Conditions: Colorectal Tumors Colorectal Neoplasms Colorectal Carcinoma Colorectal Adenocarcinoma Colorectal Cancer
Keywords: Anti-PDL1 Antibody Therapeutic Cancer Vaccine Mismatch Repair Deficiency Progression Free Survival Adenovirus Based, CEA-Targeting Vaccine
Allocation: RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 30
Healthy volunteers: no

Brief summary:
Background:

Colorectal cancer is a common cancer in the Unites States (U.S.) It causes the second most cancer-related deaths. The drug avelumab and vaccine Ad-CEA together help the immune system fight cancer.

Objective:

To test if avelumab and Ad-CEA plus standard therapy treats colorectal cancer that has spread to other sites better than standard therapy alone.

Eligibility:

People ages 18 and older with untreated colorectal cancer that has spread in the body

Design:

Participants will be screened with:

Test to see if their cancer has a certain deficiency

Blood, urine, and heart tests

Scans

Medical history

Physical exam

Tumor sample. This can be from a previous procedure.

A small group of participants will get Ad-CEA and avelumab plus standard therapy. This is leucovorin calcium (folinic acid), fluorouracil, and oxaliplatin (FOLFOX) plus bevacizumab for up to 24 weeks then capecitabine plus bevacizumab.

The others will have treatment in 2-week cycles. They will be Arm A or B:

Arm A: FOLFOX and bevacizumab by intravenous (IV) days 1 and 2 for 12 cycles. After that, capecitabine by mouth twice a day and bevacizumab by IV on day 1.

Arm B: Ad-CEA injection every 2-12 weeks. Avelumab by IV on day 1 of each cycle. FOLFOX and bevacizumab by IV days 2 and 3 for 12 cycles. Then, capecitabine by mouth twice a day and bevacizumab through IV on day 2.

Participants will repeat screening tests during the study.

Participants will be treated until their disease gets worse or they have bad side effects. Arm A participants can join Arm B. They will have a visit 4 5 weeks after they stop therapy.

Detailed description:
Background

* Colorectal cancer (CRC) is the fourth most common cancer diagnosis in the United States and accounts for the second most cancer-related deaths.
* Programmed death ligand 1 (PD-L1) is a transmembrane protein that was first identified for its role in the maintenance of self-tolerance and prevention of autoimmunity. Blockade of the interaction between PD-L1 on tumor cells and PD-1 on T cells is expected to reverse T cell suppression within tumors. These agents are dependent on underlying T cell activation against the tumor cell to be effective.
* Avelumab is a fully human immunoglobulin G 1 (IgG1) anti-PDL1 antibody that selectively binds to PD-L1 and competitively blocks its interaction with PD-1.
* In ongoing phase 1 trials of avelumab, the agent has been well tolerated and has shown clinical activity.
* Clinical trials with anti-PD-1/L1 agents in colorectal cancer have resulted in minimal activity in patients who do not have mismatch repair deficiency (MMR-D).
* Therapeutic cancer vaccines targeting overexpressed proteins offer a potential method to activate T cells against tumors.
* A novel adenovirus-based, carcinoembryonic antigen (CEA)-targeting vaccine has demonstrated cytolytic T cell responses in patients with metastatic colorectal cancer.
* Standard of care agents in first line metastatic colorectal cancer (CRC) have properties been associated with improved immune response via immunologic cell death and immunogenic modulation.

Primary Objective

-To determine if there is an improvement progression free survival among patients with metastatic colorectal cancer lacking a mismatch repair deficiency who are treated with standard of care + anti- PDL1 monoclonal antibody + Ad-CEA therapeutic cancer vaccine compared with standard of care alone.

Eligibility

* Subject's age 18 and older with previously untreated pathologically confirmed metastatic or unresectable colorectal cancer; prior adjuvant therapy is acceptable.
* Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2.
* Normal organ and bone marrow function.
* Subjects with active autoimmune diseases requiring treatment and subjects requiring system steroids (except for physiologic doses for steroid replacement) are not allowed.
* Tumor sample and whole blood sample must be available for proteomics, genomics and transcriptomics analyses.
* Subjects with metastatic or unresectable colorectal cancer with mismatch repair deficiency (MMR-D or microsatellite instability (MSI)-High) will not be eligible.

Design

* This is a randomized, multicenter phase II clinical trial designed to evaluate the potential improvement in progression free survival (PFS) when Avelumab and Ad-CEA vaccine are used in combination with standard of care therapy in metastatic or unresectable colorectal cancer when compared with standard of care alone (FOLFOX-A).
* A lead in cohort, comprising the first 6 evaluable subjects enrolled, will be treated with avelumab + Ad- CEA vaccine + standard of care in order to assess the safety of the combination.
* If no more than 1 subject in the lead in cohort experiences a dose limiting toxicity attributable to the investigational new drug (IND) agents, 70 evaluable subjects will be randomized on a 1:1 basis to receive either Avelumab + Ad-CEA vaccine + standard of care (Arm B) or standard of care alone (Arm A).
* Standard of care therapy consists of 6 - 12 two-week cycles of bevacizumab + FOLFOX (5-FU, leucovorin, oxaliplatin) followed by two-week cycles of bevacizumab + capecitabine until disease progression.
* Subjects assigned to Arm A that have progressive disease will be offered Avelumab + Ad-CEA vaccine in combination with a standard chemotherapy regimen.
* Kaplan-Meier curves and a two-tailed log-rank test will be the primary analysis methods.
* The accrual ceiling for the study is set at 97.

Arms:
arm 1: Participants will receive leucovorin calcium (folinic acid), fluorouracil, and oxaliplatin (FOLFOX)- + bevacizumab + for up to 12 2-week cycles followed by maintenance therapy with bevacizumab + capecitabine until disease progression. arm 2: Participants will receive leucovorin calcium (folinic acid), fluorouracil, and oxaliplatin (FOLFOX)- + bevacizumab + avelumab + Ad-CEA vaccine (given weeks 0,2,4,8,12,16 and then every 12 weeks) for up to 12 2-week cycles followed by maintenance therapy with bevacizumab + capecitabine + avelumab + Ad-CEA vaccine (following the every 12-week dosing schedule) until disease progression.

Interventions: intervention 1: Avelumab intervention 2: Ad-CEA vaccine intervention 3: Bevacizumab intervention 4: 5-Fluorouracil (FU) intervention 5: Leucovorin intervention 6: Oxaliplatin intervention 7: Capecitabine intervention 8: 5-Fluorouracil (FU)
Intervention descriptions: intervention 1: 10 mg/kg intravenous (IV) over 30-60 min on Day 1 intervention 2: Subcutaneous injection in the thigh prior to Avelumab on Day 1 of cycles 1, 2 3, 5, 7, 9; every 6 cycles thereafter. intervention 3: 5mg/kg intravenous (IV) over 30-90 min on day 1 (Arm A) or 2 (Arm B). Part of the standard of care therapy. intervention 4: 400mg/m\^2 (only Arm A) intravenous (IV) bolus on day 1. Part of the standard of care therapy. intervention 5: 400mg/m\^2 intravenous (IV) over 2 hours on day 1 (Arm A) or Day 2 (Arm B). Part of the standard of care therapy. intervention 6: 85mg/m\^2 (Arm A) or 68mg/m\^2 (Arm B) intravenous (IV) over 2 hours on day 1 (Arm A) or Day 2 (Arm B). Part of the standard of care therapy. intervention 7: 625 mg/m\^2 twice a day by mouth. Part of the standard of care therapy. intervention 8: 2400 mg/m\^2 (Arm A and B) intravenous (IV) over 46 hours (+/-2 hours) to start on Day 1 (ARM A) or Day 2 (Arm B). Part of the standard of care therapy.

Protocol document:
Prot_SAP_000.pdf: 
1 
Abbreviated Title: Chemo+antiPDL1+ vaccine in CRC 
Version Date:10.30.2019 
Abbreviated Title: Chemo+antiPDL1+ vaccine in CRC 
CC Protocol #: 17C0057 H 
IBC # RD-16-XI-10 
OSP # 1707-1636 
Version Date: October 30, 2019 
NCT Number: NCT03050814 
Title: A Randomized Phase II trial of Standard of Care Alone or in Combination with Ad-CEA 
vaccine and Avelumab in Patients with Previously Untreated Metastatic or Unresectable 
Colorectal Cancer 
 
NCI Principal Investigator: 
Julius Strauss, MD  
Laboratory of Tumor Immunology and Biology (LTIB) 
Center for Cancer Research (CCR) 
National Cancer Institute (NCI) 
Building 10, Room 13N240  
9000 Rockville Pike 
Bethesda, MD 20892  
301-480-0202 
                                                            julius.strauss@nih.gov 
 
Investigational Agents:     
Drug Name: 
avelumab; anti-PD-L1 antibody; 
MSB0010718C 
ETBX-011; adenoviral CEA 
vaccine 
BB IND 
Number: 
17056 
17056 
Sponsor: 
Center for Cancer Research 
Center for Cancer Research 
Manufacturer: 
EMD Serono, Inc. 
Etubics Corporation 
 
Commercial agents:  
bevacizumab, 5-FU, leucovorin, oxaliplatin, and capecitabine will be purchased by the pharmacy 
at each participating institution 


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Abbreviated Title: Chemo+antiPDL1+ vaccine in CRC 
Version Date:10.30.2019 
PRÉCIS 
Background: 
• Colorectal cancer (CRC) is the fourth most common cancer diagnosis in the United States 
and accounts for the second most cancer-related deaths. 
• Programmed death ligand 1 (PD-L1) is a transmembrane protein that was first identified 
for its role in the maintenance of self-tolerance and prevention of autoimmunity. Blockade 
of the interaction between PD-L1 on tumor cells and PD-1 on T cells is expected to reverse 
T cell suppression within tumors. These agents are dependent on underlying T cell 
activation against the tumor cell to be effective. 
• Avelumab is a fully human IgG1 anti-PDL1 antibody that selectively binds to PD-L1 and 
competitively blocks its interaction with PD-1.  
• In ongoing phase 1 trials of avelumab, the agent has been well tolerated and has shown 
clinical activity. 
• Clinical trials with anti-PD-1/L1 agents in colorectal cancer have resulted in minimal 
activity in patients who do not have mismatch repair deficiency (MMR-D). 
• Therapeutic cancer vaccines targeting overexpressed proteins offer a potential method to 
activate T cells against tumors.  
• A novel adenovirus based, CEA-targeting vaccine has demonstrated cytolytic T cell 
responses in patients with metastatic colorectal cancer. 
• Standard of care agents in first line metastatic CRC have properties been associated with 
improved immune response via immunologic cell death and immunogenic modulation. 
Primary Objective: 
• To determine if there is an improvement progression free survival among patients with 
metastatic or unresectable colorectal cancer who are treated with standard of care + anti-
PDL1 monoclonal antibody + Ad-CEA therapeutic cancer vaccine compared with standard 
of care alone. 
Eligibility: 
• Subjects age 18 and older with previously untreated pathologically confirmed metastatic 
or unresectable colorectal cancer; prior adjuvant therapy is acceptable. 
• ECOG performance status < 2. 
• Normal organ and bone marrow function. 
• Subjects with active autoimmune diseases requiring treatment and subjects requiring 
system steroids (except for physiologic doses for steroid replacement) are not allowed. 
• Tumor sample and whole blood sample must be available for proteomics, genomics and 
transcriptomics analyses.  
• Subjects with metastatic or unresectable colorectal cancer with mismatch repair deficiency 
(MMR-D or MSI-High) will not be eligible. 


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Abbreviated Title: Chemo+antiPDL1+ vaccine in CRC 
Version Date:10.30.2019 
Design: 
• This is a randomized, multicenter phase II clinical trial designed to evaluate the potential 
improvement in progression free survival (PFS) when Avelumab and Ad-CEA vaccine are 
used in combination with standard of care therapy in metastatic or unresectable colorectal 
cancer when compared with standard of care alone (FOLFOX-A). 
• A lead in cohort, comprising the first 6 evaluable subjects enrolled, will be treated with 
avelumab + Ad-CEA vaccine + standard of care in order to assess the safety of the 
combination. 
• If no more than 1 subject in the lead in cohort experiences a dose limiting toxicity 
attributable to the IND agents, 70 evaluable subjects will be randomized on a 1:1 basis to 
receive either Avelumab + Ad-CEA vaccine + standard of care (Arm B) or standard of care 
alone (Arm A) 
• Standard of care therapy consists of 6 – 12 two week cycles of bevacizumab + FOLFOX 
(5-FU, leucovorin, oxaliplatin) followed by two week cycles of bevacizumab + 
capecitabine/5-FU until disease progression 
• Subjects assigned to Arm A that have progressive disease will be offered Avelumab + Ad-
CEA vaccine in combination with a standard chemotherapy regimen 
• Kaplan-Meier curves and a two-tailed log-rank test will be the primary analysis methods. 
• The accrual ceiling for the study is set at 97 


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Abbreviated Title: Chemo+antiPDL1+ vaccine in CRC 
Version Date:10.30.2019 
TABLE OF CONTENTS  
PRÉCIS ...................................................................................................................................2 
TABLE OF CONTENTS ..........................................................................................................4 
1 
INTRODUCTION ..............................................................................................................7 
1.1 
Study Objectives .................................................................................................... 7 
1.2 
Background and Rationale ...................................................................................... 8 
2 
ELIGIBILITY ASSESSMENT AND ENROLLMENT ...................................................... 36 
2.1 
Eligibility Criteria..................................................................................................36 
2.2 
Screening Evaluation .............................................................................................38 
2.3 
Registration Procedures .........................................................................................39 
3 
STUDY IMPLEMENTATION ......................................................................................... 41 
3.1 
Study Design .........................................................................................................41 
3.2 
Dose Limiting Toxicity (Lead-In Period Only) .......................................................42 
3.3 
Study Stopping Rule (Lead-In Period Only) ...........................................................42 
3.4 
Drug Administration ..............................................................................................43 
3.5 
Dose Delays/Modifications ....................................................................................46 
3.6 
Study Calendar ......................................................................................................61 
3.7 
Criteria for Removal from Protocol Therapy and Off Study Criteria ........................65 
3.8 
Cost and Compensation ........................................... Error! Bookmark not defined. 
4 
CONCOMITANT MEDICATIONS/MEASURES ............................................................. 66 
4.1 
Supportive Care.....................................................................................................66 
5 
BIOSPECIMEN COLLECTION ....................................................................................... 68 
5.1 
Correlative Studies for Research/Pharmacokinetic Studies ......................................68 
5.1.1 
Immunological studies ...........................................................................................68 
5.2 
Sample Collection Summary ..................................................................................72 
5.3 
Sample Storage, Tracking, Disposition (Clinical Services Program [CSP]) ..............73 
5.4 
Samples for Genetic/Genomic Analysis..................................................................74 
6 
DATA COLLECTION AND EVALUATION ................................................................... 75 
6.1 
Data Collection .....................................................................................................75 
6.2 
Data Sharing Plans ................................................................................................76 
6.3 
Genomic Data Sharing Plan ...................................................................................76 
6.4 
Response Criteria ..................................................................................................76 


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6.5 
Toxicity Criteria ....................................................................................................83 
7 
NIHREPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN ....... 83 
7.1 
Definitions ............................................................................................................83 
7.2 
OHSRP Office of Compliance and Training IRB Reporting ....................................83 
7.3 
NCI Clinical Director Reporting ............................................................................84 
7.4 
.NCI Guidance for Reporting Expedited Adverse Events for Multi-Center Trials .....84 
7.5 
Institutional Biosafety Committee (IBC) Reporting Criteria ....................................84 
7.6 
NIH REQUIRED Data and Safety Monitoring Plan ................................................85 
8 
SPONSOR SAFETY REPORTING .................................................................................. 86 
8.1 
Definitions ............................................................................................................86 
8.2 
Assessment of Safety Events..................................................................................87 
8.3 
Reporting of Serious Adverse Events .....................................................................88 
8.4 
Waiver of expedited reporting to CCR....................................................................88 
8.5 
Safety Reporting Criteria to the Pharmaceutical Collaborators ................................88 
8.6 
Regulatory Reporting for Studies Conducted Under CCR-Sponsored IND...............90 
9 
CLINICAL MONITORING .............................................................................................. 90 
10 STATISTICAL CONSIDERATIONS ............................................................................... 91 
11 COLLABORATIVE AGREEMENTS ............................................................................... 92 
11.1 
CRADA ................................................................................................................92 
11.2 
MTA .....................................................................................................................92 
11.3 
Multi-Institutional Guidelines ................................................................................92 
12 HUMAN SUBJECTS PROTECTIONS ............................................................................. 92 
12.1 
Rationale For Subject Selection..............................................................................92 
12.2 
Participation of Children ........................................................................................92 
12.3 
Participation of subjects unable to give consent ......................................................92 
12.4 
Evaluation of Benefits and Risks/Discomforts ........................................................93 
12.5 
Consent and Assent Process and Documentation.....................................................93 
13 PHARMACEUTICAL INFORMATION........................................................................... 94 
13.1 
Avelumab (BB IND# 17056) .................................................................................94 
13.2 
Ad-CEA Vaccine (BB IND# 17056) ......................................................................98 
13.3 
Bevacizumab (Avastin)........................................................................................ 101 
13.4 
Capecitabine........................................................................................................ 104 


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13.5 
5-Fluorouracil (5-FU) .......................................................................................... 107 
13.6 
Leucovorin .......................................................................................................... 108 
13.7 
Oxaliplatin .......................................................................................................... 111 
14 REFERENCES ............................................................................................................... 115 
15 APPENDICES................................................................................................................ 121 
15.1 
Appendix A: Preclinical model evaluation of the combination of FOLFOX with anti-
PD-L1 ................................................................................................................. 121 
15.2 
Appendix B-Performance Status Criteria .............................................................. 122 
15.3 
Appendix C: CCR Problem Report Form.............................................................. 123 
 


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Abbreviated Title: Chemo+antiPDL1+ vaccine in CRC 
Version Date:10.30.2019 
1 
INTRODUCTION 
1.1 
STUDY OBJECTIVES 
1.1.1 Primary Objective: 
• To determine if there is an improvement in progression free survival among patients with 
metastatic or unresectable colorectal cancer who are treated with standard of care + Ad-
CEA vaccine + Avelumab compared with standard of care alone 
1.1.2 Secondary Objective: 
• To determine the ratio of patients that are hospitalized because of adverse events 
attributed to disease progression 
1.1.3 Exploratory Objective(s): 
• Safety of the combination versus standard of care alone 
• Immunologic effects of the combination compared with standard of care 
o Peripheral  
 Quantitate T cell responses against CEA, and other tumor associated 
antigens using methods such as intracellular cytokine staining, ELIspot, 
and/or others 
 Flow-based assay for analysis of PBMC subsets  
 T-cell clonal expansion assay 
 Serum cytokine and soluble factor analysis 
 Neutrophil lymphocyte ratio at baseline and change during treatment 
 HLA subtype correlation with clinical outcomes 
 ELISA for antibody generation against CEA  
o Tumoral 
 Immunohistochemistry analysis of T cell infiltrate (may include CD3, CD4, 
CD8, FoxP3 and others), immune regulatory markers (may include IDO, 
LAG3, TIM3, PD-1, PD-L1 and others)  
 RNA and proteomic analysis for: 
• immune signature changes 
• KRAS mutation status relationship to IL10 and TGF-beta tumor 
expression 
• Tumor subtyping into accepted molecular patterns 
• TLR4 loss of function polymorphisms and relationship to outcomes 
 Determine the genomic and proteomic profile of subjects’ tumors to identify 
gene mutations, gene amplifications, RNA-expression levels, and protein-


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Version Date:10.30.2019 
expression levels. Correlations between genome/proteomic profiles and 
efficacy outcomes will be assessed. 
• Correlative analysis of immune endpoints with clinical outcomes 
• Overall response rate (CR+PR by RECIST 1.1) 
• Overall survival 
1.2 
BACKGROUND AND RATIONALE 
1.2.1 Metastatic colorectal cancer 
Colorectal cancer (CRC) is the third most common cancer diagnosis in the United States with a 
projected 132,700 new cases diagnosed in 2015. However, this disease accounts for the second 
most cancer-related deaths, projected to be 49,700 in 2015.1  
1.2.2 Early stage colorectal cancer is immunologically modulated 
Extensive work by the Galon, Pages, and Fridman group has identified, in retrospective analyses, 
immune cell tumor infiltrate signatures to be predictive of prognosis in early stage colorectal 
cancer at the time of diagnosis. Pages et al.2 showed that signs of an immune response within 
colorectal cancers were associated with the absence of pathological evidence of early metastatic 
invasion and that an increased density of CD45RO+ memory T-cells was an independent predictor 
of increased overall survival (n = 490, P, 0.05). Five-year overall survival and disease-free survival 
were 46.3% and 43.1%, respectively, for tumors with a high density of CD45RO+ cells compared 
with 23.7% and 21.5% for tumors with a low density. Tumors without signs of early metastatic 
invasion had increased infiltrates of immune cells and increased levels of mRNA for products of 
TH1 effector cells, but not increased levels of inflammatory mediators or immunosuppressive 
molecules. Markers of T-cell migration, activation and differentiation were also increased, as well 
as the numbers of CD8+ T-cells. In addition, Galon et al.3 further characterized the tumor 
infiltrating immune cells in the same cohort of colorectal cancer patients, and found that the type, 
density and location of the immune cells were a predictor of survival superior to the 
histopathological methods currently used, and independent of the tumor node metastasis (TNM) 
system (Figure 1). By conducting genomic and in situ immunostaining on resected tumors from 
patients with colorectal cancer, they found that TH1 adaptive immunity had a beneficial effect on 
clinical outcome. Tumors from patients without recurrence had significantly higher immune cell 
densities within both the center of the tumor (CT) and the invasive margin (IM). There was a 
statistically significant correlation between the immune cell density and patient outcome (n = 490, 
P, 0.05). They looked at all T-lymphocytes (CD3+), CD8+ T-cell effectors and memory T-cells 
(CD45RO+). Further investigation of the primary tumor microenvironment showed a correlation 
between the absence of metastasis to lymph nodes or distant organs and markers of innate immune 
cells (macrophages, dendritic cells, natural killer [NK] cells and NK T-cells) and activated T-
cells.4 The co-expression of genes for cytotoxicity and TH1 predicted patient survival 
independently of metastatic status (n = 142, P, 0.05). Pages et al.5 recently published a study in 
which they classified early stage colorectal cancer patients (TNM I–II) into four different 
prognostic groups based on the density of CD45RO+ and CD8+ cells in different tumor regions. 
Six hundred and two tumors from two independent cohorts were investigated, and they found 
dramatic differences in disease-free, disease-specific and overall survival (Figure 2). Five-year 
survival in patients with high densities of both CD8+ and CD45RO+ cells was 86.2%, and only 


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Version Date:10.30.2019 
4.8% of the patients had tumor recurrence, whereas in the group with low densities of these cells, 
75% had tumor recurrence, and only 27.5% survived. The immune criteria were found to be 
independent prognostic factors in multivariate analysis (n = 602, P, 0.0001). 
Figure 1. Disease free survival according to tumor histopathology (TNM staging), versus tumor infiltrating immune 
cell density (CD3+ and CD45RO+) in two separate tumor regions. 
 
 
 
(A) Kaplan-Meier curves illustrate 
the duration of disease-free 
survival according to the UICC-
TNM stages (stage I, red line [n = 
75 patients]; stage II, green line 
[n = 137]; stage III, blue line [n = 
99] and stage IV, black line [n = 
95]) in patients w ith colorectal 
cancers. 
(B) Kaplan-Meier curves illustrate 
the duration of disease-free 
survival according to the UICC-
TNM stages (as in [a]) and 
according to the density of CD3+ 
cells in combined tumor regions 
(CD3CT LoCD3IMLo, thick lines, 
n=93 patients; CD3CTHiCD3IMHi , 
thin lines, n = 109). The 
subgroup of patients w ho did not 
appear to have a coordinated in 
situ immune reaction in tumor 
regions (Hi/Lo or Lo/Hi for CD3+ 
cell densities) presented Kaplan-
Meier curves similar to those in 
the entire cohort. 
(C) Kaplan-Meier curves illustrate 
the duration of disease-free 
survival according to the UICC-
TNM stages and to the density of 
CD3+ and CD45RO+ cells in 
combined tumor regions (CD3CT 
LoCD3IMLo  plus 
CD45ROCTLoCD45ROIMLo, thick 
lines n = 16 patients; 
CD3CTHiCD3IMHi  plus 
CD45ROCTHiCD45ROIMHi , thin 
lines,  n = 88). Cutoff values 
w ere 250, 640, 60 and 190 for 
CD3CT, CD3IM, CD45ROCT and 
CD45IM, respectively. In (b and 
c), log-rank statistical test, **p < 
10 4; ns, not significant; CT, 
center of the tumor; IM invasive 
margin. 


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Abbreviated Title: Chemo+antiPDL1+ vaccine in CRC 
Version Date:10.30.2019 
Figure 2. Overall survival in Stage I and II CRC patients according to CD8+ and CD45RO+ cell densities. 
 
 
 
 
1.2.3 Advanced colorectal cancer is poorly immunogenic 
While early stage disease appears to be immunologically relevant, the underlying immune 
response in advanced colorectal cancer appears to be very poor in the majority of patients with 
advanced colorectal cancer. This is indicated by a low number of PD-L1+ tumor cells despite the 
presence of CD8+PD-1+ T cells found in the intratumoral space in metastatic colorectal cancer 
cases.6,7 This tumor microenvironment phenotype has been associated with a low likelihood of 
(A) Pie chart illustrates the 
repartition of patients according to 
the presence of concordance 
(right part) or discrepancy (left 
part) betw een CD8+ and 
CD45RO+ cell densities in 
combined tumor regions of stages 
I and II colorectal tumors.  Fifty-
four percent of the patients 
presented w ith similar high (4)-Hi, 
low  (0)-Hi or heterogeneous (2)-Hi 
immune infiltration for markers, 
w hereas 46% presented w ith 
distinct patterns.  
(B, C) Kaplan-Meier curves for the 
duration of disease- free survival 
and overall survival according to a 
combined analysis of CD8+ and 
CD45RO+ densities in tumor 
regions (center of the tumor [CT] 
and invasive margin [IM] in 
patients w ith stage I or II CRC. 
Patients are stratified according  
to an immune score ranging from 
0 to 4, depending on the total 
number of high densities observed 
(tw o markers assessed in CT, tw o 
markers assessed  in IM).  For 
example, (4)-Hi refers to a tumor 
w ith high densities of CD8+ and 
CD45RO+ cells in CT and IM 
regions of the tumor (red line).  
Duration of disease-free survival 
and overall survival of the entire 
cohort of patients is also 
represented (gray line).  


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Abbreviated Title: Chemo+antiPDL1+ vaccine in CRC 
Version Date:10.30.2019 
anti-tumor effect when treated with PD-1/L1 blocking agents.7 It has been hypothesized that a 
tumor microenvironment without PD-L1 expression indicates a poor T cell response against the 
tumor and that specific T-cell activation against target antigens in the tumor could lead to increased 
T cell infiltration with PD-1 expression and result in PD-L1 upregulation, which would make PD-
1/L1 inhibition a viable anti-tumor strategy.8 Previous work from our group has indicated that 
vaccination against target antigens overexpressed in the tumor can lead to significant infiltration 
of T cells in patients with prostate cancer.9 Addition of therapeutic cancer vaccine capable of 
driving a specific T cell response to the tumor may overcome the poor immunogenicity of 
advanced colorectal cancer.  
1.2.4 Ad5 [E1-, E2b-]-CEA(6D) vaccine (Ad-CEA vaccine)  
1.2.4.1 Description of Ad-CEA vaccine 
Overcoming the problem of pre-existing anti-vector immunity has been a subject of intense 
investigation. Investigations using other Ad subtypes or even non-human forms of Ad have been 
examined. Even if these approaches succeed in an initial immunization, subsequent vaccinations 
may be problematic due to immune responses generated against the differing Ad subtype. To 
overcome the Ad immunization barrier, and circumvent the adverse conditions for Ad5 [E1-] 
vectors, Etubics has constructed an advanced generation Ad vector. The new Ad5 [E1-, E2b-]-
based vectors have additional deletions in the E2b region, removing the DNA polymerase and the 
preterminal protein genes. These vectors essentially do not replicate in cells, normal or 
transformed. These replication-defective vectors can only be propagated in the newly engineered, 
proprietary human 293 cell line (E.C7) that supplies the E1 and E2b gene functions in trans 
required for vector production.10-12  
Deletion of the E2b region also confers advantageous immune properties on the novel Ad vectors. 
The deletion of E2b region sequences has the beneficial effect of markedly reducing residual late 
viral gene expression (>10,000 fold reduction in Ad-fiber protein levels).10 This minimizes 
induction of anti-viral immune responses and allows for greater persistence of transduced cells. 
This enables more potent immune responses to specific, non-viral antigens while minimizing the 
immune responses to Ad viral proteins. Importantly, Ad5 [E1-, E2b-]-based vector vaccines can 
be injected multiple times in homologous immunization regimens designed to induce and increase 
specific immune responses to tumor antigens.13-21 Ad-CEA is an Ad5 [E1-, E2b-]-based vector 
vaccine that contains the insertion of a modified CEA gene (CEA(6D)) designed to increase cell 
mediated immune (CMI) responses to CEA in immunized patients.22-24 
1.2.4.2 Preclinical data 
In pre-clinical studies,16 the immunogenicity of Ad5 [E1-, E2b-]-CEA(6D) vaccine was tested in 
an Ad5 naïve and an Ad5 immune murine model. To assess the induction of cellular meditated 
immunity following immunization, Ad5 naïve C57Bl/6 mice were immunized three times 
subcutaneously (SQ) with 1010 VP of Ad5 [E1-]-CEA(6D) at weekly intervals. Three 
immunizations were used because our prior studies in an HIV-1 model demonstrated that the Ad5 
[E1-, E2b-] vector induced a maximum immune boost after three immunizations.17,18 Fourteen 
days after the final immunization, CEA-specific CMI responses were determined by IFN-γ and IL-
2 ELISpot assays. Mice immunized with Ad5 [E1-, E2b-]-CEA(6D) induced a significantly greater 
number of IFN-γ (p<0.01) and IL-2 (p<0.01) secreting splenocytes than mice immunized with Ad5 
[E1-]-CEA(6D) (Figure 3 A, B). Splenocytes from vaccinated mice and controls were assessed 


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for non-specific cytokine secretion following stimulation with HIV-1 Gag and β-galactosidase. 
Non-specific IFN-γ or IL-2 secretion was not detected in T-cells from the spleens of mice 
vaccinated with either CEA expressing vector (Figure 3). Splenocytes were also stimulated with 
Ad5-null to confirm positive vaccination against Ad5 and splenocytes derived from all such 
immunized mice harbored Ad5 specific T-cells (Figure 3). Elevated levels of CEA specific IgG 
antibody were detected after immunizations and these levels were comparable for both Ad5-CEA 
vectors.  
 
A. 
 
B. 
Figure 3. Immunization with Ad5-CEA(6D) platforms.  
Ad5 naïve C57Bl/6 mice (n=7/group) were immunized three times at one week intervals with 1010 VP of Ad5 
[E1-]-CEA(6D), Ad5 [E1-, E2b-]-CEA(6D), or injection buffer alone (control). Fourteen days after the final 
immunization splenocytes were assessed for the number of IFN-γ secreting T-cells (A) or the number of IL-2 
secreting T-cells (B) by ELISpot analysis. Splenocytes were also assessed for non-specific IFN-γ or IL-2 
secreting T cells by stimulation with the non-immunizing antigens β-galactosidase (β-gal) and HIV-1 Gag. 
There was a significantly (P<0.05) greater level of IFN-γ and IL-2 secreting T-cells in mice that were 
immunized with Ad5 [E1-, E2b-]-CEA(6D). The error bars depict the SEM.  
 
To test the hypothesis that Ad5 [E1-, E2b-]-CE(6D) is more effective than Ad5 [E1-]-CEA(6D) in 
the presence of Ad5 immunity, Ad5 naive C57Bl/6 mice were immunized twice with 1010 VP of 
Ad5 [E1-]-null to induce Ad5 immunity. The presence of anti-Ad5 IgG antibody was confirmed 
Ad5
CEA
β-gal
HIV-1 Gag
0
100
200
300
400
500
Control
Ad5 [E1-, E2b-]-CEA
Ad5 [E1-]-CEA
Stimulating Antigen
IFN-γ SFC per 106 splenocytes
Ad5
CEA
β-gal
HIV-1 Gag
0
50
100
150
Control
Ad5 [E1-, E2b-]-CEA
Ad5 [E1-]-CEA
Stimulating  Antigen
IL-2 SFC per 106 splenocytes


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by ELISA as 0.028 ± 0.028 ng Equivalents of IgG antibody for baseline samples versus 39.50 ± 
3.78 ng Equivalents of IgG antibody in samples after Ad5-null immunizations (p<0.0001). Ad5 
immune mice were then immunized three times at weekly intervals with 1010 VP of Ad5 [E1-]-
CEA(6D) or Ad5 [E1-, E2b-]-CEA(6D). Splenocytes were collected 14 days after the final 
immunization and assessed by IFN-γ and IL-2 ELISpot. Ad5-immune mice immunized with Ad5 
[E1-, E2b-]-CEA(6D) exhibited significantly higher levels of IFN-γ (p=0.04) and IL-2 (p<0.01) 
secreting splenocytes as compared to Ad5 immune mice immunized with Ad5 [E1-]-CEA(6D) 
(Figure 4). When compared to the results for naïve mice above, levels of CEA specific IgG 
antibody generated after immunizations were greatly reduced. 
 
A. 
B. 
 
Figure 4. CMI against Ad5 [E1-]-CEA(6D) and Ad5 [E1-, E2b]-CEA(6D) in Ad5 immune mice.  
C57Bl/6 mice (n=7/group) were pre-immunized two times with 1010 VP Ad5-null to induce Ad5 immunity. 
They were then immunized three times at one week intervals with 1010 VP Ad5 [E1-]-CEA(6D) or Ad5 [E1-
, E2b-]-CEA(6D). Controls received injection buffer alone. Splenocytes were collected 14 days after the 
final immunization and assessed for IFN-γ secreting T-cells (A) or IL-2 (B) by ELISpot assay. Splenocytes 
were also assessed for non-specific secreting T-cells of IFN-γ (A) or IL-2 (B) by stimulation with the non-
immunizing antigens Beta-galactosidase (β-gal) and HIV-1 Gag. Note the significantly (p<0.05) greater 
levels of IFN-γ and IL-2 secreting T-cells in mice that were immunized with Ad5 [E1-, E2b-]-CEA(6D). 
The error bars depict the SEM. 
Ad5
CEA
β-gal
HIV-1 Gag
0
100
200
300
400
Control
Ad5 [E1-]-CEA
Ad5 [E1-, E2b-]-CEA
Stimulating Antigen
IFN-γ SFC per 106 splenocytes
Ad5 
CEA
β-gal
HIV-1 Gag
0
50
100
150
200
Control
Ad5 [E1-]-CEA
Ad5 [E1-, E2b-]-CEA
Stimulating Antigen
IL-2 SFC per 106 splenocytes


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Having immunologically compared the two Ad5-CEA(6D) vectors, a study was then performed to 
determine if the Ad5 [E1-, E2b-]-CEA(6D) vector could break tolerance in the more stringent CEA 
transgenic mouse model in which CEA is a self-antigen. Mice were immunized once with 2.6 X 
1010 VP of Ad5 [E1-, E2b-]-CEA(6D) and 14 days later, their splenocytes were assessed for CMI 
responses by IFN-γ ELISpot assays. As presented in Figure 5, elevated numbers of IFN-γ secreting 
splenocytes were observed after only one injection with the vector platform. ELISpot studies 
employing Cytomegalovirus (CMVpp65) and HIV-gag antigens demonstrated that the response 
was specific to CEA.  
 
                
 
Figure 5.  Ability of the Ad5 [E1-, E2b-]-CEA(6D) vector to break tolerance.  
C57Bl/6 mice transgenic for CEA were immunized once with Ad5 [E1-, E2-]-CEA(6D) and tested for CMI 
response activity to CEA. Note the elevated levels of IFN-γ secreting splenocytes specific for CEA and not 
for irrelevant antigens such as CMV or HIV-1 Gag. The error bars depict the SEM. 
The efficacy of immunizations with Ad5 [E1-, E2b-]-CEA(6D) was evaluated by the treatment of 
CEA expressing MC-38 tumors that were growing in Ad5 naïve and Ad5 immune mice. A group 
of C57Bl/6 mice (n=7) were implanted SQ with 106 CEA expressing MC-38 tumor cells (MC38-
CEA). Six days later, when tumors were palpable (3-5mm), the mice were treated with three SQ 
injections of 1010 VP of Ad5 [E1-, E2b-]-CEA(6D) on days 7, 13 and 19. Untreated C57Bl/6 mice 
(n=7) implanted with 106 MC38-CEA cells and injected at the same time points with injection 
buffer alone served as controls. Tumor volumes were measured and reported as previously 
described.16 The sizes of treated and control tumors are presented in Figure 6A as a function of 
time. At Day 20 post implant the tumors in mice treated with Ad5 [E1-, E2b-]-CEA(6D) were 
significantly (p<0.05) smaller as compared to controls (Figure 6A). Tumors were excised and 
weighed at the termination of the study. Tumors from mice treated with Ad5 [E1-, E2b-]-CEA(6D) 
weighed significantly (p<0.05) less than tumors from control mice (Figure 6B). Splenocytes from 
both groups of mice were assessed for the number of CEA stimulated IFN-γ secreting T cells by 
ELISpot. Mice immunized with Ad5 [E1-, E2b-]-CEA(6D) had a significantly (p<0.05) greater 
number of INF-γ secreting T-cells in their spleens as compared to control mice (Figure 6C).  
CEA
CMV
HIV-1 Gag
0
50
100
150
200
250
Control
Ad5 [E1-, E2b-]-CEA
Stimulating antigen
IFNγ SFC per 106 splenocytes


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A. 
0
6
7
8
11
12
14
18
19
20
21
0
2000
4000
6000
8000
Controls
Ad5 [E1-,  E2b-]-CEA Treated
*
*
Time (days)
Tumor Volume (mm3)
( Mean ± SEM )
 
B. 
Control
Ad5 [E1- ,E2b-]-CEA
0
2
4
6
8
10
Weight (grams)
 
C. 
Ad5 [E1-, E2b]-CEA
0
1000
2000
3000
 Control
IFNγ SFC per 106 splenocytes
 
Figure 6. Treatment of CEA expressing tumors in Ad5 naïve mice. 
C57Bl/6 mice (n=7/group) were implanted in the flank with 106 MC-38 CEA expressing tumor cells and 
subsequently treated with three immunizations of 1010 VP of Ad5 [E1-, E2b-]-CEA vaccine at one week 
intervals. Tumors were measured by two opposing diameters and reported as a multiple of those numbers to 
determine tumor volumes (A). Statistical differences were determined using the Bonferroni posttests analysis 
with PRISM software. * Indicates a significant difference in the value of the means on that day. Tumors were 
excised at the termination of the study and weighed. Tumors from mice treated with Ad5 [E1-, E2b-]-CEA(6D) 
weighed significantly less (p<0.05) (B). Splenocytes were collected and assessed for T-cells which secreted 
IFN-γ by ELISpot analysis and the data is presented. Note the significantly (p<0.05) greater levels of IFN-γ 
and IL-2 secreting T-cells in mice that were immunized with Ad5 [E1-, E2b-]-CEA(6D) (C). Note that there 
was a significant reduction in tumor size in treated mice at days 20 & 21 as compared to untreated controls. 
Values represent Mean ± SEM.  
To determine if Ad5 immune MC38-CEA tumor bearing mice could be treated with Ad5 [E1-, 
E2b-]-CEA(6D), C57Bl/6 mice (n=7) were immunized two times at a two-week interval with 1010 
VP of Ad5 [E1-]-null. Two weeks after the second Ad5 [E1-]-null immunization, mice were 
implanted SQ with 106 CEA expressing MC-38 tumor cells. Six days later tumors were measurable 
(3-5mm) and the mice were treated with three SQ injections of 1010 VP of Ad5 [E1-, E2b-]-
CEA(6D) at weekly intervals. C57Bl/6 mice (n=7) which were immunized twice with Ad5 [E1-]-
null, inoculated with 106 MC38-CEA cells and injected three times SQ with injection buffer alone 
served as controls. All mice were monitored for tumor growth and tumor volumes are reported 
using previously described methods.16 Evaluation was over a 21-day period and the size of MC38-
CEA tumors was determined as a function of time. At day 19 the tumors in mice treated with Ad5 
[E1-, E2b-]-CEA(6D) were significantly smaller as compared to the controls (Figure 7A). At the 


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Abbreviated Title: Chemo+antiPDL1+ vaccine in CRC 
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end of the study all mice were sacrificed and the tumors were excised and weighed. Tumors from 
the mice treated with Ad5 [E1-, E2b-]-CEA(6D) weighed significantly less than the tumors from 
controls (Figure 7B). The number of CEA stimulated T-cells in the spleen which secreted IFN-
γ was determined by ELISpot assay. As presented in Figure 7C, mice immunized with Ad5 [E1-, 
E2b-]-CEA(6D) had a significantly greater number of IFN-γ secreting T-cells than did control 
mice that received injection buffer alone.  
A. 
0
6
7
8
9
12
13
14
19
20
21
0
5000
10000
15000
Contols
Ad5 [E1-, E2b-]-CEA Treated
*
*
*
Time (days)
Tumor Volume (mm3)
( Avg ± SEM )
 
B. 
Ad5 [E1-, E2b-]-CEA 
0
5
10
15
Control
Weight in grams
(Mean ± SEM)
 
C. 
Ad5 [E1- ,E2b-]-CEA
0
1000
2000
3000
Control
IFN-γ SPC/106 splenocytes
 
Figure 7. Treatment of CEA expressing tumors in Ad5 immune mice.  
C57Bl/6 mice (n=7/group) were immunized twice at fourteen-day intervals with 1010 VP of Ad5 [E1-]-null. Fourteen 
days later, mice were implanted with 106 MC-38 CEA expressing tumor cells in the flank and subsequently treated 
with three immunizations of 1010 VP of Ad5 [E1-, E2b-]-CEA(6D) vaccine weekly. Tumors were measured by two 
opposing diameters and a multiple of the numbers determined the tumor volume. Statistical differences were 
determined using the Bonferroni posttests analysis with PRISM software. Note that there was a significant reduction 
in tumor size in treated mice at days 20 & 21 as compared to untreated controls (A). * Indicates a significant difference 
in the value of the means on that day. Tumors were excised at the termination of the study and weighted. Tumors from 
mice treated with Ad5 [E1-, E2b-]-CEA(6D) weighed significantly less (p<0.05) (B). Splenocytes were collected and 
assessed for the number of T-cells which secreted IFN-γ by ELISpot. Note the significantly (p<0.05) greater levels of 
IFN-γ and IL-2 secreting T-cells in mice that were immunized with Ad5 [E1-, E2b-]-CEA(6D) (C). Values represent 
Mean ± SEM. 


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Abbreviated Title: Chemo+antiPDL1+ vaccine in CRC 
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In summary, Ad5 [E1-, E2b-]-CEA(6D) is a therapeutic vaccine targeting CEA that induces robust 
immune responses, even in the presence of pre-existing Ad5 immunity. When compared directly 
with a conventional Ad5 [E1-]-CEA(6D) vector, the Ad5 [E1-, E2b-]-CEA(6D) platform induced 
superior cellular mediated immune responses in both Ad5 naïve and Ad5 immune animals. In 
therapeutic efficacy studies, treatment with Ad5 [E1-, E2b-]-CEA(6D) resulted in significantly 
decreased established MC38-CEA tumor growth even in mice which had been pre-immunized 
against Ad5. Treatment with Ad5 [E1-, E2b-]-CEA(6D) did not result in any adverse effects in 
pre-clinical studies. Our goal is to further develop this therapeutic vaccine against CEA and utilize 
this novel Ad5 vector system that overcomes barriers found with other Ad5 systems. The results 
of these pre-clinical studies establish the technical and immunological merit of using the Ad5     
[E1-, E2b-]-CEA(6D) vaccine as a therapeutic agent. 
1.2.4.3 Clinical safety 
Etubics Corporation has performed a Phase I/II clinical trial of Ad-CEA (Ad5 [E1-, E2b-]-
CEA(6D)) (IND#14325).13,19 The Phase I/II study consisted of a dose-escalation study of four 
dosage levels (1x109, 1x1010, 1x1011, 5x1011 VP/dose) of ETBX-011 (Phase I component), and the 
maximally tolerated dose of ETBX-011 (Phase II and 5x1011 VP/dose components). Ad-CEA was 
administered by SQ injection every 3 weeks. Thirty-two patients with metastatic colorectal cancer, 
median age 57.5 (range 38–77) who had failed a median of three prior chemotherapeutic regimens 
(range 2–5), had a performance status of 90 % (range 70–100 %), and had three sites of metastatic 
disease (range 1–4), were enrolled. The majority of patients were able to receive all three 
immunizations. Four patients who stopped immunizations early did so due to significant disease 
progression.  
A total of 94 immunization treatments were administered to all patients. There was no dose-
limiting toxicity and no serious adverse effects (SAE) that resulted in treatment discontinuation at 
any vaccine dose level. The most common toxicity was a self-limited, injection site reaction. Other 
reactions occurred with less than a 10% incidence of all adverse effects (AE) reported and included 
fever, flu-like symptoms, anorexia, chills, nausea, and headache. These symptoms were also self-
limiting 
and did not require intervention 
other than symptomatic measures such as 
acetaminophen.13,19  
1.2.4.4 Clinical immune response 
A secondary objective was to evaluate CEA specific immune responses following immunization 
treatments with the product candidate. As determined by an ELISA technique,13,19 we observed no 
antibody activity directed against CEA. We assessed CMI responses in colorectal cancer patients 
treated in cohort 1, cohort 2, cohort 3/Phase II, and cohort 5. PBMCs were isolated prior to 
immunotherapy treatment and after all treatments as well as three weeks following the last 
treatment from patients. CEA specific ELISpot assays were performed on PBMC as previously 
described13,16,19 to determine the numbers of interferon gamma (IFN-γ) secreting lymphocytes 
(SFC) after exposure to CEA peptides in vitro. We determined the highest CMI responses during 
immunizations, regardless of time point (weeks 3, 6, or 9) in the patients treated in cohort 1, cohort 
2, cohort 3/Phase II, and cohort 5. This analysis revealed a dose response to increasing levels of 
product (Figure 8). The highest CMI levels occurred in patients that received the highest dose of 
5x1011 VP (Cohort 5). In a preliminary study, we observed a population of polyfunctional CD8+ 
T cells (those that secrete more than 1 cytokine when activated) after immunizations that secreted 
multiple cytokines, a sign of greater functionality of T cells induced by the vaccine. In further 


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Abbreviated Title: Chemo+antiPDL1+ vaccine in CRC 
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follow-up analysis of a few patient blood samples, we noted a decrease in CEA directed immune 
responses after immunizations were stopped (Figure 9). This observation supports a rationale for 
booster immunizations. 
 
 
Pre
Post
Pre
Post
Pre
Post
Pre
Post
0
100
200
300
400
500
Cohort 1
Cohort 2
Cohort 3/Phase II
Cohort 5
IFNγ SFC per 106 PBMC
 
Figure 8. CMI responses in treated patients. CMI (IFN-γ secretion) was assessed at baseline (Pre) and after 
administrations of Ad5 [E1-, E2b-]-CEA(6D) (Post). The highest CMI responses (regardless of time point) 
observed in the patients after treatment revealed a dose response. The highest CMI levels occurred in patients 
that received the highest dose of 5x1011 VP (Cohort 5). The CMI responses for Cohort 3/Phase II and Cohort 5 
were significantly elevated (P=0.0002 and P=0.0317, respectively; Mann-Whitney test) as compared to their 
baseline (Pre) values. Specificity of the responses was demonstrated by the lack of reactivity with the irrelevant 
antigens β-galactosidase and HIV-gag (data not shown). For positive controls, PBMCs were exposed to 
concanavalin A (data not shown).  SFC: spot forming cells. Values = Mean ± SEM for each Cohort. 


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Abbreviated Title: Chemo+antiPDL1+ vaccine in CRC 
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We also measured Ad5 NAb and CMI against Ad5 and correlated it with CEA-specific CMI. Each 
patient had their serum and PBMC sample tested at baseline (prior to treatment) and at 9 weeks 
after completion of 3 treatments. Nineteen of 31 colorectal cancer patients (61%) tested in this 
study had Ad5 neutralizing activity in serum samples prior to the onset of treatment with Ad5 [E1-
, E2b-]-CEA(6D). The mean pre-treatment Ad5 NAb titer value obtained among all patients was 
1:189 ±1:71 SEM and the mean pre-treatment Ad5 NAb titer among seropositive patients was 
1:308 ± 1:108. Analysis of serum samples from patients who received 3 immunizations revealed 
Ad5 NAb titers that were significantly increased (P<0.0001, Mann-Whitney test) by week 9 (mean 
1:4767 ± 1:1225 SEM) when compared with their respective baseline values. Analysis of PBMC 
for CMI responses to Ad5 also revealed a significant increase (P<0.01, Mann-Whitney test) in Ad5 
directed CMI responses after immunizations with Ad5 [E1-, E2b-]-CEA(6D) (22.6 ± 9.3 SEM 
IFN-γ secreting SFC at week 0 versus 191.1 ± 83.7 IFN-γ SFC at week 9). 
1.2.4.5 Clinical evidence of activity 
The Ad-CEA treated colorectal cancer patients (total=32) were followed for survival and Kaplan-
Meier plots and survival proportions performed (PRISM software).13,19 Events were determined 
by information from the social security death index (SSDI) database, clinical charts and telephone 
calls (Figure 10).  
0
20
40
60
80
100
0
3
   6
9
26
56
Weeks
Patient  005
IFNγ SFC per 106 PBMC
0
3
9
26
0
100
200
300
400
500
Weeks
Patient 024
IFNγ SFC per 106 PBMC
0
3
6
9
26
0
150
300
450
Weeks
Patient 031
IFNγ SFC per 106 PBMC
0
3
6
9
26
39
0
10
20
30
40
50
60
Weeks
Patient 501
IFNγ SFC per 106 PBMC
0
500
1000
1500
0
3
6
9
26
Weeks
Patient 507
39
IFNγ SFC per 106 PBMC
 
Figure 9. Profiles of CEA directed CMI responses in 5 mCRC patients during and after the course of 
immunotherapy. Note the decrease in CMI responses from their peak values after immunizations ended. Values 
are Mean ± SEM.  


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Abbreviated Title: Chemo+antiPDL1+ vaccine in CRC 
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The seven patients in cohorts 1 and 2 experienced a 12-month survival proportion of 29%. The 21 
patients in cohort 3 and Phase II experienced a 12-month survival proportion of 48%. The six 
patients in cohort 5 experienced a 12-month survival proportion of 50%. Twenty-nine month 
overall survival of the intent-to-treat population (32 patients) was 20% (Figure 10A) with a 
median survival time of 11 months from informed consent/first injection. For the subset of 28 
patients that received all 3 immunizations, the 29-month survival was 23% (Figure 10B) with a 
median survival time of 13 months. For the 22 patients optimally dosed with the two highest doses 
of vaccine (1 and 5 x 1011) and receiving all 3 immunizations, the 28-month overall survival was 
19% (Figure 10C). Median overall survival was 13 months in the optimally treated patients. Since 
there was no active control group in the study, comparisons for significance in survival time cannot 
be made. There were 3 stable disease events observed immediately after completion of treatment. 
1.2.4.6 Evidence of an Ad5 [E1-, E2b-]-based vaccine driving T cell infiltration and PD-L1 
upregulation  
High-risk human papillomavirus (HPV) such as HPV type-16 is associated with the etiology of 
cervical and more than 90% of HPV-related head and neck squamous cell carcinomas (HNSCC).25-
27 Preventive vaccines such as Human Papillomavirus Bivalent [Types 16 and 18] Vaccine and 
Human Papillomavirus Quadrivalent [Types 6, 11, 16, and 18] Vaccine are currently being used 
as a primary defense against HPV associated cancers by preventing infection with the virus but 
reports indicate that they are not effective for active immunotherapy of established disease.28 
Immunotherapeutic treatment of HPV induced malignances has been investigated by us and others. 
The HPV early 6 (E6) and early 7 (E7) genes are expressed at high levels in HPV-induced cancers 
and are involved in the immortalization of primary human epidermal cells.26,28-32 Thus, these are 
ideal targets for tumor-specific immunotherapy because unlike many other tumor-associated 
antigens these viral antigens are “non-self” and thus do not have the potential to induce 
autoimmunity.21,28-33  
Using the Ad5 [E1-, E2b-]-based vector platform, we investigated in a murine model of HPV-
associated E6/E7 expressing cancer if immunotherapy against human papilloma virus (HPV) using 
a viral gene delivery platform to immunize against HPV 16 genes E6 and E7 (Ad5 [E1-, E2b-]-
E6/E7) combined with programmed death-ligand 1 (PD-1) blockade could increase therapeutic 
0
4
8
12
16
20
24
28
0
20
40
60
80
100
a
Months
Percent Survival Proportion
0
4
8
12
16
20
24
28
0
20
40
60
80
100
b
Months
Percent Survival Proportion
0
4
8
12
16
20
24
28
0
20
40
60
80
100
c
Months
Percent Survival Proportion
  
Figure 10. Kaplan-Meier survival plots on long-term overall survival of treated mCRC patients. Panel a 
represents all treated patients. Panel b represents patients that received all 3 treatments. Panel c represents 
patients immunized 3 times with the 2 highest doses of vaccine. There were 23 events during the study. 


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Abbreviated Title: Chemo+antiPDL1+ vaccine in CRC 
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effect as compared to the vaccine alone.33 Ad5 [E1-, E2b-]-E6/E7 as a single agent induced HPV-
E6/E7 cell-mediated immunity. Immunotherapy using Ad5 [E1-, E2b-]-E6/E7 resulted in 
clearance of small tumors and an overall survival benefit in mice with larger established tumors. 
When immunotherapy was combined with immune checkpoint blockade, an increased level of 
anti-tumor activity against large tumors was observed (Figure 11). Analysis of the tumor 
microenvironment in Ad5 [E1-, E2b-]-E6/E7 treated mice revealed elevated CD8+ tumor 
infiltrating lymphocytes (TILs); however, we observed induction of suppressive mechanisms such 
as programmed death-ligand 1 (PD-L1) expression on tumor cells and an increase in PD-1+ TILs. 
When Ad5 [E1-, E2b-]-E6/E7 immunotherapy was combined with anti-PD-1 antibody, we 
observed CD8+ TILs at the same level but a reduction in tumor PD-L1 expression on tumor cells 
and reduced PD-1+ TILs providing a mechanism by which combination therapy favors a tumor 
clearance state and a rationale for pairing antigen-specific vaccines with checkpoint inhibitors in 
future clinical trials. 


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Abbreviated Title: Chemo+antiPDL1+ vaccine in CRC 
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1.2.4.7 Rationale for combining chemotherapy treatment with Ad5 [E1-, E2b-]-based vaccine 
immunotherapy  
Using the same murine model of HPV-associated E6/E7 expressing cancer described above (see 
section 1.2.4.6), we investigated if immunotherapy using Ad5 [E1-, E2b-]-E6/E7 could be 
combined with cisplatin/radiation treatment that is utilized to treat HNSCC.21 We observed that 
when immunotherapy was combined with cisplatin/radiation treatment, a significant increase in 
survival time demonstrated in tumor bearing mice treated with the combination of immunotherapy 
P D -1
+ C D 4  T IL
P D -1
+ C D 8  T IL
0
2 0
4 0
6 0
8 0
%  T IL s
n s
n s
n s
*
***
**
**
*
F re q u e n c y  o f P D -1 +  C D 4 +  a n d  C D 8 +  T IL s
L A G -3
+ C D 4  T IL
L A G -3
+ C D 8  T IL
0
5
1 0
1 5
2 0
2 5
%  T IL s
n s
n s
n s
**
**
*
F re q u e n c y  o f L A G -3 +  C D 8 +  T IL s
C D 4 5
- T u m o r C e lls
0
1 0 0 0
2 0 0 0
3 0 0 0
4 0 0 0
P D -L 1  m e d ia n  flu o re s c e n c e
n s
**
**
**
*
**
A d 5  [E 1 -,E 2 b -]-n u ll +  c o n tro l A b
A d 5  [E 1 -,E 2 b -]-n u ll +  a n ti-P D -1
A d 5  [E 1 -,E 2 b -]-E 6 /E 7  +  c o n tro l A b
A d 5  [E 1 -,E 2 b -]-E 6 /E 7  +  a n ti-P D -1
E x p re s s io n  le v e l o f P D -L 1  o n  tu m o r c e lls
A
B
C
 
Figure 11. Ad5 [E1-, E2b-]-E6/E7 plus anti-PD-1 combination therapy promotes a pro-
inflammatory tumor microenvironment. C57BL/6 mice (n=5/group) were tumor implanted, treated, and 
tumors were analyzed. The frequency of PD-1+ CD4+ and CD8+ TILs (A), LAG-3+ CD8+ TILs (B), and 
expression level of PD-L1 on tumor cells (C) is increased in tumors from mice treated with Ad5 [E1-, 
E2b-]-E6/E7. Tumors from mice treated with a combination of Ad5 [E1-, E2b-]-E6/E7 and anti-PD-1 have 
a significantly lower frequency of PD-1+ CD4+ and CD8+ TILs (A), a significantly lower frequency of 
LAG-3+ CD8+ TILs (B), and the expression level of PD-L1 on the tumor cells significantly reduced (C), 
bringing these levels more in line with tumors from control mice. Significance analysis was 
performed sing npairedt tests and is denoted b ns (p>0 05) * (p<0 05) ** (p<0 01) or ***


23 
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and cisplatin/radiation treatment as compared to control mice receiving cisplatin/radiation 
treatment alone (Figure 12). 
In light of the above results, we then investigated the effects of combining immunizations with 
Ad5 [E1-, E2b-]-E6/E7 with cisplatin/radiation treatment versus cisplatin/radiation treatment 
alone in a murine model. We observed that the combination of Ad5 [E1-, E2b-]-E6/E7 
immunizations plus cisplatin/radiation treatment resulted in the induction greater CMI responses 
as compared to immunizations with Ad5 [E1-, E2b-]-E6/E7 alone (Figure 13). These results 
provide us with a rationale for combining immunotherapy with chemotherapy treatment in order 
to achieve greater anti-tumor CMI responses. 
E 6  p e p tid e  p o o l
E 7  p e p tid e  p o o l
S IV -N e f p e p tid e  p o o l
S IV -V if p e p tid e  p o o l
0
2 0 0
4 0 0
6 0 0
8 0 0
1 0 0 0
IF N -γ  S P C /1 0
6  s p le n o c y te s
A d 5 [E 1 ,E 2 b -]-n u ll
A d 5 [E 1 ,E 2 b -]-m E 6 /E 7
A d 5 [E 1 ,E 2 b -]-m E 6 /E 7 /C R T
 
 
 
 
 
 
 
 
Figure 12. Immunotherapy 
combined with chemotherapy/ 
radiation treatment of established 
HPV-E6/E7 expressing tumors.  
Established HPV-E6/E7 expressing 
tumors were treated by 
immunotherapy on days 7, 14, & 21 
combined with cisplatin/radiation 
treatment on days 13, 20, & 27. 
Control tumor bearing mice were 
treated by injections with Ad-null 
combined with cisplatin/radiation 
treatment. 
Figure 13. Non-tumor bearing mice 
were treated as described in Figure 11 
above. Two weeks after the last 
treatment, mice were assessed for CMI 
activity as determined by ELISpot 
assays for IFN-γ secreting splenocytes. 
Note the increased CMI responses in 
mice treated with combination therapy 
(Ad5 [E1-, E2b-]-mE6/E7/CRT). 


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1.2.5 Anti-PD-L1 Monoclonal Antibody: Avelumab 
Programmed death ligand 1 (PD-L1) is a transmembrane protein that was first identified for its 
role in the maintenance of self-tolerance and prevention of autoimmunity.34 Engagement of PD-
L1 on dendritic cells with the programmed death 1 (PD-1) receptor on T cells delivers an inhibitory 
signal that promotes T cell anergy or apoptosis.35 This immunoinhibitory checkpoint is often 
subverted by tumor cells that over-express PD-L1 in order to escape immunosurveillance in the 
tumor microenvironment. Indeed, there is a strong correlation between PD-L1 expression and 
prognosis in cancer. Blockade of the interaction between PD-L1 on tumor cells and PD-1 on T 
cells is expected to reverse T cell suppression within tumors, thereby promoting effective anti-
tumor immune responses. 
Several antibodies directed against the PD-L1 / PD-1 pathway are in clinical development for 
cancer treatment.36 Compared with anti-PD-1 antibodies that target T-cells, anti-PDL1 antibodies 
that target tumor cells are expected to have less side effects, including a lower risk of autoimmune-
related safety issues, as blockade of PD-L1 leaves the PD-L2 / PD-1 pathway intact to promote 
peripheral self-tolerance.37 To this end, avelumab, a fully human IgG1 anti-PDL1 antibody (drug 
code MSB0010718C) has been produced. Avelumab selectively binds to PD-L1 and competitively 
blocks its interaction with PD-1.  
Avelumab is also cross-reactive with murine PD-L1, thus allowing in vivo pharmacology studies 
to be conducted in normal laboratory mice. However, due to immunogenicity directed against the 
fully human avelumab molecule, the dosing regimen was limited to three doses given within a 
week. The key preclinical pharmacology findings for avelumab are summarized below. 
• Functional enhancement of primary T cell activation in vitro in response to antigen-
specific and antigen non-specific stimuli. 
• Significant inhibition of in vivo tumor growth (PD-L1 expressing MC38 colon 
carcinoma) as a monotherapy. 
• In vivo efficacy is driven by CD8+ T cells, as evidenced by complete abrogation of anti-
tumor activity when this cell type was systemically depleted. 
• Combination with localized, fractionated radiotherapy resulted in complete regression of 
established tumors with generation of anti-tumor immune memory. 
• Chemotherapy combinations also showed promising activity: 
o Additive combination effect when partnered with oxaliplatin and 5-fluorouracil 
(5-FU) (core components of FOLFOX [oxaliplatin, 5-FU, and folinic acid]) 
against MC38 colon tumors. (Summarized in section 2.5) 
o Significant increase in survival when partnered with gemcitabine against 
PANC02 pancreatic tumors. 
• Antibody-dependent cell-mediated cytotoxicity (ADCC) was demonstrated against 
human tumor cells in vitro; furthermore, studies in ADCC deficient settings in vivo 
support a contribution of ADCC to anti-tumor efficacy. 
• No complement-dependent cytotoxicity was observed in vitro. 
• Immunomonitoring assays with translational relevance for the clinic further support an 
immunological mechanism of action: 
o Consistent increases in CD8+PD-1+ T cells and CD8+ effector memory T cells as 
measured by fluorescence-activated cell sorter (FACS). 


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o Enhanced tumor-antigen specific CD8+ T cell responses as measured by pentamer 
staining and enzyme-linked immunosorbent spot (ELISPOT) assays. 
1.2.5.1 Outcomes in colorectal cancer in trials using agents blocking PD-1 – PD-L1 interaction 
Despite reports indicating that anti-tumor radiographic responses were unlikely using agents that 
interfere with PD-1 -- PD-L1 binding in colorectal cancer,38 there have been reports of 
radiographic responses.39-41 Additionally, a correlation has been demonstrated in multiple clinical 
trials indicating that PD-L1 expression levels on tumor tissue predict the likelihood of radiographic 
response.38,40 However, it has become clear that PD-L1 expression, as it is currently measured, is 
not a definitive requirement for anti-tumor efficacy.39,40 It has been noted that colorectal tumors 
rarely express PD-L1 compared with other tumors that are more likely to respond to PD-1 – PD-
L1 blockade.38 However, it is known that a strong anti-tumor T cell response, producing IFN-
gamma, will induce PD-L1 expression. Together, this data strongly supports the conclusion that 
an underlying immune response is necessary for PD-1 – PD-L1 blockade to have an anti-tumor 
effect. This is part of the rationale for this combination with the standard therapy and Ad-CEA 
vaccine that may be capable of induction of PD-L1 expression (described in section 1.2.8 below) 
and thereby increase the anti-tumor activity of PD-1 – PD-L1 blockade. 
1.2.5.2 Avelumab Phase I (13-C-0063) Safety  
We have recently completed the dose escalation portion of clinical 
trial 13-C-0063 
(NCT01772004). 4, 14 (1 withdrew before treatment), 12 and 21 patients, respectively, were 
enrolled into 4 escalating dose levels: 1 mg/kg, 3 mg/kg, 10 mg/kg, and 20 mg/kg. The maximum 
tolerated dose was not exceeded. At the 20 mg/kg dose level, 1 dose limiting toxicity was 
experienced out of 6 patients treated. This DLT was associated with a significant anti-tumor 
response and was attributed to drug because of the possibility that it was an immune-related 
adverse event (with transient elevated creatine kinase, muscle weakness, myalgia, transaminitis, 
myocarditis with elevated troponin and inferiolateral ST-elevation on ECG). To date, 80 patients 
have been enrolled. 55pts (71.2%) have come off-study: 43 (53.7%) for progression and 6 (7.5 %) 
for toxicity. Grade 3 AEs attributable to drug comprised of 7 laboratory abnormalities (4 increased 
liver transaminases, 1 decreased lymphocytes,1 elevated creatine kinase and 1 elevated lipase) in 
5 patients and symptomatic myositis requiring intervention in 2 other patients 
1.2.5.3 Pharmacokinetics and Receptor Occupancy data 
Data from 25 patients was evaluable for PK and RO analysis. Median time to maximum 
concentration was approximately 1.5 to 2 hours after infusion (for all doses with a linear PK). 
Half-life was 63.4, 80.7, 93.9 and 115.1 hours for dose levels 1, 2, 3 and 4 respectively, measured 
by ELISA. Target RO data was available for 13 patients, measured by PD-L1 binding on peripheral 
leucocytes via flow cytometry. Mean RO was 75.7, 93.8 and 93.2% for dose levels 1, 2 and 3 
respectively. 
1.2.5.4 Clinical outcomes in patients with colorectal cancer 
1.2.5.4.1 Progression Free survival (PFS) 
At the time of the writing of this document, 18 patients have enrolled on the single-agent phase I 
study of avelumab with mCRC at the 10mg/kg dose level. Of these 18, 14 had reached the first 
restaging for evaluation. Of the 14 evaluable patients, 3 remain on study without evidence of 
progression for >100 days. Two of these patients have had stable disease for >200 days. The patient 


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to be detailed in section 1.2.5.4.2 with a significant fall in CEA has remained on study with stable 
disease through day 350. Of the remaining evaluable patients (n = 11), 9 have had disease 
progression within 85 days of initial treatment. The remaining 2 patients came off study for adverse 
events (transaminase elevation and infusion reaction, respectively). Figure 14 illustrates the 
outcomes to date for patients with CRC treated with avelumab (MSB0010718C) by Response 
Evaluation Criteria for Solid Tumors (RECIST) criteria. 
Figure 14. Observed changes in target lesions by size (RECIST) 
 
 
1.2.5.4.2 CEA response 
One patient with mCRC on the phase I study had a remarkable decrease in serum CEA. At baseline 
his CEA was 267. After starting avelumab, he had a rapid and consistent fall in CEA over the 
following 5 months with stable disease on scans. He has now been on study for over 11 months 
with stable disease on scans. Notably, a biopsy of one of his retroperitoneal lymph nodes, being 
followed as measurable disease on CT scan, revealed “fibroadipose tissue with focal chronic 
inflammation. No tumor seen.” This patient still has elevated CEA in the range of 22-41 that has 
been holding in this range for 5 months. Figure 15 demonstrates the change in this patient’s CEA.  


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Figure 15. CEA change in patient with mCRC receiving single agent avelumab (MSB0010718C) 
 
 
1.2.5.4.3 Immune data 
An analysis of immune cell subset changes from baseline to day 15 and day 43 was performed on 
PBMC samples from the first 23 patients enrolled on the phase I study of avelumab on clinical 
trial 13-C-0063 (NCT01772004), which included patients at 4 dose levels (1, 3, 10, and 20mg/kg). 
There was no clear pattern of change (defined as 20% increase or decrease) pre- versus post-
treatment in absolute lymphocyte count. A panel of markers was used to define >50 immune cell 
subsets by flow-cytometry at the same intervals. There were no significant changes in any of the 
immune cell subsets. Notably, there was no decrease in the number of circulating immune cells 
expressing PD-L1 (including B lymphocytes and dendritic cells).  
1.2.6 Colorectal cancer standard of care 
1.2.6.1 FOLFOX (5-fluorouracil, leucovorin, oxaliplatin)  
A randomized trial comparing irinotecan and bolus fluorouracil plus leucovorin (IFL, control 
combination), oxaliplatin and infused fluorouracil plus leucovorin (FOLFOX), or irinotecan and 
oxaliplatin (IROX) established the FOLFOX combination, given for a total of 6 months, as the 
standard of care for first line treatment in patients with metastatic colorectal cancer (mCRC).42 
Though multiple infusion schedules of FOLFOX have been validated, typically denominated as 
‘modified FOLFOX, there are no essential changes in the constituent cytotoxic agents of the 
regimen. Of these, mFOLFOX6 is one of the most widely used. 
Oxaliplatin, however, is very difficult for patients to receive for greater than 6 months (12 cycles) 
due to progressive neurotoxicity. Though 6 months of combination therapy remains the standard 
of care in mCRC, clinical judgment may influence the decision to limit the number of oxaliplatin-
containing cycles towards the end of treatment Other trials, including the CAIRO3 study, have 
demonstrated the feasibility and benefit of discontinuation of oxaliplatin after a 3 month 
“induction” period with continuation of 5-FU and leucovorin as “maintenance” therapy.43  


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1.2.6.2 Bevacizumab (Avastin®) 
Addition of bevacizumab to first-line 5-FU and Oxaliplatin containing regimens was demonstrated 
to increase time to progression in mCRC patients with a manageable side effect profile and non-
overlapping toxicities.44,45 Later trials indicated that continuing bevacizumab beyond first 
progression (in combination with subsequent chemotherapy) improved overall survival in an 
unselected group of patients by KRAS mutational status, which has led to its approved use in the 
maintenance setting.46,47 
1.2.6.3 Capecitabine 
This agent is a prodrug that is enzymatically converted to 5-fluorouracil by 3 enzymatic steps 
following oral ingestion. As an orally active fluoropyrimidine, capecitabine has been approved 
for use in the adjuvant setting.48 In the advanced colon cancer setting, it has been shown to be 
equally efficacious as 5-fluorouracil, though with more reported rates of hand-foot syndrome.49 
This agent offers the convenience of the oral route with its benefits of reducing infusion 
commitments for patients in the maintenance setting, while achieving high concentrations 
intratumorally, given the higher concentrations of thymidine phosphorylase in tumor as 
compared to normal tissues.50 
1.2.6.4 Population expected outcomes 
Using the above noted standard of care, the expected radiographic progression free survival is 
approximately 10 months in patients with metastatic colorectal adenocarcinoma.46,47 At the time 
of progression, patients will typically be treated with a similar regimen, using 5-FU, leucovorin, 
and irinotecan (FOLFIRI). Unfortunately, that therapy also has a limited duration of benefit and 
patients have very few choices in the third line setting. Clearly, there is a significant need to 
improve outcomes in patients overall with metastatic colorectal cancer. Combining agents with 
non-overlapping toxicity and different mechanisms of action in the front line setting may be an 
excellent way to improve short and long term clinical outcomes. 
1.2.7 Rationale for combination of FOLFOX-A, Ad-CEA vaccine, and Avelumab  
As previously noted, PD-1/L1 blockade has had minimal effect in the majority of patients with 
advanced colorectal cancer. The notable exception has been patients with microsatalite instability 
(MSI-Hi, also called MisMatch Repair Deficiency, MMR-D).51 It has been hypothesized that the 
increased mutation burden in these tumors provides a greater number of potential neo-epitopes for 
T-cell receptors to recognize and bind, resulting in killing.52,53 Combining anti-PD-L1 antibody 
with a therapeutic cancer vaccine capable of inducing CEA-specific T cell immune responses plus 
the standard of care creates multiple advantages that may allow for improved clinical outcomes.  
As previously discussed, advanced colorectal cancer appears to be weakly immunogenic. 
Therapeutic cancer vaccines are designed to drive T cell activation against a tumor-associated 
antigen. The Ad-CEA vaccine targets CEA, an antigen overexpressed universally in colorectal 
cancer. T cell activation against the target antigen should result in greater trafficking and 
infiltration of T cells in to the tumor microenvironment. When combined with Avelumab, a PD-
L1 inhibitor, those activated T cells are more likely to have a direct anti-tumor effect, resulting in 
radiographic tumor response and delayed time to progression. 
Both 5-FU and oxaliplatin have been identified as agents which can induce immunogenic cell 
death and/or decrease the number of regulatory T cells 54, which increases the antigen targets 


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available to active T cells and T cell activation and killing of tumor cells. This effect is known to 
be capable of inducing an anti-tumor immune response.54-58 There is also evidence that 
immunotherapy in combination with 5-FU is capable of increasing the immune response against 
tumor cells. As has been discussed, an underlying anti-tumor T cell response appears to be 
necessary for PD-L1 induction in the tumor tissue. PD-L1 expression has been correlated with the 
likelihood of PD-1 – PD-L1 blockade to induce anti-tumor immune response and cause tumor 
volume reduction and clinical benefit.  
Another mechanism by which the underlying anti-tumor immune response may be improved when 
patients are exposed to the standard of care regimen is through a process known as immunogenic 
modulation. Hodge and colleagues in the LTIB have demonstrated repeatedly the potential 
improvement in antigen presentation, FAS upregulation, and T cell mediated killing in 
combination with chemotherapeutics, including 5-FU and oxaliplatin.59  
Decreased tumor burden induced by standard of care therapy may allow better immune response 
by debulking the tumor and improving the microenvironment for immunologic killing.60-65 The 
addition of standard of care therapy also provides ample time for an immune response to occur, 
which may be important considering the occasional delayed responses and prolonged stable 
disease findings that have been described with anti-PD-1 and anti-PD-L1 targeting agents. Given 
the findings with ipilimumab improving overall survival while not necessarily improving PFS66, 
it may be that delayed immunologic effects create long term clinical benefit in some populations 
despite lack of immediate tumor volume reduction. By using a therapy in combination with 
standard agents known to induce tumor volume reduction, we may be able to capture that long 
term benefit. 
Preclinical evidence indicates that vascular endothelial growth factor (VEGF) signaling in the 
tumor microenvironment causes disorganized perfusion, resulting in poor T cell trafficking to the 
tumor site, increased hypoxia, and an immunosuppressive microenvironment. Rakesh Jain’s 
group has demonstrated significant improvement in T cell infiltration with the addition of VEGF 
inhibition in preclinical models.67 In this study, VEGF inhibition increased the efficacy of a 
vaccine to induce T cell infiltration into the tumor, resulting in better anti-tumor effect. 
Similarly, Dr. Hwu’s group has found VEFG blockade to result in greater T cell infiltration in 
adoptively transferred T cells in a murine model.68 Alfaro, et al., found VEGF inhibition to be 
valuable for dendtritic cell differentiation and T cell activation.69 Taken together, these data 
indicate a potential synergy between VEGF inhibition and immunotherapy, supportive of 
combining these agents in patients. 
1.2.7.1 Rationale for exclusion of MSI-high mCRC 
While PD-1/L1 blockade has resulted in objective tumor responses in patients with microsatellite 
instability, there is an unmet need for better therapeutic interventions for patients who have 
microsatellite stable colorectal cancer. In these patients, who make up the large majority of 
patients with metastatic colorectal cancer (>90%), there has been little or no evidence of clinical 
benefit with PD-1/L1 blockade. Our hypothesis is that the combination of the agents comprising 
FOLFOX-bevacizumab and Ad-CEA vaccine will increase specific T cell activation, which will 
result in PD-1/L1 blockade allowing T cell mediated killing of tumor cells. As a result, patients 
who are known to respond to PD-1/L1 blockade are excluded from this study as they may not 
need chemotherapy at all. Ongoing studies in the population of MSI-Hi colorectal cancer are 


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ongoing to answer this question and we would not want to confound our study by including 
patients in the MSI-Hi population.  
 
1.2.7.2 Preclinical data support 
Our CRADA partner, EMD-Serono, has already performed a preclinical model evaluation of the 
combination of FOLFOX with anti-PD-L1. The study was conducted in compliance with GLP and 
the global policy “Quality management system (QMS) for Merck Serono research (MSR)” of 
Merck KGaA. Materials and methods and additional data available in Appendix A. 
The study investigated the potential of combining avelumab with the core components of FOLFOX 
(5-fluorouracil and oxaliplatin) in two separate studies (TI10-079 & TI11-001) conducted in mice 
bearing subcutaneous MC38 tumors. 
The therapeutic combination of oxaliplatin/5-FU and anti-PD-L1 blockade using avelumab in 
MC38 tumor-bearing mice yielded superior tumor growth inhibition relative to control mice and 
either form of monotherapy (Figure 16). Additionally, the avelumab and oxaliplatin/5-FU 
combination significantly extended survival compared to mice receiving either vehicle control or 
monotherapy (Figure 17). 
Figure 16. MC 38 Tumor Growth Inhibition in Mice Receiving Avelumab (Anti-PD-L1) in Combination with 
Oxaliplatin and 5-FU 
 
Female C57BL/6 mice w ere 
inoculated in the right 
subcutaneous flank w ith 
1x106 MC38 colon 
carcinoma cells. When 
tumors reached a mean 
volume of ~50 mm3, mice 
w ere sorted into treatment 
groups (N=10). 5-FU (60 
mg/kg by i.v. injection) and 
OX (5 mg/kg by i.p. 
injection) w ere administered 
on days 0 and 14. 
MSB0010718C (400 μg by 
i.v. injection) w as given on 
days 3, 6, and 9. Tumor 
volumes w ere measured 
tw ice w eekly via calipers. 
Data are mean ± SEM. 


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Figure 17. Survival of MC38 Tumor-Bearing Mice Receiving Avelumab (Anti-PD-L1) in Combination with 
Oxaliplatin and 5-FU 
 
 
In both in vivo studies (TI10-079 and TI11-001), a subset of mice in each treatment group was 
sacrificed to evaluate trends in immune phenotype in the spleen and tumor tissues. Using a 
pentamer analysis of splenic tissue, the avelumab and oxaliplatin/5-FU combination was shown 
to significantly elevate the precursor frequency of tumor-reactive P15E-specific CD8+ T cells 
(P15E is a known tumor antigen expressed in MC38 colorectal cancer tumor lines,70 (Figure 18). 
Additionally, avelumab therapy was shown to consistently and significantly increase the 
percentage of splenic CD8+ T cells expressing the PD-1 receptor (Figure 19). 
 
Female C57BL/6 mice w ere 
inoculated in the right 
subcutaneous flank w ith 
1x106 MC38 colon carcinoma 
cells. When tumors reached a 
mean volume of ~50 mm3, 
mice w ere sorted into 
treatment groups (N=10). 5-
FU (60 mg/kg by i.v. injection) 
and OX (5 mg/kg by i.p. 
injection) w ere administered 
on days 0 and 14. 
MSB0010718C (400 μg by i.v. 
injection) w as given on days 
3, 6, and 9. Kaplan-Meier 
plots and Log Rank statistics 
w ere used to calculate 
survival differences betw een 
groups. Survival w as 
censored at the time tumor 
volumes reached 2000 mm3. 
Data are expressed as 
median survival time in days. 


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Figure 18. Pentamer Analysis of Tumor-Antigen Specific T Cells 
Figure 19. Splenic CD8+/PD-1+ T cell Counts 
 
Consistent with our findings in the spleen, intratumoral CD8+ T cells and NK1.1+ cells were 
elevated in mice receiving combination therapy with avelumab and oxaliplatin/5-FU (see Figure 
20 and Figure 21, respectively). Taken together, the phenotypic data from mice treated with the 
avelumab and oxaliplatin/5-FU combination suggest that this immunotherapeutic regimen is 
successfully activating immune effector cell populations with known tumoricidal potential 
(NK1.1+ and CD8+ T cells). 
 
Subsets of 5 animals from each 
study group w ere sacrificed on 
study day 21 for FACS-based 
detection of p15Especific T cells 
using a fluorescently-labeled 
synthetic MHC class I pentamer 
loaded w ith a p15E-derived 
antigenic peptide epitope. The 
spleen from each animal w as 
dissociated into single cell 
suspensions and subsequently 
stained w ith an anti-CD8 antibody 
and the p15E pentamer. From the 
total splenocyte gate, the 
percentage of cells positive for 
both CD8 and the pentamer w as 
determined. Data w ere acquired 
using a BD LSR II flow  cytometer.  
Subsets of 5 animals from each 
group w ere sacrificed for FACS-
based immunophenotyping on 
day 21 after the start of treatment. 
Spleens w ere harvested and 
dissociated into single cell 
suspensions by mechanical 
disruption. 
Suspensions w ere then stained 
w ith fluorescently-labeled 
antibodies specific for relevant T 
cell surface markers (i.e. CD8, 
PD-1, CD44, CD62L) and data 
w ere acquired on a BD LSR II 
flow  cytometer. 


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Figure 20. CD8+ Tumor-Infiltrating Lymphocyte Levels 
 
 
Figure 21. Tumor-Infiltrating NK Cell Levels 
 
The frequency of IFN-γ producing CD8+ T effector cells directed against the p15E tumor 
antigen was also measured using an ELISPOT assay that detects IFN-γ secretion as a marker of 
T cell activation. Using the ELISPOT assay, a strong p15E-specific response was detected in all 
treated groups in study TI10-079 (see Figure 22A). In study TI11-001, the highest p15E-specific 
response was measured in the combination treatment group (see Figure 21B). 
Subsets of 5 animals from 
each group w ere sacrificed 
for FACS-based 
immunophenotyping 
analysis on day 21 follow ing 
the start of treatment. 
Tumors w ere harvested and 
dissociated into single cell 
suspensions by enzymatic 
digestion (collagenase) and 
mechanical disruption. 
Suspensions w ere then 
stained w ith a fluorescently-
labeled antibodies specific 
for the NK1.1 surface 
marker and data w ere 
acquired using a BD LSR II 
flow  cytometer. 
Subsets of 5 animals from each 
group w ere sacrificed for FACS-
based immunophenotyping 
analysis on day 21 follow ing the 
start of treatment. Tumors w ere 
harvested and dissociated into 
single cell suspensions by 
enzymatic digestion (collagenase) 
and mechanical disruption. 
Suspensions w ere then stained 
w ith a fluorescently-labeled 
antibodies specific for the NK1.1 
surface marker and data w ere 
acquired using a BD LSR II flow  
cytometer. 


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Figure 22. Combination of Avelumab (MSB0010718C) with 5-FU and Oxaliplatin: ELISPOT Measurement 
of Tumor Antigen Specific CD8+ T cells 
 
 
One interpretation of this data is that chemotherapy initiates a cascading sequence in which 
tumor cell destruction and the shedding of tumor antigen in the tumor microenvironment 
activates innate and adaptive immune responses to the tumor. In this scenario, PD-L1 blockade is 
thought to potentiate the adaptive immune response, which may indirectly activate innate 
effector cells such as NK cells. 
By blocking negative costimulation of tumor-reactive T cells mediated by the PD-1/PD-L1 
interaction, avelumab may be employed in a variety of settings and indications to maximize the 
potential efficacy of standard of care cytotoxic therapies as well as immunotherapy 
combinations. 
1.2.7.3 Clinical data support 
We have looked into the use of standard chemotherapy in patients with previously untreated 
metastatic colorectal cancer and have found no difference in the number of 40+ different immune 
cell subsets pre- versus post-treatment with standard therapy (5-FU based chemotherapy71). This 
was done in collaboration with Dr. John Marshall at Georgetown, who assisted with collecting 
For the ELISPOT assay, spleens from treated animals w ere harvested on day 21 after the start of 
treatment and processed into single cells suspensions (splenocytes from 5 mice from each group w ere 
pooled). The splenocytes w ere cultured for six days in the presence of a p15E-derived peptide antigen 
epitope (amino acid sequence KSPWFTTL) in order to stimulate expansion of antigen-specific CD8+ T 
cells. As a control for non-specific activation, the assay w as run in parallel using an irrelevant peptide 
derived from chicken ovalbumin (OVA). Follow ing the six day period of in vitro antigen stimulation, the 
CD8+ T cells w ere isolated from the cultures and placed in co-culture w ith antigen presenting cells (APCs) 
loaded w ith the same p15E antigenic peptide or OVA as a control. The cocultures w ere prepared in 
ELISPOT assay plates coated w ith an antibody that captured secreted IFN-γ. Follow ing assay plate 
development, each IFN-γ positive “spot” represented a CD8+ T cell that had become activated by p15E-
specific stimulation. 


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clinical samples from 6 patients pre- and post-standard therapy. Thus, chemotherapy should not 
diminish the potential immune benefits of anti-PD-L1 therapy. 
1.2.7.4 Clinical safety data combining FOLFOX + PD-1/PD-L1+ Bevacizumab  therapy 
The first patient enrolled on this trial developed febrile neutropenia and shortly thereafter passed 
away from a grade 5 bowel perforation event attributed to bevacizumab. Data from a phase II 
trial of a mFOLFOX6 + bevacizumab + a PD-L1 inhibitor 72 showed no reported episodes of 
bowel perforation among 30 patients with colorectal cancer enrolled on this combination. Given 
this data and the fact that the episode of bowel perforation on this study is a solo event, we think 
it is appropriate to continue with bevacizumab on the combined chemotherapy/ immunotherapy 
arm (Arm B) of the study for now. Should any similar events of bowel perforation occur we will 
plan on discontinuing bevacizumab from this arm of the study. 
In addition, in the phase II trial of mFOLFOX6 + bevacizumab + a PD-L1 inhibitor cited above 
there was an unexpectedly high percentage of grade ≥ 3 neutropenia (43%) in patients receiving 
this combination. In addition, a second phase II trial 73 evaluating mFOLFOX6 + pembrolizumab 
had an unexpectedly high rate of febrile neutropenia (3/6 pts) in their safety lead in cohort. As it 
is generally standard clinical practice to first remove the 5-FU bolus infusion in the setting of 
neutropenia and based upon the expected high rate of neutropenia with this combination, we are 
prophylactically removing the 5-FU bolus infusion from the chemotherapy/ immunotherapy arm 
(Arm B) of the study. 
1.2.8 Summary 
• Colorectal cancer (CRC) is the fourth most common cancer diagnosis in the United States 
and accounts for the second most cancer-related deaths. 
• Programmed death ligand 1 (PD-L1) is a transmembrane protein that was first identified 
for its role in the maintenance of self-tolerance and prevention of autoimmunity. 
Blockade of the interaction between PD-L1 on tumor cells and PD-1 on T cells is 
expected to reverse T cell suppression within tumors. These agents are dependent on 
underlying T cell activation against the tumor cell to be effective. 
• Avelumab is a fully human IgG1 anti-PDL1 antibody that selectively binds to PD-L1 and 
competitively blocks its interaction with PD-1.  
• In ongoing phase 1 trials of avelumab, the agent has been well tolerated and has shown 
clinical activity. 
• Clinical trials with anti-PD-1/L1 agents in colorectal cancer have resulted in minimal 
activity in patients who do not have mismatch repair deficiency (MMR-D) 
• Therapeutic cancer vaccines targeting overexpressed proteins offer a potential method to 
activate T cells against tumors.  
• A novel adenovirus based, CEA-targeting vaccine has demonstrated cytolytic T cell 
responses in patients with metastatic colorectal cancer. 
• Standard of care agents in first line metastatic CRC have properties been associated with 
improved immune response via immunologic cell death and immunogenic modulation 
• A preclinical model combining 5-FU and oxaliplatin plus avelumab has demonstrated 
potential synergy of this combination 


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2 
ELIGIBILITY ASSESSMENT AND ENROLLMENT  
2.1 
ELIGIBILITY CRITERIA 
2.1.1 Inclusion Criteria 
2.1.1.1 Subjects must have previously untreated metastatic or unresectable colorectal cancer and 
have no contraindications to treatment with the standard of care regimen (as defined in 
section 3.4.1) as determined by the investigator. Prior adjuvant therapy for surgically 
resectable disease (including 
oligometastatic 
disease) is acceptable (including 
immunotherapy), but must have been completed at least 6 months prior to enrollment.  
2.1.1.2 Patients should not be eligible for potentially curative surgical intervention in the case of 
oligometastic disease at the time of enrollment or must have actively refused after explicit 
discussion of potential benefit of this intervention with multidisciplinary team. 
2.1.1.3 Histologically confirmed colorectal cancer. 
2.1.1.4 Patients must have measurable disease by RECIST criteria as defined in section 6.4. 
2.1.1.5 Age ≥18 years. Because safety data is not known with this agent in patients less than 18 
years old, children are excluded from this study. 
2.1.1.6 ECOG performance status ≤ 2 (see Appendix B). 
2.1.1.7 Patients must have normal organ and marrow function as defined below:  
• Creatinine clearance (Per Institutional standard or 24-hour urine) ≥ 30 mL/min. 
• Adequate hepatic function defined by a total bilirubin level ≤ 1.5 × the upper limit 
of normal range (ULN), an aspartate aminotransferase (AST), level ≤ 2.5 × ULN, 
and an alanine aminotransferase (ALT) level ≤ 2.5 × ULN or, for subjects with 
documented metastatic disease to the liver, AST and ALT levels ≤ 5 × ULN 
• Hematological eligibility parameters (within16 days of enrollment): 
o 
Granulocyte count ≥ 1,500/mm3 
o 
Platelet count ≥100,000/mm3 
o 
Hemoglobin ≥ 9 g/dL 
2.1.1.8 The effects of Ad-CEA vaccine and avelumab on the developing human fetus are 
unknown. For this reason and because Ad-CEA vaccine and avelumab as well as other 
therapeutic agents used in this trial are known to be teratogenic, women of child-bearing 
potential and men must agree to use adequate contraception (hormonal or barrier method 
of birth control; abstinence) prior to study entry and for the duration of study participation 
and for a period of 4 months after the last treatment with avelumab or 6 months after the 
last administration of bevacizumab, whichever occurs later. Should a woman become 
pregnant or suspect she is pregnant while she or her partner is participating in this study, 
she should inform her treating physician immediately. 
2.1.1.9 Ability of subject to understand and the willingness to sign a written informed consent 
document. 


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2.1.2 Exclusion Criteria 
2.1.2.1 Metastatic or unresectable colorectal cancer with mismatch repair deficiency (MMR-D 
or MSI-High). 
2.1.2.2 Concurrent treatment for cancer except agents specified within the treatment protocol.  
2.1.2.3 Prior major surgery or gastrointestinal perforation within 28 days of enrollment. 
2.1.2.4 Persisting toxicity related to prior therapy (NCI CTCAE v5.0 Grade > 1); however 
alopecia, sensory neuropathy Grade <=2, or other Grade <=2 AEs not constituting a 
safety risk based on investigator's judgment are acceptable. 
2.1.2.5 Known history of testing positive for HIV or known acquired immunodeficiency 
syndrome. 
2.1.2.6 Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening (positive 
HBV surface antigen or HCV RNA if anti-HCV antibody screening test positive). 
2.1.2.7 Any significant disease that, in the opinion of the investigator, may impair the patient’s 
tolerance of study treatment.  
2.1.2.8 Active autoimmune disease that might deteriorate when receiving an immuno-stimulatory 
agent. Patients with diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroid diseases 
not requiring immunosuppressive treatment are eligible. 
2.1.2.9 Current use of immunosuppressive medication, EXCEPT for the following: a. intranasal, 
inhaled, topical steroids, or local steroid injection (e.g., intra-articular injection); b. 
Systemic corticosteroids at physiologic doses ≤ 10 mg/day of prednisone or equivalent; 
c. Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication). 
2.1.2.10 Patients who are receiving any other investigational agents within 28 days before start of 
study treatment. 
2.1.2.11 Prior organ transplantation including allogenic stem-cell transplantation. 
2.1.2.12 Subjects with active central nervous system (CNS) metastases causing clinical 
symptoms or metastases that require therapeutic intervention are excluded. Subjects 
with a history of treated CNS metastases (by surgery or radiation therapy) are not 
eligible unless they have fully recovered from treatment, demonstrated no progression 
for at least 2 months, and do not require continued steroid therapy. Subjects with CNS 
metastases incidentally detected during Screening which do not cause clinical 
symptoms and for which standard of care suggests no therapeutic intervention is needed 
are eligible. 
2.1.2.13 Active infection, requiring systemic therapy.  
2.1.2.14 Clinically 
significant 
(i.e., 
active) 
cardiovascular 
disease: 
cerebral 
vascular 
accident/stroke (< 3 months prior to enrollment), myocardial infarction (< 3 months prior 
to enrollment), unstable angina, congestive heart failure (≥ New York Heart Association 
Classification Class II), or uncontrolled arrhythmias. 
2.1.2.15 Other severe acute or chronic medical conditions including immune colitis, 
inflammatory bowel disease, immune pneumonitis, pulmonary fibrosis or psychiatric 
conditions including recent (within the past year) or active suicidal ideation or behavior; 
or laboratory abnormalities that may increase the risk associated with study 


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participation or study treatment administration or may interfere with the interpretation 
of study results and, in the judgment of the investigator, would make the patient 
inappropriate for entry into this study. 
2.1.2.16 Pregnant women and breastfeeding mothers are excluded due to unknown impact on 
embryos or infants.  
2.1.2.17 Known alcohol or drug abuse. 
2.1.2.18 “Known prior severe hypersensitivity to investigational product or any component in its 
formulations, including known severe hypersensitivity reactions to monoclonal 
antibodies (NCI CTCAE v5.0 Grade ≥ 3). 
2.1.2.19 Patients with a known hypersensitivity/allergy to any of the standard of care agents used 
in this study or related compounds (e.g. platinum compounds) are excluded. 
2.1.2.20 Prior history of hypertensive emergency or hypertensive encephalopathy (for those 
expected to receive bevacizumab).   
2.1.2.21 Serious, non-healing wound, active ulcer, or untreated bone fracture, including tumor-
related pathological fracture.  
2.1.2.22 Evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic 
anticoagulation).  
2.1.2.23 Patients being treated with medications with drug-drug interactions with study agents will 
require evaluation by to determine if full doses of all study treatments can be given safely. 
Significant drug-drug interactions will need to be addressed prior to enrollment. 
Alternatively, the patient will not be eligible. 
2.1.2.24 Vaccination within 4 weeks of the first dose of avelumab and while on trials is prohibited 
except for administration of inactivated vaccines. 
2.1.3 Recruitment Strategies 
2.2 
THIS STUDY WILL BE POSTED ON WWW.CLINICALTRIALS.GOV, NIH WEBSITES AND ON 
NIH SOCIAL MEDIA FORUMS.SCREENING EVALUATION 
2.2.1 Screening activities performed prior to obtaining informed consent 
Minimal risk activities that may be performed before the subject has signed a consent include the 
following:  
• Email, written, in person or telephone communications with prospective subjects  
• Review of existing medical records to include H&P, laboratory studies, etc.   
• Review of existing  MRI, x-ray, or CT images 
• Review of existing photographs or videos 
• Review of existing pathology specimens/reports from a specimen obtained for diagnostic 
purposes 
 
A waiver of consent for these activities has been requested in section 12.5.2 


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2.2.2 Screening activities performed after a consent for screening has been signed 
The following activities will be performed only after the subject has signed the consent for this 
study for screening. Assessments performed at outside facilities or on another NIH protocol 
within the timeframes below may also be used to determine eligibility once a patient has signed 
the consent. 
 
Studies should be done within 16 days prior to treatment unless otherwise noted below. 
• History and physical exam including performance status and vital signs 
• Scans (within 28 days prior to treatment) 
o CT CAP (chest abdomen and pelvis) with oral and IV contrast (MRI 
abdomen/pelvis with contrast + chest CT without contrast if IV contrast is 
contraindicated or CT CAP is inadequate) 
o Brain MRI – if clinically indicated 
• Hepatic Panel (Alkaline Phosphatase, ALT/GPT, AST/GOT, Total Bilirubin, Direct 
Bilirubin) 
• Acute Care Panel (Sodium [NA], Potassium [K], Chloride [CL] Total CO2 
[Bicarbonate], Creatinine, Glucose, Urea nitrogen, eGFR) 
• CBC with differential 
• Serum or urine HCG in women of childbearing potential 
• HBV (HBsAg), HCV (anti-HCV), HIV (anti-HIV) screening (within 3 months prior 
to treatment) 
• Urine dipstick  
• PT/INR, PTT 
• Histologic confirmation of diagnosis (including MSI or MMR status; any time prior 
to treatment) 
2.3 
REGISTRATION PROCEDURES 
2.3.1 Registration at the Clinical Center 
Registration will be a two-part process as patients are screened on this protocol. Authorized staff 
must register an eligible candidate with NCI Central Registration Office (CRO) within 24 hours 
of signing consent. To initially register a subject after the participant has signed the consent, 
complete the top portion of the registration Eligibility Checklist from the website 
(http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) indicating that the patient is being 
registered for screening and send via encrypted email to: NCI Central Registration Office 
ncicentralregistration-l@mail.nih.gov. Once eligibility is confirmed after completion of 
screening studies, complete the remainder of the form which is the eligibility checklist, 
indicating that the patient is being registered for treatment and email the completed registration 
checklist to the CRO at NCI Central Registration Office ncicentralregistration-


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l@mail.nih.gov.  After confirmation of eligibility at Central Registration Office, CRO staff will 
call pharmacy to advise them of the acceptance of the patient on the protocol prior to the release 
of any investigational agents.  Verification of Registration will be forwarded electronically via e-
mail to the research team. A recorder is available during non-working hours.  
Subjects that do not meet screening criteria should be removed from the study following the 
procedure in section 3.7.2. 
2.3.2 For Participating Site Registration  
Registration will be a two-part process as patients are screened on this protocol. A protocol 
registration form will be supplied by the CCR study coordinator and updates will be provided as 
needed. To initially register a subject, after the participant has signed consent, complete the top 
portion of the form and send to CCR study coordinator. Once eligibility is confirmed, after 
completion of screening studies, complete the remainder of the form which is the eligibility 
checklist, indicating that the patient is being registered for treatment and send to CCR study 
coordinator. In addition, source documents supporting the eligibility criteria must be sent to the 
CCR study coordinator. The CCR study coordinator will notify you either by e-mail or fax that the 
protocol registration form has been received which will include the unique patient/subject ID 
number. Questions about eligibility should be directed to the CCR study coordinator or PI. 
Questions related to registration should be directed to the CCR study coordinator.  
Subjects that do not meet screening criteria should be removed from the study following the 
procedure in section 3.7.4. 
2.3.3 Treatment Assignment and Randomization Procedures 
Cohorts 
Number 
Name 
Description 
1 
Lead in, Cohort 1 
Patients with Previously Untreated Metastatic or Unresectable 
Colorectal Cancer enrolled for safety assessment 
2 
Cohort 2 
Patients with Previously Untreated Metastatic or Unresectable 
Colorectal Cancer enrolled for efficacy assessment 
 
Arms 
Number 
Name 
Description 
A 
FOLFOX-A alone 
Subjects will receive FOLFOX + bevacizumab for up to 12 2-week 
cycles followed by maintenance therapy with bevacizumab + 
capecitabine/5-FU until disease progression. 
B 
Lead in, FOLFOX-A + 
Avelumab +Ad-CEA 
Subjects will receive FOLFOX + bevacizumab + avelumab + Ad-
CEA vaccine (given weeks 0, 2, 4, 8, 12, 16, and then every 12 
weeks) for up to 12 2-week cycles followed by maintenance 
therapy with bevacizumab + capecitabine/5-FU + avelumab + Ad-
CEA vaccine (following every 12 weeks dosing schedule per 
schema in 3.1.1.2) until disease progression. 


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Randomization and Arm Assignment 
Randomization will be performed at study entry by the NCI Central Registration Office. The first 
6 evaluable subjects (Cohort 1) will be assigned to the Arm B regimen. Thereafter, if the study 
proceeds, subjects in Cohort 2 will be randomized on a 1:1 basis to Arm A and Arm B. 
3 
STUDY IMPLEMENTATION 
3.1 
STUDY DESIGN 
This is an open-label, randomized, multicenter phase 2.5 clinical trial designed to evaluate the 
potential improvement in progression free survival (PFS) when avelumab is used in combination 
with standard of care therapy and Ad-CEA vaccine in metastatic or unresectable colorectal cancer 
when compared with standard of care alone. Patients in the standard of care alone arm will be 
offered the opportunity to cross-over and receive avelumab + Ad-CEA vaccine in combination 
with any combination of the Arm A standard of care deemed appropriate by the investigator after 
disease progression (as defined by RECIST 1.1. in section 6.4). Cross-over will not be offered in 
the case of rapid or symptomatic progression due to the need for implementation of a standard 
option with known efficacy. Other clinical and immunologic endpoints will be captured with the 
goal of establishing correlative data that can later be prospectively tested in a larger phase 3 study. 
Initially, we will enroll 6 patients assigned to receive the combination of chemotherapy, Ad-CEA 
vaccine and avelumab to evaluate safety and feasibility of this treatment schedule. These patients 
will be enrolled at NCI only. Patients will be enrolled in a staggered fashion with 5 days minimum 
between each patient enrolled. If there are no dose limiting toxicities, as defined in section 3.2, we 
will proceed to the phase 2.5 portion of the trial. If > 1/6 patients experience a DLT attributable to 
the IND agents, we will not proceed with the phase 2.5 portion of the trial. 
3.1.1 Study Schema 
3.1.1.1 Randomization 
 
Patients on standard of care are allowed to cross-over to Avelumab + 
Ad-CEA vaccine + standard of care after progression of disease 
 
Note: 5-FU bolus is not given in the FOLFOX-A + Avelumab +Ad-CEA vaccine Arm B 
Note: 5-FU may be substituted for capecitabine in the maintenance phase  
 


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3.1.1.2 Dosing 
 
Note: 5-FU bolus is not given in the FOLFOX-A + Avelumab +Ad-CEA vaccine Arm B 
Note: 5-FU may be substituted for capecitabine in the maintenance phase  
 
 
3.2 
 DOSE LIMITING TOXICITY (LEAD-IN PERIOD ONLY) 
The DLT evaluation period will be defined as the period from the first dose of avelumab until 28 
days have passed. DLT will be assessed in the first 6 patients enrolled. Patients will be enrolled at 
least 5 days from each other to allow adequate assessment of acute toxicity for each patient prior 
to enrolment of the next patient. If > 1/6 patients experience a DLT, with the combination, the 
study will be stopped and will not proceed to the randomized phase 2 portion of the study. Subjects 
who do not complete the DLT observation period for reasons other than a DLT will be replaced. 
The goal of the safety evaluation for the combination is to determine if there are any increased or 
unexpected toxicities due to the combination of therapies that would not be expected with either 
regimen alone (FOLFOX-A or avelumab). As such, a DLT for the combination will be defined as 
any adverse event that is unexpected relative to the known safety profile of the standard and 
investigational agents in the opinion of the investigator. The phase 2.5 portion of the study will 
not proceed until the DLT evaluation period for 6 patients has been completed.  
3.3 
STUDY STOPPING RULE (LEAD-IN PERIOD ONLY) 
Any adverse event meeting criteria for DLT and any death within 30 days of receiving 
investigational agents, regardless of attribution, will result in the study halting enrollment until an 


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expedited safety report has been sent to the FDA and the SAE has been evaluated by the 
investigators. 
3.4 
DRUG ADMINISTRATION 
3.4.1 All Subjects 
During the course of the study subjects in study Arm A will receive intravenous (IV) bevacizumab 
plus FOLFOX (first line therapy) on Days 1 and 2 of a 2 weeks cycle as tolerated per investigator 
discretion for up to a total of 12 cycles in keeping with standard of care treatment guidelines. 
Subjects in study Arm B will receive bevacizumab plus FOLFOX (first line therapy) on Days 2 
and 3. After completion of first-line induction therapy, both study arm subjects will continue 
treatment with capecitabine/5-FU plus bevacizumab on a 2-week cycle in the maintenance period. 
Body surface area (BSA) and dosing will be calculated based on the weight recorded within 2 days 
prior to avelumab dosing. 
3.4.1.1 Administration of Bevacizumab plus FOLFOX (Induction Therapy) 45,46 
Arm A: 
• Bevacizumab 5 mg/kg IV over 30 - 90 min on day 1 (infusion rate will be dependent on 
rate escalation tolerance, section 3.4.1.3), 
• Oxaliplatin 85mg/m2 IV over 2 hours on day 1 (infusion rate may be adjusted based on 
tolerance as described in section 3.4.1.4), 
• Leucovorin* 400mg/m2 IV over 2 hours on day 1,  
• 5-FU* 400 mg/m2 IV bolus on day 1, 
• 5-FU* 2400 mg/m2 IV over 46 hours (+/- 2 hours) to start on day 1. 
Arm B: 
• Bevacizumab 5 mg/kg IV over 30 - 90 min on day 2 (infusion rate will be dependent on 
rate escalation tolerance, section 3.4.1.3), 
• Oxaliplatin 85mg/m2 IV over 2 hours on day 2 (infusion rate may be adjusted based on 
tolerance as described in section 3.4.1.4), 
• Leucovorin* 400mg/m2 IV over 2 hours on day 2,  
• 5-FU* 2400 mg/m2 IV over 46 hours (+/- 2 hours) to start on day 2. 
 
* 5-Fluorouracil and leucovorin should be administered separately to avoid the formation of a 
precipitate. Per package insert, leucovorin is administered first. 
* Note: Same dose of chemotherapy may be used from previous cycle if patients weight has not 
changed by more than 10%. 
See section 1.2.7.4 for rationale for the removal of 5-FU bolus infusion in Arm B. 


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3.4.1.2 Administration of Capecitabine plus Bevacizumab (Maintenance Therapy)43 
• Capecitabine 625 mg/m2 twice a day every day by mouth. Patients should be instructed to 
take capecitabine with water within 30 minutes after a meal. Doses should be rounded to 
the nearest dose achievable without splitting pills.  
• Bevacizumab 5 mg/kg IV over 30 - 90 min on day 1, repeat every 14 days (infusion rate 
will be dependent on rate escalation tolerance, section 3.4.1.3). 
• 5-FU (+/- leucovorin) may be substituted for capecitabine in the maintenance phase. 5FU 
(+/- leucovorin) dosing during the maintenance phase will be the same as the induction 
phase (see section 3.4.1.1). 
• Note: Same dose of chemotherapy may be used from previous cycle if patient’s weight 
has not changed by more than 10%. 
3.4.1.3 Bevacizumab rate escalation  
The first dose of bevacizumab will be given over 90 minutes. If the dose is well tolerated with no 
infusion reactions, the rate will be increased for the second dose, which will be given over 60 
minutes. If the second dose is well tolerated, the third dose and all subsequent doses will be 
given over 30 minutes. If there is an initial infusion reaction at 90 or 60 minute infusion times, 
but subsequent doses are well-tolerated, the rate may be escalated at the investigator’s discretion. 
Bevacizumab will be permanently discontinued in subjects who experience a grade 3 or 4 
infusion reaction suspected to be related to bevacizumab.  
3.4.1.4 Oxaliplatin rate 
Subjects who experience a grade 1 or 2 hypersensitivity reaction suspected to be related to 
oxaliplatin, may continue treatment with oxaliplatin at the investigator’s discretion. Subsequent 
infusions must be administered at a slower rate (i.e. over 4 to 6 hours) in addition to 
premedication (e.g. dexamethasone, ranitidine, and diphenhydramine) 30-60 minutes prior to 
oxaliplatin.  
Subjects who experience a grade 3 or 4 hypersensitivity reaction suspected to be related to 
oxaliplatin, may continue treatment with oxaliplatin if in the investigator’s discretion benefits of 
continuing therapy outweigh risks. In this situation, the allergy team must be consulted and be in 
agreement with the plan of care. Skin test and desensitization protocols may be used. However, 
patients who experience anaphylactic shock or severe immune thrombocytopenia should 
discontinue oxaliplatin. 
3.4.2 Lead-in, Arm A crossovers and Arm B subjects  
Subjects in the lead in portion of the study and subjects in Arm B will additionally receive the 
study drugs, avelumab and Ad-CEA vaccine, during the induction treatment period as well as 
during the maintenance phase of therapy. Avelumab and Ad-CEA vaccine will be given on day 1 
and FOLFOX + bevacizumab will be given on day 2. Subjects in arm A that progress will be 
offered the opportunity to receive Ad-CEA vaccine and avelumab in combination with a standard 
chemotherapy regimen as described in section 3.4.2.4. 


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3.4.2.1 Avelumab administration 
As a routine precaution, subjects enrolled in this trial must be observed for 30 minutes post 
infusion, in an area with resuscitation equipment and emergency agents. At all times during 
avelumab treatment, immediate emergency treatment of an infusion-related reaction or a severe 
hypersensitivity reaction according to institutional standards must be assured. In order to treat 
possible anaphylactic reactions, dexamethasone 10 mg and epinephrine in a 1:1000 dilution or 
equivalents should always be available along with equipment for assisted ventilation. 
Subjects will receive intravenous infusion of avelumab over 1 hour (-10 minutes / +20 minutes, 
i.e., 50 to 80 minutes) according to the schedule in sections 3.4.2.3 or 3.4.2.4 as applicable at a 
dose of 10 mg/kg. Modifications of the infusion rate due to infusion-related reactions are 
described in section 3.5.1. 
Premedication with an antihistamine and with acetaminophen approximately 30 to 60 minutes 
prior to the first 4 infusions of avelumab is mandatory (for example, 25-50 mg diphenhydramine 
and 500-650 mg acetaminophen I.V or oral equivalent). Premedication should be administered for 
subsequent avelumab infusions based upon clinical judgment and presence/severity of prior 
infusion reactions. This regimen may be modified based on local treatment standards and 
guidelines, as appropriate. 
The dose of avelumab will be calculated based on the weight of the subject obtained within 2 
days prior to avelumab administration. Subjects will receive avelumab at the appropriate 
schedule until confirmed progression, unacceptable toxicity, or any criterion for withdrawal from 
the therapy.  
Avelumab should be given prior to IV chemotherapy during each cycle, when possible. 
Note: Same dose of avelumab may be used from previous cycle if patients weight has not 
changed by more than 10%. 
3.4.2.2 Ad-CEA vaccine administration  
Ad-CEA vaccine will be administered as subcutaneous injection in the thigh on Day 1 of specific 
cycles, prior to avelumab. Ad-CEA will be administered on cycles 1, 2, and 3; 5, 7, and 9; and 
every 6 cycles thereafter. 
Ad-CEA will be provided in a frozen state in a 2 ml vial with a fill volume of 1 ml of extractable 
vaccine which contains 5x1011 total virus particles. The product should be stored at –20°C until 
used and immediately thawed before use. 
 
To administer 5x1011 virus particles by subcutaneous injection: 
Withdraw 1.0 mL of contents from the previously thawed, supplied Ad-CEA from the vial and 
administer subcutaneously to the patient without any further manipulation. 
3.4.2.3 Lead-in and Arm B Induction and Maintenance 
During the induction and maintenance phases (FOLFOX plus bevacizumab, and capecitabine 
plus bevacizumab, respectively), avelumab should be given on day 1 of each cycle. In addition, 
D1 of each cycle of treatment may be moved +/- 2 days for logistical reasons.  


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3.4.2.4 Crossovers from Arm A 
Subjects that have progressed during the induction phase on Arm A will be given the option to 
cross over to avelumab + Ad-CEA vaccine in combination FOLFOX in order to exploit the 
synergistic effects of the combination therapy. Subjects on Arm A who have progressed during 
the maintenance phase will be given the option to cross over to avelumab + Ad-CEA vaccine in 
combination 
with 
either 
capecitabine/5-FU 
+ 
bevacizumab 
or 
capecitabine/5-
FU+bevacizumab+oxaliplatin based on investigator choice. Subjects that cross over will be treated 
on a 2 week cycle. Avelumab should be given on day 1 of each cycle and prior to the other agents 
to avoid giving steroids prior to avelumab. In addition, D1 of each cycle of treatment may be 
moved +/- 2 days for logistical reasons.  
Cross-over will not be offered in the case of rapid or symptomatic progression due to the need 
for implementation of a standard option with known efficacy.  
Definitions: 
1. Rapid or symptomatic progression is defined by clinical context including what is 
commonly termed a “visceral crisis.” In these cases, there are increased symptoms of 
disease progression, laboratory abnormalities due to disease progression, or a 
combination of both.  
2. Radiographic disease progression that is not felt to put a patient in imminent danger by 
the investigator would meet criteria for standard progression with eligibility for cross-
over. 
3.5 
DOSE DELAYS/MODIFICATIONS 
3.5.1 Avelumab 
Note: standard of care therapy will be continued during any AE related delay or discontinuation 
of avelumab. 
3.5.1.1 Treatment Modification for Symptoms of avelumab infusion related reactions. 
Note: These are just guidelines for consideration and may be deviated from on a case by case 
basis at the investigator’s discretion. When deviating from the below guidelines the investigator 
should document the reason in the medical record.  
 
 
NCI-CTCAE Grade 
Treatment Modification for Avelumab 
Grade 1 – mild 
Mild transient reaction; infusion interruption not 
indicated; intervention not indicated. 
Decrease the avelumab infusion rate by 50% and 
monitor closely for any worsening. 
 


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NCI-CTCAE Grade 
Treatment Modification for Avelumab 
Grade 2 – moderate 
Therapy or infusion interruption indicated but 
responds promptly to symptomatic treatment (e.g., 
antihistamines, NSAIDs, narcotics, i.v. fluids); 
prophylactic medications indicated for ≤ 24 hours. 
Temporarily discontinue avelumab infusion. 
Resume infusion at 50% of previous rate once 
infusion related reaction has resolved or decreased 
to at least Grade 1 in severity, and monitor closely 
for any worsening. 
Grade 3 or Grade 4 – severe or life-threatening 
Grade 3: Prolonged (e.g., not rapidly responsive 
to symptomatic medication and/or brief 
interruption of infusion); recurrence of symptoms 
following initial improvement; hospitalization 
indicated for clinical sequelae. 
Grade 4: Life-threatening consequences; urgent 
intervention indicated. 
Stop the avelumab infusion immediately and 
disconnect infusion tubing from the subject. 
Subjects have to be withdrawn immediately from 
avelumab treatment and must not receive any 
further avelumab treatment. 
If avelumab infusion rate has been decreased by 50% or interrupted due to an infusion reaction, 
it must remain decreased for the next scheduled infusion. If no infusion reaction is observed in 
the next scheduled infusion, the infusion rate may be returned to baseline at the subsequent 
infusions based on investigator’s medical judgment.  
If hypersensitivity reaction occurs, the subject must be treated according to the best available 
medical practice. 
3.5.1.2 Management of Immune-mediated Adverse Reactions 
Note: These are just guidelines for consideration and may be deviated from on a case by case 
basis at the investigator’s discretion. When deviating from the below guidelines the investigator 
should document the reason in the medical record.  
 
Gastrointestinal irAEs 
Severity of Diarrhea/Colitis 
(NCI-CTCAE v5) 
Initial Management 
Follow-up Management 
Grade 1 
Diarrhea: < 4 stools/day over 
Baseline 
Colitis: asymptomatic  
Continue avelumab therapy 
Symptomatic treatment (e.g. 
loperamide) 
Close monitoring for worsening symptoms 
Educate subject to report worsening immediately 
If worsens: 
Treat as Grade 2, 3 or 4.  


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Grade 2  
Diarrhea: 4 to 6 stools per day over 
Baseline; IV fluids indicated < 24 
hours; not interfering with ADL 
Colitis: abdominal pain; blood in 
stool  
 
Withhold avelumab therapy 
Symptomatic treatment 
If improves to Grade ≤ 1:  
Resume avelumab therapy 
 
If persists > 5-7 days or recurs: 
Treat as Grade 3 or 4. 
Grade 3 to 4 
Diarrhea (Grade 3): ≥ 7 stools per 
day over Baseline; incontinence; IV 
fluids ≥ 24 h; interfering with ADL 
Colitis (Grade 3): severe abdominal 
pain, medical intervention indicated, 
peritoneal signs 
Grade 4: life-threatening, 
perforation 
Withhold avelumab for 
Grade 3. 
Permanently discontinue 
avelumab for Grade 4 or 
recurrent Grade 3. 
 
1.0 to 2.0 mg/kg/day 
prednisone IV or equivalent 
Add prophylactic antibiotics 
for opportunistic infections  
Consider lower endoscopy  
If improves:  
Continue steroids until Grade ≤ 1, then taper over at least 
1 month; resume avelumab therapy following steroids 
taper (for initial Grade 3).  
 
If worsens, persists > 3 to 5 days, or recurs after 
improvement: 
Add infliximab 5mg/kg (if no contraindication). Note: 
infliximab should not be used in cases of perforation or 
sepsis.  
Dermatological irAEs 
Grade of Rash 
(NCI-CTCAE v5) 
Initial Management 
Follow-up Management 
Grade 1 to 2  
Covering ≤ 30% body surface area  
Continue avelumab therapy 
Symptomatic therapy (for 
example, antihistamines, 
topical steroids)  
If persists > 1 to 2 weeks or recurs:  
Withhold avelumab therapy  
Consider skin biopsy  
 
Consider 0.5-1.0 mg/kg/day prednisone or equivalent. 
Once improving, taper steroids over at least 1 month, 
consider prophylactic antibiotics for opportunistic 
infections, and resume avelumab therapy following 
steroids taper. 
If worsens:  
Treat as Grade 3 to 4.  
Grade 3 to 4 
Grade 3: Covering > 30% body 
surface area;  
Grade 4: Life threatening 
consequences  
Withhold avelumab for 
Grade 3. 
Permanently discontinue for 
Grade 4 or recurrent Grade 3.  
Consider skin biopsy  
Dermatology consult  
1.0 to 2.0 mg/kg/day 
prednisone or equivalent 
Add prophylactic antibiotics 
for opportunistic infections  
If improves to Grade ≤ 1:  
Taper steroids over at least 1 month; resume avelumab 
therapy following steroids taper (for initial Grade 3). 


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Pulmonary irAEs 
Grade of Pneumonitis 
(NCI-CTCAE v5) 
Initial Management 
Follow-up Management 
Grade 1 
Radiographic changes only  
Consider withholding 
avelumab therapy  
Monitor for symptoms every 
2 to 3 days  
Consider Pulmonary and 
Infectious Disease consults  
Re-assess at least every 3 weeks 
If worsens:  
Treat as Grade 2 or Grade 3 to 4.  
Grade 2 
Mild to moderate new symptoms  
Withhold avelumab therapy 
Pulmonary and Infectious 
Disease consults 
Monitor symptoms daily; 
consider hospitalization  
1.0 to 2.0 mg/kg/day 
prednisone or equivalent 
Add prophylactic antibiotics 
for opportunistic infections  
Consider bronchoscopy, lung 
biopsy  
Re-assess every 1 to 3 days  
If improves:  
When symptoms return to Grade ≤ 1, taper steroids over 
at least 1 month, and then resume avelumab therapy 
following steroids taper  
If not improving after 2 weeks or worsening:  
Treat as Grade 3 to 4.  
Grade 3 to 4 
Grade 3: Severe new symptoms; 
New/worsening hypoxia; 
Grade 4: Life-threatening  
Permanently discontinue 
avelumab therapy. 
Hospitalize. 
Pulmonary and Infectious 
Disease consults. 
1.0 to 2.0 mg/kg/day 
prednisone or equivalent  
Add prophylactic antibiotics 
for opportunistic infections  
Consider bronchoscopy, lung 
biopsy  
If improves to Grade ≤ 1:  
Taper steroids over at least 1 month  
If not improving after 48 hours or worsening:  
Add additional immunosuppression (for example, 
infliximab, cyclophosphamide, IV immunoglobulin, or 
mycophenolate mofetil)  
Hepatic irAEs 
Grade of Liver Test Elevation 
(NCI-CTCAE v5) 
Initial Management 
Follow-up Management 
Grade 1 
Grade 1 AST or ALT > ULN to 3.0 
x ULN and/or Total bilirubin > 
ULN to 1.5 x ULN  
Continue avelumab therapy 
Continue liver function monitoring  
If worsens:  
 Treat as Grade 2 or 3 to 4.  
Grade 2 
AST or ALT > 3.0 to ≤ 5 x ULN 
and/or total bilirubin > 1.5 to ≤ 3 x 
ULN  
Withhold avelumab therapy 
Increase frequency of 
monitoring to every 3 days. 
 
If returns to Grade ≤ 1: 
Resume routine monitoring; resume avelumab therapy. 
If elevation persists > 5 to 7 days or worsens:  
Treat as Grade 3 to 4. 


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Grade 3 to 4 
AST or ALT > 5 x ULN and/or total 
bilirubin > 3 x ULN  
Permanently discontinue 
avelumab therapy  
Increase frequency of 
monitoring to every 1 to 
2 days  
1.0 to 2.0 mg/kg/day 
prednisone or equivalent 
Add prophylactic antibiotics 
for opportunistic infections  
Consult gastroenterologist/ 
hepatologist 
Consider obtaining MRI/CT 
scan of liver and liver biopsy 
if clinically warranted  
If returns to Grade ≤ 1:  
Taper steroids over at least 1 month  
If does not improve in > 3 to 5 days, worsens or 
rebounds:  
Add mycophenolate mofetil 1 gram (g) twice daily  
If no response within an additional 3 to 5 days, consider 
other immunosuppressants per local guidelines. 
Renal irAEs 
Grade of Creatinine Increased 
(NCI-CTCAE v5) 
Initial Management 
Follow-up Management 
Grade 1 
Creatinine increased > ULN to 1.5 x 
ULN 
Continue avelumab therapy 
Continue renal function monitoring 
If worsens: 
Treat as Grade 2 to 3 or 4. 
Grade 2 to 3 
Creatinine increased > 1.5 and ≤ 6 x 
ULN 
 
 
 
 
 
Withhold avelumab therapy 
Increase frequency of monitoring to 
every 3 days 
1.0 to 2.0 mg/kg/day prednisone or 
equivalent. 
Add prophylactic antibiotics for 
opportunistic infections 
Consider renal biopsy 
If returns to Grade ≤1: 
Taper steroids over at least 1 month, and resume 
avelumab therapy following steroids taper. 
If worsens:  
Treat as Grade 4. 
Grade 4 
Creatinine increased > 6 x ULN 
 
 
 
 
 
 
 
Permanently discontinue avelumab 
therapy 
Monitor creatinine daily 
1.0 to 2.0 mg/kg/day prednisone or 
equivalent. 
Add prophylactic antibiotics for 
opportunistic infections 
Consider renal biopsy 
Nephrology consult 
If returns to Grade ≤1: 
Taper steroids over at least 1 month. 


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Cardiac irAEs 
Myocarditis 
Initial Management 
Follow-up Management 
New onset of cardiac signs or 
symptoms and / or new laboratory 
cardiac biomarker elevations (e.g. 
troponin, CK-MB, BNP) or cardiac 
imaging abnormalities suggestive 
of myocarditis.  
Withhold avelumab therapy. 
Hospitalize. 
In the presence of life threatening cardiac 
decompensation, consider transfer to a 
facility experienced in advanced heart 
failure and arrhythmia management. 
Cardiology consult to establish etiology 
and rule-out immune-mediated 
myocarditis.  
Guideline based supportive treatment as 
per cardiology consult.* 
 
Consider myocardial biopsy if 
recommended per cardiology consult. 
If symptoms improve and immune-mediated 
etiology is ruled out, re-start avelumab therapy. 
 
If symptoms do not improve/worsen, viral 
myocarditis is excluded, and immune-mediated 
etiology is suspected or confirmed following 
cardiology consult, manage as immune-
mediated myocarditis. 
Immune-mediated myocarditis 
Permanently discontinue avelumab. 
Guideline based supportive treatment as 
appropriate as per cardiology consult.* 
1.0 to 2.0 mg/kg/day prednisone or 
equivalent 
Add prophylactic antibiotics for 
opportunistic infections. 
Once improving, taper steroids over at least 1 
month. 
 
If no improvement or worsening, consider 
additional immunosuppressants (e.g. 
azathioprine, cyclosporine A). 
*Local guidelines, or e.g. ESC or AHA guidelines  
ESC guidelines website: https://www.escardio.org/Guidelines/Clinical-Practice-Guidelines 
AHA guidelines website: http://professional.heart.org/professional/GuidelinesStatements/searchresults.jsp?q=&y=&t=1001 
Endocrine irAEs 
Endocrine Disorder 
Initial Management 
Follow-up Management 
Grade 1 or Grade 2 
endocrinopathies 
(hypothyroidism, 
hyperthyroidism, adrenal 
insufficiency, type I diabetes 
mellitus) 
Continue avelumab therapy 
Endocrinology consult if needed 
 
Start thyroid hormone replacement 
therapy (for hypothyroidism), 
anti-thyroid treatment (for 
hyperthyroidism), corticosteroids (for 
adrenal insufficiency) or insulin (for 
Type I diabetes mellitus) as 
appropriate.  
 
Rule-out secondary endocrinopathies 
(i.e. hypopituitarism / hypophysitis) 
Continue hormone replacement/suppression 
and monitoring of endocrine function as 
appropriate. 


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Grade 3 or Grade 4 
endocrinopathies 
(hypothyroidism, 
hyperthyroidism, adrenal 
insufficiency, type I diabetes 
mellitus) 
Withhold avelumab therapy 
Consider hospitalization 
Endocrinology consult 
 
Start thyroid hormone replacement 
therapy (for hypothyroidism), 
anti-thyroid treatment (for 
hyperthyroidism), corticosteroids (for 
adrenal insufficiency) or insulin (for 
type I diabetes mellitus) as 
appropriate.  
 
Rule-out secondary endocrinopathies 
(i.e. hypopituitarism / hypophysitis) 
Resume avelumab once symptoms and/or 
laboratory tests improve to Grade ≤ 1 (with or 
without hormone replacement/suppression). 
 
Continue hormone replacement/suppression 
and monitoring of endocrine function as 
appropriate.  
Hypopituitarism/Hypophysitis 
(secondary endocrinopathies) 
If secondary thyroid and/or adrenal 
insufficiency is confirmed (i.e. 
subnormal serum FT4 with 
inappropriately low TSH and/or low 
serum cortisol with inappropriately 
low ACTH): 
• 
Refer to endocrinologist for 
dynamic testing as indicated and 
measurement of other hormones 
(FSH, LH, GH/IGF-1, PRL, 
testosterone in men, estrogens in 
women)  
• 
Hormone 
replacement/suppressive therapy 
as appropriate  
• 
Perform pituitary MRI and visual 
field examination as indicated 
 
If hypophysitis confirmed: 
• 
Continue avelumab if mild 
symptoms with normal MRI. 
Repeat the MRI in 1 month 
• 
Withhold avelumab if moderate, 
severe or life-threatening 
symptoms of hypophysitis and/or 
abnormal MRI. Consider 
hospitalization. Initiate 
corticosteroids (1 to 2 mg/kg/day 
prednisone or equivalent) 
followed by corticosteroids taper 
during at least 1 month. 
• 
Add prophylactic antibiotics for 
opportunistic infections. 
 
Resume avelumab once symptoms and 
hormone tests improve to Grade ≤ 1 (with or 
without hormone replacement). 
 
In addition, for hypophysitis with abnormal 
MRI, resume avelumab only once shrinkage of 
the pituitary gland on MRI/CT scan is 
documented.  
 
Continue hormone replacement/suppression 
therapy as appropriate. 
Other irAEs (not described above) 


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Grade of other irAEs 
(NCI-CTCAE v5) 
Initial Management 
Follow-up Management 
Grade 2 or Grade 3 clinical signs 
or symptoms suggestive of a 
potential irAE 
Withhold avelumab therapy pending 
clinical investigation 
If irAE is ruled out, manage as appropriate 
according to the diagnosis and consider re-
starting avelumab therapy 
If irAE is confirmed, treat as Grade 2 or 3 irAE. 
Grade 2 irAE or first occurrence 
of Grade 3 irAE 
Withhold avelumab therapy 
1.0 to 2.0 mg/kg/day prednisone or 
equivalent  
Add prophylactic antibiotics for 
opportunistic infections  
Specialty consult as appropriate 
If improves to Grade ≤ 1:  
Taper steroids over at least 1 month and resume 
avelumab therapy following steroids taper. 
Recurrence of same Grade 3 
irAEs 
Permanently discontinue avelumab 
therapy 
1.0 to 2.0 mg/kg/day 
prednisone or equivalent 
Add prophylactic antibiotics for 
opportunistic infections  
Specialty consult as appropriate 
If improves to Grade ≤ 1:  
Taper steroids over at least 1 month. 
Grade 4  
 
Permanently discontinue avelumab 
therapy 
1.0 to 2.0 mg/kg/day 
prednisone or equivalent and/or other 
immunosuppressant as needed 
Add prophylactic antibiotics for 
opportunistic infections  
Specialty consult. 
If improves to Grade ≤ 1:  
Taper steroids over at least 1 month 
Requirement for 10 mg per day 
or greater prednisone or 
equivalent for more than 12 
weeks for reasons other than 
hormonal replacement for 
adrenal insufficiency 
 
Persistent Grade 2 or 3 irAE 
lasting 12 weeks or longer 
Permanently discontinue avelumab 
therapy 
Specialty consult 
 
Abbreviations: ACTH=adrenocorticotropic hormone; ADL=activities of daily living; BNP=B-
type natriuretic peptide; CK-MB=creatine kinase MB; FSH=follicle-stimulating hormone; 
GH=growth hormone; IGF-1=insulin-like growth factor 1; LH=luteinizing hormone; 
PRL=prolactin. 
 


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3.5.2 Active Immunotherapy with Ad-CEA vaccine will be discontinued for: 
3.5.2.1 Life-threatening anaphylactic reactions related to the Ad-CEA vaccine. 
3.5.2.2 DLT related to active immunotherapy with Ad-CEA as follows: If one or more patients 
develop a Grade 4 allergic reaction without a clear attributable cause, other than study 
vaccine. 
3.5.3 Bevacizumab 
Note: These are just guidelines for consideration and may be deviated from on a case by case 
basis at the investigator’s discretion. When deviating from the below guidelines the investigator 
should document the reason in the medical record.  
 
3.5.3.1 Hypertension 
3.5.3.1.1 Bevacizumab should not be administered unless SBP< 150 and DBP < 90. Management 
of hypertension is outlined below. 
3.5.3.1.2 Mild/Moderate Hypertension 
For SBP > 140 and < 210 mm Hg or DBP > 90 and < 120 mm Hg that is sustained over at least a 
two week period, initiate or adjust anti-hypertensive therapy. Bevacizumab should be delayed until 
the blood SBP< 150 and DBP < 90.  
3.5.3.1.3 Severe Hypertension 
For SBP ≥ 210 mm Hg or DBP ≥ 120 mm Hg but without end organ damage, begin anti-
hypertensive therapy. Bevacizumab should be delayed until blood SBP< 150 and DBP < 90.  
3.5.3.1.4 Hypertensive Urgency or Emergency 
Bevacizumab therapy should be permanently discontinued in the presence of hypertensive urgency 
(DBP >120 with evidence of optic disc edema or progressive end-organ complications) or 
hypertensive emergency (SBP > 210 and DBP > 120 presenting with headaches, blurred vision, or 
focal neurological symptoms, or papilledema). .  
3.5.3.2 Thrombotic Events 
3.5.3.2.1 Deep Vein Thrombosis 
Bevacizumab should not be administered in the presence of deep vein thrombosis or pulmonary 
embolism. Anticoagulation may be used and bevacizumab may be restarted when thrombosis is 
resolved.  
3.5.3.2.2 Arterial Thromboembolic Events 
Bevacizumab should be permanently discontinued in the presence of new arterial thrombotic 
disease, including but not limited to, myocardial infarct due to coronary thrombosis and ischemic 
stroke. 
3.5.3.3 Neutropenia 
Bevacizumab should be held if the absolute neutrophil count (ANC) is less than 750 cells/µL until 
ANC is again above 750 cells/µL. 


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3.5.3.4 Hemorrhage 
3.5.3.4.1 Life Threatening 
In the case of hemoptysis, hematemesis, hematochezia, intracranial hemorrhage or any significant 
blood loss, bevacizumab should not be administered.  
3.5.3.5 Proteinuria 
If urine dipstick indicates ≥2+ proteinuria, bevacizumab administration should be delayed pending 
the results of a 24-hour urine collection for protein. If the 24-hour urine protein is ≥2 grams, 
bevacizumab will be delayed for up to 6 weeks, until the proteinuria is <2+ or the 24-hour urine 
protein is < 1 grams/24 hr. 
3.5.3.6 Liver Function Abnormalities 
Bevacizumab should be withheld in the event of ≥ Grade 3 LFT elevations attributed to 
bevacizumab and should not resume until the abnormalities have recovered to ≤ Grade 1.  
3.5.3.7 Allergic Reaction 
In case of flushing, shortness of breath, facial edema, headache, chills, back pain, tightness of the 
chest and throat, and/or hypotension, fever or rash, the infusion should be suspended until the 
patient is assessed until the events have subsided. For grade 3 or 4 allergic reactions, bevacizumab 
should be permanently discontinued. 
3.5.3.8 Surgical or periodontal procedures 
If there is need for an elective major surgical or periodontal procedure, bevacizumab should be 
held beginning at least 6 weeks prior to the procedure and must not be resumed before 4 weeks 
after the surgical procedure. For urgent or emergent surgery or endoscopic procedures, 
bevacizumab should be held for 4 weeks after the procedure. Longer delays may be necessary, if 
clinically indicated, in order to ensure that adequate healing has taken place prior to bevacizumab 
resumption. For minor procedures (i.e. interventional 
radiology diagnostic procedures), 
bevacizumab will be held only if there is evidence that healing is compromised.  
3.5.3.9 Reversible Posterior Leukoencephalopathy Syndrome (RPLS) 
Bevacizumab should not be administered to patients with signs or symptoms of RPLS. Evaluation 
should include neurologic evaluation, ocular examination, head MRI, and blood pressure 
assessment. If these clinical criteria are consistent with the diagnosis of RPLS, bevacizumab will 
be permanently discontinued. 
3.5.3.10 Gastrointestinal Perforations and Fistula Formation 
Bevacizumab should be discontinued in the event of a gastrointestinal perforation or the formation 
of a fistula. 
3.5.3.11 Miscellaneous 
Bevacizumab may be held at any point when in the opinion of the investigator the risks of giving 
bevacizumab outweigh the potential benefit. 
 


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3.5.4 Capecitabine 
Dose adjustments for toxicities per CTCAE as per table. 
Note: These are just guidelines for consideration and may be deviated from on a case by case 
basis at the investigator’s discretion. When deviating from the below guidelines the investigator 
should document the reason in the medical record.  
 
Summary of management of common Capecitabine toxicities  
Toxicity 
Capecitabine dose modification 
Grade 2 hand foot syndrome 
Interrupt until ≤ grade 1. May then restart 
capecitabine at full dose. For second occurrence, 
hold capecitabine until ≤ grade 1, then restart 
capecitabine one dose level lower (75% of starting 
dose first occurrence, 50% of the starting dose the 
second occurrence, discontinue the third occurrence). 
Grade 3 hand foot syndrome 
Interrupt until ≤ grade 1. Then restart capecitabine 
one dose level lower (75% of starting dose first 
occurrence, 50% of the starting dose the second 
occurrence, discontinue the third occurrence). 
Grade 2 Nausea/Vomiting 
Continue at current dose, modify anti-emetic 
regimen 
Grade 3 Nausea/Vomiting 
Hold until recovery to grade 1 (or grade 2 if present 
at baseline) then resume one dose level lower* 
Grade 2 Diarrhea 
Continue current dose, add optimal anti-diarrheal 
therapy 
Grade 3 (or greater) Diarrhea 
Hold until recovery to grade 1 (or grade 2 if present 
at baseline) then resume one dose level lower* 
Grade 3 (or greater) fatigue 
Hold until recovery to grade 1 (or grade 2 if present 
at baseline) then resume one dose level lower* 
Grade 3 (or greater) mucositis 
Hold until recovery to grade 1 (or grade 2 if present 
at baseline) then resume one dose level lower* 
Grade 2 thrombocytopenia 
Continue at current dose 
Grade 3 thrombocytopenia 
Hold until recovery until < grade 1 then resume one 
dose level lower* 


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Summary of management of common Capecitabine toxicities  
Toxicity 
Capecitabine dose modification 
Grade 4 thrombocytopenia 
Hold until recovery until < grade 1 then resume one 
dose level lower* 
Grade 3 neutropenia 
Hold until recovery until < grade 1 then resume one 
dose level lower* 
Grade 4 neutropenia 
Hold until recovery until < grade 1 then resume one 
dose level lower* 
> Grade 3 febrile neutropenia 
Hold until resolution of fever and neutropenia to < 
grade 1. Then resume on dose level lower* 
*Dose reductions for capecitabine 
1. Starting dose: 625 mg/m2 BID continuously 
2. DL -1: 470 mg/m2 BID continuously 
3. DL -2: 310 mg/m2 BID continuously 
4. Discontinuation of capecitabine. 
Capecitabine may be held in the maintenance setting (i.e., chemo holiday) when in the opinion 
of the investigator the risks of giving capecitabine outweigh the potential benefit. The same is 
true for 5-FU when given as an alternative in the maintenance setting.  


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3.5.5 FOLFOX dose adjustment 
Note: These are just guidelines for consideration and may be deviated from on a case by case basis at the investigator’s discretion. 
When deviating from the below guidelines the investigator should document the reason in the medical record.   
For Arm A 
Adverse Event 
First Occurrence 
Second Occurrence 
Third Occurrence 
Fourth Occurrence 
Hematologic Toxicity 
ANC <1000/mL 
OR 
Platelets <75000/mL 
OR 
Any Febrile Neutropenia 
1. Hold all therapy and check CBC weekly until 
recovery to: ANC ≥1000/mL and Platelets 
≥75000/mL 
AND 
2. Discontinue 5-FU bolus on Day 1 at the next 
cycle and consider adding growth factor 
support for neutropenia  
1. Hold all therapy and check CBC weekly until 
recovery to: ANC ≥1000/mL and Platelets 
≥75000/mL 
AND 
2. Decrease Oxaliplatin to 65mg/m2 on Day 1 at 
the next cycle 
1. Hold all therapy and check CBC weekly until 
recovery to: ANC ≥1000/mL and Platelets 
≥75000/mL 
AND 
2. Decrease 5-FU continuous infusion to 
1800mg/m2 and decrease Oxaliplatin to 50mg/m2 
on Day 1 at the next cycle 
1. Hold all therapy and check CBC weekly until 
recovery to: ANC ≥1000/mL and Platelets 
≥75000/mL 
AND 
2. Decrease 5-FU continuous infusion to 
1200mg/m2 and discontinue Oxaliplatin on Day 
1 at the next cycle 
ANC ≥1000/ml but 
<1500/mL 
OR 
Platelets ≥75000/ml but 
<100000/mL 
1. Discontinue 5-FU bolus on Day 1 at the next 
cycle and consider adding growth factor 
support for neutropenia  
1. Decrease Oxaliplatin to 65mg/m2 on Day 1 at 
the next cycle 
1. Decrease Oxaliplatin to 50mg/m2 on Day 1 at 
the next cycle 
1. Decrease 5-FU continuous infusion to 
1800mg/m2 on Day 1 at the next cycle 
Any other CTC ≥ Grade 3 
hematologic toxicity, (e.g. 
HgB <8.0g/dL) 
1. Hold all therapy until recovery to Grade 1 (or 
Grade 2 level, if present at baseline) 
AND 
2. Discontinue 5-FU bolus on Day 1 at the next 
cycle 
1. Hold all therapy until recovery to Grade 1 (or 
Grade 2 level, if present at baseline) 
AND 
2. Decrease Oxaliplatin to 65mg/m2 on Day 1 at 
the next cycle 
1. Hold all therapy until recovery to Grade 1 (or 
Grade 2 level, if present at baseline) 
AND 
2. Decrease Oxaliplatin to 50mg/m2 on Day 1 at 
the next cycle 
1. Hold all therapy until recovery to Grade 1 (or 
Grade 2 level, if present at baseline) 
AND 
2. Decrease 5-FU continuous infusion to 
1800mg/m2 on Day 1 at the next cycle 
Non-Hematologic Toxicity 
Nausea/Vomiting CTC ≥ 
Grade 3 
1. Hold all therapy until recovery to Grade 1 (or 
Grade 2 level, if present at baseline) 
AND 
2. Add a aprepitant if not already receiving. 
If already 
receiving, 
consider 
adding 
olanzapine 
and/or 
administering 
dexamethasone 4mg PO 24 and 48 hrs after 
oxaliplatin 
1. Hold all therapy until recovery to Grade 1 (or 
Grade 2 level, if present at baseline) 
AND 
2. Discontinue 5-FU bolus and reduce 
oxaliplatin to 65mg/m2 on Day 1 at the next 
cycle 
1. Hold all therapy until recovery to Grade 1 (or 
Grade 2 level, if present at baseline) 
AND 
2. Decrease 5-FU continuous infusion to 
1800mg/m2 and decrease Oxaliplatin to 50mg/m2 
on Day 1 at the next cycle 
1. Hold all therapy until recovery to Grade 1 
(or Grade 2 level, if present at baseline) 
AND 
2. Decrease 5-FU continuous infusion to 
1200mg/m2 and discontinue Oxaliplatin on Day 1 
at the next cycle 
Diarrhea CTC ≥ Grade 3, 
despite optimal 
antidiarrheal therapy 
1. Hold all therapy until recovery to Grade 1 (or 
Grade 2 level, if present at baseline) 
AND 
2. Discontinue 5-FU bolus at the next cycle 
1. Hold all therapy until recovery to Grade 1 (or 
Grade 2 level, if present at baseline) 
AND 
2. Decrease 5-FU continuous infusion to 
1800mg/m2 on Day 1 at the next cycle 
1. Hold all therapy until recovery to Grade 1 (or 
Grade 2 level, if present at baseline) 
AND 
2. Decrease 5-FU continuous infusion to 
1200mg/m2 at the next cycle 
1. Hold all therapy until recovery to Grade 1 (or 
Grade 2 level, if present at baseline) 
AND 
2. Decrease Oxaliplatin to 65mg/m2 on Day 1 at 
the next cycle 


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Fatigue CTC ≥ Grade 3  OR 
Mucositis CTC ≥ Grade 3 
OR  Other Toxicity Not 
Defined Herein CTC ≥ 
Grade 3 despite optimal 
supportive care 
1. Hold all therapy until recovery to Grade 1 (or 
Grade 2 level, if present at baseline) 
AND 
2. Discontinue 5-FU bolus on Day 1 at the next 
cycle 
1. Hold all therapy until recovery to Grade 1 (or 
Grade 2 level, if present at baseline) 
AND 
2. Decrease Oxaliplatin to 65mg/m2 on Day 1 at 
the next cycle 
1. Hold all therapy until recovery to Grade 1 (or 
Grade 2 level, if present at baseline) 
AND 
2. Decrease 5-FU continuous infusion to 
1800mg/m2 on Day 1 at the next cycle 
1. Hold all therapy until recovery to Grade 1 (or 
Grade 2 level, if present at baseline) 
AND 
2. Decrease 5-FU continuous infusion to 
1200mg/m2 and decrease Oxaliplatin to 50mg/m2 
on Day 1 at the next cycle 
FOLFOX-Specific Toxicities 
Peripheral Neuropathy CTC 
≥ Grade 2 
1. Hold all therapy until recovery to Grade ≤ 2 
AND 
2. Decrease Oxaliplatin to 65mg/m2 on Day 1 at 
the next cycle 
1. Hold all therapy until recovery to Grade ≤ 2 
AND 
2. Decrease Oxaliplatin to 50mg/m2 on Day 1 at 
the next cycle 
1. Hold all therapy until recovery to Grade ≤ 2 
AND 
2. Discontinue Oxaliplatin on Day 1 at the next 
cycle 
N/A 
Hand-Foot syndrome CTC 
≥ Grade 3 
1. Hold all therapy until recovery to Grade 1 (or 
Grade 2 level, if present at baseline) 
AND 
2. Decrease 5-FU continuous infusion to 
1800mg/m2 on Day 1 at the next cycle 
1. Hold all therapy until recovery to Grade 1 (or 
Grade 2 level, if present at baseline) 
AND 
2. Discontinue 5-FU bolus on Day 1 at the next 
cycle 
1. Hold all therapy until recovery to Grade 1 (or 
Grade 2 level, if present at baseline) 
AND 
2. Decrease 5-FU continuous infusion to 
1200mg/m2 at the next cycle 
1. Hold all therapy until recovery to Grade 1 (or 
Grade 2 level, if present at baseline) 
AND 
2. Decrease Oxaliplatin to 65mg/m2 on Day 1 at 
the next cycle 
 
 
For Arm B 
Adverse Event 
First Occurrence 
Second Occurrence 
Third Occurrence 
Fourth Occurrence 
Hematologic Toxicity 
ANC <1000/mL 
OR 
Platelets <75000/mL 
OR 
Any Febrile Neutropenia 
Hold all therapy and check CBC weekly until 
covery to: ANC ≥1000/mL and Platelets 
≥75000/mL  
3. For thrombocytopenia: Decrease Oxaliplatin 
to 65mg/m2 on Day 1 at the next cycle  
 
For neutropenia: Add growth factor support 
 
Hold all therapy and check CBC weekly until 
covery to: ANC ≥1000/mL and Platelets 
≥75000/mL  
For  thrombocytopenia: Decrease Oxaliplatin to 
0mg/m2 on Day 1 at the next cycle 
For neutropenia: Decrease Oxaliplatin to 
65mg/m2 on Day 1 at the next cycle  
Hold all therapy and check CBC weekly until 
recovery to: ANC ≥1000/mL and Platelets 
≥75000/mL  
For thrombocytopenia: Decrease 5-FU continuous 
infusion to 1800mg/m2  
 
For neutropenia: Decrease 5-FU continuous 
infusion to 1800mg/m2 and decrease Oxaliplatin to 
50mg/m2 on Day 1 at the next cycle  
Hold all therapy and check CBC weekly until 
recovery to: ANC ≥1000/mL and Platelets 
≥75000/mL  
Decrease 5-FU continuous infusion to 
1200mg/m2 and discontinue Oxaliplatin on Day 
1 at the next cycle  
ANC ≥1000/ml but 
<1500/mL 
OR 
Platelets ≥75000/ml but 
<100000/mL 
For thrombocytopenia: Decrease Oxaliplatin to 
65mg/m2 on Day 1 at the next cycle  
For neutropenia: Add growth factor support 
 
For thrombocytopenia: Decrease Oxaliplatin to 
50mg/m2 on Day 1 at the next cycle 
For neutropenia: Decrease Oxaliplatin to 
65mg/m2 on Day 1 at the next cycle 
For thrombocytopenia: Decrease 5-FU continuous 
infusion to 1800mg/m2  
 
For neutropenia: Decrease Oxaliplatin to 
50mg/m2 on Day 1 at the next cycle 
For thrombocytopenia: Decrease 5-FU 
continuous infusion to 1200mg/m2  
 
For neutropenia: Decrease 5-FU 
continuous infusion to 1800mg/m2 
Any other CTC ≥ Grade 3 
hematologic toxicity, (e.g. 
HgB <8.0g/dL) 
Hold all therapy until recovery to Grade 1 (or 
Grade 2 level, if present at baseline) 
AND 
Decrease Oxaliplatin to 65mg/m2 on Day 1 at 
the next cycle  
Hold all therapy until recovery to Grade 1 (or 
Grade 2 level, if present at baseline) 
AND 
Decrease Oxaliplatin to 50mg/m2 on Day 1 at 
the next cycle 
Hold all therapy until recovery to Grade 1 (or 
Grade 2 level, if present at baseline) 
AND 
Decrease 5-FU continuous infusion to 1800 mg/m2 
on Day 1 at the next cycle 
Hold all therapy until recovery to Grade 1 (or 
Grade 2 level, if present at baseline) 
AND 
Decrease 5-FU continuous infusion to 
1200mg/m2 on Day 1 at the next cycle 


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Non-Hematologic Toxicity 
Nausea/Vomiting CTC ≥ 
Grade 3 
Hold all therapy until recovery to Grade 1 (or 
Grade 2 level, if present at baseline) 
AND 
Add a aprepitant if not already receiving. If 
already 
receiving, 
consider 
adding 
olanzapine 
and/or 
administering 
dexamethasone 4mg PO days at 24 and 48 
hrs after oxaliplatin.  
Hold all therapy until recovery to Grade 1 (or 
Grade 2 level, if present at baseline) 
AND 
Reduce oxaliplatin to 65mg/m2 on Day 1 at 
the next cycle 
Hold all therapy until recovery to Grade 1 (or 
Grade 2 level, if present at baseline) 
AND 
Decrease 5-FU continuous infusion to 
1800mg/m2 and decrease Oxaliplatin to 50mg/m2 
on Day 1 at the next cycle  
Hold all therapy until recovery to Grade 1 (or 
Grade 2 level, if present at baseline) 
AND 
Decrease 5-FU continuous infusion to 
1200mg/m2 and discontinue Oxaliplatin on Day 1 
at the next cycle  
Diarrhea CTC ≥ Grade 3, 
despite optimal 
antidiarrheal therapy 
Hold all therapy until recovery to Grade 1 (or 
Grade 2 level, if present at baseline) 
AND 
Decrease 5-FU continuous infusion to 
1800mg/m2 on Day 1 at the next cycle 
Hold all therapy until recovery to Grade 1 (or 
Grade 2 level, if present at baseline) 
AND 
Decrease 5-FU continuous infusion to 
1200mg/m2 on Day 1 at the next cycle 
Hold all therapy until recovery to Grade 1 (or 
Grade 2 level, if present at baseline) 
AND 
Decrease Oxaliplatin to 65mg/m2 on Day 1 
at the next cycle 
Hold all therapy until recovery to Grade 1 (or 
Grade 2 level, if present at baseline) 
AND 
Decrease Oxaliplatin to 50mg/m2 on Day 1 at 
the next cycle 
Fatigue CTC ≥ Grade 3  OR 
Mucositis CTC ≥ Grade 3 
OR  Other Toxicity Not 
Defined Herein CTC ≥ 
Grade 3 despite optimal 
supportive care 
Hold all therapy until recovery to Grade 1 (or 
rade 2 level, if present at baseline) 
AND 
Decrease Oxaliplatin to 65mg/m2 on Day 1 at 
the next cycle 
Hold all therapy until recovery to Grade 1 (or 
Grade 2 level, if present at baseline) 
AND 
Decrease 5-FU continuous infusion to 
1800mg/m2 on Day 1 at the next cycle 
Hold all therapy until recovery to Grade 1 (or 
Grade 2 level, if present at baseline) 
AND 
Decrease Oxaliplatin to 50mg/m2 on Day 1 
at the next cycle 
Hold all therapy until recovery to Grade 1 (or 
Grade 2 level, if present at baseline) 
AND 
Decrease 5-FU continuous infusion to 
1200mg/m2 on Day 1 at the next cycle 
FOLFOX-Specific Toxicities 
Peripheral Neuropathy CTC 
≥ Grade 2 
Hold all therapy until recovery to Grade ≤ 2 
AND 
Decrease Oxaliplatin to 65mg/m2 on Day 1 at 
the next cycle 
Hold all therapy until recovery to Grade ≤ 2 
AND 
Decrease Oxaliplatin to 50mg/m2 on Day 1 at 
the next cycle 
Hold all therapy until recovery to Grade ≤ 2 
AND 
Discontinue Oxaliplatin on Day 1 at the next 
cycle 
                                      N/A 
Hand-Foot syndrome CTC 
≥ Grade 3 
Hold all therapy until recovery to Grade 1 (or 
Grade 2 level, if present at baseline) 
AND 
Decrease 5-FU continuous infusion to 
1800mg/m2 on Day 1 at the next cycle 
Hold all therapy until recovery to Grade 1 (or 
Grade 2 level, if present at baseline) 
AND 
Decrease 5-FU continuous infusion to 
1200mg/m2 on Day 1 at the next cycle 
Hold all therapy until recovery to Grade 1 (or 
Grade 2 level, if present at baseline) 
AND 
Decrease Oxaliplatin to 65mg/m2 on Day 1 
at the next cycle 
Hold all therapy until recovery to Grade 1 (or 
Grade 2 level, if present at baseline) 
AND 
Decrease Oxaliplatin to 50mg/m2 on Day 1 at 
the next cycle 
 
 
 
 


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3.6 
STUDY CALENDAR 
• 
Weight may be assessed within 2 days prior to avelumab dosing for all cycles 
• 
Cycle 1 day 1 assessments may be performed within 16 days prior to what is indicated 
• 
Other day 1 assessments in cycles 2 and beyond may be performed within 1 week prior to indicated time 
• D1 and D2 of each cycle may be moved +/- 2 days for logistical reasons 
• When a cycle must be delayed for logistical or medical reasons that cycle can be given the following week (as opposed to 
waiting 2 weeks) and future dosing should reset to every other week following that administration. 
 
Procedure 
Screen-
ing1 
Base-
line2 
Induction Therapy 
Maintenance 
Therapy 
Post Therapy 
Follow-up 
C1 
D13 
C2 
D1 
C3 
D1 
C4 
D1 
C5 
D1 
C6 
D1 
C7 
D1 
C8 
D1 
C9 
D1 
C10 
D1 
C11 
D1 
C12 
D1 
CX 
D1 
30 
day 
safety 
visit4 
Long 
term 
follow up 
Bevacizumab12 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
FOLFOX13 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Capecitabine/5-FU 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Avelumab 14 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Ad-CEA vaccine 14 
 
 
X 
X 
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
History and PE 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Every 4 cycles 
X 
 
Height 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X  
X 
 
Vital signs 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Performance Score 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
CBC with 
differential 
X 
X 
X2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Hepatic +Acute 
Care Panels5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Mineral Panel4 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ACTH, ANA, RF, 
TSH, T46 
 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Every 4 cycles 
X 
 
PT/INR, PTT 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Urinalysis7 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 


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Procedure 
Screen-
ing1 
Base-
line2 
Induction Therapy 
Maintenance 
Therapy 
Post Therapy 
Follow-up 
C1 
D13 
C2 
D1 
C3 
D1 
C4 
D1 
C5 
D1 
C6 
D1 
C7 
D1 
C8 
D1 
C9 
D1 
C10 
D1 
C11 
D1 
C12 
D1 
CX 
D1 
30 
day 
safety 
visit4 
Long 
term 
follow up 
12 lead EKG 
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
      Every 4 cycles 
 
 
HBV, HCV and 
HIV testing 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum or urine 
HCG in women of 
childbearing 
potential 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Pathology 
confirmation of dx 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HLA profiling, 
HLA A, B, C 
subtype 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Archival tumor 
tissue  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Optional Biopsy8 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Correlative 
research blood9 
 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
Every 4 cycles 
(with restaging)   
 
 
CT CAP or CT 
chest + MRI 
abdomen/pelvis  
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
Every 4 cycles 
 
 
Brain MRI if 
clinically indicated 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse Events 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
Medications 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Consent 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
NIH Advanced 
Directives Form10 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Procedure 
Screen-
ing1 
Base-
line2 
Induction Therapy 
Maintenance 
Therapy 
Post Therapy 
Follow-up 
C1 
D13 
C2 
D1 
C3 
D1 
C4 
D1 
C5 
D1 
C6 
D1 
C7 
D1 
C8 
D1 
C9 
D1 
C10 
D1 
C11 
D1 
C12 
D1 
CX 
D1 
30 
day 
safety 
visit4 
Long 
term 
follow up 
Annual phone call 
for survival 11 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
1 Screening assessments are performed within 16 days prior to enrollment except for: scans - done within 28 days prior to enrollment; viral screens 
(HIV, HBV, HCV) – done within 3 months prior to enrollment; confirmation of dx which requires specimens collected within 6 month prior to 
study enrollment 
2 May be performed within 16 days prior to initiation of study therapy. 
3 Cycle 1 day 1 assessments may be performed within 16 days prior to what is indicated. 
4 30 day safety visit occurs approximately 4 – 5 weeks after the last administration of study drug regardless of reason for discontinuation.  
Information may be obtained by telephone if patient refuses visit. 
5 Acute Care Panel: Sodium (NA), Potassium (K), Chloride (CL) Total CO2 (Bicarbonate), Creatinine, Glucose, Urea nitrogen, eGFR; Hepatic 
Panel: Alkaline Phosphatase, ALT/GPT, AST/GOT, Total Bilirubin, Direct Bilirubin; Mineral Panel: Albumin, Calcium, Magnesium (Mg), 
Phosphorus 
6 ACTH: adrenocorticotropic hormone; ANA: anti-nuclear antibody; RF: rheumatoid factor; TSH: Thyroid-stimulating hormone; T4: Free 
thyroxine. 
7 Only urine dipstick required initially. If positive for protein content, a 24 hour urine collection for protein will be performed. 
8 Two optional biopsies can be performed: one at Baseline and second at any time after completion of C4 per PI discretion.  
9 Correlative blood samples: baseline sample: 2.5 mL in PAX gene tube; On therapy: blood collected pre-dose: 5 (10mL) green top sodium heparin 
tubes for PBMC; 1 (8mL) SST tube for serum samples. Samples will be collected in selected patients at the investigator’s discretion. 
10 As indicated in section 12.3, all subjects will be offered the opportunity to complete an NIH advanced directives form. This should be done 
preferably at baseline but can be done at any time during the study as long as the capacity to do so is retained. The completion of the form is 
strongly recommended, but is not required. 
11 Patients who have come off treatment for disease progression will be followed by phone annually for survival. Patients who have not 
progressed on treatment will continue to be followed and scanned per investigator discretion until progression.     
 
12 On Day 1 in Arm A and Day 2 in Arm B (Day 1 for Arm B maintenance) 
13 On Days 1 and 2 in Arm A and Days 2 and 3 in Arm B 


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14 Only Arm B; While avelumab will be given at every cycle, Ad-CEA will only be given on C 1, 2, 3, 5, 7, 9 and every 6 cycles (approximately 
12 weeks) thereafter. 


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3.7 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA 
Prior to removal from study, effort must be made to have all subjects complete a safety visit 
approximately 30 days following the last dose of study therapy. 
3.7.1 Criteria for removal from protocol therapy 
• Completion of protocol therapy. 
• Progressive disease requiring a change in systemic therapy (exception: patients Arm A 
that have opted to cross over to Avelumab + Ad-CEA vaccine + standard of care). 
• Participant requests to be withdrawn from active therapy. 
• Unacceptable Toxicity as defined as any serious adverse event that is unexpected 
relative to the known safety profile of the investigational agents in the opinion of the 
investigator, many of which are described in sections 3.5 and 3.2.  
• Start of another systemic anticancer treatment or participation in another 
investigational therapeutic trial. Focal palliative radiotherapy, ablation, or surgery to a 
site of disease will not necessitate removal from protocol therapy. Although where 
appropriate progressive disease per RECIST v1.1 should be clearly documented and 
the decision to continue treatment beyond PD should be noted in the medical records 
(e.g. overall response to treatment except for isolated progressive lesion which has 
been treated by local intervention).   
• Positive pregnancy test.  
• Investigator discretion. 
Regardless of reason for removal from study therapy, patients will be asked to have a 30 day follow 
up safety visit. Patients who refuse to return for this visit will be asked to review any safety 
concerns by phone within this time period. 
3.7.2 Off-Study Criteria 
• Screen Failure 
• Investigator discretion 
• Participant requests to be withdrawn from study 
• Death 
• PI decision to end the study 
3.7.3 Clinical Center Site Off Protocol Therapy and Off-Study Procedure 
Authorized staff must notify Central Registration Office (CRO) when a subject is taken off 
protocol therapy and when a subject is taken off-study. A Participant Status Update Form from the 
web site (http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) main page must be completed 
and sent via encrypted email to: NCI Central Registration Office ncicentralregistration-
l@mail.nih.gov . 


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3.7.4 Participating Site Off Therapy and Off-Study Procedure 
4 
THE PARTICIPANT STATUS UPDATE FORM WILL BE SUPPLIED BY THE CCR 
STUDY COORDINATOR. SEND THE COMPLETED FORM TO THE CCR STUDY 
COORDINATOR.CONCOMITANT MEDICATIONS/MEASURES 
4.1 
SUPPORTIVE CARE 
4.1.1 Recommended Management for Severe Hypersensitivity Reaction and Flu-like 
Symptoms 
Management 
1. Epinephrine injection and dexamethasone infusion (or equivalent) 
2. Patient should be placed on monitor immediately 
3. Alert intensive care unit (ICU) for possible transfer if required 
For prophylaxis of flu-like symptoms, 25 mg indomethacin or comparable NSAID dose (e.g., 
ibuprofen 600 mg, naproxen sodium 500 mg) may be administered 2 hours before and 8 hours 
after the start of each dose of avelumab i.v. infusion. Alternative treatments for fever (e.g., 
acetaminophen) may be given to subjects at the discretion of the investigator. 
4.1.2 Recommendations for the management of tumor lysis syndrome 
Since avelumab can induce ADCC, there is a potential risk of tumor lysis syndrome. Should this 
occur, subjects should be treated as per local guidelines and the management algorithm (Figure 
23) published by Howard et al.74  


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Figure 23. Assessment and Initial Management of Tumor Lysis Syndrome (TLS) 
 


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4.1.3 General supportive care 
Additional supportive care guidelines for avelumab are found in the management tables in section 
3.5.1.2 
Because there is a potential for interaction of capecitabine with other concomitantly administered 
drugs through the CYP2C9 system, the case report form (CRF) must capture the concurrent use of 
all other drugs, over-the-counter medications, or alternative therapies. The Principal Investigator 
should be alerted if the patient is taking any agent known to affect or with the potential to interact 
with capecitabine. Patients will be transitioned to an acceptable alternative if available. Common 
examples include aluminum and magnesium hydroxide containing antacids, coumadin, and 
phenytoin. 
Diarrhea will be managed with the following regimen: loperamide (4 mg PO) at onset of 
symptoms, followed by 2 mg loperamide every 2 hours while awake (or 4 mg PO every 4 hours 
while sleeping) up to a maximum of 16 mg loperamide per day. Additional agents may be used 
concurrently if loperamide is not adequate to control diarrhea as a single agent. 
Nausea and vomiting will be managed through the use of appropriate simple supportive measures. 
Recommended premedication for oxalaplatin includes aprepitant 125mg PO, dexamethasone 
12mg PO, ondansetron 24mg PO and aprepitant 80mg 24 and 48 hours after receiving oxaliplatin. 
Alternative options may be considered, including 10-20mg IV dexamethasone and 16mg 
ondansetron intravenously 30-60 minutes prior to infusion, for example.  
Patients will receive full supportive care per NIH CC guidelines as needed while on this study 
including blood product support, intravenous hydration, antibiotic treatment and treatment of other 
newly diagnosed or concurrent medical conditions. 
 
Patients should be advised to drink plenty of water or take rehydration fluids to avoid dehydration 
if diarrhea occurs. 
5 
BIOSPECIMEN COLLECTION 
5.1 CORRELATIVE STUDIES FOR RESEARCH/PHARMACOKINETIC STUDIES 
5.1.1 IMMUNOLOGICAL STUDIES 
Samples from patients enrolled at Georgetown and the Clinical Center will be available for 
immunologic correlative studies as described below.  Samples will be collected in selected patients 
at the investigator’s discretion. 
5.1.1.1 Peripheral blood 
Five (10mL) green top sodium heparin tubes for PBMC; 1 (8mL) SST tubes for serum samples 
will be drawn on day 1 of Cycle 1, 3, 5, 9 and every 4 cycles thereafter as described in the Study 
Calendar. The following assessments are planned in the Laboratory of Tumor Immunology and 
Biology (LTIB), CCR, NCI for the samples collected. Please see section 5.1.1.3.1 for sample 
processing information. 
5.1.1.1.1 Leukocyte subpopulations and immune activation status: 


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Leukocyte subpopulations and immune activation status will be assessed by flow cytometry 
(FACS) on PBMC. Multiparameter FACS analysis using combination of markers will be 
performed to characterize leukocyte subpopulations and their functional state such as: 
• T-cells subsets and activation state  
• T-cells functionality 
• PD-1 signaling pathway  
• Regulatory T-cells  
• Other leukocytes subsets including B-cells, monocytes  
• NK cells and related cytotoxicity  
• Differentiation stage of T-cells subsets  
• Myeloid derived suppressor cells and APCs  
5.1.1.1.2 Comparison presence of TAA-specific T lymphocytes using TAA-specific peptides will 
be performed on pre- and post-treatment samples if enough PBMCs are available 
5.1.1.1.3 Further exploratory markers related to the mechanism of action of the drug such as 
soluble PD-L1 sera level, cytokine profile, and auto-antigen proteomic arrays may be 
explored. 
5.1.1.1.4 T Cell Clonal Expansion Assay 
cDNA from PBMC will be amplified using locus specific primers for TCR-β. 
Previously described methods will be used to map the V region and identify the J region 
(Klinger) and identify clonal sequences of interest. Analytics tools will be used to sort 
and identify clonal populations of interest in the post- versus pre-treatment samples. 
Correlation of expansion of a clonal TCR population post treatment will be correlated 
with clinical outcomes. 
5.1.1.1.5 Serum soluble factors and ADCC-related side effects (such as in vitro ADCC activity 
assays, sCD40L and/or sCD27) may be explored. 
5.1.1.2 Tissue analysis (Optional) 
Patents will be asked to provide archival tumor sample if available. Tumor specimens may be 
collected at baseline and any time after completion of C4 per DI discretion by the CT guided 
biopsies. . Biopsies may be obtained from primary tumor sites and metastatic sites (if applicable). 
No more than 4 cores may be obtained per site. When possible, the same site of disease should be 
biopsied on repeat evaluation. 
Specimens are used for the following studies conducted in the LTIB, CCR, NCI: 
5.1.1.2.1 Level of PD-L1 expression will be assessed by immunohistochemistry staining (IHC). 
Of note, further techniques to evaluate the expression of PD-L1 and/or marker 
candidates impacting the targeting or contributing to improve its expression may be also 
investigated if needed. 
5.1.1.2.2 Frequency and localization of tumor-infiltrated leukocytes (e.g., CD8, CD4 T-cells, 
Treg, NK cells, macrophage (M1/2 profile) by IHC 


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5.1.1.2.3 Gene expression-based subtyping 
Analysis to be performed in an outside lab, to be determined, using the methods described in 
Guinney, et al.75. We will evaluate the clinical and immunologic effects of treatment in the standard 
and combination arms by subtype. Additional analysis may be performed to evaluate the 
expression of immune-related genes in tumor tissue pre- and post-treatment in each arm. 
5.1.1.3 Sample Processing 
5.1.1.3.1 Blood samples will be processed at:  
Clinical Services Program 
NCI Frederick Cancer Research and Development Center 
PO Box B 
Frederick, MD 21702 
301-846-1000 
On days samples are drawn, Jennifer Bangh at CSP should be notified (phone: [301] 846-5893; 
fax [301] 846-6222). She will arrange courier delivery of the specimens to the processing lab. 
Couriers are assigned to CCR and Georgetown and this mechanism is in place. 
The weekly patient lists of samples drawn will be emailed to Caroline Jochems at 
jochemscm@mail.nih.gov, Jen Bangh at jb478s@nih.gov, and Theresa Burks at 
burkst@mail.nih.gov. 
5.1.1.3.2 Tissue samples will be processed immediately after acquisition by a member of the 
clinical staff. Core biopsy material will be separated (if necessary) into 3 samples. One 
sample will be placed in formalin and taken to the Laboratory of Pathology and stored 
as FFPE (formalin fixed paraffin embedded) for IHC examination at a later time. The 
second sample will be placed in a 1-2mL cryovial and snap-frozen in liquid nitrogen. 
The third sample will be placed in OCT media for preservation and stored at –70˚C. 
Any additional samples, if available, will be flash frozen. 
After processing, all non-FFPE samples will be transferred for labeling and tracking at: 
Clinical Services Program 
NCI Frederick Cancer Research and Development Center 
PO Box B 
Frederick, MD 21702 
301-846-1000 
On days samples are drawn, Jennifer Bangh at CSP should be notified (phone: [301] 846-
5893; fax [301] 846-6222). She will arrange courier delivery of the specimens to the 
processing lab. Couriers are assigned to CCR and Georgetown and this mechanism is in 
place. 
The weekly patient lists of samples drawn will be emailed to Caroline Jochems at 
jochemscm@mail.nih.gov, Jen Bangh at jb478s@nih.gov and Theresa Burks 
(burkst@mailnih.gov). 
5.1.2 Omics Studies 
Coded, linked, formalin-fixed, paraffin-embedded tissue and blood samples will be sent to 
NantOmics per the Genomic and Proteomic Sample Collection Manual under an existing CRADA 


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agreement for analysis of genetic mutations, RNA expression profiling, and proteomic profiling 
of patient tumor samples from baseline and on treatment. 
5.1.2.1 Rationale 
Genomic sequencing of tumor cells relative to non-tumor cells from whole blood will be profiled 
to identify the genomic variances that may contribute to response or disease progression and 
provide an understanding of molecular abnormalities. RNA sequencing will be conducted to 
provide expression data and give relevance to DNA mutations. Quantitative proteomics will be 
conducted to determine the exact amounts of specific proteins and to confirm expression of genes 
that are correlative of response and disease progression. All genomic, transcriptomic, and 
proteomic molecular analysis will be retrospective and exploratory, and used for future hypothesis 
generation. 
5.1.2.2 Sampling 
Please follow the instructions in the Genomics and Proteomic Sample Collection Manual to 
become familiar with the materials provided, to register and to create a patient order. For 
additional questions, please contact the study coordinator as listed on the title page. 
Exploratory genomics and proteomics molecular profiling will be performed on formalin-fixed, 
paraffin embedded (FFPE) tumor tissue and whole blood (subject matched normal comparator 
against the tumor tissue) by next-generation sequencing and mass spectrometry-based quantitative 
proteomics. Collection of whole blood at baseline is mandatory for this study. Tumor samples may 
be collected at baseline and any time after completion of C4 per PI discretion if the patient is 
willing. 
5.1.2.2.1 General Information for Collection of Tumor Tissues and Whole Blood 
Tumor tissue and whole blood samples are to be collected according to the instruction cards 
included in the Tissue Specimen Kit and Blood Specimen Kit. The kits include the materials 
necessary to collect and ship FFPE tumor tissue samples and whole blood samples.  
The Investigational Site is responsible for obtaining the subject’s written Informed Consent Form 
for genomic and proteomic molecular profiling; the Investigator is to confirm that the written 
informed consent was obtained before collection of genomic and proteomic samples. 
The Investigational Site is responsible for completing the P152525 Clinical Trial Requisition 
Form with the following information: 
- Clinical Site Information 
- Patient Information  
- Specimen Information 
- Specimen Collection Information 
The Investigational Site will return the completed Clinical Trial Requisition Form via Fax per the 
instructions provided on the form. 


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Detailed specimen requirements and procedural instructions for FFPE tumor tissue samples and 
whole blood samples are provided in the P152525 Genomic and Proteomic Sample Collection 
Manual.  
5.1.2.3 Genomic and Proteomic Analysis of Tumor Tissue and Whole Blood 
A single FFPE tumor tissue block is required for the extraction of tumor DNA, tumor RNA, and 
tumor protein. A whole blood sample is required for the extraction of subject normal DNA. 
Tumor tissue and whole blood will be processed in the NantOmics, LLC CLIA-registered and 
CAP accredited/CLIA certified laboratories.  
5.1.2.4 Genomic and Proteomic Analysis Results 
The individual subject’s summary report of cancer-related genomic and proteomic data can be 
provided to the investigator upon request after the individual subject has completed or 
discontinued the clinical study. Procedural instructions for requesting the cancer-related genomic 
and proteomic summary report are provided in the P152525 Genomic and Proteomic Sample 
Collection Manual. 
5.2 
SAMPLE COLLECTION SUMMARY 
Test/assay 
Sample/ volume 
blood 
Type of 
tube 
Collection point 
(+/- 48hrs) 
Location of 
specimen analysis 
Tissue analysis 
(5.1.1.2) 
Optional core 
biopsy 
N/A 
Baseline (from 
optional fresh or 
archival samples 
collected); any 
time after 
completion of C4 
per DI discretion 
Clinical Services 
Program, Frederick 
Omics studies 
(5.1.2) 
Single block FFPE 
with tissue surface 
area 25 mm2, 75 
µm thick, at least 
30% malignant 
tissue 
N/A 
 
NantOmics 
Optional biopsy 
N/A 
leftover samples 
from biopsies 
collected on 
study will be 
utilized 
NantOmics 


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Test/assay 
Sample/ volume 
blood 
Type of 
tube 
Collection point 
(+/- 48hrs) 
Location of 
specimen analysis 
2. 5 mL blood 
PAXgene 
Blood 
DNA 
Tube 
(provided 
in kit) 
Baseline 
NantOmics 
CEA-specific T 
cell response  
(5.1.1.1.2) 
15 mL blood 
Two 10 
mL 
Sodium 
heparin 
C1D1, C3D1, 
C5D1, C9D1 and 
every 4 cycles 
thereafter 
Clinical Services 
Program, Frederick 
PMBC subset 
correlation  
(5.1.1.1.1) 
15 mL blood 
Two 10 
mL 
Sodium 
heparin 
C1D1, C3D1, 
C5D1, C9D1 and 
every 4 cycles 
thereafter 
Clinical Services 
Program, Frederick 
T cell clonality 
(5.1.1.1.4)  
4 mL blood 
One 10 
mL 
Sodium 
heparin 
C1D1, C3D1, 
C5D1, C9D1 and 
every 4 cycles 
thereafter 
Clinical Services 
Program, Frederick 
Cytokine 
analysis 
(5.1.1.1.3, 
5.1.1.1.5) 
8 mL blood 
One SST 
C1D1, C3D1, 
C5D1, C9D1 and 
every 4 cycles 
thereafter 
Clinical Services 
Program, Frederick 
 
5.3 
SAMPLE STORAGE, TRACKING, DISPOSITION (CLINICAL SERVICES PROGRAM [CSP]) 
Samples collected at NIH will be ordered in CRIS and tracked through a Clinical Trial Data 
Management system. Should a CRIS screen not be available, the CRIS downtime procedures will 
be followed. At participating sites, samples will be ordered and tracked per local SOPs. Samples 
will not be sent outside NIH without IRB notification and an executed MTA. 
All data associated with the patient samples is protected by using a secure database. All samples 
drawn at the NIH Clinical Center and the Georgetown Lombardi Cancer Center will be transported 
to the NCI Frederick Central Repository by couriers. 
Samples will be tracked and managed by the Central Repository database. All samples will be 
stored in liquid nitrogen. These freezers are located at NCI Frederick Central Repository in 
Frederick, Maryland. 


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NCI Frederick Central Repositories store, among other things, biological specimens in support of 
NIH clinical studies. All specimens are stored in secure, limited access facilities with sufficient 
security, back-up and emergency support capability and monitoring to ensure long-term integrity 
of the specimens for research.  
It is the intent and purpose of ATCC to accept only coded, linked,  samples and sample 
information. To the best of our ability, every effort will be made to ensure that protected 
information is not sent electronically or by hard copy or on vial labels.  
Sample data is stored in the BioSpecimen Inventory (BSI) System II. This inventory tracking 
system is used to manage the storage and retrieval of specimens as well as maintain specimen data. 
BSI is designed for controlled, concurrent access. It provides a real-time, multi-user environment 
for tracking millions of specimens. The system controls how and in what order database updates 
and searches are performed. This control prevents deadlocks and race conditions. For security, BSI 
has user password access, 3 types of user access levels, and 36 user permissions (levels of access) 
that can be set to control access to the system functions. BSI provides audit tracking for processes 
that are done to specimens including shipping, returning to inventory, aliquoting, thawing, 
additives, and other processes. BSI tracks the ancestry of specimens as they are aliquoted, as well 
as discrepancies and discrepancy resolution for specimens received by the repository. If a 
specimen goes out of the inventory, the system maintains data associated with the withdrawal 
request. Vials are labeled with a unique BSI ID which is printed in both eye-readable and bar-
coded format. No patient-specific information is encoded in this ID.  
Investigators are granted view, input and withdrawal authority only for their specimens. They may 
not view specimen data or access specimens for which they have not been authorized. Access to 
specimen storage is confined to repository staff. Visitors to the repositories are escorted by 
repository staff at all times. 
5.3.1 Protocol Completion/Sample Destruction 
All specimens obtained in the protocol are used as defined in the protocol. Any specimens 
remaining at the completion of the protocol will be stored in the conditions described above. The 
study will remain open as long as sample or data analysis continues. Samples from consenting 
subjects will be stored until they are no longer of scientific value or until a subject withdraws 
consent for their continued use, at which time they will be destroyed. Once primary research 
objectives for the protocol are achieved, intramural researchers can request access to remaining 
samples, provided they have an IRB-approved protocol and patient consent or an exemption from 
OHSRP. The PI will record any loss or unanticipated destruction of samples as a deviation. 
Reporting will be per the requirements of section Error! Reference source not found.. 
 
5.4 
SAMPLES FOR GENETIC/GENOMIC ANALYSIS 
5.4.1 Whole Genome / RNA expression / Proteomic Analysis 
Please see section 5.1.2. 
5.4.2 Certificate of Confidentiality 
As part of study efforts to provide confidentiality of subject information, this study has obtained a 
Certificate of Confidentiality which helps to protect personally identifiable research information. 


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The Certificate of Confidentiality allows investigators on this trial to refuse to disclose identifying 
information related to the research participants, should such disclosure have adverse consequences 
for subjects or damage their financial standing, employability, insurability or reputation. The 
informed consent includes the appropriate coverage and restrictions of the Certificate of 
Confidentiality. 
5.4.3 Management of Results 
Subjects at NIH and at participating sites will not be contacted with information about their gene 
variant changes because NantOmics will provide the individual subject’s report of genomic data 
to the investigator only after subject has completed or discontinued the clinical study.  
6 
DATA COLLECTION AND EVALUATION  
6.1 
DATA COLLECTION 
Data will be entered in C3D at all study sites. All data will be kept secure. The PI will be 
responsible for overseeing entry of data into an in-house password protected electronic system and 
ensuring data accuracy, consistency and timeliness. The principal investigator, associate 
investigators/research nurses and/or a contracted data manager will assist with the data 
management efforts. All human subjects personally identifiable information (PII) as defined in 
accordance to the Health Insurance Portability and Accountability Act, eligibility and consent 
verification will be recorded. Primary data obtained during the conduct of the protocol will be kept 
in secure network drives or in approved alternative sites that comply with NIH security standards. 
Primary and final analyzed data will have identifiers so that research data can be attributed to an 
individual human subject participant. 
All adverse events, including clinically significant abnormal findings on laboratory evaluations, 
regardless of severity, will be followed until return to baseline or stabilization of event.  
Document AEs from the first study intervention, Study Day 1 through 30 days after removal 
from study treatment or until off-study, whichever comes first. Adverse events that are serious 
need to be recorded through 30 days after the last intervention. Beyond 30 days after the last 
intervention and through long term follow up (survival of subject), only adverse events which are 
serious and related to the study intervention need to be recorded. 
An abnormal laboratory value will be recorded in the database as an AE only if the laboratory 
abnormality is characterized by any of the following: 
• 
Results in discontinuation from the study 
• 
Is associated with clinical signs or symptoms  
• 
Requires treatment or any other therapeutic intervention 
• 
Is associated with death or another serious adverse event, including hospitalization.  
• 
Is judged by the Investigator to be of significant clinical impact 
• 
If any abnormal laboratory result is considered clinically significant, the investigator will 
provide details about the action taken with respect to the test drug and about the patient’s 
outcome. 
Exceptions to data collection: Grade 1 adverse events will not be recorded. 


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End of study procedures: Data will be stored according to HHS,  FDA regulations and NIH 
Intramural Records Retention Schedule as applicable.  
Loss or destruction of data: Should we become aware that a major breach in our plan to protect 
subject confidentiality and trial data has occurred, this will be reported expeditiously per 
requirements in section Error! Reference source not found...  
6.2 
DATA SHARING PLANS 
6.2.1 Human Data Sharing Plan 
What data will be shared? 
I will share human data generated in this research for future research as follows: 
_X_ Coded, linked data in an NIH-funded or approved public repository.  
_X_ Coded, linked data in BTRIS (automatic for activities in the Clinical Center) 
_X_ Identified or coded, linked data with approved outside collaborators under appropriate 
agreements. 
 
How and where will the data be shared?  
Data will be shared through: 
_X_ An NIH-funded or approved public repository clinicaltrials.gov. 
_X_ BTRIS (automatic for activities in the Clinical Center) 
_X_ Approved outside collaborators under appropriate individual agreements. 
_X_ Publication and/or public presentations. 
 
When will the data be shared? 
_X_ Before publication. 
_X_ At the time of publication or shortly thereafter. 
 
6.3 
GENOMIC DATA SHARING PLAN 
Unlinked genomic data will be deposited in public genomic databases such as dbGaP in 
compliance with the NIH Genomic Data Sharing Policy. 
6.4 
RESPONSE CRITERIA 
For the purposes of this study, patients should be re-evaluated for response every 8 weeks. In 
addition to a baseline scan, confirmatory scans should also be obtained up to 6 (not less than 4) 
weeks following initial documentation of objective response. 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 


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(version 1.1).76 Changes in the largest diameter (unidimensional measurement) of the tumor 
lesions and the shortest diameter in the case of malignant lymph nodes are used in the RECIST 
criteria. 
6.4.1 Definitions 
Evaluable for toxicity: All patients will be evaluable for toxicity from the time of their first 
treatment with avelumab. 
Evaluable for DLT: The first 6 subjects enrolled will be evaluable for DLT from the time of their 
first treatment with avelumab until 28 days have passed. Subjects who do not complete the DLT 
observation period for reasons other than a DLT will be replaced. 
Evaluable for objective response: Only those patients who have measurable disease present at 
baseline, have received at least one cycle of therapy, and have had their disease re-evaluated will 
be considered evaluable for response. These patients will have their response classified according 
to the definitions stated below.  
Evaluable Non-Target Disease Response: Patients who have lesions present at baseline that are 
evaluable but do not meet the definitions of measurable disease, have received at least one cycle 
of therapy, and have had their disease re-evaluated will be considered evaluable for non-target 
disease. The response assessment is based on the presence, absence, or unequivocal progression 
of the lesions.  
6.4.2 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:   
• By chest x-ray: >20 mm;  
• By CT scan:  
o Scan slice thickness 5 mm or under as >10 mm with CT scan 
o Scan slice thickness >5 mm: double the slice thickness  
• With calipers on clinical exam: >10 mm.   
All tumor measurements must be recorded in millimeters (or decimal fractions of centimeters). 
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/pericardia l 
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. 


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‘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 patient, 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 
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.  
6.4.3 Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or calipers. All 
baseline evaluations should be performed as closely as possible to the beginning of treatment and 
never more than 4 weeks before the beginning of the treatment. 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 
Clinical lesions: Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes) and ≥10 mm diameter as assessed using calipers 
(e.g., skin nodules). In the case of skin lesions, documentation by color photography, including a 
ruler to estimate the size of the lesion, is recommended.  
Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung. However, CT is preferable.  
Conventional CT and MRI: This guideline has defined measurability of lesions on CT scan based 
on the assumption that CT slice thickness is 5 mm or less. If CT scans have slice thickness greater 
than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness. MRI is 
also acceptable in certain situations (e.g. for body scans).  
Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal resolution; 
however, there are many image acquisition variables involved in MRI, which greatly impact image 
quality, lesion conspicuity, and measurement. Furthermore, the availability of MRI is variable 
globally. As with CT, if an MRI is performed, the technical specifications of the scanning 
sequences used should be optimized for the evaluation of the type and site of disease. Furthermore, 
as with CT, the modality used at follow-up should be the same as was used at baseline and the 


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lesions should be measured/assessed on the same pulse sequence. It is beyond the scope of the 
RECIST guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body 
parts, and diseases. Ideally, the same type of scanner should be used and the image acquisition 
protocol should be followed as closely as possible to prior scans. Body scans should be performed 
with breath-hold scanning techniques, if possible. 
PET-CT: At present, the low dose or attenuation correction CT portion of a combined PET-CT is 
not always of optimal diagnostic CT quality for use with RECIST measurements. However, if the 
site can document that the CT performed as part of a PET-CT is of identical diagnostic quality to 
a diagnostic CT (with IV and oral contrast), then the CT portion of the PET-CT can be used for 
RECIST measurements and can be used interchangeably with conventional CT in accurately 
measuring cancer lesions over time. Note, however, that the PET portion of the CT introduces 
additional data which may bias an investigator if it is not routinely or serially performed.  
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement. Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to the 
next. If new lesions are identified by ultrasound in the course of the study, confirmation by CT or 
MRI is advised. If there is concern about radiation exposure at CT, MRI may be used instead of 
CT in selected instances. 
Endoscopy, Laparoscopy: The utilization of these techniques for objective tumor evaluation is not 
advised. However, such techniques may be useful to confirm complete pathological response when 
biopsies are obtained or to determine relapse in trials where recurrence following complete 
response (CR) or surgical resection is an endpoint. 
Tumor markers: Tumor markers alone cannot be used to assess response. If markers are initially 
above the upper normal limit, they must normalize for a patient to be considered in complete 
clinical response. Specific guidelines for both CA-125 response (in recurrent ovarian cancer) and 
PSA response (in recurrent prostate cancer) have been published77-79. In addition, the Gynecologic 
Cancer Intergroup has developed CA-125 progression criteria which are to be integrated with 
objective tumor assessment for use in first-line trials in ovarian cancer80. 
Cytology, Histology: These techniques can be used to differentiate between partial responses (PR) 
and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as germ cell 
tumors, where known residual benign tumors can remain). 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease (an effusion may be a side effect of 
the treatment) and progressive disease. 
FDG-PET: While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in assessment 
of progression (particularly possible 'new' disease). New lesions on the basis of FDG-PET imaging 
can be identified according to the following algorithm:  
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion. 


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b. No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDG-
PET at follow-up corresponds to a new site of disease confirmed by CT, this is PD. If 
the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal FDG-
PET scan). If the positive FDG-PET at follow-up corresponds to a pre-existing site of 
disease on CT that is not progressing on the basis of the anatomic images, this is not 
PD. 
c. FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy 
in cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring. The use of FDG-PET in this circumstance should be prospectively described 
in the protocol and supported by disease-specific medical literature for the indication. 
However, it must be acknowledged that both approaches may lead to false positive CR 
due to limitations of FDG-PET and biopsy resolution/sensitivity. 
 Note: A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake greater 
than twice that of the surrounding tissue on the attenuation corrected image. 
6.4.4 Response Criteria 
6.4.4.1 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 of 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 of diameters while on study. 
6.4.4.2 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 patient 
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.  


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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). 
6.4.4.3 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 patient's best response assignment will depend on the 
achievement of both measurement and confirmation criteria. 
For Patients with Measurable Disease (i.e., Target Disease) 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non-
CR/Non-PD 
No 
PR 
>4 wks. Confirmation** 
CR 
Not 
evaluated 
No 
PR 
PR 
Non-
CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-
CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at least once >4 
wks. from baseline** 
PD 
Any 
Yes or 
No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or 
No 
PD 
Any 
Any 
Yes 
PD 
* 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
** 
Only for non-randomized trials with response as primary endpoint. 
*** 
In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as 
disease progression. 
Note: 
Patients 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 


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deterioration.” Every effort should be made to document the objective progression even after 
discontinuation of treatment. 
For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
 
6.4.5 Duration of Response 
Duration of overall response: The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started). 
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that progressive disease is objectively documented. 
 
Duration of stable disease: Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest measurements recorded since the 
treatment started, including the baseline measurements.  
6.4.6 Progression-Free Survival (PFS)  
PFS is defined as the duration of time from start of treatment to time of progression or death, 
whichever occurs first. 
6.4.7 Response Review 
An independent review of CT scans and MRIs used in determining response will be undertaken at 
the end of the study by a collaborator in the Radiology and Imaging Sciences. Images will be 
reviewed using RECIST 1.1. Initial evaluation of progression should be confirmed with a follow 
up scan in 4-6 weeks, if clinically reasonable. Date of progression should be the initial date of 
progression when confirmation is obtained. If no confirmation scan is performed, the initial scan 
demonstrating progression will determine progression.  
The image data which is collected from the sites outside the NIH LAN, will be using the NIH 
provided secure e-mail system or FEDEX of a CD with images. The system provides the ability to 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
* ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is increasingly used 
as an endpoint for assessment of efficacy in some trials so to assign this category when no lesions can be 
measured is not advised 


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e-mail large attachments which would include the dicom images collected at the remote sites 
collaborating with the clinical trial.  
When a remote site has an image data set which is ready to be transferred to the NCI site for central 
storage, they should send a non-secure e-mail to a designated e-mail recipient in the NCI informing 
them that data is ready to be transferred. The recipient of that e-mail will send an NIH secure e-
mail to the offsite person requesting that they send the data. The offsite person will then, by 
replying to the NIH secure e-mail, attach the DICOM image data set to the replied too e-mail. The 
NCI person will receive the replied too e-mail with the data attached. The NCI person will extract 
the attachment and upload the offset dicom image data set to the NCI PACS for final storage and 
archival.  
Alternatively, the images can be loaded to a CD and FEDEX to the NCI designated person.  
NCI designated recipients: 
Chrisa Thomas 
10 Center Drive, Building 10 
Room 13N210 
Bethesda, MD 20892. 
6.5 
TOXICITY CRITERIA 
The following adverse event management guidelines are intended to ensure the safety of each 
patient while on the study. The descriptions and grading scales found in the revised NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for AE reporting. 
All appropriate treatment areas should have access to a copy of the CTCAE version 5.0. A copy 
of 
the 
CTCAE 
version 
5.0 
can 
be 
downloaded 
from 
the 
CTEP 
web 
site 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40).  
7 
NIHREPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN  
7.1 
DEFINITIONS 
Please refer to definitions provided in Policy 801: Reporting Research Events found here. 
 
7.2 
OHSRP OFFICE OF COMPLIANCE AND TRAINING IRB REPORTING 
7.2.1 Expedited Reporting 
Please refer to the reporting requirements in Policy 801: Reporting Research Events and Policy 
802 Non-Compliance Human Subjects Research found here. Note: Only IND Safety Reports that 
meet the definition of an unanticipated problem will need to be reported per these policies. 
7.2.2 IRB Requirements for PI Reporting at Continuing Review 
Please refer to the reporting requirements in Policy 801: Reporting Research Events found here.  


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7.3 
NCI CLINICAL DIRECTOR REPORTING  
Problems expeditiously reported to the OHSRP in iRIS will also be reported to the NCI Clinical 
Director.  A separate submission is not necessary as reports in iRIS will be available to the 
Clinical Director. 
In addition to those reports, all deaths that occur within 30 days after receiving a research 
intervention should be reported via email to the Clinical Director unless they are due to 
progressive disease. 
To report these deaths, please send an email describing the circumstances of the death to Dr. 
Dahut at NCICCRQA@mail.nih.gov within one business day of learning of the death   
7.4 
.NCI GUIDANCE FOR REPORTING EXPEDITED ADVERSE EVENTS FOR MULTI-CENTER 
TRIALS 
Please refer to the reporting requirements in Policy 801: Reporting Research Events and Policy 
802: Non-compliance in Human Subjects Research, found here.  Until such time as direct 
electronic reporting mechanisms are available to participating sites, the site PI must immediately 
report to the coordinating center PI any deaths possibly related to the research within 24 hours of 
PI awareness of the event.  The Site PI must also report any other events required by Policy 801 
to the coordinating center PI within 7 days of PI awareness  using the CCR Problem Report Form 
(See Appendix C).  
Once direct electronic reporting mechanisms are available, these will be utilized. Please also 
notify the coordinating center PI and study coordinator of your submission at the time you make 
it. 
For IND studies, the site PI will also directly submit reports to the CCR as IND sponsor per section 
8.3. 
7.5 
INSTITUTIONAL BIOSAFETY COMMITTEE (IBC) REPORTING CRITERIA 
7.5.1 Serious Adverse Event Reports to IBC 
The Principal Investigator (or delegate) will notify IBC of any unexpected fatal or life-threatening 
experience associated with the use of Ad-CEA vaccine as soon as possible but in no event later 
than 7 calendar days of initial receipt of the information. Serious adverse events that are 
unexpected and associated with the use of Ad-CEA vaccine, but are not fatal or life-threatening, 
much be reported to the NIH IBC as soon as possible, but not later than 15 calendar days after the 
investigator’s initial receipt of the information. Adverse events may be reported by using the  FDA 
Form 3500a. 
7.5.2 Annual Reports to IBC 
Within 60 days after the one-year anniversary of the date on which the IBC approved the initial 
protocol, and after each subsequent anniversary until the trial is completed, the Principal 
Investigator (or delegate) shall submit the information described below. Alternatively, the IRB 
continuing review report can be sent to the IBC in lieu of a separate report. Please include the IBC 
protocol number on the report.  


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7.5.2.1 Clinical Trial Information  
A brief summary of the status of the trial in progress or completed during the previous year. The 
summary is required to include the following information:  
• the title and purpose of the trial;  
• clinical site; 
• the Principal Investigator; 
• clinical protocol identifiers;  
• participant population (such as disease indication and general age group, e.g., adult or 
pediatric);  
• the total number of participants planned for inclusion in the trial; the number entered into 
the trial to date whose participation in the trial was completed; and the number who 
dropped out of the trial with a brief description of the reasons;  
• the status of the trial, e.g., open to accrual of subjects, closed but data collection ongoing, 
or fully completed;  
• if the trial has been completed, a brief description of any study results.  
7.5.2.2 Progress Report and Data Analysis 
Information obtained during the previous year's clinical and non-clinical investigations, including:  
• a narrative or tabular summary showing the most frequent and most serious adverse 
experiences by body system; 
• a summary of all serious adverse events submitted during the past year; 
• a summary of serious adverse events that were expected or considered to have causes not 
associated with the use of the gene transfer product such as disease progression or 
concurrent medications; 
• if any deaths have occurred, the number of participants who died during participation in 
the investigation and causes of death; 
• a brief description of any information obtained that is pertinent to an understanding of the 
gene transfer product’s actions, including, for example, information about dose-response, 
information from controlled trials, and information about bioavailability.  
7.6 
NIH REQUIRED DATA AND SAFETY MONITORING PLAN 
7.6.1 Principal Investigator/Research Team 
The clinical research team will meet on a regular basis (every two weeks by teleconference with 
participating sites) when patients are being actively treated on the trial to discuss each patient, 
enrollment and data management issues. Decisions about dose level enrollment and dose escalation 
(NCI site only) will be made based on the toxicity data from prior patients.  


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All data will be collected in a timely manner and reviewed by the principal investigator or a lead 
associate investigator. Events meeting requirements for expedited reporting as described in section 
Error! Reference source not found. will be submitted within the appropriate timelines. 
The principal investigator will review adverse event and response data on each patient to ensure 
safety and data accuracy. The principal investigator will personally conduct or supervise the 
investigation and provide appropriate delegation of responsibilities to other members of the 
research staff.  
7.6.2 Safety Monitoring Committee (SMC) 
This protocol will require oversight from the Safety Monitoring Committee (SMC). Initial review 
will occur as soon as possible after the annual NIH Intramural IRB continuing review date. 
Subsequently, each protocol will be reviewed as close to annually as the quarterly meeting 
schedule permits or more frequently as may be required by the SMC. For initial and subsequent 
reviews, protocols will not be reviewed if there is no accrual within the review period. Written 
outcome letters will be generated in response to the monitoring activities and submitted to the 
Principal investigator and Clinical Director or Deputy Clinical Director, CCR, NCI. 
8 
SPONSOR SAFETY REPORTING 
8.1 
DEFINITIONS 
8.1.1 Adverse Event  
Any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this 
treatment. An adverse event (AE) can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product (ICH E6 (R2)) 
8.1.2 Serious Adverse Event (SAE) 
An adverse event or suspected adverse reaction is considered serious if in the view of the 
investigator or the sponsor, it results in any of the following: 
• 
Death, 
• 
A life-threatening adverse event (see section 8.1.3) 
• 
Inpatient hospitalization or prolongation of existing hospitalization  
o A hospitalization/admission that is pre-planned (i.e., elective or scheduled surgery 
arranged prior to the start of the study), a planned hospitalization for pre-existing 
condition, or a procedure required by the protocol, without a serious deterioration in 
health, is not considered a serious adverse event. 
o A hospitalization/admission that is solely driven by non-medical reasons (e.g., 
hospitalization for patient convenience) is not considered a serious adverse event.  


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o Emergency room visits or stays in observation units that do not result in admission to 
the hospital would not be considered a serious adverse event. The reason for seeking 
medical care should be evaluated for meeting one of the other serious criteria. 
• 
Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• 
A congenital anomaly/birth defect 
• 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 
8.1.3 Life-threatening  
An adverse event or suspected adverse reaction is considered "life-threatening" if, in the view of 
either the investigator or sponsor, its occurrence places the patient or subject at immediate risk of 
death. It does not include an adverse event or suspected adverse reaction that, had it occurred in a 
more severe form, might have caused death. (21CFR312.32) 
8.1.4 Severity 
The severity of each Adverse Event will be assessed utilizing the CTCAE version 5.0. 
8.1.5 Relationship to Study Product 
All AEs will have their relationship to study product assessed using the terms:  related or not 
related.   
• Related – There is a reasonable possibility that the study product caused the adverse 
event. Reasonable possibility means that there is evidence to suggest a causal relationship 
between the study product and the adverse event. 
• Not Related – There is not a reasonable possibility that the administration of the study 
product caused the event. 
8.2 
ASSESSMENT OF SAFETY EVENTS 
AE information collected will include event description, date of onset, assessment of severity 
and relationship to study product and alternate etiology (if not related to study product), date of 
resolution of the event, seriousness and outcome. The assessment of severity and relationship to 
the study product will be done only by those with the training and authority to make a diagnosis 
and listed on the Form FDA 1572 as the site principal investigator or sub-investigator.  AEs 
occurring during the collection and reporting period will be documented appropriately regardless 
of relationship.  AEs will be followed through resolution. 
SAEs will be: 
• 
Assessed for severity and relationship to study product and alternate etiology (if not 
related to study product) by a licensed study physician listed on the Form FDA 1572 as 
the site principal investigator or sub-investigator. 


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• 
Recorded on the appropriate SAE report form, the medical record and captured in the 
clinical database. 
• 
Followed through resolution by a licensed study physician listed on the Form FDA 1572 
as the site principal investigator or sub-investigator. 
For timeframe of recording adverse events, please refer to section Error! Reference source not 
found.. All serious adverse events recorded from the time of first investigational product 
administration must be reported to the sponsor with the exception of any listed in section 8.4.  
8.3 
REPORTING OF SERIOUS ADVERSE EVENTS 
Any AE that meets protocol-defined serious criteria or meets the definition of Adverse Event of 
Special Interest that require expedited reporting must be submitted immediately (within 24 hours 
of awareness) to OSRO Safety using the CCR SAE report form.  Any exceptions to the 
expedited reporting requirements are found in section 8.4. 
All SAE reporting must include the elements described in section 8.2. 
SAE reports will be submitted to the Center for Cancer Research (CCR) at: 
OSROSafety@mail.nih.gov and to the CCR PI and study coordinator.  CCR SAE report form 
and instructions can be found at: 
https://ccrod.cancer.gov/confluence/pages/viewpage.action?pageId=157942842 
Following the assessment of the SAE by OSRO, other supporting documentation of the event 
may be requested by the OSRO Safety and should be provided as soon as possible. 
8.4 
WAIVER OF EXPEDITED REPORTING TO CCR  
As hospitalization due to disease progression is part of the secondary objective, and captured as 
an endpoint in this study, hospitalization due to disease progression will not be reported in 
expedited manner to the sponsor. However, if there is evidence suggesting a causal relationship 
between the study drug and the event, report the event in an expedited manner according to section 
Error! Reference source not found.. 
8.5 
SAFETY REPORTING CRITERIA TO THE PHARMACEUTICAL COLLABORATORS 
8.5.1 EMD-Serono (Avelumab) 
To be sent by Office of Sponsor and Regulatory Oversight, CCR, NCI/NIH: 
The following reportable events must be submitted to EMD Serono within 2 business days or 3 
calendar days (whichever comes first) using the applicable safety report form provided. The 
Sponsor will assume responsibility for submitting the reportable event(s) to EMD Serono as well 
as ensuring that any local reporting requirements are completed in parallel. 
• Serious Adverse Events 
• Exposure during Pregnancy or Breastfeeding (even if not associated with an adverse 
event) 
• Occupational exposure (even if not associated with an adverse event) 


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• Potential drug-induced liver injury (Hy’s Law cases): These events are considered 
important medical events and should be reported as SAEs. 
Contact information for submission of reportable events to EMD Serono: 
Fax: +49 6151 72 6914 
OR 
E-mail: GlobalDrugSafety@merckgroup.com 
Specifying: 
PROTOCOL Number and/or Title 
EMD Serono assigned Study Number 
SUBJECT Number 
SITE Number/PI Name 
SAE/ONSET DATE. 
8.5.2 Etubics Corporation (Ad-CEA Vaccine) 
In the event of any new SAE (of any Grade) occurring during the reporting period, the 
Manufacturer (Etubics Corporation) or designee must immediately (i.e., within a maximum 24 
hours after becoming aware of the event) be informed by telephone, by fax, or by email. 
When an event (or follow-up information) is reported by telephone, a written report must be sent 
immediately thereafter by fax or email. 
Reporting procedures and timelines are the same for any new information on a previously reported 
SAE (follow-up). 
Joseph Balint 
Address: 410 West Harrison Street, Suite 100, Seattle, WA 98119 
Telephone: +1-206-838-5110 ext. 107 
Email: joe@etubics.com 
OR 
Frank Jones 
Address: 410 West Harrison Street, Suite 100, Seattle, WA 98119 
Telephone: +1-206-838-5110 ext. 101 (office) 
+1-206-818-2857 (cell) 
Email: frank@etubics.com 
All Medwatch 3500a forms and written reports should be transmitted, which must be completed 
by the investigator following specific completion instructions. Relevant pages from the CRF may 
be provided in parallel (e.g., medical history, concomitant drugs). 
In all cases, the information provided in the SAE Report Form must be consistent with the data 
on the event that is recorded in the corresponding sections of the CRF. 


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8.5.3 Reporting Pregnancy  
8.5.3.1 Maternal exposure 
If a patient becomes pregnant during the course of the study, the study treatment should be 
discontinued immediately, and the pregnancy reported to the Sponsor no later than 24 hours of 
when the Investigator becomes aware of it. The Investigator should notify the Sponsor no later 
than 24 hours of when the outcome of the Pregnancy becomes known, 
Pregnancy itself is not regarded as an SAE. However, congenital abnormalities or birth defects 
and spontaneous miscarriages that meet serious criteria (section 8.1.2) should be reported as 
SAEs.  
The outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic 
pregnancy, normal birth, or congenital abnormality) should be followed up and documented. 
8.5.3.2 Paternal exposure 
Male patients should refrain from fathering a child or donating sperm during the study and for 4 
months after the last treatment with avelumab or 6 months after the last administration of 
bevacizumab, whichever occurs later.  
Pregnancy of the patient’s partner is not considered to be an AE. However, the outcome of all 
pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, or 
congenital abnormality) occurring from the date of the first dose until 4 months after the last 
treatment with avelumab or 6 months after the last administration of bevacizumab, whichever 
occurs later should, if possible, be followed up and documented. 
8.6 
REGULATORY REPORTING FOR STUDIES CONDUCTED UNDER CCR-SPONSORED IND 
Following notification from the investigator, CCR, the IND sponsor, will report any suspected 
adverse reaction that is both serious and unexpected.  CCR will report an AE as a suspected 
adverse reaction only if there is evidence to suggest a causal relationship between the study 
product and the adverse event.  CCR will notify FDA and all participating investigators (i.e., all 
investigators to whom the sponsor is providing drug under its INDs or under any investigator’s 
IND) in an IND safety report of potential serious risks from clinical trials or any other source, as 
soon as possible, in accordance to 21 CFR Part 312.32.  
All serious events will be reported to the FDA at least annually in a summary format. 
9 
CLINICAL MONITORING  
As a sponsor for clinical trials, FDA regulations require the CCR to maintain a monitoring 
program. The CCR’s program allows for confirmation of: study data, specifically data that could 
affect the interpretation of primary and secondary study endpoints; adherence to the protocol, 
regulations, ICH E6, and SOPs; and human subjects protection. This is done through 
independent verification of study data with source documentation focusing on: 
• Informed consent process 
• Eligibility confirmation 
• Drug administration and accountability 
• Adverse events monitoring 
• Response assessment. 


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The monitoring program also extends to multi-site research when the CCR is the coordinating 
center. 
This trial will be monitored by personnel employed by a CCR contractor. Monitors are qualified 
by training and experience to monitor the progress of clinical trials. Personnel monitoring this 
study will not be affiliated in any way with the trial conduct.   
 
10 STATISTICAL CONSIDERATIONS  
Following an initial 6 patient safety evaluation, the primary objective of the trial is to determine 
if there is a difference in progression free survival among patients with metastatic or unresectable 
colorectal cancer who are treated with standard of care vs. standard of care + anti-PD-L1+ Ad-
CEA vaccine monoclonal antibody. A secondary hypothesis (objective) will be to obtain 
preliminary data on ratio of patients that are hospitalized because of adverse events attributed to 
disease progression. 
Based upon results in the literature, patients who would be eligible to be randomized on this trial 
would be expected to have an estimated 10-month median progression free survival with standard 
of care alone. The goal of this study will be to determine if the use of the anti-PD-L1 monoclonal 
antibody + the Ad-CEA vaccine along with standard of care will result in patients having an 
increased median progression free survival of 18 months. Kaplan-Meier curves and a two-tailed 
log-rank test will be the primary analysis methods. Assuming exponential progression free survival 
curves, the hazard rate for standard of care alone is 0.0693 or approximately a 7% probability of 
progressing each month when the median progression free survival is 10 months. If we assume 
that the combination arm will be associated with a median progression free survival of 18 months, 
this corresponds to a hazard rate of 0.0385 and the resulting hazard ratio for the comparison of the 
two overall actuarial curves would be 1.80. Following the principals of a phase 2.5 design, to 
compare these curves and detect a difference with a 0.10 one-tailed log-rank test, a total of 35 
evaluable subjects per arm (70 total) will need to be randomized over a one year period and a 
maximum follow-up of three years, with occurrence of 52 total progressions, in order to have 80% 
power to compare the curves.  
In addition, during the randomized portion of the trial, beginning with the 4th patient on a given 
arm, if the cumulative fraction of patients at any point who experience a grade 3 or 4 toxicity on 
either arm is greater than or equal to 1/3, then accrual to the randomized trial will be suspended 
and will only resume following modifications to the treatment on the appropriate arm, detailed in 
an amendment created for that purpose. Thus, for example, one patient with a DLT in the first 3 
randomized patients on an arm would be permitted, but if there are 2 patients with a DLT in the 
first 4 on either arm, this would be considered excessive. 
It is expected that all 76 patients (6 for safety lead-in plus 70 for phase 2.5) can be accrued onto 
this trial in three to four years. In order to allow for a number of inevaluable patients, due to screen 
failures at the other sites, the accrual ceiling will be set at 97 patients. 


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11 COLLABORATIVE AGREEMENTS  
11.1 CRADA 
11.1.1 EMD Serono 
A CRADA (02666) is in place between the Laboratory of Tumor Immunology and Biology 
(LTIB), CCR NCI and EMD Serono, the manufacturer of avelumab. 
11.1.2 Etubics Corporation 
A CRADA (02997) is in place between the Laboratory of Tumor Immunology and Biology 
(LTIB), CCR NCI and Etubics Corporation, the manufacturer of Ad-CEA vaccine. 
11.1.3 NantOmics 
The studies referenced in section 5.1.2 will be conducted under a CRADA (03063) agreement 
between the Laboratory of Tumor Immunology and Biology (LTIB), CCR NCI and NantOmics. 
11.2 MTA 
11.2.1 EMD Serono 
A MTA (41326-16) is in place between the CCR NCI and EMD Serono  
11.3 MULTI-INSTITUTIONAL GUIDELINES 
11.3.1 IRB Approvals 
The PI will provide the NIH Intramural IRB with a copy of the participating institution’s 
approved yearly continuing review. Registration will be halted at any participating institution in 
which a current continuing approval is not on file at the NIH Intramural IRB. 
11.3.2 Amendments and Consents 
The CCR PI will provide the NIH Intramural IRB with copies of all amendments, consents and 
approvals from each participating institution. 
12 HUMAN SUBJECTS PROTECTIONS  
12.1 RATIONALE FOR SUBJECT SELECTION 
Subjects from all racial and ethnic groups are eligible for this trial if they meet the eligibility 
criteria. Efforts will be made to extend the accrual to a representative population. 
12.2 PARTICIPATION OF CHILDREN 
The age group for enrollment on this trial is ≥ 18 years of age. 
12.3 PARTICIPATION OF SUBJECTS UNABLE TO GIVE CONSENT  
Adults unable to give consent are excluded from enrolling in the protocol. However, re-consent 
may be necessary and there is a possibility, though unlikely, that subjects could become 
decisionally impaired. For this reason and because there is a prospect of direct benefit from 
research participation (section 12.4), all subjects will be offered the opportunity to fill in their 
wishes for research and care, and assign a substitute decision maker on the “NIH Advance 


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Directive for Health Care and Medical Research Participation” form so that another person can 
make decisions about their medical care in the event that they become incapacitated or cognitively 
impaired during the course of the study. Note: The PI or AI will contact the NIH Ability to Consent 
Assessment Team (ACAT) for evaluation as needed for the following: an independent assessment 
of whether an individual has the capacity to provide consent; assistance in identifying and 
assessing an appropriate surrogate when indicated; and/or an assessment of the capacity to appoint 
a surrogate. For those subjects that become incapacitated and do not have pre-determined 
substitute decision maker, the procedures described in NIH HRPP SOP 14E for appointing a 
surrogate decision maker for adult subjects who are (a) decisionally impaired, and (b) who do not 
have a legal guardian or durable power of attorney, will be followed. 
12.4 EVALUATION OF BENEFITS AND RISKS/DISCOMFORTS 
Adult subjects, including those that have lost the capacity to consent 
Patients will receive evaluation of their disease at the National Cancer Institute’s Clinical Center 
and/or MedStar Georgetown University Hospital (Lombardi Cancer Center). This protocol may or 
may not benefit an individual, but the results may help the investigators learn more about the 
disease and develop new treatments for patients with this disease. 
Potential 
adverse reactions attributable 
to the administration 
of avelumab and the 
chemotherapeutic agents utilized in this trial are discussed in section 13. All care will be taken to 
minimize side effects, but they can be unpredictable in nature and severity. Patients will be 
examined and evaluated prior to enrollment. All evaluations to monitor the treatment of patients 
will be recorded in the patient chart. If patients suffer any physical injury as a result of the 
participation in this study, immediate medical treatment is available at the Clinical Center, 
National Cancer Institute, Bethesda, Maryland and/or MedStar Georgetown University Hospital 
(Lombardi Cancer Center). 
In addition, the study may involve up to two CT guided biopsies (optional) collected for research 
purposes only. Subjects undergoing two optional biopsy collection will be exposed to 1.5 rem. 
This amount of radiation is below the guideline of 5 rem per year allowed for adult research 
subjects by the NIH Radiation Safety Committee. 
Although no compensation is available, any injury will be evaluated and treated in keeping with 
the benefits or care to which patients are entitled under applicable regulations. In all publications 
and presentations resulting from this trial, patients’ anonymity will be protected to the maximum 
extent possible. Authorized personnel from the National Cancer Institute (NCI) and Food and Drug 
Administration (FDA) or other regulatory authorities may have access to research files in order to 
verify that patients’ rights have been safeguarded. In addition, patient names will be given to the 
Central Registration to register and verify patients’ eligibility. 
12.5 CONSENT AND ASSENT PROCESS AND DOCUMENTATION 
The investigational nature and research objectives of this trial, the procedures and treatments 
involved and their attendant risks and discomforts and benefits, and potential alternative therapies 
will be carefully explained to the patient, and a signed informed consent document will be obtained 
by a study investigator prior to entry onto the study. 


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The PI or associate investigator will meet with the patient to discuss the protocol treatment and 
alternative options in detail. It will be stated clearly that participation in the research study is 
voluntary and that participants can withdraw from the study without losing benefits they would 
otherwise be entitled to. The patient will be encouraged to ask questions, and additional meetings 
to discuss the treatment options will be arranged as necessary. 
If there is an optional biopsy for research in the protocol, then the patient will consent at the time 
of the procedure. If the patient refuses the optional biopsy at that time, the refusal will be 
documented in the medical record. 
12.5.1 Telephone re-consent procedure 
Re-consent on this study may be obtained via telephone according to the following procedure: the 
informed consent document will be sent to the subject. An explanation of the study will be 
provided over the telephone after the subject has had the opportunity to read the consent form. The 
subject will sign and date the informed consent. The original informed consent document will be 
sent back to the consenting investigator who will sign and date the consent form with the date the 
consent was obtained via telephone. A fully executed copy will be returned via mail for the 
subject’s records. The informed consent process will be documented in the medical record. 
12.5.2 Request for Waiver of Consent for Screening Activities 
Prior to the subject signing the consent for this study pre-screening activities listed in section 
2.2.1 may be performed.  
We request a waiver of consent for these activities as they involve only minimal risk to the 
subjects.  A waiver will not adversely affect the rights and welfare of the subjects given that the 
activities are only intended to determine suitability for screening for participation in research 
protocols.  These activities could not practicably be carried out without the wavier as central 
recruiting services, utilized in the NIH Clinical Center, perform pre-screening activities for 
multiple studies and obtaining consent for each one is beyond their resources.  The subjects will 
be provided with additional pertinent information after participation as they will be informed 
whether or not they are eligible to sign a consent for additional screening. 
 
13 PHARMACEUTICAL INFORMATION  
All commercial agents are used as indicated, therefore these agents will not be included in the 
IND.  
13.1 AVELUMAB (BB IND# 17056) 
13.1.1 Source  
Avelumab will be supplied by the manufacturer, EMD Serono, Inc., through a Cooperative 
Research and Development Agreement (CRADA). The Clinical Trial Supplies department of the 
manufacturer will supply the trial medication of avelumab, which will be distributed to the sites 
by EMD Serono, the manufacturer of avelumab. 


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13.1.2 Toxicity  
The available safety data for current EMR100070-001 trial are summarized below based on the 
safety data cut-off date, 05 November 2014. In addition to subjects treated during dose escalation, 
a total of 480 subjects were enrolled during the dose expansion (NSCLC: 184; metastatic breast 
cancer: 169; gastric cancer: 47; colorectal cancer: 22; castrate-resistant prostate cancer: 11; ovarian 
cancer: 37, melanoma: 5; mesothelioma: 1; adrenocortical carcinoma: 1; and urothelial carcinoma: 
3), treated with the recommended dose of 10 mg/kg avelumab once every 2 weeks and followed 
up for at least 4 weeks up to the cut-off date. 
For all subjects treated during the dose expansion, the most frequently affected System Organ 
Classes (with an incidence > 30%) were general disorders and administration site conditions 
(59.6%), gastrointestinal disorders (57.3%), respiratory, thoracic and mediastinal disorders 
(39.8%), musculoskeletal and connective tissue disorders (38.8%), and metabolic and nutrition 
disorders (32.3%). 
Most Frequently Reported Treatment-related TEAEs During Dose Expansion (≥ 5% of Subjects) 
Treatment-emergent Adverse Eventsa 
Preferred Term (MedDRA) 
Subjects (Safety Population, N = 480) 
N (%) 
Fatigue 
97 (20.2%) 
Nausea 
62 (12.9%) 
Infusion-related reaction 
47 (9.8%) 
Chills 
33 (6.9%) 
Diarrhea 
33 (6.9%) 
Decreased appetite 
30 (6.3%) 
Pyrexia 
27 (5.6%) 
Influenza like illness 
25 (5.2%) 
Arthralgia 
24 (5.0%) 
MedDRA = Medical Dictionary for Regulatory Activities. 
a Only treatment-emergent adverse events started during the on-treatment period are summarized. 
Treatment-related TEAEs Grade ≥ 3 
Of the Grade ≥ 3 treatment-related TEAEs (59 subjects; 12.3%), the following occurred in more 
than 2 subjects: fatigue (5 subjects, 1.0%), anemia (5 subjects, 1.0%), infusion-related reaction, 
lipase increased, and GGT increased (each in 4 subjects, 0.8%). 
Of the 59 subjects who had Grade ≥ 3 treatment-related TEAEs, 44 (9.2%) had Grade 3 treatment-
related TEAEs, 11 (2.3%) had Grade 4 treatment-related TEAEs, and 4 (0.8%) had Grade 5 


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treatment-related TEAEs. One Grade 3 event of encephalopathy (Subject 101-0032), which was 
initially considered as posterior reversible encephalopathy syndrome, was assessed as related to 
trial medication with an alternative explanation of hypertension. 
Serious Adverse Events 
Overall, 176 of the 480 subjects (36.7%) treated during the dose expansion had serious TEAEs. 
Of these, 22 (4.6%) subjects reported dyspnea, which was the most frequent serious TEAE in this 
group, followed by 19 subjects (4.0%) reporting disease progression, 12 subjects (2.5%) reporting 
pleural effusion, 11 subjects (2.3%) reporting pneumonia, and 7 subjects (1.5%) reporting anemia. 
All other serious TEAEs were each reported in less than 1.5% of subjects. 
Of the serious TEAEs considered treatment-related by the investigator (31 subjects; 6.5%), the 
following were reported for 2 or more subjects: infusion-related reaction (4 subjects, 0.8%), 
pneumonitis (3 subjects, 0.6%), and disease progression, dyspnea, and hypercalcemia (each in 2 
subjects, 0.4%). 
Deaths 
In total, 134 subjects (27.9%) treated during the dose expansion died up to the cut-off date (05 
November 2014). Of these, the majority of deaths (101 deaths; 21.0%) were due to disease 
progression. An additional 8 deaths (1.7%) were due to TEAEs unrelated to trial treatment, 4 
deaths (0.8%) were due to TEAEs related to trial treatment, and the reason for 8 deaths (1.7%) 
was labeled as other. The reason for 13 deaths (2.7%) was unknown at the time of the data cut-
off. Of the 134 subjects who died, 53 subjects (11.0%) died within 30 days of the last 
administration of trial treatment. Among these deaths, 39 (8.1%) were due to disease 
progression, 7 (1.5%) were due to TEAEs unrelated to trial treatment, 4 (0.8%) were due to 
TEAEs related to trial treatment, and 3 (0.6%) were due to other reasons. No death of unknown 
reason was reported in the 30-day period. 
Immune-related Adverse Events 
As of 05 November 2014, a cumulative review revealed 56 cases of potential immune-related 
AEs out of 480 subjects (11.7%) treated in the dose expansion part of trial EMR 100070-001 and 
4 cases out of 50 subjects (8.0%) treated in the dose escalation part of trial EMR 100070-001. A 
customized Medical Dictionary for Regulatory Activities (MedDRA) query was used for data 
retrieval from the clinical database with predefined Preferred Terms of potential immune-related 
AEs (irAEs). 
Of 69 potential irAEs reported, 13 were SAEs (18.8%) and 56 were non-serious AEs (81.1%). In 
the majority of the cases, there was a plausible temporal association between the event onset and 
the drug administration. Of these 69 events, 46 events (66.7%) were assessed as treatment related 
by the investigator and 23 events (33.3%) were assessed as not treatment-related by the 
investigator. 
Twenty-six events were assessed as Grade 1, 29 events as Grade 2, 11 events as Grade 3, 2 
events as Grade 4, and 1 event (pneumonitis) as Grade 5 (Please note: 2 more events of 
autoimmune hepatitis had a fatal outcome; however, they were assessed as Grade 3 with a 
consequent fatal liver failure). 


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Infusion-related Reactions 
Two suspected unexpected serious adverse reactions (SUSARs; anaphylactic reaction and 
infusion-related reaction) involving 2 subjects were reported in December 2013 and triggered a 
cumulative review of serious and non-serious cases of infusion-related reactions / 
hypersensitivity across the avelumab program. Following evaluation of safety signals, infusion 
related reactions / hypersensitivity have been classified as a newly identified risk (previously 
classified as a potential risk) and a mandatory premedication regimen of histamine H1 receptor 
(H1) blockers plus acetaminophen was implemented for all trial subjects as of 28 January 2014. 
As of 05 November 2014, 49 (10.2%) of the 480 subjects in the expansion cohort experienced at 
least 1 episode of an infusion-related reaction when receiving avelumab monotherapy. Most of 
the events were Grade 1 (8 subjects, 1.7%) or Grade 2 (36 subjects, 7.5%) in intensity, and Grade 
3 (3 subjects, 0.6%) or Grade 4 events (2 subjects, 0.4%) were less frequent. No Grade 5 events 
were reported. Most of the infusion-related reaction events had an onset after the first (30 
subjects, 6.3%) or second (16 subjects, 3.3%) avelumab infusion. In 8 subjects (1.7%), avelumab 
treatment was discontinued because of infusion-related reaction events. 
In addition, 1 subject (2.0%) in the dose escalation cohort reported an infusion-related reaction 
event (Grade 2). 
In addition to the aforementioned 49 subjects, 1 case of Grade 4 cardiac arrest occurred 1.5 hours 
after the third infusion of avelumab (10 mg/kg). The subject died due to an anoxic brain injury 7 
days later; no autopsy was performed. 
Starting from 29 January 2014, the Sponsor has implemented a mandatory premedication with 
H1 blockers plus acetaminophen for all subjects who are to receive avelumab. This 
premedication procedure was applied to 28 and 440 subjects in the dose escalation and the 
pooled treatment expansion cohort, respectively. Under this premedication procedure, 33 of 440 
subjects (7.5%) in the expansion cohort experienced infusion-related reaction events, with 6 
subjects (1.4%) having Grade 1, 26 subjects (5.9%) having Grade 2, and 1 subject (0.2%) having 
Grade 3 events. No infusion-related reaction events were reported in the 28 subjects in the dose 
escalation cohort. 
13.1.3 Formulation and preparation  
Avelumab is formulated as a 10.0 mg/mL solution in single-use glass vials, with a rubber 
stopper. Packaging and labeling will be in accordance with applicable local regulatory 
requirements and applicable Good Manufacturing Practice (GMP) guidelines. Avelumab will be 
packed in boxes containing a suitable number of vials. The information on the medication will be 
in accordance with approved submission documents. 
Avelumab will be shipped in transport cool containers (2°C to 8°C) that are monitored with 
temperature control devices. 
Prior to preparation, the day of usage, avelumab must be allowed to warm to room temperature 
(15-25°C) for 30 minutes. 
The calculated dose of avelumab must be diluted with 0.9% sterile sodium chloride injection to a 
total volume of 250 mL in an infusion bag. Prior to the addition of avelumab, an equal volume of 
0.9% sodium chloride injection must be removed from the infusion bag and must be discarded. 


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13.1.4 Stability and Storage  
Avelumab drug product must be stored at 2°C to 8°C until use, with a temperature log 
maintained daily. All medication boxes supplied to each study center must be stored carefully, 
safely, and separately from other drugs. 
Avelumab drug product stored at room temperature (15°C to 25°C) or at elevated temperatures 
(38°C to 42°C) for extended periods is subject to degradation. Avelumab must not be frozen. 
Rough shaking of avelumab must be avoided. 
Chemical and physical in-use stability has been demonstrated for 24 h at 25°C for the diluted 
medication in the approved infusion bags. However, from a microbiological point of view, the 
diluted solution should be used immediately and is not intended to be stored unless dilution has 
taken place in controlled and validated aseptic conditions. 
13.1.5 Administration procedures 
Please see section 3.4.2.1. 
13.1.6 Incompatibilities  
The following treatments must not be administered during the study: 
• Immunotherapy, immunosuppressive drugs (i.e., chemotherapy or systemic 
corticosteroids except for short term treatment of allergic reactions, for the treatment of 
irAEs, or for management of radiation induced tumor swelling), or other experimental 
pharmaceutical products. Short term administration of systemic steroid (i.e., for allergic 
reactions, the management of irAEs, and management of radiation induced tumor 
swelling) is allowed. Steroids with no or minimal systemic effect (topical, inhalation) are 
allowed. 
• Any vaccine therapies for the prevention of infectious disease (e.g., seasonal flu vaccine, 
human papilloma virus vaccine) except administration of the inactive influenza vaccine. 
 
13.2 AD-CEA VACCINE (BB IND# 17056) 
13.2.1 Source 
Ad-CEA will be supplied by the manufacturer, Etubics Corporation, through a Cooperative 
Research and Development Agreement (CRADA). The manufacturing department of Etubics 
will supply the vaccine, which will be distributed to the sites by Etubics Corporation. 
13.2.2 Toxicity 
A Phase I/II clinical trial of ETBX-011 (Ad5 [E1-, E2b-]-CEA(6D)) (IND#14325) that expresses 
the tumor-associated antigen carcinoembryonic antigen (CEA) has been performed. A summary 
of the study results on the clinical trial is presented below.  
Schedule, Dosing, and Safety: The primary objective of the Phase I/II dosing trial was to assess 
safety and a secondary objective was to evaluate CEA-specific immune responses to CEA and to 
obtain preliminary data on response rate. The study was performed under an FDA-approved IND 
(IND14325) and registered at ClinicalTrials.gov (NCT01147965). Participants were recruited 
from oncology clinics at Duke University Medical Center and Medical Oncology Associates, 


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Spokane, WA and provided informed consent that was approved by IRB’s. Patients with a 
histological confirmed diagnosis of metastatic malignancy who were previously treated with 
standard therapy known to have a possible survival benefit were enrolled into the study. For this 
study, the carcinoma must have had over expression of CEA as defined by immunohistochemical 
staining (at least 50% of the tumor with at least moderate intensity of staining) or a carcinoma 
known to be universally CEA positive i.e. colorectal adenocarcinoma). Patients were not treated 
until 4 or more weeks after any prior chemotherapy or radiation therapy. They could not have a 
history of autoimmune disease, serious intercurrent chronic or acute illness, active hepatitis, 
serologic evidence for HIV infection, or be receiving steroid or immunosuppressive therapy. All 
patients were >21 years old and had a Karnofsky Performance Score of 70% or higher and a life 
expectancy of at least 3 months. Pregnant women and nursing mothers were excluded. Dose 
Limiting Toxicities (DLTs) were defined as any Grade 3 or 4 immediate hypersensitivity reactions, 
Grade 3 or 4 fever that may possibly be associated with the immunization, Grade ≥2 autoimmune 
events except for vitiligo or fever for less than 2 days and less than 101.5 ºF, Grade ≥2 allergic 
reactions (Grade 2 is defined as generalized urticaria as defined by NCI Common Terminology 
Criteria for Adverse Events (CTCAE version 5.0), or Grade ≥3 non-hematologic toxicity. The Ad5 
[E1-, E2b-]-CEA(6D) injections were given subcutaneously in the same thigh. The doses were 
administered every 3 weeks for 3 treatments as follows: Cohort 1 (3 patients) 109 VP in 0.5 ml; 
Cohort 2 (3 patients): 1010 VP; Cohort 3 (6 patients) 1011 VP. Following establishment of safety 
in Phase I, 12 additional patients were entered into a Phase II using the 1011 VP/dose. To evaluate 
a higher dose, 6 additional patients (cohort 5) received 5x1011 VP/dose.  
Patient Demographics: One patient with CEA expressing bladder and one patient with lung 
carcinoma was enrolled. Thirty two patients, median age 57.5 (range 38-77) with metastatic 
colorectal cancer, who had failed a median of three prior chemotherapeutic regimens (range: 2–5), 
had a median performance status of 90% (range 70-100%), and had a median of three sites of 
metastatic disease (range 1-5), were enrolled. The majority was able to receive all three 
immunizations. Five patients who stopped immunizations early did so due to significant disease 
progression. The colorectal adenocarcinoma patient demographics compares favorably with 
previously published studies of patients with chemotherapy-refractory colorectal cancer [44-46]. 
Adverse Effects: A total of 94 immunization treatments were administered to all patients. 
There was no dose limiting toxicity and no serious adverse events that resulted in treatment 
discontinuation at any dose level. The most common toxicity was a self-limited, injection site 
reaction. Other reactions that occurred at a low frequency include fever, flu-like symptoms, 
anorexia, chills, nausea, and headache. These symptoms were also self-limiting and did not require 
intervention other than symptomatic measures such as acetaminophen. There were no SAE 
associated with immunizations. A summary of the adverse events reported on 34 patients treated 
and evaluated for safety are presented below. 
 
Adverse Events: ≥ 5% Frequency Based on Incidence of Total Treatments 
Adverse Events as 
of 07/31/12 
# of 
Events 
Unrelated/Unlikely  Possible Probably/ 
Definite  
Incidence % 
(based on 94 
total 
treatments) 
  
  


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Injection Site 
Reaction 
21 
2 
  
21 
22.3 
Flu-like symptoms 
10 
4 
5 
3 
10.6 
Fever 
9 
6 
1 
4 
9.5 
Fatigue 
8 
6 
 2 
  
8.5 
Shortness of Breath 
6 
6 
  
  
6.3 
Pain 
6 
4 
  
  
6.3 
Anorexia 
5 
  
1 
  
5.3 
Chills 
5 
5 
1 
4 
5.3 
Constipation 
5 
5 
  
  
5.3 
Edema 
5 
4 
  
  
5.3 
Nausea 
5 
4 
1 
  
5.3 
 
Grade 3 and Grade 4 Adverse Events in ≥ 2% of Patients* 
 
Adverse Events 
Number of 
Grade 3 (G3) 
 
Number of 
Grade 4 (G4) 
Percent (Based 
on 34 patients 
evaluated for 
safety) 
Pain (all types) 
2 
 
5.6 
Fatigue 
1 
 
2.9 
Anemia  
1 
 
2.9 
Pleural effusion 
1 
 
2.9 
Alkaline Phosphatase Increase 
1 
 
2.9 
Abdominal Bloating 
1 
 
2.9 
Bowel obstruction 
1 
 
2.9 
GI disorder  
1 
 
2.9 
Acute renal failure  
1 
 
2.9 
 
 
 
 
 
*Represents reported adverse events whether or not related to ETBX-011 vaccine 
 
Of 34 total patients entered into the trial, 28 received all three treatments and the blood 
hematology, chemistry, and ANA values at week 0 (prior to first treatment) were compared with 
those obtained at week 9 (three weeks after the third treatment). There were no biologically 
significant changes in chemistry, hematology, or ANA values.  
13.2.3 Formulation and Preparation 
ETBX-011 is a clear colorless liquid filled in a 2-mL amber vial containing 1.0 mL of 
extractable vaccine. There are total of 5x1011 total virus particles in 1.0 mL of the product. Each 
vial is sealed with a rubber stopper and has a white flip off seal. End user of the product will need 
to flip the white plastic portion of the cap up/off with their thumb to expose the rubber stopper, 


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and then puncture the stopper with an injection needle to withdraw the liquid. The rubber stopper 
is secured to the vial with an aluminum crimped seal.  
13.2.4 Stability and Storage 
Individual vials (in the desired number) of ETBX-011 will be packaged in a cardboard box 
and will be shipped over dry ice (<-80 °C) by overnight courier with a temperature monitoring 
device included. Upon receipt, one will inspect contents of package for any noticeable damages 
or defects. Unpack the shipment contents and place the cardboard box containing ETBX-011 
vials into a freezer with a temperature control of ≤-20 °C. Receiver must stop the temperature 
monitoring device by turning off the power switch (instructions for handling and operation of 
temperature monitoring device will be provided with the package). 
13.2.5 Administration Procedures 
Please see section 3.4.2.2 
13.2.6 Incompatibilities 
ETBX-011 is administered as a separate subcutaneous injection, with no known 
incompatibilities. 
13.3 BEVACIZUMAB (AVASTIN) 
(Please see package insert for complete information) 
13.3.1 Source 
Bevacizumab will be supplied by the local pharmacy using supply purchased from commercial 
sources. 
13.3.2 Toxicity 
The most common adverse reactions observed in bevacizumab patients at a rate > 10% and at 
least twice the control arm rate, are epistaxis, headache, hypertension, rhinitis, proteinuria, taste 
alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain and exfoliative dermatitis 
Some of the adverse reactions are commonly seen with chemotherapy; however, bevacizumab 
may exacerbate these reactions when combined with chemotherapeutic agents. Examples include 
palmar-plantar erythrodysaesthesia syndrome with pegylated liposomal doxorubicin or 
capecitabine peripheral sensory neuropathy with paclitaxel or oxaliplatin, and nail disorders or 
alopecia with paclitaxel. 
13.3.2.1 Gastrointestinal Perforations and Fistulae  
Serious and sometimes fatal gastrointestinal perforation occurs at a higher incidence in 
bevacizumab treated patients compared to controls. The incidence of gastrointestinal perforation 
ranged from 0.3 to 3.2% across clinical studies. From a clinical trial in patients with persistent, 
recurrent, or metastatic cervical cancer (Study 9), gastrointestinal perforations were reported in 
3.2% of bevacizumab treated patients, all of whom had a history of prior pelvic radiation. Fatal 
outcome was reported in <1% of bevacizumab-treated patients. In a platinum-resistant ovarian 
cancer trial (Study 10), the incidence of GI perforation was 1.7% (3/179). In this trial, patients 
with evidence of recto-sigmoid involvement by pelvic examination or bowel involvement on CT 
scan or clinical symptoms of bowel obstruction were excluded.  


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13.3.2.2 Non-Gastrointestinal Fistulae 
Serious and sometimes fatal fistula formation involving tracheo-esophageal, bronchopleural, 
biliary, vaginal, renal and bladder sites occurs at a higher incidence in bevacizumab -treated 
patients compared to controls. Uncommon (<1%) reports of fistulae that involve areas of the 
body other than the gastrointestinal tract were observed in clinical trials across various 
indications and have also been reported in post-marketing experience. Most events occurred 
within the first 6 months of bevacizumab therapy. 
13.3.2.3 Surgery and Wound Healing Complications 
Bevacizumab impairs wound healing in animal models. In clinical trials, administration of 
bevacizumab was not allowed until at least 28 days after surgery. In a controlled clinical trial, the 
incidence of wound healing complications, including serious and fatal complications, in patients 
with mCRC who underwent surgery during the course of bevacizumab treatment was 15% and in 
patients who did not receive bevacizumab, was 4%. 
13.3.2.4 Hemorrhage 
Bevacizumab can result in two distinct patterns of bleeding: minor hemorrhage, most commonly 
Grade 1 epistaxis; and serious, and in some cases fatal, hemorrhagic events. Severe or fatal 
hemorrhage, including hemoptysis, gastrointestinal bleeding, hematemesis, CNS hemorrhage, 
epistaxis, and vaginal bleeding occurred up to five-fold more frequently in patients receiving 
bevacizumab compared to patients receiving only chemotherapy. Across indications, the incidence of 
Grade ≥ 3 hemorrhagic events among patients receiving bevacizumab ranged from 0.4 to 6.9 %. 
13.3.2.5 Arterial Thromboembolic Events  
Serious, sometimes fatal, arterial thromboembolic events (ATE) including cerebral infarction, 
transient ischemic attacks, myocardial infarction, angina, and a variety of other ATE occurred at 
a higher incidence in patients receiving bevacizumab compared to those in the control arm. 
Across indications, the incidence of Grade ≥ 3 ATE in the bevacizumab containing arms was 
2.6% compared to 0.8% in the control arms. Among patients receiving bevacizumab in 
combination with chemotherapy, the risk of developing ATE during therapy was increased in 
patients with a history of arterial thromboembolism, diabetes, or age greater than 65 years. 
13.3.2.6 Hypertension 
The incidence of severe hypertension is increased in patients receiving bevacizumab as 
compared to controls. Across clinical studies the incidence of Grade 3 or 4 hypertension ranged 
from 5-18%. 
13.3.2.7 Posterior Reversible Encephalopathy Syndrome (PRES) 
PRES has been reported with an incidence of < 0.5% in clinical studies. The onset of symptoms 
occurred from 16 hours to 1 year after initiation of bevacizumab. PRES is a neurological disorder 
which can present with headache, seizure, lethargy, confusion, blindness and other visual and 
neurologic disturbances. Mild to severe hypertension may be present. Magnetic resonance 
imaging (MRI) is necessary to confirm the diagnosis of PRES. 
13.3.2.8 Proteinuria 
The incidence and severity of proteinuria is increased in patients receiving bevacizumab as 
compared to controls. Nephrotic syndrome occurred in < 1% of patients receiving bevacizumab 


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in clinical trials, in some instances with fatal outcome. In a published case series, kidney biopsy 
of six patients with proteinuria showed findings consistent with thrombotic microangiopathy. 
13.3.2.9 Infusion Reactions 
Infusion reactions reported in the clinical trials and post-marketing experience include 
hypertension, hypertensive crises associated with neurologic signs and symptoms, wheezing, 
oxygen desaturation, Grade 3 hypersensitivity, chest pain, headaches, rigors, and diaphoresis. In 
clinical studies, infusion reactions with the first dose of bevacizumab were uncommon (< 3%) 
and severe reactions occurred in 0.2% of patients.  
13.3.2.10 
Ovarian Failure  
The incidence of ovarian failure was higher (34% vs. 2%) in premenopausal women receiving 
bevacizumab in combination with mFOLFOX chemotherapy as compared to those receiving 
mFOLFOX chemotherapy alone for adjuvant treatment for colorectal cancer, a use for which 
bevacizumab is not approved. Inform females of reproductive potential of the risk of ovarian 
failure prior to starting treatment with bevacizumab 
13.3.3 Formulation and Preparation 
Bevacizumab is supplied as a clear to slightly opalescent, sterile liquid ready for parenteral 
administration in vials of two sizes: 
• 100 mg/4 mL, single use vial  
• 400 mg/16 mL, single use vial  
Use appropriate aseptic technique. Parenteral drug products should be inspected visually for 
particulate matter and discoloration prior to administration, whenever solution and container 
permit. Withdraw necessary amount of bevacizumab and dilute in a total volume of 100 mL of 
0.9% Sodium Chloride Injection, USP. Discard any unused portion left in a vial, as the product 
contains no preservatives. 
Do not administer or mix with dextrose solution.  
13.3.4 Stability and Storage 
Bevacizumab vials should be stored according to FDA-approved labeling. Do not freeze or 
shake. 
Diluted bevacizumab solutions may be stored at 2−8°C (36−46°F) for up to 24 hours, per site 
pharmacy guidelines. Store in the original carton until time of use. No incompatibilities between 
bevacizumab and polyvinylchloride or polyolefin bags have been observed.  
13.3.5 Administration Procedures 
Please see section 3.4.1. 
13.3.6 Incompatibilities 
A drug interaction study was performed in which irinotecan was administered as part of the 
FOLFIRI regimen with or without bevacizumab. The results demonstrated no significant effect 
of bevacizumab on the pharmacokinetics of irinotecan or its active metabolite SN38.  


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In a study assessing the safety and efficacy of bevacizumab as first line therapy in non-small cell 
lung cancer, based on limited data, there did not appear to be a difference in the mean exposure 
of either carboplatin or paclitaxel when each was administered alone or in combination with 
bevacizumab. However, 3 of the 8 patients receiving bevacizumab plus paclitaxel/carboplatin 
had substantially lower paclitaxel exposure after four cycles of treatment (at Day 63) than those 
at Day 0, while patients receiving paclitaxel/carboplatin without bevacizumab had a greater 
paclitaxel exposure at Day 63 than at Day 0. 
13.4 CAPECITABINE 
(Please see package insert for complete information) 
13.4.1 Source  
Capecitabine will be supplied by the local pharmacy using supply purchased from commercial 
sources. 
13.4.2 Toxicity  
Most common adverse reactions (≥30%) were diarrhea, hand-and-foot syndrome, nausea, 
vomiting, abdominal pain, fatigue/weakness, and hyperbilirubinemia. Other adverse reactions, 
including serious adverse reactions, have been reported. 
Pooled Phase 3 Colorectal Trials: Percent Incidence of Adverse Reactions in ≥5% of 
Patients 
Adverse Event 
Capecitabine (n=596) 
Total 
% 
Grade 3 
% 
Grade 4 
% 
Number of Patients With > One Adverse Event 
96 
52 
9 
Body System/Adverse Event 
GI 
55 
13 
2 
Diarrhea 
Nausea 
43 
4 
– 
Vomiting 
27 
4 
<1 
Stomatitis 
25 
2 
<1 
Abdominal Pain 
35 
9 
<1 
Gastrointestinal Motility Disorder 
10 
<1 
– 
Constipation 
14 
1 
<1 
Oral Discomfort 
10 
– 
– 
Upper GI Inflammatory Disorders 
8 
<1 
– 
Gastrointestinal Hemorrhage 
6 
1 
<1 
Ileus 
6 
4 
1 
Skin and Subcutaneous 
54 
17 
NA 
Hand-and-Foot Syndrome 
Dermatitis 
27 
1 
– 


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Adverse Event 
Capecitabine (n=596) 
Total 
% 
Grade 3 
% 
Grade 4 
% 
Number of Patients With > One Adverse Event 
96 
52 
9 
Body System/Adverse Event 
Skin Discoloration 
7 
<1 
– 
Alopecia 
6 
– 
– 
General 
42 
4 
– 
Fatigue/Weakness 
Pyrexia 
18 
1 
– 
Edema 
15 
1 
– 
Pain 
12 
1 
– 
Chest Pain 
6 
1 
– 
Neurological 
10 
– 
– 
Peripheral Sensory Neuropathy 
Headache 
10 
1 
– 
Dizziness* 
8 
<1 
– 
Insomnia 
7 
– 
– 
Taste Disturbance 
6 
1 
– 
Metabolism 
26 
3 
<1 
Appetite Decreased 
Dehydration 
7 
2 
<1 
Eye 
13 
– 
– 
Eye Irritation 
Vision Abnormal 
5 
– 
– 
Respiratory 
14 
1 
– 
Dyspnea 
Cough 
7 
<1 
1 
Pharyngeal Disorder 
5 
– 
– 
Epistaxis 
3 
<1 
– 
Sore Throat 
2 
– 
– 
Musculoskeletal 
10 
2 
– 
Back Pain 
Arthralgia 
8 
1 
– 


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Adverse Event 
Capecitabine (n=596) 
Total 
% 
Grade 3 
% 
Grade 4 
% 
Number of Patients With > One Adverse Event 
96 
52 
9 
Body System/Adverse Event 
Vascular 
Venous Thrombosis 
 
8 
 
3 
 
<1 
Psychiatric 
 
5 
 
– 
 
– 
Mood Alteration 
Depression 
5 
– 
– 
Infections 
Viral 
 
5 
 
<1 
 
– 
Blood and Lymphatic 
80 
2 
<1 
Anemia 
Neutropenia 
13 
1 
2 
Hepatobiliary 
Hyperbilirubinemia 
48 
18 
5 
– Not observed 
* Excluding vertigo 
NA = Not Applicable 
 
13.4.3 Formulation and preparation  
Tablets: 150 mg and 500 mg 
Capecitabine is supplied as biconvex, oblong film-coated tablets for oral administration. Each 
light peach-colored tablet contains 150 mg capecitabine and each peach-colored tablet contains 
500 mg capecitabine. The inactive ingredients in capecitabine include: anhydrous lactose, 
croscarmellose sodium, hydroxypropyl methylcellulose, microcrystalline cellulose, magnesium 
stearate and purified water. The peach or light peach film coating contains hydroxypropyl 
methylcellulose, talc, titanium dioxide, and synthetic yellow and red iron oxides. 
13.4.4 Stability and Storage  
Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F). KEEP TIGHTLY 
CLOSED. 
Care should be exercised in the handling of capecitabine. Capecitabine tablets should not be cut 
or crushed. Procedures for the proper handling and disposal of anticancer drugs should be 
considered. Any unused product should be disposed of in accordance with local requirements, or 
drug take back programs. Several guidelines on the subject have been published. 
13.4.5 Administration procedures 
Please see section 3.4.1.2 


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13.4.6 Incompatibilities  
• Anticoagulants: Monitor anticoagulant response (INR or prothrombin time) frequently in 
order to adjust the anticoagulant dose as needed. 
• Phenytoin: Monitor phenytoin levels in patients taking capecitabine concomitantly with 
phenytoin. The phenytoin dose may need to be reduced. 
• Leucovorin: The concentration of 5-fluorouracil is increased and its toxicity may be 
enhanced by leucovorin.  
• CYP2C9 substrates: Care should be exercised when capecitabine is coadministered with 
CYP2C9 substrates.  
• Food reduced both the rate and extent of absorption of capecitabine.  
13.5 5-FLUOROURACIL (5-FU) 
(Please see package insert for complete information) 
13.5.1 Source  
5-FU will be supplied by the local pharmacy using supply purchased from commercial sources. 
13.5.2 Toxicity  
5-FU should be used with extreme caution in poor risk patients with a history of high-dose pelvic 
irradiation or previous use of alkylating agents, those who have a widespread involvement of 
bone marrow by metastatic tumors or those with impaired hepatic or renal function. 
Rarely, unexpected, severe toxicity (e.g., stomatitis, diarrhea, neutropenia and neurotoxicity) 
associated with 5-fluorouracil has been attributed to deficiency of dipyrimidine dehydrogenase 
activity. A few patients have been rechallenged with 5-fluorouracil and despite 5-fluorouracil 
dose lowering, toxicity recurred and progressed with worse morbidity. Absence of this catabolic 
enzyme appears to result in prolonged clearance of 5-fluorouracil. 
The administration of 5-fluorouracil has been associated with the occurrence of palmar-plantar 
erythrodysesthesia syndrome, also known as hand-foot syndrome. Interruption of therapy is 
followed by gradual resolution over 5 to 7 days. Although pyridoxine has been reported to 
ameliorate the palmar-plantar erythrodysesthesia syndrome, its safety and effectiveness has not 
been established. 
Stomatitis and esophagopharyngitis (which may lead to sloughing and ulceration), diarrhea, 
anorexia, nausea and emesis are commonly seen during therapy. 
Leukopenia usually follows every course of adequate therapy with fluorouracil. The lowest white 
blood cell counts are commonly observed between the 9th and 14th days after the first course of 
treatment, although uncommonly the maximal depression may be delayed for as long as 20 days. 
By the 30th day the count has usually returned to the normal range. 
Alopecia and dermatitis may be seen in a substantial number of cases. The dermatitis most often 
seen is a pruritic maculopapular rash usually appearing on the extremities and less frequently on 
the trunk. It is generally reversible and usually responsive to symptomatic treatment. 
Other adverse reactions are: 


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• Hematologic: pancytopenia, thrombocytopenia, agranulocytosis, anemia.  
• Cardiovascular: myocardial ischemia, angina.  
• Gastrointestinal: gastrointestinal ulceration and bleeding.  
• Allergic Reactions: anaphylaxis and generalized allergic reactions.  
• Neurologic: acute cerebellar syndrome (which may persist following discontinuance of 
treatment), nystagmus, headache.  
• Dermatologic: dry skin; fissuring; photosensitivity, as manifested by erythema or 
increased pigmentation of the skin; vein pigmentation; palmar-planter erythrodysesthesia 
syndrome, as manifested by tingling of the hands and feet followed by pain, erythema 
and swelling.  
• Ophthalmic: lacrimal duct stenosis, visual changes, lacrimation, photophobia.  
• Psychiatric: disorientation, confusion, euphoria.  
• Miscellaneous: thrombophlebitis, epistaxis, nail changes (including loss of nails) 
13.5.3 Formulation and preparation  
13.5.3.1 Formulation 
Fluorouracil injection, USP an antineoplastic antimetabolite, is a sterile, nonpyrogenic injectable 
solution for intravenous administration. Each 10 mL contains 500 mg fluorouracil; pH is 
adjusted to approximately 9.2 with sodium hydroxide. 
For intravenous use. Fluorouracil injection, USP is available at a concentration of 50mg/mL.  
The 50 mL and 100 mL pharmacy bulk packages are packaged 5 vials per shelf pack. 
13.5.3.2 Preparation 
No dilution is required. 
13.5.4 Stability and Storage  
Store at room temperature 15° to 30°C (59° to 86°F). Protect from light. Retain in carton until 
time of use. 
13.5.5 Administration procedures 
Please see section 3.4.1.1. 
13.5.6 Incompatibilities 
Leucovorin calcium may enhance the toxicity of fluorouracil. 
13.6 LEUCOVORIN 
(Please see package insert for complete information) 
13.6.1 Source  
Leucovorin will be supplied by the local pharmacy using supply purchased from commercial 
sources. In the event of a leucovorin drug shortage, levoleucovorin may be substituted using 
equivalent doses at the investigator’s discretion and administered according to FDA-approved 
labeling. 


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13.6.2 Toxicity  
Allergic sensitization, including anaphylactoid reactions and urticaria, has been reported 
following the administration of both oral and parenteral leucovorin. No other adverse reactions 
have been attributed to the use of leucovorin per se. 
Table 1 below summarizes significant adverse events occurring in 316 patients treated with the 
leucovorin/5-fluorouracil combinations compared against 70 patients treated with 5-fl uorouracil 
alone for advanced colorectal carcinoma. These data are taken from the Mayo/NCCTG large 
multicenter prospective trial evaluating the efficacy and safety of the combination regimen. 
 
Table 1 : Percentage of Patients Treated with Leucovorin/Fluorouracil for Advanced Colorectal Carcinoma 
Reporting Adverse Experiences or Hospitalized for Toxicity 
Toxicity 
(High LV) /5-FU  
(N=155) 
(Low LV) /5-FU  
(N=161) 
5-FU Alone 
(N=70) 
Any (%) 
Grade 3+ 
(%) 
Any (%) 
Grade 3+ 
(%)  
Any (%) 
Grade 3+ 
(%) 
Leukopenia 
69 
14 
83 
23 
93 
48 
Thrombocytopenia 
8 
2 
8 
1 
18 
3 
Infection 
8 
1 
3 
1 
7 
2 
Nausea 
74 
10 
80 
9 
60 
6 
Vomiting 
46 
8 
44 
9 
40 
7 
Diarrhea 
66 
18 
67 
14 
43 
11 
Stomatitis 
75 
27 
84 
29 
59 
16 
Constipation 
3 
0 
4 
0 
1 
- 
Lethargy/Malaise/Fatigue 
13 
3 
12 
2 
6 
3 
Alopecia 
42 
5 
43 
6 
37 
7 
Dermatitis 
21 
2 
25 
1 
13 
- 
Anorexia 
14 
1 
22 
4 
14 
- 
Hospitalization for 
Toxicity 
5% 
15% 
7% 


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Toxicity 
(High LV) /5-FU  
(N=155) 
(Low LV) /5-FU  
(N=161) 
5-FU Alone 
(N=70) 
Any (%) 
Grade 3+ 
(%) 
Any (%) 
Grade 3+ 
(%)  
Any (%) 
Grade 3+ 
(%) 
High LV = Leucovorin 200 mg/m2, Low LV = Leucovorin 20 mg/m2 
Any = percentage of patients reporting toxicity of any severity 
Grade 3+ = percentage of patients reporting toxicity of Grade 3 or higher 
13.6.3 Formulation and preparation  
13.6.3.1 Formulation 
Leucovorin Calcium Injection USP is a sterile, preservative-free solution indicated for 
intramuscular (IM) or intravenous (IV) administration in a 50 mL single-dose vial. Each mL 
contains leucovorin calcium equivalent to 10 mg Leucovorin, USP; 8 mg sodium chloride; 
sodium hydroxide and/or hydrochloric acid for pH adjustment pH 7.8 (6.5 to 8.5). 
There is 0.004 mEq of calcium per mg of leucovorin. Solution contains no bacteriostat or 
antimicrobial agents. 
Leucovorin Calcium for Injection is a sterile product indicated for intramuscular (IM) or 
intravenous (IV) administration and is supplied in 50 mg, 100 mg, 200 mg, and 350 mg vials. 
Each 50 mg vial of Leucovorin Calcium for Injection, when reconstituted with 5 mL of sterile 
diluent, contains leucovorin (as the calcium salt) 10 mg/mL. 
Each 100 mg vial of Leucovorin Calcium for Injection, when reconstituted with 10 mL of sterile 
diluent, contains leucovorin (as the calcium salt) 10 mg/mL. 
Each 200 mg vial of Leucovorin Calcium for Injection, when reconstituted with 20 mL of sterile 
diluent, contains leucovorin (as the calcium salt) 10 mg/mL. 
Each 350 mg vial of Leucovorin Calcium for Injection, when reconstituted with 17.5 mL of 
sterile diluent, contains leucovorin (as the calcium salt) 20 mg/mL. 
In each dosage form, one milligram of leucovorin calcium contains 0.002 mmol of leucovorin 
and 0.002 mmol of calcium. 
 
13.6.3.2 Preparation 
These lyophilized products contain no preservative. The inactive ingredient is Sodium Chloride, 
USP, added to adjust tonicity.  
Because of the benzyl alcohol contained in certain diluents used for reconstituting Leucovorin 
Calcium for Injection, when doses greater than 10 mg/m2 (as in this study) are administered, 
Leucovorin Calcium for Injection should be reconstituted with Sterile Water for Injection, USP, 
and used immediately. 


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13.6.4 Stability and Storage  
Store at 20°C to 25°C (68° to 77° F). [See USP Controlled Room Temperature.] Protect from 
light. Retain in carton until time of use. 
Reconstituted form should be used immediately. 
13.6.5 Administration procedures 
Please see section 3.4.1.1. 
13.6.6 Incompatibilities  
Folic acid in large amounts may counteract the antiepileptic effect of phenobarbital, phenytoin 
and primidone, and increase the frequency of seizures in susceptible pediatric patients. 
Preliminary animal and human studies have shown that small quantities of systemically 
administered leucovorin enter the CSF primarily as 5-methyltetrahydrofolate and, in humans, 
remain 1 to 3 orders of magnitude lower than the usual methotrexate concentrations following 
intrathecal administration. However, high doses of leucovorin may reduce the efficacy of 
intrathecally administered methotrexate. 
Leucovorin may enhance the toxicity of 5-fluorouracil 
13.7 OXALIPLATIN 
(Please see package insert for complete information) 
13.7.1 Source  
Oxaliplatin will be supplied by the local pharmacy using supply purchased from commercial 
sources. 
13.7.2 Toxicity  
The most common side effects of oxaliplatin include:  
• neutropenia, anemia, thrombocytopenia, hypertension, diarrhea, nausea, vomiting, 
constipation, oral mucositis, abdominal pain, anorexia, fatigue, injection site reactions, 
alopecia and dehydration 
Potentially serious toxicities include: 
• Grade 3/4 hypersensitivity, including anaphylactic/anaphylactoid reactions, to 
oxaliplatin has been observed in 2-3% of colon cancer patients. These reactions are 
usually managed with standard epinephrine, corticosteroid, antihistamine therapy, and 
require discontinuation of therapy or desensitization protocol for continuation of therapy. 
• Peripheral sensory neuropathy (acute ≤ 14 days and persistent > 14 days) was reported 
in adjuvant patients treated with ELOXATIN as part of FOLFOX with a frequency of 
92% (all grades) and 13% (grade 3). At the 28-day follow-up after the last treatment 
cycle, 60% of all patients had any grade (Grade 1=40%, Grade 2=16%, Grade 3=5%) 
peripheral sensory neuropathy decreasing to 39% at 6 months follow-up (Grade 1=31%, 
Grade 2=7%, Grade 3=1%) and 21% at 18 months of follow-up (Grade 1=17%, Grade 
2=3%, Grade 3=1%). 


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Overall, neuropathy was reported in patients previously untreated for advanced colorectal 
cancer in 82% (all grades) and 19% (grade 3/4), and in the previously treated patients in 
74% (all grades) and 7% (grade 3/4) events. Information regarding reversibility of 
neuropathy was not available from the trial for patients who had not been previously 
treated for colorectal cancer. 
• Reversible Posterior Leukoencephalopathy Syndrome (RPLS, also known as PRES, 
Posterior Reversible Encephalopathy Syndrome) has been observed in clinical trials (< 
0.1%) and postmarketing experience. Signs and symptoms of RPLS could be headache, 
altered mental functioning, seizures, abnormal vision from blurriness to blindness, 
associated or not with hypertension. Diagnosis of RPLS is based upon confirmation by 
brain imaging. 
• Pulmonary Toxicity. oxaliplatin has been associated with pulmonary fibrosis (<1% of 
study patients), which may be fatal. The combined incidence of cough and dyspnea was 
7.4% (any grade) and < 1% (grade 3) with no grade 4 events in the oxaliplatin plus 
infusional 5-fluorouracil/leucovorin arm compared to 4.5% (any grade) and no grade 3 
and 0.1% grade 4 events in the infusional 5- fluorouracil/leucovorin alone arm in 
adjuvant colon cancer patients. In this study, one patient died from eosinophilic 
pneumonia in the oxaliplatin combination arm. The combined incidence of cough, 
dyspnea and hypoxia was 43% (any grade) and 7% (grade 3 and 4) in the oxaliplatin plus 
5-fluorouracil/leucovorin arm compared to 32% (any grade) and 5% (grade 3 and 4) in 
the irinotecan plus 5-fluorouracil/leucovorin arm of unknown duration for patients with 
previously untreated colorectal cancer. In case of unexplained respiratory symptoms such 
as non-productive cough, dyspnea, crackles, or radiological pulmonary infiltrates, 
ELOXATIN should be discontinued until further pulmonary investigation excludes 
interstitial lung disease or pulmonary fibrosis. 
• Hepatotoxicity as evidenced in the adjuvant study, by increase in transaminases (57% vs. 
34%) and alkaline phosphatase (42% vs. 20%) was observed more commonly in the 
oxaliplatin combination arm than in the control arm. The incidence of increased bilirubin 
was similar on both arms. Changes noted on liver biopsies include: peliosis, nodular 
regenerative hyperplasia or sinusoidal alterations, perisinusoidal fibrosis, and veno-
occlusive lesions. Hepatic vascular disorders should be considered, and if appropriate, 
should be investigated in case of abnormal liver function test results or portal 
hypertension, which cannot be explained by liver metastases 
13.7.3 Formulation and preparation 
13.7.3.1 Formulation 
13.7.3.1.1 Powder 
Oxaliplatin is supplied in single-use vials containing 50 mg or 100 mg of oxaliplatin as a sterile, 
preservative-free lyophilized powder for reconstitution. Lactose monohydrate is also present as 
an inactive ingredient. 
13.7.3.1.2 Solution 


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Oxaliplatin is supplied in single-use vials containing 50 mg, 100 mg or 200 mg of oxaliplatin as 
a sterile, preservative-free, aqueous solution at a concentration of 5 mg/ml. Water for Injection, 
USP is present as an inactive ingredient. 
13.7.3.2 Preparation 
13.7.3.2.1 Powder 
Reconstitution or final dilution must never be performed with a sodium chloride solution or other 
chloride containing solutions. 
The lyophilized powder is reconstituted by adding 10 mL (for the 50 mg vial) or 20 mL (for the 
100 mg vial) of Water for Injection, USP or 5% Dextrose Injection, USP. Do not administer the 
reconstituted solution without further dilution. The reconstituted solution must be further diluted 
in an infusion solution of 250-500 mL of 5% Dextrose Injection, USP. 
After reconstitution in the original vial, the solution may be stored up to 24 hours under 
refrigeration [2-8°C (36-46°F)]. After final dilution with 250-500 mL of 5% Dextrose Injection, 
USP, the shelf life is 6 hours at room temperature [20-25°C (68-77°F)] or up to 24 hours under 
refrigeration [2-8°C (36-46°F)]. 
Oxaliplatin is not light sensitive. 
13.7.3.2.2 Solution 
Do not freeze and protect from light the concentrated solution. 
A final dilution must never be performed with a sodium chloride solution or other chloride 
containing solutions. 
The solution must be further diluted in an infusion solution of 250-500 mL of 5% Dextrose 
Injection, USP. 
After dilution with 250-500 mL of 5% Dextrose Injection, USP, the shelf life is 6 hours at room 
temperature [20-25°C (68-77°F)] or up to 24 hours under refrigeration [2-8°C (36-46°F)]. 
After final dilution, protection from light is not required. 
Oxaliplatin is incompatible in solution with alkaline medications or media (such as basic 
solutions of 5-fluorouracil) and must not be mixed with these or administered simultaneously 
through the same infusion line. The infusion line should be flushed with 5% Dextrose Injection, 
USP prior to administration of any concomitant medication. 
13.7.3.2.3 General 
Parenteral drug products should be inspected visually for particulate matter and discoloration 
prior to administration and discarded if present. 
Needles or intravenous administration sets containing aluminum parts that may come in contact 
with oxaliplatin should not be used for the preparation or mixing of the drug. Aluminum has 
been reported to cause degradation of platinum compounds. 


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13.7.4 Stability and Storage  
13.7.4.1 Powder for solution for infusion: 
Store under normal lighting conditions at 25°C (77°F); excursions permitted to 15-30°C (59-
86°F). 
13.7.4.2 Concentrate for solution for infusion: 
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F). Do not freeze and protect from 
light (keep in original outer carton). 
13.7.5 Administration procedures 
Please see section 3.4.1.1. 
13.7.6 Incompatibilities  
No specific cytochrome P-450-based drug interaction studies have been conducted. No 
pharmacokinetic interaction between 85 mg/m2 oxaliplatin and 5-fluorouracil/leucovorin has 
been observed in patients treated every 2 weeks. Increases of 5-fluorouracil plasma 
concentrations by approximately 20% have been observed with doses of 130 mg/m2 oxaliplatin 
dosed every 3 weeks. Because platinum-containing species are eliminated primarily through the 
kidney, clearance of these products may be decreased by co-administration of potentially 
nephrotoxic compounds; although, this has not been specifically studied. 


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49. 
Seymour MT, Thompson LC, Wasan HS, et al. Chemotherapy options in elderly and frail 
patients with metastatic colorectal cancer (MRC FOCUS2): an open-label, randomised factorial 
trial. Lancet 2011;377:1749-59. 
50. 
Amatori F, Di Paolo A, Del Tacca M, et al. Thymidylate synthase, dihydropyrimidine 
dehydrogenase and thymidine phosphorylase expression in colorectal cancer and normal mucosa 
in patients. Pharmacogenetics and genomics 2006;16:809-16. 
51. 
Le DT, Uram JN, Wang H, et al. PD-1 Blockade in Tumors with Mismatch-Repair 
Deficiency. The New England journal of medicine 2015;372:2509-20. 
52. 
Diaz LA, Jr., Le DT. PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. The 
New England journal of medicine 2015;373:1979. 
53. 
Segal NH, Parsons DW, Peggs KS, et al. Epitope landscape in breast and colorectal 
cancer. Cancer research 2008;68:889-92. 
54. 
Zitvogel L, Apetoh L, Ghiringhelli F, Andre F, Tesniere A, Kroemer G. The anticancer 
immune response: indispensable for therapeutic success? The Journal of clinical investigation 
2008;118:1991-2001. 
55. 
Apetoh L, Ghiringhelli F, Tesniere A, et al. Toll-like receptor 4-dependent contribution 
of the immune system to anticancer chemotherapy and radiotherapy. Nature medicine 
2007;13:1050-9. 
56. 
Hannani D, Sistigu A, Kepp O, Galluzzi L, Kroemer G, Zitvogel L. Prerequisites for the 
antitumor vaccine-like effect of chemotherapy and radiotherapy. Cancer journal 2011;17:351-8. 
57. 
Ma Y, Conforti R, Aymeric L, et al. How to improve the immunogenicity of 
chemotherapy and radiotherapy. Cancer metastasis reviews 2011;30:71-82. 
58. 
Zitvogel L, Kepp O, Kroemer G. Decoding cell death signals in inflammation and 
immunity. Cell 2010;140:798-804. 


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59. 
Hodge JW, Kwilas A, Ardiani A, Gameiro SR. Attacking malignant cells that survive 
therapy: Exploiting immunogenic modulation. Oncoimmunology 2013;2:e26937. 
60. 
Fu T, Shen Y, Fujimoto S. Tumor-specific CD4(+) suppressor T-cell clone capable of 
inhibiting rejection of syngeneic sarcoma in A/J mice. International journal of cancer Journal 
international du cancer 2000;87:680-7. 
61. 
Piccirillo CA, Shevach EM. Cutting edge: control of CD8+ T cell activation by 
CD4+CD25+ immunoregulatory cells. Journal of immunology 2001;167:1137-40. 
62. 
Ghiringhelli F, Larmonier N, Schmitt E, et al. CD4+CD25+ regulatory T cells suppress 
tumor immunity but are sensitive to cyclophosphamide which allows immunotherapy of 
established tumors to be curative. European journal of immunology 2004;34:336-44. 
63. 
Woo EY, Yeh H, Chu CS, et al. Cutting edge: Regulatory T cells from lung cancer 
patients directly inhibit autologous T cell proliferation. Journal of immunology 2002;168:4272-6. 
64. 
Teicher BA. Transforming growth factor-beta and the immune response to malignant 
disease. Clinical cancer research : an official journal of the American Association for Cancer 
Research 2007;13:6247-51. 
65. 
Muller AJ, Prendergast GC. Indoleamine 2,3-dioxygenase in immune suppression and 
cancer. Current cancer drug targets 2007;7:31-40. 
66. 
Hodi FS, O'Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients 
with metastatic melanoma. The New England journal of medicine 2010;363:711-23. 
67. 
Huang Y, Goel S, Duda DG, Fukumura D, Jain RK. Vascular normalization as an 
emerging strategy to enhance cancer immunotherapy. Cancer research 2013;73:2943-8. 
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Liu C, Peng W, Xu C, et al. BRAF inhibition increases tumor infiltration by T cells and 
enhances the antitumor activity of adoptive immunotherapy in mice. Clinical cancer research : an 
official journal of the American Association for Cancer Research 2013;19:393-403. 
69. 
Alfaro C, Suarez N, Gonzalez A, et al. Influence of bevacizumab, sunitinib and sorafenib 
as single agents or in combination on the inhibitory effects of VEGF on human dendritic cell 
differentiation from monocytes. British journal of cancer 2009;100:1111-9. 
70. 
Zeh HJ, 3rd, Perry-Lalley D, Dudley ME, Rosenberg SA, Yang JC. High avidity CTLs 
for two self-antigens demonstrate superior in vitro and in vivo antitumor efficacy. Journal of 
immunology 1999;162:989-94. 
71. 
Heery CR, Jochems C, O'Sullivan Coyne GH, et al. Impact of standard chemotherapy on 
peripheral blood immune cell subsets in metastatic colorectal cancer. Journal of clinical 
oncology : official journal of the American Society of Clinical Oncology 2015;33:(suppl 3; abstr 
597). 
72. 
Hingorani SR, Harris WP, Beck JT, et al. Phase Ib Study of PEGylated Recombinant 
Human Hyaluronidase and Gemcitabine in Patients with Advanced Pancreatic Cancer. Clin 
Cancer Res 2016;22:2848-54. 
73. 
Vedat Bayoglu I, Yildiz I, Varol U, et al. Comparison of first-line bevacizumab in 
combination with mFOLFOX6 or XELOX in metastatic colorectal cancer. J BUON 
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Howard SC, Jones DP, Pui CH. The tumor lysis syndrome. The New England journal of 
medicine 2011;364:1844-54. 
75. 
Guinney J, Dienstmann R, Wang X, et al. The consensus molecular subtypes of 
colorectal cancer. Nature medicine 2015;21:1350-6. 
76. 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228-47. 
77. 
Scher HI, Halabi S, Tannock I, et al. Design and end points of clinical trials for patients 
with progressive prostate cancer and castrate levels of testosterone: recommendations of the 
Prostate Cancer Clinical Trials Working Group. J Clin Oncol 2008;26:1148-59. 
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Rustin GJ, Quinn M, Thigpen T, et al. Re: New guidelines to evaluate the response to 
treatment in solid tumors (ovarian cancer). J Natl Cancer Inst 2004;96:487-8. 
79. 
Bubley GJ, Carducci M, Dahut W, et al. Eligibility and response guidelines for phase II 
clinical trials in androgen-independent prostate cancer: recommendations from the Prostate-
Specific Antigen Working Group. J Clin Oncol 1999;17:3461-7. 
80. 
Vergote I, Rustin GJ, Eisenhauer EA, et al. Re: new guidelines to evaluate the response 
to treatment in solid tumors [ovarian cancer]. Gynecologic Cancer Intergroup. J Natl Cancer Inst 
2000;92:1534-5. 
 


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Version Date:10.30.2019 
15 APPENDICES 
15.1 APPENDIX A: PRECLINICAL MODEL EVALUATION OF THE COMBINATION OF FOLFOX 
WITH ANTI-PD-L1 
 


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Version Date:10.30.2019 
15.2 APPENDIX B-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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Version Date:10.30.2019 
15.3 APPENDIX C: CCR PROBLEM REPORT FORM 
CCR REPORTABLE EVENT FORM (REF) 
NCI Protocol #: Click or tap here to enter text. 
 
Protocol Title: Click or tap here to enter text. 
Report version: (select one) 
☐ 
Initial Report  
☐ 
Follow-up  
Site Principal Investigator:  Click or tap here to enter text. 
  
Date site PI was notified of the 
problem: Click or tap to enter a date.    
Date of problem:  
Click or tap to enter a date. 
If delay in reporting to the coordinating center, please explain: 
Click or tap here to enter text. 
Location of problem: (e.g.,  patient’s home, doctor’s office ) 
Click or tap here to enter text. 
 
Description of Subject 
Does this problem apply to a subject? 
☐ yes 
☐ not applicable (more than one subject is involved) 
 
If yes, enter details below: 
Subject ID: Click or tap here to enter text.  (do not use medical record number) 
Sex:  ☐Male  ☐ Female 
 
Age: Click or tap here to enter text.  


124 
Abbreviated Title: Chemo+antiPDL1+ vaccine in CRC 
Version Date:10.30.2019 
Diagnosis: Click or tap here to enter text. 
 
Name the problem: (select all that apply)   
☐ Specimen collection issue   
☐ Informed consent issue   
☐ Ineligible for enrollment   
☐ Breach of PII  
☐ Other, briefly state the nature of the problem: Click or tap here to enter text. 
 
Detailed Description of the problem: (Include any relevant treatment, outcomes or pertinent 
history): Click or tap here to enter text. 
 
What are you reporting? 
☐ 
unanticipated problem 
☐ 
death 
☐ 
non-compliance (other than a protocol deviation) 
☐ 
protocol deviation 
☐ 
new information that might affect the willingness of subjects to enroll or continue     
participation in this study 
 
If interventional or expanded access study, please answer the following questions about 
your site: 
 


125 
Abbreviated Title: Chemo+antiPDL1+ vaccine in CRC 
Version Date:10.30.2019 
How many participants are still receiving the study intervention?  
Click or tap here to enter text. 
 
How many participants completed study interventions but remain in follow up? 
Click or tap here to enter text. 
 
How many participants are enrolled but not yet receiving study interventions? 
Click or tap here to enter text. 
Have similar problems occurred on this protocol at your site? 
☐ Yes      ☐ No 
Describe what steps you have already taken or will be taking as a result of this problem: 
Click or tap here to enter text. 
 
INVESTIGATOR’S SIGNATURE:  
 
DATE:   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


126 
Abbreviated Title: Chemo+antiPDL1+ vaccine in CRC 
Version Date:10.30.2019 
 
 
 
 
 
 
 
 
 
 
 

ICF_001.pdf: 
PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 10/30/2019
Page 1 of 19
CC ICF template v. 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
PRINCIPAL INVESTIGATOR:  Julius Strauss, MD
STUDY TITLE:     A Randomized Phase II Trial of Standard of Care Alone or in 
                                 Combination with Ad CEA Vaccine and Avelumab in Patients 
                                 with Previously Untreated Metastatic or Unresectable Colorectal Cancer
STUDY SITE:        NIH Clinical Center (CC) 
Cohort:                  Affected patient
Consent Version:  October 30, 2019 
WHO DO YOU CONTACT ABOUT THIS STUDY? 
Julius Strauss, MD
Phone: 301-480-0202 
Email: julius.strauss@nih.gov
This consent form describes a research study and is designed to help you decide if you would like 
to be a part of the research study.  
You are being asked to take part in a research study at the National Institutes of Health (NIH). 
Members of the study team will talk with you about the information described in this document. 
Some people have personal, religious, or ethical beliefs that may limit the kinds of medical or 
research treatments they would want to receive (such as blood transfusions). Take the time needed 
to ask any questions and discuss this study with NIH staff, and with your family, friends, and 
personal health care providers. Taking part in research at the NIH is your choice.
If the individual being asked to participate in this research study is not able to give consent to be 
in this study, you are being asked to give permission for this person as their decision-maker. The 
term “you” refers to you as the decision-maker and/or the individual being asked to participate in 
this research, throughout the remainder of this document. 
IT IS YOUR CHOICE TO TAKE PART IN THE STUDY
You may choose not to take part in this study for any reason. If you join this study, you may change 
your mind and stop participating in the study at any time and for any reason. In either case, you 
will not lose any benefits to which you are otherwise entitled. However, to be seen at the NIH, you 
must be taking part in a study or are being considered for a study. If you do choose to leave the 
study, please inform your study team to ensure a safe withdrawal from the research.  
WHY IS THIS STUDY BEING DONE?
The purpose of this study is to investigate whether the study drugs avelumab and the Ad-CEA 
vaccine, given in combination with the standard of care therapy increases the time it takes for your 
disease to get worse in comparison to standard of care alone.  
IRB NUMBER: 17C0057
IRB APPROVAL DATE: 12/23/2019


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 10/30/2019
Page 2 of 19
CC ICF template v. 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Avelumab is an investigational agent that targets and inhibits a pathway that prevents your immune 
system from effectively fighting your cancer. Ad-CEA is an investigational vaccine that may 
promote your immune system’s response against cancer. Investigational means that they have not 
been approved by the FDA for treatment of your cancer.  
The standard of care therapy used on this study is FOLFOX (folinic acid [leucovorin] +5-
fluorouracil [5-FU] + oxaliplatin) plus bevacizumab for up to 24 weeks, followed by capecitabine 
plus bevacizumab.  These agents are approved by the FDA for the treatment of colorectal cancer 
that has spread to other sites. 
WHY ARE YOU BEING ASKED TO TAKE PART IN THIS STUDY?
You are being asked to take part in this study because you have been diagnosed with and have not 
been treated for colorectal cancer that has spread to other parts of the body. During the screening 
process, you will be tested to determine if your cancer has a mismatch repair deficiency (MMR-
D), a mechanism of DNA repair that is not working properly in some cases. It is very important to 
identify if your tumor has this deficiency as it would mean that other treatment would be more 
appropriate. We will enroll only patients who do not have this mismatch repair deficiency.
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY? 
Up to 97 subjects at the National Cancer Institute and at the Georgetown Lombardi Cancer Center 
will take part in this study.
DESCRIPTION OF RESEARCH STUDY
For your safety, some medications and therapies are not allowed during the study. You should tell 
the study doctor before you take any new medications (includes prescription, herbal, and over-the-
counter remedies) or start a new therapy during the study.
Before you begin the study
Before you can enroll on the study, you will have standard blood tests (including a pregnancy test 
if you are a woman that can have children), imaging studies (CT, MRI), a physical exam and any 
other tests needed to be certain that it is safe for you to participate in this study. You will not able 
to participate in the study if you are pregnant.
To be enrolled in this trial you will also need to provide a documentation, confirming your tumor 
and if it has a mismatch repair deficiency (MMR-D). If this is not available, we will perform a 
biopsy, a procedure using a needle to remove a piece of tissue or a sample of cells from your body 
so that it can be analyzed in a laboratory and is used to diagnose or evaluate the cancer. 
During the study
We will ask you to provide a sample of your tumor if available from a previous surgery or biopsy. 
The first 6 subjects enrolled (lead-in group) on the study will receive Ad-CEA, avelumab plus 
standard of care.  If more than one of these 6 patients experience a side effect that is considered 
too serious by the study doctor during the first 28 days of treatment, we will not enroll any further 
participants.  
IRB NUMBER: 17C0057
IRB APPROVAL DATE: 12/23/2019


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 10/30/2019
Page 3 of 19
CC ICF template v. 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
If fewer than two experience unexpected side effects, the rest of the subjects will be selected by a 
computer to participate in one of two treatment arms on a 1:1 basis. This means that there is a 50% 
chance of being assigned to one arm or the other.
If you are assigned to Arm A you will receive standard of care therapy for colorectal cancer.  If 
you are assigned to Arm B, you will receive Ad-CEA + avelumab + standard of care.  For all 
participants, study treatment will be divided into cycles each lasting 14 days (2 weeks).  You will 
be treated until your disease worsens or you have intolerable side effects.  If you were assigned to 
Arm A and your disease worsens, your doctor will offer you the option of crossing over to Arm B. 
In this case, you will be treated until your disease worsens further or you experience intolerable 
side effects.
All Participants
Induction Therapy
For the first 12 cycles, standard of care chemotherapy will consist of FOLFOX + bevacizumab.
On the first day (Arm A) or second day (Arm B) of each cycle, you will receive FOLFOX + 
bevacizumab through an IV (intravenous catheter, a small plastic tube that is put into a vein, 
usually in your arm). The infusion will last approximately 2 days.  
Note:  If you experience intolerable side effects during the induction therapy, your study doctor 
may begin maintenance therapy prior to the completion of 12 cycles of induction therapy.
Maintenance Therapy
After you have completed induction therapy, standard of care chemotherapy will consist of 
capecitabine + bevacizumab.  Your study doctor may also choose to add oxaliplatin if you have 
crossed over from Arm A during the maintenance phase.  
You will be given a supply of capecitabine to take home.  You will take capecitabine by mouth 
twice a day every day with water within 30 minutes after a meal.
On the first day (Arm A) or second day (Arm B) of each cycle, you will also receive bevacizumab 
(and oxaliplatin if it has been added to your treatment) through an IV. The infusion will last 
approximately 1 - 2 hours.  
You will have a physical exam, answer questions about your health and have blood and urine tests 
each cycle to help us monitor your health.  An EKG will be performed every 4 weeks (every other 
cycle) during the first four cycles and then every 8 weeks (every 4 cycles) starting with cycle 5.  
You will also have scans every 8 weeks (every 4 cycles) to monitor your disease.
Lead-in or Arm B (including crossovers) only 
Ad-CEA vaccine will be injected every 2 weeks for three doses, every 4 weeks for three doses, 
then every 12 weeks. 
Avelumab will be given to you through an IV on the first day of each 14-day cycle.  Each infusion 
lasts for about an hour.
IRB NUMBER: 17C0057
IRB APPROVAL DATE: 12/23/2019


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 10/30/2019
Page 4 of 19
CC ICF template v. 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
About 30 - 60 minutes before each dose of avelumab you will be given 2 medicines to help prevent 
any side effects or allergic reactions:
1) Acetaminophen (Tylenol) 
2) An antihistamine such as Benadryl 
Research tests
In addition to the tests that we will conduct to determine whether you are having side effects or if 
you are responding to the study therapy, we will also collect samples from you for purposes of 
research only. These studies include:

Blood samples to study the effects of therapy on your immune system will be collected 
during cycles 1, 3, 5, 9 and every 4 cycles thereafter.

Tumor biopsies (optional) might be collected before you start treatment and any time while 
you are on treatment after you have completed 4 cycles of therapy.  These biopsies are not 
necessary for your treatment or evaluation of your disease, samples will be used for 
research only. Please see page 13 for the risks of biopsy. You will be asked to sign a 
separate consent each time you agree to have an optional biopsy. You can participate in the 
study even if you decide not to undergo the biopsy procedures.  

Genetic testing – Your tissue samples contain genes, which are made up of DNA 
(deoxyribonucleic acid) which serves as the "instruction book" for the cells that make up 
our bodies. We will use the tissue samples you provided at screening and other time points 
to learn about how the genes in your tumor compare to genes in normal tissue. Your tissue 
will help us study how genes might play a role in colorectal cancer and other diseases. We 
will not share the results of these research tests with you.
When you are finished taking the drugs
About 4 – 5 weeks after you have finished taking the study drugs, you will be asked to return for 
a safety follow up visit.  At this visit, your will be asked questions about your health, get a physical 
exam and undergo routine blood and urine tests.  If you are unable to return for this visit, we will 
obtain the information from you by telephone.
After the safety visit, we will call you or your physician approximately once a year to ask about 
survival and about any other medications you may have taken for your cancer.
BIRTH CONTROL
If you are a woman who is breast feeding or pregnant, you may not take part in the study because 
we don’t know how this medicine would affect your baby or your unborn child. If you are a woman 
who can become pregnant, or are the partner of a woman who can become pregnant, you will need 
to practice an effective form of birth control before starting study treatment, during study 
treatment, and for 4 months after the last avelumab infusion or 6 months after the last bevacizumab 
infusion, whichever occurs later.  If you think that you or your partner is pregnant, you should tell 
your study doctor or nurse at once.  
IRB NUMBER: 17C0057
IRB APPROVAL DATE: 12/23/2019


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 10/30/2019
Page 5 of 19
CC ICF template v. 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Effective forms of birth control include: 
•
abstinence 

intrauterine device (IUD)
•
hormonal [birth control pills, injections, or implants]
•
tubal ligation
•
vasectomy
RISKS OR DISCOMFORTS OF PARTICIPATION
If you choose to take part in this study, there is a risk that:

You may lose time at work or home and spend more time in the hospital or doctor’s office 
than usual

You may be asked sensitive or private questions which you normally do not discuss
The vaccine and chemotherapy used in this study may affect how different parts of your body work 
such as your liver, kidneys, heart, and blood. The study doctor will be testing your blood and will 
let you know if changes occur that may affect your health.
There is also a risk that you could have side effects from the study drug(s).  
Here are important points about side effects:

The study doctors do not know who will or will not have side effects.

Some side effects may go away soon, some may last a long time, or some may never go 
away.

Some side effects may interfere with your ability to have children.

Some side effects may be serious and may even result in death.
Here are important points about how you and the study doctor can make side effects less of a 
problem:

Tell the study doctor if you notice or feel anything different so they can see if you are 
having any symptoms.

The study doctor may be able to treat some side effects.

The study doctor may adjust the study drugs to try to reduce side effects.
Late side effects of the investigational agents may affect your ability to tolerate subsequent 
regimens of standard of care chemotherapy.
Below we show the most common and the most serious side effects that researchers know about. 
There might be other side effects that researchers do not yet know about. If important new side 
effects are found, the study doctor will discuss these with you.
IRB NUMBER: 17C0057
IRB APPROVAL DATE: 12/23/2019


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 10/30/2019
Page 6 of 19
CC ICF template v. 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Risks from study therapy
All Participants
Possible Side Effects of FOLFOX (Leucovorin, 5-Fluorouracil, Oxaliplatin)
Common (occurring in more than 20% of patients)
Hair loss
Redness, pain or peeling of palms and soles
Rash, increased risk of sunburn, itching
Heartburn
Headache
Sores in mouth which may cause difficulty 
swallowing
Anemia which may require blood 
transfusion
Diarrhea, nausea, vomiting, constipation, 
loss of appetite
Tiredness
Bruising, bleeding
Infection, especially when white blood cell 
count is low
Numbness and tingling of the arms and legs
Feeling of "pins and needles" in arms and 
legs
Pain
Fever, cough
Occasional (occurring in 4-20% of patients)
Chest pain
Hoarseness
Allergic reaction which may cause rash, low 
blood pressure, wheezing, shortness of 
breath, swelling of the face or throat
Abnormal eye movement, blurred vision, 
watering eyes
Discomfort from light
Swelling, redness, tingling and pain of 
hands and feet
Blood clot which may cause swelling, pain, 
or shortness of breath
Abnormal heartbeat which may cause 
fainting
Hearing loss
Dry eye, mouth, skin
Swelling and redness of the eye
Blurred vision with chance of blindness
Visual loss
Problem with eyelid
Fluid in the belly
Passing gas
Internal bleeding which may cause black 
tarry stool, blood in vomit or urine, or 
coughing up blood
Damage to organs which may cause 
shortness of breath
Chills
Swelling and redness at the site of the 
medication injection
Liver damage which may cause yellowing 
of eyes and skin
Kidney damage which may require dialysis
Weight gain, weight loss, dehydration
Dizziness
Changes in taste, voice
Abnormal body movement
Stroke which may cause paralysis, 
weakness
Inability to move shoulder or turn head
Bleeding from multiple sites including 
vaginal bleeding, bleeding of the testis, or 
bleeding of the brain 
Muscle weakness
Seizure
Worry, confusion, depression
IRB NUMBER: 17C0057
IRB APPROVAL DATE: 12/23/2019


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 10/30/2019
Page 7 of 19
CC ICF template v. 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Difficulty walking, opening mouth, talking, 
with balance and hearing, smelling, eating, 
sleeping, emptying the bladder
Swelling of the body which may cause 
shortness of breath
Blockage of the airway which may cause 
shortness of breath, wheezing
Increased urination
Stuffy nose, hiccups, sinus problems
Scarring of the lungs
Increased sweating, flushing, hot flashes
High blood pressure 
Rare and serious (occurring in fewer than 4% of patients) 
A new cancer resulting from treatment of earlier cancer
Brain damage, Reversible Posterior Leukoencephalopathy Syndrome, which may cause 
headache, seizure, blindness
Possible Side Effects of Bevacizumab
Common (occurring in more than 20% of patients)

high blood pressure

blood clots in a vein 
(possible pain, swelling, 
and/or redness) 

pain

nerve damage (loss of 
sensory function)

headache

dizziness

fatigue

hair loss (partial or total)

abdominal pain

loss of appetite

constipation

diarrhea

mouth blisters/sores 
(possible difficulty 
swallowing)

digestive system bleeding

upset stomach

vomiting

abnormal taste

failure of the ovaries to 
produce hormones, which 
may be permanent 
(possible stopped 
menstrual cycle)

bleeding 

nosebleed

low white blood cell 
counts

difficulty breathing

weakness

abnormal kidney test 
(possible kidney damage)
Occasional (occurring in 3-20% of patients)

blood clots in an artery 
(possible organ damage 
such as stroke and/or 
heart attack)

low blood pressure 
(possible 
dizziness/fainting) 

heart failure

fainting

bleeding in the brain 
and/or spinal cord

stroke

shedding and scaling of 
the skin (possible fatal 
loss of bodily fluids)

change of skin color

low blood levels of 
sodium (possible 
headache, confusion, 
seizures, and/or coma) 

dehydration

gas

dry mouth 

inflammation or paralysis 
of the intestines 

weight loss

nausea 

uterine and/or vaginal 
bleeding 

low platelet cell counts

pain (back/muscle)

voice changes

runny nose
IRB NUMBER: 17C0057
IRB APPROVAL DATE: 12/23/2019


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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY

difficulty walking

dry skin

skin sores

opening of a wound

hole in the intestines 
(possibly leaking contents 
into the abdomen) 

bleeding gums 

lung inflammation 
(possible difficulty 
breathing)

infusion reaction 
(possible chills and/or 
hives)
Rare but serious (occurring in fewer than 3% of patients) 

severe heart problems

heart attack

chest pain due to heart 
trouble

severe increase in blood 
pressure (possible stroke)

brain injury that may be 
reversible (possible 
headache, confusion, 
seizures, and/or vision 
loss) 

decreased brain function 
due to high blood pressure

decreased blood flow to 
part of the bowel 
(possibly causing death of 
tissue)

bleeding around the brain

temporary stroke 
symptoms

intestinal blockage

stomach and/or small 
intestine ulcer

vein blockage in the 
abdomen hole in the gall 
bladder (possible 
abdominal pain, gall 
stones, nausea, and/or 
infection)

hole in the bladder 

destruction of red blood 
cells 

low red blood cell counts 

bone destruction 
(including destruction of 
the jaw bone)

inflammation inside the 
eye

blurry vision 

increased pressure in the 
eye (possible pain and/or 
blurry vision)

detached retina (possible 
partial blindness)

deafness 

kidney failure

decreased kidney function 
(possible kidney failure)

coughing up blood

increased blood pressure 
in the lungs (possible 
difficulty breathing and/or 
heart failure)

blockage in the lung 
(possible pain, shortness 
of breath, and/or failure to 
breathe) 

abnormal hole inside the 
nose

life-threatening allergic 
reaction (such as 
difficulty breathing, low 
blood pressure, and/or 
organ failure)

wound healing problems
Bevacizumab may rarely cause an abnormal opening that develops between one area of the body 
and another (for example, an abnormal connection and opening in one or more places between the 
trachea [breathing tube] and esophagus, which may interfere with swallowing, digestion, and/or 
choking).  This may result in death. 
If you are taking Coumadin (warfarin) or other blood-thinning drugs, you may be at higher risk of 
blood clots and/or bleeding.
IRB NUMBER: 17C0057
IRB APPROVAL DATE: 12/23/2019


PATIENT IDENTIFICATION
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Possible Side Effects of Capecitabine
Common (occurring in more than 20% of patients)
Swelling of the body
Blisters on the skin
Redness, pain or peeling of palms and soles
Pain
Diarrhea, loss of appetite, nausea, vomiting
Sores in mouth which may cause difficulty 
swallowing
Fever
Anemia which may require blood 
transfusions
Infection, especially when white blood cell 
count is low
Bruising, bleeding
Feeling of "pins and needles" in arms and 
legs
Tiredness
Occasional (occurring in 4-20% of patients)
Blurred vision, dry or itchy eyes
Muscle spasms, body aches
Abnormal heartbeat
Restlessness, irritability
Swelling of face, fingers and lower legs
Constipation
Difficulty with balancing
Rare and serious (occurring in fewer than 4% of patients) 
Allergic reaction which may cause rash, low blood pressure, wheezing, shortness of breath, 
swelling of the face or throat
Difficulty speaking, walking or seeing
Internal bleeding which may cause blood in vomit or black tarry stools
Damage to the heart
Lead in and Arm B (including crossovers)
Possible Side-Effects of Ad-CEA
Common (occurring in more than 5 % of patients)
Redness, pain and swelling at the injection 
site
Flu-like symptoms
Fever
Fatigue (tiredness)
Shortness of breath
Pain 
Loss of appetite
Chills
Constipation
Swelling arms, legs
Nausea
Occasional (occurring in less than 5% but more than 2 % of patients)
Fluid around lungs
Anemia which may require transfusion
Bloating
Blockage of the stomach
IRB NUMBER: 17C0057
IRB APPROVAL DATE: 12/23/2019


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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Abnormal laboratory result
Damage to the kidneys
Possible Side Effects of Avelumab
Common (occurring in more than 5 % of patients)

Fatigue (tiredness) 

Nausea 

Diarrhea

Decreased appetite

Infusion-related reaction

Chills (feeling cold)
Occasional (occurring in less than 5% of patients)

Shortness of breath

Rash

Abdominal pain

Non-cardiac chest pain
Allergic reactions or reactions in the context with the infusions might occur during treatment. 
Although avelumab is a fully human protein the risk cannot be completely excluded. In general, 
these reactions are mild to moderate and can be handled with appropriate drugs, but in very rare 
cases severe to life-threatening and even fatal reactions might occur, which require advanced 
cardiac life support. 
For the prevention of infusion-related adverse effects and possible allergic reactions you will 
receive a premedication of an antihistamine drug (so-called H1 blocker) and acetaminophen 30 to 
60 minutes before every infusion.
In addition, immune-mediated side effects might be possible.  These are:

joint pain

arthritis (inflammatory disease of the joint)

pneumonitis (inflammatory disease of the lung)

hypothyroidism (decreased function of the thyroid gland)

hyperthyroidism (increased function of thyroid gland)

thyroiditis (inflammatory disease of the thyroid gland)

autoimmune hepatitis (inflammatory disease of the liver caused by the body’s immune 
system)

thrombocytopenia (decrease of the blood platelets)

dry eyes

inflammatory eye disease 

diabetes mellitus (high blood sugar levels)

decreased function of the adrenal glands

inflammatory disease of muscles characterized by pain and tenderness

colitis (inflammatory disease of the large intestine)

impairment of the brain function

psoriasis 

nerve irritation
IRB NUMBER: 17C0057
IRB APPROVAL DATE: 12/23/2019


PATIENT IDENTIFICATION
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NIH-2977 (4-17)
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY

autoimmune disorder (body’s immune system approaches own cells)

myocarditis 
There is a risk of tumor lysis syndrome due to tumor shrinkage. This complication is caused by 
the breakdown products of dying cells and includes elevated blood potassium, elevated blood 
phosphorus, elevated blood uric acid and elevated urine uric acid, low blood calcium, and 
consequent acute kidney failure.
If any of these side effects occur, you must inform your study doctor immediately. 
Subjects Treated with Oxaliplatin but not FOLFOX
Possible Side Effects of Oxaliplatin
COMMON, SOME MAY BE SERIOUS
In 100 people receiving Oxaliplatin, more than 20 and up to 100 may have:
Anemia which may require blood transfusion
Diarrhea, nausea, vomiting, constipation, loss of appetite
Tiredness
Bruising, bleeding
Infection, especially when white blood cell count is low
Numbness and tingling of the arms and legs
Feeling of "pins and needles" in arms and legs
Pain
Fever, cough
OCCASIONAL, SOME MAY BE SERIOUS
In 100 people receiving Oxaliplatin, from 4 to 20 may have:
Blood clot which may cause swelling, pain, or shortness of breath
Abnormal heartbeat which may cause fainting
Hearing loss
Dry eye, mouth, skin
Swelling and redness of the eye
Blurred vision with chance of blindness
Visual loss
Problem with eyelid
Fluid in the belly
Heartburn, passing gas
Difficulty walking, opening mouth, talking, with balance and hearing, smelling, eating, 
sleeping, emptying the bladder
Swelling of the body which may cause shortness of breath
Blockage of the airway which may cause shortness of breath, cough, wheezing
Bleeding from multiple sites including vaginal bleeding, bleeding of the testis, or 
bleeding of the brain
IRB NUMBER: 17C0057
IRB APPROVAL DATE: 12/23/2019


PATIENT IDENTIFICATION
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
OCCASIONAL, SOME MAY BE SERIOUS
In 100 people receiving Oxaliplatin, from 4 to 20 may have:
Internal bleeding which may cause black tarry stool, blood in vomit or urine, or coughing 
up blood
Damage to organs which may cause shortness of breath
Sores in throat or mouth which may cause difficulty swallowing
Chills
Swelling and redness at the site of the medication injection
Liver damage which may cause yellowing of eyes and skin
Kidney damage which may require dialysis
Allergic reaction which may cause rash, low blood pressure, wheezing, shortness of 
breath, swelling of the face or throat
Weight gain, weight loss, dehydration
Dizziness, headache
Changes in taste, voice
Abnormal body movement including the eye and eyelid
Stroke which may cause paralysis, weakness
Inability to move shoulder or turn head
Muscle weakness
Seizure
Worry, confusion, depression
Increased urination
Stuffy nose, shortness of breath, hiccups, sinus problems
Scarring of the lungs
Hair loss, itching, rash, hives
Increased sweating, flushing, hot flashes
High blood pressure
Low blood pressure which may cause feeling faint
RARE, AND SERIOUS
In 100 people receiving Oxaliplatin, 3 or fewer may have:
Redness, pain or peeling of palms and soles
Brain damage, Reversible Posterior Leukoencephalopathy Syndrome, which may cause 
headache, seizure, blindness
IRB NUMBER: 17C0057
IRB APPROVAL DATE: 12/23/2019


PATIENT IDENTIFICATION
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Risks from Blood Collection 
Side effects of blood draws include pain and bruising in the area where the needle was placed, 
lightheadedness, and rarely, fainting. When large amounts of blood are collected, low red blood 
cell count (anemia) can develop.
Risks from Biopsy 
This procedure usually causes only brief discomfort at the site from which the biopsy is taken.  
Rarely, infection or bleeding may occur at the needle site.
Tumor biopsies may be done by a specialist using the CT scanner or ultrasound machine to guide 
the biopsy needle into the tumor to ensure accuracy. To collect the optional research biopsies, you 
may be exposed to 2 CT scans. This radiation exposure is not required for your medical care and 
is for research purposes only. The amount of radiation you will receive in this procedure is 1.5 rem 
which is below the guideline of 5 rem per year allowed for research subjects by the NIH Radiation 
Safety Committee.  The average person in the United States receives a radiation exposure of 0.3 
rem per year from natural sources, such as the sun, outer space, and the earth's air and soil.  If you 
would like more information about radiation, please ask the investigator for a copy of the pamphlet, 
An Introduction to Radiation for NIH Research Subjects.
Risks Associated with Genetic Testing
Your privacy is very important to us and we will use many safety measures to protect your privacy. 
However, in spite of all of the safety measures that we will use, we cannot guarantee that your 
identity will never become known. While neither the public nor the controlled-access databases 
developed for this project will have information such as your name, address, telephone number, or 
social security number, it may be possible to identify you based on the information in these 
databases and other public information (including information you tell people or post about 
yourself).  The risk of this happening is currently very low. 
Protections against misuse of genetic information
Since some genetic variations can help to predict future health problems for you and your relatives, 
this information might be of interest to health care providers, life insurance companies, and others.  
However, Federal and State laws provide some protections against discrimination based on genetic 
information.  For example, the Genetic Information Nondiscrimination Act (GINA) makes it 
illegal for health insurance companies, group health plans, and most employers to discriminate 
against you based on your genetic information.  However, GINA does not prevent companies that 
sell life insurance, disability insurance, or long-term care insurance from using genetic information 
as a reason to deny coverage or set premiums.  GINA also does not apply to members of the United 
States military, individuals covered by the Indian Health Service, or veterans obtaining health care 
through the Veteran’s Administration.  Lastly, GINA does not forbid insurance medical 
underwriting based on your current health status though the Affordable Care Act limits 
consideration of pre-existing conditions by insurers.
POTENTIAL BENEFITS OF PARTICIPATION
Are there benefits to taking part in this study? 
IRB NUMBER: 17C0057
IRB APPROVAL DATE: 12/23/2019


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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
The aim of this study is to find out whether the experimental treatment increases the time it takes 
colorectal cancer to worsen when compared to standard of care.  We do not know if you will 
receive personal, medical benefit from taking part in this study.    Potential benefits could include 
shrinking of your tumor or lessening of your symptoms, such as pain, that are caused by the cancer.  
Because there is not much information about the drug’s effect on your cancer, we do not know if 
you will benefit from taking part in this study, although the knowledge gained from this study may 
help others in the future who have cancer.  
ALTERNATIVE APPROACHES OR TREATMENTS
Instead of being in this study, you have these options:

Getting treatment or care for your cancer without being in a study

Taking part in another study

Getting comfort care, also called palliative care.  This type of care helps reduce pain, 
tiredness, appetite problems and other problems caused by the cancer.  It does not treat the 
cancer directly.  Instead, it tries to improve how you feel.  Comfort care tries to keep you 
as active and comfortable as possible.
Please talk to your doctor about these and other options.
STOPPING THERAPY
Your doctor may decide to stop your therapy for the following reasons:

if he/she believes that it is in your best interest

if your disease comes back during treatment

if you have side effects from the treatment that your doctor thinks are too severe

if new information shows that another treatment would be better for you

if the investigator decides to end the study

if you have a positive pregnancy test
In this case, you will be informed of the reason therapy is being stopped.
You can stop taking part in the study at any time. However, if you decide to stop taking part in the 
study, we would like you to talk to the study doctor and your regular doctor first.
If you decide at any time to withdraw your consent to participate in the trial, we will not collect 
any additional medical information about you. However, according to FDA guidelines, 
information collected on you up to that point may still be provided to EMD Serono or designated 
representatives. If you withdraw your consent and leave the trial, any samples of yours that have 
been obtained for the study and stored at the NCI can be destroyed upon request. However, any 
samples and data generated from the samples that have already been distributed to other 
researchers or placed in the research databases cannot be recalled and destroyed.
IRB NUMBER: 17C0057
IRB APPROVAL DATE: 12/23/2019


PATIENT IDENTIFICATION
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
CONFLICT OF INTEREST
The National Institutes of Health (NIH) reviews NIH staff researchers at least yearly for conflicts 
of interest.  This process is detailed in a Protocol Review Guide.  You may ask your research team 
for a copy of the Protocol Review Guide or for more information.  Members of the research team 
who do not work for NIH are expected to follow these guidelines but they do not need to report 
their personal finances to the NIH.
Members of the research team working on this study may have up to $15,000 of stock in the 
companies that make products used in this study.  This is allowed under federal rules and is not a 
conflict of interest. 
The National Institutes of Health and the research team for this study are using therapies developed 
by EMD Serono and Etubics and a test developed by NantOmics through a joint study with your 
researchers and the companies.  The companies also provide financial support for this study. 
USE OF SPECIMENS AND DATA FOR FUTURE RESEARCH
To advance science, it is helpful for researchers to share information they get from studying human 
samples.  They do this by putting it into one or more scientific databases, where it is stored along 
with information from other studies. A researcher who wants to study the information must apply 
to the database and be approved.  Researchers use specimens and data stored in scientific databases 
to advance science and learn about health and disease.  
These specimens and data will be used for future research and shared with other researchers. We 
will not contact you to ask about each of these future uses.  These specimens and data will be 
stripped of identifiers such as name, address or account number, so that they may be used for future 
research on any topic and shared broadly for research purposes. Your specimens and data will be 
used for research purposes only and will not benefit you.  It is also possible that the stored 
specimens and data may never be used.  Results of research done on your specimens and data will 
not be available to you or your doctor.  It might help people who have cancer and other diseases 
in the future.  
If you do not want your stored specimens and data used for future research, please contact us in 
writing and let us know that you do not want us to use your specimens and/or data.  Then any 
specimens that have not already been used or shared will be destroyed and your data will not be 
used for future research. However, it may not be possible to withdraw or delete materials or data 
once they have been shared with other researchers.
Genomic Data Sharing
As part of this research study, we will put your genomic data in a large database for broad sharing 
with the research community. These databases are commonly called data repositories. The 
information in this database will include but is not limited to genetic information, race and 
ethnicity, and sex.  If your individual data are placed in one of these repositories, they will be 
labeled with a code and not with your name or other information that could be used to easily 
identify you, and only qualified researchers will be able to access them. These researchers must 
IRB NUMBER: 17C0057
IRB APPROVAL DATE: 12/23/2019


PATIENT IDENTIFICATION
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
receive prior approval from individuals or committees with authority to determine whether these 
researchers can access the data.
Summary information about all of the participants included in this study (including you) is being 
placed in a database and will be available through open access. That means that  researchers and 
non-researchers will be able to access summary information about all the participants included in 
the study, or summary information combined from multiple studies, without applying for 
permission. The risk of anyone identifying you with this information is very low.
NIH policies require that genomic data be placed in a repository for sharing. Therefore, we cannot 
offer you a choice of whether your data will be shared.  If you do not wish to have your data placed 
in a repository, you should not enroll in this study.
COMPENSATION, REIMBURSEMENT, AND PAYMENT
Will you receive compensation for participation in the study?
Some NIH Clinical Center studies offer compensation for participation in research. The amount 
of compensation, if any, is guided by NIH policies and guidelines.
You will not receive compensation for participation in this study. 
Will you receive reimbursement or direct payment by NIH as part of your participation?
Some NIH Clinical Center studies offer reimbursement or payment for travel, lodging or meals 
while participating in the research. The amount, if any, is guided by NIH policies and guidelines.
On this study, the NCI will cover the cost for some of your expenses.  Some of these costs may be 
paid directly by the NIH and some may be reimbursed after you have paid.  Someone will work 
with you to provide more information.
Will taking part in this research study cost you anything? 
NIH does not bill health insurance companies or participants for any research or related clinical 
care that you receive at the NIH Clinical Center. 

If some tests and procedures are performed outside the NIH Clinical Center, you may have 
to pay for these costs if they are not covered by your insurance company.

Medicines that are not part of the study treatment will not be provided or paid for by the 
NIH Clinical Center.

Once you have completed taking part in the study, medical care will no longer be provided 
by the NIH Clinical Center.
CLINICAL TRIAL REGISTRATION AND RESULTS REPORTING 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this Web site at any time.
IRB NUMBER: 17C0057
IRB APPROVAL DATE: 12/23/2019


PATIENT IDENTIFICATION
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
CONFIDENTIALITY PROTECTIONS PROVIDED IN THIS STUDY  
Will your medical information be kept private? 
We will do our best to make sure that the personal information in your medical record will be kept 
private.  However, we cannot guarantee total privacy.  Organizations that may look at and/or copy 
your medical records for research, quality assurance, and data analysis include:

The NIH and other government agencies, like the Food and Drug Administration (FDA), 
which are involved in keeping research safe for people.

National Institutes of Health Intramural Institutional Review Board

Qualified representatives from EMD Serono, the pharmaceutical company who produces 
avelumab.

Qualified representatives from Etubics, the pharmaceutical company who produces the Ad-
CEA vaccine.

Qualified representatives from NantOmics, the company that will perform the genetic 
testing on this study.
When results of an NIH research study are reported in medical journals or at scientific meetings, 
the people who take part are not named and identified.  In most cases, the NIH will not release any 
information about your research involvement without your written permission.  However, if you 
sign a release of information form, for example, for an insurance company, the NIH will give the 
insurance company information from your medical record.  This information might affect (either 
favorably or unfavorably) the willingness of the insurance company to sell you insurance.
If we share your specimens or data with other researchers, in most circumstances we will remove 
your identifiers before sharing your specimens or data. You should be aware that there is a slight 
possibility that someone could figure out the information is about you. 
Further, the information collected for this study is protected by NIH under a Certificate of 
Confidentiality and the Privacy Act. 
Certificate of Confidentiality
To help us protect your privacy, the NIH Intramural Program has received a Certificate of 
Confidentiality (Certificate). With this certificate, researchers may not release or use data or 
information about you except in certain circumstances.  
NIH researchers must not share information that may identify you in any federal, state, or local 
civil, criminal, administrative, legislative, or other proceedings, for example, if requested by a 
court.  
The Certificate does not protect your information when it:  
1. is disclosed to people connected with the research, for example, information may be used 
for auditing or program evaluation internally by the NIH; or 
2. is required to be disclosed by Federal, State, or local laws, for example, when information 
must be disclosed to meet the legal requirements of the federal Food and Drug 
Administration (FDA); 
IRB NUMBER: 17C0057
IRB APPROVAL DATE: 12/23/2019


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 10/30/2019
Page 18 of 19
CC ICF template v. 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
3. is for other research;
4. is disclosed with your consent. 
The Certificate does not prevent you from voluntarily releasing information about yourself or your 
involvement in this research. 
The Certificate will not be used to prevent disclosure to state or local authorities of harm to self or 
others including, for example, child abuse and neglect, and by signing below you consent to those 
disclosures. Other permissions for release may be made by signing NIH forms, such as the Notice 
and Acknowledgement of Information Practices consent.
Privacy Act
The Federal Privacy Act generally protects the confidentiality of your NIH medical records we 
collect under the authority of the Public Health Service Act.  In some cases, the Privacy Act 
protections differ from the Certificate of Confidentiality.  For example, sometimes the Privacy Act 
allows release of information from your medical record without your permission, for example, if 
it is requested by Congress. Information may also be released for certain research purposes with 
due consideration and protection, to those engaged by the agency for research purposes, to certain 
federal and state agencies, for HIV partner notification, for infectious disease or abuse or neglect 
reporting, to tumor registries, for quality assessment and medical audits, or when the NIH is 
involved in a lawsuit.  However, NIH will only release information from your medical record if it 
is permitted by both the Certificate of Confidentiality and the Privacy Act.
POLICY REGARDING RESEARCH-RELATED INJURIES  
The NIH Clinical Center will provide short-term medical care for any injury resulting from your 
participation in research here. In general, no long-term medical care or financial compensation for 
research-related injuries will be provided by the NIH, the NIH Clinical Center, or the Federal 
Government. However, you have the right to pursue legal remedy if you believe that your injury 
justifies such action.
PROBLEMS OR QUESTIONS
If you have any problems or questions about this study, or about your rights as a research 
participant, or about any research-related injury, contact the Principal Investigator, Julius Strauss, 
MD, Phone: 301-480-0202, Email: julius.strauss@nih.gov. You may also call the NIH Clinical 
Center Patient Representative at 301-496-2626, or the NIH Office of IRB Operations at 301-402-
3713, if you have a research-related complaint or concern.
CONSENT DOCUMENT 
Please keep a copy of this document in case you want to read it again.
IRB NUMBER: 17C0057
IRB APPROVAL DATE: 12/23/2019


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 10/30/2019
Page 19 of 19
CC ICF template v. 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Adult Research Participant: I have read the explanation about this study and have been given the opportunity 
to discuss it and to ask questions. I consent to participate in this study.
Signature of Research Participant
Print Name of Research Participant
Date
Legally Authorized Representative (LAR) for an Adult Unable to Consent: I have read the explanation 
about this study and have been given the opportunity to discuss it and to ask questions. I am legally authorized 
to make research decisions on behalf of the adult participant unable to consent and have the authority to provide 
consent to this study. As applicable, the information in the above consent was described to the adult participant 
unable to consent who agrees to participate in the study.
Signature of LAR
Print Name of LAR
Date
Investigator:
Signature of Investigator
Print Name of Investigator
Date
Witness to the oral short-form consent process only: This section is only required if you are doing the oral 
short-consent process and this English consent form has been approved by the IRB for use as the basis of 
translation.
Witness:
Signature of Witness*
Print Name of Witness
Date
*NIH ADMINISTRATIVE SECTION TO BE COMPLETED REGARDING THE USE OF AN 
INTERPRETER:
An interpreter, or other individual, who speaks English and the participant’s preferred language facilitated
the administration of informed consent and served as a witness. The investigator obtaining consent may not 
also serve as the witness.
An interpreter, or other individual, who speaks English and the participant’s preferred language facilitated
the administration of informed consent but did not serve as a witness. The name or ID code of the person 
providing interpretive support is:
.
IRB NUMBER: 17C0057
IRB APPROVAL DATE: 12/23/2019