Conditions: Metastatic Pancreatic Adenocarcinoma
Keywords: Pancreatic cancer Vaccine Immunotherapy Pembrolizumab PD-1 IDO CRS-207 Epacadostat
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 41
Healthy volunteers: no

Brief summary:
This study will enroll patients who have metastatic pancreatic cancer and have progressed on prior chemotherapy.

Part 1 (dose escalation) participants will receive epacadostat/pembrolizumab/cyclophosphamide(CY)/GVAX pancreas vaccine followed by epacadostat/pembrolizumab/CRS-207, Part 1X (dose escalation) participants will receive epacadostat/pembrolizumab/CRS-207. Part 2X (dose expansion) participants will receive epacadostat/pembrolizumab/CRS-207.

The primary objectives of this study are to determine the recommended dose of epacadostat in this combination and assess survival of subjects in both treatment groups.

Detailed description:

Arms:
arm 1: Epacadostat/Pembrolizumab/CY/GVAX/CRS-207 arm 2: Epacadostat/Pembrolizumab/CY/GVAX/CRS-207 arm 3: Epacadostat/Pembrolizumab/CRS-207 arm 4: Epacadostat/Pembrolizumab/CRS-207 arm 5: Epacadostat/Pembrolizumab/CRS-207

Interventions: intervention 1: Epacadostat intervention 2: Pembrolizumab intervention 3: CRS-207 intervention 4: Cyclophosphamide intervention 5: GVAX Pancreas Vaccine
Intervention descriptions: intervention 1: Patients will receive treatment every 3 weeks for 6 cycles of treatment within a course (total of 18 weeks). Epacadostat (100, 300, or 600 mg) is taken by mouth twice a day, every day. intervention 2: Patients will receive treatment every 3 weeks for 6 cycles of treatment within a course (total of 18 weeks). Pembrolizumab (200 mg) will be administered IV on day 1 of Cycles 1-6. intervention 3: CRS-207: Patients will receive treatment every 3 weeks for 6 cycles of treatment within a course (total of 18 weeks). CRS-207 (1 × 10\^9 CFU) will be administered IV on Day 2 of Cycles 3-6. intervention 4: Patients will receive treatment every 3 weeks for 6 cycles of treatment within a course (total of 18 weeks). Cyclophosphamide (200 mg/m\^2) will be administered IV on day 1 of Cycles 1 and 2. intervention 5: Patients will receive treatment every 3 weeks for 6 cycles of treatment within a course (total of 18 weeks). GVAX will be administered on Day 2 of Cycles 1 and 2.

Protocol document:
Prot_SAP_000.pdf: 
Cover Page for Protocol – J16173 
NCT Number: 
NCT03006302 
Official Title of Study 
A Phase 2 Study of Epacadostat, 
Pembrolizumab, and CRS-207, with or 
without Cyclophosphamide and GVAX 
Pancreas Vaccine in Patients with 
Metastatic Pancreatic Cancer 
Document Date: 
April 20, 2021 


 
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Title: A Phase 2 Study of Epacadostat, Pembrolizumab, and CRS-207, with or without 
Cyclophosphamide and GVAX Pancreas Vaccine in Patients with Metastatic Pancreatic 
Cancer 
 
Johns Hopkins Protocol #:   
J16173, IRB00118520 
 
Merck Protocol #: 
 
 
3475-520 
 
Incyte Protocol #: 
 
 
I-24630-16-06 
 
Principal Investigator: 
Dr. Dung Le (Protocol Chair) 
 
 
 
Co-Investigator: 
 
Dr.  Katherine Bever 
 
IND Sponsor: 
 
 
 
 
 
 
 
 
 
 
   
 
 
IND:  
 
 
 
  
 
 
 
BB IND 16147 
 
Merck Supplied Agent: 
 
 
 
 
Pembrolizumab (MK-3475; anti-PD-1 mAb) 
Incyte Supplied Agent: 
 
 
 
Epacadostat (INCB024360) 
Johns Hopkins University Supplied Agent:  GVAX pancreas vaccine  (Panc 10.05 pcDNA-1 
/GM-Neo, Panc 6.03 pcDNA-1/GM-Neo); 
CRS-207 (Lm ΔactA/ΔinlB/hMesothelin) 
Commercial Agent:   
 
 
 
 
 
 
Cyclophosphamide (CY, Cytoxan®) 
 
Date of Issue: 
Version 1.1 / December 14, 2016 
Version 1.2 / January 18, 2017 
Version 1.3 / March 3, 2017 
Version 2.0 / November 29, 2018 
Version 3.0 / May 31, 2019 
Version 4.0 / June 17, 2020 
Version 5.0/ June 25, 2020 
Version 6.0/ December 10, 2020 
Version 7.0/ April 20, 2021 


 
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TABLE OF CONTENTS 
TABLE OF CONTENTS ..............................................................................................................2 
TABLE OF TABLES .....................................................................................................................4 
 OBJECTIVES 
......................................................................................................................5 
 
Primary Objectives...................................................................................................5 
 
Secondary Objective ................................................................................................5 
 
Exploratory Objectives ............................................................................................5 
 
Study Design ............................................................................................................6 
 BACKGROUND ......................................................................................................................8 
 
Study Disease ...........................................................................................................8 
 
Rationale ..................................................................................................................9 
 PATIENT SELECTION ..........................................................................................................12 
 
Inclusion Criteria ...................................................................................................12 
 
Exclusion Criteria ..................................................................................................14 
 
Inclusion of Women and Minorities ......................................................................17 
 TREATMENT PLAN ..............................................................................................................17 
 
Dose Escalation (Part 1/1X)...................................................................................17 
 
Dose Expansion (Part 2X) .....................................................................................19 
 
Agent Administration.............................................................................................19 
 
Dosing Criteria .......................................................................................................22 
 
General Concomitant Medication and Supportive Care Guidelines ......................22 
 
Prohibited and/or Restricted Medications and Treatments ....................................27 
 
Antibiotic Regimen for Semi-Permanent Indwelling Device Placement ..............29 
 
Antibiotic Administration after Last CRS-207 Dose in Each Treatment Course, 
Suspected CRS-207 Infection, or Administration of Steroids or 
Immunosuppressive Agents for Suspected Treatment-Related AEs .....................29 
 
Definition of an Overdose for this Protocol ...........................................................31 
 
Unacceptable Toxicity ...........................................................................................32 
 
Contraception, Use in Pregnancy, Use in Nursing ................................................32 
 
Duration of Therapy ...............................................................................................35 
 
Criteria for Removal from Treatment ....................................................................35 
 
End of Treatment (EOT)/Safety Follow-up Visit ..................................................36 
 
Duration of Follow-Up ..........................................................................................37 
 
Blood Cultures for CRS-207 Surveillance .............................................................38 
 DOSING DELAYS, MODIFICATIONS, DISCONTINUATION .........................................38 
 
Dose Modifications ................................................................................................38 
 
Dosing Delays ........................................................................................................39 
 PHARMACEUTICALINFORMATION .................................................................................44 
 
Epacadostat (INCB024360) ...................................................................................44 
 
Cyclophosphamide (Cytoxan®, CY) ......................................................................45 
 
GVAX Pancreas Vaccine .......................................................................................47 
 
CRS-207 .................................................................................................................49 
 
Pembrolizumab ......................................................................................................52 


 
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 ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ..................................54 
 
Definitions..............................................................................................................54 
 
Assessment of Causality ........................................................................................56 
 
Assessment of Grade..............................................................................................57 
 
Expectedness ..........................................................................................................57 
 
Handling of Expedited Safety Reports ..................................................................58 
 
Reporting................................................................................................................58 
 CORRELATIVE / SPECIAL STUDIES .................................................................................60 
 
Tumor Tissue Studies ............................................................................................60 
 
Peripheral Blood Mononuclear Cells (PBMCs) ....................................................61 
 
Serum and Plasma Marker Studies ........................................................................61 
 
Stool and Oral Wash Studies .................................................................................62 
 
Diagnostic Tissue Samples ....................................................................................62 
 
Genomic Analysis ..................................................................................................62 
 STUDY CALENDAR .............................................................................................................63 
 
Treatment Part 1 .....................................................................................................64 
 
Treatment Part 1X/Part 2X ....................................................................................68 
 
End of Treatment and Follow-Up ..........................................................................72 
 STUDY ENDPOINTS .............................................................................................................73 
 
Primary Endpoint ...................................................................................................73 
 
Secondary Endpoint ...............................................................................................73 
 
Exploratory Endpoints ...........................................................................................73 
 DATA REPORTING / REGULATORY REQUIREMENTS .................................................74 
 
Data Management ..................................................................................................74 
 
Safety Meetings .....................................................................................................74 
 
Monitoring .............................................................................................................75 
 STATISTICAL CONSIDERATIONS.....................................................................................75 
 
Sample Size ............................................................................................................75 
 
Analysis sets...........................................................................................................76 
 
Statistical Analyses ................................................................................................76 
 
Safety Analysis ......................................................................................................77 
 
Safety monitoring...................................................................................................77 
REFERENCES 
....................................................................................................................79 
APPENDIX A.   
Performance Status Criteria .......................................................................81 
APPENDIX B.   
Prohibited MAOIs and Drugs Associated with Significant MAOI Activity
....................................................................................................................82 
APPENDIX C.   
Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for 
Evaluating Response in Solid Tumors .......................................................83 
APPENDIX D.  
Immune-Related Response Criteria ...........................................................86 
 
 


 
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TABLE OF TABLES 
Table 1:  Epacadostat Dose Escalation Guidance ......................................................................... 17 
Table 2: Treatment Schedule ........................................................................................................ 19 
Table 3: Regimen Description ...................................................................................................... 19 
Table 4: Pembrolizumab Infusion Reaction Treatment Guidelines .............................................. 24 
Table 5: Dose Modifications of Epacadostat ................................................................................ 39 
Table 6: Pembrolizumab/Epacadostat Dose Modification Guidelines for Drug-Related AEs ..... 40 
 
 


 
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 OBJECTIVES 
 
 
Primary Objectives 
 
 The primary objective of Part 1/1X of this study is to determine the recommended 
dose of epacadostat, 
in 
combination 
with 
pembrolizumab, 
CRS-207, 
cyclophosphamide (CY), and GVAX pancreas vaccine in Part 1, and in 
combination with pembrolizumab and CRS-207 only in Part 1X. 
 
 The primary objective in Part 2X of this study is to determine the 6 month survival 
rate in previously treated metastatic pancreatic cancer patients receiving 
epacadostat, pembrolizumab, and CRS-207.  
 
 
Secondary Objective 
 
 To assess safety and characterize toxicities of anti-programmed death-1 (PD-1), 
indoleamine 2,3-dioxygenase 1 (IDO1) blockade, and CRS-207 with or without 
CY/GVAX pancreas vaccine. 
 
 
Exploratory Objectives 
 
 To assess overall survival (OS), progression-free survival (PFS), objective response 
rate (ORR), best overall response (BOR), duration of response (DOR), duration of 
clinical benefit (DCB), time to objective response (TTOR), and disease control rate 
(DCR) per RECIST 1.1, as well as by immune related response criteria (irPFS, 
irORR, irBOR, irDOR, irDCB, irTTOR, irDCR).  
  
 To measure tumor marker kinetics (CA 19-9) in subjects receiving treatment and 
correlate with OS, PFS and best overall response. 
 
 To collect baseline and longitudinal peripheral blood mononuclear cells (PBMC), 
plasma, and serum to identify potential therapeutic targets, biomarkers, and 
predictors of response and autoimmune toxicity. 
• Measure post-treatment cellular changes in PBMCs including effector, 
helper, and regulatory T cells, NK cells, monocytes, and macrophages 
through flow cytometry (FACS) and gene expression profiling.  
• Correlate induction of Listeria monocytogenes (Lm)-specific and mesothelin 
antigen-specific T cell responses and changes to the T cell receptor repertoire 
with response assessments. 
 
 To collect archived tissue and pre- and on-treatment biopsies to test for predictors 
of response (OS, PFS and BOR) and future targets for combinatorial therapy.   
• Immunohistochemistry (IHC) and/or gene expression profiling will be used 
to compare the nature of tumors and immune infiltrates for responders versus 
non-responders.   


 
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• Up-regulation of immune inhibitory molecules (such as programmed death-
ligand 1 [PD-L1] and IDO1) will be evaluated in the pre- and on-treatment 
samples.  
• RNA expression and proteomic analysis to quantify expression and activation 
of specific signaling pathways in tumors from responders versus non-
responders 
• TCR repertoire analysis pre and on-treatment 
 
 To collect stool and oral wash samples pre- and on-treatment to identify candidate 
gut microbial biomarkers and predictors of response (OS, PFS and BOR)   
• Microbial community analysis to correlate gut microbiome composition with 
response (OS, PFS and BOR)  
• Whole metagenome functional profiling analysis via shotgun sequencing to 
correlate microbiome composition and microbial functions and pathways 
with response (OS, PFS and BOR) 
 
1.3.6   To explore the effects of therapy on tumor and peripheral blood and tumor 
infiltrating immune cells, and to explore potential molecular determinants of 
response, progression and disease stability. 
 
 
Study Design 
 
 
 
This is an open-label, phase 2 study consisting of 2 parts. Part 1 consists of a 3+3 dose escalation 
design to determine the dose of epacadostat for use in combination with pembrolizumab, 
CY/GVAX Pancreas Vaccine, and CRS-207. In Part 1X, patients will continue dose escalation 


 
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and will receive epacadostat, pembrolizumab and CRS-207 only. Enrollment will be staggered by 
at least 1 week for patients enrolled on dose level 3 in Part 1X. The doses of pembrolizumab, CY, 
GVAX, and CRS-207 are fixed (Table 3). Dose limiting toxicities (DLTs) will be assessed through 
Cycle 4 Day 1 in Part 1, and through Cycle 2 Day 1 in Part 1X. Complete information on the 
definition of DLTs and dose escalation rules can be found in Section 4.1. Treatment in Part 2X 
will be initiated once the maximum tolerated dose (MTD) for Part 1X has been determined. This 
will be the dose used in Part 2X. 
 
Part 2X consists of a dose expansion cohort to evaluate the safety and clinical activity of previously 
treated metastatic pancreatic cancer patients who receive epacadostat, pembrolizumab, and CRS-
207.  Approximately 20 evaluable patients will be treated (for a total of 26 evaluable patients in 
Part 2X, including the 6 patients who are treated at the same dose level in Part 1X).  Clinical 
activity will be evaluated in comparison to historical controls, with a 25% 6 month survival being 
used as the benchmark1. 
 
For all patients, the study will consist of a screening period, a treatment period, and a follow-up 
period.  Screening evaluations will be done within 21 days prior to start of treatment.  Each cycle 
will be 3 weeks.  Each course of treatment will be 6 cycles and courses can be repeated.  
 
Treatment in Part 1 consisted of 2 cycles of pembrolizumab, CY/GVAX pancreas vaccine and 
epacadostat, followed by 4 cycles of pembrolizumab, CRS-207 and epacadostat. In Part 1X and 
Part 2X, treatment will consist of 6 cycles of pembrolizumab, CRS-207 and epacadostat. Complete 
information on study drug administration, schedule, and dosing can be found in Section 4.3. 
 
It is estimated that 5% of the subjects who complete screening will not receive study treatment, so 
approximately 46 subjects are expected to be enrolled to achieve up to 44 treated subjects (up to 
24 on Part 1/1X and 20 on Part 2X of the study).  If the investigator assesses a drug-related toxicity 
(that requires discontinuation) to be related to an individual component of the treatment schedule, 
dosing for that study drug alone may be discontinued while dosing is delayed until the subject 
meets criteria to resume treatment of the other study drugs. The relationship to the discontinued 
study drug should be well documented in the source documents and permission from the Protocol 
Chair needs to be obtained prior to continuation with the other study drugs. 
 
The proportion of treated subjects in Part 2X with unacceptable toxicity will be monitored 
routinely using a Bayesian stopping guideline (Section 12.5). Complete unacceptable toxicity 
criteria can be found in Section 4.9. 
 
Clinical and immune responses will be evaluated at baseline and during treatment through tumor 
biopsies, PBMC, serum, and plasma collection, and computed tomography (CT) scans or magnetic 
resonance imaging (MRI), if CT is contraindicated. Tumor assessments will be made using 
RECIST 1.1 and irRC.  
 
At the investigator’s discretion, subjects may receive additional courses of the assigned treatment 
regimen if they are clinically stable and meet dosing eligibility criteria.  All subjects may continue 
in the treatment period up to a maximum of 2 years, or until discontinuation due to unacceptable 
toxicity, lack of clinical benefit as determined by the investigator, subject withdrawal, or 


 
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termination of the study by sponsor. Subjects that begin a new course prior to the 2 year cut-off 
may complete that course prior to coming off study.  Subjects may continue on treatment with 
radiographic disease progression if subject is clinically stable and investigator believes the 
treatment is providing benefit.  Criteria for removal from treatment are found in Section 4.12.  To 
eliminate any potentially residual CRS-207, subjects will initiate a 7-day course of antibiotics 7 
days after the subject’s last CRS-207 and prior to receiving any subsequent cancer-related therapy  
(or if the patient will be having a semi-permanent indwelling device placed while on study) per 
Section 4.7. Blood cultures through a peripheral vein and also through a central line (if applicable) 
will be collected to monitor for the presence of CRS-207 for up to 1 year post-treatment per 
Section 4.15. 
 
Subjects will return to the study site 28 days after the final administration of study treatment for 
an end-of-treatment (EOT) evaluations and AE assessments.  Subjects who are still receiving 
treatment at the time of study close may complete the current treatment course and the EOT 
evaluation prior to transitioning to long-term follow-up. Subjects will be considered in the 
treatment period until 28 days after the last dose of study drug. Subjects will also be contacted 90 
days from the last dose of pembrolizumab for safety follow-up.  Complete information on safety 
reporting can be found in Section 7. After completion of treatment and EOT assessments, all 
subjects, including those who did not receive treatment, will continue to be followed every 12 
weeks by telephone, e-mail, or optional clinic visit until death, withdrawal of consent, or closure 
of study.  Information on survival and new cancer therapies will be collected. Subjects who 
discontinue treatment for reasons other than disease progression will also continue to be monitored 
by radiologic imaging every 12 weeks until start of a new anti-cancer therapy, disease progression, 
death, withdrawal of consent, or the close of the study, whichever occurs first.   
 
The study will be not be closed until all subjects have been followed for at least 12 months from 
first treatment and the primary analysis timing criteria have been met, or when all subjects have 
withdrawn from study.  Patients will continue to be followed after study closure for survival data. 
The primary analysis will be conducted when the first of the following has occurred: 6 month 
survival data is available for the last enrolled and treated subject, or study is closed by sponsor.  
At the conclusion of the study, all remaining subjects will be offered enrollment in a long-term 
follow-up study and continue to be followed for survival and clinical and immunological 
responses. 
 
 BACKGROUND 
 
 
Study Disease 
 
Despite decades of basic and clinical research, effective therapy for the treatment of patients with 
pancreatic ductal adenocarcinoma (PAC) remains one of the greatest unmet clinical needs in 
oncology today. Currently, PAC accounts for approximately 7% of all cancer-related mortality 
and has the lowest 5-year survival rate among all cancer types in the United States. PAC is 
currently the 4th leading cause of death from cancer in the U.S. with estimates in 2016 for 53,070 
people diagnosed and about 41,780 dying from the disease2.  Worldwide it will claim more than 
300,000 lives this year3.  It is projected that by 2030, pancreatic cancer will become the second 
leading cause of cancer-related death in the US4.  


 
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Most patients are initially diagnosed with advanced disease that is inoperable with median survival 
of less than 1 year. Patients with advanced disease are usually treated with chemotherapy, with the 
intent of prolonging survival and palliating symptoms (pain, weight loss and decrease in 
performance status). From 1997, gemcitabine was the standard chemotherapy for advanced 
pancreatic cancer after demonstrating a significant improvement in survival compared to 5-
fluorouracil (5-FU)5. Median survival was 5.65 months for gemcitabine-treated patients and 4.41 
months for 5-FU treated patients, while overall tumor response rates were 5.4% and 0%, 
respectively. 
 
Until recently, only erlotinib, an oral epidermal growth factor (EGF) inhibitor, was shown in a 
Phase 3 study to modestly improve median OS in combination with gemcitabine over gemcitabine 
alone (6.24 months for the doublet versus 5.91 months for gemcitabine alone) without a significant 
difference in ORR between the treatments6. In 2011, a Phase 2/3 trial conducted by a French 
consortium study group demonstrated FOLFIRINOX, a combined regimen of oxaliplatin, 
irinotecan, fluorouracil, and leucovorin significantly increased survival in patients with pancreatic 
cancer over gemcitabine alone. Median OS was 11.1 months versus 6.8 months for each treatment, 
respectively (hazard ratio [HR] for death, 0.57; 95% confidence interval [CI], 0.45 to 0.73; p < 
0.001). The ORR was also increased to 31.6% from 9.4% (p < 0.001). Adverse events were 
increased in the FOLFIRINOX group and 5.4% of patients in this group experienced febrile 
neutropenia7. Although FOLFIRINOX represents an efficacious regimen in pancreatic cancer, 
there are still concerns about its potential toxicity and it is being reserved for the most fit patients. 
 
In the MPACT (Metastatic Pancreatic Adenocarcinoma Clinical Trial) study, nab-paclitaxel 
combined with gemcitabine demonstrated a statistically significant and clinically meaningful 
median OS of 8.5 versus 6.7 months (HR 0.72, p < 0.0001 including a 59% increase in one-year 
survival (35% versus 22%, p=0.0002) and demonstrated double the rate of survival at two years 
(9% versus 4%, p=0.02) as compared to gemcitabine alone in previously untreated patients with 
metastatic pancreatic cancer. nab-/gemcitabine also demonstrated a statistically significant 
improvement in key secondary endpoints compared to gemcitabine alone, including a 31% 
reduction in the risk of progression or death with a median PFS of 5.5 versus 3.7 months (HR 0.69, 
p < 0.0001) and an ORR of 23% compared to 7% (response rate ratio of 3.19, p < 0.0001)8. The 
MPACT study and regimen formed the basis for full FDA approval in September 2013 for the 
first-line treatment of metastatic adenocarcinoma of the pancreas. 
 
Nanoliposomal irinotecan in combination with 5-FU was recently approved for patients with 
previously treated pancreatic cancer.  However, it is unknown if this combination is better than 5-
FU and irinotecan (FOLFIRI) as 5-FU was the comparator and there was no benefit in patients 
who previously received irinotecan so the value of this drug is questionable in FOLFIRINOX 
treated patients9.  Therapies for patients with metastatic pancreatic cancer are urgently needed.  
 
Novel approaches, such as immunotherapy, hold promise in this very difficult cancer. 
 
 
Rationale 
 


 
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Therapeutic benefit of immunotherapy in pancreatic cancer remains to be seen.  Single agent 
therapy using vaccines to induce antigen-specific T cells or targeting immune checkpoints such as 
PD-1 or cytotoxic T-lymphocyte associated protein-4 (CTLA-4) does not address the complex 
immunosuppressive mechanisms at play both at the systemic level and in the tumor 
microenvironment.  Effective immunotherapy in pancreatic cancer may require combinations of 2 
or more agents to overcome this tolerance.  Various combination strategies are being tested in less 
immunogenic tumors.  IDO1 inhibition in combination with PD-1 targeting is currently under 
evaluation in clinical trials.  PD-1 and IDO1 inhibition have been combined with vaccines in 
preclinical models as well.  Furthermore, PD-1 inhibition with pancreatic cancer vaccines is 
currently being studied using nivolumab (anti-PD-1) with GVAX Pancreas (allogeneic pancreatic 
cancer cells modified to express GM-CSF) and CRS-207 (attenuated Lm expressing the tumor 
associated antigen mesothelin).    
 
Pancreatic cancer has been refractory to immunotherapy and a doublet or triplet approach may be 
necessary.  Numerous studies are targeting various immune checkpoints and stimulatory agonists 
but it could possibly be futile without a vaccine to induce infiltration of an inflammatory infiltrate 
including effector T cells into the tumor. 
 
Immunotherapies in Pancreatic Cancer 
 
GVAX Pancreas has been combined with immune-modulatory doses of CY to target regulatory T 
cells (Tregs) and CRS-207 is a live, attenuated, double-deleted Lm engineered to secrete 
mesothelin, a tumor-associated antigen which is overexpressed in most pancreatic cancers, into 
infected antigen presenting cells, facilitating its presentation in the context of major 
histocompatibility complexes. GVAX Pancreas and CRS-207 were found to work synergistically 
in preclinical models and a heterologous prime boost strategy using CY/GVAX Pancreas as a 
prime and CRS-207 as a boost vaccine has shown, in one study, to provide a survival benefit in 
patients with metastatic pancreatic cancer with an acceptable safety profile compared to 
CY/GVAX Pancreas alone10.  The most frequent grade 3 to 4 related toxicities were transient 
fevers, lymphopenia, elevated liver enzymes, and fatigue. 
 
 
 
 GVAX Pancreas 
has also been combined with ipilimumab resulting in delayed responses and prolonged survival in 
a subset of patients11.  
 
 
  A 
multipronged approach with vaccines and targeting the inhibitory tumor microenvironment is 
likely necessary in this stromal rich cancer. 
 
IDO and Pancreatic Cancer 


 
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IDO is found in pancreatic cancer cell lines12 and IDO inhibition shows activity in a PANC02 
mouse tumor model13.  In a study of resected pancreatic cancer specimens, IDO expression was 
associated with an increase in Tregs and was upregulated in the metastases compared to the 
primary14.  These authors also showed upregulation of IDO in pancreatic cancer cell lines with 
IFNγ which would suggest the possibility of IDO as a suppressive mechanism in the 
microenvironment even with an inflammatory infiltrate.  In an analysis of intraductal papillary 
mucinous neoplasms (IPMN) and pancreatic tumors, high IDO expression was positively 
correlated with tumor size, TNM stage and tumor markers and high IDO status corresponded with 
high Treg level as well15.  These data support IDO as being a promising target for pancreatic 
cancer. 
 
IDO Inhibition, Immune Checkpoint Blockade, & Vaccines 
 
The inhibition of IDO has been combined with immune checkpoint blockade to enhance treatment 
effects in difficult tumor models16,17.  Holmgaard et al demonstrated that IDO-deficient mice had 
better tumor control than their wild type counterparts when treated with anti-CTLA-4 or anti-PD-
1/anti-PDL-1.  They were also able to demonstrate efficacy of the combination of anti-CTLA-4 
and 1-MT (an IDO inhibitor).  Importantly, adding a B16 equivalent of GVAX promoted rejection 
of 45% of tumors in a difficult tumor model.  1-MT has also been shown to decrease Tregs and 
slow PANC02 tumor growth in combination with tumor lysate pulsed dendritic cells.   
 
 
 
 
 
Pembrolizumab 
 
Pembrolizumab is a selective humanized monoclonal antibody of the IgG4/kappa subclass 
designed to block the interaction between PD-1 and its ligands. It has recently been approved in 
the United States for the treatment of unresectable or metastatic melanoma, metastatic PD-L1 
positive non-small cell lung cancer (NSCLC), and recurrent or metastatic head and neck squamous 
cell carcinoma (HNSCC) based on tumor response and durability of response18-21. 
 
Epacadostat 
 


 
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Epacadostat is a selective and reversible oral inhibitor of IDO1, resulting in reduced conversion of 
tryptophan to kynurenine. An optimal dose of epacadostat for clinical study has not been 
established; however, higher doses are associated with enhanced enzyme inhibition. When 
administered at 600mg BID, epacadostat resulted in enzyme inhibition of approximately 90% at 
steady state, compared to 70% at 300mg BID. Furthermore, in the phase 1 study ECHO-203 of 
epacadostat plus durvalumab, lower peak exposures were observed in pancreatic cancer patients, 
suggesting higher doses may be necessary in this group. 
 
 PATIENT SELECTION 
 
 
Inclusion Criteria 
 
 Age ≥18 years.   
 
 Have histologically- or cytologically-proven ductal adenocarcinoma of the 
pancreas.  Patients with mixed histology (>30% non-adenocarcinoma component) 
will be excluded.   
 
 Have metastatic disease. 
 
 Have radiographic disease progression at the time of study enrollment, after 
previous systemic chemotherapy given in a neoadjuvant, adjuvant, locally 
advanced or metastatic setting. 
 


 
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 Presence of at least one lesion with measurable disease as defined by 10 mm in 
longest diameter for a soft tissue lesions or 15 mm in short axis for a lymph node 
by RECIST 1.1. 
 
 Patients’ acceptance to have a tumor biopsy of an accessible lesion at baseline and 
on treatment if the lesion can be biopsied with acceptable clinical risk (as judged 
by the investigator). 
 
 ECOG performance status 0 or 1 (Appendix A). 
 
 Life expectancy of greater than 3 months. 
 
 Patients must have adequate organ and marrow function as defined below: 
 
− 
Leukocytes 
 
  
 
 
 
≥ 3,000/mcL 
− 
Absolute lymphocyte count  
≥ 800/mcL 
− 
Absolute neutrophil count 
 
≥ 1,500/mcL 
− 
Platelets 
 
  
 
 
 
 
≥ 100 × 103/uL 
− 
Hemoglobin    
 
 
 
 
≥ 9.0 g/dL 
− 
Total bilirubin   
 
 
 
≤ upper limit of normal (ULN) except 
subjects with Gilbert Syndrome, who can 
have total bilirubin < 3.0 mg/dL 
− 
AST(SGOT) and ALT(SGPT) 
≤2.0 × ULN 
− 
Alkaline phosphatase  
 
 
≤5.0 × ULN  
− 
Albumin  
 
  
 
 
 
≥3.0 g/dL 
− 
Creatinine  
 
  
 
 
 
≤1.5 × ULN or creatinine clearance (CrCl) 
≥ 40 mL/min (if using the Cockcroft-Gault 
formula below): 
 
 
Female CrCl = (140 - age in years) x weight in kg x 0.85 
                              72 x serum creatinine in mg/dL 
 
    Male CrCl = (140 - age in years) x weight in kg x 1.00  
                    
 
 
 
 
72 x serum creatinine in mg/dL 
 
 Women of childbearing potential (WOCBP) must have a negative serum pregnancy 
test (minimum sensitivity 25 IU/L or equivalent units of human chorionic 
gonadotropin [HCG]).  Childbearing potential is defined in Section 4.11.1. Patients 
with a positive HCG due to tumor secretion may be permitted to enroll if lack of 
pregnancy can be documented (e.g. transvaginal ultrasound or serial HCG) and with 
approval by the Protocol chair. 
 
 Both women and men of childbearing potential must agree to use adequate method 
of contraception from the screening visit through 120 days after the last dose of 


 
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study treatment.  Childbearing potential and methods of contraception are outlined 
in Section 4.10.1.  
 
 All sexually active patients (male and female), must use at least one barrier method 
of contraception to prevent transfer of body fluids, regardless of other methods or 
childbearing status. 
 
 Ability to understand and willingness to sign a written informed consent document. 
 
 
Exclusion Criteria 
 
 Known history or evidence of brain metastases. 
 
 Chemotherapy, radiation, or biological cancer therapy within 14 days prior to the 
first dose of study drug. 
 
 Patient has received an investigational agent or used an investigational device 
within 28 days of the first dose of study drug. 
 
 Patient is expected to require any other form of systemic or localized antineoplastic 
therapy while on study. 
 
 Surgery within 28 days of dosing of investigational agent, excluding minor 
procedures (dental work, skin biopsy, etc.), celiac plexus block, and biliary stent 
placement. 
 
 Has received any prophylactic vaccine within 14 days of first dose of study drug (7 
days for the COVID vaccine) or received a live vaccine or live-attenuated vaccine 
within 30 days of study treatment. Examples of live vaccines include, but are not 
limited to, the following: measles, mumps, rubella, chicken pox, yellow fever, 
rabies, BCG, typhoid, and the intranasal flu vaccine.  
 
 History of prior treatment with anti-CTLA-4, anti-PD-1, anti-PD-L1, or anti-PD-
L2 antibodies or with IDO inhibitor. 
 
 Use of any systemic steroids within 14 days of study treatment. 
 
 Use more than 2 g/day of acetaminophen. 
 
 Patients on immunosuppressive agents (e.g., TNF pathway inhibitors, PI3 kinase 
inhibitors) within 7 days of study treatment.  
 
 Use of UGT1A9 inhibitors or medications that may result in epacadostat metabolite 
inhibition of CYP1A2, CYP2C8 and CYP2C19, OATP1B1 and OATP1B3 
transporters (per Section 4.6) 


 
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 Use of 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.  
 
 Known allergy to both penicillin and sulfa. 
 
 History of severe hypersensitivity reaction to any monoclonal antibody. 
 
 Known or suspected allergy or hypersensitivity to any component of study 
treatment. 
 
 Have current or prior history of infection or clinically significant adverse events 
(AEs) associated with an exogenous implant(s) or device(s) that has not and cannot 
be easily removed.  
 
 Subjects who have implanted medical devices that pose high risks for colonization 
and cannot be easily removed (e.g. artificial heart valves, pacemakers, prosthetic 
joints, orthopedic screw(s), metal plate(s)) if infection occurs. Other common 
devices such as venous access devices (e.g. Port-a-Cath or Mediport) may be 
permitted, as well as arterial and venous stents and dental and breast implants. 
 
 Evidence of clinical ascites.  Trace or small amounts of radiographic ascites without 
prior concern for malignant ascites may be approved by the protocol chair. 
 
 Clinically significant and/or malignant pleural effusion (pleural effusions that are 
not clinically significant are allowed, defined as no more than 25% fluid level of 
the corresponding hemithorax and stable fluid level [non-progressive] over at least 
6 weeks documented radiographically). 
 
 New pulmonary embolism, extremity deep venous thromboembolism, or portal 
vein thrombosis within 2 months of study enrollment (asymptomatic, incidental 
thrombosis within 2 months of study enrollment may be approved by the Protocol 
Chair). 
 
 Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, or psychiatric illness/social situations that would limit compliance with 
study requirements. 
 
 Active, known or suspected autoimmune disease. Subjects with Graves or 
Hashimoto’s disease, vitiligo, type I diabetes mellitus, psoriasis not requiring 
systemic treatment, or conditions not expected to recur in the absence of an external 
trigger are permitted to enroll. 
 
 Presence of any tissue or organ allograft, regardless of need for 
immunosuppression, including corneal allograft. Exceptions can be approved by 


 
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the Protocol Chair if loss of the graft is not a clinical concern. Patients with a history 
of allogeneic hematopoietic stem cell transplant will be excluded. 
 
 All toxicities attributed to prior anti-cancer therapy other than alopecia and fatigue 
must have resolved to grade 1 (National Cancer Institute Common Terminology 
Criteria for Adverse Events [CTCAE], version 4.03) or baseline before 
administration of study drug. Subjects with toxicities attributed to prior anti-cancer 
therapy which are not expected to resolve and result in long-lasting sequelae, such 
as neuropathy after chemotherapy, are permitted to enroll. 
 
 Diagnosis of human immunodeficiency virus (HIV), hepatitis B or hepatitis C 
(patients who are hepatitis C antibody positive may be enrolled if they are 
confirmed with undetectable viral load at screening) 
 
 Pulse oximetry of < 92% on room air. 
 
 Need for supplemental home oxygen. 
 
 Unhealed surgical wound or ulcer, or a bone fracture considered non-healing. 
 
 Clinically significant heart disease (such as uncontrolled angina, myocardial 
infarction) within the last 3 months or congestive heart failure of New York Heart 
Association III or IV.   
 
 Valvular heart disease that requires antibiotic prophylaxis for prevention of 
endocarditis. 
 
 Insufficient peripheral venous access to permit completion of the study dosing and 
compliance with study phlebotomy regimen 
 
 Regular use at the time of consent (including “recreational use”) of any illicit drugs 
or other substance abuse (including alcohol) that could potentially interfere with 
adherence to study procedures or requirements. 
 
 Unwillingness or inability to follow the study schedule for any reason. 
 
 Patient is pregnant or breastfeeding. 
 
 Have rapidly progressing disease, as judged by the investigator (e.g., rapid 
progression through prior treatment[s]). 
 
 Presence of a gastrointestinal condition that may affect drug absorption.  
 
 Use of MAOIs or drug which has significant MAOI activity (meperidine, linezolid, 
methylene blue) within the 21 days before first dose of study drug.  See Appendix 
B for prohibited medications associated with MAO inhibition. 


 
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 Any history of serotonin syndrome (SS) after receiving serotonergic drugs.  
 
 History or presence of an abnormal electrocardiogram (ECG) that, in the 
investigator's opinion, is clinically meaningful.  Screening QTc interval > 480 
milliseconds is excluded. For subjects with an intraventricular conduction delay 
(QRS interval > 120 milliseconds), the JTc interval may be used in place of the 
QTc with sponsor approval.  The JTc must be < 340 milliseconds if JTc is used in 
place of the QTc.  Subjects with left bundle branch block are excluded.  
 
 History of organ transplant that requires use of immunosuppressive therapy.  
 
 Use of warfarin. 
 
 Any condition that would jeopardize the safety of the subject or compliance with 
the protocol. 
 
 History of (non-infectious) pneumonitis that required steroids, evidence of 
interstitial lung disease or active, non-infectious pneumonitis. 
         
 
Inclusion of Women and Minorities 
 
Both men and women of all races and ethnic groups are eligible for this trial.   
 
 TREATMENT PLAN 
 
 
Dose Escalation (Part 1/1X) 
 
Part 1 consists of a 3+3 dose escalation design to determine the dose of epacadostat for use in 
combination with pembrolizumab, CY/GVAX Pancreas Vaccine, and CRS-207. Dose escalation 
rules are outlined below. In protocol version 2.0, enrollment will begin on Part 1X, on which 
subjects will receive escalating doses of epacadostat given in combination with pembrolizumab 
and CRS-207 only. Subjects on Part 1X will begin enrollment on Dose Level 2 and will follow the 
dose escalation schema in Table 1. The dose levels being evaluated during dose escalation are 
provided in Table 5. Enrollment on the highest dose level (DL 3) will be staggered by at least one 
week between patients. DLTs will be assessed from the first day of treatment through Cycle 4 Day 
1 in Part 1, and through Cycle 2 Day 1 in Part 1X.  Dose escalation will be based on the number 
of patients experiencing a DLT during this DLT evaluation period. Additional patients may be 
enrolled to account for patients who have disease progression, die, or drop out without receiving 
at least one dose of CRS-207 or ≥ 80% of the prescribed dose of epacadostat at the level assigned 
but have not experienced toxicity. Three to six patients may be enrolled in a cohort, unless 
unacceptable toxicity is encountered in that dose level.  
 
Table 1:  Epacadostat Dose Escalation Guidance 
 


 
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Number of Patients 
with DLT at a Give 
Dose Level 
Dose Escalation Decision Rule 
0 out of 3 
Enter 3 patients at the next higher dose level 
1 out of 3 
Enter 3 more patients at this dose level 
• 
If ≤ 1 of 6 subjects in this cohort experience a DLT, proceed to the 
next higher dose level  
• 
If ≥ 2 of 6 subjects in this cohort experience a DLT, this dose level 
exceeded the MTD and dose escalation will be stopped. 3 subjects will 
be entered at the next lower dose level. 
≥ 2 out of 3 or 6 
This dose level exceeded the MTD and dose escalation will be stopped.  3 
additional patients will be entered at the next lower dose level. 
≤ 1 of 6 (and the next 
higher level has 
exceeded the MTD) 
This is the MTD.  At least 6 patients must be entered at the MTD level to 
determine the dose to be used in Part 2X of this study. 
 
Individual subject dose reductions of epacadostat may be made based on events observed at any 
time during treatment; however, for the purposes of dose cohort escalation/de-escalation, 
expanding a dose cohort, and determining the optimal dose of epacadostat, decisions will be made 
based on events that are observed from the first day of study drug administration through the DLT 
evaluation period.  A lower dose may subsequently be chosen based on relevant toxicities that 
become evident after the DLT period. 
 
 Dose-Limiting Toxicities  
 
Criteria for determining DLT will be defined the same as for Unacceptable Toxicity 
(Section 4.9) but limited to occurrence through the Cycle 4, day 1 evaluation in Part 1 and 
through the Cycle 2 Day 1 evaluation in Part 1X.  Any toxicity requiring a dose reduction 
of epacadostat that occurs through Cycle 4 Day 1 in Part 1 or Cycle 2 Day 1 in Part 1X will 
also be considered as a DLT.  Subjects that have had an epacadostat dose-reduction may 
continue on study at the lower dose once the toxicity resolves to a treatable grade (see 
Section 5.2 for dose delay and restart criteria).  Subjects that have experienced an 
unacceptable toxicity will be permanently discontinued from treatment.   
 
All DLTs will be assessed by the investigator using CTCAE v4.03 criteria.  
 
 Management and Follow-Up of Dose-Limiting Toxicities  
Investigators may employ any measures or concomitant medications necessary to 
optimally treat the subject. 
Any DLT should be followed until it resolves to baseline or appears to have stabilized.  
During follow-up, subjects should be seen as often as medically indicated to assure safety. 
 


 
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Dose Expansion (Part 2X) 
 
Part 2X consists of a dose expansion cohort with 26 evaluable patients (including the 6 patients 
who are treated at the same dose level in Part 1X).  Treatment in Part 2X will be initiated once the 
recommended dose for expansion has been determined from Part 1X.  
 
All patients will receive epacadostat, pembrolizumab, and CRS-207. 
 
 
Agent Administration  
 
Treatment will be administered on an outpatient basis.  Dosing delays are described in Sections 
4.4 and 5.  No investigational or commercial agents or therapies other than those described below 
may be administered with the intent to treat the subject’s malignancy.   
 
Subjects will receive treatment every 3 weeks for 6 cycles of treatment within a course. A course 
of treatment will be 6 cycles (18 weeks). At the investigator’s discretion, all subjects may receive 
additional courses of the assigned treatment regimen up to a maximum of 2 years if they are 
clinically stable and meet dosing eligibility criteria.  Subjects that begin a new course prior to the 
2 year cut-off may complete that course prior to coming off study. 
 
Table 2: Treatment Schedule 
 
TREATMENT SCHEDULE 
 
Epacadostat 
CY 
Pembrolizumab 
GVAX 
CRS-207 
Course 
Length 
Part 1 
BID 
Cycles 1-6 
Day 1 
Cycles 1, 2 
Day 1 
Cycles 1-6 
Day 2 
Cycles 1, 2 
Day 2 
Cycles 3 -6 
18 weeks 
(6 cycles) 
Part 1X/2X 
BID 
Cycles 1-6 
- 
Day 1 
Cycles 1-6 
- 
Day 2 
Cycles 1-6 
 
Table 3: Regimen Description 
 
REGIMEN DESCRIPTION 
Agent 
Supportive Medications; Precautions 
Dose 
Route 
Epacadostat 
No premedication; taken Q12h without 
regard to food  
100, 300, 400, or 
600 mg 
Oral 
CY 
Subjects may be pre-medicated with 
anti-emetics prior to CY administration.  
200 mg/m2 
IV infusion 
over 30 min* 


 
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REGIMEN DESCRIPTION 
Agent 
Supportive Medications; Precautions 
Dose 
Route 
Pembrolizumab 
No prophylactic premedication will be 
given unless indicated by previous 
experience in an individual subject per 
Table 4  
200 mg 
IV over 30 
minutes* 
GVAX 
EMLA cream (approximately 2.5 grams 
per site, at least 1 hour prior to 
vaccination)  
5 × 108 cells 
Six intradermal 
injections 
CRS-207 
650 mg acetaminophen; NS pre- and 
post-infusion to total 1500ml 
(suggested: 500ml pre and 1000ml post) 
Subjects may also be pre-medicated with 
anti-emetics (suggested: IV ondansetron 
and IV fosaprepitant)  
1 × 109CFU 
IV infusion 
over 1 hour** 
* Infusion times are approximate (-10/+15 min) and may be adjusted based on subject tolerability. 
**Infusion times are approximate (+/- 15 min) and may be adjusted based on subject tolerability.  
 
See Section 5.1 for information regarding dose reductions.  See Section 5.2 for dosing delay 
guidelines. If the investigator assesses a drug-related toxicity (that requires discontinuation) to be 
related to an individual component of the treatment schedule, dosing for that study drug alone may 
be discontinued while dosing is delayed until the subject meets criteria to resume treatment of the 
other study drugs. The relationship to the discontinued study drug should be well documented in 
the source documentation and permission from the Protocol Chair needs to be obtained prior to 
continuation with the other study drugs. 
 
 Epacadostat 
 
 
 Compliance with Epacadostat 
 


 
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 Cyclophosphamide (CY) 
 
 
 Pembrolizumab 
 
 GVAX Pancreas Vaccine 
 
 
 CRS-207 


 
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Dosing Criteria 
 
Dosing of study therapy will be delayed for the following laboratory criteria:  
 
• AST/ALT >3 × ULN   
• Total bilirubin > 1.5 x ULN  or direct bilirubin > 2.0 × ULN for subjects with 
Gilbert’s disease 
• Creatinine > 1.5 × ULN 
• Hemoglobin < 8 g/dL 
• ANC < 1000/uL  
• Platelets < 80 × 103/uL 
Please see Section 5.2 for further guidance regarding dosing delays.   
 
 
General Concomitant Medication and Supportive Care Guidelines 
 
 Epacadostat 
 
Acute reactions will be managed using standard therapy for acute drug reactions as per 
institutional guidelines.  
 
 Cyclophosphamide (CY) 
 
Acute reactions will be managed using standard therapy for acute drug reactions as per 
institutional guidelines.  
 
 GVAX Pancreas Vaccine 
 
Local vaccine site reaction may be treated with topical applications of aloe vera or vitamin 
E gel or lotion. Significant local inflammation that is causing the subject severe pain or is 
interfering with the activities of daily living may be treated with oral analgesics. Local 
toxicities of pruritus at the vaccine sites and systemic pruritus may be treated with topical 


 
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or oral diphenhydramine hydrochloride (Benadryl®) or topical aloe vera. If oral 
diphenhydramine hydrochloride is used the recommended dose shall be 25-50 mg every 
four to six hours as needed for pruritus, not to exceed 300 mg/day. Cases of local ulceration 
should be manageable with local wound care, with or without antibiotics. Severe local 
inflammation or significant clinical autoimmunity will be managed on a case-by-case basis. 
 
 CRS-207 
 
Guidance on treatment of the common infusion reactions related to CRS-207 dosing is as 
follows: 
• Fevers: Despite the acetaminophen premedication, subjects can spike fevers up 
to 40°C starting at the end of the CRS-207 infusion generally through the next 
24 hours. Oral ibuprofen (400 to 800 mg) and acetaminophen (650 to 1000 mg) 
may be used in alternate sequence every 4 hours. 
 
• Rigors: Rigors (generally once or twice per infusion) have been observed to 
start during or at the end of a CRS-207 infusion through 24 hours. IV narcotics 
such as morphine or meperidine may be administered per institutional policy. 
Oral morphine or non-steroidal anti-inflammatory drugs (NSAIDs) (e.g., 
aspirin, ibuprofen, naproxen) may be used as home treatment. 
 
• Blood pressure: Decreases in blood pressure have been observed necessitating 
additional IV fluids during the 4 hour observation period (up to 1 or 2 liters). 
Reasons for this include the development of fever, compartmental shifts of fluid 
resulting from the CRS-207 infusion and the use of narcotics. Some subjects 
have also been slightly hypotensive at 24 hours upon arrival to the clinic after 
CRS-207 administration. Subjects are encouraged to hydrate themselves 
liberally at home with oral fluids. 
 
• Nausea and vomiting: Nausea and vomiting have been reported and observed 
within 24 hours after CRS-207 infusion. Subjects may be given anti-emetics as 
needed. 
 
Any 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. Some expected grade 3 or greater laboratory abnormalities such as 
AST/ALT or bilirubin elevation should also be closely monitored for resolution as 
clinically indicated. 
 
 Pembrolizumab 
 
Pembrolizumab is a fully human monoclonal immunoglobulin (Ig) G4 antibody. Subjects 
should be closely monitored for potential AEs during antibody infusion and potential AEs 
throughout the study.  
 


 
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Any 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. 
 
 Infusion Reactions 
 
Pembrolizumab infusion reactions may consist of fever, chills/rigor, nausea, 
pruritus, angioedema, hypotension, headache, bronchospasm, urticaria, rash, 
vomiting, myalgia, dizziness or hypertension.  Severe reactions may include acute 
respiratory distress syndrome, myocardial infarction, ventricular fibrillation, and 
cardiogenic shock.  Patients should be closely monitored for such reactions.  
Guidelines for patients who experience an infusion related or allergic reaction 
during or after infusion with pembrolizumab are shown in the table below. 
 
Table 4: Pembrolizumab Infusion Reaction Treatment Guidelines 
 
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 pembrolizumab administration. 
Subject may be 
premedicated 1h  
(± 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). 


 
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NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
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  
 
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 
pembrolizumab administration. 
No subsequent 
dosing 
• 
Appropriate resuscitation equipment should be available in the room and a physician readily available 
during the period of drug administration. 
• 
May use institutional guidelines for management of infusion related reactions 
 
Refer to Section 5.2 for guidelines regarding GVAX and CRS-207 treatment delays 
following a pembrolizumab infusion-related reaction.  
 
  Immune Related Adverse Events 
 
Subjects should receive appropriate supportive care measures as deemed necessary 
by the treating investigator.  Suggested supportive care measures for the management 
of adverse events with potential immunologic etiology are outlined below. Where 
appropriate, these guidelines include the use of oral or intravenous treatment with 
corticosteroids as well as additional anti-inflammatory agents if symptoms do not 
improve with administration of corticosteroids.   Note that several courses of steroid 
tapering may be necessary as symptoms may worsen when the steroid dose is 
decreased. For each disorder, attempts should be made to rule out other causes such 
as metastatic disease or bacterial or viral infection, which might require additional 
supportive care. The treatment guidelines are intended to be applied when the 
investigator determines the events to be related to pembrolizumab.  
 
Note: if after the evaluation the event is determined not to be related, the investigator 
does not need to follow the treatment guidance (as outlined below). Refer to Section 
5.2 for dose modification. It may be necessary to perform conditional procedures 
such as bronchoscopy, endoscopy, or skin photography as part of evaluation of the 
event.  
 
• Pneumonitis:  
o For Grade 2 events, treat with systemic corticosteroids. When 
symptoms improve to Grade 1 or less, steroid taper should be started 
and continued over no less than 4 weeks. 
o For Grade 3-4 events, immediately treat with intravenous steroids.  
Administer additional anti-inflammatory measures, as needed. 


 
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o Add prophylactic antibiotics for opportunistic infections in the case of 
prolonged steroid administration. 
 
• Diarrhea/Colitis:  
Subjects should be carefully monitored for signs and symptoms of enterocolitis 
(such as diarrhea, abdominal pain, blood or mucus in stool, with or without 
fever) and of bowel perforation (such as peritoneal signs and ileus).   
o All subjects who experience diarrhea/colitis should be advised to drink 
liberal quantities of clear fluids.  If sufficient oral fluid intake is not 
feasible, fluid and electrolytes should be substituted via IV infusion.  
For Grade 2 or higher diarrhea, consider GI consultation and 
endoscopy to confirm or rule out colitis. 
o For Grade 2 diarrhea/colitis, administer oral corticosteroids.  
o For Grade 3 or 4 diarrhea/colitis, treat with intravenous steroids 
followed by high dose oral steroids.   
o When symptoms improve to Grade 1 or less, steroid taper should be 
started and continued over no less than 4 weeks. 
 
• Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis 
[DKA]) or ≥ Grade 3 Hyperglycemia, if associated with ketosis (ketonuria) 
or metabolic acidosis (DKA) 
o For T1DM or Grade 3-4 Hyperglycemia 
▪ Insulin replacement therapy is recommended for Type I 
diabetes mellitus and for Grade 3-4 hyperglycemia associated 
with metabolic acidosis or ketonuria.  
▪ Evaluate patients with serum glucose and a metabolic panel, 
urine ketones, glycosylated hemoglobin, and C-peptide.  
 
• Hypophysitis: 
o For Grade 2 events, treat with corticosteroids. When symptoms 
improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. Replacement of appropriate 
hormones may be required as the steroid dose is tapered. 
o For Grade 3-4 events, treat with an initial dose of IV corticosteroids 
followed by oral corticosteroids. When symptoms improve to Grade 1 
or less, steroid taper should be started and continued over no less than 
4 weeks. Replacement of appropriate hormones may be required as the 
steroid dose is tapered. 
 
• Hyperthyroidism or Hypothyroidism:  
Thyroid disorders can occur at any time during treatment. Monitor patients for 
changes in thyroid function (at the start of treatment, periodically during 
treatment, and as indicated based on clinical evaluation) and for clinical signs 
and symptoms of thyroid disorders. 
o Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism): 
▪ In 
hyperthyroidism, 
non-selective 
beta-blockers 
(e.g. 
propranolol) are suggested as initial therapy. 


 
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▪ In hypothyroidism, thyroid hormone replacement therapy, with 
levothyroxine or liothyronine, is indicated per standard of care. 
o Grade 3-4 hyperthyroidism  
▪ Treat with an initial dose of IV corticosteroid followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, 
steroid taper should be started and continued over no less than 
4 weeks. Replacement of appropriate hormones may be 
required as the steroid dose is tapered. 
 
• Hepatic: 
o For Grade 2 events, monitor liver function tests more frequently until 
returned to baseline values (consider weekly). 
▪ Treat with IV or oral corticosteroids 
o For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 
48 hours.  
o When symptoms improve to Grade 1 or less, a steroid taper should be 
started and continued over no less than 4 weeks. 
o Transient Grade 3-4 events are expected immediately after each CRS-
207 infusion.  Steroid treatment is not indicated for transient elevations.  
 
• Renal Failure or Nephritis: 
• For Grade 2 events, treat with corticosteroids. 
• For Grade 3-4 events, treat with systemic corticosteroids. 
• When symptoms improve to Grade 1 or less, steroid taper should be 
started and continued over no less than 4 weeks.  
 
• Myocarditis 
• For events of any grade, treat with corticosteroids as appropriate based 
on severity 
• Ensure adequate evaluation to confirm etiology and/or exclude other 
causes 
 
 
Prohibited and/or Restricted Medications and Treatments 
 
The following therapies are not permitted during the treatment period: 
 
• Any non-study anticancer chemotherapy or immunotherapy (approved or investigational) 
• TNF pathway inhibitors or PI3 kinase inhibitors 
• Any other investigational agent 
• Any other immunosuppressive-based treatment  (see exception for steroid treatment 
below) 
• Use of any MAOI or drug associated with significant MAOI activity agents is prohibited 
from 21 days prior to first dose through 2 weeks after the final dose of epacadostat has 
been administered.  See Appendix B for list of prohibited MAOI-associated agents. 
• Filgrastim (Neupogen® or G-CSF) or sargramostim (Leukine® or GM-CSF) 


 
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• Live vaccines (examples of live vaccines include, but are not limited to: measles, mumps, 
rubella, chicken pox, yellow fever, rabies, BCG, and typhoid [oral] vaccine). Seasonal 
influenza vaccines for injection are generally killed virus vaccines and are allowed. 
However, intranasal influenza vaccines (e.g. Flu-Mist®) are live attenuated vaccines, and 
are not allowed. 
• Chronic use of systemic antibiotics (> 14 days) unless approved by the Principal 
Investigator. 
• Use of any UGT1A9 inhibitors including: acitretin, amitriptyline, androsterone, 
cyclosporine, dasatinib, diclofenac, diflunisal, efavirenz, erlotinib, flutamide, gefitinib, 
gemfibrozil, glycyrrhetinic acid glycyrrhizin, imatinib, imipramine, ketoconazole 
(systemic), mycophenolic acid, niflumic acid, nilotinib, phenobarbital, phenylbutazone, 
phenytoin, probenecid, quinidine, ritonavir, sorafenib, sulfinpyrazone, valproic acid, and 
verapamil. 
• The following medications will be prohibited for concomitant use due to the potential 
concern for epacadostat metabolite inhibition of CYP1A2, CYP2C8 and CYP2C19, 
OATP1B1 and OATP1B3 transporters with doses of epacadostat greater than 300 mg 
BID: 
 
OATP1B1 & 1B3 
Transporters 
CYP1A2 
Substrates 
CYP2C8 
Substrates 
CYP2C19 
Substrates 
atorvastatin 
bosentan 
cerivastatin 
danoprevir 
docetaxelb 
fexofenadine 
glyburide 
nateglinide 
paclitaxelb 
repaglinide 
pitavastatin 
pravastatin 
rosuvastatin 
simvastatin acid 
fimasartan 
glecaprevir 
maraviroc 
tacrolimus 
voxilaprevir 
Sensitive: 
alosetron 
caffeinea 
duloxetine 
melatonin 
pirfenidone 
ramelteon 
selegiline 
tacrine 
tasimelteon 
theophylline 
tizanidine 
Sensitive: 
repaglinide 
daprodustat 
dasabuvir 
montelukast 
pioglitazone 
rosiglitazone 
Sensitive: 
s-mephenytoin 
lansoprazole 
omeprazole 
tilidine 
pantoprazole 
hexobarbital 
diazepam 
gliclazide 
rabeprazole 
voriconazole 
proguanil 
aAn epacadostat metabolite is a moderate in vitro inhibitor of CYP1A2, thus it is 
recommended to avoid or limit caffeine consumption (e.g., no more than 1 cup of coffee 
or 2-3 soft drinks per day) 
bDocetaxel and paclitaxel as part of combination therapy with epacadostat at doses < 600 
mg BID are permitted. 
 


 
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• Warfarin use is not allowed.  The use of anticoagulants is known to increase the risk of 
gastrointestinal hemorrhage. Since gastrointestinal hemorrhage is an adverse reaction with 
pembrolizumab, subjects who require concomitant anticoagulant therapy should be 
monitored closely.  
• Implanted medical devices that pose high risks for colonization and cannot be easily 
removed (e.g., artificial heart valves, pacemakers, prosthetic joints, orthopedic screw(s), 
metal plate(s)) if infection occurs are prohibited. Other common devices such as venous 
access devices (e.g., Port-a-Cath or Mediport), arterial and venous stents, and dental and 
breast implants may be permitted if approved by the Protocol Chair. 
• Palliative (limited-field) radiation therapy is permitted, but only for pain control and with 
approval by the Protocol Chair or IND Sponsor. 
• Systemically active steroids can be used but should be reported to the Protocol Chair 
and/or IND Sponsor. Steroid treatment should be completed at least 14 days prior to 
resuming study-related treatments. Patients requiring adrenal replacement steroid doses 
are required to discontinue treatment with CRS-207, but may resume treatment with other 
study drugs if on ≤10 mg daily prednisone equivalent (in the absence of active 
autoimmune disease) and if approved by the Protocol Chair or the IND Sponsor. 
• If steroids or immunosuppressive agents are required during treatment, prophylactic 
antibiotics will be administered as outlined in Section 4.7. 
 
In addition, the following therapies should not be administered during the treatment period unless 
medically necessary. Approval must be obtained from the Protocol Chair or IND Sponsor for a 
subject to continue dosing if any of the following therapy is given concurrently with study 
participation: 
 
•  General anesthesia 
•  Aspirin >325 mg/day (chronic daily use of aspirin ≤325 mg/day and heparin flushes for 
central lines are allowed) 
•  More than 2 g/day of acetaminophen 
•  Systemic antibiotics 
 
 
Antibiotic Regimen for Semi-Permanent Indwelling Device Placement 
 
An antibiotic regimen should be initiated for any patient that is having a semi-permanent 
indwelling device placed such as biliary stents/drains, vascular devices, and pleuryx catheters. If 
possible, it is recommended that patients receive a dose of Ampicillin/Sulbactam (Unasyn, 3g) 
with Gentamicin (3 mg/kg) pre-operatively. This should be followed by 8-hour intervals of 1g 
Amoxicillin (160 mg trimethoprim/800 mg sulfamethoxazole at 12-hour intervals for allergic 
patients) for 3 days post-operatively. 
 
 
Antibiotic Administration after Last CRS-207 Dose in Each Treatment Course, 
Suspected CRS-207 Infection, or Administration of Steroids or Immunosuppressive 
Agents for Suspected Treatment-Related AEs 
 
An antibiotic course will be initiated for each subject 7 days after the subject’s last dose of CRS-
207 for each treatment course or within 7 days of the decision to discontinue treatment if treatment 


 
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is discontinued mid-course to ensure clearance of CRS-207 before additional courses or 
subsequent cancer-related therapy. For subjects who do not have a central line, a 7-day course of 
oral amoxicillin (1 gram at 8-hour intervals) or trimethoprim/sulfamethoxazole in penicillin-
allergic subjects (160 mg trimethoprim/800 mg sulfamethoxazole at 12-hour intervals) will be 
initiated for each subject. If the patients do not tolerate the 1 gram dose, the antibiotics can be 
reduced to 500 mg. Subjects with a central line will receive 2 doses [2 g ampicillin 6 hours apart 
or 3-5 mg/kg trimethoprim/ sulfamethoxazole 8 hours apart (in penicillin-allergic subjects)] of IV 
antibiotics through the port, followed by 6 days of oral antibiotics [amoxicillin or 
trimethoprim/sulfamethoxazole (in penicillin-allergic subjects)] started within 6 hours of 
completeling the IV ampicillin (or within 8 hours from IV trimethoprim/sulfamethoxazole).  If the 
subject is withdrawn from the study more than 7 days after administration of CRS-207, antibiotics 
will be administered as soon as possible after study withdrawal.    
 
Should a patient require emergent implant of a prohibited device (as described in Section 4.6) 
while on therapy, the patient will receive a 14-day IV antibiotic regimen appropriate for the 
coverage of wild-type listeriosis.  
 
Antibiotics will also be administered to subjects who have not yet received antibiotics for CRS-
207 if the subject requires steroids or immunosuppressive agents for a suspected treatment-related 
AE. Antibiotic prophylaxis should be given for the duration of the treatment with the steroid 
(recommended oral 80 mg trimethoprim / 400 mg sulfamethoxazole once daily or 160 mg 
trimethoprim / 800 mg sulfamethoxazole (DS) three days a week).  
 
During or after study, subjects who are confirmed to have a blood culture positive for CRS-207 
after more than 7 days post-infusion, will receive a minimum 14-day course of IV antibiotics (see 
below).  In addition, IV ampicillin (or trimethoprim/sulfamethoxazole in penicillin-allergic 
subjects) plus gentamicin should be initiated earlier for possible infectious complications of CRS-
207 for subjects who are suspected of having CRS-207 infection and meet the specified criteria 
(see below). 
 
In the case of suspected persistent CRS-207 infection, blood, urine and stool samples should be 
obtained in duplicate. One set of samples should be cultured locally for Lm per institutional 
guidelines. Culture of cerebrospinal fluid should be obtained for subjects with suspected central 
nervous system infection. In such instances, analysis of cerebrospinal fluid should also include cell 
count, protein, glucose, and Gram stain. If samples are positive for Lm, the Sponsor must be 
notified immediately and the duplicate samples sent for testing to confirm CRS-207. Instructions 
on collection, storage and shipping of samples for CRS-207 testing are provided in the Laboratory 
Manual.  
IV ampicillin (or trimethoprim/sulfamethoxazole in penicillin-allergic subjects) plus gentamicin 
should be initiated for possible infectious complications of CRS-207 for subjects who are 
suspected of having CRS-207 infection and meet the criteria listed below: 
 
• 
Flu-like symptoms Grade 3 or greater lasting for ≥12 hours 
• 
Fever Grade 4 or higher (>40.0ºC for >24 hours) 
• 
Persistent fever >39ºC lasting for ≥48 hours 


 
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• 
Infection Grade 3 or higher (infection with interventional radiology or operative 
intervention indicated) 
• 
Evidence of abscess 
• 
Clinical signs or symptoms (e.g., neurologic signs or symptoms), which, in the 
judgment of the investigator, necessitate starting antibiotics 
 
The preferred antibiotic regimen if CRS-207 infection is suspected or confirmed is IV 
administration of ampicillin (or trimethoprim/sulfamethoxazole in penicillin-allergic subjects) 
plus gentamicin. For this purpose, initial doses of ampicillin should be approximately 12 g/day 
(divided doses every 3 to 4 hours), with gentamicin 3 mg/kg daily in divided doses every 8 hours 
(with adjustments according to renal function and serum levels of gentamicin). In penicillin-
allergic subjects, initial IV doses of trimethoprim/sulfamethoxazole should be 15 to 20 mg/kg/day 
(based on trimethoprim component) divided four times per day, with gentamicin 3 mg/kg/day in 
divided doses every 8 hours (with adjustments according to renal function and serum levels of 
gentamicin). For those individuals who receive IV antibiotics, the course of therapy is anticipated 
to be greater than or equal to 14 days, depending on clinical course. Antibiotic treatment may be 
completed with use of oral antibiotics, if clinically indicated. 
 
If during the course of treatment the subject develops a reaction to antibiotics such that neither 
penicillin derivatives nor trimethoprim/sulfamethoxazole can be safely administered, alternative 
antibiotics such as tetracyclines should be given in all of the above situations. The choice of 
alternative should be made in discussion with the Protocol Chair, and consultation with infectious 
disease should be considered. 
 
Follow-up cultures will be obtained periodically to confirm absence/clearance of any CRS-207 
infection. The Protocol Chair should be consulted regarding continuation of study drug treatment 
and treatment of suspected or confirmed infection 
 
Suspected or confirmed infection with CRS-207 and/or Listeria is considered an adverse event of 
special interest (AESI) and should be reported following SAE reporting procedures (Section 7.1.4) 
irrespective of temporal relationship to study drug administration.  This includes scheduled blood 
cultures during surveillance monitoring that are positive for CRS-207 or if a subject presents with 
symptoms suspicious for a Listeria-like infection and/or is tested positive for Listeria at a local 
hospital/clinic. 
 
 
Definition of an Overdose for this Protocol 
 
An overdose is defined as the accidental or intentional administration of any dose of a product that 
is considered both excessive and medically important. For pembrolizumab and epacadostat, 
overdose will be defined as the administration of a dose equal to or greater than 1000mg. All 
occurrences of overdose must be reported as SAEs (see Section 7.6.1 for reporting details). 
Appropriate supportive treatment should be provided if clinically indicated. 
 
All reports of overdose with or without sequelae be reported within 24 hours to the Protocol Chair, 
IND Sponsor, Merck, and Incyte Corporation (Incyte). Contact information for IND Sponsor, 
Merck and Incyte can be found in Section 7.6.1. 


 
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32
 
 Unacceptable Toxicity  
 
Unacceptable toxicities are defined as:  
 
• Treatment-related  concurrent blood bilirubin > 2 x ULN and AST or ALT > 3 x ULN 
 
• Treatment-related eye pain ≥ grade 2 or reduction of visual acuity that does not respond to 
topical therapy and does not improve to ≤ grade 1 severity within 2 weeks of starting 
therapy, or requires systemic therapy is an unacceptable toxicity.  
 
• Any of the following toxicities related to CRS-207: 
- 
A fever of >40°C that lasts for greater than 24 hours and does not respond to 
antipyretics. 
- 
Clinically significant hypotension unresponsive to IV fluids (e.g., systolic blood 
pressure [BP] <90 mm Hg or mean arterial pressure <55 mm Hg as measured on two 
separate occasions at least 10 minutes apart). 
- 
Initiation of antibiotic therapy, coincident with simultaneous isolation of CRS-207 
from a normally sterile body site, other than blood (e.g., cerebrospinal fluid, joint fluid). 
 
• Any toxicity that requires permanent discontinuation per Table 6 (Dose Delay Guidelines) 
 
• Any treatment-related ≥ grade 3 AE, EXCEPT: 
- 
Asymptomatic lab abnormalities 
- 
Grade 3 fatigue 
- 
Grade 3 dermatologic AEs that are considered mild in severity but only considered 
grade 3 because of >30% body surface involvement  
- 
Fever, chills, rigors, hypertension, hypotension, syncope, or hypoxia occurring within 
12 hours of CRS-207 administration 
- 
Diarrhea, nausea, or vomiting that resolves to < grade 3 within 24 hours of intervention 
- 
Grade 3-4 hyperglycemia or grade 3 endocrinopathies where symptoms are controlled 
on hormone replacement therapy 
 
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. Any 
unacceptable toxicity should be followed until it resolves to baseline or appears to have stabilized.   
 
The proportion of unacceptable toxicities will be monitored. If the toxicity levels are unacceptable 
(>33% of subjects), then enrollment will be suspended until further review and consideration by 
the Protocol Chair, IND Sponsor, and the Medical Expert Committee (MEC).  
 
See Section 12.5 for details regarding safety monitoring and stopping rules. 
 
 Contraception, Use in Pregnancy, Use in Nursing 
 
 Contraception 


 
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The investigational agents used in this protocol may have adverse effects on a fetus in 
utero. Furthermore, it is not known if the investigational agents have transient adverse 
effects on the composition of sperm.   
 
Male subjects will be considered to be of non-childbearing potential if they have 
azoospermia (whether due to having had a vasectomy or due to an underlying medical 
condition).   
 
Female subjects will be considered of non-childbearing potential if they are either:  
1. postmenopausal (defined as at least 12 months with no menses without an 
alternative medical cause; in women < 45 years of age a high follicle stimulating 
hormone (FSH) level in the postmenopausal range may be used to confirm a post-
menopausal state in women not using hormonal contraception or hormonal 
replacement therapy. In the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient.); OR 
2. have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or 
bilateral tubal ligation/occlusion, at least 6 weeks prior to screening; OR 
3. have a congenital or acquired condition that prevents childbearing. 
 
Female and male subjects of childbearing potential must agree to avoid becoming pregnant 
or impregnating a partner, respectively, while receiving study drug and for 120 days after 
the last dose of study drug by complying with one of the following:   
1. practice abstinence† from heterosexual activity; OR 
2. use (or have their partner use) acceptable contraception during heterosexual 
activity.   
 
Acceptable methods of contraception are:  
 
Single method (must use one of the following): 
• Intrauterine device (IUD) or Intrauterine hormone-releasing system (IUS)† 
• Contraceptive rod implanted in the skin† 
• Bilateral tubal occlusion or ligation† 
• Vasectomy of a female subject’s male partner†, ‡ 
• Sexual abstinence¥ 
 
Combination method (must use of two of the following): 
• Other hormonal contraceptive:  
− oral contraceptive pill (estrogen/progestin pill or progestin-only pill)  
− contraceptive skin patch 
− vaginal contraceptive ring  
− subcutaneous contraceptive injection 
• Diaphragm with spermicide (cannot be used with cervical cap/spermicide) 


 
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• Cervical cap with spermicide (nulliparous women only) 
• Contraceptive sponge (nulliparous women only) 
• Male Condom or female condom (cannot be used together) 
 
† Contraception methods that in the context of this guidance are considered to have low 
user dependency. 
‡ Vasectomised partner is a highly effective method provided of avoiding pregnancy that 
partner is the sole sexual partner of the WOCBP trial participant and that the 
vasectomised partner has received medical assessment of the surgical success. 
¥ Abstinence can be used as the sole method of contraception if it is used consistently and 
is part of your preferred or usual lifestyle.  Abstinence during fertile dates (e.g., calendar, 
ovulation, sympto-thermal, post-ovulation methods, etc.) and withdrawal are not 
acceptable methods of contraception.   
 
Subjects should be informed that taking the study medication may involve unknown risks 
to the fetus (unborn baby) if pregnancy were to occur during the study.  In order to 
participate in the study subjects of childbearing potential must adhere to the contraception 
requirement (described above) from the day of study medication initiation (or 14 days prior 
to the initiation of study medication for oral contraception) throughout the study period up 
to 120 days after the last dose of trial therapy.  If there is any question that a subject of 
childbearing potential will not reliably comply with the requirements for contraception, 
that subject should not be entered into the study. 
 
Subjects should be informed that taking the study medication may involve unknown risks 
to the fetus (unborn baby) if pregnancy were to occur during the study.  In order to 
participate in the study subjects of childbearing potential must adhere to the contraception 
requirement (described above) from the day of study medication initiation (or 14 days prior 
to the initiation of study medication for oral contraception) throughout the study period up 
to 120 days after the last dose of trial therapy.  If there is any question that a subject of 
childbearing potential will not reliably comply with the requirements for contraception, 
that subject should not be entered into the study. 
 
 Use in Pregnancy 
 
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab, the 
subject will immediately be removed from the study.  The site will contact the subject at 
least monthly and document the subject’s status until the pregnancy has been completed or 
terminated.  The outcome of the pregnancy will be reported to the Protocol Chair, IND 
Sponsor, Incyte, and Merck without delay and within 24 hours 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).   
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.   If a male subject 
impregnates his female partner the study personnel at the site must be informed 


 
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immediately and the pregnancy reported and followed as described above and in Section 
7.6.3. 
 
 Use in Nursing Women 
 
Since many drugs are excreted in human milk, and because of the potential for serious 
adverse reactions in the nursing infant, subjects who are breast-feeding are not eligible for 
enrollment. 
 
 All Subjects (Male and Female) 
 
All sexually active patients (male and female) must use at least one barrier method of 
contraception (i.e. condom) to prevent the transfer of body fluids, regardless of other 
methods of contraception or childbearing status. 
 
 Duration of Therapy 
 
Subjects who are clinically stable and meet dosing requirements (per Section 4.4) at the end of the 
first course may receive additional courses of their assigned treatment based on investigator 
discretion, up to a maximum of 2 years. Subjects that begin a new course prior to the 2 year cut-
off may complete that course prior to coming off study. The additional course(s) will start 3 weeks 
(+7 days) from last dose of previous course and all assessments will be followed per the study 
schedule in Section 9, with the first dose of the additional course corresponding to Day 1, Cycle 1 
of the study schedule. The following assessments are not required during additional courses: 
• HLA-typing 
• Tumor biopsies 
• Whole blood for isolation of PBMCs 
• Whole blood draw for plasma and serum Lm- and mesothelin-specific immunity assays  
 
 Criteria for Removal from Treatment 
 
The reason for study removal and the date the subject was removed will be documented in a CRF.  
 
A subject will be discontinued from study treatment (but may continue to be monitored in the post-
treatment follow-up portion of the trial) for any of the following reasons: 
• The subject withdraws consent for treatment 
• Intercurrent illness that prevents further administration of treatment 
• Unacceptable toxicity (see Section 4.10) Exceptions may be considered and must 
be approved by the IND Sponsor if they study treatment has provided clinical 
benefit (as defined in Section 4.13.1). 
• Disease progression as defined in Section 4.13.1 and Appendices C and D 
• Severe or life-threatening study drug-related AE(s) (see Section 5.2) 
• Need for >2 dose delays due to the same treatment-related toxicity as per the dose 
delay guidelines (see Section 5.2) 
• If, in the opinion of the Investigator, a change or temporal or permanent 
discontinuation of therapy would be in the best interest of the subject 


 
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• Noncompliance with trial treatment or procedure requirements 
• Subject is lost to follow-up 
• Subject becomes pregnant 
 
 Disease Progression 
 
Epacadostat, GVAX pancreas vaccine, CRS-207, and pembrolizumab are expected to 
trigger immune-mediated responses, which require activation of the immune system prior 
to the observation of clinical responses.  Such immune activation may take weeks to 
months to be evident.  Some subjects may have objective volume increase of tumor lesions 
or other disease parameters within weeks following the start of immunotherapy.  Such 
subjects may not have had sufficient time to develop the required immune activation or, in 
some subjects, tumor volume or other disease parameter increases may represent 
infiltration of lymphocytes into the original tumor.  In conventional studies, such tumor 
volume or relevant laboratory parameter increases during the first 2-4 months of the study 
would constitute disease progression and lead to discontinuation of imaging to detect 
response, thus disregarding the potential for subsequent immune-mediated clinical 
response.  
 
Subjects will be permitted to continue with treatment beyond RECIST 1.1 defined PD as 
long as they meet the following criteria: 
• 
Investigator-assessed clinical benefit, and 
• 
Subject is tolerating study drug. 
 
The assessment of clinical benefit should take into account whether the subject is clinically 
deteriorating and unlikely to receive further benefit from continued treatment. The 
following criteria need to be taken into consideration: 
• 
No decline in ECOG performance status. 
• 
Absence of rapid progression of tumor at critical anatomical sites (e.g., cord 
compression) requiring urgent alternative medical intervention. 
 
All decisions to continue treatment beyond PD must be discussed with the Protocol Chair 
and documented in the study records. 
 
Tumor assessments will be made using RECIST 1.1 (Appendix C) and irRC (Appendix D).  
 
 End of Treatment (EOT)/Safety Follow-up Visit 
 
All subjects will return to the study site approximately 28 days (± 7 days) after the last infusion of 
study drug (i.e., completion of the final course or upon early discontinuation) for an EOT 
evaluation. Procedures and assessments performed at these visits and beyond should follow the 
respective guidelines described in Sections 4.14 and 9.2 as appropriate.  
 
The EOT visit is conducted only once after the final study treatment. If the EOT visit occurs early 
(e.g., 1 week prior to the expected visit as protocol allows) or if the patient cannot return due to 


 
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disease progression, an assessment for AEs should be made by telephone or email on day 30 (± 1 
day) after last dose of study drug and documented.  
 
To eliminate any potentially residual CRS-207, subjects will be administered a 7-day course of 
antibiotics 7 days after the last CRS-207 dose in each treatment course or after their final dose of 
CRS-207 if treatment is discontinued early (or if the patient will be having a semi-permanent 
indwelling device placed per Section 4.7. Blood cultures for surveillance of CRS-207 will also be 
collected per Section 4.15. 
 
The subject will be monitored for AEs up to the mandatory EOT/Safety Follow-Up Visit or to 
resolution of toxicity to ≤ Grade 1, whichever occurs later.  SAEs that occur within 90 days (+14 
day reporting window) of last dose of pembrolizumab (or for 30 days from the last dose of 
epacadostat, cyclophosphamide, GVAX, or CRS-207 if the subject is no longer receiving 
pembrolizumab due to toxicity, whichever reporting period is longer), and before initiation of a 
new antineoplastic treatment (whichever comes first) should also be followed and recorded. 
 
 Duration of Follow-Up 
 
All enrolled subjects, including those never treated, will enter a follow-up period.  Treated subjects 
will begin the follow-up period after they complete the EOT / Safety Follow-Up Visits.  Subjects 
will be contacted every 12 weeks (and at 90 days [+14 days] from the last dose of pembrolizumab 
if the subject was still receiving pembrolizumab at the time of treatment discontinuation) to 
monitor Overall Survival until death, withdrawal of consent, or study closure.  Information of other 
cancer therapies after discontinuation from the study treatment will be collected.   
 
Subjects who discontinued study treatment without documented disease progression 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) documented disease progression, 3) death, 4) 
withdrawal of consent, or 5) study closure, whichever occurs first. 
 
Subjects who are discontinued from the study treatment due to an unacceptable drug-related AE 
will be monitored for safety until the resolution of the AE to ≤ grade 1 or stabilization or until 
initiation of a new therapy for their cancer, whichever occurs first. 
 
All subjects will be followed for at least 4 weeks after their last dose of study drug for the 
development of AEs. SAEs that occur within 90 days (+14 day reporting window) after the last 
dose of pembrolizumab or within 30 days (+7 day reporting window) from the last dose of 
epacadostat cyclophosphamide, GVAX, or CRS-207, if the subject is no longer receiving 
pembrolizumab due to toxicity (whichever reporting period is longer) should be followed and 
recorded.   
 
At the conclusion of the study, all remaining subjects who have received at least one dose of study 
treatment will be offered enrollment in a long-term follow-up study and continue to be evaluated 
for survival. Subjects who are still receiving treatment at the time of study close may complete the 


 
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current treatment course (up to 6 cycles) and EOT/Safety Follow-Up Visit prior to transitioning to 
participation in the separate long-term follow-up study. 
 
 Blood Cultures for CRS-207 Surveillance 
 
Blood samples from subject’s peripheral vein will be obtained at the EOT visit to assess clearance 
of CRS-207. Subjects who discontinue treatment mid-course should have blood cultures drawn 
within 4 weeks of the last dose of antibiotics. After EOT, blood will continue to be collected for 
CRS-207 culture at 3, 6, 9, and 12 months (+/- 1 week window for each collection) for up to 1 year 
to monitor for the presence of CRS-207. For subjects with a central line, a blood sample will also 
be taken through the central line at time points indicated for CRS-207 testing.  Subjects with 
samples positive for the presence of CRS-207 will initiate IV antibiotics per Section 4.7 and be 
re-tested until negative cultures are confirmed.  
 
 Confirmed Listeria Infection 
 
In the event a subject has a positive Listeria culture at any time during or after study 
participation, the IND Sponsor should be notified within 24 hours of the adverse event of 
special interest (AESI) per Section 7.1.4.  
 
If Listeria has been confirmed at the clinical site or an external laboratory, all efforts should 
be made to obtain a sample of the bacterial isolate from the original positive culture and 
submit to the IND Sponsor or designee for strain confirmation; records on all samples 
cultured during this period must be obtained and provided to the Sponsor.  Refer to the 
Central Laboratory Manual for sample collection and shipping instructions. 
 
 Suspected Infection with CRS-207 or Listeria 
 
In the case of a suspected persistent CRS-207 or Listeria infection that has not been 
confirmed by culture, collection of blood, urine and stool samples in duplicate is 
recommended. One set of samples should be cultured locally for Listeria per institutional 
guidelines. Culture of cerebrospinal fluid should be obtained for subjects with suspected 
central nervous system infection. In such instances, analysis of cerebrospinal fluid should 
also include cell count, protein, glucose, and Gram stain. If samples are positive for 
Listeria, the IND Sponsor must be notified immediately, and the duplicate samples and 
Listeria isolate must be sent to the IND Sponsor or designee for testing to confirm CRS-
207. Instructions on collection, storage and shipping of samples for CRS-207 testing are 
provided in the Central Laboratory Manual. 
 
 DOSING DELAYS, MODIFICATIONS, DISCONTINUATION 
 
 
Dose Modifications 
 
Dose reduction or dose increase of CY, GVAX pancreas vaccine, CRS-207 and pembrolizumab 
will not be permitted.  Dose reduction of epacadostat may be permitted after discussion with the 
Protocol Chair or IND sponsor.   


 
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Table 5: Dose Modifications of Epacadostat 
Dose Level 
Dose of Epacadostat 
1st Reduction of  
Epacadostat 
2nd Reduction of  
Epacadostat 
DL -1* 
50 mg BID 
25 mg BID 
- 
DL 1 
100 mg BID 
- 
- 
DL 2 
300 mg BID 
100 mg BID 
- 
DL 3 
600 mg BID 
400 mg BID 
- 
*DL -1 will not be explored in Parts 1X/2X 
 
See Section 4.1 for Dose Limiting Toxicity (DLT) criteria and determination of the Maximum 
Tolerated Dose (MTD) 
 
See Section 5.2 and Table 6 for specific epacadostat dose modification criteria. 
 
 
Dosing Delays 
 
See Section 4.4 for dosing parameters.  All scheduled cycles within a course are to be given 
approximately 3 weeks apart. If necessary, a scheduled cycle may be delayed for up to 1 week. In 
this case, subsequent cycles should continue so that a subject can still receive all 6 cycles given 
that the cycles are approximately 3 weeks apart and they have not experienced an AE necessitating 
discontinuation. If delayed more than 1 week, the Protocol Chair must be contacted for further 
instructions on continued treatment. Additional delays or modifications to the treatment schedule 
must be approved by the Protocol Chair and / or IND Sponsor.  
 
If a delay occurs between Day 1 and 2 in a cycle: 
• Pembrolizumab-related infusion reactions must resolve to baseline prior to administration 
of either GVAX or CRS-207.  
• Resume Day 2 treatment schedule (GVAX or CRS-207) and assessments without repeating 
Day 1 study treatments (CY and/or pembrolizumab) if the delay is within 72 hours. 
• If the delay is longer than 72 hours, repeat Day 1 and Day 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. 
 
Immune-related adverse events may be attributable to a single agent or a combination of agents.  
If the event is clearly related to one of the agents, follow the instructions specific for that agent.  If 
the event is related to multiple agents, follow the action taken instructions for each of them. 
 
Epacadostat and pembrolizumab must be withheld for drug-related toxicities per Table 6 below.    
See Section 4.5 for supportive care guidelines, including use of corticosteroids.   


 
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Table 6: Pembrolizumab/Epacadostat Dose Modification Guidelines for Related AEs 
 
General instructions: 
1. Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. Other immunosuppressive treatment should begin 
if the irAEs are not controlled by corticosteroids. 
2. Study intervention must be permanently discontinued if the irAE does not resolve or the corticosteroid dose is not ≤10 mg/day within 12 weeks of the 
last study intervention treatment.  
3. The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 weeks. 
4. If study intervention has been withheld, study intervention may resume after the irAE decreased to ≤ Grade 1 after corticosteroid taper. 
 
Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting 
Treatment 
Epacadostat Dose 
Reduction 
Other Criteria for Treatment 
Discontinuation 
Corticosteroid and/or Other 
Therapies 
Monitoring and Follow-up 
Diarrhea / 
Colitis 
 
2-3 
 
Toxicity resolves to 
Grade 0-1 
First occurrence: Same 
dose level 
Second occurrence: 
Reduce by 1 level 
Toxicity does not resolve within 12 
weeks of last dose or inability to 
reduce corticosteroid to 10 mg or 
less of prednisone or equivalent per 
day within 12 weeks 
Administer corticosteroids 
(initial dose of 1 to 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 
4 or 
Recurrent 
Grade 3 
Permanently 
discontinue 
N/A 
Permanently discontinue 
AST, ALT 
Increased 
2 
Toxicity resolves to 
Grade 0-1 (see 
exception below)b 
First occurrence: Same 
dose level 
Second occurrence: 
Reduce by 1 level 
Toxicity does not resolve within 12 
weeks of last dose 
Administer corticosteroids 
(initial dose of 0.5 to 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) 


 
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Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting 
Treatment 
Epacadostat Dose 
Reduction 
Other Criteria for Treatment 
Discontinuation 
Corticosteroid and/or Other 
Therapies 
Monitoring and Follow-up 
3-4 
Permanently 
discontinue.  
If transient elevation 
related to CRS-207 (not 
pembrolizumab or 
epacadostat), may 
resume once toxicity 
resolves to Grade 0-1 at 
the discretion of the 
protocol chair (see 
exception below)b. 
N/A 
Permanently discontinue if related 
to pembrolizumab or epacadostat 
Administer corticosteroids 
(initial dose of 1 to 2 mg/kg 
prednisone or equivalent) 
followed by taper 
 
Increased 
bilirubin 
2 
Toxicity resolves to 
Grade 0-1 (see 
exception below)b 
First occurrence: Same 
dose level 
Second occurrence: 
Reduce by 1 level 
Toxicity does not resolve within 12 
weeks of last dose 
Administer corticosteroids 
(initial dose of 0.5 to 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) 
 
 
3-4 
Permanentlly 
discontinue. 
N/A 
Permanently discontinue. 
Administer corticosteroids 
(initial dose of 1 to 2 mg/kg 
prednisone or equivalent) 
followed by taper 
Type 1 diabetes 
mellitus 
(if new onset) or 
Hyperglycemia 
T1DM  
or 3-4 
Hold for new onset 
Type 1 diabetes 
mellitus or Grade 3-4 
hyperglycemia 
associated with 
evidence of beta cell 
failure. Resume when 
subjects are clinically 
and metabolically 
stable. 
Same dose level 
Resume when patients are 
clinically and metabolically stable 
•  Initiate insulin replacement 
therapy for participants with 
T1DM 
•  Administer 
antihyperglycemic in 
participants with 
hyperglycemia 
 
Monitor participants for 
hyperglycemia or other signs and 
symptoms of diabetes 
Hypophysitis 
2 
Once stable on 
endocrine replacement 
therapy if patient is 
asymptomatic. 
Same dose level 
Toxicity does not resolve within 12 
weeks of last dose or inability to 
reduce corticosteroid to 10 mg or 
less of prednisone or equivalent per 
day within 12 weeks.  May also 
discontinue at the discretion of the 
investigator for G3-4 events. 
Administer corticosteroids 
and initiate hormonal 
replacements as clinically 
indicated 
Monitor for signs and symptoms of 
hypophysitis (including 
hypopituitarism and adrenal 
insufficiency) 
3-4 
Once stable on 
endocrine replacement 
therapy if patient is 
asymptomatic. 


 
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Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting 
Treatment 
Epacadostat Dose 
Reduction 
Other Criteria for Treatment 
Discontinuation 
Corticosteroid and/or Other 
Therapies 
Monitoring and Follow-up 
Hyperthyroidism 
3-4 
Toxicity resolves to 
Grade 0-2 
Same dose level 
Toxicity does not resolve within 12 
weeks of last dose or inability to 
reduce corticosteroid to 10 mg or 
less of prednisone or equivalent per 
day within 12 weeks.  
May also discontinue at the 
discretion of the investigator. 
Treat with nonselective beta-
blockers (eg, propranolol) or 
thionamides as appropriate 
Monitor for signs and symptoms of 
thyroid disorders 
Hypothyroidism 
N/A 
Therapy can be 
continued while thyroid 
replacement therapy is 
instituted 
N/A 
Therapy can be continued while 
thyroid replacement therapy is 
instituted 
Initiate thyroid replacement 
hormones (eg, levothyroxine 
or liothyronine) per standard 
of care 
Monitor for signs and symptoms of 
thyroid disorders 
 
Infusion 
Reaction 
2c 
Toxicity resolves to 
Grade 0-1  
N/A 
Permanently discontinue if toxicity 
develops despite adequate 
premedication 
See Section 4.5.5.1 
See Section 4.5.5.1 
3-4 
Permanently 
discontinue 
N/A 
Permanently discontinue 
Pneumonitis 
2 
Toxicity resolves to 
Grade 0-1 
First occurrence: Same 
dose level 
Second occurrence: 
Reduce by 1 level 
Toxicity does not resolve within 12 
weeks of last dose or inability to 
reduce corticosteroid to 10 mg or 
less of prednisone or equivalent per 
day within 12 weeks 
•  Administer corticosteroids 
(initial dose of 1 to 2 mg/kg 
prednisone or equivalent) 
followed by taper 
•  Add prophylactic antibiotics 
for opportunistic infections 
•  Monitor participants for signs 
and symptoms of pneumonitis 
•  Evaluate participants with 
suspected pneumonitis with 
radiographic imaging and initiate 
corticosteroid treatment 
3-4 or 
recurrent 
grade 2 
Permanently 
discontinue 
N/A 
Permanently discontinue 
Renal Failure or 
Nephritis 
2 
Toxicity resolves to 
Grade 0-1 
First occurrence: Same 
dose level 
Second occurrence: 
Reduce by 1 level 
Toxicity does not resolve within 12 
weeks of last dose or inability to 
reduce corticosteroid to 10 mg or 
less of prednisone or equivalent per 
day within 12 weeks 
Administer corticosteroids 
(prednisone 1 to 2 mg/kg or 
equivalent) followed by taper 
Monitor changes of renal function 
3-4 
Permanently 
discontinue 
N/A 
Permanently discontinue 
Myocarditis 
1 
Toxicity resolves 
completely 
First occurrence: Same 
dose level 
Second occurrence: 
Reduce by 1 level 
Toxicity dose not resolve within 12 
weeks of last dose or inability to 
reduce corticosteroid to 10 mg or 
less of prednisone or equivalent per 
day within 12 weeks 
Based on severity of AE 
administer corticosteroids 
Ensure adequate evaluation to 
confirm etiology and/or exclude 
other causes 
 
2-4 
Permanently 
discontinue 
N/A 
Permanently discontinue 


 
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Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting 
Treatment 
Epacadostat Dose 
Reduction 
Other Criteria for Treatment 
Discontinuation 
Corticosteroid and/or Other 
Therapies 
Monitoring and Follow-up 
Neurological 
Toxicities 
Grade 2 
Toxicity resolves to 
Grade 0-1 
First occurrence: Same 
dose level 
Second occurrence: 
Reduce by 1 level 
Toxicity dose not resolve within 12 
weeks of last dose or inability to 
reduce corticosteroid to 10 mg or 
less of prednisone or equivalent per 
day within 12 weeks 
Based on severity of AE 
administer corticosteroids 
Ensure adequate evaluation to 
confirm etiology and/or exclude 
other causes 
Grade 3 
or 4 
Permanently 
discontinue 
N/A 
Permanently discontinue 
Exfoliative 
Dermatologic 
Conditions 
Suspected 
SJS, TEN, 
or DRESS 
Toxicity resolves to 
Grade 0-1 
First occurrence: Same 
dose level 
Second occurrence: 
Reduce by 1 level 
Toxicity dose not resolve within 12 
weeks of last dose or inability to 
reduce corticosteroid to 10 mg or 
less of prednisone or equivalent per 
day within 12 weeks 
Based on severity of AE 
administer corticosteroids 
Ensure adequate evaluation to 
confirm etiology or exclude other 
causes 
Confirme
d SJS, 
TEN, or 
DRESS 
Permanently 
discontinue 
N/A 
Permanently discontinue 
All Other Drug-
Related 
Toxicitiesd 
3 or 
intolerable/ 
persistent 
grade 2 
Toxicity resolves to 
Grade 0-1e 
Same dose level or 
reduce by 1 dose level 
at the discretion of the 
protocol chair. 
Toxicity does not resolve within 12 
weeks of last dose or inability to 
reduce corticosteroid to 10 mg or 
less of prednisone or equivalent per 
day within 12 weeks.  
May also discontinue at discretion 
of investigator. Guillain-Barre 
Syndrome and encephalitis require 
permanent discontinuation. 
Based on severity of AE 
administer corticosteroids 
Ensure adequate evaluation to 
confirm etiology or exclude other 
causes 
4 or 
recurrent 
grade 3 
Permanently 
discontinue 
(see exceptions below) 
N/A 
Permanently discontinue 
Note: Permanently discontinue for any severe or Grade 3 drug-related AE that recurs and is life-threatening event. 
a Hold Epacadostat for grade 3 or persistent grade 2 diarrhea (grade 2 diarrhea lasting ≥3 days despite symptomatic therapy (i.e. antidiarrheals)) 
b  Blood bilirubin > 5 x ULN requires permanent discontinuation. Concurrent blood bilirubin > 2 x ULN and AST or ALT > 3 x ULN requires discontinuation.   
c 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; Refer to Table 4 – Infusion Treatment Guidelines for further management details. 
d Asymptomatic grade 3-4 lab abnormalities do not require dose discontinuation or delay unless specified in Section 4.4 (Dosing Criteria).  
  Patients with intolerable or persistent Grade 2 drug-related AE may hold study medication at physician discretion.  Permanently discontinue study drug for persistent Grade 2 adverse reactions for which treatment with 
study drug has been held, that do not recover to Grade 0-1 within 12 weeks of the last dose.  
eSubjects may resume treatment with grade 2 fatigue. Events that require discontinuation include, but are not limited to: encephalitis and other clinically important irAEs (eg, vasculitis and sclerosing cholangitis). 
 


 
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Subjects that are required to stop treatment with pembrolizumab and/or epacadostat due to toxicity 
may stay on study and receive the remainder of the study drugs once the drug-related toxicity(s) 
has resolved per the restarting criteria in Table 6 above and only if they are clinically benefiting 
from the regimen (as per Section 4.13.1). 
 
 PHARMACEUTICALINFORMATION 
 


 
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 ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS 
 
This study will use the descriptions and grading scales found in the revised CTCAE version 4.03 
for 
AE 
reporting 
that 
can 
be 
found 
at 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.   
 
Information about all AEs, whether volunteered by the subject, discovered by investigator 
questioning, or detected through physical examination, laboratory test or other means, will be 
collected, recorded, and followed as appropriate.  
 
All AEs experienced by subjects will be collected and reported from the first dose of the 
investigational agent, throughout the study, and will be followed for 30 days after last dose of 
study drug unless related to the investigational agent.  All SAEs will be collected and reported 
through 90 (+14 day reporting window) days following the last dose of pembrolizumab or 30 days 
(+7 day reporting window) from the last dose of study drug, if the subject is no longer receiving 
pembrolizumab due to toxicity, whichever reporting period is longer. Subjects who have an 
ongoing AE/SAE related to the study procedures and/or medication(s) may continue to be 
periodically contacted by a member of the study staff until the event is resolved or determined to 
be irreversible by the investigator. 
 
Subjects who experience a grade 3 or higher study drug-related AE should be discussed with the 
Protocol Chair.  
 
 
Definitions 
 
 Adverse Event  
An adverse event (AE) is defined as any undesirable sign, symptom or medical 
condition occurring after starting the study drug (or therapy) even if the event is not 
considered to be related to the study. An undesirable medical condition can be 
symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the 
abnormal results of an investigation (e.g., laboratory findings, electrocardiogram).  
 
Medical conditions/diseases present before starting the study treatment are only 
considered AEs if they worsen grade after starting the study treatment (any procedures 
specified in the protocol). Conditions that were already present at the time of informed 
consent and new medical conditions / diseases occurring before starting the study 
treatment but after signing the informed consent should be recorded on the Medical 
History CRF and will not be recorded as AEs.   
 


 
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Expected progression of the disease being studied will not be recorded as an adverse 
event; however, all deaths from time of first administration of study drug through 90 
days (+14 day reporting window) after the last dose of pembrolizumab or 30 days (+7 
day reporting window) from the last dose of study drug, if the subject is no longer receiving 
pembrolizumab due to toxicity or before initiation of a new antineoplastic treatment 
(whichever comes first), regardless of causality or whether subjects have discontinued 
earlier from treatment, are to be reported as SAEs.  Deaths that occur after this reporting 
window or before initiation of a new antineoplastic treatment (whichever comes first), 
must be reported as SAEs if they are considered related to study drug. 
 
Laboratory abnormalities: Laboratory abnormalities present at the screening visit will 
be recorded as pre-treatment signs and symptoms. After study treatment administration, all 
grade 3 and 4 clinical laboratory results that represent an increase in severity from baseline 
will be reported as AEs. Grade 1 or 2 clinical laboratory abnormalities should be reported 
as an AE only if they induce clinical signs or symptoms, are considered clinically 
significant by the investigator, require therapy, or require changes in the study drug(s). 
 
 Serious Adverse Event  
 
An SAE is an undesirable sign, symptom or medical condition which:  
• 
Results in death  
• 
Is life threatening (defined as an event in which the subject was at risk of death at 
the time of the event; it does not refer to an event which hypothetically might have 
caused death if it were more severe)  
• 
Requires inpatient hospitalization or causes prolongation of existing hospitalization 
(see note below for exceptions) for >24 hours 
• 
Results in persistent or significant disability or incapacity 
• 
Constitutes a congenital anomaly or birth defect (note: reports of congenital 
anomalies/birth defects must also be reported on the Pregnancy Form)  
• 
Is another important medical event or medically significant event 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 medical or surgical intervention 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 
• 
Note: In addition to the above criteria, adverse events meeting any of the below 
criteria, although not serious per ICH definition, are reportable in the same 
timeframe as SAEs to meet certain local requirements. Therefore, these events are 
considered serious by Merck for collection purposes. 
• 
Is a new cancer (that is not a condition of the study) 
• 
Is associated with an overdose 
• 
Is a pregnancy or pregnancy outcome of spontaneous abortion, missed 
abortion, benign hydatidiform mole, blighted ovum, fetal death, intrauterine 
death, miscarriage, or stillbirth.  
 


 
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Events not considered to be SAEs are hospitalizations for:  
• 
Admissions as per protocol for a planned medical/surgical procedure or to facilitate 
a procedure 
• 
Routine health assessment requiring admission for baseline/trending of health status 
(e.g., routine colonoscopy)  
• 
Medical/surgical admission for purpose other than remedying ill health state and 
was planned prior to entry into the study. Appropriate documentation is required in 
these cases.  
• 
Admission encountered for another life circumstance that carries no bearing on 
health status and requires no medical/surgical intervention (e.g., lack of housing, 
economic inadequacy, care-giver respite, family circumstances, administrative). 
• 
Admissions for monitoring of treatment-related infusion reactions that do not 
otherwise meet the criteria for a SAE. 
 
 Events of Clinical Interest 
 
Selected non-serious and serious adverse events 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 and reported within 24 hours to the IND Sponsor, Incyte, and Merck Global 
Safety. Events of clinical interest for this trial include: 
• 
An overdose of research product (as defined in Section 4.8) that is not associated 
with clinical symptoms or abnormal laboratory results.  
• 
AST or ALT ≥ 3x the ULN and total bilirubin ≥ 2x ULN and, at the same time, an 
alkaline phosphatase < 2x ULN 
 
 Adverse Events of Special Interest 
 
Suspected infection with CRS-207 and/or Listeria are considered adverse events of special 
interest (AESI) and should be reported following reporting procedures in Section 7.6 
irrespective of temporal relationship to study drug administration. 
 
In the event a subject has a positive Listeria culture at any time during or after study 
participation, the event should be reported to the Sponsor within 24 hours of the event. 
 
All AESIs must be reported for the duration of the study regardless of causality. 
 
 
Assessment of Causality 
 
The relationship of an AE to the administration of the study drug is to be assessed by the 
investigator according to the following definitions:  
• No (unrelated, not related, no relation):  The time course between the administration of 
study drug and the occurrence or worsening of the adverse event rules out a causal 
relationship and another cause (concomitant drugs, therapies, complications, etc.) is 
suspected.  
• Yes (related): The time course between the administration of study drug and the occurrence 
or worsening of the adverse event is consistent with a causal relationship and no other cause 


 
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(concomitant drugs, therapies, complications, etc.) can be identified.  
 
The following factors should also be considered:  
• The temporal sequence from study drug administration - The event should occur after 
the study drug is given. The length of time from study drug exposure to event should 
be evaluated in the clinical context of the event.  
• Underlying, concomitant, intercurrent diseases - Each report should be evaluated in the 
context of the natural history and course of the disease being treated and any other 
disease the subject may have.  
• Concomitant medication - The other medications the subject is taking or the treatment 
the subject receives should be examined to determine whether any of them might be 
recognized to cause the event in question.  
• Known response pattern for this class of study drug - Clinical and/or preclinical data 
may indicate whether a particular response is likely to be a class effect.  
• Exposure to physical and/or mental stresses - The exposure to stress might induce 
adverse changes in the recipient and provide a logical and better explanation for the 
event.  
• The pharmacology and pharmacokinetics of the study drug - The known pharmacologic 
properties (absorption, distribution, metabolism, and excretion) of the study drug 
should be considered.  
 
 
Assessment of Grade 
 
The investigator will make an assessment of grade for each AE and SAE reported during the study, 
which will be recorded in the CRF. The assessment will be based on the National Cancer Institute’s 
CTCAE (Version 4.03) and graded as shown below: 
 
• 
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic  
 
observations only; intervention not indicated 
• 
Grade 2: Moderate; minimal, local or noninvasive intervention indicated;  
 
limiting age-appropriate instrumental activities of daily living 
• 
Grade 3: Severe or medically significant but not immediately  
life-threatening; hospitalization or prolongation of hospitalization  
indicated; disabling; limiting self-care activities of daily living 
• 
Grade 4: Life-threatening consequences; urgent intervention indicated 
• 
Grade 5: Death related to AE 
 
When the severity of an AE changes over time for a reporting period, each change in severity will 
be reported as a separate AE until the event resolves.   
 
 
Expectedness 
 
Unexpected AE: An AE, which varies in nature, intensity or frequency from information on the 
investigational drug/agent provided in the product IB, package insert or safety reports. Any AE 
that is not included in the IB, consent, package insert, or safety reports is considered “unexpected”.  
 


 
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Expected (known) AE: An AE, which has been reported in the IB, package insert, safety reports 
or in the Reference Safety Information as applicable. An AE is considered “expected”, only if it is 
included in the IB document as a risk. 
 
 
Handling of Expedited Safety Reports 
 
In accordance with local regulations, the IND Sponsor or designee will notify investigators of all 
SAEs that are unexpected (i.e., not previously described in the IB, package insert, or safety 
reports), and related to epacadostat, CY, GVAX pancreas vaccine, CRS-207, and/or 
pembrolizumab. This notification will be in the form of an expedited safety report (ESR) that is to 
be faxed to the investigators and the study coordinators. Upon receiving such notices, the 
investigator must review and retain the notice with the IB and where required by local regulations, 
the investigator will submit the ESR to the appropriate IRB. The investigator and IRB will 
determine if the informed consent requires revision. The investigator should also comply with the 
IRB procedures for reporting any other safety information.  
 
 
Reporting 
 
 Adverse Events and Serious Adverse Events 
 
All AEs (both expected and unexpected) will be captured on the appropriate study-specific 
case report forms (CRFs).  
 
All SAEs and AESI occurring from the first dose of study drug, throughout the study, and 
90 days (+14 day reporting window) after the last dose of pembrolizumab or before 
initiation of a new antineoplastic treatment (whichever comes first) must be reported. All 
SAEs that the investigator considers related to the study drug occurring after the follow-up 
periods must be reported.  
 
SAEs will be reported promptly to the IND Sponsor, Merck Global Safety (Merck GS), 
and Incyte within 24 hours of recognition of the adverse event using the form provided.  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 Clinical Interest will also be submitted to the IND sponsor, Incyte, and 
Merck GS within 24 hours using the ECI Reporting Form and will be handled in the same 
manner as SAEs.  
 
SAE reports and any other relevant safety information are to be sent to:  
 
Elizabeth Jaffee:  
Dung Le: 
Merck GS:  
Incyte: 
 
 
 Overdose 


 
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An overdose is defined as the accidental or intentional administration of any dose of a 
product that is considered both excessive and medically important. All occurrences of 
overdose must be reported as SAEs.  See Section 7.6.1 for reporting details 
 
 Pregnancy Reporting 
 
Although pregnancy and lactation are not considered adverse events, it is the responsibility 
of investigators or their designees to report as an SAE any pregnancy or lactation in a subject 
(spontaneously reported to them) that occurs during the trial or within 120 days following 
cessation of Sponsor’s product.  This also includes the pregnancy of a male subject's female 
partner who has provided written consent to provide information regarding pregnancy, 
which occurs during the trial or within 120 days following the male subject’s cessation of 
study drug. 
 
All subjects who become pregnant or partners of 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) and submitted to the Sponsor, Merck Global Safety, and Incyte.  
If the pregnancy continues to term, the outcome (health of infant) must also be reported to 
the Sponsor, Merck Global Safety, and Incyte. 
 
 Institutional Review Board (IRB) and Institutional Biosafety Committee (IBC) 
 
SAEs will be reported to the IRB and IBC per institutional guidelines. Follow-up 
information will be submitted to the IRB and IBC per institutional standards as soon as 
relevant information is available. 
 
 Food and Drug Administration (FDA) 
 
All reporting to the FDA for the trial will be completed by the IND Sponsor. Each of Merck 
Global Safety (Merck GS), and Incyte will follow its own standard operating procedures 
for reporting, if any, to FDA for their respective filings covering the provided 
investigational products. 
 
 Expedited IND Safety Reports 
 
7 Calendar-Day Telephone or Fax Report:   
The IND Sponsor is required to notify the FDA of any fatal or life-threatening 
adverse event that is unexpected and assessed by the investigator to be possibly 
related to the investigational agent.  Such reports are to be telephoned or faxed 
(301-827-9796) to the FDA within 7 calendar days of first learning of the event. 
Follow-up information will be submitted to the FDA as soon as relevant 
information is available.  
 


 
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15 Calendar-Day Written Report:   
The IND Sponsor is required to notify the FDA of any SAE that is unexpected and 
related to the investigational agent in a written IND Safety Report.   
 
Written IND Safety Reports should include an Analysis of Similar Events in 
accordance with regulation 21 CFR § 312.32.  All safety reports previously filed 
with the IND concerning similar events should be analyzed.  The new report should 
contain comments on the significance of the new event in light of the previous, 
similar reports.   
 
Written IND safety reports with Analysis of Similar Events are to be submitted to 
the FDA within 15 calendar days of first learning of the event. Follow-up 
information will be submitted to the FDA as soon as relevant information is 
available. 
 
Investigators will submit a copy of these reports to Merck & Co., Inc, and Incyte 
Corporation at the time of submission to FDA, using the contact information 
provided in Section 7.6.1 
 
 IND Annual Reports 
 
In accordance with the regulation 21 CFR § 312.33, the IND Sponsor shall within 
60 days of the anniversary date that the IND went into effect submit a brief report 
of the AEs and progress of the investigation.  Please refer to Code of Federal 
Regulations, 21 CFR § 312.33 for a list of the elements required for the annual 
report.  All IND annual reports will be submitted to the FDA by the IND Sponsor. 
 
 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. 
 
 CORRELATIVE / SPECIAL STUDIES 
 
Sample collection, processing, storage, and shipment instructions will be provided in the 
Laboratory Manual. 
 
 
Tumor Tissue Studies 
 
Tumor biopsies (4-6 cores per time point) will be collected at baseline and Cycle 3, only if a 
subject’s tumor is thought to be reasonably safe and easy to biopsy.  Fine needle aspiration (FNA) 


 
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will not be acceptable.  Additional optional biopsies may be obtained later in the course of study 
treatment.  
 
Attempts will be made to obtain archived tissue samples from all subjects.  Archived FNA biopsy 
samples do not contain sufficient tissue and will not be collected.   
 
Detailed instructions for tissue collection, processing and shipment will be provided in the 
Laboratory Manual. 
 
To explore the association of OS, PD-L1 positivity, and tumor-infiltrating lymphocyte 
characteristics with clinical responses, archived tumor tissue and tumor tissue obtained at baseline 
and during treatment (Cycle 4) will be compared. PD-L1 expression may predict response to anti-
PD-122,23.  However, PD-L1 is also upregulated in response to IFN-γ released by infiltrating T cells 
and could potentially be a predictor of response to any active immunotherapy.  Pre- and on-
treatment tumor biopsies will also be analyzed for PD-1 expression as well as infiltration of 
immune cells (effector T cells, Tregs, B cells, dendritic cells, etc).  Characterization of immune 
checkpoint expression as well as immune infiltrates may be predictive of response to therapy and 
may also give insight into next generation combinatorial approaches.  Preliminary data from a 
pancreatic cancer immunotherapy study suggests that induction of a Th1and Th17 phenotype at the 
tumor itself predicts response.  Evaluation of T cell receptor repertoire and gene expression as well 
as genomic changes will be conducted on pre and on-treatment biopsy samples.  Furthermore, 
upregulation of other inhibitory molecules such as IL-10 and TGF-β may identify other targets for 
combinatorial strategies. 
 
 
Peripheral Blood Mononuclear Cells (PBMCs) 
 
Whole blood for isolation of PBMCs will be collected prior to dosing on Day 1 of Cycles 1, 2, 4, 
and 6 only during Course 1. Pre- and post-treatment changes in PBMCs including effector, helper, 
and regulatory T cells, NK cells, and macrophages through cell phenotyping analysis and gene 
expression profiling will be measured. In addition, induction of Listeria and mesothelin antigen-
specific T cell responses and changes to the T cell epitope reperitoire will also be evaluated. 
 
The cellular immune responses directed against Lm and mesothelin will be evaluated by using 
enzyme-linked immunosorbent spot (ELISPOT) and intracellular cytokine staining. Post-
treatment expression of PD-1 and other lymphocyte activation markers will be measured as well. 
These responses will be correlated with OS. PBMCs are isolated and stored frozen (liquid nitrogen) 
until use.  Detailed instructions for processing and storage are provided in the Laboratory Manual. 
 
 
Serum and Plasma Marker Studies 
 
Sera will be collected prior to dosing on Day 1 of Cycles 1-6 of Course 1 only. Additionally, whole 
blood for serum will be drawn 20-26 hours post each CRS-207 infusion during Cycles 1-6 of 
Course 1.  Plasma will be collected prior to dosing on Day 1 of Cycles 1, 2, 4, and 6 of Course 1. 
Humoral immune responses, including anti-Lm and anti-mesothelin antibodies will be evaluated 
by using enzyme-linked immunosorbent assay (ELISA). In addition, potential therapeutic targets, 
biomarkers, and predictors of response and autoimmune toxicity will be evaluated. Sera and 


 
J16173 / Version 7.0 / April 20, 2021 
62
plasma are isolated and stored frozen (-80oC) until use. Detailed instructions for processing and 
storage are provided in the Laboratory Manual. 
 
 
Stool and Oral Wash Studies 
 
Stool and oral wash specimens will be obtained when available.  Baseline specimens may be 
obtained on Cycle 1 Day 1 of Course 1 +/- 30 days. Additional samples will be collected at Course 
1 Cycle 4 Day 1 (+/- 30 days), Course 1 Cycle 6 Day 1 (+/- 30 days), and EOT (+/- 30 days).  
Additional samples may be obtained if patient has drug-related toxicity or at other timepoints of 
interest at the discretion of the PI at any point during the trial. All stool samples should be collected 
within 72 hours (ideally within 24 hours) of the patient’s appointment.  
 
Patients will be asked to complete a questionnaire when they provide stool samples, which asks 
about specific medications, dental health, and diet. 
 
Microbial DNA will be isolated from stool and oral wash samples and prepared for sequencing to 
profile microbial species represented in the gut pre- and post-treatment.  In addition, microbial 
DNA will be subjected to whole genome metagenomics profiling of microbial species via shotgun 
sequencing for detailed functional and pathway analysis to determine the change in the species 
and functions in response to treatment.  Further bioinformatics analyses will be performed with 
these sequencing data to identify candidate microbial biomarkers, and predictors of 
response.  Detailed instructions for stool and oral wash collection, shipment, and storage are 
provided in the Laboratory Manual.  
 
 
Diagnostic Tissue Samples 
 
Tissue, fluid, or blood may be collected from standard of care procedures used to treat or diagnose 
immune-related toxicities. 
 
 
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.  
 
Clinical analysis.  Several CLIA-certified laboratories now offer molecular profiling of 
cancer specimens in commercial and noncommercial settings and provide these results to patients 
and their physicians (e.g. Foundation Medicine, PGDx, Michigan Center for Translational 
Pathology, or JHU CLIA Laboratories). It is possible, therefore, that some of our research analyses 
will be conducted in these CLIA-certified environments.  If tissue or cells are evaluated with next 
generation sequencing strategies to provide a molecular profile of individual cancer specimens in 
a CLIA-certified facility, these results will be made available to the patient and their 
physician.  Patient confidentiality will be maintained, and the patient’s identity will not be publicly 
linked to any study results.  Researchers may use the data set generated in the CLIA assay setting 


 
J16173 / Version 7.0 / April 20, 2021 
63
to study genetic alterations across a large number of genes important in cancer. Germline mutations 
are only identified in punitive cancer genes. Researchers will use the data set for exploratory 
research to study cancer cell heterogeneity. Some of the sequencing data obtained from the NGS 
strategies will be uploaded to government sponsored databases, such as GEO and dbGAP.  The 
results of the research studies may be published but subjects will not be identified in any 
publication. 
 
If a germline alteration of clinical importance (as judged by the Investigator) to the subject and his 
or her family members is identified by a CLIA-certified test in the course of this analysis, attempts 
will be made in writing to contact the subject and/or family members for genetic counseling 
referral. 
 
 STUDY CALENDAR 
 
Subjects will receive treatment every 3 weeks for 6 cycles of treatment within a course. A course 
of treatment will be 18 weeks. 


 
J16173 / Version 7.0 / April 20, 2021 
64
 
Treatment Part 1 
 
Study Procedures 
Screening21 
Treatment Course (approx. 18 weeks) 
Cycle 122 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Cycle 6 
D1 
D2 
D823 
D1 
D2 
D823 
D1 
D2 
D3 
D923 
D1 
D2 
D3 
D923 
D1 
D2 
D3 D923 
D1 
D2 
D3 
D923 
Visit Windows (days)1 
D-21 
to D1 
- 2/ 
+7 
- 
±1 
- 2/ 
+7 
- 
±1 - 2/ 
+7 
- 
- 
+1 - 2/ 
+7 
- 
- 
+1 
- 2/ 
+7 
- 
- 
+1 
- 2/ 
+7 
- 
- 
+1 
CY 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
GVAX Pancreas Vaccine 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pembrolizumab2 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
CRS-207 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
Epacadostat 
 
X 
X 
X 
X 
X 
X 
Antibiotics3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical-, Cancer-, & Con Med- 
History4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Con Meds, Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Exam, ECOG  PS5 
X 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Vitals, Weight, & Height6 
X 
X 
X 
 
X 
X 
 
X 
X 
 
 
X 
X 
 
 
X 
X 
 
 
X 
X 
 
 
Hematology, Chemistry7, 13 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
Endocrine8, 13 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Urinalysis9, 13 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CD4 count, virology10 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Coagulation panel11 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test12, 13 
X 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
CA19-9 13 
X 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
ECG14 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CT/MRI, RECIST/irRC15 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Vaccine Site Reactions eval. 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
J16173 / Version 7.0 / April 20, 2021 
65
Study Procedures 
Screening21 
Treatment Course (approx. 18 weeks) 
Cycle 122 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Cycle 6 
D1 
D2 
D823 
D1 
D2 
D823 
D1 
D2 
D3 
D923 
D1 
D2 
D3 
D923 
D1 
D2 
D3 D923 
D1 
D2 
D3 
D923 
Whole blood for PBMC16 
 
X 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
Whole blood for plasma16 
 
X 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
Serum16 
 
X 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
HLA17 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Stool and Oral Wash Samples18 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Microbiome Questionnaire18 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Archival Tissue19 
X 
Tumor Biopsies20 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1:  Scheduled cycle may be delayed up to 1 week. Longer delays to be approved by the IND Sponsor, and/or Protocol Chair. 
2:  Subjects should be observed for a minimum of 30 minutes between CY and pembrolizumab administrations. 
3: 7-day course of antibiotics (abx) will be administered 7 days after final dose of CRS-207 in each course (or within 7 days of decision 
to discontinue treatment if discontinued mid-course) per Section 4.7.  Subjects with a central line port will receive 1 dose of IV 
antibiotics followed by 6 days of oral antibiotics; all other subjects will receive 7 days of oral antibiotics. Antibiotic regimens must 
be completed prior to initiation of any other cancer-related therapy. Abx should also be administered to subjects who receive steroids 
for the treatment of suspected pembrolizumab-related AE if they have not yet received abx after most recent CRS-207 treatment. Site 
personnel will contact the subject by telephone to facilitate compliance with antibiotic treatment and document in source. 
4: Cancer history includes: primary site of cancer, gross location of primary tumor, secondary sites of cancer, histology, histologic 
grade, date of initial diagnosis, date of metastatic diagnosis, prior cancer therapy regimens. 
5: Complete physical examination and assessment of ECOG PS will be completed at baseline; focused physical examinations and 
assessment of ECOG PS will be conducted thereafter.  Day 1 Physical examination and ECOG status may be done up to 1 day prior 
to dosing.  
6:  Height will be taken at or prior to screening only. Weight and pulse oximetry will be obtained at screening and prior to each cycle.  
Blood pressure, pulse, and temperature are required at baseline and as indicated:  
CY: vitals will be collected prior to administration.  
Pembrolizumab: vitals will be collected prior to and at the end of infusion (-5/+15 minutes).  
GVAX pancreas vaccine: vitals will be collected prior to and after administration. 


 
J16173 / Version 7.0 / April 20, 2021 
66
CRS-207: vitals will be obtained every 30 minutes (± 15 minutes) during infusion and every hour (-5/+15 minutes) during post-
infusion follow-up. Subjects will be observed for at least 4 hours after each CRS-207 infusion. Subjects who are not stable enough 
to be released at 4 hours after infusion should continue to be monitored until stable. Presence of fever alone does not indicate 
subject is not clinically stable. 
7:  Clinical Hematology: CBC with differential ANC, ALC, AEC, monocyte count, and platelet count; Serum Chemistry: sodium, 
potassium, chloride, bicarbonate, glucose, BUN, creatinine, ALT, AST, alkaline phosphatase, total bilirubin, direct bilirubin, total 
protein, albumin, calcium, magnesium, and phosphate. Amylase and lipase will be checked only on Day 1 of each cycle. LDH, uric 
acid, and c reactive protein at baseline only. 
8:  TSH (total T3 and free T4 only if TSH abnormal as clinically indicated). Prolactin, luteinizing hormone, and ACTH will be done at 
baseline and repeated only if patient is symptomatic. Cortisol stim test should be considered as clinically indicated if ACTH is 
abnormal. 
9:  Color, specific gravity, pH, protein, glucose, ketones, bilirubin, nitrite, blood, leukocytes, WBC and RBC count. 
10: Virology screen: HIV antibody, Hepatitis B surface antigen and Hepatitis C antibody; additional virology may also be evaluated.  
11: Coagulation panel: D-dimer, fibrinogen, PT, aPTT, and INR 
12: Pregnancy tests will be administered to WOCBP: serum pregnancy test is required at screening; urine pregnancy tests are required 
before doses on Day 1 of dosing weeks.  
13: Labs may be collected within a window of up to 3 days prior to Day 1 dosing. Blood draws must not be collected from a central line 
for at least 4 days after infusion of CRS-207. Day 8/9 labs will only be collected during the first course. Any unexpected or clinically 
significant Grade 3 or greater abnormality should be repeated within 24-72 hours. 
14: ECG should be performed at baseline prior to treatment, as clinically indicated while on study, and at the EOT visit.  
15: Spiral CT of thorax, abdomen and pelvis (other imaging studies as clinically indicated). If a subject cannot have a CT scan (e.g., 
allergy to contrast dye), an MRI should be performed. 3-D and RECIST reads will not be used to determine eligibility. On study 
radiologic evaluations and tumor measurements (RECIST and irRC per Appendix C and Appendix D) will be performed every 10 
weeks (± 1 week; starting from the date of first treatment) including the EOT evaluation (± 4 weeks). EOT scans does not need to 
be repeated if one has been done within the past 6 weeks. Weeks are in reference to calendar week and should not be adjusted due 
to dosing delays. 
16: Approximately 120 mL of whole blood, 5.0 mL blood for serum, and 20 mL blood for plasma will be drawn as indicated during 
Course 1 only.  Blood may be drawn up to 72 hours prior to Day 1 dosing. Day 3 blood draws (5 mL for serum) should be taken 
between 20 and 26 hours after start of CRS-207 dosing.  
17: HLA-typing to include HLA class I type A and B, low resolution. HLA typing is only done during the first course of study treatment. 
18: Stool and oral wash samples (and questionnaire) will be obtained when available.  Specimens should be collected within 72 hours 
(ideally within 24 hours) of the patient’s appointment.  Baseline specimens may be obtained at Cycle 1 Day 1 +/- 30 days of Course 
1. Additional samples will be collected at Course 1 Cycle 4 Day 1 (+/- 30 days), Course 1 Cycle 6 Day 1 (+/- 30 days), and EOT 


 
J16173 / Version 7.0 / April 20, 2021 
67
(+/- 30 days).  Additional samples may be obtained if patient has drug-related toxicity or at other timepoints of interest at the 
discretion of the PI at any point during the trial. 
19: Attempts will be made to obtain surgical or biopsy archival tumor samples (other than FNA) for every subject until the sample is 
obtained or documentation that the sample cannot be obtained is provided. Archived fine needle aspirate (FNA) biopsy samples do 
not contain sufficient tissue and do not need to be collected.   
20: Tumor biopsies (4-6 cores) to be taken at baseline (-1 week) and at Cycle 3 Day 1 (+/- 1 week) of only the first course of treatment. 
Biopsies will only be collected if subject’s tumor is thought to be reasonably safe and easy to biopsy. Additional optional biopsies 
may be obtained later in the course of study treatment. Fine needle aspiration will not be acceptable. Biopsies will not be collected 
for patients enrolled in Part 1 of the study (dose escalation). 
21: Once a subject meets all eligibility criteria and is randomized/enrolled, the subject does not need to repeat screening evaluations in 
the event that the first dose is delayed 
22: Cycle 1 Day 1 evaluations do not need to be repeated if they were conducted within 3 days of the pre-study evaluations. 
23: Day 8 and 9 assessments may be conducted by phone. 
 


 
J16173 / Version 7.0 / April 20, 2021 
68
   
 
Treatment Part 1X/Part 2X 
 
Study Procedures 
Screening21 
Treatment Course (approx. 18 weeks) 
Cycle 122 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Cycle 6 
D1 
D2 D3 
D923 
D1 
D2 
D3 
D923 
D1 
D2 D3 
D923 
D1 
D2 D3 
D923 
D1 
D2 D3 
D923 
D1 
D2 D3 
D923 
Visit Windows (days)1 
D-21 
to D1 
- 2/ 
+7-  - 
- 
±1 
- 2/ 
+7 
- 
- 
±1 
- 2/ 
+7 
- 
- 
±1 
- 2/ 
+7 
- 
- 
±1 
- 2/ 
+7 
- 
- 
±1 
- 2/ 
+7 
- 
- 
±1 
Pembrolizumab 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
CRS-207 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
Epacadostat 
 
X 
X 
X 
X 
X 
X 
Antibiotics2,3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X24 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent25 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization (R) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical-, Cancer-, & Con 
Med- History4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Con Meds, Adverse Events 
 
X 
X X 
X 
X 
X 
X 
X 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Exam, ECOG  PS5 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Vitals, Weight, & Height6 
X 
X 
X 
 
 
X 
X 
 
 
X 
X 
 
 
X 
X 
 
 
X 
X 
 
 
X 
X 
 
 
Hematology, Chemistry7, 13 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
Endocrine8, 13 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Urinalysis9, 13 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CD4 count, virology10 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Coagulation panel11 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test12, 13 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
CA19-9 13 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
ECG14 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
J16173 / Version 7.0 / April 20, 2021 
69
Study Procedures 
Screening21 
Treatment Course (approx. 18 weeks) 
Cycle 122 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Cycle 6 
D1 
D2 D3 
D923 
D1 
D2 
D3 
D923 
D1 
D2 D3 
D923 
D1 
D2 D3 
D923 
D1 
D2 D3 
D923 
D1 
D2 D3 
D923 
CT/MRI, RECIST/irRC15 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Whole blood for PBMC16 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
pWhole blood for plasma16 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
Serum16 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Microbiome Questionnaire 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
HLA17 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Stool and Oral Wash 
Samples18 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
Microbiome Questionnaire18 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
Archival Tissue19 
X 
Tumor Biopsies20 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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. 
1:  Scheduled cycle may be delayed up to 1 week. Longer delays to be approved by the IND Sponsor and/or Protocol Chair. 
2: 7-day course of antibiotics (abx) will be administered 7 days after final dose of CRS-207 in each course (or within 7 days of decision 
to discontinue treatment if discontinued mid-course) per Section 4.8.   
3: Refer to Section 4.7 for recommended antibiotic regimen for patients having semi-permanent indwelling device placed while on 
study 
4: Cancer history includes: primary site of cancer, gross location of primary tumor, secondary sites of cancer, histology, histologic 
grade, date of initial diagnosis, date of metastatic diagnosis, prior cancer therapy regimens. 
5: Complete physical examination and assessment of ECOG PS will be completed at baseline; focused physical examinations and 
assessment of ECOG PS will be conducted thereafter.  Day 1 Physical examination and ECOG status may be done up to 1 day prior 


 
J16173 / Version 7.0 / April 20, 2021 
70
to dosing. 
6:  Height will be taken at or prior to screening only. Weight and pulse oximetry will be obtained at screening and prior to each cycle.  
Blood pressure, pulse, and temperature are required at baseline and as indicated:  
Pembrolizumab: vitals will be collected prior to and at the end of infusion (-5/+15 minutes).  
CRS-207: vitals will be obtained every 30 minutes (± 15 minutes) during infusion and every hour (-5/+15 minutes) during post-
infusion follow-up. Subjects will be observed for at least 4 hours after each CRS-207 infusion. Subjects who are not stable enough 
to be released at 4 hours after infusion should continue to be monitored until stable. Presence of fever alone does not indicate 
subject is not clinically stable. 
7:  Clinical Hematology: CBC with differential ANC, ALC, AEC, monocyte count, and platelet count; Serum Chemistry: sodium, 
potassium, chloride, bicarbonate, glucose, BUN, creatinine, ALT, AST, alkaline phosphatase, total bilirubin, direct bilirubin, total 
protein, albumin, calcium, magnesium, and phosphate. Amylase and lipase will be checked only on Day 1 of each cycle. LDH, uric 
acid, and c reactive protein at baseline only. 
8:  TSH (total T3 and free T4 only if TSH abnormal as clinically indicated). Prolactin, luteinizing hormone, and ACTH will be done at 
baseline and PRN. Cortisol stim test should be considered as clinically indicated if ACTH is abnormal. 
9:  Color, specific gravity, pH, protein, glucose, ketones, bilirubin, nitrite, blood, leukocytes, WBC and RBC count. 
10:  Virology screen: HIV antibody, Hepatitis B surface antigen and Hepatitis C antibody; additional virology may also be evaluated.  
11: Coagulation panel: D-dimer, fibrinogen, PT, aPTT, and INR 
12: Pregnancy tests will be administered to WOCBP: serum pregnancy test is required at screening; urine pregnancy tests are required 
before doses on Day 1 of dosing weeks.  
13: Labs may be collected within a window of up to 3 days prior to Day 1 dosing. Blood draws must not be collected from a central line 
for at least 4 days after infusion of CRS-207. Day 8/9 labs will be collected during the first course.  Any unexpected or clinically 
significant Grade 3 or greater abnormality should be repeated within 24-72 hours. 
14: ECG should be performed at baseline prior to treatment, as clinically indicated while on study, and at the EOT visit.  
15: Spiral CT of thorax, abdomen and pelvis (other imaging studies as clinically indicated). If a subject cannot have a CT scan (e.g., 
allergy to contrast dye), an MRI should be performed. 3-D and RECIST reads will not be used to determine eligibility. On study 
radiologic evaluations and tumor measurements (RECIST and irRC per Appendix C and Appendix D) will be performed every 10 
weeks (± 1 week; starting from the date of first treatment) including the EOT evaluation (± 4 weeks). EOT scans does not need to 
be repeated if one has been done within the past 6 weeks. Weeks are in reference to calendar week and should not be adjusted due 
to dosing delays. 
16: Approximately 120 mL of whole blood, 5.0 mL of blood for serum, and 20 mL blood for plasma will be drawn as indicated during 
Course 1 only. Blood may be drawn up to 72 hours prior to Day 1 dosing. Day 3 blood draws (5 mL for serum) should be taken 
between 20 and 26 hours after start of CRS-207 dosing. 
17: HLA-typing to include HLA class I type A and B, low resolution. HLA typing is only done during the first course of study treatment. 


 
J16173 / Version 7.0 / April 20, 2021 
71
18: Stool and oral wash samples (and questionnaire) will be obtained when available.  Specimens should be collected within 72 hours 
(ideally within 24 hours) of the patient’s appointment.  Baseline specimens may be obtained at Cycle 1 Day 1 +/- 30 days of Course 
1. Additional samples will be collected at Course 1 Cycle 4 Day 1 (+/- 30 days), Course 1 Cycle 6 Day 1 (+/- 30 days), and EOT 
(+/- 30 days).  Additional samples may be obtained if patient has drug-related toxicity or at other timepoints of interest at the 
discretion of the PI at any point during the trial. 
19: Attempts will be made to obtain surgical or biopsy archival tumor samples (other than FNA) for every subject until the sample is 
obtained or documentation that the sample cannot be obtained is provided. Archived fine needle aspirate (FNA) biopsy samples do 
not contain sufficient tissue and do not need to be collected.   
20: Tumor biopsies (4-6 cores) to be taken at baseline (-1 week) and at Cycle 3 Day 1 (+/- 1 week) of only the first course of treatment. 
Biopsies will only be collected if subject’s tumor is thought to be reasonably safe and easy to biopsy. Additional optional biopsies 
may be obtained later in the course of study treatment. Fine needle aspiration will not be acceptable.  
21: Once a subject meets all eligibility criteria and is randomized/enrolled, the subject does not need to repeat screening evaluations in 
the event that the first dose is delayed 
22: Cycle 1 Day 1 evaluations do not need to be repeated if they were conducted within 3 days of the pre-study evaluations. Additional 
course(s) will start 3 weeks (+7 days) from last dose of previous course. 
23: Day 8 and 9 assessments may be conducted by phone.   
24: Site personnel will contact the subject by telephone (prior to and within 3 days after completion) to facilitate compliance with 
antibiotic treatment and document in soruce. 
25: 30 day window


 
J16173 / Version 7.0 / April 20, 2021 
72
 
End of Treatment and Follow-Up 
Visit Day  
(Range) 
EOT 
Follow-Up Phase 
Comments 
Safety 
Follow-Upi) 
Survival 
Follow-Up 
 
28 Days After 
last Dose of 
Study Drug 
90 Days 
After Last 
Dose of 
Study Drug 
Every 12 
Weeks 
Evaluation/Wind
ow 
+/- 7 Days 
+14 Days 
+/- 2 
Weeks 
 
Survival Follow-
Up 
 
 
X 
Subjects will be assessed by either a clinic visit or phone contact 
every 12 weeks (+/- 2 wks) from the last dose of study treatment.   
Post-Study Anti-
Cancer Tx 
 
 
X 
The nature and start and stop dates of any new cancer therapies 
during follow-up period will be recorded. 
Physical Exam, 
ECOG PS 
X 
 
 
 
Vital signs, weight 
X 
 
 
 
ECG 
X 
 
 
 
Con Meds 
X 
 
 
 
Adverse Events 
X 
X 
 
AEs must be monitored for 30 days after the last dose of study 
drug; however, SAEs must be monitored up to 90 days. 
Laboratory 
assessments 
X 
 
 
 
CT/MRI, 
RECIST/irRC 
X 
 
X 
EOT imaging may be done +/- 4 weeks from EOT visit. Subjects 
discontinuing treatment for reasons other than disease 
progression, should continue imaging every 12 weeks (+/- 2 
weeks) until (1) start of new anticancer therapy, (2) documented 
disease progression, (3) death, (4) withdrawal of consent or (5) 
the end of study, whichever occurs first. 
Hematology, 
Chemistry 
X 
 
 
Hematology: CBC with differential ANC, ALC, AEC, and 
platelet count;  
Serum Chemistry: sodium, potassium, chloride, bicarbonate, 
glucose, BUN, creatinine, ALT, AST, alkaline phosphatase, total 
bilirubin, direct bilirubin, total protein, albumin, calcium, 
magnesium, and phosphate.  
Endocrine 
X 
 
 
TSH (total T3 and free T4 if TSH abnormal as clinically 
indicated). Prolactin, luteinizing hormone, and ACTH if patient is 
symptomatic. Cortisol stim test only if ACTH abnormal). 
Blood sample for 
CRS-207 testing 
X 
 
 
Blood for CRS-207 culture will be collected at EOT (or within 4 
weeks of last dose of antibiotics if patients discontinue treatment 
mid-course) to assess clearance of CRS-207. After EOT, blood 
will continue to be collected for CRS-207 culture at 3, 6, 9, and 
12 months from last dose of CRS-207  (+/- 1 week window for 
each collection) to monitor for the presence of CRS-207. 
Stool and Oral 
Wash Samples, 
Microbiome 
Questionnaire 
X 
 
 
Stool and oral wash samples (and questionnaire) will be obtained 
when available.  Specimens should be collected within 72 hours 
(ideally within 24 hours) of the patient’s appointment.   
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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 STUDY ENDPOINTS 
 
 Primary Endpoint 
 
The primary endpoint is 6 month survival rate, measured from date of first treatment. 
 
 Secondary Endpoint 
 
The secondary endpoint is as follows: 
• Safety assessed by the following measures: 
– Number of patients who have grade 3 or higher drug-related toxicities  
– Frequency of drug-related toxicity by grade  
– Injection-site reactions (after GVAX pancreas vaccine injections only) 
– Pembrolizumab-related infusion reactions 
– CRS-207-related infusion reactions 
– Immune-related AEs 
– Unacceptable toxicities 
– Vital signs: BP, pulse, temperature 
– Physical examination 
– Changes in ECG readings  
– Clinical hematology: complete blood count (CBC) with differential ANC, 
ALC, AEC, and platelet count 
– Clinical serum chemistry: sodium, potassium, chloride, bicarbonate, glucose, 
blood urea nitrogen (BUN), creatinine, lactate dehydrogenase (LDH), ALT, 
AST, alkaline phosphatase, amylase, bilirubin (total), total protein, albumin, 
calcium, magnesium and phosphate 
 
 Exploratory Endpoints 
 
Exploratory endpoints are as follows: 
• Overall Survival (OS), Progression-Free Survival (PFS), Objective Response Rate (ORR), 
Best Overall Response (BOR),  Duration of Response (DOR), Duration of Clinical Benefit 
(DCB), Time to Objective Response (TTOR), and Disease Control Rate (DCR) measured 
by RECIST 1.1.  The same endpoints will be measured using irRC (irPFS, irORR, irBOR, 
irDOR, irDCB, irTTOR, irDCR) 
− 
OS  will be measured from date of first treatment until death or end of follow-up 
(OS will be censored on the date the subject was last known to be alive for subjects 
without documentation of death at the time of analysis). 
− 
Progression-free survival (PFS) is defined as the number of months from the date 
of first treatment to disease progression (PD or relapse from CR) or death due to 
any cause. 
− 
Objective Response Rate (ORR) is defined as the percentage of subjects achieving 
a partial response or better (PR + CR) 
− 
Best Overall Response (BOR) is defined in Appendix C. 


 
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− 
Duration of Response (DOR) is defined as the number of months from the first 
documentation of a response to date of disease progression. 
− 
Duration of Clinical Benefit (DCB) is defined as the number of months from first 
treatment to date of disease progression in those achieving a PR or CR. 
− 
Time to Objective Response (TTOR) is defined as the number of months from the 
date of first treatment to the date of documented partial or complete response  
− 
Disease Control Rate (DCR) is defined as the percentage of subjects achieving 
stable disease or better (SD + PR + CR) 
• Tumor marker kinetics measured by change in serum CA19-9 concentrations from baseline  
• Humoral and cellular immune responses directed against Lm and mesothelin assessed by 
using the following measures: 
– ELISPOT or intracellular cytokine staining assays of PBMC 
– Induction of proinflammatory cytokines and chemokines in the serum 
– ELISA detection of mesothelin- and Lmspecific- antibodies in the serum 
• Immune subset analyses by IHC and gene expression profiling of tumor tissue  
• Immune subset analyses by FACS in PBMCs including effector, helper, and regulatory T 
cells, NK cells, and macrophages  
• T cell receptor (TCR) repertoire analysis in PBMCs and tumors  
• Gene expression analysis of PBMCs  
• Microbial community analysis and whole metagenome functional profiling analysis of 
stool samples 
• Peripheral blood specimens, intratumoral core biopsy specimens, and resection specimens 
will be studied using a variety of laboratory techniques including but not limited to: 
immunohistochemistry (IHC), flow cytometry, CITE-Seq, RNA-Seq, whole exome 
sequencing, whole genome sequencing, T cell receptor and B cell receptor sequencing, 
ChIP-seq, ATAC-seq, and MBD-seq. 
 
 DATA REPORTING / REGULATORY REQUIREMENTS 
 
Adverse event guidelines, and instructions for AE reporting can be found in Section 7.0 (Adverse 
Events: List and Reporting Requirements). 
 
Dr. Elizabeth Jaffee will be holding the IND for this study.  She will comply with all regulated 
reporting requirements to the FDA. 
 
 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.  
 
 Safety Meetings 
 
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, 


 
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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. 
 
 Monitoring 
 
The SKCCC Compliance Monitoring Program will provide external monitoring for JHU affiliated 
sites in accordance with SKCCC DSMP (Version 6.0, 02/21/2019). The SMC Subcommittee will 
determine the level of patient safety risk and level/frequency of monitoring. The protocol will be 
internally monitored by Dr. Dung Le. 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-Investigator after each meeting. In turn, the study team will 
forward these summaries to the JHU and IRB, 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; 
 
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, and the FDA immediately.  
 
 STATISTICAL CONSIDERATIONS 
 
 Sample Size 
 
Part 1 of the trial evaluated up to 3 dose levels of epacadostat in combination with pembrolizumab, 
CY/GVAX pancreas vaccine, and CRS-207 (including dose level -1) using a 3+3 dose escalation 
approach. Enrollment will continue according to this approach on Part 1X, but with an additional 
dose level to be evaluated, and patients will receive epacadostat with pembrolizumab and CRS-
207 only. Up to 24 patients will be enrolled in Part 1/Part 1X. 
 
For Part 2X, the primary endpoint is 6 month overall survival (6mo OS), and will be calculated as 


 
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the proportion of subjects who are alive 6 months or longer after the date of first treatment.   
 
A total of 26 evaluable patients are planned, and will include the 6 subjects from part 1X treated 
at the same dose. mTOR inhibitor sirolimus showed 26% 6mo OS in gemcitabine-resistant 
pancreatic cancer1, and we expect the combination immunotherapy to achieve better efficacy. A 
sample size of 26 provides greater than 90% power to reject the null hypothesis of 25% 6mo OS 
rate in favor of 50% 6mo OS, with type I error of 0.1. If 10 or more patients survive beyond 6 
months, we conclude that treatment is effective and further study is warranted. No early stopping 
for futility is planned due to the relatively rapid enrollment of patient in relation to the 6-months 
OS endpoint. It is estimated that 5% of the subjects who complete screening and are enrolled will 
ultimately not receive study treatment, so approximately 28 subjects are expected to be enrolled to 
achieve 26 treated subjects.   
 
 Analysis sets 
The Full Analysis Set (FAS) is defined as all subjects who received at least 1 dose of study 
treatment. The FAS will be used for the analysis of efficacy endpoints. 
The Safety Set includes all subjects who received any study treatment. In all safety analyses, the 
treatment group at analysis will be based on actual treatment received. All analyses of safety data 
will be conducted using the safety set. 
 
 Statistical Analyses   
 
Data will be summarized descriptively.  The descriptive summary for the categorical variables will 
include counts and percentages. The descriptive summary for the continuous variables will include 
means, medians, standard deviations and minimum and maximum values.  The descriptive 
summary of time to event data will include median, 25th and 75th percentiles and standard error.  
All data will be listed for all subjects. 
 
Primary endpoint of 6mo OS will be estimated as the fraction of patients who are alive beyond 
180 days after first treatment, with corresponding 95% confidence interval. In the rare event that 
survival status is not available for one of more subjects, these will be treated as a death event for 
this endpoint. 
 
Objective response rate (ORR) will be estimated as the proportion of patients who achieve 
complete response (CR) or partial response (PR) per RECIST 1.1. Time to objective response 
(TTOR) and duration of response (DOR), defined as time from first treatment to CR/PR and from 
response to disease progression among responders, respectively, will be summarized. Disease 
control rate (DCR) is defined as fraction of patients who have CR, PR or stable disease.  Time-to-
event outcomes such as progression-free survival (PFS) and OS will be analyzed using Kaplan-
Meier estimates. PFS is defined as the time from first treatment to the first documented disease 
progression per RECIST 1.1 or death due to any cause, whichever occurs first, and OS is defined 
as the time from first treatment to death due to any cause. Those who are lost to follow up will be 
censored at the last date they were known to be alive.  The same analysis will be performed to 
describe these outcomes based on immune related response criteria (irPFS, irORR, irDOR, 
irTTOR, irDCR).     
 


 
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For correlative studies, plots will be used to show the changes in immune response over time for 
each individual. Comparisons in the pre and post-treatment responses will be compared using 
paired t-tests (or Wilcoxon signed rank tests if appropriate) for continuous variables and 
McNemar’s tests for dichotomous or categorical variables. Associations between immune 
parameters will be explored graphically (e.g. scatterplots, boxplots) and numerically (e.g., 
correlations, Fisher’s exact tests). Regression techniques will be used to explore the differences 
between groups for cross-sectional data (e.g., linear and logistic regression) and longitudinally 
with appropriate correction for correlation between repeated measurements (e.g., linear mixed 
effects models). 
 
Demographics and baseline characteristics will be summarized. 
 
 Safety Analysis 
 
The safety analysis will be performed in all treated subjects. AE data will be listed individually 
and incidence of AEs summarized by system organ class and preferred terms within a system organ 
class.  When calculating the incidence of AEs, each AE (based on preferred terminology defined 
by Medical Dictionary for Regulatory Activities (MedDRA; Version 13.1, or later) will be counted 
only once for a given subject.  In analyses of grade and causality, if the same AE occurs on multiple 
occasions, the highest grade and strongest relationship to study drug will be assumed.  If 2 or more 
AEs are reported as a unit, the individual terms will be reported as separate experiences.  Vaccine-
site reactions will be listed and tabulated separately from the AEs. 
 
Changes in vital signs, hematology and clinical chemistry parameters from baseline to the end of 
the study will be examined.  Toxicity will be tabulated by type and grade. Toxicities will be 
characterized according to the CTCAE version 4.03.  Treatment-emergent changes from normal 
to abnormal values in key laboratory parameters will be identified. 
 
 Safety monitoring 
 
The proportion of treated subjects with unacceptable toxicity will be monitored routinely using a 
Bayesian stopping guideline in Part 2X of the trial. If the unacceptable toxicity events appear to 
be higher than 33%, we will temporarily halt the study pending further review and consideration. 
Specifically, we will apply a Bayesian toxicity monitoring rule that suspends the enrollment if the 
posterior probability of risk being larger than 0.33 is 65% or higher. The monitoring rule uses beta 
(1.5, 5.5) as prior distribution. This means that our prior guess at the proportion of toxicity is 21%, 
and there is 90% probability that this proportion is between 3% and 49%.  The decision rule for 
safety stopping among the additional 20 patients enrolled is as follows: 
 
 
Stop if: 
 
#  AE 
3 
4 
5 
6 
7 
8 
9 
 
 
Out of  
3-4 
5-7 
8-10 
11-12 
13-15 
16-18 
19-20 
 
 
 


 
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For example, if three out of the first 3-4 patients have unacceptable toxicity events, we will stop 
the accrual. If four or more out of the first 5-7 patients have unacceptable toxicity events, we will 
stop.  
  
The operating characteristics of the stopping rule are shown below and are based on 5000 
simulations: 
 
True AE rate 
% simulated trials 
declaring unsafe 
Average sample size 
(out of 20) 
0.2 
7.5 
19 
0.25 
14.9 
18.2 
0.3 
27.6 
16.9 
0.35 
43.4 
15.2 
0.4 
59.4 
13.3 
0.45 
73.3 
11.5 
 


 
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1 
Garrido-Laguna, I. et al. Integrated preclinical and clinical development of mTOR 
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2 
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3 
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Burris, H. A., 3rd et al. Improvements in survival and clinical benefit with gemcitabine as 
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Moore, M. J. et al. Erlotinib plus gemcitabine compared with gemcitabine alone in 
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Conroy, T. et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. The 
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Von Hoff, D. D. et al. Increased survival in pancreatic cancer with nab-paclitaxel plus 
gemcitabine. The New England journal of medicine 369, 1691-1703, 
doi:10.1056/NEJMoa1304369 (2013). 
9 
Wang-Gillam, A. et al. Nanoliposomal irinotecan with fluorouracil and folinic acid in 
metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a 
global, randomised, open-label, phase 3 trial. Lancet 387, 545-557, doi:10.1016/S0140-
6736(15)00986-1 (2016). 
10 
Le, D. T. et al. Safety and survival with GVAX pancreas prime and Listeria 
Monocytogenes-expressing mesothelin (CRS-207) boost vaccines for metastatic 
pancreatic cancer. Journal of clinical oncology : official journal of the American Society 
of Clinical Oncology 33, 1325-1333, doi:10.1200/JCO.2014.57.4244 (2015). 
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Le, D. T. et al. Evaluation of ipilimumab in combination with allogeneic pancreatic 
tumor cells transfected with a GM-CSF gene in previously treated pancreatic cancer. J 
Immunother 36, 382-389, doi:10.1097/CJI.0b013e31829fb7a2 (2013). 
12 
Uyttenhove, C. et al. Evidence for a tumoral immune resistance mechanism based on 
tryptophan degradation by indoleamine 2,3-dioxygenase. Nature medicine 9, 1269-1274, 
doi:10.1038/nm934 (2003). 
13 
Koblish, H. K. et al. Hydroxyamidine inhibitors of indoleamine-2,3-dioxygenase potently 
suppress systemic tryptophan catabolism and the growth of IDO-expressing tumors. Mol 
Cancer Ther 9, 489-498, doi:10.1158/1535-7163.MCT-09-0628 (2010). 
14 
Witkiewicz, A. et al. Expression of indoleamine 2,3-dioxygenase in metastatic pancreatic 
ductal adenocarcinoma recruits regulatory T cells to avoid immune detection. J Am Coll 
Surg 206, 849-854; discussion 854-846, doi:10.1016/j.jamcollsurg.2007.12.014 (2008). 


 
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15 
Kobayashi, N. et al. FOXP3+ regulatory T cells and tumoral indoleamine 2,3-
dioxygenase expression predicts the carcinogenesis of intraductal papillary mucinous 
neoplasms of the pancreas. Pancreatology 10, 631-640, doi:10.1159/000308966 (2010). 
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Holmgaard, R. B., Zamarin, D., Munn, D. H., Wolchok, J. D. & Allison, J. P. 
Indoleamine 2,3-dioxygenase is a critical resistance mechanism in antitumor T cell 
immunotherapy targeting CTLA-4. The Journal of experimental medicine 210, 1389-
1402, doi:10.1084/jem.20130066 (2013). 
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Spranger, S. et al. Mechanism of tumor rejection with doublets of CTLA-4, PD-1/PD-L1, 
or IDO blockade involves restored IL-2 production and proliferation of CD8(+) T cells 
directly within the tumor microenvironment. J Immunother Cancer 2, 3, 
doi:10.1186/2051-1426-2-3 (2014). 
18 
Ribas, A. et al. Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-
refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. The 
Lancet. Oncology 16, 908-918, doi:10.1016/S1470-2045(15)00083-2 (2015). 
19 
Robert, C. et al. Pembrolizumab versus Ipilimumab in Advanced Melanoma. The New 
England journal of medicine 372, 2521-2532, doi:10.1056/NEJMoa1503093 (2015). 
20 
Herbst, R. S. et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-
positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised 
controlled trial. Lancet 387, 1540-1550, doi:10.1016/S0140-6736(15)01281-7 (2016). 
21 
Seiwert, T. Y. et al. Safety and clinical activity of pembrolizumab for treatment of 
recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): 
an open-label, multicentre, phase 1b trial. The Lancet. Oncology 17, 956-965, 
doi:10.1016/S1470-2045(16)30066-3 (2016). 
22 
Topalian, S. L. et al. Safety, activity, and immune correlates of anti-PD-1 antibody in 
cancer. The New England journal of medicine 366, 2443-2454, 
doi:10.1056/NEJMoa1200690 (2012). 
23 
Brahmer, J. R. et al. Phase I study of single-agent anti-programmed death-1 (MDX-1106) 
in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic 
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Clinical Oncology 28, 3167-3175, doi:10.1200/JCO.2009.26.7609 (2010). 
 
 
 
 


 
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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.   Prohibited MAOIs and Drugs Associated with Significant 
MAOI Activity1 
 
Monoamine Oxidase Inhibitors  
Drugs Associated With Significant Monoamine 
Oxidase Inhibitory Activity 
Hydrazines (example phenelzine) 
Meperidine2 
Caroxazone 
Linezolid 
Echinopsidine 
Methylene blue 
Furazolidone 
 
Tranylcypromine 
 
Brofaromine 
 
Metralindole 
 
Minaprine 
 
Moclobemide 
 
Pirlindole 
 
Toloxatone 
 
Lazbemide 
 
Pargyline 
 
Rasagiline 
 
Selegiline 
 
 
 
 
 
 
 
1 Review of serotonin syndrome:  
Edward W. Boyer, M.D., Ph.D., and Michael Shannon, M.D., M.P.H. The Serotonin Syndrome. 
N Engl J Med 352:1112-1120, http://www.nejm.org/doi/full/10.1056/NEJMra041867  
 
2 Up to 2 doses of meperidine may be used for the treatment of rigors during CRS-207 infusion. 


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


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


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


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


 
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RECIST 1.1 
irRC RECIST 1.1 
Handling of lymph 
nodes 
Lymph nodes are considered 
pathologically enlarged if > 10 mm in 
SAD. To be measurable, nodal lesions 
must be ≥ 15 mm in SAD. Nodal lesions 
with SAD > 10 mm and < 15 mm are 
non- measurable. The sum of the 
diameters (LD for extranodal target 
lesions, SAD for nodal lesions) is 
followed through the course of therapy 
Not differentiated from 
other tumor measurements 
Derivation of irRC Overall Responses  
(Modified for RECIST 1.1. Criteria) 
 
Measurable 
response 
Non-measureable response 
Overall 
response 
Index and new, 
measurable 
lesions; tumor 
b
d
* (%)
Non-index lesions 
New, non- 
measurable 
lesions 
Using irRC 
↓ 100 
Absent 
Absent 
irCR± 
↓ 100 
Stable 
Any 
irPR± 
↓ 100 
Unequivocal progression
Any 
irPR± 
↓ ≥ 30 
Absent/ Stable 
Any 
irPR± 
↓ ≥ 30 
Unequivocal progression
Any 
irPR± 
↓ <30 to <20↑ 
Absent/ Stable 
Any 
irSD 
↓ <30 to <20↑ 
Unequivocal progression
Any 
irSD 
≥ 20↑ 
Any 
Any 
irPD± 
*Decreases assessed relative to baseline, including measurable lesions only (>5 x 5 mm). 
±Assuming response (irCR or irPR) and progression (irPD) are confirmed by a second 
consecutive assessment at least 4 weeks apart. 
 
 
Defining immune-related Response Criteria by RECIST 1.1 criteria at 20 weeks (irDCR at 20 
weeks): 
1. Any patient with stable disease or progressive disease at any time in the trial with "rapid 
clinical deterioration" felt to be related to disease progression is irPD 
 
2. Any patient who meets the criteria for RECIST 1.1 CR at 20 weeks is irCR 
 
3. Any patient who meets the criteria for RECIST 1.1 PR at 20 weeks is irPR 
 
4. Any patient who meets the criteria for RECIST 1.1 SD at 20 weeks is irSD 
 


 
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5. A patient with RECIST 1.1 PD but no rapid clinical deterioration may stay on study if 
his/her next tumor measurement evaluation is stable disease or better. 
 
6. If patient has first time PD by RECIST 1.1 criteria, call it unconfirmed PD for irRC 
RECIST 1.1. 
 
7. A patient with unconfirmed irPD at 20 weeks whose next tumor measurement is SD or 
better will be considered to be included in the irDCR at 6 months. 
 
8. A patient with unconfirmed irPD at 20 weeks who fails to qualify for RECIST 1.1 SD or 
unconfirmed CR or PR by next tumor measurement will be considered to have RECIST 
1.1 PD and irPD at 20 weeks.