A Phase 2, Randomized, Multicenter Study of PEGPH20 (PEGylated Recombinant Human Hyaluronidase) Combined With Nab-Paclitaxel Plus Gemcitabine Compared With Nab-Paclitaxel Plus Gemcitabine in Subjects With Stage IV Previously Untreated Pancreatic Cancer
Phase: PHASE2
Conditions: Metastatic Pancreatic Cancer
Sponsor: Halozyme Therapeutics

Halozyme, Inc. 
Protocol HALO-109-202 
CONFIDENTIAL 
Page 1 of 128 
09 February 2018 
CLINICAL STUDY PROTOCOL 
Title: 
A Phase 2, Randomized, Multicenter Study of PEGPH20 
(PEGylated Recombinant Human Hyaluronidase) 
Combined with nab-Paclitaxel Plus Gemcitabine 
Compared With nab-Paclitaxel Plus Gemcitabine in 
Subjects With Stage IV Previously Untreated Pancreatic 
Cancer 
Protocol Number: 
HALO-109-202 
IND: 
102770 
Version: 
7 (Amendment 6.0) 
Version Date: 
09 February 2018 
Previous Version date: 
06 April 2015 
Sponsor: 
Halozyme, Inc. 
11388 Sorrento Valley Road 
San Diego, CA 92121 
 
Confidential: This document and the information it contains are the property of Halozyme, Inc. 
and are provided for the sole and exclusive use of Investigators in this clinical study. The 
information in this document may not be disclosed unless such disclosure is required by Federal 
or applicable State Law or Regulations, or unless there is prior written consent from Halozyme, 
Inc. Subject to the foregoing, this information may be disclosed only to those persons involved in 
the clinical investigation who need it, and who share the obligation not to disseminate this 
information further. 
NCT#: NCT01839487

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1. 
SYNOPSIS 
Sponsor/Company 
Halozyme, Inc. 
11388 Sorrento Valley Road 
San Diego, CA 92121 
Protocol Number 
HALO-109-202 
Study Title 
A Phase 2, Randomized, Multicenter Study of PEGPH20 (PEGylated Recombinant Human 
Hyaluronidase) Combined With nab-Paclitaxel Plus Gemcitabine Compared With nab-Paclitaxel 
Plus Gemcitabine in Subjects with Stage IV Previously Untreated Pancreatic Cancer 
NOTE: The purpose of this Protocol Amendment 6 (Version 7) is to introduce study closeout 
procedures. These include a reduction of study procedures for the 1 subject still on 
treatment and discontinuation of study procedures for subjects in long-term follow-up. The 
closeout procedures are effective as of the date of this protocol amendment and supersede all 
study procedures required per previous Protocol Amendment 5 (Version 6) dated 06 April 
2015. See Synopsis section titled “Study Closeout Procedures” and Section 6.1.4 for details. 
Study Objectives  
Primary: 
• To estimate the progression-free survival (PFS) duration of PEGPH20 combined with 
nab-paclitaxel (NAB) plus gemcitabine (GEM) (PAG treatment). 
• To evaluate the thromboembolic events in subjects treated in the PAG arm in Stage 2 
of the study as of this protocol amendment. 
Secondary: 
• To estimate the relative benefit of PAG treatment versus NAB plus GEM (AG 
treatment), as assessed by the PFS hazard ratio. 
• To estimate the relative benefit of PAG treatment versus AG treatment, as assessed by 
the PFS hazard ratio based on subject tumor-associated hyaluronan (HA) levels.  
• To estimate the objective response rate (ORR), as defined by the Response Evaluation 
Criteria in Solid Tumors (RECIST v1.1), of PAG treatment and the relative benefit of 
PAG treatment versus AG treatment.  
• To estimate the overall survival (OS) duration of PAG treatment and the relative 
benefit of PAG treatment versus AG treatment, as assessed by the OS hazard ratio.  
• To evaluate the safety and tolerability profile of the PAG and AG treatment groups.  
• To characterize the plasma pharmacokinetics (PK) of PEGPH20 when given in 
combination with NAB plus GEM. 

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Exploratory: 
• To estimate the OS benefit of PAG treatment versus AG treatment based on HA levels 
from tumor biopsies. 
• To estimate the duration of response (DR) of responders (complete response [CR] and 
partial response [PR]) of PAG and AG treatment. 
• To compare the disease control rate (DCR; CR, PR and stable disease [SD]) between 
the PAG and AG treatment groups.  
• To compare CA19-9 changes between the PAG and AG treatment groups. 
• To assess treatment effect of PAG with regard to hyaluronan (HA) levels in plasma and 
in tumor biopsies. 
Study Design 
This is a Phase 2, multicenter, open-label, randomized study of PEGylated recombinant human 
hyaluronidase (PEGPH20) combined with nab-paclitaxel (NAB) plus gemcitabine (GEM) (PAG 
treatment) compared with NAB plus GEM (AG treatment) in subjects with Stage IV previously 
untreated pancreatic cancer. The study has two run-in phases and 2 stages, as described below.  
A dose of 3.0 μg/kg was identified as the maximum-tolerated dose for PEGPH20 as either a single 
agent or in combination with GEM in two separate Phase 1 clinical studies. In both studies, 
PEGPH20 was administered twice weekly for the first 4 weeks, then once weekly for 3 out of 
every 4 weeks for the duration of participation.  
Since PEGPH20 has not been evaluated in clinical studies in combination with NAB and GEM, 
this study will have a run-in phase to evaluate the safety and tolerability of PAG treatment 
(original PEGPH20 formulation) compared with AG treatment before initiating Phase 2. The 
Phase 2 portion is an open-label randomized study. With Amendment 1.0, an additional run-in 
phase will be conducted to incorporate a new formulation of PEGPH20 during the Phase 2 
enrollment. 
The dosing schedule for subjects randomized to the PAG and AG treatment groups will be the 
same in the run-in phases and Phase 2 (see Table S-1). The treatment period will consist of 4-week 
treatment cycles (28 days) with Week 4 of every cycle as a washout week (i.e., no treatment will 
be given). Treatment will continue until disease progression or unacceptable toxicity is 
documented.  
Run-in Phases 
In the first run-in phase, approximately 8 subjects will be randomized in a 3:1 ratio to receive 
PEGPH20 (3.0 µg/kg; original formulation) in combination with standard dosing of NAB+GEM 
(PAG treatment) or NAB+GEM (AG treatment). No stratification factors will be used. Additional 
subjects may be enrolled to further assess the tolerability of PEGPH20 in order to establish the 
acceptable safety profile prior to the randomization of the Phase 2 study. 
The Sponsor, the participating Investigators, and the independent safety physician will determine 
if the dose and regimen for Phase 2 is acceptable after reviewing all available safety data from 
Cycle 1 from all subjects in the run-in phase.  

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With Amendment 1.0, a second run-in phase will be conducted to evaluate a new formulation of 
PEGPH20. Approximately 8 subjects will be randomized in a 3:1 ratio to receive the new 
formulation of PEGPH20 at 3.0 µg/kg in combination with standard dosing of NAB+GEM (PAG 
treatment) or NAB+GEM (AG treatment).  
The Sponsor, the participating Investigators, and the independent safety physician will determine 
if the dose and regimen for the new formulation of PEGPH20 is acceptable after reviewing 
available safety data from Cycle 1 from all subjects in the second run-in phase. If the safety profile 
and the PK profile of the new formulation are deemed acceptable, the new formulation of 
PEGPH20 will be available to all subjects on the study.  
Phase 2 
In Phase 2, approximately 237 subjects will be randomized to receive PEGPH20 (3.0 µg/kg, 
pending outcome of run-in phase safety assessment) in combination with standard dosing of 
NAB+GEM (PAG treatment) or NAB+GEM (AG treatment). Randomization will be stratified by 
Karnofsky Performance Status (70% to 80% and 90% to 100%). 
Phase 2 will have 2 stages due to a partial clinical hold that occurred from April through July 2014 
(see Section 6.1.2.1 for additional details). The first stage will randomize subjects in a 1:1 ratio. 
The second stage will randomize subjects in a 2:1 ratio (PAG:AG). The second stage of the study 
will start as of Amendment 3.0, in which the inclusion and exclusion criteria were modified, re-
start procedures were added, and low molecular weight heparin prophylaxis use was added.  

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Table S-1: 
Overview of Study Medication Schedule by Treatment Group 
Timepoint 
PAG Treatment Group 
AG Treatment Group 
Cycle 1 
Day 1 
PEGPH20 
NAB and GEM 
Day 2 
NAB and GEM (24 ± 4 hours after Day 1 dose of PEGPH20) 
No visit 
Day 4 
PEGPH20 
No visit 
Day 8  
PEGPH20 
NAB and GEM (2-4 hours after PEGPH20) 
NAB and GEM 
Day 11  
PEGPH20 
No visit 
Day 15  
PEGPH20 
NAB and GEM (2-4 hours after PEGPH20) 
NAB and GEM 
Day 18 
PEGPH20 
No visit 
Day 22 
No treatment (i.e., washout) 
No treatment (i.e., washout) 
Cycle 2 onwards 
Day 1  
PEGPH20 
NAB and GEM (2-4 hours after PEGPH20) 
NAB and GEM 
Day 8  
PEGPH20 
NAB and GEM (2-4 hours after PEGPH20) 
NAB and GEM 
Day 15  
PEGPH20 
NAB and GEM (2-4 hours after PEGPH20) 
NAB and GEM 
Day 22 
No treatment (i.e., washout) 
No treatment (i.e., washout) 
Abbreviations: AG = nab-paclitaxel plus gemcitabine; GEM = gemcitabine; PAG = PEGPH20 in combination with 
nab-paclitaxel plus gemcitabine; NAB = nab-paclitaxel. 
Note: Each treatment cycle is 28 days. Dose interruption and modifications are permitted; refer to Section 8.3 for 
further guidance. 
Dexamethasone 8 mg will also be given to each treatment group as follows: 
• PAG treatment group: Within 2 hours prior to the beginning of each PEGPH20 
infusion and 8 to 12 hours after the completion of the PEGPH20 infusion.  
• AG treatment group: Within 2 hours prior to the beginning of each NAB infusion and 8 
to 12 hours after the completion of the GEM infusion.  
Effective with amendment 4.0 (protocol version 5.0), all subjects on both arms will be treated with 
enoxaparin at a dose of 1 mg/kg/day. Enoxaparin should be started immediately following consent 
for amendment 4.0 for ongoing subjects and on Day 1 for new subjects entered into the trial.    

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Study Re-starting Procedures Overview Following Temporary Hold 
The following thromboembolic event risk factors will be assessed for all subjects (both treatment 
groups) after signing the updated ICF (protocol amendment 3.0) and prior to the next scheduled 
treatment:  
• Prior history of cerebrovascular accident or transient ischemic attack 
• Pre-existing carotid artery disease 
• Concomitant use of megestrol acetate (subjects on the PAG arm must discontinue use 
>10 days before re-starting PEGPH20 treatment and subjects on the AG arm should 
discontinue use immediately) 
• DVT on Doppler ultrasound or pulmonary embolism (PE) on chest CT prior to re-
initiating therapy after study hold  
Subjects who were randomized to the PAG treatment arm and answer yes to one or more of the 
questions above cannot re-start PEGPH20 therapy. Subjects who were randomized to the AG arm who 
answer yes to one or more questions may continue. All subjects (in both treatment arms) will continue 
receiving Gemcitabine and Nab Paclitaxel regardless of how the above questions were answered. Subjects 
re-starting PEGPH20 should re-start on the next scheduled visit day of the cycle they are currently in (i.e., 
do not “make up” visits). 
Additionally, all subjects will begin enoxaparin therapy. Subjects who are contraindicated to 
receive enoxaparin (see the exclusion criteria) will be discontinued from study treatment (PAG 
and AG).  
Study Closeout Procedures 
With this protocol amendment 6 (Version 7), the Sponsor is implementing study closeout 
procedures as described below. These include a reduction of study procedures for the 1 subject 
still on treatment (PAG group) and discontinuation of study procedures for subjects in long-term 
follow-up.  
The closeout procedures are effective as of the date of this Protocol Amendment 6, 09 February 
2018, and supersede all study procedures required per previous Protocol Amendment 5 
(Version 6) dated 06 April 2015.  
Study closeout procedures for subjects that are either on treatment or in long-term follow-up are 
described below: 
• The remaining subject on treatment will continue to receive study medication (PAG) 
until disease progression or other protocol-specified reasons for treatment 
discontinuation (see Section 7.3.1) or study discontinuation (see Section 7.3.2). For this 
subject, all procedures required per Protocol Amendment 5 will be immediately 
discontinued except for the following (see Table 10): 
− Administration of PEGPH20 on Days 1, 8, and 15 (as in Protocol Amendment 5); 
and NAB and GEM every 2 weeks (Days 1 and 15) or at the Investigator’s 

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discretion and per standard of care (vs. on Days 1, 8, and 15 in Protocol 
Amendment 5) 
− Administration of dexamethasone and enoxaparin (see Section 6.1.3.1 and 
Section 6.1.2.3 for additional details) 
− Imaging assessments performed locally (vs. sent to a CIR in Protocol 
Amendment 5) at a reduced frequency (every 4 cycles or less frequently, at the 
Investigator’s discretion and per standard of care [vs. every 2 cycles in Protocol 
Amendment 5]) to minimize radiation exposure 
− Clinical laboratory assessments (blood chemistry, hematology, and coagulation) by 
a local laboratory, all at a reduced frequency (Days 1, 8, and 15 [vs. Days 1, 8, 15, 
and 22 in Protocol Amendment5]) and at the End of Treatment visit. The clinical 
laboratory tests on Days 1, 8, and 15 will also be reduced in scope with fewer 
assessments (details in Table 10) to ensure the subject’s well-being and monitor 
key safety parameters through the remainder of study treatment. 
− Collection/reporting of serious adverse events (SAEs) and adverse events of special 
interest (TE events) for 30 days after the last dose of study treatment (additional 
details on SAE and TE event reporting in Section 10.3 and Section 10.4, 
respectively) (no other adverse events [AEs] will be collected). 
− Collection/reporting of pregnancy information as specified in Section 8.2.13 and 
Section 10.7 
• For subjects in long-term follow-up, the long-term follow-up will be discontinued 
immediately. For the 1 subject still on treatment, long-term follow-up will not be 
implemented when this subject discontinues treatment and completes the End of 
Treatment Visit (Section 8.1.3.2). This subject’s End of Treatment Visit will 
correspond to the end of the study. 
The end of the study is defined by the time when all subjects have discontinued treatment. 
Study Population 
Subjects with newly diagnosed, previously untreated Stage IV pancreatic cancer will be enrolled. 
See below for a list of all inclusion and exclusion criteria. 
Planned Total Sample Size 
This study is planned to randomize approximately 253 subjects. 
Run-in phases: Approximately eight subjects will be randomized in a 3:1 ratio to receive PAG 
(original formulation of PEGPH20) or AG treatment. With Amendment 1.0, an additional 
8 subjects will be randomized 3:1 to receive PAG (new formulation of PEGPH20) or AG 
treatment.  
Phase 2: Approximately 237 subjects will be randomized to receive PAG or AG treatment. Stage 1 
enrolled 123 subjects (1:1 ratio), Stage 2 planned to enroll 114 subjects (2:1 ratio, PAG:AG). 

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Inclusion Criteria 
• Signed, written Institutional Review Board/Ethics Committee-approved Informed 
Consent Form. 
• Histologically confirmed Stage IV pancreatic ductal adenocarcinoma (PDA) with 
documented disseminated neoplasm to the liver and/or the lung. Prior to enrollment, 
confirmation of the following must be obtained: 
− Available tumor tissue block or a minimum of five unstained core biopsy slides that 
meet specific tissue sample requirements (see Study Laboratory Manual).  
Note: Fine needle aspirates or brushing biopsies will not be acceptable. If an 
archived sample is not available, a pre-dose core tumor biopsy will be required in 
order to enter the study (i.e., an archived or fresh pre-dose core biopsy is required). 
• One or more metastatic tumors measurable on computed tomography (CT) scan per 
RECIST v1.1 criteria, excluding the primary pancreatic lesion. 
• Subject must have received no previous radiotherapy, surgery, chemotherapy, or 
investigational therapy for the treatment of metastatic disease.  
− Prior treatment with 5-FU or GEM administered as a radiation sensitizer during and 
up to 4 weeks after radiation therapy is allowed (if there is lingering toxicity, then 
the Sponsor should be consulted).  
− If a subject received therapy in the adjuvant setting, tumor recurrence or disease 
progression must have occurred no sooner than 6 months after completing the last 
dose of  the adjuvant therapy.  
• Karnofsky Performance Status ≥70%.  
• Life expectancy ≥3 months. 
• Age ≥18 years. 
• A negative pregnancy test, if female subject is of reproductive potential. 
• Screening clinical laboratory values as follows:  
− Total bilirubin ≤1.5 times upper limit of normal (ULN). 
− Aspartate aminotransferase (serum glutamic oxaloacetic transaminase) and alanine 
aminotransferase (serum glutamic pyruvate transaminase) ≤2.5 times ULN, (if liver 
metastases are present, then ≤5 times ULN is allowed). 
− Serum creatinine ≤2.0 mg/dL or calculated creatinine clearance ≥60 mL/min. 
− Serum albumin ≥3.0 g/dL. 
− Prothrombin time/international normalized ratio within normal limits (±15%) or 
within therapeutic range if on warfarin. 
− Partial thromboplastin time within normal limits (±15%).  
− Hemoglobin ≥ 10 g/dL.  

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− Absolute neutrophil count ≥1,500 cells/mm3. 
− Platelet count ≥100,000 /mm3  
• For men and women of reproductive potential, agreement to use an effective 
contraceptive method from the time of screening and throughout their time on study. 
Effective contraceptive methods consist of prior sterilization, intra-uterine device, oral 
or injectable contraceptives, and/or barrier methods. Abstinence alone is not considered 
an adequate contraceptive measure for the purposes of this study. 
Exclusion Criteria 
• Non-metastatic PDA. 
• Evidence of deep vein thrombosis (DVT) or pulmonary embolism (PE) or other known 
thromboembolic event present during the screening period. 
• Previous neoadjuvant treatment for pancreatic cancer 
• Known central nervous system involvement or brain metastases. 
• New York Heart Association Class III or IV cardiac disease or myocardial infarction 
within the past 12 months.  
• Prior history of cerebrovascular accident or transient ischemic attack 
• Pre-existing carotid artery disease 
• Active, uncontrolled bacterial, viral, or fungal infection requiring systemic therapy. 
• Known infection with human immunodeficiency virus, hepatitis B, or hepatitis C. 
• Known allergy to hyaluronidase. 
• Current use of megestrol acetate (use within 10 days of Day 1). 
• Contraindication to heparin as per NCCN guidelines: 
− Recent central nervous system bleed, intracranial or spinal lesion at high risk for 
bleeding 
− Active bleeding (major): more than 2 units transfused in 24 hours  
− Spinal anesthesia/lumbar puncture 
− Chronic, clinically significant measurable bleeding >48 hours 
− Severe platelet dysfunction (uremia, medications, dysplastic hematopoiesis) 
− Recent major operation at high risk for bleeding 
− Underlying hemorrhagic coagulopathy 
− High risk for falls (head trauma) 

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• Previous major bleed (bleeding requiring transfusion of red blood cells) on low 
molecular weight heparin (LMWH)  
• Women currently pregnant or breastfeeding. 
• Intolerant of dexamethasone. 
• History of another primary cancer within the last 3 years with the exception of 
non-melanoma skin cancer, early stage prostate cancer, or curatively-treated cervical 
carcinoma in-situ. 
• Any other disease, metabolic dysfunction, physical examination finding or clinical 
laboratory finding that leads to reasonable suspicion of a disease or condition that 
contraindicates the use of an investigational drug, that may affect the interpretation of 
the results, or that may render the subject at high risk for treatment complications. 
• Other unspecified reasons that, in the opinion of the Investigator or Sponsor, make the 
subject unsuitable for the study. 
• Inability to comply with study and follow-up procedures as judged by the Investigator. 
Study Medication 
For the purposes of this study, study medication is defined as PEGPH20, NAB, and/or GEM.  
PEGPH20: PEGPH20 drug product (original formulation) is supplied as an aqueous solution 
containing 3.5 mg/mL PEGPH20 with 10 mM histidine and 130 mM NaCl at pH 6.5. Each vial 
contains 1.2 mL (4.2 mg) or 0.6 mL (2.1 mg) of PEGPH20 drug product. This PEGPH20 drug 
product is provided as a frozen formulation. It should be stored at or below -20°C before use.  
PEGPH20 drug product (new formulation) is supplied as an aqueous solution containing 
0.30 mg/mL PEGPH20 with 10 mM succinic acid, 130 mM NaCl, and 10 mM L-methionine at 
pH 6.2. Each vial contains 1.2 mL (0.36 mg, current investigational material) or 1.0 mL (0.30 mg, 
commercial-scale material) of PEGPH20 drug product. This PEGPH20 drug product is provided 
as a refrigerated formulation and should be stored at 2°C to 8°C before use.  
PEGPH20 mixing instructions will be provided for both formulations. PEGPH20 will be 
administered as an intravenous (IV) infusion over 10 minutes, approximately 1 mL/minute (a 
window of +2 minutes is allowed, i.e., infusion can be 10 to 12 minutes). 
Nab-paclitaxel: NAB is an albumin-bound form of paclitaxel and is an approved anti-cancer 
therapy. It is supplied as a lyophilized powder in single-use vials containing 100 mg of paclitaxel. 
NAB will be given as an IV infusion at 125 mg/m2 over 30 minutes and prior to the GEM 
infusion. For subjects in the PAG treatment group, NAB will be given after the PEGPH20 infusion 
is completed.  
Gemcitabine: GEM is an approved chemotherapy. It is supplied as a solid lyophilized powder in 
single-use vials: 200 mg in 10-mL vials or 1 g in 50-mL vials. GEM will be given as an IV 
infusion at 1000 mg/m2 over 30 minutes after the NAB infusion is complete. 
 

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Study Duration 
Subjects will be allowed to continue treatment on study until disease progression or unacceptable 
toxicity is documented. Disease progression will be defined by presence of one or both of the 
following: 
• Disease progression documented by CT scan based on RECIST v1.1, as determined by the 
Central Imaging Reader (CIR).  
• Clinical tumor-related progression that is well documented in the absence of radiologic 
disease progression. 
Disease progression is based on the assessment of the CIR. Investigators should continue study 
treatment until the CIR’s progressive disease determination. Investigators may discontinue study 
treatment if there is documented clinical disease progression and/or study treatment is no longer in 
the best interest of the subject. Subjects who discontinue treatment should remain in the study for 
long-term follow-up assessments unless they withdraw consent, die, or become lost to follow-up. 
Criteria for Evaluation 
Primary Endpoint 
• PFS (measured from the date of randomization until disease progression or death from any 
cause). 
• Proportion of subjects in the PAG arm who experience any thromboembolic event in Stage 
2 of the study, as of Amendment 3.0. 
Secondary Efficacy Endpoints 
• PFS in relation to HA levels.  
• ORR (defined as the percentage of subjects with a RECIST v1.1 PR or CR).  
• OS (measured from the date of randomization until death from any cause). 
Exploratory Efficacy Endpoints 
• OS in relation to HA levels. 
• DR (measured from the date of the first CR/PR until disease progression). 
• DCR (defined as the percentage of subjects with SD, PR, or CR). 
• Serum CA 19-9 response rate between the PAG and AG treatment groups. 
• PEGPH20 anti-tumor activities based on HA levels in plasma and in tumor biopsies. 

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Statistical Methods 
Analysis Populations 
Intent-to-treat (ITT) Population: All subjects who are randomized, including the run-in phase, will 
be included in the ITT Population. The ITT Population will be used for subject disposition, 
demographics, and overall efficacy analyses. 
Overall Evaluable Population: All randomized subjects, including the run-in phase, who have a 
post-baseline response assessment, or have clinical disease progression without a post-baseline CT 
scan, or have died on study, while they are on randomized treatment after randomization, will be 
included in the Evaluable Population for Efficacy. The Overall Evaluable Population will be used 
as the primary analysis population for overall efficacy analyses. 
Overall Safety Population: All subjects who received any part of a dose of study medication will 
be included in the Safety Population. Subjects in the Safety Population will be grouped according 
to the treatment they received. The Safety Population will be used for all safety analyses.  
Safety Population of Stage 2: Subjects in the Overall Safety Population at Stage 2 of the study. The Safety 
Population of Stage 2 will be used for analyses of safety data of Stage 2 of the study. This is the analysis 
population for the primary safety endpoint. 
PK Analysis Population: All subjects who received any part of a dose of PEGPH20 and had 
measurable PEGPH20 concentrations in at least one sample collected for PK analysis will be 
included in the PK Analysis Population.  
Efficacy 
Median PFS, OS, and DR will be estimated using the Kaplan-Meier method. The median and its 
95% confidence intervals, and quartiles, will be presented by treatment group. The PFS and OS 
comparisons of the two treatment groups will be based on stratified log-rank tests, where the 
stratum is the Karnofsky Performance Status (70% to 80% and 90% to 100%). The estimated 
hazard ratio (and 95% confidence interval) for the treatment effect will be prepared using a 
stratified Cox regression model. ORR (CR+PR) will be descriptively summarized. The ORR and 
DCR for each treatment group will be estimated and a comparison between the two treatment 
groups will be analyzed using the Cochran-Mantel-Haenszel test.  
All efficacy analyses will be conducted based on tumor HA status (HA high and HA low). Tumor 
samples will be analyzed in a prospective-retrospective fashion using an affinity histochemistry 
diagnostic assay, the VENTANA HA RxDx assay (see Section 8.2.20 for additional details). 
Safety  
The primary safety endpoint is the proportion of subjects in the PAG arm who experience any 
thromboembolic event in Stage 2 of the study (P). Subjects with multiple events will be counted 
only once for the primary safety analysis.  
The hypothesis test will be conducted using the one-sided exact binomial test against the null 
hypothesis test of P ≤ 12%. 
For 76 newly enrolled subjects in the PAG arm in Stage 2, four safety analyses, three interim and 
one final analyses as shown in Table 1 will be conducted when the last subject in each analysis has 

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been treated for one PAG treatment cycle or has discontinued from PAG treatment during the first 
treatment cycle as follows: 
• Interim #1: enoxaparin dose: 40 mg/day (12 PAG patients). 
• Interim #2: enoxaparin dose: 1 mg/kg/day (12 PAG patients). 
• Interim #3: enoxaparin dose: 1 mg/kg/day (29 PAG patients). 
• Final analysis: enoxaparin dose: 1 mg/kg/day (58 PAG patients).. 
Table S-2: Stopping Boundaries for Subjects in the PAG Arm of Study 202, Stage 2 
Safety Analyses 
1st Interim 
(IA#1) 
Cumulative 
IA#1 Follow-up 
2nd Interim 
(IA#2) 
3rd Interim 
(IA#3) 
Final 
Prophylactic 
enoxaparin dose 
level 
40 mg/day 
40 mg/day OR  
40 mg/day and  
1 mg/kg/day 
1 mg/kg/day 
1 mg/kg/day 
1 mg/kg/day 
No. of Subjects in 
PAG Arm 
12 
18 
12 
29 
58 
(last subject) 
Stopping boundary: 
TE** Rate 
>25% 
n/a 
>25% 
>24% 
>22% 
Stopping boundary: 
Subjects with TE** 
>3 
n/a 
>3 
>7 
>12 
Stopping boundary: 
p-value 
<0.05* 
n/a 
<0.05* 
<0.035 
<0.035 
The shaded columns indicate PAG patients who have received the 40 mg/day enoxaparin dose only (IA#1) or have 
received the 40 mg/day OR the 40 mg/day and the 1 mg/kg/day enoxaparin doses after IA#1. 
* The p-value boundary for the 1st and 2nd safety analyses was increased to 0.05 from the Pocock boundary of 0.035 to 
increase the chance of early stop.  
** Thromboembolic event 
For subjects in Stage 1 who are eligible to re-initiate PEGPH20 treatment, an interim analysis will 
be conducted after the last re-entry subject has had one cycle of PAG treatment or has 
discontinued from treatment during the first treatment cycle after re-entry. If the thromboembolic 
event rate exceeds 25%, all re-entry subjects will be discontinued from PEGPH20 treatment.  
All AEs will be presented in incidence tables coded by the Medical Dictionary for Regulatory 
Activities (MedDRA) preferred term and system organ class. Additionally, separate AE incidence 
tables, coded by MedDRA type, will be presented for each treatment group and overall by: 1) 
toxicity grade (severity) graded by the Common Terminology Criteria for Adverse Events v4.03 
or the current version (CTCAE), and 2) relationship to study mediation (PEGPH20, NAB, and/or 
GEM), as determined by the Investigator. 
All AEs, SAEs, treatment discontinuations due to AEs, and deaths occurring during the course of 
the study will be summarized. 

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Laboratory toxicity will be summarized for all post-baseline data. Shift tables will be presented for 
selected laboratory parameters: liver function tests (ALT, AST, alkaline phosphatase, total 
bilirubin), WBC, ANC, hemoglobin, platelet count, PT, PTT, INR, and creatinine. Shift tables will 
use CTCAE grades, v4.03 (or current version). Selected laboratory parameters and vital signs 
(blood pressure, pulse, respiratory rate temperature) and the corresponding change from baseline 
over time will be summarized using descriptive statistics and data listings. 
Pharmacokinetics 
For PEGPH20, noncompartmental and population PK modeling will be performed. The 
area-under-the-concentration time curve, the maximum-observed concentration, and 
time-to-maximum concentration will be summarized along with descriptive statistics. Other 
PK/pharmacodynamic analyses will be performed, and estimation of PK parameters including 
terminal half-life, volume of distribution, and clearance will be evaluated and reported if the data 
are sufficient. For HA, descriptive statistics will be used to summarize the measured plasma 
concentrations.  
Interim Analysis 
No formal interim analyses of efficacy were initially planned for this study. However, 2 interim 
analyses of efficacy data from Stage 1 were performed to develop the HA algorithm and determine 
the cut--point to define HA-high subjects using a prototype HA assay and the investigational 
VENTANA HA RxDx assay, respectively. The 50% HA cut-point identified based on the Stage 1 
data was defined based on the VENTANA HA RxDx assay prior to the analysis of Stage 2 data. 
Stage 2 data were used to validate the HA algorithm and 50% cut-point. A third, comprehensive 
interim analysis of efficacy and safety data was performed to validate the VENTANA HA RxDx 
assay algorithm and cut-point of 50% and enable a thorough benefit/risk assessment based on HA 
status.  
Sample Size Considerations 
Approximately 16 subjects with newly diagnosed, previously untreated Stage IV pancreatic cancer 
will be randomized in 3:1 ratio to receive PAG and AG treatment in the run-in Phase. 
123 subjects with newly diagnosed, previously untreated Stage IV pancreatic cancer were 
randomized in a 1:1 ratio to either the PAG or AG treatment group in the Phase 2 portion of the 
study in stage 1.  
In Stage 2 of this study, 114 subjects were planned to be randomized in a 2:1 ratio to receive PAG 
or AG treatment: 76 subjects in the PAG arm and 38 subjects in the AG arm. To ensure adequate 
assessment of the primary safety endpoint of TE event incidence and a meaningful number of 
HA-high subjects in Stage 2, 133 subjects were actually randomized.   
The primary safety endpoint is the proportion of subjects who experience any thromboembolic 
event in Stage 2 of the study (P).  
The hypothesis test will be conducted using the one-sided exact binomial test against the null 
hypothesis test of P ≤ 12%. 
Four safety analyses will be conducted using the stopping boundary of the one-sided p-value of 
0.05 for the first two analyses and 0.035 for the remaining two analyses based on the Pocock 
method. 

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It is expected that a total of 237 subjects in Phase 2 will be enrolled in approximately 20 months 
and these subjects will be followed up for additional 15 months. There will be approximately 200 
subjects, including subjects from the run-in phase, in the Overall Efficacy Evaluable Population 
for the primary comparisons. The study planned to provide approximately 80% statistical power to 
detect a 45% treatment effect in median PFS (5.5 months for AG versus 8 months for PAG) with 
182 PFS events based on the two-sided log-rank test at the significance level of 0.1. However, the 
interim data showed a low likelihood of achieving 182 PFS events from a total of 256 subjects 
actually randomized in Phase 2, and therefore the final analysis will be conducted when at least 
95% of the enrolled subjects and 95% of HA-high subjects have discontinued study treatment. 
In addition, the study will provide 80% statistical power to detect 40% benefit in median OS 
(8.5 months for AG versus 11.9 months for PAG) at one-sided alpha level of 0.1. Assuming 35% 
subjects with high HA, the study has 80% statistical power for the high HA subgroup to detect 
90% benefit in median PFS (5.5 months for AG versus 10.5 months for PAG) at two-sided alpha 
level of 0.1 and 80% benefit in median OS (8.5 months for AG versus 15.3 months for PAG) at 
one-sided alpha level of 0.1.  

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2. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES  
TABLE OF CONTENTS 
1. 
SYNOPSIS ...................................................................................................................2 
2. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............16 
3. 
STUDY SCHEDULES OF EVENTS ........................................................................24 
4. 
BACKGROUND AND RATIONALE .......................................................................33 
4.1. 
Thromboembolic Events in Cancer ............................................................................36 
4.2. 
Clinical Experience with PEGPH20 and Clinical Development Plan ........................37 
4.2.1. 
Phase 1 Study HALO-109-101 ...................................................................................37 
4.2.2. 
Phase 1 Study HALO-109-102 ...................................................................................38 
4.2.3. 
Phase 1b/2 Study HALO-109-201 ..............................................................................39 
4.2.4. 
Thromboembolic events reported in the current study ...............................................40 
4.2.5. 
Clinical Pharmacokinetics ..........................................................................................41 
4.2.6. 
Pharmacodynamic Evaluations ...................................................................................44 
4.2.7. 
Evaluation of the New Formulation of PEGPH20 .....................................................44 
4.3. 
Study Rationale ...........................................................................................................45 
4.3.1. 
Rationale for Selection of the PEGPH20 Starting Dose .............................................48 
4.4. 
Background of Nab-paclitaxel ....................................................................................49 
4.5. 
Background of Gemcitabine .......................................................................................50 
5. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................51 
5.1. 
Study Objectives .........................................................................................................51 
5.1.1. 
Primary Objective .......................................................................................................51 
5.1.2. 
Secondary Objectives .................................................................................................51 
5.1.3. 
Exploratory Objectives ...............................................................................................51 
5.2. 
Study Endpoints ..........................................................................................................51 
5.2.1. 
Primary Endpoint ........................................................................................................51 
5.2.2. 
Secondary Efficacy Endpoints ....................................................................................52 
5.2.3. 
Exploratory Efficacy Endpoints .................................................................................52 
6. 
INVESTIGATIONAL PLAN .....................................................................................53 
6.1. 
Overall Study Design and Plan: Description ..............................................................53 
6.1.1. 
Run-in Phases .............................................................................................................53 

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6.1.1.1. 
Original Formulation of PEGPH20 ............................................................................53 
6.1.1.2. 
New Formulation of PEGPH20 ..................................................................................53 
6.1.2. 
Phase 2 ........................................................................................................................54 
6.1.2.1. 
Clinical Hold ...............................................................................................................54 
6.1.2.2. 
Study Re-Starting Procedures Overview Following Temporary Hold .......................54 
6.1.2.3. 
Treatment with Enoxaparin ........................................................................................55 
6.1.2.4. 
Use of Doppler ultrasound and Chest CT ...................................................................55 
6.1.3. 
Overview of Treatment Schedule ...............................................................................55 
6.1.3.1. 
PAG Treatment Group ................................................................................................55 
6.1.3.2. 
AG Treatment Group ..................................................................................................56 
6.1.4. 
Study Closeout Procedures .........................................................................................59 
7. 
SELECTION AND WITHDRAWAL OF SUBJECTS AND STUDY 
TERMINATION .........................................................................................................63 
7.1. 
Inclusion Criteria ........................................................................................................63 
7.2. 
Exclusion Criteria .......................................................................................................64 
7.3. 
Subject Withdrawal Criteria .......................................................................................65 
7.3.1. 
Discontinuation of Treatment .....................................................................................65 
7.3.2. 
Study Discontinuation ................................................................................................66 
7.4. 
Sponsor Study Stopping Rules ...................................................................................66 
8. 
STUDY PROCEDURES AND ASSESSMENTS......................................................67 
8.1. 
Study Procedures by Visit ..........................................................................................67 
8.1.1. 
Screening Visits (PAG and AG Treatment Groups) ...................................................67 
8.1.1.1. 
Within 20 Days Prior to Day 1 ...................................................................................67 
8.1.1.2. 
Within 14 Days Prior to Day 1 ...................................................................................67 
8.1.1.3. 
Within 7 Days Prior to Day 1 .....................................................................................68 
8.1.2. 
Treatment Period (PAG Treatment Group) ................................................................68 
8.1.2.1. 
Treatment Cycle 1 .......................................................................................................68 
8.1.2.2. 
Treatment Cycle 2 Onwards (repeats every 4 weeks) ................................................72 
8.1.2.3. 
End of Treatment Visit ...............................................................................................74 
8.1.3. 
Treatment Period (AG Treatment Group) ..................................................................75 
8.1.3.1. 
All Treatment Cycles ..................................................................................................75 
8.1.3.2. 
End of Treatment Visit ...............................................................................................77 
8.1.4. 
Long-term Follow-up (PAG and AG Treatment Groups) ..........................................78 

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8.1.5. 
Procedures for Study Treatment Discontinuation .......................................................78 
8.2. 
Study Assessments......................................................................................................78 
8.2.1. 
Informed Consent .......................................................................................................78 
8.2.2. 
Inclusion/Exclusion Criteria .......................................................................................78 
8.2.3. 
Medical History ..........................................................................................................79 
8.2.4. 
Concomitant Medications ...........................................................................................79 
8.2.5. 
Adverse Events ...........................................................................................................79 
8.2.6. 
Physical Examination .................................................................................................79 
8.2.7. 
Height and Weight/Body Surface area .......................................................................79 
8.2.8. 
Karnofsky Performance Status ...................................................................................79 
8.2.9. 
Vital Signs ..................................................................................................................79 
8.2.10. 
Tumor Biopsy Tissue Samples ...................................................................................79 
8.2.11. 
12-lead ECG ...............................................................................................................80 
8.2.12. 
Blood Chemistry, Hematology, Coagulation Parameters, and Urinalysis ..................80 
8.2.13. 
Pregnancy Test ............................................................................................................80 
8.2.14. 
Immunogenicity ..........................................................................................................80 
8.2.15. 
CA19-9 .......................................................................................................................80 
8.2.16. 
Imaging/Radiologic Evaluation ..................................................................................80 
8.2.16.1. 
Chest CT To Exclude Pulmonary Embolism ..............................................................81 
8.2.17. 
Doppler Ultrasound ....................................................................................................81 
8.2.18. 
Pharmacokinetic Assessments ....................................................................................81 
8.2.19. 
Pharmacodynamic Endpoints .....................................................................................81 
8.2.20. 
Tumor-Associated Hyaluronan Investigational VENTANA HA RxDx Assay .........82 
8.3. 
Study Drug Administration.........................................................................................82 
8.3.1. 
PEGPH20 ....................................................................................................................82 
8.3.1.1. 
Hypersensitivity to PEGPH20 ....................................................................................83 
8.3.1.2. 
PEGPH20 Dose Modification Guidelines ..................................................................83 
8.3.2. 
Nab-paclitaxel and Gemcitabine .................................................................................85 
8.3.2.1. 
Nab-paclitaxel Administration ....................................................................................85 
8.3.2.2. 
Gemcitabine Administration .......................................................................................85 
8.3.2.3. 
Nab-paclitaxel and Gemcitabine Dose Adjustment and Toxicity 
Management ...............................................................................................................86 
8.4. 
Excluded Concomitant Medications and Study Restrictions ......................................89 

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8.5. 
Treatment Compliance ................................................................................................89 
8.6. 
Randomization and Blinding ......................................................................................89 
8.6.1. 
Run-in Phase Randomization .....................................................................................89 
8.6.2. 
Phase 2 Randomization ...............................................................................................90 
9. 
STUDY DRUG AND MATERIALS .........................................................................91 
9.1. 
Study Drug Description ..............................................................................................91 
9.1.1. 
PEGPH20 ....................................................................................................................91 
9.1.2. 
Nab-paclitaxel .............................................................................................................91 
9.1.3. 
Gemcitabine ................................................................................................................92 
9.2. 
Study Drug Packaging and Labeling ..........................................................................92 
9.2.1. 
PEGPH20 ....................................................................................................................92 
9.2.2. 
Nab-paclitaxel .............................................................................................................92 
9.2.3. 
Gemcitabine ................................................................................................................92 
9.3. 
Study Drug Storage .....................................................................................................93 
9.3.1. 
PEGPH20 ....................................................................................................................93 
9.3.2. 
Nab-paclitaxel .............................................................................................................93 
9.3.3. 
Gemcitabine ................................................................................................................93 
9.4. 
Study Drug Preparation ..............................................................................................93 
9.4.1. 
PEGPH20 ....................................................................................................................93 
9.4.2. 
Nab-paclitaxel .............................................................................................................93 
9.4.3. 
Gemcitabine ................................................................................................................93 
9.5. 
Study Drug Accountability .........................................................................................94 
10. 
SAFETY ASSESSMENTS ........................................................................................95 
10.1. 
Management of Thromboembolic Events ..................................................................95 
10.1.1. 
Enoxaparin Management ............................................................................................95 
10.2. 
Adverse Event Definitions ..........................................................................................96 
10.3. 
Reporting Serious Adverse Events .............................................................................97 
10.4. 
Reporting Adverse Events of Special Interest ............................................................97 
10.4.1. 
Thromboembolic Event Grading ................................................................................97 
10.4.2. 
Disease-Related Events That Are Endpoints ..............................................................99 
10.5. 
Adverse Events ...........................................................................................................99 
10.5.1. 
Classification of Adverse Events by Severity ..........................................................100 
10.5.2. 
Classification of Adverse Events by Relationship to Study Drug ............................100 

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10.6. 
Abnormal Laboratory Results ...................................................................................101 
10.7. 
Pregnancy .................................................................................................................101 
10.8. 
Overdose ...................................................................................................................102 
10.9. 
Data Monitoring Committee .....................................................................................102 
10.10. 
Unblinding ................................................................................................................102 
10.11. 
Reporting Safety Information to the Institutional Review Board .............................103 
10.12. 
Concomitant Medications .........................................................................................103 
10.12.1. 
Dexamethasone .........................................................................................................103 
10.12.2. 
Enoxaparin ................................................................................................................103 
11. 
STATISTICS ............................................................................................................104 
11.1. 
Statistical Methods ....................................................................................................104 
11.1.1. 
Randomization and Blinding ....................................................................................104 
11.1.2. 
Sample Size ..............................................................................................................104 
11.1.3. 
Analysis Populations ................................................................................................107 
11.1.3.1. 
Intent-to-Treat Population (ITT) ...............................................................................107 
11.1.3.2. 
Overall Evaluable Population ...................................................................................107 
11.1.3.3. 
Overall Safety Population .........................................................................................107 
11.1.3.4. 
Safety Population of Stage 2 .....................................................................................107 
11.1.3.5. 
PK Analysis Population ............................................................................................107 
11.1.4. 
Efficacy Analyses .....................................................................................................107 
11.1.4.1. 
Analyses of the PFS Efficacy Endpoint ....................................................................107 
11.1.5. 
Analysis of Other Efficacy Endpoints ......................................................................108 
11.1.6. 
Analysis of Primary Safety Endpoint .......................................................................108 
11.1.7. 
Safety Analyses ........................................................................................................109 
11.1.8. 
Pharmacokinetic Analysis ........................................................................................110 
11.1.9. 
Analysis of the Conduct of the Study .......................................................................110 
11.1.10. 
Analysis of Treatment Group Comparability ...........................................................110 
11.1.11. 
Interim Analysis ........................................................................................................110 
12. 
SPONSOR AND INVESTIGATOR RESPONSIBILITIES ....................................112 
12.1. 
Protocol Compliance ................................................................................................112 
12.1.1. 
Protocol Waivers ......................................................................................................112 
12.1.2. 
Protocol Deviations ..................................................................................................112 
12.2. 
Study Monitoring ......................................................................................................112 

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12.3. 
Data Collection and Case Report Forms ..................................................................112 
12.4. 
Financial Disclosure .................................................................................................113 
12.5. 
Investigator’s Final Report .......................................................................................113 
12.6. 
Data Disclosure and Publication ...............................................................................113 
13. 
QUALITY CONTROL AND QUALITY ASSURANCE .......................................114 
14. 
ETHICS ....................................................................................................................115 
14.1. 
Institutional Review Board and Approval ................................................................115 
14.2. 
Written Informed Consent ........................................................................................115 
15. 
DATA HANDLING AND RECORD KEEPING ....................................................117 
15.1. 
Record Inspection .....................................................................................................117 
15.2. 
Study Documentation and Record Retention ...........................................................117 
16. 
REFERENCES .........................................................................................................118 
17. 
APPENDICES ..........................................................................................................123 
APPENDIX A. ABBREVIATIONS .........................................................................................123 
APPENDIX B. KARNOFSKY/ECOG PERFORMANCE STATUS ......................................127 
APPENDIX C. NEW YORK HEART ASSOCIATION CLASSIFICATIONS ......................128 
 
 
 

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LIST OF TABLES 
Table 1: 
Study Schedule of Events: Screening (PAG and AG Treatment Groups)..................24 
Table 2: 
Study Schedule of Events: PEGPH20+nab-Paclitaxel+Gemcitabine (PAG 
Treatment Group) .......................................................................................................26 
Table 3: 
Study Schedule of Events: nab-Paclitaxel+Gemcitabine (AG Treatment 
Group) .........................................................................................................................29 
Table 4: 
Study Schedule of Events: Pharmacokinetic and HA Sample Collection 
(Run-in Phases PAG Treatment Groups) ...................................................................31 
Table 5: 
Study Schedule of Events: Pharmacokinetic and HA Sample Collection 
(Phase 2; PAG Treatment Group)...............................................................................32 
Table 6: 
Descriptive Pharmacokinetic Parameters (Mean ± SD) after Initial 
IV PEGPH20 Dosing at 0.5 to 1.5 µg/kg (Study HALO-109-101) ............................42 
Table 7: 
Descriptive Pharmacokinetic Parameters (Mean ± SD) after Initial IV 
PEGPH20 Dosing at 0.5 to 5.0 µg/kg (Study HALO-109-102) .................................43 
Table 8: 
Descriptive Pharmacokinetic Parameters (Mean ± SD) after Initial IV 
PEGPH20 Dosing at 1.0 to 3.0 μg/kg in Combination With Gemcitabine 
(Study HALO-109-201) ..............................................................................................43 
Table 9: 
Overview of Study Medication Schedule by Treatment Group .................................57 
Table 10: Study Procedures for the Remaining Subject on Treatment (PAG Group) ................61 
Table 11: PEGPH20 Dose Adjustment and Toxicity Management Guidelines .........................84 
Table 12: Nab-paclitaxel and Gemcitabine Dose Level Reductions ..........................................86 
Table 13: Day 1 Dose Modification Guidelines for Non-Hematologic Toxicity .......................86 
Table 14: Day 1 Dose Modification Guidelines for Hematologic Toxicity ...............................87 
Table 15: Day 8 and Day 15 Dose Modification Guidelines for Non-Hematologic 
Toxicity .......................................................................................................................87 
Table 16: Day 8 and Day 15 Dose Modification Guidelines for Hematologic Toxicity ............88 
Table 17: CTCAE Version 4.03 Grading for Thromboembolic Events .....................................97 
Table 18: Statistical Power Calculation Based on Log-rank Test ............................................106 
Table 19: Stopping Boundaries for Subjects in the PAG Arm of Study 202, Stage 2 ..............109 
 
 

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LIST OF FIGURES 
Figure 1: 
Hyaluronan is Expressed in High Levels in a Variety of Human Cancer 
Tissues ........................................................................................................................35 
Figure 2: 
Survival by High and Low Hyaluronan levels in Pancreatic Ductal 
Adenocarcinoma Tumors ............................................................................................46 
Figure 3: 
PEGPH20 Combined with Gemcitabine Significantly Increased Survival in 
the KPC Mouse Model of Pancreatic Ductal Adenocarcinoma .................................47 
Figure 4: 
PEGPH20 Combined with Gemcitabine and Nab-Paclitaxel Significantly 
Increased Survival in the KPC Mouse Model of Pancreatic Ductal 
Adenocarcinoma .........................................................................................................48 
Figure 5: 
Example of PEGPH20+nab-Paclitaxel+Gemcitabine (PAG) Treatment 
Schedule ......................................................................................................................58 
Figure 6: 
Example of nab-Paclitaxel+Gemcitabine (AG) Treatment Schedule .........................59 
Figure 7: 
Structure of PEGPH20 ................................................................................................91 
 

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3. 
STUDY SCHEDULES OF EVENTS 
With Protocol Amendment 6, the procedures listed in Section 6.1.4 will supersede all the procedures listed in Table 1 through Table 5. 
Table 1: 
Study Schedule of Events: Screening (PAG and AG Treatment Groups) 
 
Screening 
Tests and Assessmentsa 
≤20 Days Prior to D1 
≤14 Days Prior to 
D1 
≤7 Days Prior to D1 
Sign and Date ICF 
X 
 
 
Confirm Availability of Tumor Tissueb 
Xb 
 
 
Subject Registration/Randomization 
 
X 
 
Medical History 
X 
 
 
Physical Examination 
 
Xc 
 
Vital Signs 
 
Xc 
 
Karnofsky Performance Status 
 
X 
 
Height 
 
Xc 
 
Weight/BSA 
 
Xc 
 
Disease Assessment (CT)d 
Xc 
 
 
Doppler Ultrasound of lower extremities 
 
 
X 
Local Laboratory Tests 
 
 
 
Urine/Serum Pregnancy Test  
(female subjects of reproductive potential) 
 
X 
 

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Table 1: 
Study Schedule of Events: Screening (PAG and AG Treatment Groups) (Continued) 
 
Screening 
Tests and Assessmentsa 
≤20 Days Prior to D1 
≤14 Days Prior to 
D1 
≤7 Days Prior to D1 
Central Laboratory Tests  
 
 
 
Hematology 
 
X 
 
Blood Chemistry 
 
X 
 
Urinalysis 
 
X 
 
Coagulation Tests (PT, PTT, INR) 
 
X 
 
CA19-9 
 
X 
 
Plasma HA levels 
 
X 
 
Prior Medication History 
X 
 
 
a See Section 8.2 for details on individual assessments. 
Abbreviations: AG = nab-paclitaxel+gemcitabine; BSA = body surface area; CT = computed tomography; D1 = Study Day 1; HA = 
hyaluronan; ICF = Informed Consent Form; PAG = PEGPH20 in combination with nab-paclitaxel+gemcitabine.  
b Archived or fresh tissue from the primary or a metastatic lesion is required. Availability of a minimum of five unstained core 
biopsy slides or a block are required to send to central laboratory. 
c If these procedures are performed as part of standard of care prior to signing the ICF, the results may be used for screening 
purposes providing they were performed within the screening window. 
d Chest CT should also be read locally to evaluate for the presence of PE. This can be the same scan that is sent to the central lab. If a subject shows signs or 
symptoms of a PE after the initial scan was done, the scan should be repeated prior to randomization to verify whether the subject has a PE. If a PE is present 
the subject may not enter the trial.  
 

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Table 2: 
Study Schedule of Events: PEGPH20+nab-Paclitaxel+Gemcitabine (PAG Treatment Group) 
Tests and  
Assessmentsa 
Treatment Cycle 1 (4 Weeks) 
Treatment Cycles 2+ 
(Repeats every 4 weeks) 
End of 
Treatmentb 
Long- 
term 
Follow-
up 
Week  
1 
Week  
2 
Week  
3 
Week 
4 
Week 
1 
Week 
 2 
Week 
 3 
Week 
 4 
D1 D2 D4 
D8 
D11 
D15 
D18 
D22 
D1 
D8 
D15 
D22 
Physical Examination 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
Vital Signs 
Xc 
Xc 
Xc 
Xc 
Xc 
Xc 
Xc 
X 
Xc 
Xc 
Xc 
X 
X 
 
Karnofsky Performance 
Status 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
Weight/BSA 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
12-lead ECGd 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Disease Assessment (CT) 
 
 
 
 
 
 
 
 
 
 
 
Xe 
Xf 
 
Central Laboratory Tests 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology 
X 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
Blood Chemistry 
X 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
Immunogenicity 
Xg 
 
 
 
 
 
 
 
Xg 
 
 
 
X 
 
CA19-9 
 
 
 
 
 
 
 
X 
 
 
 
X 
X 
 
PK & HA levels 
Refer to Table 4 and Table 5 for schedule for PK & HA sampling timepoints 
PEGPH20 Administration 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
 
 
Coagulation Testing  
(PT, PTT, INR- Local 
Lab) 
X 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
Dexamethasone 
Administrationh 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
 
 

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Table 2: 
Study Schedule of Events: PEGPH20+nab-Paclitaxel+Gemcitabine (PAG Treatment Group) (Continued) 
Tests and  
Assessmentsa 
Treatment Cycle 1 (4 Weeks) 
Treatment Cycles 2+ 
(Repeats every 4 weeks) 
End of 
Treatmentb 
Long- 
term 
Follow-
up 
Week  
1 
Week  
2 
Week  
3 
Week 
4 
Week 
1 
Week 
 2 
Week 
 3 
Week 
 4 
D1 D2 D4 
D8 
D11 
D15 
D18 
D22 
D1 
D8 
D15 
D22 
Nab-paclitaxel  
Administration 
 
Xi 
 
Xj 
 
Xj 
 
 
Xj 
Xj 
Xj 
 
 
 
Gemcitabine 
Administration 
 
Xi 
 
Xj 
 
Xj 
 
 
Xj 
Xj 
Xj 
 
 
 
Optional Post-dose 
Tumor Biopsyk 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
Concomitant Therapy  
and Procedure Recording 
X 
X 
 
Adverse Event Recording 
X 
X 
 
Long-term Follow-upl 
 
 
X 
Abbreviations: BSA = body surface area; CT = computed tomography; D = day; ECG = electrocardiogram; HA = hyaluronan; PAG = PEGPH20 in combination 
with nab-paclitaxel+gemcitabine; PK = pharmacokinetics 
a See Section 8.2 for details on individual assessments. 
b Subjects should return to the study site for an End of Treatment Visit within approximately 7 days after determination of progressive disease or within 7 days 
after treatment discontinuation for other reasons. 
c Vital signs will be done pre-dose. 
d 12-lead ECG, done in triplicate, will be done pre dose and between 1 and 4 hours after PEGPH20 dosing but before the nab-paclitaxel dose. 
e CT scans will be obtained and sent to the Central Imaging Reader at the end of Cycle 2 and at the end of every second treatment cycle thereafter (i.e., Week 4 
of Cycles 4, 6, 8, etc.) Scans may be obtained any time after dosing on Day 15 to allow for enough time for the scan to be sent to and reviewed by the central 
reader prior to the subject’s next scheduled dosing visit. The results should be interpreted and sent to the site before dosing in the next cycle begins. For 
subjects who are withdrawn from the study due to clinical disease progression, a CT scan should be requested as soon as possible after clinical progression is 
determined. A Chest CT should also be done after PEGPH20 study hold (both treatment groups), after signing updated ICF (Amendment 3.0) to evaluate for 
the presence of pulmonary embolism. 
f CT should only be done if radiologic progressive disease was not documented in the previous CT scan. 
g Plasma PEGPH20 immunogenicity will be drawn prior to PEGPH20 dosing.  

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h Dexamethasone should be given within 2 hours prior to the start of each PEGPH20 dose and 8-12 hours after each PEGPH20 dose. 
i Nab- paclitaxel and gemcitabine will be given 24 hours (±4 hours) after the dose of PEGPH20. Nab-paclitaxel will be given first. 
j Nab-paclitaxel and gemcitabine will be given 2 to 4 hours after the PEGPH20 dose. Nab-paclitaxel will be given first. 
k Optional post-dose tumor biopsy may be done anytime in Week 4 of any Cycle. See Section 8.2.10 for tissue requirements. 
l After the End of Treatment Visit, subjects will enter long-term follow-up during which information on the subject’s survival will be obtained by the site on a 
monthly basis. In addition, efforts should be made to collect data on the subject’s next anti cancer therapy on a monthly basis. Long term follow-up will 
continue until the subject dies, is lost to follow-up, or withdraws consent. 
 

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Table 3: 
Study Schedule of Events: nab-Paclitaxel+Gemcitabine (AG Treatment Group) 
Tests and  
Assessmentsa 
All Treatment Cycles  
(Repeats every 4 weeks) 
End of  
Treatmentb 
Long-term  
Follow-up  
 
Week 1 
Week 2 
Week 3 
Week 4 
D1 
D8 
D15 
D22 
Physical Examination 
X 
 
 
 
X 
 
Vital Signs 
Xc 
Xc 
Xc 
X 
X 
 
Karnofsky  
Performance Status 
X 
 
 
 
X 
 
Weight/BSA 
X 
 
 
 
X 
 
12-lead ECGd 
X 
 
X 
 
 
 
Disease Assessment (CT) 
 
 
 
Xe 
Xf 
 
Central Laboratory Tests 
 
 
 
 
 
 
Hematology 
X 
X 
X 
X 
X 
 
Blood Chemistry 
X 
X 
X 
X 
X 
 
CA19-9 
 
 
 
X 
X 
 
Plasma HA Levels 
Xg 
 
 
 
 
 
Coagulation Testing (PT, PTT, 
INR - local Lab) 
X 
X 
X 
X 
X 
 
Dexamethasone Administrationh 
X 
X 
X 
 
 
 
Nab-paclitaxel Administrationi 
X 
X 
X 
 
 
 
Gemcitabine Administrationi 
X 
X 
X 
 
 
 
Optional Post-dose Tumor Biopsyj 
 
 
 
X 
 
 

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Table 3: 
Study Schedule of Events: nab-Paclitaxel+Gemcitabine (AG Treatment Group) (Continued) 
Tests and  
Assessmentsa 
All Treatment Cycles  
(Repeats every 4 weeks) 
End of  
Treatmentb 
Long-term  
Follow-up  
 
Week 1 
Week 2 
Week 3 
Week 4 
D1 
D8 
D15 
D22 
Concomitant Therapy and  
Procedure Recording 
X 
 
Adverse Event Recording 
X 
 
Long-term Follow-upk 
 
X 
Abbreviations: AG = nab-paclitaxel+gemcitabine; BSA = body surface area; CT = computed tomography; D = day; ECG = electrocardiogram; HA = hyaluronan.  
a See Section 8.2 for details on individual assessments. 
b Subjects should return to the study site for an End of Treatment Visit within approximately 7 days after determination of progressive disease or within 7 days 
after treatment discontinuation for other reasons. 
c Vital signs will be done before nab-paclitaxel dosing. 
d 12-lead ECG, done in triplicate, will be done before nab-paclitaxel dose and within 1 to 4 hours after the gemcitabine dose in Cycle 1 only. 
e CT scans will be obtained and sent to the Central Imaging Reader at the end of Cycle 2 and at the end of every second treatment cycle thereafter (i.e., Week 4 
of Cycles 4, 6, 8, etc.) Scans may be obtained any time after dosing on Day 15 to allow for enough time for the scan to be sent to and reviewed by the central 
reader prior to the subject’s next scheduled dosing visit. The results should be interpreted and sent to the site before dosing in the next cycle begins. For 
subjects who are withdrawn from the study due to clinical disease progression, a CT scan should be requested as soon as possible after clinical progression is 
determined. A Chest CT should also be done after PEGPH20 study hold (both treatment groups), after signing updated ICF (Amendment 3.0) to evaluate for 
the presence of pulmonary embolism.  
f CT should only be done if radiologic progressive disease was not documented in the previous CT scan. 
g HA level plasma sample should be drawn prior to the first nab-paclitaxel dose in each cycle. 
h Dexamethasone should be given within 2 hours prior to each nab-paclitaxel dose and 8-12 hours post each gemcitabine dose. 
i Nab-paclitaxel will be given first, followed by gemcitabine. 
j Optional post-dose tumor biopsy may be done anytime in Week 4 of any Cycle. See Section 8.2.10 for tissue requirements. 
k After the End of Treatment Visit, subjects will enter long-term follow up during which information on the subject’s survival will be obtained by the site on a 
monthly basis. In addition, efforts should be made to collect data on the subject’s next anti cancer therapy on a monthly basis. Long term follow-up will 
continue until the subject dies, is lost to follow-up, or withdraws consent. 

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Table 4: 
Study Schedule of Events: Pharmacokinetic and HA Sample Collection (Run-in Phases PAG Treatment Groups) 
Treatment 
Group 
Treatment Cycle 1 (4 Weeks) 
Treatment Cycles 2+ 
(Repeats every 4 weeks) 
Week 1 
Week 2 
Week 3 
Week 4 
Week 1 
Week 2 
Week 3 
Week 4 
D1 
D2 
D4 
D8 
D11 
D15 
D18 
D22 
D1 
D8 
D15 
D22 
PK and HA 
Sample 
Collectiona 
Xb 
Xc 
Xd 
Xe 
Xd 
Xb 
Xd 
 
Xf 
Xd 
 
 
Abbreviations: D = day; HA = hyaluronan; PAG = PEGPH20 in combination with nab-paclitaxel+gemcitabine; PK = pharmacokinetics.  
a Windows for blood draws: Pre-dose: within 2 hours of dosing. Post-dose: 15 minutes ±5 minutes, 1 hr (±15 minutes), 2 hour (±15 minutes), 4 hour 
(±30 minutes), Post gemcitabine= within 2 hours of completion of gemcitabine administration. 
b PK: Pre-PEGPH20 dosing, and 15 minutes, 1 hour, 2 hours, and 4 hours post-PEGPH20 dosing. A Cycle 1 Day 15, 24 hour post-dose sample is optional.  
HA: Pre-PEGPH20 dose (Day 1 only). 
c PK and HA: 24 hours post-PEGPH20 dose (±4 hours) and prior to nab-paclitaxel dose. 
d PK: Pre-PEGPH20 dose and 1 hour post-PEGPH20 dose. 
e PK: Pre-PEGPH20 dose and 1 hour post-PEGPH20 dose, and immediately after gemcitabine dose. 
f HA: Collect 1 HA sample pre-PEGPH20 and a second HA sample after gemcitabine administration. 
 

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Table 5: 
Study Schedule of Events: Pharmacokinetic and HA Sample Collection (Phase 2; PAG Treatment Group) 
Treatment 
Group 
Treatment Cycle 1 (4 Weeks) 
Treatment Cycles 2+ 
(Repeats every 4 weeks) 
Week 1 
Week 2 
Week 3 
Week 4 
Week 1 
Week 
2 
Week 
3 
Week 4 
D1 
D2 
D4 
D8 
D11 
D15 
D18 
D22 
D1 
D8 
D15 
D22 
PK and HA 
Sample 
Collectiona 
Xb  
Xc 
 
 
 
Xd 
 
 
Xe 
Xf  
 
 
 
Abbreviations: D = day; HA = hyaluronan; PAG = PEGPH20 in combination with nab-paclitaxel+gemcitabine; PK = pharmacokinetics. Post gemcitabine= 
within 2 hours of completion of gemcitabine administration. 
a Windows for blood draws: Pre-dose: within 2 hours of dosing. Post-dose: 1 hour (± 15 minutes). 
b PK: Pre-PEGPH20 dose and 1 hour post-PEGPH20 dose. HA: Pre-PEGPH20 dose. 
c PK and HA: 24 hours post-PEGPH20 dose (±4 hours) and prior to nab-paclitaxel dose. 
d PK: Pre-PEGPH20 dose and 1 hour post-PEGPH20 dose. 
e HA: Collect 1 HA sample pre-PEGPH20 and a second HA sample after gemcitabine administration. 
f PK: Pre-PEGPH20 dose and 1 hour post PEGPH20 dose. 
 

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4. 
BACKGROUND AND RATIONALE 
Halozyme, Inc. (Halozyme) has developed an investigational new molecular entity, PEGylated 
recombinant human hyaluronidase PH20 (PEGPH20), which uses a novel mechanism of action 
to systemically target tumors that accumulate the substrate for this enzyme, hyaluronan (HA). In 
preclinical models, depletion of HA in the tumor microenvironment has been shown to inhibit 
the growth of tumors characterized by accumulation of HA (Thompson 2010). A detailed 
background rationale for HA as a target in cancer therapy is described in Kultti et al. 
(Kultti 2012). 
Tumor accumulation of HA has been shown to occur in the most aggressive forms of several 
malignancies (Sironen 2011). Enzymatic HA depletion from the extracellular matrix (ECM) 
microenvironment, with PEGPH20 either alone or in combination with chemotherapy, represents 
an innovative potential treatment that may provide improved therapeutic outcomes for patients.  
HA is a linear, repeating polysaccharide comprised of N-acetylglucosamine and glucuronic acid 
disaccharide units. The metabolism of HA is a dynamic process, with normal turnover in tissues 
ranging from several weeks to less than a day in skin (Fraser 1997). HA is synthesized at the 
plasma membrane by three conserved HA synthases (HAS) and degraded by cell associated or 
acid-active hyaluronidases and exoglycosidase enzymes (Tammi 2011). 
Local aberrations of HA metabolism have been reported in many solid tumor malignancies, 
where elevated levels of HA frequently correlate with poor prognosis in tumors such as 
pancreatic, breast, gastric, colorectal, ovarian, prostate and lung carcinoma.  
Approximately 87% of all pancreatic cancers express high levels of HA (Figure 1; Kultti 2012). 
As discussed below, log-rank analysis of HA levels in tumor tissue revealed that the survival rate 
was significantly lower among patients with high HA levels than patients with low HA levels 
(738 days versus 229 days, respectively; p<0.05; Figure 2). These data suggest that HA levels in 
pancreatic adenocarcinoma patients may be predicative of survival(Whatcott 2011).  
In breast carcinoma, the five-year survival rate deteriorated with increasing stromal HA levels; 
the five-year overall survival (OS) for low, moderate, and high HA levels, was 45%, 39%, and 
26%, respectively (p = 0.002) and the recurrence-free survival was 66%, 56%, and 40%, 
respectively (p = 0.008). The presence of HA-positive carcinoma cells correlated significantly 
with axillary lymph node positivity and poor differentiation. The five-year OS of patients 
exhibiting HA-positive carcinoma cells was significantly lower compared with patients without 
HA-positive carcinoma cells (54% versus 81%, respectively, p = 0.01) (Auvinen 2000).  
Gastrointestinal cancers are among those diseases with a significant proportion of cases 
characterized by HA accumulation. In gastric carcinoma, Setälä et al. examined the HA profile 
of 215 Stage I-IV gastric carcinoma patients. A high proportion of HA-positive cells were found 
and were significantly associated with deep tumor invasion, nodal metastasis, positive lymphatic 
invasion, poor differentiation grade, as well as with inferior prognosis in univariate survival 
analysis. Forty-four percent of the tumors evaluated had a HA labeling index of 30 to100% 
HA-positive cells (Setälä 1999).  
In colorectal carcinomas, Ropponen et al. examined the cellular association of HA to survival 
and recurrence-free survival in colorectal carcinoma samples from 202 patients followed for a 

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mean of 14 years. Both high HA intensity and labeling indices were frequently found and 
significantly associated with poorer OS, shorter recurrence-free survival, and elevated Dukes 
classification for 187 evaluable patients (Ropponen 1998). Halozyme has shown that 87% of all 
pancreatic cancers are characterized by significant accumulation of HA (Figure 1; Kultti 2012) 
Anttila et al. studied HA levels in 309 epithelial ovarian cancers and 45 matched metastatic 
lesions. While in 73% (227 of 309) of the cases, the fraction of HA-positive cancer cells was 
<10%, high stromal HA levels were significantly correlated with poor differentiation, serous 
histologic type, advanced stage, and large primary residual tumor (Anttila 2000). 
Profiles of HA deposition in solid tumors have generally been categorized as pericellular or 
stromal. Elevated plasma levels of HA have been observed most notably in patients with Wilms’ 
tumor, mesothelioma, and liver metastases (Wu 1984, Dahl 1989, Thylen 1999, Rosenthal 2005). 
The underlying cause for local HA accumulation in solid tumors has not been well characterized. 
HA synthase overexpression, poor lymphatic drainage or unbalanced synthesis and degradation 
have been proposed as potential mechanisms. Nevertheless, studies that have investigated HA 
levels in tumors have shown that aberrant accumulation of HA occurs in many solid tumor 
malignancies, and HA is an indicator of poor prognosis when associated with stromal or cellular 
compartments (Sironen 2011). 
Substantial human data exist for non-PEGylated, animal-derived hyaluronidase products for 
multiple therapeutic applications (Dunn 2010, Frost 2007). Intravenously administered 
hyaluronidase from animal sources has shown potential for improving the clinical efficacy of 
chemotherapy in doses up to 200,000 U/day (Pillwein 1998, Baumgartner 1998, Klocker 1998). 
In addition, previous preclinical studies have attributed chemopotentiation by hyaluronidase to a 
reduction in interstitial tumor pressure that facilitates enhanced drug penetration into HA-rich 
tumors (Spruss 1995, Brekken 1998, Eikenes 2005). Increased production of HA in tumor cells, 
via ectopic expression of HA synthases, has been shown to induce microvillus structures, 
suppress contact inhibition, and increase tumor growth rates in vivo (Kosaki 1999, Kultti 2006, 
Koyama 2007). Conversely, reduction of tumor HA levels in preclinical studies, either by 
addition of hyaluronidase or by inhibition of HA-synthase activity, has been reported to reduce 
in vitro tumor cell proliferation, motility and invasion, and to reduce the growth of implanted 
tumors (Shuster 2002, Simpson 2002, Kim 2004, Nishida 2005, Udabage 2005, Li 2007, 
Thompson 2010). 
While early hyaluronidase clinical investigations in cancer patients demonstrated potential 
therapeutic activity, these studies were curtailed because of concerns of potential anaphylactic 
responses to the foreign proteins that are found in hyaluronidase products from animal sources. 
Animal-derived hyaluronidase enzymes also have a very short half-life of enzymatic activity in 
blood (approximately 5 min) limiting the duration of action of intravenous (IV) doses. Halozyme 
has developed a recombinant human hyaluronidase enzyme, rHuPH20, derived from the human 
PH20 DNA sequence. The PH20 enzyme is a soluble domain of the endogenous human PH20 
glycoprotein, devoid of its carboxy-terminal, lipid anchor attachment site. The enzyme has been 
approved by the Food and Drug Administration (FDA) in an injectable formulation and is 
marketed as HYLENEX® recombinant.  

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Figure 1: 
Hyaluronan is Expressed in High Levels in a Variety of Human Cancer 
Tissues 
 
 
 
 
Over-expression of HA (HAhigh) was demonstrated in a variety of human cancer tissue utilizing a biotinylated HA 
binding protein-based staining method in tissue biopsies. Columns represent tumor expression of HA and. The 
bottom micrographs are representative histochemically stained tissue demonstrating HA is high in pancreatic ductal 
adenocarcinoma (PDA) compared with normal pancreas (brown stain indicates HA and blue stain is tumor stroma 
detected via H&E). (Kultti 2012) 
The native recombinant human PH20 enzyme has a very short plasma half-life (t1/2 <3 minutes), 
making depletion of tumor HA in vivo impractical. Attempts to utilize rHuPH20 for systemic 
therapy in murine cancer models have shown it to be ineffective as a single agent (Jiang 2012). 
Therefore, to maximize the hyaluronidase activity, Halozyme developed a PEGylated version of 
PH20 to provide a longer half-life and enable systemic therapeutic exposure. Like rHuPH20, 
PEGPH20 removes HA from the ECM by depolymerizing the substrate (Thompson 2010). The 
PEGPH20 protein demonstrates a significantly increased plasma half-life relative to the 
non-PEGylated rHuPH20 protein. In many different tumor types tested in murine xenograft 
models, response to PEGPH20 has been shown to be more robust for tumors characterized by 

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higher HA expression (Jiang 2012). PEGPH20 has a terminal plasma half-life of approximately 
10 hours in rodents and 50 hours in monkeys. In humans, data from two subjects dosed with 
50 μg/kg PEGPH20 in Study HALO-109-101 demonstrated a plasma half-life of 2.5 to 4.8 hours 
for the initial phase and 26 to 49 hours (1 to 2 days) for the terminal phase. The increased plasma 
half-life of PEGPH20 makes sustained depletion of tumor-associated HA feasible.  
4.1. 
Thromboembolic Events in Cancer 
It has been well documented that patients with cancer are at a higher risk for thromboembolic events 
(TE), specifically of venous origin, venous thromboembolic event (VTE), than the general population. 
Based on a review by Timp and colleagues, the odds ratio of risk of a VTE for individuals with cancer 
versus those with no cancer ranges between 4.1 (95% CI; 1.9-8.5, Heit 2000) and 6.7 (95% CI; 5.2-8.6, 
Blom 2005). Multiple factors can further increase the risk, such as the type of malignancy, the stage of 
cancer, the time since cancer diagnosis, and the type of treatment (Timp 2013). Khorana and colleagues 
summarized a predictive model for chemotherapy- associated VTE (Khorana 2010). They identified the 
following patient characteristics as high risk for developing thromboembolic events: site of cancer (very 
high risk [stomach and pancreas]; high risk [lung, lymphoma, gynecologic, bladder and testicular]), 
prechemotherapy platelet count 350 x 109/L or more; hemoglobin level <10.0 g/dL or use of 
erythropoiesis-stimulating agents; prechemotherapy leukocyte count > 11 x 109/L; and BMI 35 kg/m2 or 
more.  
Pancreatic cancer is at higher risk of VTE among various cancer types (NCCN Guideline 2013). 
Several studies reported the incidence rate between 5-36% in retrospective studies and between 
19-67% in autopsy cases series (Epstein and O’Reilly 2012). In a meta-analysis of 38 papers in 
cancer patients, pancreas cancer had approximately 102 VTE in 1000 person-years, as compared 
to brain (116/1000 PY), lung (52/1000 PY), and hematologic cancer (35/1000 PY) 
(Horsted 2012). Epstein and O’Reilly studied selected factors relevant to pancreas cancer and 
thrombosis in the molecular associations and clinical and treatment variables, they found that 
factors associated with coagulation included fibrin, plasminogen, thrombin, etc. The associated 
clinical and treatment variables included hospitalization/sedentary status, surgery, venous 
access/catheterization, weight extremes, anemia, medications (erythropoietin-stimulating agents, 
chemotherapy, and megestrol), and other co-morbidities (e.g., heart, liver, and kidney disease; 
diabetes) (Epstein and O’Reilly 2012).  
Epstein and colleagues conducted a comprehensive analysis of the incidence and clinical 
outcomes in patients with thromboembolic events and pancreatic cancer at Memorial Sloan-
Kettering Cancer Center. They identified 1,915 patients who had a diagnosis of pancreatic cancer 
between 1 Jan 2000 and 31 Dec 2009, of which 36% (N=690 patients) had at least one 
documented TE. Of the 690 subjects, venous events predominated in 614 of patients presenting 
with a noncatheter-related deep vein thromboembolic event and/or a pulmonary embolism (89%, 
614/690) (Epstein 2012). This equates to a 32% incidence amongst all subjects in the sample 
cohort (614/1,915). In this study, arterial events were rare and were reported in 30 patients 
(4.4%). The majority of patients (n = 638, 92.5%) had locally advanced or metastatic disease at 
the time of first TE. Of those, 78% had Stage IV disease. 
Two clinical studies were conducted to specifically assess the rate of symptomatic VTEs with or 
without the use of prophylactic low molecular weight heparin (LMWH) in patients receiving 
standard chemotherapy agents.  

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The CONKO-004 (Riess 2010) was a prospective, open-label, randomized, multicenter and 
group-sequential phase IIb study in patients with locally advanced or metastasized pancreatic 
cancer who are treated with a palliative chemotherapy (stratified for risk) using either 
gemcitabine alone or in combination with cisplatin, 5-fluorouracil (5-FU) and folinic acid, both 
with or without enoxaparin at 1 mg/kg once daily. The primary endpoint was the incidence of 
clinically relevant VTE (symptomatic deep venous thrombosis (DVT) of the leg and/or pelvic 
and/or pulmonary embolism (PE)) within the first 3 months. Secondary endpoints included the 
incidence of symptomatic and asymptomatic VTE after 6, 9 and 12 months as well as remission 
at 3, 6, 9 and 12 months, overall survival and bleeding. A total of 312 subjects were recruited. 
The event rate of all-type TE events (venous and arterial) in patients not receiving LMWH 
prophylaxis was 10% at 3 months and 15% at 12 months as compared to 1.3% and 5% at 3 and 
12 months, respectively, with LMWH. Since the data are presented in abstract form, the 
breakdowns of arterial versus venous TE rates are not presented. 
The FRAGEM study (Maraveyas 2012) was a randomized controlled phase IIb trial to assess the 
effectiveness of LMWH in reducing VTE events in the selected population. Patients were 
eligible if they had histopathological or cytological diagnosis of non-resectable, recurrent or 
metastatic pancreatic adenocarcinoma with no obvious thromboembolism, not on 
anticoagulation, and should not have had a thromboembolic event in the 6 months before 
randomization. Central venous access devices and inferior vena cava filters were not allowed. 
Exclusion criteria included previous gemcitabine-containing treatment, comorbidities which in 
the opinion of the investigator would compromise informed consent or compliance, history of 
other advanced malignancy, ongoing anticoagulation treatment and treatment with antiplatelet 
agents for vascular disease (i.e., aspirin at a dose >75 mg, clopidogrel, etc.). Subjects were 
randomized to receive either gemcitabine (GEM) or gemcitabine with dalteparin (GEMWAD) 
for up to 12 weeks. A total of 123 patients were randomized. A total of 31% (19/62) of subjects 
sustained a VTE in the GEM arm as compared to 12% (7/59) on the GEMWAD arm. VTE 
events leading to death were reported as 8% (5/62) in the GEM arm and 0% (0/59) in GEMWAD 
arm. 
4.2. 
Clinical Experience with PEGPH20 and Clinical Development Plan  
PEGPH20 is being developed as an investigational, novel therapeutic agent for use in 
combination with chemotherapy for the treatment of patients with cancers that accumulate HA.  
As of 01 April 2014, 68 subjects have been treated with PEGPH20 in two Phase 1 clinical 
studies (Studies HALO-109-101 and HALO-109-102) and one Phase 1b/2 study 
(Study HALO-109-201). Both Phase 1 studies are closed to enrollment. A total of 14 subjects 
were dosed in Study HALO-109-101 and 26 in Study HALO-109-102. Enrollment in the 
Phase 1b/2 study is complete; 28 subjects have been dosed.  
4.2.1. 
Phase 1 Study HALO-109-101 
The first Phase 1 study (Study HALO-109-101) was initiated in 2009. This study enrolled 
14 subjects with advanced malignancies (including two subjects with advanced pancreatic 
cancer) who experienced disease progression after previous therapy. The first two subjects 
received one administration of PEGPH20 at 50 μg/kg and experienced severe musculoskeletal 
pain starting between 4 and 10 hours after the initial PEGPH20 dose. For the first subject, the 

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joint and muscle pain resolved over 16 days; however, residual muscle weakness remained and 
interfered with daily activities until death, 19 days after the first dose. The cause of death was 
pulmonary edema due to congestive heart failure, which was deemed not related to study drug. 
For the second subject, the musculoskeletal pain returned to baseline (Grade 1) within 8 days.  
The protocol was amended to reduce the dose by 100-fold for the next subject. The third subject 
was dosed at 0.5 μg/kg dose level twice weekly. Grade 1 transient right calf cramping occurred 
prior to the second dose. Intermittent muscle cramping returned in the feet, calves, and thighs 
one day after the second dose and had increased to Grade 3; it was accompanied by Grade 3 
muscle pain. The muscle spasms and pain began improving within five days and decreased to 
Grade 1 within 10 days and all were resolved within 30 days.  
The protocol was again amended due to the severe musculoskeletal events, and the treatment 
cycle was reduced to one dose every 21 days. On this schedule, three subjects were dosed at 
0.5 μg/kg, four were dosed at 0.75 μg/kg, three were dosed at 1 μg/kg, and one was dosed at 
1.5 μg/kg. Subjects received one to three doses prior to disease progression. No dose-limiting 
toxicities (DLTs) occurred at these dose levels and dosing frequency. The majority of 
musculoskeletal events (MSEs) reported were Grade 1 or 2 and were variable in duration. One 
subject at the 0.75 μg/kg dose level experienced Grade 3 intermittent muscle pain, which was 
resolved within four days. Of the 14 subjects received PEGPH20, 1 subject had advanced 
NSCLC experienced grade 1 superficial phlebitis. Subject was treated as an outpatient with 
Lovenox and the event was resolved without sequelae.  
This study was closed due to musculoskeletal toxicities and the slow dose escalation scheme. To 
attenuate and prophylactically manage the musculoskeletal symptoms, Study HALO-109-102 
was initiated to define the maximum-tolerated dose (MTD) of PEGPH20 when used with 
dexamethasone. Dexamethasone is commonly used in oncology to treat symptoms associated 
with IV anti-cancer therapy. Premedication with dexamethasone completely prevented the 
development of PEGPH20-induced musculoskeletal observations in beagle dogs at doses that are 
approximately 60 to 200 times higher than any dose to be evaluated in this study. This was 
accomplished with preservation of the anti-tumor growth effect of PEGPH20 in preclinical 
studies in mice.  
4.2.2. 
Phase 1 Study HALO-109-102 
Study HALO-109-102 was initiated to evaluate the safety profile of PEGPH20 using the regimen 
of once or twice weekly PEGPH20 administration. Dexamethasone (pre- and post-PEGPH20 
doses) was added to the regimen to alleviate musculoskeletal toxicities. PEGPH20 doses 
administered ranged from 0.5 to 5.0 μg/kg either once or twice weekly (Days 1 and 4) schedule 
for the first cycle (4 weeks) and once per week for subsequent cycles. In addition, subjects 
received 4 or 8 mg dexamethasone 1 hour prior to and 8 to 12 hours after PEGPH20 
administration. 
There were 3 DLTs reported. One subject at 5.0 μg/kg PEGPH20 on a twice weekly schedule 
with 4 mg dexamethasone treatment experienced Grade 3 muscle pain following the third dose in 
Cycle 1 (Cycle 1, Day 8). The event resolved within four days. Following this event, 
dexamethasone treatment was increased to 8 mg. One subject at 3.0 µg/kg on a once weekly 
schedule with the 8 mg dexamethasone experienced a DLT with generalized Grade 2 muscle 
spasms. The third DLT occurred at 5.0 μg/kg PEGPH20 on a once weekly schedule with 8 mg 

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dexamethasone treatment. The subject developed Grade 3 muscle cramps 1 day after the first 
dose; the muscle cramps decreased to Grade 1 within 2 days. Therefore 5.0 µg/kg either once or 
twice weekly was not tolerated. 
In summary, of the total of 26 subjects enrolled in this study, six were treated at 3.0 µg/kg once 
weekly and 15 received 3.0 µg/kg twice weekly schedule. Only one subject experienced a DLT 
at the 3.0 µg/kg once weekly schedule. Intermittent dose interruption due to MSEs was rare and 
dose reduction from 3.0 µg/kg to 1.6 µg/kg occurred in one subject, in Cycle 1 Day 18. The 
number of PEGPH20 doses received ranged from 1 to 22 doses (median is approximately 7). 
Treatment duration ranged from one week up to five cycles (20 weeks). The MTD was 
determined to be 3.0 µg/kg once or twice weekly. PEGPH20 doses up to and including 3.0 µg/kg 
administered once or twice weekly with 8 mg dexamethasone treatment have been fairly well 
tolerated with mostly Grade 1 or 2 musculoskeletal events. These musculoskeletal symptoms 
include muscle cramping, muscle pain, joint pain, back pain, cramping and drawing in of hands 
and fingers, and muscle weakness. Subjects also received symptomatic treatment with other 
medications, including muscle relaxants and pain medications. 
Of the 26 subjects received PEGPH20, 4 subjects had advanced pancreatic cancer. One advanced 
pancreatic cancer experienced a grade 2, non-serious thromboembolic event (embolism). He was 
treated as an outpatient with warfarin and the event was resolved without sequelae.  
4.2.3. 
Phase 1b/2 Study HALO-109-201 
The objective of the Phase 1b portion of Study HALO-109-201 study is to identify the 
recommended Phase 2 dose of PEGPH20 in combination with gemcitabine (GEM) in subjects 
with metastatic pancreatic cancer. Subjects were treated with PEGPH20 administered by IV 
infusion twice per week for the first 4 weeks, then weekly for three weeks, followed by one week 
rest. GEM was administered at 1000 mg/m2 IV over 30 minutes once per week for 7 weeks 
followed by one week rest. Dexamethasone was used 1 hour pre and 8 hours post PEGPH20 
dosing. From Cycle 2 onward, PEGPH20 and GEM were administered once weekly for three 
weeks in a 4-week cycle. As of 01 April 2013, 28 subjects were enrolled and all received study 
medication. Four subjects received PEGPH20 at 1 µg/kg dose level, four received PEGPH20 at 
1.6 µg/kg dose level, and 20 subjects received PEGPH20 at 3.0 µg/kg dose level. Treatment 
duration ranges from 1 day to more than 10 months. Enrollment is ongoing. Two subjects 
(1 µg/kg and 3.0 µg/kg dose levels) had infusion reaction when PEGPH20 was administered as 
an IV push or IV slow push. The protocol has since been amended to administer PEGPH20 as an 
IV infusion over 10 minutes. No additional infusion reactions have been reported.  
The safety profile of PEGPH20 in combination with GEM is similar to what was observed in the 
first 2 Phase 1 studies, with MSEs as the most common toxicities. The most common toxicities 
observed for GEM were myelosuppression (such as neutropenia) and GI toxicities (such as 
nausea and vomiting). In addition, most of the AEs related to GEM were similar in frequency 
and severity regardless of the PEGPH20 dose levels. Of the 24 subjects who received either 
1.6 or 3.0 µg/kg, treatment duration ranged from one dose to up to 9 cycles. Two subjects 
experienced infusion reactions when PEGPH20 was administered as a 2 mL slow push. After 
this event, the protocol was amended to administer PEGPH20 as a 10 mL IV infusion over 
10 minutes (1 mL/minute). Additionally, the protocol amendment clarified that hypersensitivity 
related reactions are not considered DLTs because hypersensitivity reactions in general are not 

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related to the dose level of a drug since even a small amount of exposure can lead to 
hypersensitivity reactions. There were no DLTs reported according to study DLT definition.  
In general, the most commonly reported toxicities associated with PEGPH20 have been 
musculoskeletal events (e.g., muscle, joint, and bone pain; muscle cramping; and other 
involuntary contractions). Less commonly reported events are edema in the legs or arms, fatigue 
and generalized weakness, diarrhea, nausea, vomiting, and decreased appetite, rash, mild sore 
throat, voice hoarseness, and hiccups. Atrial fibrillation was reported in one subject (although 
high doses of steroids are well known to be associated with an irregular heartbeat (e.g., 
bradycardia, cardiac arrest, and cardiac arrhythmia), a relationship to PEGPH20 could not be 
ruled out). Pneumonitis was also reported in one subject (reported rarely following one or more 
doses of GEM, per GEM package insert; however, the relationship to PEGPH20 could not be 
ruled out).  
Treatment emergent TE events were reported in 8 subjects. The most frequently reported 
thromboembolic event was pulmonary embolism, which occurred in 5 subjects (18%, 5/28 [1 at 
1 μg/kg and 4 at 3.0 μg/kg] ). Among the five subjects with a pulmonary embolism, one subject 
also had a deep vein thrombosis, which occurred one day after the reported pulmonary 
embolism. One other subject experienced partial thrombosis of the right gonadal vein, DVT, 
splenic infraction and cerebrovascular accident. One subject experienced jugular vein thrombosis 
and one experienced cerebrovascular accident. Since the total incidence of subjects with either a 
venous or arterial TE in this single arm study is 28.5% (8/28) and was within the reported range 
of 5-36% in patients with PDA (Epstein AS 2012), these events were not identified as increased 
AEs.  
The on-study duration for all 28 patients ranged from 6 to 365 days, with a median duration of 
92 days. Responses were assessed by an independent central radiologist. Partial responses were 
reported in 10 of the 24 patients who received PEGPH20 at either 1.6 or 3.0 µg/kg dose level. In 
addition, subjects who had high HA in tissue biopsies experienced better responses (5/6 
subjects), which correlated with prolonged progression free survival (219 days) and overall 
survival (~529 days). Partial responses were seen in 4 of the 11 subjects who had lower HA in 
tissue biopsies. The PFS and OS in the low HA group was 108 days and 174 days, respectively 
(Hingorani 2013).  
The recommended Phase 2 dose for PEGPH20 in combination with GEM is 3.0 µg/kg twice 
weekly in the first 4 weeks and once weekly thereafter.  
Based on the emerging safety profile of PEGPH20, the proposed starting dose of 3.0 µg/kg is 
acceptable for the intended patient population. Considering that the subjects who will be enrolled 
in this study have an overall poor prognosis, with extra pancreatic disease precluding curative 
surgical resection, and that their Phase 3 study (Von Hoff 2013) results improved the overall 
survival for the primary objective, which further confirmed the published Phase 2 study results 
(Von Hoff 2011), it is reasonable to test the treatment effect of PEGPH20 in combination with 
nab-paclitaxel (NAB) plus GEM in advance pancreatic cancer patients.  
4.2.4. 
Thromboembolic events reported in the current study 
As of April 1 2014, a total of 146 subjects were enrolled in the HALO-109-202 study. 
Preliminary safety data suggested the possibility of an increase in TE events in the PEGPH20 

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plus nab-paclitaxel and gemcitabine (PAG) arm compared to the nab-paclitaxel and gemcitabine 
arm (AG).  
Based on a comprehensive review of literature (Section 4.1 and Section 4.2) and cancer 
treatment guidelines, and in consultation with oncology/hematology thrombosis experts , the 
current protocol is amended. To reduce the rate of TE events, subjects at high risk of venous and 
arterial thromboembolic events will be excluded from entering the study. High risk subjects will 
also be excluded from continuing PEGPH20 therapy. LMWH therapy will be used in all subjects 
on this study (see Section 6.1.3 for details).  
Subjects at higher risk of arterial events, specifically those with a prior history of cerebrovascular 
accident and a history of evidence of carotid artery disease will be excluded from trial 
participation. In Stage 2 of the study, prior to Amendment 5.0, the Khorana Risk Score factors 
(Khorana 2010) were utilized to identify those subjects at higher risk of venous thromboembolic 
events. The Khorana Risk Score is designed to stratify cancer patients into low, intermediate, and 
high risk for developing VTE. This risk score was originally derived from a development cohort 
of 2701 patients and was then validated in an independent cohort of 1365 patients from a 
prospective registry. Observed rates of VTE in the development and validation cohorts were 
0.8% and 0.3% in the low-risk category, 1.8% and 2% in the intermediate-risk category, and 
7.1% and 6.7% in the high-risk category, respectively. Among the potential risk factors for 
developing TE events, having pancreatic cancer, hemoglobin < 10 g/dL, BMI ≥ 35kg/m2, WBC 
≥ 11x109/L platelet count >350,000/L, were the key risk factors.  
Prophylactic use of enoxaparin was studied in patients with either locally advanced or 
metastasized pancreatic cancer by Riess et al (Riess 2010). In this study 312 patients were treated 
with a palliative chemotherapy (stratified for risk) using either gemcitabine alone or in 
combination with cisplatin, 5-fluorouracil (5-FU) and folinic acid, with or without enoxaparin, 
initially at a dose of 1 mg/kg, then at a dose of 40 mg daily. The event rate of all-type TE events 
(venous and arterial) in patients not receiving LMWH prophylaxis was 10% at 3 months and 
15% at 12 months as compared to 1.3% and 5% at 3 and 12 months in patients receiving 
LMWH, respectively (p=0.01). Other LMWHs, such as dalteparin, semuloparin, were also 
studied in advanced cancer patients receiving chemotherapy. In general, use of LMWH reduced 
the VTE events significantly, with no increase in major bleeds reported in pancreatic cancer, 
however some increase has been reported in other cancers (Agnelli 2009, Agnelli 2012, 
Maraveyas 2012, Farge 2013). 
It is well documented that the use of Megestrol acetate causes thrombosis. Ruiz et al reviewed over 35 
trials with 3963 patients for effectiveness and 3180 for safety with regard to appetite improvement and 
weight gain in cancer, AIDS and other underlying conditions (Ruiz 2013). The review shows that 
megestrol acetate is associated with an increased risk of blood clots (which may result in swelling, pain 
or redness of one extremity and not the other, sudden difficulty in breathing, severe headache or vision 
changes), fluid retention (resulting in swelling of the feet or hands) and death. Therefore, concomitant 
use of megestrol acetate is prohibited in this study. 
4.2.5. 
Clinical Pharmacokinetics 
Subjects enrolled in the Phase 1 studies received PEGPH20 at doses ranging from 0.5 to 
50 μg/kg with or without dexamethasone. Blood samples were collected at scheduled timepoints, 
and plasma was analyzed for PEGPH20 concentrations. Pharmacokinetic (PK) analysis suggests 

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that a linear PK model adequately described the available PEGPH20 plasma concentration versus 
time profiles. The maximum plasma concentrations were estimated to be between 0.4 and 1.0 
hours after dosing. Subjects dosed with 50 μg/kg PEGPH20 in Study HALO-109-101 
demonstrated a plasma half-life of 2.5 to 4.8 hours for the initial phase and 26 to 49 hours (1 to 
2 days) for the terminal phase. Estimates for initial distribution volume were consistent with 
expectations for therapeutic macromolecules. The prolonged plasma half-life of PEGPH20 
makes sustained depletion of tumor-associated HA feasible.  
Table 6 provides a summary of descriptive PK parameters, including the maximum-observed 
concentration (Cmax), time-to-maximum plasma concentration (tmax) and the 
area-under-the-concentration time curve (AUC) estimates for 0 to 72 hours (AUC0-72) following 
the initial dose of PEGPH20 for subjects in Study HALO-109-101. Results from this descriptive 
PK analysis indicate a dose-dependent increase in systemic exposure (Cmax, AUC0-72) after a 
single PEGPH20 dose in the 0.5 to 50 μg/kg range. 
Table 6: 
Descriptive Pharmacokinetic Parameters (Mean ± SD) after Initial 
IV PEGPH20 Dosing at 0.5 to 1.5 µg/kg (Study HALO-109-101) 
Dose 
(µg/kg) 
N 
tmax 
(h) 
Cmax 
(U/mL) 
AUC0-72 
(Uh/mL) 
0.5a 
4 
0.423 ± 0.133 
0.325 ± 0.221 
2.23 ± 2.95 
0.75 
4 
0.580 ± 0.244 
0.558 ± 0.148 
0.873 ± 0.578 
1.0 
3 
1.01 ± 0.883 
0.718 ± 0.094 
8.13 ± 6.37 
1.5 
1 
0.5 
1.61 
13.5 
50 
2 
0.625 ± 0.530 
30.9 ± 0.566 
580 ± 84.3 
Abbreviations: AUC0-72= area-under-the-concentration time curve from 0 to 72 hours; Cmax = maximum-observed 
concentration; h = hour; IV = intravenous; SD = standard deviation; tmax = time-to-maximum concentration 
a N = 3 in statistical calculations, except for Cmax (N = 4). 
Preliminary PK data are available from the initial 18 subjects who received multiple doses of 
PEGPH20 with dexamethasone in Study HALO-109-102. Table 7 provides an interim summary 
of descriptive PK parameters, including Cmax, tmax, and AUC0-72 following the initial dose of 
PEGPH20 for subjects in Study HALO-109-102. For subjects treated with 0.5 or 1.6 μg/kg 
PEGPH20, Cmax values were consistent with those measured in Study HALO-109-101. 
Concentrations typically fell to the limit of quantification within the first day. Cmax values from 
subjects treated with 5.0 μg/kg, maximum PEGPH20 concentrations were approximately one 
tenth of the Cmax values detected for subjects treated with 50 μg/kg in Study HALO-109-101. 

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Table 7: 
Descriptive Pharmacokinetic Parameters (Mean ± SD) after Initial IV 
PEGPH20 Dosing at 0.5 to 5.0 µg/kg (Study HALO-109-102) 
Dose 
(µg/kg) 
N 
tmax 
(h) 
Cmax 
(U/mL) 
AUC0-72 
(Uh/mL) 
0.5 
1 
0.25 
0.4 
NC 
1.6 
3 
0.667 ± 0.382 
0.90 ± .015 
2.27 ± 0.37 
3.0 
12 
0.792 ± 1.04 
3.76 ± 6.86 
42.42 ± 60.93 
5.0 
2 
0.875 ± 0.177 
4.33 ± 1.31 
98.71 ± 13.99 
Abbreviations: AUC0-72 = area-under-the-concentration time curve from 0 to 72 hours; Cmax = maximum-observed 
concentration; h = hour; IV = intravenous; SD = standard deviation; tmax = time-to-maximum observed plasma 
concentration. 
Plasma samples collected approximately 1 hour after repeat PEGPH20 dosing were used to 
evaluate the effects of twice-weekly dosing on plasma PK. Consistent with the limited results in 
Study HALO-109-101, there was no evidence for significant accumulation of PEGPH20 in the 
plasma. This preliminary analysis suggests that the plasma PK of PEGPH20 is similar for these 
two Phase 1 studies.  
The ongoing HALO-109-201 study is to evaluate the treatment effect of PEGPH20 in 
combination with GEM in subjects with advanced pancreatic cancer. Serial blood samples were 
drawn to characterize the pharmacokinetic profile of PEGPH20 in combination with GEM. 
Preliminary PK results are available in the first 18 subjects who received PEGPH20 at doses 
ranged from 1.0 µg/kg to 3.0 µg/kg in combination with GEM. Table 8 summarizes descriptive 
PK parameters, including Cmax, tmax, and AUC0-72 following the initial dose of PEGPH20 for 
subjects in Study HALO-109-201 
Table 8: 
Descriptive Pharmacokinetic Parameters (Mean ± SD) after Initial IV 
PEGPH20 Dosing at 1.0 to 3.0 μg/kg in Combination With Gemcitabine 
(Study HALO-109-201) 
Dose 
(μg/kg) 
N 
tmax 
(h) 
Cmax 
(U/mL) 
AUC0-72 
(Uh/mL) 
1.0 
3 
0.25 ± 0.0 
1.09 ± 0.627 
11.93 ± 13.09a 
1.6 
4 
0.438 ± 0.375 
2.89 ± 1.74 
31.56 ± 22.48 
3.0 
10 
0.25 ± 0.0 
2.607 ± 1.60 
33.80 ± 53.10 
Abbreviations: AUC0-72 = area-under-the-concentration time curve from 0 to 72 hours; Cmax = maximum-observed 
concentration; h = hour; IV = intravenous; SD = standard deviation; tmax = time-to maximum observed plasma 
concentration.  
a N=2 for AUC. 
Consistent with PK results of the two Phase 1 single agent studies, plasma concentrations of 
PEGPH20 when combined with GEM were similar to predictions from a linear PK model that 
has been established for PEGPH20 as a single agent.  

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4.2.6. 
Pharmacodynamic Evaluations 
Measurements of plasma HA catabolites (breakdown products of HA after enzymatic depletion 
by PEGPH20) were used to provide an initial indicator of PEGPH20 pharmacodynamics. Prior to 
dosing with PEGPH20, HA plasma concentrations were typically <1 μg/mL or below the level of 
quantification (0.5 μg/mL). For subjects dosed with 50 μg/kg PEGPH20 plasma concentrations 
of HA increased slowly with maximum HA measurements observed ≥72 hours post-PEGPH20 
dose, and plasma concentrations were still detectable up to 2 weeks post-PEGPH20 
administration. Analysis of reported initial 24-hour data from subjects enrolled in Studies 
HALO-109-101 and HALO-109-102 demonstrated a dose-dependent increase in HA plasma 
concentrations.  
A comparative evaluation of tumor biopsies was performed in two subjects treated with 
1.6 μg/kg PEGPH20. Histochemical staining using a biotinylated HA binding protein 
demonstrated a decrease in pericellular and stromal HA in tumor specimens collected after 
4-weekly doses of PEGPH20. Decreased levels of HA in tumor together with increased detection 
of HA in the plasma are consistent with the expected enzymatic activity of PEGPH20. 
The pharmacologic activity of PEGPH20 was also assessed using magnetic resonance imaging 
(MRI) and FDG-PEG. MRI scans were collected prior to and 2 to 4 days after PEGPH20 dosing, 
and increases in apparent diffusion coefficient values in tumors were reported in 7 of 11 subjects 
evaluated. Dynamic contrast-enhanced MRI was conducted in a subset of subjects, and permitted 
estimation of Ktrans, extracellular space volume fraction, and blood plasma volume fraction of the 
whole tissue. Transient increases in tumor Ktrans values were reported two subjects within 24 
hours of PEGPH20 dosing. FDG-PET was used to evaluate tumor metabolism in one subject 
with metastatic rectal cancer that received 3 µg/kg PEGPH20 treatment. Comparison of 
standardized uptake values (SUVs) before and after treatment demonstrated reductions in tumor 
SUVs that ranged from 19% to 42% (Infante 2012). These preliminary data are consistent with a 
mechanism for PEGPH20 that includes modification of the ECM and facilitation of tumor uptake 
of anti-tumor agents.  
4.2.7. 
Evaluation of the New Formulation of PEGPH20 
The original formulation of PEGPH20 (frozen drug product at 3.5 mg/mL) uses histidine in the 
formulation and has been tested in nonclinical pharmacology and toxicology studies and in 
clinical studies (see the Investigators Brochure for additional information).  
A new formulation of PEGPH20 (liquid drug product at 0.3 mg/mL) has been developed based 
on drug administration needs determined in earlier clinical studies. This succinic acid 
formulation provides enhanced stability, allowing the drug product to be stored at 2°C to 8°C, 
instead of -20°C, which is required for the original PEGPH20 formulation. Comparative studies 
have shown that PEGPH20 histidine and succinic acid formulations have equivalent exposure 
(AUC and Cmax) in rats. Based on these findings, the new succinic acid formulation is proposed 
for evaluation in ongoing and future studies. 
As of June 2013, over 20 subjects have been treated with the original formulation of PEGPH20 
at 3.0 µg/kg. The established safety and PK profile of PEGPH20 at this dose level was 
acceptable, with minimum toxicities in most subjects. PK and safety data from these subjects 

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will be compared with subjects receiving the new formation of PEGPH20 at 3.0 µg/kg in the 
current study.  
4.3. 
Study Rationale 
The incidence of pancreatic carcinoma has markedly increased during the past several decades 
and ranks as the fourth leading cause of cancer death in the United States (US). Approximately 
44,000 new cases of pancreatic cancer were diagnosed in the US in 2011 with an estimated 
37,600 deaths. Metastatic PDA is a lethal disease with a median survival of approximately 
6 months.  
GEM is the only approved single agent for the treatment of pancreatic carcinoma, with a median 
survival of 5.7 months versus 4.4 months for fluorouracil (5-FU), and a 1-year rate of 20% 
(Burris 1997). GEM is also given in combination with other therapies. Recently Conroy and 
colleagues reported that the median OS for treatment with FOLFIRINOX (5-FU, leucovorin, 
irinotecan, and oxaliplatin combination chemotherapy) was 11.1 months versus 6.5 months for 
treatment with GEM alone (Conroy 2011). The efficacy of GEM in combination with NAB was 
evaluated in a Phase 2 study of previously untreated advanced pancreatic cancer patients 
(Von Hoff 2011). At the MTD (the recommended dose for Phase 3), 1000 mg/m2 of GEM plus 
125 mg/m2 of NAB were administered weekly for 3 weeks and repeated every 4 weeks. The 
overall response rate (ORR) was 48%, with OS at 12.2 months, and 1-year survival rate of 48%. 
The study reported the highest response rate with significant improvement of survival benefit in 
recent years. The follow-up Phase 3 study was reported to have reached statistical significance 
on survival benefit, though the exact benefit has not yet been published. Based on the Phase 2 
study results, National Comprehensive Cancer Network guidelines recommend the combination 
treatment of GEM plus NAB as one of the front-line therapies for metastatic pancreatic cancer. It 
is reasonable to believe that NAB plus GEM may become one of the standard of care treatments 
for pancreatic cancer. Therefore, this Phase 2 study was designed to evaluate the treatment effect 
of PEGPH20 in combination with NAB plus GEM with NAB plus GEM. 
PEGPH20 is a PEGylated version of human recombinant PH20 hyaluronidase. In preclinical 
studies, PEGPH20 has been shown to remove HA from the ECM surrounding tumor cells by 
depolymerizing this substrate. In tumors that are rich in HA, such as 87% of pancreatic cancers 
(Figure 1) (Kultti 2012), tumor tissue may be especially sensitive to the HA-degradation 
properties of PEGPH20 and thus more responsive to the cytotoxic effects of a given dose of 
chemotherapy.  
In order to understand the role of HA and survival in patients with PDA, Translational Genomics 
Research Institute conducted a retrospective study of HA-specific staining in tissue microarrays 
constructed from 43 resected PDA samples for which patient survival had been followed for 
more than 8 years (Whatcott 2011). One hundred percent (100%) of the patient tumors stained 
positive for HA in at least some fraction of the tissue area (stroma). Log-rank analysis of HA 
levels in tumor tissue revealed that the survival rate was significantly lower among patients with 
high HA levels than patients with low HA levels (738 days versus 229 days, respectively; 
p<0.05; Figure 2). These data suggest that HA levels in pancreatic adenocarcinoma patients may 
be predicative of survival.  
PEGPH20 has demonstrated anti-tumor activity alone or in combination with GEM in a variety 
of preclinical tumor model systems, including xenograft and genetically engineered murine 

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models of pancreatic cancer. In a genetically engineered mouse model of PDA, mice develop 
tumors with clinical, histopathologic and molecular features indistinguishable from human PDA; 
importantly, the murine tumors are also found to express high levels of HA (Hingorani 2005). In 
this KrasLSL-G12D/+;Trp53LSL-R172H/+; Cre (KPC) model of PDA, co-treatment of PEGPH20 with 
GEM significantly prolonged survival when compared with GEM treatment alone (Figure 3). 
Mice treated with GEM alone survived for 15 days while mice treated with GEM and PEGPH20 
survived for 28.5 days (Jacobetz 2013). In a second study, both PEGPH20 and GEM were 
administered IV on a weekly regimen mimicking the proposed human study. In this study, 
median OS was increased by approximately 83%, from 55.5 days with GEM plus placebo to 
91.5 days for GEM plus PEGPH20 (Provenzano 2012).  
Figure 2: 
Survival by High and Low Hyaluronan levels in Pancreatic Ductal 
Adenocarcinoma Tumors 
 
Retrospective study utilizing a biotinylated HA binding protein-based staining method in a tissue microarray 
constructed from 43 resected PDA samples for which patient survival had been followed for more than 8 years. 
HA staining was primarily observed in the peritumoral, or stromal, compartments of the tumor tissue samples. 
100% of the patient tumors stained positive in at least some fraction of the tissue area (stroma) for HA. Staining 
with a biotinylated HA binding protein was scored according to the percentage area of HA-positivity relative to the 
total tissue area. (Whatcott 2011)  
 
HALow  (<40%) vs HAHigh (>40%) HA
0
400
800
1200
1600
2000
2400
2800
3200
0
20
40
60
80
100
High 32/43
Low 11/43
Time (days)
Percent survival

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Figure 3: 
PEGPH20 Combined with Gemcitabine Significantly Increased Survival in 
the KPC Mouse Model of Pancreatic Ductal Adenocarcinoma  
 
 
PEGPH20 combined with GEM significantly increased survival in the KPC mouse model of 
human PDA. In the first study, both PEGPH20 and GEM were administered IV and on a weekly 
regimen mimicking the proposed human study. In this study, median OS was increased by 
approximately 70%, i.e. from 55.5 days with GEM plus placebo (n=16) to 92 days for the 
combination of PEGPH20 + GEM (n=14) (p<0.004; Figure 3) (Provenzano 2012). In a second 
study, mice were treated twice per week with 100 mg/kg GEM intraperitoneally and/or 
4.5 mg/kg PEGPH20 IV. Mice treated with vehicle or PEGPH20 survived a median of 11 days, 
mice treated with GEM survived for a median of 15 days and mice treated with PEGPH20 plus 
GEM survived a median of 28.5 days with a significant difference in survival of GEM versus 
GEM plus PEGH20 of 13.5 days (Jacobetz 2013).  
In addition to studies in KPC mice, the combination of PEGPH20 with GEM and/or NAB was 
evaluated in a human PDA BxPC3 xenograft model (Figure 4). The highest tumor growth 
inhibition (TGI) measured (81%) was in the triple combination group (PEGPH20 plus GEM plus 
NAB) compared with all other combinations tested. This represented a 23% increase in TGI over 
GEM plus NAB without PEGPH20. Further, the addition of PEGPH20 increased the median 
survival time of the GEM plus NAB group by 31% (Osgood 2012). 

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Figure 4: 
PEGPH20 Combined with Gemcitabine and Nab-Paclitaxel Significantly 
Increased Survival in the KPC Mouse Model of Pancreatic Ductal 
Adenocarcinoma  
 
The addition of PEGPH20 to NAB and GEM increased TGI to 81% (p < 0.0001) relative to vehicle and was 
superior to NAB + GEM treatment (66%; p = 0.0004). In brief, mice were staged into eight treatment groups 
(n=8/group): vehicle control, PEGPH20 (4.5 mg/kg, IV, 2x/wk) ± NAB (10 mg/kg, IV, 2x/wk) ± GEM (180 
mg/kg, intraperitoneal, 1x/wk, dosed 24 hours after PEGPH20 and NAB). Note: to mimic GEM dosing in the 
clinic, mice were given a one week GEM holiday following the third GEM dose. (Osgood 2012)  
 
These data suggest that pancreatic adenocarcinomas express high levels of HA and that 
degrading tumor-associated HA may make these tumor cells more susceptible to the 
growth-inhibiting properties of GEM and NAB. 
4.3.1. 
Rationale for Selection of the PEGPH20 Starting Dose 
A total of 40 subjects received at least one dose of PEGPH20 as a single agent in the 
Studies HALO-109-101 and HALO-109-102. The MTD for PEGPH20 was 3.0 µg/kg in the once 
weekly or twice weekly dosing regimen, when dexamethasone was given at 8 mg 1 hour pre- and 
8 hours post-PEGPH20 dosing. The most common and DLTs were MSEs. At the 3.0 µg/kg dose 
level, most of the MSEs reported were Grade 1 or 2, and most resolved within one week after 
dosing was stopped. In Study HALO-109-201, PEGPH20 was tested at 3 dose levels (1.0, 1.6, 
and 3.0 µg/kg) in combination with GEM (1000 mg/m2) in 28 subjects. The MTD for PEGPH20 
was determined to be 3.0 µg/kg. 
In Study HALO-109-101, analysis of plasma samples demonstrated quantifiable levels of 
hyaluronidase activity between 15 minutes and 76 to 224 hours post-PEGPH20 dosing. Plasma 
concentrations declined exponentially with time and were frequently below the limit of assay 
sensitivity, especially after lower doses of PEGPH20. Interim PK analysis suggests that a linear 
PK model adequately described the concentration versus time profiles. Maximum measured 
plasma concentrations were 30.5 U/mL and 31.2 U/mL in subjects dosed with 50 μg/kg 

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PEGPH20. Estimates for initial distribution volume were consistent with expectations for 
therapeutic macromolecules. Plasma half-life estimates were 2.5 to 4.8 hours for the initial phase 
and 26 to 49 hours (1 to 2 days) for the terminal phase. This analysis predicts that twice weekly 
dosing with 1.6 μg/kg PEGPH20 will keep the plasma concentrations above 0.1 U/mL. The 
predicted plasma concentration-time profile can be expected to produce continuous enzymatic 
activity in vivo that acts to hydrolyze tumor HA.  
Supported by data that dexamethasone can prevent musculoskeletal observations in a canine 
model and a decreased prevalence and severity of musculoskeletal symptoms with a pre- and 
post-treatment dosing regimen of dexamethasone in Studies HALO-109-102 and 
HALO-109-201, a premedication regimen of dexamethasone 8 mg twice a day (bid) should 
accompany PEGPH20 doses. The Investigator may adjust the dose of dexamethasone based on 
the clinical presentation of each subject. 
In preclinical models, PEGPH20, either a single agent or in combination with GEM effectively 
inhibited tumor growth at doses as low as 0.01 to 0.1 mg/kg (data on file at Halozyme). To 
predict the equivalent human exposure at these doses, an interspecies scaling algorithm was used 
that assumes plasma clearance of PEGPH20 scales in proportion to (body weight)0.67. The 
efficacious doses in mice (0.01 to 0.1 mg/kg) scale to human equivalent doses of 0.75 to 
7.5 µg/kg. As mice have approximately 20 times the circulating levels of HA compared to 
humans, it is hypothesized that an equivalent dose of PEGPH20 may have relatively more 
anti-tumor activity in humans.  
In Study HALO-109-102, a dose level of 1.6 μg/kg PEGPH20 administered on a twice weekly 
schedule increased circulating concentrations of HA catabolites and reduced tumor-associated 
HA (Infante 2012). The degradation of tumor-associated HA is hypothesized to increase the 
ability of anti-cancer agents to penetrate tumor tissue and, therefore increase cytotoxic activity in 
tumors. In tumors that are rich in HA, which has been documented to occur in approximately 
87% of all pancreatic cancers (Figure 1), tumor tissue may be especially sensitive to the 
HA-degradation by PEGPH20 and thus responsive to an increase in the cytotoxic effects of a 
given dose of GEM. Modifying the extracellular environment to increase the penetration and 
efficacy of chemotherapeutics represents a novel approach to treating pancreatic cancer in a 
setting that has demonstrated limited therapeutic efficacy. 
Preliminary anti-tumor activity has been observed in metastatic pancreatic cancer subjects at 
PEGPH20 dose levels of 1.6 and 3.0 µg/kg in combination with GEM in Study HALO-109-201. 
This Phase 2 study plans to investigate PEGPH20 at a 3.0 µg/kg dose level when combined with 
NAB and GEM.  
4.4. 
Background of Nab-paclitaxel 
NAB is an albumin-bound form of paclitaxel. NAB promotes the assembly of microtubules from 
tubulin dimmers and stabilizes microtubules by preventing depolymerization. This stability 
results in the inhibition of the normal dynamic reorganization of the microtubule network that is 
essential for vital interphase and mitotic cellular functions. Paclitaxel induces abnormal arrays or 
“bundles” of microtubules throughout the cell cycle and multiple asters of microtubules during 
mitosis.  

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NAB (ABRAXANE®) is approved by FDA and other regulatory agencies as a single agent for 
the treatment of metastatic breast cancer, after failure of combination chemotherapy for 
metastatic disease or relapse within 6 months of adjuvant chemotherapy. It is also approved as a 
first-line treatment in combination with carboplatin in locally advanced or metastatic non-small 
cell lung cancer in patients who are not candidates for curative surgery or radiation therapy. 
4.5. 
Background of Gemcitabine 
GEM 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. GEM is 
metabolized intracellularly by nucleoside kinases to the active diphosphate (dFdCDP) and 
triphosphate (dFdCTP) nucleosides. The cytotoxic effect of GEM is attributed to a combination 
of two actions of the diphosphate and the triphosphate nucleosides, which leads to inhibition of 
DNA synthesis. First, GEM 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, GEM 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 GEM triphosphate into DNA 
(self-potentiation). After the GEM nucleotide is incorporated into DNA, only one additional 
nucleotide is added to the growing DNA strands. After this addition, there is inhibition of further 
DNA synthesis. DNA polymerase epsilon is unable to remove the GEM nucleotide and repair the 
growing DNA strands (masked chain termination).  
GEM (GEMZAR®) is approved by the FDA and other regulatory agencies as a single agent as 
the first-line treatment for patients with locally advanced (Stage II or Stage III when surgery is 
not an option) or metastatic (Stage IV) adenocarcinoma of the pancreas. GEM is also indicated 
for patients previously treated with 5-FU. 

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5. 
STUDY OBJECTIVES AND ENDPOINTS 
5.1. 
Study Objectives 
5.1.1. 
Primary Objective 
• To estimate the progression-free survival (PFS) duration of PEGPH20 combined with 
NAB plus GEM (PAG treatment). 
• To evaluate the thromboembolic events in subjects treated in the PAG arm in Stage 2 
of the study as of this protocol amendment. 
5.1.2. 
Secondary Objectives 
• To estimate the relative benefit of PAG treatment versus NAB plus GEM (AG 
treatment), as assessed by the PFS hazard ratio. 
• To estimate the relative benefit of PAG treatment versus AG treatment, as assessed 
by the PFS hazard ratio based on subject tumor-associated HA levels.  
• To estimate the ORR, as defined by the Response Evaluation Criteria in Solid Tumors 
(RECIST v1.1), of PAG treatment and the relative benefit of PAG treatment versus 
AG treatment.  
• To estimate the OS duration of PAG treatment and the relative benefit of PAG 
treatment versus AG treatment, as assessed by the OS hazard ratio.  
• To evaluate the safety and tolerability profile of the PAG and AG treatment groups.  
• To characterize the plasma PK of PEGPH20 when given in combination with NAB 
plus GEM.  
5.1.3. 
Exploratory Objectives 
• To estimate the OS benefit of PAG treatment versus AG treatment based on HA 
levels from tumor biopsies. 
• To estimate the duration of response (DR) of responders (complete response [CR] and 
partial response [PR]) of PAG and AG treatment. 
• To compare the disease control rate (DCR; CR, PR, and stable disease [SD]) between 
the PAG and AG treatment groups.  
• To compare CA19-9 changes between the PAG and AG treatment groups. 
• To assess treatment effect of PAG with regard to HA levels in plasma and in tumor 
biopsies. 
5.2. 
Study Endpoints 
5.2.1. 
Primary Endpoint 
• PFS (measured from the date of randomization until disease progression or death 
from any cause). 

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• Proportion of subjects in the PAG arm who experience any thromboembolic event in 
Stage 2 of the study as of Amendment 3.0.  
5.2.2. 
Secondary Efficacy Endpoints 
• PFS in relation to HA levels.  
• ORR (defined as the percentage of subjects with a RECIST v1.1 PR or CR).  
• OS (measured from the date of randomization until death from any cause). 
5.2.3. 
Exploratory Efficacy Endpoints 
• OS in relation to HA levels. 
• DR (measured from the date of the first CR/PR until disease progression). 
• DCR (defined as the percentage of subjects with SD, PR, or CR). 
• Serum CA 19-9 response rate between the PAG and AG treatment groups. 
• PEGPH20 anti-tumor activities based on HA levels in plasma and in tumor biopsies. 

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6. 
INVESTIGATIONAL PLAN 
6.1. 
Overall Study Design and Plan: Description 
This is a Phase 2, multicenter, open-label, randomized study of PEGPH20+NAB+GEM 
(PAG treatment) compared with NAB+GEM (AG treatment) in subjects with Stage IV 
previously untreated pancreatic cancer. The study has two run-in phases, one for each 
formulation of PEGPH20 (original and new formulations). The first run-in phase will evaluate 
the safety and tolerability of PAG treatment (original PEGPH20 formulation) compared with 
AG treatment before initiating Phase 2. The Phase 2 portion is an open-label randomized study 
and has two stages. With Amendment 1.0, an additional run-in phase will be conducted to 
incorporate a new formulation of PEGPH20 during the Phase 2. Stage 2 was added in 
Amendment 3.0.enrollment. 
The dosing schedule for subjects randomized to the PAG and AG treatment groups will be the 
same in the run-in phases and Phase 2 (see Section 6.1.3). The treatment period will consist of 
4-week treatment cycles (28 days) with Week 4 of every cycle as a washout week (i.e., no 
treatment will be given). Treatment will continue until disease progression or unacceptable 
toxicity is documented.  
6.1.1. 
Run-in Phases 
6.1.1.1. 
Original Formulation of PEGPH20 
In the first run-in phase, approximately 8 subjects will be randomized in a 3:1 ratio to receive 
PEGPH20 (3.0 µg/kg; original formulation) in combination with standard dosing of NAB+GEM 
(PAG treatment) or NAB+GEM (AG treatment). No stratification factors will be used. 
Additional subjects may be enrolled to further assess the tolerability of PEGPH20 in order to 
establish the acceptable safety profile prior to the randomization of the Phase 2 study. 
The Sponsor, the participating Investigators, and the independent safety physician will determine 
if the dose and regimen for Phase 2 is acceptable after reviewing all available safety data from 
Cycle 1 from all subjects in this run-in phase. 
6.1.1.2. 
New Formulation of PEGPH20  
With Amendment 1.0, a second run-in phase will be conducted to evaluate a new formulation of 
PEGPH20. Approximately 8 subjects will be randomized in a 3:1 ratio to receive the new 
formulation of PEGPH20 at 3.0 µg/kg in combination with standard dosing of NAB+GEM (PAG 
treatment) or NAB+GEM (AG treatment). All study sites will be invited to participate in this 
second run-in phase. Phase 2 enrollment using the original formulation of PEGPH20 will 
continue in parallel with this run-in phase.  
The Sponsor, the participating Investigators, and the independent safety physician will determine 
if the dose and regimen for the new formulation of PEGPH20 is acceptable after reviewing 
available safety from Cycle 1 from all subjects in the second run-in phase. If the safety profile 
and the PK profile of the new formulation are deemed acceptable, the new formulation of 
PEGPH20 will be available to all subjects on the study. Subjects currently receiving the old 
formulation of PEGPH20, will be switched to the new formulation. 

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6.1.2. 
Phase 2 
In Phase 2, approximately 237 subjects will be randomized to receive PEGPH20 (3.0 µg/kg, 
pending outcome of run-in phase safety assessment) in combination with standard dosing of 
NAB+GEM (PAG treatment) or NAB+GEM (AG treatment). Randomization will be stratified 
by Karnofsky Performance Status (70% to 80% and 90% to 100%). 
Phase 2 will have 2 stages due to a partial clinical hold that occurred from April through 
July 2014 (see Section 6.1.2.1 for additional details). The first stage will randomize subjects in a 
1:1 ratio. The second stage will randomize subjects in a 2:1 ratio (PAG:AG). The second stage of 
the study will start as of Amendment 3.0. 
6.1.2.1. 
Clinical Hold 
This study was initiated in March 2013 (first subject first visit). In April 2014, the study data 
monitoring committee (DMC) reported an imbalance in TE events with a higher incidence in 
subjects treated with PAG (28.4%) than AG (14.8%) and advised the Sponsor to stop enrollment 
and dosing of PEGPH20 pending further analysis. The Sponsor followed the recommendation 
and halted the study, after which it was placed on a partial clinical hold. All subjects in the PAG 
group stopped PEGPH20 therapy and remained on AG therapy alone (Stage 1 of the study; 
N=146 randomized, N=135 treated). 
The Sponsor presented a risk management plan to mitigate the TE events. On 4 June 2014, the 
FDA removed the partial clinical hold and the study protocol was amended (Amendment 3) to: 
(1) include concomitant use of prophylactic enoxaparin (40 mg/day), (2) provide enhanced 
pharmacovigilance by immediate reporting of all TE events to Halozyme Drug Safety, (3) 
discontinue PEGPH20 after a TE, and (4) exclude subjects with evidence of a DVT and PE as 
well as those subjects determined to be at high risk of a TE event based on the Khorana criteria 
(Khorana 2008). Subjects accrued to the study per Protocol Amendment 3 (Version 4) were 
assigned to Stage 2. 
Study enrollment reopened in June 2014 (Stage 2 of the study; N=133 randomized and enrolled 
from 24 July 2014 through 19 February 2016, N=125 treated) with all subjects receiving 
prophylactic enoxaparin (40 mg/day and then increased to 1 mg/kg/day subcutaneously [SC] 
[Protocol Amendment 4]). 
6.1.2.2. 
Study Re-Starting Procedures Overview Following Temporary Hold 
The following thromboembolic event risk factors will be assessed for all subjects (both treatment 
groups) after signing the updated ICF (protocol amendment 3.0) and prior to the next scheduled 
treatment:  
• Prior history of cerebrovascular accident or transient ischemic attack 
• Pre-existing carotid artery disease 
• Concomitant use of megestrol acetate (subjects on the PAG arm must discontinue use 
>10 days before re-starting PEGPH20 treatment and subjects on the AG arm should 
discontinue use immediately) 
• DVT on Doppler ultrasound or pulmonary embolism (PE) on chest CT prior to re-
initiating therapy after study hold  

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Subjects who were randomized to the PAG treatment arm and answer yes to one or more of the 
questions above cannot re-start PEGPH20 therapy. Subjects who were randomized to the AG 
arm who answer yes to one or more questions may continue. All subjects (in both treatment 
arms) will continue receiving Gemcitabine and Nab Paclitaxel regardless of how the above 
questions were answered. Subjects re-starting PEGPH20 should re-start on the next scheduled 
visit day of the cycle they are currently in (i.e., do not “make up” visits). 
Additionally, 1 mg/kg daily enoxaparin will be administered to or self-administered by all 
subjects on both study arms. Subjects who are contraindicated to receive enoxaparin (see the 
exclusion criteria) will be discontinued from study treatment (PAG and AG). 
6.1.2.3. 
Treatment with Enoxaparin 
A new guidance from a Scientific and Standardization Committee of the International Society of 
Thrombosis and Hemostasis recommends that all patients undergoing outpatient therapy for 
advanced pancreatic cancer should receive treatment with low molecular weight heparin 
(Khorana 2014).  The recommended dose for enoxaparin is 1.0 mg/kg SC daily as was studied in 
the CONKO-004 study (Riess 2010).  Thus, effective with amendment 4.0, the dose of 
enoxaparin is increased to 1.0 mg/kg/day SC for ongoing and newly enrolled subjects on both 
arms of the study. If a subject requires daily doses of enoxaparin greater than 1.0 mg/kg/day SC 
(e.g., a therapeutic dose), he/she may still continue in the study. Ongoing patients who have 
required enoxaparin dose reduction below 40 mg should continue at their current dose. Refer to 
Section 10.1.1 for enoxaparin management guidelines. 
6.1.2.4. 
Use of Doppler ultrasound and Chest CT 
Doppler ultrasound of both legs and chest CT will be performed during screening to exclude 
subjects with DVTs and PEs. For all subjects in either arm who are in treatment at the time the 
study is restarted, a Doppler ultrasound and chest CT will be conducted prior to the next dose of 
PEGPH20 or chemotherapy. If a DVT or PE is detected, the subject should not re-start with 
PEGPH20 treatment. The event should be noted as an adverse event (if detected after receipt of 
study treatment). Subjects should be treated with therapeutic doses of LMWH and should 
continue with chemotherapy and be monitored as per standard practice (i.e., routine Doppler 
ultrasound or chest CT scans and other routine laboratory testing).  For newly enrolling patients, 
the Doppler study should be performed within 7 days of Day 1 dosing. 
6.1.3. 
Overview of Treatment Schedule 
6.1.3.1. 
PAG Treatment Group  
In Cycle 1 Week 1, PEGPH20 will be administered alone on Day 1 and Day 4 (e.g., 
Monday/Thursday or Tuesday/Friday), and NAB+GEM will be given on Day 2, approximately 
24 hours after the first dose of PEGPH20 (e.g., Tuesday or Wednesday). In Cycle 1 Weeks 2 and 
3, PEGPH20 will be administered twice per week on Days 8, 11, 15, and 18. NAB and GEM will 
be administered once per week, 2 to 4 hours after PEGPH20 administration on Days 8 and 15.  
In Cycle 2 onwards, PEGPH20, NAB, and GEM will be given once weekly on Days 1, 8, and 15. 
NAB and GEM will be given 2 to 4 hours after the dose of PEGPH20.  

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Dexamethasone 8 mg will be administered in each treatment cycle to alleviate musculoskeletal 
toxicities. Dexamethasone will be administered within 2 hours prior to the beginning of each 
PEGPH20 infusion and 8 to 12 hours after the completion of the PEGPH20 infusion.  
See Table 9 and Figure 5 for an example of the PAG treatment schedule.  
6.1.3.2. 
AG Treatment Group 
In all cycles, NAB and GEM will be given once weekly on Days 1, 8, and 15.  
Dexamethasone 8 mg will be administered in each treatment cycle. Dexamethasone will be 
administered within 2 hours prior to the beginning of each NAB infusion and 8 to 12 hours after 
the completion of the GEM infusion.  
See Table 9 and Figure 6 for an example of the AG treatment schedule. 

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Table 9: 
Overview of Study Medication Schedule by Treatment Group 
Timepoint 
PAG Treatment Group 
AG Treatment Group 
Cycle 1 
Day 1 
PEGPH20 
NAB and GEM 
Day 2 
NAB and GEM (24 ± 4 hours after Day 1 dose of 
PEGPH20) 
No visit 
Day 4 
PEGPH20 
No visit 
Day 8  
PEGPH20 
NAB and GEM (2-4 hours after PEGPH20) 
NAB and GEM 
Day 11  
PEGPH20 
No visit 
Day 15  
PEGPH20 
NAB and GEM (2-4 hours after PEGPH20) 
NAB and GEM 
Day 18 
PEGPH20 
No visit 
Day 22 
No treatment (i.e., washout) 
No treatment (i.e., washout) 
Cycle 2 onwards 
Day 1  
PEGPH20 
NAB and GEM (2-4 hours after PEGPH20) 
NAB and GEM 
Day 8  
PEGPH20 
NAB and GEM (2-4 hours after PEGPH20) 
NAB and GEM 
Day 15  
PEGPH20 
NAB and GEM (2-4 hours after PEGPH20) 
NAB and GEM 
Day 22 
No treatment (i.e., washout) 
No treatment (i.e., washout) 
Abbreviations: AG = nab-paclitaxel plus gemcitabine; GEM = gemcitabine; PAG = PEGPH20 in combination with 
nab-paclitaxel plus gemcitabine; NAB = nab-paclitaxel. 
Note: Each treatment cycle is 28 days. Dose interruption and modifications are permitted; refer to Section 8.3 for 
further guidance. 
 

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Figure 5: 
Example of PEGPH20+nab-Paclitaxel+Gemcitabine (PAG) Treatment 
Schedule 
Cycle 1 
 
Cycle 2 onwards 
 
 
Note: Day 1 of Cycle 1 may start on any day; all subsequent study days would be adjusted. 
 
 
 
 
 
 
PEGPH20 
Gemcitabine 
Nab-paclitaxel 
Dexamethasone 
Week 1 
Week 2 
Week 3 
Week 4 
      D1   D2          D4                        D8                 D11                        D15               D18                       D22 
PEGPH20 
Gemcitabine 
Nab-paclitaxel 
Dexamethasone 
Week 1 
Week 2 
Week 3 
Week 4 
D1
D2
D4
D8
D11
D15
D18
D22

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Figure 6: 
Example of nab-Paclitaxel+Gemcitabine (AG) Treatment Schedule 
All Cycles 
 
 
Note: Day 1 of Cycle 1 may start on any day; all subsequent study days would be adjusted. 
 
6.1.4. 
Study Closeout Procedures 
The purpose of this Protocol Amendment 6 (Version 7) is to introduce study closeout procedures 
as described in this section. These include a reduction of study procedures for the 1 subject still 
on treatment (PAG group) and discontinuation of study procedures for subjects in long-term 
follow-up. 
The closeout procedures are effective as of the date of this Protocol Amendment 6, 09 February 
2018, and supersede all study procedures required per previous Protocol Amendment 5 
(Version 6) dated 06 April 2015. 
Study closeout procedures for subjects that are either on treatment or in long-term follow-up are 
described below: 
• The remaining subject on treatment will continue to receive study medication (PAG) 
until disease progression or other protocol-specified reasons for treatment 
discontinuation (see Section 7.3.1) or study discontinuation (see Section 7.3.2). For 
this subject, all procedures required per Protocol Amendment 5 will be immediately 
discontinued except for the following (details in Table 10): 
− Administration of PEGPH20 on Days 1, 8, and 15 (as in Protocol Amendment 5); 
and NAB and GEM every 2 weeks (Days 1 and 15) or at the Investigator’s 
discretion and per standard of care (vs. on Days 1, 8, and 15 in Protocol 
Amendment 5) 
− Administration of dexamethasone and enoxaparin (see Section 6.1.3.1 and 
Section 6.1.2.3 for additional details) 
− Imaging assessments performed locally (vs. sent to a CIR in Protocol 
Amendment 5) at a reduced frequency (every 4 cycles or less frequently, at the 
Gemcitabine 
Nab-paclitaxel 
Week 1 
Week 2 
Week 3 
Week 4 
      D1                                             D8                                               D15                                             D22 
Dexamethasone 

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Investigator’s discretion and per standard of care [vs. every 2 cycles in Protocol 
Amendment 5]) to minimize radiation exposure  
− Clinical laboratory assessments (blood chemistry, hematology, and coagulation) 
by a local laboratory, all at a reduced frequency (Days 1, 8, and 15 [vs. Days 1, 8, 
15, and 22 in Protocol Amendment5]) and at the End of Treatment visit. The 
clinical laboratory tests on Days 1, 8, and 15 will also be reduced in scope with 
fewer assessments to ensure the subject’s well-being and monitor key safety 
parameters through the remainder of study treatment. 
− Collection/reporting of serious adverse events (SAEs) and adverse events of 
special interest (TE events) for 30 days after the last dose of study treatment 
(additional details on SAE and TE event reporting in Section 10.3 and 
Section 10.4, respectively) (no other AEs will be collected) 
− Collection/reporting of pregnancy information as specified in Section 8.2.13 and 
Section 10.7 
• For subjects in long-term follow-up, the long-term follow-up will be discontinued 
immediately. For the 1 subject still on treatment, long-term follow-up will not be 
implemented when this subject discontinues treatment and completes the End of 
Treatment Visit as described in Section 8.1.3.2. This subject’s End of Treatment Visit 
will correspond to the end of the study. 
The end of the study is defined by the time when all subjects have discontinued treatment. 
 

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Table 10: 
Study Procedures for the Remaining Subject on Treatment (PAG Group) 
Tests and Assessmentsa 
Treatment Cycles 2+ 
(Repeats every 4 weeks) 
End of 
Treatmentb 
Week 1 
Week 2 
Week 3 
Week 4 
Day 1 
Day 8 
Day 15 
Day 22 
Disease Assessment (CT) 
Xc 
Xd 
PEGPH20 Administration 
X 
X 
X 
 
 
Dexamethasone 
Administratione 
X 
X 
X 
 
 
Enoxaparin 
Administrationf 
X 
 
Nab-paclitaxel 
Administrationg 
X 
 
X 
 
 
Gemcitabine 
Administrationg 
X 
 
X 
 
 
Local Laboratory Tests 
 
 
 
 
 
   Hematology 
Xh 
Xh 
Xh 
 
Xi 
   Blood Chemistry 
Xh 
Xh 
Xh 
 
Xi 
   Coagulation Parameters 
(PT, PTT, INR) 
X 
X 
X 
 
X 
Collection/Recording of 
SAEs and AEs of Special 
Interest (TE events)j 
X 
X 
Abbreviations: AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
BUN = blood urea nitrogen; INR = International normalized ratio; PAG = PEGPH20 in combination with nab-
paclitaxel+gemcitabine; PEGPH20 = Pegylated Recombinant Hyaluronidase; PT = Prothrombin time; PTT = partial 
thromboplastin time; SAE = serious adverse event; SC = subcutaneously; SGOT = serum glutamic oxaloacetic 
transaminase; SGPT = serum glutamic pyruvate transaminase; TE = thromboembolic. 
a See Section 8 for details on individual assessments. 
b The subject should return to the study site for an End of Treatment Visit within approximately 7 days after 
determination of progressive disease or within 7 days after treatment discontinuation for other reasons. This 
subject’s End of Treatment Visit will correspond to the end of the study. 
c CT scan assessment will be performed locally at the end of every fourth treatment cycle or less frequently, at the 
Investigator’s discretion and per standard of care. If the subject is withdrawn from the study due to clinical disease 
progression, a CT scan should be requested as soon as possible after clinical progression is determined.  
d A CT scan should only be done if radiologic progressive disease was not documented in the previous CT scan. 
e Dexamethasone should be given within 2 hours prior to the start of each PEGPH20 dose and 8-12 hours after each 
PEGPH20 dose (additional details in Section 6.1.3.1). 
f Enoxaparin 1 mg/kg will be given SC once a day during the Treatment Period (additional details in 
Section 6.1.2.3). 
g Nab-paclitaxel and gemcitabine will be given every 2 weeks or at the Investigator’s discretion and per standard of 
care, 2 to 4 hours after the PEGPH20 dose. Nab-paclitaxel will be given first. 

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h Assessments will include the following for blood chemistry: glucose, BUN, total bilirubin, alkaline phosphatase, 
ALT (SGPT), AST (SGOT), and electrolytes (potassium and calcium); and hematology: hemoglobin, white blood 
cell count, and platelet count. 
i Assessments will include the full panel for blood chemistry and hematology as specified in Section 8.2.12. 
j SAEs and TE events will be collected for 30 days after the last dose of  study treatment (additional details on SAE 
and TE event reporting in Section 10.3 and Section 10.4, respectively). 
 

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7. 
SELECTION AND WITHDRAWAL OF SUBJECTS AND STUDY 
TERMINATION 
The study plans to randomize approximately 253 subjects with previously untreated pancreatic 
cancer at study sites in the US.  
Run-in phases: Approximately eight subjects will be randomized in a 3:1 ratio to receive PAG 
(original formulation of PEGPH20) or AG treatment. With Amendment 1.0, an additional 
8 subjects will be randomized 3:1 to receive PAG (new formulation of PEGPH20) or AG 
treatment.  
Phase 2: Approximately 237 subjects will be randomized to receive PAG or AG treatment. 
7.1. 
Inclusion Criteria 
Subjects must satisfy all of the following inclusion criteria to be enrolled in the study. 
• Signed, written Institutional Review Board (IRB)/Ethics Committee (EC)-approved 
Informed Consent Form (ICF). 
• Histologically confirmed Stage IV PDA with documented disseminated neoplasm to 
the liver and/or the lung. Prior to enrollment, confirmation of the following must be 
obtained: 
− Available tumor tissue block or a minimum of five unstained core biopsy slides 
that meet specific tissue sample requirements (see Study Laboratory Manual). 
Note: Fine needle aspirates (FNA) or brushing biopsies will not be acceptable. If 
an archived sample is not available, a pre-dose core tumor biopsy will be required 
in order to enter the study (i.e., an archived or fresh pre-dose core biopsy is 
required). 
• One or more metastatic tumors measurable on computed tomography (CT) scan per 
RECIST v1.1, excluding the primary pancreatic lesion. 
• Subject must have received no previous radiotherapy, surgery, chemotherapy, or 
investigational therapy for the treatment of metastatic disease.  
− Prior treatment with 5-FU or GEM administered as a radiation sensitizer during 
and up to 4 weeks after radiation therapy is allowed (if there is lingering toxicity, 
then the Sponsor should be consulted).  
− If a subject received therapy in the adjuvant setting, tumor recurrence or disease 
progression must have occurred no sooner than 6 months after completing the last 
dose of adjuvant therapy. 
• Karnofsky Performance Status ≥70%.  
• Life expectancy ≥3 months. 
• Age ≥18 years. 
• A negative pregnancy test, if female of reproductive potential. 

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• Screening clinical laboratory values as follows:  
− Total bilirubin ≤1.5 times upper limit of normal (ULN). 
− Aspartate aminotransferase ([AST]; serum glutamic oxaloacetic transaminase 
[SGOT]) and alanine aminotransferase ([ALT]; serum glutamic pyruvate 
transaminase [SGPT]) ≤2.5 times ULN, (if liver metastases are present, then 
≤5 times ULN is allowed). 
− Serum creatinine ≤2.0 mg/dL or calculated creatinine clearance ≥60 mL/min. 
− Serum albumin ≥3.0 g/dL. 
− Prothrombin time (PT)/international normalized ratio (INR) within normal limits 
(±15%) or within therapeutic range if on warfarin. 
− Partial thromboplastin time (PTT) within normal limits (±15%).  
− Hemoglobin ≥10 g/dL.  
− Absolute neutrophil count (ANC) ≥1,500 cells/mm3. 
− Platelet count ≥100,000 /mm3  
• For men and women of reproductive potential, agreement to use an effective 
contraceptive method from the time of screening and throughout their time on study. 
Effective contraceptive methods consist of prior sterilization, intra-uterine device, 
oral or injectable contraceptives, and/or barrier methods. Abstinence alone is not 
considered an adequate contraceptive measure for the purposes of this study. 
7.2. 
Exclusion Criteria 
Subjects satisfying any of the following exclusion criteria are not allowed in the study. 
• Non-metastatic PDA. 
• Evidence of deep vein thrombosis (DVT) or pulmonary embolism (PE) or other 
known thromboembolic event present during the screening period. 
• Previous neoadjuvant treatment for pancreatic cancer 
• Known central nervous system involvement or brain metastases. 
• New York Heart Association Class III or IV cardiac disease or myocardial infarction 
within the past 12 months.  
• Prior history of cerebrovascular accident or transient ischemic attack 
• Pre-existing carotid artery disease 
• Active, uncontrolled bacterial, viral, or fungal infection requiring systemic therapy. 
• Known infection with human immunodeficiency virus, hepatitis B, or hepatitis C. 
• Known allergy to hyaluronidase. 
• Current use of megestrol acetate (use within 10 Days of Day 1). 

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• Contraindication to heparin as per NCCN guidelines: 
− Recent central nervous system bleed, intracranial or spinal lesion at high risk for 
bleeding 
− Active bleeding (major): more than 2 units transfused in 24 hours  
− Spinal anesthesia/lumbar puncture 
− Chronic, clinically significant measurable bleeding >48 hours 
− Severe platelet dysfunction (uremia, medications, dysplastic hematopoiesis) 
− Recent major operation at high risk for bleeding 
− Underlying hemorrhagic coagulopathy 
− High risk for falls (head trauma) 
• Previous major bleed (bleeding requiring transfusion of red blood cells) on LMWH  
• Women currently pregnant or breastfeeding. 
• Intolerant of dexamethasone. 
• History of another primary cancer within the last 3 years with the exception of 
non-melanoma skin cancer, early state prostate cancer, or curatively-treated cervical 
carcinoma in-situ. 
• Any other disease, metabolic dysfunction, physical examination finding or clinical 
laboratory finding that leads to reasonable suspicion of a disease or condition that 
contraindicates the use of an investigational drug, that may affect the interpretation of 
the results, or that may render the subject at high risk for treatment complications. 
• Other unspecified reasons that, in the opinion of the Investigator or Sponsor, make 
the subject unsuitable for the study. 
• Inability to comply with study and follow-up procedures as judged by the 
Investigator. 
7.3. 
Subject Withdrawal Criteria 
7.3.1. 
Discontinuation of Treatment 
The Investigator must guard the subject’s welfare and may discontinue study drug treatment at 
any time when this action appears to be in the subject’s best interest. The reason for the subject’s 
withdrawal must be recorded in the subject’s electronic case report form (eCRF). Possible 
reasons for such actions may include, but are not limited to, the following: 
• Disease progression defined by either of the following: 
− Disease progression documented by CT scan based on RECIST v1.1, as 
determined by the Central Imaging Reader (CIR).  
− Clinical tumor-related progression that is well documented in the absence of 
radiologic disease progression. 

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• Adverse event (AE). 
• Any significant protocol violation (e.g., demonstrated lack of treatment compliance, 
subject starts taking any concomitant anti-cancer therapy). 
• Withdrawal of consent by an enrolled subject.  
• Other reasons as determined by the Investigator or Sponsor: a subject may have study 
treatment discontinued if, in the opinion of the Investigator or Sponsor, it is not in the 
subject’s best interest to continue. This includes subjects who permanently 
discontinued the LMWH treatment for any reason. 
• The subject becomes pregnant (treatment must be discontinued immediately). 
Subjects who discontinue treatment should remain in the study for long-term follow-up 
assessments unless they withdraw consent, die, or become lost to follow-up. 
7.3.2. 
Study Discontinuation 
After the subject discontinues study treatment, the subject will be followed in long-term 
follow-up for assessment of survival and subsequent anti-cancer therapies (Section 8.1.4). 
Long-term follow-up will continue until the subject discontinues from the study. The reason for 
the subject’s discontinuation from the study should be documented in the subject’s eCRF. 
Possible reasons for study discontinuation include the following: 
• Death 
• Withdrawal of Consent 
• Lost to Follow Up 
• Sponsor Termination of the Study 
• Other 
7.4. 
Sponsor Study Stopping Rules 
Halozyme may terminate this study after informing Investigators at any time. Investigators will 
be notified by Halozyme (or designee) if the study is placed on hold, completed, or closed. 
Conditions that may warrant termination of the study include, but are not limited to the 
following:  
• The discovery of unexpected, serious, or unacceptable risk to the subjects in the 
study. 
• A decision on the part of the Sponsor to suspend or discontinue testing, evaluation, or 
development of the product. 
 

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8. 
STUDY PROCEDURES AND ASSESSMENTS 
With Protocol Amendment 6, the procedures listed in Section 6.1.4 will supersede the procedures 
described in this section and subsections unless noted otherwise. 
The Study Schedule of Events (Table 1, Table 2, Table 3, Table 4, and Table 5) is given as an aid 
to subject management. This section describes evaluations to be done before, during, and after 
treatment. Section 8.2 provides information on individual study assessments. 
When duplicate evaluations are performed before study commencement, the data from the 
evaluation closest in time to study entry will be recorded. When duplicate evaluations are 
performed in a given time window, the worst case value will be recorded for safety evaluations, 
unless otherwise stipulated. Unless otherwise specified, clinical laboratory tests may be 
performed one day earlier than specified in the Study Schedule of Events. Scheduled clinic 
attendance should occur within ±2 days of the specified dates, as long as doses are separated by 
the appropriate amount of time (e.g., a minimum of two days when visits are biweekly). Where 
this is not possible because of extenuating circumstances (e.g., holidays), the reason should be 
noted.  
During Weeks 1 through 3 of Cycle 1, PEGPH20 should be administered twice per week. The 
twice weekly doses should be separated by a minimum of two days (e.g., Monday and Thursday 
or Tuesday and Friday schedule). Where this is not possible because of extenuating 
circumstances (e.g., holidays), the doses should be separated by at least 45 hours. 
8.1. 
Study Procedures by Visit 
8.1.1. 
Screening Visits (PAG and AG Treatment Groups) 
If the following procedures were done as per the standard of care prior to the subject signing the 
ICF, the results may be used for this study providing they were within the screening window: 
physical examination, vital sign measurements, height, weight/body surface area (BSA), and CT 
scan. 
8.1.1.1. 
Within 20 Days Prior to Day 1 
• Sign and date ICF 
• Confirm availability of tumor tissue 
• Medical history  
• Obtain CT scan and send to Central Imaging for eligibility review (chest CT should 
be read locally to evaluate for the presence of PE. If subject has signs or symptoms of 
PE after the initial scan was completed, the chest scan should be repeated prior to 
randomization) 
• Prior medication history  
8.1.1.2. 
Within 14 Days Prior to Day 1 
• Physical examination  
• Vital sign measurements 

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• Karnofsky Performance Status 
• Height 
• Weight/BSA 
• Obtain samples for the following tests and send to local laboratory 
− Urine/serum pregnancy test (females of reproductive potential) 
• Obtain samples for the following tests: 
− Hematology 
− Blood chemistry 
− Urinalysis 
− Coagulation tests 
− CA19-9 
− Plasma HA levels 
• Subject registration and randomization  
8.1.1.3. 
Within 7 Days Prior to Day 1 
• Doppler ultrasound of lower extremities 
8.1.2. 
Treatment Period (PAG Treatment Group) 
AEs and concomitant medications will be obtained throughout every visit. Unless otherwise 
specified, the procedures listed below will be done for all PAG subjects in the run-in phases and 
Phase 2. Standard of care blood samples for local laboratories should be drawn before NAB and 
GEM dosing to confirm the subject meets the required criteria for dosing (see Section 8.3.2.3). 
8.1.2.1. 
Treatment Cycle 1 
8.1.2.1.1. Cycle 1 Day 1 
Pre-PEGPH20 Infusion 
• Physical examination 
• Vital signs 
• Karnofsky Performance Status 
• Weight/BSA 
• 12-lead electrocardiogram (ECG) (3 times within 5-minute period) 
• Obtain samples for the following tests: 
− Hematology 
− Blood chemistry 

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− Coagulation tests 
− Immunogenicity  
− PEGPH20 concentration (PK) (within 2 hours prior to PEGPH20 infusion ) 
− Plasma HA levels 
• Dexamethasone administration (within 2 hours prior to PEGPH20 infusion) 
PEGPH20 Infusion  
• PEGPH20 IV infusion over 10 to 12 minutes (approximately 1 mL/min) 
Post-PEGPH20 Infusion 
• 12-lead ECG (3 times within 5-minute period between 1 to 4 hours after completion 
of PEGPH20 infusion) 
• Obtain samples for the following tests (actual collection times to be recorded): 
− PEGPH20 concentration (PK)  
 
Run-in phases: 15 minutes (±5 minutes), 1 hour (±15 minutes), 2 hours 
(±15 minutes), and 4 hours (±30 minutes) after completion of 
PEGPH20 infusion 
 
Phase 2 subjects: 1 hour (±15 minutes) after completion of PEGPH20 
infusion 
• Dexamethasone administration (within 8 to 12 hours after completion of PEGPH20 
infusion) 
8.1.2.1.2. Cycle 1 Day 2  
Pre-NAB and GEM Infusions 
• PEGPH20 concentration (PK) and HA sample collection (24 hours ±4 hours after 
completion of Day 1 PEGPH20 infusion and prior to beginning NAB infusion) 
• Vital signs 
NAB and GEM Infusions  
NAB and GEM will be administered 24 hours (±4 hours) after completion of Day 1 PEGPH20 
infusion. 
• NAB IV infusion over 30 minutes 
• GEM IV infusion over 30 minutes (immediately after completion of NAB infusion) 
8.1.2.1.3. Cycle 1 Day 4  
Pre-PEGPH20 Infusion  
• Vital signs 
• PEGPH20 concentration (PK): Run-in phases only  

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• Dexamethasone administration (within 2 hours prior to PEGPH20 infusion) 
PEGPH20 Infusion  
• PEGPH20 IV infusion over 10 to 12 minutes (approximately 1 mL/min) 
Post-PEGPH20 Infusion  
• PEGPH20 concentration (PK) (1 hour ±15 minutes after completion of PEGPH20 
infusion): Run-in phases only 
• Dexamethasone administration (within 8 to 12 hours after completion of PEGPH20 
infusion) 
8.1.2.1.4. Cycle 1 Day 8 
Pre-PEGPH20, NAB, and GEM Infusions 
• Vital signs 
• Obtain samples for the following tests: 
− Hematology 
− Blood chemistry  
− Coagulation tests 
− PEGPH20 concentration (PK): Run-in phases only  
• Dexamethasone administration (within 2 hours prior to PEGPH20 infusion) 
PEGPH20, NAB, GEM Infusions  
• PEGPH20 IV infusion over 10 to 12 minutes (approximately 1 mL/min) 
• NAB IV infusion over 30 minutes (2 to 4 hours after completion of Day 8 PEGPH20 
infusion)  
• GEM IV infusion over 30 minutes (immediately after completion of NAB infusion) 
Post-PEGPH20, NAB, and GEM Infusions  
• PEGPH20 concentration (PK) (1 hour ±15 minutes after completion of PEGPH20 
infusion and immediately after completion of GEM infusion): Run-in phases only  
• Dexamethasone administration (within 8 to 12 hours after completion of PEGPH20 
infusion)  
8.1.2.1.5. Cycle 1 Day 11  
Pre-PEGPH20 Infusion 
• Vital signs 
• Dexamethasone administration (within 2 hours prior to PEGPH20 infusion) 
• PEGPH20 concentration (PK): Run in phases only 

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PEGPH20 Infusion  
• PEGPH20 IV infusion over 10 to 12 minutes (approximately 1 mL/min) 
Post-PEGPH20 Infusion 
• PEGPH20 concentration (PK) (1 hour ±15 minutes after completion of PEGPH20 
infusion): Run-in phases only  
• Dexamethasone administration (within 8 to 12 hours after completion of PEGPH20 
infusion) 
8.1.2.1.6. Cycle 1 Day 15 
Pre-PEGPH20, NAB, and GEM Infusions 
• Vital signs 
• 12-lead ECG (3 times within 5-minute period) 
• Obtain samples for the following tests: 
− Hematology 
− Blood chemistry 
− Coagulation tests 
− PEGPH20 concentration (PK)  
• Dexamethasone administration (within 2 hours prior to PEGPH20 infusion) 
PEGPH20, NAB, and GEM Infusions  
• PEGPH20 IV infusion over 10 to 12 minutes (approximately 1 mL/min) 
• NAB IV infusion over 30 minutes (2 to 4 hours after completion of PEGPH20 
infusion)  
• GEM IV infusion over 30 minutes (immediately after completion of NAB infusion) 
Post-PEGPH20, NAB, and GEM Infusions  
• 12-lead ECG (3 times within 5-minute period between 1 to 4 hours after completion 
of PEGPH20 infusion, and before the NAB dose) 
• Obtain samples for the following tests: 
− PEGPH20 concentration (PK)  
 
Run-in phases: 15 minutes (±5 minutes), 1 hour (±15 minutes), 2 hours 
(±15 minutes), and 4 hours (±30 minutes) after completion of 
PEGPH20 infusion. A PK sample collected 24 hours (±4 hours) after 
completion of PEGPH20 infusion is optional 
 
Phase 2: 1 hour (±15 minutes) after completion of PEGPH20 infusion 
• Dexamethasone administration (within 8 to 12 hours after completion of PEGPH20 
infusion)  

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8.1.2.1.7. Cycle 1 Day 18  
Pre-PEGPH20 Procedures 
• Vital signs 
• Dexamethasone administration (within 2 hours prior to PEGPH20 infusion) 
• PEGPH20 concentration (PK): Run-in phases only 
PEGPH20 Infusion procedures 
• Infusion of PEGPH20 IV over 10 to 12 minutes (approximately 1 mL/min) 
Post-PEGPH20 Infusion 
• PEGPH20 concentration (PK) (1 hour ±15 minutes after completion of PEGPH20 
infusion): Run-in phases only 
• Dexamethasone administration (within 8 to 12 hours after completion of PEGPH20 
infusion) 
8.1.2.1.8. Cycle 1 Day 22 
No treatments given. The following assessments should be completed: 
• Vital signs 
• Obtain samples for the following tests: 
− Hematology 
− Blood chemistry 
− Coagulation Tests 
− CA19-9 
• Optional tumor biopsy (anytime in Week 4 of Cycle 1) 
8.1.2.2. 
Treatment Cycle 2 Onwards (repeats every 4 weeks) 
8.1.2.2.1. Cycle 2+, Day 1 
Pre-PEGPH20, NAB, and GEM Infusions 
• Physical examination 
• Vital signs 
• Karnofsky Performance Status 
• Weight/BSA 
• Obtain samples for the following tests: 
− Hematology 
− Blood chemistry 

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− Coagulation Tests 
− Plasma HA sample 
− Immunogenicity  
• Dexamethasone administration (within 2 hours prior to PEGPH20 infusion) 
PEGPH20, NAB, and GEM Infusions  
• PEGPH20 IV infusion over 10 to 12 minutes (approximately 1 mL/minute) 
• NAB IV infusion over 30 minutes (2 to 4 hours after PEGPH20 infusion)  
• GEM IV infusion over 30 minutes (immediately after completion of NAB infusion) 
Post-PEGPH20, NAB, and GEM Infusions 
• HA sample collection after the administration of GEM (no more than 2 hours after 
GEM administration has been completed) 
• Dexamethasone administration (within 8 to 12 hours after completion of PEGPH20 
infusion)  
8.1.2.2.2. Cycles 2+, Day 8 
Pre-PEGPH20, NAB, and GEM Infusions 
• Vital signs 
• Obtain samples for the following tests: 
− Hematology 
− Blood chemistry 
− Coagulation Tests 
− PEGPH20 concentration (PK) 
• Dexamethasone administration (within 2 hours prior to PEGPH20 infusion) 
PEGPH20, NAB, and GEM Infusions  
• PEGPH20 IV infusion over 10 to 12 minutes (approximately 1 mL/min) 
• NAB IV infusion over 30 minutes (2 to 4 hours after PEGPH20 infusion)  
• GEM IV infusion over 30 minutes (immediately after completion of NAB infusion) 
Post-PEGPH20, NAB, and GEM Infusions 
• Obtain samples for the following tests: 
− PEGPH20 concentration (PK) (1 hour ±15 minutes after completion of PEGPH20 
infusion) 
• Dexamethasone administration (within 8 to 12 hours after completion of PEGPH20 
infusion)  

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8.1.2.2.3. Cycles 2+ Day 15 
Pre-PEGPH20, NAB, and GEM Infusions 
• Vital signs 
• Obtain samples for the following tests: 
− Hematology 
− Blood chemistry 
− Coagulation Tests 
• Dexamethasone administration (within 2 hours prior to PEGPH20 infusion) 
PEGPH20, NAB, and GEM Infusions  
• PEGPH20 IV infusion over 10 to 12 minutes (approximately 1 mL/min) 
• NAB IV infusion over 30 minutes (2 to 4 hours after completion of PEGPH20 
infusion) 
• GEM IV infusion over 30 minutes (immediately after completion of NAB infusion) 
Post-PEGPH20, NAB, and GEM Infusions 
• Dexamethasone administration (within 8 to 12 hours after completion of PEGPH20 
infusion)  
8.1.2.2.4. Cycles 2+ Day 22 
No treatments given for PAG or AG groups. The following assessments should be completed: 
• Vital signs 
• Obtain samples for the following tests: 
− Hematology 
− Blood chemistry 
− Coagulation Tests 
− CA19-9 
• Obtain CT scan and send to CIR for assessment of disease every other cycle (i.e., 
Week 4 of Cycles 2, 4, 6, 8 etc.) Scans may be obtained any time after dosing on Day 
15 to allow for enough time for the scan to be sent to and reviewed by the central 
reader prior to the subject’s next scheduled dosing visit. The results should be 
interpreted and sent to the site before dosing in the next cycle begins. 
• Optional post-dose biopsy (anytime in Week 4 of any cycle) 
8.1.2.3. 
End of Treatment Visit 
Subjects should return to the study site for an End of Treatment Visit within approximately 
7 days after determination of progressive disease or within 7 days after treatment discontinuation 

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for other reasons. AEs and concomitant medications will be obtained throughout the visit, and 
the following assessments should be completed: 
• Physical examination 
• Vital signs 
• Karnofsky Performance Status 
• Weight/BSA 
• Obtain CT scan and send to CIR (CT should only be done if radiologic progressive 
disease was not documented in the previous CT scan)  
• Obtain samples for the following tests: 
− Hematology 
− Blood chemistry 
− Coagulation Tests 
− Immunogenicity  
− CA19-9 
8.1.3. 
Treatment Period (AG Treatment Group) 
AEs and concomitant medications will be obtained throughout every visit. The procedures listed 
below will be done for all AG subjects in the run-in phases and Phase 2. Standard of care blood 
samples for local laboratories should be drawn before NAB and GEM dosing to confirm the 
subject meets the required criteria for dosing (see Section 8.3.2.3). 
8.1.3.1. 
All Treatment Cycles  
8.1.3.1.1. All Cycles Day 1 
Pre-NAB and GEM Infusions 
• Physical examination 
• Vital signs 
• Karnofsky Performance Status 
• Weight/BSA 
• 12-lead electrocardiogram (ECG) (3 times within 5-minute period) Cycle 1 only 
• Obtain samples for the following tests: 
− Hematology 
− Blood chemistry 
− Coagulation Tests 
− Plasma HA levels 

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• Dexamethasone administration (within 2 hours prior to NAB infusion)  
NAB and GEM Infusions  
• NAB IV infusion over 30 minutes 
• GEM IV infusion over 30 minutes (immediately after completion of NAB infusion) 
Post-NAB and GEM Infusions 
• 12-lead ECG (3 times within 5-minute period between 1 to 4 hours after completion 
of GEM infusion): Cycle 1 only 
• Dexamethasone administration (within 8 to 12 hours after completion of GEM 
infusion) 
8.1.3.1.2. All Cycles Day 8 
Pre-NAB and GEM Infusions 
• Vital signs 
• Obtain samples for the following tests: 
− Hematology 
− Blood chemistry 
− Coagulation Tests 
• Dexamethasone administration (within 2 hours prior to NAB infusion) 
NAB GEM Infusions  
• NAB IV infusion over 30 minutes  
• GEM IV infusion over 30 minutes (immediately after completion of NAB infusion) 
Post-NAB and GEM Infusions  
• Dexamethasone administration (within 8 to 12 hours after completion of GEM 
infusion) 
8.1.3.1.3. All Cycles Day 15 
Pre- NAB and GEM Infusions 
• Vital signs 
• 12-lead ECG (3 times within 5-minute period): Cycle 1 only 
• Obtain samples for the following tests: 
− Hematology 
− Blood chemistry 
− Coagulation Tests 
• Dexamethasone administration (within 2 hours prior to NAB infusion) 

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NAB and GEM Infusions  
• NAB IV infusion over 30 minutes  
• GEM IV infusion over 30 minutes (immediately after completion of NAB infusion) 
Post-NAB and GEM Infusions  
• 12-lead ECG (3 times within 5-minute period between 1 to 4 hours after completion 
of GEM infusion): Cycle 1 only 
• Dexamethasone administration (within 8 to 12 hours after completion of GEM 
infusion) 
8.1.3.1.4. All Cycles Day 22 
No treatments given. The following assessments should be completed: 
• Vital signs 
• Obtain samples for the following tests: 
− Hematology 
− Blood chemistry 
− Coagulation Tests 
− CA19-9 
• Optional tumor biopsy (anytime in Week 4) 
• Obtain CT scan and send to CIR for assessment of disease every other cycle (i.e., 
Week 4 of Cycles 2, 4, 6, 8 etc.) Scans may be obtained any time after dosing on Day 
15 to allow for enough time for the scan to be sent to and reviewed by the central 
reader prior to the subject’s next scheduled dosing visit. The results should be 
interpreted and sent to the site before dosing in the next cycle begins. 
8.1.3.2. 
End of Treatment Visit 
Subjects should return to the study site for an End of Treatment Visit within approximately 
7 days after determination of progressive disease or within 7 days after treatment discontinuation 
for other reasons. AEs and concomitant medications will be obtained throughout the visit, and 
the following assessments should be completed: 
• Physical examination 
• Vital signs 
• Karnofsky Performance Status 
• Weight/BSA 
• Obtain CT scan and send to CIR (CT should only be done if radiologic progressive 
disease was not documented in the previous CT scan)  
• Obtain samples for the following tests: 

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− Hematology 
− Blood chemistry 
− Coagulation Tests 
− CA19-9 
8.1.4. 
Long-term Follow-up (PAG and AG Treatment Groups) 
After the End of Treatment Visit, all subjects will enter long-term follow-up during which 
information on the subject’s survival status will be obtained by the site on a monthly basis. In 
addition, efforts should be made to collect data on all the subject’s next anti-cancer therapies 
(i.e., therapies received, responses) on a monthly basis. Information may be collected by chart 
review, phone calls, clinic visits, or by other means as appropriate. Long-term follow-up will 
continue until the subject dies, is lost to follow-up, or withdraws consent.  
8.1.5. 
Procedures for Study Treatment Discontinuation 
In the event of study treatment discontinuation, the subject should be instructed to report to the 
clinic as early as possible after the decision to discontinue study treatment has been made or for 
the next scheduled clinic visit. When the subject returns to the clinic, all End of Treatment 
procedures should be conducted (see Sections 8.1.2.3 and 8.1.3.2). The Investigator will make 
his or her best efforts to perform these procedures. 
8.2. 
Study Assessments 
8.2.1. 
Informed Consent 
The Investigator or designee must present and explain the study protocol to prospective study 
subjects before Screening. The ICF must be in a language that the subject can read and 
understand. Once the subject has had an opportunity to read the ICF, the Investigator or designee 
must be available to answer any questions the subject may have regarding the study protocol and 
procedures. The Investigator or designee must explain that the subject is not obliged to enter the 
study and is free to withdraw from it at any time for any reason. If new safety information 
becomes available and results in significant changes in risk/benefit assessment, the ICF should 
be reviewed and updated if necessary. Under this circumstance, all subjects, including those 
already being treated, should be given the new information, given a copy of the revised ICF, and 
allowed to re-evaluate their consent to continue in the study. 
A copy of the signed and dated ICF will be provided to the subject. The original ICF will be 
retained by the Investigator.  
8.2.2. 
Inclusion/Exclusion Criteria 
The inclusion/exclusion criteria (Sections 7.1 and 7.2) must be reviewed at Screening to ensure 
that the subject qualifies for the study. Subjects may be enrolled into the study if all criteria are 
met.  

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8.2.3. 
Medical History 
A complete medical history (significant past and ongoing conditions including tobacco/nicotine 
history) and demographic information will be obtained at Screening. Previous history of 
allergies/allergic reactions (e.g., allergy to bee stings, anaphylaxis, etc.) should also be captured 
on the Medical History eCRF page. 
8.2.4. 
Concomitant Medications 
Information regarding how to collect concomitant medications is defined in Section 10.12. 
8.2.5. 
Adverse Events 
AEs will be collected as defined in Section 10. 
8.2.6. 
Physical Examination 
Physical examination including ears/eyes/nose/throat/neck, respiratory, cardiovascular, 
gastrointestinal, musculoskeletal, central and peripheral nervous system, and dermatologic 
assessments will be performed when required by protocol. 
8.2.7. 
Height and Weight/Body Surface area 
Height will be recorded in cm, and weight should be recorded in kg. BSA will be calculated from 
the height and weight. 
8.2.8. 
Karnofsky Performance Status 
The subject’s Karnofsky Performance Status will be assessed (see Appendix B). 
8.2.9. 
Vital Signs 
Assessment of vital signs includes the measurement of blood pressure (systolic and diastolic), 
pulse, respiratory rate, and body temperature. Blood pressure and pulse will be measured with 
the subject at rest and in a sitting position for at least 5 minutes. 
8.2.10. 
Tumor Biopsy Tissue Samples 
Tumor biopsies will be used to assess the pharmacodynamic (PD) effects of PEGPH20 within 
the tumor/stroma. A tumor tissue block or a minimum of five unstained core biopsy slides (ten 
are requested) that meet specific tissue sample requirements will be required for this study. FNA 
or brushing biopsy is not acceptable for this study. The pathology report must be provided. If an 
archived sample is not available, a pre-dose core tumor biopsy will be required in order to enter 
the study (i.e., a pre-dose core biopsy is required; it may be archived or fresh). Specific sampling 
processing instructions will be outlined in a separate laboratory manual. The tumor biopsy, 
whether a block or unstained slides, must be sent to the appropriate laboratory as soon as 
possible after it is obtained; however, it should not be sent prior to the subject signing the ICF. 
Tumor biopsy samples will be utilized for analysis of HA and other exploratory biomarkers. The 
biopsy samples will be analyzed during the study, however some of these samples will be stored 
and may be analyzed at a later date for other potential biomarkers.  
Subjects may consent to an optional post-dose biopsy at the end of Cycle 1. 

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8.2.11. 
12-lead ECG 
All ECGs will be done in triplicate within a 5-minute period. The Investigator’s evaluation of the 
ECGs as normal or as abnormal without or with clinical significance will be recorded in the 
eCRF. 
8.2.12. 
Blood Chemistry, Hematology, Coagulation Parameters, and Urinalysis 
Blood chemistry, hematology, coagulation parameters, and urinalysis will all be analyzed by the 
central laboratory. Coagulation tests done after screening will be done at a local laboratory, 
results should be entered into the CRF. If anti-Xa testing is completed (Section 10.1), it should 
be done at a local laboratory. Standard of care blood samples for local laboratories should also be 
drawn before NAB and GEM dosing to confirm the subject meets the criteria for dosing (see 
Section 8.3.2.3). The Investigator must evaluate all results outside the reference range and 
determine the clinical significance (clinically significant or not clinically significant). If local 
laboratory data need to be used instead of central laboratory data, the local laboratory data must 
be entered in the appropriate eCRF. 
• Blood chemistry: glucose, blood urea nitrogen (BUN), albumin, total bilirubin, 
alkaline phosphatase, AST (SGOT), ALT (SGPT), electrolytes (including sodium, 
potassium, calcium, magnesium, chloride, and bicarbonate), and creatinine.  
• Hematology: hemoglobin, hematocrit, red blood cell count, white blood cell count, 
neutrophils (absolute), lymphocytes (absolute), monocytes (absolute), eosinophils 
(absolute), basophil (absolute), granulocyte (absolute), mean corpuscular hemoglobin, 
mean corpuscular volume, and platelet count.  
• Coagulation: INR, PT, and PTT. 
• Urinalysis: protein, glucose, ketones, blood, specific gravity, nitrite, pH, leukocytes.  
8.2.13. 
Pregnancy Test 
A serum or urine human chorionic gonadotropin test to determine whether a female subject is 
pregnant should be collected for all women of reproductive potential. This assessment will be 
done by the local laboratory. 
8.2.14. 
Immunogenicity 
A blood sample will be collected from PAG subjects and analyzed to determine if PEGPH20 is 
provoking a humoral immune response. Initial testing will be done during the study; however, 
samples will be stored for possible re-analysis if deemed necessary.  
8.2.15. 
CA19-9 
CA19-9 (carbohydrate antigen 19-9 or sialylated Lewis(a) antigen) is a blood test from the tumor 
marker category. Blood samples will be collected and sent to the central laboratory for analysis.  
8.2.16. 
Imaging/Radiologic Evaluation 
CT with contrast evaluations will be performed in accordance with each site’s Standard of Care 
Pancreatic CT imaging protocol (must include venous phase chest, abdomen and pelvis contrast 
enhanced CT). In the event that the subject is intolerant to the CT contrast agent, a non-contrast chest 

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CT and iodinated contrast enhanced MRI of the abdomen and pelvis is acceptable (please refer to the 
imaging manual for full directives).  
All scans should be sent to the CIR for disease assessment using RECIST v1.1. For study 
eligibility, the CIR must determine the presence of one or more metastatic tumors based on CT 
scans performed within 20 days of Day 1. During the study, CT scans for objective tumor 
assessment will occur at the end of Cycle 2, and at the end of every second treatment cycle 
thereafter (Week 4 of Cycle 4, 6, 8, etc.) CT scans should be performed post-last dose or the 
following week in each cycle (e.g. post-dose Cycle 2 Day 15 or early in Week 4 in Cycle 2) to 
allow time for reading of the scans by the CIR prior to starting subsequent cycles. The results of 
these scans should be interpreted by the CIR and sent to the site before dosing in the next cycle 
begins. For subjects who are withdrawn from the study due to clinical disease progression, a CT 
scan should be requested as soon as possible. At the End of Treatment Visit, a CT should only be 
done if radiologic progressive disease was not documented in the previous CT scan.  
8.2.16.1. Chest CT To Exclude Pulmonary Embolism 
The chest CT obtained during the screening period should be read locally to assess for the 
presence of PE (central read will only confirm RECIST 1.1 criteria, (refer to Section 8.2.16) and 
will not assess for PE). If a subject has signs and symptoms of PE after the initial screening scan 
was obtained, the scan should be repeated prior to randomization. A chest CT should also be 
done after PEGPH20 study hold is removed (both treatment groups), after signing the updated 
ICF (Amendment 3.0), and before the next chemotherapy dose or restart of PEGPH20 to 
evaluate for the presence of pulmonary embolism. This should be done per local practice and 
should not be sent to the central lab for analysis (refer to Section 6.1.2.4 for additional details). 
8.2.17. 
Doppler Ultrasound 
Doppler ultrasound should be performed as per Section 6.1.2.4. Bilateral Doppler ultrasound 
scanning of the proximal and distal veins is the current standard for routine clinical assessment 
of possible lower extremity DVT.  
8.2.18. 
Pharmacokinetic Assessments 
Plasma samples to assess the potential effects of NAB+GEM on PEGH20 PK will be collected in 
the PAG treatment group in the run-in phases and Phase 2. Post-dose PK timepoints should be 
relative to the stop time of the PEGPH20 infusion. If samples are collected from a central line, 
the line should be flushed with saline prior to collecting the PK samples. Samples should not be 
collected from the same line used to administer PEGPH20. Actual sampling times must be 
recorded. Initial testing will be done during the study; however, samples will be stored for 
possible re-analysis if deemed necessary. Additional testing to assess the potential effects of 
PEGPH20 on GEM and NAB PK may be done in the future utilizing the plasma samples 
collected in this study. 
8.2.19. 
Pharmacodynamic Endpoints  
Plasma HA is a potential biomarker indicator of tumor burden and tumor biology. Baseline and 
post-dose HA levels in plasma and in tumor biopsy samples will be analyzed to evaluate the 
PEGPH20 treatment effect on tumor response. Initial testing will be done during the study, 

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however, samples will be stored for possible re-analysis if deemed necessary.  
Note: Post-dose plasma HA sample collection will begin once central laboratory kits are 
available.  
8.2.20. 
Tumor-Associated Hyaluronan Investigational VENTANA HA RxDx Assay 
Tumor-associated HA may be a potential biomarker indicator of tumor burden and tumor 
biology.  
During the PEGPH20 clinical development, the Sponsor partnered with Ventana Medical 
Systems, Inc. (VMSI) to develop an investigational affinity histochemistry diagnostic assay 
(VENTANA HA RxDx assay) to detect HA in tumor biopsies. After the development of the 
scoring algorithm and determination of the cut-point (≥50% for PDA), the investigational 
diagnostic HA assay is used to evaluate any correlation between HA accumulation and the 
potential PEGPH20 treatment effect.  
Tumor samples will be collected and analyzed in a prospective-retrospective fashion using the 
VENTANA HA RxDx assay. Tumor samples and clinical outcome data from HALO-109-202 
Stage 1 served as the Training Set for HA algorithm and cut-point development, while tumor 
samples and clinical outcome data from Stage 2 served as the Validation Set. Additional details 
of the VENTANA HA RxDx assay are given in the PEGPH20 Investigator’s Brochure.  
8.3. 
Study Drug Administration 
Each treatment cycle is 4 weeks (28 days) and consists of 3 weeks of treatment followed by 
1 week of rest (i.e., washout week).  
Day 1 of Cycle 1 is based on the administration of PEGPH20 (PAG treatment group) or either 
NAB or GEM (AG treatment group). Day 1 of subsequent cycles is based on the administration 
of chemotherapy (for both treatment groups). If both the NAB and GEM doses are missed or 
held on Day 1 of treatment cycles 2+, the cycle will not start until the day the first dose of either 
NAB or GEM is administered to the subject (i.e., for the PAG treatment group, PEGPH20 should 
be held if both NAB and GEM are held). If one of the chemotherapy drugs (NAB or GEM) is 
held, the other study drugs may be given; if PEGPH20 is held, NAB and GEM may be given. 
If any dose (PEGPH20, NAB, or GEM) is missed on Day 8 or Day 15 of a cycle, the cycle will 
continue as scheduled with just that missed dose or all doses skipped if medically necessary.  
8.3.1. 
PEGPH20 
The PEGPH20 dose will be individually calculated for all dosing visits according to the subject’s 
screening weight. In calculating the dose, there will be no downward adjustment to “ideal” body 
weight. Doses should be re-adjusted if the subject’s weight changes by >10%. If the subject’s 
weight changes by ≤10%, no adjustment is necessary unless the site has a standard procedure to 
adjust doses based upon current weight. The dispensing pharmacist will verify the dose accuracy 
with a qualified study staff member. The appropriate dose will be diluted as per the instructions 
provided in a separate pharmacy manual. 
After completion of pre-dose activities, PEGPH20 will be administered as an IV infusion over 
10 minutes, approximately 1 mL/minute (a window of +2 minutes is allowed, i.e., infusion can 
be 10 to 12 minutes), under observation by qualified clinic staff. The volume and/or duration of 

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PEGPH20 administration may change at the discretion of the Sponsor, based upon safety 
information. The study nurse or alternate designee by the Investigator will record the time the 
infusion was started and stopped. A saline flush should follow IV delivery of the complete 
PEGPH20 dose as per standard of care for flushing IV lines. Only a peripheral line should be 
used for the administration of PEGPH20 (heparin flushes should not be used on the same line as 
PEGPH20), but heparin flushes may be used for central lines as per standard of care. In the event 
that peripheral venous access cannot be obtained, the central line may be used. If this happens, 
ensure the line is flushed with saline (minimum of 10 cc) prior to administering PEGPH20 and 
after administering PEGPH20. Ensure the PEGPH20 administration is not done immediately 
before or after the central line has been flushed with a heparin flush (e.g., ensure the line is 
flushed with a heparin flush no earlier than 1 hour before or after the PEGPH20 administration).  
8.3.1.1. 
Hypersensitivity to PEGPH20 
In the event of a hypersensitivity reaction, the PEGPH20 infusion should be stopped and the 
symptoms should be treated as necessary. If a hypersensitivity reaction is suspected, PEGPH20 
administration should be immediately stopped, and blood should be drawn and analyzed at a 
local laboratory to confirm the reaction (e.g., IgE, IgG, and serum tryptase levels). Halozyme 
should be contacted immediately (see study manual for contact information) so that current 
knowledge of laboratory testing could be provided to the site. Results should be documented in 
the eCRF.  
At the Investigator’s discretion and after discussion with the Sponsor, a re-challenge for the next 
visit may be done if the reaction is not considered anaphylaxis and is ≤ Grade 2. Any subject 
with anaphylaxis or a ≥ Grade 3 hypersensitivity reaction/infusion reaction should be 
discontinued from the study. In the event of a ≤ Grade 2 hypersensitivity/infusion reaction, the 
Sponsor and Investigator will agree on how subsequent injections will be administered. In 
general, a re-challenge should be done after pre-medication with a combination of IV 
diphenhydramine, IV H2 blockers (such as famotidine), and IV dexamethasone. If the 
hypersensitivity reactions are experienced at the re-challenge, the subject should be discontinued 
from the study. 
8.3.1.2. 
PEGPH20 Dose Modification Guidelines 
PEGPH20 dose adjustments are allowed based on toxicities that are deemed related, possibly 
related, or probably related to PEGPH20. See Table 11 for guidelines.  

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Table 11: 
PEGPH20 Dose Adjustment and Toxicity Management Guidelines 
Event 
Management/Action 
Musculoskeletal  
Any Grade 1 MSEs 
No change in dose. May give additional dexamethasone, 
muscle relaxer, or pain medication. 
Any Grade 2 intermittent muscle 
cramps or other types of MSEs 
No change in dose or frequency required, but may reduce the 
dose to 1.6 µg/kg or decrease the frequency of PEGPH20 
with mutual agreement with the Sponsor if the MSEs are 
persistent and resolved to baseline or Grade 1 with 
additional dexamethasone, muscle relaxer, or pain 
medication. 
Any Grade 3 or 4 MSEs that resolve to 
Grade ≤ 2 within 14 days 
Hold treatment. If resolved to ≤ Grade 2 within 14 days, may 
resume treatment at 1.6 µg/kg and/or decrease the frequency 
to once weekly (in the first cycle) of PEGPH20 with mutual 
agreement with the Sponsor. For Grade 4 events, 
continuation of treatment must be discussed with the 
Sponsor’s Medical Monitor prior to restarting treatment at 
1.6 µg/kg once weekly. 
Any Grade 3 or 4 MSEs 
Hold treatment if the events do not resolve (as noted above) 
and remain as Grade 3 or 4 events for >14 days. Treatment 
may resume at 1.6 µg/kg with mutual agreement with the 
Sponsor if the MSEs are resolved to ≤ Grade 2. 
All non-MSE Events (except TE events) potentially related to PEGPH20 
Grade 1 or 2 
No change. 
Grade 3 
Hold treatment. Treatment may resume at the same dose 
level if toxicity is resolved to baseline within 14 days. 
Treatment may resume but at 1.6 µg/kg or decrease the 
frequency with mutual agreement from the Sponsor if 
toxicity is reduced to ≤ Grade 2 within 14 days.  
Grade 4 
Hold treatment. Treatment may resume if toxicity is resolved 
to ≤ Grade 2 or baseline and should be at 1 dose level below 
or at a reduced frequency, at the discretion of the 
Investigator after discussion with the Sponsor. 
Thromboembolic Events (Regardless of relatedness to PEGPH20) 
Any Grade TE  
Discontinue PEGPH20 treatment permanently and treat 
event per NCCN guidelines until documented resolution of 
event. Nab-paclitaxel and gemcitabine treatment may 
continue in accordance with the chemotherapy dose 
modification guidelines listed in Table 13 and Table 15.  
Abbreviation: MSEs = musculoskeletal events.  
Only one re-challenge at the same dose level is allowed, and only one dose reduction and/or 
decrease in dosing frequency is allowed. The lower dose level for dose reduction will be 
1.6 μg/kg. PEGPH20 re-escalations are allowed at the Investigator’s discretion. 

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If both NAB and GEM are held on Day 1 of treatment cycles 2+, PEGPH20 must also be held; 
however, PEGPH20 may be given alone or in combination with either or both chemotherapy 
drugs on Days 8 and 15 of any cycle. If PEGPH20 is held during a treatment cycle, NAB and 
GEM may still be given if the subject meets all criteria for dosing. 
If PEGPH20 is permanently discontinued, PAG subjects should continue with all other visits and 
procedures as outlined in Table 2. Pre-PEGPH20 laboratory samples should be obtained as per 
protocol but should be collected before nab-paclitaxel administration (instead of the PEGPH20). 
This includes pre-dose PK, immunogenicity, and HA samples. Post-dose PEGPH20 PK samples 
will not be collected. Samples collected after chemotherapy should continue to be collected (e.g., 
HA). Dexamethasone should be given within 2 hours prior to each nab-paclitaxel dose and 8-12 
hours post each gemcitabine dose. ECGs should be collected pre-nab-paclitaxel and 1-4 hours 
after gemcitabine administration. 
8.3.2. 
Nab-paclitaxel and Gemcitabine 
8.3.2.1. 
Nab-paclitaxel Administration 
NAB will be administered by IV infusion at a dose of 125 mg/m2 over 30 minutes (study sites 
may follow standard of care dosing windows) once weekly for 3 weeks (or until toxicity 
necessitates reducing or holding a dose), followed by a week of rest from treatment.  
The NAB dose will be individually calculated for all infusion visits according to the subject’s 
screening BSA. In calculating the dose, there will be no downward adjustment to “ideal” body 
weight unless institution policy requires it. Doses should be re-adjusted if the subject’s BSA 
changes by >10%. If the subject’s BSA changes by ≤10%, no adjustment is necessary unless the 
site has a standard procedure to adjust doses based upon current BSA.  
NAB will be administered after PEGPH20 (for PAG treatment group) and before GEM (both 
PAG and AG treatment groups).  
For the PAG subjects, in Cycle 1 the first administration of NAB should occur 24 hours 
(±4 hours) after PEGPH20 administration and 2 to 4 hours after PEGPH20 administration on 
Days 8 and 15. In Cycle 2 onwards, NAB should be administered 2 to 4 hours after PEGPH20 
administration on Days 1, 8, and 15. 
If NAB is withheld, PEG and GEM may still be given if the subject meets all criteria for dosing. 
8.3.2.2. 
Gemcitabine Administration 
GEM should be administered after NAB by IV infusion at a dose of 1000 mg/m2 over 30 minutes 
(study sites may follow standard of care dosing windows) once weekly for 3 weeks (or until 
toxicity necessitates reducing or holding a dose), followed by a week of rest from treatment. 
Note: Prolongation of the infusion time >60 minutes has been shown to increase toxicity. 
The GEM dose will be individually calculated for all infusion visits according to the subject’s 
screening BSA. In calculating the dose, there will be no downward adjustment to “ideal” body 
weight unless institution policy requires it. Doses should be re-adjusted if the subject’s BSA 
changes by >10%. If the subject’s BSA changes by ≤10%, no adjustment is necessary unless the 
site has a standard procedure to adjust doses based upon current BSA.  

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The administration of GEM should occur immediately after NAB (all subjects all visit where 
chemotherapy is administered). If NAB is held on Day 2 for PAG subjects, GEM should be 
administered 24 hours (±4 hours) after PEGPH20. If NAB is held on Day 1 of Cycles 2+ or Days 
8 and 15 of any cycle, GEM should be administered 2 to 4 hours after PEGPH20 (PAG subjects).  
If GEM is held, PEGPH20 and NAB may still be given if the subject meets all criteria for 
dosing. 
8.3.2.3. 
Nab-paclitaxel and Gemcitabine Dose Adjustment and Toxicity Management 
Subjects should be monitored using standard of care local laboratory results prior to each NAB 
and GEM dose. Subjects must not begin a new treatment cycle with NAB and GEM if any 
hepatic or hematologic parameter is outside of what is listed in Table 13 and Table 14 (Day 1 
dose modification guidelines). Dose reductions are permitted as outlined in Table 12; however 
these may be superseded by updates in the GEM or NAB package inserts. Study treatment 
should be discontinued if a subject experiences toxicity that requires more than 2 dose 
reductions. Study treatment should be modified according to the dose modification guidelines 
outlined in Sections 8.3.2.3.1 and 8.3.2.3.2; however, the guidelines below may be superseded by 
updates in the GEM or NAB package inserts. For additional guidance, refer to the current NAB 
and GEM package inserts for current prescribing information and toxicity profiles.  
Table 12: 
Nab-paclitaxel and Gemcitabine Dose Level Reductions 
Dose Level 
Nab-paclitaxel (mg/m2) 
Gemcitabine (mg/m2) 
Starting Dose  
125 
1000 
Dose -1 
100 
800 
Dose -2 
75 
600 
8.3.2.3.1. Day 1 Dose Modification Guidelines for Nab-paclitaxel and Gemcitabine 
Day 1 dose modifications are outlined in Table 13 for non-hematologic toxicity and in Table 14 
for hematologic toxicity. 
Table 13: 
Day 1 Dose Modification Guidelines for Non-Hematologic Toxicity 
Non-Hematologic Toxicity 
NAB and GEM Dose Modification 
Grade ≤2 
Same as Day 1 of previous cycle 
Grade 3 
Decrease NAB and/or GEM to next lower dose 
level depending on whether the toxicity is related 
to NAB or GEM  
Grade 4 
Discontinue all study treatment. Subjects may 
only continue treatment for transient Grade 4 
toxicity after discussion with Sponsor.  
Abbreviations: GEM = gemcitabine; NAB = nab-paclitaxel  
Notes: Dose modifications apply to Day 1 of any treatment cycle. NAB and GEM should be immediately 
discontinued if interstitial pneumonitis (any grade) occurs. 
 

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Table 14: 
Day 1 Dose Modification Guidelines for Hematologic Toxicity 
Hematologic Toxicity 
NAB and GEM Dose Modification 
ANC 
 
Platelets 
 
≥1,500 cells/mm3 
and 
≥100,000 plt/mm3 
Treat as scheduled 
<1,500 cells/mm3 
and/or 
<100,000 plt/mm3 
Delay 1 week until ANC ≥1,500 cells/mm3 and 
platelets ≥100,000 plt/mm3  
Abbreviations: ANC = absolute neutrophil count; GEM = gemcitabine; NAB = nab-paclitaxel; plt = platelets.  
Note: Dose modifications apply to Day 1 of any treatment cycle. 
8.3.2.3.2. Day 8 and Day 15 Dose Modification Guidelines for Nab-paclitaxel and 
Gemcitabine 
Day 8 and Day 15 dose modifications for non-hematologic toxicity are outlined in Table 15. 
Day 8 and Day 15 dose modifications for hematologic toxicity are outlined in Table 16. Day 15 
dose modifications are based on the hematology results of Day 8 of that cycle as well as the 
hematologic results of Day 15. 
Table 15: 
Day 8 and Day 15 Dose Modification Guidelines for Non-Hematologic 
Toxicity 
Non-Hematologic Toxicity 
NAB and GEM Dose Modification 
Grade ≤2 
Treat as scheduled or at next lower dose level 
Grade 3 peripheral neuropathy 
Hold NAB dose until toxicity resolves to Grade 
≤2, then resume treatment at same dose or next 
lower dose level, but GEM dosing may continue 
as scheduled 
All other Grade 3  
(except nausea or vomiting if not treated with 
maximum prophylaxis) 
Hold both NAB and GEM dose until toxicity 
resolves to Grade ≤2, then resume treatment at 
next lower dose level 
Grade 4 
Discontinue all study treatment. Subjects may 
only continue treatment for transient Grade 4 
toxicity after discussion with Sponsor.  
Abbreviations: GEM = gemcitabine; NAB = nab-paclitaxel. 
Notes: Dose modifications apply to Day 8 and Day 15 of any treatment cycle. NAB and GEM should be 
immediately discontinued if interstitial pneumonitis (any grade) occurs. 
 

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Table 16: 
Day 8 and Day 15 Dose Modification Guidelines for Hematologic Toxicity 
Day 8 
Day 15 
ANC and Platelet 
Counts 
NAB and GEM Dose 
Modification 
ANC and Platelet 
Counts 
NAB and GEM Dose 
Modification 
ANC ≥1,000 cells/mm3 
and 
Platelets ≥75,000 plt/mm3 
Treat as scheduled 
ANC ≥1,000 cells/mm3 
and 
Platelets ≥75,000 plt/mm3 
Treat as scheduled 
 
 
ANC 500 - <1,000 
cells/mm3 
or 
Platelets 50,000 - <75,000 
plt/mm3 
Treat as scheduled plus 
treat with G-CSF 
 
 
ANC <500 cells/mm3 
or 
Platelets <50,000 plt/mm3 
Hold both drugs plus treat 
with G-CSF 
ANC 500 – <1,000 
cells/mm3 
or 
Platelets 50,000 – 
<75,000 plt/mm3 
Decrease by 1 dose level, 
treat on time with both 
drugs 
ANC ≥1,000 cells/mm3  
and  
Platelets ≥75,000 plt/mm3 
Treat with same dose as 
Day 8, treat on time plus 
with G-CSF 
 
 
ANC 500 – <1,000 
cells/mm3 
or 
Platelets 50,000 - <75,000 
plt/mm3 
Treat with same dose as 
Day 8, treat on time plus 
with G-CSF 
 
 
ANC <500 cells/mm3 
or 
Platelets <50,000 plt/mm3 
Hold both drugs plus treat 
with G-CSF 
ANC <500 cells/mm3 
or 
Platelets <50,000 plt/mm3 
Hold both drugs 
ANC ≥1,000 cells/mm3 
and 
Platelets ≥75,000 plt/mm3 
Decrease planned Day 8 
dose (not given) by 1 dose 
level plus treat with 
G-CSF 
 
 
ANC 500 – <1,000 
cells/mm3 
or 
Platelets 50,000 – 
<75,000 plt/mm3 
Decrease planned Day 8 
dose (not given) by 1 dose 
level plus treat with 
G-CSF 
 
 
ANC <500 cells/mm3 
or 
Platelets <50,000 plt/mm3 
Hold both drugs plus treat 
with G-CSF 
Abbreviations: ANC = absolute neutrophil count; G-CSF = granulocyte colony-stimulating factor; GEM = 
gemcitabine; NAB = nab-paclitaxel; plt = platelets. 
Note: Dose modifications apply to any treatment cycle.  
 

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8.3.2.3.3. Toxicity Management Guidelines 
• Prophylaxis against sepsis: At the occurrence of fever >38.5 C (regardless of 
neutrophil count) the subject should contact their physician and ciprofloxacin 500 mg 
orally twice per day or levofloxacin 500 mg orally once a day should be started. If the 
subject has a history of allergy to fluoroquinolone, then amoxicillin/clavulanate 
(AUGMENTIN®) 500 mg orally 2 to 3 times a day should be started. It is advised 
that all subjects should be given a prescription for either of the appropriate antibiotics 
so the subject can immediately begin either one with the first appearance of the fever. 
• Colony stimulation factors: These should be given according to institutional 
guidelines and as outlined in Table 16. 
• Interstitial pneumonitis: This can be seen with either NAB or GEM or the 
combination. Study drugs should be immediately discontinued. If an infection 
etiology is ruled out, corticosteroids should be initiated. 
8.4. 
Excluded Concomitant Medications and Study Restrictions 
Concurrent chronic use of IV heparin is prohibited; however, for acute thromboembolic events, 
IV heparin may be used. PEGPH20 administration must be permanently discontinued if a 
thrombosis or embolic event occurs. Use of megestrol acetate is prohibited. 
Any other anti-cancer agents or investigational agents are prohibited while subject is on study. 
After treatment is discontinued, the subjects will not have any restrictions (i.e., when being 
followed on a monthly basis to collect survival/anti-cancer therapy data). 
8.5. 
Treatment Compliance 
Trained medical personnel are to administer the IV study treatments. Treatment compliance will 
be monitored by the review of drug accountability records and study treatment administration 
data will be recorded in the subject’s medical record and eCRFs.  
8.6. 
Randomization and Blinding 
8.6.1. 
Run-in Phase Randomization 
The run-in phases of this study is open-label. Subjects will be enrolled and randomized after all 
baseline assessments have been completed and the Investigator has verified that they are eligible 
per criteria in Sections 7.1 and 7.2. Subjects will be randomized in a 3:1 ratio to PAG or AG 
treatment. No stratification factors will be in place for the run-in period. Additional subjects may 
be enrolled to further assess the tolerability of PEGPH20 in order to establish the acceptable 
safety profile prior to the randomization of the Phase 2 study.  
At randomization, the subject will be assigned a unique 6-digit subject identification number (the 
first segment of the number represents the study site and the second segment represents the 
subject at the study site). The subject’s identification number will be used on all of that subject’s 
eCRFs and SAE forms. No subject may begin study treatment prior to registration and 
assignment of a unique subject identification number. Any subject identification numbers that 

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are assigned will not be reused even if the subject does not receive treatment. Confirmation of 
subject enrollment and randomization status will be provided after registration.  
8.6.2. 
Phase 2 Randomization 
The Phase 2 portion of this study is open-label. Subjects will be enrolled and randomized after 
all screening assessments have been completed and the Investigator has verified that they are 
eligible per criteria in Sections 7.1 and 7.2. In stage 1, subjects will be randomized in a 1:1 ratio 
to PAG or AG treatment groups. In Stage 2 of the study subjects will be randomized in a 2:1 
ratio to receive PAG or AG treatment. Subjects will be stratified based upon Screening 
Karnofsky Performance Status (70% to 80% and 90% to 100%).  
Randomization will take place using a centralized Interactive Web Response System (IWRS). At 
registration, the IWRS will assign a unique 6-digit subject identification number (the first 
segment of the number represents the study site and the second segment represents the subject at 
the study site). The subject’s identification number will be used on all of that subject’s eCRFs 
and SAE forms. No subject may begin study treatment prior to registration and assignment 
of a unique subject identification number. Any subject identification numbers that are 
assigned will not be reused even if the subject does not receive treatment. 
Confirmation of subject enrollment and randomization status will be provided after registration.  

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9. 
STUDY DRUG AND MATERIALS  
9.1. 
Study Drug Description 
9.1.1. 
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. rHuPH20 
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 rHuPH20.  
Chemical Name 
PEGPH20 (PEGylated recombinant human hyaluronidase: 36-482-hyaluronoglucosaminidase 
PH20 [human]) 
Structural Formula 
The structure of PEGPH20 is represented in Figure 7. 
Figure 7: 
Structure of PEGPH20 
 
 
The empirical formula for P is rHuPH20: C2327H3565N589O667S20 (based on amino acid sequence) 
and PEG: C1371H2737NO686 (based on PEG with n = 681). The average molecular weight of 
PEGPH20 is approximately 220,000 Da (range of approximately 90,000 to 320,000 Da). 
9.1.2. 
Nab-paclitaxel 
NAB is a microtubule inhibitor indicated for the treatment of metastatic breast cancer and locally 
advanced or metastatic non-small cell lung cancer. It is an albumin-bound form of paclitaxel. 
Refer to the package insert for a thorough description and diagram of the structure of NAB. 

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9.1.3. 
Gemcitabine 
GEM is a nucleoside analogue that exhibits anti-tumor activity. It is indicated as first-line 
treatment for subjects with locally advanced (nonresectable Stage II or Stage III) or metastatic 
(Stage IV) adenocarcinoma of the pancreas.  
Refer to the package insert for a thorough description and diagram of the structure of GEM. 
9.2. 
Study Drug Packaging and Labeling 
9.2.1. 
PEGPH20 
PEGPH20 drug product (original formulation) is supplied as a frozen, sterile, single-use, 
injectable liquid. PEGPH20 drug product (clinical test article) is an aqueous solution containing 
3.5 mg/mL PEGPH20 with 10 mM histidine and 130 mM NaCl at a pH of 6.5. Each vial 
contains 1.2 mL (4.2 mg) or 0.6 mL (2.1 mg) of PEGPH20 drug product. PEGPH20 drug 
product will be packaged in clear, Type I borosilicate 2 mL glass vials with a siliconized 
bromobutyl rubber stopper and aluminum 20 mm flip-off crimped cap. PEGPH20 drug product 
is provided as a frozen formulation. It should be stored at or below -20°C before use. 
PEGPH20 drug product (new formulation) is supplied as a refrigerated, sterile, single-use, 
injectable liquid. This PEGPH20 drug product is also an aqueous solution containing 
0.30 mg/mL PEGPH20 with 10 mM succinic acid, 130 mM NaCl, and 10 mM L-methionine at a 
pH of 6.2. Each vial contains 1.2 mL (0.36 mg, current investigational material) or 1.0 mL 
(0.30 mg, commercial-scale material) of PEGPH20 drug product. PEGPH20 drug product will be 
packaged in clear, Type 1 borosilicate glass vials with a 13 mm Flurotec® coated chlorobutyl 
rubber stopper and a 13 mm aluminum overseal with plastic flip off cap. This drug product is 
provided as a refrigerated formulation and should be stored at 2°C to 8°C before use.  
PEGPH20 mixing instructions will be provided for both formulations. 
9.2.2. 
Nab-paclitaxel 
NAB is supplied as a white to yellow, sterile, lyophilized powder for reconstitution with 20 mL 
of 0.9% Sodium Chloride Injection, USP, prior to IV infusion. Each single-use vial contains 
100 mg of paclitaxel (bound to human albumin) and approximately 900 mg of human albumin 
(containing sodium caprylate and sodium acetyltryptophanate). Each milliliter of reconstituted 
suspension contains 5 mg paclitaxel and is free of solvents. The NDC number is 68817-134-50. 
9.2.3. 
Gemcitabine 
GEM is a white to off-white solid lyophilized powder. GEM is supplied in sterile single-use vials 
as follows: 
• 200 mg white to off-white, lyophilized powder in 10-mL vials (No. 7501) 
NDC 0002-7501-01. 
• 1 g white to off-white, lyophilized powder in 50-mL vials (No. 7502) 
NDC 0002-7502-01. 

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9.3. 
Study Drug Storage 
9.3.1. 
PEGPH20 
PEGPH20 drug product (original formulation), supplied at a concentration of 3.5 mg/mL, is a 
frozen formulation and should be stored at or below -20°C before use. This drug product may be 
thawed either at room temperature or at 2°C to 8°C and should be used within 24 hours after 
thawing. Stability testing of this PEGPH20 drug product was initiated following general 
International Conference on Harmonisation (ICH) guidelines at -20°C ± 5°C, and concurrent 
stability evaluation is ongoing. The Sponsor will monitor drug stability and provide updates on 
an ongoing basis. 
PEGPH20 drug product (new formulation), supplied at a concentration of 0.30 mg/mL, is a 
liquid formulation and should be stored at 2°C to 8°C before use. Stability testing of this 
PEGPH20 drug product was initiated following general 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. 
9.3.2. 
Nab-paclitaxel 
The drug should be stored in original cartons at 20°C to 25°C (68°F to 77°F). Retain in the 
original package to protect from bright light. 
9.3.3. 
Gemcitabine 
The drug should be stored at controlled room temperature from 20°C to 25°C (68°F to 77°F). 
9.4. 
Study Drug Preparation 
9.4.1. 
PEGPH20 
PEGPH20 (original formulation), supplied at a concentration of 3.5 mg/mL, should be stored at 
or below -20°C prior to use. Each vial is intended for single use and should be thawed and used 
within 24 hours after thawing.  
PEGPH20 (new formulation), supplied at a concentration of 0.30 mg/mL, should be stored at 
2°C to 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 for both formulations can be found in the pharmacy manual. 
9.4.2. 
Nab-paclitaxel 
Refer to the NAB package insert for the most current drug preparation and handling guidelines.  
9.4.3. 
Gemcitabine 
Refer to the GEM package insert for the most current drug preparation and handling guidelines.  

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9.5. 
Study Drug Accountability 
The Investigator, pharmacist or qualified designee is responsible for making an inventory of 
study drug(s) upon their receipt. All used and unused study drug supplies should be retained until 
final reconciliation or as indicated by Halozyme, or as per Institution policy. The study drug is to 
be administered/prescribed by the Principal Investigator or appropriately qualified site personnel 
named on the delegation of authority log. Under no circumstances will the Investigator allow the 
study drug to be used other than as directed by this protocol. Although appropriate personnel 
may be designated to administer/dispense drug and maintain drug accountability records, the 
Principal Investigator is ultimately responsible for all drug accountability. 
The Investigator or designee must maintain accurate records of the receipt and disposition of 
study drug supplies. Documentation of drug disposition should identify the subject receiving the 
drug, the amount and date of the dose, and any unused drug. This documentation is required in 
addition to drug accountability information recorded on eCRFs. A copy of the reconciled drug 
inventory record will be provided to Halozyme or its designee, and the study site will retain the 
original record. 
After study drug is reconciled by the study monitor, drug may be destroyed as per Institutional 
Policy, or returned to the country specific drug depot as per country regulations. If used study 
medications cannot be stored until drug accountability has been performed as per 
clinic/institution policy, the Sponsor should be notified in advance, and reconciliation procedures 
will be agreed upon. 

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10. 
SAFETY ASSESSMENTS 
Safety parameters monitored and recorded during this study include AEs; medical history; 
concomitant medications; immunogenicity, hematology, blood chemistry, coagulation, and 
urinalysis results; physical examination findings; vital signs; ECG results; pregnancy test results; 
and Karnofsky Performance Status.  
10.1. 
Management of Thromboembolic Events 
Thromboembolic disease is a common complication of pancreatic cancer and is associated with 
the generation of an intrinsic hypercoagulable state. The increase in incidence rate of clinical 
manifestations of thromboembolic disease in pancreatic cancer include deep venous thrombosis, 
pulmonary embolism, disseminated intravascular coagulation, portal vein thrombosis, and 
arterial thromboembolism has been well documented (Heit 2000, Epstein and O’Reilly 2012, 
Timp 2013). Subjects should be managed proactively to minimize the occurrence of 
thromboembolic events. With amendment 4.0, low-molecular-weight heparin (LMWH), 
specifically enoxaparin, at a dose of 1 mg/kg/day will be used in all subjects while receiving 
study treatment. If a subject is on a different LMWH prior to study entry, the subject should be 
switched over to enoxaparin. In the event the Investigator feels that an alternative anticoagulant 
is beneficial to the subject, the Investigator should obtain written pre-approval from the Sponsor 
or its designee. If pre-approval is granted, this will not be considered a deviation from the 
protocol.  
Anti-Xa testing may be done at a local lab pre-and post-dose to verify the dose of enoxaparin is 
correct as per Investigator discretion under the institution guideline (Section 10.1.1).  
Other tests may be done as per institutional policy if anti-Xa is not available locally. In addition, 
IV heparin may be used for acute management of thromboembolic events. PEGPH20 
administration should be stopped during the IV heparin treatment period.  
Any anti-coagulation therapy received by the subjects must be documented in the concomitant 
medication eCRF pages and any anti-Xa tests performed must be entered into the eCRFs as well.  
10.1.1. 
Enoxaparin Management 
All subjects should begin daily treatment with 1 mg/kg of enoxaparin. Dosage of enoxaparin should be 
based on the subject’s screening weight and should be modified if the subject’s weight changes by 10%, 
or per Insitution policy. Institution’s rounding practices may be used when calculating the dose of 
enoxaparin. If pre-filled syringes of enoxaparin are used, rounding may be performed. Note that all 
efforts should be made to administer the dose as close to 1.0 mg/kg as possible. 
Hematology and coagulation testing should be done on a weekly basis (Section 8.1). Enoxaparin 
should be held if the platelet count is <50,000 plt/mm3; however, therapy should be resumed 
once the platelet count is above 50,000 plt/mm3. Enoxaparin dose should be reduced to 0.5 
mg/kg for Grade 2 thrombocytopenia (platelet count 50,000 – 75,000 plt/mm3) until an increase 
in platelets > 75,000 plt/mm3, at which time the dose should be increased to 1 mg/kg. Sponsor 
should be consulted if the Investigator does not feel the dose of enoxaparin should be re-started 
at a dose of 1.0 mg/kg. 

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Should a subject experience a thromboembolic event while on study, the dose of enoxaparin 
should be increased to a therapeutic dose based on standard clinical practice (i.e., standard of 
care/current NCCN guidelines). Administration of PEGPH20 will be stopped during the period 
when enoxaparin dose is held. Abraxane and gemcitabine therapy may continue according to the 
dose modification sections for the respective therapy. See Section 8.3.2.3. Subjects from either 
group who permanently discontinue LMWH therapy for any reason (refer to enoxaparin package 
insert) will be withdrawn from study treatment (See Section 7.3.1).  
10.2. 
Adverse Event Definitions 
An AE is any unfavorable or unintended sign, symptom, or disease temporally associated with 
the use of a pharmaceutical product (i.e., study drug), whether or not considered related to the 
pharmaceutical product.  
The recording of AEs will begin at the start of the administration of the first dose of a study drug. 
AEs should record the development or increased severity of an undesirable medical condition or 
the worsening of a pre-existing medical condition during or following exposure to study drug, 
regardless of relationship to study drug. Additionally, changes in severity (increase or decrease) 
of a previously recorded AE will be recorded. See Section 10.5 for additional information. 
A serious adverse event (SAE) is any AE that: 
• Results in death. 
• Is life-threatening. 
A life-threatening SAE is any AE that places the subject at immediate risk of death 
from the reaction as it occurred, as assessed by the Investigator. This definition does 
not include a reaction that might have caused death if it occurred in a more severe 
form. 
• Requires inpatient hospitalization or prolongs existing hospitalization. 
• For the purposes of this protocol, any hospital admission will be considered inpatient 
hospitalization, regardless of duration. An emergency room visit without hospital 
admission will not be recorded as a SAE under this criterion, nor will cases of 
elective hospitalization for administration of chemotherapy, hospitalization for social 
admissions, or hospitalization for a procedure scheduled before study enrollment. 
However, unexpected complications that occur during elective surgery should be 
recorded as AEs and assessed for seriousness. 
• Results in persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions. 
• Results in a congenital anomaly or birth defect. 
• Is any other important medical event, 
Other medical events may be considered SAEs when, based on appropriate medical 
judgment, they may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the other outcomes in the SAE definition. Examples 
include allergic bronchospasm requiring intensive treatment in an emergency room or 

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at home, blood dyscrasias or convulsions that do not result in hospitalization of the 
subject, or the development of drug dependency or drug abuse. 
10.3. 
Reporting Serious Adverse Events  
Report all SAEs to the designated safety contact IMMEDIATELY AND NO LATER THAN 
24 HOURS OF AWARENESS, i.e., knowledge, discovery, or notification of the SAE. 
Complete the study-specific SAE Report Form and submit the completed form with any other 
available pertinent information (e.g., hospital records, laboratory results, etc.) to the designated 
safety contact (contact information is provided in the study reference binder). 
If additional follow-up information is required or becomes available for a previously reported 
SAE, a follow-up SAE Report Form with the new information should be prepared and submitted 
IMMEDIATELY AND NO LATER THAN 24 HOURS OF AWARENESS. For 
hospitalizations, all attempts to obtain the hospital record should be documented in the study file. 
10.4. 
Reporting Adverse Events of Special Interest 
Thromboembolic events (TE events) are considered AEs of special interest in the current trial. 
All TE events, regardless of type of event, severity, or seriousness must be reported. Study sites 
will report any TE event to the Sponsor IMMEDIATELY AND NO LATER THAN 
24 HOURS OF AWARENESS. Sites will complete the study-specific AE of Special Interest 
form (guidance regarding completion of this form will be provided to the sites) and send it to the 
designated safety contact (contact information is provided in the study reference binder).  
10.4.1. 
Thromboembolic Event Grading 
The current version of the NCI Common Terminology Criteria for Adverse Events (CTCAE) 
should be utilized when grading TE Events. Table 17 denotes the most commonly reported TE 
events and the associated grading scale per CTCAE Version 4.03 (14 June 2010). If the CTCAE 
is updated during the study, the current version of the CTCAE should be used.  
Table 17: 
CTCAE Version 4.03 Grading for Thromboembolic Events 
Grade 
Adverse Event 
1 
2 
3 
4 
5 
Acute coronary 
syndrome 
- 
Symptomatic, 
progressive 
angina; cardiac 
enzymes normal; 
hemodynamically 
stable 
Symptomatic, 
unstable angina 
and/or acute 
myocardial 
infarction, 
cardiac enzymes 
abnormal, 
hemodynamically 
stable 
Symptomatic, 
unstable angina 
and/or acute 
myocardial 
infarction, 
cardiac enzymes 
abnormal, 
hemodynamically 
unstable 
Death 
Definition: A disorder characterized by signs and symptoms related to acute ischemia of the myocardium secondary 
to coronary artery disease. The clinical presentation covers a spectrum of heart diseases from unstable angina to 
myocardial infarction. 
Ischemia 
cerebrovascular 
Asymptomatic; 
clinical or 
Moderate 
symptoms 
- 
- 
- 

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Grade 
Adverse Event 
1 
2 
3 
4 
5 
diagnostic 
observations 
only; 
intervention not 
indicated 
Definition: A disorder characterized by a decrease or absence of blood supply to the brain caused by obstruction 
(thrombosis or embolism) of an artery resulting in neurological damage. 
Myocardial 
infarction 
- 
Asymptomatic 
and cardiac 
enzymes 
minimally 
abnormal and no 
evidence of 
ischemic ECG 
changes 
Severe 
symptoms; 
cardiac enzymes 
abnormal; 
hemodynamically 
stable; ECG 
changes 
consistent with 
infarction 
Life-threatening 
consequences; 
hemodynamically 
unstable 
Death 
Definition: A disorder characterized by gross necrosis of the myocardium; this is due to an interruption of blood 
supply to the area. 
Portal Vein 
Thrombosis 
- 
Intervention not 
indicated 
Medical 
intervention 
indicated 
Life-threatening 
consequences; 
urgent 
intervention 
indicated 
Death 
Definition: A disorder characterized by the formation of a thrombus (blood clot) in the portal vein. 
Superficial 
thrombophlebitis 
- 
Present 
- 
- 
- 
Definition: A disorder characterized by a blood clot and inflammation involving a superficial vein of the 
extremities. 
Thromboembolic 
event 
Venous 
thrombosis 
(e.g., superficial 
thrombosis) 
Venous 
thrombosis (e.g., 
uncomplicated 
deep vein 
thrombosis), 
medical 
intervention 
indicated 
Thrombosis (e.g., 
uncomplicated 
pulmonary 
embolism 
[venous], non-
embolic cardiac 
mural [arterial] 
thrombus), 
medical 
intervention 
indicated 
Life-threatening 
(e.g., pulmonary 
embolism, 
cerebrovascular 
event, arterial 
insufficiency); 
hemodynamic or 
neurologic 
instability; urgent 
intervention 
indicated 
Death 
Definition: A disorder characterized by occlusion of a vessel by a thrombus that has migrated from a distal site via 
the blood stream. 
Vascular access 
complication 
- 
Device 
dislodgement, 
blockage, leak, or 
malposition; 
device 
Deep vein or 
cardiac 
thrombosis; 
intervention 
indicated (e.g., 
Embolic event 
including 
pulmonary 
embolism or life 
Death 

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Grade 
Adverse Event 
1 
2 
3 
4 
5 
replacement 
indicated 
anticoagulation, 
lysis, filter, 
invasive 
procedure) 
threatening 
thrombus 
Definition: A finding of a previously undocumented problem related to the vascular access site. 
Source: NCI CTCAE 4.03 June 14, 2010. 
10.4.2. 
Disease-Related Events That Are Endpoints 
For the purposes of this study in subjects with Stage IV pancreatic cancer, progression of the 
subject’s underlying disease (“disease progression”) is an efficacy assessment and should 
generally not be reported as an AE or SAE. However, if the Investigator determines that there is 
evidence suggesting a causal relationship between the event and the study medication, 
immediately report the event to the safety contact and record as an AE or SAE. 
Death resulting from disease progression is a study endpoint, and generally should not be 
reported as a SAE. This event must be recorded in the eCRF and will be reviewed by the 
Sponsor and DMC periodically for increased frequency in the treatment group. However, if the 
Investigator determines that there is evidence suggesting a causal relationship between the event 
and the study medication, immediately report the event as an SAE. 
10.5. 
Adverse Events 
Events that occur before the first administration of study drug are not considered AEs, by 
definition (Section 10.2); record these events on the Medical History eCRF. 
The Investigator or a qualified designee will question and examine subjects for evidence of AEs. 
Subjects should not be asked about specific AEs. Instead, they should be asked general questions 
(e.g., “How have you been feeling since your last visit?”). Record all AEs in the eCRF. Any 
changes of AEs in grade must also be recorded in the eCRF. 
For an event to be recorded as an AE, the onset must occur during or after the subject’s first 
exposure to study drug and no later than 30 days after the last study drug dose. However, there is 
no limit on reporting SAEs considered reasonably related to PEGPH20 (i.e., assessed as “Yes, 
Related,” “Probably Related,” or “Possibly Related,” Section 10.5.2); these should be submitted 
as SAEs per Section 10.3, even if they are first identified during the long-term follow-up period. 
The Investigator should follow all AEs that are considered reasonably related to study drug until 
resolution or stabilization. All other AEs should be followed until resolution or stabilization or 
until the End of Treatment Visit, whichever occurs first. 
Wherever possible, record syndromes rather than individual signs or symptoms to avoid 
duplication and to facilitate meaningful interpretation of data. For example, a subject presenting 
with rhinitis, fever, and headache should be reported as having “flu-like symptoms,” without 
independently recording each accompanying sign. When no clearly recognizable clinical 
syndrome can be described, record individual clinical signs and symptoms. 

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All AEs that occur during the study should be treated appropriately to protect and ensure the 
subject’s well-being. If such treatment constitutes a deviation from this protocol, Halozyme must 
be notified and the Investigator should comply with applicable IRB/EC reporting requirements. 
The Investigator is responsible for determining whether or not an AE is severe enough to require 
the subject’s removal from treatment. A subject may also voluntarily withdraw from treatment 
because of an AE. If either occurs, the subject must receive appropriate medical care, and the 
Investigator must strongly encourage the subject to return to the study site for the final protocol-
specified visit and assessments, and to continue returning to the study site for follow-up 
evaluations until the AE resolves or stabilizes. All AEs, serious or not, that result in permanent 
withdrawal from study treatment should be immediately reported to Halozyme (Section 10.3). 
Halozyme will conduct reviews of all available AEs at the end of the run-in phases and at a 
minimum of once every three months during Phase 2. 
10.5.1. 
Classification of Adverse Events by Severity 
The Investigator must categorize the severity of each AE using the National Cancer Institute 
(NCI) Common Terminology Criteria for Adverse Events v4.03 (CTCAE) or the current version. 
It’s important to distinguish between AE seriousness and severity; these terms are not 
interchangeable. Severity is a measure of intensity whereas seriousness is defined by the criteria 
in Section 10.2. 
10.5.2. 
Classification of Adverse Events by Relationship to Study Drug 
For each AE, the Investigator must document whether there is a reasonable possibility that the 
event was caused by administration of PEGPH20, NAB, and/or GEM. The Investigator should 
make this decision after careful consideration of the following questions: 
• Does the AE follow a reasonable temporal sequence from administration of study 
drug? 
• Can the AE be reasonably explained by the known characteristics of the subject’s 
clinical state, environmental or toxic factors, or other therapy? 
• Do the AE symptoms disappear or decrease on cessation of study drug or reduction in 
study drug dose? (There are exceptions when an AE does not disappear on 
discontinuation of the drug, yet drug relatedness clearly exists [e.g., bone marrow 
depression, fixed drug eruptions, tardive dyskinesia, etc.]) 
• Does the AE reappear or worsen when the study drug is re-administered? 
• Does the AE follow an expected response pattern based on the established 
pharmacologic and toxicologic effects of the study drug? 
• Does the AE follow an expected response pattern based on the known effects of other 
products in the same class? 
For this assessment, the Investigator will classify each AE as one of the following: 
• Yes, Related: The AE is definitely related to study drug administration.  

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• Probably Related: There is a high degree of certainty that the AE is related to study 
drug administration. 
• Possibly Related: The AE could be related either to study drug administration or to 
concurrent disease/medication. 
• Unlikely Related: There is a high degree of certainty that the AE is NOT related to 
study drug administration. 
• Not Related: The AE is clearly due to other causes (e.g. concurrent medication, 
underlying disease, etc.). 
For the purposes of expedited reporting to regulatory authorities, AEs assessed as “Yes, 
Related,” “Probably Related,” or “Possibly Related” will be considered suspected adverse 
reactions. 
10.6. 
Abnormal Laboratory Results  
Abnormal laboratory results may occur in the context of an AE that is a clinical syndrome (e.g., 
elevated BUN and creatinine in the setting of an AE of renal failure, or elevated AST/ALT in the 
setting of an AE of hepatitis). In these cases, do not record the abnormality itself as an AE. 
However, in the absence of an AE that encompasses an observed abnormal laboratory result, 
report the abnormality as an AE if the Investigator judges it to be clinically significant for the 
subject. 
10.7. 
Pregnancy 
Pregnancy itself is not regarded as an AE unless there is suspicion that the study drug may have 
interfered with the effectiveness of the contraceptive medication. Pregnancy within 30 days of 
study drug discontinuation in a subject must be reported to the designated safety contact (contact 
information is provided in the study reference binder) IMMEDIATELY AND NO LATER 
THAN 24 HOURS OF AWARENESS. Complete the study-specific Pregnancy Report Form 
with all available information and submit the form with pregnancy test results and any other 
pertinent information. Also, within 24 hours, complete the eCRF with all available AE, 
demographic, medical history, concomitant medication, and study drug administration 
information available. As additional information on a previously reported pregnancy becomes 
available, a follow-up Pregnancy Report Form should be prepared with the new information and 
submitted to the safety contact. 
Subjects who become pregnant during the study will not receive any additional study drug and 
will be withdrawn from the study. The Investigator must strongly encourage these subjects to 
return to the study site for the final protocol-specified visit and assessments. In addition, the 
Investigator will monitor the pregnancies of subjects exposed to study drug until final resolution 
(delivery, miscarriage, or early termination). Follow-up should occur monthly and should be 
documented in the study file. A follow-up Pregnancy Report Form must be completed following 
each follow-up contact with the subject and submitted to the Sponsor’s designated safety contact. 
Report a spontaneous miscarriage, therapeutic abortion, stillbirth, or congenital anomaly as an 
SAE (Section 10.3). 

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10.8. 
Overdose 
PEGPH20, NAB, and GEM will be administered by IV infusion at a qualified and experienced 
clinical study site. The potential for drug overdose is therefore minimal. However, should an 
overdose occur, the infusion should be stopped immediately. A blood PK plasma sample should 
be taken as soon as possible, with a notation of the time of sampling relative to the time of 
completion of the infusion. Investigator should also monitor the subject with appropriate blood 
counts and blood chemistry tests, and should also provide supportive therapy, as necessary. 
Contact the Halozyme Medical Monitor, or designee, WITHIN 24 HOURS. 
There are no data regarding PEGPH20 overdose in humans. However, the likelihood of 
significant MSEs (such as pain, spasms, and weakness) increases with increasing PEGPH20 
dose. An overdose and AEs should be treated as per standard medical practice. There is no 
known antidote for PEGPH20. 
Overdose of NAB or GEM should be managed per the relevant package insert. 
Dosing details should be captured in the eCRF. If the subject receives a dose of a study drug that 
exceeds protocol specifications and the subject is symptomatic, then the symptom(s) should be 
documented as AEs in the eCRF and, if serious, submitted to the Sponsor’s designated safety 
contact on an SAE Report Form. Do not record the overdose as an AE if the subject is not 
symptomatic. 
10.9. 
Data Monitoring Committee 
An independent DMC will be constituted and responsible for periodically reviewing safety and 
efficacy data of the Phase 2 study. Operational and logistical details will be provided in a 
separate DMC charter. 
10.10. 
Unblinding 
This study is not blinded; however, to avoid the introduction of operational bias into study 
conduct and to increase the interpretability and reliability of the data, a blinding plan was 
implemented. No interim analyses of efficacy were initially planned. However, for the purpose 
of tumor HA assay development, 2 interim analyses of Stage 1 efficacy data were performed to 
develop the HA algorithm and determine the cut-point to define HA-high subjects using a 
prototype HA assay and the VENTANA HA RxDx assay, respectively (additional details in 
Section 11.1.11). The blinding plan was updated accordingly to minimize the potential impact. 
For example, the Sponsor was blinded to the primary efficacy data and HA data of Stage 2, 
which is the validation set for HA algorithm and cut-point. A third comprehensive interim 
analysis of efficacy and safety data was performed to validate the VENTANA HA RxDx assay 
algorithm and cut-point of 50% and to enable a thorough benefit/risk assessment based on HA 
status. After the third interim analysis, the Sponsor became unblinded to all data. 
Efficacy data (ORR) were also reviewed by the DMC during the clinical hold for a preliminary 
risk versus benefit assessment.   

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10.11. 
Reporting Safety Information to the Institutional Review Board 
The Sponsor and/or a designated agent may provide written safety reports or other safety-related 
communications to the Investigator. The Investigator will ensure that these reports are reviewed 
and processed in accordance with regulatory and IRB/EC requirements and archived in the site’s 
study file.  
At the completion or early termination of the study, the Investigator will submit a final report to 
the IRB/EC within the applicable time frame. 
10.12. 
Concomitant Medications 
Any medication received during the study, other than a designated study drug (PEGPH20, NAB, 
or GEM), is regarded as concomitant medication. Record concomitant medications taken after 
the subject signs the ICF during the screening period (≤20 days prior to Study Day 1) through 
30 days after the End of Treatment Visit on the Concomitant Medications eCRF. 
Update information on concomitant medications, including medication used to treat an AE, at 
each visit according to the study schedule of events. At each visit, ask subjects if there have been 
any changes in their prescription or non-prescription medications since their last visit. 
Subjects may receive medications during the study including, but not limited to, antibiotics, 
analgesics, antipyretics, etc., when clinically indicated. Prohibited medications are identified in 
Section 8.4.  
Dexamethasone, nonsteroidal anti-inflammatory drugs, and/or cyclobenzaprine may be used for 
musculoskeletal symptoms and should be documented as a concomitant medication. 
10.12.1. 
Dexamethasone 
Refer to a current dexamethasone package insert for prescribing information and toxicity profile.  
Dexamethasone may be used to attenuate musculoskeletal symptoms. For the PAG group, 
dexamethasone 8 mg should be administered within 2 hours prior to beginning each PEGPH20 
infusion and 8 to 12 hours post the PEGPH20 infusion. For the AG group, dexamethasone 8 mg 
should be administered within 2 hours prior to the NAB infusion and 8 to 12 hours post each the 
GEM infusion. Additional doses of dexamethasone may be given 24 hours prior to PEGPH20 or 
NAB infusions or at any other time at the discretion of the Investigator based on the tolerability. 
Dexamethasone may be given PO, IM, or IV. 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 PEGPH20).  
10.12.2. 
Enoxaparin  
Refer to the current enoxaparin package insert for prescribing information and toxicity profile. 
Refer to Section 6.1.2.3 and Section 10.1.1 for additional details. 

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11. 
STATISTICS 
11.1. 
Statistical Methods 
In general, continuous variables will be summarized using descriptive statistics (N, mean, 
standard deviation, median, minimum, maximum, quartiles). Categorical variables will be 
presented using frequencies and percentages. Results will be displayed for the two treatment 
groups as well as the two groups combined (total). All statistical analyses and data listings will 
be performed using SAS (Cary, NC). The SAS version will be noted in the Statistical Analysis 
Plan. 
11.1.1. 
Randomization and Blinding 
This is a multicenter, open-label, randomized study. To minimize bias to the PFS endpoint, 
disease progression is based on the assessment of the CIR. Determination of clinical progression 
by the Investigator without corresponding CIR confirmation must be documented with the 
relevant signs and symptoms.  
11.1.2. 
Sample Size 
Approximately 16 subjects with newly diagnosed, previously untreated Stage IV pancreatic 
cancer will be randomized in 3:1 ratio to receive PAG and AG treatment in the run-in Phase. 
Approximately 237 subjects with newly diagnosed, previously untreated Stage IV pancreatic 
cancer will be randomized to either the PAG or AG treatment group in the Phase 2 portion of the 
study.  
123 subjects with newly diagnosed, previously untreated Stage IV pancreatic cancer were 
randomized in a 1:1 ratio to either the PAG or AG treatment group in the Phase 2 portion of the 
study in stage 1.  
In Stage 2 of this study, 114 subjects were planned to be randomized in a 2:1 ratio to receive 
PAG or AG treatment: 76 subjects in the PAG arm and 38 subjects in the AG arm. To ensure 
adequate assessment of the primary safety endpoint of TE event incidence and a meaningful 
number of HA-high subjects in Stage 2, 133 subjects were actually randomized.   
The primary safety endpoint is the proportion of subjects who have any thromboembolic event in 
the Safety Population of Stage 2 (P).  
The hypothesis test will be conducted using the one-sided exact binomial test against the null 
hypothesis of P ≤ 12%. 
Four safety analyses will be conducted using the stopping boundary of the one-sided p-value of 
0.05 for the first two analyses and 0.035 for the remaining two analyses based on the Pocock 
method.  
It is expected that 237 subjects in Phase 2 will be enrolled in approximately 20 months and these 
subjects will be followed up for additional 15 months. There will be approximately 200 subjects, 
including subjects from both run-in phase, in the Overall Efficacy Evaluable Population for the 
primary comparisons. It is estimated that the median PFS time is 5.5 months for AG treatment 
(Von Hoff 2013). A sample size of 100 evaluable subjects per treatment group with a total of 
182 PFS events (disease progression or death) would provide 80% statistical power to detect a 

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45% treatment effect in median PFS (5.5 months for AG versus 8 months for PAG) based on the 
two-sided log-rank test at the significance level of 0.1. However, the interim data showed a low 
likelihood of achieving 182 PFS events from a total of 256 subjects actually randomized in 
Phase 2, and therefore the final analysis will be conducted when at least 95% of the enrolled 
subjects and 95% of HA-high subjects have discontinued study treatment.  
In addition, a total of 200 subjects with 160 deaths will provide 80% statistical power to detect 
40% benefit in median OS (8.5 months for AG versus 11.9 months for PAG) at one-sided alpha 
level of 0.1. Assuming 35% subjects with high HA, the study has 80% statistical power for the 
high HA subgroup to detect 90% benefit in median PFS (5.5 months for AG versus 10.5 months 
for PAG) at two-sided alpha level of 0.1 and 80% benefit in median OS (8.5 months for AG 
versus 15.3 months for PAG) at one-sided alpha level of 0.1. Statistical powers for different PAG 
treatment effects are presented in Table 18.  
 
 

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Table 18: 
Statistical Power Calculation Based on Log-rank Test 
Assuming 35 months study duration with 20 months for enrollment, 5.5 months median PFS and 
8.5 months median OS for AG Treatment 
Statistical Power for All 200 Evaluable Subjects (10% dropout) 
Endpoint 
Alpha Level 
PAG Treatment Effect 
in Median Duration 
Median Duration 
for PAG Treatment 
Statistical 
Power 
No. of 
Events 
PFS 
0.1 (two-sided) 
40% 
7.7 months 
73% 
183 
 
 
45% 
8 months 
80% 
182 
 
 
50% 
8.3 months 
86% 
181 
OS 
0.1 (two-sided) 
40% 
11.9 months 
68% 
160 
 
 
45% 
12.3 months 
76% 
159 
 
 
50% 
12.8 months 
81% 
158 
OS 
0.1 (one-sided) 
40% 
11.9 months 
80% 
160 
 
 
45% 
12.3 months 
85% 
159 
 
 
50% 
12.8 months 
90% 
158 
Statistical Power for 70 Evaluable Subjects with High HA (35% HA high) 
Endpoint 
Alpha Level 
PAG Treatment Effect 
in Median Duration 
Median Duration 
for PAG Treatment 
Statistical 
Power 
No. of 
Events 
PFS 
0.1 (two-sided) 
80% 
9.9 months 
74% 
61 
 
 
90% 
10.5 months 
80% 
61 
 
 
100% 
11 months 
84% 
60 
OS 
0.1 (two-sided) 
80% 
15.3 months 
69% 
53 
 
 
90% 
16.2 months 
75% 
52 
 
 
100% 
17 months 
80% 
52 
OS 
0.1 (one-sided) 
80% 
15.3 months 
80% 
53 
 
 
90% 
16.2 months 
85% 
52 
 
 
100% 
17 months 
88% 
52 
Abbreviations: AG = nab-paclitaxel plus gemcitabine; PAG = PEGPH20 plus nab-paclitaxel and gemcitabine; 
PFS = progression-free survival; OS = overall survival; HA = hyaluronan. 

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11.1.3. 
Analysis Populations 
This amendment is intended to decrease thromboembolic risk. Efficacy is not expected to change 
by enoxaparin treatment and exclusion of subjects with high risk of thromboembolic events. 
Thus, efficacy data are expected to be combinable for analyses.  
11.1.3.1. Intent-to-Treat Population (ITT) 
All subjects who are randomized, including the run-in phase, will be included in the ITT 
Population. Subjects will be grouped as randomized in the ITT population. The ITT Population 
will be used for subject disposition, demographic, and overall efficacy analyses.  
11.1.3.2. Overall Evaluable Population  
All randomized subjects, including the run-in phase, who have a post-baseline response 
assessment, or have clinical disease progression without a post-baseline CT scan, or have died on 
study, while they are on randomized treatment after randomization, will be included in the 
Overall Evaluable Population. The Overall Evaluable Population will be used as the primary 
analysis population for overall efficacy analyses. 
11.1.3.3. Overall Safety Population 
All subjects who received any part of a dose of study medication will be included in the Safety 
Population. Subjects in the Safety Population will be grouped according to the treatment they 
received. The Safety Population will be used for overall safety analyses. 
11.1.3.4. Safety Population of Stage 2 
Subjects in the Overall Safety Population at Stage 2 of the study. The Safety Population of Stage 
2 will be used for analyses of safety data of Stage 2 of the study. This is the analysis population 
for the primary safety endpoint.  
11.1.3.5. PK Analysis Population 
All subjects who received any part of a dose of PEGPH20 and had measurable PEGPH20 
concentrations in at least one sample collected for PK analysis will be included in the PK 
Analysis Population. 
11.1.4. 
Efficacy Analyses 
All efficacy analyses will be conducted based on tumor HA status (HA high and HA low). 
Tumor samples will be analyzed in a prospective-retrospective fashion using an affinity 
histochemistry diagnostic assay, the VENTANA HA RxDx assay (see Section 8.2.20 for 
additional details). 
11.1.4.1. Analyses of the PFS Efficacy Endpoint 
The primary efficacy endpoint is PFS. PFS is defined as the time from randomization until the 
first occurrence of disease progression, either by central radiologic determination or by clinical 
progression determined by the Investigator, or death from any cause. PFS data for surviving 
subjects without disease progression will be censored at the date of the last available 

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post-baseline tumor assessment. Surviving subjects without any post-baseline disease assessment 
will be censored on Day 1. Sensitivity analyses will be conducted to count for the impact of 
treatment switch.  
In Stage 2 of the study, subjects in PAG arm who experience any thromboembolic event will be 
discontinued from PEGPH20 treatment. In order to minimize the potential bias due to PEGPH20 
discontinuation, all subjects in PAG and AG arms who experience any thromboembolic event in 
Stage 2 will be censored at the start date of first thromboembolic event unless a PFS event occurs 
before first thromboembolic event. Other sensitivity analysis will be conducted to assess the 
impact of discontinuation due to thromboembolic event. 
The presentation of results will include the Kaplan-Meier estimates of the medians (with 95% 
confidence intervals) and quartiles and the estimated proportion of subjects who are progression 
free at 1 year by treatment group (with 95% confidence intervals). 
The primary PFS comparison of control (AG treatment group) with treatment (PAG treatment 
group) will be based on a stratified log-rank test at 2-sided α = 0.10, where the stratum is the 
performance status. PFS will be summarized with Kaplan-Meier curves. The estimated hazard 
ratio (and 95% confidence interval) for the overall treatment effect will be prepared using a 
stratified Cox regression model with the same stratification.  
The PFS between the two groups based on HA levels on tumor biopsy will be evaluated using a 
Cox regression model with HA level as a covariate. 
11.1.5. 
Analysis of Other Efficacy Endpoints 
ORR is defined as the proportion of responders, defined as subjects who achieve either a CR or 
PR response without confirmation. Subjects without an evaluable response are grouped as non-
responders. A generalized Cochran-Mantel-Haenszel statistic with Karnofsky Performance 
Status as stratum (70% to 80% and 90% to 100%) will be used to test for difference between the 
two treatment groups. DCR will be analyzed using the same method as ORR. 
OS is defined as the time from randomization until death from any cause. OS data from 
surviving subjects will be censored at time of the last contact. The OS data will be analyzed 
using the same methods as in the PFS analysis. DR will be estimated using the Kaplan-Meier 
method. 
11.1.6. 
Analysis of Primary Safety Endpoint 
The analysis of the primary safety endpoint will be conducted using the Safety Population of 
Stage 2. 
The primary safety endpoint is the proportion of subjects in the PAG arm who experience any 
thromboembolic event in Stage 2 of the study (P). Subjects with multiple events will be counted 
only once for the primary safety analysis. The statistical test for the primary safety endpoint is as 
follows: 
Null hypothesis: P ≤ 12% 
Alternative hypothesis: P > 12% 

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The hypothesis test will be conducted using the one-sided exact binomial test. 
For 76 newly enrolled subjects in the PAG arm in Stage 2, four safety analyses, three interim and 
one final analyses, will be conducted when the last subject in each analysis has been treated for 
one PAG treatment cycle or has discontinued from PAG treatment during the first treatment 
cycle as follows:  
• Interim #1: enoxaparin dose: 40 mg/day (12 PAG patients). 
• Interim #2: enoxaparin dose: 1 mg/kg/day (12 PAG patients). 
• Interim #3: enoxaparin dose: 1 mg/kg/day (29 PAG patients). 
• Final analysis: enoxaparin dose: 1 mg/kg/day (58 PAG patients). 
The DMC may recommend terminating the study when any of the four safety analyses cross the 
stopping boundaries as described in Table 19. 
Table 19: 
Stopping Boundaries for Subjects in the PAG Arm of Study 202, Stage 2 
Safety Analyses 
1st Interim 
(IA#1) 
Cumulative 
IA#1 Follow-up 
2nd Interim 
(IA#2) 
3rd Interim 
(IA#3) 
Final 
Prophylactic 
enoxaparin dose level 
40 mg/day 
40 mg/day OR 
40 mg/day and  
1 mg/kg/day 
1 mg/kg/day 
1 mg/kg/day 
1 mg/kg/day 
No. of Subjects in 
PAG Arm 
12 
18 
12 
29 
58  
(last subject) 
Stopping boundary: 
TE** Rate 
>25% 
n/a 
>25% 
>24% 
>22% 
Stopping boundary: 
Subjects with TE** 
>3 
n/a 
>3 
>7 
>12 
Stopping boundary: 
p-value 
<0.05* 
n/a 
<0.05* 
<0.035 
<0.035 
The shaded columns indicate PAG patients who have received the 40 mg/day enoxaparin dose only (IA#1) or have 
received the 40 mg/day OR the 40 mg/day and the 1 mg/kg/day enoxaparin doses after IA#1. 
* The p-value boundary for the 1st and 2nd safety analyses was increased to 0.05 from the Pocock boundary of 0.035 
to increase the chance of early stop.  
** Thromboembolic event 
The same p-value boundaries will be used if timing of safety analyses is changed per DMC 
request. 
For subjects in Stage 1 who are eligible to re-initiate PEGPH20 treatment, an interim analysis 
will be conducted after the last re-entry subject has had one cycle of PAG treatment or has 
discontinued from treatment during the first treatment cycle after re-entry. If the TE rate exceeds 
25%, all re-entry subjects will be discontinued from PEGPH20 treatment.  
11.1.7. 
Safety Analyses 
Safety summaries will be analyzed using the overall safety population and the safety population 
of Stage 2. For the overall safety population analysis, sensitivity analyses will be conducted to 
assess the impact of potential bias of PEGPH20 treatment interruption and protocol amendment 

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limited to the PAG arm, such as PEGPH20 treatment re-initiation. For example, the following 
sensitivity analysis will be conducted to assess the impact of the criteria for re-initiating therapy 
applied to the PAG arm only. The four TE risk factors (Section 6.1.2.2) will be assessed for all 
subjects randomized to PAG or AG treatment. Subjects in the PAG arm who do not have any of 
the risk factors will be re-started with PEGPH20 treatment, other subjects will continue to 
receive AG treatment. Safety analysis will be conducted by excluding subjects in AG arm who 
have any of the risk factors in order to balance the Baseline risk level of subjects in PAG and AG 
arms.  
All AEs will be presented in incidence tables coded by MedDRA preferred term and system 
organ class. Additionally, separate AE incidence tables, coded by MedDRA type, will be 
presented for each treatment group and overall by: 1) toxicity grade (severity) graded by CTCAE 
v4.03 or the current version; and 2) relationship to PEGPH20, NAB, and/or GEM as determined 
by the Investigator. 
All AEs, SAEs, treatment discontinuations due to AEs, or deaths occurring during the course of 
the study will be summarized. 
Laboratory toxicity will be summarized for all post-baseline data. Shift tables will be presented 
for selected laboratory parameters: liver function tests (ALT, AST, alkaline phosphatase, total 
bilirubin), WBC, ANC, hemoglobin, platelet count, PT, PTT, INR, and creatinine. Shift tables 
will use CTCAE grades, v4.03 or the current version. Selected laboratory parameters and vital 
signs (blood pressure, pulse, respiratory rate temperature) and the corresponding change from 
baseline over time will be summarized using descriptive statistics and data listings. 
11.1.8. 
Pharmacokinetic Analysis 
For PEGPH20, noncompartmental and population PK modeling will be performed. The AUC, 
Cmax, and tmax will be summarized with descriptive statistics. Other PK/PD analyses will be 
performed, and estimation of PK parameters including half-life (t1/2), volume of distribution, and 
clearance will be evaluated and reported if the data are sufficient.  
11.1.9. 
Analysis of the Conduct of the Study 
An accounting of all randomized subjects over the course of the study will be reported by 
treatment group. Analysis population, study treatment administration, reasons for premature 
discontinuation and time on study will be summarized. 
11.1.10. 
Analysis of Treatment Group Comparability 
The following demographic and baseline characteristics will be summarized by treatment group: 
age, race, ethnicity, country of residence, height, weight, BSA, Karnofsky Performance Status, 
site of primary tumor and other factors to be determined. Additional details for the analysis of 
the primary, secondary, and exploratory, and safety outcomes will be provided in the Statistical 
Analysis Plan. 
11.1.11. 
Interim Analysis 
No formal interim analyses of efficacy were initially planned for this study. However, 2 interim 
analyses of efficacy data from Stage 1 were performed to develop the tumor HA algorithm and 

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determine the cut-point to define HA-high subjects using a prototype HA assay and the 
investigational VENTANA HA RxDx assay, respectively. The 50% HA cut-point identified 
based on the Stage 1 data was defined based on the VENTANA HA RxDx assay prior to the 
analysis of Stage 2 data. Stage 2 data wer used to validate the tumor HA algorithm and 50% 
cut-point (additional details on the prototype HA assay and investigational VENTANA HA 
RxDx assay are given in the PEGPH20 Investigator’s Brochure). A third, comprehensive interim 
analysis of efficacy and safety data was performed to validate the VENTANA HA RxDx assay 
algorithm and cut-point of 50% and to enable a thorough benefit/risk assessment based on HA 
status.  
The participating Investigators, the Sponsor, and the independent safety physician will review 
the safety profile of all subjects in the first run-in phase and determine that the defined dose and 
regimen are acceptable for Phase 2. In addition, after the initiation of the Phase 2 portion, the 
DMC will review aggregated safety data collected to-date on a periodic basis. Safety data 
include AEs, laboratory data, and other safety clinical observations. Efficacy data will not be 
reviewed by the DMC unless there are safety concerns to warrant a risk versus benefit 
assessment. Details of the DMC (analysis, frequency, etc.) will be captured in a separate charter.  
In addition, the PK and safety profiles of the new formulation of PEGPH20 will be assessed 
based on data from the second run-in phase. The Sponsor, the participating Investigators, and the 
independent safety physician will review available safety data from Cycle 1 from all subjects in 
the new formulation run-in phase. The PK profile will reviewed by the Sponsor. If the new 
formulation is deemed acceptable, it will be available to all subjects on the study. Subjects 
already on treatment will be switched to the new formulation. 
In Stage 2 of this study, three interim safety analyses are planned to monitor thromboembolic 
risk. If any of the interim safety analyses crosses the stopping boundary, DMC may recommend 
terminating the study. The interim safety analyses are detailed in Section 11.1.6.  

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12. 
SPONSOR AND INVESTIGATOR RESPONSIBILITIES  
12.1. 
Protocol Compliance 
Except for a change intended to eliminate an apparent immediate hazard to a study subject, the 
study must be conducted as specified. Any such change must be reported immediately to 
Halozyme and to the IRB/EC according to the applicable IRB/EC policy. 
12.1.1. 
Protocol Waivers 
Halozyme, or its designee, will not prospectively authorize any protocol waivers to study 
inclusion/exclusion criteria.  
12.1.2. 
Protocol Deviations 
Written documentation of all major protocol deviations must be kept in the study site file and 
provided to Halozyme. Examples of possible major protocol deviations include, but are not 
limited to: 
• Failure to obtain/maintain IRB/EC approval for the study. 
• Failure to obtain subject’s informed consent. 
• Failure to collect, submit or file AE reports. 
• Performance of an unapproved study procedure. 
• Performance of the study at an unapproved location.  
• Failure to adhere to the approved protocol. 
The Investigator must notify the IRB/EC of all protocol deviations according to applicable 
IRB/EC policy. Halozyme will not authorize any protocol deviations. 
12.2. 
Study Monitoring 
Site visits will be conducted by an authorized Halozyme representative, who will inspect study 
data, subject’s medical records, and eCRFs according to Good Clinical Practice (GCP) and FDA 
and ICH guidelines.  
In addition to monitoring by Halozyme or its designees, the study may be audited by 
representatives of the FDA, who will also be allowed access to study documents. The 
Investigator should immediately notify Halozyme’s Department of Clinical Development and 
Medical Affairs of any proposed or scheduled audits by regulatory authorities. 
The Investigator will permit authorized representatives of Halozyme and national or local health 
authorities to inspect facilities and records relevant to this study. 
12.3. 
Data Collection and Case Report Forms 
CRFs must be completed for each subject enrolled in the study according to GCP and FDA 
guidelines. Data collected for each study subject will be recorded on eCRFs provided or 
approved by Halozyme. 

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CRF completion is the Investigator’s responsibility. CRF completion may be delegated to other 
study personnel and documented on the log for delegation of authority. The Investigator is 
responsible for ensuring the accuracy, completeness, legibility, and timeliness of all data 
reported on CRFs and all required reports for each study subject. The Investigator is also 
responsible for maintaining any source documentation related to the study (e.g., operative 
reports, laboratory results, radiographic films, tracings, and computer discs or files). 
12.4. 
Financial Disclosure 
The Investigator is required to provide a financial disclosure statement or certification to 
Halozyme before study initiation. In accordance with 21 Code of Federal Regulations (CFR) 54, 
Investigators and all sub-Investigators are required to disclose all financial interests to the study 
Sponsor (Halozyme), to permit complete and accurate certification statements in an application 
for marketing authorization. This disclosure includes compensation affected by the outcome of a 
clinical study, significant equity interest in Halozyme’s parent entity, Halozyme Therapeutics, 
Inc., and proprietary interest in the tested product. Investigators must promptly update this 
information if any relevant changes occur during the study and for one year following/ study 
completion (21 CFR 312.64(d)). 
12.5. 
Investigator’s Final Report 
After completion of the Investigator’s participation in the study, the Investigator will submit a 
written report to Halozyme. This report may be a copy of the Investigator’s end-of-study report 
to the IRB/EC. The report to the IRB/EC will be consistent with applicable IRB/EC regulations 
and time frames. 
12.6. 
Data Disclosure and Publication 
All information concerning this study and which was not previously published is considered 
confidential information. This confidential information shall remain the sole property of 
Halozyme; it shall not be disclosed to others without written consent of Halozyme; and shall not 
be used except in the performance of this study. 
The information compiled during the conduct of this study is also considered confidential and 
may be disclosed and/or used only by Halozyme as it deems necessary. To allow the use of the 
information derived from this study and to ensure compliance to current federal regulations, the 
Investigator is obliged to furnish Halozyme with the complete test results and all data compiled 
in this study. 
This section of the protocol is intended to be a brief, high-level summary of the requirements for 
data disclosure and publication. The Clinical Study Agreement between Halozyme and the 
Investigator/Institution details the specific disclosure and publication requirements.  

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13. 
QUALITY CONTROL AND QUALITY ASSURANCE 
In addition to routine monitoring procedures, audits of clinical research activities may be 
performed to evaluate compliance with the principles of GCP. A regulatory authority may also 
wish to conduct an inspection during the study or after its completion. If an audit of this or any 
other study is requested by any regulatory authority, the Investigator must inform Halozyme 
immediately of the request (Section 12.2). The study site will permit access to all necessary 
records. 
The study protocol, each step of the data recording process, and data handling, as well as any 
study report or publication, will be subject to independent review by Halozyme or its 
representatives. 

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14. 
ETHICS 
This study will be conducted under a U.S. Investigational New Drug (IND) Application 
according to the provisions of the US CFR, the FDA regulations and guidelines, the Guidelines 
for GCP, and the Declaration of Helsinki, revised version of Seoul, October, 2008. All applicable 
U.S. regulations governing human subject protection must be followed. All ethical and 
regulatory requirements are necessary to comply with the principles of GCP. This includes 
inspection by the Sponsor, its representatives, health authority, or IRB/EC representatives at any 
time. The Investigator must agree to the inspection of study-related records by the health 
authority, the Sponsor, and/or the Sponsor's representatives. 
To ensure ethical conduct of this study, the Investigator will be expected to adhere to basic 
principles provided by generally recognized guidelines such as the Belmont Report and the 
International Ethical Guidelines for Biomedical Research Involving Human Subjects.  
14.1. 
Institutional Review Board and Approval 
In accordance with 21 CFR Parts 50 and 56, the Investigator agrees to obtain IRB/EC approval 
of all appropriate material, including a copy of the protocol, ICF, Investigator’s Brochure, and 
any proposed advertisement/study material prior to the start of the study and/or prior to its use on 
the study.  
Halozyme must also agree to the proposed ICF and any proposed study advertisements. A copy 
of the IRB/EC approval letter(s) for the protocol and ICF must be supplied to Halozyme before 
subjects are screened.  
The Investigator will supply Halozyme with the names, professions, and affiliations of IRB/EC 
member, to demonstrate compliance with membership requirements. If the Investigator or a 
sub-Investigator is a routine voting member of the IRB/EC, Halozyme will be provided with a 
statement from the IRB/EC that the Investigator/sub-Investigator did not vote on this study. 
During the study, the Investigator is responsible for satisfying all IRB/EC regulations for 
reporting study progress. Copies of all reports to and correspondence with the IRB/EC must be 
provided to Halozyme. Furthermore, at the completion or early termination of the study, the 
Investigator should make a final report to the IRB/EC. A copy of this report should be provided 
to Halozyme (Section 12.5). 
The Investigator must maintain an IRB/EC correspondence file and make this file available for 
review by Halozyme or its designated representatives as part of the study monitoring process. 
14.2. 
Written Informed Consent 
A copy of the proposed ICF must be submitted to Halozyme for review and comment before 
submission to the IRB/EC. The ICF must be approved by the IRB/EC and contain all elements 
required by all applicable federal, state, local, and institutional regulations or policies including 
subject compensation information (if applicable), before it is used to obtain a subject’s informed 
consent. Authorization to use or disclose personal health information in accordance with 
requirements of the Health Insurance Portability and Accountability Act of 1996 should be 
provided in the ICF, or in a separate document to be signed by the subject.  

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Each subject (and/or legally authorized representative if the subject is a minor, mentally 
incompetent, or physically incapacitated, if applicable) found eligible for the study must have 
voluntarily provided written informed consent, using the IRB/EC-approved ICF, before study 
Screening (i.e., before any protocol-specified procedures that are not part of normal subject 
care).  

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15. 
DATA HANDLING AND RECORD KEEPING 
15.1. 
Record Inspection  
An audit may be performed at any time after completion of the study by Halozyme personnel or 
their designees, FDA, or other regulatory agencies. All study-related documentation must be 
made available to the designated auditors. 
15.2. 
Study Documentation and Record Retention 
The Investigator must retain all records of this study, including but not limited to, the following. 
• Protocol and all protocol amendments. 
• All signed versions of the Statement of Investigator, Form FDA 1572. 
• All drug accountability records. 
• All IRB/EC approvals, correspondence and reports. 
• Signed and dated ICFs for each subject. 
• Completed eCRFs for each subject. 
• Copies of any other material distributed to subjects. 
• Any advertisements for this study. 
• The Investigator’s final report to the IRB/EC. 
• Source documents pertaining to the study, including but not limited to, any operative 
reports, laboratory results, radiographic films, tracings, and computer discs or files. 
The period for which these documents must be retained is governed by U.S. law and, when 
applicable, non-U.S. regulations. The Investigator must retain all records for at least two years 
after the FDA has approved the new drug application, or until two years after all studies of the 
drug and indication have been discontinued. However, because of international regulatory 
requirements, Halozyme may request retention for a longer period. Halozyme or its designee will 
inform the Investigator when these documents may be destroyed. Halozyme or its designee must 
be notified in writing at least 30 days before the intended date of disposal of study records. The 
Investigator must obtain written approval from Halozyme before destruction of records. 
The Investigator must advise Halozyme in writing if records are to be moved to a location other 
than the study site’s archives. If the Investigator leaves the study site, the records will be 
transferred to an appropriate designee at the site, who will assume responsibility for record 
retention. Notice of this transfer will be documented in writing and provided to Halozyme. 
If any study records are accidentally lost or destroyed, the Investigator will immediately notify 
Halozyme in writing. 

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16. 
REFERENCES 
1. Agnelli G, George DJ, Kakkar AK, Fisher W, Lassen MR, Mismetti P, Mouret P, 
Chaudhari U, Lawson F, Turpie AG; SAVE-ONCO Investigators.Semuloparin for 
thromboprophylaxis in patients receiving chemotherapy for cancer. N Engl J Med. 2012 
Feb 16;366(7):601-9. 
2. Agnelli G, Gussoni G, Bianchini G, Verso M, Mandalà M et al, Nadroparin for the 
prevention of thromboembolic events in ambulatory patients with metastatic or locally 
advanced solid cancer receiving chemotherapy: a randomised, placebo-controlled, 
double-blind study. Lancet Oncol 2009; 10: 943–49 
3. Anttila MA, Tammi RH, Tammi MI, Syrjänen KJ, Saarikoski SV, Kosma V-M. High 
levels of stroma hyaluronan predict poor disease outcome in epithelial ovarian cancer. 
Cancer Res 2000; 60:150-155. 
4. Auvinen P, Tammi R, Parkkinen J, Tammi M, Ågren U, Johansson R. Hyaluronan in 
peritumoral stroma and malignant cells associates with breast cancer spreading and 
predicts survival. Am J Pathol 2000; 156:529-536. 
5. Baumgartner G, Gomar-Hoss C, Sakr, L, Ulsperger E, Wogritsch C. The impact of 
extracellular matrix on the chemoresistance of solid tumors – experimental and clinical 
results of hylauronidase as additive to cytostatic chemotherapy. Cancer Lett 1998; 
131:85-99. 
6. Blom JW, Doggen CJ, Osanto S, Rosendaal FR. Malignancies, prothrombotic mutations, 
and the risk of venous thrombosis. JAMA. 2005 Feb 9;293(6):715-22. 
7. Brekken C, de Lange Davies C. Hyaluronidase reduces the interstitial fluid pressure in 
solid tumors in a non-linear concentration-dependent manner. Cancer Lett 1998; 131:65-
70. 
8. Burris III HA, Moore MJ, Anderson J, Green MR, Rothenberg ML, Modiano MR, et al. 
Improvements in survival and clinical benefit with gemcitabine as first-line therapy for 
patients with advanced pancreas cancer: a randomized trial. J Clin Oncol 1997; 
15:2403-2413. 
9. Cantor AB. Projecting the standard error of the Kaplan-Meier estimator. Stat Med 2001; 
20(14):2091–2097. 
10. Collett D. Modelling survival data in medical research. 2nd ed. Chapman & Hall/CRC; 
2003. 
11. Conroy T, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, et al. 
FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 2011; 
364(19):1817-1825. 
12. Dahl IM, Solheim OP, Erikstein B, Müller E. A longitudinal study of the hyaluronan 
level in the serum of patients with malignant mesothelioma under treatment. Hyaluronan 
as an indicator of progressive disease. Cancer 1989; 64:68-73. 

Halozyme, Inc. 
Protocol HALO-109-202 
CONFIDENTIAL 
Page 119 of 128 
09 February 2018 
13. Dunn AL, Heavner JE, Racz G, Day M. Hyaluronidase: a review of approved 
formulations, indications and off-label use in chronic pain management. Expert Opin Biol 
Ther 2010; 10:127-131.  
14. Eikenes L, Tari M, Tufto I, Bruland OS, de Lange Davies C. Hyaluronidase induces a 
transcapillary pressure gradient and improves the distribution and uptake of liposomal 
doxorubicin (Caelyx™) in human osteosarcoma xenografts. Br J Cancer 2005; 93:81-88. 
15. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New 
response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). 
Eur J Cancer 2009; 45:228-247. 
16. Epstein AS, O’Reilly, EM. Exocrine pancreas cancer and thromboembolic events: A 
systematic literature review. J Natl Compr Canc Netw. 2012 Jul 1;10(7):835-46. 
17. Epstein AS, Soff GA, Capanu M, Crosbie C, Shah MA, Kelsen DP, et al. Analysis of 
incidence and clinical outcomes in patients with thromboembolic events and invasive 
exocrine pancreatic cancer. Cancer. 2012 Jun 15;118(12):3053-61. 
18. Farge D, Debourdeau P, Beckers M, Baglin C, Bauersachs RM, Brenner B, et al. 
International clinical practice guidelines for the treatment and prophylaxis of venous 
thromboembolism in patients with cancer. J Thromb Haemost. 2013 Jan;11(1):56-70. 
19. Fraser JR, Laurent TC, Laurent UB. Hyaluronan: its nature, distribution, functions and 
turnover. J Intern Med 1997; 242:27-33. 
20. Frost GI. Recombinant human hyaluronidase (rHuPH20): an enabling platform for 
subcutaneous drug and fluid administration. Expert Opin Drug Deliv 2007; 4:427-440.  
21. Heit JA, Silverstein MD, Mohr DN, Petterson TM, O’Fallon WM, Melton LJ III. Risk 
factors for deep vein thrombosis and pulmonary embolism: a population-based case-
control study. Arch Intern Med. 2000;160(6):809-815. 
22. Hingorani SR, Wang L, Multani AS, Combs C, Deramaudt TB, Hruban RH, et al. 
Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely 
metastatic pancreatic ductal adenocarcinoma in mice. Cancer Cell 2005; 7:469-483. 
23. Hingorani SR, Harris WP, Beck JT, Berdov BA, et al, A Phase 1b Multicenter 
International Study of Gemcitabine Combined with PEGPH20 (PEGylated Recombinant 
Human Hyaluronidase) in Patients with Stage IV Previously Untreated Pancreatic 
Cancer. 2013 Sep 27-Oct 01, ESMO, Amsterdam, Netherlands. 
24. Horsted F, West J, Grainge MJ. Risk of venous thromboembolism in patients with 
cancer: a systematic review and meta-analysis. PLoS Med. 2012;9(7):e1001275. 
25. Hosmer DW Jr, Lemeshow S, May S. Applied survival analysis. Regression modeling of 
time-to-event data. 2nd ed. Wiley; 1999. 
26. Infante JR, Ramanathan RK, Borad M, Rosen L, Korn R, Dychter SS, et al. Targeting 
hyaluronan (HA) in tumor stroma. Interim safety and translational evaluation of 
pegylated hyaluronidase (PEGPH20) in patients with advanced solid tumors – a focus on 
GI malignancies. ASCO 2012 Gastrointestinal Cancers Symposium, Poster Abstract 246. 
J Clin Oncol 2012; 30(4):246. 

Halozyme, Inc. 
Protocol HALO-109-202 
CONFIDENTIAL 
Page 120 of 128 
09 February 2018 
27. Jacobetz MA, Chan DS, Neesse A, Cook N, Frese KK, Nakagawa T, et al. Hyaluronan 
impairs vascular function and drug delivery in a mouse model of pancreatic cancer. Gut 
2013; 62(1):112-120.  
28. Jiang P, Li X, Thompson CB, Huang Z, Araiza F, Osgood R, et al. Effective targeting of 
the tumor microenvironment for cancer therapy. Anticancer Res 2012; 32(4):1203-12. 
29. Khorana AA, Kuderer NM, Culakova E, Lyman G, Francis CW. Development and 
validation of a predictive model for chemotrhapy-associated thrombosis. Blood 
2008;111:4902-4907. 
30. Khorana AA, Venous Thromboembolism and Prognosis in Cancer. Thromb Res.2010 
June; 125(6): 490-493. 
31. Khorana AA, Otten HM, Zwicker JI, Connolly GC, Bancel DF, Pabinger I, for the 
Subcommittee on Haemostasis and Malignancy. Prevention of venous thromboembolism 
in cancer outpatients: guidance from the SSC of the ISTH. J Thromb Haemost. 2014 Sep 
10. 
32. Kim H-R, Wheeler MA, Wilson CM, Iida J, Eng D, Simpson MA, et al. Hyaluronan 
facilitates invasion of colon carcinoma cells in vitro via interaction with CD44. Cancer 
Res 2004; 64:4569-4576. 
33. Klocker J, Sabitzer H, Raunik W, Wieser S, Schumer J. Hyaluronidase as additive to 
induction chemotherapy in advanced squamous cell carcinoma of the head and neck. 
Cancer Lett 1998; 131:113-115. 
34. Kosaki R, Watanabe K, Yamaguchi Y. Overproduction of hyaluronan by expression of 
the hyaluronan synthase Has2 enhances anchorage-independent growth and 
tumorigenicity. Cancer Res 1999; 59:1141-1145. 
35. Koyama H, Hibi T, Isogai Z, Yoneda M, Fujimori M, Amano J, et al. Hyperproduction of 
hyaluronan in Neu-induced mammary tumor accelerates angiogenesis through stromal 
cell recruitment. Amer J Path 2007; 170:1086-1099. 
36. Kultti A, Li X, Jiang P, Thompson CB, Frost GI, Shepard HM. Therapeutic targeting of 
hyaluronan in the tumor stroma. Cancers 2012; 4(3):873-903. 
37. Kultti A, Rilla K, Tiihonen R, Spicer A, Tammi R, Tammi M. Hyaluronan synthesis 
induces microvillus-like cell surface protrusions. J Biol Chem 2006; 281:15821-15828. 
38. Li Y, Li L, Brown TJ, Heldin P. Silencing of hyaluronan synthase 2 suppresses the 
malignant phenotype of invasive breast cancer cells. Int J Cancer 2007; 120:2557-2567. 
39. Maraveyas A, Waters J, Roy R, Fyfe D, Propper D, et al. Gemcitabine versus 
gemcitabine plus dalteparin thromboprophylaxis in pancreatic cancer. Eur J Cancer. 2012 
Jun;48(9):1283-92. 
40. NCCN Guidelines Verion 2.2013: Venous Thromboembolic Disease 
41. Nishida Y, Knudson W, Knudson CB, Ishiguro N. Antisense inhibition of hyaluronan 
synthase-2 in human osteosarcoma cells inhibits hyaluronan retention and tumorigenicity. 
Exp Cell Res 2005; 307:194-203. 

Halozyme, Inc. 
Protocol HALO-109-202 
CONFIDENTIAL 
Page 121 of 128 
09 February 2018 
42. Osgood RJ, Skipper J, Jiang P, Zimmerman S, Shepard HM, Maneval DC, et al. 
Pegylated recombinant human hyaluronidase PH20 (PEGPH20) enhances nab-paclitaxel 
efficacy in BxPC-3 human pancreatic cancer xenografts. Poster presented at: Annual 
Meeting of the American Association for Cancer Research (AACR); March 31-April 4, 
2012; Chicago, IL. 
43. Pillwein K, Fuiko R, Slavc I, Czech T, Hawliczek G, Bernhardt G, et al. Hyaluronidase 
additional to standard chemotherapy improves outcome for children with malignant brain 
tumors. Cancer Lett 1998; 131:101-108. 
44. Provenzano PP, Cuevas C, Chang AE, Goel VK, Von Hoff DD, Hingorani SR. 
Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic 
ductal adenocarcinoma. Cancer Cell 2012; 21(3):418-429. 
45. Riess H, Pelzer U, Opitz B, Stauch M, Reitzig P, et al. A prospective, randomized trial of 
simultaneous pancreatic cancer treatment with enoxaparin and chemotherapy: Final 
results of the CONKO-004 trial. J Clin Oncol 28:15s, 2010 (suppl; abstr 4033). 
46. Ropponen K, Tammi M, Parkkinen J, Eskelinen M, Tammi R, Lipponen P, et al. Tumor 
cell-associated hyaluronan as an unfavorable prognostic factor in colorectal cancer. 
Cancer Res 1998; 58:342-347. 
47. Rosenthal MA, Gibbs P, Brown TJ, Wong S, Uren S, Ellis A, et al. Phase I and 
pharmacokinetic evaluation of intravenous hyaluronic acid in combination with 
doxorubicin or 5-fluorouracil. Chemotherapy 2005; 51:132-141. 
48. Ruiz Garcia V, López-Briz E, Carbonell Sanchis R, Gonzalvez Perales JL, Bort-Marti S. 
Megestrol acetate for treatment of anorexia-cachexia syndrome. Cochrane Database Syst 
Rev. 2013 Mar 28;3:CD004310. 
49. Setälä LP, Tammi MI, Tammi RH, Eskelinen MJ, Lipponen PK, Agren UM, et al. 
Hyaluronan expression in gastric cancer cells is associated with local and nodal spread 
and reduced survival rate. Br J Cancer 1999; 79:1133-1138. 
50. Shuster S, Frost GI, Csoka AB, Formby B, Stern R. Hyaluronidase reduces human breast 
cancer xenografts in SCID mice. Int J Cancer 2002; 102:192-197. 
51. Simpson MA, Wilson CM, McCarthy JB. Inhibition of prostate tumor cell hyaluronan 
synthesis impairs subcutaneous growth and vascularization in immunocompromised 
mice. Amer J Path 2002; 161:849-857. 
52. Sironen RK, Tammi M, Tammi R, Auvinen PK, Anttila M, Kosma VM. Hyaluronan in 
human malignancies. Exp Cell Res 2011; 317:383-391. 
53. Spruss T, Bernhardt G, Schonenberger H, Schiess, W. Hyaluronidase significantly 
enhances the efficacy of regional vinblastine chemotherapy of malignant melanoma. J 
Cancer Res Clin Oncol 1995; 121:193-202. 
54. Tammi RH, Passi AG, Rilla K, Karousou E, Vigetti D, Makkonen K, et al. 
Transcriptional and post-translational regulation of hyaluronan synthesis. FEBS J 2011; 
278:1419-1428. 

Halozyme, Inc. 
Protocol HALO-109-202 
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09 February 2018 
55. Thompson CB, Shepard HM, O'Connor PM, Kadhim S, Jiang P, Osgood RJ, et al. 
Enzymatic depletion of tumor hyaluronan induces antitumor responses in preclinical 
animal models. Mol Cancer Ther 2010; 9:3052-3064.  
56. Timp JF, Braekkan SK, Versteeg HH, Cannegieter SC. Epidemiology of cancer-
associated venous thrombosis. Blood 2013;122:1712-1723. 
57. Thylén A, Wallin J, Martensson G. Hyaluronan in serum as an indicator of progressive 
disease in hyaluronan-producing malignant mesothelioma. Cancer 1999 86(10):2000-
2005. 
58. Tuveson DA. Developing pancreatic cancer medicine. AACR-NCI-EORTC Molecular 
Targets and Cancer Therapeutics 2011, November 12-16, San Francisco, CA USA. 
http://webcast.aacr.org/portal/p/2011mol/74 
59. Udabage L, Brownlee GR, Waltham M, Blick T, Walker EC, Heldin P, et al. Antisense-
mediated suppression of hyaluronan synthase 2 inhibits the tumorigenesis and 
progression of breast cancer. Cancer Res 2005; 65:6139-6150. 
60. Von Hoff DD, Ervin T, Arena F, Chiorean E, Infante J, Moore M, et al. Increased 
survival in Pancreatic Cancer with Nab-Paclitaxel plus Gemcitabine. N Engl J Med 
2013;369:1691-1703.  
61. Von Hoff DD, Ramanathan RK, Borad MJ, Laheru DA, Smith LS, Wood TE, et al. 
Gemcitabine plus nab-paclitaxel is an active regimen in patients with advanced 
pancreatic cancer: A phase I/II trial. J Clin Oncol 2011; 29(34):4548-4554. 
62. Whatcott CJ, Jiang P, Watanabe A, Hostetter G, Hu C, Shepard HM, et al. Hyaluronan 
deposition correlates with poor survival in pancreatic cancer Abstract LB-307, AACR 
National Meeting. Cancer Res 2011; 71 Suppl. 1. 
63. Wu AH, Parker OS, Ford L. Hyperviscosity caused by hyaluronic acid in serum in a case 
of Wilms' tumor. Clin Chem 1984; 30:914-916. 
 

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17. 
APPENDICES 
APPENDIX A. ABBREVIATIONS 
The following abbreviations are used in this study protocol. 
Abbreviation 
Term  
AE 
Adverse event 
AG 
Nab-paclitaxel plus gemcitabine  
ALT 
Alanine aminotransferase  
ANC 
Absolute neutrophil count 
AST 
Aspartate aminotransferase  
AUC 
Area-under-the-concentration time curve 
AUC0-72 
Area-under-the-concentration time curve estimates for 0 to 72 hours 
bid 
Twice a day 
BSA 
Body surface area 
BUN 
Blood urea nitrogen 
C 
Celsius 
CFR 
Code of Federal Regulations 
CIR 
Central Imaging Reader 
Cl 
Clearance 
Cmax 
Maximum-observed concentration 
CR 
Complete response 
CRF 
Case report form 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CVA 
Cerebrovascular accident or 
DCR 
Disease control rate 
dL 
Deciliter 
DLT 
Dose-limiting toxicity 
DMC 
Data Monitoring Committee 
DR 
Duration of response 
DVT 
Deep vein thrombosis 

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Abbreviation 
Term  
EC 
Ethics Committee 
ECG 
Electrocardiogram 
ECM 
Extracellular matrix 
eCRF 
Electronic case report form 
5-FU 
Fluorouracil 
F 
Fahrenheit 
FDA 
Food and Drug Administration 
FNA 
Fine needle aspirates 
g 
Gram 
GCP 
Good Clinical Practice 
GEM 
Gemcitabine 
hr 
Hour 
HA 
Hyaluronan 
ICF 
Informed Consent Form  
ICH 
International Conference on Harmonisation  
INR 
International normalized ratio 
IRB 
Institutional Review Board  
ITT 
Intent-to-treat 
IV 
Intravenous  
IWRS 
Interactive Web Response System 
kg 
Kilogram 
LMWH 
Low-molecular-weight heparin 
m2 
Square meter 
µg 
Microgram 
MedDRA 
Medical Dictionary of Regulatory Activities 
mg 
Milligram  
min 
Minutes 
mL 
Milliliter  
mm 
Millimeter 
MRI 
Magnetic resonance imaging 

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Abbreviation 
Term  
MSE 
Musculoskeletal event 
MTD 
Maximum-tolerated dose 
NAB 
Nab-paclitaxel 
NaCl 
Sodium chloride 
NCI  
National Cancer Institute  
ng 
Nanogram 
ORR 
Objective response rate 
OS 
Overall survival 
PAG 
PEGPH20 in combination with nab-paclitaxel plus gemcitabine  
PD 
Pharmacodynamics 
PDA 
Pancreatic ductal adenocarcinoma 
PE 
Pulmonary embolism 
PFS 
Progression-free survival 
PK 
Pharmacokinetics 
PR 
Partial response 
PSA 
Prostate specific antigen 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
RECIST 
Response Evaluation Criteria in Solid Tumors 
rHuPH20  
Recombinant human hyaluronidase PH20 
SAE  
Serious adverse event  
SC 
Subcutaneously 
SD 
Stable disease  
SGOT 
Serum glutamic oxaloacetic transaminase  
SGPT 
Serum glutamic pyruvate transaminase  
SUV 
Standardized uptake volume 
t1/2 
Terminal half-life 
TGI 
Tumor growth inhibition 
TE 
Thromboembolic event 
TIA 
Transient ischemic attack 

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Abbreviation 
Term  
tmax 
Time-to-maximum concentration 
U 
Unit 
ULN 
Upper limit of normal 
US 
United States 
VMSI 
Ventana Medical Systems, Inc.  
VTE 
Venous thromboembolic event 
 

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APPENDIX B. KARNOFSKY/ECOG PERFORMANCE STATUS 
 
a Eastern Cooperative Oncology Group. 
b Acceptable status for enrollment in this study. 

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APPENDIX C. NEW YORK HEART ASSOCIATION CLASSIFICATIONS 
1994 Revisions to Classification of Functional Capacity and Objective Assessment of Patients 
with Diseases of the Heart 
Functional Capacity 
Objective Assessment 
Class I. Patients with cardiac disease but without 
resulting limitation of physical activity. Ordinary 
physical activity does not cause undue fatigue, 
palpitation, dyspnea, or anginal pain. 
A. No objective evidence of cardiovascular 
disease. 
Class II. Patients with cardiac disease resulting in 
slight limitation of physical activity. They are 
comfortable at rest. Ordinary physical activity 
results in fatigue, palpitation, dyspnea, or anginal 
pain. 
B. Objective evidence of minimal cardiovascular 
disease. 
Class III. Patients with cardiac disease resulting in 
marked limitation of physical activity. They are 
comfortable at rest. Less than ordinary activity 
causes fatigue, palpitation, dyspnea, or anginal 
pain. 
C. Objective evidence of moderately severe 
cardiovascular disease. 
Class IV. Patients with cardiac disease resulting in 
inability to carry on any physical activity without 
discomfort. Symptoms of heart failure or the 
anginal syndrome may be present even at rest. If 
any physical activity is undertaken, discomfort is 
increased. 
D. Objective evidence of severe cardiovascular 
disease.