Perioperative Stromal Depletion Strategies in Pancreatic Ductal Adenocarcinoma
Phase: PHASE2
Conditions: Adenocarcinoma
Sponsor: Andrew Ko

Perioperative Stromal Depletion Strategies in Pancreatic Ductal Adenocarcinoma 
Protocol Number:  CC #144515 
Study Drug:  PEGPH20, gemcitabine, nab-paclitaxel 
Version Number:  5.0 
Version Date:  06-27-2017 
IND Number:  124368 
Principal Investigator (Sponsor-Investigator) 
Andrew Ko, M.D.   
University of California San Francisco 
Helen Diller Family Comprehensive Cancer Center San Francisco, CA 
 
 
 
Co-Investigators-University of California San Francisco 
 
   
   
   
 
 
 
 
 
 
 
 
 
 
 
 
 
University of California Los Angeles 
 
 
 
  
NCT# 02487277

 
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Phase II – PEGPH20 in PDAC 
 
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Revision History 
Version 1.0  
18JUL2014  
Version 1.1 
12SEP2014   
Version 1.2  
29SEP2014   
Version 1.3 
28OCT2014 
Version 2.0 
30JUL2015 
Version 2.1 
05NOV2015 
Version 2.2 
03MAR2016 
Version 2.3 
28JUL2016 
Version 3.0 
04JAN2017 
Version 4.0 
27MAR2017 
Version 5.0 
27JUN2017 
 
 
 

 
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Protocol Signature Page 
Protocol No.: CC#144515 
Version Date: 06-27-2017 
1. I agree to follow this protocol version as approved by the UCSF Protocol Review Committee (PRC), 
Committee on Human Research (CHR), and Data Safety Monitoring Committee (DSMC).  
2. I will conduct the study in accordance with applicable CHR requirements, Federal regulations, and 
state and local laws to maintain the protection of the rights and welfare of study participants.  
3. I certify that I, and the study staff, have received the requisite training to conduct this research 
protocol.  
4. I have read and understand the information in the Investigators’ Brochure (or Manufacturer’s 
Brochure) regarding the risks and potential benefits. I agree to conduct the protocol in accordance 
with Good Clinical Practices (ICH-GCP), the applicable ethical principles, the Statement of 
Investigator (Form FDA 1572), and with local regulatory requirements. In accordance with the FDA 
Modernization Act, I will ensure the registration of the trial on the www.clinicaltrials.gov website.  
5. I agree to maintain adequate and accurate records in accordance with CHR policies, Federal, state and 
local laws and regulations. 
UCSF Principal Investigator / Study Chair 
 
 
Printed Name 
 
 
Signature 
 
Date 
 
 
Principal Investigator                                               
 
 
Site 
 
 
Printed Name 
 
 
Signature 
 
Date 
 
 
 

 
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PROTOCOL SYNOPSIS 
TITLE 
Perioperative Stromal Depletion Strategies in Pancreatic 
Ductal Adenocarcinoma 
RATIONALE 
Pancreatic ductal adenocarcinoma (PDAC) continues to be a 
challenging cancer to treat secondary to its advanced stage at the 
time of diagnosis, its aggressive behavior and its resistance to 
treatment [1, 2]While surgery provides the highest chance of cure 
for patients with localized PDAC, patients with either upfront 
resectable or borderline resectable disease may benefit from 
neoadjuvant therapy to select appropriate candidates for potentially 
curative operation, eradicate micrometastases, and increase the 
likelihood of R0 resection rate.  
 
The PDAC tumor microenvironment is complex and consists of 
multiple components including pancreatic stellate cells (PSC), 
endothelial cells, immune cells and fibroblasts with an extensive 
paracrine and autocrine network residing in a stiff extracellular 
matrix [2-5]. The desmosplastic reaction that is characteristic of the 
PDAC stroma [6, 7] has been associated with increased cell 
proliferation and migration leading to metastasis in PDAC [8-11], 
while it disturbs the pancreatic tissue architecture by changing the 
layout of blood and lymphatic vessels [7, 12]. Extracellular matrix 
in PDAC stroma also distorts the organization of capillary network, 
creating a hypoxic environment, which leads to “disorganized, 
dysfunctional and permeable” vasculature of PDAC [13]. As a 
component of the desmoplastic reaction, differentiation of PSC 
leads to accumulation of hyaluronan (HA) [14], a 
glycosaminoglycan polymer, which causes increased tumor 
interstitial fluid pressure (IFP) [15, 16]. The changes in pancreatic 
tissue architecture and increased IFP have been shown to compress 
the tumor vasculature and hinder delivery of chemotherapy, which 
may account for the resistance of PDAC to therapy [3, 17]. 
Preclinical studies with PEGPH20, which is pegylated 
recombinant human hyaluronidase and gemcitabine was 
associated with reduction in IFP, increase in vessel diameter and an 
increase of 83% in median overall survival in mice treated with 
gemcitabine and PEGPH20 [18].  
STUDY DESIGN 
This is a Phase II study investigating PEGPH20 in combination 
with gemcitabine and nab-paclitaxel in patients with both upfront 
resectable as well as borderline  
 
This trial will be conducted in two parts.  In Part I, pre-treatment 
endoscopic ultrasound (EUS)-guided core biopsies of the 

 
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pancreatic tumor and functional MRIs (fMRIs), including DCE-
MRI and DWI-MRI, will be obtained for the first fifteen patients 
enrolled as outlined in Figure 1. After a 1-week run-in period with 
PEGPH20 on days 1 and 4, these patients will have repeat EUS-
guided core biopsies, functional MRI, and undergo baseline 
CT/MRI of the chest, abdomen and pelvis.   
The following week after completing the 1 week run-in, patients in 
Part 1 will be started on treatment with PEGPH20, gemcitabine and 
nab-paclitaxel. PEGPH20, gemcitabine and nab-paclitaxel will be 
given weekly for 3 weeks, every 28 days. To evaluate the disease 
response to treatment, CA 19-9 levels will be checked monthly and 
restaging CT/MRI of the chest, abdomen and pelvis will be 
obtained every 8 weeks. If there is disease progression at any point 
in the study, patients will be taken off of study and alternative 
treatments will be offered. At the completion of 4 cycles of therapy, 
restaging CT/MRI scans will be obtained to determine resectability. 
If the patients are found to have resectable disease, an additional 
functional MRI will be obtained to evaluate the PDAC stroma. For 
patients who are able to have successful surgeries, tissue analyses 
will be performed on the resected pancreatic tumor. These patients 
may proceed to receive 2 cycles of adjuvant chemotherapy 
(physcian’s choice). If the patients are deemed to be surgical 
candidates but are found to have unresectable disease in the 
operating room, an intraoperative core biopsy of the pancreatic 
tumor will be obtained for tissue analyses.  
At the time of initiation of therapy with PEGPH20, patients will be 
started on prophylactic dose of enoxaparin 1 mg/kg subcutaneous 
daily. This will be continued throughout the study until at least 14 
days after the last infusion of PEGPH20. Patients will also take 
dexamethasone 1-2 hours before receiving PEGPH20, and 8-12 
hours after completion of PEGPH20 infusion. 
Two interim safety assessments will be performed when the first 7 
and 15 evaluable patients are enrolled in the study. Interim analyses 
and stopping rules are detailed later in this protocol.  
If the study enters Part II, an additional 21 patients will be enrolled. 
Patients in Part II will begin neoadjuvant therapy with PEGPH20, 
gemcitabine and nab-paclitaxel without the 1 week run-in of 
PEGPH20 (including pre- and post-run-in EUS-guided biopsies and 
fMRIs and post run-in CT scan.   
TEST PRODUCT, 
DOSE, AND ROUTE 
PEGPH20, pegylated recombinant HA degrading enzyme, is 
administered intravenously at MTD of 3 ug/kg on Days 1 and 4 

 
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OF 
ADMINISTRATION 
during the run-in period. Subsequently, patients will be treated with 
PEGPH20, gemcitabine and nab-paclitaxel on days 1, 8 and 15 of a 
28 day cycle. Nab-paclitaxel will be infused prior to gemcitabine. 
Patients will begin taking enoxaparin 1 mg/kg subcutaneously upon 
initiating treatment with PEGPH20 and continue until at least 14 
days after the final PEGPH20 infusion. Patients will also take 
dexamethasone 8mg PO 1-2 hours pre-PEGPH20 and again PO in 
8-12 hours post-PEG. 
NUMBER OF 
SUBJECTS 
The required number of post-operative patients is 25 evaluable 
patients for the study. We expect to enroll 36 patients total for 
required sample size. We will enroll 15 patients in the first phase of 
the trial. 21 patients will be enrolled in the expansion cohort in the 
second phase. 
RATIONALE FOR 
NUMBER OF 
SUBJECTS 
With a sample size of 25 evaluable patients, we will be able to 
estimate the 90% CI to be [4.5%-19.89%] or 95% CI to be [3.36%-
23.07%]. 
PRIMARY 
OBJECTIVES 
a) To evaluate development of clinically relevant pancreatic fistula 
within the 7-day post-operative period after neoadjuvant treatment 
with PEGPH20, gemcitabine and nab-paclitaxel. 
b) To evaluate pathologic complete response after neoadjuvant 
treatment with PEGPH20, gemcitabine and nab-paclitaxel. 
SECONDARY 
OBJECTIVES 
To evaluate early efficacy measured by percent change of CA 19-9 
response rate, R0 resection rate, overall response rate (ORR) and 
disease free survival (DFS). 
EXPLORATORY 
OBJECTIVES 
1) To evaluate the sequential effect of PEGPH20 on the fibrotic 
character and vascular perfusion of PDAC via functional MRIs. 
2) To determine degree of stromal depletion and effects of 
PEGPH20 on cell proliferation and apoptosis. 
DURATION OF 
SUBJECT 
PARTICIPATION AND 
DURATION OF STUDY 
Treatment: 4 months of chemotherapy followed by surgical 
resection if the patient’s tumor is deemed resectable post-therapy. 
Follow-up:  Patients will be followed after completion of study 
until death, by either in-person evaluation or telephone contact by 
study personnel at 2-3 month intervals (or more frequently as 
indicated by their disease state). 

 
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PRIMARY 
ENDPOINTS 
The incidence of pancreatic fistula within the 7-day post-operative 
period after neoadjuvant treatment with PEGPH20, gemcitabine 
and nab-paclitaxel. 
Rate of pathologic complete response after neoadjuvant treatment 
with PEGPH20, gemcitabine and nab-paclitaxel. 
SECONDARY 
ENDPOINTS 
Percent change of CA 19-9 response rate  
R0 resection rate 
Overall response rate (ORR) 
Disease-free survival (DFS) 
EXPLORATORY 
ENDPOINTS 
1) Tissue analyses pre-treatment and post-treatment with standard 
IHC staining for actin, hyaluronic acid staining with binding 
protein probe, proliferation as measured by ki-67% and Phospho-
histone H3 (Ph-H3); cell apoptosis as evaluated by IHC stain for 
cleaved caspase 3 (CC3) and Tunel. If limited tissue sample is 
obtained via the core biopsies, the priority of tissue analysis will be 
as follows: (1) fixed in formalin for H&E and IHC (Ph-H3; 
CC3/Tunel; HA binding); (2) fixed in OCT such that IHC with can 
be done with antibodies directed to conformational epitopes, or to 
potentially obtain mRNA or DNA. 
2) Functional MRIs including Dynamic Contrast Enhanced (DCE), 
Diffusion Weighted Imaging (DWI)) will be obtained to evaluate 
intratumoral perfusion and stromal density pre-treatment and post-
treatment prior to surgery. (Limited to patients without metallic 
biliary/enteral stents). 
SAFETY 
EVALUATIONS 
Post-operative complication of pancreatic fistula will be monitored 
per the standard clinical guidelines. Common clinical presentations 
of clinically relevant pancreatic fistula include abdominal pain, 
leukocytosis and fever (temperature >100.4 degrees). Diagnostic 
work-up of pancreatic fistula will be with CT abdomen with 
contrast, which has a sensitivity of 63% and specificity of 83% for 
detecting pancreatic fistula [33]. The pancreatic fistulas will be 
categorized into grades A, B or C as previously reported [34]. 
Clinically relevant pancreatic fistulas are categorized as grade B or 
C. Depending on the grade of pancreatic fistula, patients will be 
treated as indicated with conservative treatment options including 
bowel rest, medications and sometimes with interventional 
radiology assistance [34]. We will also track other relevant post-

 
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operative complications such as delayed wound healing, 
development of wound dehiscence or wound infection. 
 
 
 

 
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Table of Contents 
Protocol Signature Page ............................................................................................................ 3 
Table of Contents ........................................................................................................................ 9 
1 ......................................................................................................................................... BACKGROU
ND .............................................................................................................................................. 14 
1.1 
Pancreatic Cancer: Overview of Resectable and Borderline Resectable Disease ..... 14 
1.2 
Targeting the Tumor Stroma: PEGPH20 .................................................................. 14 
1.3 
Pancreatic Fistula Definition ..................................................................................... 16 
1.4 
Background on the Compounds ................................................................................ 17 
1.4.1 
Gemcitabine and nab-Paclitaxel for Pancreatic Cancer ................................ 17 
1.4.2 
Pegylated Recombinant Human Hyalurodinase (PEGPH20) ....................... 17 
2 ................................................................................................................................................... STUDY 
RATIONALE ............................................................................................................................ 19 
3 ................................................................................................................................................... STUDY 
OBJECTIVES ........................................................................................................................... 19 
3.1 
Primary Objectives .................................................................................................... 19 
3.2 
Secondary .................................................................................................................. 19 
3.3 
Exploratory Objectives, Other Assessments ............................................................. 19 
4 ................................................................................................................................................... STUDY 
DESIGN ..................................................................................................................................... 20 
4.1 
Study Overview ......................................................................................................... 20 
4.2 
Schema of Phase II clinical trial in patients with either upfront or borderline 
resectable pancreatic cancer based on the baseline pancreatic protocol CT scan, Part Ia. . 23 
5 .................................................................................................................................. CRITERIA FOR 
EVALUATION ......................................................................................................................... 23 
5.1 
Primary Endpoints ..................................................................................................... 23 
5.2 
Secondary Endpoints ................................................................................................. 24 
5.3 
Safety Evaluations ..................................................................................................... 24 
5.4 
Correlative Endpoints ................................................................................................ 24 
6 ............................................................................................................................................... SUBJECT 
SELECTION ............................................................................................................................. 24 
6.1 
Inclusion Criteria ....................................................................................................... 24 
6.2 
Exclusion Criteria ...................................................................................................... 25 
7 ................................................................................................................................... CONCURRENT 
MEDICATIONS ....................................................................................................................... 26 
7.1 
Allowed Medications and Treatments ....................................................................... 26 
8 ................................................................................................................................................... STUDY 
TREATMENTS ........................................................................................................................ 27 
8.1 
Study Agent Administration ...................................................................................... 27 
8.2 
Formulation of Study Agents .................................................................................... 28 
8.2.1 
Nab-paclitaxel ............................................................................................... 28 
8.2.2 
Gemcitabine .................................................................................................. 29 
8.2.3 
PEGPH20 ...................................................................................................... 30 

 
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Table of Contents 
8.2.4 
Rules for Dose Omissions and Modified Schedules ..................................... 32 
8.3 
Study Drug Accountability ........................................................................................ 38 
9 .......................................................................................................... STUDY PROCEDURES AND 
GUIDELINES ........................................................................................................................... 38 
9.1 
Clinical Assessments ................................................................................................. 38 
9.1.1 
Concomitant Medications ............................................................................. 38 
9.1.2 
Demographics ............................................................................................... 39 
9.1.3 
Medical History ............................................................................................ 39 
9.1.4 
Physical Examination ................................................................................... 39 
9.1.5 
Vital Signs..................................................................................................... 39 
9.1.6 
Adverse Events ............................................................................................. 39 
9.2 
Clinical Laboratory Measurements ........................................................................... 39 
9.2.1 
Hematology ................................................................................................... 39 
9.2.2 
Blood Chemistry Profile ............................................................................... 39 
9.2.3 
Pregnancies ................................................................................................... 39 
9.2.4 
Pregnancy Test .............................................................................................. 40 
9.3 
Tumor marker ............................................................................................................ 40 
9.4 
Research Tissue Analyses ......................................................................................... 40 
9.5 
Functional MRI ......................................................................................................... 40 
10 ......................................................................................................................... EVALUATIONS BY 
VISIT ......................................................................................................................................... 41 
11 ........................................................................ ADVERSE EXPERIENCE REPORTING AND 
DOCUMENTATION ............................................................................................................... 43 
11.1 
Serious Adverse Experiences (SAE) ....................................................................... 45 
11.1.1 Serious Adverse Experience Reporting ....................................................... 45 
11.1.2 Reporting of Serious Adverse Events to Halozyme .................................... 47 
11.2 
Data and Safety Monitoring Committee (DSMC) Contacts .................................... 47 
12 .................................................................. DISCONTINUATION AND REPLACEMENT OF 
SUBJECTS ................................................................................................................................ 47 
12.1 
Early Discontinuation of Study Drug ...................................................................... 47 
12.2 
Withdrawal of Subjects from the Study ................................................................... 48 
12.3 
Replacement of Subjects .......................................................................................... 48 
13 ....................................................................................................................................... PROTOCOL 
VIOLATIONS .......................................................................................................................... 48 
14 ................................................................................................. STATISTICAL METHODS AND 
CONSIDERATIONS................................................................................................................ 49 
14.1 
Data Sets Analyzed .................................................................................................. 49 
14.2 
Demographic and Baseline Characteristics ............................................................. 49 
14.3 
Analysis of Primary Endpoint ................................................................................. 49 
14.4 
Analysis of Secondary Endpoint ............................................................................. 49 
14.5 
Analyses of the Correlative Studies ......................................................................... 50 
15 ............................................................................... DATA COLLECTION, RETENTION AND 

 
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Table of Contents 
MONITORING ........................................................................................................................ 51 
15.1 
Data Collection Instruments .................................................................................... 51 
15.2 
Data Management Procedures ................................................................................. 51 
15.3 
Data Quality Control and Reporting ........................................................................ 51 
15.4 
Archival of Data....................................................................................................... 51 
15.4.1 Availability and Retention of Investigational Records ................................ 52 
15.5 
Monitoring ............................................................................................................... 52 
15.5.1 Record Keeping and Record Retention ....................................................... 54 
16 ..................................................................ADMINISTRATIVE, ETHICAL, REGULATORY 
CONSIDERATIONS................................................................................................................ 55 
16.1 
Protocol Amendments.............................................................................................. 55 
16.2 
Institutional Review Boards and Independent Ethics Committees .......................... 55 
16.3 
Informed Consent Form ........................................................................................... 56 
16.4 
Regulatory Documentation ...................................................................................... 56 
16.5 
Coordinating Center Documentation of Distribution .............................................. 57 
16.6 
Publications .............................................................................................................. 57 
16.7 
Investigator Responsibilities .................................................................................... 57 
17 .................................................................................................................. Recommended Dosing of 
Enoxaparin ................................................................................................................................ 59 
18 ................................................................................................................................................. Referen
ces ............................................................................................................................................... 60 
Appendix 1 UCSF Policy/Procedure for Required Regulatory Documents for UCSF 
Investigator-Initiated Oncology Clinical Trials with an Investigator held Investigational 
New Drug (IND)........................................................................................................................ 64 
Appendix 2 UCSF Policy/Procedure for Required Regulatory Documents for Single Site 
and Multicenter Investigator-Initiated Oncology Clinical Trials ........................................ 66 
 
List of Tables 
Table 1. Dose Reductions for Gemcitabine and Abraxane ........................................................ 33 
Table 2. Dose Reductions for PEGPH20 ................................................................................... 33 
Table 3. Dose Modifications for Hematologic Toxicities at the Start of Each Cycle or Within a 
Cycle .......................................................................................................................................... 34 
Table 4. Dose Modifications for Non-Hematologic Toxicity .................................................... 34 
Table 5. Timeline of Clinical Assessment, Studies and Treatment ........................................... 42 
Table 6.  AE Severity Grading ................................................................................................... 44 

 
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Table of Contents 
Table 7.  AE Relationship to Study Drug .................................................................................. 44 
Table 8 Rounding of Enoxaparin with Using Pre-filled Syringes ............................................. 59 
 
 
 

 
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List of Abbreviations 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BUN 
blood urea nitrogen 
CFR 
Code of Federal Regulations 
CRF 
case report form 
DMC 
Data Monitoring Committee 
DSMB 
Data Safety Monitoring Board 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IV 
intravenous 
mEq 
milliequivalent 
PI 
Principal Investigator 
PK 
pharmacokinetic 
SAE 
serious adverse experience 
 
 

 
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1 BACKGROUND 
1.1 
Pancreatic Cancer: Overview of Resectable and Borderline Resectable Disease 
Pancreatic ductal adenocarcinoma (PDAC) continues to be a challenging cancer to treat 
secondary to its advanced stage at the time of diagnosis, its aggressive behavior and its resistance 
to treatment[1].  Only a minority of patients present with localized, non-metastatic disease and 
may potentially represent surgical candidates. Such patients may be divided into two categories: 
those who have clearly resectable disease at initial diagnosis (herein referred to as upfront 
resectable), and those with borderline resectable pancreatic cancer (BRPC). BRPC represents an 
increasingly recognized, distinct clinical entity characterized by primary tumor involving 
surrounding vasculature with a high risk for margin-positive resection if resected de novo [35].    
Neoadjuvant therapy is often considered for patients with both resectable and borderline 
resectable disease to eradicate any micrometastatic disease, to identify suitable candidates most 
likely to benefit from surgery, and to improve the likelihood of margin-negative (R0) resection. 
However, consensus regarding the optimal neoadjuvant approach, including the respective roles, 
necessity, sequencing, and duration of neoadjuvant chemotherapy and chemoradiation 
(chemoRT), is lacking (reviewed in [36]). The neoadjuvant setting also represents an ideal 
setting to evaluate novel therapies to assess their on-target/pharmacodynamic effects, given that 
the majority of patients will ultimately be taken to surgery and be able to provide abundant tumor 
material for analyses. 
1.2 
Targeting the Tumor Stroma: PEGPH20 
The PDAC tumor microenvironment is complex and consists of multiple components 
including pancreatic stellate cells (PSC), endothelial cells, immune cells and fibroblasts with an 
extensive paracrine and autocrine network residing in a stiff extracellular matrix [2-5]. The 
desmosplastic reaction that is characteristic of the PDAC stroma [6, 7] has been associated with 
increased cell proliferation and migration leading to metastasis in PDAC [8-11], while it disturbs 
the pancreatic tissue architecture by changing the layout of blood and lymphatic vessels [7, 12]. 
Extracellular matrix in PDAC stroma also distorts the organization of capillary network, creating 
a hypoxic environment, which leads to “disorganized, dysfunctional and permeable” vasculature 
of PDAC [13]. As a component of the desmoplastic reaction, differentiation of PSC leads to 
accumulation of hyaluronan (HA) [14], a glycosaminoglycan polymer, which causes increased 
tumor interstitial fluid pressure (IFP) [15, 16]. The changes in pancreatic tissue architecture and 
increased IFP have been shown to compress the tumor vasculature and hinder delivery of 
chemotherapy, which may account for the resistance of PDAC to therapy[3, 17] Preclinical 
studies with PEGPH20, which is pegylated recombinant human hyaluronidase and gemcitabine 
(G) was associated with reduction in IFP, increase in vessel diameter and an increase of 83% in 
median overall survival in mice treated with gemcitabine and PEGPH20 [18].  
 
In addition to the preclinical studies, phase I studies investigating the effect of PEGPH20 
have shown that it is well tolerated when used alone or in combination with gemcitabine and 
nab-paclitaxel. The most commonly reported adverse event in phase I trials was Grade 3 myalgia 
which improved after the use of dexamethasone [19, 20]. Of note, there was no evidence of 
inflammation or muscle damage in patients treated with PEGPH20 as measured by human 

 
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inflammation multi-analyte profile of 46 different cytokines, chemokines and acute-phase 
reactants [21]. A phase 1b study (NCT01453153) testing PEGPH20 with gemcitabine was 
complete recently. Preliminary data from the phase Ib trial studying PEGPH20 plus gemcitabine 
in patients with metastatic pancreatic cancer showed that the most commonly reported adverse 
event was fatigue and musculoskeletal events [37] In this study, patients whose tumors had high 
HA staining had an overall response rate of 83% [22]. The final results of the Phase 1B study 
may be available prior to our trial’s tentative initiation date.  In additon, two phase II clinical 
trials are now in progress assessing the safety and efficacy of PEGPH20 plus nab-paclitaxel and 
gemcitabine (NCT01839487) and PEGPH20 combined with MFOLFIRINOX (NCT01959139) 
in patients with metastatic pancreatic cancer.  
  
We selected gemcitabine and nab-paclitaxel as the chemotherapy backbone due to the 
safety and efficacy profile reported in preclinical and clinical studies. In earlier preclinical 
studies, nab-paclitaxel was thought to work by binding of albumin to SPARC-positive fibroblasts 
and targeting the tumor microenvironment directly [23]. This resulted in approximately 3-fold 
increase in the intratumoral gemcitabine concentration. However, a recent study demonstrated 
that reduction of cytidine deaminase impaired gemcitabine metabolism and lead to increased 
gemcitabine concentration in the tumor [24]. While both of these studies demonstrated increased 
intratumoral concentration of gemcitabine, the latter study did not demonstrate stromal depletion 
with the use of nab-paclitaxel. Following the preclinical findings of overexpression of SPARC in 
pancreatic cancer, a phase I/II study enrolled patients with advanced pancreatic cancer for 
treatment with gemcitabine and nab-paclitaxel [19]. This study noted a median overall survival 
of 12.2 months and 1-year survival of 48%. The subsequent phase III clinical trial with 
gemcitabine and nab-paclitaxel reported median overall survival of 8.5 months compared to 6.7 
months with single-agent gemcitabine [38]. Recently, gemcitabine and nab-paclitaxel was found 
to be feasible in the preoperative setting for resectable PDAC and showed pathologic down-
staging [26]. Radiologic partial response was reported as 16% and there was a >50% decline in 
CA 19-9 in 60% of the patients.  
 
We plan to evaluate the effect of PEGPH20 with functional MRI, including DCE-MRI 
and DWI-MRI. Functional imaging became a measure of treatment response with the 
introduction of anti-angiogenic therapy[27]. Multiple studies have reported the feasibility and 
validity of DCE-MRI, including a study that compared primary PDAC, benign pancreatic tumors 
and normal pancreatic tissue histologically and with DCE-MRI [28]. Malignant pancreatic 
tumors had a significantly lower Ktrans (i.e. decreased perfusion) compared to benign pancreatic 
lesions and normal pancreatic tissue. In addition, DWI-MRI has been used for the study of 
pancreatic lesions as it is able to detect “dense cellularity and extracellular fibrosis” by 
demonstrating low apparent diffusion coefficient (ADC) values [29]. Functional MRIs have also 
been used as correlative studies in the phase I studies with PEGPH20 and showed increase in 
Ktrans and ADC 48 hours post-treatment relative to baseline [21, 30, 39]. Our project will 
address the sequential effect of PEGPH20 on stroma character and vascular perfusion. As a part 
of the clinical trial protocol, we will obtain tissue biopsies pre-treatment, post-treatment after a 
run-in period with PEGPH20 and again post-treatment after treatment with PEGPH20, 
gemcitabine and nab-paclitaxel.  To study the relationship between the potential tissue and 
radiographic modifications in the stroma, we will also utilize DCE-MRI and DWI-MRI pre-

 
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treatment, post-treatment after a run-in period with PEGPH20 and again on day 14 after 
initiation of treatment with PEGPH20, gemcitabine and nab-paclitaxel. 
 
The role of tumor microenvironment in formation of desmoplastic reaction, cell 
proliferation, migration and metastatic potential makes it an important target for therapeutic 
intervention. We hypothesize that preoperative treatment with PEGPH20 will deplete the stroma, 
increase intratumoral perfusion (and hopefully drug delivery) without increased risk of post-
operative complication of pancreatic fistula formation in patients with borderline resectable 
PDAC. We will address this by (1a) investigating the effect of preoperative treatment with the 
combination of PEGPH20, gemcitabine and nab-paclitaxel on the risk of post-operative clinically 
relevant pancreatic fistula formation (1b) evaluating pathologic complete response after 
neoadjuvant PEGPH20, gemcitabine and nab-paclitaxel treatment (2) evaluating the sequential 
effect of PEGPH20 on the fibrotic character and vascular perfusion of PDAC via functional 
MRIs. In addition, we will investigate (3) the degree of stromal depletion and the effects of 
PEGPH20 on cell proliferation and apoptosis. 
 
1.3 
Pancreatic Fistula Definition 
Pancreatic fistula is the “failure of healing/sealing of pancreatic-enteric anastomosis or it 
may represent a parenchymal leak not directly related to an anastomosis”. It is considered to be a 
common post-operative complication following pancreatic surgery with a frequency ranging 
from 5-30% [40-47]. Development of pancreatic fistula may affect timely initiation of adjuvant 
therapy following surgery due to possible longer hospital stays. A universally accepted 
Definition of pancreatic fistula was developed by the International Study Group on Pancreatic 
Fistula (ISGPF) in 2005 and classified pancreatic fistulas to 3 grading systems; A, B and C[48]. 
According to this definition, pancreatic fistula is defined as “any appreciable drainage from an 
operatively placed drain with an amylase content greater than 3 times the upper limit of normal 
serum amylase level measure on, or after, postoperative day 3”[49]. Grade A fistulas are 
diagnosed biochemically with elevated amylase but do not have any associated symptoms and 
therefore are not clinically relevant. Grade B and C fistulas on the other hand are symptomatic 
fistulas, which require diagnostic evaluation and therapeutic interventions. Patients often present 
with “abdominal pain, fever, nausea and intolerance to oral intake” and diagnostic imaging 
studies may show peripancreatic fluid collection[50]. The degree of intervention is more intense 
with grade C fistulas as these patients are often in critical condition with possible sepsis and 
organ dysfunction. While patients with grade B pancreatic fistulas may be treated with 
antibiotics and percutaneous drainage, patients with grade C pancreatic fistulas may require ICU 
admission, surgical re-exploration, antibiotics and somatostatin analogues. In the current study, 
we will be evaluating clinically relevant pancreatic fistulas, i.e. pancreatic fistulas graded as B or 
C, within in the first week following surgery. 

 
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1.4 
Background on the Compounds 
1.4.1 Gemcitabine and nab-Paclitaxel for Pancreatic Cancer 
Gemcitabine became the standard of care for systemic treatment of advanced pancreatic 
cancer in 1997 when it was shown to have clinical response and survival benefit over 5-
fluorouracil [51]. Since then, multiple combinations of other cytotoxic agents and targeted 
therapies have been studied in combination with gemcitabine. However, only erlotinib, an EGFR 
inhibitor, showed a marginal survival benefit in a Phase III clinical trial, when combined with 
gemcitabine[52]. While the recent randomized controlled trial with FOLFIRINOX revealed 
improved response in overall and progression free survival over single-agent gemcitabine in 
metastatic pancreatic cancer, there is much needed advancement in the systemic treatment of 
pancreatic cancer[53]. 
One recent phase I/II study investigated gemcitabine in combination with nab-paclitaxel, 
an albumin-bound form of paclitaxel, in patients with advanced pancreatic cancer [19]. This 
study was undertaken after molecular profiling of pancreatic adenocarcinoma tumors revealed 
overexpression of secreted protein acidic and rich in cysteine (SPARC), which is an albumin-
binding protein which is secreted by tumors [54]. It is believed that SPARC is able to bind 
albumin and then releases the active drug at the tumor cell membrane allowing for increased 
concentration of the agent at the target site of action [55]SPARC is also overexpressed in other 
tumor types including breast, lung and melanoma and nab-paclitaxel was shown to have 
antitumor effect in these tumor types secondary to its association with SPARC[56-58]  
Following the preclinical findings of overexpression of SPARC in pancreatic cancer, the 
aforementioned phase I/II study enrolled patients with advanced pancreatic cancer for treatment 
with gemcitabine and nab-paclitaxel [19]. Phase I study found the MTD of gemcitabine to be 
1000 mg/m2 and nab-paclitaxel to be 125 mg/m2 administered weekly for 3 weeks in a 28-day 
cycle. Subsequently, a phase III clinical trial showed a median overall survival of 8.5 months 
compared to 6.7 months with single-agent gemcitabine [38]. 
1.4.2 Pegylated Recombinant Human Hyalurodinase (PEGPH20) 
A potential limitation of chemotherapy in pancreatic cancer treatment has been the thick 
stromal matrix, characteristic of this disease. A pivotal preclinical study showed that the stroma 
impedes drug delivery and it was proposed that drugs that are able to disrupt the desmoplastic 
stroma may “facilitate delivery and enhance the efficacy of gemcitabine” [23]. Hyaluronan (HA), 
a glycosaminoglycan polymer may accumulate in the tumor stroma causing increased tumor 
interstitial fluid pressure (IFP) compressing tumor vasculature[59, 60]. These observations led to 
the hypothesis that depletion of HA may lead to decreased tumor IFP and increased vascular area 
with improved perfusion and drug delivery to the tumor. Preclinical studies with gemcitabine 
monotherapy plus PEGPH20, which is pegylated recombinant human hyalurodinase, showed 
decreased proliferation, increased apoptosis and decreased metastatic tumor burden in pancreatic 
cancer [18]. In this study, the use of PEGPH20 was associated with reduction in IFP, increase in 
vessel diameter and an increase of 83% in median overall survival in mice treated with 
gemcitabine and PEGPH20 compared to gemcitabine and placebo. PEGPH20 may serve as a 

 
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novel agent in treatment of tumors with high HA concentration, such as pancreatic cancer, by 
“enzymatically remodeling” the tumor stroma. 
Two Phase I studies (N=40) using PEGPH20 were conducted to determine its safety and 
tolerability. In a phase I clinical trial studying PEGPH20, the most commonly reported adverse 
event was Grade 3 myalgia at higher doses (50 ugram/kg) or higher frequency (twice a week 
rather than once a week) [21]. The musculoskeletal events were also observed in canines in a 
dose-dependent fashion as the canines had difficulty with standing and mobility. With the 
addition of dexamethasone, the musculoskeletal events were prevented in the canines without 
altering PEGPH20 pharmacokinetics. When dexamethasone was used in Phase I studies in 
addition to PEGPH20, muscle stiffness and pain were improved [21, 30]. Of note, a phase I study 
measured human inflammation multi-analyte profile (MAP) of 46 different cytokines, 
chemokines, and acute-phase reactants and did not find any evidence of inflammation or muscle 
damage [21]. A phase Ib clinical trial in subjects with Stage IV pancreatic cancer showed that 
PEGPH20 plus gemcitabine in the first-line setting was safe and showed promising results. In 
this study, patients whose tumors had high HA staining had an overall response rate of 56% [20]. 
In the over 145 subjects exposed to PEGPH20, either in the monotherapy or combination 
setting, the most frequently reported adverse events are of musculoskeletal origin (MSE) (e.g., 
muscle spasms, arthralgia, and myalgia), as well as peripheral oedema. The majority of these 
types of events are Grade1/2 in severity.  Other AEs that have been identified in both the 
monotherapy and combination therapy settings include nausea, diarrhea, and dysphonia. The 
majority of the events are Grade 1/2. Please refer to the Investigator’s brochure for additional 
safety information. 
Halozyme has recently completed enrollment to a randomized Phase 2 clinical study 
(HALO-109-202) in which approximately 253 subjects with Stage IV previously untreated 
pancreatic cancer were assigned to receive either nab-paclitaxel plus gemcitabine, or this same 
chemotherapy regimen plus PEGPH20. Interim safety analysis suggested the possibility of an 
increase in thromboembolic events in the PEGPH20 plus nab-paclitaxel and gemcitabine (PAG) 
arm compared to the nab-paclitaxel and gemcitabine arm (AG). The majority of the TE events 
were of venous origin (deep vein thrombosis and pulmonary embolism); however, arterial events 
were also reported.  It has been well cited in the medical literature that pancreatic cancer is one 
of the most thromboegenic malignancies; in a retrospective analysis of TE rates in this patient 
population, Epstein and colleagues (Epstein, 2012) identified a TE event rate at approximately 
36%. Based on this review, the study protocol was amended to exclude new subjects, as well as 
those who were previously on PAG treatment, who may be at a higher risk for developing TE 
events, and prophylactic treatment with low molecular-weight heparin for all subjects on study 
(PAG and AG) was added. With these mitigation strategies, no excess rates of TE events were 
observed with continuation and completion of study enrollment. Based on promising early 
results reported in this phase II study specific to patients with elevated intratumoral expression of 
HA[61], a subsequent phase III trial (HALO-301) is now underway evaluating this same 
strategy, again in the metastatic setting, with enrollment limited exclusively to patients with HA-
high tumors. 

 
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2 STUDY RATIONALE 
Because of its mechanism of action as mentioned above, we believe that PEGPH20 could 
have a role in the neoadjuvant setting for patients with upfront and borderline resectable 
pancreatic ductal adenocarcinoma. While this agent already has an established safety profile in 
combination with gemcitabine and nab-paclitaxel in the metastatic setting, we wish to assess 
both its safety and efficacy in this preoperative context. 
Hyaluronan and HA metabolites—medium, low, and very small molecular weight 
products of hyaluronidase degradation—are important mediators of the inflammatory and tissue-
regenerative processes of wound repair[62].   It is currently unknown what effects, if any, 
exogenously administered hyaluronidase would have on the natural rate of hyaluronan turnover 
and the dynamics of wound healing [62, 63].  As safety and toxicity will be a critical factor in 
this trial, we have chosen to include as a co-primary endpoint the development of pancreatic 
fistula, which represents the most common post-operative complication following pancreatic 
surgery. PEGPH20, whose mechanism involves breakdown of a key component of connective 
tissue, may potentially affect wound healing and anastomotic integrity and could theoretically 
increase the risk of fistula formation. 
 
3 STUDY OBJECTIVES 
3.1 
Primary Objectives 
 To evaluate development of clinically relevant pancreatic fistula in the post-operative 
period after neoadjuvant treatment with PEGPH20, gemcitabine and nab-paclitaxel. 
 To evaluate pathologic complete response after neoadjuvant PEGPH20, gemcitabine and 
nab-paclitaxel treatment. 
3.2 
Secondary 
To evaluate early efficacy measured by percent change of CA 19-9 response rate, R0 resection 
rate, overall response rate (ORR) and disease free survival (DFS). 
3.3 
Exploratory Objectives, Other Assessments 
 To evaluate the sequential effect of PEGPH20 on the fibrotic character and vascular 
perfusion of PDAC via functional MRIs. 
 To determine degree of stromal depletion and effects of PEGPH20 on cell proliferation 
and apoptosis. 
 

 
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4 STUDY DESIGN 
4.1 
Study Overview 
This is a Phase II study investigating PEGPH20 in combination with gemcitabine and nab-
paclitaxel in patients with both upfront and borderline resectable pancreatic ductal 
adenocarcinoma (PDAC).  
This trial will be conducted in two parts.  In Part I, pre-treatment endoscopic ultrasound (EUS)-
guided core biopsies of the pancreatic tumor and functional MRIs (fMRIs), including DCE-MRI 
and DWI-MRI, will be obtained for the first fifteen patients enrolled as outlined in Figure 1. 
After a 1-week run-in period with PEGPH20 on days 1 and 4, these patients will have repeat 
EUS-guided core biopsies, functional MRI, and undergo baseline CT/MRI of the chest, abdomen 
and pelvis.   
After completing the 1 week run-in, patients in Part 1 will be started on treatment with 
PEGPH20, gemcitabine and nab-paclitaxel (within 1-2 weeks). PEGPH20, gemcitabine and nab-
paclitaxel will be given weekly for 3 weeks, every 28 days. To evaluate the disease response to 
treatment, CA 19-9 levels will be checked monthly and restaging CT/MRI of the chest, abdomen 
and pelvis will be obtained every 8 weeks. If there is disease progression at any point in the 
study, patients will be taken off of study and alternative treatments will be offered. At the 
completion of 4 cycles of therapy, restaging CT/MRI scans will be obtained to determine 
resectability. If the patients are found to have resectable disease, an additional functional MRI 
will be obtained to evaluate the PDAC stroma. For patients who are able to have successful 
surgeries, tissue analyses will be performed on the resected pancreatic tumor. These patients may 
receive further adjuvant chemotherapy post-operatively based on the physician’s clinical 
judgement. If the patients are deemed to be surgical candidates but are found to have 
unresectable disease in the operating room, an intraoperative core biopsy of the pancreatic tumor 
will be obtained for tissue analyses.  
At the time of initiation of therapy with PEGPH20, patients will be started on prophylactic dose 
of enoxaparin 1 mg/kg subcutaneous daily. This will be continued throughout the study until at 
least 14 days after the last infusion of PEGPH20. Patients will also take dexamethasone 1-2 
hours before receiving PEGPH20, and 8-12 hours after completion of PEGPH20 infusion. 
Two interim safety assessments will be performed when the first 7 and 15 evaluable patients are 
enrolled in the study. Interim analyses and stopping rules are detailed later in this protocol.  
If the study enters Part II, an additional 21 patients will be enrolled. Patients in Part II will begin 
neoadjuvant therapy with PEGPH20, gemcitabine and nab-paclitaxel without the 1 week run-in 
of PEGPH20, the  pre- and post-run-in EUS-guided biopsies and fMRIs, or the post run-in 
CT/MRI scan.   
For Specific Aim 1, we will be monitoring the post-operative complication of clinically relevant 
pancreatic fistula within one week of surgery per the standard clinical guidelines as noted above. 
Common clinical presentations of pancreatic fistula include abdominal pain, leukocytosis and 
fever (temperature >100.4 degrees). Diagnostic work-up of pancreatic fistula will be with CT 

 
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abdomen with contrast, which has a sensitivity of 63% and specificity of 83% for detecting 
pancreatic fistula [33]. The pancreatic fistulas will be categorized into grades A, B or C as 
previously reported [34]. Our study will be investigating only clinically relevant pancreatic 
fistulas, i.e. grades B or C. Depending on the grade of pancreatic fistula, patients will be treated 
as indicated with conservative treatment options including bowel rest, antibiotics, somatostatin 
analogues and percutaneous drainage or surgical re-exploration[34]. We will also track other 
relevant post-operative complications such as delayed wound healing, development of wound 
dehiscence or wound infection. 
 
The tissue analyses will include review of the immunohistochemical (IHC) stains for 
actin, hyaluronic acid staining with binding protein probe, proliferation as measured by ki-67% 
and Phospho-histone H3 (Ph-H3); cell apoptosis as evaluated by IHC stain for cleaved caspase 3 
(CC3) and Tunel. If limited tissue sample is obtained via the core biopsies, the priority of tissue 
analysis will be as follows: (1) fixed in formalin for H&E and IHC (Ph-H3; CC3/Tunel; HA 
binding); (2) fixed in OCT such that IHC with difficult antibodies can be done (to potentially 
obtain mRNA or DNA). The IHC studies will be done at the UCSF Helen Diller Family 
Comprehensive Cancer Center Immunohistochemistry and Molecular Pathology Core, led by Dr. 
Rick Baehner (see letter of support).  
 
The CT and MR imaging analyses will be performed at a University of California (UC) 
campus. To decrease the impact that metal stents may have on the functional MRI results, any 
patients who has a metallic stent (biliary and/or enteral) will not participate in this MRI 
component of the study.  In addition, to reduce variability in results, the DCE-MRI and DWI-
MRI will be obtained on the same MR machine at a similar time of day as the baseline scan. The 
DCE-MRI images will be analyzed by calculating Ktrans and DWI-MRI images will be analyzed 
by calculating ADC as described elsewhere [41, 44]. We will scan patients in a torso coil on a 3T 
clinical MR scanner. Imaging will include MR diffusion with b-values of 0, 125, and 500 for 
estimates of perfusion and tumor, and dynamic contrast-enhanced MR imaging (DCE-MRI) for 
measurement of Ktrans, blood volume, and blood flow. The region of tumor will be determined 
by MR imaging in reference to the baseline CT scans. The native T1 of the pancreas and liver 
will be calculated from a series of four, 3D, spoiled gradient recalled echo (SPGR) sequences 
with different flip angles. The conventional DCE-MRI will be acquired as a 3D, fast spoiled 
gradient echo sequence, covering the targeted areas of the pancreas or liver, at a temporal 
resolution of 5 sec over 6 minutes after the administration of 0.1 mmol/kg gadobenate 
dimeglumine. DCE-MRI images will be post-processed using MIStar software 
 
 which allows for motion correction to account for any shifts in 
data. Datasets with artifacts will be eliminated before further post processing. After contrast 
delivery, the new T1 is calculated and is presumed to change with the Gd concentration such that 
[Gd] = (1/T1-1/T10)/R1 where R1 is assumed to be 4.5 sec-1 mmol/L-1 at 3T. 
Run-in Period with PEGPH20 
Days 1, 4 
PEGPH20 3 ug/kg over a 10 minute period (+2 
minute window, i.e. infusion may be 10-12 
minutes) 

 
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Dexamethasone 8mg PO 1-2 hours pre-
PEGPH20 and PO 8-to-12 hours post-
PEGPH20 
*Start enoxaparin 1 mg/kg subcutaneous daily 
on day 1 (to be continued throughout the trial 
during treatment with PEGPH20, and at least 14 
days after the last infusion of PEGPH20) 
 
 
On day 8 (± 1 day) of run-in period with PEGPH20, EUS-directed core biopsy, functional 
MRI (except for patients with metallic stents) and CT/MRI of the chest, abdomen (pancreatic 
protocol) and pelvis will be obtained. 
 
Cycle 1 and onward 
Days 1, 8, 15 
out of a 28-
day cycle 
PEGPH20 3 ug/kg over a 10 minute period (+2 
minute window, i.e. infusion may be 10-12 
minutes) + Gemcitabine 1000mg/m2 + nab-
Paclitaxel 125mg/m2. Infuse nab-Paclitaxel 
prior to gemcitabine. 
Dexamethasone 8mg PO 1-2 hours pre-
PEGPH20 and PO 8-to-12 hours post-
PEGPH20 
 
 
Gemcitabine and nab-paclitaxel will be administered 2-4 hours post-PEGPH20. 
 
Neoadjuvant therapy will be four 28-day cycles with CA 19-9 measurements every 4 weeks, 
and CT/MRI of the chest, abdomen and pelvis every 8 weeks. Patients will be taken off of 
the study if there is any evidence of disease progression. 
 
Patients will be evaluated for surgical resection depending on imaging obtained on Cycle 4 
Day 21. 
o Patients who are found to have resectable disease will have a functional MRI 
following the restaging CT scan. If patients continue on to have successful 
resection, they may receive 2 additional cycles of chemotherapy without 
PEGPH20 (physician’s choice). If a patient is found to have unresectable disease 
in the operating room, an intra-operative core biopsy will be obtained.  
o Patients who are found to have unresectable disease on the restaging scans 
following 4 cycles of therapy will be taken off of the study.  
 

 
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4.2 
Schema of Phase II clinical trial in patients with either upfront or borderline 
resectable pancreatic cancer based on the baseline pancreatic protocol CT 
scan, Part Ia. 
 
                                                         
5 CRITERIA FOR EVALUATION 
5.1 
Primary Endpoints 
 Clinically relevant pancreatic fistula in the post-operative period after neoadjuvant 
treatment with PEG, gemcitabine and nab-paclitaxel. 
 Pathologic complete response after neoadjuvant PEG, gemcitabine and nab-paclitaxel 
treatment 

 
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5.2 
Secondary Endpoints 
 Percent change of CA 19-9 response rate,  
 R0 resection rate  
 Overall response rate (ORR)  
 Disease free survival (DFS) 
5.3 
Safety Evaluations 
 Safety and tolerability (adverse events, categorized and graded according to NCI CTC v. 
4.0)  
 Other relevant post-operative complications, including: 
o delayed wound healing 
o wound dehiscence 
o wound infection 
5.4 
Correlative Endpoints 
1) Tissue analyses pre-treatment and post-treatment with standard IHC staining for actin, 
hyaluronic acid staining with binding protein probe, proliferation as measured by ki-67% 
and Phospho-histone H3 (Ph-H3); cell apoptosis as evaluated by IHC stain for cleaved 
caspase 3 (CC3) and Tunel. If limited tissue sample is obtained via the core biopsies, the 
priority of tissue analysis will be as follows: (1) fixed in formalin for H&E and IHC (Ph-
H3; CC3/Tunel; HA binding); (2) fixed in OCT such that IHC with difficult antibodies 
can be done (to potentially obtain mRNA or DNA). 
 
2) Functional MRIs including Dynamic Contrast Enhanced (DCE), Diffusion Weighted 
Imaging (DWI)) will be obtained to evaluate intratumoral perfusion and stromal density 
pre-treatment and post-treatment prior to surgery (excluding patients with pre-existing 
metallic stents). 
 
6 SUBJECT SELECTION 
6.1 
Inclusion Criteria 
1. Greater than or equal to 18 years old. 
2. Histologically confirmed pancreatic adenocarcinoma 
3. One of the following: 
a. Upfront resectable disease. This is defined as:  
i. No arterial tumor contact (celiac axis (CA), superior mesenteric artery 
(SMA), or common hepatic artery (CHA)); AND 

 
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ii. No tumor contact with the superior mesenteric vein (SMV) or portal vein 
(PV), or ≤180° contact without vein contour irregularity. 
b. Borderline resectable disease. There are multiple definitions of borderline 
resectable PDAC including the MD Anderson definition [32] and the criteria 
developed during the Consensus Conference sponsored by the American Hepato-
Pancreato-Biliary Association, Society of Surgical Oncology, and Society for 
Surgery of the Alimentary Tract [33]. Borderline resectable PDAC cases will be 
identified per the definition developed in the currently running inter-group pilot 
trial for borderline resectable pancreatic cancer (NCT01821612). Per this trial, 
borderline resectable PDAC is defined as the presence of any one or more of the 
following on CT or MRI: 
i. An interface between the primary tumor and the superior mesenteric vein 
or portal vein (SMV-PV) measuring ≥ 180° of the circumference of the 
vessel wall 
ii. Short-segment occlusion of the SMV-PV with normal vein above and 
below the level of obstruction that is amenable to resection and venous 
reconstruction 
iii. Short segment interface (of any degree) between tumor and hepatic artery 
with normal artery proximal and distal to the interface that is amenable to 
resection and reconstruction. 
iv. An interface between the tumor and SMA measuring < 180º of the 
circumference of the vessel wall. 
4. Performance status of ECOG of 0-1 
5. No prior treatment for pancreatic cancer 
6. Adequate organ function including: 
a. Bone marrow:  ANC ≥1500/mm3, platelets ≥100,000/mm3 and hemoglobin ≥ 9 
g/dL 
b. Hepatic: Serum total bilirubin ≤1.5 x upper limit of normal (ULN), ALT (SGPT) 
and AST (SGOT) ≤ 2.5 x ULN, Alkaline phosphatase ≤ 2.5X ULN  
c. Renal: Serum creatinine (sCr) ≤ 1.5 x ULN, or creatinine clearance (Ccr) ≥ 40 
mL/min as calculated by the Modified Cockcroft-Gault formula. 
7. Peripheral neuropathy < grade 2 
8. Biliary stents (plastic or metallic) are allowed; however, those patients with metallic 
stents will not undergo the functional MRI correlative component of this study. 
6.2 
Exclusion Criteria 
1. Age younger than 18 years old 
2. Locally advanced (clearly unresectable) or metastatic disease 
3. Known allergy to hyaluronidase 
4. Contraindications to prophylactic dose LMWH, including:  
a. Patients with recent gastrointestinal bleeding,  
b. History of heparin induce thrombocytopenia on LMWH  

 
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c. Subjects with previous severe hemorrhagic events on LMWH 
d. Recent central nervous system bleed, intracranial or spinal lesion at high risk for 
bleeding  
e. Active bleeding (major): more than 2 units transfused in 24 hours  
f. Spinal anesthesia/lumbar puncture  
g. Chronic, clinically significant measurable bleeding > 48 hours   
h. Severe platelet dysfunction (uremia, medications, dysplastic hematopoiesis) 
Recent major operation at high risk for bleeding 
i. Underlying hemorrhagic coagulopathy  
j. High risk for falls (head trauma) 
5. Known status of HIV which is not well-controlled at the time of study eligibility 
6. Untreated Hepatitis B infection  
7. Active infection or antibiotics within 48 hours prior to study 
8. Currently active second primary malignancy or history of malignancy less than 5 years 
prior to the time of study eligibility (Patients with history of skin cancers excluding 
melanoma will be eligible for participation). 
9. Serious medical comorbidities such as New York Heart Association Class III/IV cardiac 
disease, uncontrolled cardiac arrhythmias, myocardial infarction over the past 12 months. 
10. Known, existing uncontrolled coagulopathy. Patients who have had a venous 
thromboembolic event (e.g., pulmonary embolism or deep vein thrombosis) requiring 
anticoagulation are eligible IF: they are appropriately anticoagulated and have not had a 
Grade 2 or greater bleeding episode in the 3 weeks before Day 1. 
11. Current use of warfarin (patients will be eligible if warfarin is discontinued and low-
molecular weight heparin is used instead). 
12. Intolerance to dexamethasone 
13. Prior history of cerebrovascular accident or transient ischemic attack, or pre-existing 
carotid artery disease. 
14. Known pregnancy, nursing women or positive pregnancy test. 
15. Any condition that would preclude informed consent, consistent follow-up and 
compliance for the study participation. 
 
7 CONCURRENT MEDICATIONS 
All subjects should be maintained on the same medications throughout the entire study period, as 
medically feasible, with no introduction of new chronic therapies. 
7.1 
Allowed Medications and Treatments 
Medications Allowed: 
 Medications used for supportive therapy such as anti-emetics, anti-diarrheals, analgesics, 
bisphosphonates and antibiotics are allowed as indicated.  

 
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 Thromboembolic events will be managed with low-molecular weight heparin. 
 In addition to study medication, all subjects will be administered dexamethasone to 
reduce potential musculoskeletal symptoms, which have been reported to be associated 
with PEGPH20. Dexamethasone 8 mg will be administered, preferably orally (PO), 
within 2 hours prior to thebeginning of each PEGPH20/placebo infusion and 8 to 12 
hours after completion of the randomized study medication infusion (total dose 16 mg on 
dosing days). Parenteral administration is allowed if the subject cannot tolerate oral 
dexamethasone. Additional doses of dexamethasone may be given 24 hours prior to 
infusions of randomized study medication or at any other time at the discretion of the 
Investigator based on tolerability. The Investigator may adjust (increase or decrease) the 
dose and/or frequency of dexamethasone based on the clinical need (e.g., tapering off if 
subject is tolerating study medication). 
 At the first occurrence of fever > 38.5C (regardless of neutrophil count), either oral 
levofloxacin (500 mg daily) or amoxicillin/clavulanate (500 mg tid) will be initiated. 
 For febrile neutropenia, interrupt nab-paclitaxel and gemcitabine until fever resolves and 
ANC > 1500 then resume treatment at a reduced dose.  
Medications Prohibited: 
 Warfarin  
 Patients may not be on any therapy for their pancreatic cancer other than the current 
study’s treatment drugs.   
 
8 STUDY TREATMENTS 
8.1 
Study Agent Administration 
Each treatment cycle consists of 28 days as mentioned in Section 4.1.  
PEGPH20 3 ug/kg will be administered intravenously over a 10 minute period (+2 minute 
window, i.e. infusion may be 10-12 minutes) on days 1 and 4 during the one week run-in period. 
Starting cycle 1, PEGPH20 will be administered on days 1, 8 and 15. PEGPH20 will be 
administered 2-4 hours prior to nab-paclitaxel and gemcitabine. 
Nab-paclitaxel 125 mg/m2 will be administered on days 1, 8, 15 of each cycle over 30 minutes. 
It will be administered 2-4 hours after PEGPH20. Nab-paclitaxel will be infused prior to 
gemcitabine. 
Dexamethasone 8 mg will be administered PO 1-2 hours pre-PEGPH20 and PO 8-12 hours 
post-PEGPH20. 

 
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Gemcitabine 1000 mg/m2 will be administered intravenously on days 1, 8, 15 of each cycle over 
30 minutes. Gemcitabine will be administered after nab-paclitaxel. 
Enoxaparin 1 mg/kg subcutaneous daily will be started at the time of initiation of therapy with 
PEGPH20. This will be continued throughout the study participation. Enoxaparin will be stopped 
the day before any biopsy procedure and will resume the day after the procedure.   
8.2 
Formulation of Study Agents 
8.2.1 Nab-paclitaxel 
Abraxane (nab-paclitaxel, nanoparticle albumin-bound paclitaxel), when released as the 
active drug (paclitaxel), blocks cell replication in the G2 mitotic phase by promoting microtubule 
assembly, stabilizing existing microtubules, and inhibiting disassembly of microtubules.  
Binding of abraxane by an albumin-specific receptor (gp60) leads to activation of caveolin-1, a 
protein which mediates internalization of the compound into the endothelial cell and transport to 
the tumor insterstitium. SPARC (Secreted Protein And Rich in Cysteine), a tumor-secreted 
protein, binds albumin, releasing the active drug at the tumor cell membrane, thereby increasing 
its concentration at the target site of action.  
Drug Storage and Stability  
Nab-Paclitaxel (Abraxane) is supplied in single-use 50 mL vials, each vial containing 
paclitaxel (100 mg) and approximately 900 mg human albumin (HA) as a stabilizer. 
Unreconstituted Abraxane should be stored at controlled room temperature (20º to 25º C or 68º 
to 77ºF) in its carton, and should be protected from bright light. Unopened vials of Abraxane are 
stable until the date indicated on the package when stored at the above temperatures in the 
original package. Reconstituted Abraxane should be used immediately, but may be refrigerated 
at 2º to 8ºC (36º to 46 ºF) for a maximum of 8 hours if necessary. If not used immediately, each 
vial of reconstituted suspension should be replaced in the original carton to protect it from bright 
light. Discard any unused portion. Also, after the suspension for infusion reconstituted as 
recommended is stable in an IV bag at room temperature 20º to 25º C (68º to 77ºF) and ambient 
lighting conditions for up to 8 hours if necessary.  
Drug Administration  
The number of vials required will be calculated using the following formula:  
Total number of vials = Total dose / 100 (mg/vial)  
If a fractional number of vials is obtained using this formula, it should be rounded-up to 
the next higher whole number. The vials should be prepared for reconstitution using sterile 
technique. Each Abraxane vial should be reconstituted by injecting 20 mL of 0.9% Sodium 
Chloride Injection, USP or equivalent into each vial over a minimum of 1 minute, using the 
sterile syringe directing the solution flow onto the inside wall of the vial. The 0.9% Sodium 
Chloride Injection, USP solution should not be injected directly onto the lyophilized cake as this 
will result in foaming. Once the injection is complete, the vial should sit for a minimum of 5 

 
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minutes to ensure proper wetting of the lyophilized cake/powder. The vial should be gently 
swirled and/or inverted for at least 2 minutes until complete dissolution of any cake/powder 
occurs. Rapid agitation or shaking will result in foaming. If foaming or clumping occurs, stand 
solution for at least 15 minutes until foam subsides. Each ml of reconstituted product will contain 
5 mg of paclitaxel. Calculate the exact total dosing volume of 5 mg/ml suspension required for 
the patient:  
Dosing volume (ml) = Total dose(mg) / 5 (mg/ml)  
The reconstituted sample should be milky and homogeneous without visible particulates. 
If unsuspended powder is visible, the vial should be gently inverted again to ensure complete 
resuspension, prior to use. Once the exact volume of reconstituted Abraxane has been withdrawn 
from the vials, discard any excess solution left over in accordance with standard operating 
procedures. Further dilution is not necessary. Inject the calculated dosing volume of reconstituted 
Abraxane suspension into an empty sterile, standard PVC IV bag using an injection port. Inject 
perpendicularly into the center of the injection port to avoid dislodging plastic material into the 
IV bag. Administer the calculated dosing volume of reconstituted Abraxane suspension by IV 
infusion over 30 minutes. The use of in-line filters is not necessary. If used, in-line filters with 
pore sizes of < 15μ should not be used. Use within 8 hours of reconstitution.  
Albumin-bound paclitaxel should be administered by IV over 30 minutes.  
Side Effects  
Most common side effects include myelosuppression, nausea/vomiting, diarrhea, 
mucositis, sensory neuropathy, myalgia/arthralgia, infections, hypotension, abnormal ECG 
changes, cough, dyspnea, edema, bilirubin/liver enzyme elevations, allergic reactions, alopecia, 
asthenia. Rare but serious side effects include hypersensitivity reactions and cardiovascular 
events.  
8.2.2 Gemcitabine 
Gemcitabine (2‘-Deoxy-2‘,2‘-difluorocytidine monohydrochloride, Gemzar) exhibits cell 
phase specificity, primarily killing cells undergoing DNA synthesis (S phase) and also blocking 
the progression of cells through the G1/S phase boundary. Gemcitabine is metabolized 
intracellularly by nucleoside kinases to the active diphosphate (dFdCDP) and triphosphate 
(dFdCTP) nucleosides. The cytotoxic effect of gemcitabine is attributed to a combination of two 
actions of the diphosphate and the triphosphate nucleosides, which leads to inhibition of DNA 
synthesis. First, gemcitabine diphosphate inhibits ribonucleotide reductase, which is responsible 
for catalyzing the reactions that generate the deoxynucleoside triphosphates for DNA synthesis. 
Inhibition of this enzyme by the diphosphate nucleoside causes a reduction in the concentrations 
of deoxynucleotides, including dCTP. Second, gemcitabine triphosphate competes with dCTP 
for incorporation into DNA. The reduction in the intracellular concentration of dCTP (by the 
action of the diphosphate) enhances the incorporation of gemcitabine triphosphate into DNA 
(self-potentiation). After the gemcitabine nucleotide is incorporated into DNA, only one 
additional nucleotide is added to the growing DNA strands. After this addition, there is inhibition 

 
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of further DNA synthesis. DNA polymerase epsilon is unable to remove the gemcitabine 
nucleotide and repair the growing DNA strands (masked chain termination). In CEM T 
lymphoblastoid cells, gemcitabine induces internucleosomal DNA fragmentation, one of the 
characteristics of programmed cell death.  
Drug Storage and Stability  
Unreconstituted drug vials are stored at controlled room temperature. Gemcitabine is 
commercially available in 200 mg and 1 gm vials. Reconstituted solution should be stored at 
controlled room temperature and used within 24 hours. Reconstitute the 200 mg vial with 5ml 
and the 1 gm vial with 25 ml preservative free normal saline to make a solution containing 38 
mg/ml. Shake to dissolve. Solutions of gemcitabine should not be refrigerated; crystallization 
may occur. The unused portion should be discarded.  
Drug Administration  
The drug may be administered as prepared above or further diluted with normal saline to a 
minimum concentration of 0.1 mg/ml. Gemcitabine is commonly diluted in 500 ml of saline. The 
drug will be infused over 30 mins. Gemcitabine will be paid for by the patient or his/her 
insurance.  
Side Effects  
Most common side effects include myelosuppression, rash, nausea/vomiting, fever, fatigue, flu-
like symptoms, fluid retention, diarrhea, and transaminitis. Rare but serious side effects include 
pulmonary syndromes, bronchospasm, and hemolytic-uermic syndrome. 
8.2.3 PEGPH20 
The investigational material in PEGPH20 is a PEGylated, neutral-pH-active human 
hyaluronidase PH20 produced by recombinant DNA technology.  Recombinant human 
hyaluronidase PH20 (rHuPH20) degrades HA under physiologic conditions and acts as a 
spreading factor in vivo. 
PEGPH20 is a multi-site PEGylated enzyme generated by conjugating N-hydroxysuccinimidyl 
ester of methoxypoly(ethylene glycol)-butanoic acid (MSBA30K or PEG) and PH20. PH20 and 
PEG are covalently linked via a stable amide bond between PEG and the N-terminal amino 
group or the ε-amino groups present on lysine amino acid side chains of PH20.   
Chemical Name 
PEGPH20 (PEGylated recombinant human hyaluronidase: 36-482-hyaluronoglucosaminidase 
PH20 [human]) 
Structural Formula 
The structure of PEGPH20 is represented in . 

 
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Figure . 
Figure 2: 
Structure of PEGPH20 
 
 
The empirical formula for PEGPH20 is rHuPH20: C2327H3565N589O667S20 (based on amino acid 
sequence) and PEG: C1371H2737NO686 (based on PEG with n = 681).  PEGPH20 is a multi-site 
PEGylated enzyme.  Its measured molecular weight is generally between 100,000 and 
270,000 Da. 
Drug Packaging and Labeling 
The PEGPH20 drug product is supplied as a refrigerated, sterile, single-use, injectable 
liquid. PEGPH20 drug product (clinical test article) is an aqueous solution containing 0.3 mg/mL 
PEGPH20 with 10 mM succinate, 130 mM NaCl, and 10 mM Methionine at a pH of 6.2.  Each 
vial contains 1.2 mL (0.36 mg) of PEGPH20 drug product.  PEGPH20 drug product will be 
packaged in clear, Type I, 2 mL glass vials with a 13 mm chlorobutyl Flurotec® coated stopper 
and 13 mm flip-off overseal.  It should be stored at 2-8°C before use. 
Drug Storage 
PEGPH20 drug product is a liquid formulation and should be stored at 2-8°C before use.  
Stability testing of PEGPH20 drug product was initiated following general International 
Conference on Harmonisation (ICH) guidelines at 5°C ± 3°C, and concurrent stability evaluation 
is ongoing.  The Sponsor will monitor drug stability and provide updates on an ongoing basis. 
Drug Preparation 
PEGPH20 should be stored at 2-8°C prior to use.  Each vial is intended for single use.  
All used and unused study drug must be stored and kept for reconciliation by the study monitor, 
unless clinic policy requires immediate disposal.  If this is the case, the Sponsor should be 
notified in advance, and reconciliation procedures will be agreed upon. Instructions for preparing 
the PEGPH20 can be found in the pharmacy manual. 
Side Effects 

 
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Most common side effect was grade 3 muscle stiffness and pain in preclinical and phase I 
studies. These symptoms were dose and frequency related with the higher doses and twice a 
week dosing causing more muscle stiffness and pain compared to lower doses or once a week 
dosing. Phase I studies reported that 7 days after the discontinuation of PEGPH20, myalgia 
resolved[30]. In addition, they reported that there was no increase in the inflammatory markers 
from the serum of patients who experienced myalgias. With the use of dexamethasone 8mg 1-2 
hours prior to the administration of PEGPH20 and 8-12 hours after the administration of 
PEGPH20, symptoms of myalgia improved.  
Recently, increased rates of venous thromboembolic events (VTE) were reported in the 
Phase II trial investigating the combination of PEGH20 with gemcitabine and nab-paclitaxel. 
Patients treated in the combination arm were reported to have approximately doubled the rate of 
VTE compared to patients treated with gemcitabine and nab-paclitaxel alone. Per the advisory 
board and FDA recommendations, this trial resumed with implementation of prophylactic dosing 
of enoxaparin 1 mg/kg subcutaneous daily in the treatment arm receiving PEGPH20. Due to this 
reported adverse event, patients in the current trial will start receiving a prophylactic dose of 
enoxaparin 1 mg/kg subcutaneous daily at the time of initiation of therapy with PEGPH20. This 
will be continued throughout the study during treatment with PEGPH20.  Daily injections of 
enoxaparin should stop at least 14 days after the last dose of PEGPH20 is administered. Please 
see Appendix 1 for recommended dosing.  Thromboembolic events will be managed with 
therapeutic doses of low-molecular weight heparin.   
Allergic reactions are not considered a likely source of toxicity for this recombinant 
human-derived molecule, and current human experience with PEGPH20 shows that allergic 
reactions during the use of PEGPH20 are uncommon. To date, infusion reactions have been 
observed in less than 5% of subjects treated with PEGPH20 in 
sponsored clinical 
studies. 
 
 
Other potential adverse reactions for PEGPH20 based on cumulative clinical data include 
neutropenia and thrombocytopenia, edema, and rash. 
8.2.4 Rules for Dose Omissions and Modified Schedules 
Gemcitabine, nab-Paclitaxel and PEGPH20 
Day 1 (+/- 1 day) dose missed: 
If the dose held or missed was to be given on Day 1 (+/- 1 day) of the next cycle, that 
next cycle will not be considered to start until the day the first dose is actually administered to 
the patient (i.e., 1-2-3-Rest, X-1-2-3-Rest, etc.). All components of study treatment should be 
held and resumed at the same time. 
Day 8 (+/- 1 day) dose is missed: 
Cycle continues per protocol, with one dose not given (i.e., 1-2-3-Rest, 1-X-3-Rest, 1-2-
3- Rest, etc.). The missed dose will not be made up.  Day 15 is administered as per cycle 
calendar if counts and chemistries permit. Depending on the specific toxicity, PEGPH20 may be 

 
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administered on Day 8 even if gemcitabine/nab-paclitaxel have to be held, or can also be held at 
the discretion of the treating physician. 
Day 15 (+/- 1 day) dose missed: 
That week becomes the week of rest. Next dose (if counts and chemistries permit) 
becomes Day 1 of a new cycle, and the patient is considered to have had a x2q3 (21-day) cycle 
(i.e., 1-2-3-Rest, 1-2-X, 1-2-3-Rest, etc.). Depending on the specific toxicity, PEGPH20 may be 
administered on Day 15 even if gemcitabine/nab-paclitaxel have to be held, or can also be held at 
the discretion of the treating physician. 
Doses will be reduced for hematologic and other non-hematologic toxicities. Dose 
adjustments are to be made according to the system showing the greatest degree of toxicity. 
Toxicities will be graded using the NCI CTCAE Version 4.03. If recurrent toxicities require dose 
modifications below those listed in Tables 1 and 2 below, the patient should be removed from 
study treatment. If patients experience study drug-related toxicities that require all treatment to 
be held for ≥ 14 days from their scheduled dose, they will be discontinued from further 
participation in this study. In special circumstances noted below, one component of study 
treatment may be permanently discontinued but the patient may remain on study. When the dose 
of one or more drugs is reduced due to toxicities, dose re-escalation will not be permitted for the 
duration of study treatment. 
 
 
Table 1. Dose Reductions for Gemcitabine and Nab-paclitaxel 
 
Nab-Paclitaxel 
Gemcitabine 
Starting dose level 
125 mg/m2 
1000 mg/m2 
Dose level -1 
100 mg/m2 
800 mg/m2 
Dose level -2 
75 mg/m2 
600 mg/m2 
 
Table 2. Dose Reductions for PEGPH20 
 
28-day dosing cycle in 
combination with gem/Abrax 
Starting dose level 
3 μg/kg on days 1, 8, and 15 
Dose level -1 
1.6 μg/kg on days 1, 8, and 15 
Dose level -2 
na 
 

 
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During the initial one-week run-in period, PEGPH20 is to be administered at a dose of 3 μg/kg 
on days 1 and 4. Depending on AEs that occur following the day 1 dose (refer to Tables 3 and 4), 
the scheduled day 4 dose can be reduced to 1.6 μg/kg and administered with a delay of up to 7 
days. Patients who cannot receive their second dose of PEGPH20 during this run-in period will 
be removed from study and replaced. 
Doses of study drugs may be held or adjusted as detailed in Tables 3 and Table 4 below. The 
start of a new treatment cycle should be held until ANC >1500 and platelet count > 100,000, and 
until toxicities from the prior cycle have improved to grade 1 or baseline. If the start of a new 
cycle is delayed, all components of study treatment should be held and resumed at the same time. 
Table 3. Dose Modifications for Hematologic Toxicities at the Start of Each Cycle or 
Within a Cycle 
Cycle 
Day 
ANC 
(cells/mm3) 
 
Platelet count (cells/mm3) 
Nab-Paclitaxel, Gemcitabine and 
PEGPH20 
Day 1 
<1500 
OR 
<100,000 
Delay doses until recovery 
Days 8 
and 15 
500 to <1000 
OR 
50,000 to <75,000 
Withhold nab-Paclitaxel and 
gemcitabine; resume at one dose level 
lower once counts adequately recover. 
Continue PEGPH20 at same dose. 
Consider growth factor support. 
 
< 500 
OR 
<50,000 
Withhold all doses (including 
PEGPH20). Resume nab-Paclitaxel 
and gemcitabine at one dose level 
lower, and PEGPH20 at same dose 
level, once counts adequately recover. 
Consider growth factor support. 
Abbreviations: ANC = Absolute Neutrophil Count 
 
Table 4. Dose Modifications for Non-Hematologic Toxicity 
For grade 3 or higher clinically relevant non-hematologic toxicities, treatment cycles will be 
delayed. Therapy may be resumed when the toxicity improves to grade 0-1 (or baseline). If the 
patients are unable to resume therapy within 2 weeks of a planned dose, the will be removed 
from the study. Dose adjustments in subsequent cycles will be made as follows depending on the 
highest grade of toxicity observed in prior cycles. 
 
 
nab-Paclitaxel 
Gemcitabine 
PEGPH20 
Diarrhea 
Grade 1 -2 
Continue at same dose 
Grade 3 
Interrupt until grade 0-1 
1st = Resume at same dose 
2nd = Decrease dose to 
level-1 
Interrupt until grade 0-1 
1st = Resume at same dose 
2nd = Decrease dose to 
level-1 
Continue at same dose 

 
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nab-Paclitaxel 
Gemcitabine 
PEGPH20 
Grade 4 
Interrupt until grade 0-1 
1st = Decrease dose to 
level-1 
Interrupt until grade 0-1 
1st = Resume at same dose 
Interrupt until 
gemcitabine and nab-
paclitaxel resumed* 
Symptomatic management of diarrhea: IV hydration and loperamide. Loperamide can be used at 4 
mg at the first onset of loose stools and then 2 mg every 2 hours until the patient is diarrhea-free 
for at least 12 hours. If control takes longer than 2 days, medical evaluation including relevant 
diagnostic procedures and alternative treatments should be considered. 
Nausea/Vomiting 
Grade 1-2 
Continue at same dose 
Grade 3 
Interrupt until grade 0-1 
1st = Decrease dose to 
level-1 
2nd = Decrease dose to 
level-2 
Interrupt until grade 0-1 
1st = Resume at same dose 
2nd = Decrease dose to 
level-1 
Continue at same dose 
Grade 4 
Interrupt until grade 0-1 
1st = Decrease dose to 
level-1 
2nd = Discontinue study 
treatment 
Interrupt until grade 0-1 
1st = Decrease dose to 
level-1 
2nd = Discontinue study 
treatment 
Interrupt until 
gemcitabine and nab-
paclitaxel resumed* 
Liver Function Tests (AST, ALT, total bilirubin, NOT alkaline phosphatase) 
Grade 1-2 
Continue at same dose 
Grade 3 
Interrupt until grade 0-1 
1st = Decrease dose to 
level-1 
2nd = Resume at same 
dose 
Interrupt until grade 0-1 
1st = Resume at same dose 
2nd = Decrease dose to 
level-1 
Continue at same dose 
Grade 4 
Interrupt until grade 0-1 
1st = Decrease dose to 
level-1 
2nd = Off study 
Interrupt until grade 0-1 
1st = Decrease dose to 
level-1 
2nd = Off study 
Interrupt until 
gemcitabine and nab-
paclitaxel resumed* 
nab-Paclitaxel is not recommended for patients with moderate to severe hepatic impairment and 
the nab-Paclitaxel starting dose of 125mg/m2 is recommended for patients with mild hepatic 
impairment, defined as (total bilirubin greater than ULN and less than or equal to 1.5 X ULN and 
AST less than or equal to 10 X ULN).  Do not administer Abraxane to patients with total bilirubin 
greater than 5 X ULN or AST greater than 10 X ULN. 
 
 
Peripheral neuropathy 
Note: As observed in other clinical trials, ≥ Grade 3 neuropathy related to nab-Paclitaxel is usually seen 
in later phases of the treatment (cycle 6 and beyond). If ≥ Grade 3 neuropathy occurs in early treatment cycles, 
other factors predisposing the patient to neuropathy might be present (e.g., Diabetes, alcohol consumption, 
concomitant medications). To maintain dose intensity during the first 4 treatment cycles, careful consideration 
should be exercised when these predisposing factors are present.  

 
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nab-Paclitaxel 
Gemcitabine 
PEGPH20 
 
Grade 1-2 
Continue at same dose 
 
 
 
 
 
Continue at same dose 
 
 
 
 
 
Continue at same dose 
Grade 3 
Interrupt until grade 0-1 
1st = Decrease dose to 
level-1 
2nd = Decrease dose to 
level-2 
 
Patients experiencing 
peripheral neuropathy that 
requires a delay in 
scheduled nab-Paclitaxel 
dosing for  21 days 
should have their nab-
paclitaxel permanently 
discontinued, but may 
remain on gemcitabine 
and PEGPH20. 
Grade 4 
Interrupt until grade 0-1 
1st = Decrease dose to 
level-2 
2nd = Off study 
 
Patients experiencing 
peripheral neuropathy that 
requires a delay in 
scheduled nab-Paclitaxel 
dosing for  21 days 
should have their nab-
paclitaxel permanently 
discontinued, but may 
remain on gemcitabine 
and PEGPH20. 
Musculoskeletal events (i.e. myalgias) 
Grade 1 
Continue at same dose 
Continue at same dose. 
May give additional 
dexamethasone, muscle 
relaxer, or pain 
medication. 
Grade 2 
Continue at same dose 
Continue at same dose 
OR reduce dose to 1.6 
ug/kg. May give 
additional 
dexamethasone, muscle 
relaxer, or pain 
medication. 
Grade 3-4 
Interrupt until grade 0-1, then resume at one dose level 
lower.  
Hold treatment. If 
resolved to ≤ Grade 2 
within 14 days, may 
resume treatment at 1.6 
µg/kg For Grade 4 events,  

 
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nab-Paclitaxel 
Gemcitabine 
PEGPH20 
patient may be removed 
from the study at the 
discretion of the 
Investigator. If lasts > 14 
days, patients should be 
removed from study 
treatment. 
Cutaneous toxicity 
Grade 1 
Continue at same dose. 
Continue at same dose. 
Grade 2-3 
Continue treatment but reduce to next lower dose level; 
discontinue treatment if toxicity persists 
Continue at same dose. 
Grade 4 
Hold treatment until toxicity resolves to grade 2 or less, 
then reduce to next lower dose level. Discontinue 
treatment if toxicity persists. 
Hold treatment. Resume 
at same dose level when 
gemcitabine/nab-
paclitaxel is resumed. 
Other non-hematologic toxicity 
Grade 1-2 
Continue at same dose 
Continue at same dose 
Grade 3 
Interrupt until grade 0-1; Decrease dose for both drugs 
to level-1 Maximum of two dose reductions allowable. 
Hold treatment if deemed 
potentially related to 
PEGPH20. Treatment 
may resume at the same 
dose level if toxicity is 
resolved to 0-1 (or 
baseline) within 14 days. 
For second event, dose 
should be decreased to 1.6 
µg/kg. 
Grade 4 
Interrupt until grade 0-1; Decrease dose for both drugs 
to level-1. For repeated grade 4 event, discontinue from 
study. 
Hold treatment. 
Treatment may resume at 
1.6 µg/kg if toxicity is 
resolved to 0-1 (or 
baseline) within 14 days. 
* If PEGPH20 dosing is interrupted, daily self-administration of enoxaparin should be continued 
until the patient is off study, for at least 14 days after the last dose of PEGPH20. 
 
Toxicities of special note 
 For any grade 2 or higher thromboembolic event, regardless of relatedness to 
PEGPH20, patients will discontinue PEGPH20 treatment permanently and should be 
treated per NCCN guidelines. Patients may remain on study and continue receiving nab 
paclitaxel and gemcitabine according to standard practice and the treating physician’s 
clinical judgment. 
 

 
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 Patients who develop Grade 3 or higher pulmonary toxicity or hemolytic uremic 
syndrome will be taken off study.  
 
 Hypersensitivity reactions with nab-paclitaxel are rare. If they do occur, minor symptoms 
such as flushing, skin reactions, dyspnea, lower back pain, hypotension, or tachycardia 
may require temporary interruption of the infusion. However, severe reactions, such as 
hypotension requiring treatment, dyspnea requiring bronchodilators, angioedema or 
generalized urticaria require immediate discontinuation of study drug administration and 
aggressive symptomatic therapy. Patients who experience severe hypersensitivity 
reactions to nab-paclitaxel should not be re-challenged. They may continue on study with 
just gemcitabine/PEGPH20. It is not recommended to administer nab-paclitaxel to 
patients with prior hypersensitivity to a taxane. 
 
 All treatment should be held for grade 3 or 4 febrile neutropenia, and not resumed until 
the fever has resolved and ANC ≥ 1500. Gemcitabine and nab-paclitaxel should then be 
resumed at the next lower dose level, while PEGPH20 may be resumed at the same dose 
level as previously. 
 
 Patients who experience any other unexpected Grade 4 toxicities may be taken off study 
at the first or second episode, at the discretion of the investigator, per Table 4 above. 
 
8.3 
Study Drug Accountability 
An accurate and current accounting of the dispensing and return of study drug for each 
subject will be maintained on an ongoing basis by a member of the study site staff.  The study 
monitor will verify these documents throughout the course of the study. 
 
9 STUDY PROCEDURES AND GUIDELINES 
A Schedule of Events representing the required testing procedures to be performed for the 
duration of the study is presented in Section 10. 
Prior to conducting any study-related activities, written informed consent and the Health 
Insurance Portability and Accountability Act (HIPAA) authorization must be signed and dated 
by the subject or subject’s legal representative.  
 
9.1 
Clinical Assessments 
9.1.1 Concomitant Medications 
All concomitant medication and concurrent therapies will be documented at screening/pre-
treatment and on day 1 during the clinical assessment by the physician, and at early termination 

 
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when applicable.  Dose, route, unit frequency of administration, and indication for administration 
and dates of medication will be captured. 
9.1.2 Demographics 
Demographic information (date of birth, gender, race) will be recorded at screening. 
9.1.3 Medical History 
Relevant medical history, including history of current disease, other pertinent respiratory history, 
and information regarding underlying diseases will be recorded at screening. 
9.1.4 Physical Examination 
A complete physical examination will be performed by either the investigator or a qualified 
delegate on day 1 of each cycle.   
9.1.5 Vital Signs 
Body temperature, blood pressure, pulse, oximetry and respirations will be performed after 
resting for 5 minutes on each day that the patient receives PEGPH20, nab-paclitaxel and 
gemcitabine. 
9.1.6 Adverse Events 
Information regarding occurrence of adverse events will be captured throughout the study. 
Duration (start and stop dates), severity/grade, outcome, treatment and relation to study drug will 
be recorded on the case report form (CRF). 
9.2 
Clinical Laboratory Measurements 
9.2.1 Hematology 
Blood will be obtained and sent to clinical hematology lab for a complete blood count 
(hemoglobin, hematocrit, red blood cell count, white blood cell count, white blood cell 
differential, and platelet count). Hematology labs should be drawn within 2 days before each 
infusion (days 1, 8 and 15 of each cycle). 
9.2.2 Blood Chemistry Profile 
Blood will be obtained and sent to clinical chemistry lab for determination of serum albumin, 
alkaline phosphatase, total and direct bilirubin, bicarbonate, BUN, chloride, creatinine, glucose, 
potassium, SGOT [AST], SGPT [ALT], calcium, sodium. Blood chemistry profiles should be 
drawn within 2 days before each infusion (days 1, 8 and 15 of each cycle). 
9.2.3 Pregnancies 
Pregnancies and suspected pregnancies (including a positive pregnancy test regardless of age or 
disease state) of a female subject occurring while the subject is on IP, or within (insert time-
frame which must be at least 28 days of the subject’s last dose of IP), are considered immediately 
reportable events. IP is to be discontinued immediately.  

 
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The Investigator will follow the female subject until completion of the pregnancy.  If the 
outcome of the pregnancy was abnormal (e.g., spontaneous or therapeutic abortion), the 
Investigator should report the abnormal outcome as an AE. If the abnormal outcome meets any 
of the serious criteria, it must be reported as an SAE. 
All neonatal deaths that occur within 28 days of birth should be reported, without regard to 
causality, as SAEs.  
Male Subjects 
If a female partner of a male subject taking investigational product becomes pregnant, the male 
subject taking IP should notify the Investigator, and the pregnant female partner should be 
advised to call their healthcare provider immediately. 
9.2.4 Pregnancy Test 
A urine or serum pregnancy test will be obtained from female subjects who are of childbearing 
age prior to their participation in the study. 
9.3 
Tumor marker 
CA19-9 levels will be measured during screening (prior to initiation of therapy) and then 
monthly (i.e., first day of every cycle). 
9.4 
Research Tissue Analyses 
EUS-guided core biopsies will be obtained at baseline and after a run-in period with PEGPH20 
from the 15 patients enrolled in the run-in/Part 1 of the study.  Three core biopsies via 22-gauge 
“Pro-Core” needle will be obtained and will be submitted for research analyses purposes. Tissue 
will be placed in OCT in the EUS suite and will be picked up by the CC Tissue Bank for 
storage.  Tissue analyses will include standard IHC staining for actin, hyaluronic acid staining 
with binding protein probe, proliferation as measured by ki-67% and Phospho-histone H3 (Ph-
H3); cell apoptosis as evaluated by IHC stain for cleaved caspase 3 (CC3) and Tunel. If limited 
tissue sample is obtained via the core biopsies, the priority of tissue analysis will be as follows: 
(1) fixed in formalin for H&E and IHC (Ph-H3; CC3/Tunel; HA binding); (2) fixed in OCT such 
that IHC with difficult antibodies can be done (to potentially obtain mRNA or DNA). 
9.5 
Functional MRI 
The CT and MR imaging analyses will be at a UC campus. To decrease the impact that 
metal stents may have on the functional MRI results, those patients who have existing metallic 
stents (biliary or enteral) will not partake in the fMRI component of this study.  In addition, to 
reduce variability in results, the DCE-MRI and DWI-MRI will be obtained on the same MR 
machine at a similar time of day as the baseline scan. The DCE-MRI images will be analyzed by 
calculating Ktrans and DWI-MRI images will be analyzed by calculating ADC as described 
elsewhere[41, 44]. We will scan patients in a torso coil on a 3T clinical MR scanner. Imaging 
will include MR diffusion with b-values of 0, 125, and 500 for estimates of perfusion and tumor, 
and dynamic contrast-enhanced MR imaging (DCE-MRI) for measurement of Ktrans, blood 

 
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volume, and blood flow. The region of tumor will be determined by MR imaging in reference to 
the baseline CT scans. The native T1 of the pancreas and liver will be calculated from a series of 
four, 3D, spoiled gradient recalled echo (SPGR) sequences with different flip angles. The 
conventional DCE-MRI will be acquired as a 3D fast spoiled gradient echo sequence, covering 
the targeted areas of the pancreas or liver, at a temporal resolution of 5 sec over 6 minutes after 
the administration of 0.1 mmol/kg gadobenate dimeglumine. DCE-MRI images will be post-
processed using MIStar software (Apollo Medical Imaging, Melbourne, Australia), which allows 
for motion correction to account for any shifts in data. Datasets with artifacts will be eliminated 
before further post processing. After contrast delivery, the new T1 is calculated and is presumed 
to change with the Gd concentration such that [Gd] = (1/T1-1/T10)/R1 where R1 is assumed to be 
4.5 sec-1 mmol/L-1 at 3T. 
 
10 EVALUATIONS BY VISIT 
Patients will have baseline clinical and laboratory screening evaluations within 21 days prior to 
start of protocol therapy. Scans must be performed within 4 weeks prior to initiation of therapy. 
Patients’ clinical assessment may take place on day 1 of each cycle. Laboratory measurements 
should be done within 48 hours prior to the day of treatment with nab-paclitaxel and 
gemcitabine. 
 
 
 
 

 
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Table 5. Timeline of Clinical Assessment, Studies and Treatment 
 
Pre-
Treatment 
Period 
Run-ind 
Period 
(n=15) 
Chemotherapy Cycle 
(n=36) 
End of 
Treatmentn 
1 
2 
3 
4 
PEGPH20 
 
X  
(days 1, 4) 
X 
X 
X 
X 
 
Enoxaparina 1 mg/kg subcutaneous daily 
 
Xa 
X 
X 
X 
X 
 
Dexamethasone 8mg (PO 1-2 hours pre- and PO 
8-12 hours post-PEGPH20) 
 
X  
(days 1, 4) 
X 
X 
X 
X 
 
Nab-paclitaxelk  
 
 
X 
X 
X 
Xl 
 
Gemcitabinek 
 
 
X 
X 
X 
Xl 
 
Informed Consent and Eligibility Review 
X 
 
 
 
 
 
 
Demographics (date of birth, gender, race) 
X 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
Review of Concurrent Medicationsh 
X 
 
X 
X 
X 
X 
X 
Physical Examinationh 
X 
 
X 
X 
X 
X 
X 
Vital Signsb 
X 
 
X 
X 
X 
X 
 
Height 
X 
 
 
 
 
 
 
Weight b 
X 
 
X 
X 
X 
X 
X 
ECOG Performance Statush 
X 
 
X 
X 
X 
X 
X 
CBC with Differentialb 
X 
 
X 
X 
X 
X 
X 
Blood Chemistry Profilec, b 
X 
 
X 
X 
X 
X 
X 
CA 19-9 
X 
 
X 
X 
X 
X 
X 
Plasma HA leveli 
 
X (days 1, 
4) 
X 
X 
X 
X 
 
Hepatitis B serology (Hepatitis B core Antibody, 
Hepatitis B surface Antibody, Hepatitis B surface 
Antigen) 
X 
 
 
 
 
 
 
Serum or urine β-hcG 
X 
 
 
 
 
 
 
Adverse Event Evaluation 
X 
X 
X 
X 
X 
X 
X 
CT/MRI Chest, Abdomen, Pelvis with Contrast  
X j 
 
 
X 
 
X 
(day 
21) 
 
Run-in Cohort: CT/MRI Chest, Abdomen, Pelvis 
with contrast d (n=15) 
 
X 
(day 8 ±1 
day) 
 
 
 
 
 
Run-in Cohort: Functional MRId, (n=15) 
X 
X  
(day 8 ±1 
day) 
 
 
 
X e 
 
Run- in Cohort: EUS-guided Core Biopsyd (n=15) 
X 
X 
(day 8) 
 
 
 
 
 
a. Enoxaparin administration will commence on day 1 of run-in period. Daily self-administration will stop 24 hours before and 
resume 24 hrs after the post-run-in biopsy, and continue throughout neoadjuvant therapy. Enoxaparin will be administered 
subcutaneously (SC) at a dose of 1 mg/kg/day. Rounding of the dose may be done per Institution policy and when using 
prefilled syringes. All efforts should be made to administer the calculated 1 mg/kg dose (± 10%); however, if prefilled syringes 

 
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are used, the treating physician may use medical judgment regarding the appropriate pre-filled syringe. If the rounded dose is 
greater than 20% of the expected dose based on weight, the Sponsor should be consulted. Refer to Table 8 in Appendix 1 for 
examples of rounding based on the expected enoxaparin dose. 
b. These measurements will be obtained before infusion on days 1, 8 and 15 (drawn within 2 days of infusion) while receiving 
chemotherapy. 
c. Basic metabolic panel::  Albumin, alkaline phosphatase, total and direct bilirubin, bicarbonate, BUN, chloride, creatinine, 
glucose, potassium, SGOT [AST], SGPT [ALT], calcium, sodium.  
d. The 7 day PEGPH20 run-in, pre- and post-run-in EUS guided biopsies, and Functional MRIs, and post run-in CT/MRI only 
apply to the 15 patients enrolled in Part I. fMRIs will not be performed in patients with metallic (biliary or enteral) stents. 
e. Functional MRI will be obtained only in those patients who were enrolled in the run-in period and who are found to have 
resectable disease on cycle 4, day 21 CT scan (n=10).  
f. Enoxaparin administration will be stopped 24 hours before surgery. 
h. Physical examination, with concommittant medicines and ECOG, will be performed by the treating MD or qualified 
delegateon day 1 of each cycle of neoadjuvant chemotherapy (or more frequently at the treating provider’s discretion). 
i. EDTA plasma (1-2 mls) to be drawn prior to each PEGPH20 dose. 
j. The diagnostic CT scan or MRI confirming borderline resectability must have been performed within 4 weeks prior to the 
day of the intiation of therapy. 
k. After the first week of loading doses of PEGPH20 alone, the combination therapy of nab-paclitaxel, gemicitabine and 
PEGPH20 should start the following week, preferably on Monday, (but within a 2 days window without protocol violation).  
The allowable window for all subsequent chemotherapy treatment timepoints is +/- 1 day. 
l. Surgery should be scheduled no earlier than 2 weeks and, ideally, no later than 4 weeks post-neoadjuvant therapy.  
Scheduling of surgery is at the discretion of the physician according to the clinical condition of the patient. 
m. Adjuvant chemotherapy should start no earlier than 8 weeks and no later than 12 weeks post-surgery. Choice of therapy 
will be made according to the treating MD’s discretion. 
n. For patients having surgery, End of Treatment assessments should be performed post-surgery. 
11 ADVERSE EXPERIENCE REPORTING AND DOCUMENTATION 
An adverse event (AE) is any untoward medical occurrence in a clinical investigation of a patient 
administered a pharmaceutical product and that does not necessarily have a causal relationship 
with the treatment.  An AE is therefore any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom or disease temporally associated with the administration 
of an investigational product, whether or not related to that investigational product.  An 
unexpected AE is one of a type not identified in nature, severity, or frequency in the current 
Investigator’s Brochure or of greater severity or frequency than expected based on the 
information in the Investigator’s Brochure. 
The Investigator and the study team will record any occurrences of AEs reported during 
conversations with the patients or their family members or care providers..  This will occur from 
the signing of the informed consent to 28 days after the last dose of study drug, or longer if the 
PI deems the event is related to the drug. Adverse events will be recorded in the patient CRF.  
Adverse events will be described by duration (start and stop dates and times), severity, outcome, 
treatment and relation to study drug, or if unrelated, the cause. 
AE Severity 
The National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE) 
Version 4.0 should be used to assess and grade AE severity, including laboratory abnormalities 
judged to be clinically significant. The modified criteria can be found in the study manual.  If the 
experience is not covered in the modified criteria, the guidelines shown in Table 5 below should 
be used to grade severity.  It should be pointed out that the term “severe” is a measure of 
intensity and that a severe AE is not necessarily serious. 
 

 
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IND Annual Reports 
Since the FDA has granted an IND number, it is a requirement of 21 CFR 312.33, that an annual 
report is provided to the FDA within 60-days of the IND anniversary date.  21 CRF 312.33 
provides the data elements that are to be submitted in the report.  The Annual Report should be 
filed in the study's Regulatory Binder, and a copy provided 
 supporter of this 
study as follows. 
 
 
 
 
 
Table 6.  AE Severity Grading 
Severity (Toxicity Grade) 
Description 
Mild (1) 
Transient or mild discomfort; no limitation in activity; no medical 
intervention or therapy required. The subject may be aware of the sign 
or symptom but tolerates it reasonably well. 
Moderate (2) 
Mild to moderate limitation in activity, no or minimal medical 
intervention/therapy required. 
Severe (3) 
Marked limitation in activity, medical intervention/therapy required 
hospitalizations possible. 
Life-threatening (4) 
The subject is at risk of death due to the adverse experience as it 
occurred. This does not refer to an experience that hypothetically 
might have caused death if it were more severe. 
Death related to adverse events 
(5) 
While the subject is on study, death attributed to any cause will be 
reported. 
 
AE Relationship to Study Drug 
The relationship of an AE to the study drug should be assessed using the following the guidelines 
in NCI CTCAE v. 4.03. 
Table 7.  AE Relationship to Study Drug 
Relationship 
to Drug 
Comment 

 
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Definitely 
Previously known toxicity of agent; or an event that follows a reasonable temporal 
sequence from administration of the drug; that follows a known or expected response 
pattern to the suspected drug; that is confirmed by stopping or reducing the dosage of 
the drug; and that is not explained by any other reasonable hypothesis. 
Probably 
An event that follows a reasonable temporal sequence from administration of the 
drug; that follows a known or expected response pattern to the suspected drug; that is 
confirmed by stopping or reducing the dosage of the drug; and that is unlikely to be 
explained by the known characteristics of the subject’s clinical state or by other 
interventions. 
Possibly 
An event that follows a reasonable temporal sequence from administration of the 
drug; that follows a known or expected response pattern to that suspected drug; but 
that could readily have been produced by a number of other factors. 
Unrelated 
An event that can be determined with certainty to have no relationship to the study 
drug. 
 
11.1 
Serious Adverse Experiences (SAE) 
An SAE is defined as any AE occurring at any dose that results in any of the following 
outcomes: 
 
death 
 
a life-threatening adverse experience 
 
inpatient hospitalization or prolongation of existing hospitalization 
 
a persistent or significant disability/incapacity 
 
a congenital anomaly/birth defect  
 
Other important medical events (e.g. secondary cancer, etc.) may also be considered an SAE 
when, based on appropriate medical judgment, they jeopardize the subject or require intervention 
to prevent one of the outcomes listed.  
 
11.1.1 Serious Adverse Experience Reporting 
Study sites will document all SAEs that occur (whether or not related to study drug) per UCSF 
IRB Guidelines. The collection period for all SAEs will begin after informed consent is obtained 
and end after procedures for the final study visit have been completed and at 28 days after the 
last dose of study drug or longer if the PI determines the event is related to the study drug. 
 
In accordance with the standard operating procedures and policies of the local Institutional 
Review Board (IRB)/Independent Ethics Committee (IEC), the site investigator will report SAEs 
to the IRB/IEC.   
 

 
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Expedited Reporting  
 
Reporting to the UCSF Data and Safety Monitoring Committee (DSMC)  
If a death occurs during the treatment phase of the study or within 30 days after the last 
administration of the study drug(s) and it is determined to be related either to the study drug(s) or 
to a study procedure, the Investigator or his/her designee must notify the DSMC Chair (or 
qualified alternate) within 1 business day of knowledge of the event. The contact may be by 
phone or e-mail.  
 
Reporting to UCSF’s Institutional Review Board (IRB)  
The Study Chair must report events meeting the IRB definition of “Unanticipated Problem” (UP) 
within 10 business days of his/her awareness of the event.  
Guidance on Adverse Event Reporting to the IRB is available online at the UCSF Human 
Research Protection Program website.  
 
Expedited Reporting to the Food and Drug Administration (FDA) 
 
As this study is being conducted under an Investigational New Drug Application (IND), the 
Sponsor-Investigator is responsible for determining whether or not the suspected adverse 
reaction meets the criteria for expedited reporting in accordance with Federal Regulations (21 
CFR §312.32).  
The Investigator must report in an IND safety report any suspected adverse reaction that is both 
serious and unexpected. The Sponsor-Investigator needs to ensure that the event meets all three 
definitions:  
 Suspected adverse reaction  
 Serious  
 Unexpected 
If the adverse event does not meet all three of the definitions, it should not be submitted as an 
expedited IND safety report.  
 
The timeframe for submitting an IND safety report to FDA is no later than 15 calendar days 
after the Investigator determines that the suspected adverse reaction qualifies for reporting (21 
CFR 312.32(c)(1)).  
 
Any unexpected fatal or life-threatening suspected adverse reaction must be reported to FDA no 
later than 7 calendar days after the Investigator’s initial receipt of the information (21 CFR 
312.32(c)(2)).  
 
Any relevant additional information that pertains to a previously submitted IND safety report 
must be submitted to FDA as a Follow-up IND Safety Report without delay, as soon as the 
information is available (21 CFR 312.32(d)(2)).  
 
The investigator (or designee) should prepare Form FDA 3500A (MedWatch) detailing the 
event, and contact the Institutional Trials Unit for assistance in the preparation of the IND Safety 
Report.  

 
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11.1.2 Reporting of Serious Adverse Events to Halozyme 
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the patient 
has provided informed consent and during the study period will be reported to 
 within 
24 hours of learning of its occurrence. SAEs will be reported to 
 by completed SAE 
Form or MedWatch 3500A form via email at
.  
The form should include a description of the event, subject number/initials, criteria for 
seriousness, severity, assessment of relationship to study drug(s), whether the event was 
expected or unexpected per the Investigator’s Brochure or package insert, and other available 
information relevant to the event.  Any new information about a previously reported SAE must 
also be sent to Halozyme within 24 hours of the initial awareness.  The investigator must also 
provide 
 with a copy (MedWatch 3500A form) of any FDA submissions (expedited 7-
Day or 15-Day initial and follow-up safety reports) within 24 hours of submission.   
Thromboembolic events will be considered Adverse Event of Special Interest (AESI) and will 
also be reported
at the above number or email. AESI will be reported using an 
AESI form. 
11.2 
Data and Safety Monitoring Committee (DSMC) Contacts  
  
 
  
  
 
  
 
 
 
 
 
 
 
 
 
 
12 DISCONTINUATION AND REPLACEMENT OF SUBJECTS 
12.1 
Early Discontinuation of Study Drug  
A subject may be discontinued from study treatment at any time if the subject or the investigator 
feels that it is not in the subject’s best interest to continue.  The following is a list of possible 
reasons for study treatment discontinuation: 
 Subject withdrawal of consent  
 Subject is not compliant with study procedures 
 Adverse event that in the opinion of the investigator would be in the best interest of the 
subject to discontinue study treatment. This includes unexpected delay in wound healing, 
development of wound dehiscence or pancreatic anastomotic leak. 
 Protocol violation requiring discontinuation of study treatment 
 Lost to follow-up 
 Sponsor request for early termination of study 
 Positive pregnancy test (females) 
 Initiation of other anticancer therapy 

 
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 Development of intercurrent medical condition or need for concomitant treatment that 
precludes further safe participation in the trial such as the occurrence of any Grade 
thromboembolic event. 
If a subject is withdrawn from treatment due to an adverse event, the subject will be followed 
and treated by the Investigator until the abnormal parameter or symptom has resolved or 
stabilized.   
All subjects who discontinue study treatment should come in for an early discontinuation visit as 
soon as possible and then should be encouraged to complete all remaining scheduled visits and 
procedures. 
All subjects are free to withdraw from participation at any time, for any reason, specified or 
unspecified, and without prejudice. 
Reasonable attempts will be made by the investigator to provide a reason for subject 
withdrawals.  The reason for the subject’s withdrawal from the study will be specified in the 
subject’s source documents Refer to Section 9 for early termination procedures. 
12.2 
Withdrawal of Subjects from the Study 
A subject may be withdrawn from the study at any time if the subject or the investigator feels 
that it is not in the subject’s best interest to continue.   
All subjects are free to withdraw from participation at any time, for any reason, specified or 
unspecified, and without prejudice. 
Reasonable attempts will be made by the investigator to provide a reason for subject 
withdrawals.  The reason for the subject’s withdrawal from the study will be specified in the 
subject’s source documents.  As noted above, subjects who discontinue study treatment early 
(i.e., they withdraw prior to visit 2) should have an early discontinuation visit. Refer to Section 9 
for early termination procedures.  Subjects who withdraw after first cycle with study therapy but 
prior to second treatment cycle should be encouraged to come in for a final visit (and the 
procedures to be followed would include those for their next scheduled visit).   
12.3 
Replacement of Subjects 
Patients will be included in the primary AE evaluation if the full 28-day treatment cycle is 
completed. In the event that a patient is unable to complete the 28-day cycle unrelated to 
treatment toxicity, this patient will be removed from study and will be replaced for primary MTD 
evaluation. In the event that a patient withdraws from study due to treatment-related toxicity, this 
patient will be included in the AE evaluation for this study and will not be replaced.   
 
13 PROTOCOL VIOLATIONS 
A protocol violation occurs when the subject or the investigator fails to adhere to significant 
protocol requirements affecting the inclusion, exclusion, subject safety and primary endpoint 
criteria.  Protocol violations for this study include, but are not limited to, the following: 
 Failure to meet inclusion/exclusion criteria 

 
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 Use of a prohibited concomitant medication 
Failure to comply with Good Clinical Practice (GCP) guidelines will also result in a protocol 
violation. The investigator will determine if a protocol violation will result in withdrawal of a 
subject. 
When a protocol violation occurs, it will be discussed with the investigator and a Protocol 
Violation Form detailing the violation will be generated. A copy of the form will be filed in the 
site’s regulatory binder. 
 
14 STATISTICAL METHODS AND CONSIDERATIONS 
Prior to the analysis of the final study data, a detailed Statistical Analysis Plan (SAP) will be 
written describing all analyses that will be performed.  The SAP will contain any modifications 
to the analysis plan described below.   
14.1 
Data Sets Analyzed 
All eligible patients who are enrolled into the study and receive at least one complete, 28-day 
cycle of the study drugs will be included in the safety analysis. If the patient withdraws from the 
study prior to completing the first cycle of chemotherapy secondary to reasons other than toxicity 
related to the study therapy, they will not be included in the primary analysis. However, if the 
patients’ enrollment in the trial is terminated secondary to toxicity secondary to the study drugs, 
they will be evaluated as having an AE and will be included in the analyses. 
In addition, the patients who have received at least 2 complete, 28-day cycles of study drugs will 
be included in the secondary analyses as they will have had monthly CA 19-9 measurements and 
restaging scans which would be obtained after 8 weeks of therapy.  
14.2 
Demographic and Baseline Characteristics 
The following demographic variables at screening will be summarized: race, gender, age, height 
and weight. 
14.3 
Analysis of Primary Endpoint 
The primary endpoint of the study is to evaluate development of clinically relevant pancreatic 
fistula in the post-operative period after neoadjuvant treatment with PEG, gemcitabine and nab-
paclitaxel. The co-primary endpoint is to evaluate pathologic complete response after 
neoadjuvant PEG, gemcitabine and nab-paclitaxel treatment. Descriptive statistics with 
frequency and proportion will be used to evaluate the primary endpoints.  
 
14.4 
Analysis of Secondary Endpoint 
Secondary endpoints include early efficacy as measured by percent change of CA 19-9 response 
rate, R0 resection rate, overall response rate (ORR) and disease free survival (DFS). Descriptive 

 
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statistics with frequency and proportion will be used to analyze the CA19-9 response rate and 
ORR. Kaplan-Meier methods will be used to analyze DFS with median and 95% CI. 
 
14.5 
Analyses of the Correlative Studies  
Tissue Analyses: 
We will examine the tissue from baseline to post-therapy at the time of surgery. We will 
use descriptive statistics and graphical displays to compare the percent change in stromal 
depletion overall and to describe the association with cell proliferation and death.  
 
 
Imaging Studies: 
The images will be analyzed using MIStar software 
 
 using a modified Tofts model. We will explore the percent change in Ktrans and ADC 
from baseline to post-therapy as reported from the DCE-MRI and DWI-MRI, respectively, using 
descriptive statistics. Due to substantial interscan variability, a 50% change in DWI or DCE 
parameters is considered significant. 
14.6 
Additional Stopping Rules for Safety 
In order to ensure patient safety, this trial includes early stopping rules in the event of 
unexpected postoperative complications such as development of pancreatic fistula. Two interim 
safety assessments will be performed when the first 7 and 15 evaluable patients are enrolled in 
the study. If three out of first 7 patients or four out of first 15 patients show unexpected post-
operative complications with delayed wound healing, development of wound dehiscence, wound 
infection or pancreatic fistula, this trial will be stopped. The early stopping rules of declaring the 
trial unsafe based on assumed postoperative complications of < 11% and type I alpha of 10% are 
described in Table 9.  
 
Table 9. Early Stopping Criteria (assuming %complications < 11%) 
 
# of evaluable patients enrolled 
7 
15 
Alpha (Type I error rate) 
10% 
10% 
5% 
# of post-op complications 
3 
4 
5 
 
Furthermore, the development of venous thromboembolic events (DVT and/or PE) or arterial 
thromboembolic events during the preoperative treatment period may affect the safety and timing 
of surgery. Therefore, at the same interim assessment time points as above, we will consider the 
development of VTE/ATEs in 3 or more of the first 7 patients, or 4 or more of the first 15 
patients, occurring during the preoperative treatment period through one week postoperatively, 
as a signal to stop the trial early.  

 
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15 DATA COLLECTION, RETENTION AND MONITORING 
15.1 
Data Collection Instruments 
The Investigator will prepare and maintain adequate and accurate source documents designed to 
record all observations and other pertinent data for each subject treated with the study drug.   
Study personnel will enter data from source documents corresponding to a subject’s visit into the 
protocol-specific electronic Case Report Form (eCRF) OR paper CRF when the information 
corresponding to that visit is available.   
For eCRFs: If a correction is required for an eCRF, the time and date stamps track the person 
entering or updating eCRF data and creates an electronic audit trail.  For paper CRFs:  If a 
correction is made on a CRF, the study staff member will line through the incorrect data, write in 
the correct data and initial and date the change. 
The Investigator is responsible for all information collected on subjects enrolled in this study.  
All data collected during the course of this study must be reviewed and verified for completeness 
and accuracy by the Investigator.  A copy of the CRF will remain at the Investigator’s site at the 
completion of the study. 
15.2 
Data Management Procedures 
The data will be entered into a validated database.  The Data Management group will be 
responsible for data processing, in accordance with procedural documentation.  Database lock 
will occur once quality assurance procedures have been completed. 
All procedures for the handling and analysis of data will be conducted using good computing 
practices meeting FDA guidelines for the handling and analysis of data for clinical trials. 
15.3 
Data Quality Control and Reporting 
After data have been entered into the study database, a system of computerized data validation 
checks will be implemented and applied to the database on a regular basis. For EDC studies: 
Queries are entered, tracked, and resolved through the EDC system directly.  For paper studies: 
Query reports (Data Clarification Requests) pertaining to data omissions and discrepancies will 
be forwarded to the Investigators and study monitors for resolution.  The study database will be 
updated in accordance with the resolved queries.  All changes to the study database will be 
documented. 
15.4 
Archival of Data 
The database is safeguarded against unauthorized access by established security procedures; 
appropriate backup copies of the database and related software files will be 
maintained.  Databases are backed up by the database administrator in conjunction with any 
updates or changes to the database.   
At critical junctures of the protocol (e.g., production of interim reports and final reports), data for 
analysis is locked and cleaned per established procedures. 

 
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15.4.1 Availability and Retention of Investigational Records 
The Investigator must make study data accessible to the monitor, other authorized 
representatives of the Sponsor (or designee), IRB/IEC, and Regulatory Agency (e.g., FDA) 
inspectors upon request.  A file for each subject must be maintained that includes the signed 
Informed Consent, HIPAA Authorization and Assent Form and copies of all source 
documentation related to that subject.  The Investigator must ensure the reliability and 
availability of source documents from which the information on the CRF was derived. 
All study documents (patient files, signed informed consent forms, copies of CRFs, Study File 
Notebook, etc.) must be kept secured for a period of two years following marketing of the 
investigational product or for two years after centers have been notified that the IND has been 
discontinued.  There may be other circumstances for which the investigator is required to 
maintain study records and, therefore, the investigator should be contacted prior to removing 
study records for any reason. 
15.5 
Monitoring 
Data and Safety Monitoring Plan for Multicenter Institutional Study (Phase 2 or 3 
Institutional Study) 
 
The UCSF Helen Diller Family Comprehensive Cancer Center (HDFCCC) Data and Safety 
Monitoring Committee (DSMC) is responsible for monitoring data quality and subject safety for 
all HDFCCC institutional clinical studies.  A summary of DSMC activities for this study 
includes:  
 
Review of subject data 
 
Review of suspected adverse reactions considered “serious” 
 
Monthly monitoring (depending on study accrual) 
 
Minimum of a yearly regulatory audit 
Monitoring and Reporting Guidelines 
All institutional Phase 2 or 3 therapeutic studies are designated with a moderate risk assessment. 
The data is monitored every six months, with twenty percent of the subjects monitored (or at 
least three subjects if the calculated value is less than three). 
The UCSF Coordinating Center provides administration, data management, and organizational 
support for the participating sites in the conduct of a multicenter clinical trial. The UCSF 
Coordinating Center will also coordinate quarterly conference calls with the participating sites to 
communicate the review of adverse events, safety data, and other study matters. 
The Principal Investigator at the UCSF Coordinating Center will hold the role of Study Chair. 
The Study Chair is responsible for the overall conduct of the study and for monitoring its safety 
and progress at all participating sites. The Study Chair will conduct continuous review of data 
and subject safety and discuss each subject’s treatment at monthly UCSF Site Committee 
meetings. The discussions are documented in the UCSF Site Committee meeting minutes. 
 
Multicenter communication 
 

 
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The UCSF Coordinating Center provides administration, data management, and organizational 
support for the participating sites in the conduct of a multicenter clinical trial.  The UCSF 
Coordinating Center will also coordinate, at minimum, monthly conference calls with the 
participating sites at the completion of each cohort or more frequently as needed to discuss risk 
assessment.  The following issues will be discussed as appropriate: 
 
 
Enrollment information  
 
Adverse events (i.e. new adverse events and updates on unresolved adverse events 
and new safety information) 
 
Protocol violations 
 
Other issues affecting the conduct of the study 
Adverse events reporting to the DSMC will include reports from both the UCSF Coordinating 
Center, as well as the participating sites.  The DSMC will be responsible for monitoring all data 
entered in OnCore® at the UCSF Coordinating Center and the participating sites.  The data (i.e. 
copies of source documents) from the participating sites will be sent electronically or faxed over 
to the UCSF Coordinating Center prior to the monitoring visits in order for the DSMC to monitor 
the participating site’s compliance with the protocol, patient safety, and to verify data entry. 
 
Adverse Event Review and Monitoring 
Adverse Event Monitoring 
 
All Grade 3-5 Adverse Events, whether or not unexpected, and whether or not considered to be 
associated with the use of study drug, will be entered into OnCore®, UCSF’s Clinical Trial 
Management System. 
 
All Grade 3-5 adverse events entered into OnCore® will be reviewed on a monthly basis at the 
UCSF Site Committee meetings. All clinically significant adverse events must be reported to the 
UCSF Coordinating Center by the participating sites within 10 business days of becoming aware 
of the event or during the next scheduled quarterly conference call, whichever is sooner. The 
UCSF Site Committee will review and discuss the selected toxicity, the toxicity grade, and the 
attribution of relationship of the adverse event to the administration of the study drug(s) from the 
UCSF Coordinating Center and the participating sites. 
In addition, all suspected adverse reactions considered “serious” must be entered in OnCore® 
and reported to the UCSF Coordinating Center within 1 business day. The suspected adverse 
reactions considered “serious” will be reviewed and monitored by the Data and Safety 
Monitoring Committee on an ongoing basis and discussed at the DSMC meeting, which take 
place every six (6) weeks. 
 
If a death occurs during the treatment phase of the study or within 30 days after the last 
administration of the study drug(s) and is determined to be related either to the investigational 
drug or any research related procedure, the Study Chair at the UCSF Coordinating Center or the 
assigned designee must be notified within 1 business day from the participating site(s) and the 
Study Chair must then notify the DSMC Chair or qualified alternate within 1 business day of this 
notification. The contact may be by phone or e-mail. 

 
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Increase in Adverse Event Rates 
 
If an increase in the frequency of Grade 3 or 4 adverse events (above the rate reported in the 
Investigator Brochure or package insert), the Study Chair at the UCSF Coordinating Center is 
responsible for notifying the DSMC at the time the increased rate is identified.  The report will 
indicate if the incidence of adverse events observed in the study is above the range stated in the 
Investigator Brochure or package insert. 
 
If at any time the Study Chair stops enrollment or stops the study due to safety issues, the DSMC 
Chair and DSMC Manager must be notified within 1 business day via e-mail.  The DSMC must 
receive a formal letter within 10 business days and the CHR must be notified. 
 
Data and Safety Monitoring Committee Contacts: 
 
  
 
  
  
 
  
 
 
 
 
 
 
 
 
 
 
 
15.5.1 Record Keeping and Record Retention 
The Principal Investigator is required to maintain adequate records of the disposition of the drug, 
including dates, quantity, and use by subjects, as well as written records of the disposition of the 
drug when the study ends.   
The Principal Investigator is required to prepare and maintain adequate and accurate case 
histories that record all observations and other data pertinent to the investigation on each 
individual administered the investigational drug or employed as a control in the investigation. 
Case histories include the case report forms and supporting data including, for example, signed 
and dated consent forms and medical records including, for example, progress notes of the 
physician, the individual's hospital chart(s), and the nurses' notes. The case history for each 
individual shall document that informed consent was obtained prior to participation in the study. 
Study documentation includes all CRFs, data correction forms or queries, source documents, 
Sponsor-Investigator correspondence, monitoring 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. 
In accordance with FDA regulations, the investigator shall retain records for a period of 2 years 
following the date a marketing application is approved for the drug for the indication for which it 
is being investigated; or, if no application is to be filed or if the application is not approved for 
such indication, until 2 years after the investigation is discontinued and FDA is notified. 

 
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16 ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS 
The study will be conducted according to the Declaration of Helsinki, Protection of Human 
Volunteers (21 CFR 50), Institutional Review Boards (21 CFR 56), and Obligations of Clinical 
Investigators (21 CFR 312). 
To maintain confidentiality, all laboratory specimens, evaluation forms, reports and other records 
will be identified by a coded number and initials only.  All study records will be kept in a locked 
file cabinet and code sheets linking a patient’s name to a patient identification number will be 
stored separately in another locked file cabinet.  Clinical information will not be released without 
written permission of the subject, except as necessary for monitoring by the FDA.  The 
Investigator must also comply with all applicable privacy regulations (e.g., Health Insurance 
Portability and Accountability Act of 1996, EU Data Protection Directive 95/46/EC). 
16.1 
Protocol Amendments 
Any amendment to the protocol will be written by the investigator.  Protocol amendments cannot 
be implemented without prior written IRB/IEC approval except as necessary to eliminate 
immediate safety hazards to patients.  A protocol amendment intended to eliminate an apparent 
immediate hazard to patients may be implemented immediately, provided the IRBs are notified 
within five working days. 
16.2 
Institutional Review Boards and Independent Ethics Committees 
The protocol and consent form will be reviewed and approved by the IRB/IEC of each 
participating center and Halozyme prior to study initiation.  Serious adverse experiences 
regardless of causality will be reported to the IRB/IEC in accordance with the standard operating 
procedures and policies of the IRB/IEC, and the Investigator will keep the IRB/IEC informed as 
to the progress of the study.  The Investigator will obtain assurance of IRB/IEC compliance with 
regulations. 
Any documents that the IRB/IEC may need to fulfill its responsibilities (such as protocol, 
protocol amendments, Investigator’s Brochure, consent forms, information concerning patient 
recruitment, payment or compensation procedures, or other pertinent information) will be 
submitted to the IRB/IEC.  The IRB/IECs written unconditional approval of the study protocol 
and the informed consent form will be in the possession of the Investigator before the study is 
initiated.  The IRB/IECs unconditional approval statement will be transmitted by the Investigator 
to Halozyme Therapeutics prior to the shipment of study supplies to the site.  This approval must 
refer to the study by exact protocol title and number and should identify the documents reviewed 
and the date of review. 
Protocol and/or informed consent modifications or changes may not be initiated without prior 
written IRB/IEC approval except when necessary to eliminate immediate hazards to the patients 
or when the change(s) involves only logistical or administrative aspects of the study.  Such 
modifications will be submitted to the IRB/IEC and written verification that the modification 
was submitted and subsequently approved should be obtained.   
The IRB/IEC must be informed of revisions to other documents originally submitted for review; 
serious and/or unexpected adverse experiences occurring during the study in accordance with the 

 
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standard operating procedures and policies of the IRB; new information that may affect 
adversely the safety of the patients of the conduct of the study; an annual update and/or request 
for re-approval; and when the study has been completed. 
16.3 
Informed Consent Form 
Informed consent will be obtained in accordance with the Declaration of Helsinki, ICH GCP, US 
Code of Federal Regulations for Protection of Human Subjects (21 CFR 50.25[a,b], CFR 50.27, 
and CFR Part 56, Subpart A), the Health Insurance Portability and Accountability Act (HIPAA, 
if applicable), and local regulations. 
The Investigator will prepare the informed consent form, assent and HIPAA authorization prior 
to submission to the IRB/IEC.  The consent form generated by the Investigator must be 
acceptable to the Sponsor and be approved by the IRB/IEC.  The written consent document will 
embody the elements of informed consent as described in the International Conference on 
Harmonisation and will also comply with local regulations. The Investigator will send an 
IRB/IEC-approved copy of the Informed Consent Form to the Sponsor (or designee) for the 
study file. 
A properly executed, written, informed consent will be obtained from each subject prior to 
entering the subject into the trial.  Information should be given in both oral and written form and 
subjects (or their legal representatives) must be given ample opportunity to inquire about details 
of the study.  If appropriate and required by the local IRB/IEC, assent from the subject will also 
be obtained.  If a subject is unable to sign the informed consent form (ICF) and the HIPAA 
authorization, a legal representative may sign for the subject.   A copy of the signed consent form 
(and assent) will be given to the subject or legal representative of the subject and the original will 
be maintained with the subject’s records. 
16.4 
Regulatory Documentation 
Prior to implementing this protocol at UCSF HDFCCC, the protocol, informed consent form, 
HIPAA authorization and any other information pertaining to participants must be approved by 
the UCSF IRB.  Prior to implementing this protocol at the participating sites, approval for the 
UCSF IRB approved protocol must be obtained from the participating site’s IRB.  
The following documents must be provided to UCSF HDFCCC before the participating site can 
be initiated and begin enrolling participants:  
 Participating Site IRB approval(s) for the protocol, appendices, informed consent form 
and HIPAA authorization  
 Participating Site IRB approved consent form  
 Participating Site IRB membership list  
 Participating Site IRB’s Federal Wide Assurance number and OHRP Registration number  
 Curriculum vitae and medical license for each investigator and consenting professional  
 Documentation of Human Subject Research Certification training for investigators and 
key staff members at the Participating Site  
 Participating site laboratory certifications and normals  
Upon receipt of the required documents, UCSF HDFCCC will formally contact the site and grant 
permission to proceed with enrollment. 

 
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16.5 
Coordinating Center Documentation of Distribution 
It is the responsibility of the Study Chair to maintain adequate files documenting the distribution 
of study documents as well as their receipt (when possible). The HDFCCC recommends that the 
Study Chair maintain a correspondence file and log for each segment of distribution (e.g., FDA, 
drug manufacturer, participating sites, etc.). 
Correspondence file: should contain copies (paper or electronic) of all protocol versions, cover 
letters, amendment outlines (summary of changes), etc., along with distribution documentation 
and (when available) documentation of receipt. 
Correspondence log: should be a brief list of all documents distributed including the date sent, 
recipient(s), and (if available) a tracking number and date received. 
At a minimum, the Study Chair must keep documentation of when and to whom the protocol, its 
updates and safety information are distributed. 
16.6 
Publications 
The preparation and submittal for publication of manuscripts containing the study results shall be 
in accordance with a process determined by mutual written agreement among the Halozyme and 
participating institutions.  The publication or presentation of any study results shall comply with 
all applicable privacy laws, including, but not limited to, the Health Insurance Portability and 
Accountability Act of 1996. 
16.7 
Investigator Responsibilities 
By signing the Agreement of Investigator form, the Investigator agrees to: 
1. Conduct the study in accordance with the protocol and only make changes after notifying 
the Sponsor (or designee), except when to protect the safety, rights or welfare of subjects. 
2. Personally conduct or supervise the study (or investigation). 
3. Ensure that the requirements relating to obtaining informed consent and IRB review and 
approval meet federal guidelines, as stated in § 21 CFR, parts 50 and 56. 
4. Report to the Sponsor or designee any AEs that occur in the course of the study, in 
accordance with §21 CFR 312.64. 
5. Ensure that all associates, colleagues and employees assisting in the conduct of the study are 
informed about their obligations in meeting the above commitments. 
6. Maintain adequate and accurate records in accordance with §21 CFR 312.62 and to make 
those records available for inspection with the Sponsor (or designee). 
7. Ensure that an IRB that complies with the requirements of §21 CFR part 56 will be 
responsible for initial and continuing review and approval of the clinical study. 
8. Promptly report to the IRB,
, (or designee) all changes in the 
research activity and all unanticipated problems involving risks to subjects or others (to 
include amendments and IND safety reports). 

 
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9. Seek IRB approval before any changes are made in the research study, except when 
necessary to eliminate hazards to the patients/subjects. 
10. Comply with all other requirements regarding the obligations of clinical investigators and all 
other pertinent requirements listed in § 21 CFR part 312. 
 
 

 
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17 Recommended Dosing of Enoxaparin 
Enoxaparin will be administered to all subjects to minimize the risk of thromboembolic events 
(TE) events. Enoxaparin will be administered subcutaneously (SC) at a dose of 1 mg/kg/day. 
Rounding of the dose may be done per Institution policy and when using prefilled syringes 
supplied 
 Refer to Table 8 for examples of rounding based on the expected 
enoxaparin dose.  If the rounded dose is greater than 20% of the expected dose based on weight, 
the Sponsor should be consulted.  
 
Table 8 Rounding of Enoxaparin with Using Pre-filled Syringes 
Enoxaparin Expected Dose 
(mg) 
Rounded Enoxaparin Dose 
(mg) 
Syringes Dispensed 
50-69 
60 
60 mg x1 
70-89 
80 
80 mg x1 
90-109 
100 
100 mg x 1 
110-134 
120 
120 mg x 1 
  
 
 

 
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18 References 
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spot in the tissue microenvironment. Front Immunol, 2015. 6: p. 231. 
 
 
 
 
 
 
 

 
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Appendix 1 UCSF Policy/Procedure for Required Regulatory Documents for UCSF 
Investigator-Initiated Oncology Clinical Trials with an Investigator held Investigational 
New Drug (IND) 
Purpose 
This policy defines the required Regulatory Documents for Single Site and Multicenter Investigator 
Initiated Oncology Clinical Trials at the Helen Diller Family Comprehensive Cancer Center (HDFCCC) 
where the Principal Investigator (PI) holds the IND. 
Background 
The International Conference on Harmonization (ICH) Good Clinical Practices (GCP) Guidelines define 
Essential Regulatory Documents as those documents which individually and collectively permit 
evaluation of the conduct of a trial and the quality of data produced. These documents serve to 
demonstrate compliance with standards of GCP and with all applicable regulatory requirements. Filing 
essential documents in a timely manner can greatly assist in the successful management of a clinical trial. 
The Regulatory Documents will consist of electronic files in both iMedRIS and OnCore®, as well as 
paper files in the Regulatory Binders for both the Coordinating Site and the Participating Site(s) in the 
HDFCCC Investigator Initiated Oncology Clinical Trials. 
Procedures 
1.   HDFCCC Essential Regulatory Documents 
Documents Filed in iMedRIS: 
 
IRB approvals for initial submission of application, all modifications, and continuing annual 
renewals 
 
Current and prior approved protocol versions with signed protocol signature page(s) 
 
Committee for Human Research (IRB) approval letters and Informed Consent Form(s) (ICF) 
 
Current and prior versions of the Investigator Brochure (IB). 
 
Serious Adverse Event Reporting 
 
Protocol Violations and Single Patient Exception (SPE) Reports to IRB with supporting fax 
documentation 
Documents Filed in OnCore®: 
 
Package Insert (if the study drug is commercial) or Investigator Brochure 
 
Protocol Review Committee (PRC) approved protocols, protocol amendments and Summary of 
Changes (SOC) 
 
Patient handouts 
 
Screening/enrollment log 
 
Data and Safety Monitoring Committee (DSMC) monitoring reports 
 
OnCore® Case Report Form (CRF) completion manual 
 
 

 
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Documents Filed in Regulatory Binder: 
 
Completed Food and Drug Administration (FDA) 1572 document with Principal Investigator’s 
signature 
 
For all Principal Investigators and Sub-Investigators listed on the FDA 1572, will need Financial 
Disclosure Forms, CVs, MD Licenses, Drug Enforcement Agency (DEA) Licenses, and Staff 
Training Documents (i.e. Collaborative Institute Training Initiative (CITI), etc.) 
 
Site Initiation Visit (SIV) minutes and correspondence with participating site(s). 
 
As applicable, approvals for Biosafety Committee, Radiation Committee, and Infusion Center 
 
Serious Adverse Event (SAE) reports to IRB and sponsor. 
 
MedWatch reporting to FDA and sponsor 
 
Delegation of Authority Form 
 
Drug Destruction Standard Operating Procedure (SOP) 
 
For all laboratories listed on the FDA 1572, will need CLIA certifications, CAP certifications, lab 
licenses, CVs of Lab Directors, and laboratory reference ranges 
 
 

 
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Appendix 2 UCSF Policy/Procedure for Required Regulatory Documents for Single Site 
and Multicenter Investigator-Initiated Oncology Clinical Trials 
Purpose 
This policy defines the required Regulatory Documents for Single Site and Multicenter 
Investigator Initiated Oncology Clinical Trials at the Helen Diller Family Comprehensive Cancer 
Center (HDFCCC) for both IND and IND-exempt trials. 
Background 
The International Conference on Harmonization (ICH) Good Clinical Practices (GCP) 
Guidelines define Essential Regulatory Documents as those documents which individually and 
collectively permit evaluation of the conduct of a trial and the quality of data produced. These 
documents serve to demonstrate compliance with standards of GCP and with all applicable 
regulatory requirements. Filing essential documents in a timely manner can greatly assist in the 
successful management of a clinical trial. 
The Regulatory Documents will consist of electronic files in both iRIS and OnCore®, as well as 
paper files in the Regulatory Binders for both the Coordinating Site and the Participating Site(s) 
in the HDFCCC Investigator Initiated Oncology Clinical Trials. 
Procedures 
1.   Single Site (HDFCCC) Therapeutic Essential Regulatory Documents: 
Documents Filed in iRIS: 
 Current and prior versions of the Informed Consent Form(s) (ICFs). 
  IRB approvals for initial submission of application, all modifications, and continuing 
annual renewals. 
 Current and prior approved protocol versions. 
 Current IRB roster 
 Current and prior versions of the Investigator Brochure (IB). 
 Serious Adverse Event (SAE) Reports. 
 Subject diary and handouts (if applicable). 
 Single Patient Exception (SPE) Report(s) to  IRB with Approval Letter(s) from IRB. 
 Protocol Violation (PV) Reports with acknowledgement from the  IRB. 
 
Documents Filed in OnCore®: 
 Package Insert (if the study drug is commercial). 
 Protocol signature page(s) with Pl signature(s) for all protocol versions. 
 Protocol Review Committee (PRC) approved protocols, protocol amendments and 
Summary of Changes (SOC) document. 

 
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 Screening/enrollment log. 
 Data and Safety Monitoring Committee (DSMC) monitoring reports. 
 DSMC dose escalation approvals with study status summary forms. 
 Case Report Form (CRF) completion manual. 
 Drug Destruction Standard Operating Procedure (SOP). 
 Completed Food and Drug Administration (FDA) 1572 document with Principal 
Investigator's signature. 
 For all Principal Investigators and Sub-Investigators listed on the FDA 1572, will need 
Financial Disclosure Forms, CVs, MD Licenses, and Staff Training Documents (i.e., 
Collaborative Institute Training Initiative (CITI), etc.). 
 As applicable, approvals for Biosafety Committee, Radiation Committee, and Infusion 
Center. 
 Serious Adverse Event (SAE) reports to IRB and sponsor. 
 MedWatch reporting to FDA and sponsor. 
 Drug Destruction Standard Operating Procedure (SOP). 
 For all laboratories listed on the FDA 1572, will need CUA certifications, CAP 
certifications, lab licenses, CV(s) and Medical License(s) of Lab Director(s), and 
laboratory reference ranges. 
 
Documents Filed in Regulatory Binder: 
 Delegation of Authority Log with signatures (to be scanned in OnCore once the trial is 
complete). 
 
2. Additional Essential Documents for Therapeutic Multicenter Trials for the 
Coordinating Center (filed in OnCore or Zip Drive): 
 
 Institutional Review Board (IRB) approval letters, IRB roster, Informed Consent Form 
(ICF), and Health Insurance Portability and Accountability Act {HIPAA) Consent Form 
for the Participating Site(s). 
 For all Principal Investigators and Sub-Investigators listed on the 1572 at the 
Participating Site(s), will need Financial Disclosure Forms, CVs, MD Licenses, and Staff 
Training documents (i.e. Collaborative Institute Training Initiative (CITI), etc.) (for 
investigational New Drug Application). 
 Site Initiation Visit (SIV) minutes and correspondence with the Participating Site(s). 

 
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 As applicable, approvals for Biosafety Committee, Radiation Committee, and Infusion 
Center for the Participating Site(s). 
 Protocol Violations (PV) Reports to IRB with acknowledgement from IRB for 
Participating Site(s). 
 Single Patient Exception (SPE) Reports to IRB with IRB Approval Letters for 
Participating Site(s). 
 Drug Destruction Standard Operating Procedure (SOP) for the Participating Site(s).  
 Data and Safety Monitoring Committee (DSMC) monitoring reports for the Participating 
Site(s). 
 For all laboratories listed on FDA 1572, will need CUA certifications, CAP certifications, 
lab licenses, CVs and Medical License(s) of Lab Director(s), and laboratory reference 
ranges for the Participating Site(s). 
 Copy of the Data and Safety Monitoring Plan (DSMP) Monitoring Plan for all 
participating site(s) in Multicenter studies or Contract Research Organization (CRO) 
Monitoring Plan (if an outside CRO is used for the study). 
 Serious Adverse Event (SAE) forms submitted to the IRB for the Participating Site(s). 
 
3. Required Multicenter Essential Regulatory Document Checklist for Therapeutic 
and Non-Therapeutic Trials (For Start-Up Only): 
 See attached checklist(s). 
 
4. Required Essential Regulatory Documents for Single Site and Multicenter 
Therapeutic IND-Exempt Studies (filed in OnCore): 
 For IND Exempt studies, the Essential Regulatory Documents for UCSF would 
include all documents in Section #1 of this policy. The Essential Regulatory 
Documents from the participating site(s) for Multicenter Trials when UCSF is the 
Coordinating Center would only include the signed protocol signature page, CV of 
the Pl, and the IRB approval letters. All other documents in Section #2 of this policy 
would be the responsibility of the Participating Site(s). 
 
5. Required Essential Regulatory Documents for Single Site Non-Therapeutic 
Studies (filed in OnCore): 

 
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 For Single Site non-therapeutic trials, all Regulatory Documents in Section #1 of this 
policy are required except for: current and prior versions of the Investigator Brochure 
(IB), package insert (if the study drug is commercial), DSMC dose escalation 
approvals with study status summary forms, approvals for Biosafety Committee, 
Radiation Committee, and Infusion Center, and drug destruction SOPs. 
 
6. Required Essential Regulatory Documents for Multicenter Non-Therapeutic 
Studies (filed in OnCore): 
 For Multicenter non-therapeutic trials with UCSF as the Coordinating Site, all 
required Regulatory Documents listed above in Section #5 for Single Site non-
therapeutic trials are required for the Coordinating Site. The only required Regulatory 
Documents from the Participating Site(s) will be: IRB approval letters, IRB roster, 
and ICF and HIPAA consent forms, the Delegation of Authority Log (with NIH or 
CITI human subject protection training certificates or GCP training certification), 
Protocol Violations and Single Patient Exception (SPE) reports to the IRB with 
supporting fax documentation (if applicable), Serious Adverse Event (SAE) forms 
submitted to both the IRB and the sponsor, and the Data and Safety Monitoring 
Committee (DSMC) monitoring reports for the Participating Site(s). If applicable, a 
copy of the Data and Safety Monitoring Plan (DSMP) Monitoring Plan for all 
participating site(s) in Multicenter studies or Contract Research Organization (CRO) 
Monitoring Plan (if an outside CRO is used for the study) will be required. 
 
Alternate Procedures 
There are no alternate procedures to the HDFCCC policy for requirements for Essential 
Regulatory Documents for Multicenter Investigator-Initiated Oncology Clinical Trials. 
References 
 
 ICH Guidance for Industry: E6 Good Clinical Practice: Consolidated Guidance 
(current version). 
 International Conference on Harmonization: Good Clinical Practice: Consolidated 
Guideline (current version). 
 International Conference on Harmonization: Essential Documents for the Conduct of 
a Clinical Trial (current version). 
 21CFR50 

 
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 21 CFR56.11 
 45CFR46 
 21 CFR312 
 
Required Regulatory Documents for Sub-sites Participating in Therapeutic UCSF Investigator 
Initiated Multicenter trial  
Directions: Scan the documents in a zip drive and upload to OnCore. 
1572 
  PI and Sub investigators: 
 CV and Medical license  
 Financial disclosure form 
 NIH or CITI human subject protection training certification 
 
  Laboratories:   
 CLIA &CAP and Lab Licenses 
 CV and Medical License of Lab Director 
 Laboratory reference ranges 
 
Local Institutional Review Board  
 
  IRB Approval letter 
  Reviewed/Approved documents 
 
Protocol version date:   
___________ 
 
Informed consent version date:  ___________ 
 
Investigator Brochure version date:  ___________ 
 
HIPAA 
  Current IRB Roster 
 
Other  
  Delegation of Authority Log  
 
Include NIH or CITI human subject protection training certificates or GCP training certification 
  Pharmacy 
 
Drug destruction SOP and Policy 
  Protocol signature page  
  Executed sub contract