Clinical trial NCT03161379
Conditions: Pancreatic Cancer
Keywords: Neoadjuvant therapy immunotherapy Cytoxan Cyclophosphamide Pancreatic Vaccine SBRT GVAX Nivolumab borderline resectable Radioimmunotherapy Vaccine Antibody Anti-PD-1
Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Start date: 2018-02-02; Completion date: 2024-02-28
Enrollment: 31 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to evaluate the safety and clinical activity of FOLFIRINOX along with a whole cell vaccine with immune modulating doses of cyclophosphamide and nivolumab combined with Stereotactic Body Radiation Therapy (SBRT) in patients with pancreatic cancer.

Detailed description:

Arms: arm 1: CY, Nivolumab, GVAX, and SBRT
Interventions: intervention 1: Cyclophosphamide intervention 2: Nivolumab intervention 3: GVAX Pancreas Vaccine intervention 4: Stereotactic Body Radiation (SBRT)
Intervention descriptions: intervention 1: Cyclophosphamide 200 mg/m2 will be administered one day prior to vaccination (day 0). First dose will be given within 4 to 6 weeks after chemotherapy. 3 weeks after the first dose of immunotherapy the second dose will be given. intervention 2: Nivolumab (240 mg) will be administered one day prior to vaccination. First dose will be given within 4 to 6 weeks after chemotherapy. 3 weeks after the first dose of immunotherapy the second dose will be given. intervention 3: Vaccine will be administered one day after cyclophosphamide and nivolumab. 3 weeks after the first dose of immunotherapy the second dose will be given. intervention 4: SBRT (6.6 Gy over 5 days) will be started during the second dose of immunotherapy (3 weeks after the first dose of immunotherapy).

Protocol documents:
Prot_SAP_000.pdf: 
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TITLE: A Phase II Clinical Trial of GVAX Pancreas Vaccine (with Cyclophosphamide) in 
Combination with Nivolumab and Stereotactic Body Radiation Therapy (SBRT) Followed 
by Definitive Resection for Patients with Borderline Resectable Pancreatic 
Adenocarcinoma 
 
Johns Hopkins Protocol #: 
J1756/IRB00130075 
 
BMS Protocol #: 
CA 209-9CY 
 
Coordinating Center:  
 
 
Sidney Kimmel Comprehensive Cancer Center,  
 
 
 
 
 
 
 
 
 
Johns Hopkins University 
 
Principal Investigator 
Daniel Laheru, M.D. (Protocol Chair) 
(JHU):  
Sidney Kimmel Comprehensive Cancer Center  
 
 
 
 
 
 
 
Co-Principal Investigators  
Arsen Osipov, M.D. 
(JHU): 
 
 
 
Parul Agarwal, M.D. 
 
 
 
Principal Investigator 
Colin D. Weekes, M.D.  
(MGH): 
  
 
Principal Investigator  
Ben George, M.D. 
(MCW): 
 
 
ClinicalTrials.gov ID: 
NCT03161379 
 
IND#: 
BB IND 16454 
 
IND Sponsor: 
Elizabeth Jaffee, MD 
 
 
 
 
 
 
 
 
 
   
 
 
 
Lead Research Nurse: 
Anna Ferguson, RN, 
 
 
Statistician: 
Elizabeth A Sugar, PhD, 
 
 
Program Manager:  
Katrina Purtell, RN, 
 
 
External Regulatory Affairs:  
Rose Parkinson, PhD, 
 
 
 
 
Lead Study Coordinator: 
Jeanne Harrison, 
 


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Version:  
Version 1/January 18, 2017  
Version 1.1/April 17, 2017 
Version 1.2/June 20, 2017 
Version 1.3/August 4, 2017 
Version 2/February 6, 2018 
Version 3/April 20, 2018 
Version 4/July 19, 2018 
Version 5/October 3, 2018 
Version 6/December 5, 2018 
Version 7/April 15, 2019 
Version 8/October 2, 2019 
Version 9/February 19, 2020 
Version 10/July 8, 2020 
Version 11/September 15, 2020 
Version 12/May 18, 2021 
Version 12.1/August 2, 2023 
 
 
 


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1. SCHEMA 
 
 
 
Figure 1: Overview of the treatment plan for subjects who are enrolled in this clinical trial. 
 


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TABLE OF CONTENTS 
 
1. 
SCHEMA .............................................................................................................................3 
2. 
OBJECTIVES ......................................................................................................................6 
2.1 
Primary Objectives...................................................................................................6 
2.2 
Secondary Objectives...............................................................................................6 
2.3 
Exploratory Objectives ............................................................................................6 
2.4 
Primary Endpoints ...................................................................................................7 
2.5 
Secondary Endpoints ...............................................................................................7 
2.6 
Exploratory Endpoints .............................................................................................7 
3. 
STUDY DESIGN.................................................................................................................7 
4. 
BACKGROUND .................................................................................................................8 
4.1 
Study Disease(s).......................................................................................................8 
4.2 
GVAX pancreas vaccine ........................................................................................10 
4.3 
Rationale ................................................................................................................16 
5. 
PATIENT SELECTION ....................................................................................................18 
5.1 
Eligibility Criteria ..................................................................................................18 
5.2 
Exclusion Criteria ..................................................................................................20 
5.3 
Inclusion of Women and Minorities ......................................................................22 
6. 
REGISTRATION PROCEDURES ...................................................................................22 
6.1 
General Guidelines.................................................................................................22 
6.2 
Registration Process ...............................................................................................22 
7. 
TREATMENT PLAN ........................................................................................................22 
7.1 
Agent Administration.............................................................................................22 
7.2 
General Concomitant Medication and Supportive Care Guidelines ......................27 
7.3 
Prohibited and Restricted Therapies ......................................................................29 
7.4 
Definition of an Overdose for this Protocol ...........................................................30 
7.5 
WOCBP, Contraception, Use in Pregnancy, Use in Nursing: ...............................30 
7.6 
Nivolumab Treatment Discontinuation..................................................................32 
7.7 
Unacceptable Toxicities .........................................................................................33 
7.8 
Criteria for Removal from Treatment ....................................................................34 
7.9 
Off Study Treatment Visit .....................................................................................35 
7.10 
Duration of Follow Up ...........................................................................................35 
8. 
DOSING DELAYS/DOSE MODIFICATIONS ...............................................................36 
8.1 
Dose Modifications ................................................................................................36 
8.2 
Dosing Criteria for the investigational immunotherapy agents .............................36 
8.3 
Treatment Delays ...................................................................................................37 
9. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................38 
9.1 
Definitions..............................................................................................................38 


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9.2 
Relationship and Grading ......................................................................................40 
9.3 
Expectedness ..........................................................................................................41 
9.4 
Handling of Expedited Safety Reports ..................................................................41 
9.5 
Reporting................................................................................................................41 
9.6 
Special considerations for adverse events that occur during the surgery and 
postoperative course...............................................................................................44 
10. 
PHARMACEUTICAL INFORMATION ..........................................................................49 
10.1 
Cyclophosphamide (Cytoxan®, CY) .....................................................................49 
10.2 
GVAX ....................................................................................................................50 
10.3 
Nivolumab..............................................................................................................53 
11. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................55 
11.1 
Tumor Tissue Studies ............................................................................................55 
11.2 
Whole Blood for Peripheral Blood Lymphocytes (PBLs) .....................................56 
11.3 
Serum and Plasma Marker Studies ........................................................................56 
11.4 
Diagnostic Tissue Samples ....................................................................................56 
11.5 
Genomic Analysis ..................................................................................................56 
12. 
STUDY SCHEDULE ........................................................................................................57 
12.1 
Study Calendar .......................................................................................................58 
13. 
MEASUREMENT OF EFFECT........................................................................................60 
13.1 
Definitions..............................................................................................................60 
14. 
Data Reporting and STUDY MONITORING ...................................................................62 
14.1 
Data Collection and Processing .............................................................................62 
14.2 
Study Documentation.............................................................................................63 
14.3 
Protocol Compliance ..............................................................................................64 
14.4 
Monitoring .............................................................................................................64 
15. 
STATISTICAL CONSIDERATIONS...............................................................................65 
15.1 
Overview ................................................................................................................65 
15.2 
Sample Size and Accrual .......................................................................................65 
15.3 
Analysis..................................................................................................................66 
15.4 
Safety Monitoring ..................................................................................................67 
15.5 
Interim Analysis for Efficacy .................................................................................69 
REFERENCES ..............................................................................................................................70 
APPENDIX A: PERFORMANCE STATUS CRITERIA .............................................................73 
APPENDIX B: Management Algorithms ......................................................................................74 
APPENDIX C: SAE Reporting form .............................................................................................82 
Appendix D: Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 
Criteria for Evaluating Response in Solid Tumors ............................................................85 


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2. OBJECTIVES 
 
2.1 
Primary Objectives 
 
2.1.1 To determine whether the CD8 count in the tumor microenvironment is higher for patients 
with borderline resectable pancreatic ductal adenocarcinoma (BR-PDAC) treated with 
neoadjuvant sequential chemotherapy, SBRT, and Cy/GVAX/nivolumab immunotherapy 
as compared to that observed in archived samples from patients treated with FOLFIRINOX 
and SBRT. 
 
2.2 
Secondary Objectives 
 
2.2.1 To determine the pathologic complete response (pCR) rate at surgical resection of BR-
PDAC 
treated 
with 
neoadjuvant 
sequential 
chemotherapy, 
SBRT, 
and 
Cy/GVAX/nivolumab immunotherapy. 
 
2.2.2 To assess the safety and tolerability of sequential neoadjuvant chemotherapy, SBRT, and 
Cy/GVAX/nivolumab immunotherapy. 
 
2.3 
Exploratory Objectives 
 
2.3.1 To determine the percentage of patients with BR-PDAC who obtain an R0 resection at 
week 25 following neoadjuvant chemotherapy, SBRT, and Cy/GVAX/nivolumab 
immunotherapy. 
 
2.3.2 To determine the objective response rate (ORR) at week 25, in patients with BR-PDAC 
treated with sequential neoadjuvant chemotherapy, SBRT, and Cy/GVAX/nivolumab 
immunotherapy. 
 
2.3.3 To determine the overall survival (OS), 12 month OS, 18 month OS, and 24 month OS, of 
subjects with BR-PDAC treated with sequential neoadjuvant chemotherapy, SBRT, and 
Cy/GVAX/nivolumab immunotherapy. 
 
2.3.4 To evaluate the distant metastasis free survival (DMFS), 12 month DMFS, 18 month 
DMFS, and 24 month DMFS, of subjects with BR-PDAC receiving sequential neoadjuvant 
chemotherapy, SBRT, and Cy/GVAX/nivolumab immunotherapy. 
 
2.3.5 To explore changes to the tumor microenvironment (TME) induced by sequential 
neoadjuvant chemotherapy, SBRT, and Cy/GVAX/nivolumab immunotherapy, and 
explore correlations between immune markers and clinical outcomes. 
 
2.3.6 To assess tumor burden, mutational status, and immune dynamics through circulating 
biomarkers in serial collections of sera and plasma at baseline and throughout treatment. 
 
 
 


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2.4 
Primary Endpoints 
 
2.4.1 The CD8 count in resected tumor samples from patients in the study compared with 
historical controls.  
 
2.5 
Secondary Endpoints 
 
2.5.1 pCR rate at week 25, as defined by no residual cancer in the primary pancreatic tissue or 
nodes (ypT0ypN0). 
 
2.5.2 Adverse events as graded by NCI CTCAE version 4.03 
 
2.6 
Exploratory Endpoints 
 
2.6.1 Percentage of subjects who receive an R0 surgical resection following neoadjuvant 
treatment with chemotherapy, SBRT, and Cy/GVAX/nivolumab immunotherapy. 
 
2.6.2 ORR at week 25, defined as the proportion of patients achieving a complete response (CR) 
or partial response (PR) based on the Response Evaluation Criteria in Solid Tumors 
(RECIST 1.1) 
 
2.6.3 The overall survival (OS) 
 
2.6.4 Distant metastasis free survival (DMFS), defined as the time from enrollment to distant 
metastasis, or death. 
 
2.6.5 Intratumoral immune infiltrates pre- and post-treatment biopsy specimens will be studied 
using immunohistochemistry (IHC) and transcriptional analysis. 
 
2.6.6 Serum level of CA 19-9, and exploratory circulating biomarkers including plasma tumor 
DNA (ptDNA). 
 
 
3. STUDY DESIGN 
 
This is a multi-center, single arm, open label, phase II clinical trial to evaluate the safety and 
clinical activity of a combination of neoadjuvant Cy/GVAX/nivolumab immunotherapy following 
standard chemotherapy in patients with borderline resectable pancreatic ductal adenocarcinoma 
(BR-PDAC). 
 
We will enroll up to 32 subjects with BR-PDAC diagnosed based upon criteria defined by the 2009 
consensus 
statement 
issued 
by 
The 
Americas 
Hepatopancreatobiliary 
Association 
(AHPBA)/Society for Surgery of the Alimentary Tract (SSAT)/Society of Surgical Oncology 
(SSO)/National Comprehensive Cancer Network (NCCN), assessed by review of imaging and 
pathology at our institutional multidisciplinary pancreatic tumor clinic and tumor board 1.   
 
Patients with BR-PDAC according to CT, PET, or MRI imaging will receive between two to eight 


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(recommended four) 28-day cycles of FOLFIRINOX based chemotherapy or other standard 
chemotherapy. After receiving the last dose of chemotherapy, patients at select sites will 
subsequently undergo EUS-guided fiducial placement along with an SBRT simulation, core biopsy 
of the pancreas tumor and research blood draws. Within two to six weeks after receiving the last 
dose of standard chemotherapy, participants will receive their first dose of combination 
immunotherapy, consisting of cyclophosphamide (Cy) 200 mg/m2 given intravenously (IV) and 
nivolumab 240mg (flat dose) IV on day 1 followed by 5 x 108 GVAX vaccine cells, administered 
as six intradermal injections, on day 2.  Approximately three weeks later, subjects will receive 
their second dose of combined immunotherapy on the same day as initiation of SBRT (6.6 Gy x 5 
days, or a similar six day treatment at the discretion of the treating radiation oncologist).   
 
After completion of immunotherapy and SBRT, patients will undergo repeat imaging with FDG-
PET, CT, or MRI to evaluate for metastatic disease, progression, and/or surgical resectability.  If 
participants are deemed a surgical candidate, they will be offered definitive surgical resection. 
After receiving definitive surgical resection, or if definitive resection is not performed, patients 
will be off study treatment and can continue with standard of care evaluations and treatment. 
However, patients will continue to be followed through periodic phone calls or mail to determine 
their clinical outcome after surgery.  Patients will remain on study until death, withdrawal of 
consent, or completion or withdrawal of the study.  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 once they have been followed for 2 years per protocol or the study closes 
(Section 7.10). 
 
The primary endpoint is the CD8 count in resected tumor samples from patients in the study 
compares with historical control samples. Secondary endpoints and exploratory objectives 
(described above) will also be evaluated. 
 
4. BACKGROUND 
 
4.1 
Study Disease(s) 
 
Pancreatic ductal adenocarcinoma (PDAC) remains the fourth leading cause of cancer 
mortality 
in 
adults. 
Although 
20-30% 
of 
patients 
are 
eligible 
for 
a 
pancreaticoduodenectomy, the reported median survival is only 13-20 months 2. The 
addition of adjuvant radiation and/or chemotherapy has demonstrated limited improvement 
in survival 3. New multidisciplinary therapeutic approaches are needed for all stages of this 
disease.  
 
The entity of borderline resectable PDAC (BR-PDAC) is generally defined by disease that 
is neither definitely resectable nor definitely unresectable. Although different anatomical 
definitions of BR-PDAC have been proposed, no single definition is universally accepted. 
In 2009, a definition of BR-PDAC was put forth by The Americas Hepatopancreatobiliary 
Association (AHPBA)/Society for Surgery of the Alimentary Tract (SSAT)/Society of 
Surgical Oncology (SSO), that has also been adopted by the National Comprehensive 
Cancer Network NCCN. This consensus definition will be used in this clinical trial. In this 
definition, pancreatic cancer is borderline resectable if there is (1) venous involvement of 
the superior mesenteric vein/portal vein (SMV/PV) demonstrating tumor abutment, 


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encasement, or short segment venous occlusion, but with suitable vessel proximal and 
distal to the area of vessel involvement, allowing for safe resection and reconstruction; (2) 
gastroduodenal artery encasement up to the hepatic artery and short segment 
encasement/direct tumor abutment of the hepatic artery with no extension to the celiac axis; 
or (3) tumor superior mesenteric artery (SMA) involvement < 180° 4. 
 
The optimal management of BR-PDAC remains somewhat undefined. Although large 
randomized trials have established therapeutic standards for patients with resectable and 
metastatic PDAC 5,6, borderline resectable disease is still managed in a heterogeneous 
manner. A strong rationale exists for the use of preoperative therapy followed by surgery 
in patients with BR-PDAC, because upfront surgery in these patients results in a high 
probability of incomplete resection. This is especially important because the prognosis of 
resected pancreatic cancer is highly dependent on margin status. Patients with total excision 
and negative margins (R0 resection) have a better prognosis than those with positive 
margins (R1 resection) and patients with residual gross tumor (R2 resection) have a 
prognosis that is similar to non-operative therapy, inferring no benefit from surgery at all 
7. Although neoadjuvant chemotherapy implies a greater chance of complete resection than 
upfront surgery, the majority of data relating to this disease stage have been generated from 
a handful of single institution case series in which patients received a variety of treatment 
regimens 8,9. The only historical multi-institutional trial ever designed to specifically study 
this population, Eastern Cooperative Group (ECOG) Trial 1200 10, closed prematurely 
almost a decade ago for multiple reasons including the absence of a well-defined study 
population and the absence of therapeutic and surgical standards. Indeed, the ongoing 
failure to study borderline resectable PDAC can be attributed in large part to the historical 
absence of a standardized infrastructure of definitions, decision-making processes and 
technical procedures that is required to properly evaluate and treat this complex population 
11. 
 
More recently, the Alliance for Clinical Trials in Oncology (Alliance), Southwest 
Oncology Group (SWOG), Eastern Cooperative Oncology Group (ECOG), and Radiation 
Therapy Oncology Group (RTOG), collaborated to conduct a multi-institutional treatment 
trial for patients with borderline resectable PDAC (Alliance A021101). Patients on this 
protocol received neoadjuvant modified FOLFIRINOX (infusional 5-FU, oxaliplatin, 
leucovorin and irinotecan) followed by chemoradiation (CRT). Although final results of 
this trial have not been published at this time, initial results were reported at the ASCO 
annual meeting in mid-2015 12. Encouragingly, radiologic responses (by RECIST criteria) 
were observed in 6 of 23 (26%) enrolled patients, and the efficacy of this preoperative 
regimen was further supported by a 93% rate of R0 resection and 9% pathologic CR rate. 
These results provided initial support for neoadjuvant therapy in BR-PDAC.  
 
Each year, less than 5,000 patients with resectable PDAC undergo potentially curative 
resection in the United States. An additional 16,000 patients are diagnosed with locally 
advanced PDAC. Of these, approximately 30% (5000 patients annually) might be 
considered to have borderline resectable primary cancers using modern definitions 4,13. In 
many cases such patients are treated with palliative chemotherapy as though they are 
inoperable/incurable. If these patients were treated with aggressive neoadjuvant systemic 
therapy and SBRT, with successful pathologic down-staging of their tumor, followed by 


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definitive resection, there is the potential to significantly increase the percentage of PDAC 
achieving potentially curative therapy.  
 
4.2 
GVAX pancreas vaccine 
 
4.2.1 Rationale for the GM-CSF-modified allogeneic tumor cell vaccine in pancreatic cancer 
immunotherapy. 
 
The use of whole-cell vaccines is promising because it delivers a range of peptide antigens 
without the need for specific knowledge of the relevant target antigens 14–21.  Preclinical 
studies show that GM-CSF is the cytokine most effective in inducing anti-tumor immunity 
16–21.  GM-CSF is an important growth and differentiation factor for dendritic cells, which 
are potent antigen-presenting cells (APCs) that can take up cellular proteins that encode 
for tumor antigens. The use of allogeneic tumor cells for vaccine development over 
autologous tumor cells is attractive for several reasons.  Autologous tumor cells are 
unavailable or technically infeasible to produce.  In addition, the characterization of tumor-
associated antigens in melanoma revealed that most tumors share common antigens 
regardless of HLA type 14–21.  Furthermore, both preclinical and human data demonstrate 
that GM-CSF vaccine-induced host derived APCs rather than the tumor cells themselves 
prime CD8+ T cells 14–21.  Importantly, we previously reported that the allogeneic GM-CSF 
pancreatic vaccine induced CD8+ mesothelin specific T cells in patients who demonstrated 
prolonged disease-free and overall survival in phase I and II testing 22,23.  Thus, the vaccine 
cells and the host do not have to be HLA compatible to prime effective CD8+ T cell 
responses against pancreatic tumor antigens. 
 
4.2.2 Results of a Phase I study of an allogeneic GM-CSF-secreting tumor vaccine in patients 
with resected pancreatic cancer treated at Johns Hopkins Medicine (JHMI). 
 
This study was the first clinical trial to test the hypothesis that allogeneic GM-CSF 
secreting pancreatic tumor cell lines can prime a systemic immune response in patients 
with resected pancreatic adenocarcinoma 18. Fourteen patients with stage 2 or 3 disease 
received an initial vaccination 8 weeks following resection. This was a dose escalation 
study in which patients each received 107, 5X107, 108, and 5X108 vaccine cells.  Study 
patients were jointly enrolled in an adjuvant chemoradiation protocol for 6 months, then 
given 3 additional vaccinations one month apart at the same original dose that they received 
for the first vaccination. Toxicities were limited to grade I/II local reactions at the vaccine 
site, and self-limited systemic rashes.  Systemic GM-CSF levels were evaluated as an 
indirect measure of the longevity of vaccine cells at the immunizing site. GM-CSF levels 
peaked at 48 hours following vaccination.  The vaccine sites were also evaluated as a 
measure of the local immune reaction to the vaccine. Eleven of 14 patients demonstrated a 
local inflammatory response, similar to what has been observed in pre-cinical models and 
autologous GM-CSF vaccine clinical trials. Post-vaccination delayed-type hypersensitivity 
(DTH) responses to autologous tumor cells were observed in 1 of 3 (33%) patients 
receiving 108 and in 2 of 5 (40%) patients receiving 5X108 vaccine cells. 
 
4.2.3 Results of a follow-up phase II study of the GM-CSF-secreting pancreatic tumor vaccine. 
 


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We completed a follow-up adjuvant study (study J9988) in 60 patients (88% lymph node 
positive) with operable pancreatic cancer23.  Patients received an initial vaccination (5x108) 
8 weeks after pancreaticoduodenectomy, followed by chemoradiation, and then 4 more 
immunizations with the vaccine.  Primary endpoints of this trial were to:  1) estimate the 
disease-free and overall survival benefit associated with this treatment; 2) further 
characterize the toxicities associated with the vaccine; 3) assess the induction of 
mesothelin-specific T cell responses and correlate with clinical response rates. With a 
follow-up of median follow up of 25.1 months, median disease-free survival is 17.3 months 
(95% CI: 13.4 – 19.1) with median survival of 24.8 months (95% CI: 21.2 - 31.6).  A non-
matched cohort analysis comparing patients to the Johns Hopkins Surgery database treated 
concurrently with similar adjuvant chemoradiation suggest that there might be an initial 
improvement for immunotherapy treated patients during the first 2 years of treatment.  
 
Based on the analysis, the study concluded that the administration of the GM-CSF 
allogeneic cancer vaccine is safe and well tolerated. Treatment related side effects were 
similar to those side effects seen in the phase I study. The most common side effects were 
vaccine injection site reactions of induration and erythema that were transient in all 
research participants.  In addition, some subjects also had transient vaccine injection site 
reactions of tenderness and pruritus. The systemic reactions included transient elevation in 
eosinophil counts, rashes and flu-like symptoms that have included low grade fever, chills, 
malaise, arthralgias, myalgias, and fatigue. Most patients had a transient elevation in their 
eosinophil count which demonstrates the bioactivity of GM-CSF. All vaccine related 
toxicities have been of the same intensity and duration as those observed in the phase I 
study 18. 
 
4.2.4 Phase II Study of the GM-CSF allogeneic vaccine alone and given in sequence with 
immune modulating doses of IV Cyclophosphamide in subjects with advanced (Stage 4) 
pancreatic cancer 
 
A feasibility study of the GM-CSF allogeneic vaccine administered alone or in sequence 
with Cyclophosphamide in subjects with advanced pancreatic cancer has been completed24. 
This study was an open label multi-center study sponsored by Cell Genesys, Inc in 
collaboration with US Oncology.  Subjects were enrolled into one of two cohorts: Cohort 
A- 30 subjects administered a maximum of six doses of the same pancreatic cancer vaccine 
as described above using the two pancreas cancer cell lines each delivering 2.5 x 108 cells 
intradermally administered at 21 day intervals; Cohort B- 20 subjects administered 
cyclophosphamide 250 mg/m2 IV one day prior to vaccine as in Cohort A. The primary 
objective was to evaluate the safety and induction of immune responses when treated with 
either vaccine alone or in sequence with cyclophosphamide. Secondary objectives include 
time to disease progression (TTP), median overall survival (OS), and assessment of the 
feasibility of detecting mesothelin-specific T cell responses in patients with advanced 
pancreatic cancer. 
 
From this study, we concluded that the administration of a GM-CSF allogeneic pancreatic 
cancer vaccine is safe, feasible, and tolerated both alone and when given in sequence with 
cyclophosphamide. It was well-tolerated by patients with advanced pancreatic cancer, and 
the majority of these patients had received two or more prior chemotherapy regimens. The 


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median number of vaccines administered was 2 in Cohort A and 3 in Cohort B. Treatment 
related adverse events reported in > 5% of subjects included local vaccine injection site 
reactions (100%), fever (14%), rigors (10%) and rash (6%). 
 
Stable disease was noted in 16.7% of subjects in Cohort A (vaccination alone) and 40% of 
subjects in Cohort B (vaccination plus Cytoxan).  Median survival in Cohort A and Cohort 
B were 2.3 months and 4.7 months respectively in a subject population that had received ≥ 
2 prior chemotherapies in 12/20 (60%) subjects for Cohort B and in 30/50 (60%) subjects 
overall.  This compares well with what is reported for first and second line therapy in this 
patient population.  Furthermore, mesothelin-specific T cell responses have been observed 
in treated patients. Interestingly, unlike patients with resected cancer, mesothelin-specific 
T cell responses can be detected at baseline, prior to vaccination, in patients with metastatic 
pancreatic cancer. In addition, there was some evidence of prolonged progression-free 
survival in those patients who demonstrated persistent mesothelin-specific T cell responses 
with therapy but it did not achieve statistical significance. These data would suggest that 
even in metastatic patients, tumor-specific T cells can be detected.  
 
This study represents the first demonstration that integrating immunomodulatory doses of 
Cy with a GM-CSF-secreting vaccine in patients with advanced pancreatic cancer is safe 
and feasible to administer. These data suggest that the vaccine given in sequence with Cy 
results in anti-tumor activity that is at least similar to gemcitabine-containing 
chemotherapy. In addition, mesothelin-specific CD8+ T cell responses can be detected in 
stage 4 patients treated with the vaccine and may correlate with time to progression and 
overall survival. Thus, these findings provide the scientific rationale to continue to test 
combinations of vaccine with other more potent immune modifying agents. 
 
4.2.5 Clinical study of ipilimumab vs. GVAX + ipilimumab for treatment of advanced 
unresectable PDA 
 
The Phase 1b study of ipilimumab (IPI, anti-CTLA-4 blockade antibody) versus GVAX + 
IPI in advanced PDA represents the first clinical study of a checkpoint inhibitor in 
combination with a vaccine for PDA25.  Thirty patients with previously treated PDAC were 
randomized 1:1 to IPI at 10mg/kg alone (arm 1) or in combination with GVAX (arm 2). 
Patients received 4 induction doses of IPI or GVAX/IPI at 3-week intervals and then 
maintenance with the same treatment every 3 months. CA19-9 declines in association with 
GVAX + IPI treatment were seen for 7/15 (47%) patients. In contrast, 0/15 (0%) patients 
receiving IPI alone had CA19-9 declines. Median overall survival (OS) was 3.7 months for 
arm 1 and 5.7 months for arm 2 (p=0.072). The percentage of patients alive after one year 
also favored the combination arm (7% vs 27%). The best RECIST response was stable 
disease (SD) in two patients in arm 1 and two patients in arm 2. Using the immune-related 
RECIST criteria (irRC), arm 2 had an additional patient with SD for 81 weeks. Immune-
related response criteria (irRC) account for the kinetics of both old and new lesions given 
the known potential delayed responses with IPI. The quality of the responses in the two 
arms was different. Patients with SD on arm 1 had continuous disease progression that did 
not reach the 20% growth cutoff for 7 and 22 weeks. Arm 2 had three SD responses (one 
patient demonstrated a regression starting at week 14 that was maintained until week 31, 
another patient’s disease stabilized starting at week 22 and was maintained for 81 weeks, 


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and the third SD was maintained for 71 weeks while that patient was on study). The second 
patient initially received GVAX as a participant in the above mentioned neoadjuvant and 
adjuvant vaccine study.  After he had recurrence, he received additional chemotherapy and 
radiation therapy, but continued to have disease progression.  Later, when we analyzed his 
tumor together with the other PDA tumors from the neoadjuvant and adjuvant vaccine 
study, we found that the lymphoid aggregates that formed in his surgically resected PDA 
showed an immune suppressive signature, characterized by a relatively high density of 
Foxp3+ cells, albeit high density of CD8+ cells, and relatively high expression of CTLA-
4.  However, after he received the combination of IPI and GVAX treatments, even after he 
had an early local progression and developed a new omental lesion at week 7 after 
beginning the combinatorial treatment, he had a delayed, albeit durable disease 
stabilization starting at week 22.  Four years after recurrence, this patient is still alive and 
is 2 years out from his last treatment. Although his CT scan still showed soft tissue density 
in the local pancreatic region and peritoneal nodularity, biopsy of these lesions failed to 
demonstrate malignant cells.  This data, albeit anecdotal, suggests that the combination of 
checkpoint inhibitor and vaccine therapies may reverse an unfavorable TME that is 
dominated by immune suppressive signals and allow for the generation of a productive 
antitumor response.  Nevertheless, IPI was associated with high grade including immune-
related adverse events (irAE); thus, a checkpoint inhibitor such as anti-PD-1 therapy that 
is associated with less frequent irAE and has the same efficacy as IPI has gained much 
interest. 
 
4.2.6 The J0810 study of neoadjuvant and adjuvant GM-CSF allogeneic vaccine alone and given 
in sequence with immune modulating doses of IV or oral Cyclophosphamide in subjects 
with resectable pancreatic cancer 
 
Between July 2008 and September 2012, 59 patients were enrolled into a study 
(NCT00727441, J0810) of an irradiated, allogeneic GM-CSF-secreting pancreatic tumor 
vaccine (GVAX) administered intradermally either alone or in combination with immune 
modulatory doses of cyclophosphamide (Cy) as neoadjuvant and adjuvant treatment for 
patients with resectable PDA. The immune modulatory role of low dose Cy in depleting 
regulatory T cells were demonstrated in a number of pre-clinical and clinical studies 26–33. 
Most of these 59 patients were enrolled during a 24-month active enrollment period. 
Patients were randomized 1:1:1 to 3 treatment arms 34.  In Arm A, patients received GVAX 
alone; in Arm B, patients received GVAX plus a single intravenous dose of Cy at 200 
mg/m2 1 day prior to each vaccination; in Arm C, patients received GVAX plus oral Cy at 
100 mg once daily for 1 week on and 1 week off.  Up to 6 GVAX treatments were 
administered and all of the patients remained in their initial treatment arms throughout the 
duration of the study.  All 59 of the patients received the 1st GVAX treatment 2 weeks +/-
4 days prior to surgery. Fifty-four (92%) patients successfully underwent 
pancreaticoduodenectomy (the Whipple surgery) and received the 2nd GVAX treatment. 
Eligible patients must have a mass in the head, neck and uncinate process of the pancreas 
suspected for adenocarcinoma by a multidisciplinary clinical trial team comprised of 
radiologists, surgical oncologists and medical oncologists.  Biopsy would not be routinely 
required prior to surgical resection of a mass of pancreas suspected for PDA; therefore, 
biopsy was also not required at the entry of this vaccine study.  Five patients were found 
intraoperatively to have liver metastases, which were not radiographically identified prior 


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to surgery, and instead underwent a bypass surgery.  Among 54 patients who had 
pancreaticoduodenectomy, 1 patient was found to have ampullary cancer, 1 to have 
neuroendocrine tumor, 2 to have undifferentiated carcinoma, and 1 to have autoimmune 
pancreatitis. These patients’ preoperative CT scans did not distinguish their disease process 
from PDA.  In addition, 1 patient had grossly residual tumors and another 11 patients had 
recurrence immediately following the surgery. They were all taken off the study 
postoperatively. The 39 patients remaining on the study received standard adjuvant 
chemotherapy and radiation therapy.  Patients remaining disease-free following 
chemoradiation therapy received up to 4 additional PDA GVAX treatments every 4 weeks.   
 
This study demonstrated that it is safe to treat patients suspected to have PDA with 
pancreatic GVAX in the neoadjuvant setting, including patients who end up not having 
PDA.  The sample size of this study was later increased to 90 in order to generate more 
preliminary data to support future research directions including the current application. 
Clinical outcome data in this study have not matured at the time of submitting this 
application.  The study was not powered to compare the clinical efficacy analysis between 
arms; the primary focus was safety and immunologic correlates.  We also do not anticipate 
that one additional vaccination in the neoadjuvant setting would significantly change 
patients’ clinical outcome comparing to our prior study (clinical study J9988) of treating 
the patients with vaccines in the adjuvant setting 23 An interim preliminary analysis did 
show that the DFS and OS of patients in this neoadjuvant and adjuvant study is similar to 
our prior J9988 adjuvant vaccine study. More importantly, as described above and below, 
this neoadjuvant and adjuvant vaccine study has pioneered the neoadjuvant research 
approach for cancer immunotherapy and supported the use of the same neoadjuvant 
approach for the study of the combination of anti-PD-1 therapy and vaccine therapy.  
 
Furthermore, the primary objective of that study was to analyze the effects of treatment on 
the TME.  Pathologic examination of resected PDAs revealed the formation of vaccine-
induced intratumoral tertiary lymphoid aggregates within two weeks following a single 
GVAX vaccine treatment, regardless of whether GVAX was combined with Cy or not.  
Gene microarray analysis of microdissected vaccine-induced lymphoid aggregates 
identified gene signatures representing five signaling pathways including the NF-kB, 
Treg/TH17, chemokine, integrin/adhesion, and ubiquitin-dependent proteosome pathways.  
Gene expression and immunohistochemistry analyses further demonstrated that the Treg 
pathway is suppressed and the TH17 pathway is enhanced in lymphoid aggregates from 
patients who survive more than 3 years, in patients who demonstrate vaccine-enhanced 
mesothelin-specific T cell responses, and in patients with increased Teffector/Treg 
(CD8/Foxp3) ratios in their tumors. Overall, this study showed for the first time that 
GVAX-based immunotherapy can convert an immunologically inactive TME into an 
immunologically active TME; and that GVAX induces the formation of intratumoral 
tertiary lymphoid aggregates that facilitate a TH17-dominated anti-cancer response within 
the PDA TME following immunotherapy treatment. 
 
The primary objective of the study described above is to compare IL17 expression in 
vaccine-induced lymphoid aggregates between resected PDAs from patients treated with 
the combination of GVAX/Cy and anti-PD-1 antibody vs. GVAX/Cy alone. Our prior 
studies showed that higher IL17A expression in lymphoid aggregates was associated with 


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longer OS in patients who received neoadjuvant and adjuvant GVAX (Figures 4-6, Lutz et 
al. 34). This is the strongest biomarker identified through this prior study.  Published studies 
have suggested that PD-1 blockade enhances TH17 response in patients with melanoma 
and prostate cancer. Therefore, we hypothesize that anti-PD-1 therapy will enhance IL17A 
expression in vaccine induced lymphoid aggregates.  We are also going to analyze other 
immune parameters as part of explorative endpoints. 
 
Consistent with the induction of an adaptive immune response, treatment with GVAX 
induced interferon gamma (IFN-y)-production in Teffs infiltrating PDAs, but also induced 
the upregulation of immunosuppressive regulatory mechanisms, including upregulation of 
the PD-1/PD-L1 pathway34. At baseline, only a small fraction of PDA epithelial tumor cells 
express low levels of membranous PD-L1.  By contrast, GVAX  
therapy induced moderate expression of membranous PD-L1 on the epithelial tumor cells, 
and also induced the infiltration of innate 
immune cells expressing high levels of 
PD-L1 into the intratumoral lymphoid 
aggregates (see Figure 2) 34. PD-L1 
expression 
may 
be 
regulated 
by 
oncogenic pathways. However, in most 
cancers, PD-L1 is induced by cytokines 
produced by infiltrating immune cells 
during the induction of an adaptive 
immune response, such as IFN-y 34.  In 
melanoma, NSCLC and renal cell 
carcinoma, PD-L1 expression by tumor 
cells has been observed in approximately 
53-89% of untreated patients' tumors and 
by tumor infiltrating immune cells in 
approximately 50-100% of tumors 35.  
PD-L1 expression by both tumor cells 
and tumor infiltrating immune cells in 
untreated patients with these cancers is 
associated with PD-1 expression in tumor 
infiltrating lymphocytes (TILs), more 
abundant infiltration of immune effector cells, and the presence of lymphoid aggregates.  
The high prevalence of immune cell infiltration and PD-L1 expression in these particular 
malignancies may explain their relatively high response rates to single therapy with anti-
PD-1 or anti-PD-L1.  By contrast, PDA demonstrates a minimal response to anti-PD-1/PD-
L1 single therapies that is likely due to the absence of immune effector cell infiltration and 
low PD-L1 expression in vaccine-naïve PDAs.  However, we hypothesize that by inducing 
immune cell infiltration and PD-L1 expression in the TME, GVAX therapy primes the 
PDA TME for anti-PD-1/PD-L1 therapies.  Therefore, in this application, we will test this 
hypothesis through a novel clinical trial designed to test the combination of GVAX and 
anti-PD-1 antibody in both neoadjuvant and adjuvant settings in patients with resectable 
PDA. 
 
Figure 2 (from Lutz et al.34): GVAX therapy 
induces the infiltration of innate immune cells 
expressing high levels of PD-L1 into the 
intratumoral lymphoid aggregates. Here, a 
representative intratumoral lymphoid aggregate 
from a vaccine-treated patient with pancreatic 
ductal adenocarcinoma is shown. This supports 
the hypothesis that vaccine-based therapies can 
convert a "non-immunogenic" neoplasm into an 
"immunogenic" neoplasm that may be sensitive 
to immune checkpoint inhibitors. 


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4.3 
Rationale 
 
A multi-institutional study of BR-PDAC is now justified and appropriate given the 
following considerations: First, the optimal management of BR-PDAC remains undefined. 
Second, the recent publication of national “consensus statements” regarding BR-PDAC 
has provided a definition through which this disease can be studied, and reflects a growing 
interest in serving this unique patient population. Third, the prognosis for BR-PDAC with 
current approaches to therapy remains poor and novel approaches to treating these patients 
are needed. 
 
A strong rationale exists for the use of preoperative therapy followed by surgery in patients 
with BR-PDAC, because upfront surgery in these patients results in a high probability of 
incomplete resection, and the prognosis of resected pancreatic cancer is highly dependent 
on margin status. The reported results of the Alliance A021101 trial, which utilized the 
preoperative regimen of FOLFIRINOX and chemoradiation (CRT), provide initial support 
for neoadjuvant therapy in BR-PDAC 12. However, the results of this leave significant room 
for improvement; objective responses were uncommon and only 9% of patients achieved 
a pathologic CR. 
 
Importantly the use of preoperative chemoradiotherapy in patients with BR-PDAC, has 
also been shown to promote infiltration of CD8+ T Cells into the TME of PDAC. 
Additionally, among the patients who received  neoadjuvant chemoradiotherapy those with 
higher accumulation of CD8+ experienced a longer survival as compared to those who had 
lower CD8+ T cell infiltration. 36 This is consistent with our own experience in patients 
with borderline or locally advanced PDAC, who received neoadjuvant chemoradiotherapy. 
In these patients we appreciated that higher CD8+ infiltration relative to 
immunosuppressive T reg cells correlated with both improved local progression free 
survival and overall survival (figure 3).  
 


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The present study builds upon the Alliance A021101 trial, our experiences and others with 
borderline resectable pancreatic cancer, by taking advantage of a number of recent 
advancements in pancreatic immunotherapy and radiation therapy. Initially, patients will 
be treated with FOLFIRINOX, a regimen that is highly effective for metastatic PDAC5,37 
and appears to be effective in the preoperative setting on the basis of the Alliance study 12. 
The goal of the chemotherapy is not only to reduce the size of the primary pancreatic lesion, 
but also to eliminate micrometastatic disease that might be present, and to reset the immune 
system. Although the appropriate sequencing of chemotherapy and immunotherapy in 
diseases where both therapies are known to be active remains unclear, there is emerging 
evidence that chemotherapies can modulate the host immune system through the 
expression of cancer neoantigens and in other ways that are just starting to be understood. 
 
After chemotherapy, patients will be treated with Cy/GVAX/nivolumab immunotherapy. 
As discussed above, preclinical and clinical research conducted at Johns Hopkins has 
shown that the GVAX vaccine, either alone or in combination with immune modulating 
doses of Cy to deplete regulatory T cells, can have profound effects on the tumor 
microenvironment. Pathological examination of PDA tumor tissue resected just two weeks 
following a single neoadjuvant dose of GVAX identified the formation of novel vaccine-
induced, immunologically active, tertiary lymphoid aggregates, organized lymph node-like 
structures that are not observed in tumor tissue resected from unvaccinated patients. 
However, activated T cells secrete interferon-gamma, which in turn upregulates the PD-
1/PD-L1 pathway. Therefore, in this protocol, we have combined Cy/GVAX with a PD-
1/PD-L1 pathway inhibitor (nivolumab) in order to prevent immune escape.  
 
Finally, the immunotherapy will be administered concurrently with SBRT, an important 
recent advance in the treatment of localized pancreatic cancer. While studies using 


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conventional chemoradiation for non-metastatic pancreatic cancer have had conflicting 
results, SBRT is a contemporary form of RT that involves a short course of radiation 
delivered at a higher dose than conventional RT. Studies of SBRT have been encouraging 
and suggest that it can cause tumor regression away from involved vasculature, thereby 
improving the chances of negative surgical margins. Importantly, because the radiation 
course is short, the potential for delay of definitive surgery is reduced. Additionally, shorter 
courses of radiation may be immunologically preferential, resulting in acute rather than 
chronic antigen exposure and thereby reducing T cell anergy, exhaustion, and senescence. 
In this study, radiation has been combined with immunotherapy (Cy/GVAX/nivolumab) 
because of emerging evidence of synergy between these treatment modalities. Through the 
killing of tumor cells, radiation can stimulate antigen-specific CD8+ T cells through the 
presentation of antigen, thereby potentiating antitumor immune responses with 
Cy/GVAX/nivolumab. 
 
 
5. PATIENT SELECTION 
 
5.1 
Eligibility Criteria  
 
5.1.1 Histologically confirmed pancreatic adenocarcinoma* that is borderline resectable. 
Borderline resectable is defined by the 2009 consensus statement issued by The Americas 
Hepatopancreatobiliary Association (AHPBA)/Society for Surgery of the Alimentary Tract 
(SSAT)/Society of Surgical Oncology (SSO)/National Comprehensive Cancer Network 
(NCCN): 
 
 
venous involvement of the SMB/PV demonstrating tumor abutment, encasement, or 
short segment venous occlusion, but with suitable vessel proximal and distal to the area 
of vessel involvement, allowing for safe resection and reconstruction 
OR 
 
gastroduodenal artery encasement up to the hepatic artery and short segment 
encasement/direct tumor abutment of the hepatic artery with no extension to the celiac 
axis 
OR 
 
tumor-SMA involvement <180 degrees 
 
*Pancreatic adenocarcinoma with squamous features is considered pancreatic 
adenocarcinoma (malignant squamous cells comprise <30%)  
 
5.1.2 The patient has received no more than 1 month or 1 cycles (28 days) of systemic therapy 
for PDAC (prior symptomatic treatments such as pain medicines are acceptable). Patients 
receiving neoadjuvant chemotherapy who have not received more than 28 days or 1 month 
of therapy are eligible. The patient has not received any radiation therapy for PDAC. 
 
5.1.3 Age >18 years 
 


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5.1.4 ECOG performance status 0-1 (Appendix A) 
 
5.1.5 Patients must have normal organ and marrow function as defined below: 
 
 
White blood cell count 
≥3,000/mcL 
 
absolute neutrophil count 
≥1,500/mcL 
 
hemoglobin 
 
 
≥ 9.0g/dl 
 
platelets 
≥100,000/mcL 
 
total bilirubin  
 
 
≤1.5 × institutional upper limit of normal 
 Exception #1 Patients with an elevated bilirubin 
>1.5 x ULN due to biliary obstruction from PDAC 
may enroll if they have undergone an obstruction 
relieving intervention with at least 2 serial bilirubins 
decreasing 
 Exception #2: Subjects with Gilbert syndrome may 
enroll as long as total bilirubin <3.0 mg/dL) 
 
AST(SGOT)/ALT(SGPT) 
≤5 × institutional upper limit of normal 
 *Note: Patient’s AST and ALT will need to be ≤3 x 
the upper limit of normal prior to the first cycle of 
immunotherapy 
 
serum creatinine 
≤1.5 × institutional upper limit of normal 
OR 
 
creatinine clearance 
≥40 mL/min/1.73 m2 for patients with creatinine levels 
above institutional normal 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 
 
    Male CrCl = (140 - age in years) x weight in kg x 1.00  
                     
 
 
 
 
72 x serum creatinine in mg/dL 
 
5.1.6 Women of childbearing potential (WOCBP) must have a negative urine or serum 
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic 
gonadotropin [HCG]).  WOCBP is defined in Section 7.5. NOTE: If a patient has a positive 
or indeterminate serum or urine pregnancy test, then an ultrasound must be done to rule 
out pregnancy to enroll on trial.  
 


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5.1.7 WOCBP must be willing to use either two adequate barrier methods or a barrier method 
plus a hormonal method of contraception to prevent pregnancy, or to abstain from 
heterosexual activity (complete abstinence) throughout the study, starting with visit 1 
through 5 months after the last dose of study therapy. Approved contraceptive methods 
include, for example; intrauterine device, diaphragm with spermicide, cervical cap with 
spermicide, male condoms, female condoms with spermicide, or oral contraceptives. 
Spermicides alone are not an acceptable method of contraception. Should a woman become 
pregnant or suspect she is pregnant while she or her partner is participating in this study, 
she should inform her treating physician immediately. 
 
5.1.8 Male patients must agree to use an adequate method of contraception, or to abstain from 
heterosexual activity (complete abstinence), starting with the first dose of study drug 
through 7 months after the last dose of study therapy. 
 
5.1.9 Patient must be a candidate for SBRT (Stereotactic body radiation therapy). 
 
5.1.10 Patient must be willing to be treated with SBRT and have surgical resection (if eligible) 
only at the clinical trial site at which they are enrolled.  
 
5.1.11 Ability to understand and the willingness to sign a written informed consent document. 
 
 
5.2 
Exclusion Criteria 
 
5.2.1 Patient has histologically confirmed squamous pancreatic cancer or adenosquamous 
pancreatic cancer with malignant squamous cells >30% 
 
5.2.2 Patients who have had surgery within 28 days, excluding minor procedures (dental work, 
skin biopsy, etc.), celiac plexus block, and biliary stent placement. 
 
5.2.3 Patient has received or is receiving an investigational agent or used an investigational 
device for pancreatic cancer (or otherwise) within 28 days of the first dose of study drug. 
 
5.2.4 Patients with a history of prior treatment with anti-PD-1, anti-PD-L1, anti-PD-L2, anti-
CTLA4 antibodies or any other antibody or drug specifically targeting T-cell costimulation 
or immune checkpoint pathways. 
 
5.2.5 Patient has completed more than 1 month or 1 cycle (28 days) of chemotherapy. 
 
5.2.6 Has a diagnosis of immunodeficiency, is receiving systemic steroid therapy, or is receiving 
any other form of immunosuppressive therapy. 
 


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5.2.7 Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. 
with use of disease modifying agents, corticosteroids or immunosuppressive drugs). 
Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement 
therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic 
treatment. Any patient bearing an allograft is not eligible. 
 
5.2.8 Has a known additional histologically confirmed malignancy that is likely to be life-
limiting in the opinion of the treating investigator, interfere with the evaluation of 
pancreatic cancer treatment response, or is likely to require treatment that would interfere 
with the treatment of the patient’s pancreatic cancer. Superficial bladder cancer, non-
melanoma skin cancers, or low grade prostate cancer not requiring therapy would not 
exclude participation in this trial. 
 
5.2.9 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to agents used in study: 
 
Nivolumab 
 
Cyclophosphamide 
 
GM-CSF, hetastarch, corn, dimethyl sulfoxide, fetal bovine serum, trypsin (porcine 
origin), yeast or any other component of the GVAX vaccine. 
 
5.2.10 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. 
 
5.2.11 Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or 
psychiatric illness/social situations that would limit compliance with study requirements. 
 
5.2.12 Pregnant or breastfeeding. 
 
5.2.13 Has a known diagnosis of human immunodeficiency virus (HIV), active tuberculosis (TB), 
active hepatitis B (e.g., HBsAg reactive) or hepatitis C (patients who are hepatitis C 
antibody positive may be enrolled if they have a confirmed negative viral load at 
screening). 
 
5.2.14 Patient is on supplemental home oxygen. 
 
5.2.15 Patient is unwilling or unable to follow the study schedule for any reason. 
 
5.2.16 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. 
 
5.2.17 Presence of any tissue or organ allograft, regardless of need for immunosuppression, 
including corneal allograft. Patients with a history of allogeneic hematopoietic stem cell 
transplant will be excluded. 
 


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5.3 
Inclusion of Women and Minorities 
 
Both men and women of all races and ethnic groups are eligible for this trial.  
 
 
6. REGISTRATION PROCEDURES 
 
6.1 
General Guidelines 
 
Eligible patients will be entered on study centrally at the Sidney Kimmel Comprehensive 
Cancer Center at the Johns Hopkins University by the Lead Study Coordinator. All sites 
should email
 to verify drug availabilities.  The fax cover 
sheet, Registration Form, and Eligibility Worksheet will be supplied to each participating 
site. 
 
If a patient does not receive protocol therapy following registration, the patient’s 
registration on the study may be canceled.  The Study Coordinator should be notified of 
cancellations as soon as possible. 
 
6.2 
Registration Process 
 
To register a patient, the following de-identified documents should be completed by the 
Research Nurse or Study Coordinator and e-mailed to
 
 Fax cover sheet 
 Registration Form 
 Signed patient consent form 
 HIPAA authorization form 
 Eligibility Screening Checklist 
 Copy of required screening tests and scans 
 
The Research Nurse or Study Coordinator at the participating site will then e-mail 
 to verify eligibility.  To complete the registration process, 
the Lead Study Coordinator will: 
 Assign a patient study number 
 Register the patient on the study 
 Fax or e-mail the patient study number to the participating site 
 Call or e-mail the research nurse or data manager at the participating site and 
verbally confirm registration. 
 
7. TREATMENT PLAN 
 
7.1 
Agent Administration 
 
Treatment will be administered on an outpatient basis.  Dosing delays are described in 
Section 8.2.  After completing course of standard chemotherapy (2-8 cycles) 


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(FOLFIRINOX), subjects will receive two cycles of combined immunotherapy (nivolumab 
and Cy/GVAX). The combination immunotherapy should begin 2-4 weeks after last dose 
of FOLFIRINOX. Each cycle of combined immunotherapy consists of nivolumab and Cy 
on day 1, and GVAX on day 2, of a 21-day cycle. SBRT will be administered for 5 or 6 
days concurrently with the start of the second cycle of combination immunotherapy. After 
receiving the first two treatments of immunotherapy, patients will be reevaluated for 
surgery.  If eligible for surgery, they will undergo definitive resection. Following surgery 
(or if they do not receive surgical resection), they will resume standard of care management 
for their pancreatic cancer, which may consist of adjuvant chemotherapy.   
 
Table 1: Study Regimen 
 
Agent 
Premedications, Precautions Dose 
Route 
Cyclophosphamide 
Subjects may be pre-
medicated with anti-emetics
200 mg/m2 in 
100 mL NS
IV infusion 
over 30 minutes
GVAX 
Lidocaine based topical 
anesthetic cream (approx 
2.5gms/site at least 1 hour 
prior to vaccination)
5x108 cells 
Six intradermal 
injections 
nivolumab 
No prophylactic pre-
medications unless indicated 
by previous experience in an 
individual subject
240mg (flat 
dose) 
IV over 60 
minutes 
Infusion times are approximate (+/- 10 min) and may need to be adjusted based on subject 
tolerability. 
 
Please see Section 8.2 for guidance regarding dosing delays. In the case that a participant 
develops intolerance or side effect that is attributable to one agent (for example, intolerance 
only to nivolumab) during cycle 1 of immunotherapy, the participant may choose to 
continue treatment only with the other active agent(s) on study as otherwise indicated. 
 
7.1.1 FOLFIRINOX 
 
FOLFIRINOX is a standard treatment for PDAC, and treatment may be may be modified 
based on local treatment standards and guidelines as appropriate. FOLFIRINOX 
chemotherapy consists of 1) FOL – folinic acid (leucovorin), 2) F – fluorouracil (5-FU), 3) 
IRIN – irinotecan, and 4) OX – oxaliplatin. General recommendations for treatment with 
FOLFIRINOX are provided here (see Conroy et al. 5 ). Patients who are unable to receive 
FOLFIRINOX or are intolerant to it may be switched to another standard chemotherapy 
regimen (gemcitabine/Abraxane 3>) at the discretion of the patient’s treating oncologist for 
the remaining portion of the standard chemotherapy portion of the study. Patients are 
considered to have completed the standard chemotherapy portion of the study when they 
have completed at least two 28-day cycles of FOLFIRINOX, or have completed at least 
two months of standard chemotherapy. It is recommended that patients receive four cycles 
of FOLFIRINOX but they may receive anywhere from two to eight cycles. 
 


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7.1.2 GM-CSF Vaccine  
 
The vaccine consists of equal numbers (2.5 x 108 each) of Panc 6.03pcDNA1GM-CSF and 
Panc 10.05 pcDNA1/GM-CSF combined into a single vaccination. Each of the vaccine 
components consists of a cultured, irradiated, allogeneic pancreatic tumor cell line that has 
been genetically modified with a plasmid vector encoding the cDNA for human GM-CSF. 
Vaccine cells from each pancreas tumor cell line frozen at 1.25 x108 cells/vial (2 vials per 
cell line) in an injectable formulation (6% hetastarch, 2% human serum albumin, 5% 
dimethyl sulfoxide [DMSO]) will be thawed on the day of vaccination and taken up into 
syringes. Each vaccination will consist of six total intradermal injections, two each in the 
right and left upper thighs, and two in the non-dominant arm. In the event that the specified 
limb is contraindicated, the dominant arm may be used.  A-lidocaine based topical 
anesthetic cream will be applied to the injection site at least 1 hour prior to vaccination to 
diminish the discomfort associated with intradermal injections. 
 
7.1.3 Cy (CytoxanR)  
 
The single intravenous (IV) dose of 200 mg/m2 Cy is chosen based on our data showing 
that this single low IV dose given with a GM-CSF-secreting breast cancer vaccine is 
effective in reducing Treg levels in the PDA TME and facilitating enhanced T cell 
activation. Cy is a FDA-approved standard chemotherapy agent.  Subjects may be pre-
medicated prior to administration with anti-emetics per institutional guidelines. Subjects 
should be observed for a minimum of 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 IND 
Sponsor. 
 
Dosing calculation based on weight: 
 
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 
 
7.1.4 Nivolumab (OPDIVO ®, BMS-936558; MDX-1106)  
 
This is a is a potent and selective monoclonal antibody that binds to the PD-1 receptor and 
blocks its interaction with PD-L1 and PD-L2, thereby releasing PD-1 pathway-mediated 
inhibition of the immune response, including anti-tumor immune response.  It is FDA-
approved for treating metastatic melanoma, metastatic non-small cell lung cancer 
(NSCLC), Hodgkin lymphoma, recurrent or metastatic squamous cell carcinoma of the 
head and neck, and kidney cancer. In this study, nivolumab will administered IV over 60 
minutes at 240mg (flat dose). The drug can be diluted with 0.9% normal saline, USP or 5% 
Dextrose Injection, USP to protein concentrations as low as 1 mg/mL for delivery but the 
total drug concentration of the solution cannot be below 0.35 mg/ml. It is not to be 
administered as an IV push or bolus injection. At the end of the infusion, flush the line with 
a sufficient quantity of normal saline. Antiemetic medications should not be routinely 
administered prior to dosing except as indicated by patient’s prior reaction. See Section 


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7.2.3.1 for subsequent premedication recommendations following a nivolumab-related 
infusion reaction. 
 
7.1.5 SBRT and Fiducial placement  
 
Fiducial Placement 
1) Treatment on this protocol requires placement of 1-5 gold (99.9% pure, 1-5 mm length, 
visicoils, or other) fiducials for targeting purposes.  The fiducials will be used as 
surrogates for visualizing and targeting the daily tumor position during treatment. The 
fiducials will be placed directly into the tumor and/or periphery under endoscopic 
ultrasound or CT guidance. Fiducials may be implanted prior to enrollment as this is 
an acceptable standard of care procedure for any patient receiving radiotherapy for 
pancreatic cancer. If a patient had an attempted surgical resection that was aborted, 
fiducials or surgical clips may have been implanted intraoperatively, which can 
subsequently be used if they can be sufficiently visualized during daily image guidance. 
If fiducials are not placed intraoperatively or prior to enrollment, placement will be 
done and is expected to be done on an outpatient basis.  In rare occurrences when 
fiducials/clips cannot be placed, patients may be treated at the discretion of the PI. 
2) If treatment is conducted on a linear accelerator with sufficient image guidance that 
allows daily visualization of target positioning without the need for fiducials (i.e. CT 
on rails or an MRI-guided linear accelerator), treatment without fiducials will be 
allowed. 
 
SBRT Simulation 
1) Simulation should be done following placement of fiducials; however, this may 
vary and is at the discretion of the principal investigator. 
2) Typically, patients will be positioned supine in an Alpha Cradle, Vac-loc, or 
equivalent immobilization device that will be custom-made for each patient. 
3) Patients should fast at least 2 hours prior to CT simulation, and similar 
instructions should be given at the time of treatment. Specific instructions 
regarding duration of fasting will be left to the discretion of the treating radiation 
oncologist and will be individualized to the patient. 
4) IV should be used for simulation, unless the patient has renal insufficiency or an 
iodine allergy. Oral contrast may also be used for small bowel visualization. MRI 
simulation can also be performed to assist in target delineation. 
5) Motion management can be addressed using respiratory gating, breath-hold, 
abdominal compression, and/or respiratory tracking.  Specific motion management 
decisions will be made by the treating radiation oncologist. 
6) Simulation CT slice thickness must be no greater than 3mm. 
7) As long as the specified dosimetric parameters for SBRT are reached, patients may 
be treated on any IGRT-enabled machine. 
8) All patients must start Linac based SBRT within 4 weeks of the simulation scan. 
 
 
SBRT Treatment Planning 


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1) An SBRT treatment plan will be developed using the preferred institutional 
treatment planning system. Institutional standards for radiation quality 
assurance and radiation delivery will be utilized.  
2) The gross tumor volume (GTV) will consist of the primary tumor, as defined on 
all available contrasted diagnostic imaging (CT/MRI/PET), along with CT 
simulation scan. 
3) Consideration will also be given to include the following, either in the GTV or a 
separate clinical tumor volume (CTV) 
A. The full circumference of involved vasculature 
B. Suspicious regional nodes (greater than 1.0cm or other suspicious 
features) 
C. The initial extent of disease involvement prior to initiation of 
chemotherapy 
D. At-risk elective nodal basins such as the celiac, SMA, SMV, PV, and para-
aortic nodal basins (Dholakia et al., IJROBP, 2013), particularly if there is 
concerning stranding or other suspicious features on imaging. 
4) Decisions regarding target coverage will factor in the ability to safely meet dose 
constraints. 
5) Depending on the motion management strategy employed, subsequent volumes 
and margins will be constructed. For free-breathing treatment, an internal tumor 
volume (ITV) will be constructed to reflect the volume through which the target 
moves with respiration. For active-breathing control, multiple CT scans may be 
taken at the time of simulation to understand reproducibility of this approach. A 
planning tumor volume (PTV) will be further created to capture additional 
uncertainty in patient positioning during and between treatments. The PTV 
margin will depend on the specific clinical circumstances, but will likely be on the 
order of 2-5mm. 
6) Critical structures to be contoured include the stomach, duodenum, bowel, left 
and right kidneys, liver, and spinal cord. Separate contours can be created for 
large and small bowel. Radiation dose to the adjacent normal tissue will be 
minimized. Dose constraints to be used include: 
A) Stomach: required: V33<1cc; recommended: V20<20cc 
B) Duodenum: required: V33<1cc; recommended: V20<20cc 
C) Other small bowel: required V33<1cc; recommended V20<20cc 
D) Large bowel: required V33<1cc; recommended V20<20cc 
E) Liver:  50% should be limited to <12 Gy 
F) Right Kidney:  V12<25% 
G) Left kidney: V12<25% 
H) Spinal cord: max dose <8 Gy 
7) Coverage of target volumes (i.e. GTV, CTV, ITV, PTV, etc.) with 25 Gy and 33 
Gy isodose lines will be assessed 
A)  If coverage is poor due to dose constraints, the radiation oncologist may 
decide that the patient is a poor candidate for SBRT. A minimum of 100% of 
coverage of the GTV with 25 Gy must be achieved to be eligible for the protocol. 
8) Contours of the fiducials used for target localization will be generated on the 
applicable image sets, to be used for patient set-up on treatment. 
 


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If this constraint cannot be met, the patient should be removed from the protocol. 
 
SBRT Treatment Delivery 
7) Patients will receive 5 fractions of 6.6 Gy delivered over consecutive business days, 
as delineated above.  Ideally, all 5 fractions should be delivered Monday through 
Friday; however, treatment may be delivered over 2 weeks, as long as the patient 
receives at least two fractions per week.  
8) Daily treatment set-up will include the following steps: 
A) Patients should be positioned as in the simulation 
B) Volumetric image-guidance will be employed to align the patient, initially to 
bony landmarks, follow by a shift to the tumor/fiducials 
C) Target, OAR, PRV, and isodose line structures can be sent to the machine to 
allow assessment of daily dose deposition and any additional shifts required or 
whether it is safe to proceed with treatment. 
D) Intra-fraction image guidance can be assessed to allow intra-fraction 
adjustment of positioning  
 
7.1.6 Definitive Surgical Resection 
 
Following the interventions/treatments above, patients who are determined to have 
resectable disease will undergo a definitive surgical resection. The surgical procedure 
performed will result in either a R0, R1 or R2 resection as determined by the operating 
surgeon. 
 
7.2 
General Concomitant Medication and Supportive Care Guidelines 
 
7.2.1 Cyclophosphamide (Cy) 
 
Acute reactions will be managed using standard therapy for acute drug reactions as per 
institutional guidelines. 
 
7.2.2 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. 
 
7.2.3 Nivolumab 
 
Nivolumab is a fully human monoclonal immunoglobulin (Ig) G4 antibodies. Subjects 
should be closely monitored for potential AEs during antibody infusion and potential AEs 


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28 
 
throughout the study. 
 
7.2.3.1 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 IND Sponsor and BMS as an 
SAE if the 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) 
 
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 paracetamol 325 to 1000 mg (acetaminophen) 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 paracetamol 325 to 1000 mg 
(acetaminophen); 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, then 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 electronic case report form (eCRF). 
The following prophylactic premedications are recommended for future infusions: 
diphenhydramine 50 mg (or equivalent) and/or paracetamol 325 to 1000 mg 
(acetaminophen) should be administered at least 30 minutes before additional nivolumab 
administrations. If necessary, corticosteroids (recommended dose: up to 25 mg of IV 
hydrocortisone or equivalent) may be used.  
 
For Grade 3 or Grade 4 symptoms: (Severe reaction, Grade 3: prolonged [ie, not rapidly 
responsive to symptomatic medication and/or brief interruption of infusion]; recurrence of 
symptoms following initial improvement; hospitalization indicated for other clinical 
sequelae [eg, renal impairment, pulmonary infiltrates]). Grade 4: (life threatening; pressor 
or ventilatory support indicated).  


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29 
 
 
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 (eg, appearance of a 
localized or generalized pruritis within 1 week after treatment), symptomatic treatment 
may be given (eg, oral antihistamine, or corticosteroids).  
 
Please refer to Section 8.2 for guidelines regarding GVAX treatment delays following a 
nivolumab infusion-related reaction. 
 
7.2.3.2 Nivolumab-Related Adverse Events  
 
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 CRF. Identification and treatment of nivolumab-related AEs 
can be found in Appendix B. Additional guidance can be found in the nivolumab 
Investigator’s Brochures (IB).  
 
7.3 
Prohibited and Restricted Therapies 
 
Patients may not use any of the following agents during the study: 
 
- 
Any non-study anticancer or immunotherapy agent (investigational or non-
investigational) 
- 
Any other investigational agents 
- 
Systemically active steroids can be used but should be reported to the Principal 
Investigator and IND Sponsor.  Steroid treatment should be completed at least 14 days 
prior to resuming study-related treatments unless approval to resume sooner is obtained 
from the IND Sponsor (See Section 8.2 for dosing delays for steroids) 
- 
Filgrastim (Neupogen® or G-CSF) or sargramostim (Leukine® or GM-CSF) 
- 
Live vaccines (examples of live vaccines include, but are not limited to: measles, 
mumps, rubella, chicken pox, yellow fever, rabies, BCG, and typhoid [oral] vaccine). 
Seasonal influenza vaccines for injection are generally killed virus vaccines and are 


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allowed. However, intranasal influenza vaccines (e.g. Flu-Mist®) are live attenuated 
vaccines, and are not allowed. 
- 
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. 
 
7.4 
Definition of an Overdose for this Protocol 
 
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 
WOCBP, Contraception, Use in Pregnancy, Use in Nursing: 
 
7.5.1 WOCBP 
 
A WOCBP is defined as any female who has experienced menarche and who has not 
undergone surgical sterilization (hysterectomy, bilateral oophorectomy, or bilateral tubal 
ligation) and is not postmenopausal. Menopause is defined as 12 months of amenorrhea in 
a woman over age 45 years in the absence of other biological or physiological causes.  
 
7.5.2 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 (a woman who is ≥45 years of age 
and has not had menses for greater than 2 years 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 4) 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 5 months after the last 
dose of study medication.  Male subjects enrolled in this study must also agree to use an 
adequate method of contraception starting with Visit 1 through 7 months 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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31 
 
 
 
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 
 
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 medication 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. 
 
7.5.3 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 treatment.  The study team will contact the 
subject at least monthly and document the subject’s status until the pregnancy has been 
completed or terminated.   
 
The investigator must immediately notify the IND Sponsor and BMS of any pregnancy 
using the Pregnancy Surveillance Form within 24 hours of notification and in accordance 


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with the SAE reporting procedures described in Section 9.5. Any pregnancy that occurs in 
a female partner of a male study participant should also be reported to the IND Sponsor 
and BMS. 
 
Protocol required procedures for study treatment 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 perinatal and 
neonatal outcome and where applicable, offspring information must be reported on the 
Pregnancy Surveillance Form.  
 
7.5.4 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. 
 
7.6 
Nivolumab Treatment Discontinuation 
 
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 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 OR requires systemic treatment 
 
 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 of 
any duration requires discontinuation 
 Grade 3 treatment-related endocrinopathies adequately controlled with only 
physiologic hormone replacement do not require discontinuation 
 Grade 3 treatment-related laboratory abnormalities do not require treatment 
discontinuation except: 
 
o Grade 3 treatment-related thrombocytopenia > 7 days OR 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 


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33 
 
 
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: 
 Grade 4 amylase or lipase abnormalities that are not associated with 
symptoms or clinical manifestations, or radiographic signs of pancreatitis.  
 Isolated grade 4 electrolyte imbalances/abnormalities that are not associated 
with clinical sequelae and are corrected with supplementation/appropriate 
management within 72 hours of their onset. 
 Grade 4 lymphopenia and leukopenia. 
 Grade 4 treatment-related endocrinopathy adverse events, such as adrenal 
insufficiency, ACTH deficiency, hyper- or hypothyroidism, or glucose 
intolerance, which resolve or are adequately controlled with physiologic 
hormone replacement (corticosteroids, thyroid hormones) or glucose-
controlling agents, respectively, may not require discontinuation after 
discussion with and approval from the IND Sponsor. 
 
7.7 
Unacceptable Toxicities 
 
Monitoring 
for 
unacceptable 
toxicities 
will 
occur 
during 
the 
experimental 
radioimmunotherapy portion of the study (initiation of SBRT plus Cy/GVAX/nivolumab 
until the Off Treatment Visit) and only toxicities probably associated with this therapy will 
be reported as an unacceptable toxicity (Section 15.4). Since FOLFIRINOX and surgery 
are a standard of care for this disease, toxicity commonly attributable to the FOLFIRINOX, 
surgery, or postoperative course will not be reported as an unacceptable toxicity. During 
this portion of the study, unacceptable toxicities are defined as: 
 
Treatment-related ≥ grade 4 AEs, or  
 
Treatment-related grade 3 AEs that do not improve to ≤ grade 2 under therapy 
within 2 weeks. 
 
Exceptions include: 
 
Asymptomatic amylase and lipase elevation 
 
Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated with 
clinical sequelae and are corrected with supplementation/appropriate management 
within 72 hours of their onset. 
 
Grade 3 or 4 lymphopenia or leukopenia 
 
< Grade 3 skin rash treated with steroids for less than 4 weeks  
 
≥ 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.  
 
Grade 3 endocrinopathies adequately controlled with only physiologic hormone 
replacement.  Grade 4 endocrinopathy adverse events, such as adrenal 
insufficiency, ACTH deficiency, hyper- or hypothyroidism, or glucose intolerance, 
which resolve or are adequately controlled with physiologic hormone replacement 


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(corticosteroids, thyroid hormones) or glucose-controlling agents, respectively, 
may not require discontinuation after discussion with and approval from the IND 
Sponsor. 
 
Unexpected Grade 3 or greater laboratory abnormalities should be repeated within 24-72 
hours if clinically indicated and monitored as necessary to determine if the event meets the 
toxicity criteria. The proportion of unacceptable toxicities will be continuously monitored.  
See Section 15.4 for details of toxicity monitoring.  
 
7.8 
Criteria for Removal from Treatment 
 
A subject must be discontinued from the trial for any of the following reasons: 
 
The patient or legal representative (such as a parent or legal guardian) withdraws 
consent for follow-up. 
 
Termination of the study 
 
Patient is lost to follow up 
 
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: 
 
Development of distant metastatic disease 
 
The patient or legal representative (such as a parent or legal guardian) withdraws 
consent for treatment but not follow-up 
 
Intercurrent illness that prevents further administration of treatment, 
 
Unacceptable adverse event(s) (see Section 7.8) 
 
Need for >2 dose delays due to the same drug-related toxicity as per the dose delay 
guidelines (see Section 8.2).   
 
If in the opinion of the Investigator, a change or temporal or permanent discontinuation 
of therapy would be in the best interest of the patient.  The Sponsor should be included 
in this decision, 
 
Noncompliance with trial treatment or procedure requirements, 
 
Patient becomes pregnant. All women of child bearing potential should be instructed 
to contact the investigator immediately if they suspect they might be pregnant (e.g., 
missed or late menstrual period) at any time during study participation. 
 
Patient is lost to follow-up 
 
In the case that a participant develops intolerance or side effect that is attributable to one 
agent (for example, intolerance only to nivolumab) during cycle 1 of immunotherapy, the 
participant may choose to continue treatment only with the other active agent(s) on study 
as otherwise indicated. 
 


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7.9 
Off Study Treatment Visit 
 
Patients are considered off study treatment beginning 60 days after surgical resection or 
after a decision not to resect has been made. Follow-up visits will be scheduled at the 
discretion of the patient’s local oncologist and the results sent to us if the patient agrees. 
All attempts will be made to obtain disease-free and overall survival data on each patient.  
 
A mandatory Off Study Treatment/Safety Follow-Up Visit should be performed 
approximately 30-60 days after surgical resection has been performed (or 30 days +/- 7 
days after the last infusion of study medication in patients who are not a surgical candidate, 
or within 7 days prior to initiation of a new anti-cancer treatment, whichever comes first).  
All subjects will be followed for 30 days after their last dose of study drug for the 
development of AEs. 
 
The patient will be monitored for adverse events up to the mandatory Off Study 
Treatment/Safety Follow-Up Visit or to resolution of toxicity to Grade 0-1, whichever 
occurs later.  Surgical-related AEs will not be collected. 
 
7.10 
Duration of Follow Up 
 
All subjects should continue to be monitored for disease status at the discretion of the 
treating oncologist.  Subjects who complete or discontinue from treatment will be contacted 
(by phone or email) every three months (+/- 2 weeks) to monitor overall survival until 1) 
until death, 2) withdrawal of consent, or 3) study closure, whichever occurs first. 
Information of other cancer therapies after discontinuation from the study treatment will 
also be collected. In addition, SAEs that occur within 100 days (+14 day reporting window) 
of the end of treatment or before initiation of a new antineoplastic treatment should also be 
followed and recorded. 
 
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. 
  
Per the FDA requirement, all research patients treated with genetically modified products 
(pancreatic tumor vaccine) will be followed annually (+/- 2 months) for 2 years per 
protocol either at Johns Hopkins or locally until study termination. Follow up visits for 
study participants should include:  
 Detection of gene therapy-related delayed adverse events 
 Documentation of all exposures to mutagenic agents and other medicinal products 
 History, physical exam, or laboratory testing at minimum intervals of one year 
 Documentation of any of the following: 
-New malignancy(ies) 
-New incidence or exacerbation of a pre-existing neurologic disorder 
-New incidence or exacerbation of a prior rheumatologic or other autoimmune 
disorder 
-New incidence of a hematologic disorder 
 


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If consent is granted, patients at Johns Hopkins who chose to enroll will be followed for 
disease progression, survival and potential long term toxicity of gene therapy in an existing 
protocol entitled “Long term follow-up of patients who received lethally irradiated 
allogeneic pancreatic tumor cells transfected with the GM-CSF gene (IRB # 02-10-14-03, 
SKCCC J0248)”. Consent for this long-term follow up protocol may be obtained at any 
point during treatment on this protocol.  
 
8. DOSING DELAYS/DOSE MODIFICATIONS 
 
8.1 
Dose Modifications 
 
Dose modifications for the standard of care chemotherapy (eg FOLFIRINOX) is at the 
discretion of the treating medical oncologist.  Dose reduction or dose increase of Cy, 
GVAX, and nivolumab will not be permitted in individual patients.  
 
8.2 
Dosing Criteria for the investigational immunotherapy agents 
 
Dosing criteria for the standard of care chemotherapy (eg FOLFIRINOX) is at the 
discretion of the treating medical oncologist and is not be addressed in this protocol. This 
section pertains only to dosing criteria for the investigational immunotherapy. 
 
Dosing for the investigational immunotherapy will be delayed for any of the criteria listed 
below: 
 
 
AST, ALT > 3.0 x ULN  
 
Total bilirubin >1.5 x ULN (for patients with diagnosed Gilbert’s Syndrome, direct 
bilirubin should be within normal institutional limits) 
 
Hemoglobin < 8 g/dL 
 
ANC < 1000/uL  
 
Platelets < 80 x 103/uL 
 
 
Any > Grade 2 non-skin, drug-related adverse event, with the following exception: 
o Grade 2 drug-related fatigue does not require a treatment delay. 
o Grade 2 hypothyroidism or thyroiditis 
 
Any > Grade 3 skin, drug-related adverse event 
 
Any > Grade 3 drug-related laboratory abnormality with the following exceptions: 
o Grade 3 lymphopenia does not require dose delay 
o Any Grade ≥ 3 drug-related amylase or lipase abnormality that is not 
associated with symptoms or clinical manifestations of pancreatitis does not 
require dose delay.  
o Isolated grade 3 or 4 electrolyte imbalances/abnormalities that are not 
associated 
with 
clinical 
sequelae 
and 
are 
corrected 
with 
supplementation/appropriate management 
- 
Any adverse event, laboratory abnormality, or intercurrent illness which, in the 
judgment of the investigator, warrants delaying the dose of study medication 
 
Subjects who require delay of nivolumab should be re-evaluated weekly or more frequently 


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if clinically indicated and resume nivolumab dosing when re-treatment criteria are met. 
 
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 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 
 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 hyperglycemia, 
hypothyroidism and thyroiditis. 
 
8.3 
Treatment Delays 
 
Treatment delays for standard of care chemotherapy (eg FOLFIRINOX) are at the 
discretion of the treating medical oncologist. Patients are considered to have completed the 
standard chemotherapy portion of the study when they have completed two 28-day cycles 
of chemotherapy, or have completed at least two months of standard chemotherapy.  
 
The first cycle of Cy, GVAX, and nivolumab should optimally be administered within two 
to four weeks of receiving the last dose of chemotherapy. However, if necessary due to 
resolving adverse events related to chemotherapy or any other reason, the first cycle of 
Cy/GVAX/nivolumab may be delayed by up to 2 weeks (i.e. AST/ALT are not below 3x 
ULN). If the first cycle of Cy/GVAX/nivolumab is delayed by more than 2 weeks, the 
Principal Investigator must be contacted for further instructions on continued treatment 
versus preceding to definitive resection.   
 
The second cycle of Cy, GVAX, and nivolumab is to be administered approximately 3 
weeks after the first cycle. If the second cycle is delayed by more than 1 week, the Protocol 
Chair must be contacted for further instructions on continued treatment versus preceding 
directly to definitive resection. Additional delays or modifications to the treatment 
schedule must be approved by the Protocol Chair or the IND Sponsor. 
 
SBRT should ideally be administered over five days or six days, beginning concurrently 
with cycle 2 day 1 of Cy/GVAX/nivolumab. An attempt will be made to schedule C2D1 
on a Monday with a five-day treatment schedule, so that the patient may receive SBRT on 
a Monday-Friday schedule. If necessary, the start of SBRT may be delayed by up to 1 
week, and can be delivered over 2 weeks, as long as the patient receives at least 2 fractions 
per week. Longer delays must be approved by the Protocol Chair. If cycle 2 day 1 of 
Cy/GVAX/nivolumab is delayed, SBRT should also be delayed to occur on the same day 
as the immunotherapy treatment.  


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8.3.1 If a delay occurs between day 1 and 2 of an immunotherapy cycle: 
 
Nivolumab-related infusion reactions must resolve to baseline prior to administration 
of GVAX.   
 
Day 2 GVAX treatment and assessments can be resumed without repeating Day 1 study 
treatments (Cy and nivolumab) if the delay less than 72 hours. 
 
If the delay is longer than 72 hours and is in cycle 1, omit day 2 and proceed to cycle 2 
with a minimum of 2 weeks from the previous Day 1 treatment. This includes steroid 
treatment requiring at least a 14-day washout prior to resuming study-related 
treatments. 
 
If the delay is longer than 72 hours and is in cycle 2, omit day 2 and proceed to 
definitive resection on study as otherwise indicated. 
 
9. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
This study will use the descriptions and grading scales found in the revised National Cancer 
Institute Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 for 
adverse 
event 
reporting 
that 
can 
be 
found 
at 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.   
 
Information about all adverse events, 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.  
 
The PI has the primary responsibility for continuous internal monitoring for safety, protocol 
compliance, and identification, grading, coding, and required reporting of all anticipated and 
unanticipated adverse events and protocol problems. Although this responsibility is usually 
shared among the PI, research nurse, and data manager, the PI is ultimately responsible for 
grading and attribution of all events. 
 
9.1 
Definitions 
 
9.1.1 Adverse Event (AE) 
 
An adverse event 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 adverse events if they worsen after starting 
the study treatment (any procedures specified in the protocol). The adverse event profile of 
the standard chemotherapy has already been well characterized. Therefore, adverse events 
occurring during the 2-8 cycles of standard chemotherapy portion of the study (before the 
initiation of the investigational agents, Cy/GVAX/nivolumab plus SBRT), will not be 
recorded. Additionally, expected progression of the disease being studied will not be 


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recorded as an adverse event. Abnormal laboratory values or test results constitute adverse 
events only if they induce clinical signs or symptoms or require therapy. 
 
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 adverse events. A grade 1 or 2 clinical laboratory abnormality should 
be reported as an adverse event only if it is considered clinically significant by the 
investigator (induce clinical signs or symptoms or require therapy). 
 
9.1.2 Serious Adverse Event (SAE) 
 
A serious adverse event 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) > 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 Supplemental 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 [eg, 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.) 
 
Is a new cancer (that is not a condition of the study) 
 
Is associated with an overdose 
 
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 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 serious adverse events are hospitalizations for the:  
 
 
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 
(eg, routine colonoscopy)  


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 
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 (eg, 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. 
 
9.2 
Relationship and Grading 
 
The relationship between the AE and the study treatment will be determined by the 
principal investigator. 
 
 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.  
 
 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. 
 
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 


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• 
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. 
 
9.3 
Expectedness 
 
Unexpected adverse event: An adverse event, which varies in nature, intensity or frequency 
from information on the investigational drug/agent provided in the Investigator’s Brochure, 
package insert or safety reports. Any adverse event that is not included in the informed 
consent is considered “unexpected”.  
 
Expected (known) adverse event: An adverse event, which has been reported in the 
Investigator’s Brochure. An adverse event is considered “expected”, only if it is included 
in the informed consent document as a risk. 
 
9.4 
Handling of Expedited Safety Reports 
 
In accordance with local regulations, the IND Sponsor will notify investigators of all SAEs 
that are unexpected (i.e., not previously described in the Investigator’s Brochure (IB) 
and/or package inserts), and possibly, probably, or definitely related to CY, GVAX 
pancreas vaccine, 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.  
 
9.5 
Reporting 
 
9.5.1 Adverse Events and Serious Adverse Events 
 
All AEs (both expected and unexpected) will be captured on the appropriate study-specific 
CRFs. All adverse events experienced by subjects will be collected and reported from the 
first dose of the investigational agent (Cy/GVAX/nivolumab), throughout the study, and 
will be followed for 28 days after last dose of study drug unless related to the 
investigational agent. Adverse events that occur prior to the experimental treatment (i.e. 
during the standard chemotherapy portion of the study) will not be collected or reported. 
Subjects who have an ongoing adverse event related to the study drug(s) may continue to 
be periodically contacted by a member of the study staff until the event is resolved or 


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determined to be irreversible by the investigator. AEs that are an unacceptable toxicity will 
be reported to the IND Sponsor (Dr. Elizabeth Jaffee, e-mail:
 and 
 within 24 hours once identified as such. 
 
All SAEs (including deaths) occurring from the first dose of the study drug through 100 
days (+ 14 day reporting window) after the last dose of nivolumab or within 7 days prior 
to initiation of a new antineoplastic treatment (whichever comes first) will be collected and 
reported. SAEs will be reported promptly to the IND sponsor (e-mail: 
 
and 
 and BMS (e-mail: 
 
within 24 hours of recognition of the SAE (Appendix C).  If this falls on a weekend or 
holiday, an email notification is acceptable but must be followed by an SAE reporting form 
on the next business day.  
 
9.5.2 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. 
 
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 or dies 
 
Once the event is resolved, the appropriate AE or SAE report page will be updated. The 
investigator will also ensure that the follow-up includes any supplemental information that 
may explain the causality of the event(s). New or updated information will be recorded on 
the originally completed AE or SAE report, with all changes signed and dated by the 
investigator or designee.  The updated AE or SAE report will then be signed by the 
investigator and resubmitted to the IND Sponsor. 
 
9.5.3 Reconciliation of SAEs 
 
The Protocol Chair will reconcile the clinical database SAE cases (case level only) 
transmitted to the IND Sponsor and BMS Global Pharmacovigilance 
). Frequency of reconciliation should be approximately 
every 3 months and prior to the database lock or final data summary. BMS GPVE will 
email, upon request from the Investigator, the reconciliation report. Requests for 
reconciliation should be sent to
 
The data elements listed on the BMS GPVE reconciliation report will be used for case 
identification purposes. If the Sponsor determines a case was not transmitted to the IND 
Sponsor and/or BMS GVPE, the case should be sent immediately to the IND Sponsor and 
BMS.  
 
9.5.4 Overdose 
 


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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. 
 
9.5.5 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. Potential drug induced liver 
injury is defined as: 
 
 
ALT or AST elevation > 3 times upper limit of normal (ULN)  
 
AND 
 
 
Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum 
alkaline phosphatase) 
 
AND 
 
 
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. 
 
9.5.6 Pregnancy Reporting 
 
Although pregnancy and lactation are not considered AEs, 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 120 days after the 
last dose of nivolumab. This also includes the pregnancy of a male subject's female partner 
who has provided written consent to provide information regarding pregnancy, that occurs 
during the trial or within 120 days of completing the trial.  All subjects who become 
pregnant must be followed to the completion/termination of the pregnancy.  Pregnancy 
outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, blighted 
ovum, fetal death, intrauterine death, miscarriage and stillbirth must be reported as SAEs 
(Important Medical Events).  If the pregnancy continues to term, the outcome (health of 
infant) must also be reported to the IND sponsor. 
 
9.5.7 Institutional Review Board (IRB) and Institutional Biosafety Committee (IBC) 
 
All SAEs will be reported to the IRB and IBC per institutional standards. Follow-up 
information will be submitted to the IRB and IBC as soon as relevant information is 
available. 
 


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9.5.8 Food and Drug Administration (FDA) 
 
All reporting to the FDA will be completed by the IND Sponsor. 
 
9.5.8.1 
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 accordance 
with regulation 21 CFR § 312.32.  All safety reports previously filed with the IND 
concerning similar events should be included in the analysis.  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. 
 
9.5.8.2 
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. 
 
9.5.8.3 
Recombinant DNA Advisory Committee (RAC) 
 
Unexpected SAEs believed to be possibly 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. 
 
9.6 
Special considerations for adverse events that occur during the surgery and 
postoperative course 
 


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Pancreatic surgery is one of the highest-risk procedures, requires prolonged hospitalization, 
has significant toxicities and is commonly associated with complications and 
comorbidities.  It is a standard of care, therefore, is not part of this research study.  From 
the day of surgery throughout the postoperative course day 30, participants will be 
primarily followed by their primary surgeons for monitoring and managing the 
complications and comorbidities attributable to the surgery.  Table 2 summarizes 
complications commonly associated with the pancreatic surgery based on several published 
analyses of more than 1000 patients at Johns Hopkins Medicines and other institutions.  A 
normal, uncomplicated postoperative course is still commonly associated with laboratory 
abnormalities (grade1/2 AEs and occasionally grade 3 AEs) without needs of therapeutic 
interventions.  At least one complication was associated with 58.5% of patients based on a 
recent 
analysis 
of 
a 
consecutive 
series 
of 
633 
patients 
undergoing 
pancreaticoduodenectomy at Johns Hopkins Medicine between February 2003 and August 
2005.   Grade I, II, III complications were common, in 10%, 30%, 13.5% of the patients, 
respectively.   These complications and comorbidities are commonly associated with 
toxicities and laboratory abnormalities of CTCAE grade 3 and even grade 4.  By contrast, 
Grade IV and V complications are relatively uncommon, in 3.0% and 2.0% of the patients, 
respectively (Table 3).   
 
 


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Table 2 Complications after Pancreaticoduodenectomy  
Anastomotic leak, pancreas
Wound infection
Delayed gastric emptying
Hemorrhage, immediate postoperative or delayed
Intraabdominal abscess
Fascial dehiscence or evisceration
Supraventricular arrhythmia
Urinary tract infection
Anastomotic leak, biliary
Pancreatitis
Hypotension, shock
Cellulitis
Clostridium difficile colitis
Congestive heart failure, left ventricular dysfunction
Myocardial infarction
Renal failure
Apnea or hypoxia
Atelectasis
Catheter-related infection
Deep venous thrombosis
Dehydration
Anastomotic leak, intestinal
Gastrointestinal bleeding
Pleural effusion
Pneumonitis
Sepsis
Acute respiratory distress syndrome 
Angina, cardiac ischemia
Aspiration
Cardiopulmonary arrest
Catheter-related infection
Constipation
Delerium tremens
Fever
Fluid imbalance
Gastroesophageal reflux disease
Congestive heart failure
Ileus
Interstitial pneumonitis and fibrosis
Prolonged intubation
Salivary gland infection
Small bowel obstruction
 


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Table 3 Classification of Surgical Complication Adopted for Pancreatic Surgery 
 
Pancreatic surgery is commonly associated with laboratory abnormalities in blood cell 
counts, serum electrolytes, liver function, and renal function, etc., with a range of severity 
from grade 1 to grade 4 by CTCAEv3.0 criteria.  Grade I-III complications are common; 
therefore, laboratory abnormalities associated with a normal postoperative course or Grade 
I-III complications are considered to be within the commonly expected range of grades of 
severity (Table 4).   Laboratory abnormalities beyond these commonly expected ranges of 
severity should be considered uncommon. Although Grade IV and V complications have 
still occurred, any SAE including laboratory abnormalities associated with Grade IV/V 
complications should be considered uncommon.   
 
 
 


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Table 4 Laboratory abnormalities commonly associated with pancreatic surgery 
Lab test Abnormality      Ranges of severity by CTCAEv3.0 criteria 
Amylase
Elevated
Grade 1-4
Lipase
Elevated
Grade 1-4
Bilirubin
Elevated
Grade 1-4
AST 
Elevated
Grade 1-4
ALT
Elevated
Grade 1-4
Albumin
Decreased
Grade 1-3
Glucose
Elevated
Grade 1-4
Glucose
Decreased
Grade 1-4
Alk Phosphatase
Elevated
Grade 1-4
Creatinine
Elevated
Grade 1-3
Glomerular filtration rate 
Decreased
Grade 1-3
Bicarbonate
Decreased
Grade 1-4
Acidosis
Increased
Grade 1-4
Alkylosis
Increased
Grade 1-4
CPK
Elevated
Grade 1-4
WBC
Elevated
Not graded by CTCAE
Hemoglobin
Decreased
Grade 1-3
Platelets
Elevated
Not graded by CTCAE
Platelets
Decreased
Grade 1-3
Sodium
Elevated
Grade 1-3
Sodium
Decreased
Grade 1-3
Potassium
Elevated
Grade 1-3
Potassium
Decreased
Grade 1-3
Magnesium
Elevated
Grade 1-3
Magnesium
Decreased
Grade 1-3
Phosphate
Elevated
Grade 1-3
Phosphate
Decreased
Grade 1-4
Calcium
Elevated
Grade 1-3
Calcium
Decreased
Grade 1-4
 
Therefore, during this period, first, the study will be focused on monitoring and reporting 
the complications with uncommon grades of severity such as Grade IV and Grade V 
complications by criteria used at Johns Hopkins (Table 3).  The severity of any SAEs 
associated with such grades of complications should be considered uncommon.  Second, 
any unusual complication not seen commonly with this operation will be reported.  Third, 
the study will also be focused on monitoring and reporting any laboratory abnormality 
beyond the common ranges of severity (Table 4).  Fourth, the study will also be focused 
on monitoring and reporting any type of toxicity not commonly attributable to the surgery 
or postoperative course.   These events will be recorded as described in Section 9.1 and 
their severities will still be categorized by NCI CTCAEv4.0 criteria.  Relationship of these 
events to the investigational drug will be determined by the principal investigator together 
with surgical co-investigators of the study team and, if necessary, with primary surgeons, 
and will be categorized as described in Section 9.   Reporting of these events will follow 
the same guidelines described in Sections 9.5. 


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10. PHARMACEUTICAL INFORMATION 


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11. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
11.1 
Tumor Tissue Studies 
 
4-6 core tumor biopsies will be collected (if a subject’s tumor is thought to be reasonably 
safe and easy to biopsy) during scheduled endoscopy with fiducial placement at select sites.  
Additional tissue will also be requested of patients after completion of 2 doses of combined 
immunotherapy and SBRT via surgical resection specimen, or intraoperative biopsy (if 
surgery is attempted but aborted). Archival tumor samples may also be collected for every 
patient (slides and/or blocks). Detailed instructions for tissue collection, processing, and 
shipment are provided in the Laboratory Manual. 
 
The tissue samples will be banked for the evaluation of CD8+ T Cell effectors, MHC 1 
expression, PD-L1 expression on tumor and PD-L1 on tumor-infiltrating immune cells, 
and their associated immune suppressive pathways and other immune activation pathways 
to assess the effect of treatment upon the tumor microenvironment and the correlations 
between these immune parameters and clinical response. Immunohistochemistry, flow 
cytometry, quantitative PCR assays and microarray analysis will be employed.  In addition, 
to identify potential neoantigens as a result of radiation therapy, the banked tumor tissues 
will be used for whole exome sequencing (WES) to identify tumor-specific non-
synonymous mutations.  Peripheral Blood Lymphocytes (PBL) and tumor infiltrating 
lymphocytes (TIL), either directly from FFPE tumor sections, or following isolation, will 
be used for the TCR repertoire analysis by next-generation sequencing. 
 
 


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11.2 
Whole Blood for Peripheral Blood Lymphocytes (PBLs) 
 
Post-treatment expression of PD-1 and other lymphocyte activation markers will be 
measured and correlated with OS and DMFS.  Whole blood for PBL will be collected with 
each immunotherapy and after completion of immunotherapy at select sites.  Detailed 
instructions for blood collection, processing, and shipment are provided in the Laboratory 
Manual. PBL will be banked for measuring peripheral mesothelin-specific T cell responses 
as an established parameter of immune response to treatment with GVAX.  PBL will also 
be banked for an ELISPOT-based approach similar to the approach we used to define the 
mesothelin T cell epitopes to validate mutant neoepitopes predicted for HLA-A1 and HLA-
A2, including the HLA-A2-binding neoepitopes for the common Kras exon 12 mutations 
(KrasG12V and G12D).   
 
11.3 
Serum and Plasma Marker Studies 
 
Sera and plasma will be collected at the time points detailed in the study schedule to 
identify potential therapeutic targets, biomarkers, and predictors of response and 
autoimmune toxicity. Detailed instructions for blood collection, processing, and shipment 
are provided in the Laboratory Manual.  
 
11.4 
Diagnostic Tissue Samples 
 
Tissue, fluid, or blood may be collected from standard of care procedures used to treat or 
diagnoses immune related toxicities. 
 
11.5 
Genomic Analysis 
 
Genomic sequencing library construction, whole genome/exome sequencing, whole 
transcriptome sequencing, microbial sequencing, neoepitope prediction, mutation burden, 
and bioinformatic analysis will be performed either at an on-campus laboratory or at an 
off-campus sequencing service. All the samples will be de-identified before sending to 
any laboratory for sequencing.  The FASTQ files, BAM files and VCF files will be 
generated and analyzed. 
 
Results from the sequencing studies will not be released to the patients. These studies are 
for research purposes only and are not using a clinically validated platform. 
 
 
 
 
 


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12. STUDY SCHEDULE 
 
1) Consent – Study consent should be obtained prior to the completion of one cycle (28 
days) of standard of care chemotherapy for pancreatic cancer. 
2) Standard of care chemotherapy – After consenting to the study, the patients should 
receive four 28 day cycles of standard of care chemotherapy (FOLFIRINOX). Patients 
may choose to receive this standard chemotherapy through a local oncologist, and 
follow-up visits, blood work, and restaging scans during this portion of the study will 
be scheduled at the discretion of the patient’s local oncologist.  
3) Pre-immune (After SOC chemo) – Approximately two weeks (+2 to +4 weeks) after 
the last dose of standard of care chemotherapy, patients at select sites should receive a 
simulation scan, EUS Fiducial Placement, and EUS Core Biopsy. The EUS core biopsy 
should occur prior to the administration of radioimmunotherapy. 
4) Radioimmunotherapy – Beginning two to four weeks after the last dose of 
chemotherapy, the patient will receive two 21 day cycles of Cy/GVAX/nivolumab (see 
dosing delays, section 8.3, if patients are unable to begin radioimmunotherapy due to 
resolving adverse events related to chemotherapy or any other reason). The second 
cycle will be combined with SBRT. For logistical reasons, for patients planning to 
receive 5 days of SBRT, it is recommended that C1D1 of immunotherapy commence 
on a Monday (so that SBRT can proceed over a continuous Monday through Friday 
period). 
5) Surgical evaluation – Approximately two weeks after the last dose of SBRT the patient 
will be restaged and assessed for surgical resectability. For patients who are determined 
to be surgically resectable, surgical resection will be scheduled at the discretion of the 
treating surgeon but will generally occur within 30 days of surgical evaluation.  
6) Off study treatment – A mandatory Off Study/Safety Follow-Up Visit should be 
performed 30-60 days after surgical resection has been performed (or 30 days +/- 7 
days after the last infusion of study medication in patients who are determined not to 
be surgical candidates, or within 7 days prior to initiation of a new anti-cancer 
treatment, whichever comes first). After the off-study treatment visit, subjects will be 
contacted every 12 weeks (+/- 2 weeks) to monitor OS until death, withdrawal of 
consent, or study closure.    
 
 




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to and after GVAX pancreas vaccine administration. Presence of fever alone does not indicate subject is not clinically stable. 
4) Complete physical exam will be completed at baseline; focused physical examinations will be conducted thereafter. Exams, concomitant 
medication, AE assessments can be made up to 3 days prior to infusion. 
5) Labs may be collected within a window of up to 4 days prior to dosing. 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. 
6) Pre-immune screening bloodwork does not need to be repeated if performed within 4 days of C1D1. TSH and CA 19-9 only need to be 
completed at either Pre-Immune Visit or at C1D1. If completed at Pre-Immune time point then TSH and CA 19-9 do not need to be repeated 
even if greater than 4 days prior to dosing. 
7) Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, potassium, total protein, SGOT 
[AST], SGPT [ALT], sodium. 
8) T3 and Free T4 to be checked reflexively if TSH is abnormal 
9) Serum or urine pregnancy for women of childbearing potential should be completed within 24 hours of first dose of Cy/Nivolumab and then 
monthly thereafter. 
10) Prior to the administration of immunotherapy to assess baseline toxicity due to chemotherapy. 
11) Radiographic evaluations and tumor measurements will be performed with contrast CT chest/abdomen/pelvis. Noncontrast CT 
chest/abdomen/pelvis or nonconstrast CT Chest and MRI Abdomen/pelvis will be performed in subjects with contrast allergies. 
12) Repeat imaging is only necessary in patients who have not received at least one restaging CT, MRI, or PET/CT after completion of the first 
two 28 day cycles of chemotherapy as part of standard of care therapy, to exclude progressive and/or metastatic disease.  
13) Prior to the administration of immunotherapy. If completed at Pre-Immune Visit research labs do not need to be collected again at Immune 
C1. 
14) Subjects will be contacted (by phone or email) every three months (+/- 2 weeks) to monitor OS until until death, withdrawal of consent, or 
study closure, whichever occurs first. Information of other cancer therapies after discontinuation from the study treatment will also be 
collected. In addition, SAEs that occur within 100 days (+14 day reporting window) of the end of treatment or before initiation of a new 
antineoplastic treatment should also be followed and recorded. 
15) Research blood draw at consent visit is optional and has a visit window of +2 weeks from time of consent 
16) Biopsy will occur at select sites. Surgical specimen or intraoperative biopsy (if surgery is attempted but aborted) will also be obtained at the 
time of surgical resection.  
17) Study consent can be obtained up until 28 days following the first administration of chemotherapy but cannot occur beyond one cycle (1 
month or 28 days) 
18) Research samples will be collected at the discretion of the PI based on availability of supplies and safety of patient and staff.


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13. MEASUREMENT OF EFFECT 
 
13.1 
Definitions 
 
13.1.1 Evaluable 
 
Evaluable for toxicity. All enrolled subjects are evaluable for toxicity. Monitoring of 
unacceptable toxicity will focus on patients receiving any part of one dose of 
immunotherapy (any component of Cy/GVAX/nivolumab) in order to exclude expected 
toxicities related to chemotherapy or resection.  
 
Evaluable for response.  All subjects who have received at least one dose of treatment for 
pancreatic cancer (including chemotherapy) as part of this study and undergo a surgical 
evaluation are evaluable for response. Methods for evaluation of response are described 
below. 
 
Evaluable for CD8 cell density (primary outcome).  All subjects who have received at least 
one dose of investigational agent, undergo surgery or intraoperative biopsy, and have 
sufficient biopsy for CD8 cell density evaluation. 
 
Note: Patients enrolled with bilirubin >1.5 x ULN who are not able to be treated with 
experimental therapy due to elevated bilirubin will be considered not evaluable and will 
be replaced. 
 
13.1.2 CD8 cell density 
 
CD8 cell density is defined as the number of CD8+ cells per area assessed (e.g. # cells/mm2). 
 
13.1.3 R0 resection rate 
 
R0 resection is defined by a microscopically margin-negative resection, in which no tumor 
(gross or microscopic) remains in the primary tumor bed. 
 
13.1.4 Resection rate 
 
Proportion of patients who go on to receive a surgical resection. 
 
13.1.5 pCR rate in surgical specimens 
 
The pCR rate is defined as the proportion of patients who receive a definitive surgical 
resection with no residual cancer in the primary pancreatic tissue or nodes (ypT0ypN0). 
 
13.1.6 Distant metastases free survival (DMFS) 
 
DMFS is defined as the duration of time from start of enrollment in study to identification 
of recurrent disease on imaging or death, whichever occurs first.  The pattern of recurrence 
(local vs. metastatic, or both) will also be inquired. Individuals will be censored at the date 


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of the last scan if no event occurs. 
 
13.1.7 Overall Survival (OS)  
 
OS is defined as the duration of time from start of enrollment in study to time of death.  
Individuals will be censored at the date of the last contact if no event occurs.  
 
13.1.8 Overall Response Rate (ORR)  
 
ORR is defined as the proportion of patients achieving a complete response (CR) or partial 
response (PR) based on the Response Evaluation Criteria in Solid Tumors (RECIST 1.1) 
(See Appendix D).  
 
 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  
All baseline evaluations should be performed as closely as possible to the time of study 
enrollment.  Subjects will be evaluated for anti-tumor effect by follow-up imaging 
(pancreas protocol CT, CT Chest/Abd/Pelvis, PET-CT imaging, and/or non-contrast CT 
chest and MRI Abd/pelvis) as outlined above. All subsequent scans (during and post-
treatment) will be compared to the same pretreatment CT, PET/CT, or MRI that was used 
prior to initiating of study treatment. 
 
 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at the time of study enrollment and during follow-up. 
Imaging-based evaluation is preferred to evaluation by clinical examination unless the 
lesion(s) being followed cannot be imaged but are assessable by clinical exam. 
 
 
Conventional CT and MRI: This guideline has defined measurability of lesions on CT scan 
based on the assumption that CT slice thickness is 5 mm or less.  If CT scans have slice 
thickness greater than 5 mm, the minimum size for a measurable lesion should be twice the 
slice thickness.  MRI is also acceptable in certain situations (e.g. for body scans).   
 
Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement.  Furthermore, the 
availability of MRI is variable globally.  As with CT, if an MRI is performed, the technical 
specifications of the scanning sequences used should be optimized for the evaluation of the 
type and site of disease.  Furthermore, as with CT, the modality used at follow-up should 
be the same as was used at study enrollment and the lesions should be measured/assessed 
on the same pulse sequence.  It is beyond the scope of the RECIST guidelines to prescribe 
specific MRI pulse sequence parameters for all scanners, body parts, and diseases.  Ideally, 
the same type of scanner should be used and the image acquisition protocol should be 
followed as closely as possible to prior scans.  Body scans should be performed with breath-
hold scanning techniques, if possible. 
 
13.1.9 ptDNA  
 
ptDNA will be assessed as the presence or absence of detectable neoepitopes for the 


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common Kras mutations in peripheral blood.  
 
14. DATA REPORTING AND STUDY MONITORING 
 
14.1 
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 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. 
 
Protocol Chair 
The Protocol Chair and/or designee is responsible for performing the following tasks: 
 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. 


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 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. 
 
14.2 
Study Documentation 
 
14.2.1 Case Report Forms and Source Documentation 
 
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. 
 
14.2.2 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. 
 
14.2.3 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, 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. 
 


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14.3 
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 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. 
 
14.4 
Monitoring 
 
The SKCCC Compliance Monitoring Program will provide external monitoring for JHU-
affiliated sites in accordance with SKCCC DSMP (Version 6.0, 02/21/2019). The SMC 
Subcommittee will determine the level of patient safety risk and level/frequency of 
monitoring. Data monitoring of this protocol will occur on a regular basis with the 
frequency dependent on the rate of subject accrual and the progress of the 
study.   Eligibility for all sites will be monitored by the Protocol Chair. The protocol will 
be internally monitored by the Principal Investigator at each site. Data monitoring of this 
protocol will occur on a regular basis with the frequency dependent on the rate of subject 
accrual and the progress of the study. (per the DSMP). External monitoring will occur 
according to the following guidelines: 
 
Johns Hopkins SKCCC: The protocol will be monitored externally by the SKCCC CRO in 
accordance with SKCCC guidelines. Trial monitoring and reporting will be done through 
the Safety Monitoring Committee (SMC) at SKCCC.  
 
Participating site(s): The protocol will be monitored by authorized representatives of the 
coordinating center. A report of the reviews will be submitted to the Johns Hopkins 
principal investigator and SKCCC CRO. 
 
Authorized representatives of the Coordinating Center may visit the satellite sites to 
perform audits or inspections, including source data verification. The purpose of these 
audits or inspections is to systematically and independently examine all trial-related 
activities and documents to determine whether these activities were conducted and data 


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were recorded, analyzed, and accurately reported according to the protocol, Good Clinical 
Practice (GCP), and any applicable regulatory requirements. 
 
Additional data and safety monitoring oversight will also be performed by the SKCCC 
Safety Monitoring Committee (SMC - as defined in the DSMP) and a Medical Expert 
Committee (MEC) as detailed below. The purpose of these audits or inspections is to 
systematically and independently examine all trial-related activities and documents to 
determine whether these activities were conducted and data were recorded, analyzed, and 
accurately reported according to the protocol, Good Clinical Practice (GCP), and any 
applicable regulatory requirements. The Medical Expert Committee (MEC) for this clinical 
study contains three oncologists from other disciplines who are not affiliated with this 
clinical trial protocol. The MEC will review safety data on at least a semi-annual basis. The 
MEC will provide a written summary of each assessment to the IND Sponsor after each 
meeting. In turn, the study team will forward these summaries to the JHU SKCCC SMC. 
The 
operating 
plan 
of 
the 
MEC 
will 
be 
as 
follows: 
 
 
Meetings will be held at least semi-annually, and potentially more frequently if needed. 
 
Meetings will be conducted in-person or via video/teleconference, with a participant 
sign-in sheet collected at each meeting. 
 
Approximately one week prior to each MEC meeting, the study team will submit the 
following items to MEC personnel for review and discussion at the meeting (The PI 
may join the MEC meeting in order to answer any questions the MEC might have): 
o A summary of the clinical trial’s progress to date; 
o The latest IRB-approved consent document; 
o A summary of all adverse events, serious adverse events, deaths, and withdrawals 
to date; 
 
Note that the MEC reserves the right to halt trial accrual or all study activity if, after review, 
serious safety concerns warrant this action. If the MEC halts study accrual or all study 
activity, then the study team must notify the JHU SKCCC SMC, JHU IRB, JHU IBC, RAC, 
and the FDA immediately. 
 
15. STATISTICAL CONSIDERATIONS 
 
15.1 
Overview 
 
The proposed study is an open-label, single-arm phase II study of neoadjuvant sequential 
chemotherapy, SBRT, and Cy/GVAX/nivolumab immunotherapy in patient with 
borderline resectable pancreatic ductal adenocarcinoma (BR-PDAC). The primary 
objective of the trial is to determine whether sequential chemotherapy, SBRT, and 
Cy/GVAX/nivolumab administered in this patient population increases CD8 cell count in 
resected tumor tissue compared to historical controls. The study is planned with up to 32 
participants. The study will be continuously monitored for adverse events.  
 
15.2 
Sample Size and Accrual 
 
A total of 20 historical control samples are available from BR-PDAC patients treated with 


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FOLFIRINOX and SBRT prior to resection.  We expect that approximately 15 out of the 
32 (47%) participants enrolled in this study will be evaluable for CD8 cell density, i.e. 
received at least one dose of treatment for pancreatic cancer (including chemotherapy) as 
part of this study, undergo surgery, and have sufficient biopsy for CD8 cell density 
evaluation.    A sample size of 15 evaluable patients and 20 controls would provide 80% 
power to detect a CD8 count that is 3.01-fold higher for the novel treatment samples as 
compared to the control treatment samples.   
 
More than 100 patients with BR-PDAC annually present for evaluation and treatment at 
JHH, MGH, and MCW. We anticipate the majority of these patients would be potentially 
eligible for enrollment on this the proposed study. 
 
15.3 
Analysis 
 
The primary outcome is the CD8 count, which will be measured on the log-scale due to 
skewness.  Summary statistics (e.g. median, range, mean, standard deviation) and plots 
(e.g. boxplots, histograms) will be used to explore the data.  Log-linear models will be used 
to compare the CD8 count between samples from patients in the study and the historical 
control as well as to explore characteristics associated with CD8 count.  
 
An important secondary outcome is the proportion of patients with a pathologic CR at week 
21 (the time of surgical resection).   The proportion with exact 95% confidences intervals 
will be computed.  Individuals who are lost to follow-up prior to surgical evaluation, or 
who do not undergo surgical resection, will be counted as not achieving a pathologic CR.  
Other binary outcomes (e.g. resection rate) will be analyzed in a similar manner.  
 
Time to event outcomes (e.g. OS, DMSF, time to pathologic CR) will be summarized using 
Kaplan-Meier estimates of the survival function.  The median and proportion alive at 
specific time points (e.g. 6 months, 1 year) will be calculated with 95% confidence 
intervals.   
 
Tumor biopsies will be collected at during EUS and fiducial placement at select sites.  A 
second sample will be collected at approximately week 25 either during resection or, for 
those whose surgery is attempted but aborted, with an intraoperative biopsy.  In prior 
studies, we have been able to obtain paired tumor samples in ~ 65% of patients (N = 32).  
The remaining 35% were missing due to patient refusal, loss to follow-up, or issues with 
the sample quality.   Summary statistics (e.g. mean, standard deviation, median, IQR, 
proportion, correlation) will be calculated at both time-points and graphical techniques 
(e.g. boxplots, histograms) will be used to visual inspect the data.  Log or other 
transformations will be applied as need based upon the exploratory analysis.  Cross-
sectional comparisons between different immunologic endpoints (e.g. correlation, Fisher’s 
exact test, t-tests, scatter plots) will be explored. Paired t-tests, or Wilcoxon rank sum tests 
if appropriate, will be used to evaluate changes in paired continuous measurements.  The 
percent agreement and McNemar’s test will be used to compare patterns in paired binary 
outcomes. 
 
PBL, sera and plasma will be collected throughout and at the end of immunotherapy 


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treatment.  In addition to the cross-section explorations described above spaghetti plots and 
boxplots over time will be used to graphically visualize longitudinal patterns.  Generalized 
estimating equations will be used to model immunologic outcomes over time while 
accounting for the correlation between repeated measurements on the same person.  
Multiple mean (e.g. indicator for each time point, linear function) and correlation (e.g. 
unstructured, exchangeable, AR(1)) structures will be explored. 
 
Logistic regression and Cox proportional hazards models will be used to assess the 
relationship between immunologic measurements from tumor, PBL, sera, and plasma 
samples and clinical outcomes including pathologic CR and OS and DMSF, respectively. 
 
The relationship between tumor tissue with ptDNA will be explored.  The percent 
agreement will be calculated with exact 95% confidence intervals and Fisher’s exact test 
and McNemar’s test will be used assess the association between the measurements and 
imbalances in discordant measurements, respectively.  The relationship between presence 
of detectible ptDNA and binary outcomes (e.g. pCR) will be assessed using standard ROC 
techniques including ROC curves, sensitivity, specificity, positive predictive values (PPV), 
and negative predictive values (NPV).  Heagerty’s time varying ROC analysis will be used 
to calculate these metrics for time to event outcomes (e.g. OS, DMSF)38.   
 
Genomic sequencing library construction, whole genome/exome sequencing, whole 
transcriptome sequencing, microbial sequencing, neoepitope prediction, mutation burden, 
and bioinformatic analysis will be performed either at an on-campus laboratory or at an 
off-campus sequencing service. All the samples will be de-identified before sending to any 
laboratory for sequencing.  The FASTQ files, BAM files and VCF files will be generated 
and analyzed. Results from the sequencing studies will not be released to the patients. 
These studies are for research purposes only and are not using a clinically validated 
platform.  
 
Genomic sequencing data will be stored and computations conducted using a JH IT 
managed subscription of Azure. 
 
15.4 
Safety Monitoring 
 
The safety analysis will be performed in all enrolled patients.  AE data will be listed 
individually and will be tabulated by type, grade, and relatedness both overall and by organ 
class.  In addition to raw counts, the rates of AEs will be calculated based (number of 
events/length of follow-up).   
 
Monitoring of unacceptable toxicities will focus on patients receiving immunotherapy (any 
component of Cy/GVAX/nivolumab) excluding expected toxicities due to chemotherapy 
or resection.  The proportion of subjects with an unacceptable toxicity (See Section 7.7) 
resulting from immunotherapy will be using a Bayesian stopping guideline.  A toxicity 
level 45% would be considered the upper boundary.  We expect the actual toxicity level to 
be 25%.  A Beta (2.5, 5.5) prior, representing a toxicity rate of 31% (slightly above our 
expected rate), will be used to be conservative.  After the first 6 patients have been treated, 
safety will be monitored continuously.   If the probability that the proportion of 


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unacceptable toxicities exceeds 45% is above 50%, we will halt accrual and re-evaluate the 
trial.  Table 5 shows the number of toxicities that would need to be observed in order to 
trigger the stopping guidelines throughout the course of the trial. 
 
Table 5.  The number of toxicities needed to trigger stopping guidelines throughout the 
course of the study. 
 
Number of Patients 
Number of toxicities needed 
to trigger re-evaluation 
6
4
7-8
5
9-10
6
11-13
7
14-15
8
16-17
9
18-19
10
20-21
11
22-24
12
25-26
13
27-28
14
29-30
15
 
The probability of trigger the stopping guidelines was assessed for a range of true 
underlying toxicity rates using simulations with 10,000 replicates (Table 6).  The 
probability of stopping to re-evaluate is 6.6% if the true proportion with an unacceptable 
toxicity was 25%.  In contrast, the probability of early stopping is 67.0% if the true 
proportion with an unacceptable toxicity was 45%, the threshold for acceptable levels of 
toxicity. 
 
Table 6.  Probability of triggering a re-evaluation for a range of unacceptable toxicity 
levels. 
 
True probability of 
unacceptable toxicity 
Number of toxicities needed 
to trigger re-evaluation 
5%
< 0.1%
10%
0.1%
15%
0.9%
20%
2.3%
25%
6.6%
30%
14.2%
35%
27.8%
40%
46.1%
45%
67.0%
50%
84.3%
55%
94.3%
 


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15.5 
Interim Analysis for Efficacy 
 
Given the small sample size, no interim efficacy analyses will be performed. 
 
 
 


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APPENDIX B: MANAGEMENT ALGORITHMS 
 
These general guidelines constitute guidance to the Investigator and may be supplemented by 
discussions with 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: SAE REPORTING FORM 
 
 






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APPENDIX D: 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 patient, 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. 
 
Non-target lesions: All other lesions (or sites of disease) including any measurable lesions over 
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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 patient 
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 patient's best response assignment will depend on the 
achievement of both measurement and confirmation criteria.