A Phase 2, Open-label Evaluation of CRS-207 and Pembrolizumab in Adults With Recurrent or Metastatic Gastric, Gastroesophageal Junction, or Esophageal Adenocarcinomas
Phase: PHASE2
Conditions: Gastric Adenocarcinoma, Gastroesophageal Junction Adenocarcinoma, Esophageal Adenocarcinoma
Sponsor: Aduro Biotech, Inc.

  
CLINICAL STUDY PROTOCOL 
 
A Phase 2, Open-label Evaluation of CRS-207 and Pembrolizumab 
in Adults with Recurrent or Metastatic Gastric, Gastroesophageal 
Junction, or Esophageal Adenocarcinomas 
 
Protocol Number: 
 
ADU-CL-14 
Original Protocol: 
 
20 December 2016 
Amendment 1: 
 
17 July 2017 
Amendment 2: 
 
22 August 2017 
Investigational Products: 
CRS-207 (live, attenuated, double-deleted 
Listeria monocytogenes encoding human 
mesothelin [Lm ∆actA/∆inlB hMeso]) 
 
Pembrolizumab (MK-3475) 
IND Number: 
 
13,389 
Sponsor: 
 
 
Aduro Biotech, Inc. 
740 Heinz Avenue 
Berkeley, CA 94710 USA 
Telephone: +1 510-848-4400 
 
 
 
Confidentiality Statement 
The information in this document is the confidential information of Aduro Biotech, Inc. Disclosure of this 
document is subject to an agreement between you or your institution and Aduro Biotech, Inc. When using 
this document: 
- Limit disclosure to the Institutional Review Board or Independent Ethics Committee and study 
personnel directly involved with conducting this protocol. 
- Inform the recipient of the confidential nature of this document and limit its use to the conduct of 
the study. 
- Direct any questions to Aduro Biotech, Inc. 

Aduro Biotech, Inc. 
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1 
SYNOPSIS 
TITLE: A Phase 2, Open-label Evaluation of CRS-207 and Pembrolizumab in Adults with 
Recurrent or Metastatic Gastric, Gastroesophageal Junction, or Esophageal Adenocarcinomas 
PROTOCOL NUMBER: ADU-CL-14 
INVESTIGATIONAL PRODUCTS:  
CRS-207 (live, attenuated, double-deleted Listeria monocytogenes encoding human mesothelin [Lm 
ΔactA/ΔinlB hMeso])  
Pembrolizumab (MK-3475) 
PHASE: 2 
SITES: Approximately 10 – 15 sites planned in the United States  
INDICATION: Treatment of patients with recurrent or metastatic gastric, gastroesophageal 
junction (GEJ), or esophageal adenocarcinomas following prior systemic chemotherapy 
OBJECTIVES: 
The objectives of the study are to evaluate CRS-207/pembrolizumab when administered to subjects 
with recurrent or metastatic gastric, GEJ, or esophageal adenocarcinomas with respect to: 
• Safety and tolerability 
• Tumor response and survival 
• Characterization of immune responses, biomarker expression, and molecular characteristics of the 
tumor microenvironment 
STUDY DESIGN: 
The study is an open-label, single-arm, multicenter clinical study in approximately 79 adults with 
recurrent or metastatic gastric, GEJ, or esophageal adenocarcinomas who have received one or two 
prior systemic chemotherapy treatment regimens for advanced disease.  Of the approximately 79 
evaluable subjects, the study will seek to enroll approximately 50 subjects with gastric/GEJ 
adenocarcinomas and approximately 29 subjects with esophageal adenocarcinoma to achieve 
adequate representation of each tumor type. 
The study design consists of a 28-day Screening Period, Treatment and Evaluation Period (including 
a Safety Run-in), and a Follow-up Period. CRS-207 and pembrolizumab will be administered in 3-
week cycles.  For Cycle 1, pembrolizumab (200 mg) will be administered by intravenous infusion 
(IV) over 30 minutes on Day 1 and CRS-207 (starting dose 1 × 109 colony-forming units [CFU]) 
will be administered IV over 1 hour on Day 2.  If the infusions are well tolerated, pembrolizumab 
and CRS-207 may be administered on the same day (Day 1) for subsequent cycles. After 4 cycles, 
pembrolizumab will continue to be administered on Day 1 at each treatment cycle (every 3 weeks; 
Q3W), and CRS-207 will be administered once every 6 weeks (i.e. every other treatment cycle; 
Q6W). Treatment cycles will continue for up to 24 months as long as there is adequate safety and 
potential for clinical benefit. If radiographic disease progression is observed, clinically stable 

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subjects who meet dosing eligibility may continue to receive CRS-207 and pembrolizumab 
according immune-related Response Criteria in Solid Tumors (irRECIST) guidelines in Section 11. 
Subjects who experience an unacceptable toxicity directly attributable to either pembrolizumab or 
CRS-207 may continue on study and receive either pembrolizumab or CRS-207 as single agent 
study treatment with approval by the Medical Monitor. Alternatively, study drug administration may 
revert back to consecutive day-dosing regimen as performed in Cycle 1 (Day 1 pembrolizumab and 
Day 2 CRS-207). 
The Treatment and Evaluation Period is defined as the time from Day 1 until discontinuation of both 
CRS-207 and pembrolizumab, completion of an End-of-Treatment (EOT) Visit, and documented 
disease progression.  
Blood will be collected at EOT to assess clearance of CRS-207 and at 
 
.  The EOT Visit will occur no more 
than 28 days after the last dose of study drug. If the subject has discontinued CRS-207 but continues 
on pembrolizumab, the subject will be asked to come back to the clinic for CRS-207 blood cultures 
. If 
the subject begins another anticancer therapy before the end of the 28-day period, all EOT Visit 
assessments should be completed prior to commencing the new therapy. Unresolved adverse events 
(AEs) will be monitored until resolution or confirmed stability of the event. Subjects that 
discontinue all study drugs and complete the EOT without documented progressive disease (based 
on Response Evaluation Criteria in Solid Tumors [RECIST v1.1]) will be asked to complete 
Evaluation Visits for tumor imaging every 6 weeks until documented disease progression or start of 
another anticancer therapy.  To eliminate any potentially residual CRS-207, subjects will be 
administered a 7-day course of antibiotics beginning at the EOT visit or 7 days after the last dose of 
CRS-207 (for patients continuing on pembrolizumab) and prior to receiving any subsequent cancer-
related therapy.  
At the end of the Treatment and Evaluation Period subjects will enter the Follow-up Period of the 
study and will be followed for survival and subsequent cancer-related therapies every 12 weeks until 
death or close of study by the Sponsor. The Sponsor may request survival status be assessed at 
additional time points during the course of the study. Sites will attempt to obtain vital status data 
from public records or other external sources where possible if a subject withdraws consent from 
study (i.e. refuse follow-up for vital status) or is documented as lost to follow up. Follow-up will 
continue for at least 12 months from last dose of study drug. 
ADU-CL-14 Study Schematic 

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A Safety Run-in will be completed since there are no precedent data on the use of pembrolizumab 
with CRS-207. Subjects will be monitored for unacceptable toxicity during the first 28 days 
(through 7 days after the Cycle 2 dose). During the Safety Run-in evaluable subjects are defined as 
those who remain on study for the 28-day monitoring period, subjects with unacceptable toxicity, 
and subjects who are discontinued for safety reasons at the Investigator’s discretion (even if criteria 
for unacceptable criteria are not met). Treatment of the first 6 subjects that are followed for the 28-
day period will be staggered with no more than 1 subject treated per week. In the event that 4 in up 
to 12 safety-evaluable subjects experience an unacceptable toxicity, the subsequent cohort of 12 
subjects enrolled will be administered CRS-207 at a dose reduced by a half-log (dose level -1). In 
the event of 4 subjects in up to the next 12 safety-evaluable subjects enrolled experience an 
unacceptable toxicity, the subsequent cohort of 12 subjects enrolled will be administered a reduced 
dose of CRS-207 (dose level -2). For each dose reduction (to a minimum of 1 × 108 CFU) the first 
12 subjects will be treated and unacceptable toxicities assessed as described above. No adjustments 
will be made to the pembrolizumab dose.   
Safety data and all unacceptable toxicities will be reviewed by a Safety Review Team (SRT) 
comprised of participating investigators in the study, the Medical Monitor, and Sponsor 
representatives. Once the Safety Run-in is complete, safety will continue to be evaluated on an 
ongoing basis in this open-label study. Cumulative clinical experience with CRS-207 and 
pembrolizumab will be used to assess whether AEs are considered expected.  
The Schedule of Events is provided in Table 1-1. Subjects who experience tolerability issues with 
same-day dosing may continue to follow the consecutive-day dosing regimen as in Cycle 1 with 
Day 1 pembrolizumab followed by Day 2 CRS-207 dosing (Table 1-2). 
Tumor imaging and evaluation will be assessed at Screening and during the Treatment and 
Evaluation Period approximately every 6 weeks after initiation of study drug. Tumor measurement 
and assignment of response will be determined by local Investigators. For subjects on treatment 
more than 12 months, the frequency of imaging may be reduced to every 12 weeks. Peripheral blood 
will be collected to assess immune responses directed against Listeria monocytogenes (Lm), 
mesothelin, and other tumor-associated antigens. Archived tumor tissue and paired tumor biopsies 
(collected at Screening and during Cycle 2) will be used to explore the association of programmed 
death receptor ligand-1 (PD-L1) expression, mesothelin expression, and tumor-infiltrating 
lymphocyte (TIL) characteristics with clinical responses. 
INCLUSION AND EXCLUSION CRITERIA: 
Inclusion Criteria 
Individuals eligible to participate in this study must meet all of the following criteria: 
1. Aged 18 years or older 
2. Diagnosis with confirmed histology (pathology report required) of one or more of the following: 
• Histologically-confirmed gastric or GEJ adenocarcinoma (Siewert type II/III 
classification) 
[GEJ adenocarcinoma will be defined as primary tumor site within 5 cm proximal and 
distal of anatomic cardia]  
Or 

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• Histologically-confirmed inoperable superior, medial, or distal third esophageal 
adenocarcinoma (Siewert type I classification may be included, provided there is no 
mixed histology) 
3. Confirmed recurrent or metastatic disease 
4. Received and experienced disease progression on, or following one or two prior chemotherapy 
regimens for advanced disease. Prior treatment must have included a platinum and a 
fluoropyrimidine. 
5. HER-2/neu negative or, if HER-2/neu positive, disease must have previously progressed on 
treatment with trastuzumab 
6. Measurable/assessable disease, as defined by RECIST v1.1. Target lesions situated in a 
previously irradiated area are considered measurable if progression has been demonstrated in 
such lesions. 
7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 
8.  Can provide the following tissue for PD-L1 and mesothelin biomarker analysis: 
• Archived primary tumor tissue (tissue from metastatic site acceptable if archived primary 
tissue is not available and primary site is not accessible for biopsy) 
• Pre-Treatment biopsy of either primary tumor or metastatic site 
• On-Treatment biopsy at Cycle 2, Day 15 
9. Adequate organ and marrow function at Screening, as defined by: 
Hematologic 
Renal 
Hepatic 
WBC ≥ 3000/µL 
ANC ≥ 1500/µL 
ALC ≥ 800/µL 
Platelets ≥ 100,000/µL 
Hemoglobin  ≥ 9 g/dL 
Albumin ≥ 3.0 g/dL 
INR or PT ≤ 1.5 × ULN 1 
aPTT ≤ 1.5 × ULN 1 
Creatinine ≤ 1.5 × ULN; or 
measured /calculated creatinine 
clearance ≥ 60 mL/min if 
creatinine levels >1.5× ULN  
AST/ALT ≤ 2.5 × ULN; or  
≤5 × ULN for subjects with liver metastases  
Total bilirubin ≤ 1.5 × ULN; or  
≤ 3 × ULN if due to Gilbert’s disease; or 
direct bilirubin ≤ ULN if total bilirubin > 1.5 × 
ULN 
ALC = absolute lymphocyte count; ALT = alanine aminotransferase; ANC = absolute neutrophil count; aPTT = 
activated partial thromboplastin time; AST = aspartate aminotransferase; INR = international normalized ratio PT = 
prothrombin time; ULN = institutional upper limit of normal; WBC = white blood cell 
1 If receiving anticoagulant therapy, values should be within therapeutic range of intended use 
Any Grade 3 or higher abnormality in any serum chemistry or hematology parameter should be 
discussed and approved by the Medical Monitor prior to enrollment (even if considered not clinically 
significant) 
10. Women of childbearing potential (WOCBP) and fertile males with WOCBP partners must use 
highly effective contraception (CTFG, 2014) throughout the Treatment and Evaluation Period 
(from first dose and through 120 days after final dose of study drug). Contraception must 
include at least one barrier method to minimize risk of fluid transmission. 

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11. Provide written informed consent and is willing and able to comply with all study procedures. 
Exclusion Criteria 
Individuals who meet any of the following exclusion criteria will not be eligible to participate in the 
study: 
1. Diagnosis of squamous or undifferentiated gastric cancer 
2. Individuals with inaccessible tumors or for whom biopsy is contraindicated  
3. Participated in any other study in which receipt of an investigational new drug or investigational 
device occurred within 28 days of first dose of study drug 
4. Diagnosis of immunodeficiency, receiving TNF pathway inhibitors, PI3 kinase inhibitors, 
chronic systemic steroid therapy (> 10 mg/day of prednisone or equivalent) or any other form of 
immunosuppressive therapy within 7 days prior to the first dose of study drug 
5. Clinical evidence of ascites by physical exam 
6. Prior anti-cancer monoclonal antibody within 4 weeks prior to first dose of study drug or has not 
recovered from adverse effects due to agents administered more than 4 weeks earlier 
7. Prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior 
to first dose of study drug, or has not recovered from adverse effects (i.e. ≤ Grade 1 or baseline) 
from adverse effects due to a previously-administered agent 
Note:  Subjects with ≤ Grade 2 neuropathy or ≤ Grade 2 alopecia are an exception to this 
criterion. 
8. Active second malignancy with the exception of any of the following: 
• Adequately treated basal cell carcinoma  
• Squamous cell carcinoma of the skin, or in situ cervical cancer 
• Low-risk prostate cancer (i.e. Gleason score < 7 and prostate specific antigen < 10 
ng/mL); or 
• Any other cancer from which the individual has been disease-free for ≥ 3 years 
9. Received transfusion of blood products (including platelets or red blood cells) or administration 
of colony stimulating factors (including G-CSF, GM-CSF or recombinant erythropoietin) within 
4 weeks prior to first dose of study drug. 
10. Active infection requiring systemic therapy 
11. Known active central nervous system metastases and/or carcinomatous meningitis. Subjects 
with previously treated brain metastases may participate provided they are stable (without 
evidence of progression by imaging at least 4 weeks prior to the first dose of study drug and 
neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain 
metastases, and are not using steroids for at least 7 days prior to first dose of study drug. This 
exception does not include carcinomatous meningitis which is excluded regardless of clinical 
stability. 
12. History of (non-infectious) pneumonitis that required steroids, or current pneumonitis 
13. History of interstitial lung disease 

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14. Prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent, or agents targeting other 
checkpoint pathways (e.g. CTLA-4, LAG-3, GITR, OX40), or prior participation in Merck MK-
3475 clinical trials 
15. Prior immunotherapy with CRS-207 or any other Listeria-based agent, therapeutic cancer 
vaccine, adoptive T cell immunotherapy 
16. Major surgery or significant traumatic injury occurring within 28 days prior to first dose of 
study drug 
Note:  If major surgery occurred > 28 days prior to first dose of study drug, individual must have 
recovered adequately from the toxicity and/or complications from the intervention prior to first 
dose of study drug  
17. Previous treatment with >2 systemic chemotherapy regimens for advanced disease 
18. Known allergy to both penicillin and sulfa antibiotics 
19. Unable or unwilling to withhold or discontinue any prohibited or restricted 
medications/procedures/immunizations for the specified windows during the study 
20. If WOCBP, pregnant or breastfeeding; negative pregnancy status must be confirmed within 24 
hours of first dose of study drug 
21. Known valvular heart disease that requires antibiotic prophylaxis for prevention of endocarditis 
22. Clinically significant heart disease (such as uncontrolled angina, myocardial infarction within 3 
months of study initiation, congestive heart failure, or New York Heart Association Class III or 
IV heart failure) 
23. History of autoimmune disease that has required systemic treatment in the past 2 years, 
including:  
• Inflammatory bowel disease (including ulcerative colitis and Crohn’s Disease) 
• Rheumatoid arthritis 
• Systemic progressive sclerosis (scleroderma) 
• Systemic lupus erythematosus 
• Autoimmune vasculitis (e.g. Wegener’s granulomatosis) 
• Central nervous system or motor neuropathy considered of autoimmune origin (e.g. 
Guillain-Barre syndrome, myasthenia gravis, multiple sclerosis) 
Note: Individuals with vitiligo, Sjogren’s syndrome, interstitial cystitis, Graves’ or Hashimoto’s 
Disease, celiac disease, diabetes mellitus type 1, or hypothyroidism stable on hormone 
replacement will be allowed with Medical Monitor approval. 
24. Intercurrent illness that is either life-threatening or of clinical significance such that it might 
limit compliance with study requirements or in the Investigator’s assessment would place the 
subject at an unacceptable risk for study participation; 
25. Received a diagnosis of human immunodeficiency virus (HIV) 
26. Received a diagnosis of hepatitis B, or hepatitis C for which there is no clear evidence of natural 
immunity, immunity subsequent to vaccination, or successful eradication of the virus following 

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antiviral therapy (individuals who are hepatitis C antibody positive may be enrolled if negative 
viral load confirmed at screening) 
27. Subjects who have 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 that were placed more than 3 months prior to first dose of 
study drug.  
28. Prior severe hypersensitivity (≥ Grade 3) to CRS-207, pembrolizumab, or any study drug 
excipients (e.g. yeast, glycerol) 
29. Unhealed wound  
30. History or evidence of inherited bleeding diathesis or coagulopathy 
31. Received any prophylactic vaccine within 14 days of first dose of study drug or received a live 
vaccine within 30 days of planned start of study therapy. Seasonal flu vaccines that do not 
contain a live virus are permitted. 
DURATION OF SUBJECT PARTICIPATION: 
The Screening Period may last up to 4 weeks. The duration of 1 treatment cycle is 3 weeks. Subjects 
may continue to receive CRS-207/pembrolizumab for up to 24 months. After EOT or 7 days after 
last dose of CRS-207,
 
. Subjects will be observed for survival for at least 12 months from 
last dose of study drug. At the conclusion of the study, all remaining subjects in the Follow-up 
Period will be offered enrollment in a long-term observational study for survival. 
DOSAGE FORMS AND ROUTE OF ADMINISTRATION: 
CRS-207 is formulated as 1 × 109 CFU suspended in 
 
, filled into a single-use 2-mL glass vial with a gray butyl stopper and aluminum 
crimp seal with a flip off cap. 1.0 mL of CRS-207 is diluted in sterile saline and administered by IV 
infusion over approximately 1 hour.  
Pembrolizumab for injection is a sterile, preservative-free, clear to slightly opalescent, colorless to 
slightly yellow solution. Each vial contains 100 mg/4 mL (25 mg/mL) solution in a single-use vial. 
Each 1 mL of solution contains 25 mg of pembrolizumab formulated in L-histidine (1.55 mg), 
polysorbate 80 (0.2 mg), sucrose (70 mg), and Water for Injection, USP. Pembrolizumab will be 
diluted in sterile saline administered at a dose of 200 mg via IV infusion over 30 minutes. 
EFFICACY CRITERIA FOR EVALUATION: 
Efficacy assessments will include a baseline tumor assessment by radiographic imaging to be 
performed within 28 days of starting study drug treatment, and repeat assessments approximately 
every 6 weeks after initiation of study drug using the same assessment technique (preferably by CT 
with contrast or magnetic resonance imaging (MRI) in case of contrast dye allergy). Tumor 
response will be assessed by investigators using RECIST v1.1 and irRECIST. Survival data will be 

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collected at least every 12 weeks after the EOT Visit for at least 12 months from the initiation of 
study drug. 
Primary Efficacy Variable: 
• Objective response rate (ORR), defined as the proportion of subjects with complete response 
(CR) or partial response (PR) as measured by RECIST v1.1 
Secondary Efficacy Variables: 
• Disease control rate (DCR), defined as the percentage of subjects with CR, PR, or stable disease 
(SD) per RECIST v1.1 
• Progression-free survival (PFS) defined as time from first dose of study drug until disease 
progression or death   
• Duration of response (DOR) 
• Overall survival (OS), as measured from date of first dose of study drug until death 
TUMOR TISSUE AND BIOMARKER ANALYSES: 
PD-L1 and mesothelin expression along with additional markers of biological and immunological 
activity may be evaluated to explore the relationship to clinical response.  
Archived primary tumor tissue will be collected for all enrolled subjects, when possible.  Paired 
tumor biopsies of primary tumor or metastases (pre-treatment and on Cycle 2 Day 15) are required. 
If at Cycle 2 a subject’s tumor is thought to be unsafe for biopsy by the Investigator, the site must 
discuss with the Medical Monitor.  
Tumor tissue samples will be used to perform the following immunological and tumor biomarker 
analyses: PD-L1 status and mesothelin status; phenotyping and characterization of TILs and tumor 
microenvironment, functional genomic analyses, and T cell receptor (TCR) sequencing.  
Baseline and longitudinal immune analysis of peripheral blood will be performed including immune 
cellular, molecular and genomic phenotyping and functional responses. Circulating proteins 
(cytokines, chemokines, tumor biomarkers and antibody responses) including mesothelin, 
carcinoembryonic antigen (CEA), vascular endothelial growth factor (VEGF), and cancer antigen 
19-9 (CA19-9) will be assessed in serum and/or plasma.  
Humoral and cellular immune responses directed against Lm, mesothelin, and other tumor-
associated antigens may be evaluated by multiple approaches, including using enzyme-linked 
immunospot (ELISPOT), intracellular cytokine staining, and enzyme-linked immunosorbent assay 
(ELISA).  
Additional exploratory immune and biomarker analyses on tumor tissue, peripheral blood 
mononuclear cells, serum, and plasma may be conducted. 
SAFETY VARIABLES: 
Safety parameters include serious adverse events (SAEs), treatment-emergent adverse events 
(TEAEs), infusion-related reactions, ECOG performance status, vital sign measurements, standard 
clinical laboratory parameters (serum chemistry, hematology, coagulation, thyroid function, and 
urinalysis), electrocardiogram (ECG) parameters, and blood cultures for CRS-207 clearance. AEs 

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will be graded according to the National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events (CTCAE v4.03). 
STATISTICAL ANALYSES 
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, 
Q1, Q3, and minimum and maximum values. The descriptive summaries of time to event data will 
include median, 25th and 75th percentiles, and standard error. All data will be listed for all subjects. 
This study is descriptive in nature; no formal hypothesis testing will be performed. All confidence 
intervals (CIs) will be 95%, unless stated otherwise. 
The final analysis will be performed after all subjects have completed at least 6 cycles of treatment 
or discontinued study treatment and completed the EOT Visit. A supplemental analysis may be 
completed at the end of study that includes the cumulative data collected after the final analysis (i.e. 
through the Follow-up Period). 
Safety Set (SAF) includes all subjects who received any study treatment (pembrolizumab or CRS-
207). The SAF will be used for all analyses of safety data and may be used for select biomarker 
data. 
Full Analysis Set (FAS) is defined as all subjects who received at least 1 dose of CRS-207. The 
FAS will be used for analysis of OS, immunogenicity and other biomarker data, and sensitivity 
analysis of select tumor-related endpoints. 
Evaluable Analysis Set (EAS) is defined as all subjects who received at least 1 dose of CRS-207 
and have at least one evaluable post-baseline RECIST tumor response assessment or were 
discontinued due to toxicity. The EAS will be the primary analysis set for the analyses of tumor-
related endpoints (ORR, DCR, DOR, and PFS). 
AE data will be coded to system organ class and preferred term using Medical Dictionary for 
Regulatory Activities (MedDRA; Version 18.1, or later). The number and percentage of subjects 
experiencing any TEAE, overall, and by system organ class and preferred term will be tabulated. 
The incidence rates adjusted by cumulative exposure will also be presented overall and by cycle. 
AEs associated with clinical laboratory parameters will be characterized according to NCI CTCAE, 
Version 4.03. Shifts in toxicity grades from baseline to each visit will be summarized.   
Disease responses as determined by RECIST will be summarized by response level at each visit and 
best overall response. The ORR and DCR, along with a 95% CI will be summarized. PFS, DOR, 
and OS will be summarized using Kaplan-Meier methods. 
SAMPLE SIZE DETERMINATION 
This study is descriptive in nature, as such the sample size for this study is determined by practical 
rather than statistical considerations. Approximately 79 subjects will be enrolled with evaluable 
post-baseline tumor data. With 79 subjects, the precision for point estimate for ORR is as follows: 
the 95% CI width for ORR based on Wilson score intervals are at most the observed proportion +/- 
0.108.  If the observed ORR = 30.4% (24 of 79 subjects with PR or CR), the lower bound of the 
95% CI would be 19.5%. 

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Table 1-1 
Schedule of Events: Same-day (D1) Dosing Regimen 
Study Phase 
Screen 
Cycle 1 [1] 
 
Cycle 2 [1] 
Cycle 3 [1] 
Cycle 4 
[1] 
Cycle 5 and all 
future odd 
numbered 
cycles [1] 
Cycle 6 and all 
future even 
numbered 
cycles [1] 
EOT 
[2] 
Follow-
up 
 
Study Day 
-28 to -1 
1 
2 
3 
7 
1 
2 
7 
15 
1 
2 
7 
1 
7 
1 
1 
±7 
 
Visit Window (days) 
- 
- 
- 
- 
±1 
±3 
±1 
±1 
-7 
±3 
±1 
±
1 
±3 
±1 
±3 
±3 
Study Procedures 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History, Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Archived Tumor Specimen [3] 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor Biopsy [4] 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
CT Tumor Evaluation [5] 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
X 
 
Survival, additional treatment [6] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
ECOG Performance Status 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
X 
X 
X 
 
Vital Signs, Pulse Oximetry [7,19, 
20] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Physical Examination and Weight [8] 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
X 
X 
X 
 
Adverse Events [9] 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant Medications 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Electrocardiogram [10] 
X 
X 
X 
 
 
X 
 
 
 
X 
 
 
X 
 
X 
X 
X 
 
Laboratory Sample Collection [11] 
Virology Screen [12] 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CD4 and CD8 Counts [13] 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Thyroid Function [14] 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
X 
 
Hematology, Chemistry [15] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Coagulation Panel [15, 16] 
X 
X 
X 
 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
X 
 
Urinalysis 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
 
X 
 
Pregnancy Test [17] 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
X 
X 
X 
 
HLA-typing [13] 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Whole Blood for PBMC [18] 
 
X 
 
 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
 
Serum and Plasma for immune 
monitoring [18] 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Blood for CRS-207 Surveillance [19] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Study Medications 
Pembrolizumab [20] 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
X 
X 
 
 
CRS-207 [21] 
 
 
X 
 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
Antibiotics (with diary) [22] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 

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Table 1-2 
Schedule of Events: Consecutive-day (Day 1 and 2) Dosing Regimen (for Subjects with Tolerability Issues) 
Study Phase 
Screen 
Cycle 1 [1] 
 
Cycle 2 [1] 
Cycle 3 [1] 
Cycle 4 [1] 
Cycle 5 
and all 
future odd 
numbered 
cycles [1] 
Cycle 6 
and all 
future even 
numbered 
cycles [1] 
EOT 
[2] 
Follow
-up 
 
Study Day 
-28 to -1 
1 
2 
3 
7 
1 
2 
3 
7 
15 
1 
2 
3 
7 
1 
2 
7 
1 
1 
2 
±7 
 
Visit Window (days) 
- 
- 
- 
- 
±1 
±3 
- 
±1 
±1 
-7 
±3 
- 
±
1 
±1 
±3 
- 
±1 
±3 
±3 
- 
Study Procedures 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History, Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Archived Tumor Specimen [3] 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor Biopsy [4] 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
CT Tumor Evaluation [5] 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
X 
 
Survival, additional treatment [6] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
ECOG Performance Status 
X 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
X 
X 
 
X 
 
Vital Signs, Pulse Oximetry [7,19,20] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Physical Examination and Weight [8] 
X 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
X 
X 
 
X 
 
Adverse Events [9] 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant Medications 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Electrocardiogram [10] 
X 
X 
X 
 
 
X 
X 
 
 
 
X 
X 
 
 
X 
X 
 
X 
X 
X 
X 
 
Laboratory Sample Collection [11] 
Virology Screen [12] 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CD4 and CD8 Counts [13] 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Thyroid Function [14] 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
X 
 
Hematology, Chemistry [15] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Coagulation Panel [15, 16] 
X 
X 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
Urinalysis 
X 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
Pregnancy Test [17] 
X 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
X 
X 
 
X 
 
HLA-typing [13] 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Whole Blood for PBMC [18] 
 
X 
 
 
X 
X 
 
 
X 
X 
X 
 
 
X 
X 
 
X 
 
X 
 
X 
 
Serum and Plasma for immune 
monitoring [18] 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Blood for CRS-207 Surveillance [19] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Study Medication 
Pembrolizumab [20] 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
X 
X 
 
 
 
CRS-207 [21] 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
Antibiotics (with diary) [22] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 

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FOOTNOTES FOR Table 1-1 AND Table 1-2 
1. CRS-207 administered each cycle for 4 cycles (i.e. Cycles 1-4) and then every 6 weeks (i.e. every other cycle) beginning Cycle 5 and beyond. Treatment with 
pembrolizumab may continue up to 24 months. After Cycle 4, initiation of a new cycle may be delayed up to 3 days due to subject scheduling.  
2. EOT Visit will occur within 28 days (±7 days) after the last dose of study drug or prior to commencing the new therapy. If an AE requires monitoring beyond 
the EOT Visit, follow until resolution or confirmed stability of the event. After the EOT Visit, 
 
 
3. Archived Tumor Specimen of primary tumor is required and obtained prior to enrollment.  Tissue from metastatic site acceptable if archived primary tissue is 
not available and primary site is not accessible for biopsy. 
4. Tumor Biopsies must be processed for analysis as described in Laboratory Manual. Cycle 2 Day 15 biopsy should not be collected until at least 7 days have 
passed since CRS-207 administration, but no later than Day 15 of cycle to allow sufficient recovery time prior to CRS-207 administration. Fine needle 
aspiration is not acceptable. If additional biopsies are obtained during study period for any reason, residual tissue should be retained for Sponsor analysis. 
5. Tumor Evaluation using CT with contrast (or MRI in case of contrast dye allergy) of the chest, abdomen and pelvis within 28 days prior to first dose of study 
drug, and repeated using the same assessment technique. For subjects on treatment more than 12 months, imaging may be reduced to 12 week intervals. 
Subjects that discontinue all study drugs and complete the EOT without documented PD will be asked to complete Evaluation Visits for tumor evaluation 
every 6 weeks until documented PD or start of another anticancer therapy. Response assessment performed using RECIST v1.1 and irRECIST. 
6. Survival Follow up:
 
. A telephone contact should also be scheduled at 
least 90 days post-treatment discontinuation to satisfy reporting requirements for SAEs and events of clinical interest. 
7. Vital Signs and Pulse Oximetry: BP, pulse, respiratory rate, and temperature are collected at indicated visits without drug administration.  
8. Physical Exam and Weight: Complete physical examinations conducted at screening and EOT; symptom-directed physical examinations conducted on Day 1 
of all other cycles. Assessment may be done up to 72 hours prior to visit. 
9. Follow-up contact for AEs and concomitant medications will be conducted 1 day after each CRS-207 infusion (and one day after pembrolizumab infusions 
Cycle 5 and beyond where CRS-207 is not administered).  Contact must be documented in the study records. 
10. Electrocardiogram: For visits where pembrolizumab and CRS-207 are administered consecutively (Day 1 and Day 2), routine 12-lead ECGs will be 
performed prior to each infusion, immediately after the infusion, and at 1-hour post infusion. For visits where pembrolizumab and CRS-207 are administered 
on the same day, routine 12-lead ECGs will be performed prior to pembrolizumab infusion, immediately after pembrolizumab infusion, immediately after 
CRS-207 infusion, and at 1-hour post CRS-207 infusion. If abnormal at 1-hour post-infusion, repeat until baseline achieved. Beginning at Cycle 6 frequency 
may be reduced to every 12 weeks unless clinically indicated. 
11. BLOOD DRAWS MUST NOT BE COLLECTED FROM A CENTRAL LINE FOR AT LEAST 4 DAYS AFTER INFUSION OF CRS-207 
12. Virology screen includes: HIV antibody, hepatitis B surface antigen, and hepatitis C antibody; additional virology may also be evaluated. Subjects who are 
hepatitis C antibody positive and confirmed negative viral load at screening will be allowed to enroll. 
13. CD4 and CD8 Counts and HLA typing are performed by central laboratory. Collection is described in the Laboratory Manual. If HLA sample is rejected for 
analysis, an additional sample may be collected at a later time point 
14. Thyroid panel should be collected during ODD NUMBERED cycles only (i.e. every 6 weeks). Blood draws may be taken up to 72 hours before each required 
dosing cycle. Unresolved abnormal labs considered drug related AEs should be followed until resolution. Panel not required at EOT if labs are within normal 
range during treatment. 
15. Hematology, serum chemistry: Blood draws may be taken up to 72 hours before each dosing cycle where study drug is administered.  

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16. Coagulation Panel may be repeated at same frequency as hematology/serum chemistry if clinically indicated; beginning at Cycle 6 frequency may be reduced 
to every 12 weeks unless clinically indicated.  
17. Pregnancy Test: Serum pregnancy test required at screening, and urine pregnancy tests are required before doses on Day 1 of each cycle and EOT for 
WOCBP. 
18. Whole blood for PBMC and Serum and plasma for immune monitoring collected and processed per Laboratory Manual. Samples should be collected prior to 
study drug administration. Cycle 2 Day 15 collection should be taken on day of biopsy. Additional samples may be collected at Investigator’s discretion. 
19. Blood for CRS-207 Surveillance will be collected at EOT or 7 days after last CRS-207 dose to assess clearance of CRS-207. Obtain sample(s) prior to 
initiation of antibiotics (blood must additionally be collected from the central venous access device if applicable). After last dose of CRS-207, blood will 
continue to be collected at 
. Collection and shipment are described in the Laboratory Manual. 
20. Pembrolizumab will be administered via IV infusion for 30 minutes. Obtain vital signs (BP, pulse, respiratory rate, temperature) prior to, and immediately 
following each pembrolizumab infusion. Pembrolizumab may be administered up to 3 days before or after the scheduled Day 1 of each cycle due to 
administrative reasons. If subjects on same-day dosing schedule experience severe infusion-related reactions related to the pembrolizumab infusion, the CRS-
207 infusion may be delayed to Day 2. 
21. CRS-207 will be administered as indicated via IV infusion over approximately 1 hour. Obtain vital signs (BP, pulse, respiratory rate, temperature) every 
30 minutes during infusion and every hour during post-infusion follow-up. Subjects should be observed at least 4 hours after the first infusion and every cycle 
where there is a change in dose or dosing regimen. For all subsequent infusions observe subjects for at least 2 hours post infusion. Subjects may be released 
once they are considered stable; fever alone does not preclude release. 
22. 
 
 
ABBREVIATIONS FOR Table 1-1 AND Table 1-2 
AE = adverse event; BP = blood pressure; CT = computed tomography; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EOT = 
End-of-Treatment; HIV = human immunodeficiency virus; HLA = human leukocyte antigen; irRECIST = immune-related RECIST; IV = intravenous; Lm 
= Listeria monocytogenes; MRI = magnetic resonance imaging; PBMC = peripheral blood mononuclear cells; 
; RECIST = 
response evaluation criteria for solid tumors; WOCBP = women of child-bearing potential. 
 

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2 
TABLE OF CONTENTS 
1 
SYNOPSIS .......................................................................................................................... 2 
2 
TABLE OF CONTENTS .................................................................................................. 15 
LIST OF TABLES .................................................................................................................. 18 
LIST OF FIGURES ................................................................................................................ 18 
3 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ..................................... 19 
4 
INTRODUCTION ............................................................................................................ 22 
4.1 
CRS-207 Immunotherapy ........................................................................................... 22 
4.1.1 Listeria monocytogenes-Based Immunotherapy ................................................... 22 
4.1.2 CRS-207 ................................................................................................................ 23 
4.1.3 Summary of Nonclinical Studies with CRS-207 .................................................. 24 
4.1.4 Summary of Clinical Studies with CRS-207 ........................................................ 24 
4.2 
Pembrolizumab in Gastric, Gastroesophageal Junction, and Esophageal 
Adenocarcinomas ........................................................................................................ 25 
4.3 
Rationale for CRS-207 and Pembrolizumab Immunotherapy in Gastric, 
Gastroesophageal, and Esophageal Adenocarcinomas ............................................... 26 
4.3.1 CRS-207 Dose Selection Rationale ...................................................................... 27 
4.3.2 Pembrolizumab Dose Selection Rationale ............................................................ 27 
5 
STUDY OBJECTIVES ..................................................................................................... 29 
6 
INVESTIGATIONAL PLAN ........................................................................................... 30 
6.1 
Study Design and Duration ......................................................................................... 30 
6.1.1 Discussion of Study Design .................................................................................. 32 
6.2 
Study Population ......................................................................................................... 33 
6.2.1 Inclusion Criteria .................................................................................................. 33 
6.2.2 Exclusion Criteria ................................................................................................. 34 
6.2.3 Dosing Eligibility and Delayed Dosing ................................................................ 37 
6.2.4 Subject Discontinuation ........................................................................................ 37 
6.3 
Study Treatments and Additional Medications........................................................... 39 
6.3.1 Safety Run-In Period............................................................................................. 39 
6.3.2 Method of Assigning Subjects to Treatment ........................................................ 41 
6.3.3 Blinding................................................................................................................. 41 

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6.3.4 Investigational Product: CRS-207 ........................................................................ 41 
6.3.5 Investigational Product:  Pembrolizumab ............................................................. 43 
6.3.6 Antibiotics ............................................................................................................. 49 
6.3.7 Concomitant Medications and Procedures............................................................ 51 
6.3.8 Prohibited Medications and Procedures ................................................................ 51 
6.3.9 Treatment Compliance .......................................................................................... 52 
6.4 
Study Assessments and Procedures ............................................................................ 52 
6.4.1 General Assessments ............................................................................................ 53 
6.4.2 Efficacy Measures ................................................................................................. 55 
6.4.3 Safety Assessments ............................................................................................... 56 
6.4.4 Laboratory Assessments ....................................................................................... 58 
6.4.5 Appropriateness of Measures ................................................................................ 61 
6.5 
Statistical Analysis ...................................................................................................... 62 
6.5.1 Sample Size Determination................................................................................... 62 
6.5.2 General Considerations ......................................................................................... 63 
6.5.3 Subject Information .............................................................................................. 63 
6.5.4 Analysis Sets ......................................................................................................... 63 
6.5.5 Efficacy Analyses ................................................................................................. 64 
6.5.6 Safety Analyses ..................................................................................................... 65 
6.5.7 Research Laboratory Analyses ............................................................................. 65 
6.5.8 Timing of Analysis ............................................................................................... 66 
6.5.9 Data Monitoring Committee ................................................................................. 66 
7 
ADVERSE EVENT REPORTING AND FOLLOW UP ................................................. 67 
7.1 
Adverse Events ........................................................................................................... 67 
7.1.1 Disease Progression and Other Events of Clinical Interest .................................. 68 
7.1.2 Assessment of Adverse Events by the Investigator .............................................. 69 
7.2 
Serious Adverse Events .............................................................................................. 70 
7.3 
Serious Adverse Event Reporting − Procedures for Investigators.............................. 71 
7.3.1 Initial Reports........................................................................................................ 71 
7.3.2 Safety Reporting Contact Information .................................................................. 72 
7.3.3 Expedited Reporting Requirements ...................................................................... 72 

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7.3.4 Follow-Up Reports................................................................................................ 72 
7.3.5 Adverse Events of Special Interest ....................................................................... 72 
7.4 
Pregnancy Reporting ................................................................................................... 72 
8 
DATA MANAGEMENT AND RECORD KEEPING..................................................... 74 
8.1 
Data Handling ............................................................................................................. 74 
8.2 
Data Entry ................................................................................................................... 74 
8.3 
Medical Information Coding....................................................................................... 74 
8.4 
Data Validation ........................................................................................................... 74 
8.5 
Record Keeping .......................................................................................................... 74 
9 
INVESTIGATOR REQUIREMENTS AND QUALITY CONTROL ............................. 76 
9.1 
Ethical Conduct of the Study ...................................................................................... 76 
9.2 
Investigator Requirements .......................................................................................... 76 
9.2.1 Disposition and Accountability of Investigational Products ................................ 76 
9.3 
Institutional Review Board/Ethics Committee ........................................................... 77 
9.4 
Informed Consent........................................................................................................ 77 
9.5 
Study Monitoring Requirements ................................................................................. 77 
9.6 
Disclosure of Data....................................................................................................... 78 
9.7 
Retention of Records................................................................................................... 78 
9.8 
Publication Policy ....................................................................................................... 78 
9.9 
Financial Disclosure.................................................................................................... 79 
9.10 
Insurance and Indemnity ............................................................................................. 79 
9.11 
Legal Aspects .............................................................................................................. 79 
10 
REFERENCES ................................................................................................................. 80 
11 
IMMUNE-RELATED RESPONSE CRITERIA IN SOLID TUMORS .......................... 83 
SIGNATURE PAGE .................................................................................................................... 87 
INVESTIGATOR AGREEMENT................................................................................................ 88 
 
 
 

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LIST OF TABLES 
Table 1-1 Schedule of Events: Same-day (D1) Dosing Regimen ............................................... 11 
Table 1-2 Schedule of Events: Consecutive-day (Day 1 and 2) Dosing Regimen (for Subjects 
with Tolerability Issues) ............................................................................................. 12 
Table 6-1 Dosing-Eligibility Requirements ................................................................................ 37 
Table 6-2 ADU-CL-14 Study Treatment Course ........................................................................ 39 
Table 6-3 Safety Run-in Dose Levels and Dose Reduction Plan ................................................ 39 
Table 6-4 Dose Modification and Toxicity Management Guidelines for Immune-Related 
Adverse Events Associated with Pembrolizumab ...................................................... 45 
Table 6-5 Pembrolizumab Infusion Reaction Dose Modification and Treatment Guidelines .... 48 
 
LIST OF FIGURES 
Figure 6-1 ADU-CL-14 STUDY DESIGN .................................................................................. 31 
 

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3 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Definition 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALC 
Absolute lymphocyte count 
ANC 
Absolute neutrophil count 
ALT 
Alanine aminotransferase 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
CA19-9 
Cancer antigen 19-9 
CEA 
Carcinoembryonic antigen 
CFR 
Code of Federal Regulations 
CFU 
Colony-forming units 
CI 
Confidence interval 
CR 
Complete response 
CRA 
Clinical research associate 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria For Adverse Events 
DCR 
Disease control rate 
DOR 
Duration of response 
EAS 
Evaluable analysis set 
EBV 
Epstein-Barr virus 
EC 
Ethics committee 
ECG 
Electrocardiogram 
ECI 
Event of clinical interest 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
ELISA 
Enzyme-linked immunosorbent assay 
ELISPOT 
enzyme-linked immunospot 
EOT 
End of Treatment 
EU 
European Union 
FAS 
Full analysis set 
FDA 
United States Food and Drug Administration 
FT3 
free triiodothyronine 
FT4 
free thyroxine 
GCP 
Good Clinical Practice 
G-CSF 
Granulocyte colony-stimulating factor 
GEJ 
gastroesophageal junction 
GM-CSF 
Granulocyte-macrophage colony-stimulating factor 

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Abbreviation 
Definition 
GVAX pancreas 
Irradiated, whole-cell, allogeneic tumor immunotherapy 
HIV 
Human immunodeficiency virus 
HLA 
Human leukocyte antigen 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
IHC 
Immunohistochemistry 
INR 
International normalized ratio of prothrombin time 
IRB 
Institutional Review Board 
irAE 
Immune-related adverse event 
irRECIST 
immune-related RECIST 
IV 
Intravenous 
LADD 
Live, attenuated, double-deleted 
Lm 
Listeria monocytogenes 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHC 
Major histocompatibility complex 
mOS 
Median overall survival 
MRI 
Magnetic resonance imaging 
MSI 
Microsatellite instability 
MTD 
Maximum tolerated dose 
NCI 
National Cancer Institute  
NSCLC 
non-small cell lung carcinoma 
ORR 
Objective response rate 
OS 
Overall survival 
PBMC 
Peripheral blood mononuclear cells 
PD-1 
programmed death receptor-1 
PD-L1 
programmed death receptor ligand 1 
PFS 
Progression-free survival 
PR 
Partial response 
PT 
Prothrombin time 
 
Q3W 
 
Once every 3 weeks 
Q6W 
Once every 6 weeks 
RECIST 
Response evaluation criteria in solid tumors 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SRT 
Safety review team 
T3 
Triiodothyronine 
TIL 
Tumor infiltrating lymphocytes 
TCR 
T cell receptor 

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Abbreviation 
Definition 
TSH 
thyroid stimulating hormone 
ULN 
Upper limit of normal 
VEGF 
Vascular endothelial growth factor 
WBC 
White blood cell 
 

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4 
INTRODUCTION 
In 2015, the National Cancer Institute estimated 16,980 new diagnoses of esophageal cancer and 
24,590 new diagnoses of gastric cancer will occur in the United States (US). Together these 
cancers account for approximately 3% of all new cancer cases. Overall 5-year survival rates are 
approximately 20% for esophageal cancer and 30% for gastric cancer; approximately 50% of 
patients present with unresectable or locally advanced disease at the time of diagnosis (NIH, 
2015). 
Gastric cancer remains the fourth commonest diagnosed cancer and is the second leading cause 
of cancer-related death (Jemal, 2011). Patients with gastric cancer typically present with 
advanced disease. More than 50% of patients undergo surgical resection; however, the majority 
of them relapse locally or with distant metastases. 
With new diagnoses in more than 480,000 patients annually, esophageal cancer is the eighth 
most common cancer worldwide (Siegel, 2015). It is a highly lethal disease, causing more than 
400,000 deaths per year (Ferlay, 2010). The incidence of esophageal adenocarcinoma is rapidly 
rising, whereas that of squamous-cell carcinoma remains unchanged (Parkin, 2001). Despite 
adequate preoperative staging, 25% of patients treated with primary surgery have 
microscopically positive resection margins (R1) and the 5-year survival rate rarely exceeds 40% 
(Devesa, 1998). 
Numerous advances have been made in the management and understanding of gastric and 
esophageal cancer, including improvements in diagnosis, histologic classification, and molecular 
biology. Despite these advances, patients with gastric and esophageal cancer have a poor 
prognosis and there is a clear unmet medical need for new treatment. New therapeutic strategies 
such as immunotherapy are under investigation. 
Several lines of evidence suggest gastroesophageal cancers are good targets for immunotherapy 
(reviewed in Wang, 2016). An association between tumor infiltrating lymphocytes (TIL) and 
survival was first proposed over 100 years ago. Since then numerous studies have shown an 
increased density of TILs (including intratumoral B cells and NK cells) is associated with 
favorable clinical outcomes in gastric and esophageal cancer. In particular, the Epstein-Barr virus 
(EBV) and Microsatellite Instability (MSI) subtypes have been shown to have significant 
immune signatures including increased density of TILs. MSI cancers are also characterized by 
increased mutational load and presentation of neo-antigens. With the significant clinical benefits 
from immune checkpoint blockade drugs, novel opportunities are emerging for immunotherapy 
of gastric and esophageal cancers. 
4.1 
CRS-207 Immunotherapy 
4.1.1 
Listeria monocytogenes-Based Immunotherapy 
Listeria monocytogenes (Lm) is an attractive platform for presentation of tumor-associated 
antigens and activation of immune response directed against cancer cells. Lm provides both a 

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potent stimulation of innate immunity and also induces an adaptive immune response through 
recruitment and activation of CD4+ and CD8+ T-cells specific for encoded heterologous antigens 
(Bahjat, 2006; Portnoy, 2002; Shen, 1995; Slifka, 1996). Repeat dosing with Lm is feasible; 
previously existing anti-Lm immunity did not affect generation of a T cell response to a Lm-
expressed antigen, nor reduce resulting therapeutic efficacy in a mouse B16 melanoma model 
system (Starks, 2004). 
In wild-type form, Lm is a bacterium commonly found in soil and water, and may be present in a 
variety of raw and processed foods. Listeriosis is a foodborne illness caused by wild-type Lm 
which primarily affects pregnant women and immunocompromised individuals. To address this 
safety concern a live, attenuated, double-deleted Lm (LADD) based immunotherapy platform 
was developed (ANZ-100). ANZ-100 has deletions of 2 genes, actA and inlB (Lm ∆actA/∆inlB). 
These genes encode the virulence-determinant proteins ActA and Internalin B, two proteins that 
facilitate cell-to-cell spread and invasion of nonphagocytic cells, in particular hepatocytes 
(Brockstedt, 2004). The deletions limit growth in the liver, a principal target organ of infection 
by wild-type Lm, by blocking direct hepatocyte infection via the InlB-hepatocyte growth factor 
receptor interaction and ActA-mediated cell-to-cell spread into hepatocytes from infected liver-
resident Kupffer cells (Dramsi, 1995; Portnoy, 2002). Uptake of ANZ-100 by macrophages and 
other phagocytic cells in the liver and spleen is retained and results in a local inflammatory 
response as well as activation and recruitment of natural killer cells and T cells to the liver. In 
mice, ANZ-100 retains the immunostimulatory potency of wild-type Lm but with 1000-fold 
attenuation of virulence (Brockstedt, 2004). In a Phase 1 dose-escalation study, ANZ-100 doses 
up to 3 × 108 colony-forming units (CFU) administered by intravenous (IV) infusion in adults 
with carcinoma and liver metastases were well-tolerated (Le, 2012).  
4.1.2 
CRS-207 
Mesothelin is a tumor-associated antigen with limited expression on the surface of normal 
tissues, but highly expressed in many human tumors including virtually all mesothelioma 
(Hassan, 2004). Mesothelin is expressed in 44-50% of human gastric cancer; presence of luminal 
or membranous staining of mesothelin has been correlated with poor patient outcome (Einama, 
2012; Illei, 2016). In esophageal adenocarcinoma, 29-46% of tumors stained positive for 
mesothelin; expression correlated with development of malignancy in cases of Barrett’s 
esophagus (Alvarez, 2008; Rizk, 2012). These features make mesothelin an attractive target for 
active tumor-specific immunotherapy.  
ANZ-100 was subsequently engineered to express mesothelin, resulting in CRS-207 
(Lm ΔactA/ΔinlB/hMeso). CRS-207 contains an expression cassette encoding human mesothelin 
integrated at the inlB locus. After uptake of CRS-207 by dendritic cells and macrophages, 
mesothelin is expressed and released into the cytosolic compartment and subsequently processed 
through the endogenous major histocompatibility complex (MHC) Class I presentation pathway, 
resulting in activation of mesothelin-specific cell-mediated immunity (Le, 2012). Other 
mechanisms to activate mesothelin-specific, cell-mediated immunity may include uptake and 

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cross-presentation of antigens by dendritic cells and other cells after infection by CRS-207 and 
apoptosis. CRS-207 is a LADD construct rendering it greater than 1000-times less toxic in mice 
than wild-type Lm (Brockstedt, 2004). Nonclinical and clinical data are available and support 
continued clinical development. 
4.1.3 
Summary of Nonclinical Studies with CRS-207 
A series of nonclinical studies in rodents (mice) and non-human primates (cynomolgus 
macaques) evaluated the pharmacology, pharmacokinetics (PK) and toxicology of CRS-207. In 
these studies, CRS 207 elicited mesothelin-specific cellular immunity and therapeutic efficacy in 
tumor-bearing mice. Repeated-dose safety studies in cynomolgus macaques with CRS-207 and 
the parent strain, ANZ-100, resulted in an equivalent pro-inflammatory response characterized 
by transient fluctuations in selected hematological and clinical chemistry parameters and 
reversible histopathology. Findings of the repeated-dose studies were consistent with a systemic 
proinflammatory response to a bacterial infection. At the highest dose, CRS-207 was detected in 
the blood 24 hours after administration, but was undetectable at 72 hours. There were transient 
and dose dependent decreases in red blood cell, platelet and white blood cell (WBC) counts. 
Hepatic and renal function changes were transient and generally less than two-fold from 
baseline. There were no discernible additive effects of repeat dosing. 
 
  
Overall, nonclinical studies support use of CRS-207 in humans at the proposed dose. A complete 
summary of nonclinical information on CRS-207 is provided in the Investigator’s Brochure (IB). 
4.1.4 
Summary of Clinical Studies with CRS-207 
CRS-207 is being evaluated in multiple clinical studies and multiple oncologic indications. CRS-
207, either alone or in combination (sequential or concomitant) with other investigational or 
approved agents, has been administered to more than 350 subjects with advanced cancers. 
Information related to this study is briefly summarized below; a complete summary of current 
clinical information on CRS-207 is provided in the IB.  
A Phase 1, first-in-human, multiple-dose, dose-escalation trial (VAC07001) was completed in 
adults with treatment-refractory malignant mesothelioma, advanced non-small cell lung 
carcinoma (NSCLC), or advanced carcinoma of the ovary or pancreas. The maximum tolerated 
dose (MTD) was 1 × 109 CFU; CRS-207 was generally well tolerated. While the study enrolled 
subjects with multiple disease types and was not powered to assess survival, 6/17 subjects (with 
prior immunotherapy or subsequent radiation) survived at least 15 months after receiving the 
first dose of CRS-207. 
Treatment emergent adverse events (TEAEs) temporally related to CRS-207 administration 
which are common and may vary in degree of severity include fevers, chills, nausea, vomiting, 
fatigue, headache and hypotension; generally, these were reported as immediate, transient, and 

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mild and resolve within 48 hours following CRS-207 infusion. Changes in hepatic enzyme levels 
and hematological parameters (lymphopenia) are also anticipated to varying degrees of severity. 
These effects are likely a consequence of the mechanism of action of CRS-207 through the 
activation of the innate immune system and release of proinflammatory cytokines and 
chemokines. Some of these infusion-related events may be mitigated by pre-medication with 
acetaminophen and administration of saline prior to and following CRS-207 infusion. Based on 
available results from clinical studies, continued clinical development of CRS-207 is warranted. 
4.2 
Pembrolizumab in Gastric, Gastroesophageal Junction, and Esophageal 
Adenocarcinomas 
Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody (mAb) 
with high specificity of binding to the programmed cell death 1 (PD 1) receptor, thus inhibiting 
its interaction with programmed cell death ligand 1 (PD-L1) and programmed cell death ligand 2 
(PD-L2).  Based on preclinical in vitro data, pembrolizumab has high affinity and potent receptor 
blocking activity for PD 1.  Pembrolizumab has an acceptable preclinical safety profile and is in 
clinical development as an intravenous (IV) immunotherapy for advanced malignancies.  
Keytruda™ (pembrolizumab) is indicated for the treatment of patients across a number of 
indications.  For more details on specific indications refer to the Investigator brochure.  
Pembrolizumab has demonstrated initial clinical efficacy in single arm monotherapy trials in 
subjects with NSCLC, head and neck squamous cell carcinoma, urothelial cancer, gastric cancer, 
triple negative breast cancer and Hodgkin’s Lymphoma as determined by response rate.  
Ongoing clinical trials are being conducted in these tumor types as well as a number of other 
advanced solid tumor indications and hematologic malignancies. For study details please refer to 
the pembrolizumab IB. 
KEYNOTE-012 (NCT01848834) enrolled patients with recurrent or metastatic adenocarcinoma 
of the stomach or gastroesophageal junction (GEJ). Subjects were treated with pembrolizumab 
10 mg/kg every 2 weeks for up to 24 months or until CR, disease progression, or unacceptable 
toxicity. Of 162 patients screened 65 (40%) were PD-L1 positive, of which 39 enrolled; 67% 
received ≥2 prior therapies. Median follow-up duration was 8.8 months. Objective response rate 
(ORR) was 22% (95% CI 10-39) by central review and 33% (95% CI 19-50) by investigator 
review. Median time to response was 8 weeks (range 7-16), with median response duration of 24 
weeks (range 8+ to 33+ weeks). PD-L1 expression level was associated with ORR (1-sided P = 
0.10). The 6-month progression-free survival (PFS) rate was 24%. Four subjects experienced 5 
total Grade 3-5 drug-related adverse events (AEs): peripheral sensory neuropathy, fatigue, 
decreased appetite, hypoxia, and pneumonitis (n = 1 each). There was 1 drug-related death 
(hypoxia) (Muro, 2015).   
KEYNOTE-028 (NCT02054806) enrolled a cohort (N=23) of esophageal patients with advanced 
squamous cell carcinoma or adenocarcinoma of the esophagus or GEJ whose tumors were PD-
L1 positive (44.6% of evaluable screened patients). Subjects received pembrolizumab 10 mg/kg 

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every 2 weeks for up to 24 months or until confirmed progression, unacceptable toxicity, or 
investigator decision. ORR by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 was 
30% overall (investigator review). Within the squamous histology group, the ORR was 29% (5 
of 17) and ORR was 40% (2 of 5) for subjects with adenocarcinoma. Median time to response 
was 3.7 months (range 1.8 - 8.3 months) and median duration of response (DOR) was not yet 
reached (range 5.5 - 11.8+ months) (Doi, 2016).  
4.3 
Rationale for CRS-207 and Pembrolizumab Immunotherapy in Gastric, 
Gastroesophageal, and Esophageal Adenocarcinomas 
PD-1 is a checkpoint protein on T cells that normally inhibits T cells from attacking other cells in 
the body. Overexpression of the ligand PD-L1 on cancer cells further evades immune attack by T 
cells. Checkpoint inhibitors, including antibodies targeting PD-1, block the PD-1/PD-L1 
interaction and boost the immune response against cancer cells. Monoclonal antibodies targeting 
PD-1, including pembrolizumab and nivolumab, have been approved for use in multiple tumor 
types and are currently being studied in several additional indications including gastric, GEJ, and 
esophageal adenocarcinomas. 
The addition of a checkpoint inhibitor to CRS-207 may enhance the immunotherapeutic potential 
of these agents by enabling stimulation of targeted immune responses to specific tumor antigens. 
Nonclinical and clinical studies with CRS-207 to date have demonstrated an acceptable safety 
profile and evidence of clinical benefit, supported by significant changes in the local tumor 
microenvironment (unpublished data). 
 
 
 
 
Initial data from an ongoing clinical study of CRS-207 with agents targeting the PD-1 blockade 
(i.e. nivolumab) suggests an acceptable tolerability profile.  
The current study is designed to evaluate whether CRS-207 with pembrolizumab effectively 
primes specific immune responses and results in clinical benefit for patients with previously 
treated gastric, GEJ, or esophageal adenocarcinoma. It is hypothesized the expansion of tumor-
specific T cells in context of blocking the PD-1/PD-L1 pathway may ultimately provide 
enhanced anti-tumor efficacy. Although there are no precedent data on the safety of CRS-
207/pembrolizumab, CRS-207 is currently being evaluated with the PD-1 inhibitor, nivolumab in 
an investigator-sponsored Phase 2 study (ADU-CL-06; NCT02243371). The study is evaluating 
survival, safety and immune response following treatment with CRS-207/GVAX 
pancreas/cyclophosphamide with or without nivolumab in subjects with previously-treated 
pancreatic cancer. Initial data from this ongoing clinical study suggests an acceptable tolerability 
profile of both agents at full dose (nivolumab at 3 mg/kg on Day 1 and CRS-207 1 × 109 CFU on 
Day 2).  These data suggest that a dose escalation phase 1 component in the current study is not 
required. 

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For the first cycle, pembrolizumab and CRS-207 will be dosed on consecutive days 
(pembrolizumab on Day 1 and CRS-207 on Day 2).  If Cycle 1 is well tolerated, dosing of both 
agents will occur on the same day (Day 1) for subsequent cycles.  Based on prior clinical 
experience and expected infusion reactions, it is anticipated that the same-day regimen will be 
tolerated and more convenient for patients.  A Safety Run-in is planned to monitor safety for the 
first 6 subjects.   
4.3.1 
CRS-207 Dose Selection Rationale 
CRS-207 has been shown to be well-tolerated at the proposed route of administration and dose 
for this study (Le, 2012). The dose of CRS-207 was chosen based on the Phase 1, dose-
escalation study (VAC07001) in which 1 × 109 CFU was determined to be the MTD and shown 
to be well-tolerated in patients with advanced cancer and induced a mesothelin-specific immune 
response. The 1 × 109 CFU dose level was also used in the Phase 1B trial (ADU-CL-02) in 
malignant pleural mesothelioma where initial analysis demonstrates clinical response and 
acceptable tolerability (Hassan, 2015). CRS-207 dosing at 1 × 109 CFU has been associated with 
mostly limited and transient infusion-related reactions including rigors/chills, nausea/vomiting, 
and changes in blood pressure. 
The initial CRS-207 dosing regimen (Q3W Cycles 1-4) in this study was designed to synergize 
with pembrolizumab to optimally prime an immune response. If subjects are clinically stable 
and/or responding to treatment, CRS-207 infusions will continue every other cycle (Q6W) to 
sustain the immune response.  
4.3.2 
Pembrolizumab Dose Selection Rationale 
 
 
 
 
 
 
 
 
 
 
 
  

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5 
STUDY OBJECTIVES 
The objectives of the study are to evaluate CRS-207/pembrolizumab when administered to 
subjects with recurrent or metastatic gastric, GEJ, or esophageal adenocarcinomas with respect 
to: 
• Safety and tolerability 
• Tumor response and survival 
• Characterization of immune responses, biomarker expression, and molecular 
characteristics of the tumor microenvironment 

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6 
INVESTIGATIONAL PLAN 
6.1 
Study Design and Duration 
The study is an open-label, single-arm, multicenter clinical study in approximately 79 adults with 
recurrent or metastatic gastric, GEJ, or esophageal adenocarcinomas who have received one or 
two prior systemic chemotherapy treatment regimens for advanced disease. Of the approximately 
79 evaluable subjects, the study will seek to enroll approximately 50 subjects with gastric/GEJ 
adenocarcinomas and approximately 29 subjects with esophageal adenocarcinoma to achieve 
adequate representation of each tumor type. 
The study design consists of a 28-day Screening Period, Treatment and Evaluation Period 
(including a Safety Run-in), and a Follow-up Period. CRS-207 and pembrolizumab will be 
administered in 3-week cycles.  For Cycle 1, pembrolizumab (200 mg) will be administered by 
IV over 30 minutes on Day 1 and CRS-207 (starting dose 1 × 109 CFU) will be administered IV 
over 1 hour on Day 2.  If the infusions are well tolerated, pembrolizumab and CRS-207 may be 
administered on the same day (Day 1) for subsequent cycles. After 4 cycles, pembrolizumab will 
continue to be administered on Day 1 at each treatment cycle (every 3 weeks; Q3W), and CRS-
207 will be administered once every 6 weeks (i.e. every other treatment cycle; Q6W). Treatment 
cycles will continue for up to 24 months as long as there is adequate safety and potential for 
clinical benefit. If radiographic disease progression is observed, clinically stable subjects who 
meet dosing eligibility may continue to receive CRS-207 and pembrolizumab according 
irRECIST guidelines (Section 11). Subjects who experience an unacceptable toxicity directly 
attributable to either pembrolizumab or CRS-207 may continue on study and receive either 
pembrolizumab or CRS-207 as single agent study treatment with approval by the Medical 
Monitor. Alternatively, study drug administration may revert back to consecutive day-dosing 
regimen as performed in Cycle 1 (Day 1 pembrolizumab and Day 2 CRS-207). 
The Treatment and Evaluation Period is defined as the time from Day 1 until discontinuation of 
both CRS-207 and pembrolizumab, completion of an End-of-Treatment (EOT) Visit, and 
documented disease progression. 
Blood will be collected at EOT to assess clearance of CRS-207 and at 
 
.  The EOT Visit will occur 
no more than 28 days after the last dose of study drug. If the subject has discontinued CRS-207 
but continues on pembrolizumab, the subject will be asked to come back to the clinic 
 
 If the subject begins another anticancer therapy before the end of the 28-day 
period, all EOT Visit assessments should be completed prior to commencing the new therapy. 
Unresolved AEs will be monitored until resolution or confirmed stability of the event. Subjects 
that discontinue all study drugs and complete the EOT without documented progressive disease 
(based on RECIST v1.1) will be asked to complete Evaluation Visits for tumor imaging every 6 
weeks until documented disease progression or start of another anticancer therapy.  
 

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At the end of the Treatment and Evaluation Period subjects will enter the Follow-up Period of 
the study and will be followed for survival, subsequent cancer-related therapies, and post 
treatment monitoring for CRS-207 
 until death or close of study by the Sponsor. 
The Sponsor may request survival status be assessed at additional time points during the course 
of the study. Sites will attempt to obtain vital status data from public records or other external 
sources where possible if a subject withdraws consent from study (i.e. refuse follow-up for vital 
status) or is documented as lost to follow up. Follow-up will continue for at least 12 months from 
last dose of study drug. 
Figure 6-1 
ADU-CL-14 STUDY DESIGN 
 
A Safety Run-in will be completed since there are no precedent data on the use of 
pembrolizumab with CRS-207. Subjects will be monitored for unacceptable toxicity during the 
first 28 days (through 7 days after the Cycle 2 dose). During the Safety Run-in, evaluable 
subjects are defined as those who remain on study for the 28-day monitoring period, subjects 
with unacceptable toxicity, and subjects who are discontinued for safety reasons at the 
Investigator’s discretion (even if criteria for unacceptable criteria are not met). Treatment of the 
first 6 subjects that are followed for the 28-day period will be staggered with no more than 1 
subject treated per week. In the event that 4 in up to 12 safety-evaluable subjects experience an 
unacceptable toxicity, the subsequent cohort of 12 subjects enrolled will be administered CRS-
207 at a dose reduced by a half-log (dose level -1; Table 6-3). In the event of 4 subjects in up to 
the next 12 safety-evaluable subjects enrolled experience an unacceptable toxicity, the 
subsequent cohort of 12 subjects enrolled will be administered a reduced dose of CRS-207 (dose 
level -2; Table 6-3). For each dose reduction (to a minimum of 1 × 108 CFU) the first 12 subjects 
will be treated and unacceptable toxicities assessed as described above. No adjustments will be 
made to the pembrolizumab dose.   
Safety data and all unacceptable toxicities will be reviewed by a Safety Review Team (SRT) 
comprised of participating investigators in the study, the Medical Monitor, and Sponsor 

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representatives. Once the Safety Run-in is complete, safety will continue to be evaluated on an 
ongoing basis in this open-label study. Cumulative clinical experience with CRS-207 and 
pembrolizumab will be used to assess whether AEs are considered expected.  
The Schedule of Events is provided in Table 1-1. Subjects who experience tolerability issues 
with same-day dosing may continue to follow the consecutive-day dosing regimen as in Cycle 1 
with Day 1 pembrolizumab followed by Day 2 CRS-207 dosing (Table 1-2). 
Tumor imaging and evaluation will be assessed at Screening and during the Treatment and 
Evaluation Period approximately every 6 weeks after initiation of study drug. Tumor 
measurement and assignment of response will be determined by local Investigators. For subjects 
on treatment more than 12 months, the frequency of imaging may be reduced to every 12 weeks. 
Peripheral blood will be collected to assess immune responses directed against Lm, mesothelin, 
and other tumor-associated antigens. Archived tumor tissue and paired tumor biopsies (collected 
at Screening and during Cycle 2) will be used to explore the association of PD-L1 expression, 
mesothelin expression, and TIL characteristics with clinical responses. 
6.1.1 
Discussion of Study Design 
The study was designed as a single-arm, open-label, multicenter Phase 2 study. The study is 
intended to provide the maximum amount of information regarding CRS-207/pembrolizumab 
safety and tolerability, along with indicators of clinical efficacy and overall survival (OS). Paired 
tumor biopsies and blood samples will provide an initial investigation into the mechanism of 
action of this regimen.  
For second line patients, standard of care therapies include ramucirumab plus paclitaxel, 
ramucirumab, paclitaxel or taxanes monotherapies (Mahipal, 2015). In the 3rd line, there is 
currently no approved therapy for third-line treatment of recurrent or metastatic gastric, GEJ or 
esophageal adenocarcinomas. Given the life-threatening nature of the disease, a placebo-
controlled trial is not appropriate in this setting. Since all subjects will receive the same 
investigational products, randomization and blinding are unnecessary; study drug will be 
provided open-label. The study is being conducted as a single-arm trial to evaluate initial safety 
and efficacy signals before initiating a larger randomized trial. 
The study is an exploratory study. The sample size is based on clinical and practical 
considerations, rather than statistical considerations, and is intended to explore whether the 
proportion responding to CRS-207/pembrolizumab is similar to or better than what may expected 
based on data from other clinical studies with checkpoint inhibitors in subjects with recurrent or 
metastatic gastric, GEJ, or esophageal adenocarcinomas. For reference benchmarks in the second 
line, ORR ranged from 7% to 28% (Mahipal, 2015). For 3rd line patients,  the ORR was 22% for 
pembrolizumab monotherapy in PD-L1 expressing patients (Muro, 2015). 

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6.2 
Study Population 
The population for this study will consist of approximately 79 adults with recurrent or metastatic 
gastric, GEJ, or esophageal adenocarcinomas who have received one or two prior systemic 
chemotherapy treatment regimens for advanced disease. Due to overlap in the diagnosis of 
esophageal, GEJ, and gastric cancers, the study population will consist of adenocarcinomas from 
all 3 anatomic sites; however, enrollment will be targeted to a minimum of 26 subjects with 
esophageal cancer (the less prevalent phenotype) to balance the study population. Prior treatment 
must have included a platinum and a fluoropyrimidine since this is approved therapy and 
recognized as standard of care in clinical practice. Similarly, eligible subjects must have tumor 
which are HER-2/neu negative or, if HER-2/neu positive, disease must have previously 
progressed on treatment with trastuzumab. 
Individuals with immunosuppressive disorders or who require immunosuppressive medications 
will be excluded. An Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 
and serum albumin levels serve as prognostic indicators of participants more likely to benefit 
from treatment.  
6.2.1 
Inclusion Criteria 
Individuals eligible to participate in this study must meet all of the following criteria: 
1. Aged 18 years or older 
2. Diagnosis with confirmed histology (pathology report required) of one or more of the 
following: 
• Histologically-confirmed gastric or GEJ adenocarcinoma (Siewert type II/III 
classification) 
[GEJ adenocarcinoma will be defined as primary tumor site within 5 cm proximal and 
distal of anatomic cardia]  
Or 
• Histologically-confirmed inoperable superior, medial, or distal third esophageal 
adenocarcinoma (Siewert type I classification may be included, provided there is no 
mixed histology) 
3. Confirmed recurrent or metastatic disease 
4. Received and experienced disease progression on, or following one or two prior 
chemotherapy regimens for advanced disease. Prior treatment must have included a platinum 
and a fluoropyrimidine. 
5. HER-2/neu negative or, if HER-2/neu positive, disease must have previously progressed on 
treatment with trastuzumab 
6. Measurable/assessable disease, as defined by RECIST v1.1. Target lesions situated in a 
previously irradiated area are considered measurable if progression has been demonstrated in 
such lesions. 
7. ECOG performance status of 0 or 1 

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8. Can provide the following tissue for PD-L1 and mesothelin biomarker analysis: 
• Archived primary tumor tissue (tissue from metastatic site acceptable if archived 
primary tissue is not available and primary site is not accessible for biopsy)  
• Pre-Treatment biopsy of either primary tumor or metastatic site 
• On-Treatment biopsy at Cycle 2, Day 15 
9. Adequate organ and marrow function at Screening, as defined by: 
Hematologic 
Renal 
Hepatic 
WBC ≥ 3000/µL 
ANC ≥ 1500/µL 
ALC ≥ 800/µL 
Platelets ≥ 100,000/µL 
Hemoglobin  ≥ 9 g/dL 
Albumin ≥ 3.0 g/dL 
INR or PT ≤ 1.5 × ULN 1 
aPTT ≤ 1.5 × ULN 1 
Creatinine ≤ 1.5 × ULN; or 
measured /calculated creatinine 
clearance ≥ 60 mL/min if 
creatinine levels >1.5× ULN  
AST/ALT ≤ 2.5 × ULN; or  
≤5 × ULN for subjects with liver metastases  
Total bilirubin ≤ 1.5 × ULN; or  
≤ 3 × ULN if due to Gilbert’s disease; or 
direct bilirubin ≤ ULN if total bilirubin > 1.5 × 
ULN 
ALC = absolute lymphocyte count; ALT = alanine aminotransferase; ANC = absolute neutrophil count; aPTT = 
activated partial thromboplastin time; AST = aspartate aminotransferase; INR = international normalized ratio PT 
= prothrombin time; ULN = institutional upper limit of normal; WBC = white blood cell 
1 If receiving anticoagulant therapy, values should be within therapeutic range of intended use 
Any Grade 3 or higher abnormality in any serum chemistry or hematology parameter should be 
discussed and approved by the Medical Monitor prior to enrollment (even if considered not clinically 
significant) 
10. Women of childbearing potential (WOCBP) and fertile males with WOCBP partners must 
use highly effective contraception  (CTFG, 2014) throughout the Treatment and Evaluation 
Period ( from first dose and through 120 days after final dose of study drug). Contraception 
must include at least one barrier method to minimize risk of fluid transmission. 
11. Provide written informed consent and is willing and able to comply with all study 
procedures. 
6.2.2 
Exclusion Criteria 
Individuals who meet any of the following exclusion criteria will not be eligible to participate in 
the study: 
1. Diagnosis of squamous or undifferentiated gastric cancer 
2. Individuals with inaccessible tumors or for whom biopsy is contraindicated  
3. Participated in any other study in which receipt of an investigational new drug or 
investigational device occurred within 28 days of first dose of study drug 
4. Diagnosis of immunodeficiency, receiving TNF pathway inhibitors, PI3 kinase inhibitors, 
chronic systemic steroid therapy (> 10 mg/day of prednisone or equivalent) or any other form 
of immunosuppressive therapy within 7 days prior to the first dose of study drug 
5. Clinical evidence of ascites by physical exam 

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6. Prior anti-cancer monoclonal antibody within 4 weeks prior to first dose of study drug or has 
not recovered from adverse effects due to agents administered more than 4 weeks earlier 
7. Prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks 
prior to first dose of study drug, or has not recovered from adverse effects (i.e. ≤ Grade 1 or 
baseline) from adverse effects due to a previously-administered agent 
Note:  Subjects with ≤ Grade 2 neuropathy or ≤ Grade 2 alopecia are an exception to this 
criterion. 
8. Active second malignancy with the exception of any of the following: 
• Adequately treated basal cell carcinoma  
• Squamous cell carcinoma of the skin, or in situ cervical cancer 
• Low-risk prostate cancer (i.e. Gleason score < 7 and prostate specific antigen < 10 
ng/mL); or 
• Any other cancer from which the individual has been disease-free for ≥ 3 years 
9. Received transfusion of blood products (including platelets or red blood cells) or 
administration of colony stimulating factors (including G-CSF, GM-CSF or recombinant 
erythropoietin) within 4 weeks prior to first dose of study drug. 
10. Active infection requiring systemic therapy 
11. Known active central nervous system metastases and/or carcinomatous meningitis. Subjects 
with previously treated brain metastases may participate provided they are stable (without 
evidence of progression by imaging at least 4 weeks prior to the first dose of study drug and 
neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain 
metastases, and are not using steroids for at least 7 days prior to first dose of study drug. This 
exception does not include carcinomatous meningitis which is excluded regardless of clinical 
stability. 
12. History of (non-infectious) pneumonitis that required steroids, or current pneumonitis 
13. History of interstitial lung disease 
14. Prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent, or agents targeting other 
checkpoint pathways (e.g. CTLA-4, LAG-3, GITR, OX40), or prior participation in Merck 
MK-3475 clinical trials 
15. Prior immunotherapy with CRS-207 or any other Listeria-based agent, therapeutic cancer 
vaccine, or adoptive T cell immunotherapy 
16. Major surgery or significant traumatic injury occurring within 28 days prior to first dose of 
study drug 
Note:  If major surgery occurred > 28 days prior to first dose of study drug, individual must 
have recovered adequately from the toxicity and/or complications from the intervention prior 
to first dose of study drug  
17. Previous treatment with >2 systemic chemotherapy regimens for advanced disease 
18. Known allergy to both penicillin and sulfa antibiotics 

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19. Unable or unwilling to withhold or discontinue any prohibited or restricted 
medications/procedures/immunizations for the specified windows during the study 
20. If WOCBP, pregnant or breastfeeding; negative pregnancy status must be confirmed within 
24 hours of first dose of study drug 
21. Known valvular heart disease that requires antibiotic prophylaxis for prevention of 
endocarditis 
22. Clinically significant heart disease (such as uncontrolled angina, myocardial infarction within 
3 months of study initiation, congestive heart failure, or New York Heart Association Class 
III or IV heart failure) 
23. History of autoimmune disease that has required systemic treatment in the past 2 years, 
including:  
• Inflammatory bowel disease (including ulcerative colitis and Crohn’s Disease) 
• Rheumatoid arthritis 
• Systemic progressive sclerosis (scleroderma) 
• Systemic lupus erythematosus 
• Autoimmune vasculitis (e.g. Wegener’s granulomatosis) 
• Central nervous system or motor neuropathy considered of autoimmune origin (e.g. 
Guillain-Barre syndrome, myasthenia gravis, multiple sclerosis) 
Note: Individuals with vitiligo, Sjogren’s syndrome, interstitial cystitis, Graves’ or 
Hashimoto’s Disease, celiac disease, diabetes mellitus type 1, or hypothyroidism stable on 
hormone replacement will be allowed with Medical Monitor approval. 
24. Intercurrent illness that is either life-threatening or of clinical significance such that it might 
limit compliance with study requirements or in the Investigator’s assessment would place the 
subject at an unacceptable risk for study participation; 
25. Received a diagnosis of human immunodeficiency virus (HIV) 
26. Received a diagnosis of hepatitis B, or hepatitis C for which there is no clear evidence of 
natural immunity, immunity subsequent to vaccination, or successful eradication of the virus 
following antiviral therapy (individuals who are hepatitis C antibody positive may be 
enrolled if negative viral load confirmed at screening) 
27. Subjects who have 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 that were placed more than 3 months prior 
to first dose of study drug.  
28. Prior severe hypersensitivity (≥ Grade 3) to CRS-207, pembrolizumab, or any study drug 
excipients (e.g. yeast, glycerol) 
29. Unhealed wound  
30. History or evidence of inherited bleeding diathesis or coagulopathy 

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31. Received any prophylactic vaccine within 14 days of first dose of study drug or received a live
vaccine within 30 days of planned start of study therapy. Seasonal flu vaccines that do not
contain a live virus are permitted.
6.2.3 
Dosing Eligibility and Delayed Dosing 
Subjects must have adequate organ function confirmed (as defined by the laboratory values in 
Table 6-1) prior to each dosing cycle where CRS-207 is administered; laboratory tests may be 
performed up to 3 days before dosing. 
Table 6-1 
Dosing-Eligibility Requirements 
Hematologic 
Renal 
Hepatic 
WBC ≥ 3000/µL 
ANC ≥ 1000/µL 
Platelets ≥ 90,000/µL 
Hemoglobin  ≥ 8 g/dL 
Creatinine ≤ 1.5 × ULN 
AST/ALT ≤ 5× ULN 
Bilirubin ≤ 1.5× ULN OR ≤ 3 
× ULN if due to Gilbert’s 
disease 
ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = aspartate aminotransferase; 
ULN = institutional upper limit of normal; WBC = white blood cell 
Subjects who do not meet dosing eligibility requirements will be monitored; dosing may be 
delayed up to 2 weeks, after which time it will be considered missed and the subject would 
continue onto the next scheduled dose. If a dose is delayed more than 2 weeks, contact the 
Medical Monitor for further instruction on continued dosing. 
Pembrolizumab may be administered up to 3 days before or after the scheduled Day 1 of each 
cycle due to administrative reasons.  If subjects on same-day dosing schedule experience severe 
infusion-related reactions related to the pembrolizumab infusion, the CRS-207 infusion may be 
delayed to Day 2. CRS-207 must be administered one day after pembrolizumab administration. 
If the subject experiences a new AE or is recovering from an AE, CRS-207 administration may 
be delayed up to 7 days and the Sponsor must be notified. If a dose of CRS-207 is delayed 
beyond 7 days of pembrolizumab, the dose of CRS-207 should be withheld until the next cycle. 
Dosing interruptions are permitted in the case of medical / surgical events or logistical reasons 
not related to study therapy (e.g. elective surgery, unrelated medical events, vacation, and/or 
holidays). Subjects should be placed back on study therapy within 3 weeks of the scheduled 
interruption, unless otherwise discussed with the Sponsor. The reason for interruption should be 
documented in the Subject’s study record. 
6.2.4 
Subject Discontinuation 
Subjects will be encouraged to complete the study; however, they may voluntarily withdraw 
from treatment or the study at any time. The Investigator will provide a written explanation 
describing the reason for discontinuation from treatment or study in a source document, which 
will be entered into the electronic case report form (eCRF). Subjects who discontinue treatment 

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will complete the EOT assessments, 
 and post-treatment 
monitoring for CRS-207. Subjects will be encouraged to participate in the Follow-up Period. In 
the case of subjects lost to follow-up, attempts to contact the subject must be made and 
documented in the subject’s study records. Sites will attempt to obtain vital status data from 
public records or other external sources where possible if a subject withdraws consent from study 
(i.e. refuse follow-up for vital status) or is lost to follow up.   
A subject in this clinical study may be discontinued from treatment for any of the following 
reasons: 
• The subject withdraws consent or requests discontinuation for any reason 
• Occurrence of any medical condition or circumstance that exposes the subject to 
substantial risk and/or does not allow the subject to adhere to the requirements of the 
protocol 
• Any serious adverse event (SAE), clinically significant AE, severe laboratory 
abnormality, intercurrent illness, or other medical condition which indicates to the 
Investigator that continued participation is not in the best interest of the subject 
• Pregnancy 
• Subject failure to comply with protocol requirements or study-related procedures  
• Termination of the study by the Sponsor or the regulatory authority 
Subjects who experience an unacceptable toxicity directly attributable to either pembrolizumab 
or CRS-207 may continue on study and receive either pembrolizumab or CRS-207 as single 
agent treatment following completion of the Sponsor Consultation Form and approval by the 
Medical Monitor. Alternatively, study drug administration may revert back to consecutive day-
dosing regimen as performed in Cycle 1. 
6.2.4.1 
Stopping Rules 
Subjects will be monitored throughout the study for unacceptable toxicity (Section 6.3.1.1); 
provisions are in place for a Safety Run-in, CRS-207 dose reductions, dose modifications, and 
continuation on either CRS-207 or pembrolizumab as a single agent. The following safety rules 
will apply to the study to further mitigate potential risk to subjects: 
• Grade 5 toxicity (death) in any subject within 30 days of receipt of study drug(s) unless 
clearly related to an alternative cause other than study drug 
• Unacceptable toxicity occurring in >33% of subjects dosed with CRS-
207/pembrolizumab 
Should these events occur the SRT will evaluate available data within 72 hours of notification of 
the event(s) and recommend whether to stop the study, suspend dosing and/or enrollment, or 
determine whether additional dose adjustments are warranted.   

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6.3 
Study Treatments and Additional Medications 
Subjects will receive the assigned treatment course described in Table 6-2. 
Table 6-2 
ADU-CL-14 Study Treatment Course 
Study Drug  
Dose / Route 
Treatment Course 
Pembrolizumab 
200 mg administered IV over 
30 min (-5 min/+10 min) 
Day 1 of each cycle   
CRS-207 
1×109 CFU administered IV 
over ~ 1 hour 
Day 2 of Cycle 1 
Day 1 of Cycle 2, 3, 4; Q6W thereafter 1 
CFU = colony-forming unit; IV = intravenous; Q6W = every 6 weeks 
1 Subjects who experience tolerability issues may continue to follow the consecutive-day dosing regimen as in 
Cycle 1 and follow the Schedule of Events for Consecutive Day Dosing (Table 1-2). 
6.3.1 
Safety Run-In Period 
A Safety Run-in will be completed since there are no precedent data on the use of 
pembrolizumab with CRS-207. Subjects will be monitored for unacceptable toxicity during the 
first 28 days (through 7 days after the Cycle 2 dose). During the Safety Run-in, evaluable 
subjects are defined as those who remain on study for the 28-day monitoring period, subjects 
with unacceptable toxicity, and subjects who are discontinued for safety reasons at the 
Investigator’s discretion (even if criteria for unacceptable criteria are not met). Treatment of the 
first 6 subjects that are followed for the 28-day period will be staggered with no more than 1 
subject treated per week. In the event that 4 in up to 12 safety-evaluable subjects experience an 
unacceptable toxicity, the subsequent cohort of 12 subjects enrolled will be administered CRS-
207 at a dose reduced by a half-log (dose level -1). In the event of 4 subjects in up to the next 12 
safety-evaluable subjects enrolled experience an unacceptable toxicity, the subsequent cohort of 
12 subjects enrolled will be administered a reduced dose of CRS-207 (dose level -2). For each 
dose reduction (to a minimum of 1 × 108 CFU) the first 12 subjects will be treated and 
unacceptable toxicities assessed as described above. No adjustments will be made to the 
pembrolizumab dose. The dose levels and dose reduction permutations are provided in Table 
6-3. 
Table 6-3 
Safety Run-in Dose Levels and Dose Reduction Plan 
Dose level 
Pembrolizumab  
CRS-207  
1 
200 mg 
1 × 109 CFU 
-1 
-2 
200 mg 
200 mg 
3 × 108 CFU 
1 × 108 CFU 

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6.3.1.1 
Unacceptable Toxicities 
The unacceptable toxicity criteria will be any of the following unless clearly related to an 
alternative cause other than study drug: 
• Grade 5 toxicity 
• Grade 4 non-hematologic toxicity (not laboratory) 
• Grade 4 hematologic toxicity lasting ≥7 days 
• Grade 3 non-hematologic toxicity (not laboratory) lasting >3 days despite optimal 
supportive care 
• Any Grade 3 or Grade 4 non-hematologic laboratory value if: 
o Medical intervention is required to treat the subject,  
or 
o The abnormality leads to hospitalization, or 
o The abnormality persists for >1 week 
• Grade 3 or 4 febrile neutropenia 
o Grade 3 is defined as ANC <1000/mm3 with a single temperature of >38.3°C (101°F) 
or a sustained temperature of ≥38°C (100.4°F) for more than one hour 
o Grade 4 is defined as ANC <1000/mm3 with a single temperature of >38.3°C (101°F) 
or a sustained temperature of ≥38°C (100.4°F) for more than one hour, with life-
threatening consequences and urgent intervention indicated 
• Thrombocytopenia <25,000/mm3 if associated with:  
o A bleeding event which does not result in hemodynamic instability but requires an 
elective platelet transfusion,  
or 
o A life-threatening bleeding event which results in urgent intervention and admission 
to an Intensive Care Unit 
• Delay of >8 days starting Cycle 2 due to study drug-related toxicity 
• Administration of systemic steroids to treat an immune-mediated reaction 
• Serum chemistry laboratory values consistent with Hy’s Law criteria (i.e. all 3 of the 
following must coexist): 
o ALT or AST ≥ 3 × ULN 
o Total bilirubin ≥ 2 × ULN 
o ALP < 2 × ULN 
Safety data and all unacceptable toxicities will be reviewed by the SRT comprised of 
participating investigators in the study, the Medical Monitor, and Sponsor representatives. Once 
the Safety Run-in is complete, safety will continue to be evaluated on an ongoing basis in this 
open-label study. Cumulative clinical experience with CRS-207 and pembrolizumab will be used 
to assess whether AEs are considered expected.   

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Subjects who experience an unacceptable toxicity directly attributable to either pembrolizumab 
or CRS-207 may continue on study and receive either pembrolizumab or CRS-207 as single 
agent treatment following completion of the Sponsor Consultation Form and approval by the 
Medical Monitor. Alternatively, study drug administration may revert back to consecutive day-
dosing regimen as performed in Cycle 1. 
6.3.2 
Method of Assigning Subjects to Treatment 
All subjects will be sequentially assigned a unique subject identification number upon providing 
informed consent. The study is designed as a single-arm study; all subjects will receive CRS-
207/pembrolizumab as indicated. 
6.3.3 
Blinding 
ADU-CL-14 is a single-arm, open-label study. Due to the expected infusion-related reactions and 
required pre-medications associated with CRS-207 administration, and since all subjects receive 
the same study drugs, it is not feasible or necessary to conduct the study under blinded 
conditions. All study treatments will be administered open-label; no study participants or site 
personnel will be blinded to study treatment. 
6.3.4 
Investigational Product: CRS-207 
CRS-207 is a LADD strain derived by deletion of actA and inlB coding sequences from a 
streptomycin-resistant, wild-type strain and insertion of the hMeso coding sequence. The CRS-
207 drug product is formulated as 1 × 109 CFU suspended in 
 
, filled into a single-use 2-mL glass vial with a gray butyl stopper 
and aluminum crimp seal with a flip-off cap. CRS-207 is stored frozen at -60 ºC or colder until 
just before IV administration. CRS-207 is supplied by the Sponsor. Additional information on 
CRS-207 may be found in the Pharmacy Manual and IB. 
6.3.4.1 
Biosafety and Environmental Precautions 
In wild-type form, Lm is a bacterium commonly found in soil and water, and may be present in a 
variety of raw and processed foods. Listeriosis is a foodborne illness caused by wild-type Lm 
which primarily affects pregnant women and immunocompromised individuals. Direct human-
to-human spread of Lm is believed to be limited mainly to vertical transmission from mother to 
neonate. CRS-207 is a LADD construct originating from wild-type Lm which contains deletions 
of 2 virulence genes that render it greater than 1000-times less toxic than wild-type Lm in mice  
(Brockstedt, 2004). 
LADD-based immunotherapies (Lm ΔactA/ΔinlB) including CRS-207, have been designated as 
Risk Group 1 by the Aduro Institutional Biosafety Committee. Risk Group 1 is consistent with 
the guidance by the German ZKBS (Central Commission for Biological Safety) for classification 
of Lm strains with deletion in genes prFA, hly, actA, and plcB (BVL, 1999). Individuals who 
prepare CRS-207 for infusion must take appropriate precautions (e.g. gloves, laboratory coat, 

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face protection, needle stick or sharps precautions) to avoid contamination or direct contact with 
the agent. Once prepared for infusion, the chance for direct exposure to CRS-207 by study 
personnel should be greatly diminished. However, study personnel and staff should continue to 
adhere to the institutional guidelines for standard precautions. 
Based on nonclinical studies and available clearance and shedding data from clinical studies, a 
subject who receives CRS-207 is unlikely to spread an infection to others. Subjects receiving 
CRS-207 should be counseled to minimize the potential risk of spreading CRS-207 by practicing 
good health hygiene (e.g. hand-washing) as with any potential infectious agent, and adhering to 
protocol requirements for barrier method of contraception during sexual intercourse.  
6.3.4.2 
CRS-207 Administration 
CRS-207 is intended for IV administration. The intended dose of CRS-207 is 1 × 109 CFU 
diluted in sterile saline and administered by IV infusion. Additional details for storage and 
preparation of CRS-207 are provided in the study Pharmacy Manual. 
Use of Central Lines 
To avoid contamination of a central line (e.g. infusion ports, peripherally inserted central 
catheter) with CRS-207 during and after infusion: 
• CRS-207 must NOT be administered through a central line or infusion ports 
• Central lines must NOT be used or accessed for any reason once CRS-207 infusion has 
been initiated (including blood draws, medication administration or line flushing; blood 
draws prior to infusion through a port or central line are allowed) and through 4 days 
after infusion 
• Central lines must be clearly labeled with tape or other method indicating date when port 
may be used again after CRS-207 infusion 
Pre-Medication and Post-Infusion Observation 
Before each CRS-207 infusion, subjects should be pre-medicated with 650 mg (or maximum 
dose permitted by label) acetaminophen (paracetamol). Adequate hydration is important to 
mitigate infusion-related reactions. All subjects are required to receive a minimum of 0.5 L of 
normal saline immediately before CRS-207 infusion; an additional 0.5 - 1 L after infusion is 
recommended, as tolerated. Additional fluids may be given for persistent tachycardia, fever, or 
hypotension based on Investigator’s discretion.  
Subjects will be observed in the clinic for at least 4 hours after the first CRS-207 infusion.  For 
Same-day dosing on Cycle 2 only, observe subjects for at least 4 hours.  For all subsequent 
infusions observe subjects for at least 2 hours post infusion. Subjects should continue to be 
monitored after infusion and released once they are considered clinically stable. Vital signs and 
pulse oximetry will be monitored (Section 6.4.3.1). Presence of fever alone in the absence of 
other clinical signs and symptoms does not preclude the subject from being released. Hospital 

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admissions for overnight monitoring will not be considered an SAE unless the event meets 
criteria for seriousness other than hospitalization.  
During and after CRS-207 infusions, subjects may experience fever, chills/rigor, blood pressure 
changes, nausea, and vomiting. Refer to Section 6.3.7 and the IB for additional details on CRS-
207 administration and supportive care. 
6.3.4.3 
CRS-207 Dose Modification 
CRS-207 at the proposed dose level has been well tolerated and dose reductions are not 
anticipated. However, in the event of AEs of concern that are attributable to CRS-207 the 
Medical Monitor should be contacted; the dose of CRS-207 may also be modified outside the 
Safety Run-in Period as warranted on an individual basis.  
6.3.5 
Investigational Product:  Pembrolizumab 
Pembrolizumab is a humanized monoclonal antibody that blocks the interaction between PD-1 
and its ligands, PD-L1 and PD-L2. Pembrolizumab is an IgG4 kappa immunoglobulin with an 
approximate molecular weight of 149 kDa. Pembrolizumab is not currently approved for 
treatment of gastric, GEJ, or esophageal adenocarcinomas and is being used as an investigational 
agent in this study. However, the approved package insert should be consulted for additional 
product information on storage, preparation and administration, contraindications, 
warnings/precautions, adverse reactions, and drug interactions. 
Pembrolizumab for injection is a sterile, preservative-free, clear to slightly opalescent, colorless 
to slightly yellow solution that requires dilution for IV infusion. Each vial contains 100 mg of 
pembrolizumab in 4 mL of solution. Each 1 mL of solution contains 25 mg of pembrolizumab 
and is formulated in: L-histidine (1.55 mg), polysorbate 80 (0.2 mg), sucrose (70 mg), and Water 
for Injection, USP.  
6.3.5.1 
Pembrolizumab Administration 
Pembrolizumab will be diluted and administered as a dose of 200 mg using a 30-minute IV 
infusion. Sites should target infusion timing to be as close to 30 minutes as possible. However, 
given the variability of infusion pumps, a window between -5 minutes and +10 minutes is 
permitted (i.e. infusion time is 30 minutes -5 min/+10 min). Do not co-administer other drugs 
through the same infusion line. Pembrolizumab infusions will be administered Q3W for up to 24 
months. The Pharmacy Manual contains specific instructions for the preparation of the 
pembrolizumab infusion and administration of infusion solution. 
Pembrolizumab Supportive Care Guidelines 
Subjects should receive appropriate supportive care measures as deemed necessary by the 
investigator. Suggested supportive care measures for the management of pembrolizumab-related 
AEs with potential immunologic etiology along with dose modification guidelines are outlined 
below. Where appropriate, these guidelines include the use of oral or IV treatment with 

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corticosteroids as well as additional anti-inflammatory agents if symptoms do not improve with 
administration of corticosteroids. 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 the event is determined not to be related to pembrolizumab, the Investigator does not 
need to follow the treatment guidance (as outlined below).  It may be necessary to perform 
conditional procedures such as bronchoscopy, endoscopy, or skin photography as part of 
evaluation of the event. 
6.3.5.2 
Pembrolizumab Dose Modification and Toxicity Management  
Immune-related Adverse Events Associated with Pembrolizumab 
AEs associated with pembrolizumab exposure may represent an immunologic etiology. These 
immune-related AEs (irAEs) may occur shortly after the first dose or several months after the 
last dose of pembrolizumab treatment and may affect more than one body system 
simultaneously. Therefore, early recognition and initiation of treatment is critical to reduce 
complications. Based on existing clinical trial data, most irAEs were reversible and could be 
managed with interruptions of pembrolizumab, administration of corticosteroids and/or other 
supportive care. For suspected irAEs, ensure adequate evaluation to confirm etiology or exclude 
other causes. Additional procedures or tests such as bronchoscopy, endoscopy, skin biopsy may 
be included as part of the evaluation. Based on the severity of irAEs, withhold or permanently 
discontinue pembrolizumab and administer corticosteroids. 
Dose modification and toxicity management guidelines for irAEs associated with 
pembrolizumab are provided in Table 6-4. The Medical Monitor will be consulted regarding 
continued dosing of CRS-207 should any of these events occur. During the Safety Run-in Period 
withholding pembrolizumab or administering systemic steroids would define an unacceptable 
toxicity. 
 

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Table 6-4 
Dose Modification and Toxicity Management Guidelines for Immune-Related Adverse Events Associated with 
Pembrolizumab 
General Instructions: 
1. Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks. 
2. For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to Grade 1 or 0 and corticosteroid 
has been tapered. Pembrolizumab should be permanently discontinued if AE does not resolve within 12 weeks of last dose or corticosteroids cannot 
be reduced to ≤ 10 mg prednisone or equivalent per day within 12 weeks.  
3. For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other immunosuppressive treatment should 
be initiated if irAEs cannot be controlled by corticosteroids. 
 
Immune-related 
AEs 
Toxicity grade 
or conditions 
(CTCAEv4.0) 
Action taken to 
pembrolizumab 
irAE management with 
corticosteroid and/or other 
therapies  
Monitor and follow-up  
Pneumonitis  
Grade 2 
Withhold  
• Administer corticosteroids 
(initial dose of 1-2mg/kg 
prednisone or equivalent) 
followed by taper 
 
• 
Monitor subjects for signs and symptoms 
of pneumonitis 
• 
Evaluate subjects with suspected 
pneumonitis with radiographic imaging 
and initiate corticosteroid treatment 
• 
Add prophylactic antibiotics for 
opportunistic infections 
Grade 3 or 4, or 
recurrent grade 
2 
Permanently 
discontinue 
Diarrhea / colitis  
Grade 2 or 3 
Withhold 
• Administer corticosteroids 
(initial dose of 1-2mg/kg 
prednisone or equivalent) 
followed by taper 
 
• 
Monitor subjects for signs and symptoms 
of enterocolitis (i.e. diarrhea, abdominal 
pain, blood or mucus in stool with or 
without fever) and of bowel perforation 
(i.e. peritoneal signs and ileus). 
• 
Subjects with ≥ Grade 2 diarrhea 
suspecting colitis should consider GI 
consultation and performing endoscopy to 
rule out colitis.  
• 
Subjects with diarrhea/colitis should be 
advised to drink liberal quantities of clear 
fluids.  If sufficient oral fluid intake is not 
feasible, fluid and electrolytes should be 
substituted via IV infusion. 
Grade 4 
Permanently 
discontinue 

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AST / ALT 
elevation or 
Increased 
Bilirubin 
Grade 2 
Withhold 
• Administer corticosteroids 
(initial dose of 0.5- 1mg/kg 
prednisone or equivalent) 
followed by taper 
• 
Monitor with liver function tests 
(consider weekly or more frequently until 
liver enzyme value returned to baseline or 
is stable 
Grade 3 or 4  
Permanently 
discontinue 
• Administer corticosteroids 
(initial dose of 1-2mg/kg 
prednisone or equivalent) 
followed by taper 
Type 1 diabetes 
mellitus (T1DM) 
or 
Hyperglycemia 
 
Newly onset 
T1DM or  
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of β-
cell failure 
Withhold 
• Initiate insulin replacement 
therapy for subjects with T1DM  
• Administer anti-hyperglycemic 
in subjects with hyperglycemia  
 
• 
Monitor subjects for hyperglycemia or 
other signs and symptoms of diabetes. 
Hypophysitis 
Grade 2 
Withhold 
• Administer corticosteroids and 
initiate hormonal replacements 
as clinically indicated.   
 
• 
Monitor for signs and symptoms of 
hypophysitis (including hypopituitarism 
and adrenal insufficiency)  
Grade 3 or 4  
Withhold or 
permanently 
discontinue1  
Hyperthyroidism  Grade 2 
Continue  
• Treat with non-selective beta-
blockers (e.g. propranolol) or 
thionamides as appropriate  
• 
Monitor for signs and symptoms of 
thyroid disorders.  
 
Grade 3 or 4  
Withhold or  
Permanently 
discontinue1 
Hypothyroidism 
Grade 2-4 
Continue  
• Initiate thyroid replacement 
hormones (e.g. levothyroxine or 
liothyroinine) per standard of 
care 
• 
Monitor for signs and symptoms of 
thyroid disorders.  
 
Nephritis and 
renal dysfunction 
Grade 2 
Withhold  
• Administer corticosteroids 
(prednisone 1-2mg/kg or 
equivalent) followed by taper. 
• 
Monitor changes of renal function 
 
Grade 3 or 4  
Permanently 
discontinue 

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All Other 
immune-related 
AEs 
Grade 3, or 
intolerable/ 
persistent Grade 
2 
Withhold 
• Based on severity of AE 
administer corticosteroids  
• 
Ensure adequate evaluation to confirm 
etiology or exclude other causes 
 
Grade 4 or 
recurrent Grade 
3  
Permanently 
discontinue 
NOTES:  
1. Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician.   
2. For subjects with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, pembrolizumab may be resumed when AE 
resolves to ≤ Grade 2 and is controlled with hormonal replacement therapy or achieved metabolic control (in case of T1DM).   
 

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Infusion Reactions Related to Pembrolizumab 
Pembrolizumab may cause severe or life threatening infusion-reactions including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after drug 
infusion and generally resolve completely within 24 hours of completion of infusion. Dose 
modification and toxicity management guidelines on pembrolizumab associated infusion reaction 
are provided in Table 6-5.  
Table 6-5 
Pembrolizumab Infusion Reaction Dose Modification and 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 therapy or 
infusion interruption but 
responds promptly to 
symptomatic treatment 
(e.g., antihistamines, 
NSAIDs, narcotics, IV 
fluids); prophylactic 
medications indicated 
for ≤24 hrs 
Stop Infusion. 
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 1 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 study drug treatment 
Subject may be premedicated 
1.5h (± 30 minutes) prior to 
infusion of pembrolizumab 
with: 
Diphenhydramine 50 mg po 
(or equivalent dose of 
antihistamine). 
Acetaminophen 500-1000 mg 
po (or equivalent dose of 
analgesic). 
 
 
 

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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 (e.g., renal 
impairment, pulmonary 
infiltrates) 
Grade 4: 
Life-threatening; pressor 
or ventilatory support 
indicated 
Stop Infusion. 
Additional appropriate medical therapy may 
include but is not limited to: 
Epinephrine** 
IV fluids 
Antihistamines 
NSAIDs 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
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. 
**In cases of anaphylaxis, epinephrine should be 
used immediately. 
Subject is permanently discontinued from 
further study drug treatment. 
No subsequent dosing 
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during 
the period of drug administration. 
For further information, please refer to the Common Terminology Criteria for Adverse Events v4.0 (CTCAE) at 
http://ctep.cancer.gov 
 
Other Allowed Dose Interruptions for Pembrolizumab 
Pembrolizumab may be interrupted for situations other than treatment-related AEs such as 
medical / surgical events or logistical reasons not related to study therapy. Subjects should be 
placed back on study therapy within 3 weeks of the scheduled interruption, unless otherwise 
discussed with the Sponsor. The reason for interruption should be documented in the subject’s 
study record. 
6.3.6 
Antibiotics 
To eliminate any potentially residual CRS-207, subjects will be administered antibiotics at the 
EOT visit or 7 days after the last dose of CRS-207 (for patients continuing on pembrolizumab), 
prior to receiving subsequent cancer-related (non-study) therapy. 
 
 
 

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Consult the package inserts for amoxicillin, trimethoprim, and sulfamethoxazole for product 
information on dosage and administration, contraindications, warnings/precautions, adverse 
reactions, and drug interactions. 
6.3.6.1 
Suspected Infection with CRS-207 
Suspected infection with CRS-207 and/or Listeria is considered an adverse event of special 
interest (AESI; Section 7.3.5) and should be reported following SAE reporting procedures 
(Section 7.3) irrespective of temporal relationship to study drug administration. This includes 
scheduled blood cultures during surveillance monitoring that are positive for CRS-207 or if a 
subject presents with symptoms suspicious for a Listeria-like infection and/or is tested positive 
for Listeria at a local hospital/clinic. 
In the case of suspected persistent CRS-207 or Listeria infection, blood, urine and stool samples 
should be obtained in duplicate. 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 Sponsor must be notified immediately, and the duplicate samples and Listeria isolate 
must be 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 
If infection with CRS-207 is confirmed or suspected, IV antibiotics (see below) should be 
initiated as soon as possible and follow-up cultures obtained periodically to confirm 
absence/clearance of any CRS-207 infection. The Medical Monitor should be consulted 
regarding continuation of study drug treatment and treatment of suspected or confirmed 
infection. 
Antibiotic Treatment for CRS-207 Infection 
 
 
 

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6.3.7 
Concomitant Medications and Procedures 
Subjects may receive concomitant medications as required, unless specifically restricted or 
prohibited in this study (Section 6.3.8). Minor procedures such as dental work, skin biopsy, 
celiac plexus block, biliary stents, mediport/port insertion, and video-assisted thoracic surgery 
biopsy are allowed; however, CRS-207 should not be administered within 14 days of the 
procedure or until the investigator determines there is no additional risk to the subject. 
During the course of the study, subjects are anticipated to continue the use of prescribed 
medications identified during the screening procedures, consistent with study inclusion and 
exclusion criteria.  
Concomitant medications used in this study include: 
• Acetaminophen (paracetamol) prior to each CRS-207 infusion 
• Antiemetics according to American Society for Clinical Oncology guidelines (Basch, 
2011) 
• Antipyretics to treat fever or to prevent recurrence of fever post-CRS-207 infusion 
• IV narcotics such as morphine or meperidine (per institutional policy) for rigors 
associated with CRS-207 dosing 
• 7-day antibiotic regimen following last dose of CRS-207 
6.3.8 
Prohibited Medications and Procedures 
A subject may be removed from the study for use of prohibited medications or procedures. 
Approval must be obtained from the Medical Monitor for a subject to continue dosing if a 
prohibited medication is administered within the specified timeframes. The following therapies 
are not permitted or restricted during the study: 
• Non-study chemotherapy or immunotherapy (approved or investigational) 
• TNF pathway inhibitors or PI3 kinase inhibitors 
• Palliative radiation 
• 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. 
• Any major surgery or surgical procedure; if required must be discussed with the Medical 
Monitor to determine if it is appropriate for the subject to continue study treatment 
• Any other investigational product 

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If a subject requires an emergent implant of a prohibited device while on therapy, the subject will 
receive a 14-day IV antibiotic regimen (Section 6.3.6.1). 
In addition, the following medications are only restricted prior to and after CRS-207 infusions as 
indicated: 
• Systemically active steroids for more than 3 days or use of any systemic steroids within 
14 days before or after CRS-207 infusion, with the exception of inhaled and topical 
steroids 
• Filgrastim (granulocyte colony stimulating factor; G-CSF) or sargramostim (granulocyte-
macrophage colony stimulating factor; GM-CSF) within 14 days prior to or 14 days after 
CRS-207 infusion  
• Prophylactic vaccines (e.g. pneumococcal vaccine, influenza vaccine) within 14 days 
prior to or after CRS-207 infusion 
The following therapies should not be administered during the study unless medically necessary; 
approval must be obtained from the Medical Monitor for a subject to continue dosing if therapy 
is given concurrently with study participation: 
• General anesthesia or deep sedation 
• Aspirin >325 mg/day 
• Acetaminophen > 4 g/day 
• Systemic antibiotics 
There are no prohibited therapies during the Follow-up Period. 
If subjects receive immunosuppressive medications on or after study, prophylactic antibiotics to 
prevent CRS-207 infection are strongly recommended for the duration of the treatment with the 
immunosuppressant (recommended oral 80 mg trimethoprim / 400 mg sulfamethoxazole once 
daily or 160 mg trimethoprim / 800 mg sulfamethoxazole (DS) three days a week). 
6.3.9 
Treatment Compliance 
Study treatments will be administered by IV infusion by a qualified health care professional at an 
approved study site. The date, time, and volume of each dose of study drug administered to each 
subject must be recorded in the dispensing log for the study and the eCRF.  
Antibiotics will be provided to subjects following the last dose of CRS-207 as indicated in 
Table 1-1 or Table 1-2. Site personnel will contact the subject by telephone to facilitate 
compliance with antibiotic treatment; subjects will be required to record self-administration of 
antibiotics in a diary. 
6.4 
Study Assessments and Procedures 
Screening assessments will be conducted to confirm eligibility and to obtain baseline 
measurements; screening must be completed within 28 days prior to first dose of study drug. An 

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enrollment form will confirm subject eligibility after completion of all screening procedures. 
Subjects must initiate dosing of study drugs within 2 weeks of completed enrollment.  
Subjects will be requested to complete multiple clinic visits during the initial four dosing cycles; 
visit frequency is reduced beginning at Cycle 4 and beyond. An EOT Visit will occur within 28 
days after the last dose of study drug. If the subject begins another anticancer therapy before the 
end of the 28-day period, all EOT Visit assessments should be completed prior to commencing 
the new therapy. Unresolved AEs will be monitored until resolution or confirmed stability of the 
event. 
After the EOT Visit, subjects will be followed 
 to collect data on survival, CRS-
207 monitoring, and any subsequent cancer-related therapies until death or close of study by the 
Sponsor. Sites will attempt to obtain vital status data from public records or other external 
sources where possible if a subject withdraws consent from study (i.e. refuse follow-up for vital 
status) or is documented as lost to follow up. Follow-up will continue for at least 12 months from 
last dose of study drug.  
All study visits (and visit windows), assessments, and procedures will be performed as indicated 
in the Schedule of Events (Table 1-1 or Table 1-2). Further details of study procedures and 
assessments can be found in the Study Reference and Laboratory Manuals.  
6.4.1 
General Assessments  
6.4.1.1 
Informed Consent 
Before screening assessments are conducted, an individual must be given a complete explanation 
of the purpose and requirements of the study; an informed consent form (ICF) approved by the 
Institutional Review Board (IRB)/Ethics Committees (EC) and an authorization for use and 
disclosure of protected health information must be signed before any study-specific procedure is 
performed. However, assessments done as part of standard of care prior to informed consent may 
be used if they are within the required screening period. An original signed consent form will be 
retained in the subject’s source documentation at the site; a copy will be provided to the subject.  
6.4.1.2 
Demographics, Medical History, and Height 
Demographic data and a complete medical history will be collected at screening by the 
Investigator or qualified designee. Demographic information (as allowed by local regulations) 
will include date of birth, age, gender, ethnicity, and race. Medical history should include all 
active conditions and any condition considered to be clinically significant by the Investigator. 
Details regarding the disease for which the subject has enrolled in this study (e.g. date of 
diagnosis, primary tumor histology, prior surgery(ies), radiation therapy, and stage of cancer) 
will be recorded. 
Height (without shoes) will be obtained at screening with a stadiometer. Body mass index will be 
derived using height and weight. 

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6.4.1.3 
Archived Tumor Tissue and Tumor Biopsies 
Archived tissue from the primary tumor will be collected for all enrolled subjects to assess 
expression of PD-L1 and mesothelin by immunohistochemistry (IHC). Archived samples should 
be submitted with a pathology report; personal identifying information must be redacted. If 
archival primary tumor tissue from the original diagnostic formalin-fixed paraffin-embedded 
block is not available, tissue from metastatic site is acceptable if primary site is not accessible for 
biopsy.  
Paired tumor biopsies of primary tumor or a metastatic site for pre-treatment and on Cycle 2 Day 
15 will be collected to evaluate changes in PD-L1 and mesothelin status, as well as any cellular 
or genomic changes in markers of immune response or disease status. If at Cycle 2 a subject’s 
tumor is thought to be unsafe for biopsy by the Investigator, the site must discuss with the 
Medical Monitor to determine if an alternative acceptable method may be allowed. 
An image assisted core needle biopsy using standard techniques will be obtained from the 
primary tumor site(s) and/or accessible metastatic lesions. The tissue sample should have proper 
size to enable IHC analysis of PD-L1 and mesothelin. Fine needle aspirations will not be 
acceptable.  
Paired biopsies will be collected 1) any time between screening and prior to the first dose of 
study medication (baseline) and 2) during treatment (Cycle 2 Day 15 post CRS-
207/pembrolizumab administration). Cycle 2 Day 15 biopsy should not be collected until at least 
seven (7) days have passed since CRS-207 administration, but no later than Day 15 of cycle to 
allow sufficient recovery time prior to CRS-207 administration.  An additional biopsy may be 
requested at the EOT visit. If additional biopsies or relevant samples (e.g. pleural fluid) are 
collected for routine care during the course of study, a sample should be retained if possible for 
Sponsor research evaluation. Detailed instructions for tissue collection, processing and shipment 
are provided in the Laboratory Manual.  
6.4.1.4 
Eligibility  
Potential subjects will be evaluated for entry into the study according to the stated inclusion and 
exclusion criteria (Section 6.2). Individuals deemed ineligible for study enrollment do not need 
to complete all screening procedures. The reason for ineligible status will be documented. Tests 
with results that fail eligibility requirements may be repeated once during the Screening Period if 
the Investigator believes the results to be in error. Additionally, a subject who fails screening 
may repeat the screening process 1 time if the Investigator believes there has been a change in 
eligibility status (e.g. after recovery from an infection). 
For subjects who meet all inclusion/exclusion criteria, an enrollment form will be completed and 
sent to Sponsor or designee for review and approval. All screening assessments must be 
completed within a 4-week (28 day) period; treatment must be initiated within 2 weeks of 
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6.4.2 
Efficacy Measures 
Efficacy will be evaluated by changes in tumor burden and survival. The assessments that will be 
performed throughout the study to derive primary, secondary, and exploratory efficacy variables 
are described below and will be conducted according to the Schedule of Events (Table 1-1 or 
Table 1-2). Efficacy endpoints and associated analyses are described in Section 6.5.5.  
6.4.2.1 
Tumor Imaging and Response Assessments 
Computed tomography (CT) scans of the chest, abdomen and pelvis will be performed at 
screening (pre-treatment baseline assessment) within 28 days of first dose of study drug and at 
approximately 6 week intervals after initiation of study drug using the same assessment 
technique. If CT scan is contraindicated (e.g. allergy to contrast dye), magnetic resonance 
imaging (MRI) should be performed. Subjects with previously treated brain metastases must be 
stable (without evidence of progression by imaging at least 4 weeks prior to the first dose of 
study drug and neurologic symptoms have returned to baseline), have no evidence of new or 
enlarging brain metastases. Radiographic tumor evaluation should include CT of all affected 
sites. 
For each scan, tumor measurements should be obtained using RECIST v1.1 and assessment of 
response determined by the local Investigator. The investigator/local radiology review will also 
use irRECIST (Section 11) to assess tumor response and progression, and make treatment 
decisions. If radiographic disease progression is observed, another scan should be done at least 
four weeks later to confirm disease progression prior to treatment discontinuation. Subjects 
discontinued after confirmation of progression will enter the Follow-Up Period. Subjects that 
discontinue all study drugs and complete the EOT without documented progressive disease 
(based on RECIST v1.1) will be asked to complete tumor imaging every 6 weeks until 
documented disease progression or start of another anticancer therapy. 
The method of assessment and technique should be consistent throughout the study to enable 
characterization of each identified and reported lesion. 
For subjects on treatment more than 12 months, the frequency of imaging may be reduced to 
every 12 weeks. 
6.4.2.2 
Survival Follow-Up 
Following the Treatment and Evaluation Period, subjects will be contacted at 12
 
 to assess survival and subsequent cancer-related therapies. A telephone contact should 
also be scheduled at least 90 days post-treatment discontinuation to satisfy reporting 
requirements for SAEs and events of clinical interest.  
Follow-up will continue until death of the subject, loss to follow-up, or close of study by the 
Sponsor. For subjects who withdraw from the study prior to completion of the Follow-up Period, 
reasonable efforts will be made to collect survival outcome. Sites will attempt to obtain vital 

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status data from public records or other external sources where possible if a subject withdraws 
consent from study (i.e. refuse follow-up for vital status) or is documented as lost to follow up. 
All deaths must be reported on the eCRF.  
The Sponsor may request survival status be assessed at additional time points during the course 
of the study. These additional contacts may be requested for safety review, interim analysis, 
and/or final analysis. All subjects who are not known to have died prior to the request for these 
additional survival status time points will be contacted at that time. 
6.4.3 
Safety Assessments 
Safety assessments will be performed to characterize the safety of CRS-207/pembrolizumab use 
in patients with gastric, GEJ, or esophageal adenocarcinomas. Safety will be assessed by 
collection of data on parameters including SAEs, TEAEs, infusion-related reactions, ECOG 
performance status, vital sign measurements, standard clinical laboratory parameters (serum 
chemistry, hematology, coagulation, thyroid function, and urinalysis), and electrocardiogram 
(ECG) parameters. Clinically significant changes from pre-treatment values in safety 
assessments should be reported as AEs. Safety assessments described below will be conducted 
according to the Schedule of Events (Table 1-1 or Table 1-2).  
6.4.3.1 
Eastern Cooperative Oncology Group Scale of Performance Status 
The ECOG Scale of Performance Status is recognized as a standard tool to measure disease 
impact on daily living activities (Oken, 1982). The ECOG scale will be used by site personnel to 
determine eligibility and characterize a subject’s level of functioning (self-care, daily activity, 
and basic physical ability). 
6.4.3.2 
Vital Signs and Pulse Oximetry 
Vital signs, including blood pressure, pulse rate, respiratory rate, and temperature will be 
performed at each indicated study visit. Vital signs and pulse oximetry will be obtained prior to, 
and immediately following each pembrolizumab infusion. Vital signs and pulse oximetry will be 
obtained prior to and every 30 minutes during CRS-207 infusion, and every hour during post-
infusion follow-up.  
Any clinically significant abnormal findings in vital signs, pulse oximetry, or weight should be 
recorded as an AE. 
6.4.3.3 
Physical Examination and Weight 
Comprehensive Physical Examination 
Complete physical examinations will be conducted at screening and EOT. Comprehensive 
physical examinations must be performed by a medically qualified individual such as a licensed 
Physician, Physician's Assistant, or an advanced Registered Nurse Practitioner, as local law 
permits. The comprehensive physical examination will include the following organ or body 

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system assessments: skin; head, eyes, ears, nose, and throat; thyroid; lungs; cardiovascular 
system; abdomen (liver and spleen); extremities; lymph nodes; and a brief neurological 
examination. Before the first dose of study drug, clinically significant abnormal findings should 
be recorded as medical history. After the first dose of study treatment, new clinically significant 
abnormal findings should be recorded as AEs. 
Symptom-directed Physical Examination 
Symptom-directed physical examinations will be conducted at all other indicated visits (up to 3 
days prior to dosing). The Investigator or medically qualified designee will perform a symptom-
directed evaluation as clinically indicated. The targeted physical examination will include 
assessment(s) of the body systems or organs, as indicated by subject symptoms, AEs, or other 
findings. New clinically significant abnormal findings should be recorded as AEs. 
Weight 
Weight will be obtained at each indicated visit, and prior to receiving any study medication. 
6.4.3.4 
Adverse Events 
AEs will be recorded from the time of first study drug administration until 28 days following the 
last dose of study drug or initiation of subsequent cancer-related therapy, whichever occurs first. 
SAEs should be reported per the timeframe and procedures described in Section 7.3. If the EOT 
visit occurs less than 28 days from the last dose of study drug, the subject will be contacted by 
telephone 28 days (+ 3 days) after the date of last study drug administration to complete the AE 
reporting period. A follow-up contact for AEs will also be conducted 1 day after each CRS-207 
infusion (and one day after pembrolizumab infusions beyond Cycle 5 where CRS-207 is not 
administered). Contact must be documented in the study records.  
All AEs and abnormal clinical laboratory assessments will be assessed for severity using the 
NCI-CTCAE v. 4.03. The determination, evaluation, reporting, and follow-up of AEs will be 
performed as outlined in Section 7. 
6.4.3.5 
Concomitant Medications 
Medications used within 28 days prior to first dose of study drug will be recorded. A telephone 
follow-up for concomitant medications will also be conducted 1 day after each CRS-207 infusion 
(and one day after pembrolizumab infusions during Cycle 5 and beyond where CRS-207 is not 
administered). All concomitant medication administered from the first study drug administration 
until the EOT visit will be recorded in the eCRF (including pre-medications and all over the 
counter medications). The generic name, dosage, duration, and reason for the concomitant 
medication should be included. Changes in the use of concomitant medications will be captured 
at each study visit. 

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6.4.3.6 
Electrocardiogram 
At indicated visits routine 12-lead ECGs will be performed.  ECGs should be performed after the 
subject has rested for ≥5 minutes.  
For consecutive-day dosing, ECGs will be performed prior to each dose of study medication, 
immediately after the infusion, and at 1-hour post infusion. For visits where pembrolizumab and 
CRS-207 are administered consecutively (Day 1 and Day 2), routine 12-lead ECGs will be 
performed prior to each infusion, immediately after each infusion, and at 1-hour post infusion. 
For visits where pembrolizumab and CRS-207 are administered on the same day, routine 12-lead 
ECGs will be performed prior to pembrolizumab infusion, immediately after pembrolizumab 
infusion, immediately after CRS-207 infusion, and at 1-hour post CRS-207 infusion. If abnormal 
at 1-hour post-infusion, repeat until baseline achieved. Additional ECGs may be performed if 
clinically indicated.   
ECG parameters include heart rate, PR interval, QT interval, QRS duration, QTcF (Fridericia's 
correction), and QTcB (Bazett's correction). The ECG will be interpreted by the Investigator as 
normal, not clinically significant abnormal, and clinically significant abnormal results. Clinically 
significant abnormal findings should be recorded as an AE.  
6.4.3.7 
Clinical Laboratory Evaluation for Safety 
Routine hematology, serum chemistry, and urinalysis will be performed as a safety measure and 
to confirm dosing eligibility throughout the study (Section 6.4.4.2). The clinical significance of 
laboratory parameter findings will be determined by the Investigator throughout the study. The 
Medical Monitor may, depending on study criteria, be consulted before enrollment about a 
potential subject with abnormal laboratory values that are not considered clinically significant. 
Clinically significant abnormal laboratory values occurring during the clinical study will be 
followed until repeat tests return to normal, stabilize, or are no longer clinically significant. All 
abnormal laboratory values considered clinically significant by the Investigator must be recorded 
in the AE page of the eCRF. Any abnormal test that is determined to be an error does not require 
reporting as an AE. 
6.4.4 
Laboratory Assessments 
A panel of laboratory assessments on blood and urine samples will be used to characterize the 
study population, and assess efficacy and safety throughout the Treatment and Evaluation Period. 
Assessments will be conducted per the Schedule of Events (Table 1-1). 
6.4.4.1 
Screening/Baseline-specific Laboratory Assessments 
Blood samples will be obtained at screening to confirm eligibility and characterize immune 
status and prognostic tumor biomarkers for each subject and the study population. These initial 
laboratory assessments may be conducted at the local laboratory and include:   

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• Virology screen for HIV antibody, hepatitis B surface antigen, and hepatitis C antibody 
o Hepatitis C viral load (if indicated) 
6.4.4.2 
Safety Laboratory Assessments 
Routine hematology, serum chemistry, thyroid function tests, coagulation panels, and urinalysis 
will be conducted as a measure of safety and dosing eligibility per protocol requirements 
(Section 6.2.3). All clinical laboratory evaluations will be performed by the institution’s local 
laboratory. Testing may be completed up to 3 days prior to each study drug administration. 
Fasting is not required. Additional tests may be performed if clinically indicated. 
The following parameters will be evaluated at Screening and throughout the Treatment and 
Evaluation Period as indicated: 
• Thyroid panel: triiodothyronine (T3) or free triiodothyronine (FT3), free thyroxine (FT4), 
thyroid stimulating hormone (TSH)   
• Hematology:  complete blood count (WBCs, red blood cells, hematocrit, and 
hemoglobin) with differential including absolute neutrophil count, absolute lymphocyte 
count, and platelet count 
• Serum chemistry:  sodium, potassium, chloride, bicarbonate, glucose, blood urea 
nitrogen, creatinine, lactate dehydrogenase, alanine aminotransferase, aspartate 
aminotransferase, alkaline phosphatase, bilirubin (total, direct, indirect), total protein, 
albumin, calcium, magnesium, uric acid, and phosphate 
• Coagulation panel: prothrombin time, international normalized ratio of prothrombin time, 
activated partial thromboplastin time, and D-dimers, fibrinogen 
• Urinalysis: bilirubin, blood, glucose, ketones, leukocytes, nitrite, pH, protein, and specific 
gravity (includes microscopy at Screening and EOT)  
Pregnancy Testing and Contraception 
The effects of CRS-207 and pembrolizumab on a fetus in utero or on the composition of sperm 
are unknown. Therefore, WOCBP and fertile males must consent to use highly effective 
contraception (CTFG, 2014) from the first dose through 120 days after their final dose of study 
drug. Contraception must include at least one barrier method to minimize risk of fluid 
transmission. Sexual abstinence is an acceptable method of contraception; if abstinence is 
employed, use of barrier method is not applicable. 
A WOCBP is defined as any female who has experienced menarche and who has not undergone 
surgical sterilization (hysterectomy or bilateral oophorectomy) and is not postmenopausal. 
Menopause is defined clinically as 12 months of amenorrhea in a woman over age 45 years in 
the absence of other biological or physiological causes. For study eligibility, WOCBP must have 
negative pregnancy tests at screening and within 24 hours of first study drug administration. A 
serum pregnancy test (human chorionic gonadotropin) is required at screening; at all other 
indicated visits, only a urine pregnancy test is required. If a urine pregnancy test is positive, the 

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results should be confirmed with a serum pregnancy test. Pregnancy of a subject or partner must 
be reported and followed (Section 7.4).  
6.4.4.3 
Biomarker and Research Laboratory Assessments  
Research assessments conducted on blood samples and tumor tissues may help to characterize 
and monitor baseline and post-treatment immune responses mediated by CRS-207 and 
pembrolizumab. Samples required for laboratory evaluations will be collected and processed by 
sites as outlined in the Laboratory Manual. All analyses will be conducted by the Sponsor or the 
Sponsor’s designee.  
Biomarker and research laboratory assessments may include:  
• Total CD4 and CD8 counts 
• Human leukocyte antigen (HLA) typing (type A and B of MHC Class I antigens; 
intermediate resolution) 
• Characterization of treatment induced humoral and cellular immune responses including T 
cell responses to Lm and mesothelin 
• Immune cellular phenotyping and functional analyses of peripheral blood mononuclear 
cells (PBMCs) and TILs 
• Tumor biomarkers or prognostic factors (e.g. PD-L1, mesothelin, plasma osteopontin, etc.) 
• Circulating (cytokines, chemokines, tumor biomarkers and antibody responses) including 
mesothelin, CEA, VEGF, and CA19-9 
• Gene expression profiling of PBMCs and tumor tissue 
• T cell receptor (TCR) profiling of PBMCs and tumors 
Specific testing may include analysis for changes in protein analytes such as cytokines, 
antibodies, relevant tumor markers and markers of immune function by using enzyme-linked 
immunospot (ELISPOT), intracellular cytokine staining, enzyme-linked immunosorbent assay 
(ELISA), or other relevant methods including peptide or protein arrays. In addition, assays of 
immune cell phenotyping and functions or responses may be conducted using whole blood 
samples and PBMCs.  
To explore whether a diverse T cell repertoire is predictive of response to therapy, sequencing of 
TCR genes may be performed on DNA isolated from peripheral blood and tumor to quantitate 
the composition of the T cell repertoire prior to and during therapy. Genetic markers associated 
with response or resistance may also be measured using peripheral blood DNA; peripheral blood 
DNA may also be used as a germline control to compare with tumor cell DNA. RNA isolated 
from peripheral blood for gene expression analysis may be used to characterize subjects who 
respond or are resistant to treatment. Additional assessments and methodologies may be used at 
the Sponsor’s discretion. 

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6.4.4.4 
Blood Cultures for CRS-207 Surveillance 
Blood samples will be obtained from subject’s peripheral vein at the EOT visit or 7 days after the 
last dose of CRS-207 (for patients continuing on pembrolizumab) (prior to initiation of 
antibiotics) to monitor for presence of CRS-207.  For subjects with a central venous access 
device, a blood sample will also be taken through the port at time points indicated for CRS-207 
testing.  Subjects with samples positive for the presence of CRS-207 
 
 and be re-tested until negative cultures are confirmed. 
6.4.4.4.1 
Confirmed Listeria Infection 
In the event a subject has a positive Listeria culture at any time during or after study participation 
(except within 7 days after a CRS-207 infusion), Sponsor should be notified within 24 hours of 
the event (refer to Section 7.3.5). 
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 Sponsor 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. 
6.4.4.4.2 
Suspected Infection with CRS-207 or Listeria 
In the case of a suspected persistent CRS-207 or Listeria infection that has not been confirmed 
by culture, collection of blood, urine and stool samples in duplicate is recommended. One set of 
samples should be cultured locally for Listeria per institutional guidelines. Culture of 
cerebrospinal fluid should be obtained for subjects with suspected central nervous system 
infection. In such instances, analysis of cerebrospinal fluid should also include cell count, 
protein, glucose, and Gram stain. If samples are positive for Listeria, the Sponsor must be 
notified immediately, and the duplicate samples and Listeria isolate must be sent to 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.  
If infection with CRS-207 is confirmed or suspected, IV antibiotics (Section 6.3.6) should be 
initiated as soon as possible and follow-up cultures obtained periodically to confirm 
absence/clearance of any CRS-207 infection. The Medical Monitor should be consulted 
regarding continuation of study drug treatment and treatment of suspected or confirmed 
infection. 
6.4.5 
Appropriateness of Measures 
Tumor imaging is the gold standard for assessing monitoring disease progression and tumor 
response in patients with cancer. The primary efficacy variable, ORR, is generally an accepted 
surrogate of efficacy appropriate for use in single-arm studies with smaller sample sizes (Food 
and Drug Administration, 2007). Tumor response will be evaluated using both RECIST v1.1 and 
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reported for immune checkpoint inhibitors such as pembrolizumab (Nishino, 2013). 
Immunotherapeutic agents such as pembrolizumab may produce antitumor effects by 
potentiating endogenous cancer-specific immune responses. The response patterns seen with 
such an approach may extend beyond the typical time course of responses seen with cytotoxic 
agents, and can manifest a clinical response after an initial increase in tumor burden or even the 
appearance of new lesions. Therefore, the standard RECIST v1.1 may not provide an accurate 
response assessment of immunotherapeutic agents such as pembrolizumab.  
Additional secondary efficacy variables will also be derived from tumor imaging and response 
assessments. OS is the universally accepted direct measure of benefit and is an objective 
measure, although may be limited by difficulties with patient follow-up in smaller studies and 
confounded by non-cancer deaths in long-term studies.  
Paired tumor biopsies and archival tissue will be analyzed for PD-L1 expression as well as other 
immune checkpoint molecules and infiltration of immune cells (e.g. T cell, myeloid and DC 
subpopulations) by IHC and gene expression profiling. PD-L1 expression may predict response 
to anti-PD-1 (Brahmer, 2010; Topalian, 2012). 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.  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. 
The safety parameters to be evaluated in this study include standard assessments such as 
recording of medical history, AEs and SAEs, physical examination, vital signs, ECGs, serum 
chemistry and hematology, urinalysis, concomitant medications, and other routine clinical and 
laboratory procedures. 
6.5 
Statistical Analysis 
The completeness of the data affects the integrity and accuracy of the final study analysis.  
Therefore, efforts will be made to ensure complete, accurate and timely data collection, and to 
avoid missing data. The procedures for handling missing, unused, or spurious data, along with 
the detailed method for analysis of each variable, transformations, and exploratory analyses will 
be presented in the Statistical Analysis Plan (SAP); the information below is intended as a guide 
to planned analyses.  
6.5.1 
Sample Size Determination 
This study is descriptive in nature, as such the sample size for this study is determined by 
practical rather than statistical considerations.  Approximately 79 subjects will be enrolled to 
achieve at least 79 treated subjects with evaluable post-baseline tumor data. With 79 subjects, the 
precision for point estimate for ORR is as follows: the 95% confidence interval (CI) width for 
ORR based on Wilson score intervals are at most the observed proportion +/- 0.108.  If the 

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observed ORR = 30.4% (24 of 79 subjects with PR or CR), the lower bound of the 95% CI 
would be 19.5%.   
Of the 79 subjects enrolled, an estimated 50 subjects will be enrolled with gastric or GEJ cancer, 
and an estimated 29 subjects will be enrolled with esophageal cancer.  Assuming at least 50 
evaluable gastric/GEJ subjects are evaluable for ORR, the precision for point estimate for ORR 
is as follows: the 95% CI width for ORR based on Wilson score intervals are at most the 
observed proportion +/- 0.134.  Assuming at least 29 evaluable esophageal cancer subjects are 
evaluable for ORR, the precision for point estimate for ORR is as follows: the 95% CI width for 
ORR based on Wilson score intervals are at most the observed proportion +/- 0.173. 
6.5.2 
General Considerations 
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, Q1, Q3, and minimum and maximum values. The descriptive summaries of time to 
event data will include median, 25th and 75th percentiles, and standard error. All data will be 
listed for all subjects. 
This study is descriptive in nature; no formal hypothesis testing will be performed. All CIs will 
be 95%, unless stated otherwise. 
All statistical analyses will be performed using SAS.  
The effects of noncompliance, dropouts, and covariates will be assessed to determine the impact 
on the general applicability of results from this study.  
6.5.3 
Subject Information 
Subject disposition summaries will include the number of enrolled subjects, the number of 
subjects receiving study drug, the number of subjects completing the study, the number of 
subjects withdrawing prematurely, and the reasons for treatment and study discontinuation. 
Demographics and baseline disease characteristics will be summarized using descriptive 
statistics. 
6.5.4 
Analysis Sets 
Evaluable Analysis Set (EAS) is defined as all subjects who received at least 1 dose of CRS-207 
and have at least one evaluable post-baseline RECIST tumor response assessment or were 
discontinued due to toxicity. The EAS will be the primary population for analyses of tumor-
related endpoints (ORR, DCR, DOR, and PFS). 
Full Analysis Set (FAS) is defined as all subjects who received at least 1 dose of CRS-207. The 
FAS will be used for analyses of OS, immunogenicity and other biomarker data, and sensitivity 
analysis of select tumor-related endpoints. 

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Safety Set (SAF) includes all subjects who received any study treatment (pembrolizumab or 
CRS-207). The SAF will be used for all analyses of safety data and may be used for select 
biomarker data. 
Additional analysis sets (e.g. per protocol set) may be defined in the SAP. 
6.5.5 
Efficacy Analyses 
All efficacy variables derived from tumor imaging and response assessments will be determined 
using RECIST v1.1 and irRECIST. The primary analyses of tumor related efficacy variables will 
be performed using objective disease responses definitions based on RECIST. Exploratory 
analyses will be performed separately using objective disease responses definitions based on 
irRECIST. 
6.5.5.1 
Primary Efficacy Variable and Analysis 
The ORR is defined as the proportion of subjects with best overall response (BOR) of partial 
response (PR) or complete response (CR) according to RECIST v1.1. The proportion of subjects 
with ORR in the EAS, along with a 95% CI based on the Wilson Score interval, will be reported.  
Analyses of ORR described above may be repeated in FAS, treating missing BOR as a non-
responder.  Objective disease response at each visit and best overall response will also be 
summarized using the EAS.  
6.5.5.2 
Secondary Efficacy Variables and Analyses 
Secondary efficacy variables in the study include: 
Disease control rate (DCR) defined as the percentage of subjects with BOR of CR, PR, or SD. 
The analysis of DCR will be performed using the EAS and conducted in the same manner as 
ORR. 
Progression-free survival (PFS) defined as time from first dose of study drug to first 
documentation of disease progression (per RECIST) or death due to any cause.  
Subjects who do not experience disease progression and are alive on or before the data cut-off 
date will be censored at the time of last evaluable tumor assessment or data cut-off date, 
whichever is earlier. Subjects who do not experience disease progression and start new systemic 
anti-cancer therapy will be censored at the last evaluable tumor assessment on or prior to the 
time the new systemic anti-cancer therapy was begun or the data cut-off date, whichever is 
earlier. For analyses conducted in the FAS, subjects with no evaluable post-baseline tumor 
assessments will be censored at the time of receipt of first study drug. Subjects who are lost to 
follow-up for assessment of disease progression will be censored at their last evaluable tumor 
assessment or data cut-off date, whichever is earlier.  The analysis of PFS will be performed in 
the EAS using Kaplan-Meier methods.  Analyses may be repeated in the FAS. 
Duration of response (DOR) includes subjects with an objective disease response (PR or CR) 
and is defined as the time from the first tumor assessment that supports the subject’s objective 

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disease response to the time of disease progression or death due to any cause.  Subjects who do 
not experience disease progression or death at the time of analysis will be censored using the 
same rules as described for PFS. The analysis of DOR will be performed in the EAS using 
Kaplan-Meier methods. 
Overall Survival (OS) defined as the time from first dose of study drug until date of death due to 
any cause. Subjects without documentation of death at the time of analysis will be censored as of 
the date the subject was last known to be alive, or the data cut-off date, whichever is earlier. OS 
will be performed in the FAS using Kaplan-Meier methods. The analysis may be repeated in the 
SAF.  
6.5.5.3 
Exploratory Variables and Analysis 
Exploratory efficacy analyses will be evaluated based on the following variables: 
• ORR, DCR, DOR and PFS using irRECIST (Nishino, 2013) 
• Association of PD-L1 expression with clinical efficacy 
• Association of mesothelin expression in tumor tissue with clinical efficacy 
Additional efficacy analyses that may be evaluated include: 
• Association of immunological responses with clinical efficacy 
• Association with circulating and molecular biomarkers with clinical efficacy 
• Impact of EBV status and other molecular characteristics including but not limited to 
human epidermal growth factor receptor 2 (HER2) status, MSI, and chromosomal 
instability (CIN), on clinical efficacy 
• Association of molecular characteristics including but not limited to HER2 status and 
IFN-related gene signature with clinical efficacy 
Exploratory analyses of the data will be conducted as deemed appropriate. Details of additional 
analysis of other variables are provided in the SAP. 
6.5.6 
Safety Analyses 
AEs will be coded according to the Medical Dictionary for Regulatory Activities (MedDRA) 
version 18.1 or higher and assessed for severity using the NCI-CTCAE v. 4.03. The number and 
percentage of subjects experiencing any TEAE, overall, and by system organ class and preferred 
term will be tabulated. The incidence rates adjusted by cumulative exposure will also be 
presented overall and by cycle. AEs associated with clinical laboratory parameters will be 
characterized according to NCI CTCAE, Version 4.03. Shifts in toxicity grades from baseline to 
each visit will be summarized. 
6.5.7 
Research Laboratory Analyses 
Analyses of research laboratory samples, tumor biopsies, and immune response data will be 
described separately outside the context of the SAP. 

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6.5.8 
Timing of Analysis 
The final analysis will be performed after all subjects have completed at least 6 cycles of 
treatment or discontinued study treatment and completed the EOT Visit. A supplemental analysis 
may be completed at the end of study that includes the cumulative data collected after the final 
analysis (i.e. through the Follow-up Period). 
6.5.9 
Data Monitoring Committee 
There will be no formal Data Monitoring Committee for this study. Safety data and all 
unacceptable toxicities will be reviewed by the SRT comprised of participating investigators in 
the study, the Medical Monitor, and representatives of the Sponsor. 

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7 
ADVERSE EVENT REPORTING AND FOLLOW UP 
7.1 
Adverse Events 
An AE is defined as any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related. An AE can therefore be any unfavorable and/or 
unintended sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of an investigational medicinal product, whether or not related to the 
investigational medicinal product. All AEs, including observed or volunteered problems, 
complaints, or symptoms, are to be recorded on the appropriate eCRF. 
AEs occurring from the time of first study drug administration and up to 28 days after the last 
dose of study drug or until a subject initiates a new cancer therapy, whichever is earlier, will be 
monitored and documented on the AE eCRF. AEs include clinical laboratory test variables and 
events observed by the Investigator; subjects should be instructed to report any AE that they 
experience to the Investigator. At each indicated visit, Investigators should make an assessment 
for AEs and record the event on the appropriate AE eCRF. 
Wherever possible, a specific disease or syndrome rather than individual associated signs and 
symptoms should be identified by the Investigator and recorded on the eCRF. However, if an 
observed or reported sign or symptom is not considered a component of a specific disease or 
syndrome by the Investigator, it should be recorded as a separate AE on the eCRF. Additionally, 
the condition that led to a medical or surgical procedure (e.g. surgery, endoscopy, tooth 
extraction, or transfusion) should be recorded as an AE, not the procedure.  
Any medical condition already present prior to the first dose of study drug should be reported in 
medical history unless the medical condition or signs or symptoms present at baseline change in 
severity or seriousness at any time during the study. In this case, it should be reported as an AE. 
Clinically significant abnormal laboratory or other examination (e.g. ECG) findings that are 
detected during the study or are present at screening and significantly worsen during the study 
should be reported as AEs. The Investigator will exercise his or her medical and scientific 
judgment in deciding whether an abnormal laboratory finding or other abnormal assessment is 
clinically significant. Clinically significant abnormal laboratory values occurring during the 
clinical study will be followed until repeat tests return to normal, stabilize, or are no longer 
clinically significant. Any abnormal test that is determined to be an error does not require 
reporting as an AE. 
Examples of AEs include the following: 
• Significant or unexpected worsening or exacerbation of the indication under study 
• Exacerbation of a chronic or intermittent preexisting condition, including an increase in 
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• New conditions detected or diagnosed after investigational agent administration even if they 
were present before the start of the study 
• Signs, symptoms, or the clinical sequelae of a suspected interaction with another medical 
product 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either investigational 
agent or a concurrent medication. 
An overdose should not be reported as an AE or SAE; instead, the symptoms resulting from the 
overdose should be reported as the AE or SAE. 
Examples of AEs do not include the following: 
• Medical or surgical procedures (e.g. endoscopy, appendectomy); instead, the medical 
condition that led to the procedure is an AE 
• Situations that are unwanted but in which an untoward medical occurrence did not occur 
(e.g. social inconvenience after admission to a hospital) 
• Anticipated day-to-day fluctuations of a pre-existing disease or condition (present or detected 
before enrollment) that does not worsen overall 
A follow-up is required for all subjects with AEs until the event has been resolved or the 
condition has stabilized. In case of unresolved AEs, including significant abnormal laboratory 
values at the EOT visit assessment, these events will be followed up until resolution or until they 
become clinically not relevant. 
7.1.1 
Disease Progression and Other Events of Clinical Interest 
7.1.1.1 
Disease Progression 
Progression of the cancer under study is not considered an AE in this study unless it is 
considered to be drug-related by the investigator. The term "disease progression" should be 
recorded as an AE/SAE only if there are no other identifiable AEs/SAEs associated with the 
disease progression at the time of reporting. For events associated with disease progression, the 
relevant signs and symptoms should be reported using a diagnosis whenever possible rather than 
individual underlying signs and symptoms. When a clear diagnosis cannot be identified, each 
sign or symptom should be reported as a separate AE. If the events resulting from disease 
progression meet the criteria for an SAE (e.g. resulted in hospitalization, a life-threatening event, 
or death), the specific event(s) should be reported as an SAE(s). In both cases (i.e. AEs or SAEs 
related to disease progression), it should be indicated that each event (reported as a diagnosis or 
as signs and symptoms) is related to disease progression on the AE eCRF. 

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7.1.1.2 
Events of Clinical Interest 
 
 
 
 
 
 
Drug-Induced Liver Injury 
Serum chemistry laboratory values consistent with Hy’s Law criteria (i.e. all 3 of the following 
must coexist): 
• ALT or AST ≥ 3 × ULN 
• Total bilirubin ≥ 2 × ULN 
• ALP < 2 × ULN 
Laboratory values meeting all criteria for potential Hy’s Law cases from the time of first study 
drug administration through the EOT visit are considered ECI and should be reported following 
SAE reporting procedures (Section 7.3). 
7.1.2 
Assessment of Adverse Events by the Investigator 
The Investigator will assess the severity (intensity) of each AE and the potential relationship 
between the AE and the study medication. 
Assessment of Severity: 
The severity of all AEs should be graded according to the NCI-CTCAE v. 4.03 
(http://ctep.cancer.gov/reporting/ctc.html). For AEs not listed in the CTCAE, the following 
grading system should be used: 
• Mild (CTCAE Grade 1): Transient symptoms, awareness of sign/symptom, but easily 
tolerated and no interference with subject’s daily activities 
• Moderate (CTCAE Grade 2): Marked signs/symptoms that interfere with subject’s usual 
activities, but still acceptable 
• Severe (CTCAE Grade 3): Incapacitating signs/symptoms which cause considerable 
interference with the subject’s daily activities, unacceptable 
• Life-threatening (CTCAE Grade 4): Life-threatening or disabling AE 
• Death (CTCAE Grade 5): Death-related AE 
Attribution: 
The Investigator is obligated to estimate the relationship between the investigational agents and 
the occurrence of each AE or SAE using best clinical judgment. Other causes, such as the 
underlying disease, concomitant therapy, other risk factors, and the temporal relationship of the 

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event to the investigational agents should be considered and investigated. The Investigator 
should consult the IB or product labeling information for marketed products in the determination 
of the assessment. The Investigator should consider all possible etiologies for the AE and render 
a causality assessment based on the most likely contributing factor to the AE. 
There may be situations when an SAE has occurred and the Investigator has minimal information 
to include in the initial report. However, the Investigator must assess causality for every event 
before the transmission of the SAE. The Investigator may change his or her opinion of the 
causality in light of follow-up information, amending the SAE report.  
The assessment of the relationship between the AE and the study medication will be determined 
using one of the following attribution categories as outlined in the NCI Guidelines: Adverse 
Event Reporting Requirements (2013).   
RELATIONSHIP 
ATTRIBUTION 
DESCRIPTION 
Unrelated to 
investigational 
agent/intervention 
Unrelated 
The AE is clearly NOT related to the 
intervention 
Unlikely Related 
The AE is doubtfully related to the 
intervention 
Related to investigational 
agent/intervention 
Possibly Related 
The AE may be related to the 
intervention 
Probably Related 
The AE is likely related to the 
intervention 
Definitely Related 
The AE is clearly related to the 
intervention 
AEs listed as possibly, probably, or definitely related are considered to have a suspected 
“reasonable causal relationship” to the investigational agent/intervention (ICH E2A). The 
expression "reasonable causal relationship" is meant to convey in general that there are facts 
(evidence) or arguments to suggest a causal relationship 
7.2 
Serious Adverse Events 
An AE or adverse reaction is considered serious if, in the view of either the Investigator or 
Sponsor, it results in any of the following outcomes: 
• Death 
• A life-threatening AE 
o NOTE: An AE or adverse reaction is considered “life-threatening” if, in view of 
either the Investigator or Sponsor, its occurrence places the subject at immediate risk 
of death. It does not include an event that, had it occurred in a more severe form, 
might have caused death. 

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• Requires hospitalization or prolongation of existing hospitalizations; 
o NOTE: Any hospital admission with at least 1 overnight stay will be considered an 
inpatient hospitalization. An emergency room visit without hospital admission will 
not be recorded as an SAE under this criterion, nor will hospitalization for a 
procedure scheduled or planned before signing of informed consent. However, 
unexpected complications and/or prolongation of hospitalization that occur during 
elective surgery should be recorded as AEs and assessed for seriousness. Admission 
to the hospital for social or situational reasons (i.e. no place to stay, live too far away 
to come for hospital visits) or for observation post-study drug administration will not 
be considered a SAE.  
• A persistent or significant disability/incapacity or substantial disruption of the ability to 
conduct normal life functions 
• A congenital anomaly/birth defect; or 
• An important medical event 
o NOTE: Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered an SAE when, based upon appropriate 
medical judgment, they may jeopardize the subject and may require medical or 
surgical intervention to prevent one of the outcomes listed above. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalizations, or the development of drug dependency. 
7.3 
Serious Adverse Event Reporting − Procedures for Investigators 
7.3.1 
Initial Reports 
SAEs will be collected from the time of first study drug administration through 90 days 
following cessation of treatment, or 28 days following cessation of treatment if the subject 
initiates new anticancer therapy, whichever is earlier. SAEs and events of clinical interest must 
be reported to the Sponsor (or designee) within 24 hours of the knowledge of the occurrence. 
Outside of the 90-day period, only SAEs considered related to the administration of study drug 
must be reported to the Sponsor. 
In the event an SAE is observed or reported, the SAE report will be completed as thoroughly as 
possible including all available details about the event and the signature of the Investigator. If the 
Investigator does not have all information about an SAE, the Investigator will not wait to receive 
additional information before notifying the Sponsor of the event and completing the form. The 
form will be updated when additional information is received.  
Complete the paper SAE form for each SAE. The SAE form will be faxed or emailed to the 
Sponsor or designee within 24 hours of awareness of the initial or any follow-up information, 
and designated study personnel will be notified electronically. If the SAE falls on a weekend or 

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holiday, an email notification is acceptable but must be followed by an SAE reporting form on 
the next business day. 
7.3.2 
Safety Reporting Contact Information 
Safety contact information may be found in the Study Reference Manual. 
7.3.3 
Expedited Reporting Requirements 
The Sponsor (or designee) will report all SAEs that are unexpected and considered related to the 
administration of the investigational agent to the appropriate health and regulatory authorities 
and Investigators in the form of an expedited safety report within 15 calendar days after 
receiving information on the SAE. The Investigators will notify their reviewing IRB/EC and 
other committee(s) as required by institutional policies. 
The Sponsor will also report to the appropriate health and regulatory authorities by facsimile, e-
mail, or phone within 7 days of receiving the information, any unexpected life-threatening or 
fatal SAEs that are considered related to the investigational agent.  
7.3.4 
Follow-Up Reports 
The Investigator must continue to follow the subject until the SAE has subsided or until the 
condition becomes chronic in nature, stabilizes (in the case of persistent impairment), or the 
subject dies. 
Within 24 hours of receipt of follow-up information, the Investigator must update the SAE form 
and submit any supporting documentation (e.g. subject discharge summary or autopsy reports) 
via fax or e-mail to the Sponsor or designee.  
7.3.5 
Adverse Events of Special Interest 
Suspected infection with CRS-207 and/or Listeria are considered AESIs and should be reported 
following SAE reporting procedures in Section 7.3 irrespective of temporal relationship to study 
drug administration. 
In the event a subject has a positive Listeria culture at any time during or after study 
participation (except within 4 days after a CRS-207 infusion), a detailed narrative of the event 
should be reported to the Sponsor within 24 hours of the event. 
All AESIs must be reported for the duration of the study regardless of causality. 
7.4 
Pregnancy Reporting 
If the subject or partner of a subject participating in the study becomes pregnant during the study 
or within 120 days of discontinuing study drug (or 28 days if the subject initiates new anticancer 
therapy, whichever is earlier) the Investigator should report the pregnancy within 24 hours of 
being notified. Designated safety personnel will then forward the Exposure In Utero form to the 
Investigator for completion.  

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A subject becoming pregnant while on study drug will immediately be withdrawn from the study 
and EOT study procedures will be performed. 
The subject or partner should be followed by the Investigator until completion of the pregnancy. 
If the pregnancy ends for any reason before the anticipated date, the Investigator should notify 
designated safety personnel. At the completion of the pregnancy, the Investigator will document 
the outcome of the pregnancy. SAE reporting procedures should be followed if the outcome of 
the pregnancy meets the criteria for immediate classification as an SAE (i.e. postpartum 
complication, spontaneous abortion, stillbirth, neonatal death, or congenital anomaly). 
 
 
 
 
 
 
 
 
 
 
 

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8 
DATA MANAGEMENT AND RECORD KEEPING 
8.1 
Data Handling 
Data will be recorded at the site on eCRFs and reviewed by the clinical research associate (CRA) 
during monitoring visits. The CRA will verify data recorded in the EDC system with source 
documents. All corrections or changes made to any study data must be appropriately tracked in 
an audit trail in the EDC system. An eCRF will be considered complete when all missing, 
incorrect, and/or inconsistent data has been accounted for and electronically signed by the 
Investigator or assignee. 
Data will be processed using a validated computer system conforming to regulatory 
requirements. 
8.2 
Data Entry 
Data must be recorded using the EDC system as the study is in progress. All site personnel must 
log into the system using their secure user name and password in order to enter, review, or 
correct study data. These procedures must comply with Title 21 of the Code of Federal 
Regulations (21 CFR Part 11) and other appropriate international regulations. All passwords will 
be strictly confidential. 
8.3 
Medical Information Coding 
For medical information, the following thesauri will be used: 
• Latest version of MedDRA (version 18.1 or higher) for medical history and AEs, and 
• World Health Organization Drug Dictionary Enhanced (Sept. 2015 or later) for prior and 
concomitant medications. 
8.4 
Data Validation 
Validation checks programmed within the EDC system, as well as supplemental validation 
performed via review of the data, will be applied to the data in order to ensure accurate, 
consistent, and reliable data. Data identified as erroneous, or data that are missing, will be 
referred to the site for resolution through data queries. 
The eCRFs must be reviewed and electronically signed by the Investigator in order to be 
considered complete. 
8.5 
Record Keeping 
Records of subjects, source documents, monitoring visit logs, eCRFs, inventory of study drugs, 
regulatory documents, and other Sponsor correspondence pertaining to the study must be kept in 
the appropriate study files at the site. Source data is defined as all information in original records 
and certified copies of original records of clinical findings, observations, or other activities in a 
clinical study necessary for the evaluation and reconstruction of the clinical study. Source data 

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are contained in source documents (original records or certified copies). These records will be 
retained in a secure file for the period as set forth in the Clinical Study Agreement. Prior to 
transfer or destruction of these records, the Sponsor must be notified in writing and be given the 
opportunity to further store such records.  

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9 
INVESTIGATOR REQUIREMENTS AND QUALITY CONTROL 
9.1 
Ethical Conduct of the Study 
Good Clinical Practice (GCP) is an international ethical and scientific quality standard for 
designing, conducting, recording, and reporting studies that involve human subjects. Compliance 
with this standard provides public assurance that the rights, safety, and well-being of study 
subjects are protected, consistent with the principles that have their origin in the Declaration of 
Helsinki, and that the clinical study data are credible. 
9.2 
Investigator Requirements 
Each Investigator must provide the Sponsor and/or its designee a completed and signed Form 
FDA 1572 and a Financial Disclosure Form. All sub-Investigators must be listed on Form FDA 
1572 and Financial Disclosure Forms must be completed for all sub-Investigators listed on Form 
FDA 1572. 
A Coordinating Investigator will be identified for multicenter trials conducted in the EU and 
Australia. The Coordinating Investigator will be selected on the basis of active participation in 
the trial, thorough knowledge of the therapeutic area being studied, and the ability to interpret 
data. 
9.2.1 
Disposition and Accountability of Investigational Products 
The Investigator is responsible for the control of investigational products under study. An 
investigational product dispensing log must be kept current and should contain the following 
information: 
• The identification number for each subject who is administered the investigational product 
• The date(s) and quantity of the investigational product administered to the subject 
• Documentation of proper disposal of used investigational product vials or unused vials 
subjected to temperature excursion 
• Documentation of proper disposal (or return, at Sponsor’s request) of unused investigational 
product vials. 
The Investigator is responsible for investigational product accountability during on-site 
monitoring visits. All records and used/unused supplies of the investigational product must be 
available for inspection at every monitoring visit. 
The study sites, per institutional guidelines, will destroy used investigational product vials after 
formulation for administration. The formulation of investigational product for administration and 
the destruction of each used vial will be documented in the investigational product accountability 
log. Unused investigational product will be destroyed at the study site after final investigational 
product accountability and notification by Sponsor, unless otherwise directed by Sponsor. 

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9.3 
Institutional Review Board/Ethics Committee 
The IRB/EC will review all appropriate study documentation in order to safeguard the rights, 
safety, and well-being of subjects. The study will only be conducted at sites where IRB/EC 
approval has been obtained. The protocol, IB, ICF, advertisements (if applicable), written 
information given to the subjects, safety updates, annual progress reports, and any revisions to 
these documents will be provided to the IRB/EC by the Investigator. 
Federal regulations and International Conference on Harmonisation (ICH) require that approval 
be obtained from an IRB/EC prior to participation of subjects in research studies. Prior to study 
onset, the protocol, any protocol amendments, ICFs, advertisements to be used for subject 
recruitment, and any other written information regarding this study to be provided to a subject or 
subject’s legal guardian must be approved by the IRB/EC. 
No study drug will be released to the site for dosing until written IRB/EC authorization has been 
received by the Sponsor. 
9.4 
Informed Consent 
The ICF and any changes to the ICF made during the course of the study must be agreed to by 
the Sponsor or designee and the IRB/EC prior to its use and must be in compliance with all ICH 
GCP, local regulatory requirements, and legal requirements.  
The Investigator must ensure each study subject is fully informed about the nature and objectives 
of the study and possible risks associated with participation and must ensure the subject has been 
informed of his/her rights to privacy. The Investigator will obtain written informed consent from 
each subject before any study-specific activity is performed and will document consent was 
obtained prior to enrollment in the study in the source documentation. The original signed copy 
of the ICF must be maintained by the Investigator and is subject to inspection by a representative 
of the Sponsor, auditors, the IRB/EC, and/or regulatory agencies. A copy of the signed ICF will 
be given to the subject. 
9.5 
Study Monitoring Requirements 
To ensure the study is conducted in accordance with the protocol and ICH GCP, the study 
monitor will aid the Investigator and, at the same time, the Sponsor in the maintenance of 
complete, legible, well organized and easily retrievable data. Before the enrollment of any 
subject in this study, the Sponsor or their designee will review with the Investigator and site 
personnel the following documents: protocol, IB, eCRFs and procedures for their completion, 
informed consent process, study drug management, and the procedure for reporting SAEs. 
The Investigator will permit the Sponsor or their designee to monitor the study as frequently as 
deemed necessary to determine that data recording and protocol adherence are satisfactory. 
During monitoring visits, information recorded on the eCRFs will be verified against source 
documents and requests for clarification or correction may be made. After the eCRF data are 
entered by the site, the monitor will review the data for safety information, completeness, 

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accuracy, and logical consistency. Computer programs that identify data inconsistencies may be 
used to help monitor the clinical study. If necessary, requests for clarification or correction will 
be sent to Investigators. The Investigator and his/her staff will be expected to cooperate with the 
monitor and provide any missing information, whenever possible. 
All monitoring activities will be reported and archived. In addition, monitoring visits will be 
documented at the site by signature and date on the study-specific monitoring log. 
9.6 
Disclosure of Data 
Data generated by this study must be available for inspection by health and regulatory authorities 
(such as FDA, Health Canada, European Medicines Authority, and others), the Sponsor or 
designee, and the IRB/EC as appropriate. Subjects or their legal representatives may request their 
medical information be given to their personal physician or other appropriate medical personnel 
responsible for their welfare. 
Subject medical information obtained during the study is confidential and disclosure to third 
parties other than those noted above is prohibited. 
9.7 
Retention of Records 
To enable evaluations and/or audits from regulatory authorities or the Sponsor, the Investigator 
will keep records, including the identity of all participating subjects (sufficient information to 
link records, e.g. eCRFs and hospital records), all original signed ICFs, copies of all eCRFs, SAE 
forms, source documents, and detailed records of treatment disposition. The records should be 
retained by the Investigator according to specifications in the ICH guidelines, local regulations, 
or as specified in the Clinical Study Agreement, whichever is longer. The Investigator must 
obtain written permission from the Sponsor before disposing of any records, even if retention 
requirements have been met. 
If the Investigator relocates, retires, or for any reason withdraws from the study, the Sponsor 
should be prospectively notified. The study records must be transferred to an acceptable 
designee, such as another Investigator, another institution, or to the Sponsor.  
9.8 
Publication Policy 
Following completion of the study, the data may be considered for publication in a scientific 
journal or for reporting at a scientific meeting. Each Investigator is obligated to keep data 
pertaining to the study confidential. The Investigator must consult with the Sponsor before any 
study data are submitted for publication. The Sponsor reserves the right to deny publication 
rights until mutual agreement on the content, format, interpretation of data in the manuscript, and 
journal selected for publication are achieved. 

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9.9 
Financial Disclosure 
Investigators are required to provide financial disclosure information to the Sponsor to permit the 
Sponsor to fulfill its obligations under 21 CFR §54. In addition, Investigators must commit to 
promptly updating this information if any relevant changes occur during the study and for a 
period of 1 year after the completion of the study. 
9.10 
Insurance and Indemnity 
In accordance with the relevant national regulations, the Sponsor has taken out subject liability 
insurance for all subjects who have given their consent to the clinical study. This cover is 
designed for the event that a fatality, physical injury, or damage to health occurs during the 
clinical study’s execution. 
9.11 
Legal Aspects 
The clinical study is submitted to the relevant national competent authorities in all participating 
countries to achieve a clinical trial authorization (CTA). 
The study will commence (i.e. initiation of study centers) when the CTA and favorable ethics 
opinion have been received.  

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10 
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Einama, T., Homma, S., Kamachi, H., et al., 2012. Luminal membrane expression of mesothelin 
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Ferlay, J., Shin, H.R., Bray, F., et al., 2010. Estimates of worldwide burden of cancer in 2008: 
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Hassan, R., Bera, T., Pastan, I., 2004. Mesothelin: a new target for immunotherapy. Clin Cancer 
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Hassan, R.A., S.J; Alley, E.W.; Kindler, H.L.; Jahan, T.; Grous, J.J.; Honarmand, S.; McDougall, 
K.; Whiting, C.C.; Nair, N.; Lemmens, E.; Tsujikawa, T.; Kumar, S.; Coussens, L.; Murphy, A. 
L.; Thomas, A.; Brockstedt, D.G., 2015. CRS-207, a mesothelin-targeted immunotherapy, in 
combination with standard of care chemotherapy as treatment for malignant pleural 
mesothelioma (MPM), European Cancer Congress 2015. 

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cancers: phase I studies of safety and immune induction. Clin Cancer Res 18:858-68. 
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clinical outcomes in patients (Pts) with advanced gastric cancer treated with the anti-PD-1 
monoclonal antibody pembrolizumab (Pembro; MK-3475) in KEYNOTE-012. J Clin Oncol 
(Meeting Abstracts) 33:abstr 3. 
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Wang, M., Busuttil, R.A., Pattison, S., et al., 2016. Immunological battlefield in gastric cancer 
and role of immunotherapies. World J Gastroenterol 22:6373-84. 
 

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11 
IMMUNE-RELATED RESPONSE CRITERIA IN SOLID TUMORS 
Based on an analysis of patients with melanoma enrolled in pembrolizumab study KEYNOTE-
001, 7% of evaluable subjects experienced delayed or early tumor pseudoprogression. Of note, 
patients who had progressive disease by RECIST v1.1 but not by immune-related response 
criteria had longer OS than patients with progressive disease by both criteria. Additionally, the 
data suggest that RECIST v1.1 may underestimate the benefit of pembrolizumab in 
approximately 15% of patients. These findings support the need to apply a modification to 
RECIST v1.1 that takes into account the unique patterns of atypical response in immunotherapy 
and enable treatment beyond initial radiographic progression.  
Immune-related RECIST (irRECIST) is RECIST v1.1 adapted to account for the unique tumor 
response seen with immuno-therapeutics as described in Nishino et al. 2013 (Nishino, 2013). The 
assessment of unidimensional target lesions and response categories per irRECIST are identical 
to RECIST v1.1.  However, Merck has implemented an adaptation related to new lesions, non-
target and tumor burden assessment in order to confirm radiographic progression. irRECIST will 
be used by local site investigators to assess tumor response and progression, and make treatment 
decisions in support of ORR endpoint.   
Therefore, RECIST v1.1 will be used with the following adaptations: 
In subjects who have initial evidence of radiological progressive disease (PD) by RECIST v1.1 
as determined by the site, it is at the discretion of the PI whether to continue a subject on study 
treatment until repeat imaging is obtained (irRECIST subject management).  This clinical 
judgment decision by the site should be based on the subject’s overall clinical condition, 
including performance status, clinical symptoms, and laboratory data.  Subjects may receive 
study treatment and tumor assessment should be repeated ≥ 4 weeks later in order to confirm PD 
by irRECIST per site assessment.  Clinical stability is defined as the following:  
1. Absence of symptoms and signs indicating clinically significant progression of 
disease, including worsening of laboratory values 
2. No decline in ECOG performance status  
3. Absence of rapid progression of disease  
4. Absence of progressive tumor at critical anatomical sites (e.g. cord compression) 
requiring urgent alternative medical intervention   
In determining whether or not the tumor burden has increased or decreased per irRECIST, the 
local site investigator should consider all target and non-target lesions as well as any incremental 
new lesion(s). 
Scenarios where PD is confirmed at repeat imaging if ANY of the following occur by irRECIST: 
• Tumor burden remains ≥ 20% and at least 5 mm absolute increase compared to nadir 
• Non-target disease resulting in initial PD is qualitatively worse 

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• New lesion resulting in initial PD is qualitatively worse 
• Additional new lesion(s) since last evaluation 
• Additional new non-target progression since last evaluation 
If repeat imaging confirms PD due to any of the scenarios listed above, subjects will be 
discontinued from study therapy (exception noted below). 
Scenarios where PD is not confirmed at repeat imaging if ALL of the following occur by 
irRECIST:  
• Tumor burden is < 20 % or < 5 mm absolute increase compared to nadir 
• Non-target disease resulting in initial PD is qualitatively stable or improved 
• New lesion resulting in initial PD is qualitatively stable or improved 
• No incremental new lesion(s) since last evaluation 
• No incremental new non-target progression since last evaluation 
If repeat imaging does not confirm PD by irRECIST and the subject continues to be clinically 
stable, treatment may continue and follow the regular imaging schedule. When feasible, subjects 
should not be discontinued until progression is confirmed by the local site investigator/radiology 
assessment.  This allowance to continue treatment despite initial radiologic PD takes into account 
the observation that some subjects can have a transient tumor flare in the first few months after 
the start of immunotherapy, and then experience subsequent disease response.  Subjects that are 
deemed clinically unstable are not required to have repeat tumor imaging for confirmation of PD. 
Tumor flare includes any of the following scenarios: 
• Worsening of existing target lesion(s) 
• Worsening of existing non-target lesion(s) 
• Development of new lesion(s) 
RECIST 1.1 will be adapted to account for the unique tumor response characteristics seen with 
treatment of pembrolizumab.  Immunotherapeutic agents such as pembrolizumab may produce 
antitumor effects by potentiating endogenous cancer-specific immune responses.  The response 
patterns seen with such an approach may extend beyond the typical time course of responses 
seen with cytotoxic agents, and can manifest a clinical response after an initial increase in tumor 
burden or even the appearance of new lesions.  Standard RECIST 1.1 may, thus, not provide an 
accurate response assessment of immunotherapeutic agents such as pembrolizumab.  
irRECIST is RECIST v1.1 adapted to account for the unique tumor response seen with immuno-
therapeutics as described in Nishino et al. 2013 (Nishino, 2013).  The assessment of 
unidimensional target lesions and response categories per irRECIST are identical to RECIST 
v1.1.  However, Merck has implemented an adaptation related to new lesions, non-target and 
tumor burden assessment in order to confirm radiographic progression. irRECIST will be used 

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by local site investigators to assess tumor response and progression, and make treatment 
decisions.   
Therefore, RECIST v1.1 will be used with the following adaptations: 
In subjects who have initial evidence of radiological PD by RECIST v1.1 as determined by the 
site, it is at the discretion of the PI whether to continue a subject on study treatment until repeat 
imaging is obtained (irRECIST subject management).  This clinical judgment decision by the site 
should be based on the subject’s overall clinical condition, including performance status, clinical 
symptoms, and laboratory data.  Subjects may receive study treatment and tumor assessment 
should be repeated ≥ 4 weeks later in order to confirm PD by irRECIST per site assessment.  
Clinical stability is defined as the following:  
1) Absence of symptoms and signs indicating clinically significant progression of disease, 
including worsening of laboratory values 
2) No decline in ECOG performance status  
3) Absence of rapid progression of disease  
4) Absence of progressive tumor at critical anatomical sites (e.g., cord compression) requiring 
urgent alternative medical intervention   
In determining whether or not the tumor burden has increased or decreased per irRECIST, the 
local site investigator should consider all target and non-target lesions as well as any incremental 
new lesion(s). 
Scenarios where PD is confirmed at repeat imaging if ANY of the following occur by irRECIST: 
• Tumor burden remains ≥ 20% and at least 5 mm absolute increase compared to nadir 
• Non-target disease resulting in initial PD is qualitatively worse 
• New lesion resulting in initial PD is qualitatively worse 
• Additional new lesion(s) since last evaluation 
• Additional new non-target progression since last evaluation 
If repeat imaging confirms PD due to any of the scenarios listed above, subjects will be 
discontinued from study therapy (exception noted below and in Section 6.4.2.1). 
Scenarios where PD is not confirmed at repeat imaging if ALL of the following occur by 
irRECIST:  
• Tumor burden is < 20 % or < 5 mm absolute increase compared to nadir 
• Non-target disease resulting in initial PD is qualitatively stable or improved 
• New lesion resulting in initial PD is qualitatively stable or improved 

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• No incremental new lesion(s) since last evaluation 
• No incremental new non-target progression since last evaluation 
If repeat imaging does not confirm PD by irRECIST and the subject continues to be clinically 
stable, treatment may continue and follow the regular imaging schedule.  
When feasible, subjects should not be discontinued until progression is confirmed by the local 
site investigator/radiology assessment.  This allowance to continue treatment despite initial 
radiologic progressive disease (PD) takes into account the observation that some subjects can 
have a transient tumor flare in the first few months after the start of immunotherapy, and then 
experience subsequent disease response.  Subjects that are deemed clinically unstable are not 
required to have repeat tumor imaging for confirmation of PD. Tumor flare includes any of the 
following scenarios: 
• Worsening of existing target lesion(s) 
• Worsening of existing non-target lesion(s) 
• Development of new lesion(s) 
 

Aduro Biotech, Inc. 
Clinical Study Protocol ADU-CL-14· 
SIGNATURE PAGE 
STUDY TITLE: A Phase 2, Open-label Evaluation of CRS-207 and Pembrolizumab in 
Adults with Recurrent or Metastatic Gastric/Gastroesophageal Junction or Esophageal 
Adenocarcinomas 
I, the undersigned, have read Protocol ADU-CL-14 and agree it contains all necessary 
information required to conduct the study. 
Signature 
·Natalie Sacks, MD 
Chief Medical Officer 
Aduro Biotech, Inc. 
Confidential & Proprietary 
Version: Amendment 2, 22 August 2017 
Date 
87 

Aduro Biotech, Inc. 
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Version: Amendment 2, 22 August 2017 
88 
INVESTIGATOR AGREEMENT 
STUDY TITLE: A Phase 2, Open-label Evaluation of CRS-207 and Pembrolizumab in 
Adults with Recurrent or Metastatic Gastric/Gastroesophageal Junction or Esophageal 
Adenocarcinomas 
By signing below I agree that: 
I have read the protocol and agree it contains all necessary details for carrying out the study as 
described. I will conduct this study in accordance with the design and specific provisions of this 
protocol and will make a reasonable effort to complete the study within the time designated. I will 
provide copies of this protocol and access to all information furnished by Aduro Biotech to study 
personnel under my supervision. I will discuss this material with them to ensure they are fully 
informed about the study product and study procedures. I will let them know this information is 
confidential and proprietary to Aduro Biotech and may not be further disclosed to third parties. I 
understand that the study may be terminated or enrollment suspended at any time by Aduro 
Biotech, with or without cause. I have the right to suspend enrollment of subjects at my study site 
if necessary to protect the best interests of the study subjects. 
I agree to conduct this study in full accordance with United States Food and Drug Administration 
Regulations, Institutional Review Board/Ethics Committee Regulations, and International 
Conference on Harmonisation (ICH) Guidelines for Good Clinical Practices. 
 
 
 
 
 
______________________________________________  
____________________ 
Investigator’s Signature 
 
 
 
 
 
Date 
 
 
 
______________________________________________ 
Investigator’s Printed Name