Conditions: Pancreatic Cancer
Keywords: Pancreas vaccine immunotherapy antibody PD-1 IMC-CS4 Pembrolizumab GVAX Borderline Resectable CY Cyclophosphamide Adenocarcinoma Neoplasms
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 11
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate whether combining cyclophosphamide (CY), pembrolizumab, GVAX and IMC-CS4 is effective and safe in patients with borderline resectable pancreatic cancer.

Detailed description:
This was a single center, open label, pilot study to evaluate the safety and intratumoral immune response of neoadjuvant/adjuvant triplet immunotherapy: CY/GVAX, Pembrolizumab, and IMC-CS4 in patients with resectable or borderline resectable Pancreatic ductal adenocarcinoma.

Patients received the combination of CY/GVAX with pembrolizumab and IMC-CS4 following completion of standard neoadjuvant chemotherapy (with or without radiation). Immunotherapy agents were given prior to and after surgical resection.

Patients receive neoadjuvant immunotherapy consisting of cyclophosphamide and pembrolizumab on day 1, IMC-CS4 on days 1, 8, and 15, and GVAX on day 2 of Cycles 1 and 2 (3 weeks/cycle). Patients will then undergo pancreaticoduodenectomy 2-3 weeks later, followed by standard of care adjuvant chemotherapy at the discretion of the primary oncologist. Patients may then receive 4 cycles (3 weeks/cycle) of adjuvant immunotherapy (same regimen as Cycles 1 and 2). Disease free patients may receive an additional 12 booster cycles (3 weeks/cycle) of immunotherapy consisting of pembrolizumab on day 1 of all 12 booster cycles, as well as cyclophosphamide on day 1 and GVAX on day 2 of the 6th and 12th booster cycle.

Arms:
arm 1: None

Interventions: intervention 1: Cyclophosphamide intervention 2: GVAX Pancreas Vaccine (GVAX) intervention 3: Pembrolizumab intervention 4: IMC-CS4
Intervention descriptions: intervention 1: 200 mg/m\^2, intravenous (IV) infusion

Patients receive neoadjuvant immunotherapy consisting of cyclophosphamide and pembrolizumab on day 1, IMC-CS4 on days 1, 8, and 15, and GVAX on day 2 of Cycles 1 and 2 (3 weeks/cycle). Patients will then undergo pancreaticoduodenectomy 2-3 weeks later, followed by standard of care adjuvant chemotherapy at the discretion of the primary oncologist. Patients may then receive 4 cycles (3 weeks/cycle) of adjuvant immunotherapy (same regimen as Cycles 1 and 2). Disease free patients may receive an additional 12 booster cycles (3 weeks/cycle) of immunotherapy consisting of pembrolizumab on day 1 of all 12 booster cycles, as well as cyclophosphamide on day 1 and GVAX on day 2 of the 6th and 12th booster cycle. intervention 2: 5x10\^8 cells, six intradermal (ID) injections

Patients receive neoadjuvant immunotherapy consisting of cyclophosphamide and pembrolizumab on day 1, IMC-CS4 on days 1, 8, and 15, and GVAX on day 2 of Cycles 1 and 2 (3 weeks/cycle). Patients will then undergo pancreaticoduodenectomy 2-3 weeks later, followed by standard of care adjuvant chemotherapy at the discretion of the primary oncologist. Patients may then receive 4 cycles (3 weeks/cycle) of adjuvant immunotherapy (same regimen as Cycles 1 and 2). Disease free patients may receive an additional 12 booster cycles (3 weeks/cycle) of immunotherapy consisting of pembrolizumab on day 1 of all 12 booster cycles, as well as cyclophosphamide on day 1 and GVAX on day 2 of the 6th and 12th booster cycle. intervention 3: 200 mg, intravenous (IV) infusion

Patients receive neoadjuvant immunotherapy consisting of cyclophosphamide and pembrolizumab on day 1, IMC-CS4 on days 1, 8, and 15, and GVAX on day 2 of Cycles 1 and 2 (3 weeks/cycle). Patients will then undergo pancreaticoduodenectomy 2-3 weeks later, followed by standard of care adjuvant chemotherapy at the discretion of the primary oncologist. Patients may then receive 4 cycles (3 weeks/cycle) of adjuvant immunotherapy (same regimen as Cycles 1 and 2). Disease free patients may receive an additional 12 booster cycles (3 weeks/cycle) of immunotherapy consisting of pembrolizumab on day 1 of all 12 booster cycles, as well as cyclophosphamide on day 1 and GVAX on day 2 of the 6th and 12th booster cycle. intervention 4: 75 mg (dose level 1) or 100 mg (dose level 2), intravenous (IV) infusion

Patients receive neoadjuvant immunotherapy consisting of cyclophosphamide and pembrolizumab on day 1, IMC-CS4 on days 1, 8, and 15, and GVAX on day 2 of Cycles 1 and 2 (3 weeks/cycle). Patients will then undergo pancreaticoduodenectomy 2-3 weeks later, followed by standard of care adjuvant chemotherapy at the discretion of the primary oncologist. Patients may then receive 4 cycles (3 weeks/cycle) of adjuvant immunotherapy (same regimen as Cycles 1 and 2). Disease free patients may receive an additional 12 booster cycles (3 weeks/cycle) of immunotherapy consisting of pembrolizumab on day 1 of all 12 booster cycles, as well as cyclophosphamide on day 1 and GVAX on day 2 of the 6th and 12th booster cycle.

Protocol document:
Prot_SAP_000.pdf: 
Cover Page for Protocol – J1766 
NCT Number: 
NCT03153410 
Official Title of Study 
A Pilot Study of a GVAX Pancreas Vaccine 
(with Cyclophosphamide) in Combination 
with a PD-1 Blockade Antibody 
(Pembrolizumab) and a Macrophage 
Targeting Agent (CSF1R inhibitor) for the 
Treatment of Patients with Borderline 
Resectable Adenocarcinoma of the Pancreas 
Document Date: 
December 7, 2020 


 
 
 
 
TITLE: A Pilot Study of a GVAX Pancreas Vaccine (with Cyclophosphamide) in Combination 
with a PD-1 Blockade Antibody (Pembrolizumab) and a Macrophage Targeting Agent (CSF1R 
inhibitor) for the Treatment of Patients with Borderline Resectable Adenocarcinoma of the 
Pancreas 
 
Johns Hopkins #: 
J1766/IRB00130267  
 
Merck Protocol #: 
MK-3475-536 
 
Principal Investigator: 
Ana De Jesus-Acosta, M.D. 
 
 
 
Translational  
Principal Investigators: 
Lei Zheng, MD, Ph.D. 
 
 
Regulatory Specialist: 
 
Julie M. Nauroth, Ph.D. 
 
 
Statistician: 
Hao Wang, Ph.D.    
 
 
 
 
 
Lead Study Coordinator: 
 
Jacqueline Kersey 
 
 
 
 
 
 
 
 
 
 


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Lead Research Nurse: 
Carol Judkins, RN 
 
Program Manager:  
Katrina Purtell, RN 
 
 
 
 
Merck Supplied Agent: 
Pembrolizumab (KEYTRUDA®, MK-3475) 
 
Eli Lilly Supplied Agent: 
IMC-CS4 (LY3022855) 
 
JHU Supplied Agent: 
GVAX pancreas vaccine  
(Panc 10.05 pcDNA-1/GM-Neo, Panc 6.03 pcDNA-1/GM-
Neo) 
 
Commercial Agent: 
Cyclophosphamide 
 
IND: 
 
BB IND16793  
 
 
 
 
 
 
 
IND Sponsor: 
 
Elizabeth Jaffee, MD  
 
Protocol Type / Version # / Version Date: Original/ Version 1 / April 18, 2017  
Original/ Version 1.1 / May 31, 2017 
Amendment 1/ Version 2 / March 6, 2018 
Amendment 2/Version 3 / October 25, 2018 
Amendment 3/Version 4 / January 3, 2019 
Amendment 3/Version 4.1/ February 1, 2019 
Amendment 4/Version 5.0/August 8, 2019 
Amendment 5/Version 6.0/June 17, 2020 
Amendment 6/Version 7.0/July 14, 2020 
Amendment 7/Version 8.0/August 10, 2020 
Amendment 8/Version 9.0/December 7, 2020 
 
 
 
 


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SCHEMA 
 
 
 
 


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TABLE OF CONTENTS 
SCHEMA ........................................................................................................................................2 
1. 
OBJECTIVES ....................................................................................................................5 
1.1 
Primary Objectives...................................................................................................5 
1.2 
Secondary Objectives...............................................................................................5 
1.3 
Exploratory Objectives ............................................................................................5 
1.4 
Primary Endpoint .....................................................................................................6 
1.5 
Secondary Endpoints ...............................................................................................7 
1.6 
Study Design ............................................................................................................7 
2. 
BACKGROUND ..............................................................................................................10 
2.1 
Disease Type ..........................................................................................................10 
2.2 
Management of Borderline and Resectable Pancreatic Cancer (BRPC) ...............10 
2.3 
Vaccine Therapy (GVAX) .....................................................................................11 
2.4 
anti-PD-1/PD-L1 blockade [Pembrolizumab (MK-3475 or Keytruda)] ................12 
2.5 
CSF-1R Inhibition (IMC-CS4) ..............................................................................14 
2.6 
Preclinical and Clinical Trial Data .........................................................................14 
2.7 
Rationale ................................................................................................................14 
3. 
PATIENT SELECTION .................................................................................................15 
3.1 
Eligibility Criteria for enrollment into study and to receive neoadjuvant 
study treatment .......................................................................................................15 
3.2 
Eligibility Criteria to receive adjuvant study treatment .........................................17 
3.3  
Eligibility Criteria to receive study booster therapy ..............................................18 
3.4 
Exclusion Criteria for enrollment into study and for the administration of   
adjuvant/booster immunotherapy: .........................................................................19 
3.5 
Inclusion of Women and Minorities ......................................................................21 
4. 
TREATMENT PLAN ......................................................................................................21 
4.1 
Agent Administration.............................................................................................21 
4.2 
General Concomitant Medication and Supportive Care Guidelines ......................24 
4.3 
Definition of an Overdose for this Protocol ...........................................................31 
4.4 
Contraception, Use in Pregnancy, Use in Nursing ................................................32 
4.5 
Unacceptable Toxicities .........................................................................................35 
4.6 
Criteria for Removal from Study Treatment ..........................................................36 
4.7 
Off Study/Safety Follow-up Visit ..........................................................................37 
4.8 
Duration of Follow Up ...........................................................................................37 
5. 
DOSING DELAYS/DOSE MODIFICATIONS ............................................................38 
5.1  
Dose Modifications ................................................................................................38 
5.2  
Dosing Delays ........................................................................................................39 
6. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ......................44 
6.1 
Definitions..............................................................................................................44 
6.2 
Relationship ...........................................................................................................46 
6.3 
Expectedness ..........................................................................................................47 
6.4 
Handling of Expedited Safety Reports ..................................................................47 
6.5  
Reporting................................................................................................................48 


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6.6 
 Special Considerations for Adverse Events that Occur During the Surgery 
and ..........................................................................................................................50 
7. 
PHARMACEUTICAL INFORMATION ......................................................................54 
7.1  
Cyclophosphamide (Cytoxan®, CY) ......................................................................54 
7.2  
GVAX Pancreas Vaccine .......................................................................................56 
7.3 
Pembrolizumab (KEYTRUDA®, MK-3475) ........................................................58 
7.4 
IMC-CS4/ LY3022855 ..........................................................................................61 
8. 
CORRELATIVE/SPECIAL STUDIES .........................................................................64 
8.1 
Tumor Tissue and Whole Blood for Peripheral Blood Mononuclear Cells 
(PBMC) and Circulating Tumor Cells (CTCs) Studies .........................................64 
8.2  
Serum and Plasma Marker Studies ........................................................................66 
8.3 
Diagnostic Tissue Samples ....................................................................................66 
8.4 Genomic Analysis ........................................................................................................66 
9. 
STUDY SCHEDULE .......................................................................................................67 
9.1  
Study Schedule Prior to Surgery ............................................................................67 
9.2  
Study Schedule After Surgery/ Adjuvant Chemotherapy ......................................71 
9.3  
Study Schedule for Booster Study Immunotherapy...............................................75 
10. 
MEASUREMENT OF EFFECT ....................................................................................78 
10.1 
Antitumor Effect – Solid Tumors ..........................................................................78 
11. 
DATA REPORTING / REGULATORY REQUIREMENTS .....................................79 
11.1 
Data Management ..................................................................................................79 
11.2 
Safety Meetings .....................................................................................................80 
11.3  Monitoring .............................................................................................................80 
12. 
STATISTICAL CONSIDERATIONS ...........................................................................81 
12.1 
Sample Size/Accrual Rate ......................................................................................81 
12.2 
Early Stopping Boundaries for Toxicity ................................................................82 
12.3 
Analysis of Primary Safety Endpoints ...................................................................83 
12.4 
Analysis of Primary Immunology Endpoints ........................................................85 
12.5 
Analysis of Secondary and Exploratory Endpoints ...............................................85 
12.6 
Biomarker Analysis ...............................................................................................86 
REFERENCES .............................................................................................................................88 
APPENDIX A: Performance Status Criteria ............................................................................91 
APPENDIX B: Adverse Event of Clinical Interest (ECI) Reporting Form ...........................92 
APPENDIX C: SAE Reporting Form ........................................................................................95 
APPENDIX D: Immune Related Response Criteria ................................................................98 
 
 
 


 
 
 
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1. OBJECTIVES 
 
1.1 
Primary Objectives 
 
1.1.1 To assess the intratumoral immune response in the primary tumor after 
neoadjuvant administration of combination immunotherapy including 
cyclophosphamide (CY), GVAX pancreas vaccine, pembrolizumab, and CSF1R 
inhibitor IMC-CS4. 
 
1.1.2 To determine the safety of the combination of GVAX Pancreas Vaccine (with 
CY), pembrolizumab, and a macrophage targeting agent (CSF1R inhibitor IMC-
CS4) in patients with resectable or borderline resectable pancreatic cancer 
(BRPC) prior to and following surgery. 
 
1.2 
Secondary Objectives 
 
1.2.1 To determine the overall survival (OS) of patients with resectable or borderline 
resectable pancreatic cancer treated with standard neoadjuvant chemotherapy 
(with 
or 
without 
radiation) 
who 
subsequently 
receive 
CY/GVAX/pembrolizumab/IMC-CS4. 
 
1.2.2 To determine the disease free survival (DFS; for those who undergo curative 
resection) of subjects with BRPC treated with neoadjuvant chemotherapy (with 
or 
without 
radiation) 
who 
subsequently 
receive 
CY/GVAX/pembrolizumab/IMC-CS4.  
 
1.2.3 To determine the objective response rate following the study immunotherapy 
prior to surgical resection.  Imaging studies to assess response will be evaluated 
using immune-related RECIST criteria (irRC). 
 
1.2.4 To assess the surgical resectability rate in subjects treated with standard 
neoadjuvant chemotherapy (with or without radiation) who subsequently receive 
CY/GVAX/pembrolizumab/IMC-CS4. 
 
1.2.5 To assess the pathologic response rate of patients with BRP and resectable 
pancreas cancer treated with neoadjuvant chemotherapy (with or without 
radiation) who subsequently receive CY/GVAX/pembrolizumab/IMC-CS4. 
 
1.3 
Exploratory Objectives 
 
1.3.1 To evaluate the effects of the combination of pembrolizumab, CY/GVAX, and 
IMC-CS4 upon the activation and expansion of T effector cells (Teffs) 
infiltrating into the tumor microenvironment (TME) compared to data from 


 
 
 
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ongoing JHU trials evaluating the TME in patients treated with 1) chemotherapy 
and radiation alone or 2) immunotherapy alone 
 
1.3.2 To assess the response to CSF1R inhibition to measure serum levels of 
CD14dimCD16+ monocyte subsets and using ELISA to measure serum CSF1 
levels and whether these changes in levels correlate with clinical response to 
CSF1R inhibition  
 
1.3.3 To monitor the IHC (immunohistochemistry) of immune parameters relevant to 
the activation of PD-L1/PD-1 associated immunosuppressive pathways, vaccine 
induced immune regulatory signatures, and peripheral and intratumoral antigen 
specific T cell responses after treatment with GVAX, pembrolizumab, CY, IMC-
CS4, and standard multimodality treatments 
 
1.3.4  To evaluate the effects of the combination of an anti-PD1 antibody, CY/GVAX, 
and CSF1R inhibitor on PD-L1/PD-1, the PD-L1/PD-1 associated pathways, M1 
vs. M2 tumor-associated macrophages (TAMs), macrophage markers (including 
CD40, 4-IBBL, OX40L), Th1 vs. Th2 vs. Th17, and Teff vs. Treg cells 
 
1.3.5  To assess tumor tissue for molecular determinants of response, progression, and 
disease stability using next generation sequencing technology 
 
1.3.6  To assess tumor burden dynamics using both standard protein biomarkers such 
as CA19-9 and other exploratory circulating biomarkers in serial collections of 
sera and plasma at baseline and throughout treatment 
 
1.3.7  To assess baseline characteristics of the subjects enrolled and to correlate these 
molecular and clinical/pathologic criteria with treatment response and toxicity. 
DNA will be extracted from whole blood and used to evaluate for any germline 
mutations which may correlate with response or toxicity. 
 
1.3.8 To collect peripheral blood mononuclear cells to explore the association of PD-1 
positivity, and lymphocyte activation markers with clinical responses 
 
1.4 
Primary Endpoint 
 
 
1.4.1 Immune endpoints 
• To evaluate intratumoral immune parameters including but not limited to the 
following: tumor-associated macrophages (TAM), effector T cell density, 
and vaccine-induced lymphoid aggregates in patients who received 
neoadjuvant combination immunotherapy and underwent surgery. 
 
1.4.2 Safety endpoints 


 
 
 
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• Number of grade 3 and higher toxicities according to National Cancer 
Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE; 
Version 4.0) that occur after Cycle 1, day 1 
• Incidence, nature and severity of all adverse events that occur on or after 
Cycle 1, Day 1 
 
1.5 
Secondary Endpoints  
 
 
1.5.1 Efficacy endpoints 
• Disease free survival (DFS) from the time of cycle 1, day 1 of 
immunotherapy until first documented evidence of disease recurrence or 
death. 
• Objective response rate to combination immunotherapy with imaging 
studies. 
• OS from the time of cycle 1, day 1 of immunotherapy until death from any 
cause 
• Surgical resectability after neoadjuvant therapy as determined by the 
number of patients able to undergo surgical resection.  
• Pathologic response as determined by surgical margins status at the time of 
surgery and response to neoadjuvant treatment per surgical specimen 
assessment.  
 
1.5.2 Exploratory endpoints 
• IHC, flow cytometry, quantitative PCR assays and microarray analysis 
compared between pre- and post-treatment tumor specimens to evaluate 
o Immune parameters relevant to the PD-L1/PD-1 pathway 
o CSF-1 serum levels and levels of CD14dimCD16+ monocyte subsets 
o Densities and distribution of T-cells in TME 
o Macrophage markers 
o Expression of T helper cell differentiation markers 
• Cytokine/chemokine assays to assess changes in intratumoral inflammatory 
markers 
• Whole exome sequencing to identify neoantigens therapy by comparing 
tumor-specific non-synonymous mutations before and after treatment 
• Peripheral antigen specific T-cell responses 
• Intratumoral antigen specific T-cell responses 
• Biomarker changes (including standard protein biomarkers such as CA 19-
9) and correlation to evaluate for prognostic or predictive factors 
• To assess correlation between immune parameters and clinical outcomes 
using univariate and multivariate Cox regression models 
 
1.6 
Study Design  
 
This is a single center, open label, pilot study to evaluate the safety, immune effect and 
early signs of clinical activity of a combination of multiple immunotherapy agents in a 


 
 
 
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neoadjuvant/adjuvant setting in patients with BRPC or resectable pancreatic cancer. 
Patients with BRPC or resectable pancreas cancer will receive the combination of 
CY/GVAX with pembrolizumab and IMC-CS4 following completion of standard 
neoadjuvant chemotherapy (with or without radiation).  Immunotherapy agents will be 
given prior to and after surgical resection.  
 
We will enroll subjects with initial diagnosis of BRPC or resectable pancreas cancer 
based upon criteria from NCCN Guidelines as determined by review of imaging and 
pathology with a multidisciplinary team (MDT). Eligible patients must have received 
neoadjuvant chemotherapy (with or without radiation) and must be considered a 
candidate for curative resection. 
 
Consented and eligible patients will undergo EUS-guided pretreatment research core 
biopsy of the pancreatic tumor and research blood draws to evaluate for circulating 
tumor cells and other immune/inflammatory markers within 14 days prior to the first 
immunotherapy treatment. Participants will receive their first dose of combination 
immunotherapy, consisting of cyclophosphamide (CY) 200 mg/m2 given intravenously 
(IV) and pembrolizumab 200 mg IV on day 1, IMC-CS4 on day 1, 8, 15, and GVAX 
administered as six intradermal injections on day 2, repeated every 21 days as one 
cycle. Patients will receive a total of two cycles of immunotherapy prior to surgical 
resection.  
 
The study will comprise of two parts for assessment of the safety of IMC-CS4 dose 
escalation.  
 
• Part One of the study will enroll three patients who will receive IMC-CS4 at 
Dose Level 1 (DL1). They will be monitored for unacceptable toxicities (as 
defined in Section 4.5) and potential immune-related adverse events through 
the first two cycles of immunotherapy and subsequent surgical resection. If 
there is ≤ 1 patient during Part One who develops an unacceptable toxicity, 
the study will progress to Part Two. If two or more patients develop an 
unacceptable toxicity, the study will be paused and the protocol will be re-
evaluated and discussed with the IND Sponsor.  
 
• Part Two of the study will enroll the remaining nine patients, who will 
receive IMC-CS4 at Dose Level 2 (DL2), which is the IMC-CS4 dose that is 
expected to be the recommended phase 2 dose from JSCA (NCT01346358). 
DL2 will not be initiated until a minimum of 6 patients have been treated 
with 100 mg flat dosing cohort in JSCA for at least one cycle and ≤ 1 patient 
experience a dose-limiting toxicity in JSCA. During Part Two, we will 
follow the Bayesian stopping guideline to monitor unacceptable toxicities as 
outlined in Section 12.2 and Table 9.  If a subject develops an unacceptable 
toxicity on DL2, treatment for that subject will be discontinued. 
Subsequently enrolled patients in Part 2 will still be initiated on DL2. If it 
becomes evident that the proportion of patients who experience an 


 
 
 
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unacceptable toxicity as defined in section 4.5 convincingly exceeds 30% 
during Part Two of the study, the study will be halted for a safety consultation 
with IND Sponsor. The stopping rule will hold enrollment if the posterior 
probability of toxicity risk exceeding 30% is 75% or higher. 
 
Seven to fourteen days following the 2 cycles of immunotherapy, patients will undergo 
restaging imaging to evaluate response to immunotherapy.  After discussion at MDC 
and/or pancreatic tumor board if patients have stable disease or further response as 
compared to baseline will be candidates for surgical resection. Standard surgical 
procedure will be determined by the operating surgeon.  Pancreatectomy is considered 
standard of care for pancreatic cancer and therefore will not be part of the protocol.   
 
An internal and external real-time monitoring plan will be put in place to ensure that 
toxicities are captured and evaluated in a timely, appropriate, and non-biased manner. 
Patients will be monitored at regular intervals for a broad range of toxicities, including 
enhanced inflammatory related complications prior to surgery, delayed surgery related 
healing, dermatologic toxicity at the vaccine site, GM-CSF-related toxicity, CY-related 
toxicity, and immune-related adverse events (irAEs). 
 
During the four to eight weeks following surgical resection, patients have the option of 
being treated with adjuvant chemotherapy at the discretion of the primary oncologist. 
While the patient is receiving the adjuvant chemotherapy, she/he will not receive any 
immunotherapy.  
 
All patients (whether or not they received adjuvant chemotherapy) who underwent 
surgical resection and have no evidence of recurrence/progression will receive four 
additional cycles of adjuvant combination immunotherapy as long as they do not fulfill 
the exclusion criteria below.  
 
The following will be the exclusion criteria to continue additional adjuvant study 
immunotherapy:  
 
1. BRPC patients: More than 90 days have elapsed since surgery (in the absence of 
adjuvant chemotherapy). The patient will be considered off study. More than 180 
days have elapsed since the surgery (for those patients who receive adjuvant 
chemotherapy). Patients with resectable disease will be allowed more than 180 days 
if a longer course of adjuvant chemotherapy is required.   
2. Patients who were found to have unresectable or metastatic disease intraoperatively  
3. Patients who develop disease progression at any point in the study. These patients 
will be monitored for the safety endpoint but will not continue to receive further 
immunotherapy. The patients will be offered an optional biopsy for research 
purposes. 
 
Following the 4 adjuvant study immunotherapy cycles, as long as the patient remains 
disease free and more than 90 days have not elapsed since the last immunotherapy 


 
 
 
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treatment, the patients will receive 12 booster cycles of pembrolizumab every 3 weeks, 
and 2 booster cycles of CY/GVAX given every 18 weeks. The first booster CY/GVAX 
will be given when receiving 6th booster dose of pembrolizumab (cycle 12), and the 
second booster CY/GVAX will be given when receiving 12th booster dose of 
pembrolizumab (cycle 18).  
 
Subjects that are required to stop treatment with pembrolizumab and/or IMC-CS4 due 
to toxicity may continue to receive CY/GVAX pancreas vaccine until they develop 
disease progression or unacceptable toxicities.  
 
After patients have completed all planned therapy, they will undergo standard of care 
evaluations through their primary oncologist, consisting of history and physical, CT of 
the chest/abdomen/pelvis (or MRI abdomen/pelvis and non-contrast CT chest if do not 
tolerate contrast) every three to six months or as indicated to evaluate for local 
progression and metastatic disease.  The study will collect the follow-up information 
from primary oncologist. 
 
Per the FDA requirement for patients treated with genetically modified products, all 
research participants will be encouraged to enroll in a long-term follow-up protocol, 
following their completion of all interventional studies. These patients 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)”. 
 
2. BACKGROUND 
 
2.1 
Disease Type 
 
Over 46,000 people were diagnosed with pancreatic ductal adenocarcinoma (PDAC) 
in the United States in 2014, with only a 6.7% expected 5 year survival.1, 2 Surgical 
resection is the only potentially curative modality of treatment. At the time of diagnosis, 
most patients present with unresectable disease and less than 20% of patients are 
considered candidates for surgery. Following resection, the majority of patients with 
initially resectable disease develop recurrence.3 There are a subgroup of patients with 
“borderline resectable” pancreatic cancer (BRPC) in which the tumor is technically 
resectable but has increased risk of positive margins, particularly if no neoadjuvant 
therapy is administered.4 
 
2.2 
Management of Borderline and Resectable Pancreatic Cancer (BRPC) 
To increase the probability of negative margins, patients with borderline resectable 
disease undergo preoperative regimens including chemotherapy and radiation to help 
downstage the primary tumor prior to surgical resection. Our analysis of BRPC patients 
who received neoadjuvant chemotherapy at the Johns Hopkins Hospital showed a 


 
 
 
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resectability rate of 48.8%. Despite this, the median overall survival of the BRPC 
patients who underwent surgical resection was only 22.9 months.5 This is shorter than 
the 31-34 months reported survival of patients with resectable disease at diagnosis who 
receive neoadjuvant chemoradiation followed by surgical resection.6, 7  The results 
suggest that there is a need for better neoadjuvant therapy to improve the resectability 
of BRPC as well as better postoperative therapy to prolong overall survival. Therefore, 
additional systemic chemotherapy and immunotherapy are needed to help prevent local 
and systemic progression.   
In patients with resectable disease standard of care has traditionally been upfront 
surgery followed by adjuvant therapy. Although multiple contemporary studies have 
clearly established the benefit of adjuvant chemotherapy, its administration is not 
uniform across all resected patients. It is estimated that up to 50% of patients do not 
receive adjuvant therapy due to variety of post-operative circumstances.  Additionally, 
post-operative recovery delays time to adjuvant therapy. As such, many any centers are 
now using chemotherapy in the neoadjuvant setting as standard of care for patients with 
resectable disease. Similarly, NCCN guidelines suggest clinical trial participation.  
 
2.3 
Vaccine Therapy (GVAX) 
 
Immunotherapy has been investigated as a potential concurrent treatment mechanism 
by stimulating the immune system to recognize a diverse array of tumor antigens. 
Vaccine therapy has been successful in stimulating immunologic killing of tumor cells 
via alternate mechanisms than that of chemotherapy or radiation.  The GVAX pancreas 
vaccine is a combination of two irradiated, granulocyte-macrophage colony-
stimulating factor (GM-CSF) secreting allogeneic pancreatic tumor cell lines.8, 9  GM-
CSF is an important cytokine in inducing the growth and differentiation of dendritic 
cells, which act as antigen-presenting cells in encoding tumor antigens.  Autologous 
GM-CSF secreting vaccines have shown immune activation in 10-40% of treated 
subjects in melanoma, renal cell, prostate, lung, breast, and pancreatic cancers.10-12 
However, autologous vaccines are often technically difficult to produce, and so 
allogeneic GM-CSF vaccines have been tried and shown to be safe, tolerable, and prime 
even HLA-incompatible CD8+ effector T cells to tumor beds.9, 13 
 
The initial Phase I study of GVAX in PDAC was a dose escalation trial of adjuvant 
vaccination in 14 patients with Stage 2 or 3 disease.9 Subjects received vaccination 8 
weeks following resection, then adjuvant chemoradiation, then three additional 
monthly vaccinations.  Treatment was well tolerated, with toxicities limited to grade 1 
and 2 local reactions at the vaccine site, and self-limited systemic rashes, with DTH 
responses observed in 1 of 3 patients receiving 108 and in 2 of 5 patients receiving 5 x 
108 vaccine cells.  Analysis of 60 patients in a follow-up phase II trial of adjuvant 
GVAX who subsequently received a total of 5 vaccinations in addition to 
chemoradiation showed 86% one-year survival and 61% two-year survival.14  The 
vaccine was again well tolerated, with transient local site reactions, mild eosinophilia, 
rashes, flu-like symptoms (low grade fever, chills, malaise, arthralgias, myalgias, and 


 
 
 
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fatigue). 
 
Further studies have shown the boosted effect of GVAX by its combination with low 
dose cyclophosphamide (Cytoxan, CY) as an immune modulator.  Tumors have several 
mechanisms for evading immune surveillance, including the development of tolerance 
with immunosuppressive regulatory T cells (Treg).15-18  In murine breast cancer models 
treatment with CY prior to vaccination showed an enhancing effect with suppression 
of Treg and increase in effector T cells (Teff).19  In a phase II trial of treatment for 
Stage IV pancreatic cancer patients, the combination of CY/GVAX was noted to be 
safe and well tolerated in gemcitabine resistant metastatic pancreatic cancer, with grade 
3/4 treatment related events in only one of 30 subjects20 Median survival was 2.3 
months versus 4.7 months in subjects receiving GVAX without and with CY, 
respectively.  Pathologic evaluation revealed that there was a trend toward prolonged 
progression-free survival in subjects who had persistent mesothelin-specific T cell 
responses with therapy.   
 
A study of GVAX given both neo-adjuvantly and adjuvantly was performed recently, 
either alone or with immune modulating doses of cyclophosphamide (Cytoxan, Cy) to 
deplete regulatory T cells (Tregs).21  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, we also found that activated T cells 
secrete interferon-ᵞ, which in turn upregulates the PD-1/PD-L1 pathway.21, 22 These 
data support an emerging concept that vaccines are required to induce a T cell response 
that is capable of infiltrating the TME.  However, vaccination is just the first step 
toward establishing an effective antitumor immune response, converting the PDA TME 
into an environment similar to what is observed in melanomas exhibiting infiltrating 
but immunosuppressed T cells prior to immunotherapy treatment. Thus, we 
hypothesize that treatment with GVAX primes the PDA TME for anti-PD-1/PD-L1-
targeted therapy.   Supporting this hypothesis, we showed in a preclinical model of 
PDA that combining anti-PD-1 and anti-PD-L1 antibodies with GVAX+Cy enhances 
the infiltration of effector T cells into PDA tumors as well as the cure rate in PDA 
tumor-bearing mice.22 
 
2.4 
anti-PD-1/PD-L1 blockade [Pembrolizumab (MK-3475 or Keytruda)] 
 
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades.23  Accumulating evidence shows a 
correlation between tumor-infiltrating lymphocytes (TILs) in cancer tissue and 
favorable prognosis in various malignancies.  In particular, the presence of CD8+ T-
cells and the ratio of CD8+ effector T-cells / FoxP3+ regulatory T-cells seems to 
correlate with improved prognosis and long-term survival in solid malignancies such 
as ovarian, colorectal and pancreatic cancer, hepatocellular carcinoma, malignant MEL 


 
 
 
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and RCC.  TILs can be expanded ex vivo and re-infused, inducing durable objective 
tumor responses in cancers such as melanoma.24, 25  
 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to 
suppress immune control.  The normal function of PD-1, expressed on the cell surface 
of activated T-cells under healthy conditions, is to down-modulate unwanted or 
excessive immune responses, including autoimmune reactions. The ligands for PD-1 
(PD-L1 and PD-L2) are constitutively expressed or can be induced in various tumors.26-
29 Binding of either PD-1 ligand to PD-1 inhibits T-cell activation triggered through 
the T-cell receptor.  PD-L1 is expressed at low levels on various non-hematopoietic 
tissues, most notably on vascular endothelium, whereas PD-L2 protein is only 
detectably expressed on antigen-presenting cells found in lymphoid tissue or chronic 
inflammatory environments.  PD-L2 is thought to control immune T-cell activation in 
lymphoid organs, whereas PD-L1 serves to dampen unwarranted T-cell function in 
peripheral tissues.30   Although healthy organs express little (if any) PD-L1, a variety 
of cancers were demonstrated to express abundant levels of this T-cell inhibitor.  High 
expression of PD-L1 on tumor cells (and to a lesser extent of PD-L2) has been found 
to correlate with poor prognosis and survival in various cancer types, including renal 
cell carcinoma (RCC),31 pancreatic carcinoma,32 hepatocellular carcinoma,33 ovarian 
carcinoma.34  Furthermore, PD-1 has been suggested to regulate tumor-specific T-cell 
expansion in patients with malignant melanoma.35 The observed correlation of clinical 
prognosis with PD-L1 expression in multiple cancers suggests that the PD-1/PD-L1 
pathway plays a critical role in tumor immune evasion and should be considered as an 
attractive target for therapeutic intervention. 
We showed in a preclinical model of PDA that combining anti-PD-1 and anti-PD-L1 
antibodies with GVAX+Cy enhances the infiltration of effector T cells into PDA 
tumors as well as the cure rate in PDA tumor-bearing mice22, helping support the 
hypothesis that GVAX primes the PDA TME for anti-PD-1/PD/L1-targeted therapy. 
Pembrolizumab is FDA-approved for unresectable or metastatic melanoma at 2 mg/kg 
every 3 weeks, and for metastatic non-small cell lung cancer and recurrent or metastatic 
head and neck squamous cell carcinoma at 200 mg flat dose every 3 weeks.  


 
 
 
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2.5 
CSF-1R Inhibition (IMC-CS4) 
 
Colony-stimulating factor 1 (CSF-1) and its receptor CSF-1R regulate the migration, 
differentiation and survival of macrophages.36 In solid tumors, tumor-associated 
macrophages (TAMs) secrete growth factors which release immunosuppressive 
cytokines which promote tumor growth and are associated with poor prognosis.37 CSF-
1R inhibition in combination with chemotherapy in preclinical models has been shown 
to result in increased CD8+ T cells, TAM-derived interleukin-10 (IL-10) production 
and a reduction in tumor burden.38 CSF-1R inhibition alone rarely produces a potent 
anti-tumor response but there is emerging evidence that CSF/CSF-1R blockade can 
reprogram TAMs and render tumors more susceptible to PD-1 blockade.39 
 
Multiple monoclonal antibody and small molecule inhibitors of CSF-1R (CSF-1Ri) 
have been developed, including Eli Lilly’s IMC-CS4 and Plexxikon’s PLX339. IMC-
CS4 is a human IgG1 monoclonal antibody designed to target the CSF-1R. In vitro, 
IMC-CS4 triggers depletion of TAMs. The CSF-1R inhibitor PLX3397 is a small 
molecule tyrosine kinase inhibitor which potently and selectively inhibits FMS, Kit, 
and Flt3-ITD kinases. It was studied in a phase I study in 26 patients with advanced 
solid tumors.40 PLX339 is mostly well tolerated with specific drug-related toxicities 
including fatigue, anemia, rash, and nausea. 
 
To help decrease risk of toxicities with the combination of GVAX/CY, Pembrolizumab 
and IMC-CS4, we will start a dose level below the recommended  phase 2 dose of the 
IMC-CS4 phase 1 dose-escalation study (as described in Section 1.6). We have 
significant clinical trial experience with GVAX/CY at our institution and the toxicities 
of pembrolizumab have been well-characterized, so this will help use elucidate 
toxicities due to the CSF-1R inhibitor, IMC-CS4. 
 
2.6 
Preclinical and Clinical Trial Data 
 
Refer to the Investigator’s Brochure [IB] for Preclinical and Clinical Data 
 
2.7 
Rationale 
Attempts to apply anti-CTLA4 and anti-PD1 agents directly to GI tumors and PDAC 
have been limited due to their nonspecific immune modulation and diminished 
reactivity in these tumor types, except in select populations.  For example, though anti-
PD-1 appears to have minimal activity in patients with colorectal cancer, a subset of 
colorectal cancer patients with microsatellite instability (MSI) disease, were noted 
incidentally to have complete response to PD-1 inhibitors.35 Pathologic review of those 
more sensitive samples is noted to have increased numbers of neo-antigens (to 
stimulate immune response) and tumor infiltrating lymphocytes (TILs).41   
GVAX administration recruits Teffs into the tumor microenvironment (TME), as well 
as upregulate the immunosuppressive regulatory mechanisms such as Treg infiltration 


 
 
 
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and increased PD-L1 expression.  This provides an opportunity to convert PDAC TME 
into an environment similar to that observed in melanomas with infiltrating, but 
immunosuppressed T cells that may be more amenable to checkpoint inhibitors.21 
The combination of ipilimumab (CTLA-4 inhibitor) with GVAX in advanced 
pancreatic cancer patients is ongoing, and has shown promise in a phase I study of 30 
patients with previously treated PDAC showing median OS 3.6 v 5.7 months and 7 
versus 27% 1-yr OS in patients treated with ipilimumab without and with GVAX 
respectively.42  However, anti-CTLA4 antibodies may have higher toxicity profiles 
than PD-1 inhibitors.  Additionally, PD-1 ligand is highly expressed in a variety of 
human tumors, including some pancreatic cancer and thus may be a more specific 
target.43 In addition, treatment of tumors with GVAX in preclinical models demonstrate 
that 
the 
increased 
Teffs 
leads 
to 
secretion 
of 
interferon-ɤ, 
which 
subsequently upregulates the PD-1/PD-L1 pathway.21, 22 The synergistic effect has 
been demonstrated in a preclinical model of PDAC where the combination of anti-PD-
1 and anti-PD-L1 antibodies with CY/GVAX leads to an enhanced infiltration of 
effector T cells into PDAC tumors as well as the cure rate in PDAC tumor-bearing 
mice.22 There is also emerging evidence that CSF/CSF-1R blockade can reprogram 
TAMs and render tumors more susceptible to PD-1 blockade.39 
This clinical trial will therefore evaluate the combination of CY/GVAX and anti-PD-1 
antibody (pembrolizumab), and CSF-1R inhibitor (IMC-CS4) for BRPC or resectable 
pancreas cancer following neoadjuvant treatment given before and after surgical 
resection. 
3. PATIENT SELECTION 
 
3.1 
Eligibility Criteria for enrollment into study and to receive neoadjuvant study 
treatment 
 
3.1.1 Patients with histologically or cytologically confirmed adenocarcinoma of the 
pancreas.  
 
3.1.2 A research core biopsy is required within 14 days prior to starting therapy.  If a 
biopsy is attempted and unsuccessful, that patient still may be treated after 
review and approval of the PI and IND Sponsor. 
 
3.1.3  Patients must have borderline or resectable pancreatic adenocarcinoma at time 
of diagnosis as defined by NCCN guidelines. Discussion will take place at 
multidisciplinary pancreatic tumor board. 
 
3.1.4  Patients must not have metastatic disease. 
 
 3.1.5 Patients must have measurable disease, defined as at least one lesion that can be 
accurately measured in at least one dimension (longest diameter to be recorded) 


 
 
 
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as >20 mm with conventional techniques or as >10 mm with spiral CT scan.  See 
Section 10.1.2 for the evaluation of measurable disease. 
 
3.1.6 Patients who received radiation therapy must have received last dose no longer 
than 28 days prior to enrollment.  
 
3.1.7  Patients must have received last dose of chemotherapy at least 14 days or longer 
prior to receiving study related immunotherapy. 
 
3.1.8 Age >18 years. 
 
3.1.9 ECOG performance status 0-1 (Appendix A). 
 
3.1.10 Adequate hematologic, renal, and liver function as defined below: 
 
Lymphocytes 
> 500 cells/mm3 
Absolute neutrophil count 
> 1,000 cells/mm3 
Hemoglobin 
> 9g/dL 
Platelets 
> 100,000 cells/mm3 
Serum creatinine 
within normal limits 
AST and ALT  
≤ 2 x ULN   
Total bilirubin 
≤ 1.5 x ULN ** 
 
**Subjects with Gilbert’s Syndrome should have direct bilirubin within 
normal institutional limits 
 
3.1.11 Female patient of childbearing potential (WOCBP) [defined in Section 4.4.1] 
must have a negative urine or serum pregnancy test.  If the urine test is positive 
or cannot be confirmed as negative, a serum pregnancy test will be required to 
be shown as negative for the patient to be eligible. 
 
3.1.12 WOCBP (defined in Section 4.4.1) must be willing to use an adequate method 
of contraception as outlined in Section 4.4.1 - Contraception, starting with Visit 
1 through 120 days after the last dose of study therapy.   
 
 
Note: Complete abstinence is acceptable if this is the usual lifestyle and preferred 
contraception for the subject. 
 
 
Male subjects of childbearing potential (Section 4.4.1) must agree to use an 
adequate method of contraception as outlined in Section 4.4.1 - Contraception, 
starting with Visit 1 through 120 days after the last dose of study therapy. 
 
 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred 
contraception for the subject. 
 


 
 
 
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3.1.13 Ability to understand and the willingness to sign a written informed consent 
document. 
 
3.2 
Eligibility Criteria to receive adjuvant study treatment 
 
3.2.1 Patients must have had surgical resection of primary tumor (R0, R1 and R2 
resections). 
 
3.2.2 Patients must not have evidence of metastatic disease by imaging or disease 
progression by imaging as per irRC.  
 
3.2.3 If no adjuvant chemotherapy was given, patient must have had surgery within 
90 days prior to planned day 1 of adjuvant study immunotherapy. If adjuvant 
chemotherapy was given BRPC patients must have had surgery within 180 days 
of adjuvant study immunotherapy.  Patients with resectable disease will be 
allowed more than 180 days if a longer course of adjuvant chemotherapy is 
required.   
 
3.2.4 ECOG performance status 0-1 (Appendix A). 
 
3.2.5 Adequate hematologic, renal, and liver function as defined below: 
 
Lymphocytes 
> 500 cells/mm3 
Absolute neutrophil count 
> 1,000 cells/mm3 
Hemoglobin 
> 9g/dL 
Platelets 
> 100,000 cells/mm3 
Serum creatinine 
within normal limit 
AST and ALT  
≤ 2 x ULN 
Total bilirubin 
≤ 1.5 x ULN ** 
 
**Subjects with Gilbert’s Syndrome should have direct bilirubin within 
normal institutional limits 
 
3.2.6 Female patient of childbearing potential (WOCBP) [defined in Section 4.4.1] 
must have a negative urine or serum pregnancy test.  If the urine test is positive 
or cannot be confirmed as negative, a serum pregnancy test will be required to 
be shown as negative for the patient to be eligible. 
 
3.2.7 WOCBP (defined in Section 4.4.1) must be willing to use an adequate method 
of contraception as outlined in Section 4.4.1 - Contraception, starting with Visit 
1 through 120 days after the last dose of study therapy.   
 
 
Note: Complete abstinence is acceptable if this is the usual lifestyle and preferred 
contraception for the subject. 
 


 
 
 
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Male subjects of childbearing potential (Section 4.4.1) must agree to use an 
adequate method of contraception as outlined in Section 4.4.1 - Contraception, 
starting with Visit 1 through 120 days after the last dose of study therapy. 
 
 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred 
contraception for the subject. 
 
3.2.8 Ability to understand and the willingness to sign a written informed consent 
document. 
 
3.3  
Eligibility Criteria to receive study booster therapy 
  
3.3.1  Patients must not have metastatic disease by interval study imaging or disease 
progression by interval study imaging as per irRC done. 
 
3.3.2 ECOG performance status 0-1 (Appendix A). 
 
3.3.3 Adequate hematologic, renal, and liver function as defined below: 
 
Lymphocytes 
> 500 cells/mm3 
Absolute neutrophil count 
> 1,000 cells/mm3 
Hemoglobin 
> 9g/dL 
Platelets 
> 100,000 cells/mm3 
Serum creatinine 
≤ 1.5 x ULN* 
AST and ALT  
≤ 2 x ULN 
Total bilirubin 
≤ 1.5 x ULN** 
 
 
*If the serum creatinine is > 1.5 x ULN, but the estimated GFR is > 30 mL/min, 
then the booster therapy can be administered. 
 
 
**Subjects with Gilbert’s Syndrome should have direct bilirubin within normal 
institutional limits 
 
3.3.4 Female patient of childbearing potential (WOCBP) [defined in Section 4.4.1]   
must have a negative urine or serum pregnancy test.  If the urine test is positive 
or cannot be confirmed as negative, a serum pregnancy test will be required to 
be shown as negative for the patient to be eligible. 
 
3.3.5 WOCBP (defined in Section 4.4.1) must be willing to use an adequate method 
of contraception as outlined in Section 4.4.1 - Contraception, starting with Visit 
1 through 120 days after the last dose of study therapy.   
 
 
Note: Complete abstinence is acceptable if this is the usual lifestyle and preferred 
contraception for the subject. 
 


 
 
 
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Male subjects of childbearing potential (Section 4.4.1) must agree to use an 
adequate method of contraception as outlined in Section 4.4.1 - Contraception, 
starting with Visit 1 through 120 days after the last dose of study therapy. 
 
 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred 
contraception for the subject. 
 
3.3.6 Ability to understand and the willingness to sign a written informed consent 
document. 
3.4 
Exclusion Criteria for enrollment into study and for the administration of  
 
adjuvant/booster immunotherapy: 
 
3.4.1 Patient is currently participating or has participated in a study of an 
investigational agent within 28 days of C1D1 of this study or is currently using 
an investigational device. 
 
3.4.2 Patients who have had surgery 28 days prior to first dose of the study drug 
excluding minor procedures (dental work, skin biopsy, etc.), celiac plexus block, 
and biliary stent placement. 
 
3.4.3 Patients must not have received systemic steroids, immunosuppressant 
medications and anti-neoplastic treatment in the past 14 days (with the exception 
of steroids utilized for the purpose of premedication for contrast CT). 
 
3.4.4 Patients with a history of prior treatment (outside of this study) with 
immunotherapy agents (including, but not limited to: IL-2, interferon, anti-PD-
1, anti-PD-L1, anti-PD-L2, anti-CD137, anti-OX-40, anti-CD40, or anti-CTLA-
4 antibodies). 
 
3.4.5 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 
during immunotherapy treatment. 
 
3.4.6 Patients who have received any prophylactic vaccine within 14 days of first dose 
of study drug or received a live vaccine within 30 days of planned start of study 
therapy. 
 
3.4.7 Uncontrolled, intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, unstable angina, cardiac 
arrhythmia, metastatic cancer, or psychiatric illness/social situations that would 
limit compliance with study requirements. 
 
3.4.8 History of any autoimmune disease, including any history of inflammatory 
bowel disease, including ulcerative colitis and Crohn’s Disease, as well as 


 
 
 
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history of symptomatic disease (e.g. rheumatoid arthritis, systemic progressive 
sclerosis [scleroderma], systemic lupus erythematosus, autoimmune vasculitis 
[e.g., Wegener’s Granulomatosis]); CNS or motor neuropathy considered of 
autoimmune origin (e.g., Guillain-Barre Syndrome and Myasthenia Gravis, 
multiple sclerosis).  Patients with thyroid disease will be allowed.  Autoimmune 
diagnoses not listed here must be approved by the Principal Investigator. 
 
3.4.9 Presence of any tissue or organ allograft, regardless of need for 
immunosuppression, including corneal allograft. Patients with a history of 
allogeneic hematopoeitic stem cell transplant will be excluded.  
 
3.4.10 Has history of (non-infectious) pneumonitis that required steroids, history or 
evidence of interstitial lung disease or active, non-infectious pneumonitis. 
 
3.4.11 Has a pulse oximetry < 92% on room air. 
 
3.4.12 Evidence of ascites on imaging at study enrollment (allowed post-surgery during 
administration of adjuvant and booster therapy). 
 
3.4.13 Requires the use of home oxygen. 
 
3.4.14 Has a known history of Human Immunodeficiency Virus (HIV) (HIV1/2 
antibodies), hepatitis B, or hepatitis C infection (patients who are hepatitis C 
antibody positive may be enrolled if they are confirmed with negative viral load 
at screening). 
 
3.4.15 Any concurrent malignancy or myeloproliferative disorder whose natural history 
or treatment has the potential to interfere with safety or efficacy assessment of this 
study’s investigational drug. Patients with a previous non-pancreatic, non-
periampullary malignancy without evidence of disease for > 5 years will be 
allowed to enter the trial.  
 
3.4.16 History of severe hypersensitivity reaction to any monoclonal antibody. 
 
3.4.17 Patient has a known or suspected hypersensitivity to GM-CSF, hetastarch, corn, 
dimethyl sulfoxide, fetal bovine serum, trypsin (porcine origin), yeast or any 
other component of GVAX pancreas vaccine. 
  
3.4.18 Women who are pregnant or breastfeeding. 
 
3.4.19 Women with a positive pregnancy test on enrollment or prior to investigational 
product administration. 
 
3.4.20 Women of child bearing potential or sexually active fertile men with partners 
who are women of child bearing potential who are unwilling or unable to use an 


 
 
 
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21 
acceptable method to avoid pregnancy for the entire study and for up to 120 days 
after the last dose of investigational product. 
 
3.4.21 Patient is unwilling or unable to follow the study schedule for any reason. 
 
3.5 
Inclusion of Women and Minorities 
 
Both men and women of all races and ethnic groups are eligible for this trial.   
 
4. TREATMENT PLAN 
 
 
 
4.1 
Agent Administration 
 
Treatment will be administered on an outpatient basis.  Dosing delays are described in 
Section 5.3.  Subjects will receive two initial treatments of combined immunotherapy 
(pembrolizumab, immuno-modulatory dose of cyclophosphamide, GVAX, and IMC-
CS4) separated by three weeks after completing neoadjuvant chemotherapy and/or 
radiation therapy and undergoing pre-screening for metastatic disease. One to two 
weeks after receiving the first two cycles of combination immunotherapy, patients with 
be reevaluated for surgery. If the patient remains a surgical candidate, he/she will 
undergo surgery two to three weeks following two cycles of neoadjuvant 
immunotherapy. Following surgery, the patient will have the option of receiving cycles 
of adjuvant chemotherapy at the discretion of primary oncologist. While the patient is 
receiving the adjuvant chemotherapy, she/he will not receive any immunotherapy. All 
patients who underwent surgical resection will receive adjuvant combination study 
immunotherapy every 3 weeks for another 4 cycles unless 1) BRPC Patients: more than 
90 days have elapsed since surgery in the absence of adjuvant chemotherapy or >180 
days for those who received adjuvant chemotherapy; Patients with resectable disease: 
will be allowed more than 180 days if a longer course of adjuvant chemotherapy is 
required or 2) there was unresectable or metastatic disease intraoperatively, or 3) there 
has been progression of disease.  
 


 
 
 
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Following the 4 adjuvant study therapy cycles, as long as the patient remains disease 
free and more than 90 days have not elapsed since the last immunotherapy treatment, 
the patients will receive 12 booster cycles of pembrolizumab every 3 weeks, and 2 
booster cycles of CY/GVAX given every 18 weeks. The first booster CY/GVAX will 
be given when receiving the 6th booster dose of pembrolizumab (cycle 12), and the 
second booster CY/GVAX will be given when receiving the 12th booster dose of 
pembrolizumab (cycle 18).  
 
Table 1: Study Regimen (listed in order of administration) 
 
Agent 
Premedications, 
Precautions 
Dose 
Schedule 
Route1 
Cyclophosphamide 
(CY) 
Subjects may be pre-
medicated with anti-
emetics 
200 mg/m2 in 
100 mL NS 
Q3W 
IV infusion 
over 30 
minutes 
GVAX Pancreas 
Vaccine 
EMLA cream 
(approximately 
2.5gms/site at least 1 
hour prior to 
vaccination) 
5x108 cells 
Q3W 
Six 
intradermal 
injections 
Pembrolizumab 
No prophylactic pre-
medications unless 
indicated by previous 
experience in an 
individual subject 
200 mg 
Q3W 
IV over 30 
minutes 
IMC-CS4 
No prophylactic pre-
medications unless 
indicated by previous 
experience in an 
individual subject  
Dose 
Level 1 
(DL1) 
75 
mg 
Q1W 
IV infusion 
duration 
will depend 
on dose 
number and 
presence or 
absence of 
previous 
infusion 
reactions2 
Dose 
Level 2 
(DL2) 
100 
mg 
Q1W 
1 Infusion times are approximate (+/- 10 min) and may need to be adjusted based on 
subject tolerability. 
2 The first dose of IMC-CS4 should be administered over 90 minutes. If there was no 
infusion reaction to the first dose, then the next dose can be administered over 60 
minutes. The third and subsequent doses can be administered over 30 minutes if there 
were no previous infusion reactions. 
Please see Section 5.3 for guidance regarding dosing delays. Subjects that are required 
to stop treatment with pembrolizumab and IMC-CS4 due to toxicity may continue to 
receive CY/GVAX pancreas vaccine (assessment schedule per Section 9). 
 
4.1.1 Cyclophosphamide (CY) 
 
Subjects may be pre-medicated prior to administration with anti-emetics per 


 
 
 
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institutional guidelines.      
 
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. 
 
Subjects should be observed for a minimum of 30 minutes after administration 
of CY, and before administration of GVAX. 
 
4.1.2 GVAX Pancreas Vaccine  
 
The vaccine consists of equal numbers (2.5 ×108 irradiated cells each) of Panc 
6.03 pcDNA1GM-CSF and Panc 10.05 pcDNA1GM-CSF cells combined for a 
total vaccination of 5 ×108 cells. 
 
 Each vaccination 
will consist of six total intradermal injections: 2 each in the upper right and left 
thighs, and 2 in the non-dominant arm.  If one of these limbs is contraindicated, 
the dominant arm may be used. A lidocaine-based topical anesthetic (may 
include, but is not limited to, EMLA or ELA-MAX) cream will be applied to the 
injection site at least 1 hour prior to vaccination to diminish the discomfort 
associated with intradermal injections. 
 
Subjects should be observed for a minimum of 30 minutes after administration 
of GVAX, and before administration of pembrolizumab and a minimum of 30 
minutes before administration of IMC-CS4. 
 
4.1.3 Pembrolizumab (KEYTRUDA®, MK-3475)  
 
 
 
 
The Pharmacy Manual contains specific instructions for pembrolizumab 
administration. Antiemetic medications should not be routinely administered 
prior to dosing of pembrolizumab (if needed, patient will already be receiving 
anti-emetics prior to cyclophosphamide per institutional guidelines). See 


 
 
 
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Section 4.2.3.1 for subsequent premedication recommendations following a 
pembrolizumab-related infusion reaction. 
 
 
Subjects should be observed for a minimum of 30 minutes after administration 
of Pembrolizumab, and before administration of pembrolizumab and a minimum 
of 30 minutes before administration of IMC-CS4. 
 
4.1.4  CSF1R inhibitor IMC-CS4    
 
 
IMC-CS4 is a human IgG1 monoclonal antibody designed to target the CSF1R. 
Premedication is not recommended to be administered prior to the first infusion 
of IMC-CS4. The recommended starting dose of IMC-CS4 is DL1 (Dose Level 
1) administered as an intravenous infusion every week.  
 
The first dose of IMC-CS4 should be administered over 90 minutes. If there was 
no infusion reaction to the first dose, then the next dose can be administered over 
60 minutes. The third and subsequent doses can be administered over 30 minutes 
if there were no previous reactions. 
 
The study will comprise of two parts for assessment of the safety and efficacy 
of IMC-CS4 dose escalation.  
 
• Part One of the study will involve three patients who will receive a flat dose 
of IMC-CS4 at Dose Level 1 (DL1) (Table 1). They will be monitored for 
unacceptable toxicities (as defined in Section 4.5) and potential immune-
related adverse events through the first two cycles of immunotherapy and 
subsequent surgical resection. If there is ≤ 1 patient during Part One who 
develops an unacceptable toxicity, then the study will progress to Part Two. 
 
• Part Two of the study will enroll the remaining 9 subjects in the study, who 
will receive IMC-CS4 at DL2, which is the IMC-CS4 dose that is expected 
to be the recommended phase 2 dose from JSCA. DL2 will not be initiated 
until a minimum of 6 patients have been treated with 100 mg flat dosing 
cohort in JSCA for at least one cycle and ≤ 1 patient experience a dose-
limiting toxicity in JSCA. If a subject develops an unacceptable toxicity on 
DL2, the next dose of IMC-CS4 will be held pending improvement of 
toxicity to grade 1 or 2. These subjects will undergo dose modification and 
transition to the DL1 dosing for subsequent cycles of immunotherapy. 
Subsequently enrolled patients will still be initiated on DL2, and the study 
will be halted for safety evaluation if the Bayesian stopping guideline 
(outlined in Section 12.2 and Table 9) is met. 
 
4.2 
General Concomitant Medication and Supportive Care Guidelines 
 
4.2.1 Cyclophosphamide (CY) 


 
 
 
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Acute reactions will be managed using standard therapy for acute drug reactions 
as per institutional guidelines. 
 
4.2.2 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. 
 
4.2.3 Pembrolizumab 
 
 
 
Pembrolizumab is a humanized monoclonal antibody. Subjects should be closely 
monitored for potential adverse reactions during antibody infusion and potential 
adverse events throughout the study.  
 
 
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. 
 
 
4.2.3.1 Infusion Reactions 
 
 
Pembrolizumab infusion reactions may consist of fever, chills/rigor, nausea, 
pruritus, angioedema, hypotension, headache, bronchospasm, urticaria, rash, 
vomiting, myalgia, dizziness or hypertension.  Severe reactions may include 
acute respiratory distress syndrome, myocardial infarction, ventricular 
fibrillation, and cardiogenic shock.  Patients should be closely monitored for 
such reactions.  Guidelines for patients who experience an infusion related or  
allergic reaction during or after infusion with pembrolizumab are shown below 
in Table 2. 
 
 
 


 
 
 
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Table 2: Guidance on Infusion and Hypersensitivity Reactions for 
Pembrolizumab 
 
 
4.2.4 IMC-CS4 (LY3022855) 
 
 
IMC-CS4 is a humanized monoclonal antibody. It is recommended that patients 
receiving IMC-CS4 should be monitored for serum levels of CK; markers of 
liver function (eg, levels of transaminases, LDH, bilirubin, coagulation 
disorders); muscle function; bone function; and signs indicative of inflammation 
(eg, leukocyte alterations, C-reactive protein) and facial/periorbital swelling. 
 
 
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. 
 
NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
Grade 1 
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated 
Increase monitoring of vital signs as medically indicated until the 
subject is deemed medically stable in the opinion of the investigator. 
None 
Grade 2 
Requires infusion 
interruption but responds 
promptly to symptomatic 
treatment (e.g., 
antihistamines, NSAIDS, 
narcotics, IV fluids); 
prophylactic medications 
indicated for < =24 hrs 
Stop Infusion and monitor symptoms. 
Additional appropriate medical therapy may include but is not 
limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as medically indicated until the 
subject is deemed medically stable in the opinion of the investigator. 
If symptoms resolve within one hour of stopping drug infusion, the 
infusion may be restarted at 50% of the original infusion rate (e.g., 
from 100 mL/hr to 50 mL/hr).  Otherwise dosing will be held until 
symptoms resolve and the subject should be premedicated for the 
next scheduled dose. 
Subjects who develop Grade 2 toxicity despite adequate 
premedication should be permanently discontinued from further 
trial treatment administration. 
Subject may be 
premedicated 1.5h 
(± 30 minutes) prior 
to infusion of 
pembrolizumab 
(MK-3475) with: 
 
Diphenhydramine 
50 mg po (or 
equivalent dose of 
antihistamine). 
 
Acetaminophen 500-
1000 mg po (or 
equivalent dose of 
antipyretic). 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial 
improvement; 
hospitalization indicated for 
other clinical sequelae (e.g., 
renal impairment, 
pulmonary infiltrates) 
Grade 4: 
Life-threatening; pressor or 
ventilatory support indicated 
Stop Infusion. 
Additional appropriate medical therapy may include but is not 
limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine 
 
Increase monitoring of vital signs as medically indicated until the 
subject is deemed medically stable in the opinion of the investigator. 
Hospitalization may be indicated. 
Subject is permanently discontinued from further trial treatment 
administration. 
No subsequent 
dosing 
Appropriate resuscitation equipment should be available in the room and a physician readily available during the period of 
drug administration. 


 
 
 
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4.2.4.1 Infusion Reactions 
 
 
As with other monoclonal antibodies, infusion-related reactions to IMC-CS4 
(LY3022855) may occur. Monitor patients during and following the infusion for 
signs and symptoms of infusion-related reactions from the start of the infusion 
until at least 1 hour after the end of the infusion, in an area containing 
resuscitation equipment and medications necessary for advanced life support and 
cardiopulmonary resuscitation. For Grade 1 or 2 infusion-related reactions, 
adjust IMC-CS4 (LY3022855) dose per Table 3. Immediately and permanently 
discontinue IMC-CS4 (LY3022855) for Grade 3 or 4 infusion- related reactions. 
 
Table 3: Guidance on Infusion and Hypersensitivity Reactions for IMC-CS4 
 
NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
Grade 1 
Mild reaction; infusion interruption not 
indicated; intervention not indicated 
The infusion rate should be decreased by 
50% for the duration of the infusion.  
 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of 
the investigator. 
Diphenhydramine 50 mg po (or 
equivalent dose of antihistamine). 
 
Additional pre-medication may be 
administered at the investigator’s 
discretion. 
Grade 2 
Requires infusion interruption but 
responds promptly to symptomatic 
treatment (e.g., antihistamines, 
NSAIDS, narcotics, IV fluids); 
prophylactic medications indicated for 
< =24 hrs 
The infusion must be stopped until 
resolution to Grade ≤1; the infusion may 
then be resumed at 50% of the prior 
infusion rate. 
 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of 
the investigator. 
Subject may be pre-medicated 1.5h 
(± 30 minutes) prior to infusion of 
LY3022855 with: 
 
Diphenhydramine 50 mg po (or 
equivalent dose of antihistamine). 
 
Additional pre-medication may be 
administered at the investigator’s 
discretion. 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not rapidly responsive 
to symptomatic medication and/or brief 
interruption of infusion); recurrence of 
symptoms following initial 
improvement; hospitalization indicated 
for other clinical sequelae (e.g., renal 
impairment, pulmonary infiltrates) 
Grade 4: 
Life-threatening; pressor or ventilatory 
support indicated 
Stop Infusion. 
 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of 
the investigator. 
Hospitalization may be indicated. 
 
Subject is permanently discontinued 
from further trial treatment 
administration. 
No subsequent dosing 
Appropriate resuscitation equipment should be available in the room and a physician readily available during the period of 
drug administration. 
 
4.2.5 Immune-Related Adverse Events (IRAEs) for Pembrolizumab and IMC-
CS4  
   
 
Subjects should receive appropriate supportive care measures as deemed 
necessary by the treating investigator. Suggested supportive care measures for 
the management of adverse events with potential immunologic etiology are 
outlined below. Where appropriate, these guidelines include the use of oral or 
intravenous treatment with corticosteroids as well as additional anti-
inflammatory agents if symptoms do not improve with administration of 


 
 
 
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corticosteroids. Note that several courses of steroid tapering may be necessary 
as symptoms may worsen when the steroid dose is decreased. For each disorder, 
attempts should be made to rule out other causes such as metastatic disease or 
bacterial or viral infection, which might require additional supportive care. The 
treatment guidelines are intended to be applied when the investigator determines 
the events to be related to pembrolizumab and IMC-CS4 (LY3022855). 
 
 
Note: if after the evaluation the event is determined not to be related, the 
investigator does not need to follow the treatment guidance (as outlined below).  
It may be necessary to perform conditional procedures such as bronchoscopy, 
endoscopy, or skin photography as part of evaluation of the event. NCCN 
guidelines have outlined management for immunotherapy related toxicities 
 
• Pneumonitis: 
 
o For Grade 2 events, treat with systemic corticosteroids. When 
symptoms improve to Grade 1 or less, steroid taper should be started 
and continued over no less than 4 weeks. 
o For Grade 3-4 events, immediately treat with intravenous steroids. 
Administer additional anti-inflammatory measures, as needed. 
o Add prophylactic antibiotics for opportunistic infections in the case of 
prolonged steroid administration. 
 
• Diarrhea/Colitis: 
 
Subjects should be carefully monitored for signs and symptoms of 
enterocolitis (such as diarrhea, abdominal pain, blood or mucus in stool, 
with or without fever) and of bowel perforation (such as peritoneal signs 
and ileus). 
 
o All subjects who experience diarrhea/colitis should be advised to drink 
liberal quantities of clear fluids. If sufficient oral fluid intake is not 
feasible, fluid and electrolytes should be substituted via IV infusion. For 
Grade 2 or higher diarrhea, consider GI consultation and endoscopy to 
confirm or rule out colitis. 
o For Grade 2 diarrhea/colitis, administer oral corticosteroids. 
o For Grade 3 or 4 diarrhea/colitis, treat with intravenous steroids 
followed by high dose oral steroids. 
o When symptoms improve to Grade 1 or less, steroid taper should be 
started and continued over no less than 4 weeks. 
 
• Type 1 diabetes mellitus (T1DM) (if new onset, including diabetic 
ketoacidosis [DKA]) or ≥ Grade 3 Hyperglycemia, if associated with 
ketosis (ketonuria) or metabolic acidosis (DKA) 
 


 
 
 
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o For T1DM or Grade 3-4 Hyperglycemia 
▪ Insulin replacement therapy is recommended for Type I diabetes 
mellitus and for Grade 3-4 hyperglycemia associated with metabolic 
acidosis or ketonuria. 
▪ Evaluate patients with serum glucose and a metabolic panel, urine 
ketones, glycosylated hemoglobin, and C-peptide. 
 
• Hypophysitis: 
 
o For Grade 2 events, treat with corticosteroids. When symptoms 
improve to Grade 1 or less, steroid taper should be started and continued 
over no less than 4 weeks. Replacement of appropriate hormones may 
be required as the steroid dose is tapered. 
o For Grade 3-4 events, treat with an initial dose of IV corticosteroids 
followed by oral corticosteroids. When symptoms improve to Grade 1 
or less, steroid taper should be started and continued over no less than 4 
weeks. Replacement of appropriate hormones may be required as the 
steroid dose is tapered. 
 
• Hyperthyroidism or Hypothyroidism: 
 
Thyroid disorders can occur at any time during treatment. Monitor patients 
for changes in thyroid function (at the start of treatment, periodically during 
treatment, and as indicated based on clinical evaluation) and for clinical 
signs and symptoms of thyroid disorders. 
 
o Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism): 
▪ In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) 
are suggested as initial therapy.  
▪ In hypothyroidism, thyroid hormone replacement therapy, with 
levothyroxine or liothyroinine, is indicated per standard of care. 
o Grade 3-4 hyperthyroidism 
▪ Treat with an initial dose of IV corticosteroid followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, steroid 
taper should be started and continued over no less than 4 weeks. 
Replacement of appropriate hormones may be required as the 
steroid dose is tapered. 
 
• Hepatic: 
 
o Elevated LFTs can occur secondary to IMC-CS4 and may improve by 
holding drug.  
o For Grade 2 events, hold immunotherapy and monitor liver function 
tests more frequently until returned to baseline values (consider every 
3-5 days). Grade 2 elevated LFTs that do not improve to < grade 1 after 


 
 
 
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holding immunotherapy drugs for two weeks should be treated with 
systemic corticosteroids. 
o For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 
48 hours followed by oral steroids.  
 
• Renal Failure or Nephritis: 
 
o For Grade 2 events, treat with corticosteroids. 
o For Grade 3-4 events, treat with systemic corticosteroids. 
o When symptoms improve to Grade 1 or less, steroid taper should be 
started and continued over no less than 4 weeks. 
 
• Elevated CK: 
 
o For Grade 2 events that have clinical or laboratory signs of end organ 
damage (e.g. elevated urine and serum myoglobin) hold IMC-CS4 
(Refer to Table 4). 
o For Grade 3-4 events hold IMC-CS4 (Refer to Table 4). 
o Based on the mechanism of action of IMC-CS4, elevated CK levels are 
expected (J Immunother Cancer. 2017; 5:53; Am J Pathol. 2011 Jul;179 
(1): 240-247). Since there is not clear inflammatory basis for these 
reactions, the need for steroids is questionable and holding drug until 
CK decreases can be advised. Corticosteroids could be considered in 
cases with clinical or laboratory signs indicative of immune mediated 
tissue inflammation.  
 
• All other drug-related toxicity: 
o For Grade 3-4 events, treat with systemic steroids.  
o When symptoms improve to Grade 1 or less, steroid taper should be 
started and continued over no less than 4 weeks. 
 
4.2.6.  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 
 
• Any other immunotherapy treatment, including, but not limited to: IL-2, 
interferon, anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, anti-OX-40, 
anti-CD40, or anti-CTLA-4 antibodies 
 


 
 
 
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• Systemic glucocorticoids for any purpose other than to modulate symptoms 
from an event of clinical interest of suspected immunologic etiology.  The 
use of physiologic doses of corticosteroids may be approved after 
consultation with the IND Sponsor. Steroid treatment should be completed 
at least 14 days prior to resuming study-related treatments.  However, study-
related treatments may be given after short-term steroid use (< 4 days) with 
prior approval by the Principal Investigator and IND Sponsor (See Section 
5.3 for dosing delays for steroids). Further, if patients require high dose 
steroids, while on study, pembrolizumab can be re-administered if the 
steroids are tapered over a 12 week period.  Steroids used as premedication 
for contrast CT allergies can be utilized when clinically indicated and do not 
require a 14 days washout. 
 
• 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 allowed. However, intranasal 
influenza vaccines (e.g. Flu-Mist®) are live attenuated vaccines, and are not 
allowed. 
 
4.3 
Definition of an Overdose for this Protocol 
 
Overdose of pembrolizumab or IMC-CS4 will be defined as: 
The patient was given (accidentally or intentionally) a dose of 1000 mg or greater (≥5 
times the indicated dose) of pembrolizumab. The patient was given (accidentally or 
intentionally) a dose of 115 (which is 15% more than the recommended phase 2 dose) 
of IMC-CS4.  No specific information is available on the treatment of overdose of 
pembrolizumab and IMC-CS4. In the event of overdose, pembrolizumab or IMC-CS4 
should be discontinued and the subject should be observed closely for signs of toxicity.  
Appropriate supportive treatment should be provided if clinically indicated. 
 
If an adverse experience(s) is associated with (“results from”) the overdose of test drug 
or vaccine, the adverse experience(s) is reported as a serious adverse experience, even 
if no other criteria for serious are met. 
If a dose of test drug or vaccine meeting the protocol definition of overdose is taken 
without any associated clinical symptoms or abnormal laboratory results, the overdose 
is reported as a non-serious Event of Clinical Interest (ECI), using the terminology 
“accidental or intentional overdose without adverse effect.” 
All reports of overdose with and without an adverse experience must be reported within 
24 hours to the IND Sponsor, Merck Global Safety, and Eli Lilly local safety 
representative (contact information can be found in Section 6.5.1). 


 
 
 
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4.4 
Contraception, Use in Pregnancy, Use in Nursing 
 
4.4.1  Contraception 
 
 
The investigational agents 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.   
 
 
Given the potential risk related to pharmacologically-mediated inhibition of the 
PD-1 pathway, no reproductive or developmental toxicity studies were 
conducted with pembrolizumab. IMC-CS4 has also not been studied in pregnant 
women and must not be given to patients who are pregnant. Furthermore, animal 
reproduction studies have not been conducted with IMC-CS4. Therefore, 
potential effects of IMC-CS4 use during pregnancy are not known and the 
potential for developmental toxicity cannot be excluded.  
 
 
For this trial, male subjects will be considered to be of non-reproductive 
potential if they have azoospermia (whether due to having had a vasectomy or 
due to an underlying medical condition).   
 
 
Female subjects will be considered of non-reproductive potential if they are 
either:  
 
 
 
(1) postmenopausal (defined as at least 12 months with no menses without 
 
an alternative medical cause; in women < 45 years of age a high follicle 
 
stimulating hormone (FSH) level in the postmenopausal range may be used 
 
to confirm a post-menopausal state in women not using hormonal 
 
contraception or hormonal replacement therapy. In the absence of 12 
 
months of  
amenorrhea, a single FSH measurement is insufficient.);  
 
 
 
OR  
 
 
 
(2) have had a hysterectomy and/or bilateral oophorectomy, bilateral 
 
salpingectomy or bilateral tubal ligation/occlusion, at least 6 weeks prior to 
 
screening;  
 
 
 
OR  
 
 
 
(3) has a congenital or acquired condition that prevents childbearing. 
 
 
Female and male subjects of reproductive potential must agree to avoid 
becoming pregnant or impregnating a partner, respectively, while receiving 
study drug and for 120 days after the last dose of study drug by complying with 
one of the following:   
 


 
 
 
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(1) practice abstinence† from heterosexual activity;  
 
 
 
OR  
 
 
 
(2) use (or have their partner use) acceptable contraception during 
 
heterosexual activity.   
 
 
Acceptable methods of contraception are‡: 
 
Single method (one of the following is acceptable): 
• 
intrauterine device (IUD) 
• 
vasectomy of a female subject’s male partner  
• 
contraceptive rod implanted into the skin 
 
Combination method (requires use of two of the following): 
• 
diaphragm with spermicide (cannot be used in conjunction with 
cervical cap/spermicide) 
• 
cervical cap with spermicide (nulliparous women only)   
• 
contraceptive sponge (nulliparous women only)  
• 
male condom or female condom (cannot be used together) 
• 
hormonal contraceptive: oral contraceptive pill (estrogen/progestin 
pill or progestin-only pill), contraceptive skin patch, vaginal 
contraceptive ring, or subcutaneous contraceptive injection 
 
 
†Abstinence (relative to heterosexual activity) can be used as the sole 
method of contraception if it is consistently employed as the subject’s 
preferred and usual lifestyle and if considered acceptable by local 
regulatory agencies and ERCs/IRBs.  Periodic abstinence (e.g., 
calendar, ovulation, sympto-thermal, post-ovulation methods, etc.) 
and withdrawal are not acceptable methods of contraception.  
 
 
‡If a contraceptive method listed above is restricted by local 
regulations/guidelines, then it does not qualify as an acceptable 
method of contraception for subjects participating at sites in this 
country/region. 
 
 
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 subjects of childbearing potential must 
adhere to the contraception requirement (described above) from the day of study 
medication initiation (or 14 days prior to the initiation of study medication for 
oral contraception) throughout the study period up to 120 days after the last dose 
of trial therapy.  If there is any question that a subject of childbearing potential 
will not reliably comply with the requirements for contraception, that subject 
should not be entered into the study. 


 
 
 
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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 patients). 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 120 days after 
the last dose of study medication.  Male patients enrolled in this study must also 
agree to use an adequate method of contraception starting with Visit 1 through 
120 days after the last dose of study drug.  
 
 
The following are considered adequate barrier methods of contraception (2 
barrier methods are required): diaphragm, condom (by the partner), copper 
intrauterine device, sponge, or spermicide.  Appropriate hormonal 
contraceptives will include any registered and marketed contraceptive agent that 
contains an estrogen and/or a progestational agent (including oral, subcutaneous, 
intrauterine, or intramuscular agents). 
 
 
Patients 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 patient will not reliably comply with the requirements for 
contraception, that patient should not be entered into the study. 
 
4.4.2  Use in Pregnancy 
 
 
The investigational agents may have adverse effects on a fetus; therefore, women 
with a positive pregnancy test at screening will not be eligible for enrollment.  If 
a patient inadvertently becomes pregnant while on treatment with combination 
immunotherapy, the patient will immediately be removed from the study.  The 
site will contact the patient at least monthly and document the patient’s status 
until the pregnancy has been completed or terminated.  The outcome of the 
pregnancy will be reported to the IND Sponsor, to Merck Global Safety, and to 
Eli Lilly local safety representative without delay.  The outcome must be 
reported to the IND Sponsor within 24 hours, Merck Global Safety and Eli Lilly 
local safety representative if the outcome is a serious adverse experience (e.g., 
death, abortion, congenital anomaly, or other disabling or life-threatening 
complication to the mother or newborn).  If a male patient’s partner becomes 
pregnant on study the pregnancy must be reported to the IND Sponsor, Merck 


 
 
 
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Global Safety and Eli Lilly local safety representative as described in Section 
6.5.1.  The study Investigator will make every effort to obtain permission to 
follow the outcome of the pregnancy and report the condition of the fetus or 
newborn to the IND Sponsor, Merck Global Safety and Eli Lilly local safety 
representative. 
 
4.4.3  Use in Nursing Women 
 
 
It is unknown whether the investigational agents are excreted in human milk.  
Since many drugs are excreted in human milk, and because of the potential for 
serious adverse reactions in the nursing infant, patients who are breast-feeding 
are not eligible for enrollment. 
 
4.5 
Unacceptable Toxicities 
 
 
Unacceptable toxicities are defined as any AE that is temporally related to study drug 
administration and is not due to the subject’s underlying malignancy and for which 
there is no clear evidence for an alternative etiology and meets one of the following 
NCI CTCAE criteria: 
 
Hematologic Toxicities  
− Grade 4 anemia  
− Grade 3 or 4 neutropenia lasting ≥ 14 days  
− Grade ≥ 3 neutropenia with fever  
− Grade 4 thrombocytopenia, or Grade 3 thrombocytopenia with clinically 
significant bleeding  
 
Other Toxicities  
− Treatment-related ≥ grade 4 AEs 
− Grade 3 Pneumonitis 
− Grade 3 Nephritis 
− Grade 3 elevated LFTs that do not improve to < grade 2 after holding IMC-CS4 
for two weeks. 
-  Grade  4 creatine kinase elevation >10 × ULN 
− 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 
− Any other clinically significant Grade ≥ 3 toxicity that do not improve to ≤ grade 
2 under therapy within 2 weeks except for the following:  
o Grade 3 nausea, vomiting, or diarrhea that resolves to Grade ≤ 1 within 7 
days, with or without appropriate supportive therapy  
o Grade ≥ 3 rash that resolves to Grade ≤ 2 within 7 days  


 
 
 
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o Grade 3 fatigue that resolves to ≤ Grade 2 within 14 days  
o Grade ≥ 3 laboratory abnormalities that, in the judgment of the 
investigator, are not clinically significant  
o Asymptomatic amylase/lipase elevation 
 
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. Hyponatremia has been reported and will be monitored. 
 
The proportion of unacceptable toxicities will be monitored. If the toxicity levels are 
unacceptable (high probability that it is >30% of subjects), then enrollment will be 
suspended until further review and consideration by the IND Sponsor and MEC.  
 
4.6 
Criteria for Removal from Study Treatment  
 
Patients will be removed from study treatment when any of the criteria listed below 
applies.  The reason for study treatment removal and the date the patient was removed 
must be documented in the Case Report Form. 
 
A subject must be discontinued from the trial for any of the following reasons: 
 
• 
The subject or legal representative (such as a parent or legal guardian) 
withdraws consent, or 
  
• 
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: 
 
• 
The subject or legal representative (such as a parent or legal guardian) 
withdraws consent for treatment, 
• 
Development of local recurrence or distant metastatic disease, 
• 
Patients who were found to have unresectable disease intraoperatively, 
 
• 
Intercurrent illness that prevents further administration of treatment, 
 
• 
Unacceptable adverse event(s) (see Section 4.5), 
 
• 
Investigator’s decision to withdraw the subject, 
 
• 
Severe or life-threatening pembrolizumab or IMC-CS4-related AE(s) per 
Table 4, 
 


 
 
 
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• 
Need for >2 dose delays due to the same toxicity as per the dose delay 
guidelines. However, if patients have undergone surgery and subsequently 
develop grade > 3 irAEs to pembrolizumab or IMC-CS4, they can be 
allowed to continue CY/GVAX booster therapy, at the discretion of the 
investigator, 
  
• 
Inability to reduce corticosteroid dose for immune-related adverse reactions 
to ≤10 mg prednisone or equivalent per day, 
 
• 
BRPC Patients: More than 90 days have elapsed since the last 
immunotherapy treatment (except for the adjuvant study immunotherapy, 
which needs to be restarted within 90 days of surgery if no adjuvant 
chemotherapy was provided or within 180 days if adjuvant chemotherapy 
is provided).  Patients with resectable disease will be allowed more than 180 
days if a longer course of adjuvant chemotherapy is required,   
 
• 
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 
IND Sponsor should be included in this decision, 
 
• 
Noncompliance with trial treatment or procedure requirements, or 
 
• 
Patient becomes pregnant. 
 
4.7 
Off Study/Safety Follow-up Visit 
 
After a patient is discontinued from treatment, a mandatory Off Study/Safety Follow-
Up Visit should be performed approximately 30 days after the last infusion of study 
medication (or within 7 days prior to initiation of a new anti-cancer treatment, 
whichever comes first).  Procedures and assessments performed at this visit and beyond 
should follow the respective guidelines described in Section 9 as appropriate.  The 
patient will be monitored for adverse events up to the mandatory Off Study/Safety 
Follow-Up Visit or to resolution of toxicity to Grade 0-1, whichever occurs later.  
Serious Adverse Events (SAEs) that occur within 90 days of the last infusion of 
pembrolizumab or before initiation of a new antineoplastic treatment should also be 
followed and recorded. 
 
4.8 
Duration of Follow Up   
 
Subjects who discontinue from treatment should continue to follow up with their 
primary oncologist and be contacted every six months (with a +/- 1 month window) to 
monitor OS and for potential disease progression.  Information of other cancer 
therapies after discontinuation from the study treatment will be collected. 
  


 
 
 
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Subjects who are discontinued from the study treatment due to an unacceptable drug-
related AE will be monitored for safety until the resolution of the AE to ≤ grade 1 or 
stabilization or until initiation of a new therapy for their cancer, whichever occurs first. 
  
All subjects will be followed for at least 30 days after their last dose of study drug for 
the development of AEs. SAEs that occur within 90 days of the last infusion of 
pembrolizumab or before initiation of a new antineoplastic treatment should also be 
followed and recorded. 
 
5. DOSING DELAYS/DOSE MODIFICATIONS 
 
5.1  
Dose Modifications 
 
5.1.1 Dose reduction or dose increase of CY, GVAX, and pembrolizumab will not be 
permitted in individual patients. 
 
5.1.2 Part One of the study will evaluate the initial three patients enrolled in the study 
for IMC-CS4 dose-related toxicities in particular transaminitis and CK elevation 
which have occurred during the single agent phase 1 study with IMC-CS4.  
 
           During Part One, patients will receive IMC-CS4 at DL1. DL1 (75 mg) is one 
dose level below recommended phase 2 dose of IMC-CS4 per phase 1 single 
agent studies to allow this evaluation. Subjects will be monitored for the number 
of grade 3 or higher toxicities through the first two cycles of immunotherapy. 
 
 
5.1.2.1   During Part One, further dose-reduction beyond DL1 will be at the 
discretion of the principal investigator and upon discussions PI or IND sponsor.  
 
5.1.3 Part Two of the study will be initiated pending monitoring of the initial Part One. 
If there is ≤ 1 patient who develops unacceptable toxicities in Part One, the study 
will progress to Part Two, where dosing of IMC-CS4 will be at Dose-Level 2 
(DL2). DL2 (100 mg) is dose that is expected to be the recommended phase 2 
dose from JSCA. DL2 will not be initiated until minimum of 6 patients have 
been treated with 100 mg flat dosing cohort in JSCA for at least one cycle and ≤ 
1 patient experience a dose-limiting toxicity in JSCA. Dose modifications and 
management of LFTs toxicities will occur the same as during Part One.  
 
5.1.4  The following table provides dose levels of the study: 
 
Dosing Table for Part 1 and Part 2 
 
Dose of IMC-CS4 
Dose 
DL-1 
50 mg 
DL1 
75 mg  
DL2 
100 mg  


 
 
 
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5.2  
Dosing Delays 
 
5.2.1. All scheduled neoadjuvant and adjuvant treatments within a cycle are to be given 
approximately 3 weeks apart.  If necessary, a cycle may be delayed for up to 1 
week.  In this case, subsequent cycles should continue so that a subject can still 
receive all cycles given that the cycles are a minimum of 3 weeks apart and they 
have not experienced an AE(s) necessitating discontinuation.  If delayed more 
than 1 week, the Principal Investigator must be contacted for further instructions 
on continued treatment.  Additional delays or modifications to the treatment 
schedule must be approved by the PI or IND Sponsor. 
 
5.2.2 Pembrolizumab and IMC-CS4 will be withheld for suspected drug-related 
toxicities and severe or life-threatening AEs as per Table 4. Modifications for 
IMC-CS4 and discontinuation criteria are specified in Table 4. 
 
5.2.3  Dosing of study therapy will be delayed if the following laboratory criteria are 
not met:  
 
Neoadjuvant Study Treatment (Day 1, 8, and 15 of Cycles 1 and 2) 
 
Absolute neutrophil count                           > 1,000 cells/mm3 
Hemoglobin                                                 > 9g/dL 
Platelets                                                        > 100,000 cells/mm3 
Serum creatinine                                          ≤ 1.5 x ULN* 
AST and ALT                                              ≤ 3.0 x ULN 
Total bilirubin                                              ≤ 1.5 x ULN ** 
 
Adjuvant Study Treatment (Day 1, 8, and 15 of Cycles 3-6) 
 
Absolute neutrophil count                           > 1,000 cells/mm3 
Hemoglobin                                                 > 9g/dL 
Platelets                                                        > 100,000 cells/mm3 
Serum creatinine                                          ≤ 1.5 x ULN* 
AST and ALT                                              ≤ 3.0 x ULN 
Total bilirubin                                              ≤ 1.5 x ULN ** 
 
Boosting Study Treatment (Day 1 of Cycle 7-18) 
 
Absolute neutrophil count                           > 1,000 cells/mm3 
Hemoglobin                                                 > 9g/dL 
Platelets                                                        > 100,000 cells/mm3 
Serum creatinine                                          ≤ 1.5 x ULN* 
AST and ALT                                              ≤ 3.0 x ULN 
Total bilirubin                                              ≤ 1.5 x ULN** 


 
 
 
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*If the serum creatinine is > 1.5 x ULN, but the estimated GFR is > 30 mL/min, 
then the booster therapy can be administered. 
 
**Subjects with Gilbert’s Syndrome should have direct bilirubin within normal 
institutional limits 


 
 
 
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Table 4: Pembrolizumab and IMC-CS4 Dose Delay, Modifications and Discontinuation Criteria 
 
Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting 
Pembrolizumab Treatment 
Timing for Restarting IMC-
CS4 Treatment and Dose 
Modifications 
Treatment Discontinuation 
Diarrhea/Colitis 
2-3 
 
Toxicity resolves to Grade 0-1. 
 
Toxicity resolves to Grade 0-1. 
 
Toxicity does not resolve within 12 weeks of last dose 
or inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
4 
Permanently discontinue 
Permanently discontinue  
Permanently discontinue 
AST1, ALT, or 
Increased Bilirubin 
21 
Toxicity resolves to Grade 0-1 
First occurrence: If resolution 
within two weeks to Grade < 1 can 
restart IMC-CS4 at same dose after 
symptoms resolve. 
 
Second occurrence: If resolution 
within two weeks to Grade < 1 can 
restart IMC-CS4 with reduction of 
one dose level. 
Toxicity does not resolve within 12 weeks of last dose. 
3 
Toxicity resolves to Grade 1-2  
 
Toxicity resolves to Grade 1-2 
Restart at one dose level reduction 
 
Permanently discontinue IF toxicity continues after two 
week period. 
4 
Permanently discontinue 
Permanently discontinue 
Permanently discontinue 
CK2 
2 with clinical 
or laboratory 
signs of end 
organ damage 
(e.g. elevated 
urine and serum 
myoglobin) 
Toxicity resolves to Grade 
0-1 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose  
3 
4 
Permanently discontinue 
Permanently discontinue  
Permanently discontinue 
Type 1 diabetes 
mellitus (if new 
onset) or 
Hyperglycemia 
T1DM or  
3-4 
Hold treatment for new onset 
Type 1 diabetes mellitus or Grade 
3-4 hyperglycemia associated 
with evidence of beta cell failure. 
Hold treatment for new onset 
Type 1 diabetes mellitus or Grade 
3-4 hyperglycemia associated 
with evidence of beta cell failure. 
Resume pembrolizumab and IMC-CS4 when patients 
are clinically and metabolically stable. 
Hypophysitis 
2-4 
Toxicity resolves to Grade 0-1. 
Therapy can be continued while 
endocrine replacement therapy is 
instituted 
Toxicity resolves to Grade 0-1. 
Therapy can be continued while 
endocrine replacement therapy is 
instituted  
Toxicity does not resolve within 12 weeks of last dose 
or inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 


 
 
 
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Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting 
Pembrolizumab Treatment 
Timing for Restarting IMC-
CS4 Treatment and Dose 
Modifications 
Treatment Discontinuation 
Hyperthyroidism  
3 
Toxicity resolves to Grade 0-1 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose 
or inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
4 
Permanently discontinue 
Permanently discontinue  
Permanently discontinue 
Hypothyroidism 
 
Therapy with pembrolizumab and 
IMC-CS4  can be continued while 
thyroid replacement therapy is 
instituted 
Therapy with pembrolizumab and 
IMC-CS4  can be continued while 
thyroid replacement therapy is 
instituted  
Therapy with pembrolizumab can be continued while 
thyroid replacement therapy is instituted. 
Infusion Reaction 
3-4 
Permanently discontinue 
Permanently discontinue  
Permanently discontinue 
Pneumonitis 
2 
Toxicity resolves to Grade 0-1 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose 
or inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
Permanently discontinue for recurrent grade 2 toxicity. 
3-4 
Permanently discontinue 
Permanently discontinue  
Permanently discontinue 
Renal Failure or 
Nephritis 
2 
Toxicity resolves to Grade 0-1 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose 
or inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
3-4 
Permanently discontinue 
Permanently discontinue  
Permanently discontinue 
All Other Drug-
Related Toxicity3 
3 
Toxicity resolves to Grade 0-1 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose 
or inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
4 
Permanently discontinue 
Permanently discontinue  
Permanently discontinue 
Note: Permanently discontinue for any severe or Grade 3 drug-related AE that recurs or any life-threatening event. 
1  Patients who develop isolated Grade 2 AST elevation (i.e. without concurrent ALT or bilirubinemia to suggest a liver source of transaminase) may continue dosing with 
combined immunotherapy of pembrolizumab and IMC-CS4 since this elevation is thought to be due to pharmacodynamics effect rather than direct muscle toxicity per the IND 
Sponsor. However, if there is grade 2 AST elevation with concurrent ALT or bilirubin elevation, then adjust treatment was written above for grade 2 AST, ALT, bilirubin 
abnormality. 
2 Patients who develop Grade 2 CK elevation will be allowed continued dosing with combined immunotherapy of pembrolizumab and IMC-CS4 as long as there is no clinical or 
laboratory signs of end organ damage and (2) urine and serum myoglobin are within normal range. 
3 Patients with intolerable or persistent Grade 2 drug-related AE may hold study medication at physician discretion.  Permanently discontinue study drug for persistent Grade 2 
adverse reactions for which treatment with study drug has been held, that do not recover to Grade 0-1 within 12 weeks of the last dose. 
 
 
 


 
 
 
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5.2.2.1 If any of the above events in Table 4 occur, the investigator should 
discuss with the Principal Investigator to make a decision on discontinuation of 
pembrolizumab study treatment.  In case toxicity does not resolve or improve to 
≤ Grade 1 within 12 weeks after last administration of study drug, study therapy 
discontinuation should be considered after discussion with the Principal 
Investigator and IND Sponsor.  With IND Sponsor and Drug Sponsor agreement, 
patients still at Grade 2 may continue in the study only if asymptomatic and 
controlled.  Two dosing delays due to the same toxicity will be permitted.  In the 
event of a third occurrence of the same toxicity which would require dosing 
delay, study therapy will be discontinued permanently, except in select cases of 
pembrolizumab-only irAEs, at which time post-surgical resection patients may 
be eligible for continuation of CY/GVAX booster therapy. 
 
5.2.2.2 In case toxicity does not resolve to Grade 0-1 within 12 weeks after last 
infusion, pembrolizumab and/or IMC-CS4 should be discontinued after 
consultation with the IND Sponsor. With IND Sponsor and drug companies’ 
agreement, subjects with a laboratory adverse event still at Grade 2 after 12 
weeks may continue treatment in the trial only if asymptomatic and controlled. 
 
5.2.3  If a delay occurs between day 1 and 2 of a cycle: 
 
• Pembrolizumab and IMC-CS4 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, pembrolizumab, and IMC-CS4) if the delay is 
within 72 hours. 
• If the delay is longer than 72 hours, repeat Day 1 and Day 2 study 
treatments/assessments 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.  
 
 
Subjects who have completed surgery that are required to stop treatment with 
pembrolizumab or IMC-CS4 due to toxicity may stay on study and receive 
CY/GVAX pancreas vaccine to complete the four-adjuvant (6 total treatments) 
once pembrolizumab-related or IMC-CS4 related toxicity(s) has resolved to a 
grade 1. 
 
5.2.4  Patients should ideally undergo surgical resection within 7-12 weeks from last 
radiation dose if this was given in the neoadjuvant setting.. If treatment delays 
occur during the administration of neoadjuvant immunotherapy, it should be 
discussed between treating physician, study PI and treating surgeon as it may 
impact the date for surgical resection. If deemed clinically necessary patients 
will proceed with surgical resection as planned and still allowed to receive 
adjuvant therapy per protocol as long as they had received one full cycle of 
neoadjuvant immunotherapy. 


 
 
 
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5.2.5  Patients who develop immune related toxicities while receiving neoadjuvant 
immunotherapy can receive shorter courses of steroids when clinically 
appropriate. This would minimize complications during standard of care surgery 
secondary to prolonged use of steroids.  
 
6. 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 4.0 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. 
 
6.1 Definitions 
 
6.1.1  Adverse Event (AE) 
 
  
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). Adverse events 
occurring before starting the study treatment but after signing the informed 
consent form will not be recorded. 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. 


 
 
 
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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. 
 
6.1.2 Serious Adverse Event (SAE) 
 
 
A serious adverse event (SAE) is an undesirable sign, symptom or medical 
condition which:  
 
 
• Results in death  
 
• Is life threatening (defined as an event in which the subject was at risk of death 
at the time of the event; it does not refer to an event which hypothetically might 
have caused death if it were more severe)  
 
• Requires inpatient hospitalization or causes prolongation of existing 
hospitalization (see note below for exceptions) > 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 
 
 
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)  
 
• 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). 
 
6.1.3   Events of Clinical Interest (ECI)  
 
 
Events of clinical interest for this trial include: 


 
 
 
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• 
An overdose of study drug, as defined in Section 4.3, that is not associated 
with clinical symptoms or abnormal laboratory results.  
 
• 
An elevated AST or ALT lab value that is greater than or equal to 3X the 
upper limit of normal and an elevated total bilirubin lab value that is greater 
than or equal to 2X the upper limit of normal and, at the same time, an 
alkaline phosphatase lab value that is less than 2X the upper limit of normal, 
as determined by way of protocol-specified laboratory testing or 
unscheduled laboratory testing.* 
 
 
*Note:  These criteria are based upon available regulatory guidance documents. 
The purpose of the criteria is to specify a threshold of abnormal hepatic tests that 
may require an additional evaluation for an underlying etiology.  
 
6.2 
Relationship 
 
The relationship of an AE to the administration of the study drug is to be assessed by 
the investigator according to the following definitions:  
 
• No (unrelated, not related, no relation):  The time course between the administration 
of study drug and the occurrence or worsening of the adverse event rules out a causal 
relationship and another cause (concomitant drugs, therapies, complications, etc.) is 
suspected.  
 
• 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 


 
 
 
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properties (absorption, distribution, metabolism, and excretion) of the study drug 
should be considered. 
 
Assessment of Grade: 
 
The investigator will make an assessment of grade for each AE and SAE reported 
during the study, which will be recorded in the CRF. The assessment will be based on 
the National Cancer Institute’s CTCAE (Version 4.0) and graded as shown below: 
 
• 
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated 
• 
Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living 
• 
Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-
care activities of daily living 
• 
Grade 4: Life-threatening consequences; urgent intervention indicated 
• 
Grade 5: Death related to AE 
 
Any AE that changes in grade during its course will be recorded in the CRF at the 
highest level experience by the subject. 
 
6.3 
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. 
 
6.4 
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 Brochure), 
and definitely, probably, or possibly related to pembrolizumab, IMC-CS4, or 
CY/GVAX. 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 Investigator’s 
Brochure 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.  


 
 
 
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6.5  
Reporting 
 
6.5.1  General 
 
All adverse events (both expected and unexpected) will be captured on the 
appropriate study-specific case report forms (CRFs). Adverse events 
experienced by subjects will be collected and reported from the first dose of the 
study drug, throughout the study, and will only be followed for 30 days (or 
within 7 days prior to initiation of a new anti-cancer treatment, whichever comes 
first) unless related to the study drug(s). Adverse events related to the study 
drug(s) will be monitored for resolution of toxicity to ≤ grade 1, stabilization, or 
determined to be irreversible by the investigator.  
 
Surgery and chemotherapy (when applicable) are considered standard of care 
(SOC). Patients will be considered off treatment between day 30 of cycle 2 
through day -1 of cycle 3, while they are receiving SOC treatment. Adverse 
events will be reviewed to ensure that the combination of CY, GVAX, 
pembrolizumab, and IMC-CS4 are not contributing to postoperative 
complications. Surgical complications will be collected in a separate log, but 
will not be recorded as adverse events unless determined to be related to 
immunotherapy.  Please refer to Section 6.6 for the assessment and recording of 
surgical AEs.  Unrelated adverse events that occur during the off study period 
between cycles 2 and 3 of treatment will not be recorded on the CRFs. 
 
ECIs will be collected and reported from the first dose of study drug through 30 
days after the last dose of study drug (or within 7 days prior to initiation of a new 
anti-cancer treatment, whichever comes first). ECIs must be reported within 24 
hours to the IND Sponsor (email: 
), Merck Global Safety 
 and Eli Lilly (Attn: Local 
Safety representative; 
 using the Adverse Event of 
Clinical Interest Case Report Form found in Appendix B. 
 
SAEs that occur from the first dose of study drug to within 90 days of the last 
infusion of pembrolizumab (or before initiation of a new antineoplastic 
treatment, whichever occurs first), with the exception of unrelated SAEs that 
occur during the off study period between cycles 2 and 3 of immunotherapy (day 
30 of cycle 2 through day -1 of cycle 3) should also be followed and recorded. 
All SAEs, regardless of causality to study drug, will be reported promptly 
to the IND Sponsor 
 Merck Global Safety (Attn: 
Worldwide Product Safety; 
, and Eli Lilly (Attn: Local 
Safety representative; 
within 24 hours of recognition 
of the adverse event using the form found in 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. 


 
 
 
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After the initial 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 SAE(s) will be followed until: 
• Resolution 
• The condition stabilizes 
• The event is otherwise explained 
• The subject is lost to follow-up 
 
 
As soon as relevant information is available, a follow-up SAE report will be 
submitted to the IND Sponsor, Merck GS, and Eli Lilly local safety 
representative. 
 
 
Although pregnancy and lactation are not considered adverse events, it is the 
responsibility of investigators or their designees to report any pregnancy or 
lactation in a subject (spontaneously reported to them), including 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 serious adverse events (Important Medical Events). If the pregnancy 
continues to term, the outcome (health of infant) must also be reported to the 
IND Sponsor, Merck GS, and Eli Lilly local safety representative. 
6.5.2  Institutional Review Board (IRB) and Institutional Biosafety Committee 
(IBC) 
 
 
  Serious adverse events will be reported to the IRB and IBC per institutional 
guidelines. Follow-up information will be submitted to the IRB and IBC as soon 
as relevant information is available. 
 
6.5.3  Food and Drug Administration (FDA) 
 
 
All reporting to the FDA will be completed by the IND Sponsor. 
 
 
6.5.3.1 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 


 
 
 
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(301-827-9796) to the FDA within 7 calendar days of first learning of the event.   
 
 
15 Calendar-Day Written Report:   
 
The IND Sponsor is required to notify the FDA of any serious adverse event that 
is unexpected and possibly 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 analyzed.  The new report 
should contain comments on the significance of the new event in light of the 
previous, similar reports. Follow-up information will be submitted to the FDA 
as soon as relevant information is available. 
 
 
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.  
 
 
6.5.3.2 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. 
 
6.5.4 Recombinant DNA Advisory Committee (RAC) 
 
 
Unexpected SAEs believed to be related to the investigational product(s) will be 
reported to RAC by email if fatal or life-threatening within 7 calendar days or 
within 15 calendar days if related and unexpected to the investigational 
product(s). 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. 
 
6.6  Special Considerations for Adverse Events that Occur During the Surgery and    
       Postoperative Course 
 
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 deemed to be standard of care, therefore, is not 
part of this research study. From the day of surgery through the initiation of adjuvant 
immunotherapy, participants will be primarily followed by their primary surgeons for 
monitoring and managing the complications and comorbidities attributable to the 


 
 
 
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surgery. Table 5 summarizes complications commonly associated with the pancreatic 
surgery based on several published analyses of more than 1000 patients at Johns 
Hopkins Medicine and other institutions44   A normal, uncomplicated postoperative 
course is still commonly associated with laboratory abnormalities (grade 1/2 AEs and 
occasionally grade 3 AEs) without need 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 6). 
 
Table 5: Complications after Pancreaticoduodenectomy  
 
Anastomotic leak, pancreas 
Anastomotic leak, intestinal 
Wound infection 
Gastrointestinal bleeding 
Delayed gastric emptying 
Pleural effusion 
Hemorrhage, immediate postoperative or delayed 
Pneumonitis 
Intraabdominal abscess 
Sepsis 
Fascial dehiscence or evisceration 
Acute respiratory distress syndrome  
Supraventricular arrhythmia 
Angina, cardiac ischemia 
Urinary tract infection 
Aspiration 
Anastomotic leak, biliary 
Cardiopulmonary arrest 
Pancreatitis 
Catheter-related infection 
Hypotension, shock 
Constipation 
Cellulitis 
Delerium tremens 
Clostridium difficile colitis 
Fever 
Congestive heart failure, left ventricular dysfunction 
Fluid imbalance 
Myocardial infarction 
Gastroesophageal reflux disease 
Renal failure 
Congestive heart failure 
Apnea or hypoxia 
Ileus 
Atelectasis 
Interstitial pneumonitis and fibrosis 
Catheter-related infection 
Prolonged intubation 
Deep venous thrombosis 
Salivary gland infection 
Dehydration 
Small bowel obstruction 
 
 
 


 
 
 
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Table 6: 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 CTCAEv4.0 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 7). 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 7: 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 
Elevated 
Grade 1-4 
Alkylosis 
Elevated 
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 6). The severity of 
any SAEs associated with such grades of complications should be considered 


 
 
 
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54 
uncommon.  Second, any unusual complications 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 7). 
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 6 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 6.2. Reporting of these events will follow the same guidelines 
described in Sections 6.5. 
 
7. PHARMACEUTICAL INFORMATION 
 
7.1  
Cyclophosphamide (Cytoxan®, CY) 
 
7.1.1   Agent Accountability 
 
 
The IND Sponsor or the Sponsor’s representative shall take responsibility for 
and shall take all steps to maintain appropriate records and ensure appropriate 
supply, storage, handling, distribution and usage of investigational product in 
accordance with the protocol and any applicable laws and regulations. 
 
7.1.2  Mode of Action 
 
 
CY is a synthetic antineoplastic drug chemically related to the nitrogen 
mustards. CY is biotransformed principally in the liver to active alkylating 
metabolites by a mixed function microsomal oxidase system. These metabolites 
interfere with the growth of susceptible rapidly proliferating malignant cells. The 
mechanism of action is thought to involve cross-linking of tumor cell DNA. 
 
7.1.3  Description 
 
 
CY (CYTOXAN®; cyclophosphamide for injection, USP) is a sterile, white 
powder containing cyclophosphamide monohydrate and is supplied in vials for 
single-dose use. 
 
7.1.4  Packaging and Labeling Information 
 
CY is commercially available. 
 
7.1.5  Preparation 
 
 
Parenteral drug products should be inspected visually for particulate matter and 
discoloration prior to administration, whenever solution and container permit. 


 
 
 
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Add the diluent to the vial and shake it vigorously to dissolve. If the powder fails 
to dissolve immediately and completely, it is advisable to allow the vial to stand 
for a few minutes. Use the quantity of diluent shown below to constitute the 
product: 
 
Dosage 
Strength 
CYTOXAN Contains 
Cyclophosphamide Monohydrate 
Quantity of Diluent 
 
500 mg 
534.5 mg 
25 mL 
1 g 
1069.0 mg 
50 mL 
2 g 
2138.0 mg 
100 mL 
 
CY may be prepared for parenteral use by infusion using any of the following 
methods: 
1. CY constituted with 0.9% sterile sodium chloride may be infused without 
further dilution. 
2. CY constituted with 0.9% sterile sodium chloride may be infused following 
further dilution in the following: 
 
• Dextrose Injection, USP (5% dextrose) 
• Dextrose and Sodium Chloride Injection, USP (5% dextrose and 0.9% 
sterile sodium chloride) 
• 5% Dextrose and Ringer’s Injection 
• Lactated Ringer’s Injection, USP 
• Sodium Chloride Injection, USP (0.45% sterile sodium chloride) 
• Sodium Lactate Injection, USP (1/6 molar sodium lactate) 
 
7.1.6  Storage 
 
Store vials at or below 77° F (25° C). 
 
7.1.7  Stability 
 
 
CY (prepared for either direct injection or infusion) is chemically and physically 
stable for 24 hours at room temperature or for 6 days in the refrigerator; it does 
not contain any antimicrobial preservative and thus care must be taken to assure 
the sterility of prepared solutions. 
 
7.1.8  Administration 
 
CY is administered at 200 mg/m2 in 100 mL NS by IV injection over 30 minutes. 
 
7.1.9  Subject Care Implications 
 
 
During treatment, the subject’s hematologic profile (particularly neutrophils and 
platelets) should be monitored regularly to determine the degree of 


 
 
 
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hematopoietic suppression. 
 
 
The rate of metabolism and the leukopenic activity of CY reportedly are 
increased by chronic administration of high doses of phenobarbital. The 
physician should be alert for possible combined drug actions, desirable or 
undesirable, involving CY even though CY has been used successfully 
concurrently with other drugs, including other cytotoxic drugs. CY treatment, 
which causes a marked and persistent inhibition of cholinesterase activity, 
potentiates the effect of succinylcholine chloride. If a subject has been treated 
with CY within 10 days of general anesthesia, the anesthesiologist should be 
alerted. 
 
 
CY may interfere with normal wound healing. 
 
7.1.10 Returns and Reconciliation 
 
N/A 
 
7.2  
GVAX Pancreas Vaccine 
 
7.2.1  Agent Accountability 
 
 
The IND Sponsor or the Sponsor’s representative shall take responsibility for 
and shall take all steps to maintain appropriate records and ensure appropriate 
supply, storage, handling, distribution and usage of investigational product in 
accordance with the protocol and any applicable laws and regulations. 
 
7.2.2  Mode of Action 
 
 
GM-CSF-secreting, irradiated, whole cell vaccines recruit and activate tumor-
specific T cells and induce a cytotoxic response through two mechanisms: 1. 
they deliver a range of peptide antigens (without the need for specific knowledge 
of the relevant target antigens), and 2. GM-CSF is an important growth and 
differentiation factor for dendritic cells, which are potent antigen-presenting 
cells. 
 
7.2.3  Description 
 
 
 
 


 
 
 
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7.2.4  Packaging and Labeling Information 
 
 
 
7.2.5  Preparation 
 
 
 
7.2.6  Storage 
 
 
 
7.2.7  Stability 
 
 
 
7.2.8  Administration 
 
 
 
7.2.9  Subject Care Implications 


 
 
 
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7.2.10 Returns and Reconciliation 
 
 
The investigator is responsible for keeping accurate records of the clinical 
supplies, the amount administered to subjects, and the amount remaining at the 
conclusion of the trial. 
 
7.3 
Pembrolizumab (KEYTRUDA®, MK-3475) 
 
7.3.1  Agent Accountability 
 
 
The IND Sponsor or the Sponsor’s representative shall take responsibility for 
and shall take all steps to maintain appropriate records and ensure appropriate 
supply, storage, handling, distribution and usage of investigational product in 


 
 
 
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accordance with the protocol and any applicable laws and regulations. 
 
7.3.2  Mode of Action 
 
 
Pembrolizumab is a highly selective humanized monoclonal antibody designed 
to block the interaction between PD-1 and its ligands, PD-L1 and PD-L2. 
Pembrolizumab is an IgG4/kappa isotype with a stabilizing sequence alteration 
in the Fc region.  
 
7.3.3  Description 
 
 
 
7.3.4  Packaging and Labeling Information 
 
 
 
7.3.5  Storage and Handling Requirements 
 
 
 
 
 
 
 
7.3.6  Returns and Reconciliation 
 
 
 
 


 
 
 
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7.3.7  Administration 
 
 
7.3.8  Patient Care Implications 
 
 
 
 
 
7.3.9  Agent Ordering 
 
 
 
 
 
7.3.10  Returns and Reconciliation 
 
 
The investigator is responsible for keeping accurate records of the clinical 
supplies received from Merck or designee, the amount administered to patients, 
and the amount remaining at the conclusion of the trial. 
 
 
Upon completion or termination of the study, all unused and/or partially used 
investigational product will be destroyed at the site per institutional policy. It is 
the Investigator’s responsibility to arrange for disposal of all empty containers, 
provided that procedures for proper disposal have been established according to 
applicable federal, state, local and institutional guidelines and procedures, and 
provided that appropriate records of disposal are kept. 
 


 
 
 
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7.4  
IMC-CS4/ LY3022855 
 
7.4.1  Agent Accountability 
 
 
The IND Sponsor or the Sponsor’s representative shall take responsibility for 
and shall take all steps to maintain appropriate records and ensure appropriate 
supply, storage, handling, distribution and usage of investigational product in 
accordance with the protocol and any applicable laws and regulations. 
 
7.4.2 Mode of Action 
   
 
IMC-CS4 is a human IgG1 monoclonal antibody designed to target the colony 
stimulating factor 1 receptor (CSF-1R) to block the interaction between the CSF-
1R and its ligand colony stimulating factor 1 (CSF1). 
 
7.4.3  Description 
 
   
 
  
 
7.4.4  Packaging and Labeling Information 
 
 
 
7.4.5  Preparation 
 
 
 


 
 
 
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7.4.6  Storage 
 
 
 
 
 
 
 
7.4.7  Stability 
 
 
 
7.4.8  Administration 
 
 


 
 
 
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7.4.9  Patient Care Implications 
 
 
 
 
 
 
 
7.4.10  Agent Ordering 
 
 
7.4.11 Returns and Reconciliation 
 


 
 
 
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The investigator is responsible for keeping accurate records of the clinical 
supplies, the amount dispensed to subjects, and the amount remaining at the 
conclusion of the trial. 
 
 
Upon completion or termination of the study, all unused and/or partially used 
investigational product will be destroyed at the site per institutional policy. It is 
the Investigator’s responsibility to arrange for disposal of all empty 
containers, provided that procedures for proper disposal have been established 
according to applicable federal, state, local and institutional guidelines and 
procedures, and provided that appropriate records of disposal are kept. 
 
8. CORRELATIVE/SPECIAL STUDIES 
 
8.1 
Tumor Tissue and Whole Blood for Peripheral Blood Mononuclear Cells 
(PBMC) and Circulating Tumor Cells (CTCs) Studies 
 
A research tumor biopsy will be collected (4 to 6 cores, fine needle aspiration will not 
be acceptable) during the scheduled endoscopy that will occur following the 
completion of chemotherapy and/or radiation and within 14 days prior to the first day 
of treatment. This post-radiation biopsy is not standard of care, but it is a mandatory 
part of the research study. If subjects have inaccessible tumors or for whom the biopsies 
are thought not in their best interest, they will be ineligible for the study. Additional 
biopsies (via surgical resection specimen) will also be requested of patients after 
completion of 2 doses of combined immunotherapy. Archival tumor samples may also 
be collected for every patient (slides and/or blocks). These tissue samples will be 
banked for the evaluation of PD-L1/PD-1, 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.  
 
Whole blood for PBMCs (up to 120cc) will be collected at the specified timepoints 
(See Section 9). Up to 20cc of whole blood may be collected for the isolation of 
circulating tumor cells.  Detailed instructions for blood collection, processing, and 
storage are provided in the Laboratory Manual.  
 
Immunohistochemistry, flow cytometry, quantitative PCR assays and microarray 
analysis will be employed. Peripheral Blood Mononuclear Cells (PBMC) 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. 
Intratumoral response to CSF-1R inhibition will be measured by IHC of 
monocytes/macrophages on the FFPE slides of pre- and post-treatment biopsy 
specimens, and measured by using ELISA to measure serum CSF1 levels.  
 
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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8.1.1 Immunohistochemistry 
 
 
 
Immunohistochemistry of immune parameters relevant to the PD-L1/PD-1 
pathway will be performed on FFPE slides of pre-treatment core biopsy and 
post- treatment surgically resected PDA specimens. The IHC protocols were 
previously established.   We will examine the densities and distribution of 
effector T cells (Teff) including CD8, CD45RO, CXCR3, CD68+ and CD69+ 
cells, expression of immune suppressive signals including PD-1, PD-L1, PD-L2, 
LAG3, TIM3, and IDO1,  immune activation signals including CD137(4-1BB), 
4-1BBL, OX40, OX40L,  CD40, and CD40L on T cells and macrophages, and 
the expression of T helper cell differentiation markers including Tbet (for Th1), 
GATA3 (for Th2), RORT (for Th17), and Foxp3 (for Treg) as previously 
described.14  Quantification of IHC on immune markers will be conducted by 
Aperio’s Immune Analysis Software Program as described previously14 and will 
be supervised by our pathologist (Dr. Robert Anders). We will particularly 
examine whether the combination of GVAX, anti-PD-1 therapy, and CSF1R 
inhibitor will collaboratively suppress the Treg pathway as our preclinical study 
in the mouse model showed that GVAX and anti-PD-1 antibody were able to 
collaboratively bring down the increased infiltration of Treg induced by either 
GVAX or anti-PD1-antibody.22 
 
8.1.2 Gene Expression Assays 
 
 
Quantitative gene expression assays such as nanostring assays and cytokine 
arrays will be used to assess whether the combination of anti-PD-1 therapy and 
CSF-1R inhibition tips the balance between Th1 vs. Th2, M1 vs. M2, Teff vs. 
Treg within tumor microenvironment.  Tissues derived from FFPE sections of 
biopsy specimens will also be subject to the analysis of Merck's nanostring 
panels in collaboration with Merck’s scientists (Shankaran et al. ASCO GI 
2015). We will particularly focus on the genes expression signatures listed in 
Table 8 and the signature founded to correlate with responses to the 
pembrolizumab treatment. In addition, fresh frozen biopsy specimens will be 
subjected to the cytokine array analysis by a well-established protocol in the 
Zheng Lab using a commercially available cytokine protein array (R&D). We 
will particularly focus on the Th1 vs. Th2 cytokines, M1 vs. M2 cytokines and 
the chemokines that are involved in T cell trafficking. 
 
8.1.3 T cell receptor repertoire analysis 
 
 
 
Tumor antigen-specific T cells that traffic into the tumor are the most relevant T 
cells to study when evaluating antitumor immune responses.  We will examine 
the TCR repertoire in PBMC and TIL from FFPE sections, using next-generation 
sequencing. We will compare TCR repertoires in pre-treatment vs. post-
treatment PBMC and pre-treatment biopsy specimens vs. post-treatment 


 
 
 
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66 
specimens from the same patients to identify TCR’s expressed by T cells that 
expand following treatment. We will also compare TCR repertoires in PBMC vs 
TIL from the same patients to identify any T cell clones that are induced or 
expanded in PBMC by vaccine+ Pembro+CSF1R inhibitor and also enriched in 
TIL.  We will use these data to determine if T cells in PBMC and TIL undergo 
clonal expansion following GVAX+Pembro+CSF1R inhibitor treatment, and if 
so, whether the vaccine-expanded T cell clones traffic to the PDA TME. 
 
Table 8. Immune-Related Gene Expression Signatures (Shankaran et al. ASCO GI 2015) 
 
IFN γ 
Expanded Immune 
TCR Signaling 
De Novo 
IDO1 
CXCL10 
CXCL9 
HLA-DRA 
STAT1 
IFNG 
CD3D NKG7 
IDO1 HLA-E 
CIITA CXCR6 
CD3E LAG3 
CCL5 TAGAP 
GZMK CXCL10 
CD2 STAT1 
HLA-DRA GZMB 
CXCL13 
IL2RG 
CD27 
TIGIT 
CD8A 
CD3D 
GRAP2 
LCK 
PTPRCAP 
CD4 
CCL5  
IL2RB IKZF3 
CD3G CD74 
IKZF3 SAMHD1 CD38 
HLA-DPB1 TIGIT CRTAM 
CD27 IL2RB CD8A 
AMICA1 TARP CXCL9 
CD74 CD3D HLA-C 
LY9 CD3G GPR18  
CD4 HLA-B IL18 
HLA-DRA IGJ CX3CR1 
B2M IRF1 CXCL10 
IGSF6 BST2 SIT1 
FASLG PTPN7 LCK 
IFN = interferon; TCR = T-cell receptor. 
 
8.2  
Serum and Plasma Marker Studies 
 
Sera (up to 5 cc) and plasma (up to 20cc) will be collected at the specified timepoints 
(See Section 9) to identify potential therapeutic targets, biomarkers, and predictors of 
response and autoimmune toxicity through proteomic approaches. ELISA will also be 
used to measure serum CSF1 levels. Detailed instructions for blood collection, 
processing, and storage are provided in the Laboratory Manual. 
 
8.3 
Diagnostic Tissue Samples 
 
Tissue, fluid, or blood may be collected from standard of care procedures used to treat 
or diagnoses immune related toxicities.  
 
8.4 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 


 
 
 
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67 
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. 
 
 
9. STUDY SCHEDULE 
 
9.1  
Study Schedule Prior to Surgery 
 
Subjects will be screened after completing neoadjuvant therapy for resectable or 
borderline resectable pancreatic cancer. Treatment should start no later than 28 days of 
last dose of neoadjuvant therapy.  


 
 
 
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Study Schedule Prior to Surgery 
Procedure 
Screening visit (7 
days from last 
dose of 
neoadjuvant 
therapy1 
Cycle 1 Immunotherapy2 
(7-28 days from last dose 
of neoadjuvant therapy) 
Cycle 2 Immunotherapy 
(3 weeks after 
Immunotherapy #1) 
Post Immunotherapy 
Evaluation 
(7-14 days after 
Immunotherapy#2)17 
C1
D1 
C1
D2 
C1
D8 
C1
D15 
C2
D1 
C2
D2 
C2
D8 
C2
D15 
Visit Window3 
 
- 
- 
- 
- 
+7 
- 
- 
- 
+7 
Cyclophosphamide 
 
X 
 
 
 
X 
 
 
 
 
GVAX 
 
 
X 
 
 
 
X 
 
 
 
Pembrolizumab 
 
X 
 
 
 
X 
 
 
 
 
IMC-CS4 
 
X 
 
X 
X 
X 
 
X 
X 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Medical History, Medications4 
X 
 
 
 
 
 
 
 
 
 
Physical Exam5 
X 
X 
 
 
 
X 
 
 
 
X 
Vital signs and pulse ox6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height6 
X 
 
 
 
 
 
 
 
 
 
Weight6 
X 
X 
 
 
 
X 
 
 
 
X 
Performance Status 
X 
X 
 
 
 
X 
 
 
 
X 
Hematology profile7,8 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
Chemistry profile8,9 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
TSH8,10 
 
X 
 
 
 
X 
 
 
 
X 
CK 
X 
X 
 
 
 
X 
 
 
 
X 
Serum or Urine Pregnancy test11 
X 
X11 
 
 
 
X 
 
 
 
 
CA 19-98 
X 
 
 
 
 
 
 
 
 
X 
Urinalysis and microscopic exam8,12 
X 
 
 
 
 
 
 
 
 
 
INR and pTT8 
X 
 
 
 
 
 
 
 
 
X 
Adverse event evaluation5 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Vaccine Site Assessment 
 
 
 
 
 
X 
 
 
 
X 
PET-CT, CT, or MRI13 
X 
 
 
 
 
 
 
 
 
X 
Tumor measurements13 
X 
 
 
 
 
 
 
 
 
X 
Pathology Review 
X 
 
 
 
 
 
 
 
 
X 
Peripheral blood for PBMC (up to 
120cc)14,18 
 
X 
 
 
 
 
 
 
 
X 


 
 
 
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Study Schedule Prior to Surgery 
Procedure 
Screening visit (7 
days from last 
dose of 
neoadjuvant 
therapy1 
Cycle 1 Immunotherapy2 
(7-28 days from last dose 
of neoadjuvant therapy) 
Cycle 2 Immunotherapy 
(3 weeks after 
Immunotherapy #1) 
Post Immunotherapy 
Evaluation 
(7-14 days after 
Immunotherapy#2)17 
C1
D1 
C1
D2 
C1
D8 
C1
D15 
C2
D1 
C2
D2 
C2
D8 
C2
D15 
Peripheral blood for plasma (up to 
20cc)14,18 
 
X 
 
 
 
 
 
 
 
X 
Peripheral blood for CTC (up to 20 
cc)14,18 
 
X 
 
 
 
 
 
 
 
X 
Serum (up to 5cc)14,18 
 
X 
 
 
 
 
 
 
 
X 
EUS Core Biopsy18 
X15 
 
 
 
 
 
 
 
 
X16 
Surgical Evaluation 
X 
 
 
 
 
 
 
 
 
X 
 
In order to minimize the need for research-only in-person visits, telemedicine visits may be substituted for inperson clinical trial visits or portions 
of clinical trial visits where determined to be appropriate and where determined by the investigator not to increase the participants risks. Prior 
to initiating telemedicine for study visits the study team will explain to the participant, what a telemedicine visit entails and confirm that the study 
participant is in agreement and able to proceed with this method. Telemedicine acknowledgement will be obtained in accordance with the 
Guidance for Use of Telemedicine in Research. In the event telemedicine is not deemed feasible, the study visit will proceed as an in-person visit. 
Telemedicine visits will be conducted using HIPAA compliant method approved by the Health System and within licensing restrictions. 
 
1.  Potential candidates will be identified when they are receiving neoadjuvant therapy.  
2.  Each immunotherapy consists of a combination of CY, GVAX, pembrolizumab, and IMC-CS4 
3.  Longer delays to be approved by the IND sponsor 
4.  Includes history of lung disease, HIV, hepatitis B or C infection, and complete cancer history, including primary site of cancer, gross 
location of primary tumor, histology, histologic grade, date of initial diagnosis, date of metastatic diagnosis, prior cancer therapy 
regimens 
5.  Complete physical exam will be completed at baseline; focused physical examinations will be conducted thereafter. Physical exams 
and AE assessments can be made up to 3 days prior to infusion. 
6.  Blood pressure, pulse, respiratory rate, and temperature will be collected at baseline, prior to CY, pembrolizumab, and IMC-CS4 
infusions, prior to and after GVAX pancreas vaccine administration, and during the post immunotherapy evaluation. Height will be 
taken at or prior to screening only. Weight will be obtained at baseline, prior to each cycle, and during the post immunotherapy 
evaluation. Pulse oximetry will be obtained at baseline and prior to dosing on Days 1, 8, and 15 of each cycle.  
7.  CBC with differential including absolute eosinophil count, absolute neutrophils, absolute lymphocytes, and platelets 


 
 
 
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8.  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. 
9.  Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, potassium, total protein, 
SGOT [AST], SGPT [ALT], sodium, CK, LDH, CRP. 
10. FT3 and FT4 to be checked reflexively if TSH is abnormal 
11. For WOCBP. Pregnancy tests must be done within 7 days of the first treatment and then will be repeated with each subsequent cycle 
(collected within a window of up to 3 days prior to dosing). 
12. Bilirubin, blood, glucose, ketones, leukocytes, nitrite, pH, color, protein, RBC and WBC count, and specific gravity 
13. Radiologic evaluations (CT pancreas protocol, chest, abdomen, and pelvis with contrast) and tumor measurements will be performed 
at baseline (within 28 days prior to the first study drug dose) and 7 to 14 days after completion of cycle 2 of combination 
immunotherapy (iRECIST per Appendix D).  Non-contrast CT Chest and MRI Abdomen/pelvis will be done for those with contrast 
allergies.  
14. Detailed instructions for blood collection, processing, and storage are provided in the Laboratory Manual.  OPTIONAL: At the 
discretion of the PI, 20 cc of whole blood may be collected for CTC as described in the Laboratory Manual.  
15. Endoscopy will be scheduled for obtaining 4-6 core biopsies at baseline. Biopsy should be obtained within 14 days prior to first dose 
of study drug. 
16. If subject is a surgical candidate, biopsy will be obtained during surgical resection.  If metastases are noted, an optional biopsy of 
metastases for research purposes will be performed. 
17. Window 7 days +/- 7 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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9.2  
Study Schedule After Surgery/ Adjuvant Chemotherapy 
 
After completing neoadjuvant therapy, subjects will be evaluated for surgical 
resectability at multidisciplinary tumor board (based upon clinical health status and 
resectability as per NCCN guidelines) and presence of distant metastatic disease 
 
• If subjects are deemed to have developed resectable tumors, they will undergo 
traditional surgical resection. 
 
• If a subject is noted to have developed metastases to the liver or other 
metastases that can be safely biopsied, optional biopsy of the metastases will 
be obtained 
 
Subjects without metastatic disease will have the option of receiving adjuvant 
chemotherapy within 4-8 weeks postoperatively, at the discretion of their primary 
oncologist. 
 
After adjuvant chemotherapy completion or after surgery if the subject does not receive 
adjuvant chemotherapy, subjects will then undergo repeat examination and further 
immunotherapy as per the below schedule: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
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Study Schedule After Surgery/ Adjuvant Chemotherapy 
 
 
 
Procedure 
Post-
surgery/chemo
-therapy 
evaluation 
(<=28 days 
before C3D1) 
Combination immunotherapy1 on 3-week cycles2 (=>28 days after standard adjuvant chemotherapy) 
 
C3 
D1 
C3 
D2 
C3 
D8 
C3 
D15 
C4 
D1 
C4 
D2 
C4 
D8 
C4 
D15 
C5 
D1 
C5 
D2 
C5 
D8 
C5 
D15 
C6 
D1 
C6 
D2 
C6 
D8 
C6 
D15 
Visit Window3 
- 
+7 
- 
- 
- 
+7 
- 
- 
- 
+7 
- 
- 
- 
+7 
- 
- 
- 
Cyclophosphamide 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
GVAX 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
Pembrolizumab 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
IMC-CS4 
 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
Physical Exam4 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Vital signs and pulse ox5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight5 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Performance Status 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Hematology profile6,7 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
Chemistry profile7,8 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
TSH7,9 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Serum or Urine Pregnancy10 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
CA 19-97 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
CK 
X  
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Adverse event evaluation4 
X13 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vaccine Site Assessment 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Con meds 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
CT or MRI11 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Tumor measurements11 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Peripheral blood for PBMC 
(up to 120cc)12,14 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Peripheral blood for plasma 
(up to 20cc)12,14 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Peripheral blood for CTC (up 
to 20cc)12,14 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Serum (Up to 5 mL)12,14 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 


 
 
 
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73 
In order to minimize the need for research-only in-person visits, telemedicine visits may be substituted for inperson clinical trial visits or portions 
of clinical trial visits where determined to be appropriate and where determined by the investigator not to increase the participants risks. Prior 
to initiating telemedicine for study visits the study team will explain to the participant, what a telemedicine visit entails and confirm that the study 
participant is in agreement and able to proceed with this method. Telemedicine acknowledgement will be obtained in accordance with the 
Guidance for Use of Telemedicine in Research. In the event telemedicine is not deemed feasible, the study visit will proceed as an in-person visit. 
Telemedicine visits will be conducted using HIPAA compliant method approved by the Health System and within licensing restrictions. 
 
1.  Each immunotherapy consists of a combination of CY, GVAX, pembrolizumab, and IMC-CS4. 
2.  Subjects will receive combination immunotherapy on a 21-day cycle.  If subjects develop irAE or toxicities precluding further 
pembrolizumab or IMC-CS4 administration, they will still be eligible to continue with CY/GVAX monotherapy to complete the 
booster treatment or until development of distant metastases.  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. 
3.  Longer delays to be approved by the IND Sponsor. 
4.  Focused physical examinations will be conducted.  Physical exams and AE assessments can be made up to 3 days prior to infusion. 
5.  Blood pressure, pulse, respiratory rate, and temperature will be collected during the post-chemotherapy evaluation, prior to CY, 
pembrolizumab, and IMC-CS4 infusions, and prior to and after GVAX pancreas vaccine administration. Weight will be obtained 
during the post-chemotherapy evaluation and prior to each cycle. Pulse oximetry will be obtained prior to dosing on Days 1, 8, and 
15 of each cycle. 
6.  CBC with differential including absolute eosinophil count, absolute neutrophils, absolute lymphocytes, and platelets. 
7.  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. 
8.  Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, potassium, total protein, 
SGOT [AST], SGPT [ALT], sodium, CK, LDH, CRP. 
9.  FT3 and FT4 to be checked reflexively if TSH is abnormal. 
10. For WOCBP. Pregnancy tests must be repeated with each subsequent therapy (collected within a window of up to 3 days prior to 
dosing). 
11. Radiologic evaluations (CT pancreas protocol, chest, abdomen, and pelvis with contrast) and tumor measurements will be performed. 
Non-contrast CT Chest and MRI Abdomen/pelvis will be done for those with contrast allergies. Cycle 5 scans may be done up to 7 
days prior to the infusion. 
12. Detailed instructions for blood collection, processing, and storage are provided in the Laboratory Manual.  OPTIONAL: At the 
discretion of the PI, 20 cc of whole blood may be collected for CTC as described in the Laboratory Manual. 
13. See Section 6.6 for the surgical toxicities that will be collected. 
 


 
 
 
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74 
14. 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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75 
 
9.3  
Study Schedule for Booster Study Immunotherapy 
 
Following the 4 adjuvant study therapy cycles, as long as the patient remains disease 
free and more than 90 days have not elapsed since the last immunotherapy treatment, 
the patients will receive 12 booster cycles of pembrolizumab every 3 weeks, and 2 
booster cycles of Cy/GVAX given every 18 weeks. The first booster Cy/GVAX will 
be given when receiving the 6th booster dose of pembrolizumab (cycle 12), and the 
second booster Cy/GVAX will be given when receiving the 12th booster dose of 
pembrolizumab (cycle 18). 
 
 
 
 
 
 
 


 
 
 
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76 
Study Schedule for Booster Immunotherapy 
Procedure 
Booster Pembrolizumab on 3-week cycle and Cy/GVAX on 18-week cycle 
Off 
Study1 
C7
D1 
C8
D1 
C9
D1 
C10
D1 
C11
D1 
C12
D1 
C12
D2 
C13
D1 
C14 
D1 
C15
D1 
C16
D1 
C17
D1 
C18
D1 
C18
D2 
 
Visit Window12 
+7 
+7 
+7 
+7 
+7 
+7 
+7 
+7 
+7 
+7 
+7 
+7 
+7 
+7 
+7 
Cyclophosphamide 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
GVAX 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
Pembrolizumab 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
Physical Exam11 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
Vital Signs and pulse ox2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
Performance Status 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
Hematology profile3,4 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
Chemistry profile4,5 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
TSH4,6 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
Serum or Urine Pregnancy4,7 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
CA 19-94 
X 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
X 
Adverse event evaluation 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
Vaccine Site Assessment 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
X 
Con meds 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
CT or MRI8 
X 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
X 
Tumor measurements8 
X 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
X 
Peripheral blood for PBMC 
(up to 120cc)9,10 
X 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
X 
Peripheral blood for plasma 
(up to 20cc)9,10 
X 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
X 
Peripheral blood for CTC 
(up to 20cc)9,10 
X 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
X 
Serum (up to 5cc)9.10 
X 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
X 
 
 
 
 


 
 
 
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77 
In order to minimize the need for research-only in-person visits, telemedicine visits may be substituted for inperson clinical trial visits or portions 
of clinical trial visits where determined to be appropriate and where determined by the investigator not to increase the participants risks. Prior 
to initiating telemedicine for study visits the study team will explain to the participant, what a telemedicine visit entails and confirm that the study 
participant is in agreement and able to proceed with this method. Telemedicine acknowledgement will be obtained in accordance with the 
Guidance for Use of Telemedicine in Research. In the event telemedicine is not deemed feasible, the study visit will proceed as an in-person visit. 
Telemedicine visits will be conducted using HIPAA compliant method approved by the Health System and within licensing restrictions. 
 
1. 30 days after the last dose of study drug or within 7 days prior to initiation of a new anti-cancer treatment, whichever comes first. If 
the off study visit occurs early, scans do not need to be repeated if one has been done within the past 6 weeks. Patients who discontinue 
from treatment should be contacted (by phone or email) every six months (+/- 1 month) for up to 24 months or study closure to monitor 
overall survival. Information of other cancer therapies after discontinuation from the study treatment will be collected. The off study 
scan does not need to be repeated if one has been performed within 6 weeks of the visit. 
2. Blood pressure, pulse, respiratory rate, and temperature will be collected prior to CY and pembrolizumab infusions, prior to and after 
GVAX pancreas vaccine administration, and during the off study evaluation. Weight will be obtained prior to each cycle and during 
the off study evaluation. Pulse oximetry will be obtained prior to dosing on Day 1 of each cycle. 
3. CBC with differential including absolute eosinophil count, absolute neutrophils, absolute lymphocytes, and platelets. 
4. 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. 
5. Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, potassium, total protein, 
SGOT [AST], SGPT [ALT], sodium. 
6.  FT3 and FT4 to be checked reflexively if TSH is abnormal. 
7.  For WOCBP. Pregnancy tests must be done within 7 days of the first treatment and then will be repeated with each subsequent therapy 
(collected within a window of up to 3 days prior to dosing). 
8. Radiologic evaluations (CT pancreas protocol, chest, abdomen, and pelvis with contrast) and tumor measurements will be performed. 
Non-contrast CT Chest and MRI Abdomen/pelvis will be done for those with contrast allergies. Cycle 7, 12, and 18 scans may be 
done up to 7 days prior to the infusion. 
9.  Detailed instructions for blood collection, processing, and storage are provided in the Laboratory Manual.  OPTIONAL: At the 
discretion of the PI, 20 cc of whole blood may be collected for CTC as described in the Laboratory Manual. 
10. Research samples will be collected at the discretion of the PI based on availability of supplies and safety of patient and staff. 
11. Physical exams and AE assessments can be made up to 3 days prior to infusion. 
12. Window for C7-C18 is -3 days/+7 days.   
 
 


 
 
 
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78 
10. MEASUREMENT OF EFFECT 
 
10.1 Antitumor Effect – Solid Tumors 
 
10.1.1 Definitions 
 
 
Evaluable for toxicity. All subjects are evaluable for toxicity after receiving first 
dose of combined immunotherapy. 
 
 
Evaluable for objective response.  All patients who have received at least one 
dose of neoadjuvant immunotherapy (i.e. prior to surgery) and have had their 
disease re-evaluated with imaging prior to surgery will be considered evaluable 
for response.  Response criteria will be classified by immune-related RECIST 
(irRC) criteria (Appendix D) 
 
10.1.2 Methods for Evaluation of Measurable Disease 
 
 
 
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 beginning of treatment and never more than 28 days before the beginning 
of the treatment.  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 (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 baseline 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 


 
 
 
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79 
same as was used at baseline and the lesions should be measured/assessed on the 
same pulse sequence.  It is beyond the scope of the immune-related 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. 
 
10.1.3 Disease free survival (DFS) 
 
 
DFS is defined as the duration of time from start of treatment to identification of 
local or metastatic disease recurrence on imaging.  Individuals will be censored 
at the date of the last scan if no event occurs. 
 
10.1.4  Overall Survival (OS)  
 
 
OS is defined as the duration of time from start of study treatment to time of 
death.  Individuals will be censored at the date of the last scan if no event occurs. 
 
10.1.5 Overall Response Rate (ORR)  
 
 
Overall response rate as defined by the sum of complete response and partial 
response rate. 
 
10.1.6 Surgical Resectability Rate 
 
 
 
Surgical resectability after neoadjuvant therapy as determined by our pancreatic 
multidisciplinary group based upon NCCN guidelines for resectability. 
 
10.1.7 Pathologic Response Rate 
 
 
Pathologic response as determined by and the presence of residual disease in 
surgical specimen. 
 
11. DATA REPORTING / REGULATORY REQUIREMENTS 
 
Adverse event guidelines and instructions for AE reporting can be found in Section 6 
(Adverse Events: List and Reporting Requirements). 
 
11.1 Data Management 
 
All information will be collected on study-specific case report forms (CRFs) by study 
staff. These data will be reviewed for completeness and accuracy by the Principal 
Investigator.  
 


 
 
 
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11.2 Safety Meetings 
 
Scheduled meetings will occur on a regular basis with the frequency dependent on the 
rate of subject accrual and the progress of the study. Meetings will include the protocol 
principal investigator, study coordinator(s), research nurses(s), sub-investigators (as 
appropriate), collaborators (as appropriate), and biostatisticians (as appropriate) 
involved with the conduct of the protocol. During these meetings matters related to the 
following will be discussed: safety of protocol participants, validity and integrity of the 
data, enrollment rate relative to expectation, characteristics of participants, retention of 
participants, adherence to protocol (potential or real protocol violations), data 
completeness, and progress of data for objectives. 
 
Monthly teleconferences will be scheduled to include the Investigator and Merck 
representatives. During these meetings, the Investigator shall provide Merck with study 
progress updates.  The Investigator will provide a summary of key points from the 
weekly meetings with a focus on safety of the protocol participants, enrollment status, 
and progress of data for objectives.  In addition, Merck will provide safety and 
applicable program updates to the IND Sponsor. 
 
11.3  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.  The 
protocol will be monitored internally by the Principal Investigator. The protocol will 
be monitored externally by the SKCCC CRO in accordance with SKCCC guidelines. 
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 Medical Expert Committee (MEC) for this clinical study contains three medical 
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 and other participating site 
IRBs and 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 


 
 
 
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81 
(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. 
  
Dr. Jaffee will be holding the IND for this study.  She will comply with all regulated 
reporting requirements to the FDA. 
 
12. STATISTICAL CONSIDERATIONS 
 
12.1 Sample Size/Accrual Rate  
 
This pilot study aims to evaluate safety and efficacy of the triple combination of 
CY/GVAX, pembrolizumab, and CSF-1R inhibitor (IMC-CS4) in 8 evaluable patients 
with resectable or borderline resectable pancreatic cancer (BRPC) following induction 
chemotherapy (with or without  radiation) given before and after surgical resection. 
Toxicities are monitored and graded per CTCAE v4.0. Safety analyses will be based 
on all enrolled subjects who received at least one dose of any study treatment, including 
those who were found intraoperatively to be unresectable after the study treatment 
initiation. Participants in the current study will be considered evaluable if they have 
completed at least one dose of combination immunotherapy, have underwent an R0, 
R1 or R2 surgical resection of PDA and  have adequate tissue specimen for 
immunologic endpoints (pre-treatment core biopsy and surgical specimen). Even if 
there is a dose-reduction or an omission of a study drug (e.g. pembrolizumab, 
Cy/GVAX or IMC-CS4), as long as the subject as received one dose of the combination 
of immunotherapy at doses specified in Table 1 in Section 4.1 and underwent an R0, 
R1 or R2 surgical resection, then the patient is evaluable for the primary immunology 
endpoint. Analyses of efficacy endpoints will be based on evaluable patients.  
 
We expect that approximately 30% of patients who may be found intraoperatively to 
be unresectable after the study treatment initiation. We expect to obtain 8 evaluable 
patients with R0, R1 or R2 resection of their tumors. At the individual patient level, a 
significant treatment-related immunologic effect (i.e  immune response) in tumor 
infiltrating CD8 density is defined as a >80% increase or decrease (post vs pre-surgery) 
AND such increase/decrease is at least 1.8 times the baseline median absolute deviation 
(MAD), where the baseline MAD is defined as the median of the absolute deviation 
from the median calculated across patients and is thus a more robust measure of the 
variability than sample standard deviation. The treatment will be judged as yielding a 


 
 
 
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82 
promising biologic effect if at least 3 of 8 patients demonstrate an immune response. 
In this case, the rate of immune response is 38% and the corresponding binomial exact 
90% confidence interval is (0.11, 0.71). In other words, we will be able to claim the 
immune response rate in terms of significant change in tumor infiltrating CD8 density 
is significantly higher than 10% at a 10% Type I error rate. 
   
Each year, approximately 250 patients with newly diagnosed locally advanced 
pancreatic cancer are seen at JHH. Approximately, 50% of these patients will 
potentially be enrolled in clinical trials.  We estimate that we could complete the accrual 
goal within 9-12 months. 
 
12.2 Early Stopping Boundaries for Toxicity 
 
This pilot study aims to evaluate safety and immune efficacy of the triple combination 
of CY/GVAX, pembrolizumab, and CSF-1R inhibitor (IMC-CS4) in patients with 
resectable or borderline resectable pancreatic cancer (BRPC) following induction 
chemotherapy (with or without  radiation) given before and after surgical resection. 
Toxicities are monitored and graded per CTCAE v4.0.  Safety analyses will be based 
on all enrolled subjects who received at least one dose of any study treatment, including 
those who were found intraoperatively to be unresectable after the study treatment 
initiation.  
 
The first three patients in Phase One of this study will be monitored closely for 
toxicities (particularly grade 3 or 4 LFT abnormalities) and potential immune-related 
adverse events. If more than one patient developed grade 3 or 4, the study be halted for 
a safety consultation. Safety in the rest 9 patients in Phase Two will be monitored by a 
Bayesian stopping rule based on the rate of Grade 3/4 toxicities. The triple combination 
of GVAX, pembrolizumab, and IMC-CS4 will be considered feasible and safety if the 
risk of Grade 3/4 toxicities is lower than 30%. We will apply a Bayesian toxicity 
monitoring rule that suspends the enrollment if the posterior probability of risk being 
larger than that threshold is 75% or higher. According to the investigator’s brochure, 
9.5% of subjects experience grade 3 and higher toxicities with single-agent 
pembrolizumab 10 mg/kg administered every 2 weeks, so we expect increased toxicity 
from this study’s combination immunotherapy, but we do not expect grade 3 and higher 
toxicities to exceed 20%. We assume a priori that this triple combination has a rate of 
Grade 3/4 toxicities around 20% and that there is about a 24% chance that the rate is 
30% or higher. This corresponds to a Beta (1,4) prior distribution. The stopping rule 
will hold enrollment if the posterior probability of toxicity risk exceeding 30% is 70% 
or higher. Table 9 gives the corresponding stopping rules. For example, if 4 patients 
out of the first 5-7 patients experience unacceptable toxicities (as defined in Section 
4.5), accrual to the trial will be temporarily halted. The principal investigator, the study 
team, and the IND sponsor will review the toxicity data and recommend either 
modification or termination of the trial.  
 
 


 
 
 
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Table 9: The number of toxicities needed in Phase Two to trigger stopping 
guidelines throughout the course of the study 
   
Number of Subjects  
Number of toxicities needed to trigger re-evaluation 
2 
2 
3-5 
3 
6-8 
4 
9 
5 
  
12.3 Analysis of Primary Safety Endpoints 
 
Safety analyses will be based on all enrolled subjects who received at least one dose of 
any study treatment, including those who were found intraoperatively to be 
unresectable after the study treatment initiation. Subjects who discontinue prior to their 
first dose of study drug will be replaced and will not be included in the primary safety 
analysis.  A complete list of all AE data will be provided along with an assessment of 
NCI CTCAE grade and relationship to study drug. The proportion of patients with 
Grade 3/4 toxicities will be reported, together with the corresponding binomial exact 
95% confidence intervals. The incidence of AEs will be tabulated by subgroups of 
interest (e.g. grade 3 or higher, organ class, relationship to study drug). For analyses at 
the individual level, the highest grade and relationship to study drug will be assumed if 
multiple events have occurred. Toxicity will be tabulated by type and grade and will be 
summarized with descriptive statistics. Other safety data will be assessed in terms of 
physical examination, clinical chemistry, hematology, vital signs, and ECGs. A 
baseline measurement and at least 1 laboratory or other safety-related measurement 
obtained after at least 1 dose of study treatment may be required for inclusion in the 
analysis of these safety parameter (e.g., lab shifts from baseline). 
 
Surgical complications will be defined based on Clavien-Dindo classification.45  The 
monitoring rule will focus on Grade IIIa surgical complication or above, which is 
beyond what may be  expected for chemotherapy or resection without immunotherapy, 
and 
that 
may 
be 
attributable 
to 
these 
drugs 
(any 
component 
of 
Cy/GVAX/pembrolizumab/ and CSF-1R inhibitor).  If the risk of Grade IIIa or higher 
surgical complications appears to be greater than 40%, the study will temporarily be 
halted pending feasibility evaluations. The study may resume after discussion between 
the principal investigator and the IND sponsor if the surgical co-investigators do not 
deem there is an association of an increased rate of high grade postoperative 
complication with any of the study treatments.  Specifically, we apply a Bayesian 
monitoring rule that suspends the enrollment if the posterior probability of risk being 
greater than 40% is 0.5 or higher. The previous study showed 26% Grade IIIa or above 
post-operative complications in patients receiving neoadjuvant stereotactic body 
radiation therapy or chemoradiation therapy. 46 Thus, a Beta (2.5, 5.5) prior, 
representing the prior guess of a post-operative complications (Grade IIIa or above) 


 
 
 
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84 
rate of 31%, will be used.  Surgical complications will be monitored continuously 
according to the protocol amendment.  Table 10 shows the number of post-operative 
complications (Grade IIIa or above) that would need to be observed in order to trigger 
the stopping guidelines throughout the course of the trial. 
 
Table 10.  The number of post-operative complications (Grade IIIa or above) needed 
to trigger stopping guidelines throughout the course of the study. 
  
Number of Patients 
Number of post-operative 
complications (Grade IIIa 
or above) needed to 
trigger re-evaluation 
2-3 
2 
4-5 
3 
6-8 
4 
9-10 
5 
11-12 
6 
 
The probability of trigger the stopping was assessed for a range of true underlying post-
operative complications (Grade IIIa or above) rates using simulations with 5,000 
replicates (Table 11).  The probability of stopping is 22.5% if the true proportion with 
post-operative complications (Grade IIIa or above) rate was 25%.  In contrast, the 
probability of early stopping is 56.8% if the true proportion with post-operative 
complications (Grade IIIa or above) was 40%, the threshold for acceptable levels of 
post-operative complications (Grade IIIa or above). 
 
Table 11.  The operating characteristics of the stopping rule based on 5000 simulations. 
 
  
True rate of post-operative 
complications (Grade IIIa or 
above) 
% time study stops  Expected total sample size 
10% 
3 
11.7 
15% 
8.2 
11.3 
20% 
15.2 
10.8 
25% 
22.5 
10.2 
30% 
34.1 
9.4 
35% 
46.4 
8.4 
40% 
56.8 
7.7 
45% 
68.7 
6.8 
50% 
78.2 
5.9 
60% 
91.9 
4.5 
 
 
 


 
 
 
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85 
12.4 Analysis of Primary Immunology Endpoints 
  
The primary immunology endpoint is tumor infiltrating CD8 density. Other 
intratumoral immune parameters include but not limited to tumor-associated 
macrophages (TAM), effector T cell density, and vaccine-induced lymphoid 
aggregates. The evaluable population for the analysis of primary immunology 
endpoints includes all subjects who have completed at least one dose of combination 
immunotherapy and have underwent an R0, R1 or R2 surgical resection. Even if there 
is a dose-reduction or an omission of a study drug (e.g. pembrolizumab, Cy/GVAX or 
IMC-CS4), as long as the subject as received one dose of the combination of 
immunotherapy at doses specified in Table 1 in Section 4.1 and underwent an R0, R1 
or R2 surgical resection, then the patient is evaluable for the primary immunology 
endpoint.  Subjects who discontinue prior to their first dose of study drug will be 
replaced and will not be included in the primary efficacy analysis.   
 
Descriptive statistics for primary immune parameters in pretreatment tumor biopsy 
specimens and that in matched posttreatment resected tumors will be computed. 
Percent change in the intratumoral immune parameters will be reported using 
descriptive statistics and displayed graphically. Comparison of primary immune 
parameters between pretreatment tumor biopsy specimens and matched posttreatment 
resected tumors will be conducted using paired t-tests (or Wilcoxon signed rank tests 
if appropriate) and McNemar’s tests for dichotomous or categorical variables, 
respectively. At the individual patient level, a significant treatment-related 
immunologic effect is defined as a >80% increase or decrease (post vs pre-surgery) in 
a specific immune parameter AND such increase/decrease is at least 1.8 times the 
baseline median absolute deviation (MAD). The proportion of immune response for 
each intratumoral immune parameter will be reported along with its corresponding 
binomial exact 95% confidence interval.  
 
12.5 Analysis of Secondary and Exploratory Endpoints 
 
Secondary endpoints include subsequent surgical resectability, pathologic response 
rates, DFS and overall survival. All subjects who receive at least one dose of study drug 
will be included in the analysis of secondary endpoints.  DFS (for resectable patients) 
and OS will be described using the Kaplan-Meier method with 95% confidence 
intervals. Surgical resectability after neoadjuvant therapy as determined by our 
pancreatic multidisciplinary group based upon NCCN guidelines for resectability.47 
Pathologic response will be determined by pathologic examination. Proportions of 
surgical resectability and pathologic response will be reported along with the 
corresponding binomial exact 95% confidence intervals.  
 
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 


 
 
 
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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 either destroyed or stored on a JHU managed, 
HIPAA-compliant, password protected hard drive or Johns Hopkins University School 
of Medicine PMAP. 
 
 
12.6 Biomarker Analysis 
 
Potential relationships between biomarker data and efficacy or safety endpoints will be 
investigated as part of an analysis plan aimed at identifying baseline biomarkers that 
may be used to prospectively identify subjects likely (or not likely) to respond to 
combination pembrolizumab, CY, GVAX, and IMC-CS4 and to identify subjects who 
may be predisposed to having adverse reactions to treatment. These exploratory 
predictive biomarker analyses will be completed with biomarkers measured in blood 
and in tumor samples and will focus on factors outlined in the exploratory objectives. 
Similar analyses will be completed with peripheral blood samples. We will also explore 
standard protein biomarkers such as CA19-9 and other exploratory circulating 
biomarkers. The evaluable population includes all subjects who receive at least one 
dose of study drug and have biomarker measures.   
 
Continuous variables will be summarized with means or medians and standard 
deviations. Dichotomous and categorical variables will be summarized using 
proportions with exact 95% confidence intervals and counts, respectively. Summaries 
for both pre and post administration of each immunotherapy will be computed. Plots 
will be used to show the changes in immune response over time. 
 
Comparison in pre- and post-treatment biomarker data will be compared using paired 
t-tests (or Wilcoxon signed rank tests if appropriate) and McNemar’s tests for 
dichotomous or categorical variables.  Associations between immune parameters will 
be explored graphically (e.g. scatterplots, boxplots) and numerically (e.g. correlations, 
Fisher’s exact tests).  Mixed effects models will be used to assess the patterns in 
biomarkers over time. 
 
Efficacy measures will include OS, objective response, pathologic response, immune 
criteria of response, and DFS. Demographic and case-history factors will be examined 
to determine whether stratification or adjustments should be made within the 
subsequent statistical analyses, and if necessary, the appropriate stratification or 
adjustment will be made. Biomarkers will be summarized graphically as they relate to 
efficacy and safety endpoints, as applicable. Summary statistics will be tabulated. The 
relationships between binary measures (e.g. response) and time to event outcomes (e.g. 


 
 
 
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OS) and candidate biomarkers will be investigated using logistic regression and Cox 
proportional hazards regression, respectively. Associations will be summarized in 
terms of point and interval estimates of hazard ratios, odds ratios, or other statistics, as 
appropriate for the analyses completed. Models to predict clinical activity based on 
combinations of biomarkers may also be investigated. 
 
The significance level is set at 0.05 for all tests in the exploratory biomarker analyses 
unless otherwise specified.  
 
 


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


 
 
 
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APPENDIX B: Adverse Event of Clinical Interest (ECI) Reporting Form 
 
 
 


 
 
 
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Adverse Event of Clinical Interest (ECI) Reporting Form 
 
Please notify: IND Sponsor within 24 hours 
Merck within 24 hours (Fax: 
Eli Lilly within 24 hours (Fax: 
 
Protocol Title: 
 
 
A Pilot Study of a GVAX Pancreas Vaccine (with Cyclophosphamide) in 
Combination with a PD-1 Blockade Antibody (Pembrolizumab) and a Macrophage 
Targeting Agent (CSF1R inhibitor) for the Treatment of Patients with Borderline 
Resectable Adenocarcinoma of the Pancreas 
 
Protocol 
Number: 
J1766 
MK-3475-536 
Signature of PI: 
 
 
 
Principal Investigator: 
 
Date: 
 
 
 
Report Type: 
 
Initial          
Follow-up          
Final Follow-up          
Addendum to: 
 
Section A: Subject Information 
Subject ID: 
Subject Initial: 
 
Subject Gender: 
Male 
Female 
Section B: Event Information 
Event diagnosis 
or symptoms: 
 
Date of First Dose: 
Action taken with the study 
drug: 
 
None 
Interrupted 
Discontinued 
Delayed 
 
Pembrolizumab  
CY 
GVAX 
IMC-
CS4 
Date of Last Dose Prior to Event: 
Pembrolizumab  
CY 
GVAX 
IMC-
CS4 
Number of Total Doses: 
 
Pembrolizumab  
CY 
GVAX 
IMC-CS4 
Event Onset 
Date: 
Event End Date: 
 
 
 
Date Event Discovered: 
 


 
 
 
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Relationship to: 
Pembro 
lizumab 
CY 
GVAX 
IMC-
CS4 
Underlying Disease 
Unrelated 
 
 
 
 
 
Related 
 
 
 
 
 
Section C: Brief Description of the Event: (please include relevant procedures and laboratory values)  
 
Section D: Relevant Medical History 
 
Section E: Concomitant Drug (Not related to ECI) 
Name of the Drug 
Start Date 
Stop Date 
Route 
Dose 
Frequency 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section F: Comments 
 
Additional Documents: 
 Please specify 
 
 
 
 
 


 
 
 
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APPENDIX C: SAE Reporting Form 
 
 
 


 
 
 
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Serious Adverse Event Reporting Form 
 
Please notify: IND Sponsor within 24 hours 
Merck within 24 hours 
Eli Lilly within 24 hours 
 
Protocol Title: 
 
 
A Pilot Study of a GVAX Pancreas Vaccine (with Cyclophosphamide) in 
Combination with a PD-1 Blockade Antibody (Pembrolizumab) and a 
Macrophage Targeting Agent (CSF1R inhibitor) for the Treatment of Patients with  
Borderline Resectable Adenocarcinoma of the Pancreas 
 
Protocol 
Number: 
J1766 
MK-3475-536 
Signature of PI: 
 
 
Principal Investigator: 
 
Date: 
 
 
 
Report Type: 
Initial    
Follow-up 
Final Follow-up 
Death 
Addendum to: 
 
Serious Criteria (check all 
that apply): 
Death    
Life-threatening 
 Hospitalization or Elongation 
of Existing Hospitalization 
 Persistent or Significant 
Disability 
 Congenital Anomaly 
 Other Important Medical 
Event 
 Cancer 
 Overdose 
Hospital Admission Date:  
 
 
 
Hospital Discharge Date: 
Date Event 
Discovered: 
Section A: Subject Information 
Subject ID: 
Subject Initial: 
 
Subject Gender: 
Male 
Female 
Section B: Event Information 
Event diagnosis or 
symptoms: 
 
Date of First Dose: 
Action taken with the study drug: 
 
None 
Interrupted 
Discontinued 
Delayed 
 
Pembroliz
umab 
 
CY 
GVAX 
IMC-
CS4 
Date of Last Dose Prior to Event: 
Pembroliz
umab 
CY 
GVAX 
IMC-
CS4 
Number of Total Doses: 
Pembroliz
umab  
 
CY 
GVAX 
IMC-
CS4 


 
 
 
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Event Onset Date: 
Event End Date: 
Relationship to: 
Pembro 
lizumab 
CY 
GVAX 
IMC-
CS4 
Underlying Disease 
Unrelated 
 
 
 
 
 
Related 
 
 
 
 
 
Section C: Brief Description of the Event: 
 
Section D: Relevant Medical History 
 
Section E: Concomitant Drug (Not related to SAE) 
Name of the Drug 
Start Date 
Stop Date 
Route 
Dose 
Frequency 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section F: Comments 
 
Additional Documents: 
 Please specify 
 
 
 
 


 
 
 
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APPENDIX D: Immune Related Response Criteria 
 
For all patients who experience disease progression on study, the date noted for of disease 
progression is the time of the scan where it is originally detected, and not the following date of the 
confirmatory scan.  
 
Definitions of measurable and non-measurable disease  
Measurable disease: Neoplastic masses that can be precisely measured in 2 in-plane 
perpendicular diameters. Both its longest diameter and its longest perpendicular must be greater 
than or equal to 10 mm. Lymph nodes must have a short-axis line-length of ≥ 15 mm.  Malignant 
lymph nodes must be measurable in 2 perpendicular diameters. Both its longest diameter and its 
longest perpendicular must be greater than or equal to 15 mm.  The quantitative endpoint will be 
defined as the product of the longest diameter with its longest perpendicular.  
Non-measurable disease: Non-measurable lesions are those that are not suitable for quantitative 
assessment over time. These include: 
1) Neoplastic masses that are too small to measure, because their longest uninterrupted diameter 
or longest perpendicular are less than 10 mm. 
2) Neoplastic masses whose boundaries cannot be distinguished.  This includes masses which 
cannot be demarcated from surrounding tissue because of inadequate contrast, masses with 
overly complex morphology, or those with highly heterogeneous tissue composition.   
3) Other types of lesions that are confidently felt to represent neoplastic tissue, but difficult to 
quantify in a reproducible manner. These include bone metastases, leptomeningeal metastases, 
malignant ascites, pleural/pericardial effusions, inflammatory breast disease, lymphangitis 
cutis/pulmonis, cystic lesions, ill-defined abdominal masses, etc. 
For irRC, only target lesions selected at baseline and measurable new lesions are taken into 
account.  
At the baseline tumor assessment, the sum of the products of the two largest perpendicular 
diameters (SPD) of all index lesions (five lesions per organ, up to 10 visceral lesions and five 
cutaneous index lesions) is calculated.   
At each subsequent tumor assessment, the SPD of the index lesions and of new, measurable lesions 
(≥ 5 X 5 mm; up to 5 new lesions per organ: 5 new cutaneous lesions and 10 visceral lesions) are 
added together to provide the total time-point tumor burden. 
 
 


 
 
 
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Overall response using irRC: 
▪ Complete Response (irCR): Complete disappearance of all tumor lesions (whether 
measureable or not, and no new lesions).  CR must be confirmed by repeated, consecutive 
assessments made no less than 4 weeks from the date first documented.  
▪ Partial Response (irPR): Decrease in SPD of 50% or greater by a consecutive assessment 
at least 4 weeks after first documentation.  
▪ Stable Disease (irSD): Failure to meet criteria for irCR or irPR, in absence of irPD.   
▪ Progressive Disease (irPD): At least 25% increase in SPD relative to nadir (minimum 
recorded tumor burden) Confirmation by a repeat, consecutive assessment no less than 4 
weeks from the data first documented.   
Please note other key differences between irRC and the original WHO criteria: 
New measurable lesions will be incorporated into the SPD  
New non measurable lesions do not define progression but preclude irCR 
Non-index lesions contribute to defining irCR (complete disappearance required). 
See the Investigators Imaging Operations Manual (IIOM) for more details. 
REFERENCE 
IrRC for the current protocol is adopted from the following reference48