Clinical trial NCT03979066
Conditions: Pancreatic Ductal Adenocarcinoma
Keywords: Neoadjuvant therapy PEGPH20 Atezolizumab Columbia Pancreatic Ductal Adenocarcinoma
Sponsor: Gulam Manji
Start date: 2019-11-01; Completion date: 2019-11-03
Enrollment: 1 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to determine if study treatment with atezolizumab and PEGPH20 given before and after surgery, followed by chemotherapy is safe and if it can further increase the immune response against the tumor rather than increase the chance of cure.

Detailed description:
Presently, surgical resection offers the only therapeutic means of cure. However only 15%-20% of patients are found to have resectable disease at time of initial diagnosis. Of the patients who undergo curative surgery, most will relapse and eventually succumb to the disease. 5-year survival rates for node-negative and -positive disease at time of pancreatic duodenectomy are 25%-30% and 10%, respectively.

Although early phase trials have not offered great success in the metastatic setting for patients with pancreas adenocarcinoma (PDA), interim analysis of a multicenter, phase 1 trial with durvalumab presented at European Society for Medical Oncology (ESMO) indicated a disease control rate of 21%. As mentioned previously, PD-L1 expression correlates with poor prognosis and decreased CD4+ and CD8+ T cell infiltration within the tumor. Targeting PD-L1 in the micrometastatic setting (resectable disease), when robust mature immunosuppressive pathways may not have yet formed, may be the optimum time to investigate anti-PD-L1 therapy. This arm of the study aims to test if atezolizumab is able to modulate CD8+ T-cell infiltration compared to historical matched controls. As a secondary endpoint we will also evaluate how clinical outcomes compare to matched historical controls.

Neoplastic, immune, and stromal cells within PDA reside in a highly dense desmoplastic environment composed of an extracellular matrix of which hyaluronidase (HA) is an abundant component. HA is a linear glycosaminoglycan and an integral component of not only PDA tumors, but has also been shown to accumulate in many solid tumors and is associated with a poor prognosis and increased immunosuppression. In a preclinical autochthonous mouse model of PDA, Sunil Hingorani's group demonstrated that the interstitial fluid pressures were unusually high within tumors that exhibited a high HA content. Furthermore, high HA tumors contained low vascularity, which compromised delivery of chemotherapeutic agents, such as gemcitabine. Mice treated with hyaluronidase resulted in decreased HA content and microvasculature re-expansion within tumors which led to a survival benefit. These preclinical studies led to early phase clinical studies in metastatic PDA where addition of PEGPH20 to gemcitabine and nab-paclitaxel (GA) in a randomized phase 2 study demonstrated a survival benefit in patients with HA-high tumors. The objective response rate for patients who were treated with a combination of PEGPH20 and GA compared to GA alone was 45% versus 31%, respectively, and the median overall survival was 11.5 versus 8.5 months, respectively (hazard ratio (HR), 0.96; 95% Confidence Interval (CI), 0.57 to 1.61). A large phase 3 randomized clinical trial in the high HA stage IV PDA population in the first line setting is ongoing.

PDA likely invokes multiple immune evading mechanisms which result in its aggressive behavior; it is expected that multiple agents will likely be needed to develop effective therapies. One such rationale is the combination of PEGPH20 and immune checkpoint blockade to allow increased cytotoxic T-cell infiltration by increasing vascular permeability and decreasing interstitial pressure. In a breast cancer preclinical model, PEGPH20 resulted in an increase accumulation of CD8+ tumor-infiltrating lymphocytes (TIL) by 176% (p=0.0025) and improved tumor growth inhibition by 38% relative to anti-PD-L1 alone (86% vs 62.4%, p=0.0024). Other preclinical studies are also demonstrating increased CD8+ T-cell infiltration with addition of PEGPH20 and improved tumor control in combination with immune checkpoint blockade. These and other preclinical studies suggest that this combination is worth pursuing in patients with resectable PDA. The combination is hoped to increase CD8+ T-cell infiltration within the primary tumor for improved immune mediated cytotoxicity and decreased interstitial pressure to allow improved surgical resections. Hypothetically, the combination should also be effective in foci of micrometastasis, where the tumor microenvironment (TME) may not be as mature.

Identified risks for PEGPH20 include musculoskeletal events (MSEs), infusion-related reactions (IRRs), and thromboembolic (TE) events.

Arms: arm 1: Atezolizumab 840mg IV every 2 weeks for 2 doses prior to surgery and 4 doses after surgery. arm 2: Atezolizumab 840mg IV every 2 weeks for 2 doses prior to surgery and 4 doses after surgery in combination with PEGPH20 3ug/kg IV twice weekly for 3 weeks prior to surgery and once weekly for 3 weeks (of 28 day cycle) for two cycles after surgery.
Interventions: intervention 1: Atezolizumab intervention 2: PEGPH20
Intervention descriptions: intervention 1: 840mg IV every 2 weeks for 2 doses prior to surgery and 4 doses after surgery. intervention 2: PEGPH20 3ug/kg IV twice weekly for 3 weeks prior to surgery and once weekly for 3 weeks (of 28 day cycle) for two cycles after surgery.

Protocol documents:
Prot_SAP_000.pdf: 
Columbia University Medical Center 
Herbert Irving Comprehensive Cancer Center 
Version Date: 05/13/2019 
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HERBERT IRVING COMPREHENSIVE CANCER CENTER 
PROTOCOL 
TITLE: NEOiPANC - A Phase 2 , Open-Label, Multicenter, Randomized Study 
Evaluating NEOadjuvant immunotherapy Based Combinations in Patients with 
Resectable PANCreatic Ductal Adenocarcinoma 
NCT03979066
Principal Investigator: Gulam Manji, MD, PhD


Columbia University Medical Center 
Herbert Irving Comprehensive Cancer Center 
Version Date: 05/13/2019 
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CUMC IRB#: AAAS1908 
TITLE: NEOiPANC - A Phase 2 , Open-Label, Multicenter, Randomized Study 
Evaluating NEOadjuvant immunotherapy Based Combinations in Patients with 
Resectable PANCreatic Ductal Adenocarcinoma 
Coordinating Center: 
Columbia University Medical Center 
Principal Investigator: 
Gulam Abbas Manji, M.D./Ph.D. 
161 Fort Washington Avenue  
New York, NY 10032 
Telephone: 212-305-0592
Email address: gam2140@cumc.columbia.edu 
Surgeons: 
John A. Chabot, M.D.  
Columbia University
161 Fort Washington Avenue  
New York, NY 10032  
Telephone: (212) 305-9468
Email address: jac4@cumc.columbia.edu 
Radiologist 
Columbia University 
Primary: Elizabeth Hecht, M.D. 
Secondary: Firas Ahmed, M.D. 
Statistician: 
Shing M Lee, Ph.D. 
722 West 168th Street,  
6th Floor, Room 645  
New York, NY 10032 
Telephone: 212-342-1266
Email address: sml2114@columbia.edu 


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Regulatory Sponsor: 
Gulam Abbas Manji, M.D./Ph.D.  
161 Fort Washington Avenue  
New York, NY 10032  
Telephone:  212-305-0592 
Email address: gam2140@cumc.columbia.edu 
Funding Source: 
Genentech/F. Hoffmann-La Roche Ltd. 
Study Agent: 
Atezolizumab (RO5541267) 
PEGPH20 
Other Agent: 
N/A 
IND Status: 
 
F. Hoffmann-La Roche Ltd. 
Study Number 
ML40000 
Affiliate Institutions: 
Site Principal Investigator and Contact Information:
Memorial Sloan Kettering Cancer Center 
Principal Investigator:  
Eileen M. O’Reilly, M.D.  
300 East 66th Street 
New York, NY 10065 
Email: oreillye@mskcc.org  
Surgeon: 
Vinod P. Balachandran, M.D. 
Radiologist:  
Primary: TBD   
Secondary: TBD  


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I confirm that I have read this protocol, I understand it, and I will work according to this 
protocol and to the ethical principles stated in the latest version of the Declaration of 
Helsinki, the applicable ICH guidelines for good clinical practices, and the applicable 
federal, state, and local laws, rules, and regulations relating to the conduct of the 
protocol. I have read and understand the information in the Investigators  Brochure (or 
Manufacturer s Brochure) regarding the risks and potential benefits. I will promptly 
submit the protocol to the applicable IRB for review and approval. Once the protocol 
has been approved by the IRB, I understand that any modification made during the 
course of the study must first be approved by the IRB, prior to implementation except 
when such modification is made to remove an immediate hazard to the patient. I certify 
that I, and the study staff, have received the requisite training to conduct this research 
protocol. I agree to maintain adequate and accurate records in accordance with 
Columbia University and Herbert Irving Comprehensive Cancer Center policies, 
Federal, state and local laws and regulations. I agree to maintain the confidentiality 
of all information received or developed in connection with this protocol. 
Signature of Principal Investigator 
Date 
Principal Investigator Name (Print) 
Name of Institution 
Instructions to Principal Investigator: Sign and Date this signature page and print your 
name. Return the original, completed and signed to the Clinical Protocol & Data 
Management Office. Retain a copy in the regulatory binder. 


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Protocol Synopsis 
Title 
NEOiPANC - A Phase 2 , Open-Label, Multicenter, Randomized Study 
Evaluating NEOadjuvant immunotherapy Based Combinations in 
Patients with Resectable PANCreatic Ductal Adenocarcinoma 
Short Title 
Neoadjuvant atezolizumab based combinations in resectable 
pancreas cancer 
Protocol Number 
AAAS1908 
Phase 
Phase 2 
Methodology 
Randomized Phase 2 trial for a total of 20 patients per cohort 
Study Duration 
3640 months 
Study Center(s) 
Multicenter; Columbia University Medical Center, and Memorial Sloan 
Kettering Cancer Center 
Objectives 
To compare the number of CD8+ T-cells within the tumor with 
neoadjuvant atezolizumab alone or in combination with PEGPH20 or 
other therapies (TBD) at time of surgery. 
To estimate the 18-month recurrence free survival rate and overall 
survival in each arm. 
Number of Patients 
Approximately 20 patients are planned for enrollment per cohort. 
Diagnosis and Main 
Inclusion Criteria 
Resectable pancreatic adenocarcinoma 
Study Product, Dose, 
Route, Regimen 
Cohort 1: Atezolizumab 840mg IV every 2 weeks for 2 doses prior to 
surgery and 4 doses after surgery.  
Cohort 2: Atezolizumab 840mg IV every 2 weeks for 2 doses prior to 
surgery and 4 doses after surgery in combination with PEGPH20 
3g/kg IV twice weekly for 3 weeks prior to surgery and once weekly for 
3 weeks (of 28 day cycle) for two cycles after surgery. (Additional 
cohorts to be added TBD) 
Duration of 
administration 
3 weeks prior and 8 weeks after surgery with study drugs 
6 months with adjuvant chemotherapy 
Reference therapy 
Atezolizumab therapy and historical matched controls who did not
receive therapy 
Statistical 
Methodology 
Primary endpoint is change in number of intratumoral CD8+ T-cells 
at time of surgery between treatment arm(s) compared to the 
atezolizumab arm. Group sample sizes of 17 achieve at least 80% 
power to detect a difference of 1 SD with a significance level (alpha) of 
0.05 using a two-sided two-sample t-test. 


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Protocol Schema  
 
 
CIT  Cancer Immunotherapy; SOC  standard of care; TBD  to be determined. 
1 Atezolizumab 840 mg IV Days 4 and 18 (neoadjuvant x 2 doses), then x 4 doses (CIT adjuvant) of 28-day cycle; 
2 PEGPH20 3 g/kg IV Days 1 and 4, weekly, for 3 weeks prior to surgery and weekly on Days 1, 8, and 15 of every 28 days for 2 cycles; 
3 TBD - Other molecules under discussion to be determined. 


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Table of Contents 
1. 
INTRODUCTION ........................................................................................ 16 
2. 
STUDY OBJECTIVES ................................................................................. 17 
2.1 
Primary Objective .................................................................. 17 
2.2 
Secondary Objective ............................................................. 17 
2.3 
Exploratory Objective............................................................. 17 
3. 
BACKGROUND .......................................................................................... 18 
3.1 
Immunotherapy in PDA ......................................................... 18 
3.2 
Mismatch Repair Pathway and Susceptibility to 
Immunotherapy ...................................................................... 19 
3.3 
Study Rationale ..................................................................... 19 
4. 
INVESTIGATIONAL AGENT ....................................................................... 21 
4.1 
Atezolizumab ......................................................................... 21 
4.1.1 
Pharmacology of Atezolizumab ............................................. 21 
4.1.2 
Effect of Atezolizumab in Humans ......................................... 21 
4.2 
Other Agents ......................................................................... 22 
5. 
STUDY DESIGN ......................................................................................... 24 
5.1 
General Design ...................................................................... 24 
5.2 
Number of Patients ................................................................ 27 
6. 
PATIENT SELECTION AND WITHDRAWAL .............................................. 28 
6.1 
Inclusion Criteria .................................................................... 28 
6.2 
Exclusion Criteria ................................................................... 29 
6.3 
Radiological Definition for Resectable ................................... 34 
6.4 
Inclusion of Women and Minorities ........................................ 36 
6.5 
Patient Recruitment ............................................................... 36 
6.6 
Early Withdrawal of Patients .................................................. 36 
6.6.1 
When and How to Withdraw Patients .................................... 36 
6.6.2 
Data Collection and Follow-up for Withdrawn 
Patients 
37 


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7. 
TISSUE CORRELATION ............................................................................ 37 
7.1 
Translational Science ............................................................ 39 
7.1.1 
PDA Subtypes as Defined by Immune Cell 
Infiltrate and Gene Expression ................................................................. 39 
7.1.2 
Laser Capture Microdissection (LCM) and PDA .................... 40 
7.2 
Sample Processing of RNA-Seq Expression Data ................. 42 
8. 
REGISTRATION PROCEDURES ............................................................... 42 
8.1 
CUMC Research Participant Registration .............................. 42 
9. 
TREATMENT PLAN .................................................................................... 44 
9.1 
Investigational Agent Administration ...................................... 44 
9.1.1 
Atezolizumab Administration ................................................. 44 
9.1.2 
PEGPH20 Administration ...................................................... 46 
9.1.3 
Atezolizumab in Combination with PEGPH20 
Administration .......................................................................................... 48 
9.1.4 
Adjuvant Chemotherapy ........................................................ 50 
9.1.5 
Cautionary Therapy ............................................................... 58 
9 . 2  
General Concomitant Medication and Supportive 
Care Guidelines ..................................................................... 58 
9.3 
Duration of Therapy ............................................................... 62 
9.4 
Tumor Sample Analysis ......................................................... 63 
9.4.1 
Biopsy Samples ..................................................................... 63 
9.4.2 
Resected Tumor Sample ....................................................... 63 
9.4.3 
Blood Samples ...................................................................... 63 
9.5 
Criteria for Removal from Study ............................................ 64 
10.  DOSE ADMINISTRATION AND MODIFICATIONS ..................................... 65 
11.  ADVERSE EVENTS: LIST AND REPORTING 
REQUIREMENTS ....................................................................................... 66 
11.1 
Safety of Atezolizumab in Humans ........................................ 66 
11.2 
Safety of PEGPH20 ............................................................... 71 
11.3 
Safety Definitons ................................................................... 73 


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11.4
Methods and Timing for Assessing AND 
Recording Safety variables .................................................... 76
11.5
Procedures For Eliciting, Recording, And 
Reporting Adverse Events ..................................................... 77
12. PHARMACEUTICAL INFORMATION ......................................................... 89
12.1
Treatment Regimen ............................................................... 89
12.1.1
Atezolizumab ......................................................................... 89
12.2
Method for Assigning Patients to Treatment 
Groups ................................................................................... 90
12.3
Preparation and Administration of Study Drug ....................... 90
12.3.1
PEGPH20 .............................................................................. 90
12.3.2
Atezolizumab ......................................................................... 90
12.4
Patient Compliance Monitoring .............................................. 93
12.5
Blinding of study Drug ............................................................ 93
12.6
Receiving, Storage, Dispensing and Return .......................... 93
12.6.1
Receipt of Drug Supplies ....................................................... 93
12.6.2
Dispensing of Study Drug ...................................................... 93
12.6.3
Disposing of Study Drug ........................................................ 93
12.7
Summary of Assessments ..................................................... 95
13. MEASUREMENT OF EFFECT ................................................................. 105
13.1
Definition of Resectable Disease ......................................... 105
13.2
Antitumor Effect  Solid Tumors .......................................... 106
14. DATA REPORTING / REGULATORY REQUIREMENTS ......................... 116
14.1
Data Collection .................................................................... 117
14.2
Data Reporting .................................................................... 117
14.3
Data and Safety Monitoring Committee ............................... 117
14.4
Quality Control and Quality Assurance ................................ 118
14.5
Confidentiality ...................................................................... 119
14.6
Source Documents .............................................................. 119
14.7
Records Retention ............................................................... 120
15. STATISTICAL CONSIDERATIONS .......................................................... 120


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15.1 
Study Design/Endpoints ...................................................... 120 
15.2 
Stratification Factors ............................................................ 122 
15.3 
Analysis of Primary, Secondary Endpoints and 
Evaluation of Tissue ............................................................ 122 
15.4 
Reporting and Exclusions .................................................... 124 
16.  PROTECTION OF HUMAN PATIENTS .................................................... 124 
17.  STUDY FINANCES ................................................................................... 125 
17.1 
Conflict of Interest ................................................................ 125 
17.2 
Patient Stipends or Payments ............................................. 125 
18.  PUBLICATION PLAN ................................................................................ 125 
19.  GUIDELINES FOR AFFILIATE INSTITUTIONS IN 
MULTICENTER STUDIES ........................................................................ 125 
19.1 
Multi-Site Communication: ................................................... 125 
19.2 
New Protocol Distribution, IRB Submission, 
Modifications, and Annual Renewals ................................... 126 
19.3 
Regulatory Documents ........................................................ 126 
19.4 
Site Activation ...................................................................... 127 
19.5 
Central Registration Procedures--Affiliate 
Institution Research Participant Registration 
Process ................................................................................ 127 
19.6 
Protocol Deviation request for Affiliate Sites: ....................... 129 
19.7 
Guidelines for Affiliate Site Monitoring ................................. 129 
19.8 
Adverse Event Reporting ..................................................... 131 
19.9 
Confidentiality ...................................................................... 133 
19.10 
Data Reporting Plan ............................................................ 133 
19.11 
Data Acquisition and Submission ........................................ 134 
19.12 
Record Keeping and Record Retention ............................... 134 
20.  REFERENCES ......................................................................................... 168 
 
 
LIST OF TABLES 


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Table 1 
Radiographic Image Assessment - Baseline Review within 
Seven Days of Initiating Therapy ................................................ 35 
Table 2 
Accrual Targets for Women and Minority .................................... 36 
Table 3 
Rounding Enoxaparin Doses ...................................................... 47 
Table 4 
Treatment Cycle and Dosages .................................................... 48 
Table 5 
 Randomized Controlled Studies of Adjuvant Chemotherapy 
in Pancreatic Cancer .................................................................. 52 
Table 6  Dose Modification Table for Neutropenia/Thrombocytopenia ............... 55 
Table 7  Dose Modification Table for Neutropenia and Thrombocytopenia 
During Nadir ................................................................................ 56 
Table 8  Dose Modification Table for Diarrhea ................................................... 56 
Table 9  Diarrhea Management Guidance .......................................................... 57 
Table 10   Dose Modification Table for Peripheral Neuropathy .......................... 57 
Table 11 
Dose Administration (Atezolizumab alone) ................................. 65 
Table 12 
Dose Administration (Atezolizumab + PEGPH20) ...................... 66 
Table 13 
Serious Adverse Drug Reactions for Atezolizumab in All 
Indications Considered Expected for Safety Reporting 
Purposes ..................................................................................... 69 
Table 14 
Administration of First and Subsequent Atezolizumab 
Infusions...................................................................................... 92 
Table 15 
Study Calendar ........................................................................... 95 
Table 16 
Comparison of RECIST v1.1 and Immune-Modified RECIST .... 108 
 
 
LIST OF FIGURES 
Figure 1 
Overall Study Design ..................... Error! Bookmark not defined. 


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Figure 2 
Study Design for Neoadjuvant Therapy ...................................... 25 
Figure 3 
Study Design for Adjuvant Therapy Error! Bookmark not defined. 
Figure 4 
Venous Tumor Contact ............................................................... 34 
Figure 5 
VECTRA Imaging of Human PDA ............................................... 39 
Figure 6 
Kaplan-Meier Survival by Molecular Subtype:  VECTRA 
Imaging of Human PDA ................. Error! Bookmark not defined. 
 
 
LIST OF APPENDICES 
Appendix 1 
Radiographic Image Assessment - Baseline Review ................ 136 
Appendix 2 
Adverse Events and Management Guidelines for 
Atezolizumab ............................................................................ 137 
Appendix 3 
Adverse Events and Management Guidelines for 
Atezolizumab + PEGPH20 ........................................................ 164 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
AE 
adverse events 
AESI 
adverse events of special interest 
CHO 
Chinese hamster ovary 
CI 
confidence interval 
CPDM 
Clinical Protocol & Data Management   
CR 
complete response 
CRF 
case report form 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTMS 
Clinical Trial Management System 
CUMC 
Columbia University Medical Center 
DLT 
dose-limiting toxicity 
DSMC 
Data and Safety Monitoring Committee 
DSMP 
Data and Safety Monitoring Plan 
ECM 
extracellular matrix 
ECOG 
Eastern Cooperative Oncology Group 
EUS 
endoscopic ultrasound 
ESMO 
European Society for Medical Oncology 
ESPAC 
European Study Group for Pancreatic Cancer 
FDA 
Food and Drug Administration 
FDG 
fluorodeoxyglucose 
GA 
Gemcitabine and Nab-Paclitaxel 
GCP 
Good Clinical Practice 
HA 
hyalouronidase 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
Hgb 
hemoglobin 
HICCC 
Herbert Irving Comprehensive Cancer Center 
HIPAA 
Health Insurance Portability and Accountability Act 
HR 
hazard ratio 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 


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IEC 
independent ethics committee 
IF
immunofluorescence
Ig
immunoglobulin
IND 
Investigational New Drug (Application) 
IRB 
Institutional Review Board 
IRR
infusion-related reactions
IV
intravenous
LCM 
laser capture microdissection 
MDCT
multiphasic CT (scan)
MedDRA 
Medical Dictionary for Regulatory Activities 
MMR-D
mismatch repair-deficient
MMR-P
mismatch repair-proficient
MRI 
magnetic resonance imaging 
MSE
musculoskeletal events
MSKCC 
Memorial Sloan Kettering Cancer Center 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NSAIDs
nonsteroidal anti-inflammatory drugs
NSCLC 
non-small cell lung cancer 
OCT 
optimum cutting temperature 
OS
overall survival
PD-1
programmed death-1
PD
progressive disease
PDA
pancreas adenocarcinoma
PD-L1 
programmed death-ligand 1 
PET 
positron emission tomography 
PHI 
protected health information 
PI
principal investigator
PT
preferred term
Q2W 
every 2 weeks 
Q3W 
every 3 weeks 
qmIF
quantitative multiplex immunofluorescence 
RECIST
(immune-modified) Response Evaluation Criteria in 
Solid Tumors 
RFS
recurrence- free survival
SAE 
serious adverse event 


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TAM 
tumor-associated macrophages 
TC 
tumor cells 
TE 
thromboembolic 
TGI 
tumor growth inhibition 
TIL 
tumor-infiltrating lymphocytes 
TME 
tumor microenvironment 
TNF- 
tumor necrosis factor  
ULN 
upper limit of normal 
UP 
unanticipated problem 
WHO 
World Health Organization 
 


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Pancreas adenocarcinoma (PDA) is an aggressive cancer for which little progress has 
been made over the past decades with 5-year survival at 7%, and is projected to be the 
second leading cause of cancer-related death in the United States in 2030 (Rahib et al. 
2014; Siegel et al. 2016). Even for early stage disease, recurrence is high. Although 
recent combination therapies for metastatic PDA have improved survival by up to 
5 months, the overall prognosis remains little changed and novel therapies are 
desperately needed (Conroy et al. 2011; Von Hoff et al. 2013). The majority of patients 
diagnosed with PDA either have locally advanced (~ 30%) or distant (~ 50%) disease, 
for which chemotherapy is the mainstay of treatment (Howlader et al. 2017). Of those 
that receive surgery followed by adjuvant chemotherapy, the median overall survival 
remains poor (20.1 to 54.4 months) (Neoptolemos et al. 2004; Oettle et al. 2007; 
Regine et al. 2008; Neoptolemos et al. 2010; Howlader et al. 2017; Conroy et al. 2008). 
Negative margins, smaller tumor size, and lack of lymph node involvement result in 
improved prognosis (Allison et al. 1998; Sohn et al. 2000; Howard et al. 2006). Patients 
with metastasis to visceral organs, peritoneum, or lymph nodes that are beyond the field 
of resection derive no benefit from surgery. 
Of the newly diagnosed patients, nearly 15% are considered to be candidates for 
immediate surgical resection (Vincent et al. 2011). Despite resection, disease recurs in a 
majority of these patients and the median disease- free survival is 6.7 months (Oettle 
et al. 2013). Addition of capecitabine to gemcitabine has improved median overall 
survival from 25.5 to 28.0 months (HR 0.82, p=0.032) compared to those patients treated 
with gemcitabine alone (Neoptolemos et al. 2017). However, preliminary experience 
with use of this regimen in the United States has posed to be a challenge as most 
patients are unable to tolerate the doses used in the European ESPAC-4 trial and 
require frequent dose reductions or schedule modifications. PRODIGE 24, a large 
randomized phase 3 study compared mFOLFIRINOX to gemcitabine monotherapy in the 
adjuvant setting and demonstrated a median overall survival benefit of 54.4 months 
compared to 35.0 months, respectively. The median disease free survival was 
21.6 months in the mFOLFIRINOX arm compared to 12.8 months in the gemcitabine 
monotherapy arm (Andre et al. 2018; Conroy et al. 2018). The reported 18-month overall 
survival (OS) is 67% with adjuvant gemcitabine in combination with capecitabine which is 
similar to the 63% reported when gemcitabine and oxaliplatin were tested in the 
neoadjuvant setting (O’Reilly et al. 2016). Although mFOLFIRINOX yielded impressive 
results, patients enrolled onto the study had a better performance status to withstand 
mFOLFIRINOX.  
A majority of resectable patients likely have micrometastatic disease at time of diagnosis 
and therefore benefit from adjuvant chemotherapy. It is in this setting that 


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immunotherapy either alone or in combination with agents that disrupt the 
immunosuppressive tumor microenvironment (TME) are likely to be effective in 
controlling micro metastatic foci of disease. Effective treatments to at least prolong the 
disease-free duration if not increasing the cure rate, are desperately needed for this 
fatal disease. 
2. 
STUDY OBJECTIVES 
2.1 
PRIMARY OBJECTIVE 
To compare the number of CD8+ T cells within the tumor after neoadjuvant 
atezolizumab alone or in combination with PEGPH20 or other therapies at time of 
surgery. 
2.2 
SECONDARY OBJECTIVE 
a) To estimate the 18-month survival rate and overall survival in patients treated with 
atezolizumab vs atezolizumab + PEGPH20 or other therapies followed by surgery 
and adjuvant therapy. 
b) To determine the R0 resection rates with atezolizumab vs atezolizumab + 
PEGPH20 or other therapies administered in the neoadjuvant setting. 
c) 
To determine the safety profile with atezolizumab vs atezolizumab + PEGPH20 or 
other therapies followed by surgery and adjuvant therapy. 
d) To evaluate Ca 19-9 biomarker responses to atezolizumab with or without 
PEGPH20 or other therapies in the neoadjuvant setting. 
e) To evaluate patterns of failure following neoadjuvant atezolizumab with or without 
PEGPH20 or other therapies and surgery. 
f) 
Intratumoral CD8+ T cells after neoadjuvant atezolizumab alone or combination with 
PEGPH20 or other therapies at time of surgery will be compared to intratumoral 
CD8+ T cells within resected tumors after no neoadjuvant therapy from matched 
historical controls. 
 
2.3 
EXPLORATORY OBJECTIVE 
a) To isolate the epithelium and stromal tumor for protein expression profiling using 
RNA-seq for subtype classification of PDA. This will be performed using laser-
capture microdissection (LCM) on resected tissue samples from patients treated 
with atezolizumab vs atezolizumab + PEGPH20 or other therapies  
b) To quantitate the change in CD8+ T cells within paired pre-treatment biopsy and on- 
treatment resected tumor treated with atezolizumab vs atezolizumab + PEGPH20 or 
other therapies. 


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c) 
To quantitate distinct immune subtypes within on-treatment resected tumor treated 
with atezolizumab vs atezolizumab + PEGPH20 or other therapies by quantitative 
multiplex immunofluorescence. 
d) To quantitate the change in immune subtypes within paired pre-treatment biopsy 
and on-treatment resected tumor treated with atezolizumab vs atezolizumab + 
PEGPH20 or other therapies. 
 
3. 
BACKGROUND 
Presently, surgical resection offers the only therapeutic means of cure. However only 
15%-20% of patients are found to have resectable disease at time of initial diagnosis. Of 
the patients who undergo curative surgery, most will relapse and eventually succumb to 
the disease. 5-year survival rates for node-negative and -positive disease at time of 
pancreatic duodenectomy are 25%-30% and 10%, respectively (Trede et al 1990; 
Geer and Brennan 1993; Yeo et al. 1995). 
3.1 
IMMUNOTHERAPY IN PDA 
Multiple studies have shown that genetic mutations in tumor DNA can lead to the 
expression of antigenic peptides which can drive the anti-tumor therapeutic immune 
response unleashed by immune checkpoint inhibitors (Snyder et al. 2014; Azuma et al 
2014; Rizvi et al. 2015). Neoantigen-specific lymphocytes can be detected in peripheral 
blood samples and their levels correlate with disease response to anti-programmed 
death-1(PD-1) therapy. PDAs are characterized by a moderate mutational burden 
(averaging 67 coding mutations) comparable to other solid tumors (Brahmer et al. 2010; 
Mu et al. 2011; Brahmer et al. 2012). However, early phase monotherapy anti-CTLA-4 
and anti-programmed death ligand-1(PD-L1) antibody trials in patients with metastatic 
and locally advanced PDA demonstrated limited activity (Royal et al. 2010; Brahmer et 
al. 2012). Interim results of a multicenter, phase 1 trial involving the anti-PD-L1 mAb, 
durvalumab, were presented at European Society for Medical Oncology (ESMO) and 
showed a disease control rate of 21% (6 of 29 patients) in PDA patients, two of whom 
achieved a partial response (Segal et al. 2014). Although PDA has been considered a 
non-immunogenic cancer, these studies demonstrate that PDA can respond to 
immunotherapy and that further study is warranted. 
A leading explanation for the lack of efficacy of single-agent immunotherapy is the 
highly immunosuppressive stroma that envelopes most malignant cells. PDAs contain 
very few effector T cells, and in surgically resected tumors a higher number of tumor-
infiltrating lymphocytes (TILs) correlates with improved survival (Fukunaga et al. 2004). 
Untreated PDAs are characterized by low PD-L1 expression, where only 12% of tumors 
analyzed expressed membranous staining of PD-L1 in more than 5% of neoplastic cells 
(Soares et al. 2015). Interestingly, a retrospective study evaluating resected PDA tissue 
identified that PD-L1 staining inversely correlated with survival and CD8+ T-cell 


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19 
 
infiltration (Nomi et al. 2007). This suggests that targeting PD-L1 may unmask at least 
part of the immunosuppression function within PDA. Furthermore, evaluation of a 
monoclonal agonist antibody targeting CD40, in combination with gemcitabine, 
detected four partial responses in 22 patients with advanced PDA while other patients 
experienced decreased fluorodeoxyglucose (FDG) uptake within their primary and/or 
metastatic lesions on positron emission tomography (PET)/computed tomography (CT) 
scans (Beatty et al. 2013). Furthermore, recent reports indicated that immunotherapy 
appears to be effective in patients with microsatellite high PDA tumors (see below). 
Collectively, these findings suggest that immunotherapy has a role in PDA. 
3.2 
MISMATCH REPAIR PATHWAY AND SUSCEPTIBILITY TO 
IMMUNOTHERAPY 
Of particular interest is the observation that patients with mismatch repair-deficient 
(MMR-D) PDA respond to checkpoint inhibitors (Rizvi et al. 2015). MMR-D colorectal 
cancer tumors have 10 to 100 times as many somatic mutations compared to mismatch 
repair-proficient (MMR-P) colorectal tumors (Timmermann et al. 2010). In a phase 2 
study that included 10 patients with MMR-D colorectal cancer, four exhibited an 
immune- related objective response compared to none of the nine within the MMR-P 
cohort when treated with pembrolizumab monotherapy. At the time the study was 
published, median progression-free survival and OS was not reached within the 
MMR-D cohort, while it was 2.2 and 5.0 months, respectively, within the MMR-P 
cohort (Rizvi et al. 2015; Neoptolemos et al. 2017). Whole-exome sequences identified 
a mean of 1782 somatic mutations per tumor in patients in nine MMR-D colorectal 
cancer patients, compared with 73 mutations per tumor in patients with MMR-P. 
Membranous PD-L1 expression occurred only in tumors of MMR-D patients and was 
prominent on TILs and tumor-associated macrophages at the invasive fronts of the 
tumor (Lee et al. 2015). The leading hypothesis to the responsiveness of MMR-D 
colorectal cancer to PD-1 targeted therapy is the increased number of 
mutation-associated neoantigens. An additional preliminary report of 4 patients with 
PDA identified that 2 had partial responses and 2 had stable disease (Rizvi et al. 2015).  
However, PDA with MMR-P tumors constitute greater than 98% of cases for which 
immunotherapy is not currently efficacious. 
3.3 
STUDY RATIONALE  
Atezolizumab Arm 
Although early phase trials have not offered great success in the metastatic setting for 
patients with PDA, interim analysis of a multicenter, phase 1 trial with durvalumab 
presented at ESMO indicated a disease control rate of 21% (Ene-Obong et al. 2013). 
As mentioned previously, PD-L1 expression correlates with poor prognosis and 
decreased CD4+ and CD8+ T cell infiltration within the tumor. Targeting PD-L1 in the 
micrometastatic setting (resectable disease), when robust mature immunosuppressive 


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pathways may not have yet formed, may be the optimum time to investigate anti-PD-L1 
therapy. This arm of the study aims to test if atezolizumab is able to modulate CD8+ 
T-cell infiltration compared to historical matched controls. As a secondary endpoint 
we will also evaluate how clinical outcomes compare to matched historical controls. 
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Neoplastic, immune, and stromal cells within PDA reside in a highly dense desmoplastic 
environment composed of an extracellular matrix of which hyalouronidase (HA) is an 
abundant component. HA is a linear glycosaminoglycan and an integral component of not 
only PDA tumors, but has also been shown to accumulate in many solid tumors and is 
associated with a poor prognosis and increased immunosuppression (Provenzano et al. 
2012; Cheng et al. 2013). In a preclinical autochthonous mouse model of PDA, Sunil 
Hingorani s group demonstrated that the interstitial fluid pressures were unusually high 
within tumors that exhibited a high HA content. Furthermore, high HA tumors contained 
low vascularity, which compromised delivery of chemotherapeutic agents, such as 
gemcitabine. Mice treated with hyaluronidase resulted in decreased HA content and 
microvasculature re-expansion within tumors which led to a survival benefit 
(Provenzano et al. 2012). These preclinical studies led to early phase clinical studies in 
metastatic PDA where addition of PEGPH20 to gemcitabine and nab-paclitaxel (GA) in a 
randomized phase 2 study demonstrated a survival benefit in patients with HA-high 
tumors. The objective response rate for patients who were treated with a combination of 
PEGPH20 and GA compared to GA alone was 45% versus 31%, respectively, and the 
median overall survival was 11.5 versus 8.5 months, respectively (hazard ratio (HR), 
0.96; 95% CI, 0.57 to 1.61) (Hingorani et al. 2018). A large phase 3 randomized clinical 
trial in the high HA stage IV PDA population in the first line setting is ongoing. 
PDA likely invokes multiple immune evading mechanisms which result in its aggressive 
behavior; it is expected that multiple agents will likely be needed to develop effective 
therapies. One such rationale is the combination of PEGPH20 and immune checkpoint 
blockade to allow increased cytotoxic T-cell infiltration by increasing vascular 
permeability and decreasing interstitial pressure. In a breast cancer preclinical model, 
PEGPH20 resulted in an increase accumulation of CD8+ TIL by 176% (p=0.0025) and 
improved tumor growth inhibition by 38% relative to anti-PD-L1 alone (86% vs 62.4%, 
p=0.0024) (Clift et al. 2017). Other preclinical studies are also demonstrating increased 
CD8+ T-cell infiltration with addition of PEGPH20 and improved tumor control in 
combination with immune checkpoint blockade (Lee et al. 2017). These and other 
preclinical studies suggest that this combination is worth pursuing in patients with 
resectable PDA. The combination is hoped to increase CD8+ T-cell infiltration within the 
primary tumor for improved immune mediated cytotoxicity and decreased interstitial 
pressure to allow improved surgical resections. Hypothetically, the combination should 
also be effective in foci of micrometastasis, where the TME may not be as mature. 


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Identified risks for PEGPH20 include musculoskeletal events (MSEs), infusion-related 
reactions (IRRs), and thromboembolic (TE) events. 
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Atezolizumab is a humanized immunoglobulin (Ig) G1 monoclonal antibody which 
targets PD-L1 on tumor-infiltrating immune cells or tumor cells. The antibody blocks 
interaction of PD-L1 to PD-1 receptor and CD80 (B7.1), which are inhibitory receptors 
on immune cells, including T cells. This inhibition is thought to enhance tumor specific 
T-cell function through enhanced priming, expansion, and effector function (Okazaki 
and Honjo 2007). Hence, disrupting this pathway by atezolizumab has been effective in 
various tumor subtypes. Atezolizumab lacks Fc-effector function as it is engineered to be 
a non-glycosylated antibody, and hence does not function in antibody-dependent 
cell-mediated cytotoxicity or antibody mediated clearance of activated effector T cells. 

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Atezolizumab is a humanized antibody containing heavy chain VHIII and light chain Vțl 
subgroup sequences. The antibody lacks the N-linked oligosaccharides due to an 
asparagine to alanine substitution at position 298 of each heavy chain resulting in a non-
glycosylated antibody. 
Atezolizumab is produced in Chinese hamster ovary (CHO) cells and is provided in 
2-mL (Formulation F01 or early Phase I/II material) and 20-mL (Formulation F03 or late 
Phase I/II and Phase III material) glass vials. The diluent used with Formulation F01 is 
provided in 50-mL glass vials. The respective protein concentrations for Formulations 
F01 and F03 are 125 mg/mL and 60 mg/mL, respectively. Atezolizumab (F01 and 
F03) and diluent are in a solution containing histidine acetate, sucrose, and 
polysorbate 20. 
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As of the August 2018 Investigator s Brochure (version 13), clinical data on 
atezolizumab as a single agent or in combination with chemotherapy or targeted agents 
are available from more than 20 studies. Atezolizumab is approved in the United States 
for the treatment of patients with locally advanced or metastatic urothelial carcinoma 
who fit the following criteria:  1) are not eligible for cisplatin-containing chemotherapy 
and whose tumors express PD-L1 (PD-L1 stained tumor-infiltrating immune cells 
covering  5% of the tumor area), as determined by a US Food and Drug Administration 
(FDA)-approved test, or 2) are not eligible for any platinum-containing chemotherapy 
regardless of PD-L1 status, or 3) have disease progression during or following any 
platinum-containing chemotherapy, or within 12 months of neoadjuvant or adjuvant 


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chemotherapy. Atezolizumab is also approved the treatment of previously treated locally 
advanced or metastatic non-small cell lung cancer (NSCLC). 
Pharmacokinetic, exposure-safety, and exposure-efficacy data analysis as reported 
in the Atezolizumab Investigator’s (version 13) identified that age, body weight, gender, 
albumin levels, tumor burden, renal impairment, mild hepatic impairment, level of PD-L1 
expression, or Eastern Cooperative Oncology Group (ECOG) status had no clinically 
relevant effect. Positive anti-drug antibody (ADA) status against atezolizumab led to 
approximately 13% reduction in overall exposure. The effect of hepatic impairment 
(bilirubin or aspartate aminotransferase > upper limit of normal) on the 
pharmacokinetics of atezolizumab is unknown. For safety of atezolizumab in humans, 
please refer to Section 11.1. 
 
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PEGPH20 is a PEGylated, neutral-pH-active human hyaluronidase PH20 produced by 
recombinant DNA technology. PEGPH20 drug product is supplied as an aqueous 
solution containing 0.330 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 mL (0.303 mg, commercial-scale material) of PEGPH20 
drug product. PEGPH20 has a terminal plasma half-life of approximately 3.2 hours in 
rodents and 50 hours in monkeys. In humans, data from 2 patients treated with 50 g/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 (1-2 days) for the terminal phase. In this study, 
atezolizumab will be given 1í3 hours after completion of PEGPH20 administration on 
days where PEGPH20 and atezolizumab are administered the same day.  
2[DOLSODWLQ
Oxaliplatin is a platinum-based antineoplastic agent. It inhibits synthesis of 
deoxyribonucleic acid (DNA) by cross-linking guanine and cytosine. Please refer to local 
prescribing information for detailed instructions on the reconstitution, storage conditions, 
intravenous (IV) administration, known precautions, and warnings of oxaliplatin. 
,ULQRWHFDQ
Irinotecan is an antineoplastic agent which is activated by hydrolysis to SN-38, an 
inhibitor of topoisomerase I. SN-38 is subsequently inactivated by glucouronidation by 
uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1). The inhibition of 
topoisomerase by SN-38 results in inhibition of DNA replication and transcription to RNA 
synthesis. Please refer to local prescribing information for detailed instructions on the 


Columbia University Medical Center 
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23 
 
reconstitution, storage conditions, intravenous (IV) administration, known precautions, 
and warnings of irinotecan. 
Leucovorin 
Leucovorin, also known as folinic acid, is a derivative of tetrahydrofolate and is used in 
combination with fluorouracil to enhance the effect of fluorouracil metabolite by 
stabilizing the bond with thymidylate synthetase. Please refer to local prescribing 
information for detailed instructions on the reconstitution, storage conditions, intravenous 
(IV) administration, known precautions, and warnings of leucovorin. 
Fluorouracil 
Fluorouracil is an antineoplastic agent which functions by multiple mechanism but 
primarily by inhibiting thymidylate synthase (TS) which is required for formation of 
thymidine. Fluorouracil results in decline of thymidine monophosphate, an essential 
nucleoside resulting in the death of rapidly dividing neoplastic cells. Please refer to local 
prescribing information for detailed instructions on the reconstitution, storage conditions, 
intravenous (IV) administration, known precautions, and warnings of fluorouracil. 
 
 
 
 
 
 
 
 
 
 


Columbia University Medical Center 
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24 
 
5. 
STUDY DESIGN 
5.1 
GENERAL DESIGN 
Newly diagnosed resectable PDA patients who meet the study criteria will be randomly 
assigned to one of the treatment arms (Figure 1Error! Reference source not found.). 
 
Figure 1  Overall Study Design  
 
 
CIT  cancer immunotherapy; SOC  standard of care; TBD  to be determined. 
Patients with tumors that are deemed resectable will be randomly assigned to receive either 
atezolizumab alone, or atezolizumab in combination with PEGPH20 or other therapies for a 
period of 3 weeks prior to undergoing surgical resection. Patients will recover for 4 to 6 weeks 
and then continue on the same treatment for an additional 8 weeks, after which they will 
receive adjuvant modified FOLFIRINOX for 6 months.


Columbia University Medical Center 
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25 
 
Subjects deemed eligible will undergo CT of the chest, and triple-phase CT of the 
abdomen and pelvis using the pancreas protocol (14-day window prior to treatment) and 
consent for the study if considered to have resectable disease and meet the eligibility 
criteria. All eligibility criteria will be reviewed during the consent process and all study 
related procedures will be performed after consenting. A fresh pancreas tumor biopsy is 
required prior to initiating therapy. Patient will recover for at least 2 days after biopsy to 
initiate therapy for 3 weeks. Atezolizumab will be administered at 840 mg IV every 
2 weeks ( for 2 doses total) prior to surgery (Days 4 and 18). PEGPH20 will be 
administered at 3 g/kg on Days 1 and 4 every 7 days for 21 days. Figure 2 depicts 
required assessments prior to surgery. Patients receiving PEGPH20 will receive 
enoxaparin to mitigate the increased risk of thromboembolism to start on Cycle 1, Day 1 
and discontinue 2 days prior to scheduled surgery and resume 2-7 days after surgery if 
deemed appropriate. Patients will continue enoxaparin for 7 days after last dose of 
PEGPH20. 
Figure 2 Study Design for Neoadjuvant Therapy 
 
atz  atezolizumab; CIT  Cancer Immunotherapy; IO  intraoperative; P20  PEGPH20; TBD  to 
be determined. 
After meeting eligibility criteria, patients will consent for the study and will undergo schedule of 
activities including repeat imaging (if needed) and tumor biopsy prior to being randomized to 
distinct treatment arms. Treatment should be initiated no later than 5 days after randomization. 
Patients will be treated either with atezolizumab alone or in combination with PEGPH20 or other 
agent for 21 days prior to intraoperative (IO) biopsy and surgical resection. 
1 Atezolizumab 840 mg IV Day 4 and 15 (neoadjuvant x 2 doses; 1 week break prior to 
resection), then x 4 doses (CIT adjuvant) every 2 weeks. 
2 PEGPH20 will be administered at 3 g/kg on Day 1 and Day 4 every seven days for 21 days 
3 Other molecules under discussion. 
 
 


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26 
 
The preoperative biopsy, intraoperative biopsy, and the resected tumor sample will be 
analyzed for CD8+ T-cell infiltration, other immune cells of interest, and undergo RNA 
expression analysis of the epithelial and stromal component by laser capture 
microdissection as described in Section 7. 
A safety committee of participating surgeons and medical oncologists at Columbia 
University Medical Center (CUMC), Memorial Sloan Kettering Cancer Center (MSKCC), 
and other participating sites will convene on a regularly scheduled basis to discuss study 
conduct. If greater than 1 of the 20 patients per cohort are unable to undergo 
surgery, or greater than 3 of the 20 patients per cohort have a greater than 
14-day delay in surgery, deemed related to study treatment, enrollment to that 
arm will be halted and an analysis performed by the Principal Investigator (PI). 
The Institutional Review Board (IRB) and the Data Safety Monitoring Committee 
(DSMC) will be notified within 14 days after every occurrence when a subject has 
surgery delayed by greater than 14 days or when the subject is considered not to 
be a surgical candidate deemed related to study treatment.The PI, in consultation 
with the safety committee, will either modify the treatment regimen or discontinue the 
arm if an alternate safe regimen is not deemed feasible. After a recovery period of 4-6 
weeks post-surgical resection, patients will resume the same treatment which they 
received prior to surgery for an additional 8 weeks (2 cycles). At the end of 
investigational therapy, patients will initiate adjuvant chemotherapy with modified 
FOLFIRINOX for 6 cycles. Patients will be followed for recurrence and survival. 
All study-related investigational treatment should end at or prior to Week 14, Day 6 after 
surgery. Adjuvant chemotherapy should begin no later than Week 16, Day 1 after 
surgery even if partial treatment is administered within a treatment cycle. All 
study-related therapy should be discontinued at least 1 week prior to initiation of 
chemotherapy (Error! Reference source not found.). Doses being held due to safety 
concerns will resume dosing at the previous schedule when treatment is deemed 
safe. Oral agents that are vomited or missed by the patient will not be made up. 
 


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atz    atezolizumab; CIT   Cancer Immunotherapy; D   Day; IO   intraoperative; P20   PEGPH20; 
TBD   to be determined. 
After completing neoadjuvant immunotherapy, intraoperative (IO) biopsy and surgical resection, 
patients will recover for 4 to 6 weeks after surgery. Patients will be treated with 2 cycles of 
either atezolizumab alone (Days 1 and 15, every 28 days) or in combination with PEGPH20 
(P20; Days 1, 8, and 15, every 28 days) starting Week 5 or 7, Day 1, weekly with PEGPH20 
(depending on duration of post-surgical recovery) and will undergo 2 cycles of therapy. 
Adjuvant chemotherapy will begin between Weeks 13 and 16, Day 1 (depending on duration of 
post-surgical recovery) for 6 months. 
1 Atezolizumab will be administered 840 mg IV on Days 1 and 15, every 28 days for 2 cycles. 
2 PEGPH20 will be administered 3 Pg/kg on Days 1, 8, and 15, every 28 days for 2 cycles. 
3 Other molecules under discussion. 
4 modified FOLFIRINOX  Oxaliplatin 85mg per square meter IV, irinotecan 150mg per square 
meter IV, leucovorin 400mg per square meter IV, and fluorouracil 2400mg per square meter IV 
continuous infusion on day 1 and pegfilgastrim 6mg SC injector kit on day 3 every 2 weeks. 
 
 
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Arm B: Atezolizumab + PEGPH20 (n=20) 
 


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6. 
PATIENT SELECTION AND WITHDRAWAL 
6.1 
INCLUSION CRITERIA 
Patients must meet the following criteria for study entry: 
6.1.1 
Histological or pathological confirmation of pancreatic adenocarcinoma 
Cytologic or histologic proof of PDA needs to be verified by the treating institution 
pathologist either from the initial diagnostic biopsy, or from the required pre-treatment 
biopsy and prior to initiation of any study-related therapy  
6.1.2 
Extent of disease. 
Stage 1 or 2 PDA (See Section 6.3 for radiological criteria and Appendix 1) and patient 
deemed a surgical candidate by the PI in consultation with the designated site radiologist 
and surgeon at the treating institution 
6.1.3 
No prior surgical, systemic or radiotherapy for PDA. 
6.1.4 
ECOG performance status of 0 or 1. 
6.1.5 
Age   18 years. 
6.1.6 
Adequate hematological and end-organ function, defined by the following 
laboratory test results, obtained within 14 days prior to initiation of study treatment: 
 
ANC ≥ 1.5  109/L without granulocyte colony-stimulating factor support. 
 
WBC count ≥2.5  109/L (2500/L). 
 
Lymphocyte count ≥0.5    109/L (500/L). 
 
Platelet count  ≥100  109/L (100,000/L) without transfusion within 4 weeks. 
 
Hemoglobin (Hgb) >9.0 g/dL without transfusion within 2 weeks. 
 
AST, ALT, and alkaline phosphatase (ALP) ≤ 2.5  upper limit of normal (ULN) unless 
elevated secondary to biliary obstruction from the pancreas mass and amenable 
to decompression prior to initiation of therapy. Prior to initiation of therapy, AST, 
ALT, and ALP ≤ 2.5  ULN. 
 
Serum total bilirubin ≤ 1.5  ULN unless in patients with known Gilbert disease 
(  3  ULN) or unless elevated secondary to biliary obstruction from the pancreas 
mass and amenable to decompression prior to administration of investigational 
therapy. A functioning biliary stent as evidenced by declining total bilirubin and   2  
ULN is required prior to initiation of therapy. 
 
Albumin ≥ 3.0 g/dL. 
 
Creatinine within ULN or calculated creatinine clearance (CrCl) >50 mL/min using 
the Cockcroft-Gault formula. 
 
INR and aPTT ≤ 1.5  ULN. 


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6.1.7 
Tumor accessible for fresh biopsy 
6.1.8 
Women of child-bearing potential must have a negative serum pregnancy test 
at screening and must agree to use two forms of effective contraception from the time of 
the negative pregnancy test and for a minimum of 5 months after the last dose of 
study drug. Effective forms of contraception include abstinence, hormonal 
contraceptive (injectable or implantable) in conjunction with a barrier method, or a 
double barrier method. Women will be considered not of child-bearing potential if 
amenorrheic at least for one year or have undergone surgical sterilization. 
6.1.9 
Fertile men must agree to use an effective method of birth control during the 
study and for up to 5 months after the last dose of study drug. 
6.1.10 
Willingness and ability to provide written informed consent prior to any 
study-related procedures and to comply with all study requirements. 
6.1.11 
Able to comply with the study protocol, in the investigator s judgment. 
  
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Patients who meet any of the following criteria will be excluded from study entry: 
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6.2.1 
Prior treatment with T-cell co-stimulating or immune checkpoint blockade 
therapies, including but not limited to anti-CTLA-4, anti-PD-1, and anti-PD-L1 
therapeutic antibodies.  
6.2.2 
Patients who are receiving any other investigational agents concurrently. 
6.2.3 
Concomitant treatment with other anti-neoplastic agents (hormonal therapy 
acceptable). 
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6.2.4 
Uncontrolled pleural effusion, pericardial effusion, or ascites. 
6.2.5 
Patient receiving therapeutic doses of anticoagulation. 
6.2.6 
Uncontrolled hypercalcemia (ionized calcium ! 1.5 mmol/L, calcium ! 12mg/dL, 
or corrected serum calcium ! ULN) or symptomatic hypercalcemia requiring continued 
use of bisphosphonate therapy. 
6.2.7 
Active or history of autoimmune disease or immune deficiency, including, but not 
limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus 
erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid 
antibody syndrome, Wegener granulomatosis, Sj gren s syndrome, Guillain-Barr  
syndrome, or multiple sclerosis, with the following exceptions: 
x 
Patients with a history of autoimmune-related hypothyroidism who are on thyroid-
replacement hormone are eligible for the study. 


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30 
 
 
Patients with controlled Type 1 diabetes mellitus who are on a stable insulin 
regimen are eligible for the study. 
 
Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with 
dermatologic manifestations only (e.g., patients with psoriatic arthritis are excluded) 
are eligible for the study provided all of following conditions are met: 
– 
Rash must cover < 10% of body surface area. 
– 
Disease is well controlled at baseline and requires only low-potency topical 
corticosteroids. 
– 
No occurrence of acute exacerbations of the underlying condition requiring 
psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, 
oral calcineurin inhibitors, or high-potency or oral corticosteroids within the 
previous 12 months. 
6.2.8 
History of idiopathic pulmonary fibrosis, interstitial lung disease, organizing 
pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic 
pneumonitis, or evidence of active pneumonitis on screening chest CT scan 
 
History of radiation pneumonitis in the radiation field (fibrosis) is permitted 
6.2.9 
Positive HIV test at screening or at any time prior to screening. 
Patients without a prior positive HIV test result will undergo an HIV test at screening, 
unless not permitted per local regulations. 
6.2.10 
Active hepatitis B virus (HBV) infection (chronic or acute), defined as having a 
positive hepatitis B surface antigen (HBsAg) test at screening. 
Note:  Patients with a past or resolved HBV infection, defined as having a negative 
HBsAg test and a positive total hepatitis B core antibody test at screening, are eligible 
for the study. 
6.2.11 
Active hepatitis C virus (HCV) infection, defined as having a positive HCV 
antibody test followed by a positive HCV RNA test at screening. The HCV RNA test will 
be performed only for patients who have a positive HCV antibody test. 
6.2.12 
Known clinically significant liver disease, including alcoholic hepatitis, cirrhosis, 
fatty liver disease, and inherited liver disease.  
6.2.13 
Known active tuberculosis. 
6.2.14 
Severe infection within 4 weeks prior to initiation of study treatment, including, 
but not limited to, hospitalization for complications of infection, bacteremia, or severe 
pneumonia. However, patients who were admitted for biliary tract infection due to bile 
duct obstruction at time of diagnosis must have a functioning biliary stent (as evidenced 
by declining total bilirubin and  2  ULN) and resolved infection (defined by 
normalization of elevated white blood cell count, absence of signs of infection) and 


Columbia University Medical Center 
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31 
 
completion of an antibiotic course (at least a seven-day course) prior to initiation of 
therapy. 
6.2.15 
Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation 
of study treatment except for biliary tract infection due to bile duct obstruction from the 
pancreas mass. Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract 
infection or chronic obstructive pulmonary disease exacerbation) are eligible for the 
study. 
6.2.16 
Significant cardiovascular disease (such as New York Heart Association Class 
II or greater cardiac disease, myocardial infarction, or cerebrovascular accident) within 
12 months prior to initiation of study treatment, seizure disorder, uncontrolled 
hypertension, or unstable arrhythmia or unstable angina within 3 months prior to 
initiation of study treatment. 
6.2.17 
Grade 3 hemorrhage or bleeding event within 28 days prior to initiation of 
study treatment. 
6.2.18 
Prior autologous stem cell, allogeneic stem cell, or solid organ transplantation. 
6.2.19 
History of malignancy other than PDA within 2 years prior to screening, with the 
exception of those with a negligible risk of metastasis or death (e.g., 5-year overall 
survival of > 90%), such as adequately treated carcinoma in situ of the cervix, non-
melanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, or Stage I 
uterine cancer. Patients with history of prior malignancies should have risk of recurrence 
within 3 years after screening to be less than 90% (to be discussed with the PI for final 
determination of eligibility).  
6.2.20 
Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of 
study treatment, or anticipation of need for such a vaccine during treatment with 
atezolizumab or within 5 months after the last dose of atezolizumab. 
6.2.21 
History of severe allergic anaphylactic reactions to chimeric or humanized 
antibodies or fusion proteins. 
6.2.22 
Known hypersensitivity to Chinese hamster ovary cell products or recombinant 
human antibodies. 
6.2.23 
Known allergy or hypersensitivity to any of the study drugs or any of their 
excipients. 
6.2.24 
Treatment with systemic immunostimulatory agents (including, but not limited 
to, interferon and interleukin 2) within 4 weeks or five half-lives of the drug (whichever is 
longer) prior to initiation of study treatment. 
6.2.25 
Treatment with systemic immunosuppressive medication (including, but not 
limited to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, 
and anti-tumor necrosis factor alpha agents) within 2 weeks prior to initiation of study 


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treatment, or anticipation of need for systemic immunosuppressive medication during the 
course of the study, with the following exceptions: 
x 
Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids for 
chronic obstructive pulmonary disease or asthma, or low-dose corticosteroids for 
orthostatic hypotension or adrenal insufficiency are eligible for the study if receiving 
equivalent to less than 10mg of prednisone daily. 
x 
Patients who received a one-time pulse dose of systemic immunosuppressant 
medication are eligible for the study after approval from the PI has been obtained. 
6.2.26 
Inability to swallow medication or malabsorption condition that would alter the 
absorption of orally administered medications. 
6.2.27 
Pregnant women are excluded from this study because there is an unknown but 
potential risk for adverse events in nursing infants secondary to treatment of the mother 
with these agents and breastfeeding should be discontinued. 
6.2.28 
Major surgical procedure or significant traumatic injury within 14 days of 
initiating study. 
6.2.29 
Previous radiotherapy to 25% or more of the bone marrow. 
6.2.30 
Any other disease, metabolic dysfunction, physical examination finding, or 
clinical laboratory finding that contraindicates the use of an investigational drug, may 
affect the interpretation of the results, or may render the patient at high risk from 
treatment complications in the opinion of the treating investigator.  
6.2.31 
Considered ineligible to receive full standard dose modified FOLFIRINOX 
therapy in the adjuvant setting. 
6.2.32 
Peripheral neuropathy > Grade 1 
6.2.33 
History of allergy or hypersensitivity to oxaliplatin, irinotecan, leucovorin, 
fluorouracil, pegfilgastrim, or any excipients.  
6.2.34 
History of Gilbert s disease or known genotype UGT1A1 *28/*28.6.2.35   
Inflammatory disease of the colon or rectum, or severe uncontrolled diarrhea. 
([FOXVLRQ&ULWHULDIRU3(*3+&RQWDLQLQJ$UP
Patients who meet any of the following criteria will be excluded from the PEGPH20-
containing arm:
6.2.35 
Risk of thromboembolic events which are defined as: 
x 
History of transient ischemic attack requiring intervention or treatment, carotid artery 
disease requiring interventions or treatment, of cerebrovascular accident 
x 
Evidence of deep vein thrombosis (DVT), pulmonary embolism, or other 
thromboembolic event at screening, except  


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±
Superficial vein thrombosis 
±
Visceral or splanchnic vein thrombosis if the thrombosis is at a location near the 
site of underlying PDAC which may contribute to the etiology of the thrombus 
x 
Treatment with megestrol acetate within 14 days prior to initiation of study treatment 
6.2.36 
Unable to use low-molecular-weight heparin 
 
&ULWHULDWRLQLWLDWHFKHPRWKHUDS\
1. Full recovery from surgery and subject able to receive chemotherapy. 
2. Subjects who have evidence of recurrent disease prior to initiation of chemotherapy 
will need to undergo biopsy to prove disease recurrence if deemed safe. 
3. Hematological  
a. ANC  1.5 u 109 /L without granulocyte colony-stimulating factor support.  
b. Platelet count 100 u109 /L (100,000/PL) without transfusion within 4 weeks. 
c. Hemoglobin (Hgb) >9.0 g/dL  
d. AST, ALT, and alkaline phosphatase (ALP)  2.5 u upper limit of normal (ULN)  
e. Albumin  3.0 g/dL.  
f. 
Creatinine within ULN or calculated creatinine clearance (CrCl) >50 mL/min using 
the Cockcroft-Gault formula.  
 
 


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Herbert Irving Comprehensive Cancer Center 
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34 
 
6.3 
RADIOLOGICAL DEFINITION FOR RESECTABLE  
Disease Criteria for Resectable Disease 
Radiographic reading must be consistent with resectable cancer of the pancreas as 
defined by National Comprehensive Cancer Network (NCCN) guidelines and must meet 
the following criteria on CT/magnetic resonance imaging (MRI): 
1. 
No tumor metastasis in the chest, abdomen, or pelvis. 
2. 
No arterial involvement: 
– 
No tumor contact (solid or hazy soft tissue) with aorta. 
– 
No tumor contact (solid or hazy soft tissue) with celiac axis. 
– 
No tumor contact (solid or hazy soft tissue) with superior mesenteric artery. 
– 
No tumor contact (solid or hazy soft tissue) with common hepatic artery. 
3. 
No inoperable venous involvement 
None or <180 degrees tumor contact with the superior mesenteric vein (without 
vein contour irregularity or thrombosis,   
– 
).  
– 
None or <180 degrees tumor contact with portal vein (without vein contour 
irregularity or thrombosis).  
 
Patients with pancreatic tumor extending to the above organs or with metastasis will be 
considered borderline resectable or non-resectable and thus should be excluded from 
the study. 
  
Figure 4  Venous Tumor Contact 
A. Less than or equal to 180o tumor contact without 
deformity. B. Greater than 180o tumor contact 
without deformity. C. Less than or equal to 180o 
contact with deformity (arrows). D. Tear drop 
deformity (arrows). T:tumor, V:vein. Dashed line: 
180o of lumen circumference. Figure adapted from 
Al-Hawary et. al. 2014. 
 


Columbia University Medical Center 
Herbert Irving Comprehensive Cancer Center 
Version Date: 05/13/2019 
 
35 
 
Table 1 
Radiographic Image Assessment - Baseline Review within Seven 
Days of Initiating Therapy 
 
CT/MRI RESULTS 
Was a CT or MRI of the abdomen performed? 
☐ Yes ☐ No  
(If yes), Date of CT or MRI of abdomen (mm/day/yyyy)   
 
(If yes), Primary tumor identified 
☐ Yes ☐ No 
 
☐ Not evaluable 
(If yes), Location of tumor 
☐ Head/Neck/Uncinate  ☐ Body/Tail 
 
(If yes), primary tumor size 
Dimension 1 
(mm) 
Dimension 2 
(mm) 
 
CRITERIA FOR RESECTABLE DISEASE 
 
 
 
 
 
 
Tumor contact with aorta 
Tumor contact with celiac axis 
Tumor contact with superior mesenteric artery 
Tumor contact with common hepatic artery 
Tumor contact with superior mesenteric vein 
☐ Yes 
☐ Yes 
☐ Yes 
☐ Yes 
☐ Yes 
☐ No 
☐ No 
☐ No 
☐ No 
☐ No 
 
o If yes 
 
 
 
 tumor involvement >180 degrees 
☐ Yes 
☐ No 
 
 SMV contour irregularity or thrombosis 
☐ Yes 
☐ No 
 Tumor contact with portal vein 
o If yes 
☐ Yes 
☐ No 
 
 tumor involvement >180 degrees 
☐ Yes 
☐ No 
 
 If yes PV contour irregularity or thrombosis 
☐ Yes 
☐ No 
 Tumor metastasis in chest, abdomen, or pelvis 
☐ Yes 
☐ No 
 
RADIOGRAPHIC STAGE 
Radiographic stage (check one) 
☐ Resectable 
☐ Non-resectable 
☐ Metastatic 
☐ Not evaluable 
 


Columbia University Medical Center 
Herbert Irving Comprehensive Cancer Center 
Version Date: 05/13/2019 
 
36 
 
6.4 
INCLUSION OF WOMEN AND MINORITIES 
Both men and women of all races and ethnic groups are eligible for this trial. 
Table 2 
Accrual Targets for Women and Minority 
Accrual Targets 
Ethnic Category 
Sex/Gender 
  
Females
Males
 
Total
Hispanic or Latino 
4 
+
4 
= 
8 
Not Hispanic or Latino 
16 
+
16 
= 
32 
Ethnic Category:  Total of All 
Patients 
20 
+
20 
= 
40 
Racial Category 
American Indian or Alaskan 
Native 
0 
+
0 
= 
0 
Asian 
0 
+
0 
= 
0 
Black or African American 
2 
+
2 
= 
4 
Native Hawaiian or other Pacific
Islander 
0 
+
0 
= 
0 
White 
18 
+
18 
= 
36 
Racial Category:  Total of All 
Patients 
20 
+
20 
= 
40 
 
(A1 = A2) 
 
(B1 = B2) 
 
(C1 = C2) 
 
6.5 
PATIENT RECRUITMENT 
Patients will be recruited for the study from investigator or co-investigator clinical 
practices and referring physicians. 
6.6 
EARLY WITHDRAWAL OF PATIENTS 
6.6.1 
When and How to Withdraw Patients 
 
If at any time the patient develops confirmed disease recurrence, he/she will be 
taken off study and referred for alternative therapy. For guidance on treatment 
beyond recurrence please refer to Section 13.2. All patients who received any 
investigational therapy will be followed for survival. 
 
Where possible, a biopsy will be required to confirm disease recurrence and the 
determination of disease recurrence will not be adjudicated on imaging or Ca 19-9 
levels alone. 


Columbia University Medical Center 
Herbert Irving Comprehensive Cancer Center 
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37 
 
 
If at any time the patient develops unacceptable toxicity, he/she will be removed 
from study. 
 
If at any time the patient is found to be ineligible for the protocol as designated in the 
section on Criteria for Patient/Patient Eligibility (i.e., a change in diagnosis), the 
patient will be removed from study. 
 
If the patient fails to comply with the defined treatment plan and follow-up 
evaluations, the patient will be removed from the study. 
 
If the patient withdraws consent for continued participation, he/she will be removed 
from study. 
 
The reasons a patient may discontinue or be withdrawn from the study include, but 
are not limited to, adverse event, clinically significant disease recurrence, patient 
request, investigator decision, protocol violation, patient noncompliance, and study 
termination by the Sponsor or institutional review board (IRB)/independent ethics 
committee (IEC). When a patient discontinues or is withdrawn, the investigator will 
notify the Sponsor and should perform the procedures indicated in the End of Study 
column in the Schedule of Events within 28 days after discontinuation of study drug 
and before initiation of any new anti-cancer therapy. Follow-up information will be 
obtained for patients who discontinue their participation in or are withdrawn from the 
study. 
 
Patients withdrawn from the study for reasons other than toxicity or clinically 
significant disease recurrence (e.g., protocol violation or noncompliance) will be 
replaced. Study drug administration may be discontinued for an adverse event or at 
the discretion of the investigator. 
 
6.6.2 
Data Collection and Follow-up for Withdrawn Patients 
 
If a patient withdraws consent to participate in the study, every attempt will be made 
to follow all patients for survival. 
 
7. 
TISSUE CORRELATION 
Sample processing for CD8+ T-cell quantification 
We believe that the combinations being tested, including atezolizumab combined with 
PEGPH20, compared to atezolizumab alone, will result in an increase in CD8+ T-cell 
infiltration within the tumor microenvironment. 
A detailed protocol of tissue processing is provided in the laboratory manual. Briefly, 
required endoscopic ultrasound-guided pre-treatment biopsy will be performed to obtain 
at least four additional tumor cores if deemed safe. Required on-treatment repeat biopsy 
to obtain at least four research tumor cores will be performed under direct visualization 
of the pancreas tumor by the operating surgeon at time of surgical resection within the 
operating room immediately preceding excision of the tumor if deemed safe. 
Alternatively, if deemed unsafe or concern for tumor seeding the resection bed or 


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contamination of tumor tissue with gastric contents, resected tumor will undergo core 
biopsies immediately post resection within the operating room. Tissue samples are to be 
sent to the address below after the laboratory has been contacted and approval given to 
ship the specimens to ensure receipt and processing on delivery. Specimens should be 
shipped either on a Monday or Tuesday of a non-holiday week to allow for shipment 
delays which would ensure timely delivery of bio-specimens. 
6DPSOHSURFHVVLQJRI51$6HTH[SUHVVLRQ
A detailed protocol of tissue processing is provided in the laboratory manual. Briefly, 
fresh frozen tissue will be obtained from endoscopic ultrasound (EUS)-guided biopsy 
and surgically resected tissue and immediately sectioned and microscopically evaluated. 
Suitable samples will be transferred into optimum cutting temperature (OCT) medium 
(Tissue Tek) and snap frozen in a 2-methylbutane dry ice slurry. The tissue blocks will 
be stored at -80oC until further processing. Frozen blocks will be sent to Dr. Manji s 
laboratory for further processing as per established protocol. Tissue samples are to be 
sent to the address below after the laboratory has been contacted and approval given to 
ship the specimens to ensure receipt and processing on delivery. Specimens should be 
shipped either on a Monday or Tuesday of a non-holiday week to allow for shipment 
delays which would ensure timely delivery of biospecimens. 
$WWHQWLRQWR±
Gulam Abbas Manji, MD/PhD 
Herbert Irving Comprehensive Cancer Center Columbia University 
1130 Saint Nicholas Avenue, ICRC 207 New York, NY 10032 
Phone:  212-851-4507 
Alternate:  518-488-4704 
 
 
 
 
 
 
 


Columbia University Medical Center 
Herbert Irving Comprehensive Cancer Center 
Version Date: 05/13/2019 
 
39 
 
7.1 
TRANSLATIONAL SCIENCE 
7.1.1 
PDA Subtypes as Defined by Immune Cell Infiltrate and Gene 
Expression 
 
CD8+ T-Cell Infiltration and PDA Survival 
CD8+ TILs, which are known anti-tumor effector cells, are rarely found in the PDA 
tumor microenvironment (Vonderheide and Bayne 2013). This may in part be 
explained by the unique desmoplastic stroma, found adjacent to PDA tumor cells, 
which may act as a physical barrier to T-cell infiltration although this hypothesis has 
been challenged by a recently reported study (Ene-Obong et al. 2013; Carstens et al. 
2017). In addition, the PDA stroma is typically infiltrated with significant numbers of 
immunosuppressive leukocytes including tumor-associated macrophages, myeloid- 
derived suppressor cells (MDSC), and regulatory T cells (Hiraoka et al. 2006; Clark et 
al. 2007). Nevertheless, recent evidence has surfaced supporting a correlation 
between increased CD8+ lymphocyte infiltration and improved prognosis, suggesting 
CD8+ infiltration may serve as a good surrogate for response to therapy (Cheng et 
al. 2013; Deng et al. 2016). Human pancreas tumor probed for distinct markers using 
quantitative multiplex 
immunofluorescence (qmIF) 
which identifies specific 
immune subtypes is depicted 
in  
 
 
. Using qmIF, Carstens et al. 
demonstrated that high 
infiltration of CD8+ and CD4+ 
T-cells correlated with 
improved survival, whereas 
infiltration of regulatory T cells 
or other T cell subtypes was 
not. In addition, increased 
infiltration of intra-tumoral 
CD8+ T cells within a 20M radius of tumor cells also correlated with prolonged patient 
survival (Deng et al. 2016).  
 


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We believe that the combinations being tested, including atezolizumab combined with 
PEGPH20, compared to atezolizumab alone, will increase CD8+ T cell infiltration within 
the tumor microenvironment. 
A detailed protocol of tissue processing is provided in the laboratory manual. Tissue 
samples are to be sent to the address below after the laboratory has been contacted and 
approval given to ship the specimens to ensure receipt and processing on delivery. 
Specimens should be shipped either on a Monday or Tuesday of a non-holiday week to 
allow for shipment delays which would ensure timely delivery of biospecimens. 
$WWHQWLRQWR±
Gulam Abbas Manji, MD/PhD 
Herbert Irving Comprehensive Cancer Center Columbia University 
1130 Saint Nicholas Avenue, ICRC 207 New York, NY 10032 
Phone:  212-851-4507 
Alternate:  518-488-4704 

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We hypothesize that PEGPH20 will change the regulatory context of PDA from an 
immunotherapy-resistant to an immunotherapy-sensitive phenotype. Fresh frozen 
tissue will be sectioned for laser capture microdissection of the neoplastic epithelial 
and stromal components for RNA extraction. 
PDA tumors are characterized by two main components: the epithelium, formed from 
aggregates of tumor cells, and the surrounding stroma. Moffitt et al. performed virtual 
microdissection on gene expression microarray data obtained from 145 PDA patients, 
and identified two distinct epithelial-specific subtypes. One subtype contained genes 
enriched for extracellular matrix (ECM) deposition and remodeling, which they termed 
basal-like , while the other was enriched in immune and interleukin pathways, which 
they termed classical . Distinct gene signatures represented by 25 distinct genes were 
able to distinguish these two phenotypes. The classical molecular subtype represented a 
patient population with an improved median OS compared to that of the basal-like 
subtype (Moffitt et al. 2015). 


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The Olive lab has performed LCM on over 200 human pancreatic tumors and RNA-seq 
to a depth of 30 million 100 base pair single-end reads. Their analyses showed clean 
separation of the two compartments and hierarchical clustering, using Neutral Matrix 
Factorization of the top 1000 variable genes of the stromal RNA-seq data, found two 
distinct clusters. One cluster was enriched for inflammatory genes while the other was 
enriched in both immune effector and immunosuppressive signatures; these groups 
were classified classical  and basal-like  subtypes, respectively [Kenneth Olive, 
submitted]. Furthermore, supervised clustering analysis of the RNA-seq data, using the 
same epithelial classifier signatures described by Moffitt et al., confirmed the prognostic 
value of PDA molecular subtypes in the CUMC cohort. As shown in (UURU5HIHUHQFH
VRXUFHQRWIRXQG, patients with the classical epithelial phenotype have significantly 
better prognoses as compared to basal-like phenotype [Kenneth Olive, submitted]. 
We hypothesize that the addition of PEGPH20 to atezolizumab, including other 
agents to be tested, compared to atezolizumab alone will result in gene regulation to 
enrich for the immune and interleukin pathways, which reflect classical/immune 
subtype compared to the basal-like/ECM subtype. In order to test this hypothesis, the 
epithelium compartment will be isolated using LCM from each resected tumor specimen 
on which RNA-seq analysis will be performed. Using epithelial classifiers, as described 
above, samples will be compared from distinct treatment groups to determine if certain 
treatments are able to alter the PDA epithelial gene expression from a basal/ECM-like  
to a classical/immune  subtype which may confer a prognostic advantage. If a 
treatment(s) leads to enrichment for classical/immune subtype and improved 
outcomes, the regulated pathways that associate with improved disease free survival 
will need to be validated in a larger sample and those pathways further exploited to 
convert the tumor into one that is more susceptible to immunotherapy. These studies 
will complement the multiplex immunofluorescence (IF) studies described above and 
will hopefully identify key regulatory pathways affected by distinct therapies. 


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
6$03/(352&(66,1*2)51$6(4(;35(66,21'$7$ 
A detailed protocol of tissue processing is provided in the laboratory manual. Briefly, 
fresh frozen tissue will be obtained from EUS-guided biopsy and surgically resected 
tissue and immediately sectioned and microscopically evaluated. Suitable samples will 
be transferred into OCT medium (Tissue Tek) and snap frozen in a 2-methylbutane dry 
ice slurry. The tissue blocks will be stored at -80oC until further processing and will be 
sent to the Dr. Manji s laboratory for further processing as per established protocol. 
Frozen blocks are to be sent to Dr. Manji s laboratory using the address listed below 
after the laboratory has been contacted and approval given to ship the specimens to 
ensure receipt and processing on delivery. Specimens should be shipped either on a 
Monday or Tuesday of a non-holiday week to allow for shipment delays which would 
ensure timely delivery of bio-specimens. 
$WWHQWLRQWR±
Gulam Abbas Manji, MD/PhD 
Herbert Irving Comprehensive Cancer Center Columbia University 
1130 Saint Nicholas Avenue, ICRC 207 New York, NY 10032 
Phone:  212-851-4507 
Alternate:  518-488-4704 
 
Figure6.KaplanͲMeiersurvivalbymolecularsubtype.VECTRAimaging
ofhumanPDA.AnalysisofRNAͲseqdatafrompatientswithresected
PDAusingepithelialclassifiersshowsdifferentialprognosisamongthe


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Confirm eligibility as defined in the section Patient Selection and Withdrawal (Section 6). 
Obtain informed consent, by following procedures along with applicable institutional 
policies and federal regulations. 
Only Investigators/Research personnel properly trained and delegated to consent 
patients for this protocol will participate in the consenting process. Furthermore, properly 
delegated/trained Physician Investigators (e.g., MD, MD/PhD) are required to sign/verify 
a protocol specific Eligibility Checklist for each patient enrolled on the study, in addition 
to providing the relevant source documentation to confirm patient eligibility. 
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Registration hours are available Monday through Friday from 9:00am  5:00pm EST 
(excluding holidays and weekends). Same day patient registrations (and after hour 
registrations) will be accommodated on a case by case basis provided that the study 
team has expressed all time sensitive registration concerns/cases in a timely manner to 
the Central Registration Office. 
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Within 48 hours of obtaining consent (excluding holidays and weekends), a 
completed/signed IRB approved informed consent Health Insurance Portability and 
Accountability Act (HIPAA) form, and demographics forms must be submitted to the 
Clinical Protocol & Data Management  (CPDM) Central Registration Office via an email 
to CPDMRegistration@cumc.columbia.edu or fax to 212.304.6330, with the subject line 
$$$6Pending Patient Registration Request (PHI) . Upon receipt, applicable 
patient information and a pending eligibility  status will be entered into Herbert Irving 
Comprehensive Cancer Center s (HICCC s) institutional database. This status will 
remain until further source documentation is made available to confirm overall patient 
eligibility. Required materials for all pending registration submissions are as follows: 
x 
Completed/signed IRB approved/stamped Informed Consent Forms (ICF), including 
additional study ICFs for tissue. 
x 
The completed/signed IRB approved HIPAA Authorization form 
x 
Completed/signed CPDM ICF checklist 
x 
Completed/signed HICCC personal census form 
x 
Completed/signed CPDM Demographics Note to File 


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In order to confirm eligibility status, Investigators/designees (e.g., study specific Clinical 
Research Coordinator/Research Nurse, etc.) must submit the following documentation 
to the Central Registration Office via email or fax: 
x 
The completed/signed study specific Eligibility Checklist (signed by a Physician 
level Investigator) 
x 
Copies of source documentation necessary for each item to be verified on the 
CPDM specific Eligibility Checklist, including but not limited to: 
±
Copy of required laboratory test and procedure reports (e.g., complete blood 
count, complete metabolic panel, cholesterol and triglycerides pregnancy test 
when applicable, MRI reports, CT/bone scans, etc.) 
±
Copy of pathology and surgical reports 
±
List of all prior malignancy-directed treatments 
±
Copy of clinic note(s) or other appropriate medical records capturing the 
consent process information, along with providing source documentation of any 
other items needed for screening/eligibility that are not captured in other source 
document forms (e.g., positive investigator statements of unique eligibility items 
not captured via other direct source documentation, concomitant medication 
lists, etc.). 
±
Protocol deviation/waiver approvals (if applicable) 
 
3OHDVHQRWH: subject line of email or fax should include the following: AAAS1908 
Complete Patient Registration Request (PHI) . 
Upon receipt of the above mentioned documentation, participant eligibility information 
will be verified by a qualified Central Registration Registrar. If any questions arise during 
the review process, queries in the form of emails will be addressed to the applicable 
study team personnel for clarification prior to enrollment. All applicable finalized 
registration/eligibility information will then be entered into HICCC s institutional Clinical 
Trial Management System (CTMS) database by the Central Registration Registrar. Upon 
completion, an official patient registration notification email will be sent to the PI/research 
team which will include eligibility/enrollment status, as well as patient ID information. 
Protocol therapy may not be initiated prior to receipt of this notification from the Central 
Registration Office. 
All screen fail/ineligible patients, as well as patient s who withdraw consent prior to 
enrollment must be submitted to the Central Registration office in a manner analogous to 
the procedures noted above. Applicable source documentation will be required within the 
corresponding submissions. 


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75($70(173/$1
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Treatment will be administered on an outpatient basis. Reported adverse events and 
potential risks for treatment are described in Section 11. Appropriate dose modifications 
are described in Section 10 and Appendix 2 and Appendix 3. No investigational or 
commercial agents or therapies other than those described below may be administered 
with the intent to treat the patient’s malignancy. 
Patients will be requested to maintain a medication diary if their treatment regimen 
contains an oral medication. The medication diary will be returned to clinic staff at the 
end of each treatment cycle. 
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Atezolizumab will be administered at a fixed dose of 840 mg IV every 2 weeks (Q2W) 
(i.e. on Days 4 and 18 prior to surgery and on Days 1 and 15 of each 28 day cycle after 
surgery). The average concentration following the 840 mg Q2W dosage is expected to 
be equivalent to that of 1200 mg every 3 weeks (Q3W), the approved dosage for 
atezolizumab (Tecentriq£ U.S. Package Insert). Anti-tumor activity has been observed 
across doses ranging from 1 mg/kg to 20 mg/kg Q3W. In Study PCD4989g, the 
maximum tolerated dose of atezolizumab was not reached and no dose-limiting toxicities 
were observed at any dose. The fixed dose of 1200 mg Q3W (equivalent to an average 
body weight-based dose of 15 mg/kg Q3W) was selected on the basis of both nonclinical 
studies and available clinical pharmacokinetic, efficacy, and safety data (refer to the 
Atezolizumab Investigator’s Brochure for details) (Deng et al. 2016). 
The atezolizumab Drug Product will be supplied by the Sponsor as a sterile liquid in a 
single-use, 20-mL glass vial. The vial contains approximately 20 mL (1200 mg) of 
atezolizumab solution. 
For information on the formulation and handling of atezolizumab, drug preparation, 
storage, and administration see the pharmacy manual and the Atezolizumab 
Investigator’s Brochure. Guidelines for medical management of infusion-related 
reactions (IRRs) for atezolizumab are provided in Appendix 2. 
Administration of atezolizumab will be performed in a monitored setting where there is 
immediate access to trained personnel and adequate equipment and medicine to 
manage potentially serious reactions. Standard anaphylaxis precautions should be taken 
when administering atezolizumab. Treatment for anaphylaxis will be administered per 
the instructions outlined below  


Columbia University Medical Center 
Herbert Irving Comprehensive Cancer Center 
Version Date: 05/13/2019 
 
46 
 
Anaphylaxis Precautions 
EQUIPMENT NEEDED 
 
Tourniquet 
 
Oxygen 
 
Epinephrine for subcutaneous, intravenous, and/or endotracheal use in accordance 
 
with standard practice 
 
Antihistamines 
 
Corticosteroids 
 
Intravenous infusion solutions, tubing, catheters, and tape 
 
PROCEDURES 
In the event of a suspected anaphylactic reaction during study treatment infusion, the 
following procedures should be performed: 
1. 
Stop the study treatment infusion. 
2. 
Apply a tourniquet proximal to the injection site to slow systemic absorption of study 
treatment. Do not obstruct arterial flow in the limb. 
3. 
Maintain an adequate airway. 
4. 
Administer antihistamines, epinephrine, or other medications as required by patient 
status and directed by the physician in charge. 
5. 
Continue to observe the patient and document observations. 
 
No dose modification for atezolizumab is allowed. Guidelines for treatment interruption 
or discontinuation because of toxicities are provided below and within Appendix 2. 
Atezolizumab Treatment Interruption for Toxicities 
Atezolizumab treatment may be temporarily suspended in patients experiencing toxicity 
considered to be related to study treatment. If corticosteroids are initiated for treatment 
of the toxicity, they must be tapered over ≥1 month to ≤10 mg/day oral prednisone or 
equivalent before atezolizumab can be resumed. Appropriate steroids supplementation 
should be provided if required prior to surgery in consultation with an endocrinologist and 
a pulmonologist in cases of pneumonitis. If atezolizumab is withheld for >12 weeks, the 
patient will be discontinued from atezolizumab. However, atezolizumab may be withheld 
for > 12  weeks to allow for patients to taper off corticosteroids prior to resuming 
treatment. Atezolizumab can be resumed after being withheld for > 12 weeks if the PI 
agrees that the patient is likely to derive clinical benefit. Atezolizumab treatment may be 
suspended for reasons other than toxicity with PI approval. 


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PEGPH20 drug product supplied at a concentration of 0.30 mg/mL and will be supplied 
in a single-use vial that contains 1.0 mL. liquid formulation and should be stored at 2 C 
to 8 C before use. Stability testing of this PEGPH20 drug product was initiated and 
following general International Conference on Harmonisation (ICH) guidelines at 5 C – 
3 C, and concurrent stability evaluation is ongoing. For additional details regarding 
formulation and handling of PEGPH20, please refer to pharmacy manual and PEGPH20 
Investigator s Brochure. 
PEGPH20 will be administered by IV infusion at a dose of 3Pg/kg on Days 1 and 4 every 
week for 3 weeks prior to surgery and on Days 1, 8, and 15 every 28 days for 2 cycles 
after surgery. PEGPH20 will be administered 2-3 hours before the atezolizumab 
infusion. 
PEGPH20 should be infused over 10í12 minutes, equivalent to approximately 
1 mL/minute. 
Piroxicam (20mg) will be administered 1-2 hours prior to PEGPH20 administration to 
minimize severe musculoskeletal events (MSE). 
Prophylactic use of a proton-pump inhibitor (e.g., 20 mg omeprazole daily or over-the 
counter equivalent) is mandated for all patients while receiving PEGPH20. 
Enoxaparin will be administered daily to all patients to minimize the risk of 
thromboembolic events (TE), a known complication of patients with pancreas 
adenocarcinoma and a known adverse event in PDA patients who receive PEGPH20. 
Enoxaparin will be administered by subcutaneous injection at a dose of 1 mg/kg/day 
rounding of dose may be done per institution policy and when using prefilled syringes. 
The dosage of enoxaparin will be based on the subject s screening weight and should be 
modified if the subject s weight changes by 10%. On days of dosing of PEGPH20, 
enoxaparin will be administered prior to infusion of PEGPH20. All efforts should be made 
to administer the calculated 1 mg/kg dose (– 10%). If prefilled syringes are used, the 
treating physician may use medical judgment regarding the appropriate prefilled syringe. 
However, if the rounded dose varies from the expected weight-based dose by 20% or 
more, the PI should be consulted. Refer to Table 3 for examples of rounding based on 
the expected enoxaparin dose. Enoxaparin should be held if the platelet count is 
<50,000 per mm3 and should be resumed once the platelet count is greater than 50,000 
per mm3. The enoxaparin dose should be reduced to 0.5mg/kg for Grade 2 
thrombocytopenia (platelet count 50,000  75,000 platelet per mm3) until an increase in 
platelets > 75,000 platelet per mm3, at which time the dose should be increased to 


Columbia University Medical Center 
Herbert Irving Comprehensive Cancer Center 
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48 
 
1mg/kg. Should a subject experience a TE event while on study, the dose of enoxaparin 
will be increased to a therapeutic dose based on standard clinical practice.  
In situations when enoxaparin is held, administration of PEGPG20 should also be held 
during that period. Subjects who permanently discontinue enoxaparin therapy for any 
reason will also permanently discontinue PEGPH20. Likewise, enoxaparin treatment 
should be discontinued unless clinically indicated when the subject discontinues 
PEGPH20.  
Table 3 
Rounding Enoxaparin Doses 
 
PEGPH20 treatment interruption for Toxicities 
PEGPH20 treatment may be interrupted for reasons other than toxicity with PI approval. 
The acceptable length of treatment interruption will be determined by the PI. 
9.1.3 
Atezolizumab in Combination with PEGPH20 Administration 
Patients in the atezolizumab + PEGPH20 arm will receive treatment as outlined in 
Table 4 until unacceptable toxicity or loss of clinical benefit as determined by the 
investigator after an integrated assessment of radiographic and biochemical data, local 
biopsy results (if available), and clinical status (e.g., symptomatic deterioration such as 
pain secondary to disease). Treatment must be initiated no later than 5 days after 
randomization. 


Columbia University Medical Center 
Herbert Irving Comprehensive Cancer Center 
Version Date: 05/13/2019 
 
49 
 
Table 4 
Treatment Cycle and Dosages 
Cycle Length 
Dose, Route, and Regimen (in order of administration) 
28 days 
Pre-surgery 
PEGPH20 3 g/kg IV on Days 1, 4 1 every week for 3 weeks 
Atezolizumab 840 mg IV on days 4 1 and 18 
 
Post-surgery 
PEGPH20 3 g/kg IV on Days 1 1, 8, and 15 every 28 days 
Atezolizumab 840 mg IV on days 1 1 and 15 
1 On days where atezolizumab and PEGPH20 are administered, atezolizumab will be 
administered 2-3 hours after completion of the PEGPH20 infusion. 
 
Atezolizumab in Combination with PEGPH20 Treatment Interruption for 
Toxicities 
If atezolizumab is discontinued, PEGPH20 should also be discontinued. If PEGPH20 is 
discontinued, atezolizumab can be continued if the patient is likely to derive clinical 
benefit, as determined by the investigator in consultation with the PI. Refer to 
Appendix 3 for guidance. 
The dose of PEGPH20 can be reduced to 1.6 g/kg for management of drug-related 
toxicities. If further dose reduction is indicated, the patient must discontinue PEGPH20 
but may continue treatment with atezolizumab if approved by the PI. After dose 
reduction, the dose of PEGPH20 may not be escalated. 
Atezolizumab treatment may be temporarily suspended in patients experiencing toxicity 
considered to be related to study treatment. If corticosteroids are initiated for treatment 
of the toxicity, they must be tapered over ≥ 1 month to ≤10 mg/day oral prednisone or 
equivalent before atezolizumab can be resumed. If atezolizumab is withheld for > 12 
weeks, the patient will be discontinued from atezolizumab. However, atezolizumab may 
be withheld for >12 weeks to allow for patients to taper off corticosteroids prior to 
resuming treatment. Atezolizumab can be resumed after being withheld for > 12 weeks if 
the if the PI agrees that the patient is likely to derive clinical benefit. PEGPH20 treatment 
may be temporarily suspended in patients experiencing toxicity considered to be related 
to study treatment. If PEGPH20 is withheld for >21 days, the patient will be discontinued 
from PEGPH20. If the investigator believes the patient is likely to derive clinical benefit 
and the PI is in agreement, PEGPH20 treatment can be resumed after being withheld for 
> 21 days. If atezolizumab is discontinued, PEGPH20 should also be discontinued. If 


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PEGPH20 is discontinued, atezolizumab can be continued if the patient is likely to derive 
clinical benefit, as determined by the PI. 
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There will be no dose modifications for atezolizumab for the study. Guidelines for 
management of patients who experience specific adverse events are provided in 
Appendix 3. 
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Adverse events of special interest are required to be reported to the PI immediately (i.e. 
no more than 24 hours after learning of the event). 
Adverse events of special interest for the atezolizumab + PEGPH20 arm are as follows: 
x 
Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either elevated bilirubin or clinical jaundice. The finding of an 
elevated ALT or AST (> 3  baseline value) in combination with either an elevated 
total bilirubin (> 2  ULN) or clinical jaundice in the absence of cholestasis or other 
causes of hyperbilirubinemia is considered to be an indicator of severe liver injury 
(as defined by Hy’s Law). Therefore, investigators must report as an adverse event 
the occurrence of either of the following: 
±
Treatment-emergent ALT or AST > 3  baseline value in combination with total 
bilirubin > 2  ULN (of which 35% is direct bilirubin)  
±
Treatment-emergent ALT or AST > 3  baseline value in combination with 
clinical jaundice. The most appropriate diagnosis or (if a diagnosis cannot be 
established) the abnormal laboratory values should be recorded on the Adverse 
Event eCRF and reported to the Sponsor immediately (i.e., no more than 24 
hours after learning of the event), either as a serious adverse event or an 
adverse event of special interest (AESI)  
x 
Suspected transmission of an infectious agent by the study treatment, as defined 
below: Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent. A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an infection in 
a patient exposed to a medicinal product. This term applies only when a 
contamination of study treatment is suspected. 
x 
Pneumonitis 
x 
Colitis 


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x 
Endocrinopathies: diabetes mellitus, pancreatitis, adrenal insufficiency,
hyperthyroidism, and hypophysitis
x 
Hepatitis, including AST or ALT > 10 upper limit of normal 
x 
Systemic lupus erythematosus  
x 
Neurological disorders: Guillain-Barr  syndrome, myasthenic syndrome or 
myasthenia gravis, and meningoencephalitis  
x 
Events suggestive of hypersensitivity, IRRs, cytokine-release syndrome, influenza-
like illness, systemic inflammatory response syndrome, and systemic immune 
activation.  
x 
Nephritis 
x 
Ocular toxicities (e.g., uveitis, retinitis)  
x 
Myositis  
x 
Myopathies, including rhabdomyolysis  
x 
Grade 2 cardiac disorders (e.g., atrial fibrillation, myocarditis, pericarditis)  
x 
Vasculitis  
x 
Autoimmune hemolytic anemia 
x 
Severe cutaneous reactions (e.g., Stevens-Johnson syndrome, dermatitis bullous, 
toxic epidermal necrolysis) 
x 
Thromboembolic events 
x 
Grade 3 musculoskeletal events persisting for >14 days
 
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Surgical resection of the pancreas adenocarcinoma with negative margins represents 
the primary modality through which cure is achieved in patients with pancreatic 
cancer. As surgical techniques and expertise have evolved, increased long-term 
survival rates have been reported, however, it was not until 2007, when the results 
of the phase 3 CONKO-001 trial were published, that the role of adjuvant 
chemotherapy became firmly established (Oettle et al. 2007). In this randomized 
controlled phase 3 trial, patients were stratified 1:1 to chemotherapy, in which 
patients were to receive 6 cycles of gemcitabine given on Days 1, 8, and 15 every 4 
weeks (n = 179), or observation (n = 175) following surgery. The trial demonstrated a 
median disease-free survival of 13.4 months in those receiving gemcitabine compared 
with 6.9 months in those who received no adjuvant therapy (95% confidence interval 
[CI], 6.1-7.8; P<0.001, log-rank). Long term follow-up of patients in this study 
demonstrated over a 10% difference in overall survival at 5 years (20.7% with 
gemcitabine versus 10.4% with observation) (Oettle et al. 2013). In 2010, gemcitabine 
was compared head-to-head with fluorouracil plus folinic acid in the randomized 


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52 
 
controlled phase 3 European Study Group for Pancreatic Cancer (ESPAC)-3 trial 
(Neoptolemos et al. 2010). Patients with resectable pancreatic cancer were treated 
with either gemcitabine (n = 537) or fluorouracil plus folinic acid (n = 551) after surgery. 
The median overall survival was 23.6 months in those treated with gemcitabine and 23.0 
months in those treated with fluorouracil plus folinic acid, however these results did not 
meet statistical significance (P = .39; HR, 0.94 [95% CI, 0.81-1.08]). Toxicity profiles 
significantly favored the use of gemcitabine compared to fluorouracil plus folinic acid. 
Regardless of the regimen used, these trials show a clear benefit to receiving adjuvant 
chemotherapy, and this practice has since become standard of care. 
This approach, surgery followed by adjuvant chemotherapy, is also supported by 
several large systematic reviews. In one large meta-analysis, 951 pancreatic cancer 
patients were pooled from multiple randomized control trials in which patients were 
either treated with adjuvant chemotherapy or observed, and the addition of adjuvant 
chemotherapy prolonged the median survival time by 3 months and increased 5-year 
survival rates by 3.1% (Boeck et al. 2007). Another large meta-analysis of 875 patients 
showed reduction in the risk of death with chemotherapy by approximately 25% 
versus surgery alone. This study also demonstrated a doubling of the 5-year survival 
rates with adjuvant chemotherapy compared to observation (Stocken et al. 2005). 
The phase 3 ESPAC-4 trial compared gemcitabine and capecitabine in the 
adjuvant setting compared to gemcitabine alone. The investigators reported an 
additional 2.5 month survival benefit with the addition of capecitabine to 
gemcitabine (28.0 months with gemcitabine plus capecitabine vs 25.5 months with 
gemcitabine alone, HR, 0.82 [95% CI, 0.68 0.98], p=0.032) (Neoptolemos et al. 
2017). This combination is now being adopted given the overall survival benefit. 
However, within the United States, the doses used within the study are intolerable and 
require frequent dose and/or schedule modifications. It is likely that the frequent dose 
adjustments impact the efficacy of the combination to a degree which is currently 
unknown. 
PRODIGE 24, a large randomized phase 3 study compared mFOLFIRINOX to 
gemcitabine monotherapy in the adjuvant setting and demonstrated a median overall 
survival benefit of 54.4 months compared to 35.0 months, respectively. The median 
disease free survival was 21.6 months in the mFOLFIRINOX arm compared to 12.8 
months in the gemcitabine monotherapy arm (Andre et al. 2018; Conroy et al. 2018). 
The reported 18-month overall survival (OS) is 67% with adjuvant gemcitabine in 
combination with capecitabine which is similar to the 63% reported when gemcitabine 
and oxaliplatin were tested in the neoadjuvant setting (O’Reilly et al. 2016). Although 
mFOLFIRINOX yielded impressive results, patients enrolled onto the study had a better 
performance status to withstand mFOLFIRINOX. Although SWOG S1313 indicated a 


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detrimental effect of adding pegylated recombinant human hyalouronidase (PEGPH20) 
to FOLFIRINOX compared to FOLFIRINOX alone, the current study is testing activity of 
PEGPH20 in combination with atezolizumab concurrently with subsequent treatment 
with mFOLFIRINOX which is distinct from concurrent therapy with PEGPH20 and 
mFOLFIRINOX as tested in SWOG S1313. Hence, we do not anticipate added risk to 
subjects who will be randomized to the atezolizumab and PEGPH20 cohort. 
7DEOH
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3DQFUHDWLF &DQFHU
 
N = number; DFS   disease-free survival; OS   overall survival. 
 
)2/),5,12;
FOLFIRINOX is an alternative regimen for healthy individuals in the first-line setting. In a 
phase 2-3 randomized trial in patients with ECOG 0 or 1, FOLFIRINOX (Fluorouracil 400 
mg/m2 as a bolus followed by 2400 mg/m2 given as a 46-hour continuous infusion, 
irinotecan 180 mg/m2, and oxaliplatin as 85 mg/m2, every 2 weeks) resulted in an 11.1 
month overall survival compared to 6.8 months with gemcitabine  a 4.3 month survival 
benefit over gemcitabine alone (HR 0.57; 95% CI, 0.37 to 0.59; P<0.001) (Conroy T, et 
al. 2011). Median PFS and objective response rate (RR) both favored FOLFIRINOX 
compared to gemcitabine alone; 6.4 months and 31.6% compared to 3.3 months and 
9.4% in the group, respectively (P<0.001). One-year overall survival was 48.4% in the 
FOLFIRINOX arm versus 20.6% in the gemcitabine arm (Conroy T, et al. 2011). 
Although FOLFIRINOX is clearly superior to gemcitabine monotherapy, treatment is 
reserved for patients with excellent performance status due to its adverse event profile, 
which includes fatigue, bone marrow suppression with 45.7% grade 3 or 4 neutropenia, 
12.7% diarrhea, and 9.0% sensory neuropathy. A follow-up of the PRODIGE 4/ACCORD 


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11 study indicated that efficacy was only mildly impacted in the 81% of the 242 patients 
who required dose reduction (mOS 10.9m versus 11.1m) (Metges JP, et al. 2014).  
Due to poor tolerability of FOLFIRINOX in a significant proportion of patients, regimens 
with reduced doses of irinotecan and bolus fluorouracil, or omission of bolus fluorouracil, 
and addition of pegfilgastrim on day 3 or 4, commonly referred to as mFOLFIRINOX  
are widely used. mFOLFIRINOX resulted in a response rate of 30%, mPFS of 8.5 
months, and mOS of 9.0 months in the 36 patients tested in the metastatic setting 
(Mahaseth H, et al. 2013). A prospective single arm phase 2 study tested the regimen 
with 25% dose reduction of bolus fluorouracil and irinotecan and found the RR, mPFS, 
and mOS to be 35.1%, 6.1 months, and 10.2 months respectively, which was 
comparable to that reported in the original PRODIGE 4/ACCORD 11 trial (Stein SM, et 
al. 2016). With the caveat of comparing distinct trials and limited number of patients, 
mFOLFIRINOX although better tolerated, may not be equivalent to full dose 
FOLFIRINOX when compared for efficacy, and it appears that the dose reduced forms 
have a shorter mOS. For patients who do not have a robust performance status or are 
intolerant to gem/QDE-p, there may not be a choice but to use the dose-reduced regimen. 
Prophylactic administration of pegylated filgastrim in the absence of severe leukocytosis 
and pretreatment with palonosetron, aprepitant and dexamethasone likely contribute to a 
decrease in adverse events (Stein SM, et al. 2016). Pretreatment with atropine also 
appears to help with the cholinergic symptoms associated with Irinotecan. Other 
FOLFIRINOX modifications are described elsewhere (Marsh R, et al. 2015). 



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All patients will receive modified FOLFIRINOX (mFOLFIRINOX) on a 14 day +/- 3day 
cycle for 12 cycles. 
*HQHUDO,QVWUXFWLRQV±
A. Subjects who experienced a reaction to oxaliplatin need to be re-challenged via 
hospitalization using desensitization protocol per local institution. 
B. Subjects should be prescribed anti-emetics and antidiarrheal (loperamide) at 
home to be used on an as needed basis. 
C. Subjects should be supplemented with pancreas enzymes if exhibiting signs of 
pancreas insufficiency. 
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55 
 
D. Ondansetron 16mg oral once 30 minutes prior the initiation of chemotherapy 
E. Dexamethasone 12mg oral once 30 minutes prior the initiation of chemotherapy 
(may be decreased by 50% if uncontrolled blood sugars) 
F. Fosaprepitant 150mg IV once 30 minutes prior the initiation of chemotherapy 
G. Atropine 0.5mg IV once 30 minutes prior the initiation of irinotecan if no 
contraindication which include but are not limited to   
a. Uncontrolled tachycardia  
b. Closed-angle glaucoma 
c. Pyloric obstruction 
d. Severe urinary retention or untreated prostatic hypertrophy 
e. Viscid plugs in patients with chronic lung disease. 
P)2/),5,12;±
A. Oxaliplatin 85 mg per square meter on day 1, IV infusion over 2 hours, followed 
by 
B. Irinotecan 150 mg per square meter on day 1, IV infusion over 90 minutes to 
begin 30 min after leucovorin infusion is started (using a Y-tube); 
C. Leucovorin 400 mg per square meter IV infusion over 2 hours 
D. Fluorouracil 2400 mg per square meter IV continuous infusion over 46 hours 
(1200 mg/m /day) 
E. Pegfilgastrim injector kit (6mg subcutaneous) on day 3 
The investigational products will be prepared according to the institutional safety 
standards. 
'RVH0RGLILFDWLRQ
If treatment cannot be given on a planned visit date, it may be administered +/- 3 
days from the scheduled date. 
 
'D\'RVH0LVVHG
If a dose was meant to be given on Day 1 was held or missed, the next cycle will 
not be considered to start until the day of the first dose which is actually 
administered. 



Columbia University Medical Center 
Herbert Irving Comprehensive Cancer Center 
Version Date: 05/13/2019 
 
56 
 
Table 6  Dose Modification Table for Neutropenia/Thrombocytopenia 
 
* To be discussed case by case with subject and principal investigator. 
 
 
 


Columbia University Medical Center 
Herbert Irving Comprehensive Cancer Center 
Version Date: 05/13/2019 
 
57 
 
Table 7  Dose Modification Table for Neutropenia and Thrombocytopenia 
During Nadir 
 
* To be discussed case by case with subject and principal investigator. 
 
Table 8  Dose Modification Table for Diarrhea 
 
 
 


Columbia University Medical Center 
Herbert Irving Comprehensive Cancer Center 
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58 
 
Table 9  Diarrhea Management Guidance 
 
 
Table 10   Dose Modification Table for Peripheral Neuropathy 
 
 
Mucositis and Hand-Foot Syndrome – 
Reduce 5FU-LV dose by 25% for the remaining treatment duration.  
 
 


Columbia University Medical Center 
Herbert Irving Comprehensive Cancer Center 
Version Date: 05/13/2019 
 
59 
 
Cardiotoxicity – 
Permanently discontinue 5FU-LV treatment for the remaining treatment duration. 
Hyperbilirubinemia – 
Rule out tumor recurrence if total bilirubin is > 1.5 of upper limit of normal. Hold 
irinotecan and consider investigational studies to rule out biliary obstruction. Hold 
irinotecan if total bilirubin persistently elevated > 1.5 of upper limit of normal. 
 
9.1.5 
Cautionary Therapy 
Systemic corticosteroids and tumor necrosis factor  (TNF-) inhibitors may attenuate 
potential beneficial immunologic effects of treatment with atezolizumab. Therefore, in 
situations in which systemic corticosteroids or TNF- inhibitors would be routinely 
administered, alternatives, including antihistamines, should be considered. If the 
alternatives are not feasible, patient will not meet eligibility criteria. 
 
9 . 2  
GENERAL CONCOMITANT MEDICATION AND SUPPORTIVE 
CARE GUIDELINES  
Concomitant therapy consists of any medication (e.g., prescription drugs, 
over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional 
supplements) used by a patient in addition to protocol-mandated study treatment from 
10 days prior to initiation of study treatment to the treatment discontinuation visit. All 
such medications should be reported to the investigator and recorded on the 
Concomitant Medications eCRF. 
Permitted Therapy for Atezolizumab and PEGPH20 
 
Oral contraceptives  
 
Hormone-replacement therapy  
 
Inactivated influenza vaccinations  
 
Mineralocorticoids (e.g., fludrocortisone)  
 
Inhaled corticosteroids administered for chronic obstructive pulmonary disease or 
asthma  
 
Low-dose corticosteroids administered for orthostatic hypotension or adrenocortical 
insufficiency  
 
Hormonal therapy with gonadotropin−releasing hormone agonists or antagonists for 
prostate cancer  


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60 
 
x 
Ketorolac for severe pain Ketorolac may be given for severe pain as recommended 
in the prescribing information. Ketorolac should not be administered on the same 
day as piroxicam or other nonsteroidal anti-inflammatory drugs (NSAIDs) because 
of the cumulative risk of inducing serious NSAID-related side effects. 
x 
Prescription medications such as narcotics, muscle relaxants, NSAIDs and other 
analgesics (with the exception of corticosteroids), over-the-counter drugs, and 
physical therapy for treatment of MSEs, at the investigator’s discretion NSAIDs 
should not be administered on the same day as piroxicam.  
x 
Intravenous heparin for acute treatment of TE events. Only PEGPH20 must be 
withheld while the patient is receiving intravenous heparin.  
x 
Palliative radiotherapy (e.g., treatment of known bony metastases or symptomatic 
relief of pain) as outlined below:  
Palliative radiotherapy is permitted, provided it does not interfere with the 
assessment of tumor target lesions (e.g., the lesion to be irradiated must not be 
the only site of measurable disease). Treatment with atezolizumab and 
PEGPH20 may be continued during palliative radiotherapy.  
x 
Radiotherapy to the brain as outlined below:  
Patients whose extracranial tumor burden is stable or responding to study 
treatment and who are subsequently found to have three or fewer brain 
metastases may receive radiotherapy to the brain (either stereotactic 
radiosurgery or whole-brain radiation therapy) provided that all of the following 
criteria are met:  
±
The patient has no evidence of progression or hemorrhage after 
completion of central nervous system (CNS)-directed therapy.  
±
The patient has no ongoing requirement for corticosteroids as therapy for 
CNS disease. Patients who require corticosteroid therapy for more than 
7 days after completion of radiotherapy must be discontinued from study 
treatment.  
±
Anti-convulsant therapy, if required, is administered at a stable dose. 
 
Premedication with antihistamines, antipyretics, and/or analgesics may be administered 
for the second and subsequent atezolizumab infusions only, at the discretion of the 
investigator. 
Hematopoietic growth factors are not to be administered prophylactically prior to the first 
doses of adjuvant chemotherapy. However, at the discretion of the investigator, 
hematopoietic growth factors may be administered prophylactically per standard local 
practice before the second and subsequent doses of study treatment. 


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In general, investigators should manage a patient s care with supportive therapies as 
clinically indicated, per local standard practice. Patients who experience infusion-
associated symptoms may be treated symptomatically with acetaminophen, ibuprofen, 
diphenhydramine, and/or H2-receptor antagonists (e.g., famotidine, cimetidine), or 
equivalent medications per local standard practice. Serious infusion-associated events 
manifested by dyspnea, hypotension, wheezing, bronchospasm, tachycardia, reduced 
oxygen saturation, or respiratory distress should be managed with supportive therapies 
as clinically indicated (e.g., supplemental oxygen and E2- adrenergic agonists; see 
Appendix 2). 
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Use of the following concomitant therapies is prohibited as described below:  
x 
Concomitant therapy intended for the treatment of cancer (including, but not limited 
to, chemotherapy, immunotherapy, radiotherapy, and herbal therapy), whether 
health authorityíapproved or experimental, is prohibited, and during study treatment 
until disease progression is documented and the patient has discontinued study 
treatment, with the exception of palliative radiotherapy and radiotherapy to the brain.  
x 
Investigational therapy (other than protocol-mandated study treatment) is prohibited 
within 28 days prior to initiation of study treatment and during study treatment.  
x 
Live, attenuated vaccines (e.g., FluMist ) are prohibited within 4 weeks prior to 
initiation of study treatment, during treatment with atezolizumab, and for 5 months 
after the last dose of atezolizumab.  
x 
Systemic immunostimulatory agents (including, but not limited to, interferons and 
interleukin-2) are prohibited within 4 weeks or five half-lives of the drug, whichever is 
longer, prior to initiation of study treatment and during study treatment because 
these agents could potentially increase the risk for autoimmune conditions when 
given in combination with atezolizumab. 
x 
Systemic immunosuppressive medications (including, but not limited to, 
cyclophosphamide, azathioprine, methotrexate, and thalidomide) are prohibited 
during study treatment because these agents could potentially alter the efficacy and 
safety of atezolizumab.  
x 
Chronic use of intravenous heparin is prohibited during treatment with PEGPH20. 
However, intravenous heparin may be given for acute treatment of TE events.  
x 
Megestrol acetate is prohibited within 10 days prior to initiation of PEGPH20 and 
during treatment with PEGPH20. 
The above lists of cautionary medications are not necessarily comprehensive. The 
investigator should consult the prescribing information when determining whether a 
concomitant medication can be safety administered with study treatment. In addition, 
the investigator should contact the PI if questions arise regarding medications not listed 
above. 


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Please refer to the must updated PEGPH20 IB. Identified risks for PEGPH20 include 
MSEs such as myalgia and arthralgia, infusion-related reactions, and TE events see 
below). Refer to the PEGPH20 Investigator’s Brochure for a detailed description of all 
anticipated risks for PEGPH20. 
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The majority of treatment-related adverse events have been MSEs. The severity of 
the MSEs appeared to be influenced by the dose and dosing frequency of 
PEGPH20. In general, symptoms tended to be more severe with higher doses of 
PEGPH20 and a more frequent dosing schedule. At the highest doses tested in 
humans (50 g/kg), Grade 3 or 4 MSEs occurred approximately 4í10 hours after 
the first dose. Reported MSEs include, but are not limited to, muscle spasms, 
arthralgia, myalgia, muscular weakness, pain in extremity, back pain, bone pain, 
musculoskeletal pain, joint swelling, joint stiffness, limb discomfort, musculoskeletal 
stiffness, myositis, and neck pain. Treatment with dexamethasone has been used to 
attenuate the severity of MSEs, improving the tolerability of higher PEGPH20 dose 
and dosing frequency combinations. However, given that corticosteroid treatment 
(i.e., dexamethasone) may potentially interfere with the efficacy of atezolizumab, 
treatment with NSAIDs is being used instead of corticosteroids in this study. 
Piroxicam and ketorolac have been investigated in an animal model of MSEs and 
may be helpful in decreasing the severity of MSEs in patients (Halozyme internal 
unpublished report). In this study, piroxicam will therefore be administered as 
premedication to decrease the severity of MSEs. Ketorolac may be given for severe 
pain per the prescribing information. Ketorolac and other NSAIDs should not be 
administered on the same day as piroxicam. 
7KURPERHPEROLF(YHQWV7( 
TE events and, more frequently, venous TE events, are reported to occur with 
higher frequency in patients with pancreatic cancer. The PEGPH20 Investigator’s 
Brochure indicates that patients with a history of cerebrovascular accident, deep 
vein thrombosis, or pulmonary embolism, or a history or evidence of carotid artery 
disease are not eligible to participate in PEGPH20 clinical studies. Patients will be 
treated prophylactically with subcutaneous enoxaparin to reduce the risk of TE 
events. It is well documented that the use of megestrol acetate causes thrombosis; 
therefore, concomitant use of megestrol acetate is prohibited during treatment with 
PEGPH20. 


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127( Thromboembolic events are considered AEs of special interest. All TE 
events, regardless of type of event, severity, or seriousness must be reported to 
Halozyme within 5 calendar days of receipt by the sponsor-investigator.  
 
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The following adverse events are potential overlapping toxicities associated with 
combination use of atezolizumab and PEGPH20:  
x 
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Patients will receive two doses of atezolizumab prior to surgery (3 weeks and 1 week 
prior to surgery) and four doses post- surgery every 2 weeks after recovery from 
surgery (starting between 4 and 6 weeks post-surgery). Patients randomized to the 
atezolizumab + PEGPH20 arm will receive PEGPH20 for 3 weeks prior to surgery and 
for two cycles after recovery from surgery. 
In the absence of treatment delays due to adverse events, treatment may continue until 
one of the following criteria applies: 
x 
Disease recurrence 
x 
Therapy may be permitted beyond recurrence if patient is deriving clinical benefit 
after initial tumor growth or ambiguity regarding the existence of disease 
recurrence in consultation with the Principle Investigator (PI) and Sponsor. If 
subsequent imaging confirms tumor growth, recurrence will be back dated to the 
prior scan. If patient agrees to treatment beyond recurrence, the patient will be 
required to sign a Treatment Beyond Recurrence  informed consent form. Biopsy 
of the lesion demonstrating recurrence will be required to determine histologic 
disease recurrence, unless it is unsafe to do so. In case where a biopsy is not 
possible, data from rise in tumor markers and/or enlarging size of lesion on repeat 
imaging in 6 weeks (+/- 2 weeks) will be used to adjudicate recurrence by the 
treating physician in consultation with the PI. 
x 
Intercurrent illness that prevents further administration of treatment 
x 
Unacceptable adverse events(s) 
x 
Patient decides to withdraw from the study 
x 
General or specific changes in the patient’s condition render the patient unacceptable 
for further treatment in the judgment of the investigator 


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64 
 
x 
Major protocol violation 
 
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Tumor specimens will be collected, processed and analyzed as described previously 
(Section 7). 

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Biopsy samples will be collected by EUS by a highly experienced interventional 
gastroenterologist using standardized technique. EUS can visualize the primary 
pancreas mass, the surrounding pancreas anatomy, and subsequently localization of the 
interposing vessels by applying Doppler signal. The EUS will guide the angle of 
puncture without causing vascular injury in hopes to obtain core tissue. Multiple core 
tissue samples (at least four if clinically safe) will be obtained and processed in the 
following order of importance for analysis which will be dependent by the amount of 
evaluable cores  
a) 1 core - Formalin fixed paraffin embedded tissue  
b) 2 cores - Fresh frozen  u  2 
c) 
1 core - FLOW cytometry 
 
Please refer to corresponding laboratory manual for instructions to process the 
specimens. 
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At the time of surgery, four random core biopsies from the tumor will be obtained by the 
surgeon performing the PDA resection by direct visualization and cores processed as 
in Section 9.4.1 above. These samples will be analyzed for multiplex 
immunofluorescence and laser capture microdissection as described in Section 7.1. 
Standard of care microsatellite instability-high (MSI-H) or mismatch repair deficient 
(dMMR) will be performed by the treating institution. 

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Patients will undergo serial blood collection within 6 hours of initiation of investigative 
therapy, within 6 hours prior to surgical resection, time of beginning of each cycle of 
investigative adjuvant therapy (within 6 hours prior to start of therapy), beginning of 
adjuvant chemotherapy (within 6 hours prior to start of therapy), and at the start of 
Cycle 4 of adjuvant chemotherapy (within 6 hours prior to start of therapy, see Table ). 


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All samples will be sent to Dr. Manji s laboratory  
$WWHQWLRQWR
Gulam Abbas Manji, MD/PhD 
Herbert Irving Comprehensive Cancer Center Columbia University 
1130 Saint Nicholas Avenue, ICRC 207 New York, NY 10032 
Phone:  212-851-4507 
Alternate:  518-488-4704 
'XUDWLRQRI)ROORZ8S
Patients will be followed after study completion or removal from study or until death, 
whichever occurs first. Patients removed from study for unacceptable adverse 
events will be followed until resolution or stabilization of the adverse event. Thereafter, 
patients will be contacted by phone/in person every 3-4 months during the first 
3 years and every 6 months thereafter to obtain information about subsequent 
treatment(s) and survival status. 
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The reasons a patient may discontinue or be withdrawn from the study include, but are 
not limited to, adverse event, clinically significant disease recurrence, patient request, 
investigator decision, deemed surgically inoperable for any reason, major protocol 
violation such that patient is deemed not suitable to continue therapy, patient 
noncompliance, and study termination by the Sponsor or IRB/ IEC. When a patient 
discontinues or is withdrawn, the investigator will notify the Sponsor and should 
perform the procedures indicated in the End of Study column in the Schedule of 
Events within 28 days after discontinuation of study drug and before initiation of any 
new anti-cancer therapy. Follow-up information will be obtained for patients who 
discontinue their participation in or are withdrawn from the study. 
Patients withdrawn from the study for reasons other than toxicity or clinically significant 
disease recurrence (e.g., protocol violation or noncompliance) may be replaced at the 
discretion of the PI and the investigator. Study drug administration may be 
discontinued for an adverse event or at the discretion of the investigator. 
The consequence of withdrawal of all consent by a patient will be that no new information 
will be collected from that patient and added to the existing data or any database. 
However, every effort will be made to follow all patients for safety. 
 


Columbia University Medical Center 
Herbert Irving Comprehensive Cancer Center 
Version Date: 05/13/2019 
 
66 
 
10. 
DOSE ADMINISTRATION AND MODIFICATIONS 
Guidelines for dose administration for the following cohorts are provided in Table 11 and 
Table 12. 
Table 11 Dose Administration (Atezolizumab alone) 
Cycle Length 
Dose, Route, and Regimen (in order of administration) 
28 days 
Pre-surgery – 
Atezolizumab 840 mg IV on days 4 and 18 
Post-surgery –  
Atezolizumab 840 mg IV on days 1 and 15 for 2 cycles 
 
Dose Modifications for Management of Atezolizumab-Specific Adverse 
Events 
There will be no dose modifications for atezolizumab in this study. 
Atezolizumab treatment may be temporarily suspended in patients experiencing toxicity 
considered to be related to study treatment. If corticosteroids are initiated for treatment 
of the toxicity, they must be tapered over 1 month to  10 mg/day oral prednisone or 
equivalent before atezolizumab can be resumed. If atezolizumab is withheld for  12 
weeks, the patient will be discontinued from atezolizumab. However, atezolizumab may 
be withheld for  12 weeks to allow for patients to taper off corticosteroids prior to 
resuming treatment. Atezolizumab can be resumed after being withheld for  12 weeks if 
the PI agrees that the patient is likely to derive clinical benefit.  
Toxicities associated or possibly associated with atezolizumab treatment should be 
managed according to standard medical practice. Additional tests, such as autoimmune 
serology or biopsies, should be used to evaluate for a possible immunogenic etiology. 
Although most immune-related adverse events observed with immunomodulatory 
agents have been mild and self-limiting, such events should be recognized early and 
treated promptly to avoid potential major complications. Discontinuation of 
atezolizumab may not have an immediate therapeutic effect, and in severe cases, 
immune-related toxicities may require acute management with topical corticosteroids, 
systemic corticosteroids, or other immunosuppressive agents. 
The investigator should consider the benefit-risk balance a given patient may be 
experiencing prior to further administration of atezolizumab. In patients who have met 
the criteria for permanent discontinuation, resumption of atezolizumab may be 
considered if the patient is deriving benefit and has fully recovered from the immune-
related event. Patients can be re-challenged with atezolizumab only after approval 


Columbia University Medical Center 
Herbert Irving Comprehensive Cancer Center 
Version Date: 05/13/2019 
 
67 
 
has been documented by both the investigator (or an appropriate delegate) and the PI. 
Please refer to Appendix 2 for management of atezolizumab-related adverse events. 
 
Table 12 Dose Administration (Atezolizumab + PEGPH20) 
Cycle Length 
Dose, Route, and Regimen (in order of administration) 
28 days 
Pre-surgery –  
Atezolizumab 840 mg IV on days 4 1 and 18 
PEGPH20 3 g/kg IV on Days 1, 4 1 every week for 3 weeks  
Post-surgery –  
Atezolizumab 840 mg IV on days 1 1 and 15 for 2 cycles  
PEGPH20 3 g/kg IV on Days 1 1, 8, and 15 every 28 days 
1 On days where atezolizumab and PEGPH20 are administered, atezolizumab will be 
administered 2-3 hours after completion of the PEGPH20 infusion. 
 
Dose Modifications and Management of PEGPH20 and Atezolizumab-
Specific Adverse Events 
Please refer to Appendix 3 for management of adverse events for the PEGPH20 + 
atezolizumab arm. 
11. 
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS 
11.1 
SAFETY OF ATEZOLIZUMAB IN HUMANS 
 As of 17 May 2018,  16,000 patients with solid tumors or hematologic malignancies 
have received atezolizumab as a single agent or in combination with cytotoxic 
chemotherapy and/or targeted therapy through participation in a clinical trial. Safety 
findings of single-agent atezolizumab across multiple tumor types in the clinical 
development program are consistent with the known mechanism of action of 
atezolizumab and the underlying disease. Overall, treatment with atezolizumab is well 
tolerated with a manageable adverse event profile. Currently, no maximum tolerated 
dose, no dose-limiting toxicities (DLTs), and no clear dose-related trends in the 
incidence of adverse events (AEs) have been determined. Among 3075 patients treated 
with single-agent atezolizumab for whom pooled safety data are available, the most 
commonly reported AEs ( 10%) include fatigue, decreased appetite, cough, nausea, 
dyspnea, constipation, diarrhea, pyrexia, vomiting, arthralgia, back pain, asthenia, 
anemia, pruritus, rash, headache, and peripheral edema. 


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The AEs observed with atezolizumab in combination with chemotherapy and/or targeted 
therapies are consistent with the known risks of the individual study treatment. Systemic 
immune activation, characterized by an excessive immune response, is a potential risk 
associated with atezolizumab when used in combination with another 
immunomodulating compound. Atezolizumab-related AEs were comparable between 
patients who received atezolizumab monotherapy and those who were treated with 
atezolizumab in combination with targeted therapy and/or chemotherapy. There are no 
atezolizumab-related AEs that are exacerbated when used in combination with other 
agents. 
Immune-related AEs are consistent with the role of the PD-L1/PD-1 pathway in 
regulating peripheral tolerance. Given the mechanism of action of atezolizumab, events 
associated with inflammation and/or immune-related AEs are closely monitored during 
the atezolizumab clinical program. Immune-related AEs associated with atezolizumab 
include pneumonitis, hepatitis, colitis, pancreatitis, diabetes mellitus, hypothyroidism, 
hyperthyroidism, adrenal insufficiency, hypophysitis, Guillain-Barr  syndrome, 
myasthenic syndrome/myasthenia gravis, meningoencephalitis, myocarditis and 
nephritis.   
Study GP28363 is evaluating combination cobimetinib and atezolizumab in patients with 
locally advanced or metastatic solid tumors. As of 4 September 2017, there were 
150 safety-evaluable patients with tumor types including colorectal cancer, metastatic 
melanoma, and NSCLC who were on different treatment regimens of 
atezolizumab  cobimetinib. 
Of the 150 safety-evaluable patients, 148 (98.7%) experienced an adverse event. The 
most frequently observed AEs (t 30%) were diarrhea (70.7%), fatigue (56.7%), rash 
(48%), vomiting (43.3%), nausea (36.7%), constipation (30%) and abdominal pain 
(22.7%). Adverse events assessed as related to atezolizumab were reported in 
117patients (78.0%). The most common such AEs (t 10%) were fatigue (31.3%), 
diarrhea (28.0%), pruritus (14.0%), rash (13.3%), and nausea (12.7%), vomiting 
(10.0%), pyrexia (10.0%)  
These findings are consistent with the known adverse event profiles for atezolizumab 
and cobimetinib and did not represent additive toxicity. 
Grade 34 AEs were observed in 99 (66.0%) of the patients, and the most common 
( t 2.7% or  t 4 patients) included fatigue (10.7%), anemia (10.0%), diarrhea (8.7%%), 
abdominal pain and blood creatinine phosphokinase increased (5.3% each), rash 
(4.7%), dyspnea, aspartate aminotransferase increased amylase increased and 
hypertension (4% each), and ascites, vomiting, peripheral edema, pleural effusion, 


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69 
 
pulmonary embolism, blood bilirubin increased, lipase increased, neutrophil count 
decreased, hyponatraemia, and hypophosphatemia (2.7% each Most of the Grade 34 
AEs considered related to atezolizumab were single reports except for fatigue (3.3%), 
rash (2.7%), diarrhea (2%), amylase increase (2.7%), lipase increased and anaemia 
(2%), dermatitis acneiform, nausea, vomiting, dyspnea, aspartate aminotransferase 
increase and neutrophil count decrease (1.3% each).  
Six patients (4%) were reported to have had Grade 5 AEs. The following events led to 
death in 6 patients (4.0%): pneumonia, large intestine perforation, small intestinal 
obstruction, sepsis, road traffic accident, and respiratory failure. The event of sepsis was 
the only Grade 5 event considered related to atezolizumab. In this case, the patient had 
a medical history of infectious disease (right temporal lobe abscess). 
Sixty-nine safety-evaluable patients (46%) had a serious adverse event, most of which 
were single reports. The exceptions were pneumonia (6%), pyrexia and dyspnea (4% 
each), abdominal pain (3.3%), vomiting and sepsis (2.7%), fatigue, pulmonary embolism 
(2% each), and bacteremia, cellulitis, lung infection, ascites, intestinal obstruction, 
nausea, peripheral edema, pain, pleural effusion, pneumonitis, dehydration, and fall 
(1.3% each).   
Twenty-three safety-evaluable patients (15.3%) experienced an adverse event leading to 
discontinuation from atezolizumab. 
Reproductive and developmental toxicity studies with atezolizumab have not been 
conducted. The PD-L1/PD-1 signaling pathway is well established as essential in 
maternal/fetal tolerance and embryo-fetal survival during gestation (Guleria et al. 2005; 
Habicht et al. 2007; D’Addio et al. 2011). Administration of atezolizumab is expected to 
have an adverse effect on pregnancy via modulation of maternal/fetal tolerance, and 
poses a risk to the human fetus, including embryo-lethality via an increased risk of 
immune-mediated rejection.  
Other possible consequences of inhibiting the PD1/PD-L1 pathway may be the 
modulation of the host immune response to acute infection, which may result in 
dysregulated immune defenses and is currently a theoretical risk. 
 


Columbia University Medical Center 
Herbert Irving Comprehensive Cancer Center 
Version Date: 05/13/2019 
 
70 
 
Table 13 Serious Adverse Drug Reactions for Atezolizumab in All 
Indications Considered Expected for Safety Reporting Purposes 
Please refer to the current IB Version for a complete list for safety of atezolizumab. 
SOC 
SADRs 
(MedDRA Preferred 
Terms) 
Total number of patients  3075 
Patient No. 
(%) 
No. of life-
threatening 
events* 
No. of fatal 
events 
General 
disorders and 
administration 
site conditions  
Asthenia 
454 (14.8%) 
N/A 
N/A 
Malaise 
76 (2.5%) 
N/A 
N/A 
Fatigue 
1093 (35.5%) 
N/A 
N/A 
Influenza-like illness 
180 (5.9%) 
N/A 
N/A 
Pyrexia 
613 (19.9%) 
N/A 
N/A 
Respiratory, 
thoracic and 
mediastinal 
disorders 
Dyspnoea 
635 (20.7%) 
N/A 
N/A 
Hypoxia 
72 (2.3%) 
N/A 
N/A 
Interstitial lung 
disease 
4 (0.1%) 
N/A 
N/A 
Pneumonitis 
69 (2.2%) 
N/A 
N/A 
Gastrointestinal 
disorder 
Colitis 
34 (1.1%) 
N/A 
N/A 
Diarrhoea 
607 (19.7%) 
N/A 
N/A 
Dysgeusia 
82 (2.7%) 
N/A 
N/A 
Nausea 
728 (23.7%) 
N/A 
N/A 
Vomiting 
471 (15.3%) 
N/A 
N/A 
Investigation 
Alanine 
aminotransferase 
increased 
160 (5.2%) 
N/A 
N/A 
Aspartate 
aminotransferase 
increased 
173 (5.6%) 
N/A 
N/A 
Blood bilirubin 
increased 
51 (1.7%) 
N/A 
N/A 
Metabolism and 
nutrition 
disorders 
Diabetes mellitus 
7 (0.2%) 
N/A 
N/A 
Hyperglycaemia 
90 (2.9%) 
N/A 
N/A 
Hyponatraemia 
163 (5.3%) 
N/A 
N/A 
Musculoskeletal 
and connective 
tissue disorders  
Muscular weakness 
103 (3.3%) 
N/A 
N/A 
Back pain 
471 (15.3%) 
N/A 
N/A 
Bone pain 
89 (2.9%) 
N/A 
N/A 


Columbia University Medical Center 
Herbert Irving Comprehensive Cancer Center 
Version Date: 05/13/2019 
 
71 
 
SOC 
SADRs 
(MedDRA Preferred 
Terms) 
Total number of patients  3075 
Patient No. 
(%) 
No. of life-
threatening 
events* 
No. of fatal 
events 
Skin and 
subcutaneous 
tissue disorders 
Rash 
337 (11.0%) 
N/A 
N/A 
Rash maculo-papular 
77 (2.5%) 
N/A 
N/A 
Infections and 
infestations 
Encephalopathy 
6 (0.2%) 
N/A 
N/A 
Meningitis 
5 (0.2%) 
N/A 
N/A 
Urinary tract infections 
311 (10.8%) 
N/A 
N/A 
Endocrine 
disorders 
Hypothyroidism 
126 (4.1%) 
N/A 
N/A 
Immune system 
disorders 
Hypersensitivity 
35 (1.1%) 
N/A 
N/A 
Hepatobiliary 
disorders 
Hepatitis  
306 (10.0%) 
N/A 
N/A 
Injury, poisoning 
and procedural 
complications 
Infusion related 
reaction 
4 (0.1%) 
N/A 
N/A 
N*    number of patients who experienced the SADR 
N/A: fatal or life-threatening SADR are not considered expected. 
All fatal or life-threatening SADRs are considered unexpected for regulatory reporting purposes. 
AE    adverse event;SAE    serious adverse event; SOC    System Organ Class. 
 
Grade 5 AEs due to PD are excluded for studies GO27831 and GO28625. Investigator text for 
AEs encoded using MedDRA v20.1. Multiple occurrences of the same AE in one individual are 
counted once at the highest grade for this patient. To the SOC Overall row counts, a patient 
contributes only with the AE occurring with the highest grade within the SOC. Percentages are 
based on number in the column headings. AEs collected after first treatment dose are included. 
Adverse events with missing grade are not included.  
Clinical cutoff dates: GO27831 (31 March 2016), GO28625 (7 January 2015), GO28753 (1 
December 2015), GO28754 (1 December 2015), GO29293 (4 July 2016), GO28915 (7 July 
2016), and GO29294 (13 March 2017). December 2015), GO28754 (1 December 2015), 
GO29293 (4 July 2016), GO28915 (7 July 2016), and GO29294 (13 March 2017). 
Immune-related myositis, nephritis, uveitis, myopathies, and cardiac toxicities, which 
can be serious, have also been reported. 


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Atezolizumab is contraindicated for patients with the following: 
a) History of severe allergic anaphylactic reactions to chimeric, human or humanized 
antibodies, or fusion proteins. 
b) Known hypersensitivity to CHO cell products or any component of the atezolizumab 
formulation. 
 
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The warnings and precautions for atezolizumab are listed below. Management guidelines 
are listed in Appendix 2 which include specific guidelines for  
a) Immune-related hepatitis 
b) Immune-related colitis 
c) 
Immune-related pneumonitis 
d) Immune-related pancreatitis  
e) Immune-related endocrinopathies (i.e., diabetes mellitus, hypothyroidism. 
hyperthyroidism, adrenal insufficiency, hypophysitis) 
f) 
Immune-related meningoencephalitis 
g) Immune-related neuropathies (i.e., myasthenic syndrome/myasthenia gravis, 
Guillain-Barr  syndrome) 
h) Immune-mediated nephritis 
i) 
Immune-related myocarditis 
j) 
Myositis 
k) 
Infusion-related reactions 
 
Immune-related adverse events remain the major safety concern for atezolizumab, as is 
the case with other agents in this class. 
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The following adverse events are classified as identified risks associated with PEGPH20: 
Neutropenia, thrombocytopenia, peripheral edema, infusion-related reaction, pulmonary 
embolism, deep vein thrombosis, cerebrovascular accident, mesenteric vein thrombosis, 
myocardial infarction, vena cava thrombosis, venous thrombosis, muscle spasms, 
arthralgia, myalgia, muscular weakness, back pain, musculoskeletal pain, and 
pneumonia. Please refer to the current IB for the most updated adverse events for 
PEGPH20.  
Please refer to the current IB Version for a complete list for safety of PEGPH20. 


Columbia University Medical Center 
Herbert Irving Comprehensive Cancer Center 
Version Date: 05/13/2019 
 
73 
 
The overall safety analysis from HALO-109-202 study in patients with stage IV PDA who 
were treated with gemcitabine, nab-paclitaxel, and PEGPH20 in a phase 2 study 
confirmed musckulosekeletal events (MSEs; primarily grade 1 or 2 severity), 
thromboembolic events, and infusion-related reactions. Additionally, adverse. Trials 
combining immune check point blockade and PEGPH20 are ongoing with limited data 
available. 
Musculoskeletal events are an important identified risk due to their high frequency and 
the need to premedicate (with dexamethasone or NSAIDs as specified in the study 
protocols) to ameliorate their intensity. These events include but are not limited to 
Medical Dictionary for Regulatory Activities (MedDRA) preferred terms (PTs) such as 
muscle spasms, arthralgia, myalgia, muscular weakness, pain in extremity, back pain, 
bone pain, musculoskeletal pain, joint swelling, joint stiffness, limb discomfort, 
musculoskeletal stiffness, myositis, and neck pain. While the incidence across the 
clinical studies has been ≥75%, the events were mostly Grade 1/2 in severity, 
nonserious, and infrequently led to study treatment discontinuation. Musculoskeletal 
events continue to be observed very commonly in PEGPH20-treated patients. These 
events are managed by the administration of dexamethasone in ongoing studies, with 
the exception of the administration of piroxicam in studies with immunotherapies (as 
administered in HALO-107-101) due to the potential effect of steroids on efficacy. The 
dexamethasone and piroxicam prophylaxis appears to attenuate the severity of these 
events.  
Thromboembolic events (TEs) and their sequelae have been observed in clinical studies 
evaluating PEGPH20 combination therapies in patients with pancreatic cancer, NSCLC, 
and gastric cancer. It is widely accepted that PDA and gastric cancer are tumor types 
with a high TE event background rate. The observed events were mainly of venous 
origin and included PTs such as pulmonary embolism, thrombosis, embolism, 
mesenteric vein thrombosis, DVT, jugular vein thrombosis, and venous thrombosis. 
Arterial events have also been observed but less frequently than venous events and 
include PTs such as cerebral ischemia, cerebrovascular accident, splenic infarction, 
basal ganglia infarction, and myocardial infarction. Due to the risks of increased TE, all 
patients treated with PEGPH20 will also receive anticoagulation. 
Infusion-related reactions remain an identified risk of PEGPH20 although their overall 
incidence remains low (<5%). This risk was initially identified in Study HALO-109-201 
when PEGPH20 was initially administered either by IV push or over 4-5 minutes. Current 
protocol instructions require that PEGPH20 be administered by a slow IV infusion over 
10 minutes. This risk is being mitigated by administering PEGPH20 over 10 minutes as 
well as excluding patients with a known allergy to hyaluronidase. 


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Safety assessments will consist of monitoring and reporting adverse events (AEs) and 
serious adverse events (SAEs) per protocol. This includes all events of death, and any 
study specific issue of concern 

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An adverse event (AE) is any untoward or unfavorable medical occurrence in a human 
patient, including abnormal sign, symptom or disease, temporally associated with 
the patient s participation in research, whether or not considered related to the 
patient s participation in the research. Abnormal results of diagnostic procedures are 
considered to be adverse events if the abnormality: 
x 
Results in study withdrawal 
x 
Is associated with a serious adverse event 
x 
Is associated with clinical signs or symptoms 
x 
Leads to additional treatment or to further diagnostic tests 
x 
Is considered by the investigator to be of clinical significance 
Note: This includes the following: 
R 
AEs not previously observed in the subject that emerge during the 
protocol-specified  
R AE reporting period, including signs or symptoms associated with 
pancreatic adenocarcinoma that were not present prior to the AE 
reporting period. 
R xComplications that occur as a result of protocol-mandated interventions 
(e.g., invasive procedures such as cardiac catheterizations) 
R  If applicable, AEs that occur prior to assignment of study treatment 
associated with medication washout, no treatment run-in, or other 
protocol-mandated intervention. 
R  Preexisting medical conditions (other than the condition being studied) 
judged by the investigator to have worsened in severity or frequency or 
changed in character during the protocol-specified AE reporting period. 
 
3OHDVHQRWHthis study will utilize Common Terminology Criteria for Adverse Events
&7&$(Yfor all adverse event reporting criteria. 
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75 
 
 
The adverse event severity grading scale for the NCI CTCAE (v. 5) will be used for assessing 
adverse event severity. Below Table should be used for assessing severity for adverse events 
that are not specifically listed in the NCI CTCAE. 
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Grade 
Severity 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
or intervention not indicated 
2 
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a 
3 
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b,c 
4 
Life-threatening consequences or urgent intervention indicated d 
5 
Death related to adverse event d 
NCI CTCAE   National Cancer Institute Common Terminology Criteria for Adverse Events. 
Note:  Based on the most recent version of NCI CTCAE 5.0, which can be found at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
a. 
Instrumental activities of daily living refer to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc. 
b. 
Examples of self-care activities of daily living include bathing, dressing and undressing, feeding oneself, using 
the toilet, and taking medications, as performed by patients who are not bedridden. 
c. 
If an event is assessed as a "significant medical event," it must be reported as a serious adverse event  
d. 
Grade 4 and 5 events must be reported as serious adverse events  
 
The maximum severity grade of AEs or the worsening of a pre-existing medical condition 
occurring during the study should be recorded, regardless of relationship to study 
medication. 
For the purposes of this study, progression of the subject s underlying disease ( disease 
progression ) is an efficacy assessment and should 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, the event should be reported 
immediately to the safety contact and recorded as an AE or SAE. 


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Adverse events are classified as serious or non-serious. A serious adverse event is any 
AE that is: 
x 
Fatal 
x 
Life-threatening 
x 
Requires inpatient hospitalization/prolongation of existing hospitalization, unless: 
R Routine treatment or monitoring of the studied indication, not 
associated with any deterioration in condition (procedures such as 
central line placements, paracentesis, pain control) 
R Elective or pre-planned treatment for a pre-existing condition that is 
unrelated to the indication under study and has not worsened since the 
start of study drug 
R Treatment on an emergency outpatient basis for an event not fulfilling 
any of the definitions of an SAE given above/below and not resulting in 
hospital admission 
R Social reasons and respite care in the absence of any deterioration in 
the patient s general condition 
x 
Results in persistent or significant disability or incapacity 
x 
A congenital anomaly or birth defect 
x 
An important medical event 
Important medical events are those that may not be immediately life threatening, but 
are clearly of major clinical significance. They may jeopardize the patient, and 
may require intervention to prevent one of the other serious outcomes noted 
above. For example, drug overdose or abuse, a seizure that did not result in in-
patient hospitalization or intensive treatment of bronchospasm in an emergency 
department would typically be considered serious. 
 
All adverse events that do not meet any of the criteria for serious events should be 
regarded as non-serious adverse events. 
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Certain events are considered AEs of special interest. All events of special interest, 
regardless of type of event, severity, or seriousness must be reported within 5 calendar 
days of receipt by the sponsor-investigator. Please see section S11.5 for a complete list. 


Columbia University Medical Center 
Herbert Irving Comprehensive Cancer Center 
Version Date: 05/13/2019 
 
77 
 
Unanticipated Problem: 
An unanticipated problem (UP) is any incident, experience or outcome involving risks 
to patients or others in any human patient/patient research that meets all of the following 
criteria: 
 
Unexpected (in terms of nature, severity or frequency) given (a) the research 
procedures that are described in the IRB-approval protocol and informed consent 
document, and (b) the characteristics of the patient population being studied; 
 
Related or possibly related to participation in such research (e.g., there is a 
reasonable possibility that the incident, experience, or outcome may have been 
caused by the procedures involved in such research); and 
 
Suggests that the research places patients or others at a greater risk of harm 
(including physical, psychological, economic or social harm) than was previously 
known or recognized. 
 
11.4 
METHODS AND TIMING FOR ASSESSING AND RECORDING 
SAFETY VARIABLES 
The investigator is responsible for ensuring that all AEs and serious adverse events 
(SAEs) that are observed or reported during the study are collected and reported to the 
FDA, appropriate IRB(s), and study collaborators, Genentech, Inc., and Halozyme in 
accordance with CFR 312.32 (Investigational New Drug [IND] Safety Reports).  
Adverse Event Reporting Period 
The study period during which adverse events must be reported is normally defined as 
the period from the initiation of any study procedures (e.g., after the first dose of study 
treatment) to the end of the study treatment (e.g., last dose of study treatment) and/or 
follow-up. The recording of AEs will begin at the start of the administration of the first 
dose of a study medication, with the exception of study-procedure-associated SAEs. Any 
AE that occurs after the time of ICF signature will be recorded as an SAE if the event is 
associated with a study procedure and meets criteria of seriousness, even if the subject 
has not yet received any study medication. For this study, the study treatment follow-
up is defined as 30 days following the last administration of study treatment, or 30 
days following the decision to remove the patient from study treatment, 
whichever is earliest. After this period, investigators should only report SAEs that are 
attributed to prior study treatment. 
Assessment of Adverse Events 
All AEs and SAEs whether volunteered by the patient, discovered by study personnel 
during questioning, or detected through physical examination, laboratory test, or other 
means will be reported appropriately. Each reported AE or SAE will be described by its 
duration (i.e., start and end dates), regulatory seriousness criteria if applicable, 


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78 
 
suspected relationship to atezolizumab and/or PEGPH20 (see following guidance), and 
actions taken. 
To ensure consistency of AE and SAE causality assessments, investigators should 
apply the following general guideline: 
<HV
There is a plausible temporal relationship between the onset of the AE and 
administration of the atezolizumab and/or PEGPH20, and the AE cannot be readily 
explained by the patient s clinical state, intercurrent illness, or concomitant therapies; 
and/or the AE follows a known pattern of response to the atezolizumab and/or 
PEGPH20; and/or the AE abates or resolves upon discontinuation of the atezolizumab 
and/or PEGPH20 or dose reduction and, if applicable, reappears upon re-challenge. 
1R
Evidence exists that the AE has an etiology other than the atezolizumab and/or 
PEGPH20 (e.g., preexisting medical condition, underlying disease, intercurrent illness, 
or concomitant medication); and/or the AE has no plausible temporal relationship to 
atezolizumab and/or PEGPH20 administration (e.g., cancer diagnosed 2 days after first 
dose of study drug). 
Expected adverse events are those adverse events that are listed or characterized in the 
Package Insert or current Investigator Brochure (I.B).  
Unexpected adverse events are those not listed in the Package Insert or current I.B or 
not identified. This includes adverse events for which the specificity or severity is not 
consistent with the description in the Package Insert or I.B. For example, under this 
definition, hepatic necrosis would be unexpected if the Package Insert or I.B only 
referred to elevated hepatic enzymes or hepatitis. 
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A consistent methodology for eliciting AEs at all patient evaluation time points should be 
adopted. Examples of non-directive questions include: 
x 
How have you felt since your last clinical visit?  
x 
Have you had any new or changed health problems since you were last here?  
 
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79 
 
Investigators should use correct medical terminology/concepts when reporting AEs or 
SAEs. Avoid colloquialisms and abbreviations. 
D 'LDJQRVLVYV6LJQVDQG6\PSWRPV
If known at the time of reporting, a diagnosis should be reported rather than individual 
signs and symptoms (e.g., record only liver failure or hepatitis rather than jaundice, 
asterixis, and elevated transaminases). However, if a constellation of signs and/or 
symptoms cannot be medically characterized as a single diagnosis or syndrome at the 
time of reporting, it is acceptable to report the information that is currently available. If a 
diagnosis is subsequently established, it should be reported as follow-up information. 
E 'HDWKV
All deaths that occur during the protocol-specified AE reporting period (see 
Section 11.4), regardless of attribution, will be reported to the appropriate parties. When 
recording a death, the event or condition that caused or contributed to the fatal outcome 
should be reported as the single medical concept. If the cause of death is unknown and 
cannot be ascertained at the time of reporting, report Unexplained Death . 
F 3UHH[LVWLQJ0HGLFDO&RQGLWLRQV
A preexisting medical condition is one that is present at the start of the study. Such 
conditions should be reported as medical and surgical history. A preexisting medical 
condition should be re-assessed throughout the trial and reported as an AE or SAE only 
if the frequency, severity, or character of the condition worsens during the study. When 
reporting such events, it is important to convey the concept that the preexisting condition 
has changed by including applicable descriptors (e.g., more frequent headaches ). 
G +RVSLWDOL]DWLRQVIRU0HGLFDORU6XUJLFDO3URFHGXUHV
Any AE that results in hospitalization or prolonged hospitalization should be documented 
and reported as an SAE. If a patient is hospitalized to undergo a medical or surgical 
procedure as a result of an AE, the event responsible for the procedure, not the 
procedure itself, should be reported as the SAE. For example, if a patient is hospitalized 
to undergo coronary bypass surgery, record the heart condition that necessitated the 
bypass as the SAE. 
Hospitalizations for the following reasons do not require reporting: 
x 
Hospitalization or prolonged hospitalization for diagnostic or elective surgical 
procedures for preexisting conditions 
x 
Hospitalization or prolonged hospitalization required to allow efficacy measurement 
for the study or 
x 
Hospitalization or prolonged hospitalization for scheduled therapy of the target 
disease of the study 


Columbia University Medical Center 
Herbert Irving Comprehensive Cancer Center 
Version Date: 05/13/2019 
 
80 
 
 
e. Pregnancy 
If a female patient becomes pregnant while receiving the study drug or within 5 months 
after the last dose of study drug, a report should be completed and expeditiously 
submitted to Columbia University who will report on behalf of all sites to its collaborators, 
Genentech, Inc., and Halozyme. Follow-up to obtain the outcome of the pregnancy 
should also occur. Abortion, whether accidental, therapeutic, or spontaneous, should 
always be classified as serious, and expeditiously reported as an SAE. Similarly, any 
congenital anomaly/birth defect in a child born to a female patient exposed to the 
atezolizumab and/or PEGPH20 should be reported as an SAE. 
f. 
Post-Study Adverse Events 
The investigator should expeditiously report any SAE occurring after a patient has 
completed or discontinued study participation if attributed to prior exposure to 
atezolizumab and/or PEGPH20. If the investigator should become aware of the 
development of cancer or a congenital anomaly in a subsequently conceived offspring of 
a female patient who participated in the study, this should be reported as an SAE. 
For studies involving collection of survival data and follow up until progression free 
period the investigator after the end of the adverse event reporting period (defined as 30 
days after the last dose of study drug) should report all deaths, (regardless of cause), 
and any serious adverse event including development of cancer or a congenital anomaly 
in a subsequently conceived offspring of a female subject, including pregnancy occurring 
in the partner of a male study subject who participated in the study that is believed to be 
related to prior exposure to study drug 
Case Transmission Verification will be performed by both parties during this period to 
ensure successful transmission of Single case reports. 
g. Abnormal Laboratory Values 
All abnormal laboratory values that are gradable per National Cancer Institute (NCI) 
CTCAE criteria; will be documented as toxicities regardless of grade, attribution, and 
clinical significance. They must be documented in the medical record directly, to include 
the CTCAE grade and applicable attribution pertaining to the investigational products. If 
the laboratory abnormality suggests a disease and/or organ toxicity and/or require 
active management, the suspected cause and course of management should also be 
documented. 
i. 
Adverse Events of Special Interest to be Reported Immediately to the 
Sponsor/Collaborator: Genentech/Roche 
AESIs are a subset of Events to Monitor (EtMs) of scientific and medical concern 
specific to the product, for which ongoing monitoring and rapid communication by the 


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81 
 
Investigator to the Sponsor is required. Such an event might require further investigation 
in order to characterize and understand it. Depending on the nature of the event, rapid 
communication by the trial Sponsor to other parties (e.g., Regulatory Authorities) may 
also be warranted. 
Adverse events listed below are required to be reported by the investigator to 
Genentech, Inc. immediately (< 48 hours, excluding holidays and weekends, after 
learning of the event). Affiliate sites should report directly to CUMC, who will report to 
Genentech on behalf of Affiliate sites.  
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x 
Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either elevated bilirubin or clinical jaundice, and based on the 
following observations: 
±
Treatment-emergent ALT or AST > 3X baseline value in combination with total 
bilirubin > 2 X upper limit of normal (ULN), of which  35% is direct bilirubin 
±
Treatment-emergent ALT or AST > 3 X baseline value in combination with clinical 
jaundice 
 
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The following AEs are considered of special interest and must be reported to the FCCC 
Investigator-Sponsored Research Unit (ISRU) (SAE.FCCC@fccc.edu) within 24 hours of 
the awareness date and must be reported to the Genentech Drug Safety expeditiously, 
irrespective of regulatory seriousness criteria: 
x 
Pneumonitis 
x 
Colitis 
x 
Endocrinopathies:  diabetes mellitus, pancreatitis, adrenal insufficiency, 
hyperthyroidism, and hypophysitis 
x 
Hepatitis, including AST or ALT > 10 x ULN 
x 
Systemic lupus erythematosus 
x 
Neurological disorders:  Guillain-Barr  syndrome, myasthenic syndrome or 
myasthenia gravis, and meningoencephalitis 
x 
Events suggestive of hypersensitivity, infusion-related reactions, cytokine release 
syndrome, influenza-like illness, systemic inflammatory response syndrome, and 
systemic immune activation 
x 
Nephritis 


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x 
Ocular toxicities (e.g., uveitis, retinitis, optic neuritis) 
x 
Myositis 
x 
Myopathies, including rhabdomyolysis 
x 
Grade > 2 cardiac disorders (e.g., atrial fibrillation, myocarditis, pericarditis) 
x 
Vasculitis 
x 
Autoimmune hemolytic anemia 
x 
Severe cutaneous reactions (e.g., Stevens-Johnson syndrome, dermatitis bullous, 
toxic epidermal necrolysis) 
 
7KH3(*3+DGYHUVHHYHQWVRIVSHFLDOLQWHUHVWDUHDVIROORZV
x 
Musculoskeletal events:  
x 
Myalgia 
x 
Muscle spasms 
x 
Arthralgia 
x 
Bone pain 
x 
Musculoskeletal chest pain 
x 
Joint stiffness 
x 
Muscular weakness 
x 
Musculoskeletal pain 
 
 
M
([FKDQJHRIVLQJOHFDVHUHSRUWV
The Sponsor agrees to conduct the Case Transmission verification to ensure that all 
single case reports have been adequately received by Genentech via 6SRQVRU
,QYHVWLJDWRUemailing Genentech a Quarterly line-listing documenting single case 
reports sent by 6SRQVRU,QYHVWLJDWRUto Genentech in the preceding time period.  
The periodic line-listing will be exchanged within seven (7) calendar days of the end 
of the agreed time period. Confirmation of receipt should be received within the time 
period mutually agreed upon. 
If discrepancies are identified, the Sponsor and Genentech will cooperate in 
resolving the discrepancies. The responsible individuals for each party shall handle 
the matter on a case-by-case basis until satisfactory resolution.  The sponsor shall 
receive reconciliation guidance documents within the Activation Package . 
Following Case Transmission Verification, single case reports which have not been 
received by Genentech shall be forwarded by 6SRQVRU,QYHVWLJDWRUto Genentech 


Columbia University Medical Center 
Herbert Irving Comprehensive Cancer Center 
Version Date: 05/13/2019 
 
83 
 
within five (5) calendar days from request by Genentech. 
At the end of the study, a final cumulative Case Transmission Verification report will 
be sent to Genentech. 
Investigator will track all protocol-defined AE and pregnancy reports originating from the 
Study for atezolizumab and PEGPH20. Investigators must report all SAEs to Columbia 
University within the timelines described below, using the HICCC DSMC SAE Report 
Form. The completed SAE report form should be sent immediately upon completion to 
Columbia University. Affiliate sites should report directly to CUMC, who will report 
simultaneously to Genentech Drug Safety at: 
Fax: 650-238-6067 
OR 
Email: usds_aereporting-d@gene.com 
Relevant follow-up information should be submitted to Genentech Drug Safety as 
soon as it becomes available and/or upon request. 
 
And to HALOZYME’s Drug Safety Department at: safety@halozyme.com 
SAEs, pregnancy reports and adverse events of special interest (AESIs), where the 
patient has been exposed to the Product, will be sent on a DSMC SAE Report Form or 
equivalent to the Roche contact and to Halozyme. Transmission of these reports (initial 
and follow-up) will be either electronically or by fax and within the timelines specified 
below for both Genentech/Roche and Halozyme:  
Reporting to Genentech/Roche: 
Serious adverse events (SAEs), AEs of Special Interest (AESIs), pregnancy reports 
(including pregnancy occurring in the partner of a male study subject), and other Special 
Situation Reports where the patient has been exposed to the Genentech Product, will be sent 
on a MedWatch form or CIOMS I form or on Genentech approved reporting forms to  
Genentech Drug Safety. Transmission of these reports (initial and follow-up) will be either 
electronically or by fax and within the timelines specified below: 
     SADRs 
Serious AE reports that are related to the Product shall be transmitted to 
Genentech within fifteen (15) calendar days of the awareness date. 


Columbia University Medical Center 
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84 
 
     Other SAEs 
Serious AE reports that are unrelated to the Product shall be transmitted to 
Genentech within thirty (30) calendar days of the awareness date. 
• 
Serious Adverse Drug Reactions (SADRs) 
Serious AE reports that are related to the Product shall be transmitted to Roche within 
fifteen (15) calendar days of the awareness date. 
• 
Other SAEs 
Serious AE reports that are unrelated to the Product shall be transmitted to Roche within 
thirty (30) calendar days of the awareness date. 
• 
Pregnancy reports 
While such reports are not serious AEs or ADRs per se, as defined herein, any reports 
of pregnancy, where the fetus may have been exposed to the Product, shall be 
transmitted to Roche within thirty (30) calendar days of the awareness date. 
Pregnancies will be followed up until the outcome of the pregnancy is known, whenever 
possible, based upon due diligence taken to obtain the follow-up information. 
Pregnancies in Female Partners of Male Patients  
Male patients will be instructed through the Informed Consent Form to immediately 
inform the investigator if their partner becomes pregnant during the study or within 30 
days after the last dose of study drug.  A Clinical Trial Pregnancy Reporting Form should 
be completed and submitted to Genentech within thirty (30) calendar days of the 
awareness date. 
• 
AESI reporting to Roche 
AESIs requiring expedited reporting shall be forwarded to Roche within fifteen (15) 
calendar days of the awareness date. Others shall be sent within thirty (30) calendar 
days. 
 
Special situation reports 
In addition to all AEs, pregnancy reports and AESIs, the following Special Situations 
Reports should be collected and transmitted to Roche even in the absence of an 
Adverse Event within thirty (30) calendar days: 
– 
Data related to the Product usage during breastfeeding 


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– 
Data related to overdose, abuse, off-label use, misuse, or medication error 
(including potentially exposed or intercepted medication errors) 
– 
Data related to a suspected transmission of an infectious agent by the study 
drug (STIAMP), as defined below: 
o Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-
pathogenic, is considered an infectious agent.  A transmission of an 
infectious agent may be suspected from clinical symptoms or laboratory 
findings that indicate an infection in a patient exposed to a medicinal 
product.  This term applies only when a contamination of the study drug is 
suspected 
– 
Lack of therapeutic efficacy 
– 
Drug interaction 
– 
Use of a Medicinal Product in a Pediatric and Elderly population (in addition, 
reasonable attempts should be made to obtain and submit the age or age group 
of the patient, in order to be able to identify potential safety signals specific to a 
particular population) 
Occasionally Genentech may contact the reporter for additional information, clarification, 
or current status of the patient for whom an adverse event was reported.  
It is understood and agreed that the Sponsor will perform adequate due 
diligence with regard to obtaining follow-up information on incomplete AE, 
Special Situations and pregnancy reports. 
Reporting to Halozyme:  
All SAEs, initial and follow-up versions of the case, should be reported to Halozyme 
within 5 calendar days of receipt by the Investigator-Sponsor. 
In addition, the Investigator-Sponsor must provide Halozyme Drug Safety with a copy of 
any FDA submissions of the following within 24 hours of submission: 
 
Expedited (7-day or 15-day) initial and follow-up safety reports 
 
IND annual reports/Development Safety Update Report (DSUR) 
All SAE information exchanges between the Investigator-Sponsor to Halozyme Drug 
Safety will be completed within 30 calendar days after closure of the study database. 
 


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For any recurring, non-serious safety issues involving possible risk to subjects, notify 
Halozyme s Drug Safety Department within 5 calendar days of the Investigator-
Sponsor s initial awareness. 
Halozyme may request additional information or clarification of details for a particular 
event.  The Investigator-Sponsor must respond to such a request within a reasonable 
amount of time, or more rapidly if the request is identified as urgent. 
Sponsor-Investigator must provide a cumulative listing of AEs to the Halozyme Drug 
Safety Department on a monthly basis unless otherwise requested by Halozyme. This 
listing must include all AEs that have occurred from the start of the study by treatment 
arm. At a minimum, the listing should include the following data for each AE: verbatim 
term; start date; stop date; serious AE (SAE) criterion met, if applicable (i.e., death, life-
threatening, hospitalization - admission or prolongation, persistent or significant disability 
or incapacity, congenital anomaly or birth defect, or other important medical event); 
severity (grade according to NCI CTCAE criteria); relationship to each study medication 
(causality assessment); actions taken as a result of the AE (e.g., none, concomitant 
medication, non-drug therapy, study drug discontinuation, study drug suspended and 
restarted, discontinuation from study due to AE, etc.); and outcome.  
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Thromboembolic events are considered AEs of special interest. All TE events, 
regardless of type of event, severity, or seriousness must be reported to Halozyme 
within 5 calendar days of receipt by the sponsor-investigator.  
 
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Sponsor of the Study will be responsible for the expedited reporting of safety reports 
originating from the Study to the Regulatory Authorities (FDA) where it has filed a clinical 
trial approval, in compliance with local regulations. 
Genentech will be responsible for the expedited reporting of safety reports originating 
from the Study to the European Medicines Agency (EMA) through Eudravigilance 
Clinical Trial Module (EVCTM). 
Sponsor will be responsible for the distribution of safety information to its own 
investigators, where relevant. 

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In addition to completing appropriate patient demographic and suspect 
medication information, the report should include the following information within 
the Event Description of the MedWatch 3500A form: 
x 
Protocol description (and number, if assigned) 
x 
Description of event, severity, treatment, and outcome if known 
x 
Supportive laboratory results and diagnostics 
x 
Investigator s assessment of the relationship of the adverse event 
to each investigational product and suspect medication
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Additional information may be added to a previously submitted report by any of the 
following methods: 
x Adding to the original MedWatch 3500A report and submitting it 
as follow-up 
x Adding supplemental summary information and submitting it as 
follow-up with the original MedWatch 3500A form  
x Summarizing new information and faxing it with a cover letter 
including patient identifiers (i.e. D.O.B. initial, patient number), 
protocol description and number, if assigned, brief adverse event 
description, and notation that additional or follow-up information 
is being submitted (The patient identifiers are important so that the 
new information is added to the correct initial report) 
MedWatch 3500A (Mandatory Reporting) form is available at        
http://www.fda.gov/downloads/AboutFDA/ReportsManualsFo rms/Forms/UCM048334.pdf 
 
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For Investigator-Initiated IND Studies, some additional reporting requirements for the 
FDA apply in accordance with the guidance set forth in 21 CFR §600.80. 


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Herbert Irving Comprehensive Cancer Center 
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88 
 
Events meeting the following criteria need to be submitted to the FDA as expedited IND 
Safety Reports according to the following guidance and timelines: 
7 Calendar Day Telephone or Fax Report: 
The PI is required to notify the FDA of any fatal or life-threatening adverse event that is 
unexpected and assessed by the Investigator to be possibly related to the use of 
atezolizumab and PEGPH20. An unexpected adverse event is one that is not already 
described in the Atezolizumab and PEGPH20 Investigator Brochure. Such reports are to 
be telephoned or faxed to the FDA and collaborators Genentech/Roche and Halozyme 
within 7 calendar days of first learning of the event. 
15 Calendar Day Written Report 
The PI is also required to notify the FDA and all participating investigators, in a written 
IND Safety Report, of any serious, unexpected AE that is considered reasonably or 
possibly related to the use of atezolizumab and PEGPH20. An unexpected adverse 
event is one that is not already described in the PEGPH20 IB. 
Written IND Safety reports should include an Analysis of Similar Events in accordance 
with regulation 21 CFR§ 312.32. All safety reports previously filed by the investigator 
with the IND concerning similar events should be analyzed and the significance of the 
new report in light of the previous, similar reports commented on. 
Written IND safety reports with Analysis of Similar Events are to be submitted to the 
FDA, Genentech/Roche and Halozyme, and all participating investigators within 15 
calendar days of first learning of the event. The FDA prefers these reports on a 
MedWatch 3500 form, but alternative formats are acceptable (e.g., summary letter). 
FDA fax number for IND Safety Reports: 
Fax: 1 (800) FDA 0178 
All written IND Safety Reports submitted to the FDA by the Investigator must also 
be faxed to Genentech/Roche Drug Safety and emailed to Halozyme Drug Safety: 
Genentech – Fax: (650) 225-4682 or (650) 225-4630 
Halozyme – safety@halozyme.com  
Investigator will be responsible for the distribution of safety information to Site IRB per 
local policies and procedures: 


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Serious adverse events not constituting unanticipated problems are to be reported to the 
HICCC DSMC. Reporting should occur within 24 hours of knowledge of the SAE 
occurring at CUMC or affiliate sites. CUMC will report to the HICCC DSMC on behalf of 
affiliate sites. )RU$IILOLDWH6LWHUHSRUWLQJJXLGHOLQHVSOHDVHUHIHUWR6HFWLRQ$OO
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Reports of all events (including follow-up information) that meet the definition of an 
unanticipated problem posing risk to patients or others must be submitted to the IRB 
within 1 week (5 business days) following the occurrence of the unanticipated 
problem or the PI s acquiring knowledge of the unanticipated problem in accordance 
with IRB policy. Additionally, the Sponsor-Investigator will submit a summary of all 
Unanticipated problems that occurred since the beginning of the study at the time of 
continuing review. Copies of each report and documentation of IRB notification and 
receipt will be kept in the Regulatory binder. 
Affiliate Sites should direct safety reporting questions to the CUMC Sponsor-Investigator 
and Multicenter Core.  
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Tel: (888) 835-2555 
Fax: (650) 225-4682 or (650) 225-4630 
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safety@halozyme.com 
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All IND annual reports submitted to the FDA by the Sponsor-Investigator should be 
copied to the collaborators, Genentech, and Halozyme. 
Copies of such reports should be emailed to Genentech at:  Genentech Drug Safety 
CTV mail box: ctvist_drugsafety@gene.com 
2WKHU5HSRUWV


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90 
 
Sponsor will forward a copy of the Publication to collaborators Genentech/Roche and 
Halozyme upon completion of the Study. 
STUDY CLOSE-OUT 
Any study report submitted to the FDA by the Sponsor-Investigator should be copied to 
collaborators Genentech and Halozyme. This includes all IND annual reports and the 
Clinical Study Report (final study report). Additionally, any literature articles that are a 
result of the study should be sent to Genentech and Halozyme. Copies of such reports 
should be mailed to the assigned Clinical Operations contact for the study: 
Atezolizumab IIS Clinical Operations: anti-pdl-1-mpd3280a-gsur@gene.com 
And to Genentech Drug Safety CTV oversight mail box at: ctvist_drugsafety@gene.com 
QUERIES 
Queries related to the Study will be answered by CUMC. However, responses to all 
safety queries from regulatory authorities or for publications will be discussed and 
coordinated between the Parties. Any additional agreements between CUMC and study 
collaborators, Genentech/Roche, and Halozyme will be outlined in the Clinical Trials 
Agreement.  
SAFETY CRISIS MANAGEMENT 
In case of a safety crisis, e.g., where safety issues have a potential impact on the 
indication(s), on the conduct of the Study, may lead to labeling changes or regulatory 
actions that limit or restrict the way in which the Product is used, or where there is media 
involvement, the Party where the crisis originates will contact the other Party as soon as 
possible. 
Any additional agreements between CUMC and study collaborators, Genentech/Roche, 
and Halozyme will be outlined in the Clinical Trials Agreement.  
12. 
PHARMACEUTICAL INFORMATION 
12.1 
TREATMENT REGIMEN 
12.1.1 
Atezolizumab 
Atezolizumab is a human immunoglobulin (Ig) G1 monoclonal antibody consisting of two 
heavy chains (448 amino acids) and two light chains (214 amino acids) and is 
produced in CHO cells. Atezolizumab was engineered to eliminate Fc-effector function 
via a single amino acid substitution (asparagine to alanine) at position 298 on the 
heavy chain, which results in a non-glycosylated antibody that has minimal binding to 


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Fc receptors and prevents Fc-effector function at expected concentrations in humans. 
Atezolizumab targets PD-L1 and inhibits its interaction with its receptor, PD-1. 
Atezolizumab also blocks the binding of PD-L1 to B7.1, an interaction that is reported to 
provide additional inhibitory signals to T cells. It is administered as an IV formulation. 
For further details, see the Atezolizumab Investigator s Brochure. 

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At randomization, patients will be assigned to one of the two cohorts in a 1:1 ratio: 
&RKRUWAtezolizumabRU&RKRUWAtezolizumab + PEGPH20. 
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Atezolizumab and PEGPH20 are prepared according to the recommendations from the 
manufacturers  label. Atezolizumab and PEGPH20are supplied by Roche/Genentech 
and Halozyme, respectively. 

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Patients will receive PEGPH20 will be administered at 3Pg/kg IV on Days 1 and 4 weekly 
for 3 weeks prior to surgery and on Days 1, 8, and 15 on a 28 cycle for 2 cycles after 
surgery. Missed doses will not be made up. 
Guidelines for dosage modification and treatment interruption or discontinuation 
because of toxicities are provided in Appendix 3. 

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Atezolizumab will be administered on Days 4 and 18 prior to surgery and on Days 1 and 
15 on a 28 day cycle for 2 cycles after surgery. 
The atezolizumab drug product is provided in a single-use, 20-cc USP/Ph. Eur. Type 1 
glass vial as a colorless-to-slightly-yellow, sterile, preservative-free clear liquid solution 
intended for IV administration. The vial is designed to deliver 20 mL (1200 mg) of 
atezolizumab solution but may contain more than the stated volume to enable 
delivery of the entire 20 mL volume. The atezolizumab drug product is formulated as 
60 mg/mL atezolizumab in 20 mM histidine acetate, 120 mM sucrose, 0.04% polysorbate 
20, pH 5.8. 
Atezolizumab must be stored per the manufacturer s label upon receipt until use. 
Atezolizumab vials should not be used beyond the expiration date provided by the 
manufacturer. No preservative is used in the atezolizumab drug product; therefore, 


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each vial is intended for single use only. Discard any unused portion of drug left in a 
vial. Vial contents should not be frozen or shaken and should be protected from direct 
sunlight. 
For further details, see the current Atezolizumab Investigator s Brochure. 
The dose level of atezolizumab to be tested in this study is 840 mg (equivalent to an 
average body weight-based dose of 15 mg/kg) administered by IV infusion every 
2 weeks for two doses pre- surgery and 4 doses post-surgery. Atezolizumab will be 
delivered in infusion bags with IV infusion lines that have product contacting surfaces 
of polyvinyl chloride (PVC) or polyolefin and 0.2 Pm in-line filters (filter membrane of 
polyethersulfone [PES]). No incompatibilities have been observed between atezolizumab 
and PVC or polyolefin infusion materials (bags or infusion lines). 
Administration of atezolizumab will be performed in a setting with emergency medical 
facilities and staff who are trained to monitor for and respond to medical emergencies. 
The initial dose of atezolizumab will be delivered over 60 (+/- 15) minutes (see Table 14). 
If the first infusion is tolerated without infusion-associated AEs, the second infusion may 
be delivered over 30 (+/- 10) minutes. If the 30-minute infusion is well tolerated, all 
subsequent infusions may be delivered over 30 (+/- 10) minutes. For the first infusion, 
the patient s vital signs (heart rate, respiratory rate, blood pressure, and temperature) 
should be determined within 60 minutes before, during (every 15 [+/- 5] minutes), and 
30 (+/- 10) minutes after the infusion. For subsequent infusions, vital signs will be 
collected within 60 minutes before and within 30 minutes after the infusion. Vital signs 
should be collected during the infusion only if clinically indicated. Patients will be informed 
about the possibility of delayed post-infusion symptoms and instructed to contact their 
study physician if they develop such symptoms. 


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Table 14 Administration of First and Subsequent Atezolizumab Infusions. 
First Infusion  
Subsequent Infusions 
 
No premedication is permitted. 
 
Vital signs (heart rate, respiratory rate, blood
pressure, and temperature) should be 
recorded within 60 minutes prior to the 
infusion. 
 
Atezolizumab should be infused over 60  
(+/- 15) minutes. 
 
If clinically indicated, vital signs should be 
recorded during the infusion at 15, 30, 45, 
and 60 minutes (+/- 5 minutes for all time 
points) during the infusion and at 30 (+/- 10) 
minutes after the infusion. 
 
Patients should be informed about the 
possibility of delayed post-infusion 
symptoms and instructed to contact their 
study physician if they develop such 
symptoms. 
 
If the patient experienced an infusion-
related reaction with any previous infusion, 
premedication with antihistamines, 
antipyretics, and/or analgesics may be 
administered for subsequent doses at the 
discretion of the investigator. 
 
Vital signs should be recorded within 
60 minutes prior to the infusion. 
 
Atezolizumab should be infused over 
30 (+/-10) minutes if the previous infusion 
was tolerated without an infusion-related 
reaction, or 60 (+/- 15) minutes if the 
patient experienced an infusion- related 
reaction with the previous infusion. 
 
If the patient experienced an infusion-
related reaction with the previous infusion 
or if clinically indicated, vital signs should 
be recorded during the infusion and at 
30 (+/- 5) minutes after the infusion. 
 
No steroid premedication will be allowed for the first dose of atezolizumab. 
Premedication may be administered for Cycles ≥ 2 at the discretion of the treating 
investigator in consultation with the PI. The management of IRRs will be according to 
severity as follows: 
 
In the event that a patient experiences a mild (NCI CTCAE Grade 1) IRR, the 
infusion rate should be reduced to half the rate being given at the time of event 
onset. Once the event has resolved, the investigator should wait for 30 minutes 
while delivering the infusion at the reduced rate. If tolerated, the infusion rate may 
then be increased to the original rate. 
 
In the event that a patient experiences a moderate IRR (NCI CTCAE Grade 2) or 
flushing, fever, or throat pain, the infusion should be immediately interrupted and 
the patient should receive aggressive symptomatic treatment. The infusion should 
be restarted only after the symptoms have adequately resolved to baseline grade. 
The infusion rate at restart should be half of the infusion rate that was in progress at 
the time of the onset of the IRR. 
 
For severe or life-threatening IRRs (NCI CTCAE Grade 3 or 4), the infusion 
should be stopped immediately, and aggressive resuscitation and supportive 
measures should be initiated. Patients experiencing severe or life-threatening 
IRRs will not receive further infusion and will be further managed as clinically 
indicated until the event resolves. 


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Oral study drugs (if applicable) will be provided only to eligible patients under the 
supervision of the investigator or identified sub-investigator(s). The appropriate study 
personnel will maintain records of study drug receipt and dispensing. Any discrepancy 
regarding the dose administered and the reason for the discrepancy will be recorded in 
the eCRF. At each clinic visit, patients will be questioned about their compliance with 
study drug administration, and their dosing diary should be reviewed. 
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Blinding methods will not be employed; PEGPH20 and other agents will be 
administered in an open-label fashion. 
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Study drug must be received by a designated person at the study site, handled and 
stored safely and properly, and kept in a secured location to which only the investigator 
and designated assistants have access. 
Upon receipt of the of the study treatment supplies, an inventory must be performed and 
a drug receipt log filled out and signed by the person accepting the shipment. It is 
important that the designated study staff counts and verifies that the shipment contains 
all the items noted in the shipment inventory. Any damaged or unusable study drug in a 
given shipment (active drug or comparator) will be documented in the study files. The 
investigator must notify agent manufacturer of any damaged or unusable study 
treatments that were supplied to the investigator s site. 
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The Study drug provided in accordance with this Protocol will be kept in a secure place, 
and will only be supplied to patients participating in this Study. The PI is accountable for 
all Study drug supplied by Genentech/Roche and Halozyme in accordance with this 
Protocol. In addition, the PI must keep accurate and up-to-date dispensation records. 
Any Study drug accidently or deliberately destroyed must be recorded in a timely 
fashion, including an explanation for the destruction in writing. Any discrepancies 
between the amounts of Study drug dispensed and returned must also be explained in 
writing. All such records of drug accountability must be entered on the corresponding 
Patient CRF s. 
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All unused and partially used Study drug must be sealed and returned to the PI or 
his/her designee, or destroyed on Site in accordance with the established procedures 


Columbia University Medical Center 
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95 
 
for drug destruction, and with approval by the PI or his/her designee. Details of 
destruction, including, but not limited to, the number of boxes destroyed, batch number, 
and the date and method of destruction must be recorded on the Study drug destruction 
logs. 
 


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12.7 
Summary of Assessments  
Table 15 Study Calendar 
Procedure 
Screening 
Cycle 1 
Pre‐
Surgery 
Cycle 2 
Cycle 3 
End of 
Study2 
Standard 
of Care 
Chemo‐
therapy 3 
End of 
Chemo‐
therapy 
Post 
Study 
Follow 
up 4‐  
Every 3 
months 
Day ‐36 
to ‐23 1 
Day 
‐22 
Day 
‐15 
± 
3d 
Day 
‐7 
± 
3d 
Day 0
± 5d 
Week 
2 
± 3d 
Week 
3 
± 3d if 
>Grade 
2 AE 
 
Weeks 4 
to 8  
± 3d 
Weeks 
4 to 8  
+ 1w 
± 3d 
Weeks 
4 to 8 
+ 2w 
± 3d 
Weeks 
8 to 
12  
± 3d 
Weeks 
8 to 
12  
+ 1w 
± 3d 
Weeks 
4 to 8 
+ 2w 
± 3d 
Consent  
X 
  
  
  
  
 
 
  
  
  
  
  
  
  
  
  
  
Medical history  
X 
  
  
  
  
 
 
  
  
  
  
  
  
  
  
  
  
PDA cytology/ 
pathology 
confirmation 5 
X  
  
  
  
  
 
 
  
  
  
  
  
  
  
  
  
  
Physical 
examination 6,  
vital signs  
X 
X 
X 
X 
X 
 
X 
 
X 
X 
  
X 
X 
  
X 
  
X 
X 
X 


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97 
 
Procedure 
Screening 
Cycle 1 
Pre‐
Surgery 
Cycle 2 
Cycle 3 
End of 
Study2 
Standard 
of Care 
Chemo‐
therapy 3 
End of 
Chemo‐
therapy 
Post 
Study 
Follow 
up 4‐  
Every 3 
months 
Day ‐36 
to ‐23 1 
Day 
‐22 
Day 
‐15 
± 
3d 
Day 
‐7 
± 
3d 
Day 0
± 5d 
Week 
2 
± 3d 
Week 
3 
± 3d if 
>Grade 
2 AE 
 
Weeks 4 
to 8  
± 3d 
Weeks 
4 to 8  
+ 1w 
± 3d 
Weeks 
4 to 8 
+ 2w 
± 3d 
Weeks 
8 to 
12  
± 3d 
Weeks 
8 to 
12  
+ 1w 
± 3d 
Weeks 
4 to 8 
+ 2w 
± 3d 
Height 
X 
X 
  
  
X 
X 
X 
X 
X 
  
  
X 
  
X 
X 
X 
X 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG 
Performance 
Status 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
  
X 
X 
  
X 
X 
X 
X 
X 
ECG 7 
X 
  
X 
  
X 
 
 
X 
  
  
X 
  
  
X 
X 
  
  
CBC with 
differential  
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Comprehensive 
Metabolic 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Procedure 
Screening 
Cycle 1 
Pre‐
Surgery 
Cycle 2 
Cycle 3 
End of 
Study2 
Standard 
of Care 
Chemo‐
therapy 3 
End of 
Chemo‐
therapy 
Post 
Study 
Follow 
up 4‐  
Every 3 
months 
Day ‐36 
to ‐23 1 
Day 
‐22 
Day 
‐15 
± 
3d 
Day 
‐7 
± 
3d 
Day 0
± 5d 
Week 
2 
± 3d 
Week 
3 
± 3d if 
>Grade 
2 AE 
 
Weeks 4 
to 8  
± 3d 
Weeks 
4 to 8  
+ 1w 
± 3d 
Weeks 
4 to 8 
+ 2w 
± 3d 
Weeks 
8 to 
12  
± 3d 
Weeks 
8 to 
12  
+ 1w 
± 3d 
Weeks 
4 to 8 
+ 2w 
± 3d 
Panel 8 
X 
X 
PT/PTT 
X 
  
  
  
X 
X 
 
  
  
  
  
  
  
  
  
X 
  
Fresh tumor 
biopsy 9 
X 
  
  
  
  
 
 
  
  
  
  
  
  
  
  
  
X 
TSH, free T3 (or 
total T3), free 
T4, Cortisol 10 
X 
  
  
  
X 
 
 
X 
  
  
  
  
  
X 
  
X 
X 
Viral serology 11 
X 
  
  
  
  
 
 
  
  
  
  
  
  
X 
  
  
  
C‐reactive 
protein 
X 
  
  
  
  
 
 
  
  
  
  
  
  
  
  
X 
  


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Procedure 
Screening 
Cycle 1 
Pre‐
Surgery 
Cycle 2 
Cycle 3 
End of 
Study2 
Standard 
of Care 
Chemo‐
therapy 3 
End of 
Chemo‐
therapy 
Post 
Study 
Follow 
up 4‐  
Every 3 
months 
Day ‐36 
to ‐23 1 
Day 
‐22 
Day 
‐15 
± 
3d 
Day 
‐7 
± 
3d 
Day 0
± 5d 
Week 
2 
± 3d 
Week 
3 
± 3d if 
>Grade 
2 AE 
 
Weeks 4 
to 8  
± 3d 
Weeks 
4 to 8  
+ 1w 
± 3d 
Weeks 
4 to 8 
+ 2w 
± 3d 
Weeks 
8 to 
12  
± 3d 
Weeks 
8 to 
12  
+ 1w 
± 3d 
Weeks 
4 to 8 
+ 2w 
± 3d 
LDH 
X 
  
  
  
  
 
 
  
  
  
  
  
  
X 
  
  
  
CPK 
X 
X 
  
  
X 
 
 
X 
  
  
X 
  
  
  
  
  
  
Ca 19‐9 and 
CEA 
X 
  
  
X 
X 
 
X 
X 
  
  
X 
  
  
X 
X 
  
  
Pregnancy Test 
12 
X 
X 
  
  
X 
 
 
X 
  
  
  
  
X 
X 
  
X 
  
Urinalysis 
X 
As clinically indicated  
X 
X 
PBMC samples 
for biomarker 
  
X 
  
  
X 
 
 
X 
  
  
X 
X 
  
X 
X 
  
  


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100 
 
Procedure 
Screening 
Cycle 1 
Pre‐
Surgery 
Cycle 2 
Cycle 3 
End of 
Study2 
Standard 
of Care 
Chemo‐
therapy 3 
End of 
Chemo‐
therapy 
Post 
Study 
Follow 
up 4‐  
Every 3 
months 
Day ‐36 
to ‐23 1 
Day 
‐22 
Day 
‐15 
± 
3d 
Day 
‐7 
± 
3d 
Day 0
± 5d 
Week 
2 
± 3d 
Week 
3 
± 3d if 
>Grade 
2 AE 
 
Weeks 4 
to 8  
± 3d 
Weeks 
4 to 8  
+ 1w 
± 3d 
Weeks 
4 to 8 
+ 2w 
± 3d 
Weeks 
8 to 
12  
± 3d 
Weeks 
8 to 
12  
+ 1w 
± 3d 
Weeks 
4 to 8 
+ 2w 
± 3d 
Tumor 
response 
assessments 13 
X 
  
  
  
  
 
 
X 
  
  
  
  
  
X 
X 
X 
X 
Concomitant 
medications 
X 
X 
  
  
X 
 
X 
 
X 
X 
  
  
X 
  
  
X 
  
  
  
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
  
X 
X 
  
X 
  
X 
X 
X 
Atezolizumab 
administration 
14 
  
X 
  
X 
  
 
 
X 
  
X 
X 
  
X 
  
  
  
  
PEGPH20 
administration 
  
117, 
3, 4 
5, 6 
  
 
 
  
7 
8 
9 
10 
11 
12 
  
  
  


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101 
 
Procedure 
Screening 
Cycle 1 
Pre‐
Surgery 
Cycle 2 
Cycle 3 
End of 
Study2 
Standard 
of Care 
Chemo‐
therapy 3 
End of 
Chemo‐
therapy 
Post 
Study 
Follow 
up 4‐  
Every 3 
months 
Day ‐36 
to ‐23 1 
Day 
‐22 
Day 
‐15 
± 
3d 
Day 
‐7 
± 
3d 
Day 0
± 5d 
Week 
2 
± 3d 
Week 
3 
± 3d if 
>Grade 
2 AE 
 
Weeks 4 
to 8  
± 3d 
Weeks 
4 to 8  
+ 1w 
± 3d 
Weeks 
4 to 8 
+ 2w 
± 3d 
Weeks 
8 to 
12  
± 3d 
Weeks 
8 to 
12  
+ 1w 
± 3d 
Weeks 
4 to 8 
+ 2w 
± 3d 
15,17 
217 
Intraoperative 
biopsy, 
surgery, 
dMMR/MSI16 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Survival follow‐
up 17 
  
  
  
  
  
 
 
  
  
  
  
  
  
  
  
  
X 
Cohort‐specific 
assessment18 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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CEA   carcinoembryonic antigen; CT  computed tomography; d  day; ECOG   Eastern Cooperative Oncology Group; HBsAb  hepatitis B surface 
antibody; HBsAg  hepatitis B surface antigen; HBV  hepatitis B virus; HCV  hepatitis B virus; MRI  magnetic resonance imaging; 
PBMC  peripheral blood mononuclear cells; PDA   pancreas adenocarcinoma; TSH  Thyroid stimulating hormone; w  week.  
1 Protocol-specified screening procedures that are performed as part of standard of care and within 14 days of Day 1 of Cycle 1 may be used 
for screening purposes. Clinical laboratory studies and baseline CT and or MRI scan must be performed within the 7-day period before Day 
1 of Cycle 1. Screening labs may be used for Cycle 1 Day 1 if performed within 72 hours prior to study visit. 
2 The End-of-Study visit should be scheduled within the 28-day period after the last dose of study drug, or 28 days after removal from study. 
3 Adjuvant modified FOLFIRINOX will be administered as described in Section 9.1.4. 
4 Patients will be seen every 3 months during years 1 through 3 (+/- 14 days) and every six months for years 4 and 5 (+/- 28 days) with blood 
work including CEA and Ca19-9 and imaging as per standard of care surveillance. 
5 Cytologic or histologic proof of PDA needs to be verified by the treating institution pathologist either on the initial diagnosis, or on the 
required pre-treatment biopsy. Pathological report from non-treating institutions is sufficient to consent if tissue sample is unavailable for 
evaluation at time of consent. However, in such a case, PDA diagnosis will need to be confirmed on the pre-treatment biopsy prior to initiation 
of treatment. 
6 A complete physical examination will be performed at screening. All subsequent physical examinations will be focused disease-specific 
exams. Subjects will be under go physical exams as indicated and every other week after surgery until initiation of cycle 2 or deemed not a 
candidate to receive therapy. Physical exam on week 3 after surgery is optional and dependent on clinical necessity. 
7 ECG recordings will be obtained during screening, prior to surgery, and during end-of-study. Patients should be resting in a supine position for at 
least 5 minutes prior to ECG recording. 


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103 
 
8 A comprehensive metabolic panel including glucose, calcium, albumin, total protein,  sodium, potassium, CO2 (carbon dioxide, bicarbonate), 
chloride, BUN (blood urea nitrogen),  creatinine, ALP (alkaline phosphatase), ALT (alanine amino transferase), AST (aspartate  amino 
transferase) and bilirubin will be performed weekly during the first cycle, prior to surgery, weeks 2 and every other week after surgery 
until start of cycle 2 or until considered not eligible to initiate adjuvant CIT, week 3 after surgery if grade 3 or higher adverse 
events during week 2 visit except for pain and fatigue, and then on day 1 and 15 of cycle 2 and 3.Blood work prior to chemotherapy 
as standard of care will be obtained and comprehensive metabolic panel obtained as per institutional guidelines and as clinically 
indicated. 
9 Fresh tumor tissue samples will be collected from all patients by means of a biopsy performed at study entry. Adequate tissue collection to 
confirm diagnosis as deemed by the on-site pathologist on a preliminary review will be required for eligibility. If diagnosis is not 
confirmed, an attempt to repeat tumor biopsy is allowed if deemed safe, patient agreeable to repeat procedure, and performed at least 
3 days prior to scheduled start of therapy. Optional tumor biopsy at time of recurrence (listed here as on follow-up). 
10 TSH, free T3 (or total T3 for sites where free T3 is not performed), free T4, and AM cortisol will be assessed at screening and on pre-surgery, 
Day 1 of Cycle 2, on end of study, and as clinically appropriate. 
11 At screening, patients without a prior positive HIV test result will undergo an HIV test, unless not permitted per local regulations. Patients will also 
be tested for HBsAg, HBsAb, total HBcAb, and HCV antibody. If a patient has a negative HBsAg test and a positive total HBcAb test at 
screening, an HBV DNA test should be performed. If a patient has a positive HCV antibody test at screening, an HCV RNA test must also be 
performed to determine if the patient has an active HCV infection. 
12 All women of childbearing potential will have a serum pregnancy test at screening, within 14 days prior to initiation of study treatment. Urine 
or serum pregnancy tests will be performed at specified subsequent visits. If a urine pregnancy test is positive, it must be confirmed by a 
serum pregnancy test. 


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13 All measurable and evaluable lesions should be assessed and documented at VFUHHQLQJZLWKLQGD\VRIF\FOHGD\, prior to start of 
investigational adjuvant therapy ('D\RI&\FOH;+/- 7 days), SULRUWRDGMXYDQWFKHPRWKHUDS\(+/- 7 days), during adjuvant FKHPRWKHUDS\
DWHYHU\ZHHNinterval (+/- 7 days), and DIWHUDGMXYDQWFKHPRWKHUDS\at HYHU\ZHHN LQWHUYDO(+/- 14 days). Tumor assessments 
performed as standard of care prior to obtaining informed consent and within GD\Vprior to initiation of study treatment do not have to be 
repeated at screening. Screening assessments must include CT scans (with IV contrast; with or without oral contrast) or MRI scans (with IV 
contrast) of the chest, abdomen, and pelvis. A spiral CT scan of the chest may be obtained but is not a requirement. If a CT scan with 
contrast is contraindicated (i.e., in patients with contrast allergy or impaired renal clearance), a non-contrast CT scan of the chest may be 
performed and MRI scans (with IV contrast) of the abdomen and pelvis should be performed. Bone scans and CT scans of the neck should 
also be performed if clinically indicated. At the investigator s discretion, other methods of assessment of measurable disease as per 
imRECIST may be used. Refer to Section 13 for further details on tumor assessments. 
14 The initial dose of atezolizumab will be delivered over 60 (+/- 15) minutes. Subsequent infusions will be delivered over 30 (+/-10) minutes if 
the previous infusion was tolerated without infusion-associated adverse events, or 60 (+/- 15) minutes if the patient experienced an infusion-
associated adverse event with the previous infusion. 
15 All patients in Cohort 2 will receive PEGPH20 at a dose of 3g/kg IV on Days 1 and 4 every week for 3 weeks SULRUWRsurgery and on Days 1, 
8, and 15 on a 28 day cycle for 2 cycles DIWHUsurgery. Patients are to receive Enoxaparin as detailed in the study protocol. 
16 At the time of surgery, four random core biopsies from the tumor will be obtained by the surgeon performing the PDA resection by direct 
visualization and cores processed if deemed safe. Standard of care microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) 
will be performed by the treating institution if not already performed. 


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17  After treatment discontinuation, information on survival follow-up and new anti-cancer therapy (including targeted therapy and 
immunotherapy) will be collected via telephone calls, patient medical records, and/or clinic visits approximately every 3 months until death 
(unless the patient withdraws consent or the Sponsor terminates the study). If a patient requests to be withdrawn from follow-up, this 
request must be documented in the source documents and signed by the investigator. If the patient withdraws from study, the study staff 
may use a public information source (e.g., county records) to obtain information about survival status only. 
18 Following screening assessments need to be performed for specific cohorts  
A. Atezolizumab in combination with PEGPH20 
i.   Doppler ultrasound of both legs will be performed during screening to exclude subjects with DVT and PE. 
ii.  2cc plasma samples should be collected prior to PEGPH20 administration on C1D1 and C1D4 (2 hour window). 
 
 


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All patients will undergo preoperative multiphasic CT (MDCT) scan for local staging 
using a dedicated pancreatic tumor imaging protocol. MRI of the abdomen may be used 
if unable to obtain contrasted CT scan or better definition for staging. 
&73URWRFRO
The multiphasic CT (MDCT) pancreatic tumor protocol consists of three phases: pre- 
contrast, post-contrast pancreatic parenchymal phase (40-50 seconds after IV contrast 
injection) and post-contrast portal venous phase (65-70 seconds after IV contrast 
injection). The rate of IV contrast injection will be 4-5 mL/sec, iodine concentration 
= 300 mg/mL, and the volume of injected contrast will be based on patient s body 
weight (100 mL for patients weighing  250 lb and 150 mL for patients weighing 
>250 lb). In addition to IV contrast, enteric contrast will be administered. CT images will 
be acquired at slice thickness of d 1 mm and reconstructed for axial sections (2-5 mm 
slice thickness) and multiplanar coronal and sagittal reformations (2-3 mm thickness). 
05,3URWRFRO
Abdominal MRI without and with IV contrast will be performed if there is any 
contraindication to iodinated CT contrast, or for further assessment of the liver 
parenchyma, or better definition of staging. MRI pancreatic protocol includes T1 
weighted imaging using in and opposed phase, axial and coronal T2 weighted, diffusion 
weighted, fat suppressed dynamic pre/post IV contrast gradient, echo T1 weighted 
imaging with slice thickness (interpolated to 2-3 mm), and heavily T2 weighted MRCP 
imaging in 2D and 3D. 
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Imaging will be interpreted by a designated radiologist as determined by the PI at the 
designated treating institution. Standard reporting of salient features will be performed as 
per consensus statement of the Society of Abdominal Radiology and American 
Pancreatic Association (Al-Hawary et al. 2014). The NCCN criteria for pancreatic 
cancer staging will be used for determining resectability in combination with institutional 
multidisciplinary pancreatic team assessment (Tempero et al. 2017). 
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Each patient CT or MRI scan will be reviewed by the treatment site designated 
radiologist to determine the respectability of the pancreatic tumor. $UHFRQFLOLDWLRQ
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Columbia University Medical Center 
Herbert Irving Comprehensive Cancer Center 
Version Date: 05/13/2019 
 
107 
 
deemed ineligible. Each evaluable patient will need a baseline image assessment form 
signed by the treatment site designated radiologist to deem eligibility for resectability 
(Appendix 1). 
13.2 
ANTITUMOR EFFECT – SOLID TUMORS 
For the purposes of this study, patients should be re-evaluated for recurrence as 
indicated in the schedule of assessments. 
Treatment Beyond Initial Radiographic Recurrence 
In studies of immunotherapeutic agents, complete response, partial response, and 
stable disease have each been shown to occur after radiographic evidence of an 
apparent increase in tumor burden. This initial increase in tumor burden caused by 
immune cell infiltration in the setting of a T-cell response has been termed pseudo-
progression (Hales et al. 2010). In Study PCD4989g, evidence of tumor growth 
followed by a response was observed in several tumor types. In addition, in some 
responding patients with radiographic evidence of progression, biopsies of new lesions or 
areas of new growth in existing lesions revealed immune cells and no viable cancer 
cells. Because of the potential for a response after pseudo-recurrence, this study will 
allow patients randomly assigned to immunotherapy-based treatment arms to continue 
combination treatment after apparent radiographic recurrence per immune-modified 
Response Evaluation Criteria in Solid Tumors (RECIST), provided the benefit-risk ratio is 
judged to be favorable by the investigator. 
Patients should be discontinued for unacceptable toxicity or loss of clinical benefit as 
determined by the investigator after an integrated assessment of radiographic and 
biochemical data, local biopsy results (if available), and clinical status (e.g., 
symptomatic deterioration such as pain secondary to disease). Because of the 
possibility of an initial increase in tumor burden caused by immune cell infiltration in 
the setting of a T-cell response (termed pseudo-progression) with atezolizumab 
treatment, radiographic recurrence per RECIST v1.1 may not be indicative of true 
disease recurrence. In the absence of unacceptable toxicity, patients who meet criteria 
for disease recurrence per RECIST v1.1 while receiving treatment with atezolizumab or 
other treatments will be permitted to continue treatment if they meet all of the following 
criteria: 
 
Evidence of clinical benefit, as determined by the investigator following a 
review of all available data 
 
Absence of symptoms and signs (including laboratory values, such as new or 
worsening hypercalcemia) indicating unequivocal recurrence of disease 
 
Absence of decline in ECOG Performance Status that can be attributed to disease 
recurrence 


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x 
Absence of tumor recurrence at critical anatomical sites (e.g., leptomeningeal 
disease) that cannot be managed by protocol-allowed medical interventions 
x 
Patient’s written consent to acknowledge deferring other treatment options in favor 
of continuing study treatment at the time of initial apparent disease recurrence. 
 
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Increasing clinical experience indicates that traditional response criteria (e.g., 
RECIST v1.1 and World Health Organization [WHO] criteria) may not adequately assess 
the activity of immunotherapeutic agents because initial radiographic evidence of 
disease progression (or in this case, disease recurrence) does not necessarily 
reflect therapeutic failure. Patients can experience a response in the presence of new 
lesions or after an increase in tumor burden. Thus, this study will employ immune-
modified RECIST for tumor assessments to account for the possible appearance of new 
lesions and allow radiographic recurrence to be confirmed at a subsequent 
assessment. It is required that radiographic recurrence be confirmed at a subsequent 
tumor assessment to take into account the potential for pseudo-recurrence (caused 
by immune cell infiltration). Given the proposed immunomodulatory mechanism of 
action of atezolizumab and the possibility of observing delayed responses, use of 
immune-modified RECIST will allow for the capture of a greater proportion of potential 
responses and allow patients to derive maximum clinical benefit. Immune-modified 
Response Evaluation Criteria in Solid Tumors (RECIST), as described within this 
appendix, were adapted from RECIST, Version 1.1 (v1.1) (Eisenhauer et al. 2009) in the 
same manner that immune- related response criteria were adapted from WHO criteria 
(Wolchok et al. 2009) and RECIST v1.0 (Nishino et al. 2014). When not otherwise 
specified, RECIST v1.1 conventions will apply. Differences between immune-modified 
RECIST and RECIST v1.1 are summarized Table 16. 
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Conventional response criteria may not be adequate to characterize the anti-tumor 
activity of immunotherapeutic agents like atezolizumab, which can produce delayed 
responses that may be preceded by initial apparent radiographic progression, 
including the appearance of new lesions. Therefore, immune-modified response 
criteria have been developed to incorporate new lesions into the assessment of total 
tumor burden and allow radiographic progression to be confirmed at a subsequent 
assessment. Immune-modified Response Evaluation Criteria in Solid Tumors 
(RECIST), as described within this appendix, were adapted from RECIST, Version 1.1 
(v1.1), in the same manner that immune-related response criteria were adapted from 
WHO criteria and RECIST v1.0 (Ritchie et al. 2015; H nzelmann S et al. 2013). When 
not otherwise specified, RECIST v1.1 conventions will apply. Differences between 
immune-modified RECIST and RECIST v1.1 are summarized in Table 16. 


Columbia University Medical Center 
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Version Date: 05/13/2019 
 
109 
 
Table 16 Comparison of RECIST v1.1 and Immune-Modified RECIST 
 
RECIST v1.1 
Immune-Modified RECIST 
Measurable new lesions 
Always represent progression 
Incorporated into the total tumor 
burden 1 and followed 
Non-measurable new 
lesions 
Always represent progression 
Do not represent progression, but 
preclude CR 
Non-target lesions 
Contribute to defining CR, PR,
SD, and PD 
Contribute to defining CR only 
CR 
Disappearance of all lesions 
Disappearance of all lesions 
PR 
≥ 30% decrease in sum of 
diameters of target lesions, in 
the absence of CR, new 
lesions, and unequivocal 
progression in non- target 
≥30% decrease in tumor burden, 1 in 
the absence of CR 
PD 
≥20% increase in sum of 
diameters of target lesions, 
unequivocal progression in 
non- target lesions, and/or 
appearance of new lesions 
≥20% increase in tumor burden 1 
SD 
Neither sufficient shrinkage to 
qualify for CR or PR nor 
sufficient increase to qualify for
PD 
Neither sufficient shrinkage to 
qualify for CR or PR nor sufficient 
increase to qualify for PD 
CR  complete response; PD  progressive disease; PR  partial response; RECIST  Response 
Evaluation Criteria in Solid Tumors; SD  stable disease. 
1 Tumor burden is the sum of diameters of target lesions and measurable new lesions. 
 
 
TUMOR MEASURABILITY 
At baseline, tumor lesions/lymph nodes will be categorized as measurable or non-
measurable as described below. All measurable and non-measurable lesions should be 
assessed at screening and at subsequent protocol-specified tumor assessment time 
points. Additional assessments may be performed as clinically indicated for suspicion 
of recurrence. 


Columbia University Medical Center 
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110 
 
 
 
 
 
 
DEFINITION OF MEASURABLE LESIONS 
Tumor Lesions 
Tumor lesions must be accurately measured in at least one dimension (longest 
diameter in the plane of measurement is to be recorded) with a minimum size as 
follows: 
 
10 mm by CT or MRI scan (CT/MRI scan slice thickness/interval   5 mm) 
 
10-mm caliper measurement by clinical examination (lesions that cannot be 
accurately measured with calipers should be recorded as non-measurable) 
 
20 mm by chest X-ray 
 
Malignant Lymph Nodes 
To be considered pathologically enlarged and measurable, a lymph node must be 
 15 mm in the short axis when assessed by CT scan (CT scan slice thickness 
recommended to be   5 mm). At baseline and follow-up, only the short axis will be 
measured and followed. Additional information on lymph node measurement is 
provided below (see "Identification of Target and Non-Target Lesions," "New Lesions," 
and "Calculation of Sum of Diameters"). 
DEFINITION OF NON-MEASURABLE LESIONS 
Non-measurable tumor lesions encompass small lesions (longest diameter < 10 mm or 
pathological lymph nodes with short axis  10 mm but   15 mm) as well as truly non-
measurable lesions. Lesions considered truly non-measurable include leptomeningeal 
disease, ascites, pleural or pericardial effusion, inflammatory breast disease, 
lymphangitic involvement of skin or lung, peritoneal spread, and abdominal 
mass/abdominal organomegaly identified by physical examination that is not 
measurable by reproducible imaging techniques. 
SPECIAL CONSIDERATIONS REGARDING LESION MEASURABILITY 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
particular comment, as outlined below. 
Bone Lesions: 
 
Technetium-99m bone scans, sodium fluoride PET scans, and plain films are not 
considered adequate imaging techniques for measuring bone lesions. However, 
these techniques can be used to confirm the presence or disappearance of bone 
lesions. 


Columbia University Medical Center 
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111 
 
 
Lytic bone lesions or mixed lytic-blastic lesions with identifiable soft tissue 
components that can be evaluated by cross-sectional imaging techniques such as 
CT scan or MRI can be considered measurable lesions if the soft tissue component 
meets the definition of measurability described above. 
 
Blastic bone lesions are non-measurable. 
 
Cystic Lesions: 
 
Lesions that meet the criteria for radiographically defined simple cysts should not 
be considered malignant lesions (neither measurable nor non-measurable) 
because they are, by definition, simple cysts. 
 
Cystic lesions thought to represent cystic metastases can be considered 
measurable lesions if they meet the definition of measurability described above. 
However, if non-cystic lesions are present in the same patient, these are preferred 
for selection as target lesions. 
 
Lesions with Prior Local Treatment: 
 
Tumor lesions situated in a previously irradiated area or in an area patiented to 
other loco- regional therapy are usually not considered measurable unless there 
has been demonstrated progression in the lesion. 
 
METHODS FOR ASSESSING LESIONS 
All measurements should be recorded in metric notation, using calipers if clinically 
assessed. All baseline evaluations should be performed as close as possible to the 
treatment start and never more than 4 weeks before the beginning of the treatment. 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during the study. 
Imaging-based evaluation should always be the preferred option. 
CLINICAL LESIONS 
Clinical lesions will only be considered measurable when they are superficial and 
 10 mm in diameter as assessed using calipers (e.g., skin nodules). For the case of skin 
lesions, documentation by color photography, including a ruler to estimate the size of 
the lesion, is suggested. 
CHEST X-RAY 
Chest CT scan is preferred over chest X-ray, particularly when recurrence is an 
important endpoint, because CT is more sensitive than X-ray, particularly in identifying 
new lesions. However, lesions on chest X-ray may be considered measurable if they are 
clearly defined and surrounded by aerated lung. 


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CT is the best currently available and reproducible method to measure lesions selected for 
response assessment. In this guideline, the definition of measurability of lesions on CT 
scan is based on the assumption that CT slice thickness is d 5 mm. When CT scans have 
slice thickness of ! 5 mm, the minimum size for a measurable lesion should be twice the 
slice thickness. MRI is also acceptable. If prior to enrollment it is known that a patient 
is unable to undergo CT scans with IV contrast because of allergy or renal 
insufficiency, the decision as to whether a non-contrast CT scan or MRI (without IV 
contrast) will be used to evaluate the patient at baseline and during the study should 
be guided by the tumor type under investigation and the anatomic location of the 
disease. For patients who develop contraindications to contrast after baseline contrast 
CT scan is done, the decision as to whether non-contrast CT scan or MRI (enhanced or 
non-enhanced) will be performed should also be based on the tumor type and the 
anatomic location of the disease, and should be optimized to allow for comparison with 
the prior studies if possible. Each case should be discussed with the site designated 
radiologist to determine if substitution of these other approaches is possible and, if 
not, the patient should be considered not evaluable from that point forward. Care must 
be taken in measurement of target lesions and interpretation of non-target disease or 
new lesions on a different modality, because the same lesion may appear to have a 
different size using a new modality. 
)'*3(7While FDG-PET response assessments need additional study, it is 
sometimes reasonable to incorporate the use of FDG-PET scanning to complement CT 
scanning in assessment of recurrence (particularly possible ’new’ disease). New lesions 
on the basis of FDG-PET imaging can be identified according to the following algorithm: 
x 
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 
progressive disease (PD) based on a new lesion. 
x 
No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive 
FDG-PET at follow-up corresponds to a new site of disease confirmed by CT 
scan, this is PD which should be confirmed by a biopsy. If the positive FDG-PET 
at follow-up is not confirmed as a new site of disease on CT, additional follow-up 
CT scans are needed to determine if there is truly progression occurring at that site 
(if so, the date of PD will be the date of the initial abnormal FDG-PET scan). If the 
positive FDG-PET at follow-up corresponds to a pre-existing site of disease on CT 
that is not progressing on the basis of the anatomic images, this is not PD. 
x 
FDG-PET may be used to upgrade a response to a complete response (CR) in a 
manner similar to a biopsy in cases where a residual radiographic abnormality is 
thought to represent fibrosis or scarring. The use of FDG-PET in this circumstance 
should be prospectively described in the protocol and supported by disease-specific 
medical literature for the indication. However, it must be acknowledged that both 


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113 
 
approaches may lead to false positive CR due to limitations of FDG-PET and 
biopsy resolution/sensitivity. 
 
Note: A positive  FDG-PET scan lesion means one that is FDG avid with an uptake 
greater than twice that of the surrounding tissue on the attenuation corrected image. 
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Endoscopy, laparoscopy, ultrasound, tumor markers, cytology, and histology cannot 
be utilized for objective tumor evaluation. 
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To assess recurrence, it is necessary to estimate the overall tumor burden at baseline 
and use this as a comparator for subsequent measurements. 
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Baseline scan should contain pancreas-specific mass to be considered eligible, and no 
measurable lesion considered concerning for metastatic disease. All measurable non-
pancreatic lesions should be biopsied to confirm benign lesion. 
Target lesions present at the time of recurrence should be selected on the basis of 
their size (lesions with the longest diameter) and be representative of all involved 
organs, but in addition should lend themselves to reproducible repeated 
measurements. It may be the case that, on occasion, the largest lesion does not lend 
itself to reproducible measurement, in which circumstance the next largest lesion that 
can be measured reproducibly should be selected. ,IDQHZOHVLRQLVLGHQWLILHG RQ
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Lymph nodes merit special mention because they are normal anatomical structures 
that may be visible by imaging even if not involved by tumor. As noted above, 
pathological nodes that are defined as measurable and may be identified as target 
lesions must meet the criterion of a short axis of t 15 mm by CT scan. Only the short 
axis of these nodes will contribute to the baseline sum. The short axis of the node is 
the diameter normally used by radiologists to judge if a node is involved by solid tumor. 
Lymph node size is normally reported as two dimensions in the plane in which the image 
is obtained (for CT, this is almost always the axial plane; for MRI, the plane of 
acquisition may be axial, sagittal, or coronal). The smaller of these measures is the short 
axis. For example, an abdominal node that is reported as being 20 mm u 30 mm has a 
short axis of 20 mm and qualifies as a malignant, measurable node. In this example, 
20 mm should be recorded as the node measurement. All other pathological nodes 


Columbia University Medical Center 
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114 
 
(those with short axis  10 mm but  15 mm) should be considered non-target lesions. 
Nodes that have a short axis of  10 mm are considered non-pathological and should 
not be recorded or followed. 
All lesions (or sites of disease) not selected as target lesions (measurable or non-
measurable), including pathological lymph nodes, should be identified as non-target 
lesions and should also be recorded at baseline. Measurements are not required. It is 
possible to record multiple non-target lesions involving the same organ as a single item 
on the CRF (e.g., "multiple enlarged pelvic lymph nodes" or "multiple liver metastases"). 
NEW LESIONS 
New lesions identified after baseline will be evaluated for measurability with use of 
the same criteria applied to prospective target lesions at baseline per RECIST (e.g., non-
lymph node lesions must be ≥10 mm on the longest diameter; new lymph nodes must 
be ≥15 mm on the short axis [see note below]). All new lesions (measurable or non-
measurable) must be assessed and recorded at the time of identification and at all 
subsequent tumor assessment time points. 
Up to a maximum of five measurable new lesions total (and a maximum of two lesions 
per organ) can be included in the calculation of tumor burden that is performed as part of 
the tumor response evaluation. New lesion types that would not qualify as target 
lesions per RECIST cannot be included in the calculation of tumor burden and thus 
will not affect overall tumor response evaluation. New lesions that are not measurable 
at first appearance but meet measurability criteria at a subsequent time point can be 
included in the tumor response evaluation from that point on, if the maximum number of 
measurable new lesions has not been reached. 
Note regarding new lymph node lesions: If at first appearance the short axis of a 
lymph node lesion is ≥15 mm, it will be considered a measurable new lesion. If at first 
appearance the short axis of a lymph node lesion is ≥10 mm and  15 mm, the lymph 
node will not be considered measurable but will still be considered a new lesion and 
should be identified as a non-measurable new lesion. If at first appearance the short axis 
of a lymph node is  10 mm, the lymph node should not be considered pathological and 
should not be considered a new lesion. A lymph node can subsequently become 
measurable, when the short axis is ≥15 mm. 
CALCULATION OF SUM OF DIAMETERS 
A sum of the diameters (longest diameter for non-lymph node lesions, short axis for 
lymph node lesions) will be calculated for all target lesions at baseline as a measure of 
tumor burden. At each subsequent tumor assessment, a sum of the diameters 
(longest diameter for non-lymph node lesions, short axis for lymph node lesions) will be 
calculated for all target lesions plus measurable new lesions (up to five new lesions, 


Columbia University Medical Center 
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115 
 
with a maximum of two new lesions per organ) that have emerged after baseline. 
Hence, each net percentage change in tumor burden per assessment accounts for 
the size and growth kinetics of both old lesions and new lesions as they appear. 
Measuring Lymph Nodes 
If at first appearance the short axis of a new lymph node lesion is  15 mm, it will be 
considered a measurable new lesion and may be included in the sum of the diameters. 
If the new lymph node lesion is included in the sum of diameters, it will continue to be 
measured and included in the sum of diameters at subsequent time points, even if the 
short axis decreases to  15 mm (or even  10 mm). However, if it subsequently 
decreases to  10 mm and all other lesions are no longer detectable or have also 
decreased to a short axis of  10 mm (if lymph nodes), a response assessment of 
complete response may be assigned. 
Lymph nodes should always have the actual short axis measurement recorded 
(measured in the same anatomical plane as the baseline examination), even if the node 
regresses to  10 mm during the study. Thus, when lymph nodes are included in the sum 
of diameters, the sum may not be zero even if complete response criteria are met, 
because a normal lymph node is defined as having a short axis of  10 mm. 
Measuring Lesions That Become Too Small to Measure 
During the study, all target lesions and up to five measurable new lesions (lymph 
node and non-lymph node) should have their actual measurements recorded at each 
subsequent evaluation, even when very small (e.g., 2 mm). However, sometimes 
lesions or lymph nodes become so faint on CT scan that the radiologist may not feel 
comfortable assigning an exact measurement and may report them as being too small 
to measure. When this occurs, it is important that a value be recorded on the CRF, as 
follows: 
 
If it is the opinion of the radiologist that the lesion has likely disappeared, the 
measurement should be recorded as 0 mm. 
 
If the lesion is believed to be present and is faintly seen but too small to measure, 
a default value of 5 mm should be assigned and "too small to measure" should be 
ticked. (Note: It is less likely that this rule will be used for lymph nodes because 
they usually have a definable size when normal and are frequently surrounded 
by fat such as in the retroperitoneum; however, if a lymph node is believed to be 
present and is faintly seen but too small to measure, a default value of 5 mm 
should be assigned in this circumstance as well, and "too small to measure" 
should also be ticked). 
 
To reiterate, however, if the radiologist is able to provide an actual measurement, that 
measurement should be recorded, even if it is  5 mm, and in that case "too small to 
measure" should not be ticked. 


Columbia University Medical Center 
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116 
 
Measuring Lesions That Split or Coalesce on Treatment 
When non-lymph node lesions fragment, the longest diameters of the fragmented 
portions should be added together to calculate the sum of diameters. Similarly, as lesions 
coalesce, a plane between them may be maintained that would aid in obtaining 
maximal diameter measurements of each individual lesion. If the lesions have truly 
coalesced such that they are no longer separable, the vector of the longest diameter in 
this instance should be the maximum longest diameter for the coalesced lesion. 
EVALUATION OF NON-TARGET LESIONS AND NON-MEASURABLE NEW 
LESIONS 
Measurements are not required for non-target lesions or non-measurable new lesions. 
Non-target lesions should be noted at baseline, and non-measurable new lesions 
should be noted at the time of identification. At subsequent evaluations, non-target 
lesions and non-measurable new lesions will be categorized as "present" or "absent." 
After baseline, changes in non-target lesions or non-measurable new lesions (or 
measurable new lesions in excess of five total or two per organ) will contribute only in 
the assessment of complete response (i.e., a complete response is attained only with 
the complete disappearance of all tumor lesions, including non-target lesions and 
non-measurable new lesions) and will not be used to assess progressive disease. 
DEFINITION OF RESPONSE CRITERIA 
Definitions of the criteria used to determine objective tumor response are provided 
below: 
 
Progressive disease (PD): At least a 20% increase in the sum of diameters of all 
target lesions plus measurable new lesions (up to a maximum of five total or 
two per organ), taking as reference the smallest sum of diameters on study 
(including baseline) 
In addition to the relative increase of 20%, the sum of diameters must also 
demonstrate an absolute increase of  5 mm. 
New lesions alone do not qualify as progressive disease. However, their 
contribution to total tumor burden is factored into the sum of the diameters, which is 
used to determine the overall immune-modified RECIST tumor response. 
 
Stable disease (SD): Neither sufficient shrinkage to qualify for CR or partial 
response (PR) nor sufficient increase to qualify for PD. 
 
MISSING ASSESSMENTS AND NOT-EVALUABLE DESIGNATION 
When no imaging/measurement is done at all at a particular time point, the patient is not 
evaluable at that time point. If measurements are made on only a subset of target or 
measurable new lesions at a time point, usually the case is also considered not 
evaluable at that time point, unless a convincing argument can be made that the 


Columbia University Medical Center 
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117 
 
contribution of the individual missing lesions would not change the assigned time point 
response. This would be most likely to happen in the case of treatment beyond 
recurrence. For example, if a patient had a recurrence sum of 50 mm with three 
measured lesions and during the study only two lesions were assessed, but those gave a 
sum of 80 mm, the patient will have achieved confirmed recurrence status, regardless 
of the contribution of the missing lesion. 
SPECIAL NOTES ON RESPONSE ASSESSMENT 
Patients with a global deterioration in health status requiring discontinuation of treatment 
without objective evidence of disease recurrence at that time should be reported as 
having "symptomatic deterioration." Every effort should be made to document 
objective recurrence even after discontinuation of treatment. Symptomatic 
deterioration is not a descriptor of an objective response; it is a reason for stopping 
study therapy. The objective response status of such patients is to be determined by 
evaluation of target and non-target lesions, as well as new lesions. 
Stopping Rules 
The study may be discontinued if the study is terminated by the data and safety 
monitoring committee, the FDA, or other regulatory authorities. 
A safety committee of participating surgeons and medical oncologists at CUMC and 
Memorial Sloan Kettering Cancer Center will convene on a regularly scheduled basis 
to discuss study conduct. If greater than two of the 20 patients per cohort are 
unable to undergo surgery, or greater than four of the 20 patients per cohort 
have a greater than 14-day delay in surgery, deemed related to study treatment, 
enrollment to that arm will be halted and an analysis performed by the PI. The 
PI, in consultation with the safety committee, will either modify the treatment regimen 
or discontinue the arm if an alternate safe regimen is not deemed feasible. 
Other Response Parameters 
Exploratory endpoints will be evaluated on tissue samples obtained from core 
biopsies and resected tissue for co-immunofluoresence for immune markers, 
RNA-sequence analysis for expression profile within neoplastic epithelium and 
stroma, and other analysis. Please refer to the laboratory manual describing sample 
collection procedures. 
14. 
DATA REPORTING / REGULATORY REQUIREMENTS 
Adverse event lists, guidelines, and instructions for AE reporting can be found in 
Section 11 (Adverse Events: List and Reporting Requirements). The Data Safety 
Monitoring Plan is described in Section 14.3. 


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The Herbert Irving Comprehensive Cancer Center has an electronic CTMS that will 
be used for data collection. CRFs for the study will be built into the CTMS for data entry. 
The system has full auditing capabilities which is web-based and housed on a server 
in a fully HIPAA compliant server room with restricted access and video camera 
monitoring. All users must login with their own application username and password. 
Users off campus must first access the Virtual Private Network with their assigned 
campus username and password and then use their application credentials. Users are 
only able to see study information if they are indicated as study personnel in our 
electronic IRB system. Users are limited to access based on the role assigned in their 
corresponding protocol. Patient data is entered directly into the system, which (in the 
case of Columbia patients) confirms the correct identity of patients via an interface with 
the electronic medical patient index. Staff with the appropriate IRB defined roles can run 
reports within the system for reporting purposes. 
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Case Report Forms will be completed for each patient enrolled into the clinical study 
through the CTMS. It is the investigator s responsibility for ensuring that all clinical and 
laboratory data entered on the corresponding CRFs are complete, accurate and 
authentic. 
Serious Adverse Events that result in the patient not being able to undergo surgery, or 
result in a delay of surgery of greater than 14 days, as described in Section 5.1, are 
required to be entered in the Adverse Event Module in Velos within 24 hours of the 
event occurring/Investigator being aware of event. 
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The NCI-approved Data Safety and Monitoring Committee (DSMC) of the Herbert Irving 
Comprehensive Cancer Center (HICCC) will monitor every patient who receives 
treatment on this protocol for toxicity. This protocol will adhere to the policies of the 
currently approved HICCC Data and Safety Monitoring Plan (DSMP), which is in 
accordance with NCI and CUMC-IRB policy and guidelines. The committee chair is 
appointed by the HICCC Director. The committee consists of HICCC faculty and staff 
with expertise in oncology, research pharmacy, research nursing, and data 
management. The DSMC convenes twice a month to review patient safety and the 
conduct of the trial. The PI will submit data and safety monitoring reports to the DSMC 
at a frequency to be determined by the DSMC based on risk to the patients. 
At the time of renewal, the study team will submit the most recent DSMC approval letter 
for safety review to the CUMC IRB. Any modifications that are required by the DSMC 
to ensure patient safety will be submitted to the IRB. All protocol deviations, violations, 


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119 
 
and eligibility waivers will be submitted to and approved by the DSMC prior to being 
reported to the IRB. All study data reviewed and discussed during these meetings will 
be kept confidential. 
For multicenter research, the PI will assure that there is a mechanism in place to 
distribute the report to all participating investigators for submission to their local IRB. 
The report will document that a review of data and outcomes across all centers took 
place on a given date. It will summarize the DSMC s review of the cumulative 
toxicities reported from all participating sites without specific disclosure by treatment 
arm. It will also inform site investigators of the study the DSMC s conclusion with 
respect to progress or need for modification of the protocol. 
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Independent monitoring of the clinical study for protocol and Good Clinical Practice 
(GCP) compliance will be conducted periodically by the CPDM Compliance Core on 
behalf of the HICCC DSMC. Additionally, the Compliance Oversight Committee of the 
IRB at CUMC may audit the study at any time per institutional policies and 
procedures. The investigator-Sponsor and CUMC will permit direct access of the 
study monitors and appropriate regulatory authorities to the study data and to the 
corresponding source data and documents to verify the accuracy of this data. 
A risk-based approach will be used by the Compliance Core to determine the frequency, 
number of patient charts, and data elements to be monitored. The Compliance 
Coordinator will review the study status and summarize enrollment, toxicities, SAEs/UPs, 
dose escalation, statistical endpoints (e.g., stopping rules), etc. for the full DSMC 
membership at the regularly scheduled meetings. 
Internal On-site Monitoring: 
x 
Initial, recurrent, and close-out on-site monitoring visits will also be conducted 
at remote clinical sites, as appropriate/feasible. Other sites will have monitoring 
performed remotely (see below for further details). 
x 
The Compliance Coordinator will communicate with the site coordinator/Site Principle 
Investigator to schedule the monitoring visit and arrange for access to study 
materials and documentation. 
x 
The assigned Compliance Coordinator will monitor IIT trials within 1 month after the 
first patient is enrolled and throughout the life of the study to ensure that the 
study is being conducted in accordance with the protocol, GCP, applicable federal 
and local regulations, and per all applicable SOPs. The Compliance Coordinator 
is responsible to notify the site s lead PI and CRNP/CRN/CRC of upcoming 
monitor visits and convey what information and documentation will be required for 
the visit(s). The Compliance Coordinator is responsible for verifying that informed 


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120 
 
consent is properly obtained, eligibility is met (via the central registration process), 
and all study procedures are conducted according to the study protocol. The 
Compliance Coordinator will also verify that the data reported in the CRF s 
accurately reflect source documents, that all toxicities have been reported to 
date, and that all SAE s/UPs/deviations/violations have been reported according 
to local IRB and HICCC DSMC requirements. The Compliance Coordinator will 
issue queries and ensure resolution in a timely and efficient manner. The 
Compliance Coordinator will also monitor for applicable regulatory compliance 
and research pharmacy compliance (if applicable) and communicate any 
deficiencies as appropriate. 
 
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Information about study patients will be kept confidential and managed according to the 
requirements of the HIPAA. Those regulations require a signed patient authorization 
informing the patient of the following: 
x 
What protected health information (PHI) will be collected from patients in this study 
x 
Who will have access to that information and why 
x 
Who will use or disclose that information 
x 
The rights of a research patient to revoke their authorization for use of their PHI. 
 
In the event that a patient revokes authorization to collect or use PHI, the 
investigator, by regulation, retains the ability to use all information collected prior to 
the revocation of patient authorization. For patients that have revoked authorization to 
collect or use PHI, attempts should be made to obtain permission to collect at least vital 
status (e.g., that the patient is alive) at the end of their scheduled study period. 
The patient binders will be maintained with in the CPDM offices, a secured floor 
within the Herbert Irving Pavilion and only the investigator and study staff will have 
access to the file. 
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Source data is all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. 
Source data are contained in source documents. Examples of these original 
documents, and data records include: hospital records, clinical and office charts, 
laboratory notes, memoranda, patients  diaries or evaluation checklists, pharmacy 
dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate and complete, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, patient files, and records 
kept at the pharmacy, at the laboratories, and at medico-technical departments involved 
in the clinical trial. 


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Records relating to a specific research activity, including research records collected 
by investigators, must be maintained for at least 3 years after completion of the research 
(45 CFR 46.115(b); 21 CFR 56.115(b); 21 CFR 312.62). This minimum retention 
period applies whether or not any patients were enrolled in the study. 
If the research is FDA regulated, records should be retained for at least 2 years after 
approval of the investigational agent by FDA; if it is not approved, records should be 
retained at least two years after the study is terminated and FDA is notified (note the 
additional requirement below for clinical research studies). 
Clinical records, including consent forms that document clinical intervention or clinical 
diagnostic procedure research-related procedures, must be retained in medical 
records by the institution for at least 7 years, per CUMC and NYP policy which is based 
on state law. 
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This is a randomized phase 2 study with a biological endpoint aimed at comparing 
CD8+ T-cell count within the resected tumor with neoadjuvant atezolizumab vs 
atezolizumab + PEGPH20 or other combinations at the time of surgery. All patients who 
meet inclusion/exclusion criteria and who receive 1 dose of study related treatment will 
be considered evaluable. 
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The primary endpoint is change in the number of intratumoral CD8+ T cells at time of 
surgery between treatment arm(s) compared to the atezolizumab arm. 
Briefly, to obtain CD8+ T-cell count, we will probe formalin-fixed paraffin-embedded 
(FFPE) biopsy and resected tissue sections with distinct markers using quantitative 
multiplex immunofluorescence (qmIF)(Deng et al. 2016). This process involves a novel 
tyramide signal amplification (TSA) multiplexing technique that enables serial staining on 
the same section enabling simultaneous examination of up to eight epitopes. Multiple 
markers for distinct cell types will be used to investigate the tumor microenvironment. 
Some of these include, but are not limited to, pan T-cell (CD3), CD8+ T-cell (CD8), 
CD4+ T-cell (CD4), regulatory T-cell (FOXP3), PD-L1, myeloid (CD68), neoplastic 
(CK19), and nuclear (DAPI) markers. Images are visualized using Vectra
 microscope 
and analyzed using inForm  Tissue Finder
 analysis software, which uses algorithms 
for machine learning based on cell morphology which includes membrane phenotype 
and cytoplasmic and nuclear stains, each cell is also assigned a coordinate on the slide 
for spacial analysis. This information is used to perform nearest neighbor analysis to 


Columbia University Medical Center 
Herbert Irving Comprehensive Cancer Center 
Version Date: 05/13/2019 
 
122 
 
determine the location of cells relative to each other. Distance between immune 
subtypes and neoplastic cells will be analyzed to correlate with tumor cell death and 
clinical outcome. A designated gastrointestinal (GI) pathologist will review each 
hematoxylin and eosin (H&E) stained serial section and qmIF slide to oversee the 
process. Representative areas within the slide will be used for cell counts and nearest 
neighbor analysis. Simple immunohistochemistry (IHC) will be used in unforeseen 
circumstances where qmIF is not possible to quantitate CD8+ T cells. 
Secondary Endpoint: 
a) To estimate the 18-month survival rate and overall survival in patients treated 
with atezolizumab vs atezolizumab + PEGPH20 followed by surgery and 
adjuvant therapy. 
b) To determine the R0 resection rates with atezolizumab vs atezolizumab + PEGPH20 
administered in the neoadjuvant setting. 
c) 
To determine the safety profile with atezolizumab vs atezolizumab + PEGPH20 
followed by surgery and adjuvant therapy. 
d) To evaluate Ca 19-9 biomarker responses to atezolizumab with or without 
PEGPH20 in the neoadjuvant setting. 
e) To evaluate patterns of failure following neoadjuvant atezolizumab with or without 
PEGPH20 and surgery. 
f) 
Intratumoral CD8+ T cells after neoadjuvant atezolizumab alone or combination with 
PEGPH20 at time of surgery will be compared to intratumoral CD8+ T cells within 
resected tumors after no neoadjuvant therapy from matched historical controls. 
 
Exploratory Endpoints: 
a) To isolate the epithelium and stromal tumor compartments for protein 
expression profiling using RNA-seq for subtype classification of PDA. This will be 
performed using LCM on resected tissue samples from patients treated with 
atezolizumab vs atezolizumab + PEGPH20. 
b) To quantitate the change in CD8+ T cells within paired pre-treatment biopsy and 
on-treated resected tumor treated with atezolizumab vs atezolizumab + PEGPH20. 
c) 
To quantitate distinct immune subtypes within on-treatment tumor treated with 
atezolizumab vs atezolizumab + PEGPH20 by quantitative multiplex 
immunofluorescence. 
d) To quantitate the change in immune subtypes within paired pre-treatment biopsy 
and on-treatment resected tumor treated with atezolizumab vs atezolizumab + 
PEGPH20. 
 
Sample size justification: 
For the primary endpoint of CD8+ T-cell infiltration, a group sample size of 17 achieves 
at least 80% power to detect a difference of 1 SD with a significance level (alpha) of 


Columbia University Medical Center 
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123 
 
0.05 using a two-sided two-sample t-test. Since PDA tumors contain sparse CD8+ T 
cells, we expect that a two- fold increase in CD8+ T- cell infiltration will have a 
clinically meaningful effect. From our experience, we estimate an attrition rate of 
15% with inevaluable tissue; therefore, 20 patients per cohort will be recruited. 
Study Arms: 
Arm A. Atezolizumab alone 
Arm B. Atezolizumab with PEGPH20 
Additional arms will be added as deemed appropriate. 
Patients will be randomly assigned to one of the study arms with an approximately equal 
ratio. 
15.2 
STRATIFICATION FACTORS 
There are no stratification factors. 
15.3 
ANALYSIS OF PRIMARY, SECONDARY ENDPOINTS AND 
EVALUATION OF TISSUE  
Primary Analysis: 
The CD8+ T-cell count within the tumor with neoadjuvant atezolizumab vs 
atezolizumab + PEGPH20 or other combinations at the time of surgery will be reported 
using means and standard deviations by group and will be compared using a two-
sample T-test. If the data are not normally distributed, non-parametric models such as 
the Wilcoxon Rank Sum test will be used. Moreover, the distribution of CD8+ T-cell count 
by treatment arm will be assessed using box plots, histograms, and q-q plots. 
Secondary Analysis: 
Overall survival (OS) and Recurrence-free survival 
Overall survival and recurrence-free survival (RFS) will be estimated using the 
Kaplan Meier method. We will calculate and report the 18-months OS rate and the 
median OS/RFS along with their 95% confidence intervals. Kaplan Meier graphs will be 
done. OS and RFS will be compared by treatment arm using the log-rank test. 
R0 Resection Rate 
R0 resection rate is defined by the proportion of patients in whom an R0 resection was 
achieved during surgery which is defined by complete removal of macroscopic 
tumor which contains negative microscopic surgical margins. The R0 resection rate will 
be estimated by the number of patients in whom R0 resection was performed divided 
by total number of patients in each study arm. The R0 resection rate will be reported 


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along with the exact 95% confidence interval. We will compare the R0 resection rates 
using Fisher s exact test. 
6DIHW\
The frequency and count of grade 3 or higher adverse events will be reported by 
treatment group. The maximum grade for each type of adverse events will also be 
reported. These will be reported over 4 periods: 
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Defined as time of starting study-related therapy until induction of anesthesia prior 
to pancreas resection surgery. 
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Surgical complications during time of surgery starting at time of induction of 
anesthesia for surgery until 90 days post- surgery or start of study-related 
adjuvant therapy, whichever is shorter. 
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Defined as period from start of study-related adjuvant therapy until start of 
adjuvant chemotherapy. 
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Defined as period from start of adjuvant chemotherapy until 28 days after 
completing adjuvant therapy. 
 
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Statistical analysis of RNA-Seq expression data derived from samples of the treatment 
arms will be carried out in the R environment for statistical computing (Team RDC 
2016). In order to identify differentially expressed genes between the conditions, we 
will make use voom-limma framework (Ritchie et al. 2015). Briefly, linear models are fit 
for each gene to estimate the coefficients (= effect size) and their standard error. 
Empirical Bayes moderated t-statistics and their associated p-values are then used to 
assess the significance of the observed expression changes. 
In order to evaluate concerted differences of biologically related genes, single sample 
gene set enrichment will be employed via the GSVA R package (H nzelmann et al. 
2013), which produces a gene-set by sample matrix with approximately normally 
distributed enrichment scores which can then be compared between treatment arms 
using for example linear models. Detailed statistical plan is as described in the 
manuscript [Kenneth Olive, submitted]. 


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125 
 
CD8+ T cell infiltration: 
Exploratory studies will measure CD8+ T-cell numbers by immunohistochemistry (IHC) 
or qmIF performed to determine tumor-infiltrating lymphocyte infiltration from paired fresh 
tumor biopsies or resection samples, if available. 
Change in CD8+ T cells before and after treatment will be evaluated and compared 
using paired T-test by treatment. If the expression levels are not normally distributed, 
non-parametric methods such as the Wilcoxon Signed Rank test will be used. The 
change in CD8+ T cells will also be compared by treatment using the two-sample 
T-test. 
Immune subtypes: 
Immune subtypes within the tumor with neoadjuvant atezolizumab vs atezolizumab + 
PEGPH20 or other combinations at the time of surgery will be reported using means and 
standard deviations by treatment group and will be compared using a two-sample T-test. 
In addition, if adequate tissue sample is available, the change in immune subtypes before 
and after treatment will be evaluated and compared using paired T-test by treatment 
group. If the expression levels are not normally distributed, non-parametric methods 
such as the Wilcoxon Signed Rank test will be used. 
15.4 
REPORTING AND EXCLUSIONS 
All patients who signed informed consent, and receive any protocol-defined treatment 
will be evaluable from the time of their first treatment with any study drug. 
16. 
PROTECTION OF HUMAN PATIENTS 
This study is to be conducted in accordance with applicable government regulations 
and Institutional research policies and procedures. An IND annual report will be 
submitted to the FDA in accordance with 21.CFR 312.33. 
This protocol and any amendments will be submitted to a properly constituted IRB, in 
agreement with local legal prescriptions, for formal approval of the study conduct. The 
decision of the IRB concerning the conduct of the study will be made in writing to 
the investigator and a copy of this decision will be obtained before commencement of 
this study. 
All patients for this study will be provided a consent form describing this study and 
providing sufficient information for patients to make an informed decision about their 
participation in this study. This consent form will be submitted with the protocol for 
review and approval by the IRB for the study. The formal consent of a patient, using 
the IRB-approved consent form, must be obtained before that patient is submitted to 


Columbia University Medical Center 
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Version Date: 05/13/2019 
 
126 
 
any study procedure. This consent form must be signed by the patient or legally 
acceptable surrogate, as outlined in the IRB approved protocol, and the investigator-
designated research professional obtaining the consent. 
17. 
STUDY FINANCES 
Investigator initiated clinical trial is supported by Genentech/Roche. 
17.1 
CONFLICT OF INTEREST 
Any investigator who has a conflict of interest with this study (patent ownership, 
royalties, or financial gain greater than the minimum allowable by their institution, etc.) 
must have the conflict reviewed by the Columbia University Conflict of Interest Committee 
with a Committee-sanctioned conflict management plan that has been reviewed and 
approved prior to participation in this study. All CUMC investigators will follow the 
University conflict of interest policy. 
17.2 
PATIENT STIPENDS OR PAYMENTS 
There are no patient stipends or payments. 
18. 
PUBLICATION PLAN 
Neither the complete results nor any part of the results of the study carried out under 
this protocol, nor any of the information provided by the Sponsor for the purposes of 
performing the study, will be published or passed on to any third party without the 
consent of the study Sponsor. Any investigator involved with this study is obligated to 
provide the Sponsor with complete test results and all data derived from the study. 
19. 
GUIDELINES FOR AFFILIATE INSTITUTIONS IN MULTICENTER 
STUDIES 
19.1 
MULTI-SITE COMMUNICATION: 
The CPDM Office at CUMC provides administration, data management, and 
organizational support for the affiliate sites in the conduct of a multicenter clinical trial. 
The CPDM Office will coordinate regularly scheduled conference calls with affiliate 
sites. 
The following issues will be discussed, as appropriate: 
 
Enrollment information 
 
Cohort updates (e.g., DLTs) 
 
Adverse events (e.g., new adverse events and updates on unresolved adverse 
events and new safety information) 


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x 
Protocol violations 
x 
Other issues affecting the conduct of the study 
 
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Protocol specific documents are distributed to affiliate sites once CUMC IRB 
approval has been obtained. 
x 
The affiliate site must submit a draft of site-specific revisions to protocol and/or 
consent form documents for review and approval by the Sponsor-Investigator prior 
to submission to the local IRB. Draft documents should be sent to the 
studyspecific email address. The site will be provided confirmation that they are 
approved to submit to their local IRB. 
x 
Protocol amendments must be approved by the affiliate site s local IRB within 
90 days of distribution to the site by the Sponsor-Investigator. 
 
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The Sponsor-Investigator will ensure that proper requests are made of sites and that 
the following documentation is collected, prior to the initiation of an affiliate site. 
x 
Curriculum vita (CV) of site s PI, Co-Investigators and other research staff listed on 
FDA 1572 (signed and dated copy within 2 years) 
x 
Medical licenses of PI and Co-Investigators (current copy) 
x 
Human patients training certificates for PI and Co-Investigators 
x 
CLIA/laboratory certifications for local laboratories listed on FDA 1572 
x 
Local laboratory Director s CV and license 
x 
Local laboratory reference ranges 
x 
IRB roster or statement of compliance 
x 
FDA Form 1572, if applicable (wet ink originals required) 
x 
Financial disclosure forms for all members listed on FDA 1572 (wet ink originals 
required) 
 
Ongoing Regulatory Documentation:  Sponsor-Investigator will ensure that proper 
requests are made of sites and that the following documentation is collected throughout 
the course of the study. 
x 
IRB approval letters for all protocol modifications and all renewals 
x 
IRB-approved consent forms 
x 
Current IRB roster, if statement of compliance is not provided as part of site initiation 
x 
FDA Form 1572, if applicable as updates are required 


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x 
Updated investigator and site information where relevant (e.g., CV, medical 
licensure and Financial Disclosure for new sub-investigator, local laboratory 
information) 
 
Regulatory documents may be sent to AAAS1908@lists.cumc.columbia.edu or to the 
following address if wet ink originals are required: 
Clinical Protocol & Data Management Office  
161 Fort Washington Ave. 
Herbert Irving Pavilion  
Mezzanine Level, M-203  
New York, NY 10032 
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Columbia University will schedule a site initiation visit once IRB approval has been 
submitted from the affiliate site. 
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All Affiliate Institutions PXVWregister patients with the coordinating center (CUMC) SULRU
to any administration of study drug/intervention/local institution registration. Please 
see instructions below: 
1. 
Within 48 hours of obtaining consent (excluding holidays and weekends), the 
Affiliate Institution CRN and/or CRC is required to submit the following documents 
to the coordinating center s Multicenter Core and the study email 
AAAS1908@lists.cumc.columbia.edu. The coordinating center s designee will 
review the documents for accurateness, and subsequently submit the documents 
to the CPDM Central Registration Office via email at with a request to register the 
patient pending eligibility.  The title of the email should read, AAAS1908 
Pending Patient Registration Request (PHI) . The following documents should be 
submitted with the pending registration request, as applicable: 
a) Redacted Completed/signed IRB approved/stamped Informed Consent 
Forms, including additional study ICFs (e.g., tissue, DNA, etc.), as applicable 
b) Redacted Signed HIPAA (or institutional equivalent) 
c) 
MCT CPDM Velos Note to File form 
2. 
The Affiliate Institution s investigator/research nurse/data manager/coordinator 
must contact the coordinating center s designee (CUMC Multicenter Core) via 
telephone or email to communicate the following: 
a) 
Notify of pending registration request 
b) Confirm method of registration request submission (email or fax) 


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c) 
Communicate expected time-line of registration request submission (e.g., same 
day, next day, within the hour, etc.) 
3. 
To complete registration, the Affiliate Institution s investigator/research 
nurse/data manager/coordinator should then submit the following documents to 
the CUMC Multicenter Core/designee: 
a) 
A signed Affiliate Site Eligibility Checklist (signed by the investigator) 
b) 
Copies of redacted source documentation necessary for each item to be 
verified on the CUMC-specific Eligibility Checklist, including but not limited to: 
±
Copy of required laboratory test and procedure reports (e.g., hematology, 
serum chemistry, pregnancy test when applicable, MRI reports, CT/bone 
scans, etc.) 
±
Copy of pathology and surgical reports 
±
Copy of clinic note(s) capturing the consent process information, along with 
providing source documentation of any other items needed for 
screening/eligibility that are not captured in other source document forms. 
(e.g., positive investigator statements of unique eligibility items not captured 
via other direct source documentation, concomitant medication lists, etc.) 
c) 
Please note: subject line of email or fax should include the following: 
AAAS1908 Complete Patient Registration Request (PHI) . 
4. 
Upon receipt of the above mentioned documents, the designated study-specific 
Clinical Research Coordinator will review all documents and verify patient eligibility. 
If any questions arise during the review process, queries in the form of emails will be 
addressed to the applicable affiliate site study team personnel for clarification prior 
to enrollment. Upon verification, the CUMC study-specific designee will then forward 
all documents to the CPDM Central Registration Office for central registration (as 
described above). The CPDM Central Registration Registrar will review all 
applicable documents and communicate to the CUMC study-specific designee in 
order to clarify any items. The CUMC study specific designee will communicate with 
the applicable site study team personnel for additional clarifications necessary prior 
to enrollment. 
5. 
Upon receipt of the patient registration notification email, the CUMC study-specific 
designee will forward the notification email (which will include the study-specific 
patient ID) to the affiliate site s PI, Consenting Professional, and applicable research 
personnel. This notification should be filed in the patient research binder 
accordingly. Protocol therapy may not be initiated prior to receipt of this notification 
from the coordinating center. 
6. 
All screenfail/ineligible patients, as well as patients who withdraw consent prior to 
enrollment/initiation of protocol therapy must be submitted to the Central 
Registration Office in a manner analogous to the procedures noted above. 


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Applicable source documentation will be required within the corresponding 
submissions. 
 
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The Affiliate site MUST submit a prospective deviation request to the CUMC lead PI for 
review and submission to the HICCC DSMC and CUMC IRB. Approvals must be 
obtained from all entities prior to implementation at the Affiliate site. If a prospective 
protocol deviation request is submitted for review (from an Affiliate site), the PI/site 
memo(s), HICCC DSMC approval(s) and correspondence and CUMC IRB deviation 
approval letter(s) should be forwarded to the Affiliate site for documentation. The 
Affiliate site is also required to obtain prospective local IRB approval as per institutional 
policies/procedures prior to implementing the proposed deviation. All documents and 
determinations must be clearly documented in the study patient s medical record, 
research chart and regulatory binder, as described. 
The HICCC DSMC and PRMC will no longer accept eligibility deviations but will still 
continue to accept deviations not related to eligibility. 
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1. 
Initial, recurrent, and close-out on-site monitoring visits will also be conducted at 
Affiliate sites, as appropriate/feasible. Other sites will have monitoring performed 
remotely (see below for further details). 
The study Monitoring Visit Log will be completed and signed by the monitor and the 
PI/CRNP/CRN and/or CRC and will be filed in the regulatory binder. 
2. 
The Compliance Coordinator will communicate with the Affiliate site coordinator/Site 
Principle Investigator to schedule the monitoring visit and arrange for access to 
study materials and documentation. 
3. 
The Compliance Coordinator will monitor IIT trials within 1 month after the first 
patient is enrolled at the Affiliate site and throughout the life of the study to ensure 
that the study is being conducted in accordance with the protocol, GCP, applicable 
federal and local regulations, and per all applicable SOPs. The Compliance 
Coordinator is responsible to notify the participating site PI and CRNP/CRN/CRC of 
upcoming monitor visits and convey what information and documentation will be 
required for the visit(s). The Compliance Coordinator is responsible for verifying that 
informed consent is properly obtained, eligibility is met (via the central registration 
process), and all study procedures are conducted according to the study protocol. 
The Compliance Coordinator will also verify that the data reported in the CRF s 
accurately reflect source documents, that all toxicities have been reported to date, 
and that all SAE s/UPs/deviations/violations have been reported according to 
Coordinating Center, local IRB and HICCC DSMC requirements. The Compliance 


Columbia University Medical Center 
Herbert Irving Comprehensive Cancer Center 
Version Date: 05/13/2019 
 
131 
 
Coordinator will issue queries and ensure resolution in a timely and efficient 
manner. The Compliance Coordinator will also monitor for applicable regulatory 
compliance and research pharmacy compliance (if applicable) and communicate 
any deficiencies as appropriate. 
4. 
A site initiation visit (SIV) (or) teleconference will be scheduled and conducted prior 
to study drug being made available (if applicable) and before any patients are 
enrolled on a study at the Affiliate site. 
 
Remote MCT Monitoring: 
 
When necessary (due to logistical constraints), Affiliate sites will be monitored 
remotely by a designated Compliance Coordinator. Sites will be informed of this 
remote monitoring process on a site by site basis. 
 
Affiliate sites will be monitored by the Compliance Coordinator on both a regulatory 
level, as well as a clinical data/source documentation review level. 
 
Redacted source documents (applicable to supporting the protocolspecific CRF 
data requirements) will be sent to the designated Compliance Coordinator via 
fax or secure email for all patients enrolled at Affiliate sites. Timelines for 
submission procedures will be defined on a case by case basis. 
 
The Compliance Coordinator will review all submitted redacted source 
documents against the data entered on the protocol specific CRFs. The 
Compliance Coordinator will issue queries when/if necessary. 
 
The Affiliate site research staff will respond to queries within 30 days. If queries 
remain outstanding, the Compliance Coordinator will send a delinquent query 
reminder for the outstanding items. 
 
The remote monitoring procedures will include review of applicable redacted 
source documentation and supporting applicable documents to determine 
compliance regarding: 
a) 
Informed consent procedures 
b) 
Eligibility criteria 
c) 
Protocol specific treatment compliance 
d) 
Protocol specific toxicity/outcome documentation/compliance 
e) 
Protocol specific schedule of events (e.g., baseline visits, pre-treatment, on 
study, follow-up) 
f) 
Participating site IRB documents (e.g., IRB amendment approvals, annual 
renewals, SAE/UP submissions, violation/deviation submissions, IND Safety 
Reports submissions, etc). 
g) 
Required specimen submissions (e.g., tissue specimens, research blood 
specimens, etc.) 
h) 
Pharmacy accountability records 


Columbia University Medical Center 
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132 
 
i) 
Adherence to the CRF submission timeframes to CUMC (within the protocol 
specified timeframes) 
 
Affiliate site remote monitoring reports will be sent to the lead PI, HICCC DSMC, 
and Affiliate sites after each remote monitoring review. Reports will include 
information regarding data submission timeliness/accuracy, protocol adherence 
items, query resolution status, regulatory status, and overall Affiliate site 
performance. These reports will be generated by the Compliance Coordinator and 
reviewed with the Compliance Core Manager prior to dissemination. 
 
19.8 
ADVERSE EVENT REPORTING 
Sponsor Reporting: Notifying participating investigators at affiliate sites of 
adverse events 
It is the responsibility of the study Sponsor to notify all affiliate sites, in a written IND safety 
report, of any adverse event associated with the use of the drug that is both serious 
and unexpected, as well as any finding from tests in laboratory animals that suggest 
a significant risk for human patients. Additionally, Sponsors are also required to 
identify in IND safety reports all previous reports concerning similar adverse events 
and to analyze the significance of the current event in light of the previous reports. 
Sub-Site Serious Adverse Event Reporting Procedures: 
Each participating investigator is required to abide by the reporting requirements set by 
Columbia University Medical Center. The study must be conducted in compliance with 
FDA regulations, local safety reporting requirements, and reporting requirements of the 
PI. 
Participating investigators must report each serious adverse event to the Columbia 
University Medical Center Overall PI within 24 hours of learning of the occurrence using 
the SAE Report Form. In the event that the participating investigator does not become 
aware of the serious adverse event immediately (e.g., participant sought treatment 
elsewhere), the participating investigator is to report the event within 24 hours after 
learning of it and document the time of his or her first awareness of the adverse event. 
Report serious adverse events by telephone, email, or facsimile to: 
 
Gulam Abbas Manji, M.D/Ph.D.  
161 Fort Washington Avenue  
New York, NY 10032 
Telephone: 212-304-6357 (Multicenter Trial Number)  
Fax: 212-304-6330 (Multicenter Trial Fax) 
Email:  CPDM Multicenter Trials Core (AAAS1908@lists.cumc.columbia.edu) 


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The participating investigator must provide follow-up information on the serious adverse 
event until resolution of the event. Follow-up information should describe whether the 
event has resolved or continues, if and how the event was treated, and whether the 
participant will continue or discontinue study participation.  
Follow-up information is sent to the same person to whom the original SAE Report Form 
was sent, using a new SAE Report Form stating that this is a follow-up to the previously 
reported SAE and giving the date of the original report. Each re-occurrence, 
complication, or progression of the original event should be reported as a follow-up to 
that event regardless of when it occurs. The follow-up information should describe 
whether the event has resolved or continues, if and how it was treated, and whether 
the patient FRQWLQXHGor withdrew from study participation or if study drug was 
interrupted or discontinued. 
If the SAE is not previously documented in the Investigator s Brochure for the study 
drug (new occurrence) and is thought to be related to the investigational agent, the 
Sponsor-Investigator may urgently require further information from the investigator for 
reporting to Health Authorities.
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Non-serious adverse events will be reported to the Columbia University Medical Center 
Overall PI on the toxicity Case Report Forms. 
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All UPs will be reported to the CUMC IRB. SAEs not constituting UPs will be reported to 
the HICCC DSMC. 
Each affiliate site will be responsible for safety reporting to their local IRB. 
Investigators are responsible for complying with their local IRB s reporting 
requirements, though must submit the required reports to their IRB no later than 
7 calendar days following the occurrence of the UP or the Principal s Investigator s 
acquiring knowledge of the UP. Copies of each report and documentation of IRB 
notification and receipt must be included in the regulatory binder. 
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The FDA regulations require Sponsors of clinical studies to notify the FDA and all 
participating investigators of any serious and unexpected adverse experiences that are 
possibly related to the investigational agent. The CUMC PI will review all applicable IND 
Safety Reports and has the responsibly for forwarding the IND Safety Reports to the 
Affiliate Institutions. The Affiliate Institution investigators are to review, send a copy to 
their IRB according to their local IRB s policies and procedures, and file a copy with 


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134 
 
their regulatory documents. All Affiliate site IND Safety Reports submissions, along 
with IRB acknowledgment (per local policies and procedures) are to be forwarded to 
CUMC for placement within the trial master file. 
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Affiliate Site investigators will report to their local Risk Management Office any patient 
safety reports or sentinel events that require reporting according to institutional policy. 
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Each affiliate site will be assigned a site number. Each patient that signs consent should 
be assigned a unique code number consisting of site number followed by a number with 
each new patient being assigned the next sequential number (e.g., 04-10). All sites will 
be required to enter their data in the Velos eResearch, the Clinical Trial Management 
System used for all Cancer- related clinical research at CUMC. All users must login with 
their own application username and password. Users off campus must first access the 
Virtual Private Network with their assigned campus username and password and then 
use their application credentials. 
Patient confidentiality must be maintained according to HIPAA regulations and 
GCP recommendations. Except when required by law, study information shared with 
persons and organizations outside of CUMC must not identify the patient by name, 
social security number, address, telephone number, or any other direct personal 
identifier. 
If the results of this research project are published or presented at a scientific or medical 
meeting, the patient not be identified. Otherwise, all results will be kept confidential and 
will not be divulged (except as required by law) without permission. 
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CUMC is deeply committed to research integrity and strong credibility when it comes 
to the discovery of new treatment concepts, implementation of new clinical research 
techniques, and acceptance of its researcher’s findings by the medical 
establishment. In accord with these ethics, CUMC encourages and supports its 
investigators in the sharing of final research data and/or details of newly developed 
clinical treatments. 
CUMC’s policies that pertain to patient data sharing conform to CUMC IRB rules, local 
and state laws, and HIPAA privacy regulations. The primary reason for this is to 
protect the privacy of patients who participate in clinical trials. The data can be made 
available for continuing review by federal agencies upon request and for ongoing study 


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135 
 
safety reviews by the PI, Statistician, Data Safety and Monitoring Board (DSMB), and, in 
other instances, the CUMC IRB. 
Data collected during the course of this clinical trial will primarily be shared with other 
investigators and University staff, the IRB, FDA, and other reporting agencies, and/or 
transferred to other collaborators. Prior to transfer, the data collected must comply with, 
and must be limited by, the CUMC’s guidelines for Protecting the Rights and Privacy of 
Human Patients. 
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Informed consent, including HIPPA authorization, must be obtained on all patients prior 
to their participation. Always keep the original signed and dated consent form, with the 
redacted source documents and eligibility checklist. Velos eResearch will be used as 
the electronic clinical trials and data management system. Affiliate sites will enter 
data directly into Velos eResearch via customized case report forms for the study. 
The research staff will generate reports from Velos eResearch to ensure timely 
submission of data by affiliate sites. This resource allows for the timely analysis of 
particular data sets for safety analysis. 
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The PI is required to maintain adequate records of the disposition of the drug, including 
dates, quantity, and use by patients, as well as written records of the disposition of the 
drug when the study ends. 
The PI is required to prepare and maintain adequate and accurate case histories that 
record all observations and other data pertinent to the investigation on each 
individual administered the investigational drug or employed as a control in the 
investigation. Case histories include the case report forms and supporting data including, 
for example, signed and dated consent forms and medical records including, for 
example, progress notes of the physician, the individual’s hospital chart(s), and the 
nurses’ notes. The case history for each individual shall document that informed 
consent was obtained prior to participation in the study. 
Study documentation includes all CRFs, data correction forms or queries, source 
documents, Sponsor-Investigator correspondence, monitoring logs/letters, and 
regulatory documents (e.g., protocol and amendments, CHR correspondence and 
approval, signed patient consent forms). 
Source documents include all recordings of observations or notations of clinical activities 
and all reports and records necessary for the evaluation and reconstruction of the 
clinical research study. 


Columbia University Medical Center 
Herbert Irving Comprehensive Cancer Center 
Version Date: 05/13/2019 
 
136 
 
In accordance with FDA regulations, the investigator shall retain records for a period of 
2 years following the date a marketing application is approved for the drug for the 
indication for which it is being investigated; or, if no application is to be filed or if the 
application is not approved for such indication, until 2 years after the investigation is 
discontinued and FDA is notified. 


Columbia University Medical Center 
Herbert Irving Comprehensive Cancer Center 
Version Date: 05/13/2019 
 
137 
 
Appendix 1  
Radiographic Image Assessment - Baseline Review  
CT/MRI RESULTS 
Was a CT or MRI of the abdomen performed?  
  ☐ Yes 
☐ No  
(If yes), Date of CT or MRI of abdomen (mm/day/yyyy)   
 
(If yes), Primary tumor identified 
  ☐ Yes 
☐ No 
 
  ☐ Not evaluable 
(If yes), Location of tumor 
☐ Head/Neck/Uncinate  ☐ Body/Tail 
 
(If yes), primary tumor size 
Dimension 1 
(mm) 
Dimension 2 
(mm) 
 
CRITERIA FOR RESECTABLE DISEASE 
 
 
 
 
 
 
Tumor contact with aorta 
Tumor contact with celiac 
axis 
Tumor contact with superior mesenteric 
artery Tumor contact with common 
hepatic artery Tumor contact with
  ☐Yes 
  ☐Yes 
  ☐Yes 
  ☐Yes 
  ☐Yes 
☐No
☐No
☐No
☐No
☐No
 
o If yes 
 
 
 
 tumor involvement >180 degrees 
  ☐Yes 
☐No
 
 SMV contour irregularity or thrombosis 
  ☐Yes 
☐No
 Tumor contact with portal vein 
o If yes 
  ☐Yes 
☐No
 
 tumor involvement >180 degrees 
  ☐Yes 
☐No
 
 If yes PV contour irregularity or 
  ☐Yes 
☐No
 Tumor metastasis in chest, abdomen, or pelvis 
  ☐Yes 
☐No
 
RADIOGRAPHIC STAGE 
Radiographic stage (check one) 
☐ Resectable 
☐ Non-resectable 
☐ Metastatic 
☐ Not evaluable 
 
Treatment Site 
☐ Columbia University 
 
☐ Memorial Sloan Kettering  
 
Cancer Center Treatment Site Designated Radiologist Signature: 
 
 
 
 
Date of Review: 
 


 
Appendix 2 
Adverse Events and Management Guidelines for Atezolizumab 
Toxicities associated or possibly associated with atezolizumab treatment should be 
managed according to standard medical practice. Additional tests, such as autoimmune 
serology or biopsies, should be used to evaluate for a possible immunogenic etiology. 
Although most immune-related adverse events observed with immunomodulatory agents 
have been mild and self-limiting, such events should be recognized early and treated 
promptly to avoid potential major complications. Discontinuation of atezolizumab may 
not have an immediate therapeutic effect, and in severe cases, immune-related toxicities 
may require acute management with topical corticosteroids, systemic corticosteroids, or 
other immunosuppressive agents.  
The investigator should consider the benefitrisk balance a given patient may be 
experiencing prior to further administration of atezolizumab. In patients who have met 
the criteria for permanent discontinuation, resumption of atezolizumab may be 
considered if the patient is deriving benefit and has fully recovered from the 
immune-related event. Patients can be re-challenged with atezolizumab only after 
approval has been documented by the investigator (or an appropriate delegate) from the 
study Principal Investigator.  
MANAGEMENT GUIDELINES 
PULMONARY EVENTS 
Dyspnea, cough, fatigue, hypoxia, pneumonitis, and pulmonary infiltrates have been 
associated with the administration of atezolizumab. Patients will be assessed for 
pulmonary signs and symptoms throughout the study and will have computed 
tomography (CT) scans of the chest performed at every tumor assessment.   
All pulmonary events should be thoroughly evaluated for other commonly reported 
etiologies such as pneumonia or other infection, lymphangitic carcinomatosis, pulmonary 
embolism, heart failure, chronic obstructive pulmonary disease, or pulmonary 
hypertension. Management guidelines for pulmonary events are provided in Table 1. 


Appendix 2: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
  
139 
 
Table 1 
Management Guidelines for Pulmonary Events, Including 
Pneumonitis 
Event 
Management 
Pulmonary 
event, Grade 1  
 Continue atezolizumab and monitor closely. 
 Re-evaluate on serial imaging. 
 Consider patient referral to pulmonary specialist. 
Pulmonary 
event, Grade 2 
 Withhold atezolizumab for up to 12 weeks after event onset. 1 
 Refer patient to pulmonary and infectious disease specialists and 
consider bronchoscopy or BAL. 
 Initiate treatment with corticosteroids equivalent to 12 mg/kg/day 
oral prednisone. 
 If event resolves to Grade 1 or better, resume atezolizumab. 2 
 If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab. 3 
 For recurrent events, treat as a Grade 3 or 4 event. 
Pulmonary 
event, Grade 3 
or 4 
 Permanently discontinue atezolizumab. 3 
 Bronchoscopy or BAL is recommended. 
 Initiate treatment with corticosteroids equivalent to 12 mg/kg/day 
oral prednisone. 
 If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
 If event resolves to Grade 1 or better, taper corticosteroids over 
 1 month. 
BAL  bronchoscopic alveolar lavage. 
1 Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
 10 mg/day oral prednisone. The acceptable length of the extended period of time will be 
determined by the investigator. 
2 If corticosteroids have been initiated, they must be tapered over  1 month to the 
equivalent of  10 mg/day oral prednisone before atezolizumab can be resumed. 
3 Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-related event. Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or 
appropriate delegate) and the Principal Investigator.  
 


Appendix 2: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
  
140 
 
HEPATIC EVENTS 
Immune-related hepatitis has been associated with the administration of atezolizumab. 
Eligible patients must have adequate liver function, as manifested by measurements of 
total bilirubin and hepatic transaminases, and liver function will be monitored throughout 
study treatment. Management guidelines for hepatic events are provided in Table 2. 
Patients with right upper-quadrant abdominal pain and/or unexplained nausea or 
vomiting should have liver function tests (LFTs) performed immediately and reviewed 
before administration of the next dose of study drug. 
For patients with elevated LFTs, concurrent medication, viral hepatitis, and toxic or 
neoplastic etiologies should be considered and addressed, as appropriate. 
Table 2 
Management Guidelines for Hepatic Events 
Event 
Management 
Hepatic event, 
Grade 1 
 Continue atezolizumab. 
 Monitor LFTs until values resolve to within normal limits or to 
baseline values.  
Hepatic event, 
Grade 2 
All events: 
 Monitor LFTs more frequently until return to baseline values.  
Events of   5 days’ duration: 
 Withhold atezolizumab for up to 12 weeks after event onset. 1 
 Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day oral prednisone. 
 If event resolves to Grade 1 or better, resume atezolizumab. 2 
 If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab. 3 
LFT  liver function tests. 
1 Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after 
event onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent 
of  10 mg/day oral prednisone. The acceptable length of the extended period of 
time will be determined by the investigator. 
2 If corticosteroids have been initiated, they must be tapered over  1 month to the 
equivalent of  10 mg/day oral prednisone before atezolizumab can be resumed. 
3 Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-related event. Patients can be 
re-challenged with atezolizumab only after approval has been documented by the 
investigator (or an appropriate delegate) and the Principal Investigator.  


Appendix 2: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
  
141 
 
Table 2 
Management Guidelines for Hepatic Events (cont.)  
Event 
Management 
Hepatic event, 
Grade 3 or 4 
 Permanently discontinue atezolizumab. 3 
 Consider patient referral to gastrointestinal specialist for 
evaluation and liver biopsy to establish etiology of hepatic 
injury.  
 Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day oral prednisone. 
 If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
 If event resolves to Grade 1 or better, taper corticosteroids over 
 1 month. 
LFT  liver function tests. 
1 Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after 
event onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent 
of  10 mg/day oral prednisone. The acceptable length of the extended period of 
time must be determined by the investigator. 
2 If corticosteroids have been initiated, they must be tapered over  1 month to the 
equivalent of  10 mg/day oral prednisone before atezolizumab can be resumed. 
3 Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-related event. Patients can be 
re-challenged with atezolizumab only after approval has been documented by the 
investigator (or an appropriate delegate) and the Principal Investigator.  
 
GASTROINTESTINAL EVENTS 
Immune-related colitis has been associated with the administration of atezolizumab. 
Management guidelines for diarrhea or colitis are provided in Table 3. 
All events of diarrhea or colitis should be thoroughly evaluated for other more common 
etiologies. For events of significant duration or magnitude or associated with signs of 
systemic inflammation or acute-phase reactants (e.g., increased C-reactive protein, 
platelet count, or bandemia): Perform sigmoidoscopy (or colonoscopy, if appropriate) 
with colonic biopsy, with three to five specimens for standard paraffin block to check for 
inflammation and lymphocytic infiltrates to confirm colitis diagnosis.  


Appendix 2: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
  
142 
 
Table 3 
Management Guidelines for Gastrointestinal Events (Diarrhea or 
Colitis) 
Event 
Management 
Diarrhea or 
colitis, Grade 1 
 Continue atezolizumab. 
 Initiate symptomatic treatment. 
 Endoscopy is recommended if symptoms persist for  7 days. 
 Monitor closely. 
Diarrhea or 
colitis, Grade 2 
 Withhold atezolizumab for up to 12 weeks after event onset. 1 
 Initiate symptomatic treatment. 
 Patient referral to GI specialist is recommended. 
 For recurrent events or events that persist  5 days, initiate treatment 
with corticosteroids equivalent to 12 mg/kg/day oral prednisone.  
 If event resolves to Grade 1 or better, resume atezolizumab. 2 
 If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab. 3 
Diarrhea or 
colitis, Grade 3 
 Withhold atezolizumab for up to 12 weeks after event onset. 1 
 Refer patient to GI specialist for evaluation and confirmatory biopsy. 
 Initiate treatment with corticosteroids equivalent to 12 mg/kg/day IV 
methylprednisolone and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement. 
 If event resolves to Grade 1 or better, resume atezolizumab. 2 
 If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab. 3 
GI  gastrointestinal. 
1 Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
 10 mg/day oral prednisone. The acceptable length of the extended period of time must 
be determined by the investigator. 
2 If corticosteroids have been initiated, they must be tapered over  1 month to the 
equivalent of  10 mg/day oral prednisone before atezolizumab can be resumed. 
3 Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-related event. Patients can be re-challenged with 
atezolizumab only after approval has been documented by the investigator (or an 
appropriate delegate) and the Principal Investigator.  


Appendix 2: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
  
143 
 
Table 3 
Management Guidelines for Gastrointestinal Events (Diarrhea or 
Colitis) (cont.) 
 
Event 
Management 
Diarrhea or 
colitis, Grade 4 
 Permanently discontinue atezolizumab. 3 
 Refer patient to GI specialist for evaluation and confirmation biopsy. 
 Initiate treatment with corticosteroids equivalent to 12 mg/kg/day IV 
methylprednisolone and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement. 
 If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
 If event resolves to Grade 1 or better, taper corticosteroids over 
 1 month. 
GI  gastrointestinal. 
1 Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
 10 mg/day oral prednisone. The acceptable length of the extended period of time must 
be determined by the investigator. 
2 If corticosteroids have been initiated, they must be tapered over  1 month to the 
equivalent of  10 mg/day oral prednisone before atezolizumab can be resumed. 
3 Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-related event. Patients can be re-challenged with 
atezolizumab only after approval has been documented by the investigator (or an 
appropriate delegate) and the Principal Investigator.  
 
ENDOCRINE EVENTS 
Thyroid disorders, adrenal insufficiency, diabetes mellitus, and pituitary disorders have 
been associated with the administration of atezolizumab. Management guidelines for 
endocrine events are provided in Table 4. 
Patients with unexplained symptoms such as headache, fatigue, myalgias, impotence, 
constipation, or mental status changes should be investigated for the presence of 
thyroid, pituitary, or adrenal endocrinopathies. The patient should be referred to an 
endocrinologist if an endocrinopathy is suspected. Thyroid-stimulating hormone (TSH) 
and free triiodothyronine and thyroxine levels should be measured to determine whether 
thyroid abnormalities are present. Pituitary hormone levels and function tests (e.g., TSH, 
growth hormone, luteinizing hormone, follicle-stimulating hormone, testosterone, 
prolactin, adrenocorticotropic hormone [ACTH] levels, and ACTH stimulation test) and 


Appendix 2: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
  
144 
 
magnetic resonance imaging (MRI) of the brain (with detailed pituitary sections) may 
help to differentiate primary pituitary insufficiency from primary adrenal insufficiency. 
Table 4 
Management Guidelines for Endocrine Events 
Event 
Management 
Asymptomatic 
hypothyroidism 
 Continue atezolizumab. 
 Initiate treatment with thyroid replacement hormone. 
 Monitor TSH weekly. 
Symptomatic 
hypothyroidism 
 Withhold atezolizumab. 
 Initiate treatment with thyroid replacement hormone. 
 Monitor TSH weekly. 
 Consider patient referral to endocrinologist. 
 Resume atezolizumab when symptoms are controlled and 
thyroid function is improving. 
Asymptomatic 
hyperthyroidism 
TSH  0.1 mU/L and  0.5 mU/L: 
 Continue atezolizumab. 
 Monitor TSH every 4 weeks. 
TSH  0.1 mU/L: 
 Follow guidelines for symptomatic hyperthyroidism. 
Symptomatic 
hyperthyroidism 
 Withhold atezolizumab. 
 Initiate treatment with anti-thyroid drug such as methimazole 
or carbimazole as needed. 
 Consider patient referral to endocrinologist. 
 Resume atezolizumab when symptoms are controlled and 
thyroid function is improving. 
 Permanently discontinue atezolizumab. 3 
MRI  magnetic resonance imaging; TSH  thyroid-stimulating hormone. 
1 Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
 10 mg/day oral prednisone. The acceptable length of the extended period of time must 
be determined by the investigator. 
2 If corticosteroids have been initiated, they must be tapered over  1 month to the 
equivalent of  10 mg/day oral prednisone before atezolizumab can be resumed. 
3 Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-related event. Patients can be re-challenged with 
atezolizumab only after approval has been documented by the investigator (or an 
appropriate delegate) and the Principal Investigator.  


Appendix 2: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
  
145 
 
Table 4 Management Guidelines for Endocrine Events (cont.) 
Event 
Management 
Symptomatic adrenal 
insufficiency, 
Grade 24  
 Withhold atezolizumab for up to 12 weeks after event onset. 1 
 Refer patient to endocrinologist. 
 Perform appropriate imaging. 
 Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day IV methylprednisolone and convert to 
12 mg/kg/day oral prednisone or equivalent upon 
improvement. 
 If event resolves to Grade 1 or better and patient is stable on 
replacement therapy, resume atezolizumab. 2 
 If event does not resolve to Grade 1 or better or patient is not 
stable on replacement therapy while withholding atezolizumab, 
permanently discontinue atezolizumab. 3 
Hyperglycemia, 
Grade 1 or 2  
 Continue atezolizumab. 
 Investigate for diabetes. If patient has Type 1 diabetes, treat 
as a Grade 3 event. If patient does not have Type 1 diabetes, 
treat as per institutional guidelines. 
 Monitor for glucose control. 
Hyperglycemia, 
Grade 3 or 4 
 Withhold atezolizumab. 
 Initiate treatment with insulin. 
 Monitor for glucose control. 
 Resume atezolizumab when symptoms resolve and glucose 
levels are stable. 
MRI  magnetic resonance imaging; TSH  thyroid-stimulating hormone. 
1 Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
 10 mg/day oral prednisone. The acceptable length of the extended period of time must 
be determined by the investigator. 
2 If corticosteroids have been initiated, they must be tapered over  1 month to the 
equivalent of  10 mg/day oral prednisone before atezolizumab can be resumed. 
3 Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-related event. Patients can be re-challenged with 
atezolizumab only after approval has been documented by the investigator (or an 
appropriate delegate) and the Principal Investigator.  


Appendix 2: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
  
146 
 
Table 4 
Management Guidelines for Endocrine Events (cont.)  
Event 
Management 
Hypophysitis 
(pan-hypopituitarism), 
Grade 2 or 3  
 Withhold atezolizumab for up to 12 weeks after event onset. 1 
 Refer patient to endocrinologist. 
 Perform brain MRI (pituitary protocol). 
 Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day IV methylprednisolone and convert to 
12 mg/kg/day oral prednisone or equivalent upon 
improvement. 
 Initiate hormone replacement if clinically indicated. 
 If event resolves to Grade 1 or better, resume atezolizumab. 2 
 If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab. 3 
 For recurrent hypophysitis, treat as a Grade 4 event. 
Hypophysitis 
(pan-hypopituitarism), 
Grade 4  
 Permanently discontinue atezolizumab. 3 
 Refer patient to endocrinologist. 
 Perform brain MRI (pituitary protocol). 
 Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day IV methylprednisolone and convert to 
12 mg/kg/day oral prednisone or equivalent upon 
improvement. 
 Initiate hormone replacement if clinically indicated. 
MRI  magnetic resonance imaging; TSH  thyroid-stimulating hormone. 
1 Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
 10 mg/day oral prednisone. The acceptable length of the extended period of time must 
be determined by the investigator. 
2 If corticosteroids have been initiated, they must be tapered over  1 month to the 
equivalent of  10 mg/day oral prednisone before atezolizumab can be resumed. 
3 Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-related event. Patients can be re-challenged with 
atezolizumab only after approval has been documented by the investigator (or an 
appropriate delegate) and the Principal Investigator.  
 


Appendix 2: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
  
147 
 
OCULAR EVENTS 
An ophthalmologist should evaluate visual complaints (e.g., uveitis, retinal events). 
Management guidelines for ocular events are provided in Table 5. 
Table 5 
Management Guidelines for Ocular Events 
Event 
Management 
Ocular event, 
Grade 1  
 Continue atezolizumab. 
 Patient referral to ophthalmologist is strongly recommended. 
 Initiate treatment with topical corticosteroid eye drops and topical 
immunosuppressive therapy. 
 If symptoms persist, treat as a Grade 2 event. 
Ocular event, 
Grade 2 
 Withhold atezolizumab for up to 12 weeks after event onset. 1 
 Patient referral to ophthalmologist is strongly recommended. 
 Initiate treatment with topical corticosteroid eye drops and topical 
immunosuppressive therapy. 
 If event resolves to Grade 1 or better, resume atezolizumab. 2 
 If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab. 3 
Ocular event, 
Grade 3 or 4 
 Permanently discontinue atezolizumab. 3 
 Refer patient to ophthalmologist. 
 Initiate treatment with corticosteroids equivalent to 12 mg/kg/day 
oral prednisone.   
 If event resolves to Grade 1 or better, taper corticosteroids over 
 1 month. 
1 Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
 10 mg/day oral prednisone. The acceptable length of the extended period of time must 
be determined by the investigator. 
2 If corticosteroids have been initiated, they must be tapered over  1 month to the 
equivalent of  10 mg/day oral prednisone before atezolizumab can be resumed. 
3 Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-related event. Patients can be re-challenged with 
atezolizumab only after approval has been documented by the investigator (or an 
appropriate delegate) and the Principal Investigator.  
 


Appendix 2: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
  
148 
 
IMMUNE-RELATED MYOCARDITIS 
Immune-related myocarditis has been associated with the administration of 
atezolizumab. Immune-related myocarditis should be suspected in any patient 
presenting with signs or symptoms suggestive of myocarditis, including, but not limited 
to, dyspnea, chest pain, palpitations, fatigue, decreased exercise tolerance, or syncope. 
Immune-related myocarditis needs to be distinguished from myocarditis resulting from 
infection (commonly viral, e.g., in a patient who reports a recent history of 
gastrointestinal illness), ischemic events, underlying arrhythmias, exacerbation of 
preexisting cardiac conditions, or progression of malignancy.   
All patients with possible myocarditis should be urgently evaluated by performing cardiac 
enzyme assessment, an ECG, a chest X-ray, an echocardiogram, and a cardiac MRI as 
appropriate per institutional guidelines. A cardiologist should be consulted. An 
endomyocardial biopsy may be considered to enable a definitive diagnosis and 
appropriate treatment, if clinically indicated. 
Patients with signs and symptoms of myocarditis, in the absence of an identified 
alternate etiology, should be treated according to the guidelines in Table 6. 


Appendix 2: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
  
149 
 
Table 6 
Management Guidelines for Immune-Related Myocarditis 
Event 
Management 
Immune-related 
myocarditis, Grade 2 
 Withhold atezolizumab for up to 12 weeks after event onset 1. 
 Refer patient to cardiologist. 
 Initiate treatment as per institutional guidelines and consider 
antiarrhythmic drugs, temporary pacemaker, ECMO, or VAD as 
appropriate. 
 Consider treatment with corticosteroids equivalent to 12 mg/kg/day 
IV methylprednisolone and convert to 12 mg/kg/day oral prednisone 
or equivalent upon improvement. 
 If event resolves to Grade 1 or better, resume atezolizumab. 2 
 If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab. 3 
Immune-related 
myocarditis, Grade 3-4 
 Permanently discontinue atezolizumab. 3 
 Refer patient to cardiologist. 
 Initiate treatment as per institutional guidelines and consider 
antiarrhythmic drugs, temporary pacemaker, ECMO, or VAD as 
appropriate. 
 Initiate treatment with corticosteroids equivalent to 12 mg/kg/day IV 
methylprednisolone and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement. 
 If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
 If event resolves to Grade 1 or better, taper corticosteroids 
over  1 month. 
ECMO  extracorporeal membrane oxygenation; VAD  ventricular assist device. 
1 Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event onset) to 
allow for corticosteroids (if initiated) to be reduced to the equivalent of  10 mg/day oral 
prednisone. The acceptable length of the extended period of time must be documented by the 
investigator. 
2 If corticosteroids have been initiated, they must be tapered over  1 month to the equivalent of 
 10 mg/day oral prednisone before atezolizumab can be resumed. 
3 Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-related event. Patients can be re-challenged with atezolizumab 
only after approval has been documented by the investigator (or an appropriate delegate) and 
the Principal Investigator. 
 
 


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Adverse Events Associated with Atezolizumab 
  
150 
 
INFUSION-RELATED REACTIONS 
No premedication is indicated for the administration of Cycle 1 of atezolizumab. 
However, patients who experience an IRR with Cycle 1 of atezolizumab may receive 
premedication with antihistamines or antipyretics/analgesics (e.g., acetaminophen) for 
subsequent infusions. Metamizole (dipyrone) is prohibited in treating atezolizumab-
associated IRRs because of its potential for causing agranulocytosis. 
Guidelines for medical management of IRRs during Cycle 1 are provided in Table 7. For 
subsequent cycles, IRRs should be managed according to institutional guidelines. 
Table 7 
Management Guidelines for Infusion-Related Reactions 
Event 
Management 
IRR, Grade 1  
 Reduce infusion rate to half the rate being given at the time of 
event onset. 
 After the event has resolved, the investigator should wait for 
30 minutes while delivering the infusion at the reduced rate. 
 If the infusion is tolerated at the reduced rate for 30 minutes after 
symptoms have resolved, the infusion rate may be increased to 
the original rate. 
IRR, Grade 2 
 Interrupt atezolizumab infusion. 
 Administer aggressive symptomatic treatment (e.g., oral or IV 
antihistamine, anti-pyretic medication, glucocorticoids, 
epinephrine, bronchodilators, oxygen, IV fluids). 
 After symptoms have resolved to baseline, resume infusion at half 
the rate being given at the time of event onset. 
 For subsequent infusions, consider administration of oral 
premedication with antihistamines, anti-pyretics, and/or analgesics 
and monitor closely for IRRs. 
IRR, Grade 3 or 4 
 Stop infusion. 
 Administer aggressive symptomatic treatment (e.g., oral or IV 
antihistamine, anti-pyretic medication, glucocorticoids, 
epinephrine, bronchodilators, oxygen, IV fluids). 
 Permanently discontinue atezolizumab. 1 
IRR  infusion-related reaction. 
1 Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-related event. Patients can be re-challenged 
with atezolizumab only after approval has been documented by the investigator (or an 
appropriate delegate) and the Principal Investigator. 
 


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Adverse Events Associated with Atezolizumab 
  
151 
 
PANCREATIC EVENTS 
Symptoms of abdominal pain associated with elevations of amylase and lipase, 
suggestive of pancreatitis, have been associated with the administration of 
atezolizumab. The differential diagnosis of acute abdominal pain should include 
pancreatitis. Appropriate workup should include an evaluation for ductal obstruction, as 
well as serum amylase and lipase tests. Management guidelines for pancreatic events, 
including pancreatitis, are provided in Table 8. 
Table 8 
Management Guidelines for Pancreatic Events, Including 
Pancreatitis  
Event 
Management 
Amylase and/or lipase 
elevation, Grade 2 
Amylase and/or lipase  1.52.0  ULN: 
 Continue atezolizumab. 
 Monitor amylase and lipase weekly. 
 For prolonged elevation (e.g.,  3 weeks), consider treatment 
with corticosteroids equivalent to 10 mg/day oral prednisone. 
Asymptomatic with amylase and/or lipase  2.05.0  ULN: 
 Treat as a Grade 3 event. 
Amylase and/or lipase 
elevation, Grade 3 or 4 
 Withhold atezolizumab for up to 12 weeks after event onset. 1 
 Refer patient to GI specialist. 
 Monitor amylase and lipase every other day. 
 If no improvement, consider treatment with corticosteroids 
equivalent to 12 mg/kg/day oral prednisone. 
 If event resolves to Grade 1 or better, resume 
atezolizumab. 2 
 If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue 
atezolizumab. 3 
 For recurrent events, permanently discontinue atezolizumab. 3
GI  gastrointestinal. 
1 Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to the equivalent of  10 mg/day oral 
prednisone. The acceptable length of the extended period of time must be determined by the 
investigator. 
2 If corticosteroids have been initiated, they must be tapered over  1 month to the equivalent 
of  10 mg/day oral prednisone before atezolizumab can be resumed. 
3 Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-related event. Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Principal Investigator. 


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152 
 
Table 8 
Management Guidelines for Pancreatic Events, Including 
Pancreatitis (cont.)  
Event 
Management 
Immune-related pancreatitis, 
Grade 2 or 3 
 
 Withhold atezolizumab for up to 12 weeks after event onset. 1 
 Refer patient to GI specialist. 
 Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day IV methylprednisolone and convert to 
12 mg/kg/day oral prednisone or equivalent upon 
improvement. 
 If event resolves to Grade 1 or better, resume atezolizumab. 2 
 If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab. 3 
 For recurrent events, permanently discontinue atezolizumab. 3  
Immune-related pancreatitis, 
Grade 4 
 Permanently discontinue atezolizumab. 3 
 Refer patient to GI specialist. 
 Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day IV methylprednisolone and convert to 
12 mg/kg/day oral prednisone or equivalent upon 
improvement. 
 If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
 If event resolves to Grade 1 or better, taper corticosteroids 
over  1 month. 
GI  gastrointestinal. 
1 Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event onset) to 
allow for corticosteroids (if initiated) to be reduced to the equivalent of  10 mg/day oral 
prednisone. The acceptable length of the extended period of time must be determined by the 
investigator. 
2 If corticosteroids have been initiated, they must be tapered over  1 month to the equivalent of 
 10 mg/day oral prednisone before atezolizumab can be resumed. 
3 Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-related event. Patients can be re-challenged with 
atezolizumab only after approval has been documented by the investigator (or an appropriate 
delegate) and the Principal Investigator.  
 


Appendix 2: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
  
153 
 
DERMATOLOGIC EVENTS 
Treatment-emergent rash has been associated with atezolizumab. The majority of cases 
of rash were mild in severity and self limited, with or without pruritus. A dermatologist 
should evaluate persistent and/or severe rash or pruritus. A biopsy should be considered 
unless contraindicated. Management guidelines for dermatologic events are provided in 
Table 9. 
Table 9 
Management Guidelines for Dermatologic Events 
Event 
Management 
Dermatologic 
event, Grade 1  
 Continue atezolizumab. 
 Consider treatment with topical corticosteroids and/or other 
symptomatic therapy (e.g., antihistamines). 
Dermatologic 
event, Grade 2  
 Continue atezolizumab. 
 Consider patient referral to dermatologist. 
 Initiate treatment with topical corticosteroids. 
 Consider treatment with higher-potency topical corticosteroids if 
event does not improve. 
Dermatologic 
event, Grade 3  
 Withhold atezolizumab for up to 12 weeks after event onset. 1 
 Refer patient to dermatologist. 
 Initiate treatment with corticosteroids equivalent to 10 mg/day 
oral prednisone, increasing dose to 12 mg/kg/day if event does 
not improve within 4872 hours. 
 If event resolves to Grade 1 or better, resume atezolizumab. 2 
 If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab. 3 
Dermatologic 
event, Grade 4 
 Permanently discontinue atezolizumab. 3 
1 Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after 
event onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent 
of  10 mg/day oral prednisone. The acceptable length of the extended period of 
time must be determined by the investigator. 
2 If corticosteroids have been initiated, they must be tapered over  1 month to the 
equivalent of  10 mg/day oral prednisone before atezolizumab can be resumed. 
3 Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-related event. Patients can be re-
challenged with atezolizumab only after approval has been documented by the 
investigator (or an appropriate delegate) and the Principal Investigator.  


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154 
 
 
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Myasthenia gravis and Guillain-Barr  syndrome have been observed with single-agent 
atezolizumab. Patients may present with signs and symptoms of sensory and/or motor 
neuropathy. Diagnostic workup is essential for an accurate characterization to 
differentiate between alternative etiologies. Management guidelines for neurologic 
disorders are provided in Table 10. 
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Event 
Management 
Immune-related 
neuropathy, 
Grade 1 
x Continue atezolizumab. 
x Investigate etiology. 
Immune-related 
neuropathy, 
Grade 2  
x Withhold atezolizumab for up to 12 weeks after event onset. 1 
x Investigate etiology. 
x Initiate treatment as per institutional guidelines. 
x If event resolves to Grade 1 or better, resume atezolizumab. 2 
x If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab. 3 
Immune-related 
neuropathy, 
Grade 3 or 4 
x Permanently discontinue atezolizumab. 3  
x Initiate treatment as per institutional guidelines. 
Myasthenia 
gravis and 
Guillain-Barr  
syndrome (any 
grade) 
x Permanently discontinue atezolizumab. 3 
x Refer patient to neurologist. 
x Initiate treatment as per institutional guidelines. 
x Consider initiation of corticosteroids equivalent to 12 mg/kg/day 
oral or IV prednisone. 
1 Atezolizumab may be withheld for a longer period of time (i.e., ! 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
d 10 mg/day oral prednisone. The acceptable length of the extended period of time 
must be determined by the investigator. 
2 If corticosteroids have been initiated, they must be tapered over t 1 month to the 
equivalent of d 10 mg/day oral prednisone before atezolizumab can be resumed. 
3 Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-related event. Patients can be re-
challenged with atezolizumab only after approval has been documented by the 
investigator (or an appropriate delegate) and the Principal Investigator.  
 


Appendix 2: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
  
155 
 
IMMUNE-RELATED MENINGOENCEPHALITIS 
Immune-related meningoencephalitis is an identified risk associated with the 
administration of atezolizumab. Immune-related meningoencephalitis should be 
suspected in any patient presenting with signs or symptoms suggestive of meningitis or 
encephalitis, including, but not limited to, headache, neck pain, confusion, seizure, motor 
or sensory dysfunction, and altered or depressed level of consciousness. 
Encephalopathy from metabolic or electrolyte imbalances needs to be distinguished from 
potential meningoencephalitis resulting from infection (bacterial, viral, or fungal) or 
progression of malignancy, or secondary to a paraneoplastic process.   
All patients being considered for meningoencephalitis should be urgently evaluated with 
a CT scan and/or MRI scan of the brain to evaluate for metastasis, inflammation, or 
edema. If deemed safe by the treating physician, a lumbar puncture should be 
performed and a neurologist should be consulted. 
Patients with signs and symptoms of meningoencephalitis, in the absence of an 
identified alternate etiology, should be treated according to the guidelines in Table 11. 
Table 11 Management Guidelines for Immune-Related 
Meningoencephalitis 
Event 
Management 
Immune-related 
meningoencephalitis, 
all grades 
 Permanently discontinue atezolizumab. 1 
 Refer patient to neurologist. 
 Initiate treatment with corticosteroids equivalent to 12 mg/kg/day IV 
methylprednisolone and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement. 
 If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
 If event resolves to Grade 1 or better, taper corticosteroids over 
 1 month. 
1 Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-related event. Patients can be re-challenged with atezolizumab 
only after approval has been documented by the investigator (or an appropriate delegate) and 
the Principal Investigator. 
 


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Adverse Events Associated with Atezolizumab 
  
156 
 
RENAL EVENTS 
Immune-related nephritis has been associated with the administration of atezolizumab. 
Eligible patients must have adequate renal function, and renal function, including serum 
creatinine, should be monitored throughout study treatment. Patients with abnormal 
renal function should be evaluated and treated for other more common etiologies 
(including prerenal and postrenal causes, and concomitant medications such as 
non-steroidal anti-inflammatory drugs). Refer the patient to a renal specialist if clinically 
indicated. A renal biopsy may be required to enable a definitive diagnosis and 
appropriate treatment. 
Patients with signs and symptoms of nephritis, in the absence of an identified alternate 
etiology, should be treated according to the guidelines in Table 12. 
Table 12 Management Guidelines for Renal Events  
Event 
Management 
Renal event, 
Grade 1 
 Continue atezolizumab. 
 Monitor kidney function, including creatinine, closely until 
values resolve to within normal limits or to baseline values.  
Renal event, 
Grade 2 
 Withhold atezolizumab for up to 12 weeks after event onset. 1 
 Refer patient to renal specialist. 
 Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day oral prednisone. 
 If event resolves to Grade 1 or better, resume atezolizumab. 2 
 If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab. 3 
Renal event, 
Grade 3 or 4 
 Permanently discontinue atezolizumab.  
 Refer patient to renal specialist and consider renal biopsy. 
 Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day oral prednisone. 
 If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
 If event resolves to Grade 1 or better, taper corticosteroids over 
 1 month. 


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Adverse Events Associated with Atezolizumab 
  
157 
 
1 Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after 
event onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent 
of  10 mg/day oral prednisone. The acceptable length of the extended period of 
time must be determined by the investigator. 
2 If corticosteroids have been initiated, they must be tapered over  1 month to the 
equivalent of  10 mg/day oral prednisone before atezolizumab can be resumed. 
3 Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-related event. Patients can be 
re-challenged with atezolizumab only after approval has been documented by the 
investigator (or an appropriate delegate) and the Principal Investigator.  
IMMUNE-RELATED MYOSITIS 
Immune-related myositis has been associated with the administration of atezolizumab.  
Myositis or inflammatory myopathies are a group of disorders sharing the common 
feature of inflammatory muscle injury; dermatomyositis and polymyositis are among the 
most common disorders.  Initial diagnosis is based on clinical (muscle weakness, muscle 
pain, skin rash in dermatomyositis), biochemical (serum creatine kinase increase), and 
imaging (electromyography/MRI) features, and is confirmed with a muscle biopsy. 
Patients with signs and symptoms of myositis, in the absence of an identified alternate 
etiology, should be treated according to the guidelines in Table 13. 
Table 13 Management Guidelines for Immune-Related Myositis 
Event 
Management 
Immune-related 
myositis, Grade 1 
 Continue atezolizumab. 
 Refer patient to rheumatologist or neurologist.  
 Initiate treatment as per institutional guidelines. 
Immune-related 
myositis, Grade 2 
 Withhold atezolizumab for up to 12 weeks after event onset. a 
 Refer patient to rheumatologist or neurologist. 
 Initiate treatment as per institutional guidelines. 
 Consider treatment with corticosteroids equivalent to 
12 mg/kg/day IV methylprednisolone and convert to 
12 mg/kg/day oral prednisone or equivalent upon 
improvement. 
 If corticosteroids are initiated and event does not improve 
within 48 hours after initiating corticosteroids, consider adding 
an immunosuppressive agent. 
 If event resolves to Grade 1 or better, resume atezolizumab. b 
 If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab. c 


Appendix 2: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
  
158 
 
a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after 
event onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent 
of  10 mg/day oral prednisone.  The acceptable length of the extended period of 
time must be determined by the investigator. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the 
equivalent of  10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-related event.  Patients can be 
re-challenged with atezolizumab only after approval has been documented by both 
the investigator (or an appropriate delegate) and the Principal Investigator.  


Appendix 2: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
  
159 
 
Table 13 Management Guidelines for Immune-Related Myositis (cont.)  
Immune-related 
myositis, Grade 3 
 Withhold atezolizumab for up to 12 weeks after event onset a 
and contact Medical Monitor. 
 Refer patient to rheumatologist or neurologist. 
 Initiate treatment as per institutional guidelines.  Respiratory 
support may be required in more severe cases. 
 Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day IV methylprednisolone, or higher-dose bolus if 
patient is severely compromised (e.g., cardiac or respiratory 
symptoms, dysphagia, or weakness that severely limits 
mobility); convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement. 
 If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
 If event resolves to Grade 1 or better, resume atezolizumab. b 
 If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact Medical Monitor. c 
 For recurrent events, treat as a Grade 4 event. 
Immune-related 
myositis, Grade 4 
 Permanently discontinue atezolizumab. c 
 Refer patient to rheumatologist or neurologist. 
 Initiate treatment as per institutional guidelines.  Respiratory 
support may be required in more severe cases. 
 Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day IV methylprednisolone, or higher-dose bolus if 
patient is severely compromised (e.g., cardiac or respiratory 
symptoms, dysphagia, or weakness that severely limits 
mobility); convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement. 
 If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
 If event resolves to Grade 1 or better, taper corticosteroids 
over  1 month. 


Appendix 2: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
  
160 
 
a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after 
event onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent 
of  10 mg/day oral prednisone.  The acceptable length of the extended period of 
time must be agreed upon by the investigator. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the 
equivalent of  10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-related event.  Patients can be 
re-challenged with atezolizumab only after approval has been documented by both 
the investigator (or an appropriate delegate) and the Principal Investigator.  
 


Appendix 2: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
  
161 
 
SYSTEMIC IMMUNE ACTIVATION 
Systemic immune activation is a rare condition characterized by an excessive immune 
response. Given the mechanism of action of atezolizumab, systemic immune activation 
is considered a potential risk for atezolizumab. 
Recommendations regarding early identification and management of systemic immune 
activation are provided below. In the event of suspected systemic immune activation, 
atezolizumab should be withheld. 
Early disease recognition is critical, and systemic immune activation should be 
suspected if, in the absence of an alternative etiology, the patient meets two or more of 
the following criteria: 
 
Hypotension that is refractory to aggressive IV fluid challenge 
Vasopressor support may be required. 
 
Respiratory distress that requires aggressive supportive care 
Supplemental oxygen and intubation may be required. 
 
Fever  38.5C 
 
Acute renal or hepatic failure 
 
Bleeding from coagulopathy 
 
Any of the following unexplained laboratory abnormalities (change from baseline):  
cytopenias (in two or more lineages), significant transaminitis, or coagulopathy 
 
For patients with suspected systemic immune activation, an initial evaluation should 
include the following: 
 
CBC with peripheral smear 
 
PT, PTT, fibrinogen, and D-dimer 
 
Ferritin 
 
Soluble interleukin 2 (IL-2) receptor (soluble CD25) 
 
Triglycerides 
 
AST, ALT, and direct bilirubin 
 
LDH 
 
Complete neurologic and abdominal examination (assess for hepatosplenomegaly) 
 


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162 
 
Laboratory tests with normal results should be repeated frequently in patients for whom 
a high clinical suspicion of systemic immune activation exists. 
If neurologic abnormalities are present, consider cerebrospinal fluid analysis and/or an 
MRI of the brain. 
If cytopenias are present (Grade  2 in two or more lineages) or ferritin is  3000 ng/mL, 
the following evaluations should also be performed:   
 
Bone marrow biopsy and aspirate (assess for evidence of hemophagocytosis) 
 
Adenovirus, cytomegalovirus, Epstein-Barr virus, herpes-simplex virus, and human 
herpesvirus 6, 7, and 8 evaluations (for reactivated or active disease) 
 
Diagnostic criteria and recommended management for systemic immune activation are 
provided in Table 14. The diagnostic criteria apply only when alternative etiologies have 
been excluded. 


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Systemic Immune Activation Diagnostic Criteria  
(applicable only when alternative etiologies have been excluded) 
Major Criteria 
Minor Criteria 
x Fever t 38.5qC on more than one occasion 
x Ferritin t 3000 ng/mL 
x Cytopenias (Grade t 2 in two or more 
lineages) 
x Age-adjusted soluble interleukin-2 receptor 
elevated by t 2 standard deviations 
x Severe (Grade t 3) or progressive 
dysfunction in two or more organs 
x Decreased fibrinogen 
x Splenomegaly  
x Hemophagocytosis in bone marrow, spleen, or 
lymph nodes 
x Elevated J-glutamyl transpeptidase (GGT) or 
liver function tests (AST, ALT, or direct bilirubin) 
x Elevated triglycerides 
x Elevated LDH 
x Decreased natural killer cell activity 
Diagnosis and Management of Systemic Immune Activation 
Number of Criteria 
Diagnosis 
Action to Be Taken 
t 4 major criteria 
Consistent 
with systemic 
immune 
activation 
x Permanently discontinue atezolizumab. 
x Consider treatment with an immunosuppressive agent 
(i.e., cytokine inhibitors) and IV corticosteroids 
(i.e., methylprednisolone 1 g once daily or equivalent, or 
dexamethasone t 10 mg/m2 once daily if neurologic 
abnormalities are present). 
x Consider HLH-2004 protocol if there is no clinical improvement.
3 major criteria 
OR 
2 major plus 
t 3 minor criteria 
Probable 
systemic 
immune 
activation 
x Depending on clinical severity, follow guidelines for Consistent 
with systemic immune activation  or Possible systemic 
immune activation  diagnosis. 
2 major plus 
d 2 minor criteria 
OR 
1 major plus 
t 4 minor criteria 
Possible 
systemic 
immune 
activation 
x Withhold atezolizumab. 
x Consider treatment with IV corticosteroids. 
x Follow guidelines for Consistent with systemic immune 
activation  diagnosis if there is no clinical improvement or if 
clinical worsening occurs. 
x If clinical improvement occurs, atezolizumab may be resumed 
following a benefit-risk assessment by the investigator. 


Appendix 2: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
  
164 
 
Notes:  Criteria are adapted from a Delphi Survey of 26 experts who provided helpful criteria in the 
positive diagnosis of hemophagocytic syndrome in adult patients (Hejblum et al. 2014). 
Grades are based on National Cancer Institute Common Terminology Criteria for Adverse Events. 
These recommendations do not replace clinical judgment and are intended as suggested guidance. 
REFERENCES 
Hejblum G, Lambotte O, Galicier L, et al. A web-based Delphi study for eliciting helpful 
criteria in the positive diagnosis of hemophagocytic syndrome in adult patients. 
PLoS ONE 2014;9(4):e94024. doi: 10.1371/journal.pone.0094024


 
165 
 
Appendix 3 
Adverse Events and Management Guidelines for Atezolizumab + 
PEGPH20 
Table 1 
Guidelines for Management of Patients Who Experience Specific 
Adverse Events in Atezolizumab + PEGPH20 Arm 
Event 
Action to Be Taken 
IRRs and anaphylaxis 
 Guidelines for management of IRRs for atezolizumab are 
provided in Appendix 2.  
 Guidelines for management of IRRs for PEGPH20 are 
provided below.  
 For anaphylaxis precautions, see Section 9.1.1. 
IRR to PEGPH20, Grade 1 
 Reduce infusion rate to half the rate being given at the time 
of event onset.  
 After the event has resolved, the investigator should wait for 
30 minutes while delivering the infusion at the reduced rate.  
 If the infusion is tolerated at the reduced rate for 30 minutes 
after symptoms have resolved, the infusion rate may be 
increased to the original rate. 
IRR to PEGPH20, Grade 2 
 Interrupt infusion.  
 Administer aggressive symptomatic treatment (e.g., oral or 
IV antihistamine, anti-pyretic, glucocorticoids, epinephrine, 
bronchodilators, oxygen). 
 After symptoms have resolved to baseline, resume infusion 
at half the rate being given at the time of event onset. 
 For subsequent infusions, administer oral premedication with 
antihistamine and anti-pyretic and monitor closely for IRRs. 
IRR to PEGPH20, Grade 3 or 4 
 Stop infusion.  
 Administer aggressive symptomatic treatment (e.g., oral or 
IV antihistamine, anti-pyretic, glucocorticoids, epinephrine, 
bronchodilators, oxygen).  
 Permanently discontinue treatment and contact the Principle 
Investigator.1  
Atezo +PEGPH20 = atezolizumab plus PEGPH20; IRR = infusion-related reaction; 
MSE=musculoskeletal event; NSAID = nonsteroidal anti-inflammatory drug; OTC =over-the-
counter; TE= thromboembolic.  
1 Resumption of treatment may be considered in patients who are deriving benefit and have fully 
recovered from the immune-related event. Patients can be re-challenged only after approval 
has been documented by both the investigator (or an appropriate delegate) and the Principal 
Investigator. 


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166 
 
7DEOH
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MSE, Grade 1 
x Continue PEGPH20 and atezolizumab 
x Initiate prescription medications such as narcotics, muscle 
relaxants, NSAIDs or other analgesics (with the exception of 
steroids), OTC drugs, or physical therapy at the 
investigator s discretion.
MSE, Grade 2 
x Withhold PEGPH20. Continue atezolizumab.  
x Initiate prescription medications such as narcotics, muscle 
relaxants, NSAIDs or other analgesics (with the exception of 
steroids), OTC drugs, or physical therapy at the 
investigator s discretion.  
x If event resolves to Grade 1 or better within 21 days, resume 
PEGPH20 at the current dose. If not, the Principal 
Investigator must be consulted to determine whether 
PEGPH20 should continue to be withheld, should be 
resumed at a lower dose (1.6 g/kg), or should be 
permanently discontinued.
MSE, Grade 3 or 4 
x Withhold PEGPH20. Continue atezolizumab. 
x Initiate prescription medications such as narcotics, muscle 
relaxants, NSAIDs or other analgesics (with the exception of 
steroids), OTC drugs, or physical therapy at the 
investigator s discretion.  
x If event resolves to Grade 2 or better within 21 days and the 
Principal Investigator agrees that PEGPH20 should be 
continued, resume PEGPH20 at a lower dose (1.6 g/kg). If 
not, permanently discontinue PEGPH20.
7KURPERHPEROLFHYHQW
TE event, Grade 1 
x Continue PEGPH20 and atezolizumab. 
TE event, Grade 2, 3, or 4 
x Permanently discontinue PEGPH20. Withhold atezolizumab. 
x If patient becomes asymptomatic, resume atezolizumab. If 
not, permanently discontinue atezolizumab. 
Atezo +PEGPH20 = atezolizumab plus PEGPH20; IRR = infusion-related reaction; 
MSE=musculoskeletal event; NSAID = nonsteroidal anti-inflammatory drug; OTC =over-the-
counter; TE= thromboembolic.  


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(YHQW
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JUDGHV
x Permanently discontinue PEGPH20. Withhold atezolizumab. 
x If patient becomes asymptomatic, resume atezolizumab. If 
not, permanently discontinue atezolizumab.
6WURNHDOOJUDGHV
x Permanently discontinue PEGPH20. Withhold atezolizumab. 
x If event resolves to Grade 1 or better, resume atezolizumab. 
If not, permanently discontinue atezolizumab.
3XOPRQDU\HYHQWV
Pulmonary event, Grade 1 or 2 
x Follow guidelines for atezolizumab in Appendix 2.  
x Continue PEGPH20. 
x For recurrent Grade 2 pneumonitis, treat as a Grade 3 or 4 
event.
Pulmonary event, Grade 3 
x Follow guidelines for atezolizumab in Appendix 2.  
x Withhold PEGPH20.  
x If event resolves to Grade 2 within 21 days and the Principal 
Investigator agrees that PEGPH20 should be continued, 
resume PEGPH20 at a lower dose (1.6 g/kg).  
x If event resolves to Grade 1 or better within 21 days, resume 
PEGPH20 at the current dose.  
x If event does not resolve to Grade 2 or better within 21 days, 
permanently discontinue PEGPH20.
Pulmonary event, Grade 4 
x Follow guidelines for atezolizumab in Appendix 2.  
x Withhold PEGPH20.  
x If event resolves to Grade 2 or better within 21 days and the 
Principal Investigator that PEGPH20 should be continued, 
resume PEGPH20 at a lower dose (1.6 g/kg). If not, 
permanently discontinue PEGPH20.
Atezo +PEGPH20 = atezolizumab plus PEGPH20; IRR = infusion-related reaction; 
MSE=musculoskeletal event; NSAID = nonsteroidal anti-inflammatory drug; OTC =over-the-
counter; TE= thromboembolic.  
. 


 
168 
 
7DEOH
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Event 
Action to Be Taken 
3(*3+UHODWHGWR[LFLWLHVQRWGHVFULEHGDERYH
Grade 1 or 2 
x Continue PEGPH20 and atezolizumab. 
Grade 3 
x Withhold PEGPH20. Continue atezolizumab.  
x If event resolves to Grade 2 within 21 days and Principal Investigator 
agrees that PEGPH20 should be continued, resume PEGPH20 at a lower 
dose (1.6 g/kg).  
x If event resolves to Grade 1 or better within 21 days, resume PEGPH20 at 
the current dose.  
x If event does not resolve to Grade 2 or better within 21 days or Principal 
Investigator does not agree that PEGPH20 should be resumed, 
permanently discontinue PEGPH20. 
Grade 4
x Withhold PEGPH20 and atezolizumab.  
x If event resolves to Grade 2 or better within 21 days and Principal 
Investigator agrees that PEGPH20 should be continued, resume 
PEGPH20 at a lower dose (1.6 g/kg). If not, permanently discontinue 
PEGPH20.  
x If event improves and the Principal Investigator agrees that atezolizumab 
should be continued, resume atezolizumab. If not, permanently discontinue 
atezolizumab.
$WH]ROL]XPDEUHODWHGWR[LFLWLHVQRWGHVFULEHGDERYH
Grade 1 or 2 
x Follow guidelines for atezolizumab in Appendix 2.  
x Continue PEGPH20. 
Grade 3 
x Follow guidelines for atezolizumab in Appendix 2.  
x Withhold PEGPH20.  
x If event resolves to Grade 2 within 21 days and the Principal Investigator 
agrees that PEGPH20 should be continued, resume PEGPH20 at the 
current dose.  
x If event resolves to Grade 1 or better within 21 days, resume PEGPH20 at 
the current dose.  
x If event does not resolve to Grade 2 or better within 21 days or the 
Principal Investigator does not agree that PEGPH20 should be resumed, 
permanently discontinue PEGPH20. 
Grade 4 
x Follow guidelines for atezolizumab in Appendix 2.  
x Withhold PEGPH20.  
x If event resolves to Grade 2 or better within 21 days and the Principal 
Investigator agrees that PEGPH20 should be continued, resume 
PEGPH20 at the current dose. If not, permanently discontinue PEGPH20. 
Atezo +PEGPH20 = atezolizumab plus PEGPH20; IRR = infusion-related reaction; 
MSE=musculoskeletal event; NSAID = nonsteroidal anti-inflammatory drug; OTC =over-the-
counter; TE= thromboembolic. 
 


 
169 
 
20. 
REFERENCES 
Al-Hawary MM, Francis IR, Chari ST, et al. Pancreatic ductal adenocarcinoma radiology 
reporting template: consensus statement of the Society of Abdominal Radiology 
and the American Pancreatic Association. Radiology. Jan 2014;270(1):248-260. 
Allison DC, Piantadosi S, Hruban RH, et al. DNA content and other factors associated 
with ten-year survival after resection of pancreatic carcinoma. Journal of surgical 
oncology. Mar 1998;67(3):151-159. 
Andre T, Vernerey D, Mineur L, et.al. J Clin Oncol. 2018 May 20;36(15):1469-1477. doi: 
10.1200/JCO.2017.76.0355. Epub 2018 Apr 5. 
Azuma K, Ota K, Kawahara A, et al. Association of PD-L1 overexpression with activating 
EGFR mutations in surgically resected nonsmall-cell lung cancer. Annals of 
oncology: official journal of the European Society for Medical Oncology. Oct 
2014;25(10):1935- 1940. 
Beatty GL, Torigian DA, Chiorean EG, et al. A phase I study of an agonist CD40 
monoclonal antibody (CP-870,893) in combination with gemcitabine in patients 
with advanced pancreatic ductal adenocarcinoma. Clinical cancer research: an 
official journal of the American Association for Cancer Research. Nov 15 
2013;19(22):6286-6295. 
Boeck S, Ankerst DP, Heinemann V. The role of adjuvant chemotherapy for patients with 
resected pancreatic cancer: systematic review of randomized controlled trials and 
meta- analysis. Oncology. 2007;72(5-6):314-321. 
Brahmer JR, Drake CG, Wollner I, et al. Phase I study of single-agent anti-programmed 
death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, 
pharmacodynamics, and immunologic correlates. Journal of clinical oncology: 
official journal of the American Society of Clinical Oncology. Jul 01 
2010;28(19):3167-3175. 
Brahmer JR, Tykodi SS, Chow LQ, et al. Safety and activity of anti-PD-L1 antibody in 
patients with advanced cancer. The New England journal of medicine. Jun 28 
2012;366(26):2455-2465. 
Carstens JL, Correa de Sampaio P, Yang D, et al. Spatial computation of intratumoral T 
cells correlates with survival of patients with pancreatic cancer. Nature 
communications. Apr 27 2017;8: 15095. 
Chen N, Li Y, Ye Y, et al. Pharmacokinetics and pharmacodynamics of nab-paclitaxel in 
patients with solid tumors: disposition kinetics and pharmacology distinct from 
solvent-based paclitaxel. Journal of clinical pharmacology. Oct 2014;54(10):1097-
1107. 
Cheng XB, Sato N, Kohi S, et al. Prognostic impact of hyalouronan and its regulator in 
pancreatic ductal adenocarcinoma. PLoS One 2013;8: e80765.  
Clark CE, Hingorani SR, Mick R, et al. Dynamics of the immune reaction to pancreatic 
cancer from inception to invasion. Cancer research. Oct 01 2007;67(19):9518-
9527. 


 
170 
 
Clift R, Lee J, Thompson CB, et al. PEGylated recombinant hyaluronidase PH20 
(PEGPH20) enhances tumor infiltrating CD8+ T cell accumulation and improves 
checkpoint inhibitor efficacy in murine syngeneic breast cancer models [abstract]. 
In: Proceedings of the American Association for Cancer Research Annual Meeting 
2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 
2017;77(13 Suppl): Abstract nr 641. doi:10.1158/1538-7445.AM2017-641. 
Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic 
pancreatic cancer. The New England journal of medicine. May 12 
2011;364(19):1817- 1825. 
Conroy T, Hammel P, Hebbar M, et al: Unicancer GI PRODIGE 24/CCTG PA.6 trial: A 
multicenter international randomized phase III trial of adjuvant mFOLFIRINOX 
versus gemcitabine in patients with resected pancreatic ductal adenocarcinomas. 
2018 ASCO Annual Meeting. Abstract LBA4001. Presented June 4, 2018. 
D’Addio F, Riella LV, Mfarrej BG, et al. THE LINK BETWEEN PDL1 COSTIMULATORY 
PATHWAY AND TH17 IN FETOMATERNAL TOLERANCE. Journal of 
Immunology (Baltimore, Md.: 1950). 09/26 2011;187(9):4530-4541. 
Deng R, Bumbaca D, Pastuskovas CV, et al. Preclinical pharmacokinetics, 
pharmacodynamics, tissue distribution, and tumor penetration of anti-PD-L1 
monoclonal antibody, an immune checkpoint inhibitor. mAbs. 2016;8(3):593-603. 
Desai N, Trieu V, Yao Z, et al. Increased antitumor activity, intratumor paclitaxel 
concentrations, and endothelial cell transport of cremophor-free, albumin-bound 
paclitaxel, ABI-007, compared with cremophor-based paclitaxel. Clinical cancer 
research: an official journal of the American Association for Cancer Research. Feb 
15 2006;12(4):1317-1324. 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1). European journal of cancer 
(Oxford, England: 1990). Jan 2009;45(2):228-247. 
Ene-Obong A, Clear AJ, Watt J, et al. Activated Pancreatic Stellate Cells Sequester 
CD8(+) T-Cells to Reduce Their Infiltration of the Juxtatumoral Compartment of 
Pancreatic Ductal Adenocarcinoma. Gastroenterology. 07/25 2013;145(5):1121-
1132. 
Fukunaga A, Miyamoto M, Cho Y, et al. CD8+ tumor-infiltrating lymphocytes together 
with CD4+ tumor-infiltrating lymphocytes and dendritic cells improve the prognosis 
of patients with pancreatic adenocarcinoma. Pancreas. Jan 2004;28(1): e26-31. 
Geer RJ, Brennan MF. Prognostic indicators for survival after resection of pancreatic 
adenocarcinoma. American journal of surgery. Jan 1993;165(1):68-72; discussion 
72-63. 
Guleria I, Khosroshahi A, Ansari MJ, et al. A critical role for the programmed death 
ligand 1 in fetomaternal tolerance. The Journal of experimental medicine. Jul 18 
2005;202(2):231- 237. 
Habicht A, Dada S, Jurewicz M, et al. A link between PDL1 and T regulatory cells in 
fetomaternal tolerance. J Immunol. Oct 15 2007;179(8):5211-5219.  


 
171 
 
Hales RK, Banchereau J, Ribas A, et al. Assessing oncologic benefit in clinical trials of 
immunotherapy agents. Annals of oncology: official journal of the European 
Society for Medical Oncology. Oct 2010;21(10):1944-1951. 
H nzelmann S, Castelo R, Guinney J. GSVA: gene set variation analysis for microarray 
and RNA-Seq data. BMC Bioinformatics. 2013 2013;14(1):1-15. 
Hingorani SR, Zheng L, Bullock AJ, et al. HALO 202: Randomized Phase II Study of 
PEGPH20 Plus Nab-Paclitaxel/Gemcitabine Versus Nab-Paclitaxel/Gemcitabine in 
Patients With Untreated, Metastatic Pancreatic Ductal Adenocarcinoma.J Clin 
Oncol. 2018 Feb 1;36(4):359-366. doi: 10.1200/JCO.2017.74.9564. Epub 2017 
Dec 12. 
Hiraoka N, Onozato K, Kosuge T, et al. Prevalence of FOXP3+ regulatory T cells 
increases during the progression of pancreatic ductal adenocarcinoma and its 
premalignant lesions. Clinical cancer research: an official journal of the American 
Association for Cancer Research. Sep 15 2006;12(18):5423-5434. 
Howard TJ, Krug JE, Yu J, et al. A margin-negative R0 resection accomplished with 
minimal postoperative complications is the surgeon’s contribution to long-term 
survival in pancreatic cancer. Journal of gastrointestinal surgery: official journal of 
the Society for Surgery of the Alimentary Tract. Dec 2006;10(10):1338-1345; 
discussion 1345-1336. 
Howlader N, Noone AM, Krapcho M, et al. SEER Cancer Statistics Review, 1975-2014, 
National Cancer Institute. Bethesda, MD, https://seer.cancer.gov/csr/1975_2014/, 
based on November 2016 SEER data submission, posted to the SEER web site, 
April 2017. 
Lee J, Leong M, Huang Y, et al. Combination of PEGylated recombinant hyaluronidase 
PH20 (PEGPH20) with live-attenuated, double-deleted (LADD) Listeria enhances 
tumor infiltrating CD8+ T cell response and antitumor efficacy in mice [abstract]. In: 
Proceedings of the American Association for Cancer Research Annual Meeting 
2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 
2017;77(13 Suppl): Abstract nr LB-198. doi:10.1158/1538-7445.AM2017-LB-198.  
 
Mahaseth HE, Brutcher J, Kauh N, et al. Modified FOLFIRINOX regimen with improved 
safety and maintained efficacy in pancreatic adenocarcinoma. 2013. Pancreas 
42:1311 1315. 
Marsh R, Talamonti M, Katz M, et al. Pancreatic cancer and FOLFIRINOX: a new era 
and new questions. 2015. Cancer Med 4(6): 853 863. 
Metges JP, Ramee JF, Douillard JY, et al. Efficacy and safety of FOLFIRINOX in 
patients with metastatic pancreatic cancer. ASCO.2014. Meeting Abstr. 32(Suppl. 
3): 305. 
Moffitt RA, Marayati R, Flate EL, et al. Virtual microdissection identifies distinct tumor- 
and stroma-specific subtypes of pancreatic ductal adenocarcinoma. Nat Genet. 
Oct 2015;47(10):1168-1178.  


 
172 
 
Mu CY, Huang JA, Chen Y, et al. High expression of PD-L1 in lung cancer may 
contribute to poor prognosis and tumor cells immune escape through suppressing 
tumor infiltrating dendritic cells maturation. Medical oncology (Northwood, London, 
England). Sep 2011;28(3):682-688. 
Neoptolemos JP, Stocken DD, Friess H, et al. A randomized trial of chemoradiotherapy 
and chemotherapy after resection of pancreatic cancer. The New England journal 
of medicine. Mar 18 2004;350(12):1200-1210. 
Neoptolemos JP, Stocken DD, Bassi C, et al. Adjuvant chemotherapy with fluorouracil 
plus folinic acid vs gemcitabine following pancreatic cancer resection: a 
randomized controlled trial. Jama. Sep 08 2010;304(10):1073-1081. 
Neoptolemos JP, Palmer DH, Ghaneh P, et al. Comparison of adjuvant gemcitabine and 
capecitabine with gemcitabine monotherapy in patients with resected pancreatic 
cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial. Lancet 
(London, England). Mar 11 2017;389(10073):1011-1024. 
Nishino M, Gargano M, Suda M, et al. Optimizing immune-related tumor response 
assessment: does reducing the number of lesions impact response assessment in 
melanoma patients treated with ipilimumab? Journal for immunotherapy of cancer. 
2014;2: 17. 
Nomi T, Sho M, Akahori T, et al. Clinical significance and therapeutic potential of the 
programmed death-1 ligand/programmed death-1 pathway in human pancreatic 
cancer. Clinical cancer research: an official journal of the American Association for 
Cancer Research. Apr 01 2007;13(7):2151-2157. 
Oettle H, Post S, Neuhaus P, et al. Adjuvant chemotherapy with gemcitabine vs 
observation in patients undergoing curative-intent resection of pancreatic cancer: a 
randomized controlled trial. Jama. Jan 17 2007;297(3):267-277. 
Oettle H, Neuhaus P, Hochhaus A, et al. Adjuvant chemotherapy with gemcitabine and 
long-term outcomes among patients with resected pancreatic cancer: the CONKO-
001 randomized trial. Jama. Oct 09 2013;310(14):1473-1481. 
Okazaki T, Honjo T. PD-1 and PD-1 ligands: from discovery to clinical application. 
International immunology. Jul 2007;19(7):813-824. 
O’Reilly EM, Perelshteyn A, Jarnagin WR, et al. A single-arm, nonrandomized phase II 
trial of neoadjuvant gemcitabine and oxaliplatin in patients with resectable 
pancreas adenocarcinoma. Annals of surgery. Jul 2014;260(1):142-148. 
Provenzano PP, Cuevas C, Chang AE, et al. Enzymatic targeting of the stroma ablates 
physical barriers to treatment of pancreatic ductal adenocarcinoma. Cancer Cell 
2012;21: 418 29. 
Rahib L, Smith BD, Aizenberg R, et al. Projecting cancer incidence and deaths to 2030: 
the unexpected burden of thyroid, liver, and pancreas cancers in the United States. 
Cancer research. Jun 01 2014;74(11):2913- 2921. 
Regine WF, Winter KA, Abrams RA, et al. Fluorouracil vs gemcitabine chemotherapy 
before and after fluorouracil-based chemoradiation following resection of 


 
173 
 
pancreatic adenocarcinoma: a randomized controlled trial. Jama. Mar 05 
2008;299(9):1019-1026. 
Ritchie ME, Phipson B, Wu D, et al. limma powers differential expression analyses for 
RNA-sequencing and microarray studies. Nucleic Acids Res. 2015/4/20 
2015;43(7): e47. 
Rizvi NA, Hellmann MD, Snyder A, et al. Cancer immunology. Mutational landscape 
determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 
(New York, N.Y.). Apr 03 2015;348(6230):124-128. 
Royal RE, Levy C, Turner K, et al. Phase 2 trial of single agent Ipilimumab (anti-CTLA-4) 
for locally advanced or metastatic pancreatic 
adenocarcinoma. Journal of 
immunotherapy (Hagerstown, Md.: 1997). Oct 2010;33(8):828-833. 
Segal NH, Hamid O, Hwu W, et al. A phase I multi-arm dose-expansion study of the anti- 
programmed cell death-ligand-1 (PD-L1) antibody MEDI4736: Preliminary data. 
Ann Oncol. 2014;25(suppl 4): iv365.  
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA: a cancer journal for 
clinicians. Jan-Feb 2016;66(1):7-30.  
Snyder A, Makarov V, Merghoub T, et al. Genetic basis for clinical response to CTLA-4 
blockade in melanoma. The New England journal of medicine. Dec 04 
2014;371(23):2189- 2199. 
Soares KC, Rucki AA, Wu AA, et al. PD-1/PD-L1 blockade together with vaccine therapy 
facilitates effector T-cell infiltration into pancreatic tumors. Journal of 
immunotherapy (Hagerstown, Md.: 1997). Jan 2015;38(1):1-11. 
Sohn TA, Yeo CJ, Cameron JL, et al. Resected adenocarcinoma of the pancreas-616 
patients: results, outcomes, and prognostic indicators. Journal of gastrointestinal 
surgery: official journal of the Society for Surgery of the Alimentary Tract. Nov-Dec 
2000;4(6):567-579. 
Stein SM, James ES, Deng Y, et al. Final analysis of a phase II study of modified 
FOLFIRINOX in locally advanced and metastatic pancreatic cancer. Br J 
Cancer. 2016 Mar 29;114(7):737-43 
Stocken DD, Buchler MW, Dervenis C, et al. Meta-analysis of randomised adjuvant 
therapy trials for pancreatic cancer. British journal of cancer. Apr 25 
2005;92(8):1372- 1381. 
Team RDC. R: A Language and Environment for Statistical Computing. Vienna, Austria 
2016. 
Tempero MA, Malafa MP, Al-Hawary M, et al. Pancreatic Adenocarcinoma, Version 
2.2017, NCCN Clinical Practice Guidelines in Oncology. Journal of the National 
Comprehensive Cancer Network: JNCCN. Aug 2017;15(8):1028-1061. 
Timmermann B, Kerick M, Roehr C, et al. Somatic mutation profiles of MSI and MSS 
colorectal cancer identified by whole exome next generation sequencing and 
bioinformatics analysis. PloS one. Dec 22 2010;5(12): e15661. 


 
174 
 
Trede M, Schwall G, Saeger HD. Survival after pancreatoduodenectomy. 118 
consecutive resections without an operative mortality. Annals of surgery. Apr 
1990;211(4):447-458. 
Vincent A, Herman J, Schulick R, et al. Pancreatic cancer. Lancet (London, England). 
Aug 13 2011;378(9791):607-620. 
Vonderheide RH, Bayne LJ. Inflammatory networks and immune surveillance of 
pancreatic carcinoma. Current opinion in immunology. 02/17 2013;25(2):200-205. 
Von Hoff DD, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with nab- 
paclitaxel plus gemcitabine. The New England journal of medicine. Oct 31 
2013;369(18):1691-1703. 
Wolchok JD, Hoos A, O’Day S, et al. Guidelines for the evaluation of immune therapy 
activity in solid tumors: immune-related response criteria. Clinical cancer research: 
an official journal of the American Association for Cancer Research. Dec 01 
2009;15(23):7412-7420. 
Yeo CJ, Cameron JL, Maher MM, et al. A prospective randomized trial of 
pancreaticogastrostomy versus pancreaticojejunostomy after 
pancreaticoduodenectomy. Annals of surgery. Oct 1995;222(4):580-588; 
discussion 588-592.