Conditions: Metastatic Colorectal Cancer Colorectal Neoplasms Colorectal Carcinoma Colorectal Cancer With Hepatic Metastases Colorectal Tumors
Keywords: Nonreplicating adenovirus Antitumor Immunity PD-1 inhibition Immune Checkpoint Inhibition
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 14
Healthy volunteers: no

Brief summary:
Background:

Gastrointestinal cancer is one of the most common cancers worldwide. Researchers think an unmet need exists to understand and improve treatment options. They want to see if a combination of drugs can help people with metastatic colorectal cancer.

Objective:

To see if using a combination of Vascular Biogenics (VB)-111 and nivolumab is safe and will cause colorectal tumors to shrink.

Eligibility:

People ages 18 and older with microsatellite stable colorectal cancer that has spread to the liver

Design:

Participants must consent to sample collection protocol 11C0112.

Participants will be screened with:

Blood tests

Scans

Tumor samples. If these are not available, participants will have a biopsy.

Before they start treatment and with every treatment cycle, participants will have:

Physical exams

Blood tests

Heart tests

Before they start treatment and every 4 cycles, participants will have computed tomography (CT) or magnetic resonance imaging (MRI) scans. For these, they will lie in a machine that takes pictures of the body. For the MRI, a soft padding or coil will be placed around their head.

Participants will have biopsies before they start therapy. They will have them again after 2 6 weeks on study.

On day 1 of 14-day cycles, participants will get one or both study drugs by vein.

After they finish treatment, participants will have monthly visits for 3 months. They will have a physical exam and blood tests.

If participants stop treatment for reasons other than their disease getting worse, they will have scans about every 8 weeks. This will continue until their disease gets worse.

Participants will be contacted by phone or email every 6 months. This will continue for life.

...

Detailed description:
Background:

* Immune based approaches in gastrointestinal (GI) cancers have unfortunately- with the notable exception of immune checkpoint inhibition in microsatellite instable (MSI-H) disease and gastric cancer-been largely unsuccessful. The reasons for this are unclear but no doubt relate to the fact that in advanced disease GI cancer appears to be less immunogenic, as evidenced by the lack of infiltrating lymphocytes with advancing T stage as well as an immunosuppressive tumor micro-environment.
* Vascular Biogenics (VB)-111 is an anti-angiogenic agent comprising of a nonreplicating E1 deleted adenovirus type 5 which contains a modified murine preproendothelin (PPE) promoter and Fas-chimera transgene
* VB-111 has been tested and shows promise in glioblastoma, ovarian and thyroid tumors
* Nivolumab is a human monoclonal antibody directed against programmed cell death protein 1 (PD-1).
* The aim of this study is to study the effects of VB-111 in colorectal cancer (CRC) and to evaluate whether the antitumor immunity induced by VB-111 therapy can be enhanced by PD-1 inhibition.

Objectives:

* To determine the safety and tolerability of VB-111 in combination with nivolumab in patients with refractory, metastatic CRC
* To determine Best Overall Response (BOR) (partial response (PR) + complete response (CR)) according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1) of combined treatment of VB-111 and nivolumab in patients with refractory, metastatic CRC.

Eligibility:

* Histopathological confirmation of colorectal cancer metastatic to the liver
* Patients must have progressed on \> 2 lines of standard of care chemotherapy for colorectal cancer or been intolerant of chemotherapy or refused prior chemotherapy.
* Patient's tumors must be documented to be microsatellite stable (MSS).
* Patients must have at least 1 focus of metastatic disease that is amenable to pre-and on-treatment biopsies and be willing to undergo this.
* All patients enrolled will be required to have measurable disease by RECIST v 1.1 criteria.

Design:

* The proposed study is a phase II study of VB-111 in combination with immune checkpoint inhibition (nivolumab) in patients with metastatic CRC
* Treatment will be delivered in cycles consisting of 2 weeks with VB-111 given every 6 weeks and nivolumab given every 2-week until progression or unacceptable toxicity.
* Disease status evaluation will be done every 8 (+/- 1) weeks after the start of study therapy.

Arms:
arm 1: Vascular Biogenics (VB)-111 and nivolumab

Interventions: intervention 1: Vascular Biogenics (VB)-111 intervention 2: Nivolumab
Intervention descriptions: intervention 1: 1E13 or 0.7E13 VP via intravenous (IV) infusion on Day 1 of cycle 1 and continue every 6 weeks intervention 2: 240 mg of nivolumab via intravenous (IV) infusion on Day 1 of each cycle starting on cycle 2 and continue every 2 weeks

Protocol document:
Prot_SAP_000.pdf: 
Abbreviated Title: VB-111_Nivolumab in mCRC 
Version Date: 01/22/21 
 
1 
Abbreviated Title: VB-111_Nivolumab in mCRC  
NIH Protocol: 20C0022  
Version Date: 01/22/2021 
NCT Number: NCT04166383 
IBC: RD-19-VI-06 
Title: Phase II trial of VB-111 in Combination with Nivolumab in Patients with Metastatic 
Colorectal Cancer (mCRC). 
 
NCI Principal Investigator:         Tim F. Greten, MD  
     Thoracic & GI Malignancies Branch 
     National Cancer Institute 
     Building 10, Room 2B38B 
     9000 Rockville Pike 
     Bethesda, MD 20892 
     240-760-6114 
     tim.greten@nih.gov 
 
Investigational Agents:     
Drug Name: 
VB-111 
IND Number: 
19164  
Sponsor: 
CCR, NCI 
Manufacturer: 
VBL Therapeutics 
 
Commercial agents: Nivolumab  


Abbreviated Title: VB-111_Nivolumab in mCRC 
Version Date: 01/22/21 
 
2 
PRÉCIS  
Background: 
• Immune based approaches in GI cancers have unfortunately – with the notable exception 
of immune checkpoint inhibition in microsatellite instable (MSI-H) disease and gastric 
cancer – been largely unsuccessful. The reasons for this are unclear but no doubt relate to 
the fact that in advanced disease GI cancer appears to be less immunogenic, as evidenced 
by the lack of infiltrating lymphocytes with advancing T stage as well as an 
immunosuppressive tumor microenvironment. 
• VB-111 is an anti-angiogenic agent comprising of a nonreplicating E1 deleted adenovirus 
type 5 which contains a modified murine preproendothelin (PPE) promoter and Fas-
chimera transgene 
• VB-111 has been tested and shows promise in glioblastoma, ovarian and thyroid tumors 
• Nivolumab is a human monoclonal antibody directed against PD-1.  
• The aim of this study is to study the effects of VB-111 in colorectal cancer (CRC) and to 
evaluate whether the antitumor immunity induced by VB-111 therapy can be enhanced by 
PD-1 inhibition. 
Objectives:  
• To determine the safety and tolerability of VB-111 in combination with nivolumab in 
patients with refractory, metastatic CRC  
• To determine Best Overall Response (BOR) (partial response (PR) + complete response 
(CR)) according to Response Evaluation Criteria (RECIST v1.1) of combined treatment of 
VB-111 and nivolumab in patients with refractory, metastatic CRC. 
Eligibility: 
• Histopathological confirmation of colorectal cancer metastatic to the liver 
• Patients must have progressed on > 2 lines of standard of care chemotherapy for colorectal 
cancer or been intolerant of chemotherapy or refused prior chemotherapy. 
• Patients tumors must be documented to be microsatellite stable (MSS).  
• Patients must have at least 1 focus of metastatic disease that is amenable to pre- and on-
treatment biopsies and be willing to undergo this. 
• All patients enrolled will be required to have measurable disease by RECIST v 1.1 criteria. 
Design: 
• The proposed study is a phase II study of VB-111 in combination with immune checkpoint 
inhibition (nivolumab) in patients with metastatic CRC 
• Treatment will be delivered in cycles consisting of 2 weeks with VB-111 given every 6 
weeks and nivolumab given every 2-week until progression or unacceptable toxicity. 
• Disease status evaluation will be done every 8 (+/- 1) weeks after the start of study therapy. 


Abbreviated Title: VB-111_Nivolumab in mCRC 
Version Date: 01/22/21 
 
3 
TABLE OF CONTENTS  
PRÉCIS .......................................................................................................................................... 2 
TABLE OF CONTENTS ............................................................................................................. 3 
STATEMENT OF COMPLIANCE ............................................................................................ 7 
1 
INTRODUCTION................................................................................................................. 8 
1.1 
STUDY OBJECTIVES ........................................................................................................ 8 
1.1.1 Primary Objectives: .................................................................................................... 8 
1.1.2 Secondary Objectives: ................................................................................................ 8 
1.1.3 Exploratory Objective: ................................................................................................ 8 
1.2 
BACKGROUND AND RATIONALE .................................................................................... 8 
1.2.1 Advanced GI Malignancies ......................................................................................... 8 
1.2.2 Immunotherapy in GI cancers ..................................................................................... 8 
1.2.3 Angiogenesis inhibitors in GI cancers ...................................................................... 10 
1.2.4 Nivolumab................................................................................................................. 11 
1.2.5 VB-111 ...................................................................................................................... 13 
1.2.6 Anti-PD-1 (nivolumab) in combination with VB-111 .............................................. 32 
1.2.7 Rationale for correlative studies. .............................................................................. 33 
2 
ELIGIBILITY ASSESSMENT AND ENROLLMENT .................................................. 34 
2.1 
ELIGIBILITY CRITERIA ................................................................................................ 34 
2.1.1 Inclusion Criteria ...................................................................................................... 34 
2.1.2 Exclusion Criteria ..................................................................................................... 35 
2.1.3 Recruitment Strategies .............................................................................................. 37 
2.2 
SCREENING EVALUATION ............................................................................................ 37 
2.2.1 Screening activities performed prior to obtaining informed consent ........................ 37 
2.2.2 Screening activities performed after a consent for screening has been signed ......... 37 
2.3 
PARTICIPANT REGISTRATION AND STATUS UPDATE PROCEDURES ........................... 38 
2.3.1 Treatment Assignment Procedures (for registration purposes only). ....................... 39 
2.4 
BASELINE EVALUATION ............................................................................................... 39 
3 
STUDY IMPLEMENTATION .......................................................................................... 39 
3.1 
STUDY DESIGN .............................................................................................................. 39 
3.2 
DRUG ADMINISTRATION .............................................................................................. 40 
3.2.1 VB-111 Administration ............................................................................................ 40 
3.2.2 Nivolumab Administration ....................................................................................... 41 
3.2.3 Sequence and Monitoring of Dose Administration .................................................. 41 
3.3 
DOSE DELAY OR MODIFICATION ................................................................................. 41 
3.3.1 Nivolumab................................................................................................................. 42 
3.3.2 VB-111 ...................................................................................................................... 44 
3.4 
STUDY STOPPING RULES .............................................................................................. 44 
3.5 
STUDY CALENDAR ........................................................................................................ 45 
3.6 
COST AND COMPENSATION .......................................................................................... 47 
3.6.1 Costs .......................................................................................................................... 47 
3.6.2 Compensation ........................................................................................................... 47 
3.6.3 Reimbursement ......................................................................................................... 47 


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3.7 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA . 47 
3.7.1 Criteria for Removal from Protocol Therapy: .......................................................... 47 
3.7.2 Off Study Criteria ..................................................................................................... 48 
3.7.3 Lost to Follow-up ...................................................................................................... 48 
4 
CONCOMITANT MEDICATIONS/MEASURES .......................................................... 48 
4.1 
EXCLUDED CONCOMITANT MEDICATIONS ................................................................. 48 
4.2 
METHODS OF CONTRACEPTION ................................................................................... 49 
4.2.1 Female patient of child-bearing potential ................................................................. 49 
4.2.2 Male patient with a female partner of child-bearing potential .................................. 49 
4.2.3 Highly effective methods of contraception ............................................................... 49 
4.3 
BLOOD DONATION ........................................................................................................ 50 
5 
BIOSPECIMEN COLLECTION ...................................................................................... 50 
5.1 
TUMOR SAMPLES .......................................................................................................... 50 
5.2 
SAMPLES FOR GENETIC/GENOMIC ANALYSIS ............................................................. 51 
5.3 
SAMPLE STORAGE, TRACKING AND DISPOSITION....................................................... 51 
5.3.1 Greten Lab Contact Information ............................................................................... 51 
5.3.2 Protocol Completion/Sample Destruction ................................................................ 51 
6 
DATA COLLECTION AND EVALUATION ................................................................. 51 
6.1 
DATA COLLECTION ...................................................................................................... 51 
6.1.1 Data Sharing Plans .................................................................................................... 52 
6.1.2 Genomic data sharing plan ........................................................................................ 53 
6.2 
RESPONSE CRITERIA .................................................................................................... 53 
6.2.1 Disease Parameters ................................................................................................... 53 
6.2.2 Methods for evaluation of measurable disease ......................................................... 54 
6.2.3 Response criteria ....................................................................................................... 54 
6.3 
TOXICITY CRITERIA ..................................................................................................... 57 
7 
NIH REPORTING REQUIREMENTS / DATA SAFETY MONITORING PLAN .... 57 
7.1 
DEFINITIONS ................................................................................................................. 57 
7.2 
OHSRP OFFICE OF COMPLIANCE AND TRAINING REPORTING ................................. 57 
7.2.1 Expedited Reporting ................................................................................................. 57 
7.2.2 IRB Requirements for PI Reporting at Continuing Review ..................................... 57 
7.3 
NCI CLINICAL DIRECTOR REPORTING ....................................................................... 57 
7.4 
INSTITUTIONAL BIOSAFETY COMMITTEE (IBC) REPORTING CRITERIA ................... 57 
7.4.1 Serious Adverse Event Reports to IBC ..................................................................... 57 
7.4.2 Annual Reports to IBC.............................................................................................. 57 
7.4.3 Clinical Trial Information ......................................................................................... 58 
7.4.4 Progress Report and Data Analysis ........................................................................... 58 
7.5 
NIH REQUIRED DATA AND SAFETY MONITORING PLAN ............................................ 58 
7.5.1 Principal Investigator/Research Team. ..................................................................... 58 
7.5.2 Safety Monitoring Committee (SMC) ...................................................................... 59 
8 
SPONSOR PROTOCOL/SAFETY REPORTING .......................................................... 59 
8.1 
DEFINITIONS ................................................................................................................. 59 


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8.1.1 Adverse Event ........................................................................................................... 59 
8.1.2 Serious Adverse Event (SAE) ................................................................................... 59 
8.1.3 Life-threatening......................................................................................................... 60 
8.1.4 Severity ..................................................................................................................... 60 
8.1.5 Relationship to Study Product .................................................................................. 60 
8.2 
ASSESSMENT OF SAFETY EVENTS ................................................................................ 60 
8.3 
REPORTING OF SERIOUS ADVERSE EVENTS ................................................................ 61 
8.4 
WAIVER OF EXPEDITED REPORTING TO CCR ............................................................ 61 
8.5 
SAFETY REPORTING CRITERIA TO THE PHARMACEUTICAL COLLABORATORS ........ 61 
8.6 
REPORTING PREGNANCY ............................................................................................. 61 
8.6.1 Maternal exposure .................................................................................................... 61 
8.6.2 Paternal exposure ...................................................................................................... 62 
8.7 
REGULATORY REPORTING FOR STUDIES CONDUCTED UNDER CCR-SPONSORED IND
 
62 
8.8 
SPONSOR PROTOCOL NON-ADHERENCE REPORTING................................................. 62 
9 
CLINICAL MONITORING .............................................................................................. 62 
10 STATISTICAL CONSIDERATIONS .............................................................................. 63 
10.1 
OBJECTIVES .................................................................................................................. 63 
10.2 
SAMPLE SIZE DETERMINATION ................................................................................... 63 
10.3 
POPULATIONS FOR ANALYSIS ....................................................................................... 64 
10.4 
STATISTICAL ANALYSES .............................................................................................. 64 
10.4.1 
General Approach ................................................................................................. 64 
10.4.2 
Analysis of the Primary Endpoints ....................................................................... 64 
10.4.3 
Analysis of the Secondary Endpoints ................................................................... 64 
10.4.4 
Safety Analyses ..................................................................................................... 64 
10.4.5 
Baseline Descriptive Statistics .............................................................................. 64 
10.4.6 
Planned Interim Analysis ...................................................................................... 64 
10.4.7 
Planned Exploratory Analysis: ............................................................................. 64 
11 COLLABORATIVE AGREEMENTS.............................................................................. 65 
11.1 
COOPERATIVE RESEARCH AND DEVELOPMENT AGREEMENT (CRADA) ................. 65 
12 HUMAN SUBJECTS PROTECTIONS ............................................................................ 65 
12.1 
RATIONALE FOR SUBJECT SELECTION ........................................................................ 65 
12.2 
PARTICIPATION OF CHILDREN ..................................................................................... 65 
12.3 
PARTICIPATION OF SUBJECTS UNABLE TO GIVE CONSENT ........................................ 65 
12.4 
RISK/BENEFIT ASSESSMENT FOR ALL PARTICIPANTS ................................................ 65 
12.4.1 
Known Potential Risks .......................................................................................... 65 
12.4.2 
Known Potential Benefits ..................................................................................... 67 
12.4.3 
Assessment of Potential Risks and Benefits ......................................................... 67 
12.5 
CONSENT PROCESS AND DOCUMENTATION ................................................................ 67 
12.5.1 
Consent Process for Adults Who Lack Capacity to Consent to Research 
Participation .......................................................................................................................... 67 
13 REGULATORY AND OPERATIONAL CONSIDERATIONS .................................... 67 
13.1 
STUDY DISCONTINUATION AND CLOSURE ................................................................... 67 


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13.2 
QUALITY ASSURANCE AND QUALITY CONTROL ......................................................... 68 
13.3 
CONFLICT OF INTEREST POLICY ................................................................................. 68 
13.4 
CONFIDENTIALITY AND PRIVACY ................................................................................ 69 
14 PHARMACEUTICAL INFORMATION ......................................................................... 69 
14.1 
VB-111 (19164) ............................................................................................................ 69 
14.1.1 
Acquisition and Accountability ............................................................................ 69 
14.1.2 
Toxicity ................................................................................................................. 69 
14.1.3 
Formulation and preparation ................................................................................. 70 
14.1.4 
Stability and storage .............................................................................................. 70 
14.1.5 
Administration procedures .................................................................................... 70 
14.2 
NIVOLUMAB .................................................................................................................. 70 
14.2.1 
Source ................................................................................................................... 70 
14.2.2 
Acquisition and Accountability ............................................................................ 70 
14.2.3 
Administration procedures .................................................................................... 70 
15 REFERENCES .................................................................................................................... 71 
16 APPENDICES ..................................................................................................................... 74 
16.1 
APPENDIX A: PERFORMANCE STATUS CRITERIA ....................................................... 74 
16.2 
APPENDIX B: MODIFIED IMMUNE-RELATED RESPONSE CRITERIA (IRRC) .............. 75 
 
 
 


Abbreviated Title: VB-111_Nivolumab in mCRC 
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7 
STATEMENT OF COMPLIANCE 
The trial will be carried out in accordance with International Conference on Harmonisation Good 
Clinical Practice (ICH GCP) and the following:  
• United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 
CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812)  
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of NIH-funded clinical trials have 
completed Human Subjects Protection and ICH GCP Training. 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the Institutional Review Board (IRB) for review and approval. Approval of both 
the protocol and the consent form must be obtained before any participant is enrolled. Any 
amendment to the protocol will require review and approval by the IRB before the changes are 
implemented to the study. In addition, all changes to the consent form will be IRB-approved; an 
IRB determination will be made regarding whether a new consent needs to be obtained from 
participants who provided consent, using a previously approved consent form. 
 
 


Abbreviated Title: VB-111_Nivolumab in mCRC 
Version Date: 01/22/21 
 
8 
1 
INTRODUCTION 
1.1 
STUDY OBJECTIVES 
1.1.1 Primary Objectives: 
• To determine the safety and tolerability of VB-111 in combination with nivolumab in 
patients with refractory, metastatic CRC.  
• To determine Best Overall Response (BOR) (PR+CR) according to Response 
Evaluation Criteria (RECIST v1.1) of combined treatment of VB-111 and nivolumab 
in patients with refractory, metastatic CRC. 
1.1.2 Secondary Objectives: 
• To evaluate a 6-month progression-free survival (PFS). 
• To evaluate progression-free survival (PFS). 
• To evaluate overall survival (OS). 
1.1.3 Exploratory Objective: 
• To evaluate VB-111 adenovector level in the tumor samples of patients treated with 
VB-111 and nivolumab. 
1.2 
BACKGROUND AND RATIONALE 
1.2.1 Advanced GI Malignancies  
Gastrointestinal (GI) cancer (including esophageal, gastric, biliary tree, small bowel, pancreas, and 
colorectal cancers) is one of the most commonly diagnosed categories of malignancies worldwide. 
In 2018, an estimated 609,640 people will die of cancer in the United States, including 50,630 
colorectal cases, 44,330 pancreas cases and 30,200 liver and intrahepatic bile duct cases which 
accounts for 20% of all expected cancer deaths [1, 2]. GI cancers encompass a heterogeneous 
group of malignancies with distinct tumor biology and molecular signatures. However, to some 
extent, many of these tumors share similar characteristics which includes staging, prognosis and 
response to fluoropyrimidines and platinum. In the last decade, understanding the pathophysiology 
of this subset of cancers and expanding treatment options have improved survival in many GI 
cancer patients (i.e. median survival of colon cancer improved from 1 year to well over 2 years), 
yet, advances in other subtypes have been disappointing (i.e. median survival of pancreatic cancer 
remains less than 1 year). Therefore, an unmet need exists to understand and improve currently 
available treatments. 
1.2.2 Immunotherapy in GI cancers 
Although checkpoint inhibitors show responses and efficacy in MSI-H or PD-L1 positive tumors, 
the majority of GI cancers are microsatellite stable with variable PD-L1 expression. Ways to 
manipulate the immune system to achieve an effect like that seen in MSI-H tumors is an ongoing 
area of research. Combination strategies to change an immunosuppressed tumor 
microenvironment to an immune-stimulated environment include using dual checkpoint inhibitors 
(i.e. anti-PD-1 with anti-CTLA4), combining checkpoint inhibitors with radiation to enhance the 
abscopal effect, or combining checkpoint inhibitors with other targeted agents and chemotherapy. 
Select ongoing studies are shown in Table 1, with a majority focusing on MSS tumors.  


Abbreviated Title: VB-111_Nivolumab in mCRC 
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9 
Table 1: ongoing studies.  
GI Cancer Type 
Study Title 
Combination 
Clinical Trial  
Colon 
A study of EDP1503 in patients 
with colorectal cancer, breast 
cancer, and checkpoint inhibitor 
relapsed tumors 
EDP1503 
Pembrolizumab 
NCT03775850 
 
Colon 
Grapiprant and pembrolizumab in 
patients with advanced or 
progressive MSS colorectal cancer 
Grapiprant 
Pembrolizumab 
NCT03658772 
 
Colon 
Gastric 
Hepatocellular 
Combination of TATE and PD-1 
inhibitor in liver cancers 
TATE 
(Transarterial 
tirapazamine 
embolization) 
Nivolumab or 
Pembrolizumab 
NCT03259867 
 
Colon 
Gastric 
Gastroesophageal 
Junction 
Hepatocellular 
Study of cabozantinib in 
combination with atezolizumab in 
subjects with locally advanced or 
metastatic solid tumors 
Cabozantinib 
Atezolizumab 
NCT03170960 
 
Pancreas 
Biliary Tract 
Immune checkpoint inhibition in 
combination with radiation therapy 
in pancreatic cancer or biliary tract 
cancer patients  
Nivolumab 
Ipilimumab 
Radiation 
therapy 
NCT02866383 
 
Pancreas 
Solid Tumors 
Defactinib combined with 
pembrolizumab and gemcitabine in 
patients with advanced cancer 
Defactinib 
Pembrolizumab 
Gemcitabine 
NCT02546531 
 
Cholangiocarcinoma 
Gallbladder Cancer 
Durvalumab and Tremelimumab 
with Gemcitabine or 
Gemcitabine/Cisplatin compared to 
Gemcitabine/Cisplatin in CCA 
patients 
Durvalumab 
Tremelimumab 
Gemcitabine 
Cisplatin 
NCT03473574 
 
 


Abbreviated Title: VB-111_Nivolumab in mCRC 
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10 
1.2.3 Angiogenesis inhibitors in GI cancers  
Monoclonal antibodies (bevacizumab, ramucirumab) and small molecule tyrosine kinase 
inhibitors (regorafenib, ziv-aflibercept) directed against the vascular endothelial growth factor 
(VEGF) are approved agents in the treatment of GI cancers. VEGF and like factors, including 
fibroblast growth factor (FGF), insulin-like growth factor (IGF) and hypoxia inducible factor (HIF-
1) are involved in angiogenesis through various mechanisms including vascular endothelial cell 
proliferation, maintenance and survival. As tumors outgrow their blood supply and undergo 
hypoxic conditions, neovascularization is achievable though stimulation of pro-vascular factors 
like VEGF[1, 2]. This results in a new blood supply allowing tumors to grow and metastasize.  
Bevacizumab, a humanized monoclonal antibody directed against VEGF-A, was the first 
angiogenesis inhibitor approved for the treatment of cancer in the United States, including 
colorectal, ovarian, renal cell, non-small cell lung cancer, glioblastoma, and cervical cancers. In 
metastatic colorectal cancer, several trials have shown a benefit of combining bevacizumab with 
chemotherapy as a first line option[3-7]. In addition, patients who continue on bevacizumab after 
progression were also shown to have a modest improvement in overall survival[8, 9]. Bevacizumab 
was also shown to improve overall survival in patients who started treatment after progression of 
metastatic disease if it was not used in the first line setting[10]. Bevacizumab does not seem 
effective as a single agent[10].  
Ziv-aflibercept is a human IgG1 recombinant protein attached with VEGF receptor 1 and 2 fusion 
to the Fc portion, which functions to inhibit angiogenesis. It was approved as a second line 
treatment option in metastatic colorectal cancer based on a small improvement in overall survival 
when combined with FOLFIRI chemotherapy compared to placebo[11]. This benefit was seen 
regardless of patients’ previous treatment with bevacizumab[12]. It does not work as a first line 
agent and was associated with increased toxicity[13]. It is not approved or been tested for other GI 
malignancies.  
Ramucirumab is a monoclonal antibody that targets the extracellular domain of VEGF receptor 2 
to inhibit VEGF signaling. It is approved as a second line treatment option in combination with 
FOLFIRI or irinotecan in metastatic colorectal cancer based on the RAISE trial[14]. Patients who 
were randomized to the addition of ramucirumab had a 2-month overall survival benefit and a 1-
month improvement in progression free survival compared to placebo. Ramucirumab is also 
approved in metastatic gastric and esophageal cancers as a second line agent either as monotherapy 
or in combination with paclitaxel[15, 16].  
Regorafenib is a small molecule multitargeted kinase inhibitor including VEGF receptor, FGF 
receptor, PDGF receptor, BRAF, KIT and RET. Regorafenib was approved as a third line agent in 
metastatic colorectal cancer based on the CORRECT trial where a 1.5-month overall survival 
benefit was seen compared to placebo and best supportive care[17]. In Asia, patients achieved 2-
month survival benefit compared to placebo[18]. 
Recent evidence suggests that VEGF, in addition to its primary role as a proangiogenic factor, also 
has a role in the immune microenvironment of tumor cells as shown in Table 2.  
 
Table 2: Immune microenvironment of tumor cells 
Cell Type 
Role of VEGF 


Abbreviated Title: VB-111_Nivolumab in mCRC 
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11 
Dendritic 
cells 
Influences function and maturation of DC; enables DC to differentiate into 
an endothelial-like cell[19, 20] 
Macrophages Prevents inflammation during infection[21] 
T 
lymphocytes 
Increase chemotaxis, involved in IFN-gamma production[22] 
Tregs 
Promotes induction and maintenance of Treg in the tumor site[23] 
Tumor cells 
Increases migration, mobility, and invasiveness of tumor cells[24, 25] 
 
Positive preliminary data in hepatocellular cancer, gastric, gastroesophageal junction (GEJ) and 
endometrial cancers suggests that the combination of immune checkpoint inhibitors and 
angiogenesis inhibitors may be synergistic in their effects across various tumor types[26-28]. In 
HCC patients, the anti-PDL1 inhibitor avelumab was used in combination with the anti-VEGF 
inhibitor bevacizumab and was shown to have a 62% partial response regardless of HCC etiology. 
In gastric and GEJ tumors, pembrolizumab and ramucirumab were combined and were shown to 
have a 6-9% response rate regardless of PDL1 status. In addition, in the patients with PDL1 
positivity, the mPFS was 4.6 months compared to 1.9 months and the OS was 14.9 months vs 5.2 
months. In endometrial cancer, the combination of pembrolizumab and lenvatinib demonstrated a 
PFS of 10.1 months. Importantly, a response rate of 50% was seen in MSS patients.  
We propose a novel treatment strategy combining the anti-PD1 inhibitor, nivolumab, with the anti-
angiogenesis inhibitor VB-111, in patients with advanced, refractory CRC.  
1.2.4 Nivolumab 
PD-1 is a negatively regulatory molecule that is expressed transiently following T-cell activation 
and on chronically stimulated T cells characterized by an “exhausted” phenotype. Subsequently, 
PD-1 positive T cells lose function and proliferative capacity while enhancing a suppressive tumor 
microenvironment. PD-1 may act together with other T-cell modulating molecules, including 
CTLA-4, TIM-3, lymphocyte-activation gene 3 (LAG-3) as well as indoleamine-pyrrole 2,3- 
dioxygenase 1 (IDO-1), cytokines, and transforming growth factor beta. Two ligands specific for 
PD-1 have been identified: PD-ligand 1 (PD-L1, also known as B7-H1 or CD274, expressed on 
tumor, antigen-presenting cells [APCs], and dendritic cells [DCs]) and PD-L2 (also known as B7- 
DC or CD273, expressed on endothelial cells). The interaction of PD-1 with PD-L1 and PD-L2 
results in negative regulatory stimuli that down-modulate the activated T-cell immune response 
through SHP-1 phosphatase. PD-L1 expression is found on a number of tumors and is associated 
with poor prognoses based on OS in many tumors.  
Nivolumab is a fully human monoclonal immunoglobulin G4 (IgG4) antibody (HuMAb) that is 
specific for human programmed death-1 (PD-1, cluster of differentiation 279 [CD279]) cell surface 
membrane receptor[29]. Nivolumab binds to cynomolgus monkey PD-1 but not mouse, rat, or 
rabbit molecules. Clinical activity of nivolumab has been evidenced by the recent FDA approval 
in patients with melanoma, non-small cell lung cancer, small cell lung cancer, renal cell carcinoma, 
hepatocellular carcinoma, MSI-H colorectal cancer, urothelial cancer and head and neck cancers.  


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1.2.4.1 Pharmacokinetics 
Pharmacokinetics (PK) of nivolumab was linear in the range of 0.3 to 10 mg/kg, with dose-
proportional increases in maximum serum concentration (Cmax) and area under the concentration- 
time curve from time zero to infinity (AUC0-∞), with low to moderate inter-subject variability 
observed at each dose level[29]. Clearance of nivolumab is independent of dose in the dose range 
(0.1 to 10 mg/kg) and tumor types studied. Body weight normalized dosing showed approximately 
constant trough concentrations over a wide range of body weights. The mean terminal elimination 
half-life of nivolumab is 17 to 25 days consistent with the half-life of endogenous IgG4.  
1.2.4.2 Efficacy 
As mentioned previously, nivolumab has been approved in multiple GI cancers, most notably in 
MSI-H metastatic colorectal cancer with or without the addition of ipilimumab based on the 
CheckMate 142 trial. In the nivolumab only arm, the overall response rate was 31.1% with 69% 
of patients achieving disease control for at least 12 weeks[30]. The 1-year progression free survival 
was 50% and overall survival was 73%. In patients treated with the combination of nivolumab and 
ipilimumab, the overall response rate was 55% and a 12-week disease control rate was achieved 
in 80% of the study population[31]. In addition, the 1-year progression free survival and overall 
survival were 71% and 85%, respectively.  
1.2.4.3 Toxicology 
A maximum tolerated dose (MTD) of nivolumab was not defined[32]. Serious adverse events 
(SAEs) occurred in 32 of 296 patients (11%) similar to the immune-related inflammatory events 
seen with ipilimumab: pneumonitis, vitiligo, colitis, hepatitis, hypophysitis, and thyroiditis (with 
noted pulmonary toxicity resulting in 3 deaths. Renal failure, symptomatic pancreatic and DM, 
neurologic events, and vasculitis have also been reported. In combination with ipilimumab in the 
concurrent-regimen, grade 3 to 4 treatment-related adverse events (AEs) occurred in 32% of 
patients and were manageable. Patients (13%) who discontinued treatment because of study drug- 
related AEs had an ORR (63%) consistent with that of the overall population[31].  
1.2.4.4 Pharmacodynamics/Biomarkers 
Tumor-cell expression (melanoma) of PD-L1 was characterized in combination with ipilimumab 
with the use of IHC staining and pharmacodynamics changes in the peripheral-blood absolute 
lymphocyte count[33]. With PD-L1 positivity defined as expression in at least 5% of tumor cells, 
biopsy specimens from 21 of 56 patients (38%) were PD-L1–positive. Among patients treated with 
the concurrent regimen of nivolumab and ipilimumab, ORs were observed in patients with either 
PD-L1–positive tumor samples (6 of 13 patients) or PD-L1–negative tumor samples (9 of 22). In 
the sequenced regimen cohorts, a higher number of overall responses was seen among patients 
with PD-L1–positive tumor samples (4 of 8 patients) than among patients with PD-L1– negative 
tumor samples (1 of 13) suggesting the possibility that these tumors have higher response rates to 
the combination. The relationship between PDL-1 expression and responses may not be present in 
patients treated with the combination. Tissue expression of PDL-2, interferon-γ (IFN- γ), IDO, and 
positive CD8 T cells are of current interest. Until more reliable data based on standardized 
procedures for tissue collection and assays are available, PD-L1 status cannot be used to select 
patients for treatment at this time.  


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1.2.5 VB-111 
VB-111 (Ofranergene obadenovec) is a vascular disruptive and anti-angiogenic agent developed 
by VBL Therapeutics. VB-111 is a non-replicating adenovector (Ad5, E1 deleted), which contains 
a proprietary modified murine pre-proendothelin promoter (PPE-1-3x) and a Fas-Chimera 
transgene (Fas and human TNF receptor). This transgene is specifically expressed in angiogenic 
endothelial cells[34-36]. In both preclinical and clinical studies, VB-111 has shown highly specific 
and antiangiogenic activity and immunotherapeutic effects.  
1.2.5.1 Mechanism of Action 
VB-111 is a viral cancer-therapy with a dual mechanism of action: vascular disruption and 
induction of a tumor directed immune response. VB-111 is based on an E1 deleted non-replicating 
adenovirus-5 vector which is administered intravenously and is internalized by endothelial cells in 
blood vessels (Figure 1). 
 
Figure 1: VB-111 promotes specific intratumor activation of the immune system, thereby 
inducing antitumor immune response such as seen in viral immune-oncology. 
 
Study data suggested that VB-111 induces an immuno-therapeutic effect. Of 46 patients who 
received at least one dose of 1x1013 Viral Particles (VPs) of VB-111 (in study VB-111-122), 25 
patients of the 46 patients who received VB-111 experienced a fever post-dosing of VB-111. 
Feverish patients demonstrated increased overall survival of 64 weeks, compared to non-feverish 
patients, who had a median overall survival of 34 weeks (p=0.038). The same type of correlation 
with fever was identified in the thyroid cancer clinical study of VB-111 (VB- 111-103). A febrile 
post-dosing response associated with improved survival suggests that VB-111 may induce an 
immune-therapeutic effect response in patients and supports a role of the immune system as part 
of VB-111's mechanism of action[37]. 


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An immunotherapeutic effect was observed in ovarian cancer patients in study VB-111-157 where 
cytotoxic CD8 T-cells and apoptotic cancer cells were detected in biopsied tumor samples 
following treatment with VB-111. 
These findings strengthen VB-111 preclinical data, which showed an elevated immune response 
in tumors of VB-111-treated animals.  
The angiogenesis-specific promoter (PPE-1-3x) leads to expression of a pro-apoptotic protein 
(Fas-TNFR-1 chimeric receptor) specifically on the surface of angiogenic endothelial leading to 
targeted apoptosis of angiogenic blood vessels nourishing the tumor.  
Specificity of PPE-1 promoter to endothelial cells:  
In-vitro studies showed that a luciferase (Luc) reporter gene, delivered by the Ad5PPE-1- Luc 
vector, showed high and specific expression in endothelial cells (Human Umbilical Vein 
Endothelial Cells, HUVEC; Bovine Aortic Endothelial Cells, BAEC), when compared to non-
endothelial cells of non-human origin (Rat Insulinoma cells, RIN) and of human origin (Human 
Cervix Epithelioid Carcinoma, HeLa; HepG2; Human Normal Skin Fibroblasts, NSF) (Figure 2).  
 
 
 
Figure 2: PPE-1 Specific expression (Luc activity) in endothelial and non-endothelial non-human and human 
cell lines transduced by AdPPE-1Luc (blue) and Ad5CMVLuc (red). 
 
Expression of PPE-1-3x promoter in proliferating cell conditions: 
In-vitro studies with proliferating endothelial cells (BAEC) or highly proliferating cells after 
treatment with 40 ng VEGF, transduced with Ad5PPE-1-3X-Luc showed significantly higher Luc 
activity when compared to non-proliferating cells (Figure 3). 


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Figure 3 Higher Luc activity in highly proliferating cells (BAEC transduced with PPE-1x-luceferase.  
 
PPE-1-3x modified promoter to increase specificity: 
To increase the specificity of the murine PPE-1 promoter, a modified PPE-1-3x promoter (1.55 
kb) was developed; by introducing a triplicate of an endothelial specific element between two NheI 
sites[35]. Luciferase activity under this promoter was higher than the activity observed with the 
precursor promoter, when tested both in- vitro in endothelial cells (HUVEC, BAEC) and in vivo, 
in mice with LLC.  
Apoptosis specificity under the PPE-1-3x promoter: 
The specificity of VB-111 (Ad5PPE-1-3x-Fas-c) in induction of apoptosis was assessed by its 
transduction in endothelial (BAEC; HUVEC) and in non-endothelial cells (NSF; Human Bronchial 
Epithelium Cells) resulting in a significant reduction in viability in endothelial cells only (Figure 
4).  


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Figure 4: Apoptosis in endothelial and non-endothelial cells with PPE-1-3x-Fas-c (blue) and 
PPE 1-3x-Luc (red) 
Additionally, the murine PPE-1 promoter contains a hypoxia-responsive element (HRE) that 
increases its expression under hypoxic conditions, as observed in tumor angiogenesis. Angiogenic 
blood vessels are targeted regardless of the status of pro-angiogenic factors/pathways, leading to 
tumor starvation thus, VB-111 can serve as means to de bulk tumor burden even in well-advanced 
metastatic disease. 
The specificity of expression is further induced by endogenous TNF-α, which is enriched in the 
tumor milieu, interacts with the Fas-TNFR-1 receptor, leading to cell apoptosis[35, 36].  
Minimal TNF- α ligand required for activation of FAS chimera gene: 
Infection of endothelial cells with lower levels of VB-111, resulted in only a minimal degree of 
cell death. The addition of 10 ng/ml or more TNFα resulted in 73% decrease in viability of cells, 
48 hours post-transfection (Figure 5). These effects were not observed in non-endothelial cells, or 
in the control Ad-PPE-Luc vector, which did not contain an apoptotic agent. In contrast, the vector 
containing the non-specific CMV promoter induced apoptosis in both endothelial and non-
endothelial cells.  
The Fas pathway effectively mediates cell death in normal and in malignant cells. VBL’s unique 
human Fas-c pro-apoptotic transgene is composed of the extracellular domain of the human 
TNFR1 (Tumor Necrosis Factor Receptor 1, P55) and of the Fas intramembrane and intracellular 
domains. The intracellular Fas gene has been shown to effectively induce cell death. The Fas-c 
transgene hooks this Fas gene to the human TNF receptor. The existence of the ligand (TNF) in 
the tumor milieu enables the activation of the Fas gene in the tumor angiogenic blood vessels, thus 
leading to the specific destruction of these vessels.  


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Figure 5 Combination of VB-111 with minimal TNFa augments the pro-apoptotic effects in 
BAEC cell line 
 
Specificity of PPE-1-3x promoter to angiogenic blood vessels: 
The specificity of the PPE-1-3x promoter to deliver reporter genes to tumor angiogenic tissue was 
evaluated in a tumor angiogenic model (Lewis Lung Carcinoma, LLC). Injections of Ad5PPE-1-
3x-Luc (1x109 PFU/mouse) resulted in high luciferase activity in a metastatic lung with 35-fold 
increased Luc expression in metastatic lungs compared to normal lung and four folds Luc 
expression increase compared to that of the precursor promoter Ad5PPE-1-Luc. Expression levels 
of a nonspecific CMV promoter were minimal in metastatic lung. (Figure 6). 


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Figure 6: Controlled delivery of PPE-1Luc/PPE-1-3x-Luc to metastases in LLC tumor 
model. 
 
Viruses have the ability to kick-start an immune reaction in the tumor, as well as exposing tumor 
neoantigens. In response to the viral infection, cells within the tumor microenvironment secrete 
cytokines that attract and activate immune cells. Exposure and presentation of tumor antigens by 
APCs triggers further immune responses[38]. 
VB-111 was found to render locally activating immuno-oncology inducing infiltration of CD8 T-
cells into the tumor, which is accompanied by apoptosis of tumor cells. This suggests an 
opportunity to combine with other immunomodulatory therapies like immune checkpoint 
blockade.  
1.2.5.2 Pharmacology 
The anti-tumor activity of VB-111 was extensively evaluated in several animal models. The results 
showed that single systemic injection of VB-111 caused tumor growth retardation and massive 
reduction in tumor burden (Figure 7) in LLC induced mice and in B16 melanoma mice models 
and a significant rate of survival prolongation in a rat glioma model. Several combination therapies 
have been tested in the LLC mice model and showed an additive effect.  
 


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Figure 7 Tumor diameter and tumor weight folloing Ad5-PPE-1-3x-Fas-c administartion in 
B16 melanoma model. 
Studies with the tumor angiogenic model (LLC) showed that systemic injections of VB-111 
(1x1011 VPs/mouse) resulted in 75% reduction in tumor burden compared to control. Metastases 
were reduced in a dose-dependent fashion in VB-111 treated mice when compared to control, as 
confirmed by the weight of the lungs, which was significantly reduced for doses of 1x108 – 1x1011 
VPs/mouse. No observable effect on metastases was noted at low virus titers (Figure 8). In the 
highest dose cohort (1x1011 VPs/mouse), most of the lungs appeared to be normal or with small 
metastases. Large metastases were only found in the lungs of vehicle treated mice.  
 


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Figure 8.VB-111 dose response in LLC model in mice. VB-111 injected IV by tail vein 5 
days after primary tumor excision. 
In studies with a U87 glioma model, rats bearing orthotopically implanted tumor cells received 
VB-111 or control. With VB-111 treatment, a significant prolongation of survival was noted in the 
U87 glioma model, with an increase in median survival of 10 days with Log rank analysis 
confirming a significant difference (p=0.024) in favor of treatment. Mean value of luciferase 
activity (photons), used as a surrogate marker for tumor volume was 4.9x106 photons for control 
and 2.4x106 photons for VB-111 treated animals one-week post treatment and showed a continued 
trend for reduced activity in the treatment group thereafter (Figure 9). 


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Figure 9: Luciferase activity (Y axis, counts) over time (X axis, week post implantation). 
 
Several combination therapies have been tested in the LLC mice model, i.e., VB-111+sunitinib, 
(anti-angiogenic agent), VB-111+carboplatin+pemetrexed and VB-111+paclitaxel (chemotherapy 
agents) and have shown additive efficacy. The highest reduction in tumor burden that was achieved 
with a high dose of 1x1011 VPs (above the No Observed Adverse Effect Level – NOAEL), could 
be maintained in the different combination therapies with the lower dose of 1x109 VPs of VB-111.  
Positive efficacy data was seen in preclinical studies assessing combination of VB-111 with Anti-
PD-L1 (Figure 10): 


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Combination of VB-111 with Anti-PD-L1 in Lewis Lung Carcinoma model: 
Study Design: 
 
 
Efficacy Data: 
 
Figure 10: Combination therapy of anti PD-L1 with VB-111 further reduces tumor burden in the Lewis 
Lung Carcinoma model. Male C57BL/6 mice (12-14 weeks) were implanted with 5x105 D122 tumor cells. 
When tumor diameter reached 7mm, the tumor was removed by amputation (day 0). Upon amputation, mice 
were randomly assigned to the different groups. Treatment began 5 days following amputation. VB-111 (1x1011 
or 1x109 VP/mouse IV) was given once on day 5. Anti PD-L1 (200µg/mouse; IP injection) was administered 
on day 5, 8 and 11. The mean number of days from amputation to death for the first three consecutive deaths 
determined the day of sacrifice from amputation for the remaining animals. Lungs were harvested for tumor 
burden evaluation. The combination of VB-111 (109 VPs) and Anti PD-L1 was at least additive and resulted in 
comparable efficacy to VB-111 at 1011 VPs, a 100-fold higher dose. 
 


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Combination Therapy in B16F10 Melanoma Model:  
Study Design:  
 
Male C57BL/6 mice (12-14 weeks) were injected with 2x105 B16F10 melanoma cells 
subcutaneously. When tumor size in the majority of mice reached 100 mm3 (day 9), animals were 
randomly assigned to the different groups based on tumor volume and body weight. VB-111 
(1x1011 VP/mouse IV) was given once on day 9. Anti PD-L1 (200 µg/mouse IP) was administered 
on days 9, 12 and 14.  
The combination of VB-111 and anti PD-L1 resulted in a higher decreased tumor volume 
compared to either agent alone and compared to control (Figure 11).  


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Efficacy Data: 
 
Figure 11: Combination Therapy of Anti PD-L1 with VB-111 Further Reduced Tumor 
Growth in the Mouse B16F10 Melanoma Model. 
 
1.2.5.3 CRC models / models that mimic the limited TIL seen in CRC. 
A study in Colon model in mice examined the efficacy of repeated treatments with 109, 1010 or 
1011 VB-111 VPs on length of survival of mice with CT26 colon carcinoma Table 3, Figure 12.  
We found that mice treated with two doses of 1011, two doses of 109, one dose of 1011 or one dose 
of 1010 VB-111 showed significantly longer survival duration as compared to vehicle-treated mice.  
Additionally, mice treated with one dose of 1011 VB-111 showed significantly longer survival time 
as compared to mice treated with two doses of 1011 or 1010.  
Table 3. Table: Test groups and dose levels 
 
Group No. 
Treatment 
Vector 
Dose 
(vp/mouse) 
No. of Animals 
1 Dosing 
2 Dosing 
Group 1 
VB-111 
1011 
6 
22 
Group 2 
VB-111 
1010 
7 
16 
Group 3 
VB-111 
109 
- 
20 
Group 4 
Vehicle 
- 
 
21 
 
 


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Figure 12. Survival of mice throughout the study. Percentage of surviving mice was 
determined once a week for each group.  
 
1.2.5.4 Toxicology in mice 
The safety of VB-111 was evaluated in two toxicology and biodistribution studies in normal and 
tumor-bearing C57BL/6 Mice. In the first study, VB-111 was administered intravenously (IV) in 
a single dose to both normal and tumor-bearing mice. In the following study two doses were 
administered to normal mice in the same manner in a repeat cycle 30 days after the initial dose. 
IV doses of the adenovirus vector VB-111 (1x109, 1x1010 and 0.8x1011 VPs per mouse) or vehicle 
were administered to C57BL/6 mice, in the single dose study. In the two-cycle repeat dose toxicity 
and biodistribution study of VB-111 in healthy mice, doses of VB-111 (1x109 and 1x1010 VPs per 
mouse) or vehicle were administered IV.  
No clinically significant toxicological findings related to the VB-111 were detected in both studies. 
Some expected tumor-related findings were seen in the tumor bearing mice. Transient responses 
to high dose viral administration were observed, specifically, mild hematological changes, and 
mild microscopic findings consistent with adenovirus vectors effects.  
The NOAEL (no observed adverse effects level) was considered to be 1x1010 VP/mouse 
representing a 3-fold safety margin for the maximum intended human dose (1x1013 VPs).  
1.2.5.5 Biodistribution 
The biodistribution of the VB-111 vector DNA and the transgene expression were investigated in 
mice after a single and a repeat intravenous (IV) administration of 1x109- 1x1011 VPs. Viral DNA 
was shown in virtually all blood and tissue samples collected throughout the study (up to 90 days 
from dosing), with levels significantly decreasing between days 5 and 91 from dosing. Additional 
studies confirmed that the transgene expression is mostly restricted to the tumor, supporting 
product specificity.  
1.2.5.6 Clinical Experience  
Completed Clinical Studies with VB-111 


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To date, VBL’s VB-111 clinical development program includes 4 completed open-label Phase I 
and II clinical trials with approximately 180 cancer patients exposed to VB-111 and one completed 
Phase III study in recurrent glioblastoma multiforme in which 126 patients were exposed to VB-
111 treatment.  
In all studies, the route of administration is multiple intravenous infusions of up to 1x1013 VPs 
every 8 weeks which was demonstrated to be safe and well tolerated. VB-111 is formulated as a 
sterile vector solution. 
VBL performed a Phase 1 “all comers” clinical trial (GT-111001), with single or multiple doses 
of VB-111 in advanced metastatic solid tumors. Results demonstrated safety, tumor response, 
improved survival, trends towards improved progression-free survival and dose-response. 
In the Phase I study the adenovirus vector VB-111 was shown to be present in high copy numbers 
in whole blood directly after the IV infusion. The levels of adenovirus vector subsequently 
decreased with time in whole blood. An analysis of the relationship of time of adenovirus DNA 
clearance from the blood related to level of neutralizing antibodies at baseline showed that the lower 
the baseline levels of neutralizing antibodies, the longer the time DNA was present in the blood. By 
day 56 post dose, levels of Ad-5 decreased by at least 2-log fold or were undetectable. In most 
patients with detectable levels of Adenovirus 5 in the urine, the presence was transient, with levels 
detectable only within the initial 24 hours after the intravenous (IV) infusion of VB-111.  
The expected selective expression of the chimeric transgene was confirmed by the fact that all of 
the blood samples were found to be negative for transgene expression, however the transgene was 
detected in an aspirate from a subcutaneous metastasis. The metastasis was sampled at baseline 
and 4 and 28 days after therapy. Although the pre-dose sample was negative, post dosing samples 
suggested that VB-111 can have a long-term expression within the tumor; the aspirate showed on 
day 4 after treatment 1.4 x 105 copies/mg RNA and on day 28 the expression level was 3.9 x 104 
copies/mg RNA), representing a 72% reduction in the transgene expression over the two time 
points. 
Cytokine and angiogenic biomarker response showed considerable variability in cytokine/cytokine 
receptor levels. An approximately 100-fold increase in IL-6 occurred at 6 hours post-dosing, 
correlating with the fever that occurred at the same time. This elevation was transient, returning to 
pre-infusion levels by day 4. Results also showed transient but smaller increases in IL-8, sTNFR-
1, and sTNFR-2 levels at the 6-hour post-dosing time point. There was no suggestion of a cytokine 
storm. 
Based on above findings the VB-111 dosing interval of Q56 days was chosen. A shorter dosing 
interval of 28 days was assessed in study VB-111-122 in patients with recurrent glioblastoma 
(GBM). However, interpretation of the results of this cohort were inconclusive due to its small 
sample size (10 patients) and the concomitant administration of bevacizumab. However, we 
believe that every 6-week dosing is feasible based on the kinetics of VB-111. As mentioned, by 
approximately 1 month, a significant amount of VB-111 expression has been lost.  
Additional bio-distribution data are available for 24 subjects, of which, 6 subjects received multiple 
doses of VB-111. Findings demonstrate that patients have a uniform peak level of adenovirus DNA of 
approximately 107 copies/μg and, there was no attenuation of peak levels with repeat dosing. All 
patients had rapid clearance of DNA levels within a few hours, with a drop of at least 3 logs or more. 
Some patients retained basal levels between doses, while in others the levels between doses dropped 
to zero. 


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Based on the results from the phase I trial, VB-111 was advanced into tumor specific, repeat dose 
trials including:  
• A Phase 1/2 clinical trial in ovarian cancer (VB-111-157), which combined VB-111 
therapy with the chemotherapeutic agent paclitaxel.  
o The population of the study included Patients ≥18 years of age with progressive 
recurrent platinum resistant or refractory ovarian cancer including epithelial 
ovarian, peritoneal or fallopian tube cancers.  
o Twenty-one patients at two US centers received up to seven repeat doses of VB-
111 in combination with weekly paclitaxel, and 17/21 received the therapeutic 
VB-111 dose. Median age was 65 (41-79) with a median of 3 prior lines of 
therapy.  
o No new toxicities nor DLTs were observed. VB-111 was associated with 
expected flu-like symptoms and mild infusion reactions and the drug was safe 
and well tolerated.  
o The study results showed an increase in OS when comparing the therapeutic 
dose group to the low dose group and to the historical control in the AURELIA 
study; Median overall survival of the 17 patients who received the therapeutic 
dose was 498 days (17 months) vs 172 days (6 months) for patients who 
received sub-therapeutic dose (P=0.03), and compared to 390 days (13 months) 
in the AURELIA study, an open label randomized study comparing 
bevacizumab plus chemotherapy to chemotherapy alone in platinum resistant 
recurrent epithelial ovarian cancer.  
o In an interim analysis, 9 of the 15 evaluable patients (60%) at the therapeutic 
dose level had a CA-125 response (defined as 50% reduction in CA-125).  
o In addition, a durable CA-125 response was observed for non-refractory 
patients treated with the therapeutic dose level and for one refractory patient. 
78% of all patients had stable disease or a partial response (according RECIST 
criteria for evaluation of target lesions).  
o A durable response was seen for five patients (36%), all from the therapeutic 
dose level group. On-study biopsies suggest that further to the anti-angiogenic 
mechanism of action, VB-111 induced antitumor immune reaction with 
increased tumor infiltrating CD8 lymphocytes.  
o VB-111 in combination with weekly paclitaxel appears to be safe and well 
tolerated in ovarian cancer patients. 
• An open-label Phase 1/2 clinical trial in recurrent glioblastoma (VB-111-122), 
evaluating the safety and efficacy of VB-111, both as monotherapy and in combination 
with bevacizumab. The study enrolled a total of 72 patients who were treated in the 
following treatment groups : 
o Sub Therapeutic Dose - VB-111 doses less than 1x1013 VPs (N=19)  
o Therapeutic Dose Limited Exposure - VB-111 at doses of 1x1013 VPs of VB-111 
every 8 weeks until disease progression (N=19) 


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o  VB-111 Primed Combination - VB-111 monotherapy continued upon disease 
progression in combination with bevacizumab (N=24). 
o VB-111 Unprimed Combination – Upfront Combination of VB-111 every 4 weeks 
in combination with biweekly bevacizumab (N=10) 
o The study met its primary endpoint and demonstrated a survival advantage for VB-
111. Patients in the Primed Combination group had median overall survival of 414 
days, compared to 223 days in the Limited Exposure group (Logrank p-value; p= 
0.043). In the Limited Exposure group, the median number of VB-111 doses 
administered to patients was 1 and the mean number of doses was 2.2, compared 
to median of 4 and mean of 4.7 doses on the Primed Combination group. The two 
groups had similar baseline characteristics. 
• A Phase 3, multisite, international, randomized, open-label, controlled trial in 
participants with recurrent GBM (GLOBE) was performed to confirm findings from 
the Phase 2 trial. However, the sequencing of VB-111 and bevacizumab was unlike the 
initial Phase 2 study. In this GLOBE study, bevacizumab was given together with VB-
111 instead of upon progression. Participants were randomized 1:1 to receive VB-111 
at 1013 VPs every 8 weeks in combination with bevacizumab 10mg/kg every 2 weeks 
(combination arm) or monotherapy with bevacizumab 10mg/kg every 2 weeks (control 
arm).  
o The study recruited 256 patients ≥18 years of age with histologically confirmed 
diagnosis of GBM and first or second progression of glioblastoma following 
standard of care treatment upon initial diagnosis with temozolomide and 
radiation.  
o The study did not meet its pre-specified endpoints of overall survival and 
progression free survival. In the combination vs the control arm, median 
exposure to VB-111 was 4 months. Median OS was 6.8 vs 7.9 months (HR 1.2 
[95% CI 0.91-1.59, p=NS]). ORR was 27.3% vs 21.9% (p=0.26), respectively. 
It seems that the change in the treatment regimen and the lack of VB-111 
monotherapy priming may explain the difference from the favorable Phase 2 
outcome. An additional study is planned to further explore the role of priming, 
assessing the effects of single-dose neo-adjuvant VB-111, followed by adjuvant 
treatment. 
• An open-label Phase 2 clinical trial in metastatic RAIR (radioiodine-refractory) advanced 
differentiated thyroid cancer (VB-111-103) evaluating the safety and efficacy of VB- 
111. Study drug was administered as a single intravenous infusion at 3x1012 (Cohort 
1), or at 1x1013 viral particles (VPs) repeated every 2 months (Cohort 2). 
VB-111 was well tolerated in the majority of patients. Adverse effects were generally 
modest, and mainly consist of flu-like symptoms developing shortly after infusion. 
Severe adverse events were rare. The primary endpoint required at least 3 patients out 
of 12 (25%) to attain at least stable disease 6 months after initial dosing. Several 
patients attained lesion responses. Six patients (37%) in Cohort 2 met the primary 
endpoint of 6-month progression free survival, compared to three patients (25%) in 
Cohort 1. The pre-specified primary study endpoint was met, with early evidence of 
disease stabilization demonstrated. 


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All these studies have been closed for recruitment and patients continue to be monitored for 
survival in all studies. Overall, VB-111 has been well tolerated with no signs of drug-related 
clinically significant safety issues reported.  
In GI cancers, a phase I dose escalation study was performed that included patients with advanced 
colorectal and esophageal cancers. Out of 11 CRC patients, 36% achieved stable disease but the 
majority, including the esophageal cancer patient, had early disease progression. However, these 
patients were not treated with the 1x1013 VP as our study proposes. In addition, we believe the 
additive effect of checkpoint inhibition to VB-111 can improve the efficacy of VB-111 as a mono 
therapeutic agent. 
For complete clinical information refer to the Investigator Brochure. 
Ongoing and planned studies with VB-111: 
• A phase III study, VB-111-701 / GOG-3018 is currently ongoing; The OVAL study is a 
Randomized, Controlled, Double-Arm, Double-Blind, Multi-Center Study of Ofranergene 
Obadenovec (VB-111) Combined with Paclitaxel vs. Paclitaxel Combined with Placebo for 
the Treatment of Recurrent Platinum-Resistant Ovarian Cancer. Study is expected to enroll 
400 subjects. 
• A phase II study in recurrent GBM that will be performed in collaboration with the Dana Farber 
Cancer Institute is expected to start enrolling during 2019: A randomized, controlled pilot 
phase II surgical trial to evaluate early immunologic pharmacodynamic parameters for the viral 
cancer therapy ofranergene obadenovec (VB-111) in patients with surgically accessible 
recurrent/progressive glioblastoma. Study is expected to enroll 45 subjects and will explore the 
effects of single-dose neo-adjuvant VB-111, followed by VB-111 adjuvant treatment. 
Repeated doses at an interval of ≤ 6 weeks. 
Rationale: The rationale for increased dosing frequency is to achieve higher transgene expression 
over time and achieve a better FAS-chimera induced apoptosis effect. Monthly MRI analysis of 
tumor response in the first 5 patients in the Phase 2 study VB-111-122 in recurrent GBM, 
demonstrated a recurring pattern where greater tumor suppression was seen in the 1st month 
following dosing compared to the 2nd month post dosing. Results suggested further efficacy may 
be gained with monthly doses, as tumor daily growth rates were reduced in the first month after 
dosing compared to the second month post dosing. It is assumed that more frequent dosing, will 
provide the level of drug needed at the tumor site for the second month and a greater overall 
reduction in tumor size.  
Data supporting safety of dosing frequency intervals ≤ 6 weeks: 
Preclinical Data: Toxicology studies in the LLC mice model with a repeat dose of VB-111 after 
30 days following the initial dose, demonstrated a very good safety profile, similar to that seen for 
the single dose toxicology study, with a No Observed Adverse Effect Level (NOAEL) of 1x1010 
VPs/ mouse, thus supporting a 30-day interval between doses.  
Clinical Data: In study VB-111-122, biodistribution data were collected from 6 subjects with 
recurrent GBM who received at least two doses of VB-111 1x1013 VPs. Findings demonstrate that 
patients have a uniform peak level of adenovirus DNA of approximately 107copies/μg in the blood, 
immediately post VB-111 infusion and there is no attenuation of peak levels with repeat dosing. 
All patients had rapid clearance of viral DNA levels within few hours post infusion, with a drop 


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of at least 3 logs or more by day 4 post infusions with repeat dosing. This elimination of viral DNA 
in the whole blood indicated that there is no accumulation of virus in the blood and supported the 
safety of monthly dosing. Some patients retained basal levels between doses only in the initial few 
doses, while in others the levels between doses dropped to zero from the initial dosing.  
Based on the above rationale and safety data, 10 patients enrolled to study VB-111-122 were 
treated with a combination of VB-111 every 28 days along with concomitant bevacizumab every 
2 weeks. No Dose Limiting Toxicities (DLT) were detected with this regimen. A relatively high 
number of patients reported SAEs (8/10), none of which were considered related to VB-111. One 
SAE (Hypertensive urgency with acute kidney injury) was considered definitely related to 
bevacizumab. Due to the small number of patients in this cohort, and to the concurrent 
administration of bevacizumab it was difficult to reach conclusive data on the safety and efficacy 
of the treatment regimen of concomitant monthly VB-111 and bi-weekly bevacizumab. 
To summarize: we believe that there is sufficient safety data to support VB-111 dosing every 6 
weeks. Based on the kinetics of VB-111 that show that after approximately 1 month, a significant 
amount of VB-111 expression has been lost, dosing frequency higher than every 8 weeks and may 
improve efficacy. 
1.2.5.7 VB-111 Toxicity in human 
VB-111 is most commonly associated with pyrexia, fatigue/asthenia, flu-like illness, nausea, 
headaches and chills. Most of these, including severe reactions, resolved following initiation of 
appropriate medical therapy or withdrawal of VB-111. Expected serious adverse reactions reported 
in previous VB-111 trials is shown in Table 4. Refer to investigator brochure for detailed toxicity 
information.  
The most frequent adverse events observed in the phase I/II trial in Ovarian cancer (VB-111-157) 
include: fatigue (14/20, 70%), nausea (11/20, 55%), pyrexia (9/20, 45%), anemia (9/20, 45%), 
diarrhea (7/20, 35%), headache (6/20, 30%), peripheral sensory neuropathy (6/20, 30%), myalgia 
(5/20, 25%), vomiting (5/20, 25%), and constipation (5/20, 25%). It should be noted that patients 
in this study (VB-111-157) were treated with paclitaxel as well, which may have contributed to 
the occurrence of these adverse events.  
In the phase 3 GLOBE study in patients with recurrent glioblastoma, treatment with a combination 
of VB-111 and bevacizumab was associated with a higher rate of grade 3-4 adverse events (68% 
vs 40%) and SAEs (52% Vs. 30%) compared to bevacizumab monotherapy. This was mainly 
attributed to a higher rate of fever events, and a higher rate of Nervous System events associated 
with the diagnosis of glioblastoma. For complete safety information refer to the Investigator 
Brochure. 
Table 4. Expected Serious Adverse Events by System Organ Class (SOC). 
 
 


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1.2.5.8 Risk of neutralizing antibodies: 
In the phase I study, GT-111001, neutralizing antibodies to Adenovirus 5 measured at baseline 
showed that 18.2% of subjects had highly elevated levels, 42.2% had moderately elevated levels, 
and 39.4% had low levels. No correlation was observed between neutralizing antibody levels at 
baseline and disease state following drug administration. Peak anti-Adenovirus 5 IgG titers were 
also not associated with pre-infusion neutralization titer.  
In study VB-111-122, total and neutralizing antibodies to Adenovirus 5 results show similar 
pattern to the phase 1 study results. Total antibodies were measured in 14 subjects in VB-111-122; 
all subjects had antibodies to Adenovirus 5 at baseline that subsequently increased at least 4-fold 
after treatment with multiple doses of VB-111. At Baseline, 7/27 (25.9%) subjects had 
undetectable levels of neutralizing antibody, and an additional 7/27 (25.9%) had low levels (titer 
<50). We believe that the administered VB-111 dose (1013 viral particles) can overcome existing 
antibodies due to the large amount. Neutralizing antibodies are more relevant for inhibition of 
virus replication and clearance, but adenoviruses can adhere and penetrate cells within minutes, 
while VB-111 is found in the blood for hours after dosing. 
As Adeno 5 is a very common virus, most patients will have pre-dose antibodies to Adenovirus 5 
(neutralizing, total and IgG). In the phase 1 study, GT-111001, all subjects had pre-dose antibody 
levels to Adenovirus 5, and titers increased following VB-111 dosing. Post-dose IgG antibody 
titers increased between 7-fold to 100-fold and then reached a plateau. All post-dose total antibody 
titers to adenovirus 5 increased between 5-fold and 625-fold.  


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There was no correlation between a pre-dose titer and fold increase in level of total anti- Adeno5 
antibodies while a negative correlation was found between the pre-dosing levels and fold increase 
for IgG (higher pre-dose levels resulted with lower fold of increase). There was no apparent 
relationship between doses administered to post-treatment antibody response.  
Baseline levels of neutralizing Adenovirus 5 antibodies ranged between high levels (>620) to low 
levels (≤ 15). No correlation was observed between neutralizing antibody levels at baseline and 
disease state following drug administration. Peak anti-Adenovirus 5 IgG titers were also not 
associated with pre-infusion neutralization titer 
1.2.6 Anti-PD-1 (nivolumab) in combination with VB-111  
Targeting the tumor vasculature by gene therapy with VB-111 has several potential advantages 
including: 
1. Angiogenesis is a crucial factor in the progression of solid tumors and metastasis.  
2. TNFα, which activates the Fas-chimera transgene, is abundant in the tumor microenvironment 
and allows VB-111 to triggers ‘targeted’ apoptosis, resulting in less tissue damage. 
3. Apoptotic tumor epitopes promote an immune response with the viral vector operating 
synergistically as an immune adjuvant. By using a specific endothelial promoter, which is not 
expressed in immune cells, the anti- transgene immune response can be avoided, thus eliminating 
immune reactions to recurrent treatments. 
4. Because of the inherent genetic stability of resting and angiogenic vascular endothelial cells, 
there is less susceptibility than in tumor cells to the emergence of drug resistance. 
5. There is evidence for an immune therapeutic effect of VB-111, based on a viral-immune 
oncology mechanism. There are multiple lines of evidence for the immunological angle of VB-
111, including: 
a. IHC staining of biopsies from ovarian cancer patients showing recruitment of CD8 T- 
cells in tumor from patients treated with VB-111, but not in untreated control samples;  
b. Preclinical histology showing mononuclear infiltrate in tumor sample from VB-111- 
treated mice;  
c. Treatment with VB-111 was associated with fever response that correlated with  
patient's OS; 
d. VB-111 treated patients exhibited a serum cytokine profile that correlated with fever  
and with OS; 
e. Ex-vivo analysis of tumors specimens from mice induced with U251 GBM model, 
demonstrated that tumor microglia recognized VB-111 in vivo and released cytokines that 
promote cytotoxic T-cells response  
6. Pre- preclinical data in LLC and B16F10 Melanoma models demonstrated increased efficacy 
for a combination of VB-111 with a PD-L1 blocker. 
7. The addition of nivolumab to VB-111 may have additive or synergistic activity and is a novel 
therapeutic strategy (Figure 13).  


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33 
 
 
 
Figure 13: The proposed study is a phase II study of VB-111 in combination with immune 
checkpoint inhibition (nivolumab) in patients with advanced refractory colorectal cancer.  
 
1.2.6.1 Dose and treatment regimen justification  
Based on the standard nivolumab dosing approved by the FDA, this study will use nivolumab at 
the flat dose of 240 mg every 2 weeks starting on Day 1 of Cycle 2. This will be in combination 
with VB-111 1 x 1013 every 6 weeks based on the treatment dose listed above.  
1.2.7 Rationale for correlative studies.  
Whilst the preclinical data suggest induction of immune cell infiltration following VB-111 
infusion, with potential for amplification with immune checkpoint therapy, the effect in colorectal 
cancer – a relatively non-immunogenic tumor – is really unknown. This is a small study evaluating 
feasibility and safety of combined therapy. If safe and feasible, next step in development will most 
likely be a larger randomized study. It is scientifically important to obtain as much information 
about the treatment effect as possible at this study. This may lead to altered and improved design 
of the next study. The best strategy for doing this is with tumor biopsies and blood in order to 
evaluate immune cell infiltration profiling (CD4/8 T-cells, MDSC, etc.), measure virus level in 
situ of tumor and exam the change of immune gene signature to have deeper understanding of 
response or resistance to treatment. 
We will perform measurement of virus level in biopsied tumor samples on this protocol. Patients 
will be co-enrolled into our 11C0112 study and all other research studies on tumor and blood 
samples will be performed as explained in protocol 11C0112.  


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2 
ELIGIBILITY ASSESSMENT AND ENROLLMENT  
2.1 
ELIGIBILITY CRITERIA 
2.1.1 Inclusion Criteria 
• Patients must have histopathological confirmation of colorectal cancer.  
• Patients must have radiologically confirmed liver metastasis. 
• Patients must: 
➢ have progressed on > 2 lines of standard of care chemotherapy for colorectal cancer 
OR 
➢ been intolerant of standard of care chemotherapy for colorectal cancer 
OR 
➢ refused prior standard of care chemotherapy for colorectal cancer.  
• Patients who have a known KRAS wild type tumor must have progressed, been intolerant 
of or refused anti-EGFR based treatment.  
• Patients tumors must be documented to be microsatellite stable (MSS).  
• Patients must have at least 1 focus of metastatic disease that is amenable to pre- and on-
treatment biopsies and be willing to undergo this. Ideally, the biopsied lesion should not 
be one of the target measurable lesions, although this can be up to the discretion of the 
investigators 
• Patients must have measurable disease by RECIST v 1.1 criteria (See Section 6.2.2).  
• Age > 18 years. Because no dosing or adverse event data are currently available on the use 
of nivolumab in combination with VB-111 in patients < 18 years of age, children are 
excluded from this study, but will be eligible for future pediatric trials.  
• ECOG performance status 0-1 (Appendix A) 
• Adequate hematological function defined by: 
o white blood cell (WBC) count ≥ 3 × 109/L 
o absolute neutrophil count (ANC) ≥ 1.5 ×109/L 
o lymphocyte count ≥ 0.5 × 109/L 
o platelet count ≥ 100 × 109/L  
o Hgb ≥9 g/ dL (more than 48 hours post-completion of blood transfusion))  
• PT and PTT (seconds) < 1.2 x ULN. Patients who are anticoagulated do not need to meet 
criteria for PT and PTT 
• INR < 1.2 x ULN. Patients who are anticoagulated do not need to meet criteria for INR.  
• Adequate hepatic function defined by: 
o a total bilirubin level ≤ 1.5 × ULN, 


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o an AST level ≤2.5×ULN in the absence of hepatic metastasis; or ≤ 5 x ULN in the 
presence of hepatic metastases, 
o an ALT level ≤2.5 ×ULN in the absence of hepatic metastasis; or ≤ 5 x ULN in the 
presence of hepatic metastases 
• Adequate renal function defined by: 
Creatinine OR 
Measured or calculated 
creatinine clearance 
(CrCl) (eGFR may also 
be used in place of 
CrCl) A 
< 1.5x institution upper limit of normal OR 
> 50 mL/min/1.73 m2 for participant with creatinine levels 
> 1.5 X institutional ULN 
A Creatinine clearance (CrCl) or eGFR should be calculated per institutional standard. 
 
• The effects of nivolumab and VB-111 on the developing human fetus are unknown. For 
this reason, women of child-bearing potential and men must agree to use adequate 
contraception as defined in section 4.2 prior to study entry and for the duration of study 
participation and up to 5 months (women) and 7 months (men) after the last dose of the 
nivolumab or 2 months after the last dose of VB-111 whichever is the longer time period. 
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.  
• Troponin level in normal range at the time of enrollment. 
• Patient must be able to understand and willing to sign a written informed consent 
document.  
• Weight > 35kg 
• Patients must be enrolled in tissue collection protocol 11C0112. 
2.1.2 Exclusion Criteria 
• Patients who have had standard-of-care anti-cancer therapy or therapy with investigational 
agents (e.g. chemotherapy, immunotherapy, endocrine therapy, targeted therapy, biologic 
therapy, tumor embolization, monoclonal antibodies or other investigation agents), large 
field radiotherapy, or major surgery within 4 weeks prior to enrollment.  
• Patients who have had anti-VEGF therapy within 4 weeks prior to enrollment. 
• Patients currently on a corticosteroid dose greater than physiologic replacement dosing 
defined as 10 mg of cortisone per day or its equivalent.  
• Patients with known brain metastases because of their poor prognosis and because they 
often develop progressive neurologic dysfunction that would confound the evaluation of 
neurologic and other adverse events.  
• Patients with signs of liver failure, e.g. clinically significant ascites, encephalopathy, or 
variceal bleeding within 6 months prior to enrollment.  


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• Prior major liver resection: remnant liver <50% of the initial liver volume. Patients with a 
biliary stent can be included.  
• Patients with active autoimmune disease or history of autoimmune disease that might recur, 
which may affect vital organ function or require immune suppressive treatment including 
systemic corticosteroids. These include but are not limited to patients with a history of 
immune related neurologic disease, multiple sclerosis, autoimmune (demyelinating) 
neuropathy, Guillain-Barre syndrome or CIDP, myasthenia gravis; systemic autoimmune 
disease such as SLE, connective tissue diseases, scleroderma, inflammatory bowel disease 
(IBD), Crohn’s, ulcerative colitis, hepatitis; and patients with a history of toxic epidermal 
necrolysis (TEN), Stevens-Johnson syndrome, or phospholipid syndrome. Such diseases 
should be excluded because of the risk of recurrence or exacerbation of disease.  
➢ Of note, patients with vitiligo, endocrine deficiencies including thyroiditis managed 
with replacement hormones including physiologic corticosteroids are eligible. 
Patients with rheumatoid arthritis and other arthropathies, Sjogren’s syndrome and 
psoriasis controlled with topical medication and patients with positive serology, such 
as antinuclear antibodies (ANA), anti-thyroid antibodies should be evaluated for the 
presence of target organ involvement and potential need for systemic treatment but 
should otherwise be eligible.  
• History of idiopathic pulmonary fibrosis (including bronchiolitis obliterans with 
organizing pneumonia) or evidence of active pneumonitis on screening chest CT scan.  
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or 
psychiatric illness/social situations (within timeframes identified in the bullets below) that 
would limit compliance with study requirements.  
• History of severe or unstable cerebrovascular disease.  
• Pulse oximetry < 92% on room air 
• Myocardial infarction within 6 months prior to enrollment 
• History of myocarditis 
• Sustained hypotension (<90/50 mmHg) or uncontrolled hypertension (>160/100 mmHg) 
• Stroke within 6 months prior to enrollment.  
• Patients with proliferative and/or vascular retinopathy. 
• Significant vascular disorders (e.g. aortic aneurysm, requiring surgical repair or recent 
peripheral arterial thrombosis) within 6 months prior to enrollment. 
• History of hemoptysis (> ½ teaspoon of bright red blood per episode) or active GI bleeding 
within 6 months prior to enrollment.  
• Evidence of a bleeding diathesis or significant coagulopathy (in the absence of therapeutic 
anticoagulation). 
• History of abdominal fistula or gastrointestinal perforation within 6 months prior to 
enrollment. 


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• HIV-positive patients are excluded because HIV causes complicated immune deficiency 
and study treatment can possess more risks for these patients.  
• Prior autologous or allogenic hematopoietic stem cell transplant.  
• Subjects with ascites.  
• Patients with unhealed surgical wounds for more than 30 days.  
• History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to nivolumab or VB-111. 
• History of severe hypersensitivity reaction to any monoclonal antibody.  
• Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for 
a minimum of 3 years prior to enrollment.  
• Pregnant women are excluded from this study because nivolumab and VB-111 potential 
for teratogenic or abortifacient effects are unknown. Because there is an unknown but 
potential risk for adverse events in nursing infants secondary to treatment of the mother 
with nivolumab and VB-111, breastfeeding should be discontinued if the mother is treated 
with nivolumab and/or and VB-111. 
2.1.3 Recruitment Strategies  
This study will be posted on the CCR website, www.clinicaltrials.gov and on NIH social media 
forums. Outside providers and colleagues may directly refer patients for screening into this study.  
2.2 
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. 
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 study 
#01-C-0129 on which screening activities will be performed. 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 28 days prior to enrollment unless otherwise noted below.  
• Complete Medical History and Physical Evaluation (including height, weight, vital signs, 
and ECOG performance status). 


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• Laboratory Evaluation  
o Hematological Profile: CBC with differential and platelet count.  
o Biochemical Profile: electrolytes, BUN, creatinine, AST, ALT, total and direct 
bilirubin, calcium, phosphorus, albumin, magnesium.  
 
o PT, INR, PTT 
o ACTH and morning cortisol 
o Thyroid tests TSH, T3, T4 
o Uric acid, amylase and lipase 
o Tumor marker CEA, AFP, CA19-9 
o 24-hour urine collection (if creatinine clearance is tested this way) 
o Serum or urine pregnancy test for female participants of child bearing potential 
(within 2 weeks prior to enrollment)  
o HIV serology 
o TB testing (if clinically indicated) 
o Troponin I  
o Urinalysis 
• Cardiology Consultation (if clinically indicated) 
• Ophthalmologic exam (if clinically indicated) 
• Echocardiogram (if clinically indicated) 
• EKG 
• CT scan of chest, abdomen and pelvis (or MRI of chest, abdomen and pelvis if clinically 
indicated) 
• Documentation of histologic confirmation of colorectal cancer (at any time point prior to 
enrollment). If there is no available documentation, biopsy will be performed to confirm 
the diagnosis.  
• Documentation of microsatellite stable (MSS) status of tumor (results of genetic analysis 
(NGS, PCR) or immunohistochemistry for MLH1, MSH2, MSH6, PMS2 and intact 
nuclear expression from any outside lab). If documentation is not available, 
immunohistochemistry analysis of MLH1, MSH2, MSH6, PMS2 and intact nuclear 
expression will be performed by the Laboratory of Pathology, NCI (at any time point prior 
to enrollment).  
2.3 
PARTICIPANT REGISTRATION AND STATUS UPDATE PROCEDURES 
Registration and status updates (e.g. when a participant is taken off protocol therapy and when a 
participant is taken off-study) will take place per CCR SOP ADCR-2, CCR Participant 
Registration & Status Updates found here.  


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2.3.1 Treatment Assignment Procedures (for registration purposes only). 
Cohorts 
Number 
Name 
Description 
1 
Cohort 1 
Patients with colorectal cancers metastasized to the liver 
 
Arms 
Number 
Name 
Description 
1 
Arm 1 
VB-111 and nivolumab 
Treatment Assignment 
Patients in Cohorts 1 will be directly assigned to Arm 1. 
2.4 
BASELINE EVALUATION  
Tests performed during screening do not need to be repeated if done in designated time frame prior 
to start of study treatment.  
Within 28 days prior to first dose: 
• CT scan of chest, abdomen and pelvis (or MRI of chest, abdomen and pelvis if clinically 
indicated) 
• Echocardiogram (if clinically indicated) 
• HLA subtype 
• Concomitant medications 
• Baseline signs and symptoms 
• Baseline research biopsy (does not need to be repeated if biopsy was done during 
screening)  
3 
STUDY IMPLEMENTATION 
3.1 
STUDY DESIGN 
The proposed study is an open label, single-arm phase II study of VB-111 in combination with 
anti-PD1, nivolumab, in patients with advanced, refractory CRC. 
Treatment will be delivered in cycles consisting of 2 weeks (+/- 3 days).  
VB-111 will be administered every 6 weeks starting on cycle 1 day 1 and nivolumab will be 
administered every 2 weeks starting on cycle 2 day 1 (Schema 1 and Table 5). 
Treatment will continue until off treatment criteria are met (see Section 3.7.1) 
If one of the study drugs is permanently discontinued because of toxicity, the patient may continue 
the other study drug per PI discretion until off treatment criteria are met (Section 3.7.1).  


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Patients will be monitored every 8 (+/- 1) weeks with imaging.  
Treatment will be delivered without planned hospitalization. Admission for logistical reasons is 
allowed (i.e. if patients cannot travel home the same day or biopsies are scheduled etc.) 
Patients will have two mandatory research biopsies: at baseline and either day 1 of cycle 2 (post 
VB-111 but pre-checkpoint inhibitor treatment) or day 1 of cycle 4 (post-VB-111 and checkpoint 
inhibitor treatments). Timing of the research biopsy will be determined in an alternating fashion 
by the research team on a 1:1 basis; i.e. the team will assign patient #1 to early second biopsy 
(day 1 of cycle 2), patient #2 to late second biopsy (day 1 of cycle 4) and so on.  
 
 
 
 
 
Schema 1: Study design. Patients will undergo pre-treatment biopsy and one post-treatment 
biopsy at Day 1 of Cycle 2 or Day 1 of Cycle 4.  
 
Table 5: Treatment regimen 
VB-111, every 6 weeks 
Nivolumab, every 2 weeks 
1x1013 VP IV (for patients with weight > 50kg) 
240 mg IV  
0.7x1013 VP IV (for patients with weight > 35kg and <50 kg) 
 
3.2 
DRUG ADMINISTRATION  
3.2.1 VB-111 Administration 
VB-111 will be given on Day 1 of cycle 1 and continue every 3 cycles (cycles 4, 7, 10 and so on) 
at a flat dose of 1x1013 or 0.7x1013 VP.  
VB-11 should be fully administered within 60 minutes (±30 minutes) after dilution in room 
temperature 0.9% sodium chloride solution. 


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Acetaminophen 500-1000 mg will be administered orally 30 minutes-2 hours prior to VB-111 
infusion and followed by 325-500 mg as needed every 4-6 hours post treatment up to 36 hours. In 
patients who develop > grade 3 fever following VB-111 administration or at the discretion of the 
investigator, dexamethasone IV 10 mg may be administered 20 minutes to 3 hours prior to 
treatment (but no sooner than 20 minutes) in subsequent VB-111 doses. 
3.2.2 Nivolumab Administration 
Nivolumab will be given on day 1 of every cycle starting at cycle 2 at a flat dose of 240 mg. 
Nivolumab will be administered over approximately 30-60 minutes via intravenous infusion.  
Do not administer as an IV push or bolus injection. Administer through a 0.2 micron to 1.2-micron 
pore size, low-protein binding in-line filter. 
3.2.3 Sequence and Monitoring of Dose Administration 
On days when both drugs are given, VB-111 will be given first. Nivolumab infusion will start 
approximately 1 hour after the end of VB-111 infusion.  
Vital signs will be collected within 1 hour before VB-111 and nivolumab infusions, at least once 
during each infusion, and within 30 minutes after the completion of the infusion.  
For nivolumab, in the event of a ≤ Grade 2 infusion-related reaction, the infusion rate of study 
drug may be decreased by 50% or interrupted until resolution of the event and re-initiated at 50% 
of the initial rate until completion of the infusion. Acetaminophen and/or an antihistamine (e.g. 
diphenhydramine) or equivalent medications per institutional standard may be administered at the 
discretion of the investigator. If the infusion related reaction is ≥ Grade 3 or higher in severity, 
study drug will be discontinued.  
As with any antibody, allergic reactions to dose administration are possible. Therefore, appropriate 
drugs and medical equipment to treat acute anaphylactic reactions must be immediately available, 
and study personnel must be trained to recognize and treat anaphylaxis, as per local institutional 
guidelines.  
3.3 
DOSE DELAY OR MODIFICATION 
When, at the beginning of a treatment cycle, when both drugs are administered, treatment delay 
related to either nivolumab or VB-111 is indicated, per PI discretion treatment with the other drug 
does not need to be delayed. 
If there is clear evidence that toxicity is caused by one study drug, per PI discretion treatment with 
another drug may continue. 
It is unclear in terms of the attitude and duration of antitumor efficacy with this drug combination 
in CRCs. If patient’s disease is controlled with the combination but the treatment is held because 
of AEs from one of agents, we think it would be beneficial for participants to continue the other 
agent and continue monitoring the disease progress accordingly. Our ongoing studies with immune 
checkpoint inhibitors demonstrate delayed immune response. In addition, single agents VB-111 or 
nivolumab have shown antitumor effect on certain degree. 
In case of myocarditis developed during treatment, study treatment will be permanently 
discontinued. 


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3.3.1 Nivolumab 
Dose modifications of nivolumab may be required in the event of treatment-related toxicity.  
There are no recommended dose modifications for hypothyroidism or hyperthyroidism. 
Interrupt or slow the rate of infusion in patients with mild or moderate infusion reactions. 
Discontinue nivolumab in patients with severe or life-threatening infusion reactions. 
Recommended Dose Modifications for nivolumab: 
 
Adverse 
Reaction 
Severity* 
Dose Modification 
Colitis 
Grade 2 diarrhea or colitis 
Withhold dosea 
Grade 3 diarrhea or colitis 
Withhold dosea when 
administered as a 
single agent 
Permanently 
discontinue when 
administered with 
VB-111 
Grade 4 diarrhea or colitis 
Permanently discontinue 
Pneumonitis Grade 2 pneumonitis 
Withhold dosea 
Grade 3 or 4 pneumonitis 
Permanently discontinue 
Hepatitis/non
-HCCb 
Aspartate aminotransferase (AST) or alanine 
aminotransferase (ALT) more than 3 and up to 
5 times the upper limit of normal (ULN) or 
total bilirubin more than 1.5 and up to 3 times 
the ULN 
Withhold dosea 
AST or ALT more than 5 times the ULN or 
total bilirubin more than 3 times the ULN 
Permanently discontinue 
Hepatitis/ 
HCCb 
• If AST/ALT is within normal limits at baseline 
and increases to more than 3 and up to 5 times 
the ULN 
• If AST/ALT is more than 1 and up to 3 times 
ULN at baseline and increases to more than 5 
and up to 10 times the ULN 
• If AST/ALT is more than 3 and up to 5 times 
ULN at baseline and increases to more than 8 
and up to 10 times the ULN 
Withhold dosec 


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Adverse 
Reaction 
Severity* 
Dose Modification 
If AST or ALT increases to more than 10 times the 
ULN or total bilirubin increases to more than 3 
times the ULN 
 
Permanently discontinue 
Hypophysitis 
Grade 2 or 3 hypophysitis 
Withhold dosea 
Grade 4 hypophysitis 
Permanently discontinue 
Adrenal 
Insufficiency 
Grade 2 adrenal insufficiency 
Withhold dosea 
Grade 3 or 4 adrenal insufficiency 
Permanently discontinue 
Type 1 
Diabetes 
Mellitus 
Grade 3 hyperglycemia 
Withhold dosea 
Grade 4 hyperglycemia 
Permanently discontinue 
Nephritis and 
Renal 
Dysfunction 
Serum creatinine more than 1.5 and up to 6 times 
the ULN 
Withhold dosea 
Serum creatinine more than 6 times the ULN 
Permanently discontinue 
Skin 
Grade 3 rash or suspected Stevens-Johnson 
syndrome (SJS) or toxic epidermal necrolysis 
(TEN) 
Withhold dosea 
Grade 4 rash or confirmed SJS or TEN 
Permanently discontinue 
Encephalitis 
New-onset moderate or severe neurologic signs or 
symptoms 
Withhold dosea 
Immune-mediated encephalitis 
 
Permanently discontinue 
 
Other 
Other Grade 3 adverse reaction 
First occurrence 
Recurrence of same Grade 3 adverse reactions 
 
Withhold dosea 
Permanently discontinue 
Life-threatening or Grade 4 adverse reaction 
Permanently discontinue 
Grade 3 myocarditis 
Permanently discontinue 
Requirement for 10 mg per day or greater 
prednisone or equivalent for more than 12 weeks 
Permanently discontinue 
Persistent Grade 2 or 3 adverse reactions lasting 
12 weeks or longer 
Permanently discontinue 
 
* Toxicity was graded per National Cancer Institute Common Terminology Criteria for Adverse 
Events. Version 5.0 (NCI CTCAE v5). 


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a Resume treatment when adverse reaction improves to Grade 0 or 1. 
b HCC: hepatocellular carcinoma. 
c Resume treatment when AST/ALT returns to baseline.  
3.3.2 VB-111  
Dose modifications of VB-111 are not allowed.  
VB-111 will be permanently discontinued for:  
• 
Any grade 2 VB-111 related adverse event that has not resolved to grade 1 within 2 weeks 
or requires systemic treatment.  
• 
Any grade 3 non-skin VB-111 related adverse events that has not resolve to grade 2 within 
7 days.  
• 
Any grade 4 VB-111 related adverse event.  
3.4 
STUDY STOPPING RULES  
For safety reasons, the enrollment will be temporarily halted until an expedited safety report is 
sent to and reviewed by the FDA and the SAE has been evaluated by the investigators for either 
of the following events attributable to treatment regimen occurring within 30 days of receiving 
investigational agent:  
➢ One occurrence of grade 5 toxicity  
➢ Two occurrences of grade 4 toxicity 
 
 


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3.5 
STUDY CALENDAR  
 
 
Screening1 
 
Baseline1  
Cycle 1 
Day 1 1 
Subsequent 
Cycles 
Day 1 
28 
Days 
Safety 
FU10,12 
Long 
Term 
FU11, 12 
Nivolumab2 
 
 
 
X 
 
 
VB-1113 
 
 
Every 6 weeks  
 
 
Microsatellite stable (MSS) status4  
X 
 
  
 
 
 
Histologic confirmation of disease  
X 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
Height 
X 
 
 
 
 
 
Physical exam, weight and ECOG 
X 
 
X 
X 
X 
X 
EKG 
X 
 
X 
X 
 
 
HIV serology  
X 
 
 
 
 
 
Cardiology consult 5 
X 
 
X 
X 
 
 
Ophthalmologic exam 5 
X 
 
 
 
 
 
Echocardiogram 5 
X 
X 
 
 
 
 
24-hour urine (if creatinine 
clearance is tested this way) 
X 
 
 
 
 
 
TB testing 5 
X 
 
 
 
 
 
Troponin I  
X 
 
X 
X 
 
 
PT, INR, PTT 
X 
 
X 
X 
X 
 
Urinalysis 
X 
 
 
 
 
 
ACTH and morning cortisol 
X 
 
 
 
 
 
Baseline signs and symptoms 
 
X 
 
 
 
 
HLA 
 
X 
 
 
 
 
Concomitant medications 
 
X 
X 
X 
 
 
Vital Signs 
X 
 
X6 
X6 
X 
 
CBC w/differential, Platelets  
X 
 
X 
X 
X 
X 
Biochemical profile7 
X 
 
X 
X 
X 
X 


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Screening1 
 
Baseline1  
Cycle 1 
Day 1 1 
Subsequent 
Cycles 
Day 1 
28 
Days 
Safety 
FU10,12 
Long 
Term 
FU11, 12 
Thyroid tests TSH, T3, T4 
X 
 
X 
X 
X 
 
Uric acid, amylase and lipase 
X 
 
X 
X 
X 
 
Tumor marker CEA, AFP, CA19-9 
X 
 
X 
X 
X 
 
Serum or urine pregnancy test 
X 
 
X 
X 
 
 
Radiologic Evaluation8 
X 
X 
Every 8 weeks 
 
X 
Adverse event evaluation 
 
 
X 
X 
X 
X 
Tumor biopsy9 
 
X 
 
X 
 
 
Phone call or e-mail for survival 
every 6 months 
 
 
 
 
 
X 
1 Baseline and C1D1 evaluations do not need to be repeated if performed at screening or baseline 
in designated time frame. All evaluations will be done within 72 hours before treatment initiation 
on Day 1 of every cycle. If treatment does not start within 28 days after enrollment, screening 
evaluations will be repeated. Cycle is 14 (+/-3) days. 
2 240 mg of nivolumab via IV infusion on Day 1 of each cycle starting on cycle 2.  
3 1x1013 VP of VB-111 IV on Day 1 of cycle 1 and every +3 cycles (4, 7, 10 and so on). 
Decreased dose of 0.7x1013 VP for patients with weight > 35kg and <50 kg.  
4 confirmed by genetic analysis or immunohistochemistry.  
5 if clinically indicated. 
6 For vital signs see Section 3.2.3. 
7 Biochemical Profile: electrolytes, BUN, creatinine, AST, ALT, total and direct bilirubin, 
calcium, phosphorus, albumin, magnesium.  
8 CT scan of chest, abdomen and pelvis (or MRI of chest, abdomen and pelvis if clinically 
indicated) on screening, baseline and every 8 (+/-1) weeks after start of study therapy. If 
treatment continues after initial estimation of PD, conformational scan will be done 4 weeks (+/- 
1 week) later. If patient is taken off treatment for a reason other than disease progression, 
imaging will continue during Follow UP until disease progression.  
9 Mandatory tumor biopsies will be performed at baseline and on Day 1 of cycle 2 or cycle 4. If 
the patient’s disease progresses before scheduled biopsy, post-treatment biopsy may be 
performed per PI discretion at the time of progression 
10 +/- 1 week 


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11 Follow up visits are planned to be performed at 60 (+/- 14 days) and 90 (+/- 14 days) days 
after treatment discontinuation to evaluate patient’s safety. After this visit, subjects will be 
followed every 6 months (± 1 month) for survival by phone call or e-mail. NOTE: if patient is 
taken off treatment for reason other than disease progression, we will continue to invite patient 
every 8 (+/-1) weeks for imaging studies. Outside scans are acceptable. 
12 If subjects are not willing to come to NIH for FU visits, they will be contacted by phone call or 
e-mail for survival and adverse events. 
 
3.6 
COST AND COMPENSATION 
3.6.1 Costs 
NIH does not bill health insurance companies or participants for any research or related clinical 
care that participants receive at the NIH Clinical Center. If some tests and procedures performed 
outside the NIH Clinical Center, participants may have to pay for these costs if they are not covered 
by insurance company. Medicines that are not part of the study treatment will not be provided or 
paid for by the NIH Clinical Center. 
3.6.2 Compensation 
N/A 
3.6.3 Reimbursement  
This study offers subject reimbursement or payment for travel, lodging and/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 the expenses. Some of the costs may be 
paid directly by the NIH and some may be reimbursed to the subject. Someone will work with 
subjects to provide more information. 
3.7 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA  
Prior to removal from study, efforts must be made to have all subjects complete a safety visit 
approximately 90 days following the last dose of study therapy.  
3.7.1 Criteria for Removal from Protocol Therapy:  
• 
Participant requests to be withdrawn from active therapy  
• 
Unacceptable toxicity as described in Section 3.3  
• 
Positive pregnancy test or intent to become pregnant  
• 
Investigator discretion  
• 
Initiation of therapy that prevents further administration of study treatment  
• 
Progressive Disease. NOTE: While RECIST PD will be noted and recorded, the immune-
related RECIST criteria (Appendix B) and conformational scan will be applied to 
determine discontinuation of study treatment.  
• 
Intercurrent illness that prevents further administration of treatment.  


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3.7.2 Off Study Criteria  
• 
Lost to follow-up  
• 
Death  
• 
Participant requests to be withdrawn from study  
• 
Investigator discretion  
• 
PI decision to end the study  
3.7.3 Lost to Follow-up 
A participant will be considered lost to follow-up if he or she fails to return for 3 scheduled visits 
and is unable to be contacted by the study site staff.  
The following actions must be taken if a participant fails to return to the clinic for a required study 
visit: 
• The site will attempt to contact the participant and reschedule the missed visits and counsel 
the participant on the importance of maintaining the assigned visit schedule and ascertain 
if the participant wishes to and/or should continue in the study. 
• Before a participant is deemed lost to follow-up, the investigator or designee will make 
every effort to regain contact with the participant (telephone calls and if necessary, a 
certified letter to the participant’s last known mailing address or local equivalent methods). 
These contact attempts should be documented in the participant’s medical record or study 
file.  
Should the participant continue to be unreachable, he or she will be considered to have withdrawn 
from the study with a primary reason of lost to follow-up.  
4 
CONCOMITANT MEDICATIONS/MEASURES 
All routine and appropriate supportive care (including blood products) will be provided during this 
study, as clinically indicated, and in accordance with the standard of care practices. Clinical 
judgment should be utilized in the treatment of any AE experienced by the patient.  
4.1 
EXCLUDED CONCOMITANT MEDICATIONS 
Prohibited medication/class of drug 
Usage 
Any investigational anticancer therapy other 
than those under investigation in this study  
Should not be given concomitantly whilst the 
patient is on study treatment 
mAbs against CTLA-4, PD-1, or PD-L1 other 
than those under investigation in this study  
Should not be given concomitantly whilst the 
patient is on study treatment  
Any concurrent chemotherapy, radiotherapy, 
immunotherapy, or biologic or hormonal 
therapy for cancer treatment other than those 
under investigation in this study  
 
Should not be given concomitantly whilst the 
patient is on study treatment. (Concurrent use 
of hormones for non- cancer-related 
conditions [e.g. insulin for diabetes and 
hormone replacement therapy] is acceptable. 
Local treatment of isolated lesions, excluding 
target lesions, for palliative intent is 


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acceptable [e.g. by local surgery or 
radiotherapy])  
Immunosuppressive medications including, 
but not limited to, systemic corticosteroids at 
doses exceeding 10 mg/day of prednisone or 
equivalent, methotrexate, azathioprine, and 
tumor necrosis factor-α blockers  
Should not be given concomitantly. (Use of 
immunosuppressive medications for the 
management of IP-related AEs, premedication 
for patients who had infusion reaction, or in 
patients with contrast allergies is acceptable). 
In addition, use of inhaled, topical, and 
intranasal corticosteroids is permitted.  
 
4.2 
METHODS OF CONTRACEPTION 
4.2.1 Female patient of child-bearing potential 
Females of childbearing potential who are sexually active with a non-sterilized male partner must 
use effective method of contraception (Table 6) from the time of screening and must agree to 
continue using such precautions for 5 months after the last dose of nivolumab + VB-111 
combination therapy. Non-sterilized male partners of a female patient must use male condom plus 
spermicide throughout this period. Cessation of birth control after this point should be discussed 
with a responsible physician. Not engaging in sexual activity for the total duration of the drug 
treatment and the drug washout period is an acceptable practice; however, periodic abstinence, the 
rhythm method, and the withdrawal method are not acceptable methods of birth control. Female 
patients should also refrain from breastfeeding throughout this period.  
4.2.2 Male patient with a female partner of child-bearing potential  
Non-sterilized males who are sexually active with a female partner of childbearing potential must 
use a male condom plus spermicide from screening through 7 months after the last dose of 
nivolumab + VB-111 combination therapy. Not engaging in sexual activity is an acceptable 
practice; however, occasional abstinence, the rhythm method, and the withdrawal method are not 
acceptable methods of contraception. Male patients should refrain from sperm donation throughout 
this period. 
Female partners (of childbearing potential) of male patients must also use a highly effective 
method of contraception throughout this period (Table 6).  
4.2.3 Highly effective methods of contraception  
Highly effective methods of contraception, defined as one that results in a low failure rate (i.e. 
less than 1% per year) when used consistently and correctly are described in Table 6. Note that 
some contraception methods are not considered highly effective (e.g. male or female condom 
with or without spermicide; female cap, diaphragm, or sponge with or without spermicide; non-
copper containing intrauterine device; progestogen-only oral hormonal contraceptive pills where 
inhibition of ovulation is not the primary mode of action [excluding Cerazette/desogestrel which 
is considered highly effective]; and triphasic combined oral contraceptive pills).  
Table 6: Highly effective methods of contraception (<1% failure rate) 


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4.3 
BLOOD DONATION 
Subjects should not donate blood while participating in this study, and for 5 months (women) 
and 7 months (men) after the last dose of nivolumab or VB-111 therapy.  
5 
BIOSPECIMEN COLLECTION 
5.1 
TUMOR SAMPLES 
Mandatory tumor biopsies will be performed at baseline and either on day 1 of cycle 2 (assessing 
VB-111) or day 1 of cycle 4 (assessing both agents). If the patient’s disease progresses before 
scheduled biopsy, post-treatment biopsy may be performed per PI discretion at the time of 
progression. It is preferred that at least two core biopsies ≥18 gauge in diameter and ≥1 cm in 
length will be obtained.  
During screening the investigators and Interventional Radiology (IR) team will discuss if there is 
a site appropriate for biopsy with minimal risk to the participant. In collaboration with 
interventional radiology we have been doing research biopsies on many, many patients. All 
patients treated had stage IV (metastatic) disease and one of the safest place to get biopsies was 
the liver. In very, very rare cases (if IR doctors feel that it safe to biopsy another area) we may also 
get biopsies from lung metastasis, lymph nodes or lesions within the abdominal wall etc. This will 
be always decided at our multidisciplinary tumor board and we only enroll patients where our 
colleagues from IR feel that it will be safe to obtain biopsies. Ultimately the IR doctor will let us 
know which the best and safest location is (which again is the liver in more than 90% of the cases). 
The use of imaging to facilitate biopsies will be decided by members of the Interventional 
Radiology team and may include ultrasound, CT scan, PET scan or MRI.  
Tumor samples will be first evaluated for clinical diagnosis (performed by the LP). Samples will 
be used for measurement of VB-111 adenovector level in the tumor. Leftover samples will be 
transferred to protocol 11C0112 for research and storage with enrollment of patients into 11-C-
0112 (mandatory on this study).  


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5.2 
SAMPLES FOR GENETIC/GENOMIC ANALYSIS 
Tumor samples will be used to measure VB-111 adenovector level in the tumor by RT-PCR in the 
Lab of Dr. Greten.  
5.3 
SAMPLE STORAGE, TRACKING AND DISPOSITION 
Samples 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. Samples 
will not be sent outside NIH without appropriate approvals and/or agreements, if required. 
All samples will be barcoded, with data entered and stored in the secure databases. These databases 
create a unique barcode ID for every sample and sample box, which cannot be traced back to 
patients without database access. The data recorded for each sample includes the patient ID, name, 
trial name/protocol number, time drawn, cycle time point, dose, material type, as well as box and 
freezer location. Patient demographics associated with the clinical center patient number are 
provided in the system. For each sample, there are notes associated with the processing method 
(delay in sample processing, storage conditions on the ward, etc.). 
Barcoded samples are stored in barcoded boxes in a locked freezer at either -20 or -800C according 
to stability requirements.  
Access to stored clinical samples is restricted. Samples will be stored until requested by a 
researcher named on the protocol. All requests are monitored and tracked in database. All 
researchers are required to sign a form stating that the samples are only to be used for research 
purposes associated with this trial (as per the IRB approved protocol) and that any unused samples 
must be returned. It is the responsibility of the NCI Principal Investigator to ensure that the samples 
requested are being used in a manner consistent with IRB approval. 
5.3.1 Greten Lab Contact Information 
Contact information: 
Sophie Wang 
Building 10 Rm 3B44 
Phone: 240-858-3218 
E-mail: sophie.wang@nih.gov 
5.3.2 Protocol Completion/Sample Destruction 
All specimens obtained in the protocol are used as defined in the protocol. Any specimens that are 
remaining at the completion of the protocol specified experiments will be transferred and stored at 
protocol 11C0112 with enrollment of patients into protocol 11C0112.  
The PI will record any loss or unanticipated destruction of samples including as a deviation. 
Reports will be made per the requirements of section 7.2. 
6 
DATA COLLECTION AND EVALUATION  
6.1 
DATA COLLECTION 
The PI will be responsible for overseeing entry of data into an in-house password protected 
electronic system C3D and Labmatrix ensuring data accuracy, consistency and timeliness. The 


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principal investigator, associate investigators/research nurses and/or a contracted data manager 
will assist with the data management efforts. All 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 of Cycle 1, through 90 days after 
removal from study treatment. After 90 days, 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.  
Adverse Events of grade 1 will not be collected.  
The results of the full diagnostic workup, blood and sputum culture, hematological parameters etc. 
will be captured in the eCRF.  
Information on all concomitant medications, administered blood products, as well as interventions 
occurring during the study must be recorded on the patient’s eCRF in C3D.  
CRF for collection of AEs in C3D will be designed to attribute separately causality for VB-111 
and the causality for nivolumab since their safety profile is very much different.  
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 breech in our plan to protect 
subject confidentiality and trial data has occurred, this will be reported expeditiously per 
requirements in section 7.2.1.  
6.1.1 Data Sharing Plans 
Human data sharing plan. 
The PI will share coded linked human data generated in this research for future research  
• in a NIH-funded or approved public repository: clinicaltrials.gov and dbGaP 
• in BTRIS 
• with approved outside collaborators under appropriate agreements  


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• in publication and/or public presentations  
at the time of publication or shortly thereafter.  
6.1.2 Genomic data sharing plan  
Genomic Data Sharing Policy does not apply for this study, as only VB-111 adenovector level 
measured by RT-PCR will be done on this study.  
6.2 
RESPONSE CRITERIA  
For the purposes of this study, patients should be re-evaluated for response every 8 weeks (+/- 1 
week). 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 
(version 1.1)[39, 40] and modified immune-related response (Appendix B). 
Whilst immune-related RECIST criteria will be taken into consideration regarding continuation of 
therapy in the event of growth, standard RECIST criteria will be the primary method used for 
evaluation of the primary endpoint. 
The study treatment may continue according to the investigator’s decision in case of progressive 
disease according to RECIST 1.1. For this situation, modified Immune-Related response criteria 
(irRC) based on RECIST 1.1 in all subjects without worsening of existing symptoms or developing 
new tumor-related symptoms at the time of progression will be used.  
If treatment continues after initial estimation of PD, conformational scan will be done 4 weeks (+/- 
1 week) later. If PD is confirmed with this scan, patient will be taken off study treatment.  
6.2.1 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/pericardial 
effusions, lymphangitis cutis/pneumonitis, inflammatory breast disease, and abdominal masses 
(not followed by CT or MRI), are considered as non-measurable.  


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Note: Cystic lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts.  
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions, if 
they meet the definition of measurability described above. However, if non-cystic lesions are 
present in the same 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.  
6.2.2 Methods for evaluation of measurable disease  
All measurements should be taken and recorded in metric notation using a ruler or calipers. All 
baseline evaluations should be performed as closely as possible to the beginning of treatment and 
never more than 4 weeks before the beginning of the treatment.  
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.  
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).  
6.2.3 Response criteria  
6.2.3.1 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.  


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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.  
6.2.3.2 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.  
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).  
6.2.3.3 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)  


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For patients with non-measurable disease (i.e., non-target disease) 
 
 
 
*‘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  
6.2.3.4 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.  


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6.3 
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_50).  
7 
NIH REPORTING REQUIREMENTS / DATA 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 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.  
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 
INSTITUTIONAL BIOSAFETY COMMITTEE (IBC) REPORTING CRITERIA 
7.4.1 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 VB-111 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 the VB-111, but are not fatal or life-threatening, must 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. 
7.4.2 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 


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continuing review report can be sent to the IBC in lieu of a separate report. Please include the IBC 
protocol number on the report. 
7.4.3 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.  
7.4.4 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 
7.5 
NIH REQUIRED DATA AND SAFETY MONITORING PLAN 
7.5.1 Principal Investigator/Research Team. 
The clinical research team will meet approximately weekly when patients are being actively treated 
on the trial to discuss each patient.  


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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 
7.2.1 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. 
7.5.2 Safety Monitoring Committee (SMC) 
This protocol will be periodically reviewed by an intramural Safety Monitoring Committee. 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 based on the risks presented 
in the study. For initial and subsequent reviews, protocols will not be reviewed if there is no accrual 
within the review period.  
The SMC review will focus on unexpected protocol-specific safety issues that are identified during 
the conduct of the clinical trial. 
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 PROTOCOL/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. 


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o A hospitalization/admission that is solely driven by non-medical reasons (e.g., 
hospitalization for patient or subject convenience) is not considered a serious adverse 
event.  
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 6.1. 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 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 
Death or hospitalization that is deemed to be due to disease progression, and not attributable to the 
intervention, will not be reported as an SAE. The event, and the assessment that it was caused by 
disease progression will be documented in the medical records. The causality assessment of 
hospitalization will be re-evaluated any time when new information is received. If the causality 
assessment changes from disease progression to related to the study intervention, SAE report will 
be sent to the Sponsor immediately in an expedited manner  according to section 8.3. If there is 
any uncertainty whether the intervention is a contributing factor to the event, the event should be 
reported as AE or SAE as appropriate. 
8.5 
SAFETY REPORTING CRITERIA TO THE PHARMACEUTICAL COLLABORATORS 
Reporting will be per the collaborative agreement 
8.6 
REPORTING PREGNANCY  
8.6.1 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 become 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. 


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8.6.2 Paternal exposure 
Male patients should refrain from fathering a child or donating sperm during the study and for 7 
months after the last dose of nivolumab or 2 months after the last dose of VB-111 whichever is the 
longer time period. 
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 7 months after the last dose 
of nivolumab or 2 months after the last dose of VB-111 should, if possible, be followed up and 
documented. 
8.7 
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. 
8.8 
SPONSOR PROTOCOL NON-ADHERENCE REPORTING 
Protocol non-adherence is defined as any noncompliance with the clinical trial protocol, GCP, or 
protocol-specific procedural requirements on the part of the participant, the Investigator, or the 
study site staff inclusive of site personnel performing procedures or providing services in support 
of the clinical trial. 
It is the responsibility of the study Staff to document any protocol non-adherence identified by the 
Staff or the site Monitor on the OSRO Site Protocol Non-Adherence Log. The protocol-specific, 
cumulative non-adherence log should be maintained in the site essential documents file and 
submitted to OSRO via OSROMonitoring@mail.NIH.gov on the first business day of each 
month over the duration of the study. In addition, any non-adherence to the protocol should be 
documented in the participant’s source records and reported to the local IRB per their guidelines. 
OSRO required protocol non-adherence reporting is consistent with E6(R2) GCP: Integrated 
Addendum to ICH E6(R1): 4.5 Compliance with Protocol; 5.18.3 (a), and 5.20 Noncompliance; 
and ICH E3 16.2.2 Protocol deviations. 
9 
CLINICAL MONITORING  
Clinical site monitoring is conducted to ensure that the rights of the participants are protected, that 
the study is implemented per the approved protocol, Good Clinical Practice and standard operating 
procedures, and that the quality and integrity of study data and data collection methods are 
maintained. Monitoring for this study will be performed by NCI CCR Office of Sponsor and 
Regulatory Oversight (OSRO) Monitoring based on OSRO standards, FDA Guidance E6(R2) 
Good Clinical Practice: Integrated Addendum to ICH E6(R1) March 2018, and applicable 
regulatory requirements. 
Details of clinical site monitoring will be documented in a Clinical Monitoring Plan (CMP) 
developed by OSRO. CMPs will be protocol-specific, risk-based and tailored to address human 


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subject protections and integrity of the study data. The intensity and frequency of monitoring will 
be based on several factors, including study type, phase, risk, complexity, expected enrollment 
rate, and any unique attributes of the study and the site. OSRO Monitoring visits and related 
activities will be conducted throughout the life cycle of each protocol, with the first activity being 
before study start to conduct a Site Assessment Visit (SAV) (as warranted), followed by a Site 
Initiation Visit (SIV), Interim Monitoring Visit(s) (IMVs), and a study Close-Out Visit (COV). 
Some monitoring activities may be performed remotely, while others will take place at the study 
site(s). Monitoring visit reports will describe visit activities, observations, findings of protocol 
non-adherence and associated action items or follow-up required for resolution of findings. 
Monitoring reports will be distributed to the study PI, NCI CCR QA, coordinating center (if 
applicable) and the OSRO regulatory file. 
If protocol non-adherence is identified by the Monitor (i.e., any noncompliance with the clinical 
trial protocol, GCP, or protocol-specific procedural requirements on the part of the participant, the 
Investigator, or the site Staff) the Monitor will note the observation, review with site Staff and if 
unresolved, request that the Staff document the non-adherence on the protocol-specific OSRO Site 
Protocol Non-Adherence Log (see Section 8.8). 
10 STATISTICAL CONSIDERATIONS 
10.1 OBJECTIVES  
Primary: 
➢ To determine the safety and tolerability of VB-111 in combination with nivolumab in 
patients with refractory, metastatic CRC.  
➢ To determine Best Overall Response (BOR) (PR+CR) according to Response Evaluation 
Criteria (RECIST v1.1) of combined treatment of VB-111 and nivolumab in patients with 
refractory, metastatic CRC.  
Secondary: 
➢ To evaluate a 6-month progression-free survival. 
➢ To evaluate progression-free survival. 
➢ To evaluate overall survival 
10.2 SAMPLE SIZE DETERMINATION 
The safety and tolerability will be evaluated on all patients who receive at least one dose of both 
agents; the sample size will be determined by the efficacy endpoint. 
Based on previous experience, patients with mCRC who have failed other treatments are unlikely 
to experience a clinical response to a single agent. However, it would be desirable if the response 
rate could exceed 10% in patients who are treated with this combination. This trial will be 
conducted using a Simon optimal two-stage phase II trial design (Simon R, Controlled Clinical 
Trials 10:1-10, 1989) to rule out an unacceptably low response rate (CR+PR) of 5% (p0=0.05) in 
favor of an improved response rate of 25% (p1=0.25). With alpha=0.10 (probability of accepting 
a poor treatment=0.10) and beta = 0.10 (probability of rejecting a good treatment=0.10), the first 
stage will enroll 9 evaluable patients, and if 0 of the 9 has a response, then no further patients will 
be accrued. If 1 or more of the first 9 patients have a response, then accrual would continue until 


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a total of 24 evaluable patients have been treated. As it may take up to several months to determine 
if a patient has experienced a response, a temporary pause in the accrual may be necessary to 
ensure that enrollment to the second stage is warranted. If there are 1-2 patients with a response 
out of 24 patients, this would be an uninterestingly low response rate. If there were 3 or more of 
24 (12.5%) who experienced a response, this would be sufficiently interesting to warrant further 
study in later trials. Under the null hypothesis (5% response rate), the probability of early 
termination is 63.0%. 
It is expected that 2.5 years may be required to enroll up to 24 evaluable patients. To allow for a 
small number of inevaluable patients, the accrual ceiling will be set at 27 patients. 
10.3 POPULATIONS FOR ANALYSIS  
Intention to treat: any subjects who enroll onto the trial and provide consent and who receive at 
least one dose of either agent will be included in the safety evaluations, and those who receive a 
least one dose of both agents will be included in the efficacy evaluations. 
10.4 STATISTICAL ANALYSES  
10.4.1 General Approach 
Following a determination of safety and tolerability based on reporting toxicities, the fraction of 
all evaluable patients who experience a response will be reported along with confidence intervals.  
10.4.2 Analysis of the Primary Endpoints 
The toxicity grades and types per patient will be tabulated and reported. 
The fraction of evaluable patients who experience a response (PR+CR) will be reported along with 
a 95% two-sided confidence interval. 
10.4.3 Analysis of the Secondary Endpoints 
PFS and OS will be determined using the Kaplan-Meier method, and the median PFS and OS will 
be reported along with 95% confidence intervals. 
10.4.4 Safety Analyses  
The fraction of patients who experience a toxicity, by grade and type of toxicity, will be tabulated. 
10.4.5 Baseline Descriptive Statistics  
Baseline demographic characteristics will be reported. 
10.4.6 Planned Interim Analysis 
As indicated in the two-stage design, the number of responses after 9 evaluable patients have been 
treated will be noted and will be used to determine if enrollment to the second stage of accrual 
may proceed. 
10.4.7 Planned Exploratory Analysis: 
VB-111 adenovector level in the blood and tumor samples of patients treated with VB-111 will be 
measured by RT-PCR. Results will be analyzed using descriptive statistics including confidence 
intervals when appropriate. Any statistical tests performed for evaluation of exploratory objective 
will be done without formal adjustment for multiple comparisons, but in the context of the number 
of tests performed. 


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11 COLLABORATIVE AGREEMENTS 
11.1 COOPERATIVE RESEARCH AND DEVELOPMENT AGREEMENT (CRADA) 
The CRADA #03295 is in place between NCI, NIH and VBL Therapeutics, the manufacturer of 
VB-111.  
12 HUMAN SUBJECTS PROTECTIONS  
12.1 RATIONALE FOR SUBJECT SELECTION 
This study was designed to include women and minorities but was not designed to measure 
differences of intervention effects. Males and females will be recruited with no preference to 
gender. No exclusion to this study will be based on race. Minorities will actively be recruited to 
participate.  
12.2 PARTICIPATION OF CHILDREN 
Children (younger than 18 years) will not be included in this protocol due to the limited data on 
nivolumab and VB-111 in children and the different biology of childhood malignancies.  
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 Error! Reference source not found.), 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 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 to assess ongoing 
capacity of the subjects and to identify a LAR, as needed. 
Please see section 12.5.1 for consent procedure.  
12.4 RISK/BENEFIT ASSESSMENT FOR ALL PARTICIPANTS  
12.4.1 Known Potential Risks 
The primary risk to patients participating in this research study is from the toxicity of nivolumab 
and VB-111. Risks of nivolumab are discussed in nivolumab package insert and risks of VB-111 
are discussed in section 1.2.5.7 and the current version of VB-111 Investigators Brochure. 
Intestinal perforation has been reported as a very rare event possibly associated with the treatment 
of VB-111 (please, see Investigators Brochure for VB-111). 
Intestinal perforation is an uncommon occurrence in colorectal cancer that has been diagnosed and 
usually undergone surgical resection, adjuvant chemotherapy or treatment for further advanced 
stages of CRC. Within populations of patients with CRC reported in the literature, those with and 
intestinal perforation are usually presenting with the disease; this is the first manifestation of the 
CRC and they usually undergo emergency surgery. Intestinal perforation is not reported in the 
literature as a common or expected complication seen in patients with diagnosed CRC who have 
already undergone surgical and systemic treatment as those that will be included in this protocol 
[41, 42]. 


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We believe that patients with CRC treated on this trial would not be at any higher risk than other 
populations of cancer patients currently being studied and treated with VB-111. 
12.4.1.1 Risk of biopsy  
All care will be taken to minimize risks that may be incurred by tumor sampling. However, there 
are procedure-related risks (such as bleeding, infection and visceral injury) that will be explained 
fully during informed consent.  
12.4.1.2 Risks of sedation 
Biopsies will be done under sedation. Potential side effects of sedation include headache, nausea 
and drowsiness. These side effects usually go away quickly. 
12.4.1.3 Risks of exposure to ionizing radiation  
The study will involve radiation from the following sources: 
• Up to 7 CT scans per year for disease assessment 
• 2 CT scans for the collection of 2 mandatory biopsies 
Subjects in this study may be exposed to approximately 9.3 rem per year. This amount is more 
than would be expected from everyday background radiation. Being exposed to excess radiation 
can increase the risk of cancer. The risk of getting cancer from the radiation exposure in this study 
is 0.9 out of 100 (0.9%) and of getting a fatal cancer is 0.5 out of 100 (0.5%). 
12.4.1.4 Risks of CT Scans 
In addition to the radiation risks discussed above, CT scans may include the risks of an allergic 
reaction to the contrast. Participants might experience hives, itching, headache, difficulty 
breathing, increased heartrate and swelling. 
12.4.1.5 Risks of Blood Collection  
Risks of blood draws include pain and bruising in the area where the needle is placed, 
lightheadedness, and rarely, fainting. When large amounts of blood are collected, low red blood 
cell count (anemia) can develop. 
12.4.1.6 Risks of EKG 
Risks include some minor skin irritation from the electrodes. 
12.4.1.7 Risk of losing data  
This includes the risk that data obtained during this study can be released to members of the public, 
insurers, employers, or law enforcement agencies. Although there are no plans to release results to 
the patients, family members or health care providers, this risk will be included in the informed 
consent document.  
12.4.1.8 Other Risks  
Risks include the possible occurrence of any of a range of side effects which are listed in the 
Consent Document or this protocol document. Frequent monitoring for adverse effects will help 
to minimize the risks associated with administration of the study agents.  


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12.4.2 Known Potential Benefits  
The study drug may help to control the disease. The results may help the investigators learn more 
about the disease and develop new treatments for patients with this disease.  
12.4.3 Assessment of Potential Risks and Benefits 
Metastatic Colorectal Cancer (mCRC) treatment needs improved therapy options. Currently 
running studies suggest that use of VB-111 in combination with nivolumab may have tremendous 
anti-tumor efficacy.  
A number of clinically appropriate strategies to minimize risks to patients have been built into the 
protocol through the means of inclusion/exclusion criteria, monitoring strategies, and management 
guidelines. Overall, the potential benefit of the use of VB-111 in combination with nivolumab in 
subjects with mCRC outweigh the risks associated with this drug. 
The potential benefit to a patient that participates in this study is better control of their tumor 
growth and disease recurrence which may or may not have a favorable impact on symptoms and/or 
survival. 
Potential adverse reactions attributable to the administration of the study drugs utilized in this trial 
are discussed in Sections 1.2.4.3 and 1.2.5.7. All care will be taken to minimize side effects, but 
they can be unpredictable in nature and severity. 
12.5 CONSENT PROCESS AND DOCUMENTATION  
The informed consent document will be provided to the participant or consent designee(s) (e.g., 
legally authorized representative [LAR] for reconsent purposes if participant is an adult unable to 
consent) for review prior to consenting. A designated study investigator will carefully explain the 
procedures and tests involved in this study, and the associated risks, discomforts and benefits. In 
order to minimize potential coercion, as much time as is needed to review the document will be 
given, including an opportunity to discuss it with friends, family members and/or other advisors, 
and to ask questions of any designated study investigator. A signed informed consent document 
will be obtained prior to entry onto the study. 
The initial consent process as well as re-consent, when required, may take place in person or 
remotely (e.g., via telephone or other NIH approved remote platforms) per discretion of the 
designated study investigator and with the agreement of the participant. Whether in person or 
remote, the privacy of the subject will be maintained. Consenting investigators (and participant, 
when in person) will be located in a private area (e.g., clinic consult room). When consent is 
conducted remotely, the participant will be informed of the private nature of the discussion and 
will be encouraged to relocate to a more private setting if needed. 
12.5.1 Consent Process for Adults Who Lack Capacity to Consent to Research Participation 
For participants addressed in section 12.3, an LAR will be identified consistent with Policy 403 
and informed consent obtained from the LAR, as described in Section 12.5 
13 REGULATORY AND OPERATIONAL CONSIDERATIONS 
13.1 STUDY DISCONTINUATION AND CLOSURE 
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause. Written notification, documenting the reason for study suspension or 
termination, will be provided by the suspending or terminating party to study participants, 


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associate investigators, the Investigational New Drug (IND) sponsor and regulatory authorities. If 
the study is prematurely terminated or suspended, the Principal Investigator (PI) will promptly 
inform study participants, the Institutional Review Board (IRB), and sponsor and will provide the 
reason(s) for the termination or suspension. Study participants will be contacted, as applicable, 
and be informed of changes to study visit schedule. 
Circumstances that may warrant termination or suspension include, but are not limited to: 
• Determination of unexpected, significant, or unacceptable risk to participants 
• Demonstration of efficacy that would warrant stopping  
• Insufficient compliance to protocol requirements 
• Data that are not sufficiently complete and/or evaluable 
• Determination that the primary endpoint has been met 
• Determination of futility 
Study may resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy the sponsor, IRB and as applicable, Food and Drug Administration (FDA). 
13.2 QUALITY ASSURANCE AND QUALITY CONTROL 
The clinical site will perform internal quality management of study conduct, data and biological 
specimen collection, documentation and completion. An individualized quality management plan 
will be developed to describe a site’s quality management. 
Quality control (QC) procedures will be implemented beginning with the data entry system and 
data QC checks that will be run on the database will be generated. Any missing data or data 
anomalies will be communicated to the site(s) for clarification/resolution. 
Following written Standard Operating Procedures (SOPs), the monitors will verify that the clinical 
trial is conducted and data are generated and biological specimens are collected, documented 
(recorded), and reported in compliance with the protocol, International Conference on 
Harmonisation Good Clinical Practice (ICH GCP), and applicable regulatory requirements (e.g., 
Good Laboratory Practices (GLP), Good Manufacturing Practices (GMP)).  
The investigational site will provide direct access to all trial related sites, source data/documents, 
and reports for the purpose of monitoring and auditing by the sponsor, and inspection by local and 
regulatory authorities. 
13.3 CONFLICT OF INTEREST POLICY 
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical. Therefore, any actual conflict of interest of persons who have 
a role in the design, conduct, analysis, publication, or any aspect of this trial will be disclosed and 
managed. Furthermore, persons who have a perceived conflict of interest will be required to have 
such conflicts managed in a way that is appropriate to their participation in the design and conduct 
of this trial. The study leadership in conjunction with the NCI has established policies and 
procedures for all study group members to disclose all conflicts of interest and will establish a 
mechanism for the management of all reported dualities of interest. 


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69 
13.4 CONFIDENTIALITY AND PRIVACY 
Participant confidentiality and privacy is strictly held in trust by the participating investigators, 
their staff, and the sponsor. This confidentiality is extended to cover testing of biological samples 
and genetic tests in addition to the clinical information relating to participants. Therefore, the study 
protocol, documentation, data, and all other information generated will be held in strict confidence. 
No information concerning the study or the data will be released to any unauthorized third party 
without prior written approval of the sponsor.  
All research activities will be conducted in as private a setting as possible. 
The study monitor, other authorized representatives of the sponsor, representatives of the 
Institutional Review Board (IRB), and/or regulatory agencies may inspect all documents and 
records required to be maintained by the investigator, including but not limited to, medical records 
(office, clinic, or hospital) and pharmacy records for the participants in this study. The clinical 
study site will permit access to such records. 
The study participant’s contact information will be securely stored at each clinical site for internal 
use during the study. At the end of the study, all records will continue to be kept in a secure location 
for as long a period as dictated by the reviewing IRB, Institutional policies, or sponsor 
requirements. 
Study participant research data will not include the participant’s contact or identifying information. 
Rather, individual participants and their research data will be identified by a unique study 
identification number. The study data entry and study management systems used by clinical sites 
will be secured and password protected. At the end of the study, all study databases will be 
archived at the NIH Clinical Center. 
To further protect the privacy of study participants, a Certificate of Confidentiality has been issued 
by the National Institutes of Health (NIH).  This certificate protects identifiable research 
information from forced disclosure. It allows the investigator and others who have access to 
research records to refuse to disclose identifying information on research participation in any civil, 
criminal, administrative, legislative, or other proceeding, whether at the federal, state, or local 
level. By protecting researchers and institutions from being compelled to disclose information that 
would identify research participants, Certificates of Confidentiality help achieve the research 
objectives and promote participation in studies by helping assure confidentiality and privacy to 
participants.  
14 PHARMACEUTICAL INFORMATION  
14.1 VB-111 (19164) 
14.1.1 Acquisition and Accountability 
VBL Therapeutics will supply investigational VB-111. Study drug vials will be supplied in 10 ml 
glass vials. Each vial contains a volume of 5 mL (1012 VP/mL).  
VB-111 will be delivered directly to the NIH Pharmacy. Individual IV bags will be prepared for 
each study participant according to assigned dose by NIH Pharmacy personnel. IV bags will be 
delivered from NIH Pharmacy to patient unit where drug will be infused to the patient 
14.1.2 Toxicity 
Please, see section 1.2.5.7. 


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70 
14.1.3 Formulation and preparation 
VB-111 is a formulated as a sterile vector solution. The solution is supplied frozen (below -65°C), 
in single use, 10 ml glass vials. Each vial contains 5ml of vector at a viral titre of 1012 VP/ml and 
vehicle (10% glycerol in Phosphate Buffered Saline). The vector solution should be thawed and 
maintained on ice until dilution. VB-111 is diluted in room temperature 0.9% sodium chloride 
solution and maintained at this temperature until administration. Note that if needed, the drug may 
be maintained on ice for up to 3 hours before the dilution. Once the drug is in its final formulation 
in saline, keep at room temperature until administration. 
14.1.4 Stability and storage 
A shelf-life of 48 months at or below -65°C.  
Open and/or diluted vials SHOULD NOT BE RE-USED. 
VB-111 vials should be stored in closed vials frozen (at or below -65°C). 
14.1.5 Administration procedures 
Please see section 3.2.1. 
14.2 NIVOLUMAB  
Please refer to the package insert for additional information. 
14.2.1 Source 
Nivolumab will be provided by the NIH Clinical Center Pharmacy according to standard pharmacy 
procedures. 
14.2.2 Acquisition and Accountability 
Nivolumab will be delivered directly to the NIH Pharmacy. Individual IV bags will be prepared 
for each study participant according to assigned dose by NIH Pharmacy personnel. IV bags will 
be delivered from NIH Pharmacy to patient unit where drug will be infused to the patient.  
14.2.3 Administration procedures  
Please see section 3.2.2.  
 
 


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71 
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Riboldi, E., et al., Cutting edge: proangiogenic properties of alternatively activated 
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gamma production. J Immunol, 2010. 184(2): p. 545-9. 
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regulatory T-cells in malignant effusions. Anticancer Res, 2009. 29(3): p. 881-8. 
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and migration involves expression and activation of matrix metalloproteinases. Int J 
Cancer, 2006. 118(4): p. 879-88. 
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Dias, S., et al., Vascular endothelial growth factor (VEGF)-C signaling through FLT-4 
(VEGFR-3) mediates leukemic cell proliferation, survival, and resistance to 
chemotherapy. Blood, 2002. 99(6): p. 2179-84. 


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26. 
S, S., Safety and clinical activity of 1L atezolizumab + bevacizumab in a phase 1b study 
in hepatocellular carcinoma (HCC). 2018. 
27. 
RS, H., Activity of ramucirumab (R) with pembrolizumab (P) by PD-L1 expression in 
advanced solid tumors: phase 1a/b study in later lines of therapy. 2018. 
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Lok, B.H., et al., PARP Inhibitor Activity Correlates with SLFN11 Expression and 
Demonstrates Synergy with Temozolomide in Small Cell Lung Cancer. Clinical Cancer 
Research, 2017. 23(2): p. 523-535. 
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Nivolumab Investigator Brochure, BMS-936558, MDX1 106. 2013. 
30. 
Overman, M.J., et al., Nivolumab in patients with metastatic DNA mismatch repair-
deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-
label, multicentre, phase 2 study. Lancet Oncol, 2017. 18(9): p. 1182-1191. 
31. 
Overman, M.J., et al., Durable Clinical Benefit With Nivolumab Plus Ipilimumab in DNA 
Mismatch Repair-Deficient/Microsatellite Instability-High Metastatic Colorectal Cancer. 
J Clin Oncol, 2018. 36(8): p. 773-779. 
32. 
Topalian, S.L., et al., Safety, activity, and immune correlates of anti-PD-1 antibody in 
cancer. N Engl J Med, 2012. 366(26): p. 2443-54. 
33. 
Wolchok, J.D., et al., Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med, 
2013. 369(2): p. 122-33. 
34. 
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the murine preproendothelin-1 promoter. J Clin Invest, 1995. 95(3): p. 1335-44. 
35. 
Varda-Bloom, N., et al., Tissue-specific gene therapy directed to tumor angiogenesis. 
Gene Ther, 2001. 8(11): p. 819-27. 
36. 
Greenberger, S., et al., Transcription-controlled gene therapy against tumor 
angiogenesis. J Clin Invest, 2004. 113(7): p. 1017-24. 
37. 
RT, P., Tumor Responses and Preliminary Survival Data in A Phase 2 Trial of 
Ofranergene Obadenovec (VB-111) Combined with Paclitaxel in Patients with Recurrent 
Platinum-Resistant Ovarian Cancer. ASCO Poster, 2016. 
38. 
Lichty, B.D., et al., Going viral with cancer immunotherapy. Nat Rev Cancer, 2014. 
14(8): p. 559-67. 
39. 
Eisenhauer, E.A., et al., New response evaluation criteria in solid tumours: revised 
RECIST guideline (version 1.1). Eur J Cancer, 2009. 45(2): p. 228-47. 
40. 
Wolchok, J.D., et al., Guidelines for the evaluation of immune therapy activity in solid 
tumors: immune-related response criteria. Clin Cancer Res, 2009. 15(23): p. 7412-20. 
41. 
Asano, H., et al., Postoperative recurrence and risk factors of colorectal cancer 
perforation. Int J Colorectal Dis, 2017. 32(3): p. 419-424. 
42. 
Banaszkiewicz, Z., et al., Colorectal cancer with intestinal perforation - a retrospective 
analysis of treatment outcomes. Contemp Oncol (Pozn), 2014. 18(6): p. 414-8. 
 
 
 


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16 APPENDICES  
16.1 APPENDIX A: PERFORMANCE STATUS CRITERIA  
 
 
 
 
 
 
 
 
 
 
 
 


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75 
16.2 APPENDIX B: MODIFIED IMMUNE-RELATED RESPONSE CRITERIA (IRRC) 
 
 
 
 
 
 
 
 
Overall responses derived from changes in index, non-index and new lesions 


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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: 01/22/2021
Page 1 of 20
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
PRINCIPAL INVESTIGATOR: Tim Greten, M.D.
STUDY TITLE:
Phase II trial of VB-111 in Combination with Nivolumab in Patients with 
Metastatic Colorectal Cancer (mCRC)
STUDY SITE: 
NIH Clinical Center
Cohort:                       Affected Patient 
Consent Version:       01/22/2021
WHO DO YOU CONTACT ABOUT THIS STUDY? 
Tim Greten, MD, by phone at 240-760-6114 or email Tim.greten@nih.gov 
KEY INFORMATION ABOUT THIS RESEARCH 
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). 
This section provides the information we believe is most helpful and important to you in making 
your decision about participating in this study. Additional information that may help you make 
a decision can be found in other sections of the document. Taking part in research at the NIH is 
your choice.
You are being asked to take part in this study because you have microsatellite stable (MSS) 
colorectal cancer that has spread to the liver. Colorectal cancer tumors are often characterized 
by an “MSI status,” meaning they will either be Microsatellite Instable (MSI) or 
Microsatellite Stable (MSS). MSI tumors can’t correct mistakes that occur when DNA is copied 
in the cell and as a result have a lot of microsatellites - short, repeated pieces of DNA. MSS 
tumors do not have large number of microsatellites, but they still have a lot of mistakes in DNA 
and abnormal number of chromosomes.
The purpose of this study is to see if using a combination of VB-111 and nivolumab is safe and 
will cause your tumors to shrink. 
The use of VB-111 in this study is considered investigational which means it has not been 
approved by the U.S. Food and Drug Administration (FDA) to treat colorectal cancer. However, 
the FDA has given us permission to use VB-111 in this study. VB-111 is a genetically 
inactivated adenovirus, modified in the lab to disrupt blood vessels which feed the tumors. It 
also and produces human proteins that help to activate your immune system. Adenoviruses are 
very common viruses that cause cold-like symptoms, sore throat, bronchitis, pneumonia, 
diarrhea, or pink eye. You can get an adenovirus infection at any age and most likely you have 
IRB NUMBER: 20C0022
IRB APPROVAL DATE: 02/16/2021


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 01/22/2021
Page 2 of 20
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
already had one. You will not be infected by VB-111 that we give you, but you may have 
symptoms similar to a cold. 
Nivolumab has been approved by the U.S. Food and Drug Administration (FDA) for patients 
with microsatellite unstable (MSI), but not microsatellite stable (MSS) colorectal cancer. 
Nivolumab is an agent that targets and blocks a pathway that prevents your immune system from 
effectively fighting your cancer.
There are other standard of care drugs and/or procedures that may be used to treat your disease, 
and these can be given to you by your regular cancer doctor if you are not in this study. For 
example: there is chemotherapy and group of drugs called kinase (regorafenib) or phosphorylase 
(tipiracil) inhibitors. You can also participate in another clinical trial using drugs called immune 
checkpoint inhibitors (such as durvalumab, cabozantinib or pembrolizumab). The treatment 
given in this study and the known possible side effects may or may not be significantly different 
than if you were to receive standard care or being in another clinical trial. For example: 
chemotherapy cause fatigue, hair loss, bruising and bleeding, infection, low blood cell counts. 
Inhibitors are known to cause changes in blood counts, high blood pressure and slow wound 
healing. Immune checkpoint inhibitors may cause inflammation of the lung, intestines or liver, 
and kidney, heart, or problems of the nervous system. Any of these treatments can cause nausea, 
vomiting, diarrhea and rash.
One study drug, nivolumab, is a checkpoint inhibitor and has similar side effects to those listed 
above. The most common side effects of VB-111 include flu-like symptoms, such as fever, 
chills, tiredness, headache and muscle pain.
If you decide to join this study, here are some of the most important things that you should know 
that will happen:

First, we will perform tests to find out if you fit the study requirements. We will do 
standard blood tests and scans to test your health and see the status of your disease.

It is very important to us to understand how your tumor is affected by study treatment. 
To answer this question, we will collect tumor biopsies (samples) from you before 
treatment and after starting treatment. You can only take part in this study if you agree 
to these biopsies. The most common risks of biopsy include pain and the chance of 
bleeding at the site of the biopsy. The site of biopsies will be determined by a group of 
doctors to obtain the safest possible location, most commonly the liver.

If you fit the study requirements and decide to take part, you will start your treatment 
with VB-111 and nivolumab and then we will need to see you at the Clinical Center 
every 14 days while you are receiving treatment. You will get your treatment without 
hospitalization, except that you might be admitted for biopsy and spend a night in the 
hospital. Each visit should last no more than 8 hours.

If your doctor is convinced that you have unacceptable side effects caused by one of 
treatment drugs, this drug will be stopped, and you may continue treatment with the other 
drug if your study doctor finds that it is in your best interest.
IRB NUMBER: 20C0022
IRB APPROVAL DATE: 02/16/2021


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 01/22/2021
Page 3 of 20
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY

As described above and later in more detail in this consent form, you may have side 
effects if you take part in this study. Some can be mild or very serious and may include 
death. You will be seen regularly during the study. You will have clinical, laboratory, 
and imaging tests to see how you are doing and see how your disease is responding. We 
will also collect required samples from you (such as: blood and urine) for clinical 
purposes.

After the study treatment has ended, we would like to see you in the Clinical Center 
monthly for 3 months to check on your health. After that we are planning to contact you 
by phone or e-mail to learn about your health status, and to see how you are doing, for 
the rest of your life or until the study is stopped. If you stop treatment for reasons other 
than worsening of your disease, we will continue to invite you for imaging studies 
approximately every 8 weeks until worsening of your disease. You can have these 
studies at home institution and send us results.
You should not donate blood while participating on this study, and for at least 5 month (if you 
are women) and 7 months (if you are men) following your last infusion of nivolumab or 2 month 
following last infusion of VB-111 whichever is the longer time period.
This study may benefit you by shrinking of your tumor or lessening of your symptoms, such as 
pain, that are caused by the cancer. Even if you do not benefit from this study, the results from 
our research will help others in the future.
You are free to stop taking part in the trial at any time. If you decide to stop, the study doctor 
may ask you to agree to certain tests to make sure it is safe for you to stop.
The remaining document will now describe more about the research study. This information 
should be considered before you make your choice. 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.
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. 
IRB NUMBER: 20C0022
IRB APPROVAL DATE: 02/16/2021


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 01/22/2021
Page 4 of 20
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
WHY IS THIS STUDY BEING DONE?
This is a research study. The purpose of this study is to see if treating of your cancer with 
combination of VB-111 and nivolumab is safe and will cause your tumors to shrink.
We are asking you to join this research study because you have microsatellite stable (MSS) 
colorectal cancer that has spread to the liver. Colorectal cancer tumors are often characterized by 
an “MSI status,” meaning they will either be Microsatellite Instable (MSI) or Microsatellite Stable 
(MSS). MSI tumors can’t correct mistakes that occur when DNA is copied in the cell and as a 
result have a lot of microsatellites - short, repeated pieces of DNA. MSS tumors do not have large 
number of microsatellites, but they still have a lot of mistakes in DNA and abnormal number of 
chromosomes.
VB-111 is considered investigational which means it has not been approved by the U.S. Food and 
Drug Administration (FDA) to treat colorectal cancer. VB-111 is designed to destroy blood vessels 
which feed the tumors and produce human proteins, that help to activate your immune system. 
Nivolumab has been approved by the U.S. Food and Drug Administration (FDA) for patients with 
microsatellite unstable (MSI), but not microsatellite stable (MSS) colorectal cancer. Nivolumab is 
an agent that targets and blocks a pathway that prevents your immune system from effectively 
fighting your cancer. 
WHAT WILL HAPPEN DURING THE STUDY?
VB-111 and/or nivolumab will be given to you by IV (through an intravenous catheter, a small 
plastic tube that is put into a vein, usually in your arm) on Day 1 of treatment cycles (1 Cycle = 14 
days).
VB-111 will be started on cycle 1 and continue every +3 cycles (cycles 4, 7, 10 and so on). 
Nivolumab will be started on cycle 2 and continue every cycle.
If your doctor is convinced that you have unacceptable side effects caused by one of treatment 
drugs, this drug will be stopped, and you may continue treatment with the other drug if your study 
doctor finds that it is in your interest. Treatment will continue until you have unacceptable side 
effects (both drugs) or you are no longer benefiting from the study therapy.
Treatment and all study related procedures will be done during outpatient visits without planned 
hospitalization.  However, we might still choose to keep your overnight if needed for biopsies and 
other situations that arise.
Before you begin the study
Before you begin this study, you will need to have standard clinical exams and tests to make sure 
you are eligible for this study. The exams and tests are part of regular cancer care. Most of these 
tests will be done under a separate protocol. 
You will be asked to provide a pathology report or similar documentation to confirm your 
diagnosis. If this documentation is not available, we will perform a biopsy (collect a sample of 
your tumor) to confirm your diagnosis.
IRB NUMBER: 20C0022
IRB APPROVAL DATE: 02/16/2021


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 01/22/2021
Page 5 of 20
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
You also need to agree to participate in our sample collection protocol 11C0112. 
If treatment does not start within 28 days after enrollment to this study, some tests may need to be 
repeated.
During the study
Procedures before treatment performed only once:

Blood test to evaluate human leukocyte antigen (HLA). HLAs are markers on most cells 
in your body and your immune system uses these markers to recognize which cells belong 
in your body and which do not.

Echocardiogram - ultrasound of your heart to evaluate your heart if your study doctor 
thinks it is needed
Ongoing procedures before treatment and with every cycle: 

Physical examination, including weight and vital signs.

Review of your symptoms, medications and your ability to perform your normal activities.

Discussion of any symptoms you might be having

Routine blood tests to find out if you are anemic, have low blood counts, and if your liver, 
kidneys, thyroid, clotting system and other organs are working well.

Blood tests to check tumor markers.

Electrocardiogram (EKG – a record of your heartbeat) to evaluate your heart.

Pregnancy test if you are a woman who can have children.
Ongoing procedures before treatment and every 4 cycles:

Imaging assessments/scans – a CT (a series of x-ray images taken of parts of your body) 
of chest, abdomen and pelvis. 
Blood draws 
You will have blood drawn to monitor your health during the study (about 4 tablespoons each 
visit/cycle). 
Additional research testing
In addition to performing the tests described above, we will also do tests for research purposes 
only. Two required tumor biopsies will be collected before therapy and after 2 or 6 weeks on study. 
If your disease gets worse before you can have this second biopsy, your doctor might choose to 
collect the biopsy at the time your disease worsens.  Please see section Risks from Biopsy for 
possible risks of biopsy. If you have a biopsy during screening to confirm your diagnosis, the 
baseline biopsy should not need to be repeated. You can take part in the study only if you agree to 
have the biopsy procedures.  
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Tumor samples collected for research purposes on this study will be used to find out if VB-111 
can be detected in the tumor. 
When you are finished taking the drugs (treatment)
Approximately 28, 60 and 90 days after you have finished taking the study drug, you will be asked 
to return to Clinical Center for a safety follow up visits. At these visits, you will be asked questions 
about your health, get a physical exam and undergo blood tests. 
If you have been taken off treatment for reasons other than worsening of your disease, you will 
continue to have imaging studies approximately every 8 weeks until worsening of your disease. 
You can have these studies at home institution and send us results.
If you are unable to return for these visits, we will obtain the information from you by telephone 
or e-mail.
Once you stop coming to Clinical Center for safety visits and your scans, we will call or e-mail 
you every 6 months to ask you about your general well-being.
HOW LONG WILL THE STUDY TAKE?
You will come for study treatments every 14 days until your disease gets worse or you have 
unacceptable side effects at which time we will stop treatment.
Visits will range from 4-8 hours in length.
After stopping treatment, we would like to see you in the NIH Clinical Center monthly for three 
months and follow you after that for the rest of your life. 
If you stop treatment for reasons other than worsening of your disease, we would like to invite you 
for imaging studies approximately every 8 weeks until worsening of your disease. 
HOW MANY PEOPLE WILL PARTICIPATE IN THIS STUDY?
We plan to have up to 27 people take part in this study.
WHAT ARE THE RISKS AND DISCOMFORTS OF BEING IN THE STUDY?
The drug 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.
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 longer.

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:
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
Tell the study doctor if you notice or feel anything different so they can see if you are 
having a side effect.

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.
Risks of VB-111
The most frequent side effects related to VB-111 have been flu-like symptoms, including fever, 
chills and fatigue. These events usually occur on the day of study treatment (often starting about 6 
hours after the infusion) and resolve on the same day. To control these symptoms, an anti-fever 
drug will be given to you prior to VB-111 infusion. 
The table below presents the common side effects that were seen in patients treated with VB-111 
according to their observed frequencies:
MOST COMMON, SOME MAY BE SERIOUS 
In 100 people receiving VB-111, more than 20 may have:
Fever
Chills
Tiredness
Nausea
Headache
VERY COMMON
In 100 people receiving VB-111, 10 to 20 may have:
Vomiting
Mild diarrhea
Constipation
High blood pressure
Shortness of breath
Muscle weakness
Worsening of your disease
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COMMON
In 100 people receiving VB-111, 5 to 10 may have:
Flu like illness
Cough
Dizziness 
Temporary elevation of enzymes in the liver – which may be an indicator of liver damage
Prolonged PTT (test of blood clotting) which may increase the risk of bleeding
Decreased platelet count, which may increase the risk of bleeding/bruising
Decrease of mineral levels in the blood (Sodium and Potassium) 
Elevation of blood glucose levels
Decrease in red blood cells
Elevation of protein level in the urine
Low blood pressure
Pain, including: abdominal pain, back pain, muscle pain and joint pain
Loss of strength
Loss of appetite
Difficulties sleeping
Urinary tract infection
Heart rate higher than normal, usually related to fever
Excess fluid around the tumor site
Some brain related adverse events were commonly experienced only by patients with brain 
tumors: seizures, partial paralysis (restricted to one side of the body), difficulty walking, 
falling, confusion, difficulty speaking
UNCOMMON, BUT POTENTIALLY SERIOUS
Bleeding (including at the tumor site)
Severe Diarrhea
Coughing up blood
Blockage of the main artery of the lung or one of its branches
Blood clot
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UNCOMMON, BUT POTENTIALLY SERIOUS
Opening of a wound along surgical incision
Heart attack or weakening of heart muscle that could result in heart failure
Serious allergic reaction that may result in death.
Stroke (blood clot in brain resulting in nervous system symptoms that may be life-
threatening and lead to death)
A tear or a hole in the intestines which may require surgery
Decrease in the level of white blood cells, which may cause greater risk for infection
 
Risks from Nivolumab
Side effects of nivolumab may happen anytime during treatment or even after your treatment has 
ended. Some of the common and less common side effects can be serious. Call or see your 
healthcare provider right away if you develop any problems listed below or if the symptoms 
get worse.
COMMON, SOME MAY BE SERIOUS
In 100 people receiving nivolumab, more than 20 and up to 100 may have:

Tiredness
OCCASIONAL, SOME MAY BE SERIOUS
In 100 people receiving nivolumab, from 4 to 20 may have:

Anemia which may require blood transfusion

Swelling and redness of the eye 

Pain

Diarrhea, nausea

Dry mouth

Fever

Swelling and redness at the site of the medication injection

Bruising, bleeding

Pain or swelling of the joints

Loss of appetite

Reaction during or following a drug infusion which may cause fever, chills, rash 

Nivolumab may cause your immune system to attack normal organs and cause side 
effects in many parts of the body. These problems may include but are not limited to:
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o
Lung problems (pneumonitis and pleural effusion). Symptoms may include: new or 
worsening cough, chest pain, shortness of breath.
o
Intestinal problems (colitis) that can rarely lead to tears or holes in your intestine. 
Signs and symptoms of colitis may include: diarrhea or increase in bowel 
movements, blood in your stools or dark, tarry, sticky stools, severe belly pain or 
tenderness.
o
Skin: itching; rash, blisters including inside the mouth; loss of skin pigment
o
Liver problems (hepatitis) which can cause liver failure. Signs and symptoms of 
hepatitis may include: yellowing of your skin or the whites of your eyes, severe 
nausea or vomiting; drowsiness; pain in the right upper belly
o
Hormone gland problems (especially the thyroid, pituitary and adrenal glands, and 
pancreas). Signs and symptoms may include: headaches that will not go away or 
unusual headaches, extreme tiredness or changes in mood or behavior; decreased 
sex drive; weight loss or weight gain; excessive thirst or urine; dizziness or 
fainting.
RARE, AND SERIOUS
In 100 people receiving nivolumab, 3 or fewer may have:

Dry eyes

Sores in the mouth which may cause difficulty swallowing

Nivolumab may cause your immune system to attack normal organs and cause side 
effects in many parts of the body. These problems may include but are not limited to:
o
Visual disturbances which may cause double vision, blurred vision, or loss of 
vision with a chance of blindness
o
A condition with high blood sugar which leads to tiredness, frequent urination, 
excessive thirst, headache, nausea and vomiting, and can result in coma
o
Kidney problems, including nephritis and kidney failure requiring dialysis. Signs of 
kidney problems may include: decrease in the amount of urine, blood in your urine, 
ankle swelling.
o
Heart problems including swelling and heart failure. Symptoms and signs of heart 
problem may include: Shortness of breath, swelling of the ankle and body.
o
Problem of the muscle, including swelling, which can cause muscle pain and severe 
muscle weakness sometimes with dark urine
o
Swelling of the brain (meningitis/encephalitis) which may cause: headache, stiff 
neck confusion, sleepiness, seizures or injury to the brain which may cause 
headache, seizure, blindness (also known as Reversible Posterior 
Leukoencephalopathy Syndrome)
o
Problem of the nerves that can cause paralysis. Signs and symptoms may include: 
numbness, tingling of hands and feet; weakness of the arms, legs and facial muscle 
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movement
o
Allergic reaction which may cause rash, low blood pressure, wheezing, shortness of 
breath, swelling of the face or throat
o
Complications associated with stem cell transplant using donor stem cells 
(allogeneic stem cell transplant). These complications are caused by attack of donor 
cells on the host organs (inducing liver, skin and gut damage), and can lead to 
death. If you are considering an allogeneic stem transplant after participating in this 
study, please tell your doctor that you have received nivolumab therapy, since the 
risk and severity of transplant-associated complications may be increased.
Getting medical treatment right away may keep these problems from becoming more serious. Let 
your study doctor know of any questions you have about possible side effects. You can ask the 
study doctor questions about side effects at any time.
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.
Risks from Sedation
Biopsy will be performed under sedation. Sedation may cause headache, nausea and drowsiness. 
These side effects usually go away quickly. 
Risks from CT scans
If contrast dye is used, there is a risk for allergic reaction to the dye. If you are allergic to or 
sensitive to medications, contrast dye, iodine, or shellfish, please notify your study doctor. If you 
have had kidney failure or other kidney problems in the past, please notify your study doctor.
Risk from Electrocardiogram
You may experience some minor skin irritation from the electrodes.
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.
What are the risks related to pregnancy? 
If you are able to become pregnant, we will ask you to have a pregnancy test before starting this 
study. You will need to practice an effective form of birth control before starting study treatment, 
during study treatment, and for 5 months after you finish study treatment (the restricted period). If 
you become pregnant, there may be unknown risks to the fetus or unborn child, or risks that we 
did not anticipate. There may be long-term effects of the treatment being studied that could 
increase the risk of harm to a fetus. You must tell the study doctor if your birth control method 
fails during the restricted period. If you think or know you have become pregnant during the 
restricted period, please contact the study team as soon as possible.
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If you are a sexually active person with a partner able to become pregnant, it is important that your 
partner not become pregnant during the restricted period. There may be unknown risks to a fetus 
or risks we did not anticipate. You and your partner must agree to use birth control if you want to 
take part in this study. If you think your partner has become pregnant during the restricted period, 
please contact the study team as soon as possible. If you and your partner plan for your partner to 
become pregnant after the restricted period, please discuss this with the study team.
What are the risks of radiation from being in the study? 
During your participation in this research study, you will be exposed to radiation from CT scans 
and two CT guided biopsies. The amount of radiation exposure you will receive from these 
procedures is equal to approximately 9.3 rem. A rem is a unit of absorbed radiation. 
Every day, people are exposed to low levels of radiation that come from the sun and the 
environment around them. The average person in the United States receives a radiation exposure 
of 0.3 rem per year from these sources. This type of radiation is called “background radiation.” 
This study will expose you to more radiation than you get from everyday background radiation. 
No one knows for sure whether exposure to these low amounts of radiation is harmful to your 
body. 
The CT scans that you get in this study will expose you to the roughly the same amount of radiation 
as 31 years of background radiation. Being exposed to too much radiation can cause harmful side 
effects such as an increase in the risk of cancer. The risk depends on how much radiation you are 
exposed to. Please be aware that about 40 out of 100 people (40%) will get cancer during their 
lifetime, and 20 out of 100 (20%) will die from cancer. The risk of getting cancer from the radiation 
exposure in this study is 0.9 out of 100 (0.9%) and of getting a fatal cancer is 0.5 out of 100 (0.5%).
You may not participate in this study if you are pregnant. If you are able to become pregnant, we 
will perform a pregnancy test before exposing you to radiation. You must tell us if you may have 
become pregnant within the previous 14 days because the pregnancy test is unreliable during that 
time.
WHAT ARE THE BENEFITS OF BEING IN THE STUDY?
You might not benefit from being in this study. 
However, the potential benefit to you might include shrinking of your tumor or lessening of your 
symptoms, such as pain, that are caused by the cancer.
Are there any potential benefits to others that might result from the study?
In the future, other people might benefit from this study because what we learn in this study may 
eventually be used to treat others with your disease. 
WHAT OTHER OPTIONS ARE THERE FOR YOU?
Before you decide whether to be in this study, we will discuss the other options that are available 
to you. Instead of being in this study, you could:
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
choose to be treated with surgery, radiation or with drugs already approved by the FDA for 
your disease

choose to take part in a different study, if one is available

choose not to be treated for cancer but you may want to receive comfort care to relieve 
symptoms.
You should discuss with your doctor your other choices and their risks and benefits.
DISCUSSION OF FINDINGS
New information about the study
If we find out any new information that may affect your choice to participate in this study, we 
will get in touch with you to explain what we have learned. This may be information we have 
learned while doing this study here at the NIH or information we have learned from other 
scientists doing similar research in other places.
Return of research results
Results of research studies will not be shared with you.
EARLY WITHDRAWAL FROM THE STUDY 
our doctor may decide to stop your therapy for the following reasons:

if your disease worsens or comes back during treatment

if you need to take medication that is not allowed on the study

if you become pregnant

if you have side effects from the treatment that your doctor thinks are too severe

if the VB-111 or nivolumab becomes unavailable

if new information shows that another treatment would be better for you

if the study is stopped for any reason
In this case, you will be informed of the reason therapy is being stopped.
After the therapy is stopped, we would like to see you for a safety visit approximately one month 
after stopping therapy.
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.
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STORAGE, SHARING AND FUTURE RESEARCH USING YOUR SPECIMENS AND 
DATA
Will Your Specimens or Data Be Saved for Use in Other Research Studies?
As part of this study, we are obtaining specimens and data from you. The specimens will only 
be used for research in the current study, but leftover specimens may be transferred to the sample 
collection protocol that we asked you to enroll in. The consent for that describes future research. 
We plan to use these data collected on the study for studies going on right now, as well as studies 
in the future. These studies may provide additional information that will be helpful in 
understanding cancer, or other diseases or conditions. This could include studies to develop other 
research tests, treatments, drugs, or devices, that may lead to the development of a commercial 
product by the NIH and/or its research or commercial partners. There are no plans to provide 
financial compensation to you if this happens. Also, it is unlikely that we will learn anything 
from these studies that may directly benefit you. By agreeing to let us use your data, you give 
the NIH any rights you may have in the data. 
We may share your data with other researchers. They may be doing research in areas similar to 
this research or in other unrelated areas. These researchers may be at NIH, other research centers 
and institutions, or industry sponsors of research.
In addition to the use and sharing of your data described above, we might remove any 
information from your data, that can identify you such as name, address, or medical record 
number, and then use your data for additional research studies at the NIH or other places. If we 
do this, we might not contact you to ask your permission or otherwise inform you.
If you change your mind and do not want us to store and use your data for future research, you 
should contact the research team member identified at the top of this document. If some research 
with your data has already been completed, the information from that research may still be used. 
Also, for example, if the data have been shared already with other researchers, it might not be 
possible to withdraw the data. 
Please place your initials in the blank next to Yes or No for each of the questions below:
My data may be stored and used for future research as described above.
_____ Yes
_____ No
Initials
Initials
My data may be shared with other researchers and used by these researchers for future research 
as described above.
_____ Yes 
_____ No
Initials
Initials
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How Long Will Your Data be Stored by the NIH?
Your data may be stored by the NIH indefinitely.
Risks of Storage and Sharing of Data
When we store your data, we take precautions to protect your information from others that should 
not have access to it. When we share your data, we will do everything we can to protect your 
identity, for example, when appropriate, we remove information that can identify you. Even with 
the safeguards we put in place, we cannot guarantee that your identity will never become known 
or someone may gain unauthorized access to your information. New methods may be created in 
the future that could make it possible to re-identify your specimens and data.
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.
CONFLICT OF INTEREST (COI)
The National Institutes of Health (NIH) reviews NIH staff researchers at least yearly for conflicts 
of interest. This process is detailed in a COI Guide. You may ask your research team for a copy of 
the COI Guide or for more information. Members of the research team who do not work for NIH 
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are expected to follow these guidelines or the guidelines of their home institution, but they do not 
need to report their personal finances to the NIH.
The NIH and the research team for this study are using VB-111 developed by VBL Therapeutics 
through a joint study with your study team and the company. The company also provides financial 
support for this study. 
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.
CONFIDENTIALITY PROTECTIONS PROVIDED IN THIS STUDY 
Some of your health information, and/or information about your specimen, from this study will 
be kept in a central database for research. Your name or contact information will not be put in 
the database. Your test results will be identified by a unique code and the list that links the code 
to your name will be kept separate from your sample and health information. Your information 
may be given out if required by law. For example, certain states require doctors to report to health 
boards if they find a disease like tuberculosis. However, the researchers will do their best to 
make sure that any information that is released will not identify you.
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

The study Sponsor Center for Cancer Research of National Cancer Institute.

Qualified representatives from VBL Therapeutics, the pharmaceutical company who 
produces VB-111.
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 and 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.
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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); 
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 information 
that 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 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.
IRB NUMBER: 20C0022
IRB APPROVAL DATE: 02/16/2021


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 01/22/2021
Page 18 of 20
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
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, Tim Greten, 
M.D., gretentf@mail.nih.gov, 240-760-6114. 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: 20C0022
IRB APPROVAL DATE: 02/16/2021


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 01/22/2021
Page 19 of 20
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
IRB NUMBER: 20C0022
IRB APPROVAL DATE: 02/16/2021


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 01/22/2021
Page 20 of 20
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Witness to the oral short-form consent process only: 
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: 20C0022
IRB APPROVAL DATE: 02/16/2021