  (GroupSOCCICROQMC@cshs.org) 
to request an eligibility exception or waiver request from the CCTO Medical Director. This 
is only a requirement for studies with a DSM category of moderate or high. An 
assessment from the CCTO Medical Director or designee must be done prior to 
submission to the IRB for review. 
 
10.6.3 Other Protocol Deviations 
Logistical deviations from the protocol (e.g., minor changes to the study schedule for an 
individual subject) do not require prior IRB approval unless the deviation has the potential 
to affect the subject’s safety or study integrity. Such planned deviations that do meet this 
definition and do not affect the subject’s safety or study integrity should be noted in the 

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subject’s research record or deviation log as described in the SOCCI CCTO’s Standard 
Operating Procedure 12: Deviation and Noncompliance Reporting. 
 
Unintentional deviations from the protocol that might affect subject safety or study 
integrity should be reported to the IRB within 10 days from when the investigator 
becomes aware that such a deviation has occurred, as outlined in the SOCCI CCTO’s 
Standard Operating Procedure 12: Deviation and Noncompliance Reporting. In this case, 
a Protocol Deviation report must be submitted in CS-IRB, per IRB policy, Reporting 
Possible Unanticipated Problems Involving Risks to Subject or Others (UPIRSO) Policy: 
Institutional Review Board/Research Compliance and Quality Improvement. All 
submissions should include a description of the plan to avoid similar deviations or 
exceptions in the future.   
 
10.6.4 Amendments to the Protocol  
Should amendments to the protocol be required, the amendments will be originated and 
documented by the Principal Investigator. It should also be noted that when an 
amendment to the protocol substantially alters the study design or the potential risk to the 
patient, a revised consent form might be required.  
 
The written amendment, and if required the amended consent form, must be sent to the 
IRB for approval prior to implementation. Repeat exceptions or deviations to the protocol 
may suggest a protocol amendment is needed. 
10.7 
Obligations of Investigators 
The Principal Investigator is responsible for the conduct of the clinical trial at the site in 
accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of 
Helsinki. The Principal Investigator is responsible for personally overseeing the treatment 
of all study patients. The Principal Investigator must assure that all study site personnel, 
including sub-investigators and other study staff members, adhere to the study protocol 
and all FDA/GCP/NCI regulations and guidelines regarding clinical trials both during and 
after study completion. 
 
The Principal Investigator will be responsible for assuring that all the required data will be 
collected and entered onto the Case Report Forms and/or into a HIPAA-compliant study 
database. Periodically, monitoring visits will be conducted and the Principal Investigator 
will provide access to his/her original records to permit verification of proper entry of data. 
At the completion of the study, all case report forms will be reviewed by the Principal 
Investigator and will require his/her final signature to verify the accuracy of the data. 
 
 
 
 
 
 

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11.0 
REFERENCES 
 
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Sikkens, E.C., et al., A prospective assessment of the natural course of the exocrine 
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Pancreatric Section, B.S.o.G., et al., Guidelines for the management of patients with 
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Bruno, M.J., et al., Placebo controlled trial of enteric coated pancreatin microsphere 
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Dominguez-Munoz, J.E., et al., Effect of the administration schedule on the therapeutic 
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Mueller, C., C. Compher, and D.M. Ellen, A.S.P.E.N. Clinical Guidelines. Journal of 
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Bruera, E.S., C., Cachexia and asthenia in cancer patients. Lancet Oncol, 2000. 1: p. 138-
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Academy of Nutrition and Dietetics Oncology Expert Work Group: Nutrition and the Adult 
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Huhmann, M.B. and D.A. August, Review of American Society for Parenteral and Enteral 
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Nutrition Screening and Assessment. Nutrition in Clinical Practice, 2008. 23(2): p. 182-
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R, L., Nutrition risk screening and assessment of the oncology patient., in Oncology 
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Bauer, J.D. and S. Capra, Nutrition intervention improves outcomes in patients with cancer 
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Davidson, W.A., S.;Capra, S.;Bauer, J.;Cancer Cachexia Study, Group, Weight 
stabilisation is associated with improved survival duration and quality of life in 
unresectable pancreatic cancer. Clin Nutr, 2004. 23(2): p. 239-47. 
21. 
Vashi, P., et al., Outcomes of Systematic Nutritional Assessment and Medical Nutrition 
Therapy in Pancreatic Cancer. Pancreas, 2015. 44(5): p. 750-755. 
22. 
Ottery, F., Supportive nutritional management of the patient with pancreatic cancer. 
Oncology (Williston Park), 1996. 10(9 Suppl): p. 26-32. 
23. 
Phillips, M.E., Pancreatic exocrine insufficiency following pancreatic resection. 
Pancreatology. 15(5): p. 449-455. 
24. 
Sikkens, E.C.M., et al., The Daily Practice of Pancreatic Enzyme Replacement Therapy 
After Pancreatic Surgery: a Northern European Survey: Enzyme Replacement After 
Surgery. Journal of Gastrointestinal Surgery, 2012. 16(8): p. 1487-1492. 
25. 
Toouli, J., et al., Management of pancreatic exocrine insufficiency: Australasian 
Pancreatic Club recommendations. Med J Aust, 2010. 193(8): p. 461-7. 
26. 
May., 
V.D.o.H.a.H.S.O.c.p.f.p.w.p.c. 
2015 
May 
8/4/2016]; 
Available 
from: 
http://www.cancervic.org.au/downloads/health-professionals/optimal-care-
pathways/Optimal_care_pathway_for_people_with_pancreatic_cancer.pdf  
27. 
Splinter, T.A., Cachexia and cancer: a clinician's view. Ann Oncol, 1992. 3 Suppl 3: p. 
25-7. 
28. 
Ryan, D.P. and M.L. Grossbard, Pancreatic Cancer: Local Success and Distant Failure. 
Oncologist, 1998. 3(3): p. 178-188. 
29. 
Hendifar, A.E., et al., Pancreas Cancer-Associated Weight Loss. Oncologist, 2018. 
30. 
Davidson, W., et al., Weight stabilisation is associated with improved survival duration 
and quality of life in unresectable pancreatic cancer. Clin Nutr, 2004. 23(2): p. 239-47. 
31. 
August, D.A., M.B. Huhmann, and A.S.f.P.a.E.N.A.S.P.E.N.B.o. Directors, A.S.P.E.N. 
clinical guidelines: nutrition support therapy during adult anticancer treatment and in 
hematopoietic cell transplantation. JPEN J Parenter Enteral Nutr, 2009. 33(5): p. 472-500. 
32. 
Ruggeri, E., et al., Home artificial nutrition in advanced cancer patients. Tumori, 2013. 
99(2): p. 218-24. 
33. 
Damerla, V., et al., Pancreatic enzyme supplementation in pancreatic cancer. J Support 
Oncol, 2008. 6(8): p. 393-6. 
34. 
Gooden, H.M. and K.J. White, Pancreatic cancer and supportive care--pancreatic 
exocrine insufficiency negatively impacts on quality of life. Support Care Cancer, 2013. 
21(7): p. 1835-41. 
35. 
Sikkens, E.C., et al., The daily practice of pancreatic enzyme replacement therapy after 
pancreatic surgery: a northern European survey: enzyme replacement after surgery. J 
Gastrointest Surg, 2012. 16(8): p. 1487-92. 

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36. 
Hendifar, A.E., et al. Evaluating outcomes of pancreatic cancer patients with cacehxia. in 
2014 ASCO Annual Meeting. 2014. Chicago, Illinois. 
37. 
Wigmore, S.J., et al., Effect of oral eicosapentaenoic acid on weight loss in patients with 
pancreatic cancer. Nutr Cancer, 2000. 36(2): p. 177-84. 
38. 
Furet, J.P., et al., Differential adaptation of human gut microbiota to bariatric surgery-
induced weight loss: links with metabolic and low-grade inflammation markers. Diabetes, 
2010. 59(12): p. 3049-57. 
39. 
Cani, P.D., et al., Changes in gut microbiota control metabolic endotoxemia-induced 
inflammation in high-fat diet-induced obesity and diabetes in mice. Diabetes, 2008. 57(6): 
p. 1470-81. 
40. 
Zambirinis, C.P., et al., Pancreatic cancer, inflammation, and microbiome. Cancer J, 2014. 
20(3): p. 195-202. 
41. 
Uronis, J.M., et al., Modulation of the intestinal microbiota alters colitis-associated 
colorectal cancer susceptibility. PLoS One, 2009. 4(6): p. e6026. 
42. 
Schwabe, R.F. and C. Jobin, The microbiome and cancer. Nat Rev Cancer, 2013. 13(11): 
p. 800-12. 
43. 
Fitzsimmons, D., et al., Development of a disease specific quality of life (QoL) 
questionnaire module to supplement the EORTC core cancer QoL questionnaire, the QLQ-
C30 in patients with pancreatic cancer. EORTC Study Group on Quality of Life. Eur J 
Cancer, 1999. 35(6): p. 939-41. 
44. 
Heffernan, N., et al., Measuring health-related quality of life in patients with hepatobiliary 
cancers: the functional assessment of cancer therapy-hepatobiliary questionnaire. J Clin 
Oncol, 2002. 20(9): p. 2229-39. 
45. 
Yount, S., et al., Assessment of patient-reported clinical outcome in pancreatic and other 
hepatobiliary cancers: the FACT Hepatobiliary Symptom Index. J Pain Symptom Manage, 
2002. 24(1): p. 32-44. 
46. 
Glare, P., et al., A systematic review of physicians' survival predictions in terminally ill 
cancer patients. BMJ, 2003. 327(7408): p. 195-8. 
47. 
Christakis, N.A. and E.B. Lamont, Extent and determinants of error in doctors' prognoses 
in terminally ill patients: prospective cohort study. BMJ, 2000. 320(7233): p. 469-72. 
48. 
Pal, S.K., V. Katheria, and A. Hurria, Evaluating the older patient with cancer: 
understanding frailty and the geriatric assessment. CA Cancer J Clin, 2010. 60(2): p. 120-
32. 
49. 
Bassett, D.R., Jr., et al., Pedometer-measured physical activity and health behaviors in 
U.S. adults. Med Sci Sports Exerc, 2010. 42(10): p. 1819-25. 
50. 
Fried, L.P., et al., Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci 
Med Sci, 2001. 56(3): p. M146-56. 
51. 
van Buuren, S. and M. Fredriks, Worm plot: a simple diagnostic device for modelling 
growth reference curves. Stat Med, 2001. 20(8): p. 1259-77. 
 
 
 
 

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12.0 
APPENDICES 
APPENDIX A: Performance Status Scales 
 
ECOG Performance Status 
SCORE DESCRIPTION 
 
0 
Fully active, able to carry on all pre-disease performance without restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, e.g., light house work, office work. 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities.  Up 
and about more than 50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours. 
4 
Completely disabled.  Cannot carry on any self-care.  Totally confined to bed or chair. 
5 
Dead. 
 
 
Karnofsky Performance Status Scale 
 
 
 

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 NOTE: APPENDICES B-D ARE UPLOADED AS SEPARATE DOCUMENTS WITHIN THE IRB 
APPLICATION 
APPENDIX E: Measures of Frailty phenotype 
 
 
 
Table from Fried et al. 2001 
 
Protocol for frailty criteria*:  
 
D1. Weight loss: Weigh patient and assess for weight loss. Someone who is frail may have unintentional 
weight loss of ≥ 10 pounds in the prior year. 
 
D2. Gait speed: Time a patient's walk for slowness. Someone who is frail has a decreased walking time 
as defined by a timed 15-foot walk test (5 meters). The time is adjusted for gender and standing height. 
Men with a height of <173 cm and women with a height <159 cm who walked 15 feet in >7 sec are 
considered frail; men >173 cm and women >159 cm who walked 15 feet in >6 sec are considered frail. 
 
D3. Weakness: Weakness is established when there is decreased grip strength measured by a 
dynamometer with the value adjusted for gender and body mass index (BMI). Men with a BMI <24 are 
considered frail if the grip strength (kg) is <29, for a BMI of 24.1-28, a man is frail if <30, for a BMI >28 a 
man is frail if <32. For women, a BMI of <23 is considered frail if the grip strength (kg) is <17, a BMI 23.1-
26 is considered frail if <17.3, a BMI of 26.1-29 is considered frail if <18, and a BMI >29 is considered frail 
if <21. 
 
D4. Physical Activity: Determine if the patient has a low physical activity level. This is established by a 
weighted score of kilocalories expended per week measured by the Minnesota Leisure Time Activity 
Questionnaire. The questionnaire asks about activities like daily living, sports and hobbies. Frailty is 
present when males use <383kcal/week, and females <270 kcal/week. 
 

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D5. Frailty Phenotype: Score will be calculated based on presence of each of these characteristics where 
presence of 1-2 criteria are categorized as prefail, and >=3 criteria categorized as frail. 
NOTE: APPENDICES F-H ARE UPLOADED AS SEPARATE DOCUMENTS WITHIN THE IRB 
APPLICATION 
 
 
APPENDIX I: SUMMARY OF CHANGES 
 
Amending Protocol Version 1 dated 12SEP2019 to Protocol Version 2 dated 28MAY2020 
 
Study Schema: Stool samples for microbiome analysis will be done at C1D1 and C3D1 only.  
 
Throughout the protocol: Dosage of study agent changed from “IU” to “units”. 
 
Study Summary, Section 1.1. Disease Background, Section 9.1 Power Analysis: Sample size reduced 
from 45 to 30 subjects (from 15 to 10 per sub-group) 
  
Section 2.5.3 Exploratory endpoints, Section 5 Study Procedures, Section 7.2: Removed genomic 
sequencing on tissue samples; changed to optional sub-study. 
  
Section 5 Study Procedures:  
 
Phosphorus, Magnesium, and CRP will be assessed at C1D1 only 
 
Research stool samples for microbiome analysis will be done at C1D1 and C3D1 only. 
 
Section 5.6 Time and Events table: Addition of row for Pancreaze treatment 
 
Bionutritional assessments (ASA-24 and Taste and Smell Alteration surveys) conducted at C1D1, 
C3D1, and End-of-Study only. 
 
Addition to footnote 7 to describe dispensing and drug accountability by Research Pharmacy. 
 
Section 6 Adverse Events: Updated per institutional boilerplate language. 
 
Section 6.5.1.4 Reporting to the External Funding Source (Vivus): Updated to require SAE reporting 
within 24 hours. 
 
Section 10 Study Management: Updated per institutional boilerplate language.  
 
Removal of patient-facing Appendices B-D, F-H, which will be uploaded to IRB application as separate 
documents. 
 
 
Amending Protocol Version 2 dated 28MAY2020 to Protocol Version 2.1 dated 02SEP2020 
 
Protocol cover page: Addition of co-investigator Dr. Osipov. 
 
Study Schema and Study Summary: Clarification of study assessment time points. 
 
Secondary Objectives 2.2.2, 2.2.3, 2.2.4, and 2.2.6, and corresponding secondary endpoints in Section 
2.5.2: Frequency of assessments updated for consistency with Section 5 Study Procedures.  
 
Section 2.2 Secondary Objectives and Section 2.5 Secondary Endpoints: Secondary objective, 
hypothesis, and endpoint related to “Assess body composition using computed tomography collected as 
standard of care” moved to exploratory.  

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Patient-Reported Outcomes / Exploratory Objectives 2.3.6 deleted for consistency with Section 5 Study 
Procedures. 
  
Section 10.4.1 Data Monitoring and Quality Assurance, Section 10.4.2 Safety Monitoring, Section 10.6.2 
Protocol Exceptions and Eligibility Waivers, and Section 10.6.3 Other Protocol Deviations: Updated in 
accordance with revised institutional boilerplate language.  
 
 
Amending Protocol Version 2.1 dated 02SEP2020 to Protocol Version 3 dated 04JAN2021 
 
Assessment of Frailty Phenotype: 
 
Section 2.5.3 Exploratory endpoints: Correction that frailty phenotype will be assessed every other 
cycle, for consistency with Section 5.3.2 Procedures During Treatment.  
 
Section 5.6 Time and Events Table: Applied footnote 1 to "Hand grip and 15 ft walk test" to clarify 
that it is done every other cycle, for consistency with Section 5.3.2 Procedures During Treatment. 
  
Stool Samples for Fecal Elastase and Microbiome Analysis: 
 
Inclusion 3.1.4 and Study Summary: “Abnormal fecal elastase <200 ug E1/g stool” changed to 
“Clinical diagnosis of exocrine pancreatic insufficiency” 
 
Section 5.2 Screening/Baseline Procedures: Fecal elastase will not be required for eligibility 
verification. Added note to allow the fecal elastase sample to be collected during screening or until 
C1D1 + 3 days; patients will be encouraged to provide the sample prior to starting treatment, if 
possible.  
 
Section 5.1.15 Stool sample: Added reference to Section 5.3.2 for stool collection procedures.  
 
Section 5.3.1 Procedures During Treatment - Day 1 of Every Cycle: For clarity, moved stool sample 
for microbiome analysis to Section 5.3.2 Day 1 of Every Other Cycle. 
 
Section 5.3.2 Procedures During Treatment - Day 1 of Every Other Cycle:  
o 
Added note to allow C1D1 microbiome stool sample to be collected during screening or until 
C1D1 + 3 days; patients will be encouraged to provide the sample prior to starting treatment, 
if possible. If the sample is collected during screening and the patient results in a screen fail, 
the sample will be destroyed unless consent is granted for its use on another IRB approved 
protocol (i.e., GI-Bank protocol). 
o 
Added note to allow the C3D1 microbiome stool sample to be collected with a window of +/- 7 
days of C3D1.  
 
Section 5.6 Time and Events Table:  
o 
Addition of footnote 8 to note the fecal elastase and C1D1 microbiome stool samples 
may be collected during screening until C1D1 + 3 days. 
o 
Addition of footnote 9 to note the window of +/- 7 days for the C3D1 microbiome sample. 
  
Other Changes: 
 
Inclusion 3.1.5: “Cachexia defined as ≥5% weight loss in the past 6 months” revised to “Cachexia 
defined as ≥5% unexplained weight loss within any 6-month period prior to screening OR as 
documented by the medical physician based on standard diagnosis of cachexia”.  
 
Section 5.2 Screening/Baseline Procedures: Correction of timeframe for screening from 6 weeks to 
4 weeks prior to Day 1, for consistency with Section 5.6 Time and Events table. 
 
Section 5.3.2 Procedures During Treatment - Day 1 of Every Other Cycle: Added note that stool 
survey will be done at C1D1 and C3D1 only, for consistency with Section 5.6 Time and Events 
Table. 
 
Appendix B. Taste and Smell Alteration Survey:  
 
Removal of item B3. 
 
Response option for item B4 (renumbered to B3) corrected. 
 
Appendix G. Stool Survey: 
 
Item 3: Revision to item text and response options for clarity. 
 
Removal of items 6-7 
 
Revision of item 8 (renumbered to item 6) for clarity. 

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Amending Protocol Version 3 dated 04JAN2021 to Protocol Version 4 dated 13SEP2021 
 
 
Cover page: Removal of co-investigators Nicholas Nissen, MD, Veronica Placencio Hickok, PhD 
and Haesoo Kim. 
 
Section 2.5, Primary Endpoint: Clarified the primary endpoint. 
 
Section 3.1.5, Inclusion Criterion: Clarification of definition of cachexia  
 
Section 4.2, Concomitant Medications: Added section and specified that only conmeds that are 
used to treat AEs need to be recorded in REDCap. 
 
Section 5.3.3, Procedures During Treatment: Clarified study treatment should follow standard 
chemotherapy schedule 
 
Section 5.3.31 Study Procedures, Day 1 of Every Cycle: Clarification that the study dosing diary 
is completed for the first two cycles, rather than the first 8 weeks, for consideration of study visit 
windows 
 
Study Procedures: Updated visit window for D1 of each cycle from ±3 to ±7 
 
Study Procedures: Revised D15 visit schedule to require research activities to occur during the 
standard chemo visits. 
 
Section 5.4 End-of-Study Visit and Section 5.6 Time and Events Table. Addition of:  
 
Following the Cycle 6 Day 15 visit, subjects will continue to take the study drug until the 
Cycle 6 Day 28 time point. Subjects should be reminded to discontinue study supply of 
Pancreaze following Cycle 6 Day 28. The End-of-Study visit is to occur 30 days following 
completion of study treatment, +/- 7 days. 
 
Section 6.1 Adverse Event Monitoring: Clarification that AE collection begins following initiation of 
treatment, rather than following informed consent. 
 
Adverse Event Monitoring: Clarified the study will adhere to CTCAE version 5 for adverse event 
reporting 
 
Section 6.2, Protocol-specific Adverse Event Monitoring Guidelines: Added section to specify 
what adverse events need to be recorded in REDCap. 
 
Amending Protocol v4 dated 13SEP2021 to Protocol v5 dated 17JAN2022 
 
 
Page 1, Abbreviations: Added abbreviation for End-of-Treatment (EOT) 
 
Page 2, Study Schema: Added EOT visit along with procedures. Clarified timing of fat-soluble 
vitamin measurements. 
 
Section 3.2, Exclusion Criteria: Removed exclusion criterion 3.2.7- other primary malignancies 
 
Section 5.3.3, Study Procedures: Addition of an EOT visit after C6D28, where patients will return 
pill bottles and transition to SoC enzymes, if applicable. The Day 15 visit was removed. The 
following study procedures will no longer occur at Day 15 of each cycle: PE, ECOG, and 
CMP/CBC 
 
Section 5.4, End-of-Study visit: Moved information pertaining to discontinuation of enzyme to 
section 5.3.3- End-of-Treatment visit. 
 
Section 5.6, Time and Events Table: Removed the Day 15 visit for each cycle and added an EOT 
visit. The footnotes were updated to reflect the changes to the study visits. 
 
Amending Protocol v5 dated 17JAN2022 to Protocol v6 dated 14OCT2022 
 
 
Study Title: Updated the title to reflect that there are 3 cohorts for this study (resectable, 
locally advanced and advanced pancreatic adenocarcinoma). 
 
Sections 2.5.3, 5.1.16, 5.2 and 5.6: Removed the optional archival tissue sub-study. 
 
Section 6.2 Protocol-specific Adverse Event Monitoring Guidelines: Clarified that all serious 
adverse events regardless of expectedness or relatedness in addition to AESI need to be 
collected. Added a table of the expected toxicities for Pancreaze as indicated in the Package 
Insert. 
 
Amending Protocol v6 dated 14OCT2022 to Protocol v7 dated 18MAY2023 

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 
Update Co-Investigators to include Dr. Sankar 
 
Increase sample size to 40 patients to allow for replacement of unevaluable patients.