Clinical trial NCT02648282
Conditions: Pancreatic Cancer
Keywords: vaccine immunotherapy antibody PD-1 radiation
Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Start date: 2016-07-18; Completion date: 2022-06-01
Enrollment: 58 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study will be looking at whether combining cyclophosphamide, pembrolizumab (an antibody that blocks negative signals to T cells), GVAX (pancreatic cancer vaccine), and SBRT (focused radiation) is effective (anti-tumor activity) and safe in patients with locally advanced pancreatic cancer.

Detailed description:

Arms: arm 1: None
Interventions: intervention 1: Cyclophosphamide intervention 2: GVAX Pancreatic Cancer Vaccine intervention 3: Pembrolizumab intervention 4: SBRT
Intervention descriptions: intervention 1: 200 mg/m2 is to be administered as a 30 minute IV infusion one day prior to GVAX Pancreas Vaccine every 21 days for a total of 8 doses. In the extended treatment phase, eligible patients may receive 200 mg/m2 as a 30 minute IV infusion one day prior to GVAX Pancreas Vaccine every 6 months for an additional 4 doses. intervention 2: 2.5E8 cells of each cell line (Panc 6.03/Panc 10.05) for a total of 5E8 cells is to be administered one day after CY and pembrolizumab for a total of 8 doses. In the extended treatment phase, eligible patients may receive 2.5E8 cells of each cell line (Panc 6.03/Panc 10.05) for a total of 5E8 cells administered one day after CY every 6 months for an additional 4 doses. intervention 3: 200 mg will be administered as a 30 minute IV infusion one day prior to the GVAX pancreas vaccine every 21 days for a total of 8 doses. In the extended treatment phase, eligible patients may receive 200 mg as a 30 minute IV infusion every 21 days for an additional 9 doses. intervention 4: Patients will receive SBRT (6.6 Gy for 5 days) with the second dose of combined immunotherapy (CY/Pembrolizumab/GVAX Pancreas Vaccine).

Protocol documents:
Prot_SAP_000.pdf: 
Official Title: A Phase II Study of GM-CSF secreting allogeneic pancreatic cancer 
vaccine in combination with PD-1 Blockade Antibody (Pembrolizumab) and 
Stereotactic Body Radiation Therapy (SBRT) for the Treatment of Patients with 
Locally Advanced Adenocarcinoma of the Pancreas 
Protocol Date: July 1, 2020 
ClinicalTrials.gov ID: NCT02648282 


Phase 2 Study of MK-3475 with GVAX in Patients with Locally Advanced Pancreatic Cancer  
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TITLE: A Phase II Study of GM-CSF secreting allogeneic pancreatic cancer vaccine in 
combination with PD-1 Blockade Antibody (Pembrolizumab) and Stereotactic Body Radiation 
Therapy (SBRT) for the Treatment of Patients with Locally Advanced Adenocarcinoma of the 
Pancreas 
 
 
Johns Hopkins #: 
J15237/IRB00083132  
 
Merck Protocol #: 
MK-3475-308 
 
Principal Investigator: 
Lei Zheng, MD, PhD 
 
 
 
 
 
 
 
Co-Principal Investigators:  
Daniel Laheru, MD 
 
 
 
Valerie Lee, MD 
 
  
 
Amol Narang, MD 
 
 
 
Regulatory Specialists: 
Julie Nauroth, PhD 
 
 
 
 
 
Statistician: 
Elizabeth Sugar, PhD 
 
 
 
 
 
Lead Study Coordinator: 
 
Christina Rodriguez 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lead Research Nurse: 
Beth Onners, RN, MSN 
 
 
 
 
 
 


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Program Manager:  
Katrina Purtell, RN 
 
 
 
 
 
 
 
 
Merck Supplied Agent: 
Pembrolizumab (MK-3475) 
 
JHU Supplied Agent: 
GVAX 
 
Commercial Agent: 
Cyclophosphamide 
 
IND: 
 
BB IND 16793 
 
 
 
 
 
 
 
IND Sponsor: 
 
Elizabeth Jaffee, MD  
 
 
 
 
 
Protocol Type / Version # / Version Date: Original/ Version 1 / November 19, 2015  
Original/ Version 1.1 / January 13, 2016 
Original/ Version 1.2 / January 29, 2016 
Original/ Version 1.3 / April 22, 2016 
Amendment 1/ Version 2 / May 12, 2016 
Amendment 2/ Version 3 / July 12, 2016 
Amendment 3/ Version 4 / August 22, 2016 
Amendment 4/ Version 5 / November 08, 2016 
Amendment 5 /Version 6/ December 15, 2016 
Amendment 6/ Version 7 / April 12, 2017 
Amendment 7/ Version 8 / January 05, 2018 
Amendment 8/ Version 9 / May 17, 2018 
Amendment 9/ Version 10 / November 12, 2018 
Amendment 10/ Version 11 / April 2, 2019 
Amendment 11/ Version 12/ August 14, 2019 
Amendment 12/ Version 13/ February 4, 2020 
Amendment 13/ Version 14/ June 17, 2020 
Amendment 14/ Version 15/ July 1, 2020 


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SCHEMA 
 
 
 
 
 
 
 
 
 
 
Extended Treatment Phase (for patients with no evidence of disease or no metastatic 
disease who opt to stay on trial) 
 
 
 
 
 
 
 
 
 
 
 
Recruitment 
Enrollment and 
core biopsy 
Pre-Trial 
Chemotherapy 
Endoscopy with 
biopsy and fiducial 
placement and 
enrollment 


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TABLE OF CONTENTS 
SCHEMA ........................................................................................................................................3 
1. 
OBJECTIVES ....................................................................................................................6 
1.1  
Primary Objectives...................................................................................................6 
1.2 
Secondary Objectives...............................................................................................6 
1.3 
Exploratory Objectives ............................................................................................6 
1.4 
Primary Endpoint .....................................................................................................7 
1.5 
Secondary and Exploratory Endpoints.....................................................................7 
1.6 
Study Design ............................................................................................................8 
2. 
BACKGROUND ..............................................................................................................10 
2.1 
Disease Type ..........................................................................................................10 
2.2 
Management of Locally Advanced Pancreatic Cancer (LAPC) ............................10 
2.3 
Vaccine Therapy (GVAX) .....................................................................................11 
2.4 
anti-PD1/PDL1 blockade (Pembrolizumab (MK-3475 or Keytruda)) ..................12 
2.5 
Preclinical and Clinical Trial Data .........................................................................13 
2.6 
Rationale ................................................................................................................13 
3. 
PATIENT SELECTION .................................................................................................14 
3.1 
Eligibility Criteria ..................................................................................................14 
3.2 
Exclusion Criteria ..................................................................................................15 
3.3 
Additional inclusion criteria for study continuation and extended treatment 
phase ......................................................................................................................17 
3.4 
Additional exclusion criteria for study continuation and extended 
treatment phase ......................................................................................................18 
3.5  
Inclusion of Women and Minorities ......................................................................19 
4. 
TREATMENT PLAN ......................................................................................................19 
4.1 
Agent Administration.............................................................................................19 
4.2 
General Concomitant Medication and Supportive Care Guidelines ......................24 
4.3  
Prohibited and Restricted Therapies ......................................................................26 
4.4  
Dosing Criteria .......................................................................................................26 
4.5 
Definition of an Overdose for this Protocol ...........................................................27 
4.6 
Contraception, Use in Pregnancy, Use in Nursing ................................................27 
4.7 
Unacceptable Toxicities .........................................................................................28 
4.8 
Duration of Therapy ...............................................................................................31 
4.9 
Off Study Treatment/Safety Follow-up Visit ........................................................32 
4.10 
Duration of Follow Up ...........................................................................................32 
4.11 
Criteria for Removal from Study Treatment ..........................................................33 
5. 
DOSING DELAYS/DOSE MODIFICATIONS ............................................................34 
5.1  
Dose Modifications ................................................................................................34 
5.2  
Dosing Delays ........................................................................................................34 
6. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ......................38 
6.1 
Definitions..............................................................................................................39 
6.2 
Relationship ...........................................................................................................41 
6.3 
Expectedness ..........................................................................................................41 


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6.4 
Handling of Expedited Safety Reports ..................................................................41 
6.5  
Reporting................................................................................................................41 
7. 
PHARMACEUTICALINFORMATION .......................................................................43 
7.1  
Cyclophosphamide (Cytoxan®, CY) ......................................................................43 
7.2  
GVAX Pancreas Vaccine .......................................................................................45 
7.3 
Pembrolizumab ......................................................................................................48 
8. 
CORRELATIVE/SPECIAL STUDIES .........................................................................50 
8.1 
Tumor Tissue Studies ............................................................................................50 
8.2 
Peripheral Blood Lymphocytes (PBLs) and Circulating Tumor Cells 
(CTC) .....................................................................................................................51 
8.3 
Serum and Plasma Marker Studies ........................................................................51 
8.4 
Diagnostic Tissue Samples ....................................................................................52 
8.5  
Genomic Analysis ..................................................................................................52 
9. 
STUDY SCHEDULE .......................................................................................................52 
10. 
MEASUREMENT OF EFFECT ....................................................................................59 
10.1 
Antitumor Effect – Solid Tumors ..........................................................................59 
11. 
 DATA REPORTING / REGULATORY REQUIREMENTS ....................................60 
11.1 
Data Management ..................................................................................................60 
11.2 
Safety Meetings .....................................................................................................60 
11.3  Monitoring .............................................................................................................61 
12. 
STATISTICAL CONSIDERATIONS ...........................................................................62 
12.1 
Study Design/Endpoints.........................................................................................62 
12.2 
Sample Size/Accrual Rate ......................................................................................63 
12.3 
Analysis of Primary Endpoints ..............................................................................63 
12.4 
Analysis of Secondary and Exploratory Endpoints ...............................................64 
12.5 
Safety Analysis ......................................................................................................65 
12.6 
Biomarker Analysis ...............................................................................................67 
REFERENCES .............................................................................................................................68 
APPENDIX A: Performance Status Criteria ............................................................................71 
APPENDIX B: Adverse Event of Clinical Interest (ECI) Reporting Form ...........................72 
APPENDIX C: SAE Reporting Form ........................................................................................74 
APPENDIX D: EORTC QLQ-C30/PAN26 ...............................................................................76 
 
 
 
 


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1. OBJECTIVES 
 
1.1  
Primary Objectives 
 
1.1.1  To determine the distant metastasis free survival (DMFS) as evidenced by CT 
scan, PET scan, or death, in subjects with locally advanced pancreatic cancer 
(LAPC) who have received standard chemotherapy, who are treated with GM-
CSF 
secreting 
allogeneic 
pancreatic 
cancer 
vaccine 
(GVAX) 
and 
pembrolizumab prior to, in conjunction with, and after stereotactic body 
radiation therapy (SBRT). 
 
1.2 
Secondary Objectives 
 
1.2.1 To assess the safety of the combination GVAX/pembrolizumab given prior to, 
in conjunction with, and after SBRT in subjects with LAPC by measuring the 
number of grade 3 and 4 toxicities according to National Cancer Institute 
Common Toxicity Criteria for Adverse Events (NCI CTCAE; Version 4.0) that 
occur after Cycle 1, Day 1 combination immunotherapy  
 
 
1.3 
Exploratory Objectives 
 
1.3.1 To evaluate the effects of combination of pembrolizumab, GVAX, and SBRT 
upon the activation and expansion of T effector cells (Teffs) infiltrating into the 
tumor microenvironment (TME) compared to data from ongoing JHU trials 
evaluating the TME in patients treated with 1) chemotherapy and SBRT alone, 
or 2) immunotherapy alone. 
 
1.3.2 To monitor the IHC of immune parameters relevant to and 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 pembrolizumab, CY, GVAX, and standard 
multimodality treatments 
 
1.3.3 To assess tumor tissue for molecular determinants of response, progression and 
disease stability using next generation sequencing technology.   
 
1.3.4 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.   
 
1.3.5 To assess the baseline characteristic of the subjects enrolled and to correlate these 
molecular and clinicopathologic 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. 
 


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1.3.5 To collect peripheral blood lymphocytes to explore the association of PD-1 
positivity, and lymphocyte activation markers with clinical responses 
 
1.3.6 To determine the overall survival (OS) of subjects with LAPC treated with 
standard chemotherapy who subsequently receive GVAX/pembrolizumab and 
SBRT. 
 
1.3.7 To determine the local progression free survival (LPFS) of subjects with LAPC 
treated 
with 
standard 
chemotherapy 
who 
subsequently 
receive 
GVAX/pembrolizumab, and SBRT using immune related response criteria 
 
1.3.8 To assess the surgical resectability rate of LAPC in subjects treated with standard 
chemotherapy who subsequently receive GVAX/pembrolizumab and SBRT. 
 
1.3.9 To assess the pathological response rate of subjects with LAPC treated with 
standard chemotherapy who subsequently receive GVAX/pembrolizumab and 
SBRT who become surgically resectable candidates as per NCCN guidelines. 
 
1.3.10 To evaluate the quality of life as per the EORTC QLQ-C30/Pan26 questionnaire 
of subjects with LAPC treated with standard chemotherapy who subsequently 
receives GVAX/pembrolizumab, and SBRT. 
 
1.4 
Primary Endpoint 
 
1.4.1 DMFS as defined as the duration of time from start of treatment to identification 
of distant metastases on imaging or death, whichever occurs first.   
 
1.5 
Secondary and Exploratory Endpoints  
 
 
1.5.1 Efficacy endpoints 
 OS from the time of cycle 1, day 1 of immunotherapy until death from any 
cause. 
 LPFS from the time of cycle 1, day 1 of immunotherapy until first 
documented local progression or death 
 Surgical resectability after therapy as determined by our pancreatic 
multidisciplinary group based upon NCCN guidelines for resectability 
 Pathologic response as determined by surgical margins and residual disease 
 Quality of life as per the EORTC QLQ-C30/Pan26 questionnaire 
 
1.5.2 Safety endpoints 
 Number of grade 3 and 4 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 
 


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1.5.3 Correlative studies endpoints 
 IHC, flow cytometry, quantitative PCR assays and microarray analysis 
compared between of pre- and post-treatment tumor specimens to evaluate 
o Immune parameters relevant to the PD-L1/PD-1 pathway 
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 secondary to radiation 
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 marker 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, phase II clinical trial to evaluate the clinical activity 
of a combination of GVAX with pembrolizumab in patients receiving standard 
chemotherapy and SBRT for LAPC.  We will enroll subjects with LAPC diagnosed 
based upon criteria from NCCN Guidelines as determined by review of imaging and 
pathology at our institutional multidisciplinary pancreatic tumor clinic and tumor 
board.  The patients will be evaluated one to five weeks after having received at least 
four 28-day cycles of FOLFIRINOX based or gemcitabine/abraxane based 
chemotherapy. Patients should not receive more than 8 cycles of chemotherapy prior 
to enrollment on study. Patients will be eligible for enrollment if they are free from 
metastatic disease according to CT, PET, or MRI imaging following chemotherapy. 
 
Within seven weeks of receiving the last dose of chemotherapy, patients will 
subsequently undergo EUS-guided fiducial placement along with core biopsy of the 
pancreas tumor and research blood draws to evaluate for circulating tumor cells and 
other inflammatory markers, as well as an SBRT simulation.  Participants will then 
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 followed by GVAX, administered as six intradermal injections, on day 
2.  Three weeks later, subjects will receive their second dose of combined 
immunotherapy on the same day as initiation of SBRT (6.6 Gy x 5 days).   
 
Three to six weeks after completion of SBRT, patients will undergo repeat imaging 
with FDG-PET, CT, or MRI to evaluate for metastatic disease, progression, and/or 
surgical resectability.  If participants are deemed a surgical candidate, they will be 
offered surgical resection or NanoKnife treatment at Johns Hopkins Hospital.  If the 


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patient is found to have an unresectable tumor during surgery, research core biopsies 
will be obtained intraoperatively. If participants still have locally advanced tumors they 
will undergo an additional EUS-guided tumor biopsy.  Patients who undergo Nanoknife 
treatment will have the post-treatment biopsy obtained intraoperatively. Both the 
surgical group and persistent LAPC group will be treated with an additional two cycles 
of FOLFIRINOX based or gemcitabine/abraxane based therapy.  Surgery and 
chemotherapy are considered standard of care. Patients will be considered off study 
between 28 days after Cycle 2 of immunotherapy and resuming Cycle 3 of 
immunotherapy, while they are receiving SOC treatment. If imaging or surgery had 
shown local progression of disease or poor pathologic response, or if chemotherapy 
intolerance has developed, patients who had received prior FOLFIRINOX can 
alternately receive gemcitabine/abraxane and vice versa.  At completion of 
chemotherapy, patients will have eligibility criteria re-confirmed to resume every 3 
week cycles of combination immunotherapy for six additional cycles or until 
development of distant metastases.  Participants with metastatic disease to the liver or 
safely biopsiable other metastases (as determined by our interventional radiology team) 
after the initial immunotherapy will additionally be offered biopsy of the metastatic 
lesions.  Patients who do not undergo surgery will be on trial for approximately nine 
months, while those who undergo surgery would be expected to be on trial for 
approximately eleven months. 
 
If patients who have received surgery develop AEs to pembrolizumab, they will be 
allowed to continue receiving CY/GVAX to complete the eight total cycles of 
immunotherapy. 
 
Patients who show no evidence of disease or do not develop metastatic disease at the 
completion of the eight total cycles of therapy will have the option of continuing on the 
Extended Treatment Phase of every three-week pembrolizumab for an additional 
nine treatments with concurrent every six-month CY/GVAX for four doses total. 
Patients who choose to continue in this phase will be on trial approximately 35 months 
if they go to surgery, and those who do not go to surgery will be on trial approximately 
33 months. 
 
All patients will undergo standard of care evaluations consisting of history and 
physical, CT of the chest/abdomen/pelvis or MRI abd/pelvis and non-contrast CT chest 
(if do not tolerate contrast) every 3 cycles/months to evaluate for local progression and 
metastatic disease while they are on study.   
 
The primary endpoint is DMFS, defined as the time from first treatment administration 
to distant metastasis as evidenced by CT scan, PET scan, or death.  Individuals will be 
censored at the date of last scan if no event has occurred.  OS is defined as the time 
from first treatment administration until death with patients censored at the last follow-
up visit.  LPFS is defined at the time from first treatment administration to local 
progression as evidenced by CT scan, PET scan, or death.  Additional endpoints 
including subsequent surgical resectability, QoL evaluations (EORTC QLQ-
C30/Pan26 questionnaire), pathologic response, and exploratory objectives (described 


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above) will be monitored. 
 
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  Surgical 
resection is the only potentially curative modality of treatment; however, only about 
8% of patients are deemed surgical candidates.  Of even those who receive treatment, 
79% will eventually succumb to recurrent disease.2  In addition, the vast majorities of 
patients are considered locally advanced (involving adjacent vessels, nerves, and other 
structures) or metastatic at diagnosis, and thus nonsurgical.  Unfortunately, there is no 
established standard of care in the United States at this time for treatment of locally 
advanced pancreatic cancer (LAPC), and its overall mortality is grim. 
 
2.2 
Management of Locally Advanced Pancreatic Cancer (LAPC) 
Though the treatment for LAPC consists of a combination of radiation therapy (RT) 
and chemotherapy, optimal treatment sequence, technique, and dosing are 
controversial.  Chemotherapy and RT are mainly effective in LAPC at improving 
local control and increasing the likelihood of a margin-negative resection (ECOG 
4201).3  Induction chemotherapy followed by chemoradiation result in better outcomes 
when compared to other treatment sequences.4  However, conventional external 
beam radiation therapy (EBRT) can take up to 6 weeks to complete, is given with low 
dose chemotherapy, delays full-dose chemotherapy, and can lead to high rates of grade 
3-4 acute toxicity (ECOG 4201 and FFCD).3, 5   
Recent advancements in RT delivery techniques have led to increased use 
of stereotactic body radiation therapy (SBRT) due to its shorter duration (3-5 days), 
increased feasibility, and established efficacy in other disease sites. Earlier 
studies evaluating SBRT in patients with LAPC have reported superior local control in 
comparison with EBRT but resulted in high rates of grade 2-4 late GI toxicity.6  A 
prospective multicenter phase II study of SBRT five fractions (5-6.6 Gy/fraction for a 
total dose of 25-33 Gy) following induction gemcitabine chemotherapy in 49 patients 
with LAPC was recently reported.7   The median OS was 13.9 months (95% CO: 10.2-
16.7) and metastasis free survival was 7.7 months (95% CI: 5.8-10.2).  The median 
local PFS was not observed and 78% were free from local progression at 1 year.   Rates 
of acute and late grade  2 gastritis, fistula enteritis, or ulcer toxicities were 2% and 
11%.  Five fraction SBRT not only provided superior local control but also resulted in 
a lower toxicity profile than the single fraction SBRT.  There was also a significant 
improvement in pain scores (p = 0.001) and no decrease in quality of life.  Studies 
evaluating combination chemotherapy and SBRT are ongoing.  However, the addition 
of immunotherapy may potentially provide further benefit by additionally targeting 
PDAC with a completely different mechanism of action. 


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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 trialed 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 
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 subjects.20  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.   
 
An ongoing neoadjuvant trial and adjuvant trial of CY/GVAX in patients with 
resectable pancreatic cancer (NCT01088789) showed that on pathological examination 
of PDAC tumor tissue resected just two weeks following a single neoadjuvant dose of 


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GVAX identified the formation of novel vaccine-induced, immunologically active, 
tertiary lymphoid aggregates, organized lymph node-like structures, with suppression 
of Treg pathway, that are not observed in tumor tissue resected from unvaccinated 
patients. 
 
2.4 
anti-PD1/PDL1 blockade (Pembrolizumab (MK-3475 or Keytruda)) 
 
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades.21  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 
and RCC.  TILs can be expanded ex vivo and re-infused, inducing durable objective 
tumor responses in cancers such as melanoma.22, 23 
 
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.24-
27  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.24  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),28 pancreatic carcinoma,29 hepatocellular carcinoma,30 ovarian 
carcinoma.31  Furthermore, PD-1 has been suggested to regulate tumor-specific T-cell 
expansion in patients with malignant melanoma.32 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. 
Pembrolizumab (previously known as SCH 900475) is a potent and highly-selective 
humanized mAb of the IgG4/kappa isotype designed to directly block the interaction 
between PD-1 and its ligands, PD-L1 and PD-L2.  Pembrolizumab contains the S228P 
stabilizing mutation and has no antibody-dependent cell-mediated cytotoxicity 
(ADCC) or complement-dependent cytotoxicity (CDC) activity.  Pembrolizumab 
strongly enhances T lymphocyte immune responses in cultured blood cells from 
healthy human donors, cancer patients, and primates.  In T- cell activation assays using 


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human donor blood cells, the EC50 was in the range of 0.1 to 0.3 nM. Pembrolizumab 
also modulates the level of interleukin-2 (IL-2), tumor necrosis factor alpha (TNFα), 
interferon gamma (IFNγ), and other cytokines.  The antibody potentiates existing 
immune responses only in the presence of antigen and does not nonspecifically activate 
T- cells. 
The FDA-approved Q2W dose of Pembrolizumab is 2 mg/kg.  A fixed dose of 200 mg 
was, however, recommended by Merck for the Q3W schedule in order to synchronize 
the schedule of pembrolizumab with GVAX.  “200 mg Q3W” is currently being tested 
in multiple ongoing Merck-sponsored clinical studies including PN012, PN021, 
PN023, PN024, PN045, PN055, etc. (Investigator’s Brochure, Table 19). According to 
the PN012 study, MK-3475 200 mg Q3W is well tolerated and has a similar toxicity 
profile as the 2 mg/kg Q2W (Investigator’s Brochure, Tables 42-46).   
2.5 
Preclinical and Clinical Trial Data 
 
Refer to the Investigator’s Brochure [IB] for Preclinical and Clinical Data 
 
2.6 
Rationale 
Attempts to apply anti-CTLA4 and anti-PD1 agents directly to GI tumors and PADC 
have been limited due to their nonspecific immune modulation and diminished 
reactivity in these tumor types, except in select populations.  For example, though anti-
PD1 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.33  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).34   
GVAX administration has been shown to activate the tumor microenvironment (TME) 
by diminishing Tregs and increasing Teffs.  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. 
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.35  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.36 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.37, 38  The synergistic effect has 
been demonstrated in a preclinical model of PDAC where the combination of anti-PD-


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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.38 
This clinical trial will therefore evaluate the combination of CY/GVAX and anti-PD-1 
antibody (pembrolizumab) for LAPC following induction chemotherapy given before 
and after local therapies including SBRT and possible surgery for those downstaged to 
the resectable stage. 
3. PATIENT SELECTION 
 
3.1 
Eligibility Criteria 
 
3.1.1 Patients with histologically proven, surgically unresectable, locally advanced 
pancreatic adenocarcinoma (at diagnosis) or with mixed cell type with 
predominant histology of adenocarcinoma (by NCCN guidelines) 
 
3.1.2 Patients 
must 
have 
received 
either 
FOLFIRINOX 
based 
or 
Gemcitabine/Abraxane based chemotherapy for 4-8 cycles with last dose of 
therapy between 1-5 weeks of study enrollment, with no evidence of metastatic 
disease 
 
 
*Note:*  
 12-24 doses of Gem/Abraxane that must be given over 16-38 weeks 
 8-16 doses of FFX that must be given over 16-38 weeks 
 
3.1.3 Age >18 years 
 
3.1.4 ECOG performance status 0-1 (Appendix A) 
 
3.1.5 Life expectancy greater than 3 months 
 
3.1.6 Adequate hematologic, renal, and liver function as defined below: 
 
White blood cell count 
> 3,500 cells/mm3 
Absolute neutrophil count 
> 1,500 cells/mm3 
Hemoglobin 
> 9g/dL 
Platelets 
> 80K/mm3 
Serum creatinine 
≤ 2.0mg/dL 
AST and ALT  
≤ 3 x ULN 
Total bilirubin 
≤ 1.5 x ULN* 
 
*Subjects with Gilbert’s Syndrome should have direct bilirubin within normal 
institutional limits 
 
3.1.7 Female patient of childbearing potential (WOCBP) [free from menses for >2 
years, post hysterectomy / oophorectomy, or surgically sterilized] must have a 


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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. 
 
3.1.8 WOCBP must be willing to use either two adequate barrier methods or a barrier 
method plus a hormonal method of contraception to prevent pregnancy or to 
abstain from heterosexual activity throughout the study, starting with Visit 1 
through 120 days after the last dose of study therapy.  Approved contraceptive 
methods include for example; intrauterine device, diaphragm with spermicide, 
cervical cap with spermicide, male condoms, female condoms with spermicide, 
or oral contraceptives.  Spermicides alone are not an acceptable method of 
contraception. 
Male patients must agree to use an adequate method of contraception starting 
with the first dose of study drug through 120 days after the last dose of study 
therapy. 
 
3.1.9 Must be willing to be treated with SBRT and have surgical resection (if eligible) 
only at Johns Hopkins Hospital 
 
3.1.10 Patients must be able to have fiducials placed.  If not, the tumor must be 
posterior and adjacent to the aorta and treatment will only be permitted at the 
discretion of the Principal Investigator. 
 
3.1.11 Ability to understand and the willingness to sign a written informed consent 
document. 
 
3.2 
Exclusion Criteria 
 
3.2.1 Patients who have been off of FOLFIRINOX or gemcitabine/abraxane therapy 
for more than 49 days prior to treatment on study 
 
3.2.2 Patients who have had more than one line of chemotherapy for LAPC (other 
than the 4-8 cycles of FOLFIRINOX based or gemcitabine/abraxane based 
chemotherapy). Patients will be allowed to switch between FOLFIRINOX and 
Gemcitabine/Abraxane due to intolerance, but cannot have switched 
chemotherapy regimens due to radiographic or clinical disease progression.   
 
3.2.3 Patients who have only received single agent Gemcitabine chemotherapy. 
Abraxane component may be reduced or modified but must be included for a 
minimum of two cycles. 
 
3.2.4 Presence of duodenal or gastric invasion by the tumor as noted by EGD at time 
of fiducial placement 
 
3.2.5 Patients with a history of prior treatment with immunotherapy agents 


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(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). 
 
3.2.6 Is currently participating or has participated in a study of an investigational 
agent or using an investigational device 
 
3.2.7 Patients receiving active immunosuppressive agents or chronic use of systemic 
corticosteroids within 14 days of vaccine treatment 
 
 
 
*Note: Special considerations for vaccination: Study-related treatments may 
be given after short-term steroid use (≤ 4 days) with prior approval by the 
protocol chair and IND sponsor. 
 
3.2.8 History of any autoimmune disease, including any history of inflammatory 
bowel disease, including ulcerative colitis and Crohn’s Disease, as well as 
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. 
 
3.2.9 Known history of interstitial lung disease, has a history of (non-infectious) 
pneumonitis that required steroids or current pneumonitis 
 
3.2.10 Has a pulse oximetry < 92% on room air. 
 
3.2.11 Requires the use of home oxygen. 
 
3.2.12 Has a known history of Human Immunodeficiency Virus (HIV) (HIV1/2 
antibodies), hepatitis B, or hepatitis C infection. 
 
3.2.13 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. 
 
3.2.14 Patients who have had surgery within 28 days of dosing of investigational agent, 
excluding minor procedures (dental work, skin biopsy, etc.), celiac plexus 
block, and biliary stent placement. 
 
3.2.15 Patients who have received any non-oncology live vaccine therapy used for 
prevention of infectious diseases within 28 days of study treatment. Examples 
include, but are not limited to, the following: measles, mumps, rubella, chicken 
pox, yellow fever, rabies, BCG, and typhoid vaccine. 
 


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*Note: 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 within 28 days of 
study treatment. 
 
3.2.16 Patients receiving growth factors including, but not limited to, granulocyte-
colony stimulating factor (G-CSF), GM-CSF, erythropoietin, within 14 days of 
study drug administration. Use of such agents while on study is also prohibited 
 
3.2.17 History of severe hypersensitivity reaction to any monoclonal antibody 
 
3.2.18 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  
  
3.2.19 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, nonperiampullary malignancy without evidence of disease for > 5 
years will be allowed to enter the trial.  
 
3.2.20 Women who are pregnant or breastfeeding. 
 
3.2.21 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 acceptable method to avoid pregnancy for the entire study and for up to 120 
days after the last dose of investigational product 
 
3.2.22 Patient is unwilling or unable to follow the study schedule for any reason. 
 
3.2.23 Presence of any tissue or organ allograft, regardless of need for 
immunosuppression, including corneal allograft. Patients with a history of 
allogeneic hematopoietic stem cell transplant will be excluded. 
 
3.3 
Additional inclusion criteria for study continuation and extended treatment phase 
  
 
Patients must have eligibility checked prior to initiation of Cycle 3 of immunotherapy. 
Research participants must meet the following criteria for post-operative/post-
chemotherapy combination immunotherapy. 
 
3.3.1 ECOG performance status 0-1 (Appendix A) 
 
3.3.2 Adequate hematologic, renal, and liver function as defined below: 
 
Absolute neutrophil count ≥ 1,000 cells/mm3 
Hemoglobin ≥ 8g/dL 


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Platelets ≥ 80K/mm3 
Serum creatinine ≤ 2.0mg/dL 
AST and ALT ≤ 3 x ULN 
Total bilirubin ≤ 1.5 x ULN* 
 
*Subjects with Gilbert’s Syndrome should have direct bilirubin within normal 
institutional limits 
 
3.3.3 Female patients of childbearing potential (WOCBP) 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 require to be shown as 
negative for the patient to be eligible.  
 
3.3.4 WOCBP must be willing to use either two adequate barrier methods OR a 
barrier method plus a hormonal method of contraception to prevent pregnancy 
or to abstain from heterosexual activity throughout the study. 
 
Male patients must agree to use an adequate method of contraception.  
Research patients with any of the following will be excluded from study 
continuation. 
 
3.4 Additional exclusion criteria for study continuation and extended treatment phase 
 
3.4.1 Radiographic evidence of metastatic disease 
 
3.4.2 Patients receiving active immunosuppressive agents or chronic use of 
systemic corticosteroids within 14 days of vaccine treatment 
 
*Note: Special considerations for vaccination: Study-related treatments 
may be given after short-term steroid use (≤ 4 days) with prior approval by 
the protocol chair and IND sponsor. 
 
3.4.3 Has pulse oximetry of < 92% on room air, or requires the use of home oxygen 
 
3.4.4 Uncontrolled illness or infection as described in 3.2.13 
 
3.4.5 Breastfeeding or pregnancy 
 
3.4.6 New diagnosis of cancer other than non-melanoma skin cancer, non-invasive 
bladder cancer, early stage prostate cancer, or carcinoma in situ of the cervix. 
 
3.4.7 Patients who have had surgery within 28 days of dosing of investigational 
agent, excluding minor procedures mentioned in 3.2.14 
 
3.4.8 Patients who have received any non-oncology live vaccine therapy used for 
prevention of infectious diseases within 28 days of study treatment. Examples 


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include, but are not limited to, the following: measles, mumps, rubella, 
chicken pox, yellow fever, rabies, BCG, and typhoid vaccine. 
 
 *Note: 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 within 
28 days of study treatment. 
 
3.4.9 Patients receiving growth factors including, but not limited to, granulocyte-
colony stimulating factor (G-CSF), GM-CSF, erythropoietin, within 14 days 
of study drug administration. Use of such agents while on study is also 
prohibited 
 
3.4.10 Patient is a WOCBP or male who is unwilling or unable to use adequate 
method of birth control to avoid pregnancy for the entire study and up to 120 
days after the last dose of investigational product 
 
3.4.11 Patient is currently participating or has participated in a study of an 
investigational agent or using an investigational device 
 
3.4.12 Patient is unwilling or unable to follow the study schedule or procedures 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 5.2.  Subjects will receive two initial treatments of combined immunotherapy 
(pembrolizumab and GVAX) separated by three weeks after completing 4-8 cycles of 
FOLFIRINOX based or gemcitabine/abraxane based therapy and undergoing pre-
screening for metastatic disease.  After receiving the first two cycles of combination 
immunotherapy and SBRT, patients will be reevaluated for surgery.  If eligible for 
surgery, they will undergo traditional surgery or NanoKnife resection at Johns Hopkins 
Hospital.  If they undergo surgery or continue to have LAPC, subjects will be treated 
with two further cycles of FOLFIRINOX based or gem/abraxane based therapy.  
Subjects who showed no obvious clinical improvement for persistent LAPC, developed 
intolerance to their previous chemotherapy regimen, or had no evidence of treatment 
effect on surgical resection can be offered gemcitabine/abraxane based therapy if they 
had previously received FOLFIRINOX or vice versa.  After completing chemotherapy, 
subjects will then start on every 3 week cycles of combination immunotherapy for six 
additional cycles (combined up to eight cycles of combined immunotherapy). 


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Patients who remain free of metastatic disease at the completion of eight cycles of 
combined immunotherapy will be eligible to enroll in the optional Extended 
Treatment Phase during which patients will receive every 3 week dosing of 
pembrolizumab for nine additional doses (total 17 doses) and every 6 month 
CY/GVAX for an additional four doses (total 12 doses). 
 
Table 1: Study Regimen 
 
Agent 
Premedications, 
Precautions 
Dose 
Route 
Cyclophosphamide 
Subjects may 
be 
pre-medicated with 
anti-emetics 
200 mg/m2 in 
100 mL NS 
IV infusion over 
30 minutes 
GVAX 
EMLA 
cream 
(approximately 
2.5gms/site at least 
1 hour prior to 
vaccination) 
5x108 cells 
Six 
intradermal 
injections 
Pembrolizumab 
No 
prophylactic 
pre-medications 
unless indicated by 
previous experience 
in 
an 
individual 
subject 
200 mg 
IV 
over 
30 
minutes 
Infusion times are approximate (+/- 10 min) and may need to be adjusted based on 
subject tolerability. 
 
Please see Section 5.2 for guidance regarding dosing delays. 
 
4.1.1 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 


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4.1.2 Cy (CytoxanR)  The single intravenous (IV) dose of 200 mg/m2 Cy is chosen 
based on our data showing that this single low IV dose given with a GM-CSF-
secreting breast cancer vaccine is equivalent to the repetitive oral metronomic 
doses of Cy in reducing Treg levels in the PDA TME and facilitating enhanced 
T cell activation. Cy is a FDA-approved standard chemotherapy agent.  Subjects 
may be pre-medicated prior to administration with anti-emetics per institutional 
guidelines.   
4.1.3 Anti-PD-1 Therapeutic Antibody Pembrolizumab (KEYTRUDA®, MK-
3475) is a potent and highly-selective humanized monoclonal antibody (mAb) 
of the IgG4/kappa isotype designed to directly block the interaction between 
PD-1 and its ligands, PD-L1 and PD-L2. It is FDA-approved for treating 
metastatic melanoma. The recommended dose of KEYTRUDA is 2 mg/kg 
administered as an intravenous infusion over 30 minutes. In this study, 
pembrolizumab will be administered IV over 30 minutes at 200 mg. 
 
Antiemetic medications should not be routinely administered prior to dosing 
except as indicated by patient’s prior reaction 
 
4.1.4   SBRT and Fiducial placement 
Treatment on this protocol requires placement of 1-5 gold (99.9% pure, 1-
5 mm length, visicoils, or other) fiducials for targeting purposes.  The 
fiducials will be used as surrogates for targeting the daily tumor position 
during treatment. The fiducials will be placed directly into the tumor and/or 
periphery under endoscopic ultrasound or CT guidance. Fiducials may be 
implanted prior to enrollment as this is an acceptable standard of care 
procedure for any patient receiving radiotherapy for locally advanced 
pancreatic or periampullary cancer. Also, if a patient had an attempted 
surgical resection that was aborted, fiducials may have been implanted 
intraoperatively, which is also allowable prior to study enrollment. 
 
 
 
If fiducials are not placed intraoperatively and/or prior to enrollment, 
placement will be done and is expected to be done on an outpatient basis.  
In rare occurrences when fiducials/clips cannot be placed, patients may be 
treated at the discretion of the PI. 
 
SBRT Simulation (planning) 
1) Simulation should be done following placement of fiducials; however, 
this may vary and is at the discretion of the principal investigator. 
2) Typically, patients will be positioned supine in an Alpha Cradle or 
equivalent immobilization device that will be custom-made for each 
patient. 
3) Standard free-breathing CT and respiratory-correlated 4-D pancreatic 
protocol CT will be obtained on each patient. The 4D-CT scan will be 
used for characterizing target motion during quiet respiration. For 
more accurate tumor delineation, an arterial phase pancreatic protocol 
CT may be obtained (typically during expiration breath hold, 1.25 mm 


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slices). Fiducial to fiducial fusions between these scans should be 
utilized whenever possible.  The simulation scan should include T4/T5 
to L5/S1 (upper abdomen). 
4) IV and oral contrast must be used for simulation, unless the patient has 
an allergy. In these situations, the plan should be fused with an MRI 
(ideally in a similar treatment position), or if not able to undergo MRI, 
premedication with steroids and antihistamines as necessary. 
5) Motion management can be addressed using respiratory gating, 
breath-hold, or respiratory tracking.  The goal is to reduce motion from 
typically 11-22 mm peak to less than 5 mm.  If the fiducial motion 
cannot be decreased to 5 mm or less, then respiratory gating using 
either the Varian Respiratory Management (RPM) system or the 
Elekta Active Breathing Coordinator (ABC) will be utilized for 
treatment delivery. Prior to simulation, standard guidelines will be 
followed. 
6) As long as the specified dosimetric parameters for SBRT are reached, 
patients may be treated on any IGRT-enabled machine. 
7) All patients must start Linac based SBRT within 4 weeks of the 
simulation scan. 
8) A research ultrasound (US) may be conducted at the time of 
simulation. In order to monitor the abdominal soft tissue motion, the 
Department of Radiation Oncology has developed a 4D ultrasound 
technique based on an ultrasound probe holder and a continuous 
motion monitoring software. The 4D ultrasound image is acquired by 
using a motorized 3D ultrasound probe and image continuously. 4D 
ultrasound is a new non-ionizing and non-invasive imaging technique 
that continuously monitors the tumor motion during the radiation 
treatment in real time. 
 
SBRT Treatment Planning 
1) When available, an FDG-PET scan is preferred for treatment planning 
purposes. 
2) An SBRT treatment plan will be developed using Pinnacle based on 
tumor geometry and location. Institutional standards for radiation 
quality assurance and radiation delivery will be utilized. 
3) The tumor volume (GTV), as identified on the treatment planning CT, 
will be contoured by an attending physician from Johns Hopkins 
Hospital.  The final GTV will be defined by the attending radiation 
oncologist after reviewing the diagnostic CT, respiratory-correlated 
4D-CT scan, pancreas protocol CT, and/or the FDG-PET/CT scan. 
These scans will be used to define the ITV (internal target volume).  
The final PTV (planning treatment volume) expansion will consist of 
an additional 2-3 mm of margin expansion, except if the margin results 
in expansion into the duodenum or stomach. In these cases, margin 
expansion is allowed to be non-uniform. The dose will be prescribed 
to the isodose line that completely surrounds the PTV. It is 


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recommended that 6-12 co-planar fields or arc fields be used in the 
radiation treatment plan. 
4) Contours of the fiducials used for target localization will be generated 
on the applicable image sets, to be used for patient setup on treatment. 
5) Radiation dose to the adjacent normal tissue will be minimized. Based 
on an analysis of duodenal toxicity representing pooled data from 3 
previous prospective studies, the following dose constraints must be 
met: V15<9cc, V20<3cc.  The duodenum (duo@PTV) as defined for 
these dosing parameters includes the entire duodenum on the same 
axial plane as the PTV and duodenum 1 cm above and 1 cm below the 
PTV.   V15  
and V20 are defined as the percent volume receiving 
15 Gy and 20 Gy, respectively.  No more than 1cc of the proximal 
duodenum or proximal stomach may exceed 33 Gy.  The remainder of 
the normal tissues will be limited as follows: 
 Liver (excluding tumor):  50% should be limited to <12 Gy 
 Kidney:  Combined volume for both should have 75% <12 Gy 
 Stomach and duodenum:  V15<9cc and V20<3cc.  50% should 
be limited to <12 Gy (no more than 1 cc of proximal stomach 
can receive >33 Gy) 
 Spinal Cord: no more than 1cc can receive >8 Gy 
6) No more than 1cc of the PTV can receive >130% of the prescription 
dose (4290cGy for 6.6Gy x 5). 
7) Greater than 90% of the PTV should receive 100% of the prescription 
dose (3300cGy for 6.6Gy x 5; 2500cGy for 5Gyx5). 
8) If above constraints cannot be achieved, then 100% of the GTV must 
receive at least 25 Gy (an allowed minor deviation, which will be 
documented). 
9) When the research 4D ultrasound is used during the simulation, the 
US probe in the CT will be contoured and we will avoid placing any 
radiation beams directly through the ultrasound probe. 
 
If this constraint cannot be met, the patient should be removed from 
the protocol. 
 
Linac based SBRT Treatment Delivery 
Patients will receive 5 fractions of 6.6 Gy delivered over a five-day period, 
as delineated above.  Ideally all 5 fractions should be delivered Monday 
through Friday; however, treatment may be delivered over 2 weeks, as long 
as the patient receives at least 2 fractions per week. 
 
Treatment Delivery (LINAC-based): 
1) Initial patient positioning will be based on volumetric kV or cone-
beam CT imaging with shifts to bony anatomy as appropriate. 


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2) Orthogonal kV/MV, kV/kV projection, or cbct imaging will be used 
to verify the location of the fiducials prior to delivery of the first 
 treatment beam. A secondary shift based on the location of fiducials 
may be utilized, as indicated by the position of the fiducials.  For free-
breathing treatments, kV fluoroscopic images should be obtained to 
confirm the anticipated position of these fiducials during the entire 
respiratory cycle. 
3) Active monitoring of treatment delivery accuracy will be 
accomplished using kV and/or MV projection imaging, either 
immediately before or during all (or a subset of) treatment fields. 
4) Patient-specific dosimetric quality assurance (QA) will be performed 
as per standard practice in the Department of Radiation Oncology and 
Molecular Radiation Sciences at Johns Hopkins Hospital. 
5) When the research 4D ultrasound is used during the simulation, active 
4D ultrasound will be used during the entire treatment, the treatment 
will not be altered during ultrasound acquisition.  
 
4.2 
General Concomitant Medication and Supportive Care Guidelines 
 
4.2.1 Cyclophosphamide (Cy) 
 
Acute reactions will be managed using standard therapy for acute drug 
reactions as per institutional guidelines 
 
4.2.2 GVAX Pancreas Vaccine 
 
 
Local skin reactions at vaccine sites may be treated topical lotions (e.g. aloe 
vera or vitamin E).  Pruritus can be managed with topical or systemic benadryl.  
Significant local inflammation leading to severe pain may be treated with oral 
analgesics.  Local ulceration should be managed with local wound care, with or 
without antibiotics, and should be evaluated on a case-by-case basis. 
 
4.2.3 Pembrolizumab 
 
Pembrolizumab is a humanized monoclonal Ab. 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, 


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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. 
 
Table 2: Guidance on Infusion and Hypersensitivity Reactions 
 
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. 
 
 
4.2.3.2 Immune-Related Adverse Events (IRAEs)  
 
Blocking PD-1 function may permit the emergence of auto-reactive T cells 
and resultant clinical autoimmunity. Rash/pruritus, diarrhea/colitis, 


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pneumonitis, hepatitis, and hypothyroidism were drug-related, presumptive 
autoimmune events, now termed IRAEs. 
 
For the purposes of this study, an IRAE is defined as an AE of unknown 
etiology, associated with drug exposure and is consistent with an immune 
phenomenon. Efforts should be made to rule out neoplastic, infectious, 
metabolic, toxin or other etiologic causes prior to labeling an AE an IRAE. 
Serological, immunological, and histological (biopsy) data should be used 
to support the diagnosis of an immune-mediated toxicity. Suspected IRAEs 
must be documented on an AE or SAE CRF.  
 
4.3  
Prohibited and Restricted Therapies 
 
Patients may not use any of the following agents during the study: 
 
 Any non-study anticancer or immunotherapy agent (investigational or non-
investigational) 
 
 Any other investigational agents 
 
 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 
 
 Systemically active steroids can be used but should be reported to the Principal 
Investigator and IND Sponsor.  Steroid treatment should be completed at least 
14 days prior to resuming study-related treatments (See Section 5.2 for dosing 
delays for steroids) 
 
 Filgrastim (Neupogen® or G-CSF) or sargramostim (Leukine® or GM-CSF) 
 
 Prophylactic live vaccines (e.g., Td/Tdap, measles, chicken pox) within 28 days 
prior to or after dosing combination immunotherapy 
 
4.4  
Dosing Criteria 
 
Dosing will be delayed for the following laboratory criteria:  
 
 AST, ALT > 3.0 x ULN  
 Total bilirubin >1.5 x ULN  (patients with diagnosed Gilbert’s Syndrome, direct 
bilirubin should be within normal institutional limits) 
 Serum creatinine > 2.0mg/dL 
 Hemoglobin < 8 g/dL 
 ANC < 1000/uL  
 Platelets < 80 x 103/uL 


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4.5 
Definition of an Overdose for this Protocol 
 
Overdose of pembrolizumab is defined as: 
The patient has taken (accidentally or intentionally) a dose exceeding the dose 
prescribed in the protocol by 20%. No specific information is available on the treatment 
of overdose of pembrolizumab. In the event of overdose, pembrolizumab 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 Sponsor and Merck Global Safety.  Merck Global Safety (GS) contact 
information can be found in Section 6.5.1. 
4.6 
Contraception, Use in Pregnancy, Use in Nursing 
 
4.6.1 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.  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 1through 
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: 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 


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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. 
 
4.6.2 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 Sponsor 
and to Merck Global Safety without delay.  The outcome must be reported to the 
Sponsor within 24 hours and to Merck Global Safety 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 Sponsor and to 
Merck Global Safety 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 Sponsor and to Merck Global Safety. 
 
4.6.3 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. 
 
4.7 
Unacceptable Toxicities 
 
 
Unacceptable toxicities are defined as: 
 Treatment-related ≥ grade 4 AEs, or  
 Treatment-related grade 3 AEs that do not improve to ≤ grade 2 under therapy 
within 2 weeks. 
 ≥ 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 
 
Exceptions include: 
 Alopecia 
 Asymptomatic amylase/lipase elevation 


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Unexpected Grade 3 or greater laboratory abnormalities should be repeated within 24-
72 hours if clinically indicated and monitored as necessary to determine if event meets 
toxicity criteria. 
 
The proportion of unacceptable toxicities will be monitored. If the toxicity levels are 
unacceptable (high probability that it is >45% of subjects), then enrollment will be 
suspended until further review and consideration by the IND Sponsor and MEC.  
 
The proportion of treated subjects with unacceptable toxicity will be monitored using 
a Bayesian stopping guideline.  Subjects will initially be staggered until 6 subjects have 
been treated and followed for 4 weeks after the completion of SBRT, which translates 
to 7.5-8 weeks after the start of treatment and includes 2 cycles of GVAX/pembro plus 
5 days of SBRT. A Beta (2, 5) prior, representing a toxicity rate of 29%, a slightly 
conservative estimate, was used in the development of our guidelines.  The therapy will 
be re-evaluated if the posterior probability that the toxicity rate exceeds the 45% 
boundary is greater than 50%.  Once the initial cohort of 6 subjects has been recruited 
and followed for at least four weeks after the completion of SBRT, toxicity will be 
monitored continuously.  If 4 or more subjects experience unacceptable toxicities 
during the toxicity assessment period in the first 6 subjects, accrual will be suspended 
until the toxicity levels have been determined to be acceptable.  Then, the remaining 
participants will be enrolled and monitored routinely.  Table 3 summarizes the stopping 
boundaries for unacceptable toxicities. 
 
 
 
Table 3: The number of toxicities needed to trigger stopping guidelines 
throughout the course of the study 
   
Number of Subjects  
Number of toxicities 
needed to trigger 
re-evaluation 
6 
4 
7-8 
5 
9-10 
6 
11-12 
7 
13-15 
8 
16-17 
9 
18—19 
10 
20-21 
11 
22-24 
12 
25-26 
13 
27-28 
14 
29-30 
15 
31-32 
16 
33-35 
17 


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Number of Subjects  
Number of toxicities 
needed to trigger 
re-evaluation 
36-37 
18 
38-39 
19 
40-41 
20 
42-44 
21 
45-46 
22 
47-48 
23 
49-50 
24 
51-52 
25 
53-54 
26 
 
The probability of triggering the stopping guidelines was assessed for a range of 
possible true toxicity rates using simulations with 5000 replicates (Table 4).  The 
probability of stopping to re-evaluate was 2.6% if the true proportion with an 
unacceptable toxicity was 25%, the expected value.  In comparison, the probability of 
stopping early is 58.4% and 82.1% if the true proportion with an unacceptable toxicity 
was 45% or 50%, respectively.  
 
 
 


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Table 4: Probability of triggering a re-evaluation based upon the proportion with 
an unacceptable toxicity for a range of true toxicity probabilities 
 
True probability of 
unacceptable toxicity 
Probability of triggering 
stopping guidelines 
10% 
0.1% 
15% 
0.8% 
20% 
2.3% 
25% 
6.3% 
30% 
14% 
35% 
27% 
40% 
46% 
45% 
67% 
50% 
86% 
60% 
99% 
 
4.8 
Duration of Therapy 
 
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. 
A subject must be discontinued from treatment (but may continue to be monitored in 
the post-treatment follow-up portion of the trial) for any of the following reasons: 
 
 
Development of distant metastatic disease (see below) 
 
The subject or legal representative (such as a parent or legal guardian) 
withdraws consent for treatment 
 
Intercurrent illness that prevents further administration of treatment, 
 
 
Unacceptable adverse event(s) (see Section 4.7), 
 
 
Need for >2 dose delays due to the same toxicity as per the dose delay 
guidelines (see Section 5.2).  However, if patients have undergone surgery 
and develop irAEs to pembrolizumab, they will be offered continuation of 
CY/GVAX monotherapy to complete 8 cycles. 
 
 
If in the opinion of the Investigator, a change or temporal or permanent 
discontinuation of therapy would be in the best interest of the patient.  The 
Sponsor and Merck should be included in this decision, 
 
 
Noncompliance with trial treatment or procedure requirements, 
 


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 
Patient is lost to follow-up 
 
 
Patient becomes pregnant. 
 
4.9 
Off Study Treatment/Safety Follow-up Visit 
 
Patients are considered off study treatment beginning 90 days after the last 
immunotherapy. Follow-up visits will be scheduled at the discretion of the patient’s 
local oncologist and the results sent to us if the patient agrees. All attempts will be 
made to obtain disease-free and overall survival data on each patient.  
 
After a patient is determined to have metastatic disease and is discontinued from 
combination immunotherapy, a mandatory Off Study Treatment/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 as appropriate.  The patient will be monitored 
for adverse events up to the mandatory Off Study Treatment/Safety Follow-Up Visit or 
to resolution of toxicity to Grade 0-1, whichever occurs later.  SAEs that occur within 
90 days of the end of treatment or before initiation of a new antineoplastic treatment 
should also be followed and recorded. 
 
4.10 Duration of Follow Up   
 
Subjects who discontinue from treatment should remain on study and be contacted 
every 12 weeks (and at 90 days [+14 days] from the EOT) to monitor OS until death, 
withdrawal of consent, or study closure.  Information of other cancer therapies after 
discontinuation from the study treatment will be collected. 
 
All subjects who discontinued study treatment should continue to be monitored for 
disease status by radiologic imaging.  Disease monitoring should continue to be 
assessed every 12 weeks until, 1) start of a new antineoplastic therapy (information of 
the new cancer therapy will be collected), 2) until death, 3) withdrawal of consent, or 
4) study closure, whichever occurs first. Patients who complete 2 years of follow up 
(designated by date of last study treatment) should continue to have their disease status 
monitored by radiologic imaging every 24 weeks (+/- 30 days), or at the discretion of 
treating oncologist. 
  
Subjects who are discontinued from the study treatment due to an unacceptable drug-
related AE will be monitored for safety until the resolution of the AE to ≤ grade 1 or 
stabilization or until initiation of a new therapy for their cancer, whichever occurs first. 
  
All subjects will be followed for at least 4 weeks after their last dose of study drug for 
the development of AEs. SAEs that occur within 90 days of the EOT or before initiation 
of a new antineoplastic treatment should also be followed and recorded. 
 


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Per the FDA requirement, all research patients treated with genetically modified 
products (pancreatic tumor vaccine) will be followed annually (+/- 2 months) for 2 
years per protocol either at Johns Hopkins or until study termination.  
If consent is granted, patients at Johns Hopkins who chose to enroll will be followed for 
disease progression, survival and potential long term toxicity of gene therapy in an existing 
protocol entitled “Long term follow-up of patients who received lethally irradiated 
allogeneic pancreatic tumor cells transfected with the GM-CSF gene (IRB # 02-10-14-03, 
SKCCC J0248)”. Consent for this long-term follow up protocol may be obtained at any 
point during treatment on this protocol.  
 
4.10.1 Continuation of Therapy (Vaccine Boost) 
After participants have completed the study, they may be eligible to receive the same 
pancreatic cancer vaccine through participation in a vaccine boosting protocol entitled 
“A safety and feasibility trial of boost vaccinations of a lethally irradiated, allogeneic 
pancreatic tumor cell vaccine transfected with the GM-CSF gene given alone or in 
combination with either a single intravenous dose or daily metronomic oral doses 
(IRB# NA_00031401, SKCCC J09100).” 
 
 
4.11 Criteria for Removal from Study Treatment 
 
Patients will be removed from study treatment when any of the criteria listed in Section 
4.8 applies.  The reason for study treatment removal and the date the patient was 
removed must be documented in the Case Report Form. 
 
4.11.1 Development of Distant Metastases as determined by imaging or laboratory 
parameters, will be considered to have reached primary outcome. 
 
4.11.2 Pembrolizumab related IRAEs 
 
Permanent discontinuation of pembrolizumab should be considered for any of the 
following: 
1. Severe or life-threatening related adverse reactions, including, but not limited to, 
any of the following (Sponsor and Merck must be notified in the event of these 
AEs, and final decision regarding treatment will be made after a discussion): 
 Grade 3-4 toxicity (non-hematologic or hematologic).  Grade 3 toxicities may 
be able to be re-dosed on a case by case basis after approval of the Sponsor and 
Merck. 
 Diarrhea with abdominal pain, fever, ileus, or peritoneal signs; increase in stool 
frequency (7 or more over baseline), stool incontinence, need for intravenous 
hydration for more than 24 hours, gastrointestinal hemorrhage, and 
gastrointestinal perforation 


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 Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >5 times 
upper limit of normal 
 Total serum bilirubin >3 times upper limit of normal 
 Steven-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by 
full thickness dermal ulceration or necrotic, bullous or hemorrhagic 
manifestations 
 Severe (i.e., CTCAE Grade 3 or 4) motor or sensory neuropathy 
 Any grade Guillain-Barré syndrome, or myasthenia gravis or other neurologic 
symptoms that impact activity of daily living 
 Severe immune-mediated reactions involving any other organs (e.g., nephritis, 
pneumonitis, pancreatitis, non-infectious myocarditis) 
 Immune-mediated 
ocular 
disease 
that 
is 
unresponsive 
to 
topical 
immunosuppressive therapy 
 Grade 4 infusion reaction 
2. Inability to reduce corticosteroid dose for immune-related adverse reactions to ≤10 
mg prednisone or equivalent per day 
If any of the above events occur, the investigator should discuss with Sponsor and 
Merck 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 pembrolizumab study drug, study therapy discontinuation should be 
considered after discussion with the Sponsor and Merck.  With Sponsor and Merck 
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 
CY/GVAX therapy to complete 8 cycles of immunotherapy. 
 
5. DOSING DELAYS/DOSE MODIFICATIONS 
 
5.1  
Dose Modifications 
 
    
Dose reduction or dose increase of CY, GVAX, and pembrolizumab will not be 
permitted in individual patients. 
 
5.2  
Dosing Delays 
 


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5.2.1 All scheduled cycles within a course 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 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 Principal Investigator or IND Sponsor. 
 
Pembrolizumab will be withheld for drug-related Grade 4 hematologic toxicities, 
non-hematological toxicity ≥ Grade 3 including laboratory abnormalities, and 
severe or life-threatening AEs as per Table 5. 
 
 
 
 


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Table 5: Pembrolizumab Dose Delay and Discontinuation Criteria 
 
General instructions: 
1. Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks. 
2. For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to Grade 1 
or 0 and corticosteroid has been tapered. Pembrolizumab should be permanently discontinued if AE does not resolve within 12 
weeks of last dose or corticosteroids cannot be reduced to ≤10 mg prednisone or equivalent per day within 12 weeks.  
3. For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other 
immunosuppressive treatment should be initiated if irAEs cannot be controlled by corticosteroids. 
 
Immune-related AEs 
Toxicity grade 
or conditions 
(CTCAEv4.0) 
Action taken to 
pembrolizumab 
irAE management with 
corticosteroid and/or other 
therapies  
Monitor and follow-up  
Pneumonitis  
Grade 2 
Withhold  
 Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper 
 
 
Monitor participants for signs and 
symptoms of pneumonitis 
 
Evaluate participants with 
suspected pneumonitis with 
radiographic imaging and initiate 
corticosteroid treatment 
 
Add prophylactic antibiotics for 
opportunistic infections 
Grade 3 or 4, 
or recurrent 
Grade 2 
Permanently 
discontinue 
Diarrhea / Colitis  
Grade 2 or 3 
Withhold 
 Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper 
 
 
Monitor participants for signs and 
symptoms of enterocolitis (ie, 
diarrhea, abdominal pain, blood or 
mucus in stool with or without 
fever) and of bowel perforation 
(ie, peritoneal signs and ileus). 
 
Participants with ≥ Grade 2 
diarrhea suspecting colitis should 
consider GI consultation and 
performing endoscopy to rule out 
colitis.  
 
Participants with 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. 
Grade 4 
Permanently 
discontinue 
AST / ALT elevation 
or Increased bilirubin 
Grade 2 
Withhold 
 Administer corticosteroids 
(initial dose of 0.5- 1 
mg/kg prednisone or 
equivalent) followed by 
taper 
 
Monitor with liver function tests 
(consider weekly or more 
frequently until liver enzyme value 
returned to baseline or is stable 
Grade 3 or 4  
Permanently 
discontinue 
 Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper 


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Type 1 diabetes 
mellitus (T1DM) or 
Hyperglycemia 
 
Newly onset 
T1DM or  
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of -
cell failure 
Withhold 
 Initiate insulin replacement 
therapy for participants 
with T1DM  
 Administer anti-
hyperglycemic in 
participants with 
hyperglycemia  
 
 
Monitor participants for 
hyperglycemia or other signs and 
symptoms of diabetes. 
Hypophysitis 
Grade 2 
Withhold 
 Administer corticosteroids 
and initiate hormonal 
replacements as clinically 
indicated.   
 
 
Monitor for signs and symptoms of 
hypophysitis (including 
hypopituitarism and adrenal 
insufficiency)  
Grade 3 or 4  
Withhold or 
permanently 
discontinue1  
Hyperthyroidism  
Grade 2 
Continue  
 Treat with non-selective 
beta-blockers (eg, 
propranolol) or 
thionamides as appropriate  
 
Monitor for signs and symptoms of 
thyroid disorders.  
 
Grade 3 or 4  
Withhold or  
permanently 
discontinue1 
Hypothyroidism 
Grade 2-4 
Continue  
 Initiate thyroid 
replacement hormones (eg, 
levothyroxine or 
liothyroinine) per standard 
of care 
 
Monitor for signs and symptoms of 
thyroid disorders.  
 
Nephritis and Renal 
dysfunction 
Grade 2 
Withhold  
 Administer corticosteroids 
(prednisone 1-2 mg/kg or 
equivalent) followed by 
taper. 
 
Monitor changes of renal function 
 
Grade 3 or 4  
Permanently 
discontinue 
Myocarditis 
Grade 1 or 2 
Withhold 
 Based on severity of AE 
administer corticosteroids 
 
Ensure adequate evaluation to 
confirm etiology and/or exclude 
other causes 
 
Grade 3 or 4 
Permanently 
discontinue 
All other immune-
related AEs 
Intolerable/ 
persistent 
Grade 2 
Withhold 
 Based on type and severity 
of AE administer 
corticosteroids  
 
Ensure adequate evaluation to 
confirm etiology and/or exclude 
other causes 
 
Grade 3 
Withhold or 
discontinue 
based on the type 
of event.  Events 
that require 
discontinuation 
include and not 
limited to:  
Gullain-Barre 
Syndrome, 
encephalitis 
Grade 4 or 
recurrent Grade 
3  
Permanently 
discontinue 
1. Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician.   
NOTE:  
For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, pembrolizumab 
may be resumed when AE resolves to ≤ Grade 2 and is controlled with hormonal replacement therapy or achieved metabolic control 
(in case of T1DM).   


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In case toxicity does not resolve to Grade 0-1 within 12 weeks after last infusion, trial treatment 
should be discontinued after consultation with the Sponsor.  With Sponsor and Merck 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. 
 
If a delay occurs between day 1 and 2 of a cycle: 
 
 Pembrolizumab-related infusion reactions must resolve to baseline prior to 
administration of GVAX.   
 Day 2 GVAX treatment and assessments can be resumed without repeating Day 1 study 
treatments (Cy and pembrolizumab) 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.  
 
Systemically active steroids can be used but should be reported to the protocol chair and/or 
IND sponsor. Extended steroid treatment (> 4 days) must be completed at least 14 days prior 
to resuming study-related treatments. Study-related treatments may resume after short-term 
steroid use (≤ 4 days) with prior approval by the protocol chair and/or IND sponsor. 
 
Subjects who have completed surgery that are required to stop treatment with pembrolizumab 
due to toxicity may stay on study and receive CY/GVAX pancreas vaccine to complete the 
six-adjuvant (8 total treatments) once pembrolizumab-related toxicity(s) has resolved to a 
grade 1. 
 
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. 
 


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All adverse events experienced by subjects will be collected and reported from the first dose 
of the investigational agent, throughout the study, and will only be followed for 30 days unless 
related to the investigational agent.  All Serious Adverse Events (SAEs) will be collected for 
90 days after the end of treatment or until a new antineoplastic treatment is initiated, whichever 
occurs first. 
 
Subjects who have an ongoing adverse event related to the study procedures and/or 
medication(s) may continue to be periodically contacted by a member of the study staff until 
the event is resolved or determined to be irreversible by the investigator. 
 
Patients who experience a Grade 2 or higher irAE should be discussed with the IND Sponsor. 
In addition, irAEs listed in Section 6.1.3 must be reported as an Event of Clinical Interest (ECI) 
within 24 hours to the Sponsor and to Merck Global Safety even if no Serious Adverse Event 
Criteria are met. 
 
Laboratory abnormalities: Laboratory abnormalities present at the screening visit will be 
recorded as pre-treatment signs and symptoms. After study treatment administration, all grade 
3 and 4 clinical laboratory results that represent an increase in severity from baseline will be 
reported as adverse events. A grade 1 or 2 clinical laboratory abnormality should be reported 
as an adverse event only if it is considered clinically significant by the investigator. 
 
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. Additionally, expected progression of the 
disease being studied will not be recorded as an adverse event. Abnormal 
laboratory values or test results constitute adverse events only if they induce 
clinical signs or symptoms or require therapy. 
 
6.1.2 Serious Adverse Event (SAE) 
 
A serious adverse event is an undesirable sign, symptom or medical condition 
which:  
• Results in death  


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• 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 Adverse Events of Clinical Interest (ECI) for pembrolizumab 
 
These selected non-serious related adverse experiences are also known as Events 
of Clinical Interest (ECI) and must be recorded as such on the Adverse Event of 
Clinical Interest Case Report Form found in Appendix B. Events of clinical 
interest for this trial include: 
 An overdose of Merck's product, as defined in Section 4.5, that is not 
associated with clinical symptoms or abnormal laboratory results.  
 An elevated AST or ALT lab value that ≥ 3x the upper limit of normal and an 
elevated total bilirubin lab value that is ≥ 2x the upper limit of normal and, at 
the same time, an alkaline phosphatase lab value that is ≤ 2x the upper limit 


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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 
 
Definite – The AE is clearly related to the study treatment. 
Probable – The AE is likely related to the study treatment. 
Possible – The AE may be related to the study treatment. 
 
Unlikely – The AE is doubtfully related to the study treatment. 
 
 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
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 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 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 within 48 hours. 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. Where required, submission of ESRs by the 
investigator to Health Authorities should be handled according to local regulations.  
 
6.5  
Reporting 
 
6.5.1  General 
 
All adverse events (both expected and unexpected) will be captured on the 


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appropriate study-specific case report forms (CRFs), with the exception of 
unrelated adverse events that occur during the off study period between cycles 2 
and 3 of immunotherapy (28 days after Cycle 2 of immunotherapy and first dose of 
study treatment in Cycle 3).  
 
In addition, all serious adverse events, regardless of causality to study drug, will be 
reported promptly to the 
IND Sponsor 
(
 
) and Merck’s Global Safety (“Merck GS”) group within 24 hours 
of recognition, with the exception of unrelated SAEs that occur during the off study 
period between cycles 2 and 3 of immunotherapy (28 days after Cycle 2 of 
immunotherapy and first dose of study treatment in Cycle 3). Serious adverse 
events should be reported 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. 
 
Non-serious Events of Interest will be forwarded to Merck GS and will be handled in 
the same manner as SAEs.  
 
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 events 
(Important Medical Events).  If the pregnancy continues to term, the outcome 
(health of infant) must also be reported to Merck GS. 
 
 
. 
 
6.5.2  Institutional Review Board (IRB) and Institutional Biosafety Committee (IBC) 
 
All serious adverse events will be reported to the IRB and IBC per institutional 
guidelines. Upon receipt of the report of the serious adverse event by IRB and IBC, 
follow-up information will be given to the IRB and IBC within 15 days. 
 
6.5.3  Food and Drug Administration (FDA) 
 
All reporting to the FDA will be completed by the sponsor. 
 
6.5.3.1 Expedited IND Safety Reports: 
 


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7 Calendar-Day Telephone or Fax Report:   
The Sponsor is required to notify the FDA of any fatal or life-threatening adverse 
event that is unexpected and assessed by the investigator to be possibly related to 
the investigational agent.  Such reports are to be telephoned or faxed (301-827-
9796) to the FDA within 7 calendar days of first learning of the event.   
 
15 Calendar-Day Written Report:   
The 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.   
 
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 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 
Sponsor-Investigator. 
 
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 by 
written report if related and unexpected to the investigational product(s) within 
15 calendar days. SAEs that are unrelated or related and expected with the 
investigational product (s) will be reported to RAC in the Annual Report. Follow-
up information will be submitted to the RAC as soon as relevant information is 
available. 
 
7. PHARMACEUTICALINFORMATION 
 
7.1  
Cyclophosphamide (Cytoxan®, CY) 
 
7.1.1 
Agent Accountability 
 


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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. 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 


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 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 
Route of Administration 
 
CY is administered 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 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 
 
 
 
 
 
 
 
 
 
 


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7.3 
Pembrolizumab 
 
7.3.1 
Agent Accountability 
 
The sponsor/investigator 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. 
 
7.3.2 
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 
 
Clinical Supplies will be provided by Merck as summarized below: 
 
 
 
Product Name & Potency 
Dosage Form 
Pembrolizumab 50 mg 
Lyophilized Powder for Injection 
MK-3475 100 mg/4 mL 
Solution for infusion 
 
7.3.4 
Packaging and Labeling Information 
 
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements. Open label kits will be provided for patient dosing.  
 
7.3.5 
Preparation 
 


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Refer to Procedures Manual for preparation instructions. 
 
7.3.6 
Storage 
 
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label. Receipt and dispensing of trial medication must be 
recorded by an authorized person.  
 
Refer to Procedures Manual for Storage conditions. 
Clinical supplies may not be used for any purpose other than that stated in the protocol. 
 
7.3.7 
Stability 
 
Refer to Procedures Manual for Stability information. 
 
7.3.8 
Route of Administration 
 
The reconstituted product is intended for IV administration.  
 
7.3.9 
Patient Care Implications 
 
Based on results from the nonclinical studies, there are currently no specific safety 
considerations. Pembrolizumab is a humanized monoclonal Ab. Thus far, serious 
infusion reactions have been infrequent and manageable. However, subjects should be 
closely monitored for potential adverse reactions during antibody infusion and potential 
adverse events throughout the study. In the event that a subject experiences an allergic 
reaction to pembrolizumab, treatment (i.e., vasopressors, H2-blockers, antihistamines, 
H1-blockers, steroids) should be administered, as appropriate, and prophylaxis should 
be considered. Surveillance for the appearance of HAH is included in all protocols. 
 
Pembrolizumab has the same mechanism of action as BMS 936558. Preclinical studies 
have suggested similar potency, and PK modeling has suggested similar human PK. 
Accordingly, the adverse events observed with BMS 936558 may serve as in indicator 
for the adverse events to expect for Pembrolizumab in cancer patients. Immune-related 
AEs (irAEs) are of special interest because of the mechanism of action of anti-PD-1 
and prior experience with anti–CTLA-4 mAbs. Up to the cut-off date for this IB, the 
only possibly irAEs included pneumonitis (Grade 2), arthralgia and myalgia. One case 
of intestinal perforation was not considered immune related. 
 
Overall, pembrolizumab has been safe and well tolerated. However, prompt 
identification of irAEs and appropriate treatment (e.g. withdrawal of study medication 
and treatment with corticosteroids) will be critical to optimizing the therapeutic index. 
Individual protocols outline specific guidance for prompt identification and treatment 
of irAEs. Timely discussions of how to manage irAEs is also encouraged. 
 
7.3.10 
Agent Ordering 


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Requests for pembrolizumab should be sent via email to: 
  
 
 
 
 
 
 
 
 
7.3.11  
Returns and Reconciliation 
 
The investigator is responsible for keeping accurate records of the clinical supplies 
received from Merck or designee, the amount dispensed to, and returned by the 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 
 
Sample collection, storage, and shipment instructions will be provided in the Procedures 
Manual. 
 
8.1 
Tumor Tissue Studies 
 
4-6 core tumor biopsies will be collected during scheduled endoscopy with fiducial 
placement.  Additional biopsies will be performed after completion of 2 doses of 
combined immunotherapy and SBRT via research endoscopic biopsy, surgical 
resection/NanoKnife specimen, or biopsy (for metastases). Post-treatment biopsies will 
only be obtained if the tumor is thought to be reasonably safe to biopsy, and biopsies 
not obtained due to concerns for patient safety will not be considered deviations. 
Additional optional biopsies may be obtained later in the course of therapy. Archival 
tumor samples may also be collected for every patient (slides and/or blocks). Archival 
tumor samples will not be collected if the biopsy was a fine needle aspiration. Detailed 
instructions for tissue collection, processing and shipment are provided in the 
procedures manual.  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. 
Immunohistochemistry, flow cytometry, quantitative PCR assays and microarray 


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analysis will be employed.  In addition, to identify potential neoantigens as a result of 
radiation therapy, the banked tumor tissues will be used for whole exome sequencing 
(WES) to identify tumor-specific non-synonymous mutations.  Peripheral Blood 
Lymphocytes (PBL) and tumor infiltrating lymphocytes (TIL), either directly from 
FFPE tumor sections, or following isolation, will be used for the TCR repertoire 
analysis by next-generation sequencing. 
 
Archived (previously collected) tumor samples and tissue collected for standard of 
care may be requested to assess tumor characteristics and the immune system. Tissue, 
fluid, or blood samples that are collected to detect or treat side effects that are thought 
to be caused by the immune system may also be collected by the study team. The 
study team may request optional biopsies to learn more about response or any 
potential toxicities.  
 
 
8.2 
Peripheral Blood Lymphocytes (PBLs) and Circulating Tumor Cells (CTC) 
 
Post-treatment expression of PD-1 and other lymphocyte activation markers will be 
measured and correlated with OS and DMFS.  PBL will be collected at baseline, 
surgical evaluation, Cycle 3, and with each subsequent CT scan.  PBL are isolated and 
stored frozen until use. PBL will be banked for measuring peripheral mesothelin-
specific T cell responses as an established parameter of immune response to treatment 
with GVAX.  PBL will also be banked for an ELISPOT-based approach similar to the 
approach we used to define the mesothelin T cell epitopes to validate mutant 
neoepitopes predicted for HLA-A1 and HLA-A2, including the HLA-A2-binding 
neoepitopes for the common Kras exon 12 mutations (KrasG12V and G12D). Of the 
blood collected for peripheral blood analysis, up to 20 cc of blood may be used for 
isolating circulating tumor cells and/or circulating tumor DNA, respectively. Whole 
blood of up to 120 cc will be used for PBL processing. During the Post-Immunotherapy 
Evaluation visit (3-6 weeks post SBRT), approx. 50 cc of whole blood will be aliquoted 
and processed to plasma to support the isolation of tumor infiltrating lymphocytes. 
Detailed instructions for blood collection, processing, and shipment are provided in the 
Laboratory Manual. 
 
8.3 
Serum and Plasma Marker Studies 
 
Sera and plasma will be collected at baseline, surgical evaluation, Cycle 3, and with 
each subsequent CT scan to identify potential therapeutic targets, biomarkers, and 
predictors of response and autoimmune toxicity through proteomic approaches. Whole 
blood will be collected in one 5 milliliter Serum Separator Tubes (SST tube) at the 
designated time points and processed using standard laboratory procedures.  Using a 
pipette, aliquots of 1 mL of serum should be transferred to cryogenic vials and stored 
at -80oC. 
 
We will also collect whole blood in two 10 mL plasma preparation tube with EDTA 
(PPT, BD Vacutainer, Franklin Lakes, NJ) and gently swirl tubes to mix blood with 


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EDTA.   Within two hours of collection, the sample will be processed using standard 
procedures for plasma separation.  Plasma will be divided into 1 mL aliquots and stored 
at -80oC.  Detailed instructions for blood collection, processing, and shipment are 
provided in the Laboratory Manual. 
 
8.4 
Diagnostic Tissue Samples 
Tissue, fluid, or blood may be collected from standard of care procedures used to treat 
or diagnose immune related toxicities. Detailed instructions for tissue collection and 
shipment are provided in the procedures manual. 
 
8.5  
Genomic Analysis 
 
Genomic sequencing library construction, whole genome/exome sequencing, whole 
transcriptome sequencing, microbial sequencing, neoepitope prediction, mutation 
burden, and bioinformatic analysis will be performed either at an on-campus laboratory 
or at an off-campus sequencing service. All the samples will be de-identified before 
sending to any laboratory for sequencing.  The FASTQ files, BAM files and VCF files 
will be generated and analyzed. 
 
Results from the sequencing studies will not be released to the patients. These studies 
are for research purposes only and are not using a clinically validated platform. 
 
9. STUDY SCHEDULE 
 
Subjects will be evaluated after completing 4-8 cycles of FOLFIRINOX based or 
gemcitabine/abraxane based chemotherapy for LAPC.  They should have a baseline evaluation 
screening during chemotherapy, and then evaluation for eligibility 14-35 days after last dose of 
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1 While participants are concurrently receiving 4-8 (28-day) cycles of FOLFIRINOX or gemcitabine/abraxane based chemotherapy 
2 Each immunotherapy consists of a combination of CY, GVAX, and pembrolizumab 
3 Longer delays to be approved by the PI and/or 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, prior cancer therapy regimens 
5 Complete physical exam will be completed at baseline; focused physical examinations will be conducted thereafter.  Exams, concomitant medication, AE assessments 
can be made up to 3 days prior to infusion. 
6 Temperature, respiration rate, blood pressure, pulse oximetry, and pulse should be taken at baseline, after Cyclophosphamide infusion, prior to MK-3475 infusion, and 
at the end of the infusion.    
7 Labs may be collected within a window of up to 3 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 CBC with differential including absolute eosinophil count, absolute neutrophils, absolute lymphocytes, and platelets 
9 Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, potassium, total protein, SGOT [AST], SGPT [ALT], sodium. 
10 T3 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 therapy (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 FDG-PET-CT is preferred for baseline evaluation for SBRT planning.  Radiologic evaluations (CT pancreas protocol, Chest, abdomen, and pelvis with contrast) and 
tumor measurements will be performed at baseline, and then 3-6 weeks after initiating SBRT.  Noncontrast CT Chest and MRI Abdomen/pelvis will be done for those 
with contrast allergies. 
14 See section on correlative studies and lab manual for complete instructions 
15 Endoscopy will be scheduled for concurrent fiducial placement and obtaining 4-6 core biopsies at baseline for archival tissue collection. Archival tissue from non-
study biopsies may be collected at any time throughout the study. 
16 EUS Guided biopsy will be obtained for research purposes and archival tissue collection if subject still has LAPC.  If subject is a surgical or NanoKnife candidate, 
biopsy will be obtained intraoperatively during surgical resection.  If metastases are noted, subjects will be offered a biopsy of metastases for research purposes. 
17 CT based simulation scan (MRI for those with contrast allergies; premedication for steroids and antihistamines will be allowed for those unable to undergo MRI). 
May be performed during Cycle 1.  
Procedure 
Screening/Baseline 
Procedures and 
Enrollment (within 
1-5 weeks of last 
dose of 
chemotherapy1 
Pre-
Immunotherapy 
(2-7 weeks after 
last dose of 
SOC chemo) 
Cycle 1 Immuno2 
(Up to 7 weeks from 
last dose of 
chemotherapy) 
Cycle 2 Immuno 
and SBRT x 5 days 
(3 weeks after 
Immunotherapy 1) 
Post Immuno 
Evaluation 
(3-6 weeks 
after SBRT) 
C1D1 
C1D2 
C2D1 
C2D2 
Visit Window3 
 
 
- 
- 
+7 
- 
+7 
Cyclophosphamide 
 
 
X 
 
X 
 
 
GVAX 
 
 
 
X 
 
X 
 
Pembrolizumab 
 
 
X 
 
X 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Medical History4 
X 
 
 
 
 
 
 
Medications 
X 
 
X 
 
X 
 
X 
Physical Exam5 
X 
 
X 
 
X 
 
X 
Vital Signs and pulse ox6 
X 
 
X 
 
X 
 
X 
Height 
X 
 
 
 
 
 
 
Weight 
X 
 
X 
 
X 
 
X 
Performance Status 
X 
 
X 
 
X 
 
X 
Hematology profile7,8 
X 
 
X 
 
X 
 
X 
Chemistry profile7, 9 
X 
 
X 
 
X 
 
X 
TSH 7, 10 
 
 
X 
 
X 
 
X 
Serum/Urine Preg11 
X 
 
X 
 
X 
 
 
CEA7 
X 
 
X 
 
X 
 
X 
CA 19-97 
X 
 
X 
 
X 
 
X 
Urinalysis and microscopic 
exam7, 12 
X 
 
 
 
 
 
 
INR7  
X 
 
 
 
 
 
 
HLA-Typing (HLA I) 
 
 
X 
 
 
 
 
Adverse event evaluation 
 
 
 
 
X 
 
X 
Vaccine Site Assessment 
 
 
 
 
X 
 
X 
PET-CT, CT, or MRI13 
X 
 
 
 
 
 
X 
Pathology Review 
X 
 
 
 
 
 
X 
PBMC (up to 120cc)14, 28 
 
 
X 
 
 
 
X 
Serum (up to 5cc)14, 28 
 
 
X 
 
 
 
X 
Plasma (up to 20cc)14, 28 
 
 
X 
 
 
 
X 
EUS Core Biopsy15, 28 
X 
 
 
 
 
 
X16, 28 
EUS Fiducial Placement 
X 
 
 
 
 
 
 
Simulation Scan17 
 
X 
 
 
 
 
 
QoL Questionnaire 
X 
 
 
 
X 
 
X 
SBRT x 5 days 
 
 
 
 
X 
 
 
Surgical Evaluation 
 
 
 
 
 
 
X 


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54
In order to minimize the need for research-only in-person visits, telemedicine visits may be 
substituted for in-person 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. 
 
After completing two cycles of combination immunotherapy and SBRT, 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 or NanoKnife intervention. If the patient will undergo NanoKnife 
treatment, the post-treatment biopsy will be obtained intraoperatively.* 
*Note: Surgery date should be determined and posted within 14 days after post-
immunotherapy/SBRT evaluation 
 
 If subjects are deemed to still have LAPC, they will have a repeat endoscopic 
core biopsy of the remaining tumor. 
 
 If a subject is noted to have developed metastases to the liver or other safely 
biopsiable metastases, they will be offered biopsy of the metastases. 
 
Subjects without metastatic disease will then receive two further cycles of FOLFIRINOX 
based or gemcitabine/abraxane based chemotherapy either: 
 
 Within 14 days after post-immunotherapy/SBRT evaluation for LAPC 
 
 Within 4-10 weeks postoperatively for subjects who undergo surgical 
resection 
 
 
Subjects who up to this point had shown evidence of local progression of disease, 
developed intolerance to their previous chemotherapy regimen, or showed minimal 
pathologic response who had previously received FOLFIRINOX will be then eligible for 
gemcitabine/abraxane for two cycles, and vice versa. 
 
After chemotherapy completion, subjects will then undergo repeat examination and re-
screening for eligibility to receive further immunotherapy as per the below schedule: 


Phase 2 Study of MK-3475 with GVAX in Patients with Locally Advanced Pancreatic Cancer  
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55
Procedure 
Post-
chemotherapy 
evaluation 
(2-3 weeks after 
last dose of SOC 
chemotherapy) 
Combination immunotherapy18 on 3-week cycles until distant metastatic disease (0-1 week after post-chemotherapy evaluation) 
Off 
Treatment19,
23 
C3D1 
C3D2 
C4D1 
C4D2 
C5D1 
C5D2 
C6D1 
C6D2 
C7D1 
C7D2 
C8D1 
C8D2 
 
Visit Window27 
- 
+7 
 
+7 
 
+7 
 
+7 
 
+7 
 
+7 
 
+7 
Cyclophosphamide 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
GVAX 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Pembrolizumab 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
Inclusion/Exclusion 
Criteria24 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medications 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Physical Exam 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Vital Signs and pulse ox 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Weight 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Performance Status 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Hematology profile20 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Chemistry profile20 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
TSH20,21 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Serum/Urine Pregnancy26 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
CEA20 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
CA 19-920 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Adverse event evaluation 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Vaccine Site Assessment 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
CT or MRI22 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
PBMC (up to 120cc)25, 28 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
Serum (up to 5cc) 25, 28 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
Plasma (up to 20cc)25, 28 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
QoL Questionnaire 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
18 Subjects will receive combination immunotherapy on a 21-day cycle.  If subjects who have undergone surgical resection develop irAE precluding further pembrolizumab administration, they will still 
be eligible to continue with CY/GVAX monotherapy to complete the total of 8 cycles 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. 
19 Approximately 30 days after their last dose of study drug or within 7 days prior to initiation of a new anti-cancer treatment, whichever comes first. Patients who discontinue from treatment should be 
contacted (by phone or email) every three months 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. 
20 Labs may be collected within a window of up to 3 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. 
21  T3 and FT4 to be checked reflexively if TSH is abnormal 
22 CT Chest, abdomen, pelvis with pancreas protocol with contrast or Non-contrast CT chest and MRI Abd, pelvis for those with contrast allergies 
23 Off study treatment visit for those patients not enrolling in the Extended Treatment Phase, otherwise patients will proceed to Extended Treatment Phase as per below  
24 Patients must have eligibility reconfirmed prior to initiation of Cycle 3 of immunotherapy. (Please see sections 3.3 and 3.4 for criteria). 
25 See section on correlative studies and lab manual for complete instructions 
26 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). 
27 Longer delays to be approved by the PI and/or sponsor 
28 Research samples will be collected at the discretion of the PI based on availability of supplies and safety of patient and staff 
 


Phase 2 Study of MK-3475 with GVAX in Patients with Locally Advanced Pancreatic Cancer  
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56
In order to minimize the need for research-only in-person visits, telemedicine visits may be substituted for in-person 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. 
 
 


Phase 2 Study of MK-3475 with GVAX in Patients with Locally Advanced Pancreatic Cancer  
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57
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1. Pembrolizumab will be dosed on an every 21 day dosing, while cyclophosphamide/GVAX will be administered every 24 weeks.  If subjects develop irAE precluding further pembrolizumab 
administration, they will still be eligible to continue with CY/GVAX monotherapy.  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. 
2. Approximately 30 days after their last dose of study drug or within 7 days prior to initiation of a new anti-cancer treatment, whichever comes first. 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 do not need to be repeated if one has been performed within 6 weeks. 
3. Temperature, respiration rate, blood pressure, pulse oximetry, and pulse should be taken at baseline, prior to pembrolizumab infusion, and at the end of the infusion.   
4. Labs may be collected within a window of up to 3 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. CBC with differential including absolute eosinophil count, absolute neutrophils, absolute lymphocytes, and platelets. 
6. Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, potassium, total protein, SGOT [AST], SGPT [ALT], sodium. 
7. T3 and FT4 to be checked reflexively if TSH is abnormal. 
8. 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). 
9. CT Chest, abdomen, pelvis with pancreas protocol with contrast or Non contrast CT chest and MRI Abd, pelvis for those with contrast allergies. Imaging can be done one month before day 1 of each 
cycle. 
10. Patients must have eligibility reconfirmed prior to initiation of Cycle 1 of extended treatment phase. (Please sections 3.3 and 3.4 for criteria). 
11. Dosing visit window for extended treatment phase is -1/+7 days from prior dose of study drug. All labs must be collected within 3 days prior to dosing. 
12. See section on correlative studies and lab manual for complete instructions 
13. Patients should continue to have CT scan and evaluation with oncologist every 3 months of GVAX only therapy during Extended Treatment Phase (after Cycle 9 of Pembrolizumab) 
14. Research samples will be collected at the discretion of the PI based on availability of supplies and safety of patient and staff 
 
Procedure 
Extended Treatment Phase: Pembrolizumab on 3-week cycle x 9 doses and Cy/GVAX on 24-week cycle x 4 doses1 
Off 
Study2 
C1D110 
C2D1 
C3D1 
C4D1 
C5D1 
C6D1 
C7D1 
C8 D1 
CY/GV
AX 
Dose 1 
CY/GV
AX 
Dose 1 
Day 2 
C9D1 
CY/GV
AX 
Dose 2 
Day 1 
CY/GV
AX 
Dose 2 
Day 2 
CY/GV
AX 
Dose 3 
Day 1 
CY/GV
AX 
Dose 3 
Day 2 
CY/GV
AX 
Dose 4 
Day 1 
CY/GV
AX 
Dose 4 
Day 2 
 
Visit Window11 
+7 
+7 
+7 
+7 
+7 
+7 
+7 
+7 
 
+7 
+7 
 
+7 
 
+7 
 
+7 
Cyclophosphamide 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
 
GVAX 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
Pembrolizumab 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
 
 
 
 
 
Physical Exam13 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
 
X 
 
X 
Vital Signs and pulse ox3 
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 profile4,5 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
 
X 
 
X 
Chemistry profile4, 6 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
 
X 
 
X 
TSH4, 7 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
 
X 
 
X 
Serum/Urine Pregnancy8 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
 
X 
 
 
CEA4 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
 
X 
 
X 
CA 19-94 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
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 
 
X 
 
X 
CT or MRI9, 14 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
PBMC (up to 120cc)12, 14 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
Serum (up to 5cc)12, 14 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
Plasma (up to 20cc)12, 14 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
QOL Questionnaire 
X 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 


Phase 2 Study of MK-3475 with GVAX in Patients with Locally Advanced Pancreatic Cancer  
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58
In order to minimize the need for research-only in-person visits, telemedicine visits may be substituted for in-person 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. 


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59
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 two doses 
of immunotherapy and have had their disease re-evaluated with imaging will be 
considered evaluable for response.   
 
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 4 weeks 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 same as was used at baseline and 
the lesions should be measured/assessed on the same pulse sequence.    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. 


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60
 
10.1.3 Distant metastases free survival (DMFS) 
 
DMFS is defined as the duration of time from start of treatment to identification of 
distant metastases on imaging or death, whichever occurs first.  DMFS will be 
evaluated through 2 years from completion of trial. 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 Local Progression-Free Survival (LPFS)  
 
LPFS is defined as the duration of time from start of treatment to time of first 
documented local progression or death, whichever occurs first.  Individuals will be 
censored at the date of the last scan if no event occurs. 
 
10.2 Quality of Life 
 
Quality of life will be assessed using the European Organization for Research and 
Treatment in Cancer quality of life core cancer questionnaire with the pancreatic cancer 
module (EORTC QLQ-C30/PAN26, Appendix D).  The EORTC QLQ-C30 is a 
multidimensional, 30-item questionnaire, which assesses five functional scales (physical, 
role, cognitive, emotional, and social), three symptom scales (fatigue, pain, and 
nausea/vomiting), a global health/QOL scale, as well as 6 single items.39  The EORTC 
QLQ-PAN26 supplements the core questionnaire with 26 items specific for patients with 
pancreatic cancer.40, 41 These instruments have been validated in patients receiving 
treatment for metastatic and resected pancreatic cancer and are sensitive to identify 
treatment related changes in quality of life.  
 
 
 
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.  
 
11.2 Safety Meetings 
 


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61
Scheduled meetings will take place weekly and will include the protocol principal 
investigator, study coordinator(s), data manager(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 Sponsor. 
 
11.3  Monitoring 
 
This is a low risk study under the Johns Hopkins Sidney Kimmel Comprehensive 
Cancer Center (SKCCC) Data Safety Monitoring Plan (DSMP, 2/21/19). 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 
(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; 


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62
  
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 
 
All statistical analyses will be performed using SAS version 9 or higher or R version 3.0 or 
higher. All statements of statistical significance will be based upon a 2-tailed test with an 
overall 0.05 level of significance and all confidence intervals will be 95%.   
 
Descriptive summaries for categorical variables will include counts and percentages.  
Descriptive summaries of continuous variables will include means, medians, standard 
deviations, and minimum and maximum values.  Where applicable, comparisons between 
groups will be made using a Chi-square test or logistic regression for binary variables and 
analysis of variance (ANOVA) for continuous variables.  Non-parametric alternatives such as 
Fisher’s exact test or Kruskal-Wallis tests will be considered as need.  Time to event outcomes 
will be analyzed using Kaplan-Meier estimates, log-rank tests, and Cox-proportional hazards 
models.  Analysis for variables collected repeated over time (e.g. quality of life outcomes) 
will include paired t-tests and linear mixed effects models to account for the within-person 
correlation. 
 
Additional post hoc statistical analyses not specified in the protocol, such as alternative 
modeling approaches may be completed. 
 
12.1 Study Design/Endpoints 
 
 This is a single center, open-label, phase 2 study to evaluate the activity of combination 
pembrolizumab, CY, and GVAX in subjects with locally advanced pancreatic cancer 
in conjunction with chemotherapy, radiation therapy, and possible surgical therapy. 
 
The primary endpoint is distant metastasis free survival (DMFS), which is defined 
above in Section 10.1. 
 
Secondary endpoints include overall survival, immune-related local progression-free 
survival (LPFS), subsequent surgical resectability, pathologic response rates, and 
quality of life. 
 
Exploratory endpoints include: 
 IHC of immune parameters relevant to the PD-L1/PD-1 pathway 
 Densities and distribution of T-cells in TME 
 Transcriptional microarray analyses 


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63
 Peripheral antigen specific T-cell responses 
 Intratumoral antigen specific T-cell responses 
 
We will also evaluate safety and toxicity of combination pembrolizumab, CY, and 
GVAX.  We will evaluate exploratory endpoints of pharmacogenomics and predictive 
biomarkers for responses. 
 
  
 
12.2 Sample Size/Accrual Rate 
 
Distant metastasis free survival (DMFS) is defined as the time from start of 
immunotherapy until distant recurrence or death, whichever occurs first.  Individuals 
who do not experience an event will be censored at the date of the last scan.  In the 
recent Phase II study, the median DMFS was 7.7 months (95% CI: 5.8-10.2) based 
upon 46 patients7.  Assuming an enrollment period of 12 months and a minimum 
follow-up of 24 months (i.e. a total trial period of 3 years), a total of 54 evaluable 
participants in the new study will provide 80% power to detect an increase in median 
DMFS from the previously observed control rate of 7.7 months to 13.6 months (HR = 
0.60) with a two-sided type I error rate of 0.05.   
 
Participants in the current study will be considered evaluable if they have completed 
two doses of combination immunotherapy and have received a follow-up scan.   
 
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 one year. The expected number of events under the alternative hypothesis 
is 39. 
 
 
12.3 Analysis of Primary Endpoints 
 
The evaluable population includes all subjects who have completed at least two doses 
of combination immunotherapy and have received at least one follow-up scan. 
 
Kaplan-Meier estimates of the survival function will be used to graphically display 
DMFS over time and to provide estimates of the median DMFS plus 1- and 2-year 
proportions.  The new combination will be considered to have significantly increased 
DMFS if the lower bound of the 95% confidence interval of the median DMFS is above 
the observed control rate of 7.7 months.   The effect of demographic, disease, and 
immunologic risk factors on DMFS will be evaluated using Kaplan-Meier estimates, 
log-rank tests, and Cox proportional hazards models. 
 
Although not powered for direct comparison of the primary outcome, exploratory 
analyses comparing DMFS for the current trial and the recently completed phase II 
study used to determine the reference control will be performed.  Log-rank tests and 
Cox proportional hazards models will be used to compare DMFS between studies.  


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64
 
We will include a preplanned subgroup analysis excluding those patients found to have 
metastatic disease intraoperatively that was not identified on pre-surgical imaging as 
they likely had existing metastatic disease and exact DMFS time period is 
indeterminate. 
 
 
12.4 Analysis of Secondary and Exploratory Endpoints 
 
As with the primary outcome, the evaluable populations includes all subjects who 
completed the initial round of chemotherapy treatment and received at least one follow-
up scan.  OS and LPFS (as defined in Section 10.1) will be analyzed using the 
techniques described for the primary outcome.   
 
Subsequent surgical resectability will be determined by review of imaging and review 
of the subject’s surgical candidacy (clinical status and tumor status) at our multi-
disciplinary tumor board as per NCCN guidelines after completion of SBRT.42  
Pathologic response will be graded after surgical resection or biopsy with comparisons 
of pre-and post-immunotherapy core biopsies or surgical samples.  For each outcome, 
the proportion will be calculated with an exact 95% confidence interval.   Individuals 
who drop out of the study due to treatment toxicity or other causes prior to outcome 
assessment will be counted as not resectable and non-responders.  Logistic regression 
will be used to assess the impact of risk factors on each outcome. Time to event 
analyses will be used to assess the timing of resection and response. 
 
Quality of life will be assessed via EORTC QLQ-C30/Pan26 (v3.0) questionnaire. Our 
study population is pancreatic cancer subjects, and the analysis will be focused on 
Global Health Status/QoL scale, symptom scale (fatigue, pain), and functional scale 
(physical functioning, role functioning, emotional functioning) comparing data from 
initiation of treatment, with each immunotherapy, and after SBRT. For each module, 
summary statistics of the score will be reported as baseline and follow up time. Changes 
of quality of life score before and after treatment will be tested via paired t-test. In 
addition, mixed effect models will be fitted for assessing the pattern of quality of life 
over time. The frequency and proportion of patients who reach minimal clinically 
important difference (MCID) of 10-points change from baseline will be tabulated by 
time. Logistic mixed effects models will be used to track the proportion over time.  The 
time to definitive deterioration in quality of life, defined as a decline of 10 points or 
more, will be analyzed using the Kaplan Meier method.  
 
Genomic sequencing library construction, whole genome/exome sequencing, whole 
transcriptome sequencing, microbial sequencing, neoepitope prediction, mutation 
burden, and bioinformatic analysis will be performed either at an on-campus laboratory 
or at an off-campus sequencing service. All the samples will be de-identified before 
sending to any laboratory for sequencing.  The FASTQ files, BAM files and VCF files 
will be generated and analyzed. Results from the sequencing studies will not be 
released to the patients. These studies are for research purposes only and are not using 


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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. 
 
 
12.5 Safety Analysis 
 
The safety analysis will be performed in all treated subjects. A complete list of all AE 
data will be provided along with an assessment of grade and relationship to study drug.  
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. Negative binomial regression and Cox 
proportional hazards models will be used to assess the rate and time to first toxicity, 
respectively. 
 
12.5.1 Post-Operative Complications 
 
The monitoring rule will focus on Grade IIIa post-operative complications or above, which 
is beyond what may be expected for chemotherapy or resection without immunotherapy, 
and that may be attributable to the immunotherapy drugs (any component of 
Cy/GVAX/Pembrolizumab). The proportion of subjects with post-operative complications 
(Grade IIIa or above) resulting from immunotherapy will be monitored using a Bayesian 
stopping guideline.  A post-operative complications (Grade IIIa or above) level 40% would 
be considered the upper boundary for acceptable toxicity.  We expect the actual post-
operative complications (Grade IIIa or above) level to be approximately 26%.  A Beta (2.5, 
5.5) prior, representing a post-operative complications (Grade IIIa or above) rate of 31% 
(slightly above our expected rate), will be used to be conservative.  After the first 6 patients 
have had surgery treatment, safety will be monitored continuously.  If the posterior 
probability that the percentage of post-operative complications (Grade IIIa or above) 
exceeds 40% is greater than 0.5,  then enrollment will be suspended until further review 
and consideration by the PI, IND Sponsor, and MEC.  If the PI, IND sponsor and the 
surgical co-investigators determine that it is safe to do so (e.g. unrelated to study treatment, 
reversible/treatable complications), the trial may resume once updated treatment and 
monitoring plans have been developed and approved by the MEC, IRB and other oversite 
agencies.  Table 1 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 1.  The number of post-operative complications (Grade IIIa or above) needed to 
trigger stopping guidelines throughout the course of the study. 
  


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Number of Patients 
Number of post-operative 
complications (Grade IIIa 
or above)needed to trigger 
re-evaluation 
6-8 
4 
9-10 
5 
11-13 
6 
14-15 
7 
16-18 
8 
19-20 
9 
21-23 
10 
24-25 
11 
26-28 
12 
29-30 
13 
31-33 
14 
34-35 
15 
36-38 
16 
39-40 
17 
41-43 
18 
44-45 
19 
46-48 
20 
49-50 
21 
51-53 
22 
54 
23 
  
 
The probability of triggering the stopping guidelines was assessed for a range of possible 
true unacceptable surgical toxicity rates using simulations with 5000 replicates (Table 2).  
The probability of stopping to re-evaluate was 19.4% if the true proportion with an 
unacceptable immunotherapy toxicity was 26%, the expected value.  In comparison, the 
probability of stopping early is 90% if the true proportion with an unacceptable 
immunotherapy toxicity was 45%, respectively.  
 
 
Table 2.  Probability of triggering a re-evaluation for a range of unacceptable post-
operative complication rates (Grade IIIa or above). 
  
True probability of 
unacceptable post-
operative complications 
(Grade IIIa or above) 
Number of post-operative 
complications (Grade IIIa 
or above)needed to trigger 
re-evaluation 
5% 
< 0.1% 
10% 
0.6% 
15% 
2.7% 


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20% 
7.4% 
26% 
19.4% 
30% 
32.9% 
35% 
53.8% 
40% 
75.1% 
45% 
90.0% 
 
 
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, and GVAX, 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. As with the primary outcome, the evaluable populations includes all 
subjects who completed the initial two cycles of immunotherapy and received at least 
one follow-up scan. 
 
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 and standard and immune criteria of response and 
PFS. 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. 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. 
 
 


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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 
 
Adverse Event of Clinical Interest (ECI) Reporting Form 
 
Please notify: IND Sponsor within 24 hours (
 
Merck within 24 hours (
) 
 
Protocol Title: 
 
 
Phase 2 Study of GM-CSF secreting allogeneic pancreatic cancer vaccine in 
combination with PD-1 Blockade Antibody (Pembrolizumab) for the Treatment 
of Patients with Locally Advanced Adenocarcinoma of the Pancreas 
Protocol Number 
(MK-3475-308): 
 
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 
 
MK-3475 
 
CY 
GVAX 
Date of Last Dose Prior to Event: 
 
MK-3475 
CY 
GVAX 
Number of Total Doses: 
 
MK-3475 
CY 
GVAX 
Event Onset Date: 
Event End Date: 
 
 
 
Date Event Discovered: 
 
Relationship to: 
MK-3475 
CY 
GVAX 
Underlying Disease 
Unrelated 
 
 
 
 
Probably Unrelated 
 
 
 
 
Possible Related 
 
 
 
 


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Probably Related 
 
 
 
 
Definitely 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 
Freque
ncy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section F: Comments 
 
Additional Documents: 
 Please specify 
 
 
 
 
 
 
 
 
 
 


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APPENDIX C: SAE Reporting Form 
 
Serious Adverse Event Reporting Form 
 
Please notify: Dr. Jaffee within 24 hours (
 
Merck within 24 hours (
) 
 
Protocol Title: 
 
 
Phase 2 Study of GM-CSF secreting allogeneic pancreatic cancer vaccine 
in combination with PD-1 Blockade Antibody (Pembrolizumab) for the 
Treatment of Patients with Locally Advanced Adenocarcinoma of the 
Pancreas 
Protocol 
Number: 
(MK-3475-308) 
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 
 
MK-3475 
 
CY 
GVAX 
Date of Last Dose Prior to Event: 
 
MK-3475 
CY 
GVAX 
Number of Total Doses: 
MK-3475 
CY 
GVAX 


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Event Onset Date: 
Event End Date: 
Relationship to: 
MK-3475 
CY 
GVAX 
Underlying Disease 
Unrelated 
 
 
 
 
Probably Unrelated 
 
 
 
 
Possible Related 
 
 
 
 
Probably Related 
 
 
 
 
Definitely 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 
Frequ
ency 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section F: Comments 
 
Additional Documents: 
 Please specify 
 
 
 
 
 
 
 


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APPENDIX D: EORTC QLQ-C30/PAN26 
 
 


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