Conditions: Pancreatic Cancer
Keywords: CY Cyclophosphamide Pancreatic Vaccine GVAX Nivolumab Vaccine Ipilimumab CRS-207 Immunotherapy PD-1 Adenocarcinoma Carcinoma Neoplasms
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 61
Healthy volunteers: no

Brief summary:
The purpose of this study is to study the safety and clinical activity of nivolumab and ipilimumab in combination with either sequential administration of CY/GVAX pancreas vaccine followed by CRS-207 (Arm A) or with administration of CRS-207 alone (Arm B) in patients with pancreatic cancer.

Detailed description:

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: Cyclophosphamide intervention 2: Nivolumab intervention 3: Ipilimumab intervention 4: GVAX Pancreas Vaccine intervention 5: CRS-207 intervention 6: CRS-207
Intervention descriptions: intervention 1: Patients will receive treatment every 3 weeks for 6 cycles of treatment within a course (total of 18 weeks). Cyclophosphamide (200 mg/m2) will be administered IV on day 1 of Cycles 1 and 2. intervention 2: Patients will receive treatment every 3 weeks for 6 cycles of treatment within a course (total of 18 weeks). Nivolumab (360 mg) will be administered IV on day 1 of Cycles 1-6. intervention 3: Patients will receive treatment every 3 weeks for 6 cycles of treatment within a course (total of 18 weeks). Ipilimumab (1 mg/kg) will be administered IV on Day 1 of Cycles 1, 3, and 5. intervention 4: Patients will receive treatment every 3 weeks for 6 cycles of treatment within a course (total of 18 weeks). Vaccine will be administered on Day 2 of Cycles 1 and 2. intervention 5: Patients will receive treatment every 3 weeks for 6 cycles of treatment within a course (total of 18 weeks). CRS-207 (1 × 109 CFU) will be administered IV on Day 2 of Cycles 3-6. intervention 6: Patients will receive treatment every 3 weeks for 6 cycles of treatment within a course (total of 18 weeks). CRS-207 (1 × 109 CFU) will be administered IV on Day 2 of Cycles 1-6.

Protocol document:
Prot_SAP_000.pdf: 
Cover Page for Protocol – J1790 
NCT Number: 
NCT03190265 
Official title of study 
A Randomized Phase 2 Study of the Safety, 
Efficacy, and Immune Response of CRS- 
207, Nivolumab, and Ipilimumab with or 
without GVAX Pancreas Vaccine (with 
Cyclophosphamide) in Patients with 
Previously Treated Metastatic Pancreatic 
Adenocarcinoma 
Document Date: 
December 10, 2020 


 
 
 
 
TITLE: A Randomized Phase 2 Study of the Safety, Efficacy, and Immune Response of CRS-
207, Nivolumab, and Ipilimumab with or without GVAX Pancreas Vaccine (with 
Cyclophosphamide) in Patients with Previously Treated Metastatic Pancreatic Adenocarcinoma 
 
Johns Hopkins Protocol #:  
 
J1790, IRB00137389 
 
BMS Protocol #: 
CA209-9LM 
 
Principal Investigator: 
Dr. Dung Le (Protocol Chair) 
 
 
 
 
 
 
 
  
 
IND Sponsor: 
Dr. Elizabeth Jaffee 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
IND:  
 
 
 
  
 
 
 
BB IND 16147 
 
Bristol-Myers Squibb Supplied Agent:  
 
Nivolumab (BMS-936558; anti-PD-1 mAb) 
  
 
 
 
 
Ipilimumab (BMS-734016; anti-CTLA-4 mAb) 
 
Johns Hopkins University Supplied Agent:  GVAX pancreas vaccine  
 
 
 
 
 
(Panc 10.05 pcDNA-1/GM-Neo, Panc 6.03 
pcDNA-1/GM-Neo); 
CRS-207 (Lm ΔactA/ΔinlB/hMesothelin) 
 
Commercial Agent:   
 
 
 
 
 
 
Cyclophosphamide (CY, Cytoxan®) 
 
Date of Issue: 
Version 1/ May 9, 2017 
Version 1.1/ June 30, 2017 
Version 2.0/ November 17, 2017 
Version 3.0/ June 1, 2018 
Version 4.0/ January 11, 2019 
Version 5.0/ June 28, 2019 
Version 6.0/ July 1, 2020 
Version 7.0/ December 10, 2020 
 
 
 


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2
TABLE OF CONTENTS 
 
1. 
OBJECTIVES ......................................................................................................................4 
1.1 
Primary Objective ....................................................................................................4 
1.2 
Secondary Objective ................................................................................................4 
1.3 
Exploratory Objectives ............................................................................................4 
1.4 
Study Design ............................................................................................................5 
2. 
BACKGROUND .................................................................................................................7 
2.1 
Study Disease ...........................................................................................................7 
2.2 
Rationale ..................................................................................................................8 
3. 
PATIENT SELECTION ....................................................................................................11 
3.1 
Inclusion Criteria ...................................................................................................11 
3.2 
Exclusion Criteria ..................................................................................................13 
3.3 
Inclusion of Women and Minorities ......................................................................16 
4.  
REGISTRATION, RANDOMIZATION, AND BLINDING ...........................................16 
4.1 
General Guidelines.................................................................................................16 
4.2 
Registration Process ...............................................................................................16 
4.3 
Randomization .......................................................................................................16 
5. 
TREATMENT PLAN ........................................................................................................16 
5.1 
Agent Administration.............................................................................................16 
5.2 
General Concomitant Medication and Supportive Care Guidelines ......................19 
5.3 
Prohibited and/or Restricted Medications and Devices .........................................22 
5.4 
Other Restrictions and Precautions ........................................................................23 
5.5 
Antibiotic Administration ......................................................................................24 
5.6 
Definition of an Overdose for this Protocol ...........................................................25 
5.7 
Unacceptable Toxicity ...........................................................................................26 
5.8 
WOCBP, Contraception, Use in Pregnancy, Use in Nursing ................................28 
5.9 
Duration of Therapy ...............................................................................................30 
5.10 
Criteria for Removal from Treatment ....................................................................30 
5.11 
End of Treatment (EOT) Visit ...............................................................................34 
5.12 
Duration of Follow-Up ..........................................................................................34 
5.13 
 
34 
6. 
DOSING DELAYS/DOSE MODIFICATIONS ...............................................................35 
6.1  
Dose Modifications ................................................................................................35 
6.2  
Dosing Delays ........................................................................................................35 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................37 
7.1 
Definitions..............................................................................................................37 
7.2 
Assessment of Causality ........................................................................................39 
7.3 
Expectedness ..........................................................................................................40 
7.4 
Handling of Expedited Safety Reports ..................................................................40 
7.5 
Reporting................................................................................................................40 
8. 
PHARMACEUTICAL INFORMATION ..........................................................................44 
8.1  
Cyclophosphamide (Cytoxan®, CY) ......................................................................44 


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8.2  
GVAX Pancreas Vaccine .......................................................................................46 
8.3  
CRS-207 .................................................................................................................48 
8.4  
Nivolumab..............................................................................................................51 
8.5  
Ipilimumab .............................................................................................................53 
9. 
CORRELATIVE/SPECIAL STUDIES .............................................................................56 
9.1 
Tumor Tissue Studies ............................................................................................56 
9.2 
Peripheral Blood Mononuclear Cells (PBMCs) ....................................................57 
9.3 
Serum and Plasma Marker Studies ........................................................................57 
9.4 
Stool and Oral Wash Samples Studies ...................................................................57 
9.5 
Diagnostic Tissue Samples ....................................................................................58 
9.6 
Genomic Analysis ..................................................................................................58 
10. 
STUDY CALENDAR .......................................................................................................59 
10.1  Treatment Arm A ...................................................................................................59 
10.2  Treatment Arm B ...................................................................................................63 
11.  
STUDY ENDPOINTS .......................................................................................................67 
11.1 
Primary Endpoint ...................................................................................................67 
11.2 
Secondary Endpoint ...............................................................................................67 
11.3 
Exploratory Endpoints ...........................................................................................67 
12. 
 DATA REPORTING / REGULATORY REQUIREMENTS ..........................................68 
12.1 
Data Collection and Processing .............................................................................68 
12.2 
Safety Meetings .....................................................................................................69 
12.3 
Monitoring .............................................................................................................70 
12.4 
Study Documentation.............................................................................................71 
13. 
STATISTICAL CONSIDERATIONS...............................................................................72 
13.1 
Study Design/Endpoints.........................................................................................72 
13.2 
Analysis Sets ..........................................................................................................74 
13.3 
Safety Analysis ......................................................................................................74 
REFERENCES ..............................................................................................................................75 
APPENDIX A: Performance Status Criteria .................................................................................77 
APPENDIX B: Management Algorithms ......................................................................................78 
APPENDIX C: Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for 
Evaluating Response in Solid Tumors ...............................................................................87 
APPENDIX D: Immune-Related Response Criteria .....................................................................90 
 


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1. OBJECTIVES 
 
1.1 
Primary Objective 
 
To determine the objective response rate (ORR) using Response Evaluation Criteria for 
Solid Tumors (RECIST 1.1) in two cohorts of subjects with previously treated metastatic 
pancreatic 
cancer: 
Arm 
A 
treated 
with 
cyclophosphamide 
(CY)/ 
nivolumab/ipilimumab/GVAX pancreas vaccine followed by nivolumab/ipilimumab/ 
CRS-207 and Arm B treated with nivolumab/ipilimumab/CRS-207. 
 
1.2 
Secondary Objective 
 
1.2.1 To assess safety and characterize toxicities of each vaccine treatment regimen when 
combined with anti-PD-1 and anti-CTLA-4 blockade in subjects with metastatic 
pancreatic adenocarcinoma. 
 
1.3 Exploratory Objectives 
 
1.3.1 To assess the overall survival (OS).  
 
1.3.2  To assess progression free survival (PFS), duration of response (DOR), and time to 
progression (TTP) by RECIST 1.1. 
 
1.3.3 To measure tumor marker kinetics (CA 19-9) in subjects receiving treatment and 
correlate with OS, PFS, and best overall response. 
 
1.3.4  To assess the ORR, PFS, and DOR by immune-related response criteria (irRC).  
 
1.3.5  To collect peripheral blood mononuclear cells (PBMC), plasma, and serum to 
identify potential therapeutic targets, biomarkers and predictors of response (OS, 
PFS and best overall response) and autoimmune toxicity.  
 
• 
Measure pre- and post-treatment changes in PBMCs including effector, 
helper, and regulatory T cells, NK cells, monocytes, and macrophages 
through cell phenotyping analysis and gene expression profiling.  
 
• 
Correlate induction of Listeria monocytogenes (Lm)- and mesothelin 
antigen-specific T cell responses and changes to the T cell epitope repertoire 
with OS, PFS, and best overall response. 
 
• 
Correlate telomere length of lymphocytes to help predict response (OS, 
PFS, and best overall response).  
 
• 
Correlate the induction of anti-thyroglobulin and anti-galectin-3 antibody 
responses with response (OS, PFS, and best overall response).   
 


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• 
Proteomic approaches will be used on pre- and post-treatment sera to 
identify targets and biomarkers of response (OS, PFS, and best overall 
response) or toxicity. 
 
1.3.6  To collect archived tissue and pre- and post-treatment biopsies to test for predictors 
of response (OS, PFS, and best overall response) and future targets for 
combinatorial therapy.   
• Immunohistochemistry (IHC) and/or gene expression profiling will be used 
to compare the nature of tumors and immune infiltrates for responders 
versus non-responders.   
• Next-generation sequencing of T cell receptor (TCR) genes may be used to 
compare the tumor infiltrating T cell repertoire in responders and non-
responders 
• Up-regulation of immune inhibitory molecules (such as programmed death-
ligand 1 [PD-L1]) will be evaluated in the pre- and post-treatment samples. 
 
• Proteomic approaches to quantify protein expression and activation of 
specific signaling pathways in tumors from responders versus non-
responders. 
1.3.7 To collect stool and oral wash samples pre- and post-treatment to identify candidate 
gut microbial biomarkers and predictors of response (OS, PFS and best overall 
response)   
• Microbial community analysis to correlate gut microbiome composition 
with response (OS, PFS and best overall response). 
 
• Whole metagenome functional profiling analysis via shotgun sequencing 
to correlate microbiome composition and microbial functions and 
pathways with response (OS, PFS and best overall response). 
 
1.4 
Study Design 
 
This is a multi-center, open-label, randomized, phase 2 study to evaluate the safety and clinical 
activity of nivolumab and ipilimumab in combination with either sequential administration of 
CY/GVAX pancreas vaccine followed by CRS-207 (Arm A) or with administration of CRS-207 
alone (Arm B) in subjects with metastatic pancreatic adenocarcinoma who have progressed after 
at least 1 prior chemotherapy regimen. The primary endpoint of this study is objective response 
rate (ORR) using RECIST 1.1. Approximately 63 subjects will be enrolled and randomized 1:1 to 
the two treatment arms to achieve 60 treated subjects (i.e. allowing for 5% loss). 
 
The study will consist of a screening period (within 21 days of first dose), a treatment period per 
the table below, and a follow-up period.  
  
 
 
 
 


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Table 1: Treatment Schedule 
 
TREATMENT SCHEDULE 
Arm 
CY 
Nivolumab 
Ipilimumab 
GVAX 
CRS-207 
A 
Day 1, 
Cycles 1, 2 
Day 1,  
Cycles 1, 2, 3, 4, 5, 6 
Day 1,  
Cycles 1, 3, 5 
Day 2,  
Cycles 1, 2 
Day 2,  
Cycles 3, 4, 5, 6 
B 
None 
Day 1,  
Cycles 1, 2, 3, 4, 5, 6 
Day 1,  
Cycles 1, 3, 5 
None 
Day 2,  
Cycles 1, 2, 3, 4, 5, 6 
 
Subjects on both arms will receive treatment every 3 weeks for 6 cycles of treatment within a 
course. A course of treatment will be 18 weeks and courses can be repeated. The treatment 
schedule for Arms A and B can be found in Table 1. Subjects will come to the clinic for dosing 
and/or assessments on Days 1 and 2 of each cycle and additional days for safety and immune 
monitoring follow-up per the study schedules in Section 10. 
 
No dose escalations or reductions are allowed. Enrollment will continue until 60 subjects have 
received at least one dose of study treatment.  It is estimated that 5% of the subjects will not receive 
treatment, so approximately 63 subjects will be randomized to achieve 30 treated subjects in Arm 
A and 30 treated subjects in Arm B. If the investigator assesses a drug-related toxicity (that requires 
discontinuation) to be related to an individual component of the treatment schedule, dosing for that 
study drug alone may be discontinued while dosing is delayed until the subject meets 
criteria to resume treatment of the other study drugs. The relationship to the discontinued study 
drug should be well documented in the source documents and permission from the Protocol Chair 
needs to be obtained prior to continuation with the other study drugs. 
  
The proportion of treated subjects with unacceptable toxicity will be monitored using a Bayesian 
stopping guideline within each treatment arm separately. Once the first 12 participants have been 
randomized (6 in each group), accrual will be suspended until the toxicity levels have been 
determined to be acceptable in both arms (i.e. confirmation that less than 3 subjects experience 
unacceptable toxicities during the first 4 weeks of treatment). Then, the remaining participants will 
be enrolled and monitored routinely. Complete unacceptable toxicity criteria can be found in 
Section 5.7.  
 
At the investigator’s discretion, subjects may receive additional courses of the assigned treatment 
regimen if they are clinically stable and meet dosing eligibility criteria. All subjects may continue 
in the treatment period up to a maximum of 2 years, or until discontinuation due to unacceptable 
toxicity, lack of clinical benefit as determined by the investigator, subject withdrawal, or 
termination of the study by IND Sponsor. Subjects that begin a new course prior to the 2 year cut-
off may complete that course prior to coming off study. Subjects may continue on treatment with 
radiographic disease progression if subject is clinically stable and investigator believes the 
treatment is providing benefit. Criteria for removal from treatment are found in Section 5.10. 
Subjects will return to the study site 28 (±7) days after the final administration of study treatment 
for an end-of-treatment (EOT) evaluation.
 
 
 
  Subjects who are still 


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7
receiving treatment at the time of study close may complete the current treatment course and the 
EOT evaluation prior to transitioning to long-term follow-up. Subjects will be considered in the 
treatment period until 28 days after the last dose of study drug. Blood cultures through a peripheral 
vein and also through a central line (if applicable) will be collected to monitor for the presence of 
CRS-207 per Section 5.13. 
 
After completion of treatment and EOT assessments, all subjects, including those who did not 
receive treatment, will continue to be followed every three months (+/- 2 weeks) by telephone, e-
mail, or optional clinic visit until death, withdrawal of consent, or closure of study.  Subjects will 
also be contacted at 100 days (+14 day reporting window) from the last dose of nivolumab/ 
ipilimumab or 28 days (+7 day reporting window) from the last dose of cyclophosphamide, 
GVAX, or CRS-207 if the subject never received nivolumab/ipilimumab or is no longer receiving 
nivolumab/ipilimumab due to toxicity, whichever reporting period is longer. Information on 
survival and new cancer therapies will be collected. In addition, all subjects that received at least 
one dose of CRS-207 will be monitored for CRS-207 infection for one year per Section 5.13. 
 
All subjects who discontinue study treatment should continue to be monitored for disease status 
by radiologic imaging every two months (+/- 2 weeks) until: 1) the start of a new antineoplastic 
therapy (information of the new cancer therapy will be collected), 2) disease progression, 3) death, 
4) withdrawal of consent, or 5) the close of the study, whichever occurs first.   
All subjects will be followed after their last dose of study drug for the development of adverse 
events (AEs) and serious adverse events (SAEs) as described in Section 7.5.1.  
 
The primary analysis will be conducted when all treated subjects have documented response or 
progression by RECIST 1.1, or have discontinued the study. Information on survival may continue 
to be gathered for supplementary analyses after the completion of the primary analysis. At the 
conclusion of the study, all remaining subjects will be offered enrollment in a long-term follow-
up study and continue to be followed for survival. 
 
2. BACKGROUND 
 
2.1 
Study Disease 
 
Despite decades of basic and clinical research, effective therapy for the treatment of patients with 
pancreatic ductal adenocarcinoma (PAC) remains one of the greatest unmet clinical needs in 
oncology today. Currently, PAC accounts for approximately 7% of all cancer-related mortality 
and has the lowest 5-year survival rate among all cancer types in the United States. PAC is 
currently the 4th leading cause of death from cancer in the U.S. with estimates in 2016 for 53,070 
people diagnosed and about 41,780 dying from the disease1.  Worldwide it will claim more than 
300,000 lives this year2.  It is projected that by 2030, pancreatic cancer will become the second 
leading cause of cancer-related death in the US3.  
 
Most patients are initially diagnosed with advanced disease that is inoperable with median survival 
of less than 1 year. Patients with advanced disease are usually treated with chemotherapy, with the 
intent of prolonging survival and palliating symptoms (pain, weight loss and decrease in 
performance status). From 1997, gemcitabine was the standard chemotherapy for advanced 
pancreatic cancer after demonstrating a significant improvement in survival compared to 5-


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8
fluorouracil (5-FU)4. Median survival was 5.65 months for gemcitabine-treated patients and 4.41 
months for 5-FU treated patients, while overall tumor response rates were 5.4% and 0%, 
respectively. 
 
Until recently, only erlotinib, an oral epidermal growth factor (EGF) inhibitor, was shown in a 
Phase 3 study to modestly improve median OS in combination with gemcitabine over gemcitabine 
alone (6.24 months for the doublet versus 5.91 months for gemcitabine alone) without a significant 
difference in ORR between the treatments5. In 2011, a Phase 2/3 trial conducted by a French 
consortium study group demonstrated FOLFIRINOX, a combined regimen of oxaliplatin, 
irinotecan, fluorouracil, and leucovorin significantly increased survival in patients with pancreatic 
cancer over gemcitabine alone. Median OS was 11.1 months versus 6.8 months for each treatment, 
respectively (hazard ratio [HR] for death, 0.57; 95% confidence interval [CI], 0.45 to 0.73; p < 
0.001). The ORR was also increased to 31.6% from 9.4% (p < 0.001). Adverse events were 
increased in the FOLFIRINOX group and 5.4% of patients in this group experienced febrile 
neutropenia6. Although FOLFIRINOX represents an efficacious regimen in pancreatic cancer, 
there are still concerns about its potential toxicity and it is being reserved for the most fit patients. 
 
In the MPACT (Metastatic Pancreatic Adenocarcinoma Clinical Trial) study, nab-paclitaxel 
combined with gemcitabine demonstrated a statistically significant and clinically meaningful 
median OS of 8.5 versus 6.7 months (HR 0.72, p < 0.0001 including a 59% increase in one-year 
survival (35% versus 22%, p=0.0002) and demonstrated double the rate of survival at two years 
(9% versus 4%, p=0.02) as compared to gemcitabine alone in previously untreated patients with 
metastatic pancreatic cancer. nab-/gemcitabine also demonstrated a statistically significant 
improvement in key secondary endpoints compared to gemcitabine alone, including a 31% 
reduction in the risk of progression or death with a median PFS of 5.5 versus 3.7 months (HR 0.69, 
p < 0.0001) and an ORR of 23% compared to 7% (response rate ratio of 3.19, p < 0.0001)7. The 
MPACT study and regimen formed the basis for full FDA approval in September 2013 for the 
first-line treatment of metastatic adenocarcinoma of the pancreas. 
 
Nanoliposomal irinotecan in combination with 5-FU was recently approved for patients with 
previously treated pancreatic cancer.  However, it is unknown if this combination is better than 5-
FU and irinotecan (FOLFIRI) as 5-FU was the comparator and there was no benefit in patients 
who previously received irinotecan so the value of this drug is questionable in FOLFIRINOX 
treated patients8.  Therapies for patients with metastatic pancreatic cancer are urgently needed.  
 
Novel approaches, such as immunotherapy, hold promise in this very difficult cancer.   
 
2.2 
Rationale 
 
Therapeutic benefit of immunotherapy in pancreatic cancer remains to be seen.  Single agent 
therapy using vaccines to induce antigen-specific T cells or targeting immune checkpoints such as 
programmed death-1 (PD-1) or cytotoxic T-lymphocyte associated protein-4 (CTLA-4) does not 
address the complex immunosuppressive mechanisms at play both at the systemic level and in the 
tumor microenvironment. Effective immunotherapy in pancreatic cancer may require 
combinations of 2 or more agents to overcome this tolerance.  Various combination strategies are 
being tested in less immunogenic tumors. CTLA-4 or PD-1 inhibition with pancreatic cancer 
vaccines is currently being studied with GVAX Pancreas (allogeneic pancreatic cancer cells 
modified to express GM-CSF) and CRS-207 (attenuated Lm expressing the tumor associated 


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9
antigen mesothelin). In each of these studies, there have been a handful of objective responses but 
in general pancreatic cancer has been refractory to immunotherapy and triplet approaches may be 
necessary.  Numerous studies are targeting various immune checkpoints and stimulatory agonists 
but it could possibly be futile without a vaccine to induce infiltration of an inflammatory infiltrate 
including effector T cells into the tumor. 
 
Immunotherapies in Pancreatic Cancer 
 
 
-
 
 
 
-
 
 
Nivolumab  
-
 
-
 
 
 
 
 


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-
-
 
 
-
-
 
-
 
 
Nivolumab Dose Selection 
 
–
-
 
 
 
 
 
 
Ipilimumab 
 


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-
 
-
 
 
 
 
 
Dual Blockade with Nivolumab and Ipilimumab 
 
 
 
 
-
 
 
 
 
-
 
 
 
3. PATIENT SELECTION 
 
3.1 
Inclusion Criteria 
 
3.1.1 Age ≥18 years.   
 
3.1.2 Have histologically- or cytologically-proven ductal adenocarcinoma of the 
pancreas.  Patients with mixed histology (>30% non-adenocarcinoma component) 
will be excluded. 
 
3.1.3 Have metastatic disease. 
 


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3.1.4 Have documented radiographic disease progression at the time of study enrollment, 
after previous systemic chemotherapy given in a neoadjuvant, adjuvant, locally 
advanced or metastatic setting.  
 
3.1.5 Presence of at least one lesion with measurable disease as defined by 10 mm in 
longest diameter for a soft tissue lesions or 15 mm in short axis for a lymph node 
by RECIST 1.1. 
 
3.1.6 Patient’s acceptance to have a tumor biopsy of an accessible lesion at baseline and 
on treatment if the lesion can be biopsied with acceptable clinical risk (as judged 
by the investigator). 
 
 
 
3.1.7 
ECOG performance status 0 or 1 (Appendix A). 
 
 
 
3.1.8 
Life expectancy of greater than 3 months. 
 
 
 
3.1.9 
Adequate organ and marrow function as defined below: 
 
− 
Leukocytes 
  
 
 
 
≥ 3,000/mcL 
− 
Absolute neutrophil count 
≥ 1,500/mcL 
− 
Lymphocyte count 
 
 
≥ 800/mcL 
− 
Platelets 
 
  
 
 
 
≥ 100 × 103/uL 
− 
Hemoglobin    
 
 
 
≥ 9.0 g/dL 
− 
Total bilirubin   
 
 
 
≤ upper limit of normal (ULN) except subjects with 
Gilbert Syndrome, who can have total bilirubin < 3.0 
mg/dL 
− 
AST(SGOT) and ALT(SGPT)≤2.0 × ULN 
− 
Alkaline phosphatase  
 
≤5.0 × ULN  
− 
Creatinine  
  
 
 
 
≤1.5 × ULN or creatinine clearance (CrCl) 
≥ 40 mL/min (if using the Cockcroft-Gault formula 
below): 
 
 
Female CrCl = (140 - age in years) x weight in kg x 0.85 
                              72 x serum creatinine in mg/dL 
 
    Male CrCl = (140 - age in years) x weight in kg x 1.00  
                    
 
 
 
 
72 x serum creatinine in mg/dL 
 
− 
Albumin  
 
  
 
 
≥3.0 g/dL 
 


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3.1.10 Women of childbearing potential (WOCBP) must have a negative serum pregnancy 
test (minimum sensitivity 25 IU/L or equivalent units of human chorionic 
gonadotropin [HCG]).  WOCBP is defined in Section 5.9. Patients with a positive 
HCG due to tumor secretion may be permitted to enroll if lack of pregnancy can be 
documented (e.g. transvaginal ultrasound or serial HCG) and with approval by the 
Protocol chair. 
 
- 
WOCBP must agree to follow instructions for method(s) of contraception from 
the time of enrollment for the duration of treatment with study drug(s) plus 5 
half-lives of study drug(s) plus 4 weeks (duration of ovulatory cycle) for a total 
of 5 months post treatment completion. 
 
- 
Men who are sexually active with WOCBP must agree to follow instructions 
for method(s) of contraception for the duration of treatment with study drug(s) 
plus 5 half-lives of study drug(s) plus 90 days (duration of sperm turnover) for 
a total of 7 months post-treatment completion. 
 
- 
At least one barrier method of contraception must be employed by all sexually 
active patients (male and female), regardless of other methods, to prevent the 
transfer of body fluids. 
 
3.1.11 Ability to understand and willingness to sign a written informed consent document. 
 
3.2 
Exclusion Criteria 
 
 
 
3.2.1 
Patient has a known history or evidence of brain metastases. 
 
3.2.2  Patient who has had chemotherapy, radiation, or biological cancer therapy within 
14 days prior to the first dose of study drug. 
 
3.2.3 Patient has received an investigational agent or used an investigational device 
within 28 days of the first dose of study drug. 
 
3.2.4  Patient is expected to require any other form of systemic or localized antineoplastic 
therapy while on study. 
 
3.2.5 Patients who have had surgery within 28 days of dosing of investigational agent, 
excluding minor procedures (dental work, skin biopsy, etc.), celiac plexus block, 
and biliary stent placement. 
 
3.2.6 Patients who have received any prophylactic vaccine within 14 days of first dose 
of study drug (7 days for the COVID vaccine) or received a live vaccine within 30 
days of planned start of study therapy. 
 
3.2.7 Patients with a history of prior treatment with anti-PD-1, anti-PD-L1, anti-PD-L2, 
anti-CTLA4 antibodies. 
  
3.2.8  Have used any systemic steroids within 14 days of study treatment. 


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14
 
3.2.9  Use more than 2 g/day of acetaminophen. 
 
3.2.10 Patients on immunosuppressive agents (e.g., TNF pathway inhibitors, PI3 kinase 
inhibitors) within 7 days of study treatment.  
 
3.2.11 Patients receiving growth factors including, but not limited to, granulocyte-colony 
stimulating factor (G-CSF), GM-CSF, erythropoietin, within 14 days of study drug 
administration. Use of such agents while on study is also prohibited.  
 
3.2.12 Patient has a known allergy to both penicillin and sulfa. 
 
3.2.13  History of severe hypersensitivity reaction to any monoclonal antibody. 
 
3.2.14 Patient has a known or suspected hypersensitivity to GM-CSF, hetastarch, corn, 
dimethyl sulfoxide, fetal bovine serum, trypsin (porcine origin), yeast or any other 
component of GVAX pancreas vaccine or CRS-207 (e.g., glycerol). 
 
3.2.15 Have current or prior history of infection or clinically significant adverse events 
(AEs) associated with an exogenous implant(s) or device(s) that has not and cannot 
be easily removed.  
 
3.2.16 Subjects who have implanted medical devices that pose high risks for colonization 
and cannot be easily removed (e.g., artificial heart valves, pacemakers, prosthetic 
joints, orthopedic screw(s), metal plate(s)) if infection occurs. Other common 
devices such as venous access devices (e.g., Port-a-Cath or Mediport) may be 
permitted as well as arterial and venous stents and dental and breast implants. 
 
3.2.17  Evidence of clinical ascites. Trace or small amounts of radiographic ascites may be 
approved by the Protocol Chair. 
 
3.2.18  Have clinically significant and/or malignant pleural effusion (pleural effusions that 
are not clinically significant are allowed, defined as no more than 25% fluid level 
of the corresponding hemithorax and stable fluid level [non-progressive] over at 
least 6 weeks documented radiographically). 
 
3.2.19  Have had a new pulmonary embolism, extremity deep venous thromboembolism, 
or portal vein thrombosis within 2 months of study enrollment (any thrombosis 
within 2 months of study enrollment may be approved by the Protocol Chair). 
 
3.2.20 Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, or psychiatric illness/social situations that would limit compliance with 
study requirements. 
 
3.2.21 Subjects with active, known or suspected autoimmune disease. Subjects with 
Graves or Hashimoto’s disease, vitiligo, type I diabetes mellitus, psoriasis not 
requiring systemic treatment, or conditions not expected to recur in the absence of 


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15
an external trigger are permitted to enroll.  
 
3.2.22 Presence of any tissue or organ allograft, regardless of need for 
immunosuppression, including corneal allograft. Instances where loss of the graft 
is not a clinical concern (such as dental bone grafts or skin grafts placed only to 
promote skin growth) can be approved by the Protocol Chair. Patients with a history 
of allogeneic hematopoietic stem cell transplant will be excluded. 
 
3.2.23 All toxicities attributed to prior anti-cancer therapy other than alopecia and fatigue 
must have resolved to grade 1 (National Cancer Institute Common Terminology 
Criteria for Adverse Events [CTCAE], version 4.03) or baseline before 
administration of study drug. Subjects with toxicities attributed to prior anti-cancer 
therapy which are not expected to resolve and result in long-lasting sequelae, such 
as neuropathy after chemotherapy, are permitted to enroll. 
 
3.2.24 Have received a diagnosis of human immunodeficiency virus (HIV), hepatitis B or 
hepatitis C (patients who are hepatitis C antibody positive may be enrolled if they 
are confirmed with negative viral load at screening) 
 
3.2.25 Patient has a pulse oximetry of <92% on room air. 
 
3.2.26 Patient is on supplemental home oxygen. 
 
3.2.27  Patient has an unhealed surgical wound or ulcer, or a bone fracture considered non-
healing. 
 
3.2.28  Patient has clinically significant heart disease (such as uncontrolled angina, 
myocardial infarction within the last 3 months or congestive heart failure of New 
York Heart Association III or IV). 
 
3.2.29  Patient has valvular heart disease that requires antibiotic prophylaxis for prevention 
of endocarditis. 
 
3.2.30 Have insufficient peripheral venous access to permit completion of the study dosing 
and compliance with study phlebotomy regimen 
 
3.2.31 Patient is, at the time of signing informed consent, a regular user (including 
“recreational use”) of any illicit drugs or other substance abuse (including alcohol) 
that could potentially interfere with adherence to study procedures or requirements. 
 
3.2.32  Patient is unwilling or unable to follow the study schedule for any reason. 
 
 
3.2.33 Patient is pregnant or breastfeeding. 
 
3.2.34 Have rapidly progressing disease, as judged by the investigator (e.g., rapid 
progression through prior treatment[s]). 
 


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3.3 
Inclusion of Women and Minorities 
 
Both men and women of all races and ethnic groups are eligible for this trial.   
 
4.  REGISTRATION, RANDOMIZATION, AND BLINDING  
 
4.1 
General Guidelines 
 
Eligible patients will be entered on study centrally at the Sidney Kimmel Comprehensive Cancer 
Center at the Johns Hopkins University by the Lead Study Coordinator.  All sites should contact 
the Lead Study Coordinator to verify ongoing study enrollment. The Registration Form and 
Eligibility Checklist will be supplied to each participating site. 
 
If a patient does not receive protocol therapy following registration, the patient’s registration on 
the study may be canceled.  The Study Coordinator should be notified of cancellations as soon as 
possible. 
 
4.2 
Registration Process 
 
To register a patient, the following de-identified documents should be completed and sent to the 
Lead Study Coordinator at 
 
• 
Fax cover sheet 
• 
Registration Form 
• 
Signed patient consent form 
• 
Eligibility Checklist 
• 
Copy of required screening tests and scans 
 
The Research Nurse or Study Coordinator at the participating site will then e-mail the Protocol 
Chair to verify eligibility. To complete the registration process, the Lead Study Coordinator will: 
• 
Assign a patient study number 
• 
Register the patient on the study 
• 
Fax or e-mail the patient study number to the participating site 
• 
Call or e-mail the research nurse or data manager at the participating site and 
verbally confirm registration. 
 
4.3 
Randomization  
 
This study is an open-label study.  As such, assignment of study treatment will not be blinded.    
 
Subjects will be randomized to Arm A (CY/nivolumab/ipilimumab/GVAX pancreas vaccine 
followed by nivolumab/ipilimumab/CRS-207) or Arm B (nivolumab/ipilimumab/CRS-207) in a 
1:1 fashion using permuted blocks of varying sizes.  
 
5. TREATMENT PLAN 
 
 
5.1 
Agent Administration 
 
Treatment will be administered on an outpatient basis.  Treatment schedule is described in Section 


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1.4.  Dosing delays are described in Section 6. No investigational or commercial agents or 
therapies other than those described below in Table 2 may be administered with the intent to treat 
the subject’s malignancy.   
 
Table 2: Regimen Description 
 
REGIMEN DESCRIPTION 
Agent 
Premedications; Precautions 
Dose 
Route 
Course Length 
CY 
Subjects may be pre-medicated 
with anti-emetics prior to CY 
administration. 
200 mg/m2 in 
100ml NS 
IV infusion 
over 30 min* 
18 weeks 
GVAX 
EMLA cream (approximately 
2.5 grams per site, at least 1 
hour prior to vaccination) 
5 × 108 cells  
Six 
intradermal 
injections 
CRS-207 
650 mg acetaminophen; NS 
pre- and post-infusion to total 
1500ml (suggested: 500ml pre 
and 1000ml post). Subjects 
may also be pre-medicated 
with anti-emetics (suggested:  
IV ondansetron and IV 
fosaprepitant). 
1 × 109 CFU 
in 100ml NS  
IV infusion 
over 1 
hour**  
Nivolumab 
No prophylactic 
pre-medication will be given 
unless indicated by previous 
experience in an individual 
subject per Section 5.3.4. 
360 mg  
IV infusion 
over 30 min* 
Ipilimumab No prophylactic 
pre-medication will be given 
unless indicated by previous 
experience in an individual 
subject per Section 5.3.4. 
1 mg/kg 
IV over 30 
minutes* 
*Infusion times are approximate (- 10/ + 15 min) and may need to be adjusted based on subject 
tolerability. 
**Infusion times are approximate (± 15 min) and may need to be adjusted based on subject 
tolerability. 
 
Please see Section 6.2 for guidance regarding dosing delays. If the investigator assesses a drug-
related toxicity (that requires discontinuation) to be related to an individual component of the 
treatment schedule, dosing for that study drug alone may be discontinued while dosing is delayed 
until the subject meets criteria to resume treatment of the other study drugs. The relationship to the 
discontinued study drug should be well documented in the source documents and permission from 
the Protocol Chair needs to be obtained prior to continuation with the other study drugs.  
 
 
 
5.1.1 Cyclophosphamide (CY) 
 
Subjects may be pre-medicated prior to administration with anti-emetics per institutional 


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guidelines. Subjects should be observed for a minimum of 30 minutes before 
administration of nivolumab. Acute reactions resulting in the delay of nivolumab or 
ipilimumab will be managed using standard therapy for acute drug reactions as per 
institutional standard of care and reported to the Protocol Chair and IND Sponsor. 
 
Dosing calculation based on weight: 
The dosing calculations should be based on the body weight. If the subject’s weight on the 
day of dosing differs by > 10% from the weight used to calculate the dose, the dose must 
be recalculated.  
 
 
 
5.1.2 GVAX Pancreas Vaccine 
 
 
 
 
 
 
 
-
 
 
 
 
5.1.3 CRS-207 
 
Use of Central Lines 
 
 
 
 
 
 
 
 
 
 
-
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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19
 
 
 
 
 
 
 
-
 
 
 
 
 
 
 
 
5.1.4  Nivolumab 
 
 
 
 
 
 
 
 
 
-
  
 
5.1.5  Ipilimumab 
 
 
 
 
 
 
 
 
 
 
Antiemetic medications should not be routinely administered prior to dosing of drugs. See 
Section 5.2.4 for subsequent premedication recommendations following an ipilimumab-
related infusion reaction. 
 
5.2 
General Concomitant Medication and Supportive Care Guidelines 
 
5.2.1 Cyclophosphamide (CY) 
 
Acute reactions will be managed using standard therapy for acute drug reactions as per 
institutional guidelines. 
 
5.2.2 GVAX Pancreas Vaccine 


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20
 
Local vaccine site reaction may be treated with topical applications of aloe vera or vitamin 
E gel or lotion. Significant local inflammation that is causing the subject severe pain or is 
interfering with the activities of daily living may be treated with oral analgesics. Local 
toxicities of pruritus at the vaccine sites and systemic pruritus may be treated with topical 
or oral diphenhydramine hydrochloride (Benadryl®) or topical aloe vera. If oral 
diphenhydramine hydrochloride is used the recommended dose shall be 25-50 mg every 
four to six hours as needed for pruritus, not to exceed 300 mg/day. Cases of local ulceration 
should be manageable with local wound care, with or without antibiotics. Severe local 
inflammation or significant clinical autoimmunity will be managed on a case-by-case basis. 
 
5.2.3 CRS-207 
 
Guidance on treatment of the common infusion reactions related to CRS-207 dosing is as 
follows: 
 
• 
Fevers: Despite the acetaminophen premedication, subjects can spike fevers up 
to 40°C starting at the end of the CRS-207 infusion generally through the next 
24 hours. Oral ibuprofen (400 to 800 mg) and acetaminophen (650 to 1000 mg) 
may be used in alternate sequence every 4 hours. 
 
• 
Rigors: Rigors (generally once or twice per infusion) have been observed to 
start during or at the end of a CRS-207 infusion through 24 hours. IV narcotics 
such as morphine or meperidine may be administered per institutional policy. 
Oral morphine or non-steroidal anti-inflammatory drugs (NSAIDs) (e.g., 
aspirin, ibuprofen, naproxen) may be used as home treatment. 
 
• 
Blood pressure: Decreases in blood pressure have been observed necessitating 
additional IV fluids during the 4 hour observation period (up to 1 or 2 liters). 
Reasons for this include the development of fever, compartmental shifts of fluid 
resulting from the CRS-207 infusion and the use of narcotics. Some subjects 
have also been slightly hypotensive at 24 hours upon arrival to the clinic after 
CRS-207 administration. Subjects are encouraged to hydrate themselves 
liberally at home with oral fluids. 
 
• 
Nausea and vomiting: Nausea and vomiting have been reported and observed 
within 24 hours after CRS-207 infusion. Subjects may be given anti-emetics as 
needed. 
 
Blood draws for clinical hematology and serum chemistry will be done the day after the 
CRS-207 infusion. Any unexpected grade 3 or greater laboratory abnormalities should be 
repeated within 24-72 hours. Grade 3 or greater creatinine, AST, ALT, and bilirubin should 
be repeated within 24-72 hours as well. 
 
5.2.4 Nivolumab and Ipilimumab 
 


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Nivolumab and ipilimumab are fully human monoclonal immunoglobulin (Ig) G4 
antibodies. Subjects should be closely monitored for potential AEs during antibody 
infusion and potential AEs throughout the study.  
 
5.2.4.1 Infusion Reactions 
Since nivolumab and ipilimumab contain only human immunoglobulin protein 
sequences, it is unlikely to be immunogenic and induce an infusion or 
hypersensitivity reaction. However, if such a reaction were to occur, it might manifest 
with fever, chills, rigors, headache, rash, pruritis, arthralgias, hypo- or hypertension, 
bronchospasm, or other symptoms. All grade 3 or 4 infusion reactions should be 
reported within 24 hours to the Protocol Chair and BMS and reported as an SAE if 
criteria are met. Infusion reactions should be graded according to CTCAE (version 
4.03) guidelines. Treatment recommendations are provided below and may be 
modified based on local treatment standards and guidelines as appropriate: 
 
For grade 1 symptoms (mild reaction; infusion interruption not indicated; 
intervention not indicated): 
 
Remain at bedside and monitor subject until recovery from symptoms. The following 
prophylactic 
premedications 
are 
recommended 
for 
future 
infusions: 
diphenhydramine 50 mg (or equivalent) and/or acetaminophen 325 to 1000 mg at 
least 30 minutes before additional nivolumab or ipilimumab administrations. 
 
For grade 2 symptoms (moderate reaction requires therapy or infusion interruption 
but responds promptly to symptomatic treatment [e.g., antihistamines, non-steroidal 
anti-inflammatory drugs, narcotics, corticosteroids, bronchodilators, IV fluids]; 
prophylactic medications indicated for 24 hours): 
 
Stop the nivolumab or ipilimumab infusion, begin an IV infusion of normal saline, 
and treat the subject with diphenhydramine 50 mg IV (or equivalent) and/or 
acetaminophen 325 to 1000 mg; remain at bedside and monitor subject until 
resolution of symptoms. Corticosteroid or bronchodilator therapy may also be 
administered as appropriate. If the infusion is interrupted, restart the infusion at 50% 
of the original infusion rate when symptoms resolve; if no further complications 
ensue after 30 minutes, the rate may be increased to 100% of the original infusion 
rate. Monitor subject closely. If symptoms recur then no further nivolumab or 
ipilimumab will be administered at that visit. Administer diphenhydramine 50 mg IV, 
and remain at bedside and monitor the subject until resolution of symptoms. The 
amount of study drug infused must be recorded on the case report form (CRF). The 
following prophylactic premedications are recommended for future infusions: 
diphenhydramine 50 mg (or equivalent) and/or acetaminophen 325 to 1000 mg 
should be administered at least 30 minutes before additional nivolumab or 
ipilimumab administrations.  
 
For grade 3 or grade 4 symptoms (severe reaction, 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 


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22
other clinical sequelae [e.g., renal impairment, pulmonary infiltrates]; grade 4: (life 
threatening; pressor or ventilator support indicated): 
 
Immediately discontinue infusion of nivolumab or ipilimumab. Begin an IV infusion 
of normal saline, and treat the subject as follows. Recommend bronchodilators, 
epinephrine 0.2 to 1 mg of a 1:1,000 solution for subcutaneous administration or 0.1 
to 0.25 mg of a 1:10,000 solution injected slowly for IV administration, and/or 
diphenhydramine 50 mg IV with methylprednisolone 100 mg IV (or equivalent), as 
needed. Subject should be monitored until the investigator is comfortable that the 
symptoms will not recur. Nivolumab and ipilimumab will be permanently 
discontinued. Investigators should follow their institutional guidelines for the 
treatment of anaphylaxis. Remain at bedside and monitor subject until recovery from 
symptoms. In the case of late-occurring hypersensitivity symptoms (e.g., appearance 
of a localized or generalized pruritis within 1 week after treatment), symptomatic 
treatment may be given (e.g., oral antihistamine, or corticosteroids). 
 
Please refer to Section 6.2 for guidelines regarding ipilimumab, GVAX and CRS-
207 treatment delays following a nivolumab or ipilimumab infusion-related reaction.  
 
5.2.4.2 Nivolumab and Ipilimumab-Related Adverse Events  
 
Blocking PD-1 or CTLA-4 function may permit the emergence of auto-reactive T 
cells 
and resultant 
clinical 
autoimmunity. 
Rash/pruritus, diarrhea/colitis, 
pneumonitis, hepatitis, and hypothyroidism were drug-related, presumptive 
autoimmune events noted in previous nivolumab and ipilimumab studies.  
 
For the purposes of this study, a nivolumab or ipilimumab-related AE is defined as 
an AE of unknown etiology, associated with drug exposure and is consistent with an 
immune phenomenon. Efforts should be made to rule out neoplastic, infectious, 
metabolic, toxin or other etiologic causes. Serological, immunological, and 
histological (biopsy) data should be used to support the diagnosis of an immune-
mediated toxicity. Suspected nivolumab or ipilimumab-related AEs must be 
documented on an AE or SAE CRF. Identification and treatment of nivolumab and 
ipilimumab-related AEs can be found in Appendix B. Additional guidance can be 
found in the nivolumab and ipilimumab Investigator’s Brochures (IB). Antibiotics 
will also be administered to subjects who have not yet received antibiotics for CRS-
207 and the subject requires steroids for a suspected nivolumab or ipilimumab-related 
AE (Section 5.5). 
 
Subjects who experience a grade 2 or higher nivolumab or ipilimumab-related AE 
should be discussed with the Protocol Chair and IND sponsor immediately.  
 
5.3 
Prohibited and/or Restricted Medications and Devices 
 
The following therapies or devices are not permitted during the treatment period (if administered, 
the subject may be removed from the study): 
 


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•  Any 
non-study 
anticancer 
chemotherapy 
or 
immunotherapy 
(approved 
or 
investigational) 
• Any major surgery or surgical procedure; if required must be discussed with the Protocol 
Chair to determine if it is appropriate for the subject to continue study treatment 
•  TNF pathway inhibitors or PI3 kinase inhibitors 
•  Another investigational agent 
•  Filgrastim (Neupogen® or G-CSF) or sargramostim (Leukine® or GM-CSF) 
• Live vaccines (examples of live vaccines include, but are not limited to: measles, mumps, 
rubella, chicken pox, yellow fever, rabies, BCG, and typhoid [oral] vaccine). Seasonal 
influenza vaccines for injection are generally killed virus vaccines and are allowed. 
However, intranasal influenza vaccines (e.g. Flu-Mist®) are live attenuated vaccines, and 
are not allowed. 
• The use of anticoagulants is known to increase the risk of gastrointestinal hemorrhage. 
Since gastrointestinal hemorrhage is an adverse reaction with nivolumab, subjects who 
require concomitant anticoagulant therapy should be monitored closely. 
• Implanted medical devices that pose high risks for colonization and cannot be easily 
removed (e.g., artificial heart valves, pacemakers, prosthetic joints, orthopedic screw(s), 
metal plate(s)) if infection occurs are prohibited. Other common devices such as venous 
access devices (e.g., Port-a-Cath or Mediport), arterial and venous stents, and dental and 
breast implants may be permitted if approved by the Protocol Chair. 
• Palliative (limited-field) radiation therapy is permitted, but only for pain control and with 
approval by the Protocol Chair or IND Sponsor. 
• Systemically active steroids can be used but should be reported to the Protocol Chair 
and/or IND Sponsor. Steroid treatment should be completed at least 14 days prior to 
resuming study-related treatments. Patients requiring adrenal replacement steroid doses 
< 10 mg daily prednisone equivalent (in the absence of active autoimmune disease) may 
resume treatment if approved by the Protocol Chair or the IND Sponsor. Patients 
requiring replacement doses of steroids are required to discontinue treatment with CRS-
207. 
• If steroids or immunosuppressive agents are required during treatment, prophylactic 
antibiotics will be administered as outlined in Section 5.5. 
 
In addition, the following therapies should not be administered during the treatment period unless 
medically necessary and approval must be obtained from the Protocol Chair for a subject to 
continue dosing if therapy is given concurrently with study participation: 
 
•  General anesthesia  
•  Aspirin >325 mg/day (chronic daily use of aspirin ≤325 mg/day and heparin flushes for 
central lines are allowed except during CRS-207 infusions through 4 days after each 
CRS-207 infusion.) 
•  More than 3 g/day of acetaminophen 
•  Systemic antibiotics 
 
5.4 
Other Restrictions and Precautions 
 
Palliative (limited-field) radiation therapy is permitted, but only for pain control to sites present at 
baseline and with approval by the Protocol Chair or IND Sponsor. 
 


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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 
 
 
5.5 
Antibiotic Administration  
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
-
 
 
 
 


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25
-
 
 
Subjects with clinical or laboratory signs or symptoms of persistent infection who require initiation 
of antibiotics other than specified by protocol should have a clinically-relevant evaluation, 
including appropriate bacterial cultures. 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. IV ampicillin 
(or trimethoprim/sulfamethoxazole in penicillin-allergic subjects) plus gentamicin should be 
initiated for possible infectious complications of CRS-207 for subjects who are suspected of 
having persistent CRS-207 infection and meet the criteria listed below: 
 
• 
Flu-like symptoms Grade 3 or greater lasting for ≥12 hours 
• 
Fever Grade 4 or higher (>40.0ºC for >24 hours) 
• 
Persistent fever >39ºC lasting for ≥48 hours 
• 
Infection Grade 3 or higher (infection with interventional radiology or operative 
intervention indicated) 
• 
Evidence of abscess 
• 
Clinical signs or symptoms (e.g., neurologic signs or symptoms), which, in the 
judgment of the investigator, necessitate starting antibiotics 
 
 
 
 
 
 
-
 
 
 
 
 
 
 
 
 
 
 
 
 
Suspected or confirmed infection with CRS-207 and/or Listeria is considered an adverse event of 
special interest (AESI) and should be reported following SAE reporting procedures (Section 7.1.3) 
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. 
 
5.6 
Definition of an Overdose for this Protocol 
 


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Overdose of nivolumab or ipilimumab are defined as: 
An overdose is defined as the accidental or intentional administration of any dose of a product that 
is considered both excessive and medically important. All occurrences of overdose must be 
reported as SAEs (see Section 7.5.1 for reporting details). Appropriate supportive treatment should 
be provided if clinically indicated. 
 
All reports of overdose with and without an AE must be reported within 24 hours to the Protocol 
Chair, IND Sponsor (Dr. Elizabeth Jaffee), and Bristol-Myers Squibb (BMS). IND Sponsor, and 
BMS contact information can be found in Section 7.5.1. 
5.7 
Unacceptable Toxicity 
 
Unacceptable toxicities are defined as: 
 
1. Any treatment-related > grade 3 AEs.  Exceptions include: 
 
• Asymptomatic laboratory abnormalities 
• Grade 3 fatigue 
• Grade 3 dermatologic AEs that are considered mild in severity but only considered grade 
3 because of >30% body surface involvement   
• Fever, chills, rigors, hypertension, hypotension, syncope, or hypoxia occurring within 12 
hours of CRS-207 administration 
• Diarrhea, nausea, or vomiting that resolves to < grade 3 within 24 hours of intervention 
• Grade 3-4 hyperglycemia or grade 3 endocrinopathies where symptoms are controlled on 
hormone replacement therapy 
 
2. Any of the following toxicities related to CRS-207: 
 
• A fever of >40°C that lasts for greater than 24 hours and does not respond to antipyretics. 
• Clinically significant hypotension unresponsive to IV fluids (e.g., systolic blood pressure 
[BP] <90 mm Hg or mean arterial pressure <55 mm Hg as measured on two separate 
occasions at least 10 minutes apart). 
• Initiation of antibiotic therapy, coincident with simultaneous isolation of CRS-207 from a 
normally sterile body site, other than blood (e.g., cerebrospinal fluid, joint fluid). 
 
3. Treatment related blood bilirubin > 5 x ULN or concurrent blood bilirubin > 2 x ULN and AST 
or ALT > 3 x ULN 
 
4. Treatment related eye pain ≥ grade 2 or reduction of visual acuity that does not respond to 
topical therapy and does not improve to ≤ grade 1 severity within 2 weeks of starting therapy, 
or requires systemic therapy is an unacceptable toxicity. 
 
Unexpected Grade 3 or greater laboratory abnormalities should be repeated within 24-72 hours if 
clinically indicated and monitored as necessary to determine if event meets toxicity criteria. Grade 
3 or greater creatinine, AST, ALT, and bilirubin should be repeated within 24-72 hours as well. 
 
The proportion of unacceptable toxicities will be monitored separately in each arm. If the toxicity 
levels in either treatment arm (A or B) are unacceptable, then enrollment will be suspended until 


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further review and consideration by the Protocol Chair, IND Sponsor, and the Medical Expert 
Committee (MEC). If treatment in one arm is permanently discontinued due to toxicity, the other 
arm may continue as long as the toxicity level remains acceptable. There will be no dose reductions 
for CY, nivolumab, ipilimumab, CRS-207, or GVAX pancreas vaccine. 
 
The proportion of treated subjects with unacceptable toxicity will be monitored using a Bayesian 
stopping guideline.  A Beta (1.5, 5.5) prior, representing a toxicity rate of 21%, a slightly 
conservative estimate, was used in the development of our guidelines.  The therapy will be re-
evaluated if the posterior probability that the toxicity rate exceeds the 33% boundary is greater 
than 50%.  Toxicity will be monitored continuously. Table 3 summarizes the stopping boundaries 
for unacceptable toxicities. 
 
Table 3.  The number of toxicities needed to trigger stopping guidelines throughout the course of 
the study.   
 
Number of Subjects Per 
Treatment Arm 
Number of toxicities 
needed to trigger 
re-evaluation 
6 
3 
7-9 
4 
10-12 
5 
13-15 
6 
16-18 
7 
19-21 
8 
22-24 
9 
25-27 
10 
28-30 
11 
 
The probability of triggering the stopping guidelines was assessed for a range of possible true 
toxicity rates using simulations with 10,000 replicates (Table 4).  The probability of stopping to 
re-evaluate was 7.3% if the true proportion with an unacceptable toxicity was 15%.  In comparison, 
the probability of stopping early is 72.6% if the true proportion with an unacceptable toxicity was 
33%.   
 
Table 4.  Probability of triggering a re-evaluation based upon the proportion with an unacceptable 
toxicity for a range of true toxicity probabilities. 
 
True probability of 
unacceptable toxicity 
Probability of triggering 
stopping guidelines 
1% 
<0.1% 
5% 
0.2% 
10% 
2.0% 
15% 
6.9% 
20% 
17.5% 
25% 
33.0% 
30% 
52.4% 
35% 
71.2% 


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5.8 
WOCBP, Contraception, Use in Pregnancy, Use in Nursing 
 
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. In addition, women under the age of 62 years 
must have a documented serum follicle stimulating hormone (FSH) level > 40mIU/mL to confirm 
menopause. 
 
Women treated with hormone replacement therapy (HRT) are likely to have artificially suppressed 
FSH levels and may require a washout period in order to obtain a physiologic FSH level. The 
duration of the washout period is a function of the type of HRT used. The duration of the washout 
period below are suggested guidelines and the investigators should use their judgment in checking 
serum FSH levels. If the serum FSH level is >40 mIU/ml at any time during the washout period, 
the woman can be considered postmenopausal: 
 
• 1 week minimum for vaginal hormonal products (rings, creams, gels) 
• 4 week minimum for transdermal products 
• 8 week minimum for oral products 
 
5.8.1 Contraception 
 
The investigational agents used in this protocol may have adverse effects on a fetus in 
utero. Furthermore, it is not known if the investigational agents have transient adverse 
effects on the composition of sperm.  Non-pregnant, non-breast-feeding women may be 
enrolled if they are considered highly unlikely to conceive. Highly unlikely to conceive is 
defined as 1) surgically sterilized, or 2) postmenopausal (defined as a woman who is > 45 
years of age and has not had menses for greater than 12 months and women under the age 
of 62 must have a documented serum follicle stimulating hormone (FSH) level less than 
40mlU/mL will be considered postmenopausal). or 3) amenorrheaic for < 2 years without 
a hysterectomy and oophorectomy and with a documented FSH value in the 
postmenopausal range, or ) not heterosexually active for the duration of the study, or 5) 
heterosexually active and willing to use 2 methods of birth control (which is also required 
for the female partners of male subjects). The 2 birth control methods can be 2 barrier 
methods or a barrier method plus a hormonal method to prevent pregnancy, used 
throughout the study starting with Visit 1 through 5 months after the last dose of study 
drug.  Male subjects enrolled in this study must also agree to use an adequate method of 
contraception starting with Visit 1 through 7 months after the last dose of study drug. 
 
Investigators shall counsel WOCBP and male subjects who are sexually active with 
WOCBP on the importance of pregnancy prevention and the implications of an unexpected 
pregnancy Investigators shall advise WOCBP and male subjects who are sexually active 
with WOCBP on the use of highly effective methods of contraception. Highly effective 
methods of contraception have a failure rate of < 1% per year when used consistently and 
correctly. 
 
 


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HIGHLY EFFECTIVE METHODS OF CONTRACEPTION 
• 
Male condoms with spermicide 
• 
Hormonal methods of contraception including combined oral contraceptive pills, 
vaginal ring, injectables, implants, and intrauterine devices (IUDs) such as Mirena 
by WOCBP subject or male subject’s WOCBP partner. 
• 
Nonhormonal IUDs, such as ParaGard 
• 
Tubal ligation 
• 
Vasectomy 
• 
Complete abstinence* 
 
*Complete abstinence is defined as complete avoidance of heterosexual intercourse and is 
an acceptable form of contraception for all study drugs. Abstinence is only acceptable when 
this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., 
calendar, ovulation, symptothermal, profession of abstinence for entry into a clinical trial, 
post-ovulation methods) and withdrawal are not acceptable methods of contraception. 
Subjects who choose complete abstinence are not required to use a second method of 
contraception, but female subjects must continue to have pregnancy tests. Acceptable 
alternate methods of highly effective contraception must be discussed in the event that the 
subject chooses to forego complete abstinence.  
 
LESS EFFECTIVE METHODS OF CONTRACEPTION 
• 
Diaphragm with spermicide 
• 
Cervical cap with spermicide 
• 
Vaginal sponge 
• 
Male condom without spermicide* 
• 
Progestin only pills by WOCBP subject or male subject’s WOCBP partner 
• 
Female condom* 
*A male and female condom must not be used together 
 
Subjects should be informed that taking the study drug may involve unknown risks to the 
fetus (unborn baby) if pregnancy were to occur during the study.  In order to participate in 
the study they must adhere to the contraception requirement (described above) for the 
duration of the study.  If there is any question that a subject will not reliably comply with 
the requirements for contraception, that subject should not be entered into the study. 
 
5.8.2 Use in Pregnancy 
 
The investigational agents used in this protocol may have adverse effects on a fetus; 
therefore, women with a positive pregnancy test at screening will not be eligible for 
enrollment.  If a subject inadvertently becomes pregnant while on treatment, the subject 
will immediately be removed from the study.  The site will contact the subject at least 
monthly and document the subject’s status until the pregnancy has been completed or 
terminated.   
 
Pregnancy in female subjects throughout the study or within 5 months of completing 
treatment as well as any pregnancy in partners of male subjects throughout the study or 
within 7 months of completing the study should be reported initially as a serious adverse 


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event (see SAE reporting procedures in section 7.5.1 and 7.5.5) by the investigator within 
24 hours of learning of its occurrence. Pregnancy information must be reported on the 
Pregnancy Form. 
 
Protocol required procedures for study discontinuation and follow-up must be performed 
on the subject unless contraindicated by pregnancy (e.g., x-ray studies). Other appropriate 
pregnancy follow-up procedures should be considered if indicated.  
 
Follow-up information regarding the course of the pregnancy, including any voluntary or 
spontaneous termination, perinatal and neonatal outcome and where applicable, offspring 
information must be reported on the Pregnancy Follow-up Form. Pregnancy outcomes 
must also be collected for the female partners of any males in this trial. Consent to report 
information regarding these pregnancy outcomes should be obtained from the female 
partner.  
 
5.8.3 Use in Nursing Women 
 
Since many drugs are excreted in human milk, and because of the potential for serious 
adverse reactions in the nursing infant, subjects who are breast-feeding are not eligible for 
enrollment. 
 
5.8.4 All Subjects (Male and Female) 
 
All sexually active patients must use at least a barrier method (i.e., condom) to prevent 
transmission of body fluids.  
 
5.9 
Duration of Therapy 
 
Subjects on both arms will receive treatment every 3 weeks for 6 cycles of treatment within a 
course (18 weeks total). At the investigator’s discretion, subjects who are clinically stable and meet 
dosing requirements (per Section 6.2) at the end of the first course may receive additional courses 
of their assigned treatment for up to a maximum of 2 years. Subjects that begin a new course prior 
to the 2 year cut-off may complete that course prior to coming off study. The additional course(s) 
may start as early as 3 weeks (+7 days) from last dose of previous course and all assessments will 
be followed per the study schedule in Section 10, with the first dose of the additional course 
corresponding to Day 1, Cycle 1 of the study schedule. The following assessments are not required 
during additional courses: 
 
• HLA-typing 
• Tumor biopsies 
 
5.10 
Criteria for Removal from Treatment 
 
The reason for study removal and the date the subject was removed will be documented in the 
CRF. A subject will be discontinued from the trial for any of the following reasons: 
• The subject or legal representative (such as a parent or legal guardian) withdraws 
consent for participation in the study. 


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A subject must be discontinued from treatment (but may continue to be monitored in the post-
treatment follow-up portion of the trial) for any of the following reasons: 
 
• The subject or legal representative (such as a parent or legal guardian) withdraws 
consent for treatment 
• Intercurrent illness that prevents further administration of treatment 
• Unacceptable toxicity (see Section 5.7). Exceptions for treatment discontinuation 
are listed in Section 5.10.2. If the study treatment has provided clinical benefit (as 
defined in Section 5.10.1), the IND sponsor may approve trial continuation for 
patients experiencing toxicities that are not life threatening or of major clinical 
concern (such as pruritis or transient hypotension). 
• Disease progression as defined in Section 5.10.1 
• Severe or life-threatening nivolumab or ipilimumab-related AE(s) (see Section 
5.10.2) 
• Need for >2 dose delays due to the same drug-related toxicity as per the dose delay 
guidelines (see Section 6.2) 
• If, in the opinion of the Investigator, a change or temporal or permanent 
discontinuation of therapy would be in the best interest of the subject, 
• Noncompliance with trial treatment or procedure requirements, 
• Subject is lost to follow-up 
• Subject becomes pregnant 
 
5.10.1 Disease Progression 
 
GVAX Pancreas vaccine, CRS-207, nivolumab, and ipilimumab are expected to trigger 
immune-mediated responses, which require activation of the immune system prior to the 
observation of clinical responses. Such immune activation may take weeks to months to be 
evident. Some subjects may have objective volume increase of tumor lesions or other 
disease parameters within weeks following the start of immunotherapy. Such subjects may 
not have had sufficient time to develop the required immune activation or, in some subjects, 
tumor volume or other disease parameter increases may represent infiltration of 
lymphocytes into the original tumor. In conventional studies, such tumor volume or 
relevant laboratory parameter increases during the first 2-4 months of the study would 
constitute disease progression and lead to discontinuation of imaging to detect response, 
thus disregarding the potential for subsequent immune-mediated clinical response. This 
phenomenon was observed in approximately 10% of subjects in the Phase 1 study of 
nivolumab and has also been reported for ipilimumab monotherapy16. 
 
Subjects will be permitted to continue with treatment beyond RECIST 1.1 defined PD as 
long as they meet the following criteria: 
• 
Investigator-assessed clinical benefit, and 
• 
Subject is tolerating study drug. 
 


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32
The assessment of clinical benefit should take into account whether the subject is clinically 
deteriorating and unlikely to receive further benefit from continued treatment. The 
following criteria need to be taken into consideration: 
• 
No decline in ECOG performance status. 
• 
Absence of rapid progression of disease or of progressive tumor at critical anatomical 
sites (e.g., cord compression) requiring urgent alternative medical intervention. 
 
All decisions to continue treatment beyond PD must be discussed with the Protocol Chair 
and documented in the study records. 
 
Tumor assessments will be made using RECIST 1.1 (Appendix C) and irRC (Appendix 
D).  
 
5.10.2 Nivolumab and Ipilimumab-Related Adverse Events  
 
Permanent discontinuation of study treatment should be considered for any of the 
following: 
1. Severe or life-threatening related AEs, including, but not limited to, any of the 
following (the IND Sponsor, and BMS must be notified in the event of these AEs): 
• Any grade 2 treatment-related uveitis, eye pain, or blurred vision that does not 
respond to topical therapy and does not improve to Grade 1 severity within 2 
weeks of starting therapy OR requires systemic treatment 
 
• Any grade 3 non-skin, drug-related AE lasting > 7 days, with the following 
exceptions: 
 
▪ Grade 3 treatment-related uveitis, pneumonitis, bronchospasm, diarrhea, 
colitis, neurologic toxicity, hypersensitivity reaction, or infusion reaction 
(applies to nivolumab and ipilimumab only) of any duration requires 
discontinuation 
▪ Grade 3 treatment-related endocrinopathies adequately controlled with 
only physiologic hormone replacement do not require discontinuation 
▪ Grade 3 treatment-related laboratory abnormalities do not require treatment 
discontinuation except: 
 
o Grade 3 treatment-related thrombocytopenia > 7 days OR that is 
associated with bleeding requires discontinuation 
 
o Any treatment-related liver function test (LFT) abnormality that 
meets the following criteria require discontinuation: 
− 
Total bilirubin > 3 × ULN 
− 
Concurrent AST or ALT > 3 × ULN and total bilirubin > 2 
× ULN 
 
• Any grade 4 treatment-related AE or laboratory abnormality, except for the 
following events which do not require discontinuation: 
 


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33
▪ Grade 4 amylase or lipase abnormalities that are not associated with 
symptoms or clinical manifestations, or radiographic signs of pancreatitis. 
It is recommended to consult with the Protocol Chair for grade 4 amylase 
or lipase abnormalities. 
 
▪ Isolated grade 4 electrolyte imbalances/abnormalities that are not associated 
with clinical sequelae and are corrected with supplementation/appropriate 
management within 72 hours of their onset. 
 
▪ Transient, self-correcting grade 4 AST or ALT that occur after the CRS-207 
infusion and resolves within 2 weeks.  
 
▪ Grade 4 lymphopenia and leukopenia. 
 
▪ Grade 4 treatment-related endocrinopathy adverse events, such as adrenal 
insufficiency, ACTH deficiency, hyper- or hypothyroidism, or glucose 
intolerance, which resolve or are adequately controlled with physiologic 
hormone replacement (corticosteroids, thyroid hormones) or glucose-
controlling agents, respectively, may not require discontinuation after 
discussion with and approval from the Protocol Chair. 
 
• Any dosing interruption lasting > 6 weeks with the following exceptions: 
 
▪ Dosing interruptions to allow for prolonged steroid tapers to manage drug-
related adverse events are allowed. Prior to re-initiating treatment in a 
subject with a dosing interruption lasting > 6 weeks, the Protocol Chair must 
be consulted. Tumor assessments should continue as per protocol even if 
dosing is interrupted. 
 
▪ Dosing interruptions > 6 weeks that occur for non-drug-related reasons may 
be allowed if approved by the Protocol Chair. Prior to re-initiating treatment 
in a subject with a dosing interruption lasting > 6 weeks, the Protocol Chair 
must be consulted. Tumor assessments should continue as per protocol even 
if dosing is interrupted.  
 
Any AE, laboratory abnormality, or intercurrent illness which, in the judgment of the 
Investigator, presents a substantial clinical risk to the subject with continued nivolumab or 
nivolumab/ipilimumab dosing.  
 
In order to standardize the management of AEs for all subjects, treatment management 
algorithms are included in Appendix B. Additional AE treatment management algorithms 
included in the nivolumab and ipilimumab IB might be considered for individual cases. 
 
Subjects that are required to stop treatment with nivolumab/ipilimumab due to toxicity may 
stay on study and receive CY/GVAX Pancreas vaccine followed by CRS-207 (assessment 
schedule per Section 10.2) once the nivolumab/ipilimumab-related toxicity(s) has resolved 
to a grade 1. 
 


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5.11 
End of Treatment (EOT) Visit 
 
All subjects will return to the study site 28 days (± 7 days) after the final study treatment (i.e., 
completion of the final course or upon early discontinuation) for an EOT evaluation. Procedures 
and assessments performed at these visits and beyond should follow the respective guidelines 
described in Sections 5.12 and 10.0 as appropriate.  
 
If the EOT visit occurs early (e.g., 1 week prior to the expected visit as protocol allows) or if the 
patient cannot return due to disease progression, an assessment for AEs should be made by telephone 
or email on day 28 (± 1 day) after last dose of study drug and documented.  
 
 
 
5.12 
Duration of Follow-Up 
 
All randomized subjects, including those never treated, will enter a follow-up period. Treated 
subjects will begin the follow-up period after they complete the EOT visit. Subjects will be 
contacted every three months (+/- 2 weeks) to monitor overall survival until death, withdrawal of 
consent, or study closure. Information of other cancer therapies after discontinuation from the 
study treatment will be collected.  Subjects will also be contacted at 100 days (+14 day reporting 
window) from the last dose of nivolumab/ipilimumab if the subject was still receiving 
nivolumab/ipilimumab at the time of treatment discontinuation to monitor drug toxicity. In 
addition, all subjects that received at least one dose of CRS-207 will be monitored for CRS-207 
infection for one year per Section 5.13. 
Subjects who discontinued study treatment without documented disease progression should 
continue to be monitored for disease status by radiologic imaging.  Disease monitoring should 
continue to be assessed every two months (+/- 2 weeks) until: 1) start of a new antineoplastic 
therapy (information of the new cancer therapy will be collected), 2) disease progression, 3) death, 
4) withdrawal of consent, or 5) study closure, whichever occurs first. 
 
Subjects who are discontinued from the study treatment due to an unacceptable drug-related AE 
will be monitored for safety until the resolution of the AE to ≤ grade 1 or stabilization or until 
initiation of a new therapy for their cancer, whichever occurs first. 
 
All subjects will be followed after their last dose of study drug for the development of AEs and 
SAEs as described in Section 7.5.1   
 
At the conclusion of the study, all remaining subjects who have received at least one dose of study 
treatment will be offered enrollment in a long-term follow-up study and continue to be evaluated 
for survival. Subjects who are still receiving treatment at the time of study close may complete the 
current treatment course (up to 6 cycles) and EOT visit prior to transitioning to participation in the 
separate long-term follow-up study. 
 
5.13 
Blood Cultures for CRS-207 Surveillance 
 


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35
 
 
 
 
-
 
 
 
 
5.13.1  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), the IND Sponsor should be 
notified within 24 hours of the adverse event of special interest (AESI) per Section 7.1.3.  
 
If Listeria has been confirmed at the clinical site or an external laboratory, all efforts should 
be made to obtain a sample of the bacterial isolate from the original positive culture and 
submit to the IND Sponsor or designee for strain confirmation; records on all samples 
cultured during this period must be obtained and provided to the Sponsor. Refer to the 
Central Laboratory Manual for sample collection and shipping instructions. 
 
5.13.2  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 (peripheral and port for those with indwelling 
ports), urine and stool samples in duplicate is recommended. One set of samples should be 
cultured locally for Listeria per institutional guidelines. Culture of cerebrospinal fluid 
should be obtained for subjects with suspected central nervous system infection. In such 
instances, analysis of cerebrospinal fluid should also include cell count, protein, glucose, 
and Gram stain. If samples are positive for Listeria, the IND Sponsor must be notified 
immediately, and the duplicate samples and Listeria isolate must be sent to the IND 
Sponsor or designee for testing to confirm CRS-207. Instructions on collection, storage 
and shipping of samples for CRS-207 testing are provided in the Central Laboratory 
Manual. 
 
 
6. DOSING DELAYS/DOSE MODIFICATIONS 
 
6.1  
Dose Modifications 
 
Dose reduction or dose increase of CY, GVAX Pancreas vaccine, CRS-207, nivolumab, and 
ipilimumab will not be permitted. 
 
6.2  
Dosing Delays 
 
Dosing of study therapy will be delayed for the following laboratory criteria:  
 
 


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• AST/ALT >3 × ULN   
• Total bilirubin > 1.5 x ULN or direct bilirubin > 2.0 × ULN for subjects with 
Gilbert’s disease 
• Creatinine > 1.5 × ULN 
• Hemoglobin < 7.5 g/dL 
• ANC < 1000/uL  
• Platelets < 80 × 103/uL 
 
All scheduled cycles within a course are to be given approximately 3 weeks apart. If necessary, a 
scheduled cycle may be delayed for up to 1 week. In this case, subsequent cycles should continue 
so that a subject can still receive all 6 cycles given that the cycles are a minimum of 3 weeks apart 
and they have not experienced an AE necessitating discontinuation. If delayed more than 1 week, 
the Protocol Chair must be contacted for further instructions on continued treatment. Additional 
delays or modifications to the treatment schedule must be approved by the Protocol Chair or IND 
Sponsor.  
 
If a delay occurs between Day 1 and 2 in a cycle: 
• Nivolumab and ipilimumab-related infusion reactions must resolve to baseline prior to 
administration of ipilimumab, GVAX, or CRS-207.  
• If a nivolumab-related infusion reaction prevents subsequent infusion of ipilimumab on the 
same day, the dose of ipilimumab should be replaced within 72 hours. In such instances, at 
least 18 days must elapse between the replacement dose of ipilimumab and the 
administration of the next dose of nivolumab combined with ipilimumab. If the dose of 
ipilimumab cannot be replaced within 72 hours, resume ipilimumab at the next scheduled 
dose per Section 10. 
• Resume Day 2 treatment schedule (GVAX or CRS-207) and assessments without repeating 
Day 1 study treatments (CY and/or nivolumab/ipilimumab) if the delay is within 72 hours. 
• If the delay is longer than 72 hours, repeat Day 1 and Day 2 (if applicable) study 
treatments/assessments with a minimum of 2 weeks from the previous Day 1 treatment.  
This includes steroid treatment requiring at least a 14 day washout prior to resuming study-
related treatments. 
 
Administration of study drug should be delayed for the following: 
 
• Dosing criteria are not met 
• Any grade ≥ 2 non-skin, treatment-related AE, with the following exceptions: 
o Grade 2 drug-related fatigue or laboratory abnormalities do not require a treatment 
delay 
o Grade 2 hypothyroidism or thyroiditis 
• Any grade >3 skin treatment-related AE  
• Any ≥ grade 3 treatment-related laboratory abnormality, with the following exceptions for 
asymptomatic amylase or lipase: 
o Grade 3 or 4 amylase or lipase abnormalities that are not associated with symptoms 
or clinical manifestations, or radiographic signs of pancreatitis do not require a dose 
delay. It is recommended to consult with the Protocol Chair for grade 3 amylase or 
lipase abnormalities. 


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o Isolated grade 3 or 4 electrolyte imbalances/abnormalities that are not associated 
with clinical sequelae and are corrected with supplementation/appropriate 
management 
• Any AE, laboratory abnormality, or intercurrent illness which, in the judgment of the 
investigator, warrants delaying the dose of study drug. 
 
In order to standardize the management of AEs for all subjects, treatment management algorithms 
are included in Appendix B. Additional AE treatment management algorithms included in the 
nivolumab and ipilimumab IB might be considered for individual cases. 
 
Subjects may resume treatment with nivolumab and ipilimumab when the treatment-related AE(s) 
resolve to grade ≤1 or baseline value, with the following exceptions:  
 
• Subjects may resume treatment in the presence of grade 2 fatigue. 
• Subjects who have not experienced a Grade 3 drug-related skin AE may resume treatment 
in the presence of Grade 2 skin adverse event 
• Treatment-related pulmonary toxicity, diarrhea, or colitis must have resolved to baseline 
before treatment is resumed. 
• Treatment-related endocrinopathies adequately controlled with only physiologic hormone 
replacement may resume treatment, which include grade 2 hyperglycemia, hypothyroidism 
and thyroiditis. 
 
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS 
 
This study will use the descriptions and grading scales found in the revised CTCAE version 4.03 
for 
AE 
reporting 
that 
can 
be 
found 
at 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.   
 
Information about all AEs, whether volunteered by the subject, discovered by investigator 
questioning, or detected through physical examination, laboratory test or other means, will be 
collected, recorded, and followed as appropriate.  
 
7.1 
Definitions 
 
7.1.1 Adverse Event  
 
An AE is defined as any undesirable sign, symptom or medical condition occurring after 
starting the study drug (or therapy) even if the event is not considered to be related to the 
study. An undesirable medical condition can be symptoms (e.g., nausea, chest pain), signs 
(e.g., tachycardia, enlarged liver) or the abnormal results of an investigation (e.g., 
laboratory findings, electrocardiogram). Medical conditions/diseases present before 
starting the study treatment are only considered AEs if they worsen after starting the study 
treatment (any procedures specified in the protocol). New medical conditions / diseases 
occurring before starting the study treatment but after signing the informed consent form 
will not be recorded as AEs. Additionally, expected progression of the disease being 
studied will not be recorded as an adverse event.  
 


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Laboratory abnormalities: Laboratory abnormalities present at the screening visit will 
be recorded as pre-treatment signs and symptoms. After study treatment administration, all 
grade 3 and 4 clinical laboratory results that represent an increase in severity from baseline 
will be reported as AEs. A grade 1 or 2 clinical laboratory abnormality should be reported 
as an AE only if it is considered clinically significant by the investigator (induce clinical 
signs or symptoms or require therapy). 
 
7.1.2 Serious Adverse Event  
 
A SAE is an undesirable sign, symptom or medical condition which:  
• 
Results in death  
• 
Is life threatening (defined as an event in which the subject was at risk of death at 
the time of the event; it does not refer to an event which hypothetically might have 
caused death if it were more severe)  
• 
Requires inpatient hospitalization or causes prolongation of existing hospitalization 
(see note below for exceptions) for >24 hours 
• 
Results in persistent or significant disability/incapacity  
• 
Is a congenital anomaly/birth defect (note: reports of congenital anomalies/birth 
defects must also be reported on the Pregnancy Form)  
• 
Is an important medical event (defined as a medical event(s) that may not be 
immediately life-threatening or result in death or hospitalization but, based upon 
appropriate medical and scientific judgment, may jeopardize the subject or may 
require intervention [e.g., medical, surgical] to prevent one of the other serious 
outcomes listed in the definition above.) Examples of such events include, but are 
not limited to, intensive treatment in an emergency room or at home for allergic 
bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization.) 
• 
Potential drug induced liver injury (DILI) is also considered an important medical 
event.  
• 
Hemophagocytic lymphohistiocytosis is also considered an important medical 
event. 
• 
Suspected transmission of an infectious agent (eg, pathogenic or nonpathogenic) 
via the study drug is an SAE. 
• 
Is a new cancer (that is not a condition of the study) 
• 
Is associated with an overdose 
• 
Is a pregnancy or pregnancy outcome of spontaneous abortion, missed abortion, 
benign hydatidiform mole, blighted ovum, fetal death, intrauterine death, 
miscarriage, or stillbirth. 
 
Events not considered to be SAEs are hospitalizations for:  
• 
Admissions as per protocol for a planned medical/surgical procedure or to facilitate 
a procedure 
• 
Routine health assessment requiring admission for baseline/trending of health 
status (e.g., routine colonoscopy)  
• 
Medical/surgical admission for purpose other than remedying ill health state and 
was planned prior to entry into the study. Appropriate documentation is required in 
these cases.  
• 
Admission encountered for another life circumstance that carries no bearing on 


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39
health status and requires no medical/surgical intervention (e.g., lack of housing, 
economic inadequacy, care-giver respite, family circumstances, administrative). 
• 
Admissions for monitoring of treatment-related infusion reactions that do not 
otherwise meet the criteria for a SAE. 
 
7.1.3 Adverse Events of Special Interest (AESI) 
 
Suspected infection with CRS-207 and/or Listeria are considered adverse events of special 
interest (AESI) and should be reported following SAE reporting procedures in Section 7.5 
irrespective of temporal relationship to study drug administration. 
 
In the event a subject has a positive Listeria culture at any time during or after study 
participation, the event should be reported to the IND Sponsor within 24 hours of the event. 
 
All AESIs must be reported for the duration of the study regardless of causality. 
 
7.2 
Assessment of Causality 
 
The relationship of an AE to the administration of the study drug is to be assessed by the 
investigator according to the following definitions:  
 
• No (unrelated, not related, no relation):  The time course between the administration of 
study drug and the occurrence or worsening of the adverse event rules out a causal 
relationship and another cause (concomitant drugs, therapies, complications, etc.) is 
suspected.  
 
• Yes (related): The time course between the administration of study drug and the occurrence 
or worsening of the adverse event is consistent with a causal relationship and no other cause 
(concomitant drugs, therapies, complications, etc.) can be identified.  
 
The following factors should also be considered:  
• The temporal sequence from study drug administration - The event should occur after the 
study drug is given. The length of time from study drug exposure to event should be 
evaluated in the clinical context of the event.  
• Underlying, concomitant, intercurrent diseases - Each report should be evaluated in the 
context of the natural history and course of the disease being treated and any other disease 
the subject may have.  
• Concomitant medication - The other medications the subject is taking or the treatment the 
subject receives should be examined to determine whether any of them might be recognized 
to cause the event in question.  
• Known response pattern for this class of study drug - Clinical and/or preclinical data may 
indicate whether a particular response is likely to be a class effect.  
• Exposure to physical and/or mental stresses - The exposure to stress might induce adverse 
changes in the recipient and provide a logical and better explanation for the event.  
• The pharmacology and pharmacokinetics of the study drug - The known pharmacologic 
properties (absorption, distribution, metabolism, and excretion) of the study drug should 
be considered.  
 


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40
Assessment of Grade: 
 
The investigator will make an assessment of grade for each AE and SAE reported during the study, 
which will be recorded in the CRF. The assessment will be based on the National Cancer Institute’s 
CTCAE (Version 4.03) and graded as shown below: 
• 
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated 
• 
Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily living 
• 
Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care 
activities of daily living 
• 
Grade 4: Life-threatening consequences; urgent intervention indicated 
• 
Grade 5: Death related to AE 
 
Any AE that changes in grade during its course will be recorded in the CRF at the highest level 
experience by the subject. 
 
7.3 
Expectedness 
 
Unexpected AE: An AE, which varies in nature, intensity or frequency from information on the 
investigational drug/agent provided in the product IB, package insert or safety reports. Any AE 
that is not included in the IB, package insert, safety reports or informed consent is considered 
“unexpected”.  
 
Expected (known) AE: An AE, which has been reported in the IB, package insert or safety reports. 
An AE is considered “expected”, only if it is included in the IB document as a risk. 
 
7.4 
Handling of Expedited Safety Reports 
 
In accordance with local regulations, the IND Sponsor or designee will notify investigators of all 
SAEs that are unexpected (i.e., not previously described in the IB), and related to CY, GVAX 
pancreas vaccine, CRS-207, nivolumab, or ipilimumab. This notification will be in the form of an 
expedited safety report (ESR) that is to be faxed to the investigators and the study coordinators. 
Upon receiving such notices, the investigator must review and retain the notice with the IB and 
where required by local regulations, the investigator will submit the ESR to the appropriate IRB. 
The investigator and IRB will determine if the informed consent requires revision. The investigator 
should also comply with the IRB procedures for reporting any other safety information.  
 
7.5 
Reporting 
 
7.5.1  Adverse Events and Serious Adverse Events 
 
All AEs (both related and unrelated) will be captured on the appropriate study-specific 
CRFs. All AEs experienced by subjects will be collected and reported from the first dose 
of the investigational agent, throughout the study, and will be followed for 28 days after 
last dose of study drug unless related to the investigational agent.   
 


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Subjects who experience a grade 2 or higher nivolumab or ipilimumab-related AE should 
be discussed with the Protocol Chair.  
 
Report AEs to the Protocol Chair and IND Sponsor within 24 hours once identified 
as an unacceptable toxicity (defined in Section 5.7).   
Elizabeth Jaffee:  
 
Dung Le: 
 
 
Report all AESI to the Protocol Chair and IND Sponsor within 24 hours once 
identified (defined in Section 7.1.3): 
Elizabeth Jaffee:  
 
Dung Le: 
 
 
All SAEs (including deaths) occurring from the first dose of the study drug through 100 
days (+ 14 day reporting window) after the last dose of nivolumab or ipilimumab or  within 
7 days prior to initiation of a new antineoplastic treatment (whichever comes first) will be 
collected and reported. If the subject never received or is no longer receiving nivolumab or 
ipilimumab due to toxicity, all SAEs (including deaths) occurring from the first dose of the 
study drug through 28 days from the last dose of cyclophosphamide, GVAX, or CRS-207 
(whichever reporting period is longer).  All SAEs (including deaths) that the investigator 
considers related to study drug occurring after the follow-up periods must be reported. 
 
Subjects who have an ongoing AE/SAE related to the study procedures and/or 
medication(s) may continue to be periodically contacted by a member of the study staff 
until the event is resolved or determined to be irreversible by the investigator. 
 
SAEs will be reported promptly to the IND Sponsor, and BMS within 24 hours of 
initial notification of the SAE. If this falls on a weekend or holiday, an email notification 
is acceptable but must be followed by an SAE reporting form on the next business day. 
 
SAE reports and any other relevant safety information are to be sent to:  
Elizabeth Jaffee:  
 
Dung Le: 
 
BMS:  
 
 
7.5.2 Follow-up of Adverse Events and Serious Adverse Events 
 
After the initial AE or SAE report, the investigator is required to proactively follow each 
subject and provide further information to the safety department in regards to the subject’s 
condition. 
 
All AE(s) and SAE(s) will be followed until: 
• 
Resolution 
• 
The condition stabilizes 
• 
The event is otherwise explained 
• 
The subject is lost to follow-up 
• 
Death 


J1790 / Version 7.0/ December 10, 2020 
42
 
As soon as relevant information is available, a follow-up SAE report will be submitted to 
the IND Sponsor, and BMS. 
 
7.5.3 Reconciliation of SAEs 
 
The Protocol Chair will reconcile the clinical database SAE cases (case level only) 
transmitted 
to 
the 
IND 
Sponsor 
and 
BMS 
Global 
Pharmacovigilance 
 Frequency of reconciliation should be approximately 
every 3 months and prior to the database lock or final data summary. BMS GPV&E will 
email, upon request from the Investigator, the reconciliation report. Requests for 
reconciliation 
should 
be 
sent 
to 
The data elements 
listed on the BMS GPV&E reconciliation report will be used for case identification 
purposes. If the Sponsor determines a case was not transmitted to the IND Sponsor and 
BMS GPV&E, the case should be sent immediately to the IND Sponsor and BMS. 
 
7.5.4 Overdose 
 
An overdose is defined as the accidental or intentional administration of any dose of a 
product that is considered both excessive and medically important. All occurrences of 
overdose must be reported as SAEs. 
 
7.5.4 Potential Drug Induced Liver Injury (DILI) 
 
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities 
should occur prior to the reporting of a potential DILI event.  All occurrences of potential 
DILIs, meeting the defined criteria, must be reported as SAEs under the seriousness 
category checked as ‘other medically important event’. Potential drug induced liver injury 
is defined as: 
 
1) ALT or AST elevation > 3 times upper limit of normal (ULN)  
AND 
2) Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum 
alkaline phosphatase) 
AND 
3) No other immediately apparent possible causes of AST/ALT elevation and 
hyperbilirubinemia, including, but not limited to, viral hepatitis, pre-existing chronic 
or acute liver disease, or the administration of other drug(s) known to be hepatotoxic. 
 
7.5.5 Pregnancy Reporting 
 
Although pregnancy and lactation are not always serious by regulatory definition, it is the 
responsibility of investigators or their designees to report any pregnancy or lactation in a 
subject (spontaneously reported to them) that occurs during the trial or within 5 months 
of completing the trial as an SAE. This also includes the pregnancy of a male subject's 
female partner who has provided written consent to provide information regarding 
pregnancy, which occurs during the trial or within 7 months of completing the trial.   


J1790 / Version 7.0/ December 10, 2020 
43
 
If a subject or partner of a subject participating in the study becomes pregnant, the 
investigator must report the pregnancy within 24 hours of discovery or knowledge of the 
event. To report a pregnancy, complete the SAE form with the seriousness category 
checked as ‘other important medical event’. When the form is completed, the IND 
Sponsor and BMS will be notified of the event.  
 
All subjects or partners of subjects who become pregnant must be followed to the 
completion/termination of the pregnancy.  If the pregnancy ends for any reason before the 
anticipated date, the investigator should notify the IND Sponsor and BMS.  At the 
completion of the pregnancy, the investigator will document the outcome of the 
pregnancy. Pregnancy outcomes of spontaneous abortion, missed abortion, benign 
hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage and 
stillbirth must also be reported as SAEs (Important Medical Events).  If the pregnancy 
continues to term, the outcome (health of infant) must also be reported to the IND Sponsor 
and BMS.  
 
7.5.6  Institutional Review Board (IRB) and Institutional Biosafety Committee (IBC) 
 
Participating sites will be responsible for reporting to their IRB and IBC. Serious adverse 
events will be reported to the IRB and IBC per institutional standards. Upon receipt, 
follow-up information will be given to the IRB and IBC (as soon as relevant information 
is available) per institutional standards. 
 
7.5.7  Food and Drug Administration (FDA) 
 
All reporting to the FDA will be completed by the IND Sponsor. 
 
7.5.7.1 Expedited IND Safety Reports 
 
7 Calendar-Day Telephone or Fax Report:   
The IND Sponsor is required to notify the FDA of any fatal or life-threatening 
adverse event that is unexpected and assessed by the investigator to be possibly 
related to the investigational agent.  Such reports are to be telephoned or faxed 
 to the FDA within 7 calendar days of first learning of the event. 
Follow-up information will be submitted to the FDA as soon as relevant 
information is available.  
 
15 Calendar-Day Written Report:   
The IND Sponsor is required to notify the FDA of any SAE that is unexpected 
and related to the investigational agent in a written IND Safety Report.   
 
Written IND Safety Reports should include an Analysis of Similar Events in 
accordance with regulation 21 CFR § 312.32.  All safety reports previously filed 
with the IND concerning similar events should be analyzed.  The new report 
should contain comments on the significance of the new event in light of the 
previous, similar reports.   
 


J1790 / Version 7.0/ December 10, 2020 
44
Written IND safety reports with Analysis of Similar Events are to be submitted 
to the FDA within 15 calendar days of first learning of the event. Follow-up 
information will be submitted to the FDA as soon as relevant information is 
available. 
 
7.5.7.2 IND Annual Reports 
 
In accordance with the regulation 21 CFR § 312.33, the IND Sponsor shall within 
60 days of the anniversary date that the IND went into effect submit a brief report 
of the adverse events and progress of the investigation.  Please refer to Code of 
Federal Regulations, 21 CFR § 312.33 for a list of the elements required for the 
annual report.  All IND annual reports will be submitted to the FDA by the IND 
Sponsor. 
 
7.5.8 Recombinant DNA Advisory Committee (RAC) 
 
Unexpected SAEs believed to be related to the investigational product(s) will be reported 
by the Protocol Chair to RAC by email if fatal or life-threatening within 7 calendar days 
or by written report if related and unexpected to the investigational product(s) within 15 
calendar days. SAEs that are unrelated or related and expected with the investigational 
product (s) will be reported to RAC in the Annual Report. Follow-up information will be 
submitted to the RAC as soon as relevant information is available. 
 
8. PHARMACEUTICAL INFORMATION 
 
8.1  
Cyclophosphamide (Cytoxan®, CY) 
 
8.1.1 Agent Accountability 
 
The IND Sponsor or the IND Sponsor’s representative shall take responsibility for and 
shall take all steps to maintain appropriate records and ensure appropriate supply, storage, 
handling, distribution and usage of investigational product in accordance with the protocol 
and any applicable laws and regulations. 
 
8.1.2 Mode of Action 
 
CY is a synthetic antineoplastic drug chemically related to the nitrogen mustards. CY is 
biotransformed principally in the liver to active alkylating metabolites by a mixed function 
microsomal oxidase system. These metabolites interfere with the growth of susceptible 
rapidly proliferating malignant cells. The mechanism of action is thought to involve cross-
linking of tumor cell DNA. 
 
8.1.3 Description 
 
CY (CYTOXAN®; cyclophosphamide for injection, USP) is a sterile, white powder 
containing cyclophosphamide monohydrate and is supplied in vials for single-dose use. 
 


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45
8.1.4 Packaging and Labeling Information 
 
CY is commercially available. 
 
8.1.5 Preparation 
 
Parenteral drug products should be inspected visually for particulate matter and 
discoloration prior to administration, whenever solution and container permit. Add the 
diluent to the vial and shake it vigorously to dissolve. If the powder fails to dissolve 
immediately and completely, it is advisable to allow the vial to stand for a few minutes. 
Use the quantity of diluent shown below to constitute the product: 
 
Dosage Strength 
CYTOXAN Contains 
Cyclophosphamide Monohydrate 
Quantity of Diluent 
 
500 mg 
534.5 mg 
25 mL 
1 g 
1069.0 mg 
50 mL 
2 g 
2138.0 mg 
100 mL 
 
CY may be prepared for parenteral use by infusion using any of the following methods: 
1. CY constituted with 0.9% sterile sodium chloride may be infused without further 
dilution. 
2. CY constituted with 0.9% sterile sodium chloride may be infused following further 
dilution in the following: 
 
• Dextrose Injection, USP (5% dextrose) 
• Dextrose and Sodium Chloride Injection, USP (5% dextrose and 0.9% sterile 
sodium chloride) 
• 5% Dextrose and Ringer’s Injection 
• Lactated Ringer’s Injection, USP 
• Sodium Chloride Injection, USP (0.45% sterile sodium chloride) 
• Sodium Lactate Injection, USP (1/6 molar sodium lactate) 
 
8.1.6 Storage 
 
Store vials at or below 77° F (25° C). 
 
8.1.7 Stability 
 
CY (prepared for either direct injection or infusion) is chemically and physically stable for 
24 hours at room temperature or for 6 days in the refrigerator; it does not contain any 
antimicrobial preservative and thus care must be taken to assure the sterility of prepared 
solutions. 
 
 


J1790 / Version 7.0/ December 10, 2020 
46
8.1.8 Route of Administration 
 
CY is administered by IV injection over 30 minutes. 
 
8.1.9 Subject Care Implications 
 
During treatment, the subject’s hematologic profile (particularly neutrophils and platelets) 
should be monitored regularly to determine the degree of hematopoietic suppression. 
 
The rate of metabolism and the leukopenic activity of CY reportedly are increased by 
chronic administration of high doses of phenobarbital. The physician should be alert for 
possible combined drug actions, desirable or undesirable, involving CY even though CY 
has been used successfully concurrently with other drugs, including other cytotoxic drugs. 
CY treatment, which causes a marked and persistent inhibition of cholinesterase activity, 
potentiates the effect of succinylcholine chloride. If a subject has been treated with CY 
within 10 days of general anesthesia, the anesthesiologist should be alerted. 
 
CY may interfere with normal wound healing. 
 
8.1.10 Returns and Reconciliation 
 
N/A 
 
8.2  
GVAX Pancreas Vaccine 
 
8.2.1 Agent Accountability 
 
The IND Sponsor or the IND Sponsor’s representative shall take responsibility for and 
shall take all steps to maintain appropriate records and ensure appropriate supply, storage, 
handling, distribution and usage of investigational product in accordance with the protocol 
and any applicable laws and regulations. 
 
8.2.2 Mode of Action 
 
GM-CSF-secreting, irradiated, whole cell vaccines recruit and activate tumor-specific T 
cells and induce a cytotoxic response through two mechanisms: 1. they deliver a range of 
peptide antigens (without the need for specific knowledge of the relevant target antigens), 
and 2. GM-CSF is an important growth and differentiation factor for dendritic cells, which 
are potent antigen-presenting cells. 
 
8.2.3 Description 
 
 
 
 
 
 


J1790 / Version 7.0/ December 10, 2020 
47
 
 
 
 
8.2.4 Packaging and Labeling Information 
 
 
 
-
-
-
-
 
 
 
 
8.2.5 Preparation 
 
 
 
 
 
8.2.6 Storage 
 
 
 
 
8.2.7 Stability 
 
 
 
 
 
8.2.8 Route of Administration 
 
 
 
 
 
8.2.9 Subject Care Implications 
 
 
 
 
 
 
 
 


J1790 / Version 7.0/ December 10, 2020 
48
 
 
 
 
 
 
 
 
 
 
 
 
8.2.10 Returns and Reconciliation 
 
The investigator is responsible for keeping accurate records of the clinical supplies, the 
amount dispensed to, and returned by the subjects and the amount remaining at the 
conclusion of the trial. 
 
Upon completion or termination of the study, all unused and/or partially used 
investigational product will be destroyed at the site per institutional policy. It is the 
Investigator’s responsibility to arrange for disposal of all empty containers, provided 
that procedures for proper disposal have been established according to applicable federal, 
state, local and institutional guidelines and procedures, and provided that appropriate 
records of disposal are kept. 
 
8.3  
CRS-207 
 
8.3.1 Agent Accountability 
 
The IND Sponsor or the IND Sponsor’s representative shall take responsibility for and 
shall take all steps to maintain appropriate records and ensure appropriate supply, storage, 
handling, distribution and usage of investigational product in accordance with the protocol 
and any applicable laws and regulations. 
 
8.3.2 Mode of Action 
 
 
 
 


J1790 / Version 7.0/ December 10, 2020 
49
  
 
8.3.3 Description 
 
 
 
 
 
  
 
8.3.4 Packaging and Labeling Information 
 
 
-
 
 
 
8.3.5 Preparation 
 
 
 
 
 
 
 
 
 
 
-
 
 
 
 
 
 
 
8.3.6 Storage 
 
 
 
8.3.7 Stability 
 
 
  
 


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50
8.3.8 Route of Administration 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
8.3.9 Subject Care Implications 
 
-
 
 
-
  
 
 
 
 
- -
 
 
 
 
 
 
 


J1790 / Version 7.0/ December 10, 2020 
51
-
 
 
-
 
 
8.3.10 Returns and Reconciliation 
 
The investigator is responsible for keeping accurate records of the clinical supplies, the 
amount dispensed to, and returned by the subjects and the amount remaining at the 
conclusion of the trial. 
 
Upon completion or termination of the study, all unused and/or partially used 
investigational product will be destroyed at the site per institutional policy. It is the 
Investigator’s responsibility to arrange for disposal of all empty containers, provided 
that procedures for proper disposal have been established according to applicable federal, 
state, local and institutional guidelines and procedures, and provided that appropriate 
records of disposal are kept. 
 
8.4  
Nivolumab 
 
8.4.1 Agent Accountability 
 
The IND sponsor or the IND Sponsor’s representative shall take responsibility for and shall 
take all steps to maintain appropriate records and ensure appropriate supply, storage, 
handling, distribution and usage of investigational product in accordance with the protocol 
and any applicable laws and regulations.  
At the end of the study period, Bristol-Myers Squibb Company will not continue to supply 
study drug to subjects/investigators unless the Sponsor-Investigator chooses to extend their 
study. The investigator is responsible to ensure that the subject receives appropriate 
standard of care or other appropriate treatment in the independent medical judgement of 
the Investigator to treat the condition under study. 
8.4.2 Mode of Action 
 
Nivolumab is a fully human monoclonal immunoglobulin (Ig) G4 antibody that binds to 
the PD-1 cell surface membrane receptor, a negative regulatory molecule expressed by 
activated T and B lymphocytes. Inhibition of the interaction between PD-1 and its ligands 
promotes immune responses and antigen-specific T cell responses to both foreign antigens 
as well as self-antigens. 
 


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8.4.3 Description 
 
 
 
 
8.4.4 Packaging and Labeling Information 
 
 
8.4.5 Preparation 
 
 
 
 
 
 
8.4.6 Storage 
 
-
 
 
 
 
 
8.4.7 Stability 
 
  


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53
 
8.4.8 Route of Administration 
 
-
-
 
  
 
8.4.9 Subject Care Implications 
 
 
-
 
 
 
-
 
 
8.4.10 Returns and Reconciliation 
 
The investigator is responsible for keeping accurate records of the clinical supplies 
received from BMS or designee, the amount dispensed to, and returned by the subjects and 
the amount remaining at the conclusion of the trial. 
 
Upon completion or termination of the study, all unused and/or partially used 
investigational product will be destroyed at the site per institutional policy. It is the 
Investigator’s responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable federal, state, 
local and institutional guidelines and procedures, and provided that appropriate records of 
disposal are kept. 
 
8.5  
Ipilimumab 
 
8.5.1 Agent Accountability 
 
The IND Sponsor or the IND Sponsor’s representative shall take responsibility for and 


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54
shall take all steps to maintain appropriate records and ensure appropriate supply, storage, 
handling, distribution and usage of investigational product in accordance with the protocol 
and any applicable laws and regulations. 
 
At the end of the study period, Bristol-Myers Squibb Company will not continue to supply 
study drug to subjects/investigators unless the Sponsor-Investigator chooses to extend their 
study. The investigator is responsible to ensure that the subject receives appropriate 
standard of care or other appropriate treatment in the independent medical judgement of 
the Investigator to treat the condition under study. 
 
8.5.2 Mode of Action 
 
Ipilimumab is a fully human immunoglobulin (IgG1) that is specific for the CTLA-4 
antigen expressed on a subset of activated T-cells. CTLA-4 interaction with the B7 
molecule, one of its ligands expressed on professional antigen presenting cells, can down-
regulate T-cell response.  Ipilimumab is, thought to act by blocking the interaction of 
CTLA-4 with the B7 ligand, resulting in a blockade of the inhibitory effect of T-cell 
activation.  The CTLA-4/B7 creates the interaction.  
 
8.5.3 Description 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.5.4 Packaging and Labeling Information 
 
 
 
8.5.5 Preparation 
 


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55
 
 
 
8.5.6 Storage 
 
-
 
 
 
 
 
 
8.5.7 Stability 
 
 
 
 
 
 
8.5.8 Route of Administration 
 
-
 
 
8.5.9 Subject Care Implications 
 
 
 
 
 
 
 
 
 
 
 


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56
8.5.10 Returns and Reconciliation 
 
The investigator is responsible for keeping accurate records of the clinical supplies 
received from BMS or designee, the amount dispensed to, and returned by the subjects and 
the amount remaining at the conclusion of the trial. 
 
Upon completion or termination of the study, all unused and/or partially used 
investigational product will be destroyed at the site per institutional policy. It is the 
Investigator’s responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable federal, state, 
local and institutional guidelines and procedures, and provided that appropriate records of 
disposal are kept. 
 
9. CORRELATIVE/SPECIAL STUDIES 
 
Research samples will be collected at the discretion of the PI based on availability of supplies and 
safety of patient and staff. Sample collection, processing, storage, and shipment instructions will 
be provided in the Laboratory Manual. 
 
9.1 
Tumor Tissue Studies 
 
Tumor biopsies will be collected (if a subject’s tumor is thought to be reasonably safe and easy to 
biopsy) at baseline and at Cycle 3 (4-6 cores per time point).  If a biopsy was done within 21 days 
before first dose, archived tissue from this biopsy may be used as baseline sample.  Fine needle 
aspiration will not be acceptable. Additional optional biopsies may be obtained later in the course 
of study treatment.  
 
Attempts will be made to obtain archived tissue samples from all subjects.  Archived FNA biopsy 
samples do not contain sufficient tissue and will not be collected.   
 
Detailed instructions for tissue collection, processing, storage, and shipment will be provided in 
the Laboratory Manual. 
 
To explore the association of OS, PD-L1 positivity, and tumor-infiltrating lymphocyte 
characteristics with clinical responses, archived tumor tissue and tumor tissue obtained at baseline 
and during treatment (Cycle 3) will be compared. PD-L1 expression may predict response to anti-
PD-118,19.  However, PD-L1 is also upregulated in response to IFN-γ released by infiltrating T cells 
and could potentially be a predictor of response to any active immunotherapy.  Pre- and post-
treatment tumor biopsies will also be analyzed for PD-1 expression as well as infiltration of 
immune cells (effector T cells, Tregs, B cells, dendritic cells, etc).  Characterization of immune 
checkpoint expression as well as immune infiltrates may be predictive of response to therapy and 
may also give insight into next generation combinatorial approaches.  Preliminary data from a 
pancreatic cancer immunotherapy study suggests that induction of a Th1and Th17 phenotype at the 
tumor itself predicts response.  Furthermore, upregulation of other inhibitory molecules such as 
IL-10 and TGF-β may identify other targets for combinatorial strategies.  Dependent on 
availability of paired tissue samples, additional analysis including determination of gene signatures 
of tumor and immune cells will be performed to look for patterns of response associated with 
immune activation and changes in the tumor. 


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Attempts will be made to obtain archived tissue samples from all subjects.   
 
9.2 
Peripheral Blood Mononuclear Cells (PBMCs) 
 
Whole blood for isolation of PBMCs will be collected prior to dosing on Day 1 of Cycles 1, 2, 4, 
and 6 only during Course 1. Pre- and post-treatment changes in PBMCs including effector, helper, 
and regulatory T cells, NK cells, and macrophages through cell phenotyping analysis and gene 
expression profiling will be measured. In addition, induction of Listeria and mesothelin antigen-
specific T cell responses and changes to the T cell epitope repertoire will also be evaluated. 
The cellular immune responses directed against Lm and mesothelin will be evaluated by using 
enzyme-linked immunosorbent spot (ELISPOT) and intracellular cytokine staining. Post-
treatment expression of PD-1 and other lymphocyte activation markers will be measured as well. 
These responses will be correlated with OS. PBMCs are isolated and stored frozen (liquid nitrogen) 
until use. Detailed instructions for collection, processing, storage, and shipment are provided in 
the Laboratory Manual. 
 
9.3 
Serum and Plasma Marker Studies 
 
Sera will be collected prior to dosing on Day 1 of Cycles 1-6 only during Course 1. Additionally, 
subjects will have whole blood for serum drawn 20-26 hours post-CRS-207 infusion during Cycles 
3-6 for patients in Arm A and during Cycles 1-6 for patients in Arm B only during Course 1.  
Plasma will be collected prior to dosing on Day 1 of Cycles 1, 2, 4, 6, and the EOT evaluation only 
during Course 1. Humoral immune responses, including anti-Lm, anti-mesothelin, anti-
thyroglobulin and anti-galectin 3 antibodies will be evaluated by using enzyme-linked 
immunosorbent assay (ELISA). In addition, potential therapeutic targets, biomarkers, and 
predictors of response and autoimmune toxicity will be evaluated. Sera and plasma are isolated 
and stored frozen (-80oC) until use. Detailed instructions for collection, processing, storage, and 
shipping are provided in the Laboratory Manual. 
 
9.4 
Stool and Oral Wash Samples Studies 
 
Stool and oral wash specimens (and questionnaire) will be obtained when available. All stool 
specimens should be collected within 72 hours (and ideally within 24 hours) of the patient's 
appointment. Baseline specimens may be obtained at Cycle 1 Day 1 ± 30 days of Course 1. 
Additional samples will be collected at Course 1 Cycle 4 Day 1 (± 30 days), Course 1 Cycle 6 Day 
1 (± 30 days) and EOT (± 30 days). Additional samples may be obtained if the patient has any 
drug-related toxicity or at other timepoints of interest at the discretion of the PI at any point during 
the trial.   
 
Microbial DNA will be isolated from stool and oral wash samples and prepared for 16S V4 
sequencing to profile microbial species represented in the gut pre- and post-treatment.  In addition, 
microbial DNA will be subjected to whole genome metagenomics profiling of microbial species 
via shotgun sequencing for detailed functional and pathway analysis to determine the change in 
the species and functions in response to treatment.  Further bioinformatics analyses will be 
performed with these sequencing data to identify candidate microbial biomarkers, and predictors 
of response.  Detailed instructions for stool and oral wash collection, storage, and shipment are 
provided in the Laboratory Manual.  


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58
 
9.5 
Diagnostic Tissue Samples 
 
Tissue, fluid, or blood may be collected from standard of care procedures used to treat or diagnose 
immune-related toxicities. 
 
9.6 
Genomic Analysis 
 
Genomic sequencing library construction, whole genome/exome sequencing, whole transcriptome 
sequencing, microbial sequencing, neoepitope prediction, mutation burden, and bioinformatic 
analysis will be performed either at an on-campus laboratory or at an off-campus sequencing 
service. All the samples will be de-identified before sending to any laboratory for sequencing.  The 
FASTQ files, BAM files and VCF files will be generated and analyzed.  
 
Genomic sequencing data will be stored and computations conducted using a JH IT managed 
subscription of Azure. 
 
Clinical analysis.  Several CLIA-certified laboratories now offer molecular profiling of 
cancer specimens in commercial and noncommercial settings and provide these results to patients 
and their physicians (e.g. Foundation Medicine, PGDx, Michigan Center for Translational 
Pathology, or JHU CLIA Laboratories). It is possible, therefore, that some of our research analyses 
will be conducted in these CLIA-certified environments.  If tissue or cells are evaluated with next 
generation sequencing strategies to provide a molecular profile of individual cancer specimens in 
a CLIA-certified facility, these results will be made available to the patient and their 
physician.  Patient confidentiality will be maintained, and the patient’s identity will not be publicly 
linked to any study results.  Researchers may use the data set generated in the CLIA assay setting 
to study genetic alterations across a large number of genes important in cancer. Germline mutations 
are only identified in punitive cancer genes. Researchers will use the data set for exploratory 
research to study cancer cell heterogeneity. Some of the sequencing data obtained from the NGS 
strategies will be uploaded to government sponsored databases, such as GEO and dbGAP.  The 
results of the research studies may be published but subjects will not be identified in any 
publication. 
 
If a germline alteration of clinical importance (as judged by the Investigator) to the subject and his 
or her family members is identified by a CLIA-certified test in the course of this analysis, attempts 
will be made in writing to contact the subject and/or family members for genetic counseling 
referral.


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10. STUDY CALENDAR 
 
10.1  Treatment Arm A 
Study Procedures 
Pre-Study 
Cycle 124 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Cycle 6 
EOT26 
D1 D2 D425 
D1 D2 D425 D927 
D1 
D2 D3 
D9 
D1 D2 D3 
D9 
D1 D2 D3 
D9 
D1 D2 D3 
D9 
Visit Windows (days)1 
-21 to 
D1 
-  
- 
±1 - 2 
- 
±1 
±1 
- 2 
- 
- 
±1 - 2 
- 
- 
±1 - 2 
- 
- 
±1 - 2 
- 
- 
±1 
+/- 7 
CY2 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Nivolumab2 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
Ipilimumab2 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
GVAX Pancreas Vaccine 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CRS-207 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization (R) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical, Cancer, & Con Med 
History3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Con Meds, Adverse Events 
 
X 
X 
X 
X 
X 
X 
X27 
X 
X 
X X25 X 
X 
X X25 X 
X 
X X25 X 
X 
X X25 
X 
Physical Exam, ECOG  PS4 
X 
X 
 
 
X 
 
 
X27 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Vitals, Weight, & Height5 
X 
X 
X 
 
X 
X 
 
X27 
X 
X 
 
 
X 
X 
 
 
X 
X 
 
 
X 
X 
 
 
X 
Hematology, Chemistry6, 12 
X 
X 
 
 
X 
 
 
X27 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
Endocrine7, 12 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Urinalysis8, 12 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CD4, Virology9 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Coagulation panel10 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test11 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
CA19-9 12 
X 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 


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60
Study Procedures 
Pre-Study 
Cycle 124 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Cycle 6 
EOT26 
D1 D2 D425 
D1 D2 D425 D927 
D1 
D2 D3 
D9 
D1 D2 D3 
D9 
D1 D2 D3 
D9 
D1 D2 D3 
D9 
ECG13 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CT/MRI, RECIST/irRC14 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Vaccine Site Reactions15 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Whole blood for PBMC16, 29 
 
X 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
Whole blood for plasma16, 29 
 
X 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
Serum16, 29 
 
X 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
Stool, Oral Wash Samples17, 29 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
Microbiome Questionnaire17 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
HLA18 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Archival Tissue19, 29 
X 
Tumor Biopsies20, 29 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Antibiotics21,22 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X28 
X28 
Blood sample for CRS-207 
testing23 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
In order to minimize the need for research-only in-person visits, telemedicine visits may be substituted for in person clinical trial visits or portions 
of clinical trial visits where determined to be appropriate and where determined by the investigator not to increase the participants risks. Prior to 
initiating telemedicine for study visits the study team will explain to the participant, what a telemedicine visit entails and confirm that the study 
participant is in agreement and able to proceed with this method. Telemedicine acknowledgement will be obtained in accordance with the Guidance 
for Use of Telemedicine in Research. In the event telemedicine is not deemed feasible, the study visit will proceed as an in-person visit. Telemedicine 
visits will be conducted using HIPAA compliant method approved by the Health System and within licensing restrictions. 
 
1:   If necessary, a scheduled cycle may be delayed for up to 1 week. Longer delays to be approved by the IND Sponsor or Protocol Chair. 
2:   Order of administration is CY, Nivolumab, and then Ipilimumab. Subjects should be observed for a minimum of 30 minutes between each infusion. 
3: Cancer history includes: primary site of cancer, gross location of primary tumor, secondary sites of cancer, histology, histologic grade, date of initial 
diagnosis, date of metastatic diagnosis, prior cancer therapy regimens. 
4: Complete physical examination and assessment of ECOG PS will be completed at baseline; focused physical examinations and assessment of ECOG 
PS will be conducted thereafter.  Day 1 Physical examination and ECOG status may be done up to 1 day prior to dosing. 


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61
5:   Blood pressure, pulse, and temperature are required as indicated. Weight and pulse oximetry will be obtained at baseline and prior to each cycle.  Height 
will be taken at or prior to screening only. Vitals should be collected prior to CY administration and prior to and after GVAX pancreas vaccine 
administration. Nivolumab: vitals will be collected prior to and at the end of the infusion (-5/+ 15 minutes). Ipilimumab: vitals will be collected prior 
to and at the end of the infusion (-5/+ 15 minutes). CRS-207: vital signs will be obtained prior to and then every 30 minutes (± 15 minutes) during 
infusion and every hour (-5/+ 15 minutes) during post-infusion follow-up. Subjects will be observed for at least 4 hours after each CRS-207 infusion. 
Subjects who are not stable enough to be released at 4 hours after infusion should continue to be monitored until stable. Presence of fever alone does 
not indicate subject is not clinically stable. 
6:  Clinical hematology: CBC with differential ANC, ALC, AEC, and platelet count; serum chemistry: sodium, potassium, chloride, bicarbonate, glucose, 
BUN, creatinine, ALT, AST, alkaline phosphatase, total bilirubin, direct bilirubin, amylase, total protein, albumin, calcium, magnesium, and phosphate. 
LDH at baseline only. Required labs on Day 2 only after CRS-207 dosing: Any unexpected Grade 3 or greater laboratory abnormalities should be 
repeated within 24-72 hours. Grade 3 or greater creatinine, AST, ALT, and bilirubin should be repeated within 24-72 hours as well. 
7:   TSH (Total T3 and free T4 if TSH abnormal and clinically indicated). 
8:   Bilirubin, blood, glucose, ketones, leukocytes, nitrite, pH, color, protein, RBC and WBC count, and specific gravity. 
9:  Virology screen: 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. 
10:  Coagulation panel: D-dimer, fibrinogen, international normalized ratio of prothrombin time, APTT 
11: Pregnancy tests will be administered to WOCBP: serum pregnancy test is required at screening; urine pregnancy tests are required before doses on Day 
1 of dosing weeks.  
12: Labs may be collected within a window of up to 3 days prior to dosing. Blood draws must not be collected from a central line for at least 4 days after 
infusion of CRS-207.  
13: ECG should be performed at baseline.  
14: Spiral CT of thorax, abdomen and pelvis (and other imaging studies as clinically indicated to evaluate suspected sites of metastatic disease). If a subject 
cannot have a CT scan (e.g., allergy to contrast dye), an MRI should be performed. 3-D CT scans and RECIST reads will not be used to determine 
eligibility at baseline. On study radiologic evaluations and tumor measurements (RECIST and irRC per Appendix C and Appendix D) will be 
performed every 10 weeks (± 1 week; starting from the date of first treatment) including the EOT evaluation (± 4 weeks). If the EOT visit occurs early, 
scans do not need to be repeated if one has been done within the past 6 weeks. Weeks are in reference to calendar week and should not be adjusted due 
to dosing delays. 
15: Injection-site reactions will be evaluated on Day 4 after GVAX pancreas vaccinations by phone or email. 
16: Up to 120 mL of whole blood for PBMC isolation may be drawn up to 72 hours prior to dosing and must be processed by sponsor-qualified operators 
within 6 hours of collection and stored in liquid nitrogen. Approximately 20 mL of whole blood for plasma collection will be drawn as indicated. 
Approximately 5.0 mL of blood for serum for immune monitoring will be drawn as indicated. Day 3 blood draws (after CRS-207 only) should be taken 
between 20 and 26 hours after start of dosing.  Collection of whole blood for isolation of PBMCs, plasma, and serum will only be drawn during Course 
1. 
17: Stool and oral wash specimens (and questionnaire) will be obtained when available. All stool specimens should be collected within 72 hours (and 
ideally within 24 hours) of the patient's appointment. Baseline specimens may be obtained at Cycle 1 Day 1 ± 30 days of Course 1. Additional samples 
will be collected at Course 1 Cycle 4 Day 1 (± 30 days), Course 1 Cycle 6 Day 1 (± 30 days), and EOT (± 30 days). Additional samples may be obtained 


J1790 / Version 7.0/ December 10, 2020 
62
if the patient has any drug-related toxicity or at other timepoints of interest at the discretion of the PI at any point during the trial. Detailed instructions 
for stool and oral wash collection and shipment are provided in the Laboratory Manual.  
18: HLA-typing to include HLA class I type A and B, low resolution. HLA typing is only done during the first course of study treatment. 
19: Attempts to obtain surgical or biopsy archival tumor samples will be made for every subject until the sample is obtained or documentation that the 
sample cannot be obtained. Detailed instructions for tissue collection, processing and shipment are provided in the Laboratory Manual.  
20: Tumor biopsies to be taken (if a subject’s tumor is thought to be reasonably safe and easy to biopsy) at baseline and at Cycle 3 (4-6 cores per timepoint). 
If a biopsy was done within 21 days before first dose, archived tissue from this biopsy may be used as baseline sample.  The Cycle 3 biopsy has a ± 1 
week window. Additional optional biopsies may be obtained later in the course of study treatment. Fine needle aspiration will not be acceptable. 
Biopsies will only be collected during the first course of study treatment. Detailed instructions for tissue collection, processing and shipment are 
provided in the Laboratory Manual.  
21
-
-
   
22
 
 
23: Blood for CRS-207 culture will be collected at EOT (or within 4 weeks of the last dose of antibiotics if patients do not complete 6 cycles of treatment) 
to assess clearance of CRS-207. After last dose of CRS-207, blood will continue to be collected for CRS-207 culture at 3, 6, 9, and 12 months from 
last dose of CRS-207 (+/- 1 week window for each collection). 
24: Cycle 1 Day 1 evaluations do not need to be repeated if they were conducted within 3 days of the pre-study evaluations. The additional course(s) may 
start as early as 3 weeks (+7 days) from last dose of previous course. 
25: Day 4 and 9 (± 1 day) adverse event assessments may be conducted by telephone or email. 
26: Subjects will return to the study site for an EOT evaluation. EOT follow-up will occur 28 (±7) days after the final dose. NOTE: CT scan assessment at 
EOT will occur 28 days (± 4 weeks) after the final dose. If the EOT visit occurs early (or if the patient cannot return due to disease progression), an 
assessment for AEs should be made by telephone or email on day 28 (±1) after last study dose. Subjects who discontinue from treatment should be 
contacted every three months (+/- 2 weeks) to monitor overall survival. Information of other cancer therapies after discontinuation from the study 
treatment will be collected as well. Subjects who discontinue treatment should be contacted by telephone or email at 100 days (+ 14 day reporting 
window) to assess for treatment related toxicities that occur in the follow-up period. 
27: The first 6 subjects randomized to Arm A will return to the study site at Cycle 2, Day 9 for a focused physical examination, assessment of ECOG status, 
vitals, labs, concomitant medications and adverse events during Course 1 only.  
28: Site personnel will contact the subject by telephone (prior to and within 3 days after completion) to facilitate compliance with antibiotic treatment and 
document in source. 
29: Research samples will be collected at the discretion of the PI based on availability of supplies and safety of patient and staff. 
 


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10.2  Treatment Arm B 
Study Procedures 
Pre-Study 
Cycle 123 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Cycle 6 
EOT25 
D1 D2 D3 
D9 
D1 D2 D3 
D924 
D1 D2 D3 
D9 
D1 D2 D3 
D9 
D1 D2 D3 
D9 
D1 
D2 
D3 
D9 
Visit Windows (days)1 
-21 to 
D1 
- 
- 
- 
+1 - 2 
- 
- 
±1 
- 2 
- 
- 
±1 - 2 
- 
- 
±1 - 2 
- 
- 
±1 - 2 
- 
- 
±1 
+/- 7 
Nivolumab2 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
Ipilimumab2 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
CRS-207 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/ exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization (R) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical, Cancer, & Con 
Med History3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Con Meds, Adverse Events 
 
X 
X 
X X24 
X 
X 
X X24,26 X 
X 
X X24 X 
X 
X X24 X 
X 
X X24 X 
X 
X X24 
X 
Physical Exam, ECOG  PS4 
X 
X 
 
 
 
X 
 
 
X26 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Vitals, Weight, & Height5 
X 
X 
X 
 
 
X 
X 
 
X26 
X 
X 
 
 
X 
X 
 
 
X 
X 
 
 
X 
X 
 
 
X 
Hematology, Chemistry6, 12 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
Endocrine7, 12 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Urinalysis8, 12 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CD4, Virology9 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Coagulation panel10 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test11 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
CA19-9 12 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
ECG13 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CT/MRI, RECIST/irRC14 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Whole blood for PBMC15, 28 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
Whole blood for plasma15, 28 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 


J1790 / Version 7.0/ December 10, 2020 
64
Study Procedures 
Pre-Study 
Cycle 123 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Cycle 6 
EOT25 
D1 D2 D3 
D9 
D1 D2 D3 
D924 
D1 D2 D3 
D9 
D1 D2 D3 
D9 
D1 D2 D3 
D9 
D1 
D2 
D3 
D9 
Serum15, 28 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
Stool, Oral Wash 
Samples16, 28 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
Microbiome 
Questionnaire16 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
HLA17 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Archival Tissue18, 28 
X 
Tumor Biopsies19, 28 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Antibiotics20,21 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X27 
X27 
Blood sample for CRS-207 
testing22 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
In order to minimize the need for research-only in-person visits, telemedicine visits may be substituted for in person clinical trial visits or portions 
of clinical trial visits where determined to be appropriate and where determined by the investigator not to increase the participants risks. Prior to 
initiating telemedicine for study visits the study team will explain to the participant, what a telemedicine visit entails and confirm that the study 
participant is in agreement and able to proceed with this method. Telemedicine acknowledgement will be obtained in accordance with the Guidance 
for Use of Telemedicine in Research. In the event telemedicine is not deemed feasible, the study visit will proceed as an in-person visit. Telemedicine 
visits will be conducted using HIPAA compliant method approved by the Health System and within licensing restrictions. 
 
1:   If necessary, a scheduled cycle may be delayed for up to 1 week. Longer delays to be approved by the IND Sponsor and/or Protocol Chair. 
2:   Order of administration is Nivolumab followed by Ipilimumab. Subjects should be observed for a minimum of 30 minutes between each infusion. 
3: Cancer history includes: primary site of cancer, gross location of primary tumor, secondary sites of cancer, histology, histologic grade, date of initial 
diagnosis, date of metastatic diagnosis, prior cancer therapy regimens. 
4: Complete physical examination and assessment of ECOG PS will be completed at baseline; focused physical examinations and assessment of ECOG 
PS will be conducted thereafter.  Day 1 Physical examination and ECOG status may be done up to 1 day prior to dosing. 
5:   Blood pressure, pulse, and temperature are required as indicated. Weight and pulse oximetry will be obtained at baseline and prior to each cycle.  Height 
will be taken at or prior to screening only. Nivolumab: vitals will be collected prior to and at the end of the infusion (-5/+ 15 minutes). Ipilimumab: 
vitals will be collected prior to and at the end of the infusion (-5/+ 15 minutes). CRS-207: vital signs will be obtained prior to and then every 30 minutes 
(± 15 minutes) during infusion and every hour (-5/+ 15 minutes) during post-infusion follow-up. Subjects will be observed for at least 4 hours after 


J1790 / Version 7.0/ December 10, 2020 
65
each CRS-207 infusion. Subjects who are not stable enough to be released at 4 hours after infusion should continue to be monitored until stable. 
Presence of fever alone does not indicate subject is not clinically stable. 
6:  Clinical hematology: CBC with differential ANC, ALC, AEC, and platelet count; serum chemistry: sodium, potassium, chloride, bicarbonate, glucose, 
BUN, creatinine, ALT, AST, alkaline phosphatase, total bilirubin, direct bilirubin, amylase, total protein, albumin, calcium, magnesium, and phosphate. 
LDH at baseline only. Required labs on Day 2 only after CRS-207 dosing: Any unexpected Grade 3 or greater laboratory abnormalities should be 
repeated within 24-72 hours. Grade 3 or greater creatinine, AST, ALT, and bilirubin should be repeated within 24-72 hours as well. 
7:   TSH (Total T3 and free T4 if TSH abnormal and clinically indicated). 
8:   Bilirubin, blood, glucose, ketones, leukocytes, nitrite, pH, color, protein, RBC and WBC count, and specific gravity. 
9:  Virology screen: 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. 
10:  Coagulation panel: D-dimer, fibrinogen, international normalized ratio of prothrombin time, APTT 
11: Pregnancy tests will be administered to WOCBP: serum pregnancy test is required at screening; urine pregnancy tests are required before doses on Day 
1 of dosing weeks.  
12: Labs may be collected within a window of up to 3 days prior to dosing. Blood draws must not be collected from a central line for at least 4 days after 
infusion of CRS-207.  
13: ECG should be performed at baseline.  
14: Spiral CT of thorax, abdomen and pelvis (and other imaging studies as clinically indicated to evaluate suspected sites of metastatic disease). If a subject 
cannot have a CT scan (e.g., allergy to contrast dye), an MRI should be performed. 3-D CT scans and RECIST reads will not be used to determine 
eligibility at baseline. On study radiologic evaluations and tumor measurements (RECIST and irRC per Appendix C and Appendix D) will be 
performed every 10 weeks (± 1 week; starting from the date of first treatment) including the EOT evaluation (± 4 weeks). If the EOT visit occurs early, 
scans do not need to be repeated if one has been done within the past 6 weeks. Weeks are in reference to calendar week and should not be adjusted due 
to dosing delays. 
15: Up to 120 mL of whole blood for PBMC isolation may be drawn up to 72 hours prior to dosing and must be processed by sponsor-qualified operators 
within 6 hours of collection and stored in liquid nitrogen. Approximately 20 mL of whole blood for plasma collection will be drawn as indicated. 
Approximately 5.0 mL of blood for serum for immune monitoring will be drawn as indicated. Day 3 blood draws should be taken between 20 and 26 
hours after start of dosing. Collection of whole blood for isolation of PBMCs, plasma, and serum will only be drawn during Course 1. 
16: Stool and oral wash specimens (and questionnaire) will be obtained when available. All stool specimens should be collected within 72 hours (and 
ideally within 24 hours) of the patient's appointment. Baseline specimens may be obtained at Cycle 1 Day 1 ± 30 days of Course 1. Additional samples 
will be collected at Course 1 Cycle 4 Day 1 (± 30 days), Course 1 Cycle 6 Day 1 (± 30 days), and EOT (± 30 days). Additional samples may be obtained 
if the patient has any drug-related toxicity or at other timepoints of interest at the discretion of the PI at any point during the trial. Detailed instructions 
for stool and oral wash collection and shipment are provided in the Laboratory Manual.  
17: HLA-typing to include HLA class I type A and B, low resolution. HLA typing is only done during the first course of study treatment. 
18: Attempts to obtain surgical or biopsy archival tumor samples will be made for every subject until the sample is obtained or documentation that the 
sample cannot be obtained. Detailed instructions for tissue collection, processing and shipment are provided in the Laboratory Manual.  
19: Tumor biopsies to be taken (if a subject’s tumor is thought to be reasonably safe and easy to biopsy) at baseline and at Cycle 3 (4-6 cores per timepoint). 
If a biopsy was done within 21 days before first dose, archived tissue from this biopsy may be used as baseline sample.  The Cycle 3 biopsy has a ± 1 
week window. Additional optional biopsies may be obtained later in the course of study treatment. Fine needle aspiration will not be acceptable. 


J1790 / Version 7.0/ December 10, 2020 
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Biopsies will only be collected during the first course of study treatment. Detailed instructions for tissue collection, processing and shipment are 
provided in the Laboratory Manual.  
20
   
21
 
-
 
22: Blood for CRS-207 culture will be collected at EOT (or within 4 weeks of the last dose of antibiotics if patients do not complete 6 cycles of treatment) 
to assess clearance of CRS-207. After last dose of CRS-207, blood will continue to be collected for CRS-207 culture at 3, 6, 9, and 12 months from 
last dose of CRS-207 (+/- 1 week window for each collection). 
23: Cycle 1 Day 1 evaluations do not need to be repeated if they were conducted within 3 days of the pre-study evaluations. The additional course(s) may 
start as early as 3 weeks (+7 days) from last dose of previous course. 
24: Day 9 (± 1 day) adverse event assessments may be conducted by telephone or email. 
25: Subjects will return to the study site for an EOT evaluation. EOT follow-up will occur 28 (±7) days after the final dose. NOTE: CT scan assessment at 
EOT will occur 28 days (± 4 weeks) after the final dose. If the EOT visit occurs early (or if the patient cannot return due to disease progression), an 
assessment for AEs should be made by telephone or email on day 28 (±1) after last study dose. Subjects who discontinue from treatment should be 
contacted every three months (+/- 2 weeks) to monitor overall survival. Information of other cancer therapies after discontinuation from the study 
treatment will be collected as well. Subjects should be contacted by telephone or email at 100 days (+ 14 day reporting window) to assess for treatment 
related toxicities that occur in the follow-up period. 
26: The first 6 subjects randomized to Arm B will return to the study site Cycle 2, Day 9 for a focused physical examination, assessment of ECOG status, 
vitals, labs, concomitant medications and adverse events during Course 1 only.      
27: Site personnel will contact the subject by telephone (prior to and within 3 days after completion) to facilitate compliance with antibiotic treatment and 
document in source. 
28: Research samples will be collected at the discretion of the PI based on availability of supplies and safety of patient and staff.


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11.  
STUDY ENDPOINTS 
 
11.1 
Primary Endpoint 
 
The primary endpoint is ORR, which is defined as the proportion of subjects with PR or CR 
according to RECIST 1.1. Subjects who discontinue due to toxicity or clinical progression prior to 
post-baseline tumor assessments will be considered as non-responders.  Subjects who discontinue 
for other reasons prior to their first dose of study drug will be replaced and not included in the 
primary efficacy analysis. 
 
11.2 
Secondary Endpoint 
 
The secondary endpoint is as follows: 
• Safety assessed by the following measures: 
– Number of patients who have grade 3 or higher drug-related toxicities  
– Frequency of drug-related toxicity by grade  
– Injection-site reactions (after GVAX pancreas vaccine injections only) 
– Nivolumab-related infusion reactions 
– Ipilimumab-related infusion reactions 
– CRS-207-related infusion reactions 
– Immune-related AEs 
– Unacceptable toxicities 
– Vital signs: BP, pulse, temperature 
– Physical examination 
– Changes in ECG readings  
– Clinical hematology: complete blood count (CBC) with differential ANC, 
ALC, AEC, and platelet count 
– Clinical serum chemistry: sodium, potassium, chloride, bicarbonate, glucose, 
blood urea nitrogen (BUN), creatinine, lactate dehydrogenase (LDH), ALT, 
AST, alkaline phosphatase, amylase, bilirubin (total), total protein, albumin, 
calcium, magnesium and phosphate 
 
11.3 
Exploratory Endpoints 
 
Exploratory endpoints are as follows: 
• Overall survival (OS), duration of response, PFS measured by RECIST, immune-
related progression-free survival (irPFS), and time to progression (TTP). 
− 
Overall survival (OS) is defined as the number of months from the date of 
randomization until death or end of follow-up (OS will be censored on the date 
the subject was last known to be alive for subjects without documentation of 
death at the time of analysis). 
− 
Progression-free survival (PFS) is defined as the number of months from the 
date of randomization to disease progression (PD or relapse from CR as 
assessed using RECIST 1.1 criteria) or death due to any cause. PFS will be 
censored at the date of the last scan for subjects without documentation of 
disease progression at the time of analysis. 
− 
Duration of Response (DOR) is defined as the number of months from the first 
documentation of a response to date of disease progression.  


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− 
Time to-progression (TTP) is defined as the number of months from the date of 
randomization to the date of documented disease progression (PD or relapse 
from CR as assessed using RECIST 1.1 criteria). It differs from PFS in that it 
does not include death in the definition of an event.  TTP will be censored at 
the date of the last scan for subjects without documentation of disease 
progression at the time of analysis. 
• Tumor marker kinetics measured by change in serum CA19-9 concentrations from 
baseline  
• Objective disease responses, progression-free survival, and duration of response 
measured by irRC  
• Humoral and cellular immune responses directed against Lm and mesothelin 
assessed by using the following measures: 
– ELISPOT or intracellular cytokine staining assays of PBMC 
– Induction of proinflammatory cytokines and chemokines in the serum 
– ELISA detection of mesothelin- and Lm-specific antibodies in the serum 
• Immune subset analyses by IHC and gene expression profiling of tumor tissue  
• Immune subset analyses in PBMCs including effector, helper, and regulatory T 
cells, NK cells, and macrophages  
• Telomere length of lymphocytes  
• Thyroglobulin and galectin-3 antibody responses  
• Microbial community analysis and whole metagenome functional profiling analysis 
of stool samples 
• Peripheral blood specimens, intratumoral core biopsy specimens, and resection 
specimens will be studied using a variety of laboratory techniques including but not 
limited to: immunohistochemistry (IHC), flow cytometry, CITE-Seq, RNA-Seq, 
whole exome sequencing, whole genome sequencing, T cell receptor and B cell 
receptor sequencing, ChIP-seq, ATAC-seq, and MBD-seq. 
 
12.  
DATA REPORTING / REGULATORY REQUIREMENTS 
 
AE guidelines and instructions for AE reporting can be found in Section 7.0 (Adverse Events: 
List and Reporting Requirements). 
 
Dr. Elizabeth Jaffee will be holding the IND for this study.  She will comply with all regulated 
reporting requirements to the FDA. 
 
12.1 
Data Collection and Processing 
 
All information will be collected on study-specific CRFs by study staff. These data will be 
reviewed for completeness and accuracy by the Principal Investigator at each site.  
 
CRFs will be used to capture study results and data. The study coordinator or other authorized 
study personnel will transcribe data from source documents onto paper or eCRFs. Before or 
between visits, the Protocol Chair, IND Sponsor, or designee may request copies of the CRFs for 
preliminary medical review. Once the CRFs are complete and source-verified, the investigator 
must sign and date all required pages, verifying the accuracy of all data contained within the CRF.  
 
Protocol Chair 


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The Protocol Chair and/or designee is responsible for performing the following tasks: 
• Coordinating, developing, submitting, and obtaining approval for the protocol as well as 
its subsequent amendments. 
• Assuring that all participating institutions are using the correct version of the protocol. 
• Taking responsibility for the overall conduct of the study at all participating institutions 
and for monitoring the progress of the study. 
• Reviewing and ensuring reporting of SAE 
• Reviewing data from all sites. 
 
Coordinating Center (Johns Hopkins University) 
The Coordinating Center (or its representative) is responsible for performing the following tasks: 
• Ensuring that IRB approval has been obtained at each participating site prior to the first 
subject registration at that site, and maintaining copies of IRB approvals from each site. 
• Monitoring subject registration. 
• Collecting and compiling data from each site. 
• Establishing procedures for documentation, reporting, and submitting of AE’s and SAE’s 
to the Protocol Chair, and all applicable parties. 
• Facilitating audits by securing selected source documents and research records from 
participating sites for audit, or by auditing at participating sites. 
 
Participating Sites 
Participating sites are responsible for performing the following tasks: 
• Following the protocol as written, and the guidelines of Good Clinical Practice (GCP). 
• Submitting data to the Coordinating Center. 
• Consent subjects promptly and randomize eligible subjects in EDC. 
• Providing sufficient experienced clinical and administrative staff and adequate facilities 
and equipment to conduct a collaborative trial according to the protocol. 
• Maintaining regulatory binders on site and providing copies of all required documents to 
the Coordinating Center. 
• Collecting and submitting data according to the schedule specified by the protocol. 
 
12.2 
Safety Meetings 
 
Scheduled meetings will take place weekly and will include the protocol principal investigator, 
study coordinator(s), data manager(s), sub-investigators (as appropriate), collaborators (as 
appropriate), and biostatisticians (as appropriate) involved with the conduct of the protocol. During 
these meetings matters related to the following will be discussed: safety of protocol participants, 
validity and integrity of the data, enrollment rate relative to expectation, characteristics of 
participants, retention of participants, adherence to protocol (potential or real protocol violations), 
data completeness, and progress of data for objectives. 
 
Monthly teleconferences will be scheduled to include the Coordinating Center and the clinical trial 
sites. During these meetings, the Coordinating Center and clinical trial sites shall discuss the 
following: study protocol updates, safety data, enrollment status, and progress of data for 
objectives.  
 


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12.3 
Monitoring 
 
The SKCCC Compliance Monitoring Program will provide external monitoring for JHU-affiliated 
sites in accordance with SKCCC DSMP (Version 6.0, 02/21/2019). The SMC Subcommittee will 
determine the level of patient safety risk and level/frequency of monitoring. Eligibility for all sites 
will be monitored by the Protocol Chair. Data monitoring of this protocol will occur on a regular 
basis with the frequency dependent on the rate of subject accrual and the progress of the study.  
Additional data and safety monitoring oversight will also be performed by the SKCCC Safety 
Monitoring Committee (SMC - as defined in the DSMP) and a Medical Expert Committee (MEC) 
as detailed below. The protocol will be monitored internally by the IND Sponsor and the Principal 
Investigator at each site. External monitoring will occur according to the following guidelines: 
 
Johns Hopkins SKCCC: The protocol will be monitored externally by the SKCCC CRO in 
accordance with SKCCC guidelines. Trial monitoring and reporting will be done through the 
Safety Monitoring Committee (SMC) at SKCCC.  
 
Participating site(s): The protocol will be monitored by the internal CRO at each site. A report of 
the reviews will be submitted to the Protocol Chair, IND Sponsor, and the SKCCC CRO. 
 
Authorized representatives of the Coordinating Center may visit the satellite sites to perform audits 
or inspections, including source data verification. The purpose of these audits or inspections is to 
systematically and independently examine all trial-related activities and documents to determine 
whether these activities were conducted and data were recorded, analyzed, and accurately reported 
according to the protocol, Good Clinical Practice (GCP), and any applicable regulatory 
requirements. 
 
The Medical Expert Committee (MEC) for this clinical study contains three medical oncologists 
from other disciplines who are not affiliated with this clinical trial protocol. The MEC will review 
safety data on at least a semi-annual basis. The MEC will provide a written summary of each 
assessment to the IND Sponsor-Investigator after each meeting. In turn, the study team will 
forward these summaries to the JHU and IRB, and JHU SKCCC SMC. The operating plan of the 
MEC will be as follows:  
 
• Meetings will be held at least semi-annually, and potentially more frequently if needed.  
• Meetings will be conducted in-person or via video/teleconference, with a participant sign-
in sheet collected at each meeting.  
• Approximately one week prior to each MEC meeting, the study team will submit the 
following items to MEC personnel for review and discussion at the meeting (The PI may 
join the MEC meeting in order to answer any questions the MEC might have):  
o A summary of the clinical trial’s progress to date;  
o The latest IRB-approved consent document;  
o A summary of all adverse events, serious adverse events, deaths, and withdrawals 
to date; 
 
Note that the MEC reserves the right to halt trial accrual or all study activity if, after review, serious 
safety concerns warrant this action. If the MEC halts study accrual or all study activity, then the 
study team must notify the JHU SKCCC SMC, JHU IRB, and the FDA immediately.   
 


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12.4 
Study Documentation 
 
12.4.1 Informed Consent and Authorization for use and Disclosure of Protected 
Health Information 
 
Written informed consent and authorization of use and disclosure of protected health 
information (PHI) must be obtained from each subject (or the subject’s legally authorized 
representative) before performing any study-specific screening/baseline period 
evaluations. The ICF and authorization for use and disclosure of PHI, which is prepared by 
the investigator or the site, must be reviewed and approved by the IND Sponsor, the study 
monitor (if applicable), and the site’s IRB before the initiation of the study.  
 
12.4.2 Investigator Study Files 
 
Documentation about the investigator and study staff, the IRB and the institution, is 
required before study site initiation. A list of required documents will be provided by the 
IND Sponsor or designee to each participating investigator. Copies of these documents as 
well as supplemental information, such as the investigator’s obligations, IB, clinical study 
protocol and amendments, safety information, investigational agent information, biological 
samples and laboratory procedures, SRM, study logs and IND Sponsor/investigator/study 
monitor correspondence will be kept on-site in study site-specific binders. 
 
The IND Sponsor or designee will be responsible for maintaining original and backup of 
all CRF data. The investigator is responsible for maintaining backup of all electronic data 
systems used for primary documentation or source documentation. Backup of electronic 
data will be performed periodically as described in the site-specific SOPs. Backup records 
must be stored at a secure location on site and backup and recovery logs must be maintained 
to facilitate data recovery. If an electronic medical records system that is not supported by 
the IND Sponsor or designee (or is discontinued or decommissioned) is used, the 
investigator must maintain a system to retrieve these records or arrange for the transfer of 
these records to an alternate electronic format or to paper. 
 
Changes to any electronic records require an audit trail, in accordance with 21 CFR 
11.10(e), and should include who made the changes and when and why the changes were 
made. An audit trail is defined as a secure, computer-generated, time-stamped electronic 
record that will allow reconstruction of the course of events relating to the creation, 
modification and deletion of an electronic record. Audit trails must be created 
incrementally, in chronological order and in a manner that does not allow new audit trail 
information to overwrite existing data. Audit trails should be in a readable format and 
readily available at the study site and any other location where electronic study records are 
maintained. 
 
Audit trails are generated automatically for eCRFs. The investigator is responsible for 
maintaining audit trails of all electronic data systems used for primary documentation or 
source documentation. 
 
12.4.3 Case Report Forms and Source Documentation 
 


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The investigator must make study data accessible to the site monitor, to other authorized 
representatives of the IND Sponsor (or designee) and to the appropriate regulatory 
authority inspectors. The original CRF for each subject will be checked against source 
documents at the study site by the site monitor. 
 
12.4.4 Retention of Study Documents 
 
According to ICH E6, Section 4.9, all CRFs, as well as supporting paper and electronic 
documentation and administrative records, must be retained for at least 2 years after the 
last approval of a marketing application and until there are no pending or contemplated 
marketing applications, or at least 2 years have elapsed since the formal discontinuation of 
clinical development of an individual product. Longer retention periods may apply. The 
IND Sponsor will notify investigators as to when documents no longer need to be retained. 
No study documents will be destroyed or moved to a new location without prior written 
approval from the IND Sponsor. If the investigator relocates, retires or withdraws from the 
clinical study for any reason, all records required to be maintained for the study should be 
transferred to an agreed-upon designee, such as another investigator at the institution where 
the study was conducted. 
 
Audit trails for electronic documents must be retained for a period at least as long as that 
required for the subject electronic records to which they pertain. The investigator must 
retain either the original or a certified copy of audit trails. 
 
12.4.5 Data Confidentiality and Subject Anonymity 
 
All information about the nature of the proposed investigation provided by the IND 
Sponsor or their representative to the investigator (with the exception of information 
required by law or regulations to be disclosed to the IRB, the subject or the appropriate 
regulatory authority) must be kept in confidence by the investigator. 
 
The anonymity of participating subjects must be maintained. Subjects will be identified by 
their initials and an assigned subject number on CRFs and other documents retrieved from 
the site or sent to the IND Sponsor, BMS, regulatory agencies, or central 
laboratories/reviewers. Documents that identify the subject (e.g., the signed ICF) must be 
maintained in strict confidence by the investigator, except to the extent necessary to allow 
auditing by the appropriate regulatory authority, the study monitor, IND Sponsor or their 
representative. 
 
13. STATISTICAL CONSIDERATIONS 
 
13.1 
Study Design/Endpoints 
 
Sample size.   
 
The primary endpoint is ORR, defined as the proportion of subjects with PR or CR according 
to RECIST 1.1.  Subjects who discontinue due to toxicity or clinical progression prior to post-
baseline tumor assessments will be considered as non-responders.  Subjects who discontinue for 
other reasons prior to their first dose of study drug will be replaced and not included in the primary 


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analysis. 
 
With a total of 30 evaluable subjects in each arm, the treatment will be considered successful if 5 
or more subjects respond in a single arm.  If the number of responses is 4 or less, the preliminary 
anti-tumor activity of the treatment will be rejected. 
 
The study is powered to assess each arm separately. The sample size is based on an A’Hern single-
stage phase 2 design20.  A sample size of 30 evaluable subjects per arm are required to decide 
whether the proportion responding is less than or equal to 0.06 or greater than or equal to 0.2221.  
If the number of responses is 5 or more, the hypothesis that P <= 0.06 is rejected with a target error 
rate of 0.05 (alpha).  If the number of responses is 4 or less, the hypothesis that P >= 0.22 is rejected 
with a target error rate of 0.20 (power = 0.80).  Each arm will be evaluated independently. 
 
The benchmark for the estimate of ORR is based on a recent study of metastatic pancreatic cancer 
patients who had failed one prior gemcitabine-based regimen where patients who received 
nanoliposomal irinotecan plus fluorouracil and folinic acid had a response rate of 16% (19/177).  
Response rates for patients receiving either nanoliposomal irinotecan monotherapy or fluorouracil 
and folinic acid were between 1-6%.  
 
Statistical Analyses   
 
Data will be summarized descriptively by treatment arm and overall.  The descriptive summary 
including demographics and baseline variables will include counts and percentages for categorical 
variables and means, medians, standard deviations and minimum and maximum values for 
continuous variables.  
 
Time-to-event outcomes such as OS will be analyzed using Kaplan-Meier estimates (to obtain 
medians with 95% CI as well as plotting survival curves), log-rank tests, and Cox proportional 
hazards models. Comparisons between the two treatment arms will be exploratory in nature due to 
the small sample size. Where applicable, comparisons between groups will be made using a Chi-
square test or logistic regression for binary variables and t-tests or analysis of covariance 
(ANCOVA) or linear regression models for continuous variables.  Non-parametric alternatives 
(e.g. Fisher’s exact test or Kruskal-Wallis tests) will be considered as needed as will 
transformations of the outcome variables (e.g. log).   
 
For correlative studies, plots will be used to show the changes in immune response over time both 
for each individual and for each treatment group. For each treatment, comparisons in the pre and 
post-treatment responses will be compared using paired t-tests (or Wilcoxon signed rank tests if 
appropriate) for continuous variables and McNemar’s tests for dichotomous or categorical 
variables. Associations between immune parameters will be explored graphically (e.g. scatterplots, 
boxplots) and numerically (e.g., correlations, Fisher’s exact tests). Regression techniques will be 
used to explore the differences between the treatment arms for cross-sectional data (e.g., linear and 
logistic regression) and longitudinally with appropriate correction for correlation between repeated 
measurements (e.g., GEE and linear mixed effects models). 
 
All statements of statistical significance will be based on a 2-tailed test with an overall 0.05 level 
of significance, unless stated otherwise.  All confidence intervals will be 95%, unless stated 
otherwise.  Sensitivity analyses will include models adjusting for baseline covariables.  These 


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covariates will be selected based upon both clinical significance and potential imbalances between 
the treatment arms. 
 
Timing of Analysis 
 
The primary analysis will be conducted when all treated subjects have documented response or 
progression by RECIST 1.1, or have discontinued the study. 
 
13.2 
Analysis Sets 
 
The Full Analysis Set (FAS) includes all randomized subjects who received at least one dose of 
study treatment. FAS analyses will be conducted on the basis of the randomized treatment. Since 
the focus of this study is on establishing the efficacy of the treatment combinations, all efficacy 
outcomes will be assessed using the FAS as the primary population for analysis. 
 
The Intent to Treat (ITT) analysis set includes all randomized subjects, regardless of the amount 
or type of treatment received. It is distinguished from the FAS in that individuals who do not 
receive any doses of study treatment will be included and therefore focuses upon the effectiveness 
of the treatment combinations.  ITT analyses will be conducted on the basis of the randomized 
treatment. This population will be used for sensitivity analyses of OS and other selected efficacy 
endpoints. 
 
The safety population includes all randomized subjects who received at least one dose of study 
treatment. The safety population will be conducted on the basis of the actual treatment received. 
All safety outcomes will be assessed using the safety population for analysis. 
 
A Per-Protocol (PP) subset may also be used to analyze select efficacy endpoints and will be based 
on study treatment exposure (compliance and/or time on study treatment) and major protocol 
deviations. The criteria for inclusion in the PP subset will be finalized and documented prior to 
database lock. 
 
13.3 
Safety Analysis 
 
The safety analysis will be performed in all treated subjects. AE data will be listed individually 
and incidence of AEs summarized by system organ class and preferred terms within a system organ 
class for each treatment group.  When calculating the incidence of AEs, each AE (based on 
preferred terminology defined by CTCAE version 4.03) will be counted only once for a given 
subject.  In analyses of grade and causality, if the same AE occurs on multiple occasions, the 
highest grade and strongest relationship to study drug will be assumed.  If 2 or more AEs are 
reported as a unit, the individual terms will be reported as separate experiences.  Vaccine-site 
reactions will be listed and tabulated separately from the AEs. 
 
Changes in vital signs, hematology and clinical chemistry parameters from baseline to the end of 
the study will be examined.  Toxicity will be tabulated by type and grade. Toxicities will be 
characterized according to the CTCAE version 4.03.  Treatment-emergent changes from normal 
to abnormal values in key laboratory parameters will be identified.  
 
 
 


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1 
Siegel, R. L., Miller, K. D. & Jemal, A. Cancer statistics, 2016. CA: a cancer journal for 
clinicians 66, 7-30, doi:10.3322/caac.21332 (2016). 
2 
Torre, L. A. et al. Global cancer statistics, 2012. CA: a cancer journal for clinicians 65, 
87-108, doi:10.3322/caac.21262 (2015). 
3 
Rahib, L. et al. Projecting cancer incidence and deaths to 2030: the unexpected burden of 
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doi:10.1158/0008-5472.CAN-14-0155 (2014). 
4 
Burris, H. A., 3rd et al. Improvements in survival and clinical benefit with gemcitabine as 
first-line therapy for patients with advanced pancreas cancer: a randomized trial. Journal 
of clinical oncology : official journal of the American Society of Clinical Oncology 15, 
2403-2413 (1997). 
5 
Moore, M. J. et al. Erlotinib plus gemcitabine compared with gemcitabine alone in patients 
with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada 
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Society of Clinical Oncology 25, 1960-1966, doi:10.1200/JCO.2006.07.9525 (2007). 
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Conroy, T. et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. The 
New England journal of medicine 364, 1817-1825, doi:10.1056/NEJMoa1011923 (2011). 
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Von Hoff, D. D. et al. Increased survival in pancreatic cancer with nab-paclitaxel plus 
gemcitabine. 
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Wang-Gillam, A. et al. Nanoliposomal irinotecan with fluorouracil and folinic acid in 
metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a 
global, randomised, open-label, phase 3 trial. Lancet 387, 545-557, doi:10.1016/S0140-
6736(15)00986-1 (2016). 
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Le, D. T. et al. Safety and Survival With GVAX Pancreas Prime and Listeria 
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Le, D. T. et al. Evaluation of ipilimumab in combination with allogeneic pancreatic tumor 
cells transfected with a GM-CSF gene in previously treated pancreatic cancer. J 
Immunother 36, 382-389, doi:10.1097/CJI.0b013e31829fb7a2 (2013). 
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Disis, M. L. Immune regulation of cancer. Journal of clinical oncology : official journal of 
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Dong, H. et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism 
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Sharpe, A. H. & Freeman, G. J. The B7-CD28 superfamily. Nat Rev Immunol 2, 116-126, 
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Brown, J. A. et al. Blockade of programmed death-1 ligands on dendritic cells enhances T 
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Francisco, L. M., Sage, P. T. & Sharpe, A. H. The PD-1 pathway in tolerance and 
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Wolchok, J. D. et al. Guidelines for the evaluation of immune therapy activity in solid 
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the American Association for Cancer Research 15, 7412-7420, doi:10.1158/1078-
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Postow, M. A., Harding, J. & Wolchok, J. D. Targeting immune checkpoints: releasing the 
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Topalian, S. L. et al. Safety, activity, and immune correlates of anti-PD-1 antibody in 
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Brahmer, J. R. et al. Phase I study of single-agent anti-programmed death-1 (MDX-1106) 
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Wang-Gillam, A. et al. Nanoliposomal irinotecan with fluorouracil and folinic acid in 
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6736(15)00986-1 (2016). 
 
 
 
 
 
 
 


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


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APPENDIX B: Management Algorithms 
 
These general guidelines constitute guidance to the Investigator and may be supplemented by 
discussions with the Protocol Chair representing the IND Sponsor. The guidance applies to all 
immuno-oncology (I-O) agents and regimens. 
 
A general principle is that differential diagnoses should be diligently evaluated according to 
standard medical practice. Non-inflammatory etiologies should be considered and appropriately 
treated. 
 
Corticosteroids are a primary therapy for immuno-oncology drug-related adverse events. The oral 
equivalent of the recommended IV doses may be considered for ambulatory subjects with low-
grade toxicity. The lower bioavailability of oral corticosteroids should be taken into account when 
switching to the equivalent dose of oral corticosteroids. 
 
Consultation with a medical or surgical specialist, especially prior to an invasive diagnostic or 
therapeutic procedure, is recommended. 
 
The frequency and severity of the related adverse events covered by these algorithms will depend 
on the immuno-oncology agent or regimen being used. 
 
 
 
 
 
 
 
 
 
 


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


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


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


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APPENDIX D: Immune-Related Response Criteria 
 
Comparison between RECIST 1.1 criteria and the irRC 
RECIST 1.1 
irRC RECIST 1.1 
New, measurable 
lesions  
(i.e., ≥ 5mm) 
Always represent PD 
Incorporated into tumor 
burden 
New, non-
measurable lesions  
(i.e., < 5mm) 
Always represent PD 
Does not define 
progression (but precludes 
irCR) 
Non-index lesions 
Changes contribute to defining best 
overall response (BOR) of CR, PR, SD, 
and PD 
Contribute to defining irCR 
(complete disappearance 
required) 
CR 
Disappearance of all lesions in two 
consecutive observations not less than 4 
week apart 
Disappearance of all 
lesions in two consecutive 
observations not less than 4 
week apart if single arm 
trial and primary endpoint 
only 
PR 
> or = 30% decrease in the sum of the 
diameters of all index lesions compared 
with baseline in two observations at least 
4 week apart, in absence of new lesions 
or unequivocal progression of non-index 
lesions 
≥ 30% decrease in tumor 
burden compared with 
baseline in two 
observations at least 4 
week apart if single arm 
trial and primary endpoint 
only 
SD 
< 30% decrease in sum of longest 
diameters of all index lesions compared 
with baseline cannot be established nor 
< 20% increase compared with nadir, in 
the absence of new lesions or 
unequivocal progression of non-index 
lesions 
< 30% decrease in tumor 
burden compared with 
baseline cannot be 
established nor < 20% 
increase compared with 
nadir 
PD 
At least 20% increase in the sum of the 
longest diameters of index lesions and/or 
unequivocal progression of non-index 
lesions 
At least 20% increase in 
tumor burden compared 
with nadir (at any single 
time point) in two 
consecutive observations at 
least 4 week apart 
Handling of lymph 
nodes 
Lymph nodes are considered 
pathologically enlarged if > 10 mm in 
SAD. To be measurable, nodal lesions 
must be ≥ 15 mm in SAD. Nodal lesions 
with SAD > 10 mm and < 15 mm are 
non- measurable. The sum of the 
diameters (LD for extranodal target 
lesions, SAD for nodal lesions) is 
followed through the course of therapy 
Not differentiated from 
other tumor measurements 


J1790 / Version 7.0/ December 10, 2020 
91
Derivation of irRC Overall Responses  
(Modified for RECIST 1.1. Criteria) 
 
Measurable response 
Non-measureable response 
Overall 
response 
Index and new, 
measurable lesions 
(tumor burden)* % 
Non-index lesions 
New, non- 
measurable lesions 
Using irRC 
↓ 100 
Absent 
Absent 
irCR/\ 
↓ 100 
Stable 
Any 
irPR/\ 
↓ 100 
Unequivocal progression 
Any 
irPR/\ 
↓ ≥ 30 
Absent/ Stable 
Any 
irPR/\ 
↓ ≥ 30 
Unequivocal progression 
Any 
irPR/\ 
↓ <30 to <20↑ 
Absent/ Stable 
Any 
irSD 
↓ <30 to <20↑ 
Unequivocal progression 
Any 
irSD 
≥ 20↑ 
Any 
Any 
irPD/\ 
*Decreases assessed relative to baseline, including measurable lesions only (>5 x 5 mm). 
/\Assuming response (irCR or irPR) and progression (irPD) are confirmed by a second consecutive 
assessment at least 4 weeks apart. 
 
 
Defining immune-related Response Criteria by RECIST 1.1 criteria at 20 weeks (irDCR at 20 
weeks): 
 
1. Any patient with stable disease or progressive disease at any time in the trial with "rapid 
clinical deterioration" felt to be related to disease progression is irPD 
 
2. Any patient who meets the criteria for RECIST 1.1 CR at 20 weeks is irCR 
 
3. Any patient who meets the criteria for RECIST 1.1 PR at 20 weeks is irPR 
 
4. Any patient who meets the criteria for RECIST 1.1 SD at 20 weeks is irSD 
 
5. A patient with RECIST 1.1 PD but no rapid clinical deterioration may stay on study if 
his/her next tumor measurement evaluation is stable disease or better. 
 
6. If patient has first time PD by RECIST 1.1 criteria, call it unconfirmed PD for irRC 
RECIST 1.1. 
 
7. A patient with unconfirmed irPD at 20 weeks whose next tumor measurement is SD or 
better will be considered to be included in the irDCR at 6 months. 
 
8. A patient with unconfirmed irPD at 20 weeks who fails to qualify for RECIST 1.1 SD or 
unconfirmed CR or PR by next tumor measurement will be considered to have RECIST 
1.1 PD and irPD at 20 weeks.