Conditions: Previously Treated Metastatic Adenocarcinoma of the Pancreas
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 93
Healthy volunteers: no

Brief summary:
The primary objective of this study is to compare the overall survival (OS) of subjects with previously treated metastatic pancreatic cancer treated with cyclophosphamide (CY)/nivolumab/GVAX pancreas vaccine followed by nivolumab/CRS-207 (Arm A) to subjects treated with CY/GVAX pancreas vaccine followed by CRS-207 (Arm B).

Detailed description:

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: CRS-207 intervention 2: CRS-207 intervention 3: nivolumab intervention 4: GVAX intervention 5: CY
Intervention descriptions: intervention 1: 1 × 10\^9 CFU administered IV on Day 2 of Cycles 3-6 intervention 2: 1 × 10\^9 CFU administered IV on Day 1 of Cycles 3-6 intervention 3: 3 mg/kg administered IV on Day 1 of Cycles 1-6 intervention 4: 5x10\^8 cells administered in 6 intradermal injections on Day 2 of Cycles 1 and 2 intervention 5: 200 mg/m\^2 administered IV on Day 1 of Cycles 1 and 2

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
 
TITLE: A Randomized Phase 2 Study of the Safety, Efficacy, and Immune Response of 
GVAX Pancreas Vaccine (with Cyclophosphamide) and CRS-207 with or without 
Nivolumab in Patients with Previously Treated Metastatic Pancreatic Adenocarcinoma 
 
Johns Hopkins Protocol #:  
 
J14113, IRB00043936 
 
Aduro Biotech, Inc. Protocol #: 
ADU-CL-06 
 
BMS Protocol #: 
CA209-248 
 
*Principal Investigator: 
Dr. Dung Le (Protocol Chair) 
 
Sidney Kimmel Comprehensive Cancer Center, 
 
Johns Hopkins University 
1650 Orleans Street, Room 407 
Baltimore MD 21287 
 
 
 
 
IND Sponsor: 
Dr. Elizabeth Jaffee 
 
 
Sidney Kimmel Comprehensive Cancer Center, 
 
 
Johns Hopkins University 
 
 
1650 Orleans Street, Room 4M07 
 
 
Baltimore MD 21287 
 
 
 
   
 
 
Contract Research Organization  
(CRO) Contacts:  
Diane Felix, Ph.D. 
Clinical Trial Manager 
Medpace 
5375 Medpace Way 
Cincinnati, Ohio 45227 
 
 
 
 
 
Lyon L. Gleich, M.D. 
Medical Monitor 
Vice President, Medical Affairs 
Medpace 
5375 Medpace Way 
Cincinnati, Ohio 45227 
 
 
 
 


J14113 / Version 3.0/ November 15, 2015 
 
2
 
IND:  
 
 
 
  
 
 
 
 
 
 
BB IND 16147 
 
Bristol-Myers Squibb Supplied Agent:  
 
Nivolumab (BMS-936558; anti-PD-1 mAb) 
 
Aduro Biotech, Inc. Supplied Agent:  
 
CRS-207 (Lm ΔactA/ΔinlB/hMesothelin) 
 
Johns Hopkins University Supplied Agent:  GVAX pancreas vaccine  
 
 
 
 
 
(Panc 10.05 pcDNA-1/GM-Neo, Panc 6.03 
pcDNA-1/GM-Neo) 
 
Commercial Agent:   
 
 
 
 
 
 
Cyclophosphamide (CY, Cytoxan®) 
 
Date of Issue: 
Version 1/ August 22, 2014 
Version 1.1/ September 25, 2014 
Version 2.0/ September 30, 2015 
Version 3.0/ November 15, 2016 
 
 


J14113 / Version 3.0/ November 15, 2015 
 
3
 
TABLE OF CONTENTS 
 
1. 
OBJECTIVES ......................................................................................................................5 
1.1 
Primary Objectives...................................................................................................5 
1.2 
Secondary Objectives...............................................................................................5 
1.3 
Exploratory Objectives ............................................................................................5 
1.4  
Study Design ............................................................................................................6 
2. 
BACKGROUND .................................................................................................................9 
2.1 
Study Disease ...........................................................................................................9 
2.2 
Rationale ..................................................................................................................9 
3. 
PATIENT SELECTION ....................................................................................................14 
3.1  
Inclusion Criteria ...................................................................................................14 
3.2 
Exclusion Criteria ..................................................................................................16 
3.3 
Inclusion of Women and Minorities ......................................................................19 
4.  
RANDOMIZATION AND BLINDING............................................................................19 
5. 
TREATMENT PLAN ........................................................................................................19 
5.1 
Agent Administration.............................................................................................19 
5.2  
Dosing Criteria .......................................................................................................22 
5.3 
General Concomitant Medication and Supportive Care Guidelines ......................22 
5.4  
Prohibited and/or Restricted Medications and Devices .........................................25 
5.5  
Other Restrictions and Precautions ........................................................................26 
5.6  
Antibiotic Administration 
 
 
) ..........................................26 
5.7 
Definition of an Overdose for this Protocol ...........................................................27 
5.8 
Unacceptable Toxicity ...........................................................................................28 
5.9  
WOCBP, Contraception, Use in Pregnancy, Use in Nursing ................................30 
5.10 
Duration of Therapy ...............................................................................................32 
5.11 
Criteria for Removal from Treatment ....................................................................32 
5.12 
End of Course (EOC)/End of Treatment (EOT)/Safety Follow-up Visit ..............35 
5.13 
Duration of Follow-Up ..........................................................................................36 
5.14  
 .............................................................37 
6. 
DOSING DELAYS/DOSE MODIFICATIONS ...............................................................37 
6.1  
Dose Modifications ................................................................................................38 
6.2  
Dosing Delays ........................................................................................................38 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................39 
7.1 
Definitions..............................................................................................................40 
7.2 
Assessment of Causality ........................................................................................41 
7.3 
Expectedness ..........................................................................................................42 
7.4 
Handling of Expedited Safety Reports ..................................................................43 
7.5  
Reporting................................................................................................................43 
8. 
PHARMACEUTICAL INFORMATION ..........................................................................46 


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4
8.1  
Cyclophosphamide (Cytoxan®, CY) ......................................................................46 
8.2  
GVAX Pancreas Vaccine .......................................................................................48 
8.3  
CRS-207 .................................................................................................................50 
8.4  
Nivolumab..............................................................................................................53 
9. 
CORRELATIVE/SPECIAL STUDIES .............................................................................55 
9.1 
Tumor Tissue Studies ............................................................................................55 
9.2  
Peripheral Blood Mononuclear Cells (PBMCs) ....................................................55 
9.3  
Serum and Plasma Marker Studies ........................................................................56 
9.4 
Stool Samples Studies ............................................................................................56 
9.5 
Diagnostic Tissue Samples ....................................................................................56 
10. 
STUDY CALENDAR .......................................................................................................57 
10.1  Treatment Arm A ...................................................................................................57 
10.2  Treatment Arm B ...................................................................................................61 
11.  
STUDY ENDPOINTS .......................................................................................................65 
11.1 
Primary Endpoint ...................................................................................................65 
11.2  Secondary Endpoints .............................................................................................65 
11.3  Exploratory Endpoints ...........................................................................................65 
12. 
 DATA REPORTING / REGULATORY REQUIREMENTS ..........................................66 
12.1 
Data Collection and Processing .............................................................................66 
12.2  Independent Data Monitoring Committee (DMC) ................................................67 
12.3  Populations of Interest ...........................................................................................68 
12.4  Study Documentation.............................................................................................68 
12.5  Protocol Compliance ..............................................................................................70 
12.6  Study Monitor Function and Responsibility ..........................................................71 
12.7  General Information ...............................................................................................71 
13. 
STATISTICAL CONSIDERATIONS...............................................................................71 
13.1 
Study Design/Endpoints.........................................................................................71 
13.2 
Safety Analysis ......................................................................................................73 
REFERENCES ..............................................................................................................................74 
APPENDIX A: Performance Status Criteria .................................................................................77 
APPENDIX B: Management Algorithms ......................................................................................78 
APPENDIX C: Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for 
Evaluating Response in Solid Tumors ...............................................................................86 
APPENDIX D: Immune-Related Response Criteria .....................................................................89 
 


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5
1. OBJECTIVES 
 
1.1 
Primary Objectives 
 
The primary objective of this study is to compare the overall survival (OS) of subjects with 
previously 
treated 
metastatic 
pancreatic 
cancer 
treated 
with 
cyclophosphamide 
(CY)/nivolumab/GVAX pancreas vaccine followed by nivolumab/CRS-207 (Arm A) to subjects 
treated with CY/GVAX pancreas vaccine followed by CRS-207 (Arm B).   
 
1.2 
Secondary Objectives 
 
1.2.1 To assess safety and characterize toxicities of heterologous prime boost vaccination 
with anti-programmed death-1 (PD-1) blockade in subjects with metastatic 
pancreatic adenocarcinoma and compare between treatment arms. 
 
1.2.2 To assess progression-free survival (PFS), immune-related progression-free 
survival (irPFS), and time to progression (TTP) and compare between treatment 
arms. 
 
1.2.3 To assess the objective response rate by Response Evaluation Criteria for Solid 
Tumors (RECIST) 1.1 and compare between treatment arms. 
 
1.2.4 To measure tumor marker kinetics (CA 19-9) in subjects receiving treatment and 
correlate with OS, PFS and best overall response and compare between treatment 
arms. 
 
1.3 
Exploratory Objectives 
 
1.3.1  To assess the objective response rate and duration of response by immune-related 
response criteria (irRC) and compare between treatment arms. 
 
1.3.2 To collect peripheral blood mononuclear cells (PBMC), plasma, and serum to 
identify potential therapeutic targets and biomarkers and predictors of response 
(OS, PFS and best overall response) and autoimmune toxicity.  
 
• 
Measure pre- and post-treatment changes in PBMCs including effector, 
helper, and regulatory T cells, NK cells, monocytes, and macrophages 
through subset analysis and gene expression profiling.  
 
• 
Correlate induction of Listeria monocytogenes (Lm)- and mesothelin 
antigen-specific T cell responses and changes to the T cell epitope 
repertoire with OS, PFS and best overall response. 
 
• 
Correlate telomere length of lymphocytes to help predict response (OS, 
PFS and best overall response).  
 
• 
Correlate the induction of thyroglobulin and galectin-3 antibody responses 
with response (OS, PFS and best overall response).   


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• 
Proteomic approaches will be used on pre- and post-treatment sera to 
identify targets and biomarkers of response (OS, PFS and best overall 
response) or toxicity. 
 
1.3.3  To collect archived tissue and pre- and post-treatment biopsies to test for 
predictors of response (OS, PFS and best overall response) and future targets for 
combinatorial therapy.   
 Immunohistochemistry (IHC) and/or gene expression profiling will be 
used to compare the nature of tumors and immune infiltrates for 
responders versus non-responders.   
 Up-regulation of immune inhibitory molecules (such as programmed 
death-ligand 1 [PD-L1]) will be evaluated in the pre- and post-treatment 
samples. 
 Proteomic approaches to quantify protein expression and activation of 
specific signaling pathways in tumors from responders versus non-
responders 
1.3.4 To collect stool samples pre- and post-treatment to identify candidate gut 
microbial biomarkers and predictors of response (OS, PFS and best overall 
response)   
 Microbial community analysis via 16S V4 sequencing to correlate gut 
microbiome composition with response (OS, PFS and best overall 
response)  
 Whole metagenome functional profiling analysis via shotgun sequencing 
to correlate microbiome composition and microbial functions and 
pathways with response (OS, PFS and best overall response) 
 
1.4  
Study Design 
 
This is a multi-center, open-label, randomized, phase 2 study to evaluate the safety and clinical 
activity of CY/nivolumab/GVAX pancreas vaccine followed by nivolumab/CRS-207 in subjects 
with metastatic pancreatic adenocarcinoma who received and failed only 1 prior chemotherapy 
regimen for metastatic disease. The primary endpoint of the trial is OS. The OS of subjects 
treated with CY/ nivolumab/GVAX pancreas vaccine followed by nivolumab/CRS-207 (Arm A) 
will be compared to subjects treated with CY/GVAX pancreas vaccine followed by CRS-207 
(Arm B). Approximately 108 subjects with previously treated metastatic pancreatic cancer will 
be enrolled and randomized 1:1 to the two treatment arms to achieve 102 treated subjects.  
 
The study will consist of a screening period (within 21 days of first dose, inclusive of a 
randomization period of up to 7 days of first dose), a treatment period per the table below, and a 
follow-up period.   
 
 


J14113 / Version 3.0/ November 15, 2016 
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Subjects on both arms will receive treatment every 3 weeks for 6 cycles of treatment within a 
course. A course of treatment will be 20 weeks, with 16 weeks of treatment followed by an end-
of-course (EOC) evaluation approximately 4 weeks after the last study treatment administration 
in the course.  Treatment Arm A will include 2 cycles of CY/nivolumab/GVAX pancreas 
vaccine, followed by 4 cycles of nivolumab/CRS-207.  Treatment Arm B will include 2 cycles of 
CY/GVAX pancreas vaccine followed by 4 cycles of CRS-207.  Subjects will come to the clinic 
for dosing and/or assessments on Days 1 and 2 of each cycle and additional days for safety and 
immune monitoring follow-up per the study schedules in Section 10. 
 
No dose escalations or reductions are allowed.  Enrollment will continue until 102 subjects have 
received at least one dose of study treatment.  It is estimated that 5% of the subjects will not 
receive treatment so approximately 108 randomized subjects are expected to achieve 102 treated 
subjects.  Subjects who are required to stop treatment with nivolumab due to toxicity may stay 
on study treatment and receive CY/GVAX pancreas vaccine followed by CRS-207. 
  
The proportion of treated subjects with unacceptable toxicity will be monitored using a Bayesian 
stopping guideline (Section 5.8).  Subjects will be randomized until 6 subjects have been treated 
in Arm A (approximately 12 subjects in Arms A and B) and followed for at least 8 weeks (so 
that 6 Arm A subjects have received 2 cycles of CY/nivolumab/GVAX pancreas vaccine and at 
least one cycle of nivolumab/CRS-207).  Accrual will be suspended until the toxicity levels have 
been determined to be acceptable (i.e. confirmation that less than 3 subjects experience 
unacceptable toxicities during the first 8 weeks in Arm A).  Then, the remaining participants will 
be enrolled and monitored routinely. For purposes of determining unacceptable toxicity during 
the initial 8 weeks of treatment, subjects will be followed for treatment-related ≥ grade 4 AEs or 
grade 3 AEs not improving to ≤ grade 2 under therapy within 2 weeks 
 
  
Asymptomatic amylase, lipase elevation, hypophosphatemia, and lymphopenia will not be 
considered unacceptable toxicities.  In addition, ≥ grade 2 eye pain or reduction of visual acuity 
that does not respond to topical therapy and does not improve to ≤ grade 1 severity within 2 
weeks of starting therapy, or requires systemic therapy is an unacceptable toxicity.   
 
Immune and clinical responses will be evaluated through the following methods at baseline and 
during treatment: 1. tumor biopsies, 2. PBMCs, 3. serum and plasma, and 4. computed 
tomography (CT) scans (magnetic resonance imaging [MRI], if CT contraindicated) will be 
obtained for assessment of activity and correlative studies. Tumor assessments will be made 
using RECIST 1.1 and irRC.  
 
At the investigator’s discretion, subjects may receive additional courses of the assigned treatment 
TREATMENT SCHEDULE 
Arm 
CY 
Nivolumab 
GVAX 
CRS-207 
A 
Day 1, Cycles 1, 2 
Day 1, Cycles 1, 
2, 3, 4, 5, 6 
Day 2, Cycles 1, 2 
Day 2, Cycles 3, 4, 
5, 6 
B 
Day 1, Cycles 1, 2 
None 
Day 2, Cycles 1, 2 
Day 1, Cycles 3, 4, 
5, 6 


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8
regimen if they are clinically stable and meet dosing eligibility criteria.  All subjects may 
continue in the treatment period until discontinuation due to unacceptable toxicity, lack of 
clinical benefit as determined by the investigator, or termination of the study by sponsor.  
Subjects may continue on treatment with radiographic disease progression if subject is clinically 
stable and investigator believes the treatment is providing benefit.  Criteria for removal from 
treatment are found in Section 5.11. Subjects will return to the study site no more than 4 weeks 
after the final administration of study treatment for an end-of-treatment (EOT) evaluation.  
 
 
 
 
 Subjects who are still receiving treatment at the time of 
study close may complete the current treatment course and the EOT evaluation prior to 
transitioning to long-term follow-up. Subjects will be considered in the treatment period until 4 
weeks after the last dose of study drug. Blood cultures through a peripheral vein and also through 
a central line (if applicable) will be collected to monitor for the presence of CRS-207 per Section 
5.14.   
 
After completion of treatment and EOT assessments, all subjects, including those who did not 
receive treatment, will continue to be followed every 12 weeks by telephone, e-mail, or optional 
clinic visit until death, withdrawal of consent, or closure of study.  Subjects treated in Arm A 
will also be contacted at 100 days from the last dose of nivolumab or 28 days from the last dose 
of cyclophosphamide, GVAX, or CRS-207 if the subject never received nivolumab or is no 
longer receiving nivolumab due to toxicity, whichever reporting period is longer.  The visit 
window for conducting this final visit is either 100 +14 days or 28 + 7 days.  Information on 
survival and new cancer therapies will be collected.   
 
All subjects who discontinue study treatment should continue to be monitored for disease status 
by radiologic imaging every 12 weeks until: the 1) start of a new antineoplastic therapy 
(information of the new cancer therapy will be collected), 2) death, 3) withdrawal of consent, or 
4) the close of the study, whichever occurs first.   
All subjects will be followed for at least 4 weeks after their last dose of study drug for the 
development of adverse events (AEs). Serious adverse events (SAEs) that occur within 100 days 
after the last dose of nivolumab for subjects in Arm A or for 28 days from the last dose of 
cyclophosphamide, GVAX, or CRS-207, if the subject never received or is no longer receiving 
nivolumab due to toxicity, whichever reporting period is longer.  SAEs will be collected for 28 
days after last dose of study drug for subjects in Arm B, or until initiation of a new anti-cancer 
treatment, whichever occurs first.  Subjects who are discontinued from study treatment due to an 
unacceptable treatment-related AE will be monitored for the resolution of the AE to ≤ grade 1 or 
stabilization or until initiation of a new therapy for their cancer, whichever occurs first.  
 
The study will be closed when all subjects have been followed for at least 12 months and the 
final analysis timing criteria have been met, or when all subjects have withdrawn from study.  
The final analysis will be conducted when the first of the following has occurred: 84 deaths in 
treated subjects, 12 months after the last treated subject was enrolled, or study is closed by 
sponsor.  At the conclusion of the study, all remaining subjects will be offered enrollment in a 
long-term follow-up study and continue to be followed for survival and clinical and 
immunological responses. 
 


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An independent Data Monitoring Committee (DMC) will monitor accumulating safety data at 
intervals throughout the study.  Additionally, an interim analysis will be conducted to assess 
efficacy in the context of subject risk/benefit when approximately 50% of the expected deaths in 
treatment subjects have occurred (approximately 42 deaths). 
 
2. BACKGROUND 
 
2.1 
Study Disease 
 
In 2013, there were an estimated 45,220 new cases of pancreatic cancer diagnosed in the United 
States1.  Generally, most new cases of pancreatic cancer are advanced with extensive tumor 
growth usually due to the lack of symptoms during the early stages of the disease. As a result, 
few patients are considered candidates for surgical resection. Patients with advanced pancreatic 
cancer are usually treated with chemotherapy in an effort to improve survival and alleviate 
symptoms. Median survival time ranges from 4 to 6 months in patients with metastatic disease. 
With treatment, survival has improved to 6 to 11 months2,3.  Overall, the 5-year survival rate is 
about 6% for all stages combined and decreases to 2% for patients with metastatic pancreatic 
cancer4. Currently, there are a few standard therapy options for patients.  Single-agent 
gemcitabine was FDA approved based on a comparative study between gemcitabine and 5-FU. 
Gemcitabine produced significant improvement in disease-related symptoms and prolonged 
survival (1-year survival: 18% versus 2%, respectively)5. Subsequently, the oral tyrosine kinase 
inhibitor, erlotinib, was approved in combination with gemcitabine based on a slight increase in 
median survival over gemcitabine alone (6.24 months compared to 5.91 months)6. Other phase 3 
studies testing combination regimens have been disappointing.  More recently, a randomized 
phase 
3 
study 
performed 
in 
France 
comparing 
FOLFIRINOX 
(5-
FU/leucovorin/irinotecan/oxaliplatin) to gemcitabine as first-line therapy resulted in an 
improvement in survival of 11.1 months versus 6.8 months2.  While this regimen is being used, 
there are still concerns about its potential toxicity in a North American population and it is being 
reserved for the most fit patients. Nab-paclitaxel has now been approved in combination with 
gemcitabine as first-line therapy with a median survival of 8.5 months compared to 6.7 months 
with gemcitabine alone7.  Therapies for patients with metastatic pancreatic cancer are urgently 
needed, in particular there are no therapies currently approved for previously treated patients 
with metastatic disease. Novel approaches, such as immunotherapy, are showing promise in this 
very difficult cancer.   
 
2.2 
Rationale 
 
Immune tolerance mechanisms both at the systemic level and in the tumor microenvironment 
inhibit activity of immunotherapy in pancreatic ductal adenocarcinoma (PDA). Combinatorial 
strategies aimed at priming tumor antigen-specific T cells while simultaneously blocking 
negative immune checkpoints will be necessary to show an effect in PDA. There is increasing 
interest in the role of immunotherapy in the treatment of cancers. Ipilimumab (Yervoy®), is an 
antagonist antibody to cytotoxic T-lymphocyte antigen-4 (CTLA-4) which downregulates T cell 
activation. Ipilimumab has been approved for the treatment of metastatic melanoma and 
Provenge® (sipuleucel-T), an autologous dendritic cell-based vaccine, has been approved for 
prostate cancer8,9. Another immune checkpoint blocker, PD-1, is showing promising results in 
melanoma, renal cell, and lung cancer10,11. Despite all of the excitement, diseases such as PDA, 
are unlikely to respond to single-agent therapy. Unlike melanoma, there are very few tumor-


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10
infiltrating lymphocytes at baseline to be targeted by these agents. Vaccines are necessary to 
prime and expand tumor-specific T cells to infiltrate the tumor and agents designed to turn off 
the brakes on the T cells can then promote tumor regression. 
 
The optimal approach to elicit anti-tumor immunity would include the use of a vaccine strategy 
that has shown promising results in patients with pancreatic cancer in combination with an agent 
that inhibits negative T cell signaling, such as anti-PD-1.  One synergistic vaccine strategy is the 
use of heterologous prime-boost vaccinations integrating two, distinct vaccine vectors to 
optimize immune responses. In murine models, GVAX (tumor cells modified to express 
granulocyte macrophage-colony stimulating factor [GM-CSF]) followed by an attenuated Lm 
modified to express a tumor-associated antigen enhances the induction of tumor antigen-specific 
T cell responses as well as delays tumor growth.  Furthermore, in a recently completed clinical 
study performed in patients with metastatic pancreatic cancer, the sequential administration of 
GVAX pancreas and CRS-207 immunotherapies resulted in improved OS in patients receiving 
the combination compared to GVAX pancreas vaccine alone. GVAX pancreas vaccine is 
composed of irradiated, allogeneic pancreatic cancer cells modified to express GM-CSF and is 
given with a low-dose of CY to inhibit regulatory T cells. In prior studies, GVAX pancreas 
vaccine induced mesothelin-specific T cell responses that correlated with survival12-15. CRS-207 
is live-attenuated, double-deleted (LADD) Lm modified to express the tumor-associated antigen, 
mesothelin. LADD Lm induces the release of stimulatory cytokines and is unique in its capacity 
to stimulate both innate and adaptive immunity by activating T cells and NK cells.  LADD Lm is 
able to deliver tumor antigens directly to antigen-presenting cells in the context of the “danger 
signals” required to promote immunity over tolerance. 
 
Importantly, the combination of GM-CSF whole cell vaccines with anti-CTLA-4 or anti-PD-1 
shows improved responses in preclinical and clinical studies, and PD-1 antibody therapy also 
synergizes with Lm-based vaccines in murine studies14,16-19.  In addition, preclinical data using 
CY in combination with GVAX, Lm, and PD-1 and PD-L1 blockade increase activity of these 
agents20,21. Nivolumab is a fully human monoclonal immunoglobulin (Ig) G4 antibody against 
PD-1 and is showing activity in multiple tumor types including melanoma, renal cell carcinoma 
(RCC), and non-small cell lung cancer (NSCLC)10.  We hypothesize that the addition of 
nivolumab to the prime-boost vaccination regimen of CY/GVAX pancreas vaccine followed by 
CRS-207 will improve the survival of patients with previously treated pancreatic cancer. 
 
The proposed timing of administration and doses of CY (200 mg/m2), GVAX pancreas vaccine 
(5 × 108 cells), and CRS-207 (1 × 109 colony-forming units [CFU]) for this study have been used 
previously and were well tolerated22. The proposed dose level of nivolumab (3 mg/kg) was also 
tolerated in a prior Phase 1 study10. Preclinical data evaluating combinatorial therapy with 
CY/GVAX and PD-1 antibody blockade (where PD-1 blockade is administered one day prior to 
vaccination) demonstrated enhanced murine survival and the infiltration of IFN-γ producing 
CD8+ lymphocytes in the tumor microenvironment23. This study will be the first to investigate 
the efficacy, immunogenicity, and safety of CY/nivolumab and GVAX pancreas vaccine therapy 
given in sequence with nivolumab/CRS-207 in subjects with metastatic pancreatic 
adenocarcinoma. 
 
Phase 2, Randomized Trial of GVAX Pancreas Vaccine and CRS-207 Immunotherapy versus 
GVAX Alone in Patients with Metastatic Pancreatic Cancer.  This heterologous prime-boost 
vaccination approach stimulates a broad immune response against pancreas tumor cells with the 


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11
GVAX pancreas vaccine and then boost the response using CRS-207 specifically targeting the 
mesothelin protein.  In our recently completed study (clinicaltrials.gov identifier NCT01417000), 
90 subjects with previously treated pancreatic cancer were randomized 2:1 to receive either 2 
doses of CY/GVAX pancreas vaccine followed by 4 doses of CRS-207 (Arm A) or 6 doses of 
CY/GVAX pancreas vaccine (Arm B) every 3 weeks.  Clinically stable subjects were offered 
additional 20-week courses.  The primary endpoint was comparison of OS between arms.  
Ninety-seven percent of subjects received prior therapy and 50% received 2 or more 
chemotherapy regimens for metastatic disease.  The full analysis set included all subjects who 
received at least one dose of CY.  OS for all subjects treated was 6.1 months in Arm A vs. 3.9 
months in Arm B (two-sided, p=0.034; HR=0.59) (Figure 1A).  The per protocol analysis set, 
which included all subjects who received ≥3 doses (at least 1 dose of CRS-207 in Arm A), had 
OS of 9.7 months in Arm A vs. 4.6 months in Arm B (p=0.034; HR=0.53) (Figure 1B).  
Combined CY/GVAX pancreas vaccine and CRS-207 was generally well-tolerated with no 
treatment-related SAEs or unexpected grade 3/4 toxicities.  Most common side effects were 
limited to vaccine site reactions related to GVAX, and transient laboratory abnormalities, fevers 
and rigors, associated with the CRS-207 infusion.  The significant difference in OS between 
treatment arms met the criteria for early stopping at the interim analysis and was confirmed at 
subsequent analyses.   
 
 
Figure 1.  Overall survival favored CY/GVAX pancreas vaccine + CRS-207 over CY/GVAX pancreas vaccine alone.  (A)  
Full analysis set.  (B)  Per protocol analysis set. 
 
This combination immunotherapy resulted in extended survival for metastatic pancreatic cancer 
patients and serves as a promising vaccine backbone for combination with immune checkpoint 
blockade. 
 
GVAX Pancreas Vaccine Induces Immune Cell Infiltration into Tumor Associated with 
Programmed Death-Ligand 1 (PD-L1) and PD-1 Expression.  In an ongoing neoadjuvant 
study, GVAX pancreas vaccine is given either alone or in combination with low-dose CY.  An 
influx of immune cells and formation of lymphoid aggregates within the tumor is induced in a 
majority of patients.  Without the vaccine, pancreatic tumors lack significant inflammation and 
the T cells that exist are primarily regulatory T cells.  In this study, GVAX pancreas vaccine was 
able to induce an influx of tumor-infiltrating lymphocytes as early as 2 weeks after vaccine 


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12
administration24.   
 
Figure 2 is an example of a resected tumor with lymphoid aggregates consisting of a number of 
cell types including B and T cells (2A-C).   Upregulation of the PD-1 checkpoint pathway (PD-
L1/PD-1) is also apparent (2D).  These lymphoid aggregates were seen in the majority of 
vaccinated subjects but the number of aggregates range from 1-35/HPF.  GVAX pancreas 
vaccine is able to generate tumor-infiltrating lymphocytes and preclinical studies suggest that 
combination with immune checkpoint inhibitors can release the brakes on vaccine-induced T 
cells 16,25,26.   
 
 
Figure 2.  GVAX pancreas vaccine induces lymphoid aggregates in pancreatic tumors.  A. Lymphoid aggregates (arrows) were 
found in intratumoral locations of pancreatic cancer 2 weeks after vaccination. B. Lymphoid aggregates (arrows) were found in 
peritumoral locations of pancreatic cancers from vaccinated subjects. C. Immunohistochemistry (IHC) staining of a representative 
lymphoid aggregate. Hematoxylin and eosin (H&E), anti-CD3, CD4, CD8 staining of T cells, anti-CD20 staining of B cells, and anti-
CD21 staining follicular dendritic cells, a hallmark of germinal centers.  D.  IHC staining demonstrates PD-L1 (left panel) staining 
on tumors and monocytes and PD-1 (right panel) staining on T cells within the same lymphoid aggregate. 
 
 
M2 Monocyte-Macrophage Phenotype Can Present Resistance to Immune Therapy in 
Pancreatic Cancer.  Suppressive immune cells are not limited to regulatory T cells.  Pancreatic 
cancer is also characterized by increased numbers of suppressive myeloid cells and tumor-
associated fibrosis which typify a chronic “wound healing”/anti-inflammatory phenotype27-29.  
 
  
 
 
 
 (M. Gough, unpublished). 
 


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13
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Reduction of both regulatory T cells and myeloid derivied suppressor cells in the periphery 
(splenic) and tumor microenvironment (conversion from M2 to M1 phenotype) are seen in 
preclinical tumor models treated with Lm-based vaccine in combination with anti-PD-1 
antibody19.  In the animal model, the vaccine is responsible for these immune cell subset changes 
and not particularly influenced by anti-PD-1.  However, addition of anti-PD-1 significantly 
increases CD8+ T cell intratumoral infiltrates.  Characterization of the effects of Lm-based 
vaccine given in prime-boost fashion with GVAX pancreas vaccine in patients with pancreatic 
cancer and the impact of the addition of anti-PD-1 will be crucial for mechanistic understanding 
and potential immunologic predictors of tumor response.  
 
Phase 1b Randomized Trial of Ipilimumab (IPI) versus GVAX Pancreas Vaccine + IPI in 
Advanced Pancreatic Cancer.  GVAX pancreas vaccine has been previously combined with 
CTLA-4 blockade14. Thirty subjects with previously treated pancreatic cancer were randomized 
1:1 to IPI at 10mg/kg alone (Arm 1) or in combination with GVAX pancreas vaccine (Arm 2).  
The higher dose of 10mg/kg of IPI was chosen because IPI at 3mg/kg in pancreatic cancer had 
previously been reported and demonstrated a low but detectable response rate.  Studies in 
melanoma also suggested that the 10 mg/kg dose was more efficacious.  Subjects received 4 
induction doses of IPI or GVAX pancreas vaccine + IPI at 3-week intervals and then 
maintenance with the same treatment every 3 months.  Two subjects in Arm 1 showed evidence 
of stable disease (7 & 22 weeks) but none demonstrated CA19-9 biochemical responses.  In 
contrast, 3 subjects in Arm 2 had evidence of prolonged disease stabilization (31, 71, & 81 
weeks) and 7 subjects experienced CA19-9 declines.  In 2 of these subjects, disease stabilization 
occurred after an initial period of progression.  The median OS (3.6 vs 5.7 months, HR: 0.51, 
p=0.072) and 1 year OS (7 vs 27%) favored Arm 2.  Induction and maintenance of T cell 
responses and enhancement of the T cell repertoire directed at mesothelin correlated with OS. 
 
Nivolumab. The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to 
suppress immune control30.   The normal function of PD-1, expressed on the cell surface of 
activated T cells under healthy conditions, is to down-modulate unwanted or excessive immune 
responses, including autoimmune reactions. The ligands for PD-1 (PD-L1 and PD-L2) are 
constitutively expressed or can be induced in various tumors31-34.  Binding of either PD-1 ligand 
to PD-1 inhibits T cell activation triggered through the T cell receptor.  The observed correlation 
of clinical prognosis with PD-L1 expression in multiple cancers suggests that the PD-1/PD-L1 


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14
pathway plays a critical role in tumor immune evasion and should be considered as an attractive 
target for therapeutic intervention. 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
The preclinical and clinical data support that the prime-boost vaccination strategy has diverse 
abilities to recruit adaptive and innate immunity as well as T cell and antibody responses and 
makes it a promising backbone to combine with immune checkpoint blockade.  Furthermore, 
data suggesting synergy of anti-CTLA-4 and anti-PD-1 with GVAX and anti-PD-1 with LADD 
Lm provide a strong rationale to quickly move this concept into the clinics for this rapidly fatal 
disease.  
 
3. PATIENT SELECTION 
 
3.1  
Inclusion Criteria 
 
3.1.1 Age ≥18 years.   
 
3.1.2 Have histologically- or cytologically-proven adenocarcinoma of the pancreas.  
Patients with mixed histology will be excluded. 
 


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3.1.3 Have metastatic disease. 
 
3.1.4 Have received and failed only 1 prior chemotherapy regimen for metastatic 
pancreatic cancer. 
 
 Must have received and failed only 1 prior regimen administered for 
pancreatic cancer in the metastatic setting; failure includes development of 
metastases on or within 3 months of adjuvant chemotherapy treatment or 
development of metastases on or within 3 months of treatment for locally 
advanced disease or radiographic disease progression on or within 3 months 
of treatments for metastatic disease.  Documented intolerance (grade 3 or 4 
toxicity or hospitalization leading to discontinuation) of treatment for 
metastatic disease will also be considered a failure.  
 Radiosensitizing doses of chemotherapy are not considered systemic 
chemotherapy 
 
3.1.5 Patients with the presence of at least one lesion with measurable disease as 
defined by 10 mm in longest diameter for a soft tissue lesions or 15 mm in short 
axis for a lymph node by RECIST 1.1. 
 
3.1.6 Patients acceptance to have a tumor biopsy of an accessible lesion at baseline and 
on treatment if the lesion can be biopsied with acceptable clinical risk (as judged 
by the investigator). 
 
 
 
3.1.7 
ECOG performance status 0 or 1 (Appendix A). 
 
 
 
3.1.8 
Life expectancy of greater than 3 months. 
 
 
 
3.1.9 
Patients must have adequate organ and marrow function as defined below: 
 
 
Leukocytes 
  
 
 
 
≥ 3,000/mcL 
 
Absolute neutrophil count 
≥ 1,500/mcL 
 
Platelets 
 
  
 
 
 
≥ 100 × 103/uL 
 
CD4 Count 
  
 
 
 
≥ 200/mcL 
 
Hemoglobin    
 
 
 
≥ 9.0 g/dL 
 
Total bilirubin   
 
 
 
≤ upper limit of normal (ULN) except subjects with 
Gilbert Syndrome, who can have total bilirubin < 
3.0 mg/dL 
 
AST(SGOT) and ALT(SGPT)≤2.0 × ULN 
 
Alkaline phosphatase  
 
≤5.0 × ULN  
 
Creatinine  
  
 
 
 
≤1.5 × ULN or creatinine clearance (CrCl) 
≥ 40 mL/min (if using the Cockcroft-Gault formula 
below): 
 
Female CrCl = (140 - age in years) x weight in kg x 0.85 
                              72 x serum creatinine in mg/dL 
 


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    Male CrCl = (140 - age in years) x weight in kg x 1.00  
                    
 
 
 
 
72 x serum creatinine in mg/dL 
 
 
Albumin  
 
  
 
 
≥3.0 g/dL 
 
3.1.10 Women of childbearing potential (WOCBP) must have a negative serum 
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human 
chorionic gonadotropin [HCG]).  WOCBP is defined in Section 5.9. 
 
- 
WOCBP must agree to follow instructions for method(s) of contraception 
from the time of enrollment for the duration of treatment with study drug(s) 
plus 5 half-lives of study drug(s) plus 4 weeks (duration of ovulatory cycle) 
for a total of 23 weeks post treatment completion. 
 
- 
Men who are sexually active with WOCBP must agree to follow instructions 
for method(s) of contraception for the duration of treatment with study drug(s) 
plus 5 half-lives of study drug(s) plus 90 days (duration of sperm turnover) for 
a total of 31 weeks post-treatment completion. 
 
- 
At least one barrier method of contraception must be employed by all sexually 
active patients (male and female), regardless of other methods, to prevent the 
transfer of body fluids. 
 
3.1.11 Ability to understand and willingness to sign a written informed consent 
document. 
 
3.2 
Exclusion Criteria 
 
 
 
3.2.1 
Patient has a known history or evidence of brain metastases. 
 
3.2.2  Patient who has had chemotherapy, radiation, or biological cancer therapy within 
14 days prior to the first dose of study drug. 
 
3.2.3 Patient has received an investigational agent or used an investigational device 
within 28 days of the first dose of study drug. 
 
3.2.4  Patient is expected to require any other form of systemic or localized 
antineoplastic therapy while on study. 
 
3.2.5 Patients who have had surgery within 28 days of dosing of investigational agent, 
excluding minor procedures (dental work, skin biopsy, etc.), celiac plexus block, 
and biliary stent placement. 
 
3.2.6 Patients who have received any non-oncology vaccine therapy used for prevention 
of infectious diseases including seasonal vaccinations within 28 days of study 
treatment. Examples include, but are not limited to, the following: measles, 
mumps, rubella, chicken pox, yellow fever, seasonal flu, H1N1 flu, rabies, BCG, 
and typhoid vaccine. 


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3.2.7 Patients with a history of prior treatment with anti-PD-1, anti-PD-L1, anti-PD-L2, 
anti-CTLA4 antibodies, or who have received both GVAX or CRS-207 will be 
excluded. 
  
3.2.8  Have used any systemic steroids within 14 days of study treatment. 
 
3.2.9  Use more than 3 g/day of acetaminophen. 
 
3.2.10 Patients on immunosuppressive agents (e.g., TNF pathway inhibitors, PI3 kinase 
inhibitors) within 7 days of study treatment.  
 
3.2.11 Patients receiving growth factors including, but not limited to, granulocyte-colony 
stimulating factor (G-CSF), GM-CSF, erythropoietin, within 14 days of study 
drug administration. Use of such agents while on study is also prohibited.  
 
3.2.12 Patient has a known allergy to both penicillin and sulfa. 
 
3.2.13  History of severe hypersensitivity reaction to any monoclonal antibody. 
 
3.2.14 Patient has a known or suspected hypersensitivity to GM-CSF, hetastarch, corn, 
dimethyl sulfoxide, fetal bovine serum, trypsin (porcine origin), yeast or any other 
component of GVAX pancreas vaccine or CRS-207 (e.g., glycerol). 
 
3.2.15 Have current or prior history of infection or clinically significant adverse events 
(AEs) associated with an exogenous implant(s) or device(s) that cannot be easily 
removed.  
 
3.2.16 Subjects who have implanted medical devices that pose high risks for colonization 
and cannot be easily removed (e.g., artificial heart valves, pacemakers, prosthetic 
joints, orthopedic screw(s), metal plate(s)) if infection occurs. Other common 
devices such as venous access devices (e.g., Port-a-Cath or Mediport) may be 
permitted as well as arterial and venous stents and dental and breast implants. 
 
3.2.17 Have any evidence of hepatic cirrhosis or clinical or radiographic ascites. 
 
3.2.18 Have clinically significant and/or malignant pleural effusion (pleural effusions that 
are not clinically significant are allowed, defined as no more than 25% fluid level 
of the corresponding hemithorax and stable fluid level [non-progressive] over at 
least 6 weeks documented radiographically). 
 
3.2.19  Have had a new pulmonary embolism, extremity deep venous thromboembolism, 
or portal vein thrombosis within 2 months of study enrollment (any thrombosis 
within 2 months of study enrollment must be approved by the Protocol Chair and/ 
or Medical Monitor). 
 
3.2.20 Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 


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arrhythmia, or psychiatric illness/social situations that would limit compliance 
with study requirements. 
 
3.2.21 History of any autoimmune disease, including but not limited to: Patients with a 
history of inflammatory bowel disease, including ulcerative colitis and Crohn’s 
Disease, patients with a history of symptomatic disease (e.g., rheumatoid arthritis, 
systemic progressive sclerosis [scleroderma], systemic lupus erythematosus, 
autoimmune vasculitis [e.g., Wegener’s Granulomatosis]); CNS or motor 
neuropathy considered of autoimmune origin (e.g., Guillain-Barre Syndrome and 
Myasthenia Gravis, multiple sclerosis).  Patients with Graves or Hashimoto’s 
disease, vitiligo, and type I diabetes mellitus will be allowed. 
 
3.2.22 All toxicities attributed to prior anti-cancer therapy other than alopecia and 
fatigue must have resolved to grade 1 (National Cancer Institute Common 
Terminology Criteria for Adverse Events [CTCAE], version 4.03) or baseline 
before administration of study drug. Subjects with toxicities attributed to prior 
anti-cancer therapy which are not expected to resolve and result in long-lasting 
sequelae, such as neuropathy after chemotherapy, are permitted to enroll. 
 
3.2.23 Have received a diagnosis of human immunodeficiency virus (HIV), hepatitis B 
or hepatitis C (patients who are hepatitis C antibody positive may be enrolled if 
they are confirmed with negative viral load at screening) 
 
3.2.24 Patient has a pulse oximetry of <92% on room air. 
 
3.2.25 Patient is on supplemental home oxygen. 
 
3.2.26  Patient has an unhealed surgical wound. 
 
3.2.27  Patient has clinically significant heart disease (such as uncontrolled angina, 
myocardial infarction within the last 3 months or congestive heart failure of New 
York Heart Association III or IV). 
 
3.2.28  Patient has valvular heart disease that requires antibiotic prophylaxis for 
prevention of endocarditis. 
 
3.2.29 Have insufficient peripheral venous access to permit completion of the study 
dosing and compliance with study phlebotomy regimen 
 
3.2.30 Patient is, at the time of signing informed consent, a regular user (including 
“recreational use”) of any illicit drugs or other substance abuse (including 
alcohol) that could potentially interfere with adherence to study procedures or 
requirements. 
 
3.2.31 Patient is unwilling or unable to follow the study schedule for any reason. 
 


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3.2.32 Patient is unable to avoid intimate contact with another individual known to be at 
high risk of listeriosis (e.g., newborn infant, pregnant woman, HIV-positive 
individual) for at least 7 days after receiving CRS-207 infusion. 
 
 
 
3.2.33 Patient is pregnant or breastfeeding. 
 
3.2.34 Have rapidly progressing disease, as judged by the investigator (e.g., rapid 
progression through prior treatment[s]). 
 
3.3 
Inclusion of Women and Minorities 
 
Both men and women of all races and ethnic groups are eligible for this trial.   
 
4.  RANDOMIZATION AND BLINDING  
 
This study is an open-label study.  As such, assignment of study treatment will not be blinded.    
 
Subjects will be randomized to Arm A (CY/nivolumab/GVAX pancreas vaccine followed by 
nivolumab/CRS-207) or Arm B (CY/GVAX pancreas vaccine followed by CRS-207) in a 1:1 
fashion. Randomization of subjects will be stratified by disease status (progressive disease [PD] 
or stable disease [SD]) and site at study entry.   
 
5. TREATMENT PLAN 
 
5.1 
Agent Administration 
 
Treatment will be administered on an outpatient basis.  Dosing delays are described in Section 6.  
No investigational or commercial agents or therapies other than those described below may be 
administered with the intent to treat the subject’s malignancy.   
 
Subjects on both arms will receive treatment every 3 weeks for 6 cycles of treatment within a 
course. A course of treatment will be 20 weeks, with 16 weeks of treatment followed by an end-
of-course (EOC) evaluation approximately 4 weeks after the last study treatment administration 
in the course.  At the investigator’s discretion, all subjects may receive additional courses of the 
assigned treatment regimen if they are clinically stable and meet dosing eligibility criteria.  
Treatment Arm A will include 2 cycles of CY/nivolumab/GVAX pancreas vaccine, followed by 
4 cycles of nivolumab/CRS-207.  Treatment Arm B will include 2 cycle of CY/GVAX pancreas 
vaccine followed by 4 cycle of CRS-207.   
 
 
 


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Table 1: Treatment Schedule 
 
TREATMENT SCHEDULE 
Arm 
CY 
Nivolumab 
GVAX 
CRS-207 
A 
Day 1, Cycles 1, 2 
Day 1, Cycles 1, 
2, 3, 4, 5, 6 
Day 2, Cycles 1, 2 
Day 2, Cycles 3, 4, 
5, 6 
B 
Day 1, Cycles 1, 2 
None 
Day 2, Cycles 1, 2 
Day 1, Cycles 3, 4, 
5, 6 
 
Table 2: Regimen Description 
 
REGIMEN DESCRIPTION 
Agent 
Premedications; Precautions 
Dose 
Route 
Course Length 
CY 
Subjects may be pre-medicated 
with anti-emetics prior to CY 
administration. 
200 mg/m2 in 
100ml NS 
IV infusion 
over 30 min* 
20 weeks 
GVAX 
EMLA cream (approximately 
2.5 grams per site, at least 1 
hour prior to vaccination) 
5 × 108 cells  
Six 
intradermal 
injections 
CRS-207 
650 mg acetaminophen; 500ml 
NS pre-infusion; 1000ml NS 
post-infusion 
1 × 109 CFU 
in 250ml NS 
IV infusion 
over 2 hours* 
Nivolumab 
No prophylactic 
pre-medication will be given 
unless indicated by previous 
experience in an individual 
subject per Section 5.3.4. 
3 mg/kg  
IV over 60 
minutes* 
*Infusion times are approximate (+/- 10 min) and may need to be adjusted based on 
subject tolerability. 
 
Please see Section 6.2 for guidance regarding dosing delays. Subjects that are required to 
stop treatment with nivolumab due to toxicity may continue to receive CY/GVAX 
pancreas vaccine followed by CRS-207 (assessment schedule per Section 10.2). 
 
 
 
5.1.1 Cyclophosphamide (CY) 
 
Subjects may be pre-medicated prior to administration with anti-emetics per institutional 
guidelines. Subjects on Arm A should be observed for 30 minutes before administration 
of nivolumab. Acute reactions (resulting in the delay of nivolumab) will be managed 
using standard therapy for acute drug reactions as per institutional standard of care and 
reported to the Protocol Chair and/or Medical Monitor and IND Sponsor. 
 
Dosing calculation based on weight: 


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The dosing calculations should be based on the body weight. If the subject’s weight on 
the day of dosing differs by > 10% from the weight used to calculate the dose, the dose 
must be recalculated.  
 
 
 
5.1.2 GVAX Pancreas Vaccine 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5.1.3 CRS-207 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
5.1.4  Nivolumab 
 
 
 
 
 
 
  
 
 


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5.2  
Dosing Criteria 
 
Dosing of study therapy will be delayed for the following laboratory criteria:  
 
 AST/ALT >3 × ULN   
 Total bilirubin > 1.5 x ULN  or direct bilirubin > 2.0 × ULN for subjects with 
Gilbert’s disease 
 Creatinine > 1.5 × ULN 
 Hemoglobin < 8 g/dL 
 ANC < 1000/uL  
 Platelets < 80 × 103/uL 
 
Please see Section 6.2 for further guidance regarding dosing delays.   
 
5.3 
General Concomitant Medication and Supportive Care Guidelines 
 
5.3.1 Cyclophosphamide (CY) 
 
Acute reactions will be managed using standard therapy for acute drug reactions as per 
institutional guidelines. 
 
5.3.2 GVAX Pancreas Vaccine 
 
Local vaccine site reaction may be treated with topical applications of aloe vera or 
vitamin E gel or lotion. Significant local inflammation that is causing the subject severe 
pain or is interfering with the activities of daily living may be treated with oral 
analgesics. Local toxicities of pruritus at the vaccine sites and systemic pruritus may be 
treated with topical or oral diphenhydramine hydrochloride (Benadryl®) or topical aloe 
vera. If oral diphenhydramine hydrochloride is used the recommended dose shall be 25-
50 mg every four to six hours as needed for pruritus, not to exceed 300 mg/day. Cases of 
local ulceration should be manageable with local wound care, with or without antibiotics. 
Severe local inflammation or significant clinical autoimmunity will be managed on a 
case-by-case basis. 
 
5.3.3 CRS-207 
 
Guidance on treatment of the common infusion reactions related to CRS-207 dosing is as 
follows: 
 


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• 
Fevers: Despite the acetaminophen premedication, subjects can spike fevers 
up to 40°C starting at the end of the CRS-207 infusion generally through the 
next 24 hours. Oral ibuprofen (400 to 800 mg) and acetaminophen (650 to 
1000 mg) may be used in alternate sequence every 4 hours. 
 
• 
Rigors: Rigors (generally once or twice per infusion) have been observed to 
start during or at the end of a CRS-207 infusion through 24 hours. IV 
narcotics such as morphine or meperidine may be administered per 
institutional policy. Oral morphine or non-steroidal anti-inflammatory drugs 
(NSAIDs) (e.g., aspirin, ibuprofen, naproxen) may be used as home treatment. 
 
• 
Blood pressure: Decreases in blood pressure have been observed 
necessitating additional IV fluids during the 4 hour observation period (up to 1 
or 2 liters). Reasons for this include the development of fever, compartmental 
shifts of fluid resulting from the CRS-207 infusion and the use of narcotics. 
Some subjects have also been slightly hypotensive at 24 hours upon arrival to 
the clinic after CRS-207 administration. Subjects are encouraged to hydrate 
themselves liberally at home with oral fluids. 
 
• 
Nausea and vomiting: Nausea and vomiting have been reported and observed 
within 24 hours after CRS-207 infusion. Subjects may be given anti-emetics 
as needed. 
 
Blood draws for clinical hematology and serum chemistry will be done the day after the 
CRS-207 infusion. Any unexpected grade 3 or greater laboratory abnormalities should be 
repeated within 24-72 hours. 
 
5.3.4 Nivolumab 
 
Nivolumab is a fully human monoclonal immunoglobulin (Ig) G4 antibody. 
Subjects should be closely monitored for potential AEs during antibody infusion 
and potential AEs throughout the study.  
 
5.3.4.1 Infusion Reactions 
Since nivolumab contains only human immunoglobulin protein sequences, it is 
unlikely to be immunogenic and induce an infusion or hypersensitivity reaction. 
However, if such a reaction were to occur, it might manifest with fever, chills, 
rigors, headache, rash, pruritis, arthralgias, hypo- or hypertension, bronchospasm, 
or other symptoms. All grade 3 or 4 infusion reactions should be reported within 24 
hours to the Protocol Chair and/or Medical Monitor and BMS and reported as an 
SAE if criteria are met. Infusion reactions should be graded according to CTCAE 
(version 4.03) guidelines. Treatment recommendations are provided below and may 
be modified based on local treatment standards and guidelines as appropriate: 
 
For grade 1 symptoms (mild reaction; infusion interruption not indicated; 
intervention not indicated): 
 


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Remain at bedside and monitor subject until recovery from symptoms. The 
following prophylactic premedications are recommended for future infusions: 
diphenhydramine 50 mg (or equivalent) and/or acetaminophen 325 to 1000 mg at 
least 30 minutes before additional nivolumab administrations. 
 
For grade 2 symptoms (moderate reaction requires therapy or infusion interruption 
but responds promptly to symptomatic treatment [e.g., antihistamines, non-steroidal 
anti-inflammatory drugs, narcotics, corticosteroids, bronchodilators, IV fluids]; 
prophylactic medications indicated for ≤ 24 hours): 
 
Stop the nivolumab infusion, begin an IV infusion of normal saline, and treat the 
subject with diphenhydramine 50 mg IV (or equivalent) and/or acetaminophen 325 
to 1000 mg; remain at bedside and monitor subject until resolution of symptoms. 
Corticosteroid or bronchodilator therapy may also be administered as appropriate. If 
the infusion is interrupted, restart the infusion at 50% of the original infusion rate 
when symptoms resolve; if no further complications ensue after 30 minutes, the rate 
may be increased to 100% of the original infusion rate. Monitor subject closely. If 
symptoms recur then no further nivolumab will be administered at that visit. 
Administer diphenhydramine 50 mg IV, and remain at bedside and monitor the 
subject until resolution of symptoms. The amount of study drug infused must be 
recorded on the case report form (CRF). The following prophylactic premedications 
are recommended for future infusions: diphenhydramine 50 mg (or equivalent) 
and/or acetaminophen 325 to 1000 mg should be administered at least 30 minutes 
before additional nivolumab administrations.  
 
For grade 3 or grade 4 symptoms (severe reaction, grade 3: prolonged [i.e., not 
rapidly responsive to symptomatic medication and/or brief interruption of infusion]; 
recurrence of symptoms following initial improvement; hospitalization indicated for 
other clinical sequelae [e.g., renal impairment, pulmonary infiltrates]; grade 4: (life 
threatening; pressor or ventilator support indicated): 
 
Immediately discontinue infusion of nivolumab. Begin an IV infusion of normal 
saline, and treat the subject as follows. Recommend bronchodilators, epinephrine 
0.2 to 1 mg of a 1:1,000 solution for subcutaneous administration or 0.1 to 0.25 mg 
of a 1:10,000 solution injected slowly for IV administration, and/or 
diphenhydramine 50 mg IV with methylprednisolone 100 mg IV (or equivalent), as 
needed. Subject should be monitored until the investigator is comfortable that the 
symptoms will not recur. Nivolumab will be permanently discontinued. 
Investigators should follow their institutional guidelines for the treatment of 
anaphylaxis. Remain at bedside and monitor subject until recovery from symptoms. 
In the case of late-occurring hypersensitivity symptoms (e.g., appearance of a 
localized or generalized pruritis within 1 week after treatment), symptomatic 
treatment may be given (e.g., oral antihistamine, or corticosteroids). 
 
Please refer to Section 6.2 for guidelines regarding GVAX and CRS-207 treatment 
delays following a nivolumab infusion-related reaction.  
 
5.3.4.2 Nivolumab-Related Adverse Events  


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Blocking PD-1 function may permit the emergence of auto-reactive T cells and 
resultant clinical autoimmunity. Rash/pruritus, diarrhea/colitis, pneumonitis, 
hepatitis, and hypothyroidism were drug-related, presumptive autoimmune events  
noted in previous nivolumab studies.  
 
For the purposes of this study, a nivolumab-related AE is defined as an AE of 
unknown etiology, associated with drug exposure and is consistent with an immune 
phenomenon. Efforts should be made to rule out neoplastic, infectious, metabolic, 
toxin or other etiologic causes. Serological, immunological, and histological 
(biopsy) data should be used to support the diagnosis of an immune-mediated 
toxicity. Suspected nivolumab-related AEs must be documented on an AE or SAE 
CRF. Identification and treatment of nivolumab-related AEs can be found in 
Appendix B. Additional guidance can be found in the nivolumab Investigator’s 
Brochure (IB). Antibiotics will also be administered to subjects who have not yet 
received antibiotics for CRS-207 and the subject requires steroids for a suspected 
nivolumab-related AE. (Section 5.6). 
 
Subjects who experience a grade 2 or higher nivolumab-related AE should be 
discussed with the Protocol Chair and/or Medical Monitor and IND sponsor 
immediately.  
 
5.4  
Prohibited and/or Restricted Medications and Devices 
 
The following therapies or devices are not permitted during the treatment period (if administered, 
the subject may be removed from the study): 
 
• Any 
non-study 
anticancer 
chemotherapy 
or 
immunotherapy 
(approved 
or 
investigational) 
• TNF pathway inhibitors or PI3 kinase inhibitors 
•  Systemically active steroids can be used but should be reported to the Protocol Chair 
and/or Medical Monitor and IND Sponsor. Steroid treatment should be completed at 
least 14 days prior to resuming study-related treatments. 
•  Another investigational agent 
•  Filgrastim (Neupogen® or G-CSF) or sargramostim (Leukine® or GM-CSF) 
•  Prophylactic vaccines (e.g., influenza, pneumococcal, Td/Tdap) within 28 days prior to 
or after dosing 
• The use of anticoagulants is known to increase the risk of gastrointestinal hemorrhage. 
Since gastrointestinal hemorrhage is an adverse reaction with nivolumab, subjects who 
require concomitant anticoagulant therapy should be monitored closely. 
• Implanted medical devices that pose high risks for colonization and cannot be easily 
removed (e.g., artificial heart valves, pacemakers, prosthetic joints, orthopedic 
screw(s), metal plate(s)) if infection occurs are prohibited. Other common devices such 
as venous access devices (e.g., Port-a-Cath or Mediport), arterial and venous stents, and 
dental and breast implants may be permitted if approved by the Protocol Chair and/or 
Medical Monitor.  
 


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In addition, the following therapies should not be administered during the treatment period 
unless medically necessary and approval must be obtained from the Protocol Chair and/or 
Medical Monitor for a subject to continue dosing if therapy is given concurrently with study 
participation: 
 
•  General anesthesia or deep sedation 
•  Aspirin >325 mg/day (chronic daily use of aspirin ≤325 mg/day and heparin flushes 
for central lines are allowed) 
•  More than 4 g/day of acetaminophen 
•  Systemic antibiotics 
 
5.5  
Other Restrictions and Precautions 
 
Palliative (limited-field) radiation therapy is permitted, but only for pain control to 
sites present at baseline and with approval by the Protocol Chair and/or Medical 
Monitor or IND Sponsor. 
 
5.6  
Antibiotic Administration 
 
 
 
 
 
 
 
 
 
 
 
 
 
    
 
Should a patient require emergent implant of a prohibited device (as described in Section 5.4) 
while on therapy, the patient will receive a 14-day IV antibiotic regimen appropriate for the 
coverage of wild-type listeriosis.  
 
Antibiotics will also be administered to subjects who have not yet received antibiotics for CRS-
207 and the subject requires steroids for a suspected nivolumab-related AE. Antibiotic 
prophylaxis should be given for the duration of the treatment with the steroid (recommended oral 
80 mg trimethoprim / 400 mg sulfamethoxazole once daily or 160 mg trimethoprim / 800 mg 
sulfamethoxazole (DS) three days a week).  
 
 
 
 
 
 


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Subjects with clinical or laboratory signs or symptoms of infection who require initiation of 
antibiotics other than specified by protocol should have a clinically-relevant evaluation, 
including appropriate bacterial cultures. Culture of cerebrospinal fluid should be obtained for 
subjects with suspected central nervous system infection. In such instances, analysis of 
cerebrospinal fluid should also include cell count, protein, glucose and Gram stain. IV ampicillin 
(or trimethoprim/sulfamethoxazole in penicillin-allergic subjects) plus gentamicin should be 
initiated for possible infectious complications of CRS-207 for subjects who are suspected of 
having CRS-207 infection and meet the criteria listed below: 
 
• 
Flu-like symptoms Grade 3 or greater lasting for ≥12 hours 
• 
Fever Grade 4 or higher (>40.0ºC for >24 hours) 
• 
Persistent fever >39ºC lasting for ≥48 hours 
• 
Infection Grade 3 or higher (infection with interventional radiology or operative 
intervention indicated) 
• 
Evidence of abscess 
• 
Clinical signs or symptoms (e.g., neurologic signs or symptoms), which, in the 
judgment of the investigator, necessitate starting antibiotics 
 
 
 
 
 
 
 
 
 
 
 
 
Suspected or confirmed infection with CRS-207 and/or Listeria is considered an adverse event of 
special interest (AESI) and should be reported following SAE reporting procedures (Section 
7.1.3) irrespective of temporal relationship to study drug administration.  This includes 
scheduled blood cultures during surveillance monitoring that are positive for CRS-207 or if a 
subject presents with symptoms suspicious for a Listeria-like infection and/or is tested positive 
for Listeria at a local hospital/clinic. 
 
5.7 
Definition of an Overdose for this Protocol 
 
Overdose of nivolumab is defined as: 
An overdose is defined as the accidental or intentional administration of any dose of a product 
that is considered both excessive and medically important. All occurrences of overdose must be 
reported as SAEs (see Section 7.5.1 for reporting details). Appropriate supportive treatment 
should be provided if clinically indicated. 
 


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28
All reports of overdose with and without an AE must be reported within 24 hours to the Protocol 
Chair and / or Medical Monitor, IND Sponsor (Dr. Elizabeth Jaffee), Aduro Biotech, Inc. 
(Aduro), and Bristol-Myers Squibb (BMS). IND Sponsor, Aduro, and BMS contact information 
can be found in Section 7.5.1. 
5.8 
Unacceptable Toxicity 
 
Unacceptable toxicities are defined as treatment-related ≥ grade 4 AEs, or treatment-related 
grade 3 AEs not improving to ≤ grade 2 under therapy within 2 weeks.  Exceptions include: 
 Asymptomatic amylase and lipase elevation 
 Grade 3 or 4 lymphopenia or hypophosphatemia  
 ≥ grade 2 eye pain or reduction of visual acuity that does not respond to topical therapy 
and does not improve to ≤ grade 1 severity within 2 weeks of starting therapy, or requires 
systemic therapy is an unacceptable toxicity.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Unexpected Grade 3 or greater laboratory abnormalities should be repeated within 24-72 hours if 
clinically indicated and monitored as necessary to determine if event meets toxicity criteria. 
 
The proportion of unacceptable toxicities will be monitored. If the toxicity levels in Treatment 
Arms A or B are unacceptable (>33% of subjects), then enrollment will be suspended until 
further review and consideration by the Protocol Chair and / or Medical Monitor, IND Sponsor, 
and the DMC. There will be no dose reductions for CY, nivolumab, CRS-207, or GVAX 
pancreas vaccine. 
 
The proportion of treated subjects with unacceptable toxicity will be monitored using a Bayesian 
stopping guideline.  A Beta (1.5, 5.5) prior, representing a toxicity rate of 21%, a slightly 
conservative estimate, was used in the development of our guidelines.  The therapy will be re-
evaluated if the posterior probability that the toxicity rate exceeds the 33% boundary is greater 
than 50%.  Toxicity will be monitored continuously.  Table 3 summarizes the stopping 
boundaries for unacceptable toxicities. 
 
 
 


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29
Table 3.  The number of toxicities needed to trigger stopping guidelines throughout the course of 
the study.   
 
Number of Subjects Per 
Treatment Arm  
Number of toxicities 
needed to trigger 
re-evaluation 
6 
3 
7-9 
4 
10-12 
5 
13-15 
6 
16-18 
7 
19-21 
8 
22-24 
9 
25-27 
10 
28-30 
11 
31-33 
12 
34-36 
13 
37-39 
14 
40-42 
15 
43-45 
16 
46-48 
17 
49-51 
18 
52-54 
19 
 
The probability of triggering the stopping guidelines was assessed for a range of possible true 
toxicity rates using simulations with 10,000 replicates (Table 4).  The probability of stopping to 
re-evaluate was 7.3% if the true proportion with an unacceptable toxicity was 15%.  In 
comparison, the probability of stopping early is 72.6% if the true proportion with an 
unacceptable toxicity was 33%.   
 
Table 4.  Probability of triggering a re-evaluation based upon the proportion with an 
unacceptable toxicity for a range of true toxicity probabilities. 
 
True probability of 
unacceptable toxicity 
Probability of triggering 
stopping guidelines 
1% 
<0.1% 
5% 
0.2% 
10% 
2.1% 
15% 
7.3% 
20% 
18.2% 
25% 
35.9% 
30% 
57.5% 
33% 
72.6% 
35% 
79.3% 
 


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5.9  
WOCBP, Contraception, Use in Pregnancy, Use in Nursing 
 
A WOCBP is defined as any female who has experienced menarche and who has not undergone 
surgical sterilization (hysterectomy or bilateral oophorectomy) and is not postmenopausal. 
Menopause is defined clinically as 12 months of amenorrhea in a woman over age 45 years in 
the absence of other biological or physiological causes. In addition, women under the age of 62 
years must have a documented serum follicle stimulating hormone (FSH) level > 40mIU/mL to 
confirm menopause.* 
 
*Women treated with hormone replacement therapy (HRT) are likely to have artificially 
suppressed FSH levels and may require a washout period in order to obtain a physiologic FSH 
level. The duration of the washout period is a function of the type of HRT used. The duration of 
the washout period below are suggested guidelines and the investigators should use their 
judgment in checking serum FSH levels. If the serum FSH level is >40 mIU/ml at any time 
during the washout period, the woman can be considered postmenopausal: 
 
 1 week minimum for vaginal hormonal products (rings, creams, gels) 
 4 week minimum for transdermal products 
 8 week minimum for oral products 
 
5.9.1 Contraception 
 
The investigational agents used in this protocol may have adverse effects on a fetus in 
utero. Furthermore, it is not known if the investigational agents have transient adverse 
effects on the composition of sperm.  Non-pregnant, non-breast-feeding women may be 
enrolled if they are considered highly unlikely to conceive. Highly unlikely to conceive is 
defined as 1) surgically sterilized, or 2) postmenopausal (defined as a woman who is > 45 
years of age and has not had menses for greater than 12 months and women under the age 
of 62 must have a documented serum follicle stimulating hormone (FSH) level less than 
40mlU/mL will be considered postmenopausal). or 3) amenorrheaic for < 2 years without 
a hysterectomy and oophorectomy and with a documented FSH value in the 
postmenopausal range, or ) not heterosexually active for the duration of the study, or 5) 
heterosexually active and willing to use 2 methods of birth control (which is also required 
for the female partners of male subjects). The 2 birth control methods can be 2 barrier 
methods or a barrier method plus a hormonal method to prevent pregnancy, used 
throughout the study starting with Visit 1 through 23 weeks after the last dose of study 
drug.  Male subjects enrolled in this study must also agree to use an adequate method of 
contraception starting with Visit 1 through 31 weeks after the last dose of study drug. 
 
Investigators shall counsel WOCBP and male subjects who are sexually active with 
WOCBP on the importance of pregnancy prevention and the implications of an 
unexpected pregnancy Investigators shall advise WOCBP and male subjects who are 
sexually active with WOCBP on the use of highly effective methods of contraception. 
Highly effective methods of contraception have a failure rate of < 1% per year when used 
consistently and correctly. 
 
HIGHLY EFFECTIVE METHODS OF CONTRACEPTION 


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• 
Male condoms with spermicide 
• 
Hormonal methods of contraception including combined oral contraceptive pills, 
vaginal ring, injectables, implants, and intrauterine devices (IUDs) such as Mirena 
by WOCBP subject or male subject’s WOCBP partner. 
• 
Nonhormonal IUDs, such as ParaGard 
• 
Tubal ligation 
• 
Vasectomy 
• 
Complete abstinence* 
 
*Complete abstinence is defined as complete avoidance of heterosexual intercourse and 
is an acceptable form of contraception for all study drugs. Abstinence is only acceptable 
when this is in line with the preferred and usual lifestyle of the subject. Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, profession of abstinence for entry 
into a clinical trial, post-ovulation methods) and withdrawal are not acceptable methods 
of contraception. Subjects who choose complete abstinence are not required to use a 
second method of contraception, but female subjects must continue to have pregnancy 
tests. Acceptable alternate methods of highly effective contraception must be discussed in 
the event that the subject chooses to forego complete abstinence.  
 
LESS EFFECTIVE METHODS OF CONTRACEPTION 
• 
Diaphragm with spermicide 
• 
Cervical cap with spermicide 
• 
Vaginal sponge 
• 
Male condom without spermicide* 
• 
Progestin only pills by WOCBP subject or male subject’s WOCBP partner 
• 
Female condom* 
*A male and female condom must not be used together 
 
Subjects should be informed that taking the study drug may involve unknown risks to the 
fetus (unborn baby) if pregnancy were to occur during the study.  In order to participate 
in the study they must adhere to the contraception requirement (described above) for the 
duration of the study.  If there is any question that a subject will not reliably comply with 
the requirements for contraception, that subject should not be entered into the study. 
 
5.9.2 Use in Pregnancy 
 
The investigational agents used in this protocol may have adverse effects on a fetus; 
therefore, women with a positive pregnancy test at screening will not be eligible for 
enrollment.  If a subject inadvertently becomes pregnant while on treatment, the subject 
will immediately be removed from the study.  The site will contact the subject at least 
monthly and document the subject’s status until the pregnancy has been completed or 
terminated.   
 
Pregnancy in female subjects throughout the study or within 23 weeks of completing 
treatment as well as any pregnancy in partners of male subjects throughout the study or 
within 31 weeks of completing the study should be reported initially as a serious adverse 
event (see SAE reporting procedures in section 7.5.1 and 7.5.5) by the investigator within 


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24 hours of learning of its occurrence. Pregnancy information must be reported on the 
Pregnancy Form. 
 
Protocol required procedures for study discontinuation and follow-up must be performed 
on the subject unless contraindicated by pregnancy (e.g., x-ray studies). Other appropriate 
pregnancy follow-up procedures should be considered if indicated.  
 
Follow-up information regarding the course of the pregnancy, including any voluntary or 
spontaneous termination, perinatal and neonatal outcome and where applicable, offspring 
information must be reported on the Pregnancy Follow-up Form. Pregnancy outcomes 
must also be collected for the female partners of any males in this trial. Consent to report 
information regarding these pregnancy outcomes should be obtained from the female 
partner.  
 
5.9.3 Use in Nursing Women 
 
Since many drugs are excreted in human milk, and because of the potential for serious 
adverse reactions in the nursing infant, subjects who are breast-feeding are not eligible 
for enrollment. 
 
5.9.4 All Subjects (Male and Female) 
 
All sexually active patients must use at least a barrier method (i.e., condom) to prevent 
transmission of body fluids.  
 
5.10 
Duration of Therapy 
 
Subjects who are clinically stable and meet dosing requirements (per Section 5.2) at the end of 
the first course may receive additional courses of their assigned treatment based on investigator 
discretion. The additional course(s) may start as early as 4 weeks from last dose of previous 
course and all assessments will be followed per the study schedule in Section 10, with the first 
dose of the additional course corresponding to Day 1, Cycle 1 of the study schedule. The 
following assessments are not required during additional courses: 
• HLA-typing 
• Tumor biopsies 
• Stool samples for microbial biomarker analyses 
• Whole blood for isolation of PBMCs except during Cycle 4 (Day 1 only) and 
Cycle 6 
• Whole blood draw for Lm- and mesothelin-specific immunity assays except 
during Cycle 4 and Cycle 6 
 
Assessments done at End of Course (EOC) which are required at Day 1, Cycle 1 do not need to 
be performed if the next course is started within 14 days of the EOC visit assessments. 
 
5.11 
Criteria for Removal from Treatment 
 


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The reason for study removal and the date the subject was removed will be documented in the 
CRF. A subject will be discontinued from the trial for any of the following reasons: 
• The subject or legal representative (such as a parent or legal guardian) withdraws 
consent for participation in the study. 
A subject must be discontinued from treatment (but may continue to be monitored in the post-
treatment follow-up portion of the trial) for any of the following reasons: 
 
 The subject or legal representative (such as a parent or legal guardian) withdraws 
consent for treatment 
 Intercurrent illness that prevents further administration of treatment 
 Unacceptable toxicity (see Section 5.8) 
 Disease progression as defined in Section 5.11.1 
 Severe or life-threatening nivolumab-related AE(s) (see Section 5.11.2) 
 Need for >2 dose delays due to the same toxicity as per the dose delay guidelines 
(see Section 6.2) 
 If, in the opinion of the Investigator, a change or temporal or permanent 
discontinuation of therapy would be in the best interest of the subject, 
 Noncompliance with trial treatment or procedure requirements, 
 Subject is lost to follow-up 
 Subject becomes pregnant 
 
5.11.1 Disease Progression 
 
GVAX pancreas vaccine, CRS-207, and nivolumab are expected to trigger immune-
mediated responses, which require activation of the immune system prior to the 
observation of clinical responses.  Such immune activation may take weeks to months to 
be evident.  Some subjects may have objective volume increase of tumor lesions or other 
disease parameters within weeks following the start of immunotherapy.  Such subjects 
may not have had sufficient time to develop the required immune activation or, in some 
subjects, tumor volume or other disease parameter increases may represent infiltration of 
lymphocytes into the original tumor.  In conventional studies, such tumor volume or 
relevant laboratory parameter increases during the first 2-4 months of the study would 
constitute disease progression and lead to discontinuation of imaging to detect response, 
thus disregarding the potential for subsequent immune-mediated clinical response. This 
phenomenon was observed in approximately 10% of subjects in the Phase 1 study of 
nivolumab and has also been reported for ipilimumab monotherapy35. 
 
Subjects will be permitted to continue with treatment beyond initial RECIST 1.1 defined 
PD as long as they meet the following criteria: 
 
Investigator-assessed clinical benefit, and 
 
Subject is tolerating study drug. 
 


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The assessment of clinical benefit should take into account whether the subject is 
clinically deteriorating and unlikely to receive further benefit from continued treatment. 
The following criteria need to be taken into consideration: 
 
Absence of clinical symptoms and signs indicating disease progression. 
 
No decline in ECOG performance status. 
 
Absence of rapid progression of disease or of progressive tumor at critical 
anatomical sites (e.g., cord compression) requiring urgent alternative medical 
intervention. 
 
All decisions to continue treatment beyond PD must be discussed with the Protocol Chair 
and / or Medical Monitor and documented in the study records. 
 
Tumor assessments will be made using RECIST 1.1 (Appendix C) and irRC (Appendix 
D).  
 
5.11.2 Nivolumab-Related Adverse Events  
 
Permanent discontinuation of study treatment should be considered for any of the 
following: 
1. Severe or life-threatening related AEs, including, but not limited to, any of the 
following (the IND Sponsor, Aduro, and BMS must be notified in the event of 
these AEs): 
 Any grade 2 treatment-related uveitis, eye pain, or blurred vision that does not 
respond to topical therapy and does not improve to Grade 1 severity within 2 
weeks of starting therapy  
 
 Any grade 3 non-skin, drug-related AE lasting > 7 days, with the following 
exceptions: 
 
 Grade 3 treatment-related uveitis, pneumonitis, bronchospasm, diarrhea, 
colitis, neurologic toxicity, hypersensitivity reaction, or infusion reaction 
(applies to nivolumab only) of any duration requires discontinuation 
 
 Grade 3 treatment-related laboratory abnormalities do not require 
treatment discontinuation except: 
 
o Grade 3 treatment-related thrombocytopenia that is associated with 
bleeding requires discontinuation 
 
o Any treatment-related liver function test (LFT) abnormality that 
meets the following criteria require discontinuation: 
 
Total bilirubin > 5 × ULN 
 
Concurrent AST or ALT > 3 × ULN and total bilirubin > 2 
× ULN 
 
 Any grade 4 treatment-related AE or laboratory abnormality, except for the 
following events which do not require discontinuation: 


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35
 
 Grade 4 amylase or lipase abnormalities that are not associated with 
symptoms or clinical manifestations, or radiographic signs of pancreatitis. 
It is recommended to consult with the Protocol Chair or Medical Monitor 
for grade 4 amylase or lipase abnormalities. 
 
 Isolated grade 4 electrolyte imbalances/abnormalities that are not 
associated 
with 
clinical 
sequelae 
and 
are 
corrected 
with 
supplementation/appropriate management. 
 
 Transient, self-correcting grade 4 AST or ALT that occur after the CRS-
207 infusion and resolves within 2 weeks.  
 
 Grade 4 lymphopenia. 
 
 Any dosing interruption lasting > 6 weeks with the following exceptions: 
 
 Dosing interruptions to allow for prolonged steroid tapers to manage drug-
related adverse events are allowed. Prior to re-initiating treatment in a 
subject with a dosing interruption lasting > 6 weeks, the Protocol Chair 
and/or Medical Monitor must be consulted. Tumor assessments should 
continue as per protocol even if dosing is interrupted. 
 
 Dosing interruptions > 6 weeks that occur for non-drug-related reasons 
may be allowed if approved by the Protocol Chair and/or Medical 
Monitor. Prior to re-initiating treatment in a subject with a dosing 
interruption lasting > 6 weeks, the Protocol Chair or Medical Monitor 
must be consulted. Tumor assessments should continue as per protocol 
even if dosing is interrupted.  
 
Any AE, laboratory abnormality, or intercurrent illness which, in the judgment of the 
Investigator, presents a substantial clinical risk to the subject with continued nivolumab 
dosing.  
 
In order to standardize the management of AEs for all subjects, treatment management 
algorithms are included in Appendix B. Additional AE treatment management 
algorithms included in the nivolumab IB might be considered for individual cases. 
 
Subjects that are required to stop treatment with nivolumab due to toxicity may stay on 
study and receive CY/GVAX pancreas vaccine followed by CRS-207 (assessment 
schedule per Section 10.2) once the nivolumab-related toxicity(s) has resolved to a grade 
1. 
 
5.12 
End of Course (EOC)/End of Treatment (EOT)/Safety Follow-up Visit 
 
At the investigator’s discretion, subjects may receive additional courses of the assigned treatment 
regimen if they are clinically stable and meet dosing eligibility requirements, as determined at an 
EOC evaluation 4 weeks after completion of each course of therapy. The EOC visit may be 


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conducted several times during the study if a subject completes more than one course of drug 
therapy. All subjects will return to the study site approximately 4 weeks (± 7 days) after the last 
infusion of study drug (i.e., completion of the final course or upon early discontinuation) for an 
EOT evaluation. Procedures and assessments performed at these visits and beyond should follow 
the respective guidelines described in Sections 5.13 and 10.0 as appropriate. Note:  If it is 
determined at an EOC visit that the subject will not move on to additional courses then the EOT 
visit can be conducted at the same time.  Assessments for EOC and EOT are the same, as 
described in Section 10.0.   
 
The EOT visit is conducted only once after the final study treatment. If the EOT visit occurs 
early (e.g., 1 week prior to the expected visit as protocol allows), an assessment for AEs should 
be made by telephone or email on day 28 (± 1 day) after last dose of study drug and documented.  
 
 
 
 
 
The subject will be monitored for AEs up to the mandatory EOT/Safety Follow-Up Visit or to 
resolution of toxicity to ≤ Grade 1, whichever occurs later.  SAEs that occur within 100 days 
(+14 day reporting window) of last dose of nivolumab for subjects in Arm A (or for 28 days 
from the last dose of cyclophosphamide, GVAX, or CRS-207 if the subject is no longer 
receiving nivolumab due to toxicity, whichever reporting period is longer) or within 28 days of 
last dose of study drug for subjects in Arm B, and before initiation of a new antineoplastic 
treatment (whichever comes first) should also be followed and recorded. 
 
5.13 
Duration of Follow-Up 
 
All randomized subjects, including those never treated, will enter a follow-up period.  Treated 
subjects will begin the follow-up period after they complete the EOC/EOT / Safety Follow-Up 
Visit.  Subjects will be contacted every 12 weeks (and at 100 days [+14 days] from the last dose 
of nivolumab for subjects in Arm A if the subject was still receiving nivolumab at the time of 
treatment discontinuation) to monitor Overall Survival until death, withdrawal of consent, or 
study closure.  Information of other cancer therapies after discontinuation from the study 
treatment will be collected.   
All subjects should continue to be monitored for disease status by radiologic imaging.  Disease 
monitoring should continue to be assessed every 12 weeks until, 1) start of a new antineoplastic 
therapy (information of the new cancer therapy will be collected), 2) until death, 3) withdrawal 
of consent, or 4) study closure, whichever occurs first. 
 
Subjects who are discontinued from the study treatment due to an unacceptable drug-related AE 
will be monitored for safety until the resolution of the AE to ≤ grade 1 or stabilization or until 
initiation of a new therapy for their cancer, whichever occurs first. 
 
All subjects will be followed for at least 4 weeks after their last dose of study drug for the 
development of AEs. SAEs that occur within 100 days (+14 day reporting window) after the last 
dose of nivolumab for subjects in Arm A or within 28 days (+7 day reporting window) from the 
last dose of cyclophosphamide, GVAX, or CRS-207, if the subject never received nivolumab or 


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37
is no longer receiving nivolumab due to toxicity (whichever reporting period is longer) should be 
followed and recorded.  SAEs that occur within 28 days (+7 day reporting window) after last 
dose of study drug for subjects in Arm B, or until initiation of a new antineoplastic treatment 
should also be followed and recorded. 
 
At the conclusion of the study, all remaining subjects who have received at least one dose of 
study treatment will be offered enrollment in a long-term follow-up study and continue to be 
evaluated for survival. Subjects who are still receiving treatment at the time of study close may 
complete the current treatment course (up to 6 cycles) and EOT/Safety Follow-Up Visit prior to 
transitioning to participation in the separate long-term follow-up study. 
 
  
 
 
 
 
 
 
 
 
   
 
5.14.1  Confirmed Listeria Infection 
 
In the event a subject has a positive Listeria culture at any time during or after study participation 
(except within 7 days after a CRS-207 infusion), the IND Sponsor and Aduro should be notified 
within 24 hours of the adverse event of special interest (AESI) per Section 7.1.3.  
 
If Listeria has been confirmed at the clinical site or an external laboratory, all efforts should be 
made to obtain a sample of the bacterial isolate from the original positive culture and submit to 
Aduro for strain confirmation; records on all samples cultured during this period must be 
obtained and provided to the Sponsor.  Refer to the Central Laboratory Manual for sample 
collection and shipping instructions. 
 
5.14.2  Suspected Infection with CRS-207 or Listeria 
 
In the case of a suspected persistent CRS-207 or Listeria infection that has not been confirmed 
by culture, collection of blood, urine and stool samples in duplicate is recommended. One set of 
samples should be cultured locally for Listeria per institutional guidelines. Culture of 
cerebrospinal fluid should be obtained for subjects with suspected central nervous system 
infection. In such instances, analysis of cerebrospinal fluid should also include cell count, 
protein, glucose, and Gram stain. If samples are positive for Listeria, the IND Sponsor and 
Aduro must be notified immediately, and the duplicate samples and Listeria isolate must be sent 
to Aduro or designee for testing to confirm CRS-207. Instructions on collection, storage and 
shipping of samples for CRS-207 testing are provided in the Central Laboratory Manual.  
 
 
6. DOSING DELAYS/DOSE MODIFICATIONS 
 


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6.1  
Dose Modifications 
 
Dose reduction or dose increase of CY, GVAX pancreas vaccine, CRS-207 and nivolumab will 
not be permitted. 
 
6.2  
Dosing Delays 
 
All scheduled cycles within a course are to be given approximately 3 weeks apart. If necessary, a 
scheduled cycle may be delayed for up to 1 week. In this case, subsequent cycles should continue 
so that a subject can still receive all 6 cycles given that the cycles are a minimum of 3 weeks 
apart and they have not experienced an AE necessitating discontinuation. If delayed more than 1 
week, the Protocol Chair and/or Medical Monitor must be contacted for further instructions on 
continued treatment. Additional delays or modifications to the treatment schedule must be 
approved by the Protocol Chair and / or Medical Monitor or IND Sponsor.  
 
If a delay occurs between Day 1 and 2 in a cycle: 
 Nivolumab-related infusion reactions must resolve to baseline prior to administration of 
either GVAX or CRS-207.  
 Resume Day 2 treatment schedule (GVAX or CRS-207) and assessments without 
repeating Day 1 study treatments (CY and/or nivolumab) if the delay is within 72 hours. 
 If the delay is longer than 72 hours, repeat Day 1 and Day 2 (if applicable) study 
treatments/assessments with a minimum of 1 week (Treatment Arm B) or 2 weeks 
(Treatment Arm A) from the previous Day 1 treatment.  This includes steroid treatment 
requiring at least a 14 day washout prior to resuming study-related treatments. 
 
Nivolumab administration should be delayed for the following: 
 
 Any grade ≥ 2 non-skin, treatment-related AE, with the following exceptions: 
o Grade 2 drug-related fatigue or laboratory abnormalities do not require a 
treatment delay 
o Grade 2 hypothyroidism or thyroiditis 
 Any grade >3 skin treatment-related AE  
 Any ≥ grade 3 treatment-related laboratory abnormality, with the following exceptions 
for asymptomatic amylase or lipase: 
o Grade 3 or 4 amylase or lipase abnormalities that are not associated with 
symptoms or clinical manifestations, or radiographic signs of pancreatitis do not 
require a dose delay. It is recommended to consult with the Protocol Chair and/or 
Medical Monitor for grade 3 amylase or lipase abnormalities. 
o Isolated grade 3 or 4 electrolyte imbalances/abnormalities that are not associated 
with clinical sequelae and are corrected with supplementation/appropriate 
management 
 Any AE, laboratory abnormality, or intercurrent illness which, in the judgment of the 
investigator, warrants delaying the dose of study drug. 
 
In order to standardize the management of AEs for all subjects, treatment management 
algorithms are included in Appendix B. Additional AE treatment management algorithms 
included in the nivolumab IB might be considered for individual cases. 
 


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Subjects may resume treatment with nivolumab when the treatment-related AE(s) resolve to 
grade ≤1 or baseline value, with the following exceptions:  
 
 Subjects may resume treatment in the presence of grade 2 fatigue. 
 Subjects who have not experienced a Grade 3 drug-related skin AE may resume 
treatment in the presence of Grade 2 skin adverse event 
 Subjects may resume treatment in the presence of grade 2 AST/ALT OR grade 1 total 
bilirubin. Subjects with combined grade 2 AST/ALT AND total bilirubin values meeting 
discontinuation parameters (Section 5.11.2) should have treatment permanently 
discontinued.  
 Treatment-related pulmonary toxicity, diarrhea, or colitis must have resolved to baseline 
before treatment is resumed. 
 Treatment-related endocrinopathies adequately controlled with only physiologic hormone 
replacement may resume treatment, which include grade 2 hypothyroidism and 
thyroiditis. 
 
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS 
 
This study will use the descriptions and grading scales found in the revised CTCAE version 4.03 
for 
AE 
reporting 
that 
can 
be 
found 
at 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.   
 
Information about all AEs, whether volunteered by the subject, discovered by investigator 
questioning, or detected through physical examination, laboratory test or other means, will be 
collected, recorded, and followed as appropriate.  
 
All AEs and SAEs experienced by subjects will be collected and reported from the first dose of 
the investigational agent, throughout the study, and will only be followed for 4 weeks unless 
related to the investigational agent.  For all subjects in Arm A, all SAEs that occur either within 
100 days (+14 day reporting window) after the last dose of nivolumab or for 28 days (+7 day 
reporting window) from the last dose of cyclophosphamide, GVAX, or CRS-207, if the subject is 
no longer receiving nivolumab due to toxicity, whichever reporting period is longer. All SAEs 
will be collected for 28 days (+7 day reporting window) after the last dose of study drug for 
subjects in Arm B, or until initiation of a new anti-cancer treatment, whichever occurs first. 
 
Subjects who have an ongoing AE related to the study procedures and/or medication(s) may 
continue to be periodically contacted by a member of the study staff until the event is resolved or 
determined to be irreversible by the investigator. 
 
Subjects who experience a grade 2 or higher nivolumab-related AE should be discussed with the 
Protocol Chair and / or Medical Monitor.  
 
Laboratory abnormalities: Laboratory abnormalities present at the screening visit will be 
recorded as pre-treatment signs and symptoms. After study treatment administration, all grade 3 
and 4 clinical laboratory results that represent an increase in severity from baseline will be 
reported as AEs. A grade 1 or 2 clinical laboratory abnormality should be reported as an AE only 
if it is considered clinically significant by the investigator. 
 


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7.1 
Definitions 
 
7.1.1 Adverse Event  
 
An AE is defined as any undesirable sign, symptom or medical condition occurring 
after starting the study drug (or therapy) even if the event is not considered to be 
related to the study. An undesirable medical condition can be symptoms (e.g., nausea, 
chest pain), signs (e.g., tachycardia, enlarged liver) or the abnormal results of an 
investigation 
(e.g., 
laboratory 
findings, 
electrocardiogram). 
Medical 
conditions/diseases present before starting the study treatment are only considered 
AEs if they worsen after starting the study treatment (any procedures specified in the 
protocol). New medical conditions / diseases occurring before starting the study 
treatment but after signing the informed consent form will not be recorded as AEs.  
 
Expected progression of the disease being studied will not be recorded as an adverse 
event; however, all deaths from time of first administration of study drug through 100 
days (+14 day reporting window) after the EOT for subjects in Arm A and 28 days 
(+7 day reporting period) after the EOT for subjects in Arm B or before initiation of a 
new antineoplastic treatment (whichever comes first), regardless of causality or 
whether subjects have discontinued earlier from treatment, are to be reported as 
SAEs.  Deaths that occur after 100 days of the EOT for subjects in Arm A and 28 
days after the EOT for subjects in Arm B or before initiation of a new antineoplastic 
treatment (whichever comes first), must be reported as SAEs if they are considered 
related to study drug. 
 
Abnormal laboratory values or test results constitute AEs only if they induce clinical 
signs or symptoms or require therapy. 
 
7.1.2 Serious Adverse Event  
 
A SAE is an undesirable sign, symptom or medical condition which:  
• 
Results in death  
• 
Is life threatening (defined as an event in which the subject was at risk of death at 
the time of the event; it does not refer to an event which hypothetically might 
have caused death if it were more severe)  
• 
Requires 
inpatient 
hospitalization 
or 
causes 
prolongation 
of 
existing 
hospitalization (see note below for exceptions) for >24 hours 
• 
Results in persistent or significant disability/incapacity  
• 
Is a congenital anomaly/birth defect (note: reports of congenital anomalies/birth 
defects must also be reported on the Pregnancy Form)  
• 
Is an important medical event (defined as a medical event(s) that may not be 
immediately life-threatening or result in death or hospitalization but, based upon 
appropriate medical and scientific judgment, may jeopardize the subject or may 
require intervention [e.g., medical, surgical] to prevent one of the other serious 
outcomes listed in the definition above.) Examples of such events include, but are 
not limited to, intensive treatment in an emergency room or at home for allergic 
bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization.) 


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• 
Potential drug induced liver injury (DILI) is also considered an important medical 
event.  
• 
Hemophagocytic lymphohistiocytosis is also considered an important medical 
event. 
• 
Suspected transmission of an infectious agent (eg, pathogenic or nonpathogenic) 
via the study drug is an SAE. 
• 
Is a new cancer (that is not a condition of the study) 
• 
Is associated with an overdose 
• 
Is a pregnancy or pregnancy outcome of spontaneous abortion, missed abortion, 
benign hydatidiform mole, blighted ovum, fetal death, intrauterine death, 
miscarriage, or stillbirth. 
 
Events not considered to be SAEs are hospitalizations for:  
• 
Admissions as per protocol for a planned medical/surgical procedure or to 
facilitate a procedure 
• 
Routine health assessment requiring admission for baseline/trending of health 
status (e.g., routine colonoscopy)  
• 
Medical/surgical admission for purpose other than remedying ill health state and 
was planned prior to entry into the study. Appropriate documentation is required 
in these cases.  
• 
Admission encountered for another life circumstance that carries no bearing on 
health status and requires no medical/surgical intervention (e.g., lack of housing, 
economic inadequacy, care-giver respite, family circumstances, administrative). 
• 
Admissions for monitoring of treatment-related infusion reactions that do not 
otherwise meet the criteria for a SAE. 
 
7.1.3. Adverse Events of Special Interest 
 
Suspected infection with CRS-207 and/or Listeria are considered adverse events of 
special interest (AESI) and should be reported following SAE reporting procedures in 
Section 7.5 irrespective of temporal relationship to study drug administration. 
 
In the event a subject has a positive Listeria culture at any time during or after study 
participation (except within 7 days after a CRS-207 infusion), the event should be 
reported to the Sponsor within 24 hours of the event. 
 
All AESIs must be reported for the duration of the study regardless of causality. 
 
7.2 
Assessment of Causality 
 
The relationship of an AE to the administration of the study drug is to be assessed by the 
investigator according to the following definitions:  
 
 No (unrelated, not related, no relation):  The time course between the administration of 
study drug and the occurrence or worsening of the adverse event rules out a causal 
relationship and another cause (concomitant drugs, therapies, complications, etc.) is 
suspected.  
 


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 Yes (related): The time course between the administration of study drug and the 
occurrence or worsening of the adverse event is consistent with a causal relationship and 
no other cause (concomitant drugs, therapies, complications, etc.) can be identified.  
 
The following factors should also be considered:  
 The temporal sequence from study drug administration - The event should occur after the 
study drug is given. The length of time from study drug exposure to event should be 
evaluated in the clinical context of the event.  
 Underlying, concomitant, intercurrent diseases - Each report should be evaluated in the 
context of the natural history and course of the disease being treated and any other 
disease the subject may have.  
 Concomitant medication - The other medications the subject is taking or the treatment the 
subject receives should be examined to determine whether any of them might be 
recognized to cause the event in question.  
 Known response pattern for this class of study drug - Clinical and/or preclinical data may 
indicate whether a particular response is likely to be a class effect.  
 Exposure to physical and/or mental stresses - The exposure to stress might induce 
adverse changes in the recipient and provide a logical and better explanation for the 
event.  
 The pharmacology and pharmacokinetics of the study drug - The known pharmacologic 
properties (absorption, distribution, metabolism, and excretion) of the study drug should 
be considered.  
 
Assessment of Grade: 
 
The investigator will make an assessment of grade for each AE and SAE reported during the 
study, which will be recorded in the CRF. The assessment will be based on the National Cancer 
Institute’s CTCAE (Version 4.03) and graded as shown below: 
• 
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated 
• 
Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily living 
• 
Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care 
activities of daily living 
• 
Grade 4: Life-threatening consequences; urgent intervention indicated 
• 
Grade 5: Death related to AE 
 
Any AE that changes in grade during its course will be recorded in the CRF at the highest level 
experience by the subject. 
 
7.3 
Expectedness 
 
Unexpected AE: An AE, which varies in nature, intensity or frequency from information on the 
investigational drug/agent provided in the product IB, package insert or safety reports. Any AE 
that is not included in the IB consent is considered “unexpected”.  
 
Expected (known) AE: An AE, which has been reported in the IB. An AE is considered 


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43
“expected”, only if it is included in the IB document as a risk. 
 
7.4 
Handling of Expedited Safety Reports 
 
In accordance with local regulations, the IND Sponsor or designee will notify investigators of all 
SAEs that are unexpected (i.e., not previously described in the IB), and related to CY, GVAX 
pancreas vaccine, CRS-207, or nivolumab. This notification will be in the form of an expedited 
safety report (ESR) that is to be faxed to the investigators and the study coordinators. Upon 
receiving such notices, the investigator must review and retain the notice with the IB and where 
required by local regulations, the investigator will submit the ESR to the appropriate IRB. The 
investigator and IRB will determine if the informed consent requires revision. The investigator 
should also comply with the IRB procedures for reporting any other safety information.  
 
7.5  
Reporting 
 
7.5.1  Adverse Events and Serious Adverse Events 
 
All AEs (both expected and unexpected) will be captured on the appropriate study-
specific CRFs. Report AEs to the Protocol Chair and/or designee within 24 hours 
once identified as an unacceptable toxicity. 
 
All SAEs and AESIs occurring from the first dose of the study drug, throughout the 
study, and 100 days (+14 day reporting window) after the EOT for subjects in Arm A 
and 28 days (+7 day reporting window) after the EOT for subjects in Arm B or before 
initiation of a new antineoplastic treatment (whichever comes first) must be reported.  
All SAEs that the investigator considers related to study drug occurring after the follow-
up periods must be reported. 
 
To report a SAE, complete the AE form electronically in the electronic data capture 
(EDC) system for the study within 24 hours of the knowledge of the occurrence. When 
the form is completed, the IND Sponsor, Aduro, BMS, and Medpace Safety will be 
notified electronically of the event.  If the event meets serious criteria and it is not 
possible to access the internet, send an email to Medpace Safety at 
 or call the Medpace SAE hotline (phone number listed 
below), and fax the completed paper Back-Up SAE form to Medpace (fax number listed 
below) within 24 hours of awareness. When the EDC system becomes available, the 
SAE information must be entered within 24 hours of the system becoming available. 
 
 
 
 
 
 
7.5.2 Follow-up of Adverse Events and Serious Adverse Events 
 
After the initial AE or SAE report, the investigator is required to proactively follow each 
subject and provide further information to the safety department in regards to the 
subject’s condition. 


J14113 / Version 3.0/ November 15, 2016 
44
 
All AE(s) and SAE(s) will be followed until: 
• 
Resolution 
• 
The condition stabilizes 
• 
The event is otherwise explained 
• 
The subject is lost to follow-up 
 
Within 24 hours of receipt of follow-up information, the investigator must update the 
SAE form electronically in the EDC system for the study and submit any supporting 
documentation (e.g., subject discharge summary or autopsy reports) to Medpace Clinical 
Safety via fax or e-mail. If it is not possible to access the EDC system, refer to the 
procedures outlined above for initial reporting of SAEs. 
 
7.5.3 Overdose 
 
An overdose is defined as the accidental or intentional administration of any dose of a 
product that is considered both excessive and medically important. All occurrences of 
overdose must be reported as SAEs. 
 
7.5.4 Potential Drug Induced Liver Injury (DILI) 
 
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities 
should occur prior to the reporting of a potential DILI event.  All occurrences of 
potential DILIs, meeting the defined criteria, must be reported as SAEs under the 
seriousness category checked as ‘other medically important event’. Potential drug 
induced liver injury is defined as: 
 
1) ALT or AST elevation > 3 times upper limit of normal (ULN)  
AND 
2) Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum 
alkaline phosphatase) 
AND 
3) No other immediately apparent possible causes of AST/ALT elevation and 
hyperbilirubinemia, including, but not limited to, viral hepatitis, pre-existing chronic 
or acute liver disease, or the administration of other drug(s) known to be hepatotoxic. 
 
 
7.5.5 Pregnancy Reporting 
 
Although pregnancy and lactation are not always serious by regulatory definition, it is 
the responsibility of investigators or their designees to report any pregnancy or lactation 
in a subject (spontaneously reported to them) that occurs during the trial or within 23 
weeks of completing the trial as an SAE. This also includes the pregnancy of a male 
subject's female partner who has provided written consent to provide information 
regarding pregnancy, which occurs during the trial or within 31 weeks of completing the 
trial.   
 


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If a subject or partner of a subject participating in the study becomes pregnant, the 
investigator must report the pregnancy within 24 hours of discovery or knowledge of the 
event. To report a pregnancy, complete the AE form electronically in the EDC system 
for the study, with the seriousness category checked as ‘other important medical event’. 
When the form is completed, the IND Sponsor, Aduro, BMS, and Medpace Safety will 
be notified of the event. Medpace Safety will then forward the Pregnancy Form to the 
investigator for completion.  
 
All subjects or partners of subjects who become pregnant must be followed to the 
completion/termination of the pregnancy.  If the pregnancy ends for any reason before 
the anticipated date, the investigator should notify Medpace Safety.  At the completion 
of the pregnancy, the investigator will document the outcome of the pregnancy. 
Pregnancy outcomes of spontaneous abortion, missed abortion, benign hydatidiform 
mole, blighted ovum, fetal death, intrauterine death, miscarriage and stillbirth must also 
be reported as SAEs (Important Medical Events).  If the pregnancy continues to term, 
the outcome (health of infant) must also be reported to Medpace Safety or the IND 
sponsor (if the trial has completed).  
 
7.5.6  Institutional Review Board (IRB) and Institutional Biosafety Committee 
(IBC) 
 
Participating sites will be responsible for reporting to their IRB and IBC. All SAEs will 
be reported to the IRB and IBC per institutional guidelines if the event is related and 
expected, related and unexpected, or related and fatal or life-threatening due to 
administration of the investigational product. If the SAE is unrelated to administration of 
the investigational agents, then it will be reported to the IRB and IBC per institutional 
guidelines. Follow-up information will be submitted to the IRB and IBC as soon as 
relevant information is available. 
 
7.5.7  Food and Drug Administration (FDA) 
 
All reporting to the FDA will be completed by the IND Sponsor. 
 
7.5.7.1 Expedited IND Safety Reports 
 
7 Calendar-Day Telephone or Fax Report:   
The IND Sponsor 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 investigational agent.  Such reports are to be telephoned or faxed 
(301-827-9796) to the FDA within 7 calendar days of first learning of the event. 
Follow-up information will be submitted to the FDA as soon as relevant 
information is available.  
 
15 Calendar-Day Written Report:   
The IND Sponsor is required to notify the FDA of any SAE that is unexpected 
and related to the investigational agent in a written IND Safety Report.   
 
Written IND Safety Reports should include an Analysis of Similar Events in 


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46
accordance with regulation 21 CFR § 312.32.  All safety reports previously filed 
with the IND concerning similar events should be analyzed.  The new report 
should contain comments on the significance of the new event in light of the 
previous, similar reports.   
 
Written IND safety reports with Analysis of Similar Events are to be submitted 
to the FDA within 15 calendar days of first learning of the event. Follow-up 
information will be submitted to the FDA as soon as relevant information is 
available. 
 
7.5.7.2 IND Annual Reports 
 
In accordance with the regulation 21 CFR § 312.33, the IND Sponsor shall 
within 60 days of the anniversary date that the IND went into effect submit a 
brief report of the adverse events and progress of the investigation.  Please refer 
to Code of Federal Regulations, 21 CFR § 312.33 for a list of the elements 
required for the annual report.  All IND annual reports will be submitted to the 
FDA by the IND Sponsor. 
 
7.5.8 Recombinant DNA Advisory Committee (RAC) 
 
Unexpected SAEs believed to be related to the investigational product(s) will be 
reported to RAC by email if fatal or life-threatening within 7 calendar days or by written 
report if related and unexpected to the investigational product(s) within 15 calendar 
days. SAEs that are unrelated or related and expected with the investigational product (s) 
will be reported to RAC in the Annual Report. Follow-up information will be submitted 
to the RAC as soon as relevant information is available. 
 
8. PHARMACEUTICAL INFORMATION 
 
8.1  
Cyclophosphamide (Cytoxan®, CY) 
 
8.1.1 Agent Accountability 
 
The IND Sponsor or the Sponsor’s representative shall take responsibility for and shall 
take all steps to maintain appropriate records and ensure appropriate supply, storage, 
handling, distribution and usage of investigational product in accordance with the 
protocol and any applicable laws and regulations. 
 
8.1.2 Mode of Action 
 
CY is a synthetic antineoplastic drug chemically related to the nitrogen mustards. CY is 
biotransformed principally in the liver to active alkylating metabolites by a mixed 
function microsomal oxidase system. These metabolites interfere with the growth of 
susceptible rapidly proliferating malignant cells. The mechanism of action is thought to 
involve cross-linking of tumor cell DNA. 
 


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8.1.3 Description 
 
CY (CYTOXAN®; cyclophosphamide for injection, USP) is a sterile, white powder 
containing cyclophosphamide monohydrate and is supplied in vials for single-dose use. 
 
8.1.4 Packaging and Labeling Information 
 
CY is commercially available. 
 
8.1.5 Preparation 
 
Parenteral drug products should be inspected visually for particulate matter and 
discoloration prior to administration, whenever solution and container permit. Add the 
diluent to the vial and shake it vigorously to dissolve. If the powder fails to dissolve 
immediately and completely, it is advisable to allow the vial to stand for a few minutes. 
Use the quantity of diluent shown below to constitute the product: 
 
Dosage Strength 
CYTOXAN Contains 
Cyclophosphamide Monohydrate 
Quantity of Diluent 
 
500 mg 
534.5 mg 
25 mL 
1 g 
1069.0 mg 
50 mL 
2 g 
2138.0 mg 
100 mL 
 
CY may be prepared for parenteral use by infusion using any of the following methods: 
1. CY constituted with 0.9% sterile sodium chloride may be infused without further 
dilution. 
2. CY constituted with 0.9% sterile sodium chloride may be infused following further 
dilution in the following: 
 
 Dextrose Injection, USP (5% dextrose) 
 Dextrose and Sodium Chloride Injection, USP (5% dextrose and 0.9% sterile 
sodium chloride) 
 5% Dextrose and Ringer’s Injection 
 Lactated Ringer’s Injection, USP 
 Sodium Chloride Injection, USP (0.45% sterile sodium chloride) 
 Sodium Lactate Injection, USP (1/6 molar sodium lactate) 
 
8.1.6 Storage 
 
Store vials at or below 77° F (25° C). 
 
8.1.7 Stability 
 
CY (prepared for either direct injection or infusion) is chemically and physically stable 
for 24 hours at room temperature or for 6 days in the refrigerator; it does not contain any 
antimicrobial preservative and thus care must be taken to assure the sterility of prepared 
solutions. 
 


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8.1.8 Route of Administration 
 
CY is administered by IV injection over 30 minutes. 
 
8.1.9 Subject Care Implications 
 
During treatment, the subject’s hematologic profile (particularly neutrophils and 
platelets) should be monitored regularly to determine the degree of hematopoietic 
suppression. 
 
The rate of metabolism and the leukopenic activity of CY reportedly are increased by 
chronic administration of high doses of phenobarbital. The physician should be alert for 
possible combined drug actions, desirable or undesirable, involving CY even though CY 
has been used successfully concurrently with other drugs, including other cytotoxic 
drugs. CY treatment, which causes a marked and persistent inhibition of cholinesterase 
activity, potentiates the effect of succinylcholine chloride. If a subject has been treated 
with CY within 10 days of general anesthesia, the anesthesiologist should be alerted. 
 
CY may interfere with normal wound healing. 
 
8.1.10 Returns and Reconciliation 
 
N/A 
 
8.2  
GVAX Pancreas Vaccine 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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8.3  
CRS-207 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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8.4  
Nivolumab 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 


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9. CORRELATIVE/SPECIAL STUDIES 
 
Sample collection, processing, storage, and shipment instructions will be provided in the 
Laboratory Manual. 
 
9.1 
Tumor Tissue Studies 
 
Tumor biopsies will be collected (if a subject’s tumor is thought to be reasonably safe and easy 
to biopsy) at baseline and at Cycle 4 (4-6 cores per timepoint).  Fine needle aspiration will not be 
acceptable.  Additional optional biopsies may be obtained later in the course of study treatment. 
Archival tumor samples will also be collected for every subject. Detailed instructions for tissue 
collection, processing and shipment will be provided in the Laboratory Manual. 
 
To explore the association of OS, PD-L1 positivity, and tumor-infiltrating lymphocyte 
characteristics with clinical responses, archived tumor tissue and tumor tissue obtained at 
baseline and during treatment (Cycle 4) will be compared. PD-L1 expression may predict 
response to anti-PD-110,11.  However, PD-L1 is also upregulated in response to IFN-γ released by 
infiltrating T cells and could potentially be a predictor of response to any active immunotherapy.  
Pre- and post-treatment tumor biopsies will also be analyzed for PD-1 expression as well as 
infiltration of immune cells (effector T cells, Tregs, B cells, dendritic cells, etc).  
Characterization of immune checkpoint expression as well as immune infiltrates may be 
predictive of response to therapy and may also give insight into next generation combinatorial 
approaches.  Preliminary data from a pancreatic cancer immunotherapy study suggests that 
induction of a Th1and Th17 phenotype at the tumor itself predicts response.  Furthermore, 
upregulation of other inhibitory molecules such as IL-10 and TGF-β may identify other targets 
for combinatorial strategies. 
 
Attempts will be made to obtain archived tissue samples from all subjects.   
 
9.2  
Peripheral Blood Mononuclear Cells (PBMCs) 
 


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56
Whole blood for isolation of PBMCs will be collected prior to dosing on Day 1 of Cycle 1, Day 
1 of Cycles 3-6, and the EOC/EOT evaluation. Additionally, subjects will have whole blood for 
isolation of PBMCs drawn 7 days post-CRS-207 infusion of Cycles 3 and 4 (volume split 
between pre-dose and 7-day draw) during the first course of treatment only.  Subjects receiving 
additional treatment courses will only have whole blood for isolation of PBMCs drawn during 
Cycle 4 and Cycle 6. Pre- and post-treatment changes in PBMCs including effector, helper, and 
regulatory T cells, NK cells, and macrophages will be measured. 
The cellular immune responses directed against Lm and mesothelin will be evaluated by using 
enzyme-linked immunosorbent spot (ELISPOT) and intracellular cytokine staining. Post-
treatment expression of PD-1 and other lymphocyte activation markers will be measured as well. 
These responses will be correlated with OS.  PBMCs are isolated and stored frozen (liquid 
nitrogen) until use.  Detailed instructions for processing and storage are provided in the 
Laboratory Manual. 
 
9.3  
Serum and Plasma Marker Studies 
 
Sera will be collected prior to dosing on Day 1 of Cycles 1-6, and the EOC/EOT evaluation. 
Plasma will be collected prior to dosing on Day 1 of Cycle 1, Cycles 3-6, and the EOC/EOT 
evaluation. Additionally, subjects will have whole blood for serum drawn 20-26 hours post-CRS-
207 infusion of Cycles 3-6.  Subjects receiving additional treatment courses will only have whole 
blood for serum and plasma drawn during Cycle 4 and Cycle 6. The humoral immune responses 
directed against Lm and mesothelin will be evaluated by using enzyme-linked immunosorbent 
assay (ELISA) for Lm- and mesothelin-specific antibodies. In addition, potential therapeutic 
targets, biomarkers, and predictors of response and autoimmune toxicity will be evaluated. Sera 
and plasma are isolated and stored frozen (-80oC) until use. Detailed instructions for processing 
and storage are provided in the Laboratory Manual. 
 
9.4 
Stool Samples Studies 
 
Stool samples for microbial biomarker analyses will be collected prior to dosing on Day 1 of 
Cycle 1, and prior to Day 8 or Day 9 (for Arms B and A respectively) of Cycle 4 when 
available.  The Cycle 4 sample may be collected at any time from Day 1 to Day 8 or 9.  Stool 
samples will only be collected during the first course.   
 
Microbial DNA will be isolated from stool samples and prepared for 16S V4 sequencing to 
profile microbial species represented in the gut pre- and post-treatment.  In addition, microbial 
DNA will be subjected to whole genome metagenomics profiling of microbial species via 
shotgun sequencing for detailed functional and pathway analysis to determine the change in the 
species and functions in response to treatment.  Further bioinformatics analyses will be 
performed with these sequencing data to identify candidate microbial biomarkers, and predictors 
of response.  Detailed instructions for stool collection, shipment, and storage are provided in the 
Laboratory Manual.  
 
9.5 
Diagnostic Tissue Samples 
 
Tissue, fluid, or blood may be collected from standard of care procedures used to treat or 
diagnose immune-related toxicities. 


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10. STUDY CALENDAR 
 
Subjects on both arms will receive treatment every 3 weeks for 6 cycles of treatment within a course. A course of treatment will be 20 
weeks, with 16 weeks of treatment followed by an end-of-course (EOC) or end-of-treatment (EOT) evaluation approximately 4 weeks after 
the last study treatment administration in the course.   
 
10.1  Treatment Arm A 
Study Procedures 
Pre-Study 
Random-
ization (R) 
Cycle 125 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Cycle 6 
EOC/ 
EOT26 
D1 D2 D424 D1 D2 D424 D1 D2 D3 D524 D9 D1 D2 D3 D524 D9 D1 D2 D3 D524 D9 D1 D2 D3 D524 D9 
Visit Windows (days)1 
-21 to 
D1 
D-7 
to D1 
-  
- 
±1 - 2 
- 
±1 - 2 
- 
- 
±1 +1 - 2 
- 
- 
±1 +1 - 2 
- 
- 
±1 +1 - 2 
- 
- 
±1 +1 
+/- 7 
CY 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
GVAX Pancreas Vaccine 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CRS-207 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
Nivolumab2 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization (R) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical, Cancer, & Con 
Med History3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Con Meds, Adverse Events 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
Physical Exam, ECOG  PS4 
X 
 
X 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
Vitals, Weight, & Height5 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
 
 
X 
X 
 
 
 
X 
X 
 
 
 
X 
X 
 
 
 
X 
Hematology, Chemistry6, 12 
X 
 
X 
 
 
X 
 
 
X 
 
X 
 
X 
X 
 
X 
 
X 
X 
 
X 
 
X 
X 
 
X 
 
X 
X 
Endocrine7, 12 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 


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Study Procedures 
Pre-Study 
Random-
ization (R) 
Cycle 125 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Cycle 6 
EOC/ 
EOT26 
D1 D2 D424 D1 D2 D424 D1 D2 D3 D524 D9 D1 D2 D3 D524 D9 D1 D2 D3 D524 D9 D1 D2 D3 D524 D9 
Urinalysis8, 12 
X 
 
X 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
CD4 count, virology9 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Coagulation panel10 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test11 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
CA19-9 12 
X 
 
X 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
ECG13 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
CT/MRI, RECIST/irRC14 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Vaccine Site Reactions15 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Whole blood for PBMC and 
plasma16 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
X 
 
 
 
X 
X 
 
 
 
 
X 
 
 
 
 
X 
Serum16 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
 
 
X 
Stool Samples17 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
HLA18 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lactoferrin19 
 
 
X 
Archival Tissue20 
X 
Tumor Biopsies21 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Antibiotics22 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Blood sample for CRS-207 
testing23 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 


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1:  If necessary, a scheduled cycle may be delayed for up to 1 week. Longer delays to be approved by the IND Sponsor, Medical Monitor and/or Protocol 
Chair. 
2:  Nivolumab will be administered to subjects randomized to Arm A only Subjects on Arm A should be observed for a minimum of 30 minutes between 
CY and nivolumab administrations. 
3: Cancer history includes: primary site of cancer, gross location of primary tumor, secondary sites of cancer, histology, histologic grade, date of initial 
diagnosis, date of metastatic diagnosis, prior cancer therapy regimens. 
4: Complete physical examination and assessment of ECOG PS will be completed at baseline; focused physical examinations and assessment of ECOG 
PS will be conducted thereafter.  Day 1 Physical examination and ECOG status may be done up to 1 day prior to dosing. 
5:  Blood pressure, pulse, respiratory rate, and temperature are required as indicated. Weight and pulse oximetry will be obtained at baseline and prior to 
each cycle.  Height will be taken at or prior to screening only. Vitals should be collected prior to CY administration and prior to and after GVAX 
pancreas vaccine administration. Nivolumab: vitals will be collected prior to, every 30 minutes during (± 15 minutes), and at the end of infusion (± 15 
minutes). CRS-207: vital signs will be obtained every 30 minutes (± 15 minutes) during infusion and every hour (± 15 minutes) during post-infusion 
follow-up. Subjects will be observed for at least 4 hours after each CRS-207 infusion. Subjects who are not stable enough to be released at 4 hours 
after infusion should continue to be monitored until stable. Presence of fever alone does not indicate subject is not clinically stable. 
6:  Clinical hematology: CBC with differential ANC, ALC, AEC, and platelet count; serum chemistry: sodium, potassium, chloride, bicarbonate, glucose, 
BUN, creatinine, LDH, ALT, AST, alkaline phosphatase, total bilirubin, direct bilirubin, amylase, total protein, albumin, calcium, magnesium, and 
phosphate. Required labs on Day 2 only after CRS-207 dosing: Any unexpected Grade 3 or greater laboratory abnormalities should be repeated within 
24-72 hours. 
7:  TSH (Total T3 and free T4 if TSH abnormal). 
8:  Bilirubin, blood, glucose, ketones, leukocytes, nitrite, pH, color, protein, RBC and WBC count, and specific gravity. 
9:  Virology screen: HIV antibody, hepatitis B surface antigen and hepatitis C antibody; additional virology may also be evaluated. Subjects who are 
hepatitis C antibody positive and confirmed negative viral load at screening will be allowed to enroll. 
10:  Coagulation panel: D-dimer, fibrinogen, international normalized ratio of prothrombin time, APTT 
11: Pregnancy tests will be administered to WOCBP: serum pregnancy test is required at screening; urine pregnancy tests are required before doses on 
Day 1 of dosing weeks.  
12: Labs may be collected within a window of up to 3 days prior to dosing. Blood draws must not be collected from a central line for at least 4 days after 
infusion of CRS-207.  
13: ECG should be performed at baseline and at the EOT visit.  
14: Spiral CT of thorax, abdomen and pelvis (and other imaging studies as clinically indicated to evaluate suspected sites of metastatic disease). If a 
subject cannot have a CT scan (e.g., allergy to contrast dye), an MRI should be performed. On study radiologic evaluations and tumor measurements 
(RECIST and irRC per Appendix C and Appendix D) will be performed every 10 weeks (± 1 week; starting from the date of first treatment) 
including the EOT evaluation (± 4 weeks). If the EOT visit occurs early, scans do not need to be repeated if one has been done within the past 6 
weeks. Weeks are in reference to calendar week and should not be adjusted due to dosing delays. 
15: Injection-site reactions will be evaluated on Day 4 after GVAX pancreas vaccinations 
16: Up to 200 mL of whole blood may be drawn up to 72 hours prior to dosing and must be processed by sponsor-qualified operators within 6 hours of 
collection and stored in liquid nitrogen. During Cycles 3 and 4 of the first course, an additional blood draw for PBMC/plasma will be taken on Day 9, 


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60
therefore the volume drawn may be split between Day 1 and Day 9 (e.g., 100 mL per timepoint). Approximately 10 mL of blood for serum for 
immune monitoring will be drawn as indicated. Day 3 blood draws (after CRS-207 only) should be taken between 20 and 26 hours after start of 
dosing.  Subjects receiving additional treatment courses will only have whole blood for isolation of PBMCs, plasma, and serum drawn during Cycle 4 
and Cycle 6. 
17: Stool samples for microbial biomarker analyses will be collected during Course 1 when available.  Stool samples for Cycle 4 may be collected any 
time from Day 1 to Day 9 when available.  Detailed instructions for stool collection and shipment are provided in the Laboratory Manual.  
18: HLA-typing to include HLA class I type A and B, low resolution. HLA typing is only done during the first course of study treatment. 
19: Lactoferrin values at baseline (Cycle 1, Day 1, prior to dosing) and when a subject is being evaluated for potential colitis will be collected when 
available. 
20: Attempts to obtain surgical or biopsy archival tumor samples will be made for every subject until the sample is obtained or documentation that the 
sample cannot be obtained. The tissue sample should have proper size to enable IHC analysis of PD-L1. Detailed instructions for tissue collection, 
processing and shipment are provided in the Laboratory Manual.  
21: Tumor biopsies to be taken (if a subject’s tumor is thought to be reasonably safe and easy to biopsy) at baseline and at Cycle 4 (4-6 cores per 
timepoint). The Cycle 4 biopsy has a ± 1 week window. Additional optional biopsies may be obtained later in the course of study treatment. The tissue 
sample should have proper size to enable IHC analysis of PD-L1. Fine needle aspiration will not be acceptable. Detailed instructions for tissue 
collection, processing and shipment are provided in the Laboratory Manual. Biopsies will only be collected during the first course of study treatment 
22: 
 
 
 
 
 
 
23: 
 
24: Day 4 and 5 (± 1 day) assessments may be conducted by telephone or email. 
25: Cycle 1 Day 1 evaluations do not need to be repeated if they were conducted within 3 days of the pre-study evaluations.26: Subjects will return to the 
study site at EOC for continuation of treatment or an EOT evaluation. EOT follow-up will occur 28 (±7) days after the final dose. NOTE: CT scan 
assessment at EOT will occur 28 days (± 4 weeks) after the final dose.  If the EOT visit occurs early, an assessment for AEs should be made by 
telephone or email on day 28 (±1) after last study dose. Subjects who discontinue from treatment should be contacted every three months (+/- 2 
weeks) to monitor overall survival.  Information of other cancer therapies after discontinuation from the study treatment will be collected as well.  
Subjects who discontinue treatment from Arm A should be contacted by telephone or email at 100 days (+ 14 day reporting window) to assess for 
SAEs that occur in the follow-up period. 
 
 


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10.2  Treatment Arm B 
Study Procedures 
Pre-Study 
Random-
ization (R) 
Cycle 123 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Cycle 6 
 
EOC/ 
EOT24 
D1 D2 D422 
D1 D2 D422 D1 D2 D422 
D8 
D1 
D2 
D422 
D8 D1 
D2 D422 D8 D1 D2 D422 D8 
Visit Windows (days)1 
-21 to 
D1 
D-7 to 
D1 
- 
- 
±1 - 2 
- 
±1 - 2 
- 
±1 
+1 - 2 
- 
±1 +1 - 2 
- 
±1 +1 - 2 
- 
±1 +1 
+/- 7 
CY 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
GVAX Pancreas Vaccine 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CRS-207 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization (R) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical, Cancer, & Con 
Med History2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Con Meds, Adverse Events 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
Physical Exam, ECOG  PS3 
X 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Vitals, Weight, & Height4 
X 
 
X 
X 
 
X 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Hematology, Chemistry5, 10 
X 
 
X 
 
 
X 
 
 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
Urinalysis6, 12 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
CD4 count, virology7 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Coagulation panel8 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test9 
X 
 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
CA19-9 10 
X 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
ECG11 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
CT/MRI, RECIST/irRC12 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 


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62
Study Procedures 
Pre-Study 
Random-
ization (R) 
Cycle 123 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Cycle 6 
 
EOC/ 
EOT24 
D1 D2 D422 
D1 D2 D422 D1 D2 D422 
D8 
D1 
D2 
D422 
D8 D1 
D2 D422 D8 D1 D2 D422 D8 
Vaccine Site Reactions13 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Whole blood for PBMC and 
plasma14 
 
 
X 
 
 
 
 
 
X 
 
 
X 
X 
 
 
X 
X 
 
 
 
X 
 
 
 
X 
Serum14 
 
 
X 
 
 
X 
 
 
X 
X 
 
 
X 
X 
 
 
X 
X 
 
 
X 
X 
 
 
X 
Stool Samples15 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
HLA16 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lactoferrin17 
 
 
X 
Archival Tissue18 
X 
Tumor Biopsies19 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Antibiotics20 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Blood sample for CRS-
207 testing21 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
1:  If necessary, a scheduled cycle may be delayed for up to 1 week. Longer delays to be approved by the IND Sponsor, Medical Monitor and/or Protocol 
Chair. 
2: Cancer history includes: primary site of cancer, gross location of primary tumor, secondary sites of cancer, histology, histologic grade, date of initial 
diagnosis, date of metastatic diagnosis, prior cancer therapy regimens. 
3: Complete physical examination and assessment of ECOG PS will be completed at baseline; focused physical examinations and assessment of ECOG 
PS will be conducted thereafter.  Day 1 Physical examination and ECOG status may be done up to 1 day prior to dosing. 
4:  Blood pressure, pulse, respiratory rate, and temperature are required as indicated. Weight and pulse oximetry will be obtained at baseline and prior to 
each cycle.  Height will be taken at or prior to screening only. Vitals should be collected prior to CY administration and prior to and after GVAX 
pancreas vaccine administration. Vital signs will be obtained every 30 minutes (± 15 minutes) during CRS-207 infusion and every hour (± 15 minutes) 
during post-infusion follow-up. Subjects will be observed for at least 4 hours after each infusion. Subjects who are not stable enough to be released at 
4 hours after infusion should continue to be monitored until stable. Presence of fever alone does not indicate subject is not clinically stable. 
5:  Clinical hematology: CBC with differential ANC, ALC, AEC, and platelet count; serum chemistry: sodium, potassium, chloride, bicarbonate, glucose, 
BUN, creatinine, LDH, ALT, AST, alkaline phosphatase, total bilirubin, direct bilirubin, amylase, total protein, albumin, calcium, magnesium, and 


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63
phosphate. Required labs on Day 2 only after CRS-207 dosing: Any unexpected Grade 3 or greater laboratory abnormalities should be repeated within 
24-72 hours. 
6:  Bilirubin, blood, glucose, ketones, leukocytes, nitrite, pH, color, protein, RBC and WBC count, and specific gravity. 
7:  Virology screen: HIV antibody, hepatitis B surface antigen and hepatitis C antibody; additional virology may also be evaluated. Subjects who are 
hepatitis C antibody positive and confirmed negative viral load at screening will be allowed to enroll 
8:  Coagulation panel: D-dimer, fibrinogen, international normalized ratio of prothrombin time, APTT 
9: Pregnancy tests will be administered to WOCBP: serum pregnancy test is required at screening; urine pregnancy tests are required before doses on Day 
1 of dosing weeks. 
10: Labs may be collected within a window of up to 3 days prior to dosing. Blood draws must not be collected from a central line for at least 4 days after 
infusion of CRS-207. Any unexpected Grade 3 or greater laboratory abnormalities should be repeated within 24-72 hours. 
11: ECG should be performed at baseline and at the EOT visit.  
12: Spiral CT of thorax, abdomen and pelvis (and other imaging studies as clinically indicated to evaluate suspected sites of metastatic disease). If a 
subject cannot have a CT scan (e.g., allergy to contrast dye), an MRI should be performed. On study radiologic evaluations and tumor measurements 
(RECIST and irRC per Appendix C and Appendix D) will be performed every 10 weeks (+/- 1 week; starting from the date of first treatment) 
including the EOT evaluation (+/- 4 weeks). If the EOT visit occurs early, scans do not need to be repeated if one has not been done within the past 6 
weeks. Weeks are in reference to calendar week and should not be adjusted due to dosing delays. 
13: Injection-site reactions will be evaluated on Day 4 after GVAX pancreas vaccinations 
14: Up to 200 mL of whole blood may be drawn up to 72 hours prior to dosing and must be processed by sponsor-qualified operators within 6 hours of 
collection and stored in liquid nitrogen. During Cycles 3 and 4 of the first course only, an additional blood draw for PBMC/plasma will be taken on 
Day 8, therefore the volume drawn may be split between Day 1 and Day 8 (e.g., 100 mL per timepoint). Approximately 10 mL of blood for serum for 
immune monitoring will be drawn as indicated. Day 2 blood draws (after CRS-207 only) should be taken between 20 and 26 hours after start of 
dosing. Subjects receiving additional treatment courses will only have whole blood for isolation of PBMCs, plasma, and serum drawn during Cycle 4 
and Cycle 6. 
15: Stool samples for microbial biomarker analyses will be collected during Course 1 when available.  Stool samples for Cycle 4 may be collected any 
time from Day 1 to Day 8 when available.  Detailed instructions for stool collection and shipment are provided in the Laboratory Manual. 
16: HLA-typing to include HLA class I type A and B, low resolution. HLA typing is only done during the first course of study treatment 
17: Lactoferrin values at baseline (Cycle 1, Day 1, prior to dosing) and when a subject is being evaluated for potential colitis will be collected when 
available. 
18: Attempts to obtain surgical or biopsy archival tumor samples will be made for every subject until the sample is obtained or documentation that the 
sample cannot be obtained. The tissue sample should have proper size to enable IHC analysis of PD-L1. Detailed instructions for tissue collection, 
processing and shipment are provided in the Laboratory Manual.  
19: Tumor biopsies to be taken (if a subject’s tumor is thought to be reasonably safe and easy to biopsy) at baseline and at Cycle 4 (4-6 cores per 
timepoint). The cycle 4 biopsy has a ± 1 week window. Additional optional biopsies may be obtained later in the course of study treatment. The tissue 
sample should have proper size to enable IHC analysis of PD-L1. Fine needle aspiration will not be acceptable. Detailed instructions for tissue 
collection, processing and shipment are provided in the Laboratory Manual. Biopsies will only be collected during the first course of study treatment 
 


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64
20: 
 
 
 
 
 
 
21: 
 
22: Day 4 (± 1 day) assessments may be conducted by telephone or email.  
23: Cycle 1 Day 1 evaluations do not need to be repeated if they were conducted within 3 days of the pre-study evaluations. 
24: Subjects will return to the study site at EOC for continuation of treatment or an EOT evaluation. EOT follow-up will occur 28 (±7) days after the final 
dose. NOTE: CT scan assessment at EOT will occur 28 days (± 4 weeks) after the final dose.  If the EOT visit occurs early, an assessment for AEs 
should be made by telephone or email on day 28 (±1) after last study dose. Subjects who discontinue from treatment should be contacted every three 
months (± 2 weeks) to monitor overall survival.  Information of other cancer therapies after discontinuation from the study treatment will be collected 
as well.  
 
 
 
 
 
 


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11.  
STUDY ENDPOINTS 
 
11.1 
Primary Endpoint 
 
The primary endpoint is OS, measured from date of randomization until death or end of follow-
up (OS will be censored on the date the subject was last known to be alive for subjects without 
documentation of death at the time of analysis).  
 
11.2  Secondary Endpoints 
 
The secondary endpoints are as follows: 
 Objective disease responses, duration of response, PFS measured by RECIST, 
immune-related progression-free survival (irPFS), and time to progression (TTP) 
 
Progression-free survival (PFS) is defined as the number of months from the 
date of randomization to disease progression (PD or relapse from CR as 
assessed using RECIST 1.1 criteria) or death due to any cause. 
 
Immune-related progression-free survival (irPFS) is defined as the number of 
months from the date of randomization to disease progression (PD or relapse 
from CR as assessed using irRC RECIST 1.1 criteria) or death due to any 
cause. 
 
Time to-progression (TTP) is defined as the number of months from the date 
of randomization to the date of documented disease progression (PD or 
relapse from CR as assessed using RECIST 1.1 criteria). 
 Tumor marker kinetics measured by change in serum CA19-9 concentrations 
from baseline  
 Safety assessed by the following measures: 
– AEs 
– Injection-site reactions (after GVAX pancreas vaccine injections only) 
– Nivolumab-related infusion reactions 
– CRS-207-related infusion reactions 
– Immune-related AEs 
– Unacceptable toxicities 
– Vital signs: BP, pulse, respiratory rate, temperature 
– Physical examination 
– Changes in ECG readings  
– Clinical hematology: complete blood count (CBC) with differential ANC, 
ALC, AEC, and platelet count 
– Clinical serum chemistry: sodium, potassium, chloride, bicarbonate, glucose, 
blood urea nitrogen (BUN), creatinine, lactate dehydrogenase (LDH), ALT, 
AST, alkaline phosphatase, amylase, bilirubin (total), total protein, albumin, 
calcium, magnesium and phosphate 
 
11.3  Exploratory Endpoints 
 
Exploratory endpoints are as follows: 
 Objective disease responses and duration of response measured by irRC 
 Humoral and cellular immune responses directed against Lm and mesothelin 
assessed by using the following measures: 


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– ELISPOT or intracellular cytokine staining assays of PBMC 
– Induction of proinflammatory cytokines and chemokines in the serum 
– ELISA detection of mesothelin- and Lm-specific antibodies in the serum 
 Immune subset analyses by IHC and gene expression profiling of tumor tissue  
 Immune subset analyses in PBMCs including effector, helper, and regulatory T 
cells, NK cells, and macrophages  
 Telomere length of lymphocytes  
 Thyroglobulin and galectin-3 antibody responses  
 Microbial community analysis and whole metagenome functional profiling 
analysis of stool samples 
 
12.  
DATA REPORTING / REGULATORY REQUIREMENTS 
 
AE guidelines and instructions for AE reporting can be found in Section 7.0 (Adverse Events: 
List and Reporting Requirements). 
 
12.1 
Data Collection and Processing 
 
All information will be collected on study-specific CRFs by study staff. These data will be 
reviewed for completeness and accuracy by the Principal Investigator at each site.  
 
CRFs will be used to capture study results and data. The study coordinator or other authorized 
study personnel will transcribe data from source documents onto paper or eCRFs. Before or 
between visits, the Protocol Chair, IND Sponsor, or designee may request copies of the CRFs for 
preliminary medical review. Once the CRFs are complete and source-verified, the investigator 
must sign and date all required pages, verifying the accuracy of all data contained within the 
CRF. Training will be provided on proper completion of CRFs.  
 
If electronic CRFs are used, training will be provided for the EDC system. All personnel using 
the EDC system must have appropriate education, training and experience. The investigator will 
be provided with EDC User’s Guide (contained in the Study Reference Manual [SRM]) on the 
use of the EDC system. The investigator will be responsible for documenting employee 
education, training and previous experience that pertains to the EDC system. 
 
The investigator must maintain adequate security of the EDC system, including documentation 
that all users have been trained on the appropriate SOPs and a list of authorized users. To ensure 
attributability, all personnel responsible for data entry must obtain a unique electronic signature 
before any data can be entered in the CRFs. The system must be configured to ensure that the 
signer cannot readily repudiate the signed record as not genuine. Authorized study personnel will 
be assigned a unique password and associated electronic signature after receiving SOP training. 
 
If EDC systems other than those provided and maintained by the IND Sponsor or designee are 
used for documentation and data capture, the investigator must ensure that the systems are 
validated and ensure data backup as described in Section 12.4. 
 
Protocol Chair 
The Protocol Chair and/or designee is responsible for performing the following tasks: 


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 Coordinating, developing, submitting, and obtaining approval for the protocol as well as 
its subsequent amendments. 
 Assuring that all participating institutions are using the correct version of the protocol. 
 Taking responsibility for the overall conduct of the study at all participating institutions 
and for monitoring the progress of the study. 
 Reviewing and ensuring reporting of SAE 
 Reviewing data from all sites. 
 
Coordinating Center 
The Coordinating Center (or its representative) is responsible for performing the following tasks: 
 Ensuring that IRB approval has been obtained at each participating site prior to the first 
subject registration at that site, and maintaining copies of IRB approvals from each site. 
 Monitoring subject registration. 
 Collecting and compiling data from each site. 
 Establishing procedures for documentation, reporting, and submitting of AE’s and SAE’s 
to the Protocol Chair, and all applicable parties. 
 Facilitating audits by securing selected source documents and research records from 
participating sites for audit, or by auditing at participating sites. 
 
Participating Sites 
Participating sites are responsible for performing the following tasks: 
 Following the protocol as written, and the guidelines of Good Clinical Practice (GCP). 
 Submitting data to the Coordinating Center. 
 Consent subjects promptly and randomize eligible subjects in EDC. 
 Providing sufficient experienced clinical and administrative staff and adequate facilities 
and equipment to conduct a collaborative trial according to the protocol. 
 Maintaining regulatory binders on site and providing copies of all required documents to 
the Coordinating Center. 
 Collecting and submitting data according to the schedule specified by the protocol. 
 
12.2  Independent Data Monitoring Committee (DMC) 
 
A DMC will monitor the study for safety, efficacy in the context of subject risk/benefit, and 
perform other functions according to a charter that defines its roles and responsibilities.  The 
DMC for this clinical study contains three medical oncologists from other disciplines and a 
statistician who are not affiliated with this clinical trial protocol. The DMC will review safety 
data after approximately 25%, 50%, 75% and 100% of total planned subjects have been 
randomized and treated and 6 months after the last subject is randomized, but not more frequent 
than every 4 months. Additionally, one pre-planned formal interim analysis to review and assess 
efficacy in the context of risk/benefit will be conducted when approximately 50% of the 
expected events occur. A meeting of the DMC will also be convened if the safety stopping 
guidelines (Section 5.8) are triggered.  Meetings will be convened by conference call or in 
person.  The DMC will provide a written summary of their recommendations after each data 
review meeting.  Further details describing the communication, dissemination and actions of 
DMC recommendations as well as committee procedures and policies, including table displays, 
will be described in the DMC charter. 
 


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12.2.1  Safety Review 
 
At each scheduled meeting, the DMC will be provided with tables and/or listings 
summarizing all AEs, laboratory toxicities, discontinuations and subject deaths by 
treatment arm. The DMC may also request additional data or analyses. Since these are 
safety evaluations with no intent of stopping for positive efficacy, there will be no 
adjustments to the overall alpha level of the efficacy analysis from these safety reviews. 
 
12.2.2  Interim Analysis 
 
At the interim analysis, the DMC will be provided with outputs summarizing overall 
survival and tumor response data by treatment arm, as well as the outputs produced for 
Safety Reviews (Section 12.2.1).  While there is no intent to stop early based on these 
results, adjustments to preserve the overall alpha level have been made to account for this 
interim analysis (Section 13.1).     
 
 
12.3  Populations of Interest 
 
The Full Analysis Set (FAS) includes all randomized subjects who received at least one dose of 
study treatment. FAS analyses will be conducted on the basis of the randomized treatment. All 
efficacy outcomes will be assessed using the FAS as the primary population for analysis. 
 
The Intent to Treat (ITT) analysis set includes all randomized subjects, regardless of the amount 
or type of treatment received. It is distinguished from the FAS in that individuals who do not 
receive any doses of study treatment will be included.  ITT analyses will be conducted on the 
basis of the randomized treatment. This population will be used for sensitivity analyses of OS 
and other selected efficacy endpoints. 
 
The safety population includes all randomized subjects who received at least one dose of study 
treatment. The safety population will be conducted on the basis of the actual treatment received. 
All safety outcomes will be assessed using the safety population for analysis. 
 
A Per-Protocol (PP) subset may also be used to analyze select efficacy endpoints and will be 
based on study treatment exposure (compliance and/or time on study treatment) and major 
protocol deviations. The criteria for inclusion in the PP subset will be finalized and documented 
prior to database lock. 
 
12.4  Study Documentation 
 
12.4.1 Informed Consent and Authorization for use and Disclosure of Protected 
Health Information 
 
Written informed consent and authorization of use and disclosure of protected health 
information (PHI) must be obtained from each subject (or the subject’s legally authorized 
representative) before performing any study-specific screening/baseline period 


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evaluations. One copy of the signed informed consent form (ICF) and authorization for 
use and disclosure of the PHI form will be given to the subject and the investigator will 
retain the original. The ICF and authorization for use and disclosure of PHI, which is 
prepared by the investigator or the site, must be reviewed and approved by the IND 
Sponsor, the study monitor (if applicable) and the site’s IRB before the initiation of the 
study. The ICF must contain the 20 elements of informed consent described in ICH E6, 
Section 4.8. The authorization for use and disclosure of PHI must contain the elements 
required by Title 45 of the Code of Federal Regulations (CFR), Section 164.508(b), for 
valid authorizations. 
 
12.4.2 Investigator Study Files 
 
Documentation about the investigator and study staff, the IRB and the institution, is 
required before study site initiation. A list of required documents will be provided by the 
IND Sponsor or designee to each participating investigator. Copies of these documents as 
well as supplemental information, such as the investigator’s obligations, IB, clinical study 
protocol and amendments, safety information, investigational agent information, 
biological samples and laboratory procedures, SRM, study logs and 
IND 
Sponsor/investigator/study monitor correspondence will be kept on-site in study site-
specific binders. 
 
The IND Sponsor or designee will be responsible for maintaining original and backup of 
all CRF data. The investigator is responsible for maintaining backup of all electronic data 
systems used for primary documentation or source documentation. Backup of electronic 
data will be performed periodically as described in the site-specific SOPs. Backup 
records must be stored at a secure location on site and backup and recovery logs must be 
maintained to facilitate data recovery. If an electronic medical records system that is not 
supported by the IND Sponsor or designee (or is discontinued or decommissioned) is 
used, the investigator must maintain a system to retrieve these records or arrange for the 
transfer of these records to an alternate electronic format or to paper. 
 
Changes to any electronic records require an audit trail, in accordance with 21 CFR 
11.10(e), and should include who made the changes and when and why the changes were 
made. An audit trail is defined as a secure, computer-generated, time-stamped electronic 
record that will allow reconstruction of the course of events relating to the creation, 
modification and deletion of an electronic record. Audit trails must be created 
incrementally, in chronological order and in a manner that does not allow new audit trail 
information to overwrite existing data. Audit trails should be in a readable format and 
readily available at the study site and any other location where electronic study records 
are maintained. 
 
Audit trails are generated automatically for eCRFs. The investigator is responsible for 
maintaining audit trails of all electronic data systems used for primary documentation or 
source documentation. 
 
12.4.3 Case Report Forms and Source Documentation 
 


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The investigator must make study data accessible to the site monitor, to other authorized 
representatives of the IND Sponsor (or designee) and to the appropriate regulatory 
authority inspectors. The original CRF for each subject will be checked against source 
documents at the study site by the site monitor. 
 
12.4.4 Retention of Study Documents 
 
According to ICH E6, Section 4.9, all CRFs, as well as supporting paper and electronic 
documentation and administrative records, must be retained for at least 2 years after the 
last approval of a marketing application and until there are no pending or contemplated 
marketing applications, or at least 2 years have elapsed since the formal discontinuation 
of clinical development of an individual product. Longer retention periods may apply. 
The IND Sponsor will notify investigators as to when documents no longer need to be 
retained. No study documents will be destroyed or moved to a new location without prior 
written approval from the IND Sponsor. If the investigator relocates, retires or withdraws 
from the clinical study for any reason, all records required to be maintained for the study 
should be transferred to an agreed-upon designee, such as another investigator at the 
institution where the study was conducted. 
 
Audit trails for electronic documents must be retained for a period at least as long as that 
required for the subject electronic records to which they pertain. The investigator must 
retain either the original or a certified copy of audit trails. 
 
12.4.5 Data Confidentiality and Subject Anonymity 
 
All information about the nature of the proposed investigation provided by the IND 
Sponsor or their representative to the investigator (with the exception of information 
required by law or regulations to be disclosed to the IRB, the subject or the appropriate 
regulatory authority) must be kept in confidence by the investigator. 
 
The anonymity of participating subjects must be maintained. Subjects will be identified 
by their initials and an assigned subject number on CRFs and other documents retrieved 
from the site or sent to the IND Sponsor, study monitor, Aduro, BMS, regulatory 
agencies, or central laboratories/reviewers. Documents that identify the subject (e.g., the 
signed ICF) must be maintained in strict confidence by the investigator, except to the 
extent necessary to allow auditing by the appropriate regulatory authority, the study 
monitor, IND Sponsor or their representative. 
 
12.5  Protocol Compliance 
 
Substantive changes in the protocol include changes that affect the safety of subjects or changes 
that alter the scope of the investigation, the scientific quality of the study, the experimental 
design, dosages, assessment variable(s), the number of subjects treated or the subject selection 
criteria. A protocol amendment must receive IRB approval before implementation. In parallel 
with the IRB approval process, the protocol amendment will be submitted to the appropriate 
regulatory authority as an amendment to the regulatory submission under which the study is 
being conducted. If a protocol amendment requires changes in the ICF, the revised ICF prepared 


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by the investigator must also be approved by the IND Sponsor, the study monitor and the IRB 
before implementation. 
 
Emergency departures from the protocol that eliminate an apparent immediate hazard to a 
particular subject and that are deemed crucial for the safety and well-being of that subject may be 
instituted for that subject only. The investigator or the attending physician also will contact the 
Protocol Chair and/or designee as soon as possible in the case of such a departure. These 
departures do not require preapproval by the IRB; however, the IRB and the Protocol Chair and/ 
or designee must be notified in writing as soon as possible after the departure has been made. In 
addition, the investigator will document in the subject’s CRF the reasons for the protocol 
deviation and the ensuing events. 
 
12.6  Study Monitor Function and Responsibility 
 
The study monitor, in accordance with the IND Sponsor (or designee) requirements, will ensure 
that the study is conducted and documented properly by carrying out the relevant activities 
outlined in ICH E6, Sections 5.18.4, 5.18.5 and 5.18.6. 
 
12.7  General Information 
 
The investigator should refer to the IB, product labels, SRM, clinical protocol and appendices 
and other information provided during the study for further information about the investigational 
agents or details of the procedures to be followed during the course of this study. 
 
13. STATISTICAL CONSIDERATIONS 
 
13.1 
Study Design/Endpoints 
 
Sample size.  The primary endpoint is OS, and will be calculated from date of randomization to 
death.  For subjects without documentation of death at the time of analysis, OS will be censored 
on the date the subject was last known to be alive.  The OS of subjects randomized to 
CY/nivolumab/GVAX pancreas vaccine followed by nivolumab/CRS-207 will be compared to 
subjects randomized to CY/GVAX pancreas vaccine followed by CRS-207.   
 
Power is computed for a 2-stage group sequential design with a single interim analysis.  To 
control the overall two-sided type I error rate of 0.15 for the primary endpoint of OS, an O’Brien 
Fleming-like spending function will be used to account for one interim analysis.  The amount of 
alpha spent (two-sided) for the interim analysis is 0.02361.  The interim analysis is performed 
when approximately 50% of the total number of events required for the final analysis have been 
observed (approximately 42 events).  Accordingly, the p-value for the final analysis needs to be 
less than 0.14278 in order to reject the null hypothesis of equal survival. 
 
Assuming a uniform accrual period of 18 months with a follow-up of 12 months, 102 subjects 
(51 per arm) will be treated to achieve 84 deaths in the CY/nivolumab/GVAX and  CY/GVAX 
arms combined.  At the time of final analysis, this will provide 80% power to detect an HR of 
1.66, i.e. an increase in median OS from 6 to 9.96 months, with a 2-sided type 1 error rate of 
0.14278. Based upon these calculations, we expect to observe 38 and 46 deaths over the course 
of the study in the CY/nivolumab/GVAX and CY/GVAX arms, respectively. No losses to 


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follow-up were included in these calculations. As noted in Section 12.3, the primary analysis will 
be performed using the FAS, which will consist of all randomized subjects who receive at least 
one dose of study treatment.  As such, subjects will be enrolled until 102 subjects have received 
at least one dose of treatment (CY, nivolumab, GVAX, or CRS-207).  Assuming that at most 5% 
of subjects do not receive study treatment, approximately 108 subjects will be enrolled.   
 
Statistical Analyses   
 
All statistical analyses will be performed using SAS® version 9 or higher.   
 
Data will be summarized descriptively by treatment arm and overall.  The descriptive summary 
for the categorical variables will include counts and percentages. The descriptive summary for 
the continuous variables will include means, medians, standard deviations and minimum and 
maximum values.  The descriptive summary of time to event data will include median, 25th and 
75th percentiles and standard error.  All data will be listed for all subjects. 
 
All statements of statistical significance will be based on a 2-tailed test with an overall 0.15 level 
of significance, unless stated otherwise.  All confidence intervals will be 95%, unless stated 
otherwise.  Time-to-event outcomes such as OS will be analyzed using Kaplan-Meier estimates, 
log-rank tests, and Cox proportional hazards models.    Where applicable, comparisons between 
groups will be made using a Chi-square test or logistic regression for binary variables and 
analysis of variance (ANOVA) or analysis of covariance (ANCOVA) for continuous variables.  
Non-parametric alternatives (e.g. Fisher’s exact test or Kruskal-Wallis tests) will be considered 
as needed.  
 
For correlative studies, plots will be used to show the changes in immune response over time 
both for each individual and for each treatment group. For each treatment, comparisons in the pre 
and post-treatment responses will be compared using paired t-tests (or Wilcoxon signed rank 
tests if appropriate) for continuous variables and McNemar’s tests for dichotomous or categorical 
variables. Associations between immune parameters will be explored graphically (e.g. 
scatterplots, boxplots) and numerically (e.g., correlations, Fisher’s exact tests). Regression 
techniques will be used to explore the differences between the treatment arms for cross-sectional 
data (e.g., linear and logistic regression) and longitudinally with appropriate correction for 
correlation between repeated measurements (e.g., GEE and linear mixed effects models). 
 
Demographics and baseline characteristics will be summarized by treatment arm.  All differences 
will be interpreted for their clinical significance and potential use as covariates in sensitivity 
analyses of efficacy endpoints. 
 
For the primary analysis of overall survival, subjects without documentation of death at the time 
of analysis will be censored as of the date the subject was last known to be alive. Kaplan-Meier 
methodology will be used to estimate the survival probabilities and median survival time for 
each treatment arm.  Comparisons among treatment groups will use the stratified log-rank test, 
using disease status at study entry as the stratification factor, to compare OS.  If proportional 
hazard assumptions are not violated, the hazard ratio will be estimated using the Cox regression 
model.  If violated, treatment effect will be summarized by 1 or more appropriate summary 
statistics, such as hazard ratios from a piecewise proportional hazards model or other semi-
nonparametric approach. Sensitivity analyses based upon the ITT and PP analysis sets will be 


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performed using the methods described above.   
 
Additional details describing the handling the secondary and exploratory endpoints will be 
described in a separate statistical analysis plan (SAP). 
 
The effects of discontinuation of nivolumab, noncompliance, time to first dose, treatment 
discontinuations, premature withdrawal from study and covariates will be assessed to determine 
the impact on the general applicability of results from this study.  Details of the analysis, 
including the definitions of endpoints, methods for censoring, handling of missing data, 
transformations and other data handling procedures will also be provided in the SAP.  
Exploratory analyses of the data will be conducted as deemed appropriate.   
 
The assumptions used in the sample size calculations may be assessed at the time of the interim 
analysis to determine if the planned duration of required follow up time and/or number of treated 
subjects is appropriate to reach the targeted number of deaths.  The sample size, i.e, targeted 
number of deaths, will not be adjusted, nor will any by-treatment results be examined to assess 
the assumptions. As such, there will be no additional adjustments needed to the overall alpha 
level from this activity.  Further details for the interim and final analysis will be described in a 
separate statistical analysis plan (SAP). 
 
13.2 
Safety Analysis 
 
The safety analysis will be performed in all treated subjects. AE data will be listed individually 
and incidence of AEs summarized by system organ class and preferred terms within a system 
organ class for each treatment group.  When calculating the incidence of AEs, each AE (based on 
preferred terminology defined by Medical Dictionary for Regulatory Activities (MedDRA; 
Version 13.1, or later) will be counted only once for a given subject.  In analyses of grade and 
causality, if the same AE occurs on multiple occasions, the highest grade and strongest 
relationship to study drug will be assumed.  If 2 or more AEs are reported as a unit, the 
individual terms will be reported as separate experiences.  Vaccine-site reactions will be listed 
and tabulated separately from the AEs. 
 
Changes in vital signs, hematology and clinical chemistry parameters from baseline to the end of 
the study will be examined.  Toxicity will be tabulated by type and grade. Toxicities will be 
characterized according to the CTCAE version 4.03.  Treatment-emergent changes from normal 
to abnormal values in key laboratory parameters will be identified. 
  
 
 
 


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


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APPENDIX B: Management Algorithms 
 
These general guidelines constitute guidance to the Investigator and may be supplemented by discussions with the Protocol Chair and/or 
Medical Monitor representing the IND Sponsor. The guidance applies to all immuno-oncology (I-O) agents and regimens. 
 
A general principle is that differential diagnoses should be diligently evaluated according to standard medical practice. Non-inflammatory 
etiologies should be considered and appropriately treated. 
 
Corticosteroids are a primary therapy for immuno-oncology drug-related adverse events. The oral equivalent of the recommended IV doses 
may be considered for ambulatory subjects with low-grade toxicity. The lower bioavailability of oral corticosteroids should be taken into 
account when switching to the equivalent dose of oral corticosteroids. 
 
Consultation with a medical or surgical specialist, especially prior to an invasive diagnostic or therapeutic procedure, is recommended. 
 
The frequency and severity of the related adverse events covered by these algorithms will depend on the immuno-oncology agent or regimen 
being used. 
 
 
 
 
 
 
 
 
 
 


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APPENDIX C: Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for 
Evaluating Response in Solid Tumors 
 
RECIST version 1.1 will be used in this study for assessment of tumor response.  While either 
CT or MRI may be used utilized, as per RECIST 1.1, CT is the preferred imaging technique in 
this study.   
Disease Parameters 
 
Measurable disease:  Measurable lesions are defined as those that can be accurately measured in 
at least one dimension (longest diameter to be recorded) as >20 mm by chest x-ray, as >10 mm 
with CT scan, or >10 mm with calipers by clinical exam.  All tumor measurements must be 
recorded in millimeters (or decimal fractions of centimeters). 
 
Note:  Tumor lesions that are situated in a previously irradiated area might or might not be 
considered measurable unless there is evidence of progression in the irradiated site. 
Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a lymph 
node must be >15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm).  At baseline and in follow-up, only the short axis 
will be measured and followed. 
 
Non-measurable disease:  All other lesions (or sites of disease), including small lesions (longest 
diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), are considered 
non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses 
(not followed by CT or MRI), are considered as non-measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts should 
not be considered as malignant lesions (neither measurable nor non-measurable) since they 
are, by definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-cystic 
lesions are present in the same subject, these are preferred for selection as target lesions. 
 
Target lesions:  All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in 
total, representative of all involved organs, should be identified as target lesions and recorded 
and measured at baseline.  Target lesions should be selected on the basis of their size (lesions 
with the longest diameter), be representative of all involved organs, but in addition should be 
those that 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 which can be measured reproducibly should be selected.  A 
sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters.  If lymph nodes are to be 
included in the sum, then only the short axis is added into the sum.  The baseline sum diameters 
will be used as reference to further characterize any objective tumor regression in the measurable 
dimension of the disease. 
 


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Non-target lesions:  All other lesions (or sites of disease) including any measurable lesions over 
and above the 5 target lesions should be identified as non-target lesions and should also be 
recorded at baseline.  Measurements of these lesions are not required, but the presence, absence, 
or in rare cases unequivocal progression of each should be noted throughout follow-up.  
 
Evaluation of Target Lesions 
 
Complete Response (CR): Disappearance of all target lesions.  Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm. 
 
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, 
taking as reference the baseline sum diameters. 
 
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study).  In addition to the relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm.  (Note:  the appearance of one or more new lesions is also 
considered progressions). 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study. 
 
Evaluation of Non-Target Lesions 
 
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level.  All lymph nodes must be non-pathological in size (<10 mm short axis). 
 
Note:  If tumor markers are initially above the upper normal limit, they must normalize for a 
subject to be considered in complete clinical response. 
 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits. 
 
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions.  Unequivocal progression should not normally trump 
target lesion status.  It must be representative of overall disease status change, not a single lesion 
increase.     
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the 
treating physician should prevail in such circumstances, and the progression status should be 
confirmed at a later time by the review panel (or Principal Investigator). 
 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started).  The subject's best response assignment will 
depend on the achievement of both measurement and confirmation criteria. 


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For Subjects with Measurable Disease (i.e., Target Disease) 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall 
Response when 
Confirmation is 
Required* 
CR 
CR 
No 
CR 
>4 wks. 
Confirmation** 
CR 
Non-CR/Non-
PD 
No 
PR 
>4 wks. 
Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at least 
once >4 wks. from 
baseline** 
PD 
Any 
Yes or 
No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or 
No 
PD 
Any 
Any 
Yes 
PD 
* 
See RECIST 1.1 manuscript for further details on what is evidence of 
a new lesion. 
** 
Only for non-randomized trials with response as primary endpoint. 
*** 
In exceptional circumstances, unequivocal progression in non-target 
lesions may be accepted as disease progression. 
 
Note: Subjects with a global deterioration of health status requiring 
discontinuation of treatment without objective evidence of disease 
progression at that time should be reported as “symptomatic 
deterioration.”  Every effort should be made to document the 
objective progression even after discontinuation of treatment. 
 
Reference 
 
E.A. Eisenhauer, P. Therasse, J. Bogaerts, L.H. Schwartz, D. Sargent, R. Ford, J. Dancey, S. 
Arbuck, S. Gwyther, M. Mooney, L. Rubinstein, L. Shankar, L. Dodd, R. Kaplan, D. Lacombe, 
J. Verweij. New response evaluation criteria in solid tumours: Revised RECIST guideline 
(version 1.1).  Eur J Cancer. 2009 Jan;45(2):228-47. 
 
 
 


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APPENDIX D: Immune-Related Response Criteria 
 
Comparison between RECIST 1.1 criteria and the irRC 
 
RECIST 1.1 
irRC RECIST 1.1 
New, measurable 
lesions  
(i.e., ≥ 5mm) 
Always represent PD 
Incorporated into tumor 
burden 
New, non-
measurable 
lesions  
(i.e., < 5mm) 
Always represent PD 
Does not define 
progression (but precludes 
irCR) 
Non-index lesions Changes contribute to defining best 
overall response (BOR) of CR, PR, SD, 
and PD 
Contribute to defining irCR 
(complete disappearance 
required) 
CR 
Disappearance of all lesions in two 
consecutive observations not less than 4 
week apart 
Disappearance of all 
lesions in two consecutive 
observations not less than 4 
week apart if single arm 
trial and primary endpoint 
only 
PR 
> or = 30% decrease in the sum of the 
diameters of all index lesions compared 
with baseline in two observations at least 
4 week apart, in absence of new lesions 
or unequivocal progression of non-index 
lesions 
≥ 30% decrease in tumor 
burden compared with 
baseline in two 
observations at least 4 
week apart if single arm 
trial and primary endpoint 
only 
SD 
< 30% decrease in sum of longest 
diameters of all index lesions compared 
with baseline cannot be established nor 
< 20% increase compared with nadir, in 
the absence of new lesions or 
unequivocal progression of non-index 
lesions 
< 30% decrease in tumor 
burden compared with 
baseline cannot be 
established nor < 20% 
increase compared with 
nadir 
PD 
At least 20% increase in the sum of the 
longest diameters of index lesions and/or 
unequivocal progression of non-index 
lesions 
At least 20% increase in 
tumor burden compared 
with nadir (at any single 
time point) in two 
consecutive observations at 
least 4 week apart 


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90
RECIST 1.1 
irRC RECIST 1.1 
Handling of 
lymph nodes 
Lymph nodes are considered 
pathologically enlarged if > 10 mm in 
SAD. To be measurable, nodal lesions 
must be ≥ 15 mm in SAD. Nodal lesions 
with SAD > 10 mm and < 15 mm are 
non- measurable. The sum of the 
diameters (LD for extranodal target 
lesions, SAD for nodal lesions) is 
followed through the course of therapy 
Not differentiated from 
other tumor measurements 


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91
Derivation of irRC Overall Responses  
(Modified for RECIST 1.1. Criteria) 
 
Measurable response 
Non-measureable response 
Overall 
response 
Index and new, 
measurable lesions 
(tumor burden)* % 
Non-index lesions 
New, non- 
measurable lesions 
Using irRC 
↓ 100 
Absent 
Absent 
irCR/\ 
↓ 100 
Stable 
Any 
irPR/\ 
↓ 100 
Unequivocal progression 
Any 
irPR/\ 
↓ ≥ 30 
Absent/ Stable 
Any 
irPR/\ 
↓ ≥ 30 
Unequivocal progression 
Any 
irPR/\ 
↓ <30 to <20↑ 
Absent/ Stable 
Any 
irSD 
↓ <30 to <20↑ 
Unequivocal progression 
Any 
irSD 
≥ 20↑ 
Any 
Any 
irPD/\ 
*Decreases assessed relative to baseline, including measurable lesions only (>5 x 5 mm). 
/\Assuming response (irCR or irPR) and progression (irPD) are confirmed by a second consecutive 
assessment at least 4 weeks apart. 
 
 
Defining immune-related Response Criteria by RECIST 1.1 criteria at 20 weeks (irDCR at 20 
weeks): 
 
1. Any patient with stable disease or progressive disease at any time in the trial with "rapid 
clinical deterioration" felt to be related to disease progression is irPD 
 
2. Any patient who meets the criteria for RECIST 1.1 CR at 20 weeks is irCR 
 
3. Any patient who meets the criteria for RECIST 1.1 PR at 20 weeks is irPR 
 
4. Any patient who meets the criteria for RECIST 1.1 SD at 20 weeks is irSD 
 
5. A patient with RECIST 1.1 PD but no rapid clinical deterioration may stay on study if 
his/her next tumor measurement evaluation is stable disease or better. 
 
6. If patient has first time PD by RECIST 1.1 criteria, call it unconfirmed PD for irRC 
RECIST 1.1. 
 
7. A patient with unconfirmed irPD at 20 weeks whose next tumor measurement is SD or 
better will be considered to be included in the irDCR at 6 months. 
 
8. A patient with unconfirmed irPD at 20 weeks who fails to qualify for RECIST 1.1 SD or 
unconfirmed CR or PR by next tumor measurement will be considered to have RECIST 
1.1 PD and irPD at 20 weeks.