Conditions: Colorectal Cancer Colorectal Carcinoma Colorectal Adenocarcinoma Refractory Cancer Colorectal Neoplasms
Keywords: Oncolytic Vaccinia Virus Tumor Cell Death Viral Therapy Anti-Tumor Immunity
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 34
Healthy volunteers: no

Brief summary:
Background:

* Immune-based approaches in colorectal cancer have unfortunately with the notable exception of immune checkpoint inhibition in microsatellite instable (MSI-hi) disease been largely unsuccessful. The reasons for this are unclear but no doubt relate to the fact that in advanced disease colorectal cancer appears to be less immunogenic, as evidenced by the lack of infiltrating lymphocytes with advancing T stage
* Pexa-Vec (JX-594) is a thymidine kinase gene-inactivated oncolytic vaccinia virus engineered for the expression of transgenes encoding human granulocyte- macrophage colony-stimulating factor (GM-CSF) and beta-galactosidase. Apart from the direct oncolytic activity, oncolytic viruses such as Pexa-Vec have been shown to mediate tumor cell death via the induction of innate and adaptive immune responses
* Tremelimumab is a fully human monoclonal antibody that binds to cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) expressed on the surface of activated T lymphocytes and causes inhibition of B7-CTLA-4-mediated downregulation of T-cell activation. Durvalumab is a human monoclonal antibody directed against programmed death-ligand 1 (PD-L1).
* The aim of the study is to evaluate whether the anti-tumor immunity induced by Pexa-Vec oncolytic viral therapy can be enhanced by immune checkpoint inhibition.

Objective:

-To determine the safety, tolerability and feasibility of Pexa-Vec oncolytic virus in combination with immune checkpoint inhibition in patients with refractory metastatic colorectal cancer.

Eligibility:

* Histologically confirmed metastatic colorectal cancer.
* Patients must have progressed on, been intolerant of or refused prior oxaliplatin- and irinotecan-containing, fluorouracil-based, chemotherapeutic regimen and have disease that is not amenable to potentially curative resection. Patients who have a known Kirsten rat sarcoma viral oncogene homolog (KRAS) wild type tumor must have progressed, been intolerant of or refused cetuximab or panitumumab based chemotherapy.
* Patients tumors must be documented to be microsatellite-stable (MSS) either by genetic analysis or immunohistochemistry OR microsatellite-high with documented disease progression following anti-programmed cell death protein 1 (PD1)/Programmed death-ligand 1 (PDL1) therapy.
* Patients must have at least one focus of metastatic disease that is amenable to pre- and on-treatment biopsy.
* Willingness to undergo mandatory tumor biopsy.

Design:

-The proposed study is Phase I/II study of Pexa-Vec oncolytic virus at two dose levels in combination with immune checkpoint inhibition in patients with metastatic colorectal cancer.

Detailed description:
Background:

* Immune-based approaches in colorectal cancer have unfortunately with the notable exception of immune checkpoint inhibition in microsatellite instable (MSI-hi) disease been largely unsuccessful. The reasons for this are unclear but no doubt relate to the fact that in advanced disease colorectal cancer appears to be less immunogenic, as evidenced by the lack of infiltrating lymphocytes with advancing T stage
* Pexa-Vec (JX-594) is a thymidine kinase gene-inactivated oncolytic vaccinia virus engineered for the expression of transgenes encoding human granulocyte- macrophage colony-stimulating factor (GM-CSF) and beta-galactosidase. Apart from the direct oncolytic activity, oncolytic viruses such as Pexa-Vec have been shown to mediate tumor cell death via the induction of innate and adaptive immune responses
* Tremelimumab is a fully human monoclonal antibody that binds to cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) expressed on the surface of activated T lymphocytes and causes inhibition of B7-CTLA-4-mediated downregulation of T-cell activation. Durvalumab is a human monoclonal antibody directed against programmed death-ligand 1 (PD-L1).
* The aim of the study is to evaluate whether the anti-tumor immunity induced by Pexa-Vec oncolytic viral therapy can be enhanced by immune checkpoint inhibition.

Objective:

-To determine the safety, tolerability and feasibility of Pexa-Vec oncolytic virus in combination with immune checkpoint inhibition in patients with refractory metastatic colorectal cancer.

Eligibility:

* Histologically confirmed metastatic colorectal cancer.
* Patients must have progressed on, been intolerant of or refused prior oxaliplatin- and irinotecan-containing, fluorouracil-based, chemotherapeutic regimen and have disease that is not amenable to potentially curative resection. Patients who have a known Kirsten rat sarcoma viral oncogene homolog (KRAS) wild type tumor must have progressed, been intolerant of or refused cetuximab or panitumumab based chemotherapy.
* Patient's tumors must be documented to be microsatellite-stable (MSS) either by genetic analysis or immunohistochemistry OR microsatellite-high with documented disease progression following anti-programmed cell death protein 1 (PD1)/Programmed death-ligand 1 (PDL1) therapy.
* Patients must have at least one focus of metastatic disease that is amenable to pre- and on-treatment biopsy.
* Willingness to undergo mandatory tumor biopsy.

Design:

* The proposed study is Phase I/II study of Pexa-Vec oncolytic virus at two dose levels in combination with immune checkpoint inhibition in patients with metastatic colorectal cancer.
* Patients will receive Pexa-Vec, administered intravenous (IV) every 2 weeks for 4 doses, in 4 separate arms A1, A2, B1, and B2. The first administration will be on Day (minus) 12, followed by administration on Days 2, 16 and 30 (i.e. 4 doses in total).

  * Arms A1 and A2: In addition to the oncolytic virus patients will also receive durvalumab at a flat dose of 1500 mg beginning on Day 1 followed by q28days until off-treatment criteria are met.
  * Arms B1 and B2: In addition to the oncolytic virus patients will also receive tremelimumab 300 mg and durvalumab 1500 mg on Day 1 followed by q28days subsequent continuation of the durvalumab alone until off-treatment criteria are met.
* All patients will undergo a baseline tumor biopsy and a post treatment biopsy.
* Accrual ceiling will be set at 35 to allow for patients replaceable for reasons other than toxicity.
* Patients will be restaged every 8 weeks +/- 3 days

Arms:
arm 1: Pexa-Vec escalation dose levels + Durvalumab arm 2: Maximum tolerated dose (MTD) of Pexa-Vec after the MTD is established +Durvalumab arm 3: Pexa-Vec escalation dose levels + Durvalumab +Tremelimumab arm 4: MTD of Pexa-Vec after the MTD is established+Durvalumab + Tremelimumab

Interventions: intervention 1: Durvalumab intervention 2: Tremelimumab intervention 3: Pexa-Vec intervention 4: Pexa-Vec
Intervention descriptions: intervention 1: 1500 mg of durvalumab via intravenous (IV) infusion on Day 1 of each cycle until patients meet off treatment criteria intervention 2: 300 mg of tremelimumab via intravenous (IV) infusion on Day 1 of cycle 1 intervention 3: 3 x 10E\^8 plaque-forming unit (pfu) (Dose Level (DL) 1) via intravenous (IV) infusion for 4 doses: Day 12, Day 2, Day 16 of Cycle 1 and Day 2 of Cycle 2. intervention 4: 1 x 10E\^9 pfu (DL 2) via intravenous (IV) infusion for 4 doses: Day 12, Day 2, Day 16 of Cycle 1 and Day 2 of Cycle 2.

Protocol document:
Prot_SAP_000.pdf: 
Abbreviated Title: Pexa-Vec Colorectal Ca 
 
Version Date: 06/15/2020 
1 
 
Abbreviated Title: Pexa-Vec Colorectal Ca  
CC Protocol: 17C0092 H  
IBC # RD-16-XII-15 
OSP # 1706-1624 
Version Date: 06/15/2020 
NCT: NCT03206073 
Title: A Phase I/II study of Pexa-Vec Oncolytic Virus in Combination with Immune Checkpoint 
Inhibition in Refractory Colorectal Cancer. 
 
NCI Principal Investigator:            Tim Greten, MD  
         Thoracic & GI Malignancies Branch 
         National Cancer Institute 
 
         Building 10, Room 2B38B 
         9000 Rockville Pike 
         Bethesda, MD 20892 
         240-760-6114  
         gretentf@mail.nih.gov 
 
Investigational Agents:     
Drug Name: 
Tremelimumab; Durvalumab; Pexastimogene Devacirepvec (Pexa-
Vec) 
BB IND Number: 
17363 
Sponsor: 
Center for Cancer Research, National Cancer Institute 
Manufacturers: 
MedImmune/AstraZeneca 
Sillajen Inc.  
 
 


Abbreviated Title: Pexa-Vec Colorectal Ca 
 
Version Date: 06/15/2020 
2 
 
PRÉCIS 
Background: 
• Immune-based approaches in colorectal cancer have unfortunately – with the notable 
exception of immune checkpoint inhibition in microsatellite instable (MSI-hi) disease – 
been largely unsuccessful. The reasons for this are unclear but no doubt relate to the fact 
that in advanced disease colorectal cancer appears to be less immunogenic, as evidenced 
by the lack of infiltrating lymphocytes with advancing T stage 
• Pexa-Vec (JX-594) is a thymidine kinase gene-inactivated oncolytic vaccinia virus 
engineered for the expression of transgenes encoding human granulocyte- macrophage 
colony-stimulating factor (GM-CSF) and β-galactosidase. Apart from the direct oncolytic 
activity, oncolytic viruses such as Pexa-Vec have been shown to mediate tumor cell death 
via the induction of innate and adaptive immune responses 
• Tremelimumab is a fully human monoclonal antibody that binds to CTLA-4 expressed on 
the surface of activated T lymphocytes and causes inhibition of B7-CTLA-4-mediated 
downregulation of T-cell activation. Durvalumab is a human monoclonal antibody directed 
against PD-L1.  
• The aim of the study is to evaluate whether the anti-tumor immunity induced by Pexa-Vec 
oncolytic viral therapy can be enhanced by immune checkpoint inhibition.  
Objective: 
• To determine the safety, tolerability and feasibility of Pexa-Vec oncolytic virus in 
combination with immune checkpoint inhibition in patients with refractory metastatic 
colorectal cancer.  
Eligibility: 
• Histologically confirmed metastatic colorectal cancer.  
• Patients must have progressed on, been intolerant of or refused prior oxaliplatin- and 
irinotecan-containing, fluorouracil-based, chemotherapeutic regimen and have disease that 
is not amenable to potentially curative resection. Patients who have a known KRAS wild 
type tumor must have progressed, been intolerant of or refused cetuximab or panitumumab-
based chemotherapy. 
• Patients tumors must be documented to be microsatellite-stable (MSS) either by genetic 
analysis or immunohistochemistry OR microsatellite-high with documented disease 
progression following anti-PD1/PDL1 therapy.  
• Patients must have at least one focus of metastatic disease that is amenable to pre- and on-
treatment biopsy. 
• Willingness to undergo mandatory tumor biopsy.  
Design: 
• The proposed study is Phase I/II study of Pexa-Vec oncolytic virus at two dose levels in 
combination with immune checkpoint inhibition in patients with metastatic colorectal 
cancer. 


Abbreviated Title: Pexa-Vec Colorectal Ca 
 
Version Date: 06/15/2020 
3 
 
• Patients will receive Pexa-Vec, administered IV every 2 weeks for 4 doses, in 4 separate 
arms A1, A2, B1, and B2. The first administration will be on Day –(minus) 12, followed 
by administration on Days 2, 16 and 30 (i.e. 4 doses in total). 
o Arms A1 and A2: In addition to the oncolytic virus patients will also receive 
durvalumab at a flat dose of 1500 mg beginning on Day 1 followed by q28days 
until off-treatment criteria are met.  
o Arms B1 and B2: In addition to the oncolytic virus patients will also receive 
tremelimumab 300 mg and durvalumab 1500 mg   on Day 1 followed by q28days 
subsequent continuation of the durvalumab alone until off-treatment criteria are 
met. 
• All patients will undergo a baseline tumor biopsy and a post treatment biopsy. 
• Accrual ceiling will be set at 35 to allow for patients replaceable for reasons other than 
toxicity. 
• Patients will be restaged every 8 weeks +/- 3 days 
 
 
 
 
 
 
 


Abbreviated Title: Pexa-Vec Colorectal Ca 
 
Version Date: 06/15/2020 
4 
 
TABLE OF CONTENTS 
PRÉCIS ........................................................................................................................................... 2 
TABLE OF CONTENTS ................................................................................................................ 4 
1 
INTRODUCTION ................................................................................................................ 10 
1.1 
Study Objectives ............................................................................................................ 10 
1.1.1 
Primary Objective ................................................................................................... 10 
1.1.2 
Secondary Objectives: ............................................................................................ 10 
1.1.3 
Exploratory Objectives: .......................................................................................... 10 
1.2 
Background and Rationale ............................................................................................. 10 
1.2.1 
Metastatic colorectal cancer (CRC) and the current therapeutic paradigm ............ 10 
1.2.2 
Pexa-Vec (pexastimogene devacirepvec; JX-594) ................................................. 11 
1.2.3 
Induction of adaptive immunity .............................................................................. 15 
1.3 
Tremelimumab ............................................................................................................... 17 
1.4 
Durvalumab .................................................................................................................... 17 
1.5 
Anti-CTLA4 in combination with anti-PD1/PD-L1 ...................................................... 18 
1.5.1 
Durvalumab and tremelimumab dose and treatment regimen justification ............ 18 
1.5.2 
Durvalumab monotherapy dose rationale ............................................................... 21 
1.5.3 
Fixed Dosing for durvalumab and tremelimumab .................................................. 22 
1.6 
Rationale for timing and mandatory nature of the biopsies ........................................... 23 
1.7 
Amendment D Rationale ................................................................................................ 23 
2 
ELIGIBILITY ASSESSMENT AND ENROLLMENT ....................................................... 24 
2.1 
Eligibility Criteria .......................................................................................................... 24 
2.1.1 
Inclusion Criteria .................................................................................................... 24 
2.1.2 
Exclusion Criteria ................................................................................................... 26 
2.1.3 
Recruitment Strategies ............................................................................................ 28 
2.2 
Screening Evaluation...................................................................................................... 29 
2.2.1 
Screening activities performed after a consent for screening has been signed ....... 29 
2.3 
Participant Registration and Status Update Procedures ................................................. 29 
2.4 
Treatment Assignment Procedures (for registration purposes only): ............................. 30 
2.5 
Baseline Evaluation ........................................................................................................ 31 
3 
STUDY IMPLEMENTATION ............................................................................................ 31 
3.1 
Study Design .................................................................................................................. 31 
3.1.1 
Dose Limiting Toxicity (DLT) ............................................................................... 34 


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3.1.2 
Maximum tolerated dose (MTD) ............................................................................ 35 
3.1.3 
Protocol Stopping Rules ......................................................................................... 35 
3.2 
Drug Administration ...................................................................................................... 35 
3.2.1 
Pexa-Vec Drug Administration............................................................................... 35 
3.2.2 
Durvalumab Administration ................................................................................... 36 
3.2.3 
Tremelimumab Administration ............................................................................... 36 
3.2.4 
Monitoring of Dose Administration........................................................................ 36 
3.3 
Dose Modifications ........................................................................................................ 37 
3.3.1 
Pexa-Vec ................................................................................................................. 37 
3.3.2 
Tremelimumab and durvalumab ............................................................................. 37 
3.4 
Management of Expected Adverse Events and Events of Special Interest .................... 37 
3.4.1 
Expected Toxicities of Pexa-Vec Treatment .......................................................... 37 
3.4.2 
Potential Mechanisms of Pexa-Vec Shedding to the Environment, 
Biodissemination and Prevention of Transmission............................................................... 39 
3.4.3 
Adverse Events of Special Interest for Durvalumab and Tremelimumab .............. 39 
3.5 
Follow Up Period ........................................................................................................... 42 
3.6 
Study Calendar ............................................................................................................... 43 
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 ................................................................................................... 47 
4 
CONCOMITANT MEDICATIONS/MEASURES .............................................................. 47 
4.1 
Recommended Medications Related to Flu-like Symptoms related to Pexa-Vec ......... 48 
4.2 
Management of Hypotension and Contraindicated Treatments ..................................... 48 
4.3 
Agents with Potential Inhibitory Activity Against Vaccinia Viruses ............................ 48 
4.4 
Contraindicated Antiviral Therapy Shown to Inhibit Vaccinia Replication .................. 48 
4.5 
Contraindicated Treatments ........................................................................................... 49 
4.6 
Other Authorized Concomitant Treatments ................................................................... 49 
4.7 
Permitted concomitant medications for any combination of investigational drugs ....... 49 
4.8 
Excluded Concomitant Medications .............................................................................. 50 
4.9 
Methods of contraception ............................................................................................... 51 
4.9.1 
Female patient of child-bearing potential ............................................................... 51 
4.9.2 
Male patients with a female partner of childbearing potential ............................... 51 
4.9.3 
Highly effective methods of contraception. ............................................................ 52 


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4.10 
Blood donation ........................................................................................................... 52 
5 
BIOSPECIMEN COLLECTION .......................................................................................... 52 
5.1 
Correlative Studies for Research .................................................................................... 52 
5.1.1 
Immune monitoring ................................................................................................ 53 
5.1.2 
Mandatory tumor biopsies ...................................................................................... 54 
5.1.3 
Tumor tissue analysis .............................................................................................. 54 
5.2 
Sample Storage, Tracking and Disposition .................................................................... 54 
5.2.1 
Samples Managed by Dr. Figg’s Blood Processing Core (BPC)............................ 55 
5.2.2 
Samples Managed by the Laboratory of Dr Greten ................................................ 55 
5.2.3 
Protocol Completion/Sample Destruction .............................................................. 55 
5.3 
Samples for Genetic/Genomic Analysis ........................................................................ 55 
5.3.1 
TCR beta sequencing .............................................................................................. 55 
5.3.2 
Nanostring analysis (nCounterPan Cancer Immunology Profile) .......................... 56 
5.3.3 
Privacy and Confidentiality of medical information/biological specimens ............ 56 
5.3.4 
Management of Results........................................................................................... 56 
6 
DATA COLLECTION AND EVALUATION ..................................................................... 56 
6.1 
Data Collection ............................................................................................................... 56 
6.2 
Data Sharing Plans ......................................................................................................... 57 
6.2.1 
Human Data Sharing plan ....................................................................................... 57 
6.2.2 
Genomic Data Sharing Plan .................................................................................... 57 
6.3 
Response Criteria ........................................................................................................... 57 
6.3.1 
Definitions............................................................................................................... 57 
6.3.2 
Disease Parameters ................................................................................................. 58 
6.3.3 
Methods for Evaluation of Measurable Disease ..................................................... 59 
6.3.4 
Response criteria ..................................................................................................... 60 
6.3.5 
Duration of Response .............................................................................................. 61 
6.3.6 
Modified Immune-related response criteria (irRC) ................................................ 62 
6.3.7 
Progression-Free Survival ....................................................................................... 62 
6.4 
Toxicity Criteria ............................................................................................................. 62 
7 
NIH REPORTING REQUIREMENTS / DATA AND SAFETY MONITORING PLAN .. 62 
7.1 
Definitions ...................................................................................................................... 62 
7.2 
OHSRP Office of Compliance and Training / IRB Reporting ....................................... 62 
7.2.1 
Expedited Reporting ............................................................................................... 62 


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7.2.2 
IRB Requirements for PI Reporting at Continuing Review ................................... 62 
7.3 
NCI Clinical Director Reporting .................................................................................... 62 
7.4 
INSTITUTIONAL BIOSAFETY COMMITTEE (IBC) REPORTING CRITERIA .... 63 
7.4.1 
Serious Adverse Event Reports to IBC ................................................................... 63 
7.4.2 
Annual Reports to IBC............................................................................................ 63 
7.4.3 
Clinical Trial Information ....................................................................................... 63 
7.4.4 
Progress Report and Data Analysis ......................................................................... 63 
7.5 
NIH Required Data and Safety Monitoring Plan ........................................................... 64 
7.5.1 
Principal Investigator/Research Team .................................................................... 64 
7.5.2 
Safety Monitoring Committee (SMC) .................................................................... 64 
8 
SPONSOR PROTOCOL/SAFETY REPORTING ............................................................... 64 
8.1 
Definitions ...................................................................................................................... 64 
8.1.1 
Adverse Event ......................................................................................................... 64 
8.1.2 
Serious Adverse Event (SAE) ................................................................................. 65 
8.1.3 
Life-threatening....................................................................................................... 65 
8.1.4 
Severity ................................................................................................................... 65 
8.1.5 
Relationship to Study Product ................................................................................ 65 
8.1.6 
Adverse Events of Special Interest (AESI) ............................................................. 65 
8.2 
Assessment of Safety Events.......................................................................................... 65 
8.3 
Reporting of Serious Adverse Events ............................................................................ 66 
8.4 
Waiver of expedited reporting to CCR .......................................................................... 66 
8.5 
Safety Reporting Criteria to the Pharmaceutical Collaborators ..................................... 67 
8.5.1 
Reporting of serious adverse events ....................................................................... 67 
8.5.2 
Overdose ................................................................................................................. 67 
8.5.3 
Hepatic function abnormality ................................................................................. 68 
8.6 
Reporting Pregnancy ...................................................................................................... 68 
8.6.1 
Maternal exposure ................................................................................................. 68 
8.6.2 
Paternal exposure .................................................................................................... 68 
8.7 
Regulatory Reporting for Studies Conducted Under CCR-Sponsored IND .................. 69 
9 
CLINICAL MONITORING ................................................................................................. 69 
10 STATISTICAL CONSIDERATIONS.................................................................................. 69 
11 COLLABORATIVE AGREEMENT ................................................................................... 71 
11.1 
Cooperative Research and Development Agreement (CRADA) ............................... 71 


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11.1.1 Medimmune/Astrazeneca ....................................................................................... 71 
11.1.2 Sillajen Inc. ............................................................................................................. 71 
11.2 
Material Transfer Agreement (MTA) ......................................................................... 71 
12 HUMAN SUBJECTS PROTECTIONS ............................................................................... 71 
12.1 
Rationale for Subject Selection .................................................................................. 71 
12.2 
Participation of Children ............................................................................................ 71 
12.3 
Participation of subjects unable to give consent ......................................................... 71 
12.4 
Evaluation of Benefits and Risks/Discomforts ........................................................... 72 
12.5 
RISKS/BENEFITS ANALYSIS ................................................................................ 72 
12.5.1 Risk of Biopsy......................................................................................................... 72 
12.5.2 Risks of exposure to ionizing radiation .................................................................. 72 
12.5.3 Risks of CT Scans ................................................................................................... 72 
12.5.4 Research Blood Collection Risks............................................................................ 73 
12.5.5 Other Risks/Benefits ............................................................................................... 73 
12.5.6 Risks/Benefits Analysis .......................................................................................... 73 
12.6 
Consent Process and Documentation ......................................................................... 73 
13 PHARMACEUTICAL INFORMATION ............................................................................. 73 
13.1 
Tremelimumab (17363) .............................................................................................. 73 
13.1.1 Source ..................................................................................................................... 73 
13.1.2 Toxicity ................................................................................................................... 73 
13.1.3 Formulation and preparation ................................................................................... 74 
13.1.4 Stability and Storage ............................................................................................... 74 
13.1.5 Administration procedures ...................................................................................... 75 
13.2 
Durvalumab (17363)................................................................................................... 75 
13.2.1 Source ..................................................................................................................... 75 
13.2.2 Toxicity ................................................................................................................... 75 
13.2.3 Formulation and Preparation................................................................................... 75 
13.2.4 Stability and Storage ............................................................................................... 76 
13.2.5 Administration procedures ...................................................................................... 76 
13.3 
Pexa-Vec (17363) ....................................................................................................... 79 
13.3.1 Source ..................................................................................................................... 79 
13.3.2 Toxicity ................................................................................................................... 79 
13.3.3 Formulation and Preparation................................................................................... 79 


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13.3.4 Stability and Storage ............................................................................................... 80 
13.3.5 Handling of Pexa-Vec ............................................................................................. 80 
13.3.6 Preparation and administration of Pexa-Vec .......................................................... 81 
13.3.7 Cleaning / Disinfection and Disposal ..................................................................... 81 
13.3.8 Spills or Environmental Contamination.................................................................. 81 
13.3.9 Unused Drug Return or Destruction ....................................................................... 81 
14 REFERENCES ..................................................................................................................... 83 
15 APPENDICES ...................................................................................................................... 85 
15.1 
Appendix A-Performance Status Criteria ................................................................... 85 
15.2 
Appendix B – Tremelimumab and Durvalumab Dosing Modifications .................... 86 
15.3 
Appendix C: Modified immune-related response criteria (irRC) ............................. 112 
15.4 
Appendix D: List of Adverse Events related to study treatment before amendment D
 
114 
 
 
 


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1 
INTRODUCTION 
1.1 
Study Objectives 
1.1.1 Primary Objective 
• To determine the safety, tolerability and feasibility of Pexa-Vec oncolytic virus in 
combination with immune checkpoint inhibition in patients with refractory metastatic 
colorectal cancer. 
1.1.2 Secondary Objectives: 
• To determine the response rate (by RECIST 1.1) of Pexa-Vec oncolytic virus in 
combination with immune checkpoint inhibition in patients with refractory metastatic 
colorectal cancer. 
• To evaluate the 5-month and overall progression-free survival and overall survival in 
patients with metastatic colorectal cancer during and following treatment with of Pexa-Vec 
oncolytic virus in combination with immune checkpoint inhibition in patients with 
refractory metastatic colorectal cancer. 
1.1.3 Exploratory Objectives: 
• To measure changes in immune parameters in the peripheral blood and tumors in patients 
with metastatic colorectal cancer during and following treatment with Pexa-Vec oncolytic 
virus in combination with immune checkpoint inhibition. 
1.2 
Background and Rationale 
1.2.1  Metastatic colorectal cancer (CRC) and the current therapeutic paradigm 
Colorectal cancer is a highly prevalent cancer, with approximately 300,000 new cases diagnosed 
annually in the U.S. and Europe. Over the past 10-15 years’ new chemotherapeutics (oxaliplatin 
and 
irinotecan) 
in 
addition 
to 
so-called 
targeted 
agents 
(bevacizumab 
and 
cetuximab/panitumumab) have resulted in improvements in the median overall survival from 10-
12 months to approximately 2 years. Once a patient progress after first line treatment however, the 
average survival is in the 12-14-month range, and a huge unmet need exists to improve options for 
patients with this disease.  
Immune-based approaches in colorectal cancer have unfortunately – with the notable exception of 
immune checkpoint inhibition in MSI-hiI disease – been largely unsuccessful. The reasons for this 
are unclear but no doubt relate to the fact that in advanced disease colorectal cancer appears to be 
less immunogenic, as evidenced by the lack of infiltrating lymphocytes with advancing T stage[1, 
2]. The prevalence of colorectal cancer and the high proportion of patients with metastatic disease 
who are microsatellite stable (85-90%) mean that this is a large territory of each oncology clinic 
for whom any advance in immunotherapy would be extremely significant. Given the apparent lack 
of intrinsic anti-tumor immunity in these patients, innovative immune-stimulative approaches are 
needed. Oncolytic virus technology falls into this category, their great potential being their ability 
to induce immunity in tumors[3] such as microsatellite-stable (MSS) colorectal cancer - where low 
mutagenic burden result in low endogenous immunity (and lack of single-agent activity to 
checkpoint inhibitors). 


Abbreviated Title: Pexa-Vec Colorectal Ca 
 
Version Date: 06/15/2020 
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1.2.2 Pexa-Vec (pexastimogene devacirepvec; JX-594) 
Oncolytic immunotherapy represents a novel therapeutic platform for the treatment of cancer with 
unique attributes compared to conventional chemotherapy. Oncolytic viruses are native or 
engineered viruses that preferentially replicate in and lyse cancer cells. Selective tumor cell 
replication is thought to depend on infection of neoplastic cells, which harbor low levels of protein 
kinase R (PKR) and dysfunctional type I IFN signaling elements. These changes allow more 
efficient viral replication, and with selected deletion of specific viral genes, replication in normal 
cells with activated PKR may not be possible. The FDA recently approved the first oncolytic virus 
for cancer [Talimogene laherparepvec (T-VEC)], for melanoma on October 15, 2015. 
Pexa-Vec (JX-594) is a thymidine kinase gene-inactivated oncolytic vaccinia virus engineered for 
the expression of transgenes encoding human granulocyte- macrophage colony-stimulating factor 
(GM-CSF) and β-galactosidase. Most of the oncolytic clinical trials to date have involved 
intratumoral injection. Whilst Pexa-Vec can (and has been) also administered in this manner, it 
has the advantage of being able to be administered systemically by intravenous administration.  
Clinical experience: More than 300 patients have been treated with Pexa-Vec administered either 
intravenously (IV), intratumorally (IT) or both IV and IT. In total, approximately 1200 patient 
doses of Pexa-Vec have been administered (IV and IT combined). Pexa-Vec treatment has 
generally been well-tolerated with main side effects being transient flu-like symptoms and 
transient hypotension. A randomized Phase 2a trial in HCC demonstrated a significant increase in 
OS at high dose Pexa-Vec versus low dose Pexa-Vec and a Phase 3 trial in first-line HCC is 
ongoing[4]. In a phase 1 trial of a single intravenous infusion of Pexa-Vec in 23 patients with 
advanced solid tumors, dose-related antitumor activity was observed and normal tissues were not 
affected clinically[5]. Pexa-Vec has been administered safely to patients with colorectal cancer 
with proof of concept for tumor penetration and selectivity[6]. Thus far, at least 60 patients with 
colorectal cancer have been treated across several Phase 1/2 studies, again demonstrating that 
Pexa-Vec therapy was well-tolerated. Reproducible infection of CRC metastases following IV 
Pexa-Vec was confirmed on post treatment biopsies[5].  
The most common adverse events (AEs) reported with Pexa-Vec have been acute, transient flu-
like symptoms, including fever and chills. Transient, hypotension responsive to fluid 
administration was also noted in a subset of patients within 24 hours of treatment. Pexa-Vec related 
skin pustules were observed in 22% (64/292) of patients receiving IV or IT treatments. Pustules 
developed after 9% (62/691) of IV infusions. The pustules were self-limited and resolved without 
sequela within 2-3 weeks of treatment, consistent with the timeline for pustule resolution utilizing 
wild-type vaccinia vaccine.  
1.2.2.1 Phase 1b Study of Patients with Colorectal Cancer Treated Intravenously Every Two 
Weeks with Pexa-Vec 
Fifteen patients with treatment- refractory colorectal cancer were enrolled on a phase 1b study of 
Pexa-Vec (also known as JX-594). Pexa-Vec was administered intravenously every 14 days, at 
dose levels of 1 × 106, 1 × 107, or 3 × 107 plaque-forming units (pfu)/kg. The primary endpoint 
was to determine the maximum tolerated dose. Secondary endpoints were pharmacokinetics and 
pharmacodynamics as well as antitumor activity. All patients received at least two Pexa-Vec doses. 
No dose-limiting toxicities were reported, and the maximum tolerated dose was not reached. The 
most common adverse events were grade 1/2 flu-like symptoms, generally lasting <24 hours. There 


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was some preliminary evidence of efficacy with the majority of patients (67%) having 
radiographically stable disease. 
1.2.2.2 Phase 1/2a Study of Patients with Colorectal Carcinoma Treated Intravenously (IV) 
Weekly with Pexa-Vec Alone and in Combination with Irinotecan  
A Phase 1/2a dose-escalation study of Pexa-Vec administered weekly alone or in combination 
with irinotecan in patients with Stage 4, chemotherapy refractory CRC has completed enrollment. 
A total of 52 patients received 5 IV doses of Pexa-Vec weekly at doses of 3x108 
pfu to 1x109 
pfu alone or in combination with irinotecan. Pexa-Vec alone and in combination with 
irinotecan was generally well-tolerated with no dose- limiting toxicities experienced. 
Pexa-Vec has been well-tolerated in study patients with most AEs being mild-to- moderate in 
severity. The most common Pexa-Vec treatment related AEs identified as a percent of total 
patients treated included generally mild-to-moderate: pyrexia (94%), chills (84%), hypotension 
(62%), nausea (46%), and rash pustular (42%). No Grade 4 or 5 AEs related to treatment were 
reported. 
The following Grade 3 AEs related to Pexa-Vec single-agent treatment were experienced 
by (3.6%, n = 1) of patient experienced each of the following: chills, hypotension, fatigue, 
hypertension, abdominal pain, blood bilirubin increased, cytokine release syndrome, hypoxia, 
ALT increased, AST increased, somnolence, and troponin increased. No Grade 4 or Grade 5 
AEs related to Pexa-Vec were reported. 
1.2.2.3 Other clinical trial data for Pexa-Vec  
1.2.2.3.1 Phase 1 Liver Tumor Trial  
A Phase 1 dose-escalation trial of Pexa-Vec in patients with primary or metastatic liver tumors 
(JX594-IT-HEP001) has been completed and the results published[6]. Pexa-Vec was administered 
by IT injection every 3 weeks in patients with refractory, injectable tumors within the liver at one 
of 4 dose levels (1 × 108 pfu to 3 × 109 pfu). Patients were scheduled to receive 2–4 treatments, 
but could subsequently receive an additional 4 treatments if there was evidence response or clinical 
benefit. Fourteen patients, including 3 HCC patients were enrolled and treated. Pexa-Vec was 
well-tolerated in study patients. All patients treated with Pexa-Vec experienced mild-to-moderate 
flu-like symptoms, which included fever, chills, anorexia, aches/pain, fatigue, headache, and/or 
nausea. No significant organ toxicity was reported. Two patients were treated at the 3 × 109 pfu 
dose and both patients experienced dose limiting toxicities (DLTs) after a single treatment with 
Pexa-Vec. The DLTs experienced by these study patients included asymptomatic Grade 3 
hyperbilirubinemia (n = 2), and Grade 3 anorexia and right upper quadrant pain (n = 1). 
Hyperbilirubinemia was apparently due to tumor swelling post-treatment and occlusion of the 
adjacent bile duct. The maximum-tolerated dose on the study was therefore defined as 1 × 109 pfu. 
Response and/or stable disease were observed in 9 out of the 10 evaluable patients. Target tumor 
responses were demonstrated in 8 patients by RECIST criteria and/or Choi criteria. Responding 
patients had various tumor types, including HCC. In 3 cases positron-emission tomography – 
computed tomography (PET-CT) scans demonstrated a decrease in injected tumor metabolic 
activity (10–100% decrease standardized uptake value [SUV]). Eight patients (57%) survived for 
at least 8 months, and up to 72+ months. The median cancer-specific survival was 9 months. 
1.2.2.3.2 Phase 2 Liver Cancer (HCC) Trial (JX594-IT-HEP007) 


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A Phase 2 randomized dose-finding trial of Pexa-Vec in patients with liver cancer (HCC) (JX594-
IT-HEP007) has been completed and the results published[4]. Pexa-Vec was administered by IT 
injection every 2 weeks for 3 total doses in patients with injectable tumors within the liver. Study 
dose levels were 1 x 108 pfu (Arm A) and 1 x 109 pfu (Arm B). Thirty patients were treated (16 
patients in Arm A, 14 patients in Arm B). Twenty-nine patients received all 3 planned injections; 
one low-dose patient received 2 Pexa-Vec treatments. IT injection was well-tolerated at both dose 
levels in this population of patients with HCC. One treatment-related serious adverse event (SAE) 
was reported in the high-dose group (nausea and vomiting requiring prolonged hospitalization). 
Flu-like symptoms (Grade 1–2) occurred in all patients over the first 12–24 hours after treatment, 
including fever, rigors, nausea or vomiting. Four patients responded to treatment based on 
mRECIST criteria (1 complete response; 3 partial responses). Responses were observed in injected 
and non-injected tumors. Further, overall survival was significantly longer in the high-dose arm 
compared with the low-dose arm (median 14.1 months versus 6.7 months, hazard ratio [HR] 0.39; 
p-value 0.020, Gehan-Breslow-Wilcoxon test; 1-sided test for superiority of high-dose (Figure 1). 
The median overall survival was 9.0 months for the entire population.  
 
Figure 1: 
Kaplan-Meier Plot of Overall Survival by Dose 
 
 
1.2.2.3.3 Phase 2 Study of HCC Patients Treated IV and IT with Pexa-Vec Prior to Sorafenib 
(JX594-HEP016) 
Twenty-five patients were enrolled on this Phase 2 study investigating one IV dose of Pexa-Vec, 
followed by 2 IT injections (one week and 3 weeks after the IV infusion), prior to initiation of 
standard sorafenib therapy. Twenty patients were resistant to sorafenib therapy before Pexa-Vec 
treatment. Transient flu-like symptoms following Pexa-Vec treatments were the most common 
AEs. Subsequent therapy with sorafenib was well-tolerated. The 2 agents were not used 
simultaneously, as sorafenib inhibits Pexa-Vec replication and can potentially impair its activity.  
Transient decreases in white blood cell (WBC) counts, in particular neutrophils and lymphocytes, 
may occur within the first 24 hours following each Pexa-Vec treatment dose. Modified Choi 


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responses and/or disease stabilization were observed following IV and IT Pexa-Vec therapy prior 
to and following standard sorafenib therapy. One patient exhibited a partial response by RECIST 
criteria in addition to a response by Choi criteria. 
1.2.2.3.4 Phase 2b Randomized Trial of Pexa-Vec Plus Best Supportive Care Versus Best 
Supportive Care in Patients with Advanced Hepatocellular Carcinoma Who Have Failed 
Sorafenib Treatment (JX594-HEP018/TRAVERSE) 
One hundred and twenty-nine patients having failed previous sorafenib therapy were enrolled on 
this Phase 2b study and randomized 2:1 to receive either Pexa-Vec plus best supportive care 
(BSC) or BSC alone. Eighty-six patients were assigned to the Pexa-Vec arm and were to receive 
one IV dose followed by up to 5 IT injections (1, 3, 6, 12, and 18 weeks after the IV infusion), 
and 43 to BSC-only arm. 
The most common AEs related to Pexa-Vec experienced by patients in Arm A included: pyrexia 
(78.6%), chills (50.0%), pustular rash (28.6%), hypotension (26.2%), and nausea (25%). These 
AEs were generally mild-to-moderate in severity and tolerable with the exception of hypotension, 
which was more severe than previously observed in other trials of Pexa-Vec. 
Grade 3 AEs possibly or probably related to Pexa-Vec included pyrexia (8.3%), hypotension 
(8.3%), blood bilirubin increased (4.8%), anemia (3.6%), blood aspartate transaminase (AST) 
increased (3.6%); fatigue, hepatic encephalopathy, hypertension, platelet count decreased, 
vomiting, (2.4% for each event); abdominal pain and blood alanine aminotransferase (ALT) 
increased (1.2% for each event). Two Grade 4 or Grade 5 events were noted: respiratory failure 
(Grade 4) and hepatic failure (Grade 5). 
Six patients presented with at least one Grade 3–4 AE possibly or probably related to IT injection 
procedure (7.1%): these AEs included hypotension (2.4%), upper abdominal pain, acute 
respiratory failure, anemia, ascites, fluid overload, hepatic hemorrhage, pleural effusion, acute 
renal failure, staphylococcal sepsis, and troponin increase (1.2% for each event). No procedure-
related AE resulted in the patient’s death. 
The most frequent Pexa-Vec-related SAE, which occurred in 6 patients (8 SAEs) was severe 
hypotension defined as a systolic blood pressure <90 mmHg, lasting and requiring a medical 
treatment for at least 24 hours after Pexa-Vec administration. Notably, anti-hypertensive 
medication was ongoing at the time of treatment with Pexa-Vec prior to the development of 
hypotension in the majority of these patients, thereby possibly exacerbating the potential for 
hypotension. 
Treatment with Pexa-Vec did not improve overall survival or other efficacy measures, compared 
with BSC, in patients with advanced HCC in this open-label study. No significant improvement 
of 
overall 
survival 
was 
shown 
in 
Arm 
A 
compared 
to 
Arm 
B  
(p = 0.426, stratified log-rank test) for the Intent-to-Treat (ITT) population. Median overall 
survival 
was 
4.2 
(95% 
confidence 
interval 
[CI]: 
3.3 
to 
5.4 
months) 
vs  
4.4 months (95% CI: 3.2 to 6.0 months) for Arm A vs Arm B, respectively. HR observed was 1.19 
(95% CI: 0.78 to 1.80). The overall disease control rate (proportion of patients with complete 
response [CR], partial response [PR], or SD) during the study was 13% (95% CI: 7% to 22%) vs 
19% (95% CI: 8% to 33%) for Arm A vs Arm B, respectively. Notably, the majority of patients in 
TRAVERSE did not receive the complete protocol specified treatment regimen of JX-594. In Arm 


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A, 12 of 86 randomized patients (13.9%) received all 6 planned treatments; and only half of the 
patients (51.2%) received at least 3 IT treatments (1 IV plus 3 IT) as administered in previous 
JX-594 HCC trials.  
The limited number of patients completing treatment on Arm A in conjunction with the 
significantly shorter median overall survival (~4.2 vs 4.4 months on Arms A and B, respectively) 
observed in this study versus studies of other agents for second line HCC (~7–9 months) suggests 
a relatively more advanced HCC patient population was included in TRAVERSE. 
1.2.3 Induction of adaptive immunity  
1.2.3.1 Pexa-Vec 
The concept of combining oncolytic viruses with immune-modulation – and specifically immune 
checkpoint inhibition – has two enormous theoretical advantages: tumor selectivity and ability to 
trigger adaptive immunity. Direct tumor cell lysis, release of soluble tumor antigens, and danger-
associated molecular patterns are all thought to help prime and promote tumor-specific 
immunity[7]. Apart from the direct oncolytic activity, oncolytic viruses such as Pexa-Vec as well 
as the herpes virus Talimogene laherparepvec (T-VEC) have been shown to mediate tumor cell 
death via the induction of innate and adaptive immune responses[8].  
Oncolytic viruses can induce immunogenic cell death and promote an antitumor inflammatory 
response. A recent preclinical study of Newcastle disease virus (NDV) demonstrated the systemic 
immune effects that can occur even when virus is injected locally[3]. In a murine model with B16 
melanomas established on the bilateral flanks, direct unilateral intratumoral injection of NDV 
produced significant increases in tumor-specific CD4 and CD8 + T cells in the contralateral 
(noninjected) tumor. Moreover, the combination of local NDV and systemic CTLA-4 blockade 
led to significant increases in tumor regression systemically. The most advanced – in terms of 
clinical development – oncolytic virus is Talimogene laherparepvec (T-VEC) which was approved 
by the FDA on October 15, 2015 for melanoma. T-VEC is a herpes simplex virus-1-based 
oncolytic immunotherapy. T-VEC is now being tested in combination with both CTLA-4 and PD-
1 blockade. In a phase 1b trial of T-VEC plus ipilimumab, 18 patients unresectable melanoma 
were enrolled. Treatment was well tolerated (grade 3–4 immune-related adverse events occurred 
in only two patients) and efficacy was promising (objective response was seen in 56%, and 33% 
had complete response)[9].  
1.2.3.2 Preclinical update  
1.2.3.2.1 Evidence of oncolytic vaccinia efficacy and immune activation in a RIP-Tag2 
transgenic mouse model of pancreatic cancer  
Anti-tumor as well as immune effects following IV oncolytic vaccinia treatment was interrogated 
in RIP-Tag2 mice, a transgenic model in which mice develop pancreatic neuroendocrine tumors. 
These tumors are VEGF driven, therefore are also representative of several angiogenic tumors, 
such as renal cell carcinoma. Experimental models such as this, represent human cancer more 
accurately than do the commonly used xenograft models -- in which human tumors are 
transplanted into nude mice. This is because xenografts do not develop in their normal tissue 
environment, the tumor-stroma interactions that support tumor growth are absent and contributions 
of adaptive immunity to efficacy cannot be interrogated.  


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Oncolytic vaccinia injected I.V. into RIP-Tag mice bearing tumors, selectively infects tumors, 
replicates, and causes tumor cell death by apoptosis. Virus spread can be monitored by anti-
vaccinia antibody staining, and tumor cell death by staining for activated caspase-3 in sections of 
excised tumors. Immunofluorescence based staining of the vasculature (anti-CD31) and 
lymphocyte infiltrate (CD45), in control and treated tumors, revealed a significant increase in both 
numbers and distribution of CD45+ leukocytes in vaccinia treated mice. T cell recruitment to 
tumors was demonstrated 5 days post IV vaccinia administration (Figure 2). CD8 T cells recruited 
to tumors were also shown to be activated (as evidenced by granzyme B positivity, data not 
shown). 
 
 
Figure 2: FACS analysis and immunohistofluorescence base staining with anti CD8 anti-bodies 
These data support a model in which oncolytic vaccinia virus treatment induces tumor lysis that 
secondarily leads to infiltration and activation of immune cells in the tumor micro-environment. 
We then explored whether this immune response could be further activated by combining 
treatment with vaccinia virus with an immune checkpoint blocking antibody targeting the protein 
PD-1. 
1.2.3.2.2 Combination of oncolytic vaccinia virus with anti-PD-1 antibody in RIP-Tag2 mice 
Anti-tumor activity of the combination of oncolytic vaccinia and anti-PD-1 antibody was evaluated 
in RIP-Tag2 mice by quantification of activated caspase 3 (marker of apoptosis).  
As demonstrated in Figure 3, while virus alone induced the expected levels of cell death, addition 
of anti-PD-1 antibody led to significantly enhanced tumor cell death, when used in combination 
(analysis performed at Day 5 post single agent or combination treatment regimen). No significant 
effect of the anti-PD-1 antibody alone were seen in this experiment. 


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These results provide for a rational basis for combining Pexa-Vec and an anti-PD1 antibody in 
clinical trials of a combination treatment for renal cell carcinoma. 
 
 
Figure 3. Enhanced tumor cell death induced by combination JX594 and anti-PD-1 treatment as 
compared with anti-PD-1 alone or oncolytic vaccinia alone 
1.3 
Tremelimumab  
Tremelimumab is a human immunoglobulin (Ig)G2 mAb that is directed against CTLA-4 and is 
being developed by AstraZeneca for use in the treatment of cancer.  
To date tremelimumab has been given to more than 1000 patients as part of ongoing studies either 
as monotherapy or in combination with other anticancer agents. Refer to the current tremelimumab 
Investigator’s Brochure for a complete summary of non-clinical and clinical information including 
safety, efficacy and pharmacokinetics.  
1.4 
Durvalumab 
Durvalumab is a human monoclonal antibody (mAb) of the immunoglobulin G (IgG) 1 kappa 
subclass that inhibits binding of PD-L1 to PD-1 and CD80 and is being developed by 
AstraZeneca/MedImmune for use in the treatment of cancer. (MedImmune is a wholly owned 
subsidiary of AstraZeneca; AstraZeneca/MedImmune will be referred to as AstraZeneca 
throughout this document.) As durvalumab is an engineered mAb, it does not induce antibody-
dependent cellular cytotoxicity or complement-dependent cytotoxicity. The proposed mechanism 
of action for durvalumab is interference of the interaction of PD-L1 with PD-1 and CD80. 
To date durvalumab has been given to more than 1800 patients as part of ongoing studies either as 
monotherapy or in combination with other anti-cancer agents. Refer to the current durvalumab 


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Investigator’s Brochure for a complete summary of non-clinical and clinical information including 
safety, efficacy and pharmacokinetics.  
1.5 
Anti-CTLA4 in combination with anti-PD1/PD-L1 
Because the mechanisms of action of CTLA-4 and PD-1 are non-redundant targeting both PD-1 
and CTLA-4 pathways may have additive or synergistic activity [10]; therefore, in addition to 
evaluating both agents in the monotherapy setting in a number of cancer indications AstraZeneca 
is also investigating the use of durvalumab + tremelimumab combination therapy for the treatment 
of cancer. 
Study D4190C00006 is a Phase Ib dose-escalation study to establish the safety, 
PK/pharmacodynamics, and preliminary anti-tumor activity of durvalumab + tremelimumab 
combination therapy in patients with advanced NSCLC. The dosing schedule utilized is 
durvalumab every 2 or 4 weeks (Q2W, Q4W) up to 12 months, combined with tremelimumab 
Q4W up to Week 24 for 7 doses then every 12 weeks (Q12W) for 2 additional doses for up to 12 
months. The study is ongoing and continues to accrue. In addition, other clinical studies have since 
started looking at the combination in both NSCLC and other oncology indications. 
To date more than 100 patients have received the combination using a number of doses and dosing 
schedules. Refer to the current editions of the durvalumab and tremelimumab IBs for a complete 
summary of non-clinical and clinical information including safety, PK and efficacy.  
1.5.1 Durvalumab and tremelimumab dose and treatment regimen justification 
The durvalumab + tremelimumab combination therapy doses and regimen selected for this study 
are based on the goal of selecting an optimal combination dose of durvalumab and tremelimumab 
that would yield sustained target suppression (sPD-L1), demonstrate promising efficacy, and have 
an acceptable safety profile.  
1.5.1.1 Pharmacokinetics/Pharmacodynamics data 
Study D4190C00006 included dose cohorts with both a Q4W and a Q2W schedule of durvalumab 
in combination with a Q4W schedule of tremelimumab. The Q4W schedule was included to align 
with the Q4W dosing of tremelimumab. PK simulations from durvalumab monotherapy data 
indicated that a similar area under the plasma drug concentration-time curve at steady state 
(AUCss; 4 weeks) was expected following both 10 mg/kg Q2W and 20 mg/kg Q4W dosing with 
durvalumab. The observed durvalumab PK data from the D4190C00006 study were in line with 
the predicted monotherapy PK data developed pre-clinically and in line with that seen in the first-
time-in-human (FTIH), single agent study (CD-ON-MEDI4736-1108) in patients with advanced 
solid tumors. This demonstrates similar exposure of durvalumab 20 mg/kg Q4W and 10 mg/kg 
Q2W, with no alterations in PK when durvalumab and tremelimumab (doses ranging from 1 to 3 
mg/kg) are dosed together. While the median maximum plasma concentration at steady state 
(Cmax,ss) is expected to be higher with 20 mg/kg Q4W (approximately 1.5-fold) and median 
trough concentration at steady state (Ctrough,ss) is expected to be higher with 10 mg/kg Q2W 
(approximately 1.25-fold), this is not expected to impact the overall safety and efficacy profile, 
based on existing preclinical and clinical data. 
Monotonic increases in pharmacodynamic activity were observed with increasing doses of 
tremelimumab relative to the activity observed in patients treated with durvalumab monotherapy. 
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with combination doses containing 1 mg/kg tremelimumab, including both the 15 and 20 mg/kg 
durvalumab plus 1 mg/kg tremelimumab combinations.  
Recent updated PK and pharmacodynamic data from regimens that used tremelimumab doses of 
greater than 1 mg/kg from Study D4190C00006 indicated superior efficacy with combination 
regimen of durvalumab 1500 mg Q4W plus tremelimumab 300 mg × 1 dose. An approximate 
dose-proportional increases in PK exposure (maximum serum concentration and area under the 
serum drug concentration-time curve from time 0 to Day 28 post-dose) was observed with 
increasing doses of tremelimumab (1, 3, and 10 mg/kg).  An exploratory pharmacodynamic 
analysis bioanalytically evaluated the effects of tremelimumab on proliferating T-cells from 
NSCLC patients who received tremelimumab (1, 3, or 10 mg/kg) and durvalumab (15 or 20 mg/kg) 
combination treatment.  Monotonic increases in pharmacodynamic activity with the combination 
(increased activation/ proliferation markers on CD4 and CD8 T-cells in periphery) were observed 
with increasing doses of tremelimumab (1, 3, 10 mg/kg).  The peak increase (%) from baseline of 
CD4+Ki67+ T-cells was observed 8 days post administration, and the peak level was significantly 
increased (p ≤ 0.05) as increasing dose of tremelimumab in the range of 1 to 10 mg/kg. Study data 
also suggested that higher peak exposure (maximum serum concentration [Cmax]) of tremelimumab 
is related to a higher maximum pharmacodynamic effect in the NSCLC patient population.  
Overall, the PK/pharmacodynamic data suggest that tremelimumab of dose greater than 1 mg/kg 
with a higher peak exposure may be associated with a higher pharmacodynamic effect. 
Additionally, based on simulation data, the Cmax (78 µg/mL) post single dose administration of 
tremelimumab 4 mg/kg is approximately 4-fold higher than the predicted Cmax (19 µg/mL) post 
the first dose of tremelimumab 1 mg/kg, and is 3-fold higher than the predicted Cmax (25 µg/mL) 
post the fourth dose of tremelimumab 1 mg/kg in a Q4W×4 doses setting.  
1.5.1.2 Clinical data 
In Study D4190C00006 various dose combinations have been explored, with doses of 
tremelimumab ranging from 1 to 10 mg/kg and doses of durvalumab ranging from 3 to 20 mg/kg. 
Tremelimumab was given on a Q4W schedule whilst durvalumab was explored in both a Q4W 
and Q2W schedule, with the goal of identifying the dose combination that best optimizes the risk: 
benefit profile in an acceptable range of PK and pharmacodynamic values. 
Patients treated with doses of tremelimumab above 1 mg/kg had a higher rate of adverse events 
(AEs), including discontinuations due to AEs, serious AEs (SAEs), and severe AEs. Between the 
10 mg/kg durvalumab + 1 mg/kg tremelimumab and 10 mg/kg durvalumab + 3 mg/kg 
tremelimumab cohorts treated at the Q2W schedule, the number of patients reporting any AE, ≥ 
Grade 3 AEs, SAEs, and treatment-related AEs was higher in the 10 mg/kg durvalumab + 3 mg/kg 
tremelimumab cohort than the 10 mg/kg durvalumab + 1 mg/kg tremelimumab cohort. A similar 
pattern was noted in the Q4W regimens, suggesting that, as the dose of tremelimumab increased 
above 1 mg/kg, a higher rate of treatment-related events may be anticipated. Further, the SAEs 
frequently attributed to immunotherapy, pneumonitis, colitis and other immune mediated events, 
were more commonly seen in cohorts using either 3 mg/kg or 10 mg/kg of tremelimumab 
compared to the 1-mg/kg dose cohorts. Together, these data suggest that a combination using a 
tremelimumab dose of 1 mg/kg appeared to minimize the rate of toxicity when combined with 
durvalumab. As a result, all combination doses utilizing either the 3 or 10-mg/kg doses of 
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In contrast, cohorts assessing higher doses of durvalumab with a constant dose of tremelimumab 
did not show an increase in the rate of AEs. The data suggested that increasing doses of durvalumab 
may not impact the safety of the combination as much as the tremelimumab dose. Further, safety 
data between the 10-mg/kg and 20-mg/kg cohorts were similar, with no change in safety events 
with increasing dose of durvalumab. 
In Study D4190C00006, of all treatment cohorts, the cohort of patients treated in the 20 mg/kg 
durvalumab + 1 mg/kg tremelimumab group had a tolerable safety profile, but still showed strong 
evidence of clinical activity. No dose-limiting toxicities (DLTs) were reported in this cohort.  
Preliminary clinical activity of the durvalumab and tremelimumab combination did not appear to 
change with increasing doses of tremelimumab. The 15- and 20-mg/kg durvalumab Q4W cohorts 
demonstrated objective responses at all doses of tremelimumab, and increasing doses of 
tremelimumab did not provide deeper or more rapid responses. 
Efficacy data suggested that the 20 mg/kg durvalumab + 1 mg/kg tremelimumab dose cohort may 
demonstrate equivalent clinical activity to other dose combinations. Of the 14 patients in this 
cohort, there were 4 patients (29%) with PR, 4 patients (29%) with SD, and 2 patients (14%) with 
PD. Two patients were not evaluable for response. 
A single dose of tremelimumab 4 mg/kg, while maintaining a similar overall exposure, has a 3- to 
4-fold higher Cmax compared to the 4 doses of tremelimumab 1 mg/kg.  Therefore, this single 
administration of the higher dose of tremelimumab may have the potential for better anti-tumor 
activity while potentially avoiding any cumulative toxicity associated with repeated dosing of the 
1 mg/kg tremelimumab.   
In the Phase I/II study (Study D4190C00022) evaluating the tolerability and clinical activity of 
durvalumab and tremelimumab in advanced HCC patients who progressed on, are intolerant of, or 
refused sorafenib-based therapy, durvalumab (1500 mg Q4W) as a single agent and in combination 
with two dosing regimens of tremelimumab (75 mg Q4W X 4 doses or 300mg X 1 dose) were 
evaluated. In the pre-planned interim analysis, safety data showed that both combination dose 
regimens were tolerable and no new safety signals were identified. While efficacy for durvalumab 
in combination with tremelimumab at the 75mg dose (Q4W X 4) was not meaningfully better than 
durvalumab monotherapy, efficacy data supports continued evaluation of durvalumab in 
combination with tremelimumab at the 300mg dose (X1). Therefore, durvalumab in combination 
with tremelimumab 300 mg x 1 dose will only be continued evaluation in the phase I/II study 
(Study D4190C00022) and Phase III study (Study D419CC00002).  
Altogether, the data suggested that a 20 mg/kg durvalumab + 1 mg/kg tremelimumab dose 
combination should be selected for further development.  
Refer to the current durvalumab Investigator’s Brochure for a complete summary of non-clinical 
and clinical information on the durvalumab + tremelimumab combination, including safety, 
efficacy and pharmacokinetics.  
1.5.1.3 Rationale for 4 cycles of combination therapy followed by durvalumab monotherapy 
Long -term follow up on melanoma patients treated with ipilimumab, an anti-CTLA-4 targeting 
antibody (dosed every 3 weeks [Q3W] for 4 doses and then discontinued), shows that patients 
responding to ipilimumab derive long-term benefit, with a 3-year OS rate of approximately 22%. 
Furthermore, the survival curve in this population reached a plateau at 3 years and was maintained 
through 10 years of follow up.  


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Similar data have been presented for other anti-PD-1/PD-L1 targeting antibodies:  
Nivolumab (anti-PD-1) was dosed Q2W for up to 96 weeks in a large Phase I dose escalation and 
expansion study, and showed responses were maintained for a median of 22.94 months for 
melanoma (doses 0.1 mg/kg to 10 mg/kg), 17 months for NSCLC (doses 1, 3, and 10 mg/kg), and 
12.9 months for renal cell carcinoma patients (doses 1 and 10 mg/kg) at the time of data 
analysis[11]. Furthermore, responses were maintained beyond treatment discontinuation in the 
majority of patients who stopped nivolumab treatment (either due to protocol specified end of 
treatment, CR, or toxicity) for up to 56 weeks at the time of data analysis.  
Similar long-term results may be expected with use of other immune-mediated cancer therapeutics 
such as tremelimumab, durvalumab, or the combination of the two agents.  
The durvalumab + tremelimumab combination regimen will be administered for 4 doses Q4W 
followed by durvalumab monotherapy Q4W for up to a maximum of 2 years’ total. 
1.5.2 Durvalumab monotherapy dose rationale 
A durvalumab dose of 20 mg/kg Q4W is supported by in vitro data, non-clinical activity, clinical 
PK/pharmacodynamics, biomarkers, and activity data from Study 1108 in patients with advanced 
solid tumors and from a Phase I trial performed in Japanese patients with advanced solid tumor 
(D4190C00002). 
1.5.2.1 PK/Pharmacodynamic data 
Based on available PK/pharmacodynamic data from ongoing Study 1108 with doses ranging from 
0.1 to 10 mg/kg Q2W or 15 mg/kg Q3W, durvalumab exhibited non-linear (dose dependent) PK 
consistent with target-mediated drug disposition. The PK approached linearity at ≥3 mg/kg Q2W, 
suggesting near complete target saturation (membrane-bound and sPD-L1), and further shows that 
the durvalumab dosing frequency can be adapted to a particular regimen given the linearity seen 
at doses higher than 3 mg/kg. The expected half-life with doses ≥3 mg/kg Q2W is approximately 
21 days. A dose-dependent suppression in peripheral sPD-L1 was observed over the dose range 
studied, consistent with engagement of durvalumab with PD-L1. A low level of immunogenicity 
has been observed. No patients have experienced immune-complex disease following exposure to 
durvalumab (For further information on immunogenicity, please see the current IB).  
Data from Study D4190C00006 (Phase I trial in NSCLC patients using the combination of 
durvalumab and tremelimumab) also show an approximately dose-proportional increase in PK 
exposure for durvalumab over the dose range of 3 to 20 mg/kg durvalumab Q4W or Q2W. (For 
further information on PK observations in Study 006, please see the current IB).  
The observed durvalumab PK data from the combination study were well in line with the predicted 
monotherapy PK data (5th median and 95th percentiles) for a Q4W regimen.  
A population PK model was developed using the data from Study 1108 (doses=0.1 to 10 mg/kg 
Q2W or 15 mg/kg Q3W (Fairman et al 2014). Multiple simulations indicate that a similar overall 
exposure is expected following both 10 mg/kg Q2W and 20 mg/kg Q4W regimens, as represented 
by AUCss (4 weeks). Median Cmax,ss is expected to be higher with 20 mg/kg Q4W (~1.5 fold) 
and median Ctrough,ss is expected to be higher with 10 mg/kg Q2W (~1.25 fold). Clinical activity 
with the 20 mg/kg Q4W dosing regimen is anticipated to be consistent with 10 mg/kg Q2W with 
the proposed similar dose of 20 mg/kg Q4W expected to (a) achieve complete target saturation in 
majority of patients; (b) account for anticipated variability in PK, pharmacodynamics, and clinical 


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activity in diverse cancer populations; (c) maintain sufficient PK exposure in case of ADA impact; 
and (d) achieve PK exposure that yielded maximal antitumor activity in animal models. 
Given the similar area under the plasma drug concentration-time curve (AUC) and modest 
differences in median peak and trough levels at steady state, the observation that both regimens 
maintain complete sPD L1 suppression at trough, and the available clinical data, the 20 mg/kg 
Q4W and 10 mg/kg Q2W regimens are expected to have similar efficacy and safety profiles, 
supporting further development with a dose of 20 mg/kg Q4W.  
1.5.3 Fixed Dosing for durvalumab and tremelimumab  
A population PK model was developed for durvalumab using monotherapy data from a Phase 1 
study (study 1108; N=292; doses= 0.1 to 10 mg/kg Q2W or 15 mg/kg Q3W; solid tumors). 
Population PK analysis indicated only minor impact of body weight (WT) on PK of durvalumab 
(coefficient of ≤ 0.5). The impact of body WT-based (10 mg/kg Q2W) and fixed dosing (750 mg 
Q2W) of durvalumab was evaluated by comparing predicted steady state PK concentrations (5th, 
median and 95th percentiles) using the population PK model. A fixed dose of 750 mg was selected 
to approximate 10 mg/kg (based on median body WT of ~75 kg). A total of 1000 patients were 
simulated using body WT distribution of 40–120 kg. Simulation results demonstrate that body 
WT-based and fixed dosing regimens yield similar median steady state PK concentrations with 
slightly less overall between-subject variability with fixed dosing regimen.  
Similarly, a population PK model was developed for tremelimumab using data from Phase 1 
through Phase 3 (N=654; doses= 0.01 to 15 mg/kg Q4W or Q90D; metastatic melanoma) [12]. 
Population PK model indicated minor impact of body WT on PK of tremelimumab (coefficient of 
≤ 0.5). The WT-based (1 mg/kg Q4W) and fixed dosing (75 mg/kg Q4W; based on median body 
WT of ~75 kg) regimens were compared using predicted PK concentrations (5th, median and 95th 
percentiles) using population PK model in a simulated population of 1000 patients with body 
weight distribution of 40 to 120 kg. Similar to durvalumab, simulations indicated that both body 
WT-based and fixed dosing regimens of tremelimumab yield similar median steady state PK 
concentrations with slightly less between-subject variability with fixed dosing regimen.  
Similar findings have been reported by others [13][, [14], [15], [16]. Wang and colleagues 
investigated 12 monoclonal antibodies and found that fixed and body size-based dosing perform 
similarly, with fixed dosing being better for 7 of 12 antibodies. In addition, they investigated 18 
therapeutic proteins and peptides and showed that fixed dosing performed better for 12 of 18 in 
terms of reducing the between-subject variability in pharmacokinetic/pharmacodynamics 
parameters [15].  
A fixed dosing approach is preferred by the prescribing community due to ease of use and reduced 
dosing errors. Given expectation of similar pharmacokinetic exposure and variability, we 
considered it feasible to switch to fixed dosing regimens. Based on average body WT of 75 kg, a 
fixed dose of 750 mg Q2W MEDI4736 (equivalent to 10 mg/kg Q2W), 1500 mg Q4W durvalumab 
(equivalent to 20 mg/kg Q4W) and 75 mg Q4W tremelimumab (equivalent to 1 mg/kg Q4W) is 
included in the current study.  
Fixed dosing of durvalumab and tremelimumab is recommended only for subjects with > 30kg 
body weight due to endotoxin exposure. Patients with a body weight less than or equal to 30 kg 
are not eligible for enrollment in the current study, and if a patient’s body weight drops below 30 


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kg while on the study, the patient should be dosed using a weight-based dosing schedule as long 
as their body weight remains < 30 kg. 
For patients treated with tremelimumab in the current study, subjects must have a body weight of 
> 35 kg to enroll and they will be treated with a fixed dose of tremelimumab. If a patient’s body 
weight drops below 33 kg while on the study, the patient should be dosed with tremelimumab 
using a weight-based dosing schedule for as long as their body weight remains < 33 kg and 
according to the study protocol.  
1.6 
Rationale for timing and mandatory nature of the biopsies 
Whilst the preclinical data suggest induction of immune cell infiltration following oncolytic viral 
therapy, with potential for amplification with immune checkpoint therapy, the effect in colorectal 
cancer – a relatively non-immunogenic tumor – is really unknown. Given that this is essentially a 
small pilot study evaluating feasibility and safety whose next step in development – if safe and 
feasible – will most likely be a larger randomized study, it is scientifically important to obtain as 
much information about the treatment effect. This may lead to altered and improved design of the 
next study. The best strategy for doing this is with tumor biopsies in order to evaluate immune cell 
infiltration (CD4/8 T-cells, MDSC). However, if a patient has technically biopsiable disease but 
the interventional radiologist has concerns that pursuing the biopsy increases the risk to above 
average, or if pursuing the biopsy creates additional logistical complications (availability, pre-
anesthesia requirements etc.) which cause delays or inconvenience to an unreasonable degree, we 
will forgo at investigator discretion. The timing of the biopsies reflects twin aims of evaluating 
immune infiltration post-virus and also post-combination therapy. The baseline –day 1 paired 
biopsies will provide data on the immune impact of the virus (within the TME) and the baseline –
day 29 paired samples will provide data on the immune impact of the combination of the vaccine 
and immune checkpoint inhibitor. Given the difficulty in obtaining three separate tumor biopsies 
we have elected to perform a baseline on all patients and then either the D1 or D29 biopsy. 
1.7 
Amendment D Rationale 
Considering recent updated PK and pharmacodynamic data from regimens that used 
tremelimumab (Section 1.5.1.1) and clinical benefit of increased single tremelimumab dose 
(Section 1.5.1.2) with Amendment D we change study design and replace 4 infusions (75 mg each) 
of tremelimumab with single infusion (300 mg). 
We completed enrollment into Arms A1 and A2 and with approval of this amendment we are 
proceeding to enrollment to Arms B1 and B2 with addition of tremelimumab to combined 
treatment. 
Overall, combination of Pexa-Vec with durvalumab even on dose level 2 of Pexa-Vec showed 
favorable safety profile. No DLT was developed. All patients who received the treatment tolerated 
well. There were no drug-related discontinuations or deaths. Drug-related AEs occurred in 100% 
of patients and were grade 3-4 in 8.6%. See (Appendix D) 
  


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2 
ELIGIBILITY ASSESSMENT AND ENROLLMENT 
2.1 
Eligibility Criteria 
2.1.1 Inclusion Criteria 
2.1.1.1 Patients must have histopathological confirmation of Colorectal Carcinoma (CRC) by the 
Laboratory of Pathology of the NCI prior to entering this study. 
2.1.1.2 Patients must have progressed on, been intolerant of or refused prior oxaliplatin- and 
irinotecan-containing, fluorouracil-based, chemotherapeutic regimen and have disease 
that is not amenable to potentially curative resection. Patients who have a known KRAS 
wild type tumor must have progressed, been intolerant of or refused cetuximab or 
panitumumab-based chemotherapy. 
2.1.1.3 Patients tumors must be documented to be microsatellite-stable (MSS) either by genetic 
analysis or immunohistochemistry OR microsatellite-high with documented disease 
progression following anti-PD1/PDL1 therapy.  
2.1.1.4 Patients must have at least one focus of metastatic disease that is amenable to pre- and 
on-treatment biopsy 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. 
2.1.1.5 All patients enrolled will be required to have measurable disease by RECIST 1.1 criteria.  
2.1.1.6 Age ≥18 years. Because no dosing or adverse event data are currently available on the 
use of Pexa-Vec in combination with tremelimumab and/or durvalumab in patients <18 
years of age, children are excluded from this study, but will be eligible for future pediatric 
trials.  
2.1.1.7 ECOG performance status 0-1 (see Appendix A)  
2.1.1.8 Patients must have acceptable organ and marrow function as defined below: 
Leukocytes 
>3,000/mcL 
absolute neutrophil count 
> 1,500/mcL 
Platelets 
>100,000/mcL 
total bilirubin 
≤1.5X institution upper limit of normal 
Hb 
> 9g/dl 
AST (SGOT)/ALT (SGPT) ≤ 2.5 x institutional upper limit of normal 
unless liver metastases are present, in which case it must be ≤ 5x ULN 
Creatinine 
<1.5X institution upper limit of normal 
 
OR 


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creatinine clearance 
>45 mL/min/1.73 m2, as calculated 
below, for patients with creatinine levels 
above institutional normal 
Estimated creatinine clearance (mL/min) 
Females = 
 
Males 
= 
 
 
May use a 24-hr. urine collection to determine creatinine clearance. 
Measured creatinine clearance (mL/min) 
 
2.1.1.9 Patient must be able to understand and willing to sign a written informed consent 
document 
2.1.1.10 The effects of Pexa-Vec, durvalumab and tremelimumab on the developing human fetus 
are unknown. For this reason, women of child-bearing potential and men must agree to 
use adequate contraception (hormonal or barrier method of birth control; abstinence) prior 
to study entry, for the duration of study participation and up to 180 days after the last dose 
of durvalumab + tremelimumab combination therapy or 90 days after the last dose of 
durvalumab monotherapy, 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. 
2.1.1.11 Evidence of post-menopausal status or negative urinary or serum pregnancy test for 
female pre-menopausal patients. Women will be considered post-menopausal if they have 
been amenorrheic for 12 months without an alternative medical cause. The following age-
specific requirements apply:  
o 
Women <50 years of age would be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of exogenous hormonal 
treatments and if they have luteinizing hormone and follicle-stimulating hormone 
levels in the post-menopausal range for the institution or underwent surgical 
sterilization (bilateral oophorectomy or hysterectomy). 
o 
Women ≥50 years of age would be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of all exogenous hormonal 
treatments, had radiation-induced menopause with last menses >1 year ago, had 
chemotherapy-induced menopause with last menses >1 year ago, or underwent 
surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or 
hysterectomy. Subject is willing and able to comply with the protocol for the 


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duration of the study including undergoing treatment and scheduled visits and 
examinations including follow up. 
2.1.1.12 Body weight >35kg 
2.1.2 Exclusion Criteria 
2.1.2.1 Patients who have had anti-cancer therapy (chemotherapy, immunotherapy, endocrine 
therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal antibodies 
or other investigation agents), large field radiotherapy, or major surgery must wait 4 
weeks after completing treatment prior to entering the study. 
2.1.2.2 No prior exposure to immune-mediated therapy including, but not limited to, other anti 
CTLA-4, anti-PD-1, anti-PD-L1, and anti-programmed cell death ligand 2 (anti-PD-L2) 
antibodies, including therapeutic anticancer vaccines. The exception to this is those 
whose tumors are MSI-hi and are refractory to anti-PD1 monotherapy.  
2.1.2.3 Involvement in the planning and/or conduct of the study  
2.1.2.4 Previous IP assignment in the present study 
2.1.2.5 Patients who are receiving any other investigational agents.  
2.1.2.6 Inability to suspend treatment with anti-hypertensive medication (including but not 
limited to: diuretics, beta-blockers, angiotensin converting enzyme [ACE] inhibitors, 
aldosterone antagonists, etc.) for 48 hours pre and post each Pexa-Vec administration.  
2.1.2.7 Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with 
the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion 
criteria  
2.1.2.8 Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis 
2.1.2.9 Patients with known brain metastases will be excluded from this clinical trial because of 
their poor prognosis and because they often develop progressive neurologic dysfunction 
that would confound the evaluation of neurologic and other adverse events. 
2.1.2.10 Uncontrolled intercurrent illness including, but not limited to, hypertension (systolic BP 
> 160, diastolic BP > 100), ongoing or active systemic infection, symptomatic congestive 
heart failure, unstable angina pectoris, cardiac arrhythmia, uncontrolled diabetes or 
psychiatric illness/social situations that would limit compliance with study requirements. 
For patients with a history of cardiovascular disease, cardiology consultation is required. 
Echocardiogram, troponin and creatinine clearance must be obtained prior to enrollment. 
NOTE: Patients with active cardiac disease (e.g. myocarditis and myocardial infarction) 
within 12 months of study entry are excluded from study participation. 
2.1.2.11 HIV-positive patients receiving anti-retroviral therapy are excluded from this study due 
to the possibility of pharmacokinetic interactions between antiretroviral medications and 
the investigational agent. HIV positive patients not receiving antiretroviral therapy are 
excluded due to the possibility that Durvalumab or Tremelimumab may worsen their 


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condition and the likelihood that the underlying condition may obscure the attribution of 
adverse events. 
2.1.2.12 Known significant immunodeficiency due to underlying illness (e.g. HIV/AIDS) and/or 
immune-suppressive medication including high-dose corticosteroids (defined as ≥20 
mg/day prednisone or equivalent which is ongoing at the time of enrollment and/or was 
taken for more than 4 weeks within the preceding 2 months of enrollment) 
2.1.2.13 History of chronic autoimmune disease (e.g. systemic lupus erythematosus or Wegener’s 
granulomatosis, Addison’s disease, multiple sclerosis, Graves’ disease, Hashimoto’s 
thyroiditis, hypophysitis, etc.) with symptomatic disease within the 3 years before 
enrollment. Note: Active vitiligo or a history of vitiligo will not be a basis for exclusion. 
In addition, a past history of certain autoimmunity e.g. rheumatoid arthritis or thyroiditis 
may be allowed per PI discretion provided it has been quiescent for a minimum of three 
years. The following are exceptions to this criterion:  
a) Patients with vitiligo or alopecia 
b) Patients with hypothyroidism (e.g. following Hashimoto syndrome) stable on 
hormone replacement  
c) Any chronic skin condition that does not require systemic therapy 
d) Patients without active disease in the last 5 years may be included  
e) Patients with celiac disease controlled by diet alone 
f) Active or history of inflammatory bowel disease (colitis, Crohn’s), irritable bowel 
disease, celiac disease, or other serious, chronic, gastrointestinal conditions 
associated with diarrhea.  
2.1.2.14 History of active primary immunodeficiency  
2.1.2.15 Active infection including tuberculosis (clinical evaluation that includes clinical history, 
physical examination and radiographic findings, and TB testing (if clinically indicated), 
hepatitis B (known positive HBV surface antigen (HBsAg) result), hepatitis C. Patients 
with a past or resolved HBV infection (defined as the presence of hepatitis B core 
antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for hepatitis C 
(HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA. 
2.1.2.16 Current or prior use of immunosuppressive medication within 14 days before the first 
dose of durvalumab or tremelimumab. The following are exceptions to this criterion: 
o Intranasal, inhaled, topical steroids, or local steroid injections (e.g. intra articular 
injection) 
o Systemic corticosteroids at physiologic doses not to exceed <<10 mg/day>> of 
prednisone or its equivalent 
o Steroids as premedication for hypersensitivity reactions (e.g. CT scan premedication) 
o Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note: 
Patients, if enrolled, should not receive live vaccine whilst receiving IP and up to 30 
days after the last dose of IP. 
2.1.2.17 Female patients who are breastfeeding. Because there is an unknown but potential risk 
for adverse events in nursing infants secondary to treatment of the mother with Pexa-Vec, 


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breastfeeding should be discontinued if the mother is treated with Pexa-Vec. These 
potential risks may also apply to other agents used in this study.  
2.1.2.18 Known allergy or hypersensitivity to IP  
2.1.2.19 Prior randomization or treatment in a previous durvalumab and/or tremelimumab clinical 
study regardless of treatment arm assignment. 
2.1.2.20 History of sarcoidosis syndrome 
2.1.2.21 Mean QT interval corrected for heart rate (QTc) ≥470 ms calculated from 3 
electrocardiograms (ECGs) using Fredericia’s Correction 
2.1.2.22 Patients with a history of Interstitial lung disease or pneumonitis 
2.1.2.23 Subjects with uncontrolled seizures 
2.1.2.24 History of leptomeningeal carcinomatosis 
2.1.2.25 History of hypersensitivity reaction to human or mouse antibody products. 
2.1.2.26 Patients with unhealed surgical wounds for more than 30 days 
2.1.2.27 Ongoing severe inflammatory skin condition (as determined by the Investigator) 
requiring medical treatment 
2.1.2.28 History of severe eczema (as determined by the Investigator) requiring medical treatment 
2.1.2.29 Patients with tumor(s) invading a major vascular structure (e.g. carotid artery) or other 
key anatomical structure (e.g. pulmonary airway) in the event of post treatment tumor 
swelling and/or necrosis (hepatic and portal vein involvement allowed) 
2.1.2.30 Patients with liver tumors in a location that would potentially result in significant clinical 
adverse effects in the opinion of investigator if post-treatment tumor swelling were to 
occur, including at the site of the common bile duct 
2.1.2.31 Clinically significant and/or rapidly accumulating ascites, pericardial and/or pleural 
effusions. Mild ascites that does not preclude safe tumor biopsy as protocol specified is 
allowed at the discretion of the treating physician.  
2.1.2.32 Medical conditions, per the investigator’s judgment, that predispose the patient to 
untoward medical risk in the event of volume loading (e.g. intravenous [IV] fluid bolus 
infusion), tachycardia, or hypotension during or following treatment with Pexa-Vec  
2.1.2.33 Any prior or planned organ transplant (e.g. liver transplant) 
2.1.2.34 Patients who experienced a severe systemic reaction or side-effect as a result of a previous 
vaccination with vaccinia 
2.1.2.35 Pulse oximetry O2 saturation <90% at rest on room air 
2.1.3 Recruitment Strategies 
The study may be abstracted into a plain language announcement posted on NIH websites and on 
NIH social media platforms. 


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2.2 
Screening Evaluation 
2.2.1 Screening activities performed after a consent for screening has been signed 
Screening evaluation testing/procedures are conducted under the separate screening protocol, 01-
C-0129 (Eligibility Screening and Tissue Procurement for the NIH Intramural Research Program 
Clinical Protocols).  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. 
• History and Physical Evaluation 
Complete medical history and physical examination (including height, weight, vital signs, ECG, 
and ECOG performance status) will be conducted prior to enrollment. 
• 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 24-hour urine collection (if creatinine clearance is measured in this manner) 
o Serum or urine pregnancy test for female participants of childbearing age and 
anatomic ability.  
o HIV, Hepatitis B and C serology and/or viral load  
o TB testing (if clinically indicated) 
• Cardiology Consultation for patients with history of cardiovascular disease (see criterion 
2.1.2.10) 
• Echocardiogram 
• CT scan of chest, abdomen and pelvis (or MRI of abdomen if clinically indicated) 
• Histologic confirmation (at any time point prior to enrollment). If there is no available 
tumor sample, biopsy will be performed to confirm the diagnosis and Microsatellite 
Stability Status. 
o A block or unstained slides of primary or metastatic tumor tissue will be required from 
each participant to confirm diagnosis with analysis being performed by the Laboratory 
of Pathology, NIH.  
o Documentation of microsatellite status (by PCR or IHC for MMR proteins, 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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2.4 
Treatment Assignment Procedures (for registration purposes only): 
Cohorts 
Number 
Name 
Description 
1 
A1 
Subjects enrolled to Pexa-Vec escalation dose levels + 
Durvalumab 
2 
A2 
Subjects enrolled at the MTD of Pexa-Vec after the 
MTD is established + Durvalumab 
3 
B1 
Subjects enrolled to Pexa-Vec escalation dose levels + 
Durvalumab + Tremelimumab 
4 
B2 
Subjects enrolled at the MTD of Pexa-Vec after the 
MTD is established+ Durvalumab + Tremelimumab 
 
Arms 
Number Name 
Description 
1 
A1  
Pexa-Vec escalation dose levels + Durvalumab 
2 
A2  
MTD of Pexa-Vec after the MTD is established + 
Durvalumab 
3 
B1  
Pexa-Vec escalation dose levels + Durvalumab + 
Tremelimumab 
4 
B2 
MTD of Pexa-Vec after the MTD is established+ 
Durvalumab + Tremelimumab 
Arm assignments 
Subjects in cohort A1 will be directly assigned to arm A1. 
Subjects in cohort A2 will be directly assigned to arm A2 after the MTD for Arm A1 has been 
determined. 
Subjects in cohort B1 will be directly assigned to arm B1 once enrollment in Arms A1 and A2 are 
complete. 
Subjects in cohort B2 will be directly assigned to arm B2 after the MTD for Arm B1 has been 
determined. 
 


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2.5 
Baseline Evaluation  
Tests performed during screening do not need to be repeated if done in designated time frame. 
• Physical exam with vital signs and ECOG performance status (obtained within 1 week 
prior to first dose of Pexa-Vec). 
• CT scan of chest, abdomen and pelvis (or MRI of abdomen if clinically indicated) 
(obtained within 28 days prior to first dose of Pexa-Vec) 
• Laboratory evaluation (obtained within 72 hours prior to first dose of Pexa-Vec): 
o Hematological profile: CBC with differential and platelet count  
o PT, INR, aPTT, fibrinogen. 
o Biochemical profile: electrolytes, BUN, creatinine, AST, ALT, total and direct 
bilirubin, calcium, phosphorus, albumin, magnesium, uric acid, amylase and lipase 
o Tumor marker profile: CEA 
o Serum or urine pregnancy test for female participants of childbearing age and 
anatomic ability. 
o Urinalysis  
o Troponins 
• Laboratory evaluation (obtained within 28 days prior to first dose of Pexa-Vec): 
o Thyroid function tests (TSH, T3, T4) 
o ACTH, morning cortisol. 
o HLA subtype  
• Electrocardiogram (obtained within 72 hrs. prior to first dose of Pexa-Vec) 
3 
STUDY IMPLEMENTATION 
3.1 
Study Design 
The proposed study is a Phase I/II study of Pexa-Vec oncolytic virus at two dose levels in 
combination with immune checkpoint inhibition in patients with metastatic colorectal cancer. 


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- 
Patients with advanced microsatellite-stable colorectal cancer (or MSI-hi disease that is 
refractory to PD-1 monotherapy) will receive Pexa-Vec, administered IV at a dose of either 3 
x 108 plaque forming units (pfu) (DL1) or 109 pfu (DL2) every 2 weeks for 4 doses, in 4 
separate arms: A1, A2, B1 and B2. The first administration will be on Day –(minus) 12, 
followed by administration on Days 2, 16 and 30 (i.e. 4 doses in total). 
- 
There will be 4 arms, as summarized in Table 1: in Arms A1 and A2 subjects will be 
treated with Pexa-Vec in combination with Durvalumab and in Arms B1 and B2 subjects 
will be treated with Pexa-Vec in combination with Durvalumab and Tremelimumab. After 
enrollment is completed for Arms A1 and A2 and full assessment of safety performed, we 
will report this data to the NIH Intramural IRB. We will only proceed to Arm B1 (Pexa-
Vec + Durvalumab + Tremelimumab) upon NIH Intramural IRB approval of updated 
safety information of ongoing combination therapy evaluating Arms A1 and A2 (Pexa-Vec 
in combination with Durvalumab). 
 
Tremelimumab 
Durvalumab 
Pexa-Vec/pfu 
N 
Arm A1 
DL 1 
NA 
1500mg q 28d  
3 x 108 
3-6 
DL 2 
NA 
1500mg q 28d  
109 
6 
Arm A2 
 
NA 
1500mg q 28d  
109 (MTD) 
4 


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Arm B1 
DL 1 
300 mg x 1 at cycle 
1 
1500mg q 28d  
3 x 108 
3-6 
DL 2 
300 mg x 1 at cycle 
1 
1500mg q 28d  
109 
6 
Arm B2 
 
300 mg x 1 at cycle 
1 
1500mg q 28d  
109 (MTD) 
4 
Table 1: Arms/Dose levels 
- 
Enrollment of the first two patients in each dose level will be staggered by 2 weeks in order 
to observe and treat any unexpected toxicities. 
- 
If 0/3 patients encounter DLT at DL1 we will proceed to DL2, or if 1/3 patients at Dose Level 
1 encounter DLT we will expand DL1 to 6 patients as per standard 3+3 criteria. 1/6 with DLT 
at DL1 will lead to enrollment onto DL2. If 2 or more of 6 patients have a DLT at Dose Level 
1, then we will not proceed with further enrollment or will need to revise the treatment regimen 
before use in a subsequent study, as appropriate.  
- 
If only 1/6 patients at Dose Level 2 encounter DLT we will expand DL2 to 10 patients. If 2 or 
more of 6 patients have a DLT at Dose Level 2, then we will not proceed with further 
enrollment and will need to revise the treatment regimen before use in a subsequent study, as 
appropriate.  
o Arms A1 and A2: In addition to the oncolytic virus patients will also receive 
durvalumab at a flat dose of 1500mg as an intravenous infusion beginning on Day 
1 followed by q28days until off-treatment criteria are met. 
o Arms B1 and B2: In addition to the oncolytic virus patients will also receive 
tremelimumab 300 mg and durvalumab 1500mg as intravenous infusions on Day 1 
followed by q28days subsequent continuation of the durvalumab alone until off-
treatment criteria are met. 
- 
Pexa-Vec will commence on Day –(minus) 12 to facilitate tumor biopsies following 
oncolytic virus alone.  
- 
All patients will undergo a baseline tumor biopsy and a post treatment biopsy. Patients will 
be assigned to receive the second biopsy on Day 1 (i.e. after one dose of Pexa-Vec alone) 
or Day 29 (i.e. after the combination of immune checkpoint inhibition and Pexa-Vec). 
(Specific dates of biopsy will have a window of 72 hrs to allow for logistical issues; 
however, the biopsy will not be performed within 48 hrs after Pexa-Vec administration). 
Patients should withhold antihypertensive medication for 48 hours pre and post Pexa-Vec 
administration. Assignment on a 1:1 basis will be performed to determine timing of the 
second research biopsy. Research Team will assign patient #1 to early second biopsy, 
patient #2 to late second biopsy and so on. 


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3.1.1 Dose Limiting Toxicity (DLT) 
A DLT is defined as any of the below listed laboratory abnormality or adverse drug reaction (ADR) 
according to the NCI-CTCAE v 4.3, that is possibly, probably, or definitely related to the 
combination of Pexa-Vec oncolytic virus with either durvalumab or the combination of 
durvalumab and tremelimumab, occurring during the DLT evaluation period unless specified as 
exceptions. ADRs are defined in this trial as any AEs suspected to be related to study treatment by 
the investigator. The DLT observation period comprises the first 28 days of combination treatment, 
extending from Day 1 to Day 28, however if later toxicities arise these may also be used to inform 
DLT determination based on the opinion of the investigator. Eligible patients for DLT evaluation 
will be those who completed the DLT period and have received at least 60% of the scheduled doses 
of Pexa-Vec and at least 1 dose of immune checkpoint blockade, or those who discontinue study 
treatment early due to a DLT. Subjects who are not fully eligible for DLT evaluation will be 
replaced. 
3.1.1.1 Immune-mediated adverse events (imAEs) 
• Any Grade 4 imAE not attributed to local tumor response (e.g. inflammatory reaction attributed 
to local tumor response or inflammatory reaction at sites of metastatic disease or lymph nodes). 
• Any Grade ≥3 colitis. 
• Any Grade 3 or 4 noninfectious pneumonitis, irrespective of duration or Grade 2 pneumonitis 
that does not resolve to ≤ Grade 1 within 3 days of the initiation of maximal supportive care. 
• Any Grade 3 imAE, excluding colitis or pneumonitis, that does not downgrade to Grade ≤1 or 
baseline status (for patients who entered the study with an existing laboratory abnormality) 
within 14 days. 
• Any > grade 2 cardiac toxicity which does not resolve to grade 1 within 3 days of initiation of 
maximum supportive care. 
3.1.1.2 Non-Immune-mediated Adverse Event (Non-imAE) 
• Any Grade ≥3 non-imAE toxicity that does not downgrade to Grade ≤1 or baseline status (for 
patients who entered the study with an existing laboratory abnormality) within 14 days 
3.1.1.3 Exclusions to Dose Limiting Toxicities 
• Grade 3/4 infusion-related reactions including fever, chills lasting less than 72 hours or 
hypotension responsive to IVF or other medical therapy (e.g. vasopressors) and resolving in < 
24 hrs.  
• Vitiligo, alopecia, rash, and Grade 3 electrolyte abnormalities that are reversed with 
appropriate medical intervention within 7 days or derived from a suboptimal prophylactic and 
curative therapy 
• Grade 4 electrolyte abnormalities lasting less than 72 hours or are clinically irrelevant. 
• Grade 3 and 4 diarrhea lasting less than 72 hours. 
• Grade 3 fatigue. 
• Grade 3 rise in creatinine, not corrected to Grade 1 or less after 2 liters or more of intravenous 
fluids within 24 hours, will be considered dose limiting.  


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• Laboratory values out of normal range that are unlikely related to trial treatment according to 
the investigator, do not have any clinical correlate, and resolve within 7 days with adequate 
medical management.  
• Transient (<7days) Grade 3 / 4 fatigue, local reactions, headache, nausea, emesis that resolves 
to ≤ Grade 1.  
• Grade 3 endocrinopathy that is managed with or without systemic corticosteroid therapy and/or 
hormone replacement therapy and the following criteria are met: 
o The subject’s hormone levels are within normal limits 
o The subject is asymptomatic 
• Grade 3 inflammatory reaction attributed to a local antitumor response (e.g. inflammatory 
reaction at sites of metastatic disease, lymph nodes, etc.). imAEs are defined as AEs of an 
immune nature (i.e., inflammatory) in the absence of a clear alternative etiology. In the absence 
of a clinically significant abnormality, repeat laboratory testing will be conducted to confirm 
significant laboratory findings prior to designation as a DLT. Laboratory abnormalities that are 
not deemed to be clinical significant will not be considered a DLT. 
3.1.2 Maximum tolerated dose (MTD) 
MTD will be that dose where no greater than 1 of 6 patients have a DLT. 
3.1.3 Protocol Stopping Rules  
This study will utilize the Common Terminology Criteria for Adverse Events (CTCAE) version 
4.3 for grading systemic toxicity. For safety reasons, the protocol will be temporarily halted 
pending discussions with the NIH Intramural IRB and Sponsor regarding necessary amendment 
for either of the following events:  
• One occurrence of grade 5 toxicity by the NCI-CTCAE version 4.3 attributable to the 
treatment regimen.  
• Two occurrences of grade 4 toxicity by the NCI-CTCAE version 4.3 attributable to the 
treatment regimen. 
3.2 
Drug Administration 
3.2.1 Pexa-Vec Drug Administration 
The Pexa-Vec dose of 3 x 108 pfu (DL 1) or 1 x 109 pfu (DL 2) will be administered via IV infusion 
over 60 minutes (±5 minutes). Patients will receive 1 L 0.9% Sodium Chloride (NaCl) prior to 
infusion. Treatments 2–4 may each be administered in a treatment window of ±72hrs. If a treatment 
is not given within the ±72hrs window, it will be considered missed (e.g. patient will not receive 
the treatment, but future treatments will be administered as originally outlined in the protocol). 
3.2.1.1 Pre-Medication for Treatment Day 
To mitigate risk of hypotension following Pexa-Vec treatment, the following are required: 
• Prehydration with 1 liter of solute-containing fluid (PO or IV) prior to each treatment 


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• Suspension of anti-hypertensive medication (including diuretics, beta-blockers, ACE 
inhibitors, aldosterone antagonists, etc.) for 48 hours prior to and 48 hours after each Pexa-
Vec injection. 
All patients should be pre-medicated with acetaminophen (or equivalent, unless contraindicated) 
on each treatment day. For acetaminophen, the following regimen may be used: 
• 500–1000 mg 2 hours’ pre-infusion 
• 500–1000 mg at 4 hours’ post-procedure 
• 500–1000 mg every 6 hours thereafter, as needed (the total acetaminophen dose should be 
carefully assessed to avoid cumulative toxicity) 
3.2.2 Durvalumab Administration 
A dose of 1500mg will be administered as an IV infusion over approximately 60 minutes (±5 
minutes).  
For details, please, see Section 13.2.5  
Less than 55 minutes is considered a deviation. 
If there are interruptions during infusion, the total allowed time should not exceed 8 hours at room 
temperature. 
3.2.3 Tremelimumab Administration 
A dose of 300 mg will be administered as an IV solution at a rate of 250 mL/hr. Standard infusion 
time is 1 hour. However, if there are interruptions during infusion, the total allowed time should 
not exceed 8 hours at room temperature. 
For details, please, see Section 13.1.5 
3.2.4 Monitoring of Dose Administration  
Pexa-Vec 
A 20-hour observation period is required after the first infusion of Pexa-Vec. Vital signs will be 
collected before infusion, at least once during the infusion, at the completion of the infusion and 
every 2 hours approximately until completion of 20-hour observation period. At the discretion of 
the treating physician patients may be admitted for additional supportive care and observation after 
the 20-hour period. If no clinically significant infusion reactions are observed during or after the 
first cycle, subsequent infusion observation periods can be at the Investigator’s discretion 
(suggested 8 hours after Pexa-Vec infusion). 
Tremelimumab and Durvalumab 
Vital signs will be collected before investigational product infusion and at the completion of the 
infusion. A 1-hour observation period is required after the first infusion of durvalumab and 
tremelimumab. If no clinically significant infusion reactions are observed during or after the first 
cycle, subsequent infusion observation periods can be at the Investigator’s discretion (suggested 
30 minutes after each durvalumab infusion). 


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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. For patients with a ≤Grade 2 infusion related reaction, 
subsequent infusions may be administered at 50% of the initial rate. 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. The standard infusion time is one hour, 
however, if there are interruptions during infusion, the total allowed time from infusion start to 
completion of infusion should not exceed 8 hours at room temperature (otherwise requires new 
infusion preparation). 
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 Modifications 
The following broad guidelines for dose delivery schedule delays and alternations apply to the 
planned dosages of Pexa-Vec, Tremelimumab and Durvalumab or Durvalumab monotherapy and 
are dependent on the clinical and laboratory assessment on the day of dosing. Pexa-Vec, 
Tremelimumab and Durvalumab can be delivered within 72 hours of planned interval to 
accommodate scheduling issues/logistics. 
3.3.1 Pexa-Vec 
If a treatment is not given within the ±72-hour window, it will be considered missed (e.g. patient 
will not receive the treatment, but future treatments will be administered as originally outlined in 
the protocol). 
3.3.2 Tremelimumab and durvalumab 
Dose modifications of Durvalumab and tremelimumab may be required in the event of treatment-
related toxicity. General guidelines regarding dose modification are provided in Appendix B.  
3.4 
Management of Expected Adverse Events and Events of Special Interest 
3.4.1 Expected Toxicities of Pexa-Vec Treatment 
3.4.1.1 Flu-Like Symptoms (mild-to-severe fever, rigors, anorexia, aches/pain, fatigue, 
headache, and/or nausea) 
These flu-like symptoms typically peak during the first 12 hours after Pexa-Vec treatment. Acute, 
fever is expected within 4–12 hours post-treatment and has a typical duration of 18–24 hours, 
although these can last up to 72 hours. 
3.4.1.2 Hypotension 
Across clinical trials and indications, mild-to-moderate transient hypotension can be observed 
within 24 hours following treatment with Pexa-Vec. However, in the TRAVERSE trial for patients 
with advanced 2nd line HCC, 6 patients (8 total SAEs) have experienced severe hypotension 
following Pexa-Vec treatment, requiring >24 hours of medical treatment, intensive care unit care, 
and vasopressor treatment. Notably, anti-hypertensive medication was ongoing at the time of 


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treatment with Pexa-Vec prior to the development of hypotension in the majority of these patients, 
thereby potentially exacerbating the potential for hypotension.  
Risk mitigation strategies for hypotension with Pexa-Vec are addressed in section 3.2.1.1. 
3.4.1.3 Hematological Events 
Transient decreases in WBC counts (including neutrophils and lymphocytes), platelets and 
hematocrit can occur. Transient thrombocytopenia (including reduced platelet count) occurred 
within days of treatment with Pexa-Vec and resolved within 1 week of treatment without medical 
intervention. Transient leukopenia (including reduced neutrophil and lymphocyte counts), has 
been observed with resolution generally occurring within 7 days of treatment. Leukopenia is a 
common finding associated with viral infection in general. Conversely, transient leukocytosis 
(including neutrophil, eosinophil, and monocyte subsets) has also been observed. An elevated 
WBC count is expected based on a GM CSF mediated effect by Pexa-Vec and the infusion of an 
attenuated vaccinia virus. 
3.4.1.4 Chemistry Changes 
Chemistry changes included hyponatremia and hyperglycemia; the relationship to Pexa-Vec 
treatment is not yet known. Dose-related direct hyperbilirubinemia (due to tumor swelling and 
occlusion of biliary tract drainage) has been noted in patients treated with Pexa-Vec whose liver 
tumors were adjacent to or impeding the biliary tract at baseline. In addition, acute respiratory 
distress secondary to airway obstruction was observed in one patient with HCC metastases to the 
lung following treatment. Therefore, patients with liver tumors in a location that would potentially 
result in significant clinical adverse effects if post-treatment tumor swelling were to occur, 
including at the site of the common bile duct, should not be included as per Exclusion Criteria. 
Biliary tract drainage should be considered as clinically indicated if biliary occlusion does not 
resolve quickly enough clinically. Acute post-treatment tumor swelling can result in 
hyperbilirubinemia within approximately one week following treatment; tumor swelling may 
resolve over time.  
3.4.1.5 Rashes 
Rashes related to latent virus reactivation have been reported, both with Varicella-Zoster (i.e., 
“shingles”) and herpes simplex virus; whether these rashes are related to Pexa-Vec itself, or due 
to the fever induced, is unknown. Small (<1 cm) superficial skin or oral mucous membrane 
pustules containing Pexa-Vec may develop after Pexa-Vec treatment. If they develop, it is typically 
within 1 week after the first IV infusion only. These pustules have rarely (<10%) been seen 
following IT injection. These pustules generally resolve within approximately the following 2–3 
weeks, a time course that is consistent with the usual course following intentional vaccination with 
wild-type [non-attenuated] vaccinia vaccine. All pustules to date have been self-limited and 
resolved without complications or the need for specific anti-viral treatment. 
3.4.1.6 Myocarditis  
Wild type vaccinia has been associated with myocarditis. Around 1 in 175 patients administered 
with ACAM2000, a wildtype vaccinia (smallpox) vaccine, experienced myocarditis and/or 
pericarditis. To date, the use of Pexa-Vec (non-wild-type), in over 300 patients, has not been 
associated with myocarditis. The risk of myocarditis may be increased in the context of 
concomitant checkpoint inhibitors. For this reason, subjects with cardiovascular disease such as 
myocarditis and history of myocardial infarction are excluded from the study. Echocardiograms 


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will be performed at the screening and during the study if clinically necessary. Troponins will be 
monitored monthly during the study and follow up period.  
3.4.1.7 Additional risks 
Additional risks include tachycardia, portal vein thrombosis, cytokine release syndrome (CRS), 
viremia, herpes infections and hypertension 
Further information on these risks (e.g. presenting symptoms) can be found in the current version 
of the Pexa-Vec Investigator Brochure. 
3.4.2 Potential Mechanisms of Pexa-Vec Shedding to the Environment, Biodissemination and 
Prevention of Transmission 
3.4.2.1 Superficial Skin Pustules  
Small (<1 cm) superficial skin or oral mucous membrane pustules containing Pexa-Vec may 
develop after Pexa-Vec treatment. If pustules develop, they do so typically within 1 week after the 
first administration. These pustules generally resolve within approximately the following 2–3 
weeks, a time course that is consistent with the usual course following intentional vaccination with 
wild-type (non-attenuated) vaccinia vaccine. All pustules to date have been self-limited and 
resolved without complications or the need for specific anti-viral treatment. 
The following steps should be carried out in the event of skin or oral mucosa pustule identification 
(patient or patient contact, which is unexpected): 
• Record the AE (event term for Pexa-Vec related pustules must be recorded as 
“papularpustular rash”). 
• Instruct the patient/contact to cover the pustule with non-occlusive dressing (or wear a 
mask when around other people if oral lesions are present).  
3.4.2.2 Urine, Feces, Blood, Throat and/or Saliva 
Testing for the presence of Pexa-Vec after patient treatment has been conducted in several 
clinical studies in throat swabs, urine, feces, and blood samples. No person-to-person 
transmission of Pexa-Vec has been reported.  
3.4.3 Adverse Events of Special Interest for Durvalumab and Tremelimumab 
An adverse event of special interest (AESI) is one of scientific and medical interest specific to 
understanding of the Investigational Product and may require close monitoring and rapid 
communication by the investigator to the sponsor. An AESI may be serious or non-serious. The 
rapid reporting of AESIs allows ongoing surveillance of these events in order to characterize and 
understand them in association with the use of this investigational product. 
AESIs for durvalumab and tremelimumab include but are not limited to events with a potential 
inflammatory or immune-mediated mechanism and which may require more frequent monitoring 
and/or interventions such as steroids, immunosuppressants and/or hormone replacement therapy. 
These AESIs are being closely monitored in clinical studies with durvalumab monotherapy and 
combination therapy. An immune-mediated adverse event (imAE) is defined as an adverse event 
that is associated with drug exposure and is consistent with an immune-mediated mechanism of 
action and where there is no clear alternate aetiology. Serologic, immunologic, and histologic 
(biopsy) data, as appropriate, should be used to support an imAE diagnosis. Appropriate efforts 


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should be made to rule out neoplastic, infectious, metabolic, toxin, or other etiologic causes of the 
imAE.  
If the Investigator has any questions in regard to an adverse event (AE) being an imAE, the 
Investigator should promptly contact MedImmune 
AESIs observed with durvalumab and tremelimumab include: 
• Diarrhea / Colitis and intestinal perforation 
• Pneumonitis / ILD 
• Hepatitis / transaminase increases 
• Endocrinopathies (i.e. events of hypophysitis/hypopituitarism, adrenal insufficiency, 
hyper- and hypothyroidism and type I diabetes mellitus) 
• Rash / Dermatitis 
• Nephritis / Blood creatinine increases 
• Pancreatitis / serum lipase and amylase increases   
•  Myocarditis 
• Myositis / Polymyositis 
• Neuropathy / neuromuscular toxicity (i.e. Guillain-Barré, and myasthenia gravis) 
• Intestinal Perforation 
Other inflammatory responses that are rare / less frequent with a potential immune-mediated 
aetiology include, but are not limited to: 
• pericarditis,  
• sarcoidosis,  
• uveitis and other events involving the eye, skin,  
• hematological and rheumatological events,  
• vasculitis,  
• non-infectious meningitis and non-infectious encephalitis 
It is possible that events with an inflammatory or immune mediated mechanism could occur in 
nearly all organs. 
In addition, infusion-related reactions and hypersensitivity/anaphylactic reactions with a different 
underlying pharmacological aetiology are also considered AESIs. 
Further information on these risks (e.g. presenting symptoms) can be found in the current version 
of the durvalumab and tremelimumab Investigator Brochure. More specific guidelines for their 
evaluation and treatment are described in detail in the Dosing Modification and Toxicity 
Management Guidelines (please see Appendix B). These guidelines have been prepared by the 
Manufacturer to assist the Investigator in the exercise of his/her clinical judgment in treating these 


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types of toxicities. These guidelines apply to AEs considered causally related to the study 
drug/study regimen by the reporting investigator. 
For durvalumab and tremelimumab, AESIs will comprise the following:  
3.4.3.1 Pneumonitis: AEs of pneumonitis are also of interest, as pneumonitis has been observed 
with use of anti-PD-1 mAbs (but not with anti-PD-L1 mAbs). Initial work-up should 
include a high-resolution CT scan, ruling out infection, and pulse oximetry. Pulmonary 
consultation is highly recommended. Guidelines for the management of patients with 
immune-mediated AEs (imAEs) including pneumonitis are provided in Appendix B.  
3.4.3.2 Infusion reactions: AEs of infusion reactions (also termed infusion-related reactions) are 
of special interest to AstraZeneca and are defined, for the purpose of this protocol, as all 
AEs occurring from the start of IP infusion up to 48 hours after the infusion start time. 
For all infusion reactions, SAEs should be reported to AstraZeneca Patient safety. 
3.4.3.3 Hypersensitivity reactions: Hypersensitivity reactions as well as infusion-related 
reactions have been reported with anti PD-L1 and anti-PD-1 therapy [17]. As with the 
administration of any foreign protein and/or other biologic agents, reactions following 
the infusion of mAbs can be caused by various mechanisms, including acute anaphylactic 
(IgE-mediated) and anaphylactoid reactions against the mAbs and serum sickness. Acute 
allergic reactions may occur, may be severe, and may result in death. Acute allergic 
reactions may include hypotension, dyspnea, cyanosis, respiratory failure, urticaria, 
pruritus, angioedema, hypotonia, arthralgia, bronchospasm, wheeze, cough, dizziness, 
fatigue, headache, hypertension, myalgia, vomiting, and unresponsiveness. Guidelines 
for the management of patients with hypersensitivity (including anaphylactic reaction) 
and infusion-related reactions are provided in Appendix B.  
3.4.3.4 Hepatic function abnormalities (hepatotoxicity): Hepatic function abnormality is defined 
as any increase in ALT or AST to greater than 3 × ULN and concurrent increase in total 
bilirubin to be greater than 2 × ULN. Concurrent findings are those that derive from a 
single blood draw or from separate blood draws taken within 8 days of each other. Follow-
up investigations and inquiries will be initiated promptly by the investigational site to 
determine whether the findings are reproducible and/or whether there is objective 
evidence that clearly supports causation by a disease (e.g. cholelithiasis and bile duct 
obstruction with distended gallbladder) or an agent other than the IP. Guidelines for 
management of patients with hepatic function abnormality are provided in Appendix B.  
3.4.3.5 Gastrointestinal disorders: Diarrhea/colitis is the most commonly observed treatment 
emergent SAE when tremelimumab is used as monotherapy. In rare cases, colon 
perforation may occur that requires surgery (colectomy) or can lead to a fatal outcome if 
not properly managed. Guidelines on management of diarrhea and colitis in patients 
receiving tremelimumab are provided in Appendix B. 
3.4.3.6 Endocrine disorders: Immune-mediated endocrinopathies include hypophysitis, adrenal 
insufficiency, and hyper- and hypothyroidism. Guidelines for the management of patients 
with immune-mediated endocrine events are provided in Appendix B. 
3.4.3.7 Pancreatic disorders: Immune-mediated pancreatitis includes autoimmune pancreatitis, 
and lipase and amylase elevation. Guidelines for the management of patients with 
immune-mediated pancreatic disorders are provided in Appendix B. 


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3.4.3.8 Neurotoxicity: Immune-mediated nervous system events include encephalitis, peripheral 
motor and sensory neuropathies, Guillain-Barré, and myasthenia gravis. Guidelines for 
the management of patients with immune-mediated neurotoxic events are provided in 
Appendix B. 
3.4.3.9 Nephritis: Consult with Nephrologist. Monitor for signs and symptoms that may be 
related to changes in renal function (e.g. routine urinalysis, elevated serum BUN and 
creatinine, decreased creatinine clearance, electrolyte imbalance, decrease in urine 
output, proteinuria, etc.)  
Patients should be thoroughly evaluated to rule out any alternative etiology (e.g. disease 
progression, infections etc.) 
Steroids should be considered in the absence of clear alternative etiology even for low grade events 
(Grade 2), in order to prevent potential progression to higher grade event. Guidelines for the 
management of patients with immune-mediated neurotoxic events are provided in Appendix B. 
3.5 
Follow Up Period 
Subjects will be followed up on a monthly basis until off-study criteria are met, with restaging 
scans being performed every 8 weeks. 


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3.6 
Study Calendar 
 
 
 
Scree
ning 
 
Baseli
ne  
 
D  
-12 
D -
5 
Cycle 1i 
 
Cycle 2i 
 
Cycle 3-4i 
 
Cycle 5-  
Off Treatment i 
FU j 
D 
1 
D 
2 
D
8 
D 
15 
D 
22 
D 
1 
D
2 
D 
8 
D 
15 
D 
22 
D 
1 
D
8 
D 
15 
D 
22 
D 
1 
D 
8 
D 
15 
D 
22 
 
Durvalumab a 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
Tremelimumab b 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pexa-Vec c  
 
 
X 
 
 
X 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
NIH Advance 
Directive Form d 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant meds 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
Formal adverse 
event evaluation  
 
X 
 
 
X 
 
 
X 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Physical exam and 
ECOG 
X 
X e 
 
 
X 
 
 
X 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Vital Signs 
X 
X e 
X 
 
X 
X 
 
X 
 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
CBC w/differential, 
Platelets f 
X 
X e 
 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X X 
X 
X 
PT, INR, PTT, 
fibrinogen f 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
Thyroid Panel f 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 


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Scree
ning 
 
Baseli
ne  
 
D  
-12 
D -
5 
Cycle 1i 
 
Cycle 2i 
 
Cycle 3-4i 
 
Cycle 5-  
Off Treatment i 
FU j 
D 
1 
D 
2 
D
8 
D 
15 
D 
22 
D 
1 
D
2 
D 
8 
D 
15 
D 
22 
D 
1 
D
8 
D 
15 
D 
22 
D 
1 
D 
8 
D 
15 
D 
22 
 
Biochemical profile 
f, n 
X 
X e 
 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X X 
X 
X 
24-hour urine per 
PI discretion 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ACTH, morning 
cortisol 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor marker 
CEA 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
ECG 
X 
X e 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
Echocardiogram p 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Troponins 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Restaging 
Radiologic 
Evaluation g 
X 
X e 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
Tumor biopsy h, m 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
k 
 
 
 
 
 
 
 
 
Immune 
monitoring l 
 
 
X 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
Blood for TCR beta 
sequencing l 
 
 
X 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 


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Scree
ning 
 
Baseli
ne  
 
D  
-12 
D -
5 
Cycle 1i 
 
Cycle 2i 
 
Cycle 3-4i 
 
Cycle 5-  
Off Treatment i 
FU j 
D 
1 
D 
2 
D
8 
D 
15 
D 
22 
D 
1 
D
2 
D 
8 
D 
15 
D 
22 
D 
1 
D
8 
D 
15 
D 
22 
D 
1 
D 
8 
D 
15 
D 
22 
 
HIV, Hepatitis B 
and C serology 
and/or viral load 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum or urine 
pregnancy test 
X 
X e 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HLA 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TB testing  
(if clinically 
indicated) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Histologic 
confirmation of dx 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Microsatellite 
stability status 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cardiology consult 
as indicated o 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
a All patients will receive 1,500 mg of durvalumab via IV infusion on Day 1 of each cycle till patients meet off treatment criteria. A 1-
hour observation period is required after the first infusion of durvalumab. If no clinically significant infusion reactions are observed 
during or after the first cycle, subsequent infusion observation periods can be at the Investigator’s discretion (suggested 30 minutes after 
each durvalumab infusion).  
b Additionally, patients in Arms B1 and B2 will receive 300 mg of tremelimumab via IV infusion on Day 1 of cycle 1. Tremelimumab 
will be administered first. Durvalumab infusion will start approximately 1 hour after the end of tremelimumab infusion. The duration 
will be approximately 1 hour for each infusion. A 1-hour observation period is required after the first infusion of durvalumab and 


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tremelimumab. If no clinically significant infusion reactions are observed during or after the first cycle, subsequent infusion observation 
periods can be at the Investigator’s discretion (suggested 30 minutes after each durvalumab  infusion).  
cPexa-Vec (JX-594) will be administered at a dose of 3 x 108 pfu (DL 1) or 1 x 109 pfu (DL 2) via IV infusion over 60 minutes (±5 
minutes) for 4 doses only, beginning on Day – (minus) 12. Patients will be observed in the clinic and/or hospital for a minimum of 20 
hours after the infusion. Treatments 2–4 may each be administered in a treatment window of ±3days. 
dAs indicated in section 12.3, all subjects will be offered the opportunity to complete an NIH Advance Directive form. This should be 
done preferably at baseline but can be done at any time during the study as long as the capacity to do so is retained. The completion of 
the form is strongly recommended, but is not required. 
e Tests done on screening do not need to be repeated on baseline if performed in designated time frame  
f For all labs a ‘+/- 72hr’ window applies, with the exception of those needed to determine proceeding with treatment. Labs may be 
performed outside of NIH. 
g Restaging CT scan (or MRI if clinically indicated) every 8 weeks +/- 3 days to evaluate TTP in target lesion. 
h Mandatory baseline and post-treatment tumor biopsies will be obtained on all patients, with the timing of second biopsy being 
determined by assignment on 1:1 basis.  
i Cycles will be 28 days in length +/- 3 days.  
j FU: Follow up visits once a month until patients are off study. If patients are not able to come to NIH, they will be followed by phone 
contact annually for survival, performance status, new cancer treatment. 
k The biopsy around day 85 (Cycle 4 day 1) is optional 
l Until PD while on protocol treatment, a ‘+/- 48hr’ window applies 
m Biopsy will have a window of +/-72 hrs. to allow for logistical issues; however, the biopsy will not be performed within 48 hrs. after 
Pexa-Vec administration 
n Electrolytes, BUN, creatinine, AST, ALT, total and direct bilirubin, calcium, phosphorus, albumin, magnesium, uric acid, amylase.  
o Performed in patients with history of cardiovascular disease. See section 2.1.2.10  
p Echocardiogram will be mandatory at the screening and performed during the study if clinically indicated.  


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3.7 
Criteria for Removal from Protocol Therapy and Off Study Criteria 
Prior to removal from study, effort must be made to have all subjects complete a safety visit 
approximately 30, 60 and 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 defined in section 3.1.1 and Appendix B 
• Positive pregnancy test or intent to become pregnant 
• Investigator discretion  
• Initiation of alternative anticancer therapy including another investigational agent 
• Progressive Disease. NOTE: While RECIST PD will be noted and recorded the immune-
related RECIST criteria will be applied to determine discontinuation of study treatment. 
• Subject who has received any amount of infliximab or other tumor necrosis factor alpha 
inhibitor 
• Intercurrent illness that prevents further administration of treatment 
3.7.2 Off Study Criteria  
• Lost to follow-up 
Subjects will be considered lost to follow-up only if no contact has been established by the 
time the study is completed such that there is insufficient information to determine the 
subject’s status at that time. Subjects who refuse continuing participation in the study 
including telephone contact should be documented as “withdrawal of consent” rather than 
“lost to follow-up.” Investigators should document attempts to re-establish contact with 
missing subjects throughout the study period. If contact with a missing subject is re-
established, the subject should not be considered lost to follow-up and any evaluations 
should resume according to the protocol. 
• Death 
• Participant requests to be withdrawn from study 
• Investigator discretion 
• PI decision to end the study 
 
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. 
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.  


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4.1 
Recommended Medications Related to Flu-like Symptoms related to Pexa-Vec 
(mild-to-severe fever, rigors, anorexia, aches/pain, fatigue, headache, and/or nausea)  
Acute Post-Treatment Symptom Management 
During the post-treatment observation period, patients should receive IV solute-containing fluid 
and other measures (e.g. vasopressor therapy) per SOC as needed for blood pressure support. Anti-
rigor medication (e.g. meperidine) or support medications may be used as needed. 
Anti-emetics may be used at the Investigator’s discretion for treatment of nausea or vomiting; it is 
noted, however, that corticosteroids should not be used. 
Analgesics, anti-pyretics (e.g. prophylactic acetaminophen), antidepressants, bisphosphonates, 
EPO growth factors and other supportive care measures may be used at the Investigator’s 
discretion. 
4.2 
Management of Hypotension and Contraindicated Treatments 
To mitigate risk of hypotension following Pexa-Vec treatment, the following are required: 
• Prehydration with 1 liter of solute-containing fluid (p.o. or IV) prior to each treatment 
• Suspension of anti-hypertensive medication for 48 hours prior to and 48 hours after all 
Pexa-Vec treatments 
• Anti-hypertensive medications include, but are not limited to, the following: 
• Diuretics 
• Beta-blockers 
• ACE inhibitors 
• Aldosterone agonists 
4.3 
Agents with Potential Inhibitory Activity Against Vaccinia Viruses  
In the extremely unlikely case of generalized vaccinia virus infection, encephalitis or another 
clinically-significant, progressive toxicity that, in the opinion of the Investigator could be related 
to Pexa-Vec replication, Investigators may consider the use of agents with vaccinia inhibitory 
activity, if available in their country for such clinical use. Such agents may include anti-vaccinia 
immune globulin (VIG), cidofovir, and/or Arestvyr (USAN tecovirimat; ST-246). In addition, 
based on limited preclinical data, interferon, ribavirin, and sorafenib may have anti-vaccinia 
activity. For clarity, none of these agents have been used or approved for this purpose to date. 
Since these agents have not been used in Pexa-Vec treated patients to date, clinical judgment 
should be used when determining the optimal regimen and duration of treatment.  
The availability of these or similar antiviral products is country-dependent; options will be 
investigated and a plan for a response to infection-related toxicities will be documented and 
communicated to study staff prior to initiation of the clinical trial.  
4.4 
Contraindicated Antiviral Therapy Shown to Inhibit Vaccinia Replication 
• Cidofovir (except to treat toxicities potentially related to uncontrolled Pexa-Vec 
replication) 


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• Interferon/PEG-interferon, ribavirin  
4.5 
Contraindicated Treatments 
• High dose systemic corticosteroids (defined as ≥20 mg/day prednisone or equivalent which 
is ongoing at the time of arm allocation and/or was taken for more than 4 weeks within the 
preceding 2 months of enrollment) or other immunosuppressive medications 
• Anti-coagulation or anti-platelet medication that cannot be interrupted prior to study 
specified biopsies injections, including:  
• Aspirin that cannot be discontinued for 7 days prior to biopsy 
• Coumadin that cannot be discontinued for 7 days prior to biopsy 
• LMWH that cannot be discontinued >24 hours prior to biopsy and UFH that cannot be 
discontinued >4 hours prior to biopsy (LMWH or UFH may be used to transition patients 
on and off the above anti-coagulants, if deemed appropriate by the treating physician) prior 
to Pexa-Vec treatments as long as the last dose of LMWH is administered 24 hours prior 
to biopsy and the last dose of UFH is administered >4 hours prior to treatments) 
• Oral direct thrombin inhibitor (dabigatran) or direct Factor Xa inhibitor (rivaroxaban, 
apixaban, and edoxaban) that cannot be discontinued for 4 days prior to biopsy 
4.6 
Other Authorized Concomitant Treatments 
• thrombopoietin, erythropoietin, G-CSF 
• antidepressants 
• steroids (NOTE: oral or parenteral steroids are not allowed during the Pexa-Vec treatment 
period, and for 1 week prior to and 2 weeks after Pexa-Vec treatment) 
• topical therapies for symptomatic relief of hand-foot skin reaction and rash related to 
sorafenib 
• bisphosphonates, vitamin B12 and vitamin D  
• Hepatitis B antivirals are ALLOWED as DO NOT inhibit vaccinia virus replication: 
lamivudine, adefovir (and adefovir dipivoxil prodrug), telbivudine, tenofovir, 
emtricitabine, clevudine and entecavir. The ability of combinations of these agents to 
inhibit vaccinia virus replication has however not been evaluated. Therefore, combination 
therapy with anti-viral agents should be avoided if at all possible. 
NOTES: 
• Please 
contact 
MedImmune 
for 
any 
questions 
regarding 
management 
of 
immunosuppressive, anticoagulant, antihypertensive, or antiviral medications prior to 
treatments. 
• Sites will be notified by MedImmune as additional information regarding allowed and 
contraindicated antivirals becomes available 
4.7 
Permitted concomitant medications for any combination of investigational drugs  
Table 2. Supportive medications 


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Supportive medication/class of drug: 
Usage: 
Concomitant medications or treatments 
(e.g. acetaminophen or diphenhydramine) 
deemed necessary to provide adequate 
prophylactic or supportive care, except for those 
medications identified as “prohibited,” as listed 
above  
To be administered as prescribed by 
the Investigator 
Best supportive care (including antibiotics, 
nutritional support, correction of metabolic 
disorders, optimal symptom control, and pain 
management [including palliative radiotherapy 
to non-target lesions, etc.]) 
Should be used, when necessary, for 
all patients 
Inactivated viruses, such as those in the 
influenza vaccine 
Permitted 
Hormone therapy for non-cancer diagnoses 
Permitted 
 
4.8 
Excluded Concomitant Medications 
Table 3. Prohibited 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 acceptable [e.g. by 
local surgery or radiotherapy]) 


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Prohibited medication/class of drug: 
Usage: 
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. 
Drugs with laxative properties and herbal 
or natural remedies for constipation 
Should be used with caution through to 90 days 
after the dose of tremelimumab during the study 
Sunitinib 
Should not be given concomitantly or through 90 
days after the dose of tremelimumab (acute renal 
failure has been reported with combination 
therapy of tremelimumab and sunitinib) 
 
4.9 
Methods of contraception 
The following restrictions apply while the patient is receiving study treatment and for the specified 
times before and after: 
4.9.1 Female patient of child-bearing potential 
Females of childbearing potential who are sexually active with a non-sterilized male partner must 
use at least 2 highly effective method of contraception (Table 4. ) from the time of screening and 
must agree to continue using such precautions for 180 days after the last dose of durvalumab + 
tremelimumab combination therapy or 90 days after the last dose of durvalumab monotherapy. 
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. 
4.9.2 Male patients with a female partner of childbearing 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 180 days after the last dose of 
durvalumab + tremelimumab combination therapy or 90 days after the last dose of durvalumab 
monotherapy. Eengaging 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 4. ).  


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N.B Females of childbearing potential are defined as those who are not surgically sterile (i.e. 
bilateral tubal ligation, bilateral oophorectomy, or complete hysterectomy) or post-menopausal. 
4.9.3 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 4. . 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 4.  
Highly Effective methods of contraception (<1% failure rate) 
Barrier/Intrauterine methods 
Hormonal Methods 
• Copper T intrauterine device 
• Levonorgesterel-releasing intrauterine 
system (e.g. Mirena®)a 
 
• Etonogestrel implants: e.g. Implanon 
or Norplant 
• Intravaginal device: e.g. 
ethinylestradiol and etonogestrel 
• Medroxyprogesterone injection: e.g. 
Depo-Provera  
• Normal and low dose combined oral 
contraceptive pill 
• Norelgestromin/ethinylestradiol 
transdermal system 
• Cerazette (desogestrel) 
a 
This is also considered a hormonal method 
4.10 Blood donation 
Subjects should not donate blood while participating in this study, and for 3 months after the last 
durvalumab infusion or 6 months after the last dose of durvalumab + tremelimumab combination 
therapy, whichever comes later.  
5 
BIOSPECIMEN COLLECTION 
5.1 
Correlative Studies for Research  
The correlative studies which we wish to perform are outlined below and summarized in the Table 
5. A description of each test including a brief statement of rationale and processing information is 
made below. 


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Table 5. Biospecimen collection  
 
Test/assay 
Sample volume 
(approx) 
Type 
of 
tube 
Collection point  Location 
of 
specimen analysis1 
Immune- 
monitoring 
120mls 
(for 
PBMC) 
EDTA 
See 
Study 
Calendar 3.6 
Greten Lab  
5-10mls 
(for 
serum) 
EDTA 
TCR 
beta 
sequencing 
1ml (for PBMC) EDTA 
Study 
Calendar 
3.6 
Adaptive 
Biotechnologies2 
Immune 
cell 
infiltration, 
IHC, 
(CD3+ CD4/8 cells 
etc), PD-L1 
tumor biopsy 
NA 
Study 
Calendar 
3.6 
Greten Lab  
TCR 
beta 
sequencing 
tumor biopsy 
NA 
Study 
Calendar 
3.6 
Adaptive 
Biotechnologies2 
RNA 
Nanostring 
analysis 
(nCounterPan 
Cancer 
Immunology 
Profile) 
tumor biopsy 
NA 
Study 
Calendar 
3.6 
Greten Lab 
1 Blood samples will initially be sent to the Figg laboratory for barcoding and storage (See Section 
5.2.1). 
2 Lara Gruye, Adaptive Biotechnologies, 1551 Eastlake Ave E #200, Seattle, WA 98102 (855) 
466-8667 
5.1.1  Immune monitoring 
We will analyze PBMC for quantitative and functional changes of effector cells as well as analyze 
sera for cytokines and chemokines. The effect on (i) CD4 T cell number and activity, (ii) CD8 T 
cell number and activity, (iii) NK cell number and activity, (iv) Treg number, (vi) MDSC: 
frequency + functional assay, (vii) selected cytokines in serum, and (viii) the detection of tumor-
associated antigens using tetramer assay.  
Patients will undergo blood sampling on the time points outlined in the Study Calendar 3.6. Blood 
will initially be sent to the Figg laboratory for barcoding and processing. 
On certain occasions the blood may also be brought to the Greten lab for processing and analysis.  


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5.1.2 Mandatory tumor biopsies 
Tumor biopsies will be collected at baseline and either day 1 +/- 3 days or day 29+/- 3 days by the 
Interventional Radiology team by a percutaneous approach (note biopsy may not be collected 
within 48 hours after Pexa-Vec administration). It is preferred that at least two core biopsies ≥18 
gauge in diameter and ≥1 cm in length will be obtained.  
If a site is deemed appropriate for biopsy with minimal risk to the participant by agreement 
between the investigators and Interventional Radiology team, an attempt for biopsy will be made. 
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. Should a CT scan be 
needed for biopsy, the number of scans for each procedure will be limited to the minimum number 
needed to safely obtain a biopsy. Tumor biopsies and local anesthesia will be administered only if 
they are considered to be of low risk to the participant, as determined by the investigators and 
Interventional Radiology. If an initial attempt at percutaneous biopsy is unsuccessful, the 
participant will be given an option to proceed with a repeated attempt at percutaneous biopsy.  
5.1.3  Tumor tissue analysis 
IHC will be performed on tumor tissue for assessment of immune cell infiltration (e.g. CD3+ 
CD4/8 cells etc.) as well as other surface markers such as PD-L1. 
5.1.3.1 Optional Tumor Biopsy 
A tumor biopsy may be performed at a subsequent timepoint (D85 approximately) if the patient is 
willing and the procedure can be performed safely. Tumor Tissue will be processed by the 
Department of Pathology, NCI, NIH (Dr. David Kleiner). Two core biopsies will be the attempted. 
Each specimen will be processed and analyzed as stated above. 
5.2 
Sample Storage, Tracking and Disposition 
Samples will be ordered in CRIS Screens and tracked through a Clinical Trial Data Management 
system. Should a CRIS screen not be available, the CRIS downtime procedures will be followed. 
All samples will be sent to Dr. Figg’s lab for processing and storage until they are distributed to 
Dr. Greten’s lab for sample analysis as described in the protocol.  
Samples will not be sent outside the National Institutes for Health (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 


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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. 
5.2.1 Samples Managed by Dr. Figg’s Blood Processing Core (BPC)  
5.2.1.1 BPC contact information  
Please e-mail NCIBloodcore@mail.nih.gov  at least 24 hours before transporting samples (the 
Friday before is preferred). 
For sample pickup, page 102-11964. 
For immediate help, call 240-760-6180 (main blood processing core number) or, if no answer, 
240-760-6190 (main clinical pharmacology lab number). 
For questions regarding sample processing, contact NCIBloodcore@mail.nih.gov . 
5.2.2 Samples Managed by the Laboratory of Dr Greten 
Contact information: 
Sophie Wang 
Building 10 Rm 3B44 
Phone: 240-858-3218 
E-mail: sophie.wang@nih.gov 
5.2.3 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 will be stored in the conditions described in sections 
above. The study will remain open so long as sample or data analysis continues. Samples from 
consenting subjects will be stored until they are no longer of scientific value or if a subject 
withdraws consent for their continued use, at which time they will be destroyed. If the patient 
withdraws consent the participant’s data will be excluded from future distributions, but data that 
have already been distributed for approved research use will not be able to be retrieved. 
The PI will record any loss or unanticipated destruction of samples as a deviation. Reports will be 
made per the requirements of section 7.2.  
If the patient withdraws consent the participant’s data will be excluded from future distributions, 
but data that have already been distributed for approved research use will not be able to be 
retrieved. 
5.3 
Samples for Genetic/Genomic Analysis 
5.3.1 TCR beta sequencing 
TCR (cell receptor) gene usage may be quantitated in samples using conventional sequencing 
techniques of the T cell receptor variable region of the beta chain. Fewer than 100 genes will be 
analyzed. For TCR Beta Sequencing the NCI Thoracic and GI Malignancies Branch will release 
coded, linked tumor and PBMC samples to Adaptive Biotechnologies. Blood and tumor samples 
will be used. 


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5.3.2 Nanostring analysis (nCounterPan Cancer Immunology Profile)  
Tumor samples will also be used for Nanostring analysis (nCounterPan Cancer Immunology 
Profile) 
5.3.3 Privacy and Confidentiality of medical information/biological specimens 
Fresh tumor and blood samples will be stored in a minus 80-degree freezer. Initially the samples 
of each patient will be sent to Dr. Figg’s lab (5.2.1). At no time will patient’s names be used on 
the blood and tissue samples. The molecular studies will be performed at the Adaptive 
Biotechnologies, 1551 Eastlake Ave E #200, Seattle, WA 98102 (855) 466-8667. Subject’s genetic 
data will be deposited in a database such as dbGaP. Although there is controlled access to such a 
database, such a submission carries theoretical risks of revealing the identity of the subject. This 
is discussed in the consent. 
5.3.4 Management of Results 
The genetic testing performed on this protocol are not of sufficient scope to generate incidental 
findings and the results of molecular studies will not be communicated to the patient due to their 
investigational nature.  
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 
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 -12, through 90 days after the subject 
received the last study drug administration. Beyond 90 days after the last intervention, 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. 


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Adverse Events of grade 1 will not be collected. 
End of study procedures: Data will be stored according to HHS, FDA regulations and NIH 
Intramural Records Retention Schedule as applicable.  
Loss or destruction of data: Should we become aware that a major breach in our plan to protect 
subject confidentiality and trial data has occurred, this will be reported expeditiously per 
requirements in section 7.2.1.  
6.2 
Data Sharing Plans 
6.2.1 Human Data Sharing plan 
I will share coded, linked human data generated in this research for future research  
− in a NIH-funded or approved public repository clinicaltrials.gov, dbGaP 
− in BTRIS 
− with approved outside collaborators under appropriate agreements 
− in publication and/or public presentations 
at the time of publication or shortly thereafter. 
6.2.2 Genomic Data Sharing Plan 
Unlinked genomic data will be deposited in public genomic databases such as dbGaP in 
compliance with the NIH Genomic Data Sharing Policy. 
6.3 
Response Criteria 
For the purposes of this study, patients should be re-evaluated for response every 8 weeks (+/- 3 
days). In addition to a baseline scan, confirmatory scans should also be obtained 4-8 weeks 
following initial documentation of objective response. Whilst immune-related RECIST criteria 
will be taken into consideration with regard to continuation of therapy in the event of growth (with 
a requirement for confirmation of PD), standard RECIST criteria will be the primary method used 
for evaluation of the primary endpoint. 
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)[18]. Changes in the largest diameter (unidimensional measurement) of the tumor 
lesions and the shortest diameter in the case of malignant lymph nodes are used in the RECIST 
criteria. 
6.3.1 Definitions 
Evaluable for toxicity: All patients will be evaluable for toxicity from the time of their first 
treatment. 
Evaluable for objective response  
Only those patients who have measurable disease present at baseline, have received at least one 
dose of each agent, and have had their disease re-evaluated will be considered evaluable for 
response. These patients will have their response classified according to the definitions stated 
below. (Note: Patients who exhibit objective disease progression prior to the end of cycle 1 will 
also be considered evaluable.) 


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Evaluable Non-Target Disease Response: Patients who have lesions present at baseline that are 
evaluable but do not meet the definitions of measurable disease, have received at least one cycle 
of each agent, and have had their disease re-evaluated will be considered evaluable for non-target 
disease. The response assessment is based on the presence, absence, or unequivocal progression 
of the lesions.  
6.3.2 Disease Parameters 
Measurable disease: Measurable lesions are defined as those that can be accurately measured in at 
least one dimension (longest diameter to be recorded) as  
• By chest x-ray: >20 mm;  
• By CT scan:  
o Scan slice thickness 5 mm or under as >10 mm with CT scan 
o Scan slice thickness >5 mm: double the slice thickness  
• With calipers on clinical exam: >10 mm.  
All tumor measurements must be recorded in millimeters (or decimal fractions of centimeters). 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph node 
must be >15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended 
to be no greater than 5 mm). At baseline and in follow-up, only the short axis will be measured 
and followed. 
Non-measurable disease: All other lesions (or sites of disease), including small lesions (longest 
diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), are considered 
non-measurable disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not 
followed by CT or MRI), are considered as non-measurable. 
Note: Cystic lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions, if 
they meet the definition of measurability described above. However, if non-cystic lesions are 
present in the same 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. 


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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. 
6.3.3 Methods for Evaluation of Measurable Disease  
All measurements should be taken and recorded in metric notation using a ruler or calipers. All 
baseline evaluations should be performed as closely as possible to the beginning of treatment and 
never more than 4 weeks before the beginning of the treatment. 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 
Clinical lesions: Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes) and ≥10 mm diameter as assessed using calipers 
(e.g., skin nodules). In the case of skin lesions, documentation by color photography, including a 
ruler to estimate the size of the lesion, is recommended.  
Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung. However, CT is preferable.  
Conventional CT and MRI: This guideline has defined measurability of lesions on CT scan based 
on the assumption that CT slice thickness is 5 mm or less. If CT scans have slice thickness greater 
than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness. MRI is 
also acceptable in certain situations (e.g. for body scans).  
Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal resolution; 
however, there are many image acquisition variables involved in MRI, which greatly impact image 
quality, lesion conspicuity, and measurement. Furthermore, the availability of MRI is variable 
globally. As with CT, if an MRI is performed, the technical specifications of the scanning 
sequences used should be optimized for the evaluation of the type and site of disease. Furthermore, 
as with CT, the modality used at follow-up should be the same as was used at baseline and the 
lesions should be measured/assessed on the same pulse sequence. It is beyond the scope of the 
RECIST guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body 
parts, and diseases. Ideally, the same type of scanner should be used and the image acquisition 
protocol should be followed as closely as possible to prior scans. Body scans should be performed 
with breath-hold scanning techniques, if possible. 
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement. Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to the 
next. If new lesions are identified by ultrasound in the course of the study, confirmation by CT or 
MRI is advised. If there is concern about radiation exposure at CT, MRI may be used instead of 
CT in selected instances. 
Endoscopy, Laparoscopy: The utilization of these techniques for objective tumor evaluation is not 
advised. However, such techniques may be useful to confirm complete pathological response when 


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biopsies are obtained or to determine relapse in trials where recurrence following complete 
response (CR) or surgical resection is an endpoint. 
Cytology, Histology: These techniques can be used to differentiate between partial responses (PR) 
and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as germ cell 
tumors, where known residual benign tumors can remain). 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease (an effusion may be a side effect of 
the treatment) and progressive disease. 
6.3.4 Response criteria 
6.3.4.1 Evaluation of Target Lesions 
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm. 
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking 
as reference the baseline sum of diameters. 
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest 
on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered 
progressions). 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum of diameters while on study. 
6.3.4.2 Evaluation of Non-Target Lesions 
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level. All lymph nodes must be non-pathological in size (<10 mm short axis). 
Note: If tumor markers are initially above the upper normal limit, they must normalize for a patient 
to be considered in complete clinical response. 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits. 
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal progression 
of existing non-target lesions. Unequivocal progression should not normally trump target lesion 
status. It must be representative of overall disease status change, not a single lesion increase.  
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). 
6.3.4.3 Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for progressive disease the smallest measurements 


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recorded since the treatment started). The patient's best response assignment will depend on the 
achievement of both measurement and confirmation criteria. 
 
For Patients with Measurable Disease (i.e., Target Disease) 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Respons
e 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non-CR/Non-PD 
No 
PR 
>4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not evaluated 
No 
SD 
Documented at least once >4 
wks. from baseline** 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
* 
See RECIST 1.1 manuscript for further details. 
** 
Only for non-randomized trials with response as primary endpoint. 
*** 
In exceptional circumstances, unequivocal progression in non-target lesions may 
be accepted as disease progression. 
Note: Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration.” Every effort should be made to 
document the objective progression even after discontinuation of treatment. 
 
For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
* ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign this 
category when no lesions can be measured is not advised 
6.3.5 Duration of Response 
Duration of overall response: The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started). 


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The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that progressive disease is objectively documented. 
 
Duration of stable disease: Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest measurements recorded since the 
treatment started, including the baseline measurements.  
6.3.6 Modified Immune-related response criteria (irRC) 
Modified immune-related response criteria (irRC) will also be employed in this study. This new 
classification is based on the recent learning from clinical studies with cancer immunotherapies 
that even if some new lesions appear at the beginning of a treatment or if the total tumor burden 
does not increase substantially, tumor regressions or stabilizations might still occur later. The irRC 
were created using bi-dimensional measurements (as previously widely used in the World Health 
Organization criteria). For this trial, the concepts of the irRC are combined with RECIST 1.1 to 
come up with the modified irRC. Please refer to Appendix C for further details. 
6.3.7 Progression-Free Survival  
PFS is defined as the duration of time from start of treatment to time of progression or death, 
whichever occurs first. 
6.4 
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 4.3 will be utilized for AE reporting. 
All appropriate treatment areas should have access to a copy of the CTCAE version 4.3. A copy 
of 
the 
CTCAE 
version 
4.3 
can 
be 
downloaded 
from 
the 
CTEP 
web 
site 
(https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_4.3). 
All 
appropriate treatment areas should have access to a copy of the CTEP Active Version of CTCAE. 
7 
NIH REPORTING REQUIREMENTS / DATA AND SAFETY MONITORING PLAN 
7.1 
Definitions 
Please refer to definitions provided in Policy 801: Reporting Research Events found here.   
7.2 
OHSRP Office of Compliance and Training / IRB Reporting 
7.2.1  Expedited Reporting 
Please refer to the reporting requirements in Policy 801: Reporting Research Events and Policy 
802 Non-Compliance Human Subjects Research found here. Note: Only IND Safety Reports that 
meet the definition of an unanticipated problem will need to be reported per these policies. 
7.2.2  IRB Requirements for PI Reporting at Continuing Review 
Please refer to the reporting requirements in Policy 801: Reporting Research Events found here.  
7.3 
NCI Clinical Director Reporting  
Problems expeditiously reported to the OHSRP/IRB 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 
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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 Pexa-Vec oncolytic virus 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 Pexa-Vec oncolytic virus, but are not fatal or life-
threatening, much be reported to the NIH IBC as soon as possible, but not later than 15 calendar 
days after the investigator’s initial receipt of the information. Adverse events may be reported by 
using the FDA Form 3500a. 
7.4.2 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 NIH 
Intramural IRB continuing review report can be sent to the IBC in lieu of a separate report. Please 
include the IBC protocol number on the report. 
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:  


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• 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 on a weekly basis when patients are being actively treated on 
the trial to discuss each patient. Decisions about dose level enrollment and dose escalation if 
applicable will be made based on the toxicity data from prior patients.  
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 require oversight from the Safety Monitoring Committee (SMC). Initial review 
will occur as soon as possible after the annual NIH Intramural IRB continuing review date. 
Subsequently, each protocol will be reviewed as close to annually as the quarterly meeting 
schedule permits or more frequently as may be required by the SMC. For initial and subsequent 
reviews, protocols will not be reviewed if there is no accrual within the review period. Written 
outcome letters will be generated in response to the monitoring activities and submitted to the 
Principal investigator and Clinical Director or Deputy Clinical Director, CCR, NCI. 
8 
SPONSOR 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 


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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 
• 
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 4.3. 
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. 
8.1.6 Adverse Events of Special Interest (AESI) 
See Section 3.4.3.  
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 


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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. 
• 
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 or meets the definition of Adverse Event of 
Special Interest that require expedited reporting must be submitted immediately (within 24 hours 
of awareness) to OSRO Safety using the CCR SAE report form. 
All SAE reporting must include the elements described in section 8.2.  
SAE reports will be submitted to the Center for Cancer Research (CCR) at: 
OSROSafety@mail.nih.gov and to the CCR PI and study coordinator.  CCR SAE report form 
and instructions can be found at:  
https://ccrod.cancer.gov/confluence/pages/viewpage.action?pageId=157942842  
Following the assessment of the SAE by OSRO, other supporting documentation of the event may 
be requested by the OSRO Safety and should be provided as soon as possible. 
8.4 
Waiver of expedited reporting to CCR  
As death due to disease progression is part of the study objectives (OS) and captured as an endpoint 
in this study, death due to disease progression will not be reported in expedited manner to the 
Sponsor. However, if there is evidence suggesting a causal relationship between the study drug 
and the event, report the event in an expedited manner according to section 8.3. 
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 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. 


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8.5 
Safety Reporting Criteria to the Pharmaceutical Collaborators 
8.5.1 Reporting of serious adverse events 
All SAEs will be reported, whether or not considered causally related to the investigational 
product, or to the study procedure(s). The reporting period for SAEs is the period immediately 
following the time that written informed consent is obtained through 90 days after the last dose of 
Pexa-Vec, durvalumab + tremelimumab or until the initiation of alternative anticancer therapy. 
The investigator and/or sponsor must inform the FDA, via a MedWatch or equivalent, of any 
serious or unexpected adverse events that occur in accordance with the reporting obligations of 21 
CFR 312.32. 
Such reports must be forwarded to AstraZeneca and Sillajen concurrently with submission to the 
FDA.  
It is the responsibility of the sponsor to compile all necessary information and ensure that the FDA 
receives a report according to the FDA reporting requirement timelines and to ensure that these 
reports are also submitted to AstraZeneca and Sillajen at the above timepoints. 
A cover page should accompany the MedWatch or equivalent form indicating the following: 
• 
“Notification from NCI Center for Cancer Research” 
• 
NCI CCR IND number assigned by the FDA 
• 
The investigator’s name and address 
• 
The trial name/title and AstraZeneca ISS reference number (ESR-16-11987) (AstraZeneca 
only) 
Sponsor must also indicate, either in the SAE report or the cover page, the causality of events in 
relation to all study medications and if the SAE is related to disease progression, as determined by 
the principal investigator. 
Send SAE report and accompanying cover page by way of email to AstraZeneca’s designated 
mailbox: AEMailboxClinicalTrialTCS@astrazeneca.com 
Send SAE report and accompanying cover page by way of email to Sillajen’s designated mailbox: 
safetyCRC027@sillajen.com  
If a non-serious AE becomes serious, this and other relevant follow-up information must also be 
provided to AstraZeneca, Sillajen and the FDA. 
8.5.2 Overdose 
Any overdose of a study subject with durvalumab + tremelimumab, with or without associated 
AEs/SAEs, is required to be reported within 24 hours of knowledge of the event to the Sponsor 
and AstraZeneca/MedImmune Patient Safety or designee using the designated Safety e-mailbox : 
AEMailboxClinicalTrialTCS@astrazeneca.com. If the overdose results in an AE, the AE must 
also be recorded as an AE. Overdose does not automatically make an AE serious, but if the 
consequences of the overdose are serious, for example death or hospitalization, the event is serious 
and must be recorded and reported as an SAE. There is currently no specific treatment in the event 
of an overdose of durvalumab or tremelimumab.  
The investigator will use clinical judgment to treat any overdose. 


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An overdose of a study subject with Pexa-Vec should be reported to the designated safety mailbox: 
safetyCRC027@sillajen.com. If the overdose results in an AE or SAE, these should be reported 
as such. 
8.5.3 Hepatic function abnormality 
Hepatic function abnormality (as defined in Section 3.4.3.4) in a study subject, with or without 
associated clinical manifestations, is required to be reported as “hepatic function abnormal” within 
24 hours of knowledge of the event to the sponsor and AstraZeneca/MedImmune Patient Safety 
using the designated Safety e-mailbox  
AEMailboxClinicalTrialTCS@astrazeneca.com, unless a definitive underlying diagnosis for the 
abnormality (e.g., cholelithiasis or bile duct obstruction) that is unrelated to investigational product 
has been confirmed. 
If the definitive underlying diagnosis for the abnormality has been established and is unrelated to 
investigational product, the decision to continue dosing of the study subject will be based on the 
clinical judgment of the investigator. 
If no definitive underlying diagnosis for the abnormality is established, dosing of the study subject 
must be interrupted immediately. Follow-up investigations and inquiries must be initiated by the 
investigational site without delay. 
Each reported event of hepatic function abnormality will be followed by the investigator and 
evaluated by the sponsor and AstraZeneca/MedImmune.  
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 (see section 8.1.2) should be reported as 
SAEs.  
The outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, 
normal birth, or congenital abnormality) should be followed up and documented. 
8.6.2 Paternal exposure 
Male patients should refrain from fathering a child or donating sperm during the study and for 180 
days after the last dose of durvalumab+ tremelimumab combined therapy or 90 days after the last 
dose of durvalumab monotherapy, 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 180 days after the last dose 
of durvalumab+ tremelimumab combined therapy or 90 days after the last dose of durvalumab 
monotherapy, whichever is the longer time period after the last dose should, if possible, be 
followed up and documented. 


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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. 
9 
CLINICAL MONITORING  
As a sponsor for clinical trials, FDA regulations require the CCR to maintain a monitoring 
program. The CCR’s program allows for confirmation of: study data, specifically data that could 
affect the interpretation of primary and secondary study endpoints; adherence to the protocol, 
regulations, ICH E6, and SOPs; and human subjects protection. This is done through independent 
verification of study data with source documentation focusing on: 
• Informed consent process 
• Eligibility confirmation 
• Drug administration and accountability 
• Adverse events monitoring 
• Response assessment. 
The monitoring program also extends to multi-site research when the CCR is the coordinating 
center. 
This trial will be monitored by personnel employed by a CCR contractor. Monitors are qualified 
by training and experience to monitor the progress of clinical trials. Personnel monitoring this 
study will not be affiliated in any way with the trial conduct 
10 STATISTICAL CONSIDERATIONS 
The primary objective of this study is to determine the response rate of Pexa-Vec oncolytic virus 
in combination with immune checkpoint inhibition in patients with refractory metastatic colorectal 
cancer based on investigator evaluation. 
Based on our analysis of data from previous trials of patients with similar eligibility requirements 
the typical response rate is much less than 10%.  
For Arm A2, provided that adequate safety has been demonstrated, a total of 10 evaluable patients 
will be enrolled and treated at DL2. The following table shows the probability of having 1 or more 
responses or 2 or more responses out of 10 patients as a function of the underlying true probability 
of a response: 
 
True response 
No. of responses 
Probability 
 


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True response 
No. of responses 
Probability 
0.02                                                         1+                            0.18 
                                                                2+                            0.016 
0.05                                                         1+                             0.40 
                                                                2+                             0.086 
0.15                                                          1+                            0.80 
                                                                 2+                            0.46 
0.25                                                          1+                            0.94 
                                                                 2+                             0.76 
0.30                                                          1+                             0.97 
                                                                 2+                             0.85 
 
Thus, observing 2+ responses out of 10 evaluable patients would have 8.6% probability of 
occurring if the true probability of a response rate were 5% and would have 76-85% probability of 
occurring if the true probability of a response were 25-30%. As such, it would be desirable if 2 or 
more responses out of 10 could be noted to rule out 5% and demonstrate consistency with a 25% 
or greater response rate. However, in the context of this preliminary pilot trial, observing a single 
response in 10 patients would provide limited evidence of at least 15% true response probability 
and thus suggests that may be minimal evidence for benefit. As a further aid to interpretation, the 
exact two-tailed 80% confidence interval about 1/10 is 0.01 to 0.34, and the exact two-tailed 80% 
confidence interval about 2/10 is 0.05-0.45.  
Biopsies from patients treated at DL2 will be taken pre-treatment and then half the patients will 
receive a second biopsy at day 1 and the other half at day 29. Thus, within Arm A2, 5 patients will 
be expected to have paired results from biopsies based on day 1- baseline and 5 will be expected 
to have paired results from biopsies based on day 29-baseline. Any statistical evaluations made for 
the 5 patients within each set of paired biopsy results will be considered exploratory, and the results 
will not be adjusted for multiple comparisons. With 5 patients in a paired comparison, there would 
be 90% power to identify a change from baseline equal to 2.0 SD of the difference (effect size 
2.0), or 71% power to identify a change with effect size 1.5, using a 0.05 significance level paired 
t-test. In practice, Wilcoxon signed rank tests may be used unless the differences are shown to be 
consistent with a normal distribution (p>0.05 by a Shapiro-Wilks test). 
After completion of Arm A2, a decision will be made – after review of all the clinical, safety and 
correlative data – whether to proceed with Arm B1 at that time. The same statistical considerations 
will apply to Arm B2 as in Arm A2. Formal comparison between the two arms will not be possible 
given patient numbers and will be considered hypothesis generating for future development. 
To address safety, tolerability and feasibility of Pexa-Vec oncolytic virus in combination with 
immune checkpoint inhibition, adverse events will be tabulated by grade according to CTCAE and 
analyzed and reported descriptively. 
In addition to evaluation of the proportion of patients that are progression-free at 5 months, the 
progression-free survival for patients will also be analyzed via a Kaplan-Meier curve. This curve 
will be compared informally to other published results in similar patients. As well, the overall 
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It is anticipated that up to 12 patients per year will be able to enroll onto this protocol. It is expected 
that accrual of up to 26 total patients will be required to complete this protocol, but up to 32 may 
be needed if DL1 requires 6 patients at each dose level. Thus, accrual is expected to be completed 
in approximately 2 to 3 years. In order to allow for a small number of unevaluable patients, the 
accrual ceiling will be set at 35 patients. 
11 COLLABORATIVE AGREEMENT 
11.1 Cooperative Research and Development Agreement (CRADA) 
11.1.1 Medimmune/Astrazeneca 
The CRADA (02853) for this protocol is finally executed between Thoracic & GI Malignancies 
Branch, NCI, NIH and Medimmune/Astrazeneca, the manufacturer of Tremelimumab and 
Durvalumab 
11.1.2 Sillajen Inc. 
The CRADA (03163) for this protocol is finally executed between Thoracic & GI Malignancies 
Branch, NCI, NIH and Sillajen Inc. the manufacturer of Pexastimogene Devacirepvec (Pexa-Vec) 
11.2 Material Transfer Agreement (MTA) 
An MTA with Adaptive Biotechnologies (40860-16) is in place to perform the studies on coded, 
linked samples indicated in sections 5.1 and 5.1.3. 
12 HUMAN SUBJECTS PROTECTIONS  
12.1 Rationale for Subject Selection 
Subjects treated on this study, will be individuals with metastatic colorectal cancer, which has 
recurred (or persisted) after appropriate standard treatment. Individuals of any gender, race or 
ethnic group will be eligible for this study. Eligibility assessment will be based solely on the 
patient’s medical status. Recruitment of patients onto this study will be through standard CCR 
mechanisms. No special recruitment efforts will be conducted. 
12.2 Participation of Children 
Individuals under the age of 18 will not be eligible to participate in this study because they are 
unlikely to have colorectal carcinoma, and because of unknown toxicities in pediatric patients. 
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 decisional 
impaired. For this reason and because there is a prospect of direct benefit from research 
participation (section 12.5), 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 as needed for the following: an independent assessment of whether 
an individual has the capacity to provide consent; assistance in identifying and assessing an 
appropriate surrogate when indicated; and/or an assessment of the capacity to appoint a surrogate. 


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For those subjects that become incapacitated and do not have pre-determined substitute decision 
maker, the procedures described in NIH HRPP SOP 14E for appointing a surrogate decision maker 
for adult subjects who are (a) decisional impaired, and (b) who do not have a legal guardian or 
durable power of attorney, will be followed. 
12.4 Evaluation of Benefits and Risks/Discomforts 
Patients will receive evaluation of their disease at the National Cancer Institute’s Clinical Center. 
This protocol may or may not benefit an individual, but the results may help the investigators learn 
more about the disease and develop new treatments for patients with this disease. 
Potential adverse reactions attributable to the administration of Pexa-Vec and the 
chemotherapeutic agents utilized in this trial are discussed in section 3.4. All care will be taken to 
minimize side effects, but they can be unpredictable in nature and severity. Patients will be 
examined and evaluated prior to enrollment. All evaluations to monitor the treatment of patients 
will be recorded in the patient chart. If patients suffer any physical injury as a result of the 
participation in this study, immediate medical treatment is available at the Clinical Center, 
National Cancer Institute, Bethesda, Maryland. 
Although no compensation is available, any injury will be evaluated and treated in keeping with 
the benefits or care to which patients are entitled under applicable regulations. In all publications 
and presentations resulting from this trial, patients’ anonymity will be protected to the maximum 
extent possible. Authorized personnel from the National Cancer Institute (NCI) and Food and Drug 
Administration (FDA) or other regulatory authorities may have access to research files in order to 
verify that patients’ rights have been safeguarded. In addition, patient names will be given to the 
Central Registration to register and verify patients’ eligibility. 
12.5 RISKS/BENEFITS ANALYSIS 
12.5.1 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. 
12.5.2 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 
• Up to 3 CT scans for the collection of 2 mandatory and 1 optional biopsy 
Subjects in this study may be exposed to approximately 10.1 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 1 out of 100 (1%) and of getting a fatal cancer is 0.5 out of 100 (0.5%). 
12.5.3 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 
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12.5.4 Research Blood Collection Risks 
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.  
12.5.5 Other Risks/Benefits 
The potential benefit to a patient that goes onto study is a reduction in the bulk of their tumor 
which may or may not have favorable impact on symptoms and/or survival. Potential risks include 
the possible occurrence of any of a range of side effects which are listed in the Consent Document. 
The procedure for protecting against or minimizing risks will be to medically evaluate patients on 
a regular basis as described. 
12.5.6 Risks/Benefits Analysis 
It is possible that treatment on this protocol may reduce tumor burden or lessen symptoms caused 
by the cancer. While treatment on this protocol may not individually benefit subjects, the 
knowledge gained from this study may help others in the future who have colorectal cancer. 
Potential risks include the possible occurrence of any of a range of side effects listed above. The 
risks and benefits of participation for adults who become unable to consent, are no different than 
those described for patients who are less vulnerable. 
12.6 Consent Process and Documentation 
The informed consent document will be provided to the participant 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. 
13 PHARMACEUTICAL INFORMATION 
13.1 Tremelimumab (17363) 
13.1.1 Source  
Tremelimumab will be supplied by AstraZeneca/MedImmune, Inc. 
13.1.2 Toxicity 
See Appendix B for details. 


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13.1.3 Formulation and preparation 
Tremelimumab is a human IgG2 anti-CTLA-4 mAb that is being developed as an 
immunotherapeutic agent for various cancers.  
 
Investigational 
Product  
Manufacturer  Concentration and Formulation as Supplied  
Tremelimumab  AstraZeneca/ 
MedImmune  
Tremelimumab will be supplied by AstraZeneca either as a 
400-mg or a 25-mg vial solution for infusion after dilution.  
The solution contains 20 mg/mL tremelimumab, 20 mM 
histidine/histidine hydrochloride, 222 mM trehalose 
dihydrate, 0.27 mM disodium edetate dihydrate, and 0.02% 
weight/volume (w/v) polysorbate 80; it has a pH of 5.5 and 
density of 1.034 g/mL.  The nominal fill volume is 20.0 mL 
for the 400-mg vial and 1.25 mL for the 25-mg vial. 
Investigational product vials are stored at 2°C to 8°C (36°F 
to 46°F) and must not be frozen. Drug product should be 
kept in original container until use to prevent prolonged 
light exposure.  
 
The 20 mg/mL solution will be diluted into a 0.9% Sodium Chloride bag for IV infusion. Vials 
containing tremelimumab may be gently inverted for mixing but should not be shaken. 
For dose preparation steps, the following ancillary items are required:  
• IV infusion bags of 0.9% sodium chloride injection (250 mL size). 0.9% Sodium Chloride 
bags must be latex-free and can be made of polyvinyl chloride (PVC) or polyolefins (e.g., 
polyethylene), manufactured with bis (2-ethylhexyl) phthalate (DEHP) or DEHP-free.  
• IV infusion lines made of PVC/DEHP or PVC/tri octyl trimellitate (TOTM) or 
polyethylene or polyurethane. All DEHP-containing or DEHP-free lines are acceptable. 
Lines should contain a 0.22 or 0.2 μm in-line filter. The in-line filter can be made of 
polyethersulfone (PES) or polyvinylidine fluoride DRF (PVDF). Lines containing 
cellulose-based filters should not be used with tremelimumab.  
• Catheters/infusion sets made of polyurethane or fluoropolymer with silicone and stainless 
steel and/or PVC components.  
• Syringes made of polypropylene and latex-free. Polycarbonate syringes should not be used 
with tremelimumab.  
• Needles made of stainless steel.  
13.1.4 Stability and Storage  
Tremelimumab does not contain preservatives and any unused portion must be discarded. 
Preparation of tremelimumab and preparation of the IV bag are to be performed aseptically. Total 
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at room temperature (25°C). However, it is recommended that the prepared final IV bag be stored 
in the dark at 2-8°C until needed. The refrigerated infusion solutions in the prepared final IV bag 
should be equilibrated at room temperature for about 2 hours prior to administration. If storage 
time exceeds these limits, a new dose must be prepared from new vials.  
The investigational product manager or qualified personnel will be responsible for preparing the 
IV doses using the following steps:  
1) Select the IXRS-assigned number of vials of investigational product required to prepare the 
subject’s dose.  
2) All investigational product vials should be equilibrated to room temperature for 30 minutes 
prior to dose preparation.  
3) To prepare the IV bag, first, calculate the dose volume of investigational product required. 
Second, remove the volume of 0.9% sodium chloride IV solution equivalent to the calculated dose 
volume of investigational product from the IV bag. Lastly, add the calculated dose volume of 
investigational product to the IV bag. Gently mix the solution in the bag by inverting up and down. 
Avoid shaking the IV bag to prevent foaming.  
Labels will be prepared in accordance with Good Manufacturing Practice (GMP). 
13.1.5 Administration procedures 
Tremelimumab is to be administered as an IV solution at a rate of 250 mL/h.  
In the event that either preparation time or infusion time exceeds the time limits a new dose must 
be prepared from new vials. Tremelimumab does not contain preservatives, and any unused portion 
must be discarded.  
No incompatibilities between tremelimumab and polyvinylchloride or polyolefin have been 
observed. However, polycarbonate syringes and administration set containing cellulose-based 
filters should not be used with tremelimumab 
13.1.5.1 Monitoring of dose administration 
See Section 3.2.4. 
13.2 Durvalumab (17363) 
13.2.1 Source 
Durvalumab will be supplied by AstraZeneca/MedImmune Inc. 
13.2.2 Toxicity 
See Appendix B for details. 
13.2.3 Formulation and Preparation 
Durvalumab is a human monoclonal antibody of the immunoglobulin G1 kappa (IgG1κ) subclass. 
Investigational Product  
Manufacturer  
Concentration 
and 
Formulation as Supplied  


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Durvalumab 
Medimmune/AstraZeneca 
Durvalumab will be supplied 
as a 500 mg vial solution for 
infusion after dilution. The 
solution contains 50 mg/mL 
durvalumab, 26 mM 
histidine/histidine 
hydrochloride, 275 mM 
trehalose dihydrate, and 
0.02% (weight/volume) 
polysorbate 80; it has a pH of 
6.0. The nominal fill volume 
is 10 mL. Investigational 
product vials are stored at 
2°C to 8°C (36°F to 46°F) 
and must not be frozen. 
Durvalumab must be used 
within the individually 
assigned expiry date on the 
label. 
13.2.4 Stability and Storage 
The dose of durvalumab for administration must be prepared by the Investigator’s or site’s 
designated IP manager using aseptic technique. Total time from needle puncture of the durvalumab 
vial to the start of administration should not exceed:  
• 24 hours at 2°C to 8°C (36°F to 46°F) 
• 4 hours at room temperature 
If in-use storage time exceeds these limits, a new dose must be prepared from new vials. Infusion 
solutions must be allowed to equilibrate to room temperature prior to commencement of 
administration.  
Protect from light. 
13.2.5 Administration procedures 
No incompatibilities between durvalumab and polyvinylchloride or polyolefin IV bags have been 
observed. Dose of 1500mg durvalumab for patients >30 kg will be administered using an IV bag 
containing 0.9% (w/v) NaCl or dextrose, with a final durvalumab concentration ranging from 1 to 
20 mg/mL and delivered through an IV administration set with a 0.2- or 0.22-μm in-line filter. 
Remove 30.0 mL of IV solution from the IV bag prior to addition of durvalumab. Next, 30.0 mL 
of durvalumab (i.e., 1500 mg of durvalumab) is added to the IV bag such that final concentration 
is within 1 to 20 mg/mL (IV bag volumes 100 to 1000 mL). Mix the bag by gently inverting to 
ensure homogeneity of the dose in the bag. 
Durvalumab will be administered at room temperature (approximately 25°C) by controlled 
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durvalumab, the entire contents of the IV bag should be administered as an IV infusion over 
approximately 60 minutes (±5 minutes), using a 0.2, or 0.22-μm in-line filter. 
The IV line will be flushed with a volume of IV solution (0.9% [w/v] NaCl equal to the priming 
volume of the infusion set used after the contents of the IV bag are fully administered or complete 
the infusion according to institutional policy to ensure the full dose is administered and document 
if the line was not flushed. In the event that either preparation time or infusion time exceeds the 
time limits a new dose must be prepared from new vials. Durvalumab (MEDI4736) does not 
contain preservatives, and any unused portion must be discarded. 
13.2.5.1 Monitoring of dose administration 
See Section 3.2.4 
13.2.5.2 Dose Calculation  
Note: The dosing for durvalumab will be a flat dosing of 1500mg. 
The corresponding volume of investigational product should be rounded to the nearest tenth of a 
mL (0.1 mL). Each vial contains a small amount of overage and the overage should be utilized as 
much as possible before using another vial.  
The number of vials required for dose preparation is the next greatest whole number of vials from 
the following formula: Number of vials = Dose (mL) ÷ 20 (mL/vial) 
13.2.5.3 Investigational Product Preparation Steps (Durvalumab) 
The investigational product manager or qualified personnel will be responsible for preparing the 
IV doses using the following steps:  
1) Select the IXRS-assigned number of vials of investigational product required to prepare 
the subject’s dose.  
2)  All investigational product vials should be equilibrated to room temperature for 30 minutes 
prior to dose preparation.  
3) To prepare the IV bag, first, calculate the dose volume of investigational product required. 
Second, remove the volume of 0.9% sodium chloride IV solution equivalent to the 
calculated dose volume of investigational product from the IV bag. 
4)  Lastly, add the calculated dose volume of investigational product to the IV bag. Gently 
mix the solution in the bag by inverting up and down. Avoid shaking the IV bag to prevent 
foaming.  
5) Labels will be prepared in accordance with Good Manufacturing Practice (GMP). 
13.2.5.4 Investigational Product Inspection  
Each vial selected for dose preparation should be inspected.  
If there are any defects noted with the investigational product, the investigator and site monitor 
should be notified immediately. Refer to the Product Complaint section (13.2.5.6) for further 
instructions.  
During the inspection if the solution is not clear or any turbidity, discoloration or particulates are 
observed, notify your site monitor and store the vial(s) in QUARANTINE at refrigerated (2-8ºC) 
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Notify the IXRS that the unusable vials are damaged. The IXRS will indicate the replacement 
vials. Select appropriate replacement vials for the preparation of the subject’s dose and perform 
the same inspection on the newly selected vials. For accountability, record the total number of 
vials removed from site inventory. Used vials should be held for accountability purposes at 
ambient storage temperature. 
13.2.5.5 Investigational Product Accountability  
The investigator’s or site’s designated investigational product manager is required to maintain 
accurate investigational product accountability records. Upon completion of the study, copies of 
investigational product accountability records will be returned to MedImmune. All unused 
investigational product will be returned to a MedImmune-authorized depot or disposed of upon 
authorization by MedImmune. 
13.2.5.6 Reporting Product Complaints  
Any defects with the investigational product must be reported immediately to the MedImmune 
Product Complaint Department by the site with further notification to the site monitor. All defects 
will be communicated to MedImmune and investigated further with the Product Complaint 
Department. During the investigation of the product complaint, all investigational products must 
be stored at labeled conditions unless otherwise instructed.  
Product defects may be related to component, product, or packaging and labeling issues. The list 
below includes, but is not limited to, descriptions of product complaints that should be reported.  
Component Issue: Defect in container or dosing mechanism of the investigational product. The 
component defect may be damaged, missing, or broken. Component examples include vials, 
stoppers, caps, spray barrels, spray nozzles, or plungers.  
Product Issue: Defect in the product itself. The product appearance has visual imperfections such 
as foreign particles, crystallization, discoloration, turbidity, insufficient volume, or anything that 
does not apply to the product description.  
Packaging/Labeling Issue: Defect in the packaging or labeling of the product. The packaging or 
labeling defects may be damaged or unreadable, or the label may be missing.  
When reporting a product complaint, site staff must be prepared to provide the following 
information:  
1) Customer information: reporter name, address, contact number, and date of complaint  
2) Product information: product name, packaging kit number or lot number, expiry date, and 
clinical protocol number  
3) Complaint information: complaint issue category and description  
MedImmune contact information for reporting product complaints:  
Email: productcomplaints@medimmune.com  
Phone: +1-301-398-2105 +1-877-MEDI-411 (+1-877-633-4411)  
Fax: +1-301-398-8800  
Mail: MedImmune, LLC Attn: Product Complaint Department One MedImmune Way, 
Gaithersburg, MD USA 20878 


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13.3 Pexa-Vec (17363) 
13.3.1 Source 
Pexa-Vec will be supplied by Sillajen Inc. 
13.3.2 Toxicity 
Toxicity of Pexa-Vec listed in Section 3.4.1 
13.3.3 Formulation and Preparation 
VACC-6.25.1, Recombinant Vaccinia/GM-CSF (VAC-6.25.1 [GM-CSF1]),  
VAC GM-CSF, Vaccinia/GM-CSF  
Generic Name: Recombinant Vaccinia GM-CSF; RAC VAC GM-CSF (thymidine kinase-
deactivated plus GM-CSF) 
Pexa-Vec is a viral suspension supplied in individual 4-mL glass vials. Each vial contains 
Pexa-Vec diluted in 30 mM Tris 10% Sucrose buffer. The recoverable volume of Pexa-Vec in each 
vial is 2 mL with an infectious titer of 1 × 109 pfu (9.0 Log pfu). Each vial is intended for single 
use (i.e., 1 injection to 1 patient). 0.6 ml of viral suspension is to be removed for the 3 x 108 pfu 
dose 
13.3.3.1 Packaging and Labeling of Pexa-Vec 
Each vial is packed in a cardboard box (secondary packaging) which constitutes a Pexa-Vec 
treatment kit (1-vial treatment kit). 
The primary labels on the vials as well as the secondary labels on the cardboard boxes are in the 
language of countries where the study is to be performed. Labels are compliant with local 
regulatory requirements and contain information including, but not limited to: Sponsor name, 
product code, lot number, concentration, volume, storage conditions, route of administration and 
a cautionary statement in proper language.  
13.3.3.2 Biosafety/Containment Level Classification of Pexa-Vec 
Pharmacies, hospitals, and clinics routinely administer infectious organisms (e.g., live viral 
vaccines, and live BCG for bladder cancer) and Pexa-Vec preparation and administration handling 
recommendations are also based on CDC guidelines for preparation of the standard vaccinia 
vaccine (CDC 2009). Pexa-Vec is classified as a biohazard safety level 1 or 2 (BSL-1 or 2) agent 
based on the very low pathogenicity and the potential to spread only by direct physical contact 
13.3.3.3 Transport of Pexa-Vec 
13.3.3.4 Interstate and International Transport 
Pexa-Vec is shipped on dry-ice with the official transport designation as a “Biological Substance, 
Category B” in compliance with International Air Transportation Association and Department of 
Transportation regulations and other local regulations for air and road transport of infectious 
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13.3.3.5 Transport within the Institution 
All transport of Pexa-Vec (in vial or IV bag) within the institution must be done using a leak-proof 
container/bag clearly-marked with a biohazard symbol. 
13.3.4 Stability and Storage  
Pexa-Vec must be stored at or below –60°C in an alarmed, temperature-monitored, secure freezer 
with restricted access. Pexa-Vec can be stored with other therapeutics but should be separate from 
lab samples.  
The study demonstrated that the diluted Pexa-Vec is stable for 24 hours at 20 to 80 and an additional 
3 hours at room temperature. 
13.3.4.1 Dispensing of Pexa-Vec 
Pexa-Vec will be dispensed only with the written authorization of the Investigator or a sub-
Investigator to staff that have been specifically designated and trained for this study. 
13.3.5 Handling of Pexa-Vec 
All applicable institutional policies for preparation, transport, and disposal of viral vectors should 
be consulted and followed. During all Pexa-Vec manipulations gloves, gown, surgical mask and 
goggles (or safety glasses with side shields) must be worn. Headgear and overshoes are not 
mandatory. 
Regardless of the BSL classification, the following are recommended as conservative measures 
for Pexa-Vec preparation, decontamination and storage: 
13.3.5.1 Individuals excluded from handling (preparation and administration): 
• pregnant or breastfeeding women 
• immunocompromised individuals (e.g., organ transplant recipient, HIV-positive 
individual, or receiving chronic immunosuppressive medication) 
• individuals with ongoing severe inflammatory skin condition requiring medical treatment 
or history of severe eczema requiring medical treatment. 
13.3.5.2 Limit access: 
• place a biohazard sign in the preparation area 
• limit access to the designated area (e.g., the hood used to prepare Pexa-Vec) during 
preparation 
13.3.5.3 Equipment 
The following are recommended as conservative measures for Pexa-Vec preparation, 
decontamination and storage: 
• Prepare in a Class IIA Biological Safety Cabinet (e.g., a standard chemotherapy hood 
equipped with a properly maintained high-efficiency particulate air [HEPA] filter) 
• Wear standard PPE - gloves, goggles, mask, and gown while preparing the agent (e.g., as 
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13.3.6 Preparation and administration of Pexa-Vec 
The Pexa-Vec dose of 3 x 108 pfu (DL 1) or 1 x 109 pfu (DL 2) will be administered via IV 
infusion over 60 minutes (±5 minutes). Patients will receive 1 L 0.9% NaCl prior to infusion. 
This dose of Pexa-Vec will be suspended in a 255 mL infusion bag, containing 250 mL sterile 
0.9% sodium chloride [NaCl] and 5 mL molar sodium bicarbonate (8.4% NaHCO3). The total 
amount of NaCl and NaHCO3 will approximately be 2.25 and 0.42 g/infusion, respectively. 
13.3.7 Cleaning / Disinfection and Disposal 
Standard institutional policies should be followed for cleaning and decontamination while 
handling vaccinia virus-based products. Hospital-grade chemical disinfectants containing: bleach 
(with at least 0.6% of active chlorine), alcohols (≥60%), aldehydes, hydrogen peroxide (3%), 
iodophor (75 ppm), phenols or quaternary ammonium compounds are adequate for routine 
cleaning and disinfection of work areas after Pexa-Vec handling. The manufacturer’s instructions 
should be followed to ensure adequate contact time and confirm the ability of the equipment to 
withstand the disinfectant used. 
All contaminated material (e.g., syringes, catheters, needles, tubing, gloves, used or unused vials, 
containers, bandages, etc.) should be disposed of in a clearly-marked biomedical waste container 
and discarded according to regular institution procedure for infectious waste i.e., autoclaving, 
incineration, or treatment with sodium hypochlorite solution. Biomedical waste will not be left 
unattended in a public area; autoclaved medical waste must not be disposed of as regular trash. 
Textiles and fabrics can be laundered in hot water (71°C) with detergent and hot air drying.  
13.3.8 Spills or Environmental Contamination 
In the event of a spill, people in the immediate area will be alerted and other institutional personnel 
will be notified as required by institutional policies. Vaccinia viruses, like most enveloped viruses, 
are sensitive to inactivation by standard physical and chemical methods of disinfection. A standard 
hospital-grade disinfectant should be used to clean non-critical patient care equipment or medical 
devices between each patient use (e.g., bedpans, commodes, blood pressure cuffs, oximeters, 
glucose meters.) Hospital-grade disinfectants include 3% hydrogen peroxide, ≥60% alcohol, 
hypochlorite (1000 ppm), 0.5% accelerated hydrogen peroxide, quaternary ammonium 
compounds, iodophors (75 ppm), phenolics, and aldehydes. The manufacturer’s instructions 
should be followed to ensure adequate contact time and confirm the ability of the equipment to 
withstand the disinfectant used. Critical 
and semi-critical devices should be cleaned and reprocessed according to institutional guidelines.  
Spills and accidents that result in overt exposures to infectious material will be reported as required 
by institutional policies.  
13.3.9 Unused Drug Return or Destruction 
During the course of the study and at termination of the study all unused Pexa-Vec patient kits will 
be destroyed locally or returned to the drug supply provider.  
For local destruction, the Investigator/Pharmacist or delegated person will ensure that all 
contaminated material should be disposed of in a clearly-marked biomedical waste container and 
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humans to any risks from Pexa-Vec. A certificate of destruction will be completed. The drug 
supply provider will coordinate the return of all unused Pexa-Vec patient kits. A certificate of 
return will be completed and provided to the drug supply provider (copy retained by the site). 
Upon completion or termination of the study at a site, the monitor will verify that all used 
Pexa-Vec patient kits have been decontaminated (if applicable) and disposed, all unused 
Pexa-Vec patient kits have been returned or destroyed, and no IP remains on site.  
 
 


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14 REFERENCES 
 
1. 
Mlecnik B, Tosolini M, Kirilovsky A et al. Histopathologic-based prognostic factors of 
colorectal cancers are associated with the state of the local immune reaction. J Clin Oncol 2011; 
29: 610-618. 
2. 
Pages F, Kirilovsky A, Mlecnik B et al. In situ cytotoxic and memory T cells predict 
outcome in patients with early-stage colorectal cancer. J Clin Oncol 2009; 27: 5944-5951. 
3. 
Zamarin D, Holmgaard RB, Subudhi SK et al. Localized oncolytic virotherapy 
overcomes systemic tumor resistance to immune checkpoint blockade immunotherapy. Sci 
Transl Med 2014; 6: 226ra232. 
4. 
Heo J, Reid T, Ruo L et al. Randomized dose-finding clinical trial of oncolytic 
immunotherapeutic vaccinia JX-594 in liver cancer. Nat Med 2013; 19: 329-336. 
5. 
Breitbach CJ, Burke J, Jonker D et al. Intravenous delivery of a multi-mechanistic 
cancer-targeted oncolytic poxvirus in humans. Nature 2011; 477: 99-102. 
6. 
Park SH, Breitbach CJ, Lee J et al. Phase 1b Trial of Biweekly Intravenous Pexa-Vec 
(JX-594), an Oncolytic and Immunotherapeutic Vaccinia Virus in Colorectal Cancer. Mol Ther 
2015; 23: 1532-1540. 
7. 
Kohlhapp FJ, Kaufman HL. Molecular Pathways: Mechanism of Action for Talimogene 
Laherparepvec, a New Oncolytic Virus Immunotherapy. Clin Cancer Res 2016; 22: 1048-1054. 
8. 
Rajani KR, Vile RG. Harnessing the Power of Onco-Immunotherapy with Checkpoint 
Inhibitors. Viruses 2015; 7: 5889-5901. 
9. 
Andtbacka RH, Kaufman HL, Collichio F et al. Talimogene Laherparepvec Improves 
Durable Response Rate in Patients With Advanced Melanoma. J Clin Oncol 2015; 33: 2780-
2788. 
10. 
Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev 
Cancer 2012; 12: 252-264. 
11. 
Brahmer J, Reckamp KL, Baas P et al. Nivolumab versus Docetaxel in Advanced 
Squamous-Cell Non-Small-Cell Lung Cancer. New England Journal of Medicine 2015; 373: 
123-135. 
12. 
Wang E, Kang D, Bae KS et al. Population pharmacokinetic and pharmacodynamic 
analysis of tremelimumab in patients with metastatic melanoma. J Clin Pharmacol 2014; 54: 
1108-1116. 
13. 
Ng CM, Lum BL, Gimenez V et al. Rationale for fixed dosing of pertuzumab in cancer 
patients based on population pharmacokinetic analysis. Pharm Res 2006; 23: 1275-1284. 
14. 
Wang DD, Zhang S, Zhao H et al. Fixed dosing versus body size-based dosing of 
monoclonal antibodies in adult clinical trials. J Clin Pharmacol 2009; 49: 1012-1024. 
15. 
Zhang S, Shi R, Li C et al. Fixed dosing versus body size-based dosing of therapeutic 
peptides and proteins in adults. J Clin Pharmacol 2012; 52: 18-28. 


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16. 
Narwal R, Roskos LK, Robbie GJ. Population pharmacokinetics of sifalimumab, an 
investigational anti-interferon-alpha monoclonal antibody, in systemic lupus erythematosus. Clin 
Pharmacokinet 2013; 52: 1017-1027. 
17. 
Brahmer JR. PD-1-targeted immunotherapy: recent clinical findings. Clin Adv Hematol 
Oncol 2012; 10: 674-675. 
18. 
Eisenhauer EA, Therasse P, Bogaerts J et al. New response evaluation criteria in solid 
tumours: Revised RECIST guideline (version 1.1). European Journal of Cancer 2009; 45: 228-
247. 
 
 
 


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15 APPENDICES 
15.1 Appendix A-Performance Status Criteria 
ECOG Performance Status Scale 
 
Grade 
Descriptions 
0 
Normal activity. Fully active, able 
to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory. 
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
2 
In bed <50% of the time. 
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities. Up and about 
more than 50% of waking hours. 
3 
In bed >50% of the time. Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
4 
100% bedridden. Completely 
disabled. Cannot carry on any 
self-care. Totally confined to bed 
or chair. 
5 
Dead. 
 
 
 


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15.2 Appendix B – Tremelimumab and Durvalumab Dosing Modifications  


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Dosing Modification and Toxicity Management Guidelines for Immune-Mediated, Infusion-Related, and  
Non-Immune–Mediated Reactions (MEDI4736 Monotherapy or Combination Therapy With Tremelimumab or 
Tremelimumab Monotherapy) 17 October 2019 Version (CTCAE v4.03) 
General Considerations regarding Immune-Mediated Reactions 
Dose Modifications 
Toxicity Management 
Drug administration modifications of study drug/study regimen will be made to 
manage potential immune-related AEs based on severity of treatment-emergent 
toxicities graded per NCI CTCAE v4.03 (unless indicated otherwise). 
In addition to the criteria for permanent discontinuation of study drug/study 
regimen based on CTC grade/severity (table below), permanently discontinue 
study drug/study regimen for the following conditions: 
• 
Inability to reduce corticosteroid to a dose of ≤10 mg of prednisone per 
day (or equivalent) within 12 weeks of the start of the immune-mediated 
adverse event (imAE) 
• 
Grade 3 recurrence of a previously experienced treatment-related imAE 
following resumption of dosing 
Grade 1 
No dose modification 
Grade 2 
Hold study drug/study regimen dose until Grade 2 resolution to 
Grade ≤1. 
If toxicity worsens, then treat as Grade 3 or Grade 4. 
Study drug/study regimen can be resumed once event stabilizes to 
Grade ≤1 after completion of steroid taper. 
Patients with endocrinopathies who may require prolonged or 
continued steroid replacement can be retreated with study 
drug/study regimen on the following conditions: 
1. 
The event stabilizes and is controlled. 
2. 
The patient is clinically stable as per Investigator or treating 
physician’s clinical judgement. 
3. 
Doses of prednisone are at ≤10 mg/day or equivalent. 
It is recommended that management of immune-mediated adverse events (imAEs) 
follows the guidelines presented in this table: 
− 
It is possible that events with an inflammatory or immune mediated 
mechanism could occur in nearly all organs, some of them not noted 
specifically in these guidelines. 
− 
Whether specific immune-mediated events (and/or laboratory indicators of 
such events) are noted in these guidelines or not, patients should be 
thoroughly evaluated to rule out any alternative etiology (e.g., disease 
progression, concomitant medications, and infections) to a possible immune-
mediated event. In the absence of a clear alternative etiology, all such events 
should be managed as if they were immune related. General 
recommendations follow. 
− 
Symptomatic and topical therapy should be considered for low-grade (Grade 
1 or 2, unless otherwise specified) events.  
− 
For persistent (>3 to 5 days) low-grade (Grade 2) or severe (Grade ≥3) 
events, promptly start prednisone 1 to 2 mg/kg/day PO or IV equivalent. 
− 
Some events with high likelihood for morbidity and/or mortality – e.g., 
myocarditis, or other similar events even if they are not currently noted in 
the guidelines – should progress rapidly to high dose IV corticosteroids 
(methylprednisolone at 2 to 4 mg/kg/day) even if the event is Grade 2, and if 
clinical suspicion is high and/or there has been clinical confirmation. 
Consider, as necessary, discussing with the study physician, and promptly 
pursue specialist consultation. 
− 
If symptoms recur or worsen during corticosteroid tapering (28 days of 
taper), increase the corticosteroid dose (prednisone dose [e.g., up to 2 to 
4 mg/kg/day PO or IV equivalent]) until stabilization or improvement of 
symptoms, then resume corticosteroid tapering at a slower rate (>28 days of 
taper). 
− 
More potent immunosuppressives such as TNF inhibitors (e.g., infliximab; 
also refer to the individual sections of the imAEs for specific type of 
immunosuppressive) should be considered for events not responding to 
systemic steroids. Progression to use of more potent immunosuppressives 
should proceed more rapidly in events with high likelihood for morbidity 
and/or mortality – e.g., myocarditis, or other similar events even if they are 


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Dosing Modification and Toxicity Management Guidelines for Immune-Mediated, Infusion-Related, and  
Non-Immune–Mediated Reactions (MEDI4736 Monotherapy or Combination Therapy With Tremelimumab or 
Tremelimumab Monotherapy) 17 October 2019 Version (CTCAE v4.03) 
General Considerations regarding Immune-Mediated Reactions 
Dose Modifications 
Toxicity Management 
Grade 3 
Depending on the individual toxicity, study drug/study regimen 
may be permanently discontinued. Please refer to guidelines below. 
Grade 4 
Permanently discontinue study drug/study regimen. 
Note: For asymptomatic amylase or lipase levels of >2.0×ULN, hold study 
drug/study regimen, and if complete work up shows no evidence of pancreatitis, 
study drug/study regimen may be continued or resumed. 
Note: Study drug/study regimen should be permanently discontinued in Grade 3 
events with high likelihood for morbidity and/or mortality – e.g., myocarditis, or 
other similar events even if they are not currently noted in the guidelines. 
Similarly, consider whether study drug/study regimen should be permanently 
discontinued in Grade 2 events with high likelihood for morbidity and/or mortality 
– e.g., myocarditis, or other similar events even if they are not currently noted in 
the guidelines – when they do not rapidly improve to Grade <1 upon treatment 
with systemic steroids and following full taper 
Note: There are some exceptions to permanent discontinuation of study drug for 
Grade 4 events (i.e., hyperthyroidism, hypothyroidism, Type 1 diabetes mellitus).  
 
not currently noted in the guidelines – when these events are not responding 
to systemic steroids. 
− 
With long-term steroid and other immunosuppressive use, consider need for 
Pneumocystis jirovecii pneumonia (PJP, formerly known as Pneumocystis 
carinii pneumonia) prophylaxis, gastrointestinal protection, and glucose 
monitoring. 
− 
Discontinuation of study drug/study regimen is not mandated for  
Grade 3/Grade 4 inflammatory reactions attributed to local tumor response 
(e.g., inflammatory reaction at sites of metastatic disease and lymph nodes). 
Continuation of study drug/study regimen in this situation should be based 
upon a benefit-risk analysis for that patient. 
AE Adverse event; CTC Common Toxicity Criteria; CTCAE Common Terminology Criteria for Adverse Events; imAE immune-mediated adverse event; IV intravenous; NCI 
National Cancer Institute; PO By mouth. 
 
 
 


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Specific Immune-Mediated Reactions 
Adverse Events 
Severity Grade of the 
Event (NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
Pneumonitis/Interstitial 
Lung Disease (ILD) 
Any Grade 
General Guidance 
For Any Grade: 
− 
Monitor patients for signs and symptoms of pneumonitis or 
ILD (new onset or worsening shortness of breath or cough). 
Patients should be evaluated with imaging and pulmonary 
function tests, including other diagnostic procedures as 
described below. 
− 
Initial work-up may include clinical evaluation, monitoring of 
oxygenation via pulse oximetry (resting and exertion), 
laboratory work-up, and high- resolution CT scan. 
Grade 1 
(asymptomatic, clinical 
or diagnostic 
observations only; 
intervention not 
indicated) 
No dose modifications required. However, 
consider holding study drug/study 
regimen dose as clinically appropriate and 
during diagnostic work-up for other 
etiologies. 
For Grade 1 (radiographic changes only): 
− 
Monitor and closely follow up in 2 to 4 days for clinical 
symptoms, pulse oximetry (resting and exertion), and 
laboratory work-up and then as clinically indicated. 
− 
Consider Pulmonary and Infectious Disease consults. 
Grade 2 
(symptomatic; medical 
intervention indicated; 
limiting instrumental 
ADL) 
Hold study drug/study regimen dose until 
Grade 2 resolution to Grade ≤1. 
• 
If toxicity worsens, then treat as 
Grade 3 or Grade 4. 
• 
If toxicity improves to Grade ≤1, 
then the decision to reinitiate study 
drug/study regimen will be based 
upon treating physician’s clinical 
judgment and after completion of 
steroid taper. 
For Grade 2 (mild to moderate new symptoms): 
− 
Monitor symptoms daily and consider hospitalization. 
− 
Promptly start systemic steroids (e.g., prednisone 1 to 
2 mg/kg/day PO or IV equivalent). 
− 
Reimage as clinically indicated. 
− 
If no improvement within 3 to 5 days, additional workup 
should be considered and prompt treatment with IV 
methylprednisolone 2 to 4 mg/kg/day started 
− 
If still no improvement within 3 to 5 days despite IV 
methylprednisolone at 2 to 4 mg/kg/day, promptly start 
immunosuppressive therapy such as TNF inhibitors 
(e.g., infliximab at 5 mg/kg every 2 weeks). Caution: It is 
important to rule out sepsis and refer to infliximab label for 
general guidance before using infliximab. 
− 
Once the patient is improving, gradually taper steroids over 
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anti-PJP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections)a 
− 
Consider Pulmonary and Infectious Disease consults. 
− 
Consider, as necessary, discussing with study physician. 
Grade 3 or 4 
(Grade 3: severe 
symptoms; limiting 
self-care ADL; oxygen 
indicated) 
 
(Grade 4: life-
threatening respiratory 
compromise; urgent 
intervention indicated 
[e.g., tracheostomy or 
intubation]) 
Permanently discontinue study drug/study 
regimen. 
For Grade 3 or 4 (severe or new symptoms, new/worsening hypoxia, 
life-threatening): 
− 
Promptly initiate empiric IV methylprednisolone 1 to 
4 mg/kg/day or equivalent. 
− 
Obtain Pulmonary and Infectious Disease consults; consider, as 
necessary, discussing with study physician. 
− 
Hospitalize the patient. 
− 
Supportive care (e.g., oxygen). 
− 
If no improvement within 3 to 5 days, additional workup 
should be considered and prompt treatment with additional 
immunosuppressive therapy such as TNF inhibitors 
(e.g., infliximab at 5 mg/kg every 2 weeks’ dose) started. 
Caution: rule out sepsis and refer to infliximab label for general 
guidance before using infliximab. 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, 
and, in particular, anti-PJP treatment (refer to current NCCN 
guidelines for treatment of cancer-related infections).a 
Diarrhea/Colitis 
Large intestine 
perforation/Intestine 
perforation 
Any Grade 
General Guidance 
For Any Grade: 
− 
Monitor for symptoms that may be related to 
diarrhea/enterocolitis (abdominal pain, cramping, or changes in 
bowel habits such as increased frequency over baseline or 
blood in stool) or related to bowel perforation (such as sepsis, 
peritoneal signs, and ileus). 
− 
When symptoms or evaluation indicate a perforation is 
suspected, consult a surgeon experienced in abdominal surgery 
immediately without any delay. 
− 
Patients should be thoroughly evaluated to rule out any 
alternative etiology (e.g., disease progression, other 
medications, or infections), including testing for clostridium 
difficile toxin, etc. 
− 
Steroids should be considered in the absence of clear 
alternative etiology, even for low-grade events, in order to 


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prevent potential progression to higher grade event, including 
perforation. 
− 
Use analgesics carefully; they can mask symptoms of 
perforation and peritonitis. 
Grade 1 
(Diarrhea: stool 
frequency of <4 over 
baseline per day) 
(Colitis: asymptomatic; 
clinical or diagnostic 
observations only) 
No dose modifications. 
For Grade 1: 
− 
Monitor closely for worsening symptoms. 
− 
Consider symptomatic treatment, including hydration, 
electrolyte replacement, dietary changes (e.g., American 
Dietetic Association colitis diet), and loperamide. Use 
probiotics as per treating physician’s clinical judgment. 
Grade 2 
(Diarrhea: stool 
frequency of 4 to 6 over 
baseline per day) 
(Colitis: abdominal 
pain; mucus or blood in 
stool) 
(Perforation: 
symptomatic; medical 
intervention indicated*) 
 
 
 
 
 
* “medical 
intervention” is not 
invasive 
Hold study drug/study regimen until 
resolution to Grade ≤1 
• 
If toxicity worsens, then treat as 
Grade 3 or Grade 4. 
• 
If toxicity improves to Grade ≤1, 
then study drug/study regimen can be 
resumed after completion of steroid 
taper. 
For Grade 2: 
− 
Consider symptomatic treatment, including hydration, 
electrolyte replacement, dietary changes (e.g., American 
Dietetic Association colitis diet), and loperamide and/or 
budesonide. 
− 
Promptly start prednisone 1 to 2 mg/kg/day PO or IV 
equivalent. 
− 
If event is not responsive within 3 to 5 days or worsens despite 
prednisone at 1 to 2 mg/kg/day PO or IV equivalent, GI consult 
should be obtained for consideration of further workup, such as 
imaging and/or colonoscopy, to confirm colitis and rule out 
perforation, and prompt treatment with IV methylprednisolone 
2 to 4 mg/kg/day started. 
− 
If still no improvement within 3 to 5 days despite 2 to 4 mg/kg 
IV methylprednisolone, promptly start immunosuppressives 
such as infliximab at 5 mg/kg once every 2 weeksa. Caution: it 
is important to rule out bowel perforation and refer to 
infliximab label for general guidance before using infliximab. 
− 
Consider, as necessary, discussing with study physician if no 
resolution to Grade ≤1 in 3 to 4 days. 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, and 
anti-PJP treatment (refer to current NCCN guidelines for 
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Grade 3 or 4 
(Grade 3 Diarrhea: 
stool frequency of ≥7 
over baseline per day; 
Grade 4 Diarrhea: life 
threatening 
consequences) 
(Grade 3 Colitis: severe 
abdominal pain, change 
in bowel habits, medi-
cal intervention indi-
cated, peritoneal signs; 
Grade 4 Colitis: life-
threatening 
consequences, urgent 
intervention indicated) 
(Grade 3 Perforation: 
severe symptoms, 
elective* operative 
intervention indicated; 
Grade 4 Perforation: 
life-threatening 
consequences, urgent 
intervention indicated) 
 
*This guidance 
anticipates that Grade 3 
operative interventions  
of perforations are 
usually not elective 
Grade 3 
Permanently discontinue study drug/study 
regimen for Grade 3 if toxicity does not 
improve to Grade ≤1 within 14 days; 
study drug/study regimen can be resumed 
after completion of steroid taper. 
 
Grade 4 
Permanently discontinue  
study drug/study regimen.  
For Grade 3 or 4: 
− 
Promptly initiate empiric IV methylprednisolone 2 to 
4 mg/kg/day or equivalent. 
− 
Monitor stool frequency and volume and maintain hydration. 
− 
Urgent GI consult and imaging and/or colonoscopy as 
appropriate. 
− 
If still no improvement within 3 to 5 days of IV 
methylprednisolone 2 to 4 mg/kg/day or equivalent, promptly 
start further immunosuppressives (e.g., infliximab at 5 mg/kg 
once every 2 weeks). Caution: Ensure GI consult to rule out 
bowel perforation and refer to infliximab label for general 
guidance before using infliximab. If perforation is suspected, 
consult a surgeon experienced in abdominal surgery 
immediately without any delay. 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, and 
anti-PJP treatment (refer to current NCCN guidelines for 
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Hepatitis  
(elevated LFTs) 
Infliximab should not be 
used for management of 
immune-related hepatitis. 
Any Elevations in 
AST, ALT or TB  as 
Described Below 
General Guidance 
For Any Elevations Described: 
− 
Monitor and evaluate liver function test: AST, ALT, ALP, and 
TB. 
− 
Evaluate for alternative etiologies (e.g., viral hepatitis, disease 
progression, concomitant medications). 
 AST or ALT >ULN 
and ≤3.0×ULN if 
baseline normal, 1.5-
3.0×baseline if 
baseline abnormal; 
and/or TB > ULN and  
≤1.5×ULN  if baseline 
normal, >1.0-
1.5×baseline if 
baseline abnormal 
• 
No dose modifications. 
• 
If it worsens, then treat as described 
for elevations in  the row below. 
− 
Continue LFT monitoring per protocol. 
 
AST or  
ALT >3.0×ULN and 
≤5.0×ULN if baseline 
normal, >3-5×baseline 
if baseline abnormal; 
and/or  
TB >1.5×ULN and  
≤3.0×ULN if baseline 
normal, >1.5- 
3.0×baseline if 
baseline abnormal 
• 
Hold study drug/study regimen dose 
until resolution to AST or ALT 
≤3.0×ULN and/or TB ≤1.5×ULN if 
baseline normal, or to AST or ALT 
≤3.0×baseline and/or TB 
≤1.5×baseline if baseline abnormal. 
• 
If toxicity worsens, then treat as  
described for elevation in the row 
below. 
• 
If toxicity improves to AST or ALT 
≤3.0×ULN and/or TB ≤1.5×ULN if 
baseline normal, or to AST or ALT 
≤3.0×baseline and/or TB 
≤1.5×baseline if baseline abnormal, 
resume study drug/study regimen 
after completion of steroid taper. 
− 
Regular and frequent checking of LFTs (e.g., every 1 to 2 days) 
until elevations of these are improving or resolved. 
− 
If no resolution to AST or ALT ≤3.0×ULN and/or TB 
≤1.5×ULN if baseline normal, or to AST or ALT ≤3.0×baseline 
and/or TB ≤1.5×baseline if baseline abnormal, in 1 to 2 days, 
consider, as necessary, discussing with study physician. 
− 
If event is persistent (>3 to 5 days) or worsens, promptly start 
prednisone 1 to 2 mg/kg/day PO or IV equivalent. 
− 
If still no improvement within 3 to 5 days despite 1 to 
2 mg/kg/day of prednisone PO or IV equivalent, consider 
additional work up and start prompt treatment with IV 
methylprednisolone 2 to 4 mg/kg/day. 
− 
If still no improvement within 3 to 5 days despite 2 to 
4 mg/kg/day of IV methylprednisolone, promptly start 
immunosuppressives (i.e., mycophenolate mofetil).a Discuss 
with study physician if mycophenolate mofetil is not available. 
Infliximab should NOT be used. 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, and 
anti-PJP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections).a 
PLEASE SEE 
shaded area 
immediately below 
this section to find 
guidance for 
management of 
“Hepatitis (elevated 
LFTS)” in HCC 
patients 


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AST or  
ALT >5.0×ULN if 
baseline normal, 
>5×baseline if baseline 
abnormal; and/or  
TB >3.0×ULN if 
baseline normal; 
>3.0×baseline if 
baseline abnormal 
 
 
 
 
 
 
For elevations in transaminases ≤8×ULN 
and/or in TB ≤5×ULN if baseline normal, 
or for elevations in transaminases 
≤8×baseline and/or TB ≤5×baseline if 
baseline abnormal: 
• Hold study drug/study regimen dose 
until resolution to AST or ALT 
≤3.0×ULN and/or TB ≤1.5×ULN  if 
baseline normal, or to AST or ALT 
≤3.0×baseline and/or TB 
≤1.5×baseline if baseline abnormal 
• Resume study drug/study regimen if 
elevations downgrade to AST or ALT 
≤3.0×ULN and/or TB ≤1.5×ULN  if 
baseline normal, or to AST or ALT 
≤3.0×baseline and/or TB 
≤1.5×baseline if baseline abnormal, 
within 14 days and after completion 
of steroid taper. 
• Permanently discontinue study 
drug/study regimen if the elevations 
do not downgrade as described in 
bullet above within 14 days 
For elevations in transaminases >8×ULN 
or elevations in TB >5×ULN if baseline 
normal, or for elevations in transaminases 
>8×baseline and/or TB >5×baseline if 
baseline abnormal, permanently 
discontinue study drug/study regimen. 
Permanently discontinue study drug/study 
regimen for any case meeting Hy’s law 
criteria (AST and/or ALT >3 × ULN + 
bilirubin >2 × ULN without initial 
findings of cholestasis (i.e., elevated 
alkaline P04) and in the absence of any 
alternative cause.b 
− 
Promptly initiate empiric IV methylprednisolone at 1 to 
4 mg/kg/day or equivalent. 
− 
If still no improvement within 3 to 5 days despite 1 to 
4 mg/kg/day methylprednisolone IV or equivalent, promptly 
start treatment with immunosuppressive therapy (i.e., 
mycophenolate mofetil). Discuss with study physician if 
mycophenolate is not available. Infliximab should NOT be 
used. 
− 
Request Hepatology consult, and perform abdominal workup 
and imaging as appropriate. 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, and 
anti-PJP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections).a 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Hepatitis  
(elevated LFTs) 
Infliximab should not be 
used for management of 
immune-related hepatitis.  
See instructions at  
bottom of shaded area  
if transaminase rise is  
not isolated but (at any 
time) occurs in setting  
of either increasing 
bilirubin or signs of 
DILI/liver 
decompensation 
Any Elevations in 
AST, ALT or TB as 
Described Below 
 
General Guidance 
 
For Any Elevations Described: 
− 
Monitor and evaluate liver function test: AST, ALT, ALP, and 
TB. 
− 
Evaluate for alternative etiologies (e.g., viral hepatitis, disease 
progression, concomitant medications, worsening of liver 
cirrhosis [e.g., portal vein thrombosis]). 
− 
For HBV+ patients: evaluate quantitative HBV viral load, 
quantitative HBsAg, or HBeAg 
− 
For HCV+ patients: evaluate quantitative HCV viral load 
− 
Consider consulting hepatologist/Infectious Disease specialist 
regarding change/implementation in/of antiviral medications 
for any patient with an elevated HBV viral load >2000 IU/ml 
− 
Consider consulting hepatologist/Infectious Disease specialist 
regarding change/implementation in/of antiviral HCV 
medications if HCV viral load increased by ≥2-fold 
− 
For HCV+ with HBcAB+: Evaluate for both HBV and HCV as 
above 
 
 
Isolated AST or ALT 
>ULN and ≤5.0×ULN, 
whether normal or 
elevated at baseline  
• 
No dose modifications. 
• 
If ALT/AST elevations represents 
significant worsening based on 
investigator assessment, then treat as  
described for elevations in the row 
below. 
For all transaminase elevations, see 
instructions at bottom of shaded area if 
transaminase rise is not isolated but (at 
any time) occurs in setting of either 
increasing bilirubin or signs of 
DILI/liver decompensation 
 
 
THIS shaded area 
is guidance only for 
management of 
“Hepatitis (elevated 
LFTs)” in HCC 
patients  


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Isolated AST or ALT 
>5.0×ULN and 
≤8.0×ULN, if normal 
at baseline 
 
Isolated AST or ALT 
>2.0×baseline and 
≤12.5×ULN, if 
elevated >ULN at 
baseline 
 
• 
Hold study drug/study regimen dose 
untilresolution to AST or ALT 
≤5.0×ULN. 
• 
If toxicity worsens, then treat as  
described for elevations in the rows 
below. 
If toxicity improves to AST or ALT 
≤5.0×ULN, resume study drug/study 
regimen after completion of steroid taper. 
− 
Regular and frequent checking of LFTs (e.g., every 1 to 3 days) 
until elevations of these are improving or resolved. 
− 
Recommend consult hepatologist; consider abdominal 
ultrasound, including Doppler assessment of liver perfusion. 
− 
Consider, as necessary, discussing with study physician. 
− 
If event is persistent (>3 to 5 days) or worsens, and investigator 
suspects toxicity to be immune-mediated AE, recommend to 
start prednisone 1 to 2 mg/kg/day PO or IV equivalent. 
− 
If still no improvement within 3 to 5 days despite 1 to 
2 mg/kg/day of prednisone PO or IV equivalent, consider 
additional workup and treatment with IV methylprednisolone 2 
to 4 mg/kg/day. 
− 
If still no improvement within 3 to 5 days despite 2 to 
4 mg/kg/day of IV methylprednisolone, consider additional 
abdominal workup (including liver biopsy) and imaging (i.e., 
liver ultrasound), and consider starting immunosuppressives 
(i.e., mycophenolate mofetil).a Discuss with study physician if 
mycophenolate mofetil is not available. Infliximab should 
NOT be used. 
 
 
Isolated AST or ALT 
>8.0×ULN and 
≤20.0×ULN, if normal 
at baseline 
 
Isolated AST or ALT 
>12.5×ULN and 
≤20.0×ULN, if  
elevated >ULN at 
baseline 
 
• Hold study drug/study regimen dose 
until resolution to  AST or ALT 
≤5.0×ULN 
• Resume study drug/study regimen if 
elevations downgrade to AST or ALT 
≤5.0×ULN within 14 days and after 
completion of steroid taper. 
• Permanently discontinue study 
drug/study regimen if the elevations 
do not downgrade to AST or ALT 
≤5.0×ULN within 14 days 
Permanently discontinue study drug/study 
regimen for any case meeting Hy’s law 
criteria, in the absence of any alternative 
cause.b 
− 
Regular and frequent checking of LFTs (e.g., every 1-2 days) 
until elevations of these are improving or resolved. 
− 
Consult hepatologist (unless investigator is hepatologist); 
obtain abdominal ultrasound, including Doppler assessment of 
liver perfusion; and consider liver biopsy. 
− 
Consider, as necessary, discussing with study physician. 
− 
If investigator suspects toxicity to be immune-mediated, 
promptly initiate empiric IV methylprednisolone at 1 to 
4 mg/kg/day or equivalent. 
− 
If no improvement within 3 to 5 days despite 1 to 4 mg/kg/day 
methylprednisolone IV or equivalent, obtain liver biopsy (if it 
has not been done already) and promptly start treatment with 
immunosuppressive therapy (mycophenolate mofetil). Discuss 
with study physician if mycophenolate is not available. 
Infliximab should NOT be used. 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, and 
anti-PCP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections).a 
 


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Isolated AST or ALT 
>20×ULN,  whether 
normal or elevated at 
baseline 
 
Permanently discontinue study drug/study 
regimen. 
 
Same as above  
(except would recommend obtaining liver biopsy early) 
 
 
If transaminase rise is not isolated but (at any time) occurs in setting of either increasing total/direct bilirubin (≥1.5×ULN, if normal at baseline; or 2×baseline, if 
>ULN at baseline) or signs of DILI/liver decompensation (e.g., fever, elevated INR): 
- 
Manage dosing for  each level of transaminase rise as instructed for the next highest level of transaminase riseFor example, manage dosing for second level of 
transaminase rise (i.e.,  AST or ALT >5.0×ULN and ≤8.0×ULN, if normal at baseline, or AST or ALT >2.0×baseline and ≤12.5×ULN, if elevated >ULN at 
baseline) as instructed for the third level of transaminase rise (i.e., AST or ALT >8.0×ULN and ≤20.0×ULN, if normal at baseline, or AST or ALT 
>12.5×ULN and ≤20.0×ULN, if  elevated >ULN at baseline) 
- 
For the third and fourth levels of transaminase rises, permanently discontinue study drug/study regimen 
 
Nephritis or renal 
dysfunction 
(elevated serum 
creatinine) 
Any Grade 
General Guidance 
For Any Grade: 
− 
Consult with nephrologist. 
− 
Monitor for signs and symptoms that may be related to changes 
in renal function (e.g., routine urinalysis, elevated serum BUN 
and creatinine, decreased creatinine clearance, electrolyte 
imbalance, decrease in urine output, or proteinuria). 
− 
Patients should be thoroughly evaluated to rule out any 
alternative etiology (e.g., disease progression or infections). 
− 
Steroids should be considered in the absence of clear 
alternative etiology even for low-grade events (Grade 2), in 
order to prevent potential progression to higher grade event. 
 
 


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Grade 1 
(Serum creatinine > 1 
to 1.5×baseline;  
> ULN to 1.5×ULN) 
No dose modifications. 
For Grade 1: 
− 
Monitor serum creatinine weekly and any accompanying 
symptoms. 
• 
If creatinine returns to baseline, resume its regular 
monitoring per study protocol. 
• 
If creatinine worsens, depending on the severity, treat 
as Grade 2, 3, or 4. 
− 
Consider symptomatic treatment, including hydration, 
electrolyte replacement, and diuretics. 
Grade 2 
(serum creatinine >1.5 
to 3.0×baseline; >1.5 to 
3.0×ULN) 
Hold study drug/study regimen until 
resolution to Grade ≤1 or baseline.  
• 
If toxicity worsens, then treat as 
Grade 3 or 4. 
• 
If toxicity improves to Grade ≤1 or 
baseline, then resume study 
drug/study regimen after completion 
of steroid taper. 
For Grade 2: 
− 
Consider symptomatic treatment, including hydration, 
electrolyte replacement, and diuretics. 
− 
Carefully monitor serum creatinine every 2 to 3 days and as 
clinically warranted. 
− 
Consult nephrologist and consider renal biopsy if clinically 
indicated. 
− 
If event is persistent (>3 to 5 days) or worsens, promptly start 
prednisone 1 to 2 mg/kg/day PO or IV equivalent. 
− 
If event is not responsive within 3 to 5 days or worsens despite 
prednisone at 1 to 2 mg/kg/day PO or IV equivalent, additional 
workup should be considered and prompt treatment with IV 
methylprednisolone at 2 to 4 mg/kg/day started. 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, and 
anti-PJP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections).a 
− 
When event returns to baseline, resume study drug/study 
regimen and routine serum creatinine monitoring per study 
protocol. 
Grade 3 or 4 
(Grade 3: serum 
creatinine 
>3.0×baseline; >3.0 to 
6.0×ULN) 
 
Permanently discontinue study drug/study 
regimen. 
For Grade 3 or 4: 
− 
Carefully monitor serum creatinine on daily basis. 
− 
Consult nephrologist and consider renal biopsy if clinically 
indicated. 
− 
Promptly start prednisone 1 to 2 mg/kg/day PO or IV 
equivalent. 
− 
If event is not responsive within 3 to 5 days or worsens despite 
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(Grade 4: serum 
creatinine >6.0×ULN) 
workup should be considered and prompt treatment with IV 
methylprednisolone 2 to 4 mg/kg/day started. 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, and 
anti-PJP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections).a 
 
 
Rash or Dermatitis 
(including Pemphigoid) 
Any Grade 
(refer to NCI CTCAE 
v 4.03 for definition of 
severity/grade 
depending on type of 
skin rash) 
General Guidance 
For Any Grade: 
− 
Monitor for signs and symptoms of dermatitis (rash and 
pruritus). 
− 
IF THERE IS ANY BULLOUS FORMATION, THE STUDY 
PHYSICIAN SHOULD BE CONTACTED AND STUDY 
DRUG DISCONTINUED IF SUSPECT STEVENS-
JOHNSON SYNDROME OR TOXIC EPIDERMAL 
NECROLYSIS. 
Grade 1 
No dose modifications. 
For Grade 1: 
− 
Consider symptomatic treatment, including oral antipruritics 
(e.g., diphenhydramine or hydroxyzine) and topical therapy 
(e.g., urea cream). 
Grade 2 
For persistent (>1 to 2 weeks) Grade 2 
events, hold scheduled study drug/study 
regimen until resolution to Grade ≤1 or 
baseline. 
• 
If toxicity worsens, then treat as 
Grade 3. 
• 
If toxicity improves to Grade ≤1 or 
baseline, then resume drug/study 
regimen after completion of steroid 
taper. 
For Grade 2: 
− 
Obtain Dermatology consult. 
− 
Consider symptomatic treatment, including oral antipruritics 
(e.g., diphenhydramine or hydroxyzine) and topical therapy 
(e.g., urea cream). 
− 
Consider moderate-strength topical steroid. 
− 
If no improvement of rash/skin lesions occurs within 3 to 
5 days or is worsening despite symptomatic treatment and/or 
use of moderate strength topical steroid, consider, as necessary, 
discussing with study physician and promptly start systemic 
steroids such as prednisone 1 to 2 mg/kg/day PO or IV 
equivalent. 
− 
Consider skin biopsy if the event is persistent for >1 to 2 weeks 
or recurs. 
 
 


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Grade 3 or 4 
For Grade 3: 
Hold study drug/study regimen until 
resolution to Grade ≤1 or baseline. 
If temporarily holding the study 
drug/study regimen does not provide 
improvement of the Grade 3 skin rash to 
Grade ≤1 or baseline within 30 days, then 
permanently discontinue study drug/study 
regimen. 
 
For Grade 4: 
Permanently discontinue study drug/study 
regimen. 
 
For Grade 3 or 4: 
− 
Consult Dermatology. 
− 
Promptly initiate empiric IV methylprednisolone 1 to 
4 mg/kg/day or equivalent. 
− 
Consider hospitalization. 
− 
Monitor extent of rash [Rule of Nines]. 
− 
Consider skin biopsy (preferably more than 1) as clinically 
feasible. 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, and 
anti-PJP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections).a 
− 
Consider, as necessary, discussing with study physician. 
Endocrinopathy 
(e.g., hyperthyroidism, 
thyroiditis, 
hypothyroidism, Type 1 
diabetes mellitus, 
hypophysitis, 
hypopituitarism, and 
adrenal insufficiency; 
exocrine event of 
amylase/lipase increased 
also included in this 
section) 
 
Any Grade 
(depending on the type 
of endocrinopathy, 
refer to NCI CTCAE 
v4.03 for defining the 
CTC grade/severity) 
General Guidance 
For Any Grade: 
− 
Consider consulting an endocrinologist for endocrine events. 
− 
Consider, as necessary, discussing with study physician. 
− 
Monitor patients for signs and symptoms of endocrinopathies. 
Non-specific symptoms include headache, fatigue, behavior 
changes, changed mental status, vertigo, abdominal pain, 
unusual bowel habits, polydipsia, polyuria, hypotension, and 
weakness. 
− 
Patients should be thoroughly evaluated to rule out any 
alternative etiology (e.g., disease progression including brain 
metastases, or infections). 
− 
Depending on the suspected endocrinopathy, monitor and 
evaluate thyroid function tests: TSH, free T3 and free T4 and 
other relevant endocrine and related labs (e.g., blood glucose 
and ketone levels, HgA1c). 
− 
For asymptomatic elevations in serum amylase and lipase 
>ULN and <3×ULN, corticosteroid treatment is not indicated 
as long as there are no other signs or symptoms of pancreatic 
inflammation. 
− 
If a patient experiences an AE that is thought to be possibly of 
autoimmune nature (e.g., thyroiditis, pancreatitis, hypophysitis, 


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or diabetes insipidus), the investigator should send a blood 
sample for appropriate autoimmune antibody testing. 
 
Grade 1 
No dose modifications. 
For Grade 1 (including those with asymptomatic TSH elevation): 
− 
Monitor patient with appropriate endocrine function tests. 
− 
For suspected hypophysitis/hypopituitarism, consider 
consultation of an endocrinologist to guide assessment of early-
morning ACTH, cortisol, TSH and free T4; also consider 
gonadotropins, sex hormones, and prolactin levels, as well as 
cosyntropin stimulation test (though it may not be useful in 
diagnosing early secondary adrenal insufficiency). 
− 
If TSH < 0.5 × LLN, or TSH >2 × ULN, or consistently out of 
range in 2 subsequent measurements, include free T4 at 
subsequent cycles as clinically indicated and consider 
consultation of an endocrinologist. 
Grade 2 
For Grade 2 endocrinopathy other than 
hypothyroidism and Type 1 diabetes 
mellitus, hold study drug/study regimen 
dose until patient is clinically stable. 
• 
If toxicity worsens, then treat as 
Grade 3 or Grade 4. 
Study drug/study regimen can be resumed 
once event stabilizes and after completion 
of steroid taper. 
Patients with endocrinopathies who may 
require prolonged or continued steroid 
replacement (e.g., adrenal insufficiency) 
can be retreated with study drug/study 
regimen on the following conditions: 
1. 
The event stabilizes and is 
controlled. 
2. 
The patient is clinically stable as per 
investigator or treating physician’s 
clinical judgement. 
3. 
Doses of prednisone are ≤10 mg/day 
or equivalent. 
For Grade 2 (including those with symptomatic endocrinopathy): 
− 
Consult endocrinologist to guide evaluation of endocrine 
function and, as indicated by suspected endocrinopathy and as 
clinically indicated, consider pituitary scan. 
− 
For all patients with abnormal endocrine work up, except those 
with isolated hypothyroidism or Type 1 DM, and as guided by 
an endocrinologist, consider short-term corticosteroids (e.g., 1 
to 2 mg/kg/day methylprednisolone or IV equivalent) and 
prompt initiation of treatment with relevant hormone 
replacement (e.g., hydrocortisone, sex hormones). 
− 
Isolated hypothyroidism may be treated with replacement 
therapy, without study drug/study regimen interruption, and 
without corticosteroids. 
− 
Isolated Type 1 diabetes mellitus (DM) may be treated with 
appropriate diabetic therapy, without study drug/study regimen 
interruption, and without corticosteroids. 
− 
Once patients on steroids are improving, gradually taper  
immunosuppressive steroids (as appropriate and with guidance 
of endocrinologist) over ≥28 days and consider prophylactic 
antibiotics, antifungals, and anti-PJP treatment (refer to current 
NCCN guidelines for treatment of cancer-related infections).a 
− 
For patients with normal endocrine workup (laboratory 
assessment or MRI scans), repeat laboratory assessments/MRI 
as clinically indicated. 


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Grade 3 or 4 
For Grade 3 or 4 endocrinopathy other 
than hypothyroidism and Type 1 diabetes 
mellitus, hold study drug/study regimen 
dose until endocrinopathy symptom(s) are 
controlled.  
Study drug/study regimen can be resumed 
once event stabilizes and after completion 
of steroid taper. 
Patients with endocrinopathies who may 
require prolonged or continued steroid 
replacement (e.g., adrenal insufficiency) 
can be retreated with study drug/study 
regimen on the following conditions: 
1. 
The event stabilizes and is 
controlled. 
2. 
The patient is clinically stable as per 
investigator or treating physician’s 
clinical judgement. 
3. 
Doses of prednisone are ≤10 mg/day 
or equivalent. 
For Grade 3 or 4: 
− 
Consult endocrinologist to guide evaluation of endocrine 
function and, as indicated by suspected endocrinopathy and as 
clinically indicated, consider pituitary scan. Hospitalization 
recommended. 
− 
For all patients with abnormal endocrine work up, except those 
with isolated hypothyroidism or Type 1 DM, and as guided by 
an  endocrinologist, promptly initiate empiric IV 
methylprednisolone 1 to 2 mg/kg/day or equivalent, as well as 
relevant hormone replacement (e.g., hydrocortisone, sex 
hormones). 
− 
For adrenal crisis, severe dehydration, hypotension, or shock, 
immediately initiate IV corticosteroids with mineralocorticoid 
activity. 
− 
Isolated hypothyroidism may be treated with replacement 
therapy, without study drug/study regimen interruption, and 
without corticosteroids. 
− 
Isolated Type 1 diabetes mellitus may be treated with 
appropriate diabetic therapy, without study drug/study regimen 
interruption, and without corticosteroids. 
− 
Once patients on steroids are improving, gradually taper 
immunosuppressive steroids (as appropriate and with guidance 
of endocrinologist) over ≥28 days and consider prophylactic 
antibiotics, antifungals, and anti-PJP treatment (refer to current 
NCCN guidelines for treatment of cancer-related infections).a 
 
Neurotoxicity 
(to include but not be 
limited to limbic 
encephalitis and 
autonomic neuropathy, 
excluding Myasthenia 
Gravis and Guillain-
Barre) 
Any Grade 
(depending on the type 
of neurotoxicity, refer 
to NCI CTCAE v4.03 
for defining the CTC 
grade/severity) 
General Guidance 
For Any Grade: 
− 
Patients should be evaluated to rule out any alternative etiology 
(e.g., disease progression, infections, metabolic syndromes, or 
medications). 
− 
Monitor patient for general symptoms (headache, nausea, 
vertigo, behavior change, or weakness). 
− 
Consider appropriate diagnostic testing (e.g., electromyogram 
and nerve conduction investigations). 
− 
Perform symptomatic treatment with Neurology consult as 
appropriate. 
− 
 


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Grade 1 
No dose modifications. 
For Grade 1: 
− 
See “Any Grade” recommendations above. 
Grade 2 
For acute motor neuropathies or 
neurotoxicity, hold study drug/study 
regimen dose until resolution to Grade ≤1. 
For sensory neuropathy/neuropathic pain, 
consider holding study drug/study 
regimen dose until resolution to Grade ≤1. 
If toxicity worsens, then treat as 
Grade 3 or 4. 
Study drug/study regimen can be resumed 
once event improves to Grade ≤1 and 
after completion of steroid taper. 
For Grade 2: 
− 
Consider, as necessary, discussing with the study physician. 
− 
Obtain Neurology consult. 
− 
Sensory neuropathy/neuropathic pain may be managed by 
appropriate medications (e.g., gabapentin or duloxetine). 
− 
Promptly start systemic steroids prednisone 1 to 2 mg/kg/day 
PO or IV equivalent. 
− 
If no improvement within 3 to 5 days despite 1 to 2 mg/kg/day 
prednisone PO or IV equivalent, consider additional workup 
and promptly treat with additional immunosuppressive therapy 
(e.g., IV IG). 
Grade 3 or 4 
For Grade 3: 
Hold study drug/study regimen dose until 
resolution to Grade ≤1. 
Permanently discontinue study drug/study 
regimen if Grade 3 imAE does not resolve 
to Grade ≤1 within 30 days. 
 
For Grade 4: 
Permanently discontinue study drug/study 
regimen. 
For Grade 3 or 4: 
− 
Consider, as necessary, discussing with study physician. 
− 
Obtain Neurology consult. 
− 
Consider hospitalization. 
− 
Promptly initiate empiric IV methylprednisolone 1 to 
2 mg/kg/day or equivalent. 
− 
If no improvement within 3 to 5 days despite IV 
corticosteroids, consider additional workup and promptly treat 
with additional immunosuppressants (e.g., IV IG). 
− 
Once stable, gradually taper steroids over ≥28 days. 
Peripheral neuromotor 
syndromes 
(such as Guillain-Barre 
and myasthenia gravis) 
Any Grade 
General Guidance 
For Any Grade: 
− 
The prompt diagnosis of immune-mediated peripheral 
neuromotor syndromes is important, since certain patients may 
unpredictably experience acute decompensations that can result 
in substantial morbidity or in the worst case, death. Special care 
should be taken for certain sentinel symptoms that may predict 
a more severe outcome, such as prominent dysphagia, rapidly 


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progressive weakness, and signs of respiratory insufficiency or 
autonomic instability. 
− 
Patients should be evaluated to rule out any alternative etiology 
(e.g., disease progression, infections, metabolic syndromes or 
medications). It should be noted that the diagnosis of immune-
mediated peripheral neuromotor syndromes can be particularly 
challenging in patients with underlying cancer, due to the 
multiple potential confounding effects of cancer (and its 
treatments) throughout the neuraxis. Given the importance of 
prompt and accurate diagnosis, it is essential to have a low 
threshold to obtain a Neurology consult. 
− 
Neurophysiologic diagnostic testing (e.g., electromyogram and 
nerve conduction investigations, and “repetitive stimulation” if 
myasthenia is suspected) are routinely indicated upon suspicion 
of such conditions and may be best facilitated by means of a 
Neurology consultation. 
− 
It is important to consider that the use of steroids as the primary 
treatment of Guillain-Barre is not typically considered 
effective. Patients requiring treatment should be started with IV 
IG and followed by plasmapheresis if not responsive to IV IG. 
 
Grade 1 
No dose modifications. 
For Grade 1: 
− 
Consider, as necessary, discussing with the study physician. 
− 
Care should be taken to monitor patients for sentinel symptoms 
of a potential decompensation as described above. 
− 
Obtain a Neurology consult. 
Grade 2 
Hold study drug/study regimen dose until 
resolution to Grade ≤1. 
Permanently discontinue study drug/study 
regimen if it does not resolve to Grade ≤1 
within 30 days or if there are signs of 
respiratory insufficiency or autonomic 
instability. 
For Grade 2: 
− 
Consider, as necessary, discussing with the study physician. 
− 
Care should be taken to monitor patients for sentinel symptoms 
of a potential decompensation as described above. 
− 
Obtain a Neurology consult 
− 
Sensory neuropathy/neuropathic pain may be managed by 
appropriate medications (e.g., gabapentin or duloxetine). 
MYASTHENIA GRAVIS: 
o 
Steroids may be successfully used to treat myasthenia 
gravis. It is important to consider that steroid therapy 
(especially with high doses) may result in transient 
worsening of myasthenia and should typically be 


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administered in a monitored setting under supervision 
of a consulting neurologist. 
o 
Patients unable to tolerate steroids may be candidates 
for treatment with plasmapheresis or IV IG. Such 
decisions are best made in consultation with a 
neurologist, taking into account the unique needs of 
each patient. 
o 
If myasthenia gravis-like neurotoxicity is present, 
consider starting AChE inhibitor therapy in addition 
to steroids. Such therapy, if successful, can also serve 
to reinforce the diagnosis. 
GUILLAIN-BARRE: 
o 
It is important to consider here that the use of steroids 
as the primary treatment of Guillain-Barre is not 
typically considered effective. 
o 
Patients requiring treatment should be started with IV 
IG and followed by plasmapheresis if not responsive 
to IV IG. 
 
Grade 3 or 4 
For Grade 3: 
Hold study drug/study regimen dose until 
resolution to Grade ≤1. 
Permanently discontinue study drug/study 
regimen if Grade 3 imAE does not resolve 
to Grade ≤1 within 30 days or if there are 
signs of respiratory insufficiency or 
autonomic instability. 
 
For Grade 4: 
Permanently discontinue study drug/study 
regimen. 
For Grade 3 or 4 (severe or life-threatening events): 
− 
Consider, as necessary, discussing with study physician. 
− 
Recommend hospitalization. 
− 
Monitor symptoms and obtain Neurology consult. 
MYASTHENIA GRAVIS: 
o 
Steroids may be successfully used to treat myasthenia 
gravis. They should typically be administered in a 
monitored setting under supervision of a consulting 
neurologist. 
o 
Patients unable to tolerate steroids may be candidates 
for treatment with plasmapheresis or IV IG. 
o 
If myasthenia gravis-like neurotoxicity present, 
consider starting AChE inhibitor therapy in addition 
to steroids. Such therapy, if successful, can also serve 
to reinforce the diagnosis. 
GUILLAIN-BARRE: 
o 
It is important to consider here that the use of steroids 
as the primary treatment of Guillain-Barre is not 
typically considered effective. 


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o 
Patients requiring treatment should be started with IV 
IG and followed by plasmapheresis if not responsive 
to IV IG. 
 
Myocarditis 
Any Grade 
General Guidance 
Discontinue drug permanently if biopsy-
proven immune-mediated myocarditis. 
For Any Grade: 
− 
The prompt diagnosis of immune-mediated myocarditis is 
important, particularly in patients with baseline 
cardiopulmonary disease and reduced cardiac function.  
− 
Consider, as necessary, discussing with the study physician. 
− 
Monitor patients for signs and symptoms of myocarditis (new 
onset or worsening chest pain, arrhythmia, shortness of breath, 
peripheral edema). As some symptoms can overlap with lung 
toxicities, simultaneously evaluate for and rule out pulmonary 
toxicity as well as other causes (e.g., pulmonary embolism, 
congestive heart failure, malignant pericardial effusion). A 
Cardiology consultation should be obtained early, with prompt 
assessment of whether and when to complete a cardiac biopsy, 
including any other diagnostic procedures. 
− 
Initial work-up should include clinical evaluation, BNP, 
cardiac enzymes, ECG, echocardiogram (ECHO), monitoring 
of oxygenation via pulse oximetry (resting and exertion), and 
additional laboratory work-up as indicated. Spiral CT or 
cardiac MRI can complement ECHO to assess wall motion 
abnormalities when needed. 
− 
Patients should be thoroughly evaluated to rule out any 
alternative etiology (e.g., disease progression, other 
medications, or infections) 
 
Grade 1 
(asymptomatic with 
laboratory [e.g., BNP] 
or cardiac imaging 
abnormalities) 
No dose modifications required unless 
clinical suspicion is high, in which case 
hold study drug/study regimen dose 
during diagnostic work-up for other 
etiologies. If study drug/study regimen is 
held, resume after complete resolution to 
Grade 0. 
For Grade 1 (no definitive findings): 
- 
Monitor and closely follow up in 2 to 4 days for clinical 
symptoms,  BNP, cardiac enzymes, ECG, ECHO, pulse oximetry 
(resting and exertion), and laboratory work-up as clinically 
indicated. 
- 
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Grade 2, 3 or 4 
(Grade 2: Symptoms 
with mild to moderate 
activity or exertion) 
 
 (Grade 3: Severe with 
symptoms at rest or 
with minimal activity 
or exertion; 
intervention indicated) 
 
(Grade 4: Life-
threatening 
consequences; urgent 
intervention indicated 
(e.g., continuous IV 
therapy or mechanical 
hemodynamic support)) 
 
- If Grade 2 -- Hold study drug/study 
regimen dose until resolution to 
Grade 0. If toxicity rapidly improves to 
Grade 0, then the decision to reinitiate 
study drug/study regimen will be based 
upon treating physician’s clinical 
judgment and after completion of 
steroid taper. If toxicity does not 
rapidly improve, permanently. 
discontinue study drug/study regimen. 
If Grade 3-4, permanently discontinue 
study drug/study regimen. 
For Grade 2-4: 
− 
Monitor symptoms daily, hospitalize. 
− 
Promptly start IV methylprednisolone 2 to 4 mg/kg/day or 
equivalent after Cardiology consultation has determined 
whether and when to complete diagnostic procedures including 
a cardiac biopsy. 
− 
Supportive care (e.g., oxygen). 
− 
If no improvement within 3 to 5 days despite IV 
methylprednisolone at 2 to 4 mg/kg/day, promptly start 
immunosuppressive therapy such as TNF inhibitors 
(e.g., infliximab at 5 mg/kg every 2 weeks). Caution: It is 
important to rule out sepsis and refer to infliximab label for 
general guidance before using infliximab. 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, or 
anti-PJP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections).a 
Myositis/Polymyositis 
(“Poly/myositis”) 
Any Grade 
General Guidance 
For Any Grade: 
− 
Monitor patients for signs and symptoms of poly/myositis. 
Typically, muscle weakness/pain occurs in proximal muscles 
including upper arms, thighs, shoulders, hips, neck and back, 
but rarely affects the extremities including hands and fingers; 
also difficulty breathing and/or trouble swallowing can occur 
and progress rapidly. Increased general feelings of tiredness 
and fatigue may occur, and there can be new-onset falling, 
difficulty getting up from a fall, and trouble climbing stairs, 
standing up from a seated position, and/or reaching up. 
− 
If poly/myositis is suspected, a Neurology consultation should 
be obtained early, with prompt guidance on diagnostic 
procedures. Myocarditis may co-occur with poly/myositis; 
refer to guidance under Myocarditis. Given breathing 
complications, refer to guidance under Pneumonitis/ILD.  


Abbreviated Title: Pexa-Vec Colorectal Ca 
 
Version Date: 06/15/2020 
108 
 
Given possibility of an existent (but previously unknown) 
autoimmune disorder, consider Rheumatology consultation. 
− 
Consider, as necessary, discussing with the study physician. 
− 
Initial work-up should include clinical evaluation, creatine 
kinase, aldolase, LDH, BUN/creatinine, erythrocyte 
sedimentation rate or C-reactive protein level, urine myoglobin, 
and additional laboratory work-up as indicated, including a 
number of possible rheumatological/antibody tests (i.e., 
consider whether a rheumatologist consultation is indicated and 
could guide need for rheumatoid factor, antinuclear antibody, 
anti-smooth muscle, antisynthetase [such as anti-Jo-1], and/or 
signal-recognition particle antibodies). Confirmatory testing 
may include electromyography, nerve conduction studies, MRI 
of the muscles, and/or a muscle biopsy. Consider Barium 
swallow for evaluation of dysphagia or dysphonia. 
Patients should be thoroughly evaluated to rule out any alternative 
etiology (e.g., disease progression, other medications, or infections). 
 
Grade 1 
(mild pain) 
- No dose modifications. 
For Grade 1: 
− 
Monitor and closely follow up in 2 to 4 days for clinical 
symptoms and initiate evaluation as clinically indicated. 
− 
Consider Neurology consult. 
− 
Consider, as necessary, discussing with the study physician. 
 
Grade 2 
(moderate pain 
associated with 
weakness; pain limiting 
instrumental activities 
of daily living [ADLs]) 
Hold study drug/study regimen dose until 
resolution to Grade ≤1. 
- Permanently discontinue study 
drug/study regimen if it does not 
resolve to Grade ≤1 within 30 days or 
if there are signs of respiratory 
insufficiency. 
For Grade 2: 
− 
Monitor symptoms daily and consider hospitalization. 
− 
Obtain Neurology consult, and initiate evaluation. 
− 
Consider, as necessary, discussing with the study physician. 
− 
If clinical course is rapidly progressive (particularly if 
difficulty breathing and/or trouble swallowing), promptly start 
IV methylprednisolone 2 to 4 mg/kg/day systemic steroids 
along with receiving input from Neurology consultant  
− 
If clinical course is not rapidly progressive, start systemic 
steroids (e.g., prednisone 1 to 2 mg/kg/day PO or IV 
equivalent); if no improvement within 3 to 5 days, continue 
additional work up and start treatment with IV 
methylprednisolone 2 to 4 mg/kg/day 
− 
If after start of IV methylprednisolone at 2 to 4 mg/kg/day 
there is no improvement within 3 to 5 days, consider start of 
immunosuppressive therapy such as TNF inhibitors 


Abbreviated Title: Pexa-Vec Colorectal Ca 
 
Version Date: 06/15/2020 
109 
 
aASCO Educational Book 2015 “Managing Immune Checkpoint Blocking Antibody Side Effects” by Michael Postow MD. 
bFDA Liver Guidance Document 2009 Guidance for Industry: Drug Induced Liver Injury – Premarketing Clinical Evaluation. 
AChE Acetylcholine esterase; ADL Activities of daily living; AE Adverse event; ALP Alkaline phosphatase test; ALT Alanine aminotransferase; AST Aspartate aminotransferase; 
BUN Blood urea nitrogen; CT Computed tomography; CTCAE Common Terminology Criteria for Adverse Events; ILD Interstitial lung disease; imAE immune-mediated 
adverse event; IG Immunoglobulin; IV Intravenous; GI Gastrointestinal; LFT Liver function tests; LLN Lower limit of normal; MRI  Magnetic resonance imaging; NCI  
National Cancer Institute; NCCN  National Comprehensive Cancer Network; PJP Pneumocystis jirovecii pneumonia (formerly known as Pneumocystis carinii pneumonia); 
PO  By mouth; T3  Triiodothyronine; T4 Thyroxine; TB Total bilirubin; TNF Tumor necrosis factor; TSH Thyroid-stimulating hormone; ULN Upper limit of normal. 
 
 
(e.g., infliximab at 5 mg/kg every 2 weeks). Caution: It is 
important to rule out sepsis and refer to infliximab label for 
general guidance before using infliximab. 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, or 
anti-PJP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections).a 
 
Grade 3 or 4 
(pain associated with 
severe weakness; 
limiting self-care 
ADLs) 
For Grade 3: 
Hold study drug/study regimen dose until 
resolution to Grade ≤1. 
Permanently discontinue study drug/study 
regimen if Grade 3 imAE does not resolve 
to Grade ≤1 within 30 days or if there are 
signs of respiratory insufficiency. 
 
For Grade 4: 
- Permanently discontinue study 
drug/study regimen. 
For Grade 3 or 4 (severe or life-threatening events): 
− 
Monitor symptoms closely; recommend hospitalization. 
− 
Obtain Neurology consult, and complete full evaluation. 
− 
Consider, as necessary, discussing with the study physician. 
− 
Promptly start IV methylprednisolone 2 to 4 mg/kg/day 
systemic steroids along with receiving input from Neurology 
consultant. 
− 
If after start of IV methylprednisolone at 2 to 4 mg/kg/day 
there is no improvement within 3 to 5 days, consider start of 
immunosuppressive therapy such as TNF inhibitors 
(e.g., infliximab at 5 mg/kg every 2 weeks). Caution: It is 
important to rule out sepsis and refer to infliximab label for 
general guidance before using infliximab. 
− 
Consider whether patient may require IV IG, plasmapheresis. 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, or 
anti-PJP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections).a 


Abbreviated Title: Pexa-Vec Colorectal Ca 
 
Version Date: 06/15/2020 
110 
 
Infusion-Related Reactions 
Severity Grade of the 
Event (NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
Any Grade 
General Guidance 
For Any Grade: 
− 
Manage per institutional standard at the discretion of investigator. 
− 
Monitor patients for signs and symptoms of infusion-related 
reactions (e.g., fever and/or shaking chills, flushing and/or itching, 
alterations in heart rate and blood pressure, dyspnea or chest 
discomfort, or skin rashes) and anaphylaxis (e.g., generalized 
urticaria, angioedema, wheezing, hypotension, or tachycardia). 
Grade 1 or 2 
For Grade 1: 
The infusion rate of study drug/study regimen may be decreased 
by 50% or temporarily interrupted until resolution of the event. 
 
For Grade 2: 
The infusion rate of study drug/study regimen may be decreased 
50% or temporarily interrupted until resolution of the event. 
Subsequent infusions may be given at 50% of the initial 
infusion rate. 
For Grade 1 or 2: 
− 
Acetaminophen and/or antihistamines may be administered per 
institutional standard at the discretion of the investigator. 
− 
Consider premedication per institutional standard prior to 
subsequent doses. 
− 
Steroids should not be used for routine premedication of Grade ≤2 
infusion reactions. 
Grade 3 or 4 
For Grade 3 or 4: 
Permanently discontinue study drug/study regimen. 
For Grade 3 or 4: 
− 
Manage severe infusion-related reactions per institutional 
standards (e.g., IM epinephrine, followed by IV diphenhydramine 
and ranitidine, and IV glucocorticoid). 
CTCAE Common Terminology Criteria for Adverse Events; IM intramuscular; IV intravenous; NCI National Cancer Institute. 
 
 
 


Abbreviated Title: Pexa-Vec Colorectal Ca 
 
Version Date: 06/15/2020 
111 
 
Non–Immune-Mediated Reactions 
Severity Grade of the Event 
(NCI CTCAE version 4.03) 
Dose Modifications 
Toxicity Management 
Any Grade 
Note: Dose modifications are not required for AEs not deemed to 
be related to study treatment (i.e., events due to underlying 
disease) or for laboratory abnormalities not deemed to be 
clinically significant. 
Treat accordingly, as per institutional standard. 
Grade 1 
No dose modifications. 
Treat accordingly, as per institutional standard. 
Grade 2 
Hold study drug/study regimen until resolution to ≤Grade 1 or 
baseline. 
Treat accordingly, as per institutional standard. 
Grade 3 
Hold study drug/study regimen until resolution to ≤Grade 1 or 
baseline. 
For AEs that downgrade to ≤Grade 2 within 7 days or resolve to 
≤Grade 1 or baseline within 14 days, resume study drug/study 
regimen administration. Otherwise, discontinue study drug/study 
regimen. 
Treat accordingly, as per institutional standard. 
Grade 4 
 
Discontinue study drug/study regimen (Note: For Grade 4 labs, 
decision to discontinue should be based on accompanying 
clinical signs/symptoms, the Investigator’s clinical judgment, and 
consultation with the Sponsor.). 
Treat accordingly, as per institutional standard. 
Note: As applicable, for early phase studies, the following sentence may be added: “Any event greater than or equal to Grade 2, please discuss with Study Physician.” 
AE Adverse event; CTCAE Common Terminology Criteria for Adverse Events; NCI National Cancer Institute. 
 
 
 
 
 


Abbreviated Title: Pexa-Vec Colorectal Ca 
 
Version Date: 06/15/2020 
112 
 
15.3 Appendix C: Modified immune-related response criteria (irRC) 
This new classification is based on the recent learning from clinical studies with cancer 
immunotherapies that even if some new lesions appear at the beginning of a treatment or if the 
total tumor burden does not increase substantially, tumor regressions or stabilizations might still 
occur later. The irRC were created using bi-dimensional measurements (as previously widely used 
in the World Health Organization criteria). For this trial, the concepts of the irRC are combined 
with RECIST 1.1 to come up with the modified irRC.  
For modified irRC, only target and measurable lesions are taken into account. In contrast to the 
RECIST 1.1 criteria, the modified irRC criteria (a) require confirmation of both progression and 
response by imaging at 6 weeks after initial imaging and (b) do not necessarily score the 
appearance of new lesions as progressive disease if the sum of lesion diameters of target lesions 
(minimum of 10 mm per lesion, maximum of 5 target lesions, maximum of 2 per organ) and 
measurable new lesions does not increase by ≥ 20%.  
The same method of assessment and the same technique should be used to characterize each 
identified and reported target lesion(s) at baseline, during the trial, and at the end of trial visit. All 
measurements should be recorded in metric notation. The modified irRC based on RECIST 1.1 are 
displayed below.  
 
 
 
 
Overall Responses Derived from Changes in Index, Non-Index, and New Lesions 
 


Abbreviated Title: Pexa-Vec Colorectal Ca 
 
Version Date: 06/15/2020 
113 
 
 
 
 
 


Abbreviated Title: Pexa-Vec Colorectal Ca 
 
Version Date: 06/15/2020 
114 
 
15.4 Appendix D: List of Adverse Events related to study treatment before amendment D  
Events 
DL1 (N=3) DL2 (N=12)  
#1 #2 #3 #4 #5 #6 
#7 #8 
#9 #10 #11 #12 #13 #14 #15 #16 
Fever 
3 
2 
3 
3 
3 
2 
2 
1 
2 
3 
3 
2 
3 
2 
2 
Hypotension 
1 
 
2 
2 
1 
2 
1 
2 
1 
 
2 
1 
2 
2 
Chills 
1 
1 
1 
2 
1 
2 
 
2 
2 
2 
1 
1 
2 
Fatigue 
1 
1 
1 
1 
2 
1 
1 
1 
Papulopustular Rash 
 
1 
1 
1 
1 
1 
1 
Sinus Tachycardia 
 
1 
 
 
 
 
2 
1 
 
1 
1 
1 
1 
Vomiting 
 
1 
 
 
 
1 
1 
1 
Nausea 
 
1 
 
 
1 
1 
1 
1 
1 
Flu Like Symptoms 
1 
 
1 
2 
1 
Headache 
1 
 
1 
2 
Nasal Congestion 
 
 
 
 
 
 
 
 
 
 
 
 
1 
1 
Pain 
1 
2 
Constipation 
 
 
 
 
 
 
 
1 
 
 
 
 
Cough 
 
 
 
 
 
 
 
 
 
 
 
 
1 
Cramp 
 
 
 
 
2 
 
 
 
 
 
 
 
Hypertension 
2 
1 
Elevated ALT 
2 
1 
1 
1 
Elevated AST 
2 
1 
1 
1 
Elevated ALP 
2 
1 
1 
Elevated Bilirubin 
1 


Abbreviated Title: Pexa-Vec Colorectal Ca 
 
Version Date: 06/15/2020 
115 
 
Lymphopenia 
1 
 
1 
4 
1 
2 
3 
2 
Neutropenia 
 
3 
1 
Anemia 
2 
2 
1 
1 
2 
3 
1 
Hyperuricemia 
 
1 
 
 
 
 
1 
Decreased platelet count  
 
 
 
 
 
 
 
 
 
 
 
1 
Hyponatremia 
 
1 
1 
 
 
1 
 
 
 
1 
Hypophosphatemia 
2 
Hypomagnesemia 
1 
Hypercalcemia 
 
 
 
 
 
 
 
 
 
 
 
 
1 
Hypoalbuminemia 
2 
1 
Elevated Lipase 
1 
1 
Elevated Amylase 
1 
Increased Creatinine 
2 
 

ICF_001.pdf: 
PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (2)
Version Date: 07/07/2020
Page 1 of 22
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
PRINCIPAL INVESTIGATOR:  Tim Greten, M.D.
STUDY TITLE:
A Phase I/II Study of Pexa-Vec Oncolytic Virus in Combination with 
Immune Checkpoint Inhibition in Refractory Colorectal Cancer
STUDY SITE:
NIH Clinical Center
Cohort: Affected patient 
Consent Version:  07/07/2020. 
WHO DO YOU CONTACT ABOUT THIS STUDY? 
Tim Greten, MD, by phone at 240-760-6114 or email Tim.greten@nih.gov 
This consent form describes a research study and is designed to help you decide if you would like 
to be a part of the research study.  
You are being asked to take part in a research study at the National Institutes of Health (NIH). 
Members of the study team will talk with you about the information described in this document. 
Some people have personal, religious, or ethical beliefs that may limit the kinds of medical or 
research treatments they would want to receive (such as blood transfusions). Take the time needed 
to ask any questions and discuss this study with NIH staff, and with your family, friends, and 
personal health care providers. Taking part in research at the NIH is your choice.
If the individual being asked to participate in this research study is not able to give consent to be 
in this study, you are being asked to give permission for this person as their decision-maker. The 
term “you” refers to you as the decision-maker and/or the individual being asked to participate in 
this research, throughout the remainder of this document. 
IT IS YOUR CHOICE TO TAKE PART IN THE STUDY
You may choose not to take part in this study for any reason. If you join this study, you may change 
your mind and stop participating in the study at any time and for any reason. In either case, you 
will not lose any benefits to which you are otherwise entitled. However, to be seen at the NIH, you 
must be taking part in a study or are being considered for a study. If you do choose to leave the 
study, please inform your study team to ensure a safe withdrawal from the research.  
WHY IS THIS STUDY BEING DONE?
The purpose of this study is to investigate whether the study drugs Pexa-Vec and Durvalumab, 
given with or without Tremelimumab cause your tumor to shrink. We will also look at the safety 
of both combinations.
Pexa-Vec, Durvalumab and Tremelimumab are investigational drugs designed to boost the body’s 
immune system. Investigational means that these drugs alone or in combination have not been 
approved by the US Food and Drug Administration either as a prescription or over the counter 
drug. 
IRB NUMBER: 17C0092
IRB APPROVAL DATE: 07/09/2020


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (2)
Version Date: 07/07/2020
Page 2 of 22
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Pexa-Vec is a genetically inactivated vaccinia virus modified in the lab to kill cancer cells and 
produce human proteins, which helps to activate your immune system. To date, over 360 patients 
in clinical trials, including at least 60 with colon cancer, have been treated with Pexa-Vec with few 
side effects. Clinical studies have also shown reduction in tumor size with no effect on normal 
tissue. 
Durvalumab targets a protein on tumor cells called PDL-1. PDL-1 normally maintains the balance 
of the immune system. In cancer, PDL-1 helps tumors evade detection and elimination by the 
immune system. Durvalumab may increase the immune system’s ability to identify and destroy 
cancer cells. To date Durvalumab has been given to more than 1800 patients as part of ongoing 
studies either alone or in combination with other anti-cancer agents. It is possible that Pexa-Vec 
and Durvalumab will work together to keep the cancer from blocking the immune response against 
the tumor. 
Although Tremelimumab is not approved by the FDA, it has been evaluated in a number of clinical 
studies, and in over 1000 patients. Tremelimumab is similar in how it works to another drug (called 
ipilimumab) which was recently approved by the FDA. Tremelimumab has been tested in a small 
group of patients with pancreatic cancer and in general was well tolerated. It has not been tested 
however in combination with Pexa-Vec, which is one of the main goals of this study. 
WHY ARE YOU BEING ASKED TO TAKE PART IN THIS STUDY?
You are being asked to take part in this study because you have been diagnosed with and have 
been treated for colorectal cancer that has spread to other parts of the body. During the screening 
process, you will be tested to determine whether your cancer cells have a certain deficiency in 
DNA repair. You will be enrolled if you do not have the deficiency (status =microsatellite stable 
(MSS) OR if you have the deficiency (status = microsatellite instability high (MSI-H) and your 
disease has gotten worse on anti-PDL-1 therapy (e.g., nivolumab, pembrolizumab).  
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY? 
Up to 35 participants will take part in this study. 
DESCRIPTION OF RESEARCH STUDY
For your safety, some medications and therapies are not allowed during the study. You should tell 
the study doctor before you take any new medications (including prescription, herbal, and over-
the-counter remedies) or start a new therapy during the study.
Before you begin the study
Before you can enroll on the study, you will have:

A review of any past or current medical conditions, medicines you are taking and cancer 
history.

Physical examination, including vital signs, height and weight

Electrocardiogram (ECG) and Echocardiogram to evaluate your heart.

Review of your symptoms and your ability to perform your normal activities.
IRB NUMBER: 17C0092
IRB APPROVAL DATE: 07/09/2020


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (2)
Version Date: 07/07/2020
Page 3 of 22
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY

Imaging Assessments –a computed tomographic scan (CT) that produces a picture of your 
body using a small amount of radiation. (Magnetic resonance imaging (MRI) that uses a 
magnetic field to produce an image of your tumor and of your brain may be done if your 
study doctor thinks MRI is needed).

You will have blood drawn for routine blood tests to find out if you are anemic, have low 
blood counts and if your liver, kidneys, and other organs are working well.

Blood tests to evaluate if you were exposed to HIV, Hepatitis B or C

Test for tuberculosis if your doctor thinks that it is needed

Pregnancy test if you are a woman who can have children.

You will be asked to provide a sample of your tumor from a previous surgery so that we 
may confirm your diagnosis and microsatellite status. If a sample is not available, you will 
need to have a biopsy of your tumor.

24-hour urine sample if the study doctor thinks it is needed

Examination by a cardiologist (heart doctor) if you have a history of heart disease
During the study
There will be two parts to this study: A and B. The first 3 - 16 participants will be enrolled in part 
A; after part A is complete, we will decide whether to enroll an additional 3 – 16 participants in 
part B. The participants enrolled in part A will receive treatment with Pexa-Vec in combination 
with Durvalumab. The participants enrolled in part B will receive treatment with Pexa-Vec in 
combination with Durvalumab and Tremelimumab. For all participants, study treatment will be 
divided into cycles each lasting approximately 28 days. 
Part A
The first 3 - 6 participants enrolled in part A will receive the lowest dose of Pexa-Vec to be tested 
in combination with Durvalumab. If more than one person experiences a side effect that is 
considered too serious by the study doctor during the first 28 days of treatment, we will not enroll 
any further participants. 
If fewer than two experience unacceptable side effects, the next 3- 10 participants enrolled in part 
A will receive a higher dose of Pexa-Vec in combination with Durvalumab. 
During first two cycles, you will get Pexa-Vec in combination with Durvalumab. Starting from 
cycle 3 you will have Durvalumab treatment only. You will be treated until your disease worsens 
or you have intolerable side effects.
Once enrollment and a full assessment of the safety in part A has been completed, we will, if 
considered safe and effective, begin enrolling participants to part B.
Part B
The first 3 - 6 participants enrolled in part B will receive the lower dose of Pexa-Vec in 
combination with Durvalumab and Tremelimumab. If more than one person experiences a side 
IRB NUMBER: 17C0092
IRB APPROVAL DATE: 07/09/2020


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (2)
Version Date: 07/07/2020
Page 4 of 22
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
effect that is considered too serious by the study doctor during the first 28 days of treatment, we 
will not enroll any further participants. 
If fewer than two experience unacceptable side effects, the next 3 - 10 participants enrolled in part 
B will receive the higher dose of Pexa-Vec in combination with Durvalumab and Tremelimumab. 
During first two cycles, you will get Pexa-Vec in combination with Durvalumab and one dose of 
Tremelimumab. Starting from cycle 3 you will have Durvalumab treatment only. You will be 
treated until your disease worsens or you have intolerable side effects.
Drug administration and schedule
Pexa-Vec will be administered to you through an IV (intravenous catheter, a small plastic tube that 
is put into a vein, usually in your arm) every 2 weeks for 8 weeks. 
Durvalumab will be administered through an IV on the Day 1 of each Cycle. (Day 1 of cycle 1 = 
12 days after the first dose of Pexa-Vec)
If you are enrolled in part B in addition to Pexa-Vec and Durvalumab you will receive 
Tremelimumab. Tremelimumab will be administered through an IV on the Day 1 of cycle 1.
The infusions of Pexa-Vec, Durvalumab and Tremelimumab will last approximately 1 hour. Your 
vital signs will be monitored for at least 20 hours after the first dose of Pexa-Vec and for at least 
1 hour after the first dose of Durvalumab +/- Tremelimumab. For subsequent doses, if there are no 
side effects related to the infusion the monitoring period may be reduced. 
During the visits
You will have a physical exam, answer questions about your health and have blood and urine tests 
each cycle to help us monitor your health. An ECG will be performed every 4 weeks (every cycle). 
You will also have scans every 8 weeks (every 2 cycles) to monitor your disease.
Pre-medication 
About 30 -60 minutes before each dose of Pexa-Vec you will be given Acetaminophen (Tylenol) 
to help prevent any side effects or allergic reactions. In addition, because there is a risk of low 
blood pressure, you will be given IV fluids before each Pexa-Vec infusion and asked to stop taking 
any medications for high blood pressure for 48 hours before and after Pexa-Vec
Research tests
In addition to the tests that we will conduct to determine whether you are having side effects or if 
you are responding to the study therapy, we will also collect samples from you for purposes of 
research only. These studies include:

Blood samples to study the effects of therapy on your immune system will be collected 
during every cycle.

Tumor biopsies: procedures using a needle to remove a piece of tissue or a sample of cells 
from your body so that it can be analyzed in a laboratory and is used to diagnose or evaluate 
the cancer. You will be required to have two biopsies: once before treatment and once after 
treatment, either on day 1 of cycle 1 or on day 1 of cycle 2 depending on a random selection 
(like a flip of a coin). We may ask you to allow us to perform third biopsy around day 1 of 
IRB NUMBER: 17C0092
IRB APPROVAL DATE: 07/09/2020


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (2)
Version Date: 07/07/2020
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
cycle 4, but this biopsy is optional and you will be asked to sign a separate consent if you 
agree to have this optional biopsy. Please see page 15 for the risks of biopsy. 

Genetic testing – Your tissue will help us study how genes might play a role in colorectal 
cancer. The testing will be limited so to genes that are not known to cause diseases; 
therefore, we will not share the results of these research tests with you.
WHEN YOU ARE FINISHED TAKING THE DRUGS
After you have finished taking the study drugs, you will be asked to return to clinic once a month 
for a safety follow up visits. At these visits, you will be asked questions about your health, get a 
physical exam and undergo routine blood and urine tests. If you are unable to return for these visits, 
we will obtain the information from you by telephone.
BLOOD DONATION
You should not donate blood while in the study and for 3 months after the last Durvalumab infusion 
or 6 months after the last dose of Durvalumab + Tremelimumab combination therapy, whichever 
comes later.
BIRTH CONTROL
If you are a woman who is breast feeding or pregnant, you may not take part in the study because 
we don’t know how this medicine would affect your baby or your unborn child. 
Women
If you are a woman who can become pregnant, you will need to practice abstinence if that is your 
usual lifestyle or two effective forms of birth control before starting study treatment, during study 
treatment, and for 3 months after the last Durvalumab infusion or 6 months after the last dose of 
Durvalumab + Tremelimumab combination therapy, whichever comes later. You should also 
refrain from breast feeding during this time.
Men
If you are the partner of a woman who can become pregnant and you have not had a vasectomy, 
you will need to practice abstinence if that is your usual lifestyle or two effective forms of birth 
control before starting study treatment, during study treatment, and for 3 months after the last 
Durvalumab infusion or 6 months after the last dose of Durvalumab + Tremelimumab combination 
therapy, whichever comes later. You should also refrain from donating sperm during this time.
All
If you think that you or your partner is pregnant, you should tell your study doctor or nurse at once. 
Effective forms of birth control include: 

intrauterine device (IUD)

hormonal [birth control pills, injections, or implants]
RISKS OR DISCOMFORTS OF PARTICIPATION
If you choose to take part in this study, there is a risk that:
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
You may lose time at work or home and spend more time in the hospital or doctor’s office 
than usual

You may be asked sensitive or private questions which you normally do not discuss
The vaccine and chemotherapy used in this study may affect how different parts of your body work 
such as your liver, kidneys, heart, and blood. The study doctor will be testing your blood and will 
let you know if changes occur that may affect your health.
There is also a risk that you could have side effects from the study drug(s). 
Here are important points about side effects:

The study doctors do not know who will or will not have side effects.

Some side effects may go away soon, some may last a long time, or some may never go 
away.

Some side effects may interfere with your ability to have children.

Some side effects may be serious and may even result in death.
Here are important points about how you and the study doctor can make side effects less of a 
problem:

Tell the study doctor if you notice or feel anything different so they can see if you are 
having any symptoms.

The study doctor may be able to treat some side effects.

The study doctor may adjust the study drugs to try to reduce side effects.
Late side effects of the investigational agents may affect your ability to tolerate subsequent 
regimens of standard of care chemotherapy.
Below we show the most common and the most serious side effects that researchers know about. 
There might be other side effects that researchers do not yet know about. If important new side 
effects are found, the study doctor will discuss these with you.
Risks from study therapy
All Participants
Pexa-Vec
COMMON, SOME MAY BE SERIOUS
In 100 people receiving Pexa-Vec, more than 20 and up to 100 may have:

Short-lived (2-3 days) flu-like feelings including fever, chills, headache, nausea, 
vomiting. 

Chills - that may be strong enough to cause shaking with a feeling of coldness. This 
reaction commonly occurs with or before fever and is called rigors. If needed, anti-rigor 
medication may be prescribed before and after treatment.
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COMMON, SOME MAY BE SERIOUS
In 100 people receiving Pexa-Vec, more than 20 and up to 100 may have:

Low blood pressure – which may cause feeling faint. In this case stop temporarily any 
medication for high blood pressure or medications which can affect your blood pressure.  
Your study doctor will know all the medications you are taking (including herbal or 
over-the-counter remedies) and will instruct you on when to stop any medications and 
when it is safe to start them.

Rashes. Small (less than 1 cm) superficial skin or oral small blister or pimple containing 
Pexa-Vec may develop after Pexa-Vec treatment.  If they develop, it is typically within 
1 week after the first IV infusion only. These blisters or pimples generally resolve within 
approximately the following 2–3 weeks. All blisters or pimples to date have been self-
limited and resolved without complications or the need for specific anti-viral treatment.
OCCASIONAL, SOME MAY BE SERIOUS
In 100 people receiving Pexa-Vec, from 4 to 20 people may have:

Muscle aches, tiredness, weakness

High blood pressure. An increase in blood pressure can lead to headache, vision 
problems, and rarely, to heart problems or stroke. In previous trials with Pexa-Vec, 
some patients experienced temporary low or high blood pressure. All patients 
recovered, but some required medications for blood pressure support and overnight 
hospital stays for observation.

Abdominal Pain. A few patients experienced pain due to temporary swelling of the 
tumor(s) following Pexa-Vec injection

Faster than usual heart rate

Injection site pain. If needed, pain medication may be prescribed before and during 
treatment.
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VERY UNCOMMON, SOME MAY BE SERIOUS
In 100 people receiving Pexa-Vec, between 1 and 4 people may have:

High liver enzyme levels. Liver enzymes are proteins found in the blood released by 
your liver. Elevated liver enzymes could be a sign that certain liver functions are 
abnormal.

High blood bilirubin levels. Bilirubin is a substance made during the normal breakdown 
of red blood cells. Higher than normal levels of bilirubin may indicate different types of 
liver problems.

Low lymphocyte count. Lymphocytes are cells found in your blood responsible for your 
immune system.

Decrease in appetite, sometimes significant, loose stools

High blood sugar (hyperglycemia) requiring more frequent monitoring

High blood platelet count

Low platelet count. Platelets are cells found in your blood to help form a blood clot. A 
very low platelet count could lead to difficulty stopping bleeding, if you experience an 
injury.

Low hemoglobin (a protein in your red blood cells that carries oxygen to your body's 
organs and tissues and transports carbon dioxide from your organs and tissues back to 
your lungs) that may cause hypoxia (low oxygen in your tissues) and dizziness.

Low red blood cell count. Red blood cells are found in your blood and carry oxygen 
throughout your body. A low red blood cell count can lead to tiredness and low energy.

Low white blood cell count and low neutrophil count (cells of the immune system that 
fight infection). This decrease is typically brief and often white blood cell counts return 
to pre-treatment levels within 4 days following treatment

High white blood cell count. Your study doctor may choose to assess you for other 
sources of infection

Low sodium in the blood (Hyponatremia), which can cause fatigue, muscle weakness, 
or cramping

Rash including herpes zoster (shingles)

Sweating, feeling hot or cold
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VERY UNCOMMON, SOME MAY BE SERIOUS
In 100 people receiving Pexa-Vec, between 1 and 4 people may have:

Insomnia or confusion

Swelling of your lower limbs

Swelling of lymph nodes

Pain in muscles, bones, joints, back pain, flank pain, and pain in extremities 

Pain in your mouth and throat, inflamed and sore mouth

Abdominal discomfort or distention, ascites (accumulation of fluid in the abdomen), 
flatulence, and indigestion.
RARE, SOME MAY BE SERIOUS
In 100 people receiving Pexa-Vec, less than 1 person may have:

Heart attack, also known as myocardial infarction (or damage of heart muscle due to 
lack of blood supply), which may be diagnosed by an increase of cardiac enzymes 
(chemicals released by the heart in the blood) associated with symptoms of chest pain 
or changes to the electrical activity of your heart traced during an electrocardiogram 
(EKG or ECG) test. It is not known if heart attack was definitely caused by Pexa-Vec 
as there were other risk factors (e.g., high blood pressure, diabetes, and others). The 
damage to your heart could be permanent and, in some cases, life-threatening or even 
lead to death. Your physician will review your medical history and current medications 
to determine if you are fit enough to participate in the study. However, the chance you 
could develop cardiac injury (or a heart attack), while rare, cannot be ruled out.

Portal vein thrombosis, which is a blockage or narrowing of the portal vein (the blood 
vessel that brings blood to the liver from the intestines) by a blood clot or liver tumor 
growing into your blood vessel. Blockage of liver blood vessels by liver tumor is a 
common finding in liver cancer patients that is seen in more than 40 out of 100 liver 
cancer patients at the time of diagnosis which may worsen spontaneously or lead to other 
complications. Your physician will review your medical history and current medications 
to determine if you are fit enough to participate in the study. It is not known if the 
worsening of portal vein thrombosis was definitely caused by Pexa-Vec as there were 
other factors that could have contributed to the events, however the chance you could 
develop worsening of portal vein thrombosis, while rare, cannot be ruled out.

Prothrombin time shortened. Prothrombin is a protein produced by your liver. It is one 
of many factors in your blood that help it to clot appropriately.

Cough, shortness of breath, flu and other upper respiratory infections

Weight loss
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RARE, SOME MAY BE SERIOUS
In 100 people receiving Pexa-Vec, less than 1 person may have:

Low protein levels, electrolyte imbalance, and increased bilirubin in your blood

Dehydration

Constipation

Night sweats

Immune reaction symptoms of which include fever, nausea, chills, low blood pressure, 
tachycardia, weakness, headache, and potentially others.

Lethargy, confusional state

Mouth ulceration, herpes

Wound complication, pain in your side and procedural pain

Enlarged lymph nodes 
  
There may be other side effects of Pexa-Vec that are unknown. You will be told about any new 
findings that develop during this study that may affect your decision to stay in the study
Durvalumab
Most of the possible side effects listed below are mild to moderate. However, some side effects 
can be very serious and life-threatening and may even result in death. Some side effects do not 
need treatment while others generally get better with treatment.  Some patients may need to delay 
doses of durvalumab to allow the side effects to get better.  The most important possible side 
effects, which are listed below, may occur because of the way durvalumab works on the immune 
system and they have been seen in patients treated with durvalumab in clinical studies. Side effects 
like these have also been seen in clinical studies with other drugs that are very similar to 
durvalumab. Management of these side effects may require the administration of drugs such as 
steroids or other agents that can affect your immune system and reduce inflammation.
Very common 
In 100 people receiving durvalumab, more than 10 may have:

Diarrhea,

Rash/dry itchy skin,

Liver problems: Increases in the blood level of substances called enzymes found 
within your liver cells. The enzyme changes are unlikely to make you feel unwell, 
however, if these blood enzyme levels become very high, your study doctor may need 
to stop the study medication. You may develop inflammation of the liver called 
hepatitis; however, this is uncommon. Signs and symptoms of this include yellowing 
of the skin or whites of the eyes, dark urine, severe nausea and vomiting, pain in the 
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Very common 
In 100 people receiving durvalumab, more than 10 may have:
upper right side of your abdomen, skin itchiness, not feeling hungry and bleeding or 
bruising more easily than normal.

Feeling tired 

Nausea 

Vomiting 

Abdominal pain

Accumulation of fluid causing swelling 

Upper respiratory tract infections

Decreased appetite 

Shortness of breath 

Cough 

Fever
Common
In 100 people receiving durvalumab, from 1 to 10 may have:

Inflammation in the lungs (pneumonitis): symptoms may include but are not limited 
to a new or worsening cough, shortness of breath possibly with fever. Preliminary 
data suggested that there may be the tendency of higher frequency and severity in 
Japanese patients compared with non-Japanese patients:  tell your study doctor right 
away if you have any of these symptoms as it may need to be treated urgently.

Low thyroid (Hypothyroidism): this is when the thyroid gland produces less thyroid 
hormone than it should which causes the metabolism to run too slow. Symptoms may 
include but are not limited to fatigue, increased sensitivity to cold, constipation, dry 
skin, unexplained weight gain, puffy face, muscle weakness, slow heart rate, thinning 
hair, impaired memory. The condition can be treated with replacement thyroid 
hormone.

High thyroid (Hyperthyroidism): this is when the thyroid gland produces too much 
thyroid hormone. Symptoms include anxiety or nervousness, weight loss, frequent 
and loose bowel movements, breathlessness, feeling hot and possibly having heart 
palpitations. Depending on the severity of the symptoms, treatment may include just 
monitoring the symptoms, treating the symptoms themselves and/or giving medicine 
to block the thyroid hormone.

Kidney problems: you may have an increase of creatinine levels in a blood test 
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Common
In 100 people receiving durvalumab, from 1 to 10 may have:
(creatinine is a protein marker that measures kidney function) but not have any 
symptoms or feel unwell. Uncommonly a patient may experience nephritis which is 
an inflammation of the kidneys that stops the kidneys from working properly. 

Nervous system problems: symptoms can include unusual weakness of legs, arms, or 
face, numbness or tingling in hands or feet. In rare situations there is the potential for 
the inflammation of the nervous system to be severe and cause damage to the nerve 
cells or breakdown in the communication between nerves and muscles: tell your study 
doctor right away if you have problems swallowing, if you start to feel weak very 
quickly and you are having trouble breathing.

Infusion Related Reactions: reactions may occur during or after the infusion of study 
medication.  The reaction may cause fever or chills and a change in blood pressure or 
difficulty in breathing which might be serious. Tell your study doctor right away if 
you experience any of these symptoms even if it has been several days after the 
infusion has been completed.  

Inflammation of the intestine (colitis). It may cause abdominal pain and diarrhea with 
or without blood. Fever may be present. It may require you to receive additional 
fluids. If left untreated, in rare occasions this may lead to a tear in the wall of the 
intestine which can be serious and life threatening. Tell your study doctor right away 
if you have any of these symptoms. 

A hoarse voice

Painful urination

Night sweats

Pneumonia

Oral thrush

Dental and oral soft tissue infection

Pain in muscles and joints

Influenza.
Uncommon
In 100 people receiving durvalumab, 1 or fewer may have:

Inflammation of the pancreas (pancreatitis). Pancreatitis usually causes symptoms of 
persistent upper abdominal pain (sometimes made worse by eating and drinking), 
nausea, vomiting and general weakness. Pancreatitis usually settles with simple 
measures but it can be a serious condition and can be fatal. You should immediately 
tell your study doctor if you develop any of these symptoms. You may get an increase 
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Uncommon
In 100 people receiving durvalumab, 1 or fewer may have:
of lipase and amylase levels in a blood test (related to the pancreas) but not have any 
symptoms or feel unwell. Lipase and amylase are enzymes or protein markers that 
measure the function of your pancreas. Uncommonly these increases may be 
associated with pancreatitis.

Allergic reactions: These can cause swelling of the face, lips and throat, breathing 
difficulties along with hives or nettle like rash. You should immediately tell your 
study doctor if you develop any of these symptoms. 

Problems with your adrenal glands (Adrenal Insufficiency): may cause stomach 
pains, vomiting, muscle weakness and fatigue, depression, low blood pressure, weight 
loss, kidney problems, and changes in mood and personality. These complications 
may be permanent and may require hormone replacement 

Problems with the pituitary gland (hypopituitarism): Hypopituitarism refers to 
decreased output of hormones from the pituitary gland in the brain and may be caused 
by inflammation of the pituitary gland (hypophysitis). Symptoms may include 
headaches, thirstiness, and trouble seeing or double vision, leakage of breast milk or 
irregular periods in women. These complications may be permanent and may require 
hormone replacement.

Inflammation of the muscles or associated tissues, such as blood vessels that supply 
the muscles (Myositis/polymyositis). Symptoms can include muscle weakness and 
aches, tired feeling when standing or walking, muscle pain and soreness that does not 
resolve after a few weeks.
Rare side effects 
In 1,000 people receiving durvalumab, 1 or fewer may have:

Type 1 Diabetes mellitus which may cause increased blood glucose levels (called 
‘hyperglycemia’): symptoms may include weight loss, increased urination, increased 
thirst, and increased hunger. Type 1 diabetes will require replacement of insulin 
through injection. Tell your study doctor right away if you have any of these 
symptoms.  

Problems with the pituitary gland (hypopituitarism): hypopituitarism refers to 
decreased output of hormones from the pituitary gland in the brain and may be caused 
by inflammation of the pituitary gland (hypophysitis). Symptoms may include 
headaches, thirstiness, and trouble seeing or double vision, leakage of breast milk or 
irregular periods in women. These complications may be permanent and may require 
hormone replacement.

Inflammation of the heart muscle (myocarditis). Symptoms can include chest pain, 
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Rare side effects 
In 1,000 people receiving durvalumab, 1 or fewer may have:
rapid or abnormal heartbeat, shortness of breath and swelling of your legs. Tell your 
study doctor right away if you experience any of these symptoms.

Inflammation of the membrane surrounding the heart

Growths of tiny collections of inflammatory cells in different parts of the body

Inflammation of the middle layer of the eye and other events involving the eye (e.g. 
inflammation of the cornea and optic nerves)

Inflammation of the brain or the membranes that cover the brain and spinal cord

Hardening and tightening of the skin and connective tissues and loss of skin color

Pemphigoid and hematological events (e.g., abnormal breakdown of the red blood 
cells and low levels of platelets)

Inflammation of the blood vessels and  rheumatological events (inflammatory 
disorder causing muscle pain and stiffness and autoimmune arthritis)

New allergies to previously exposed substances, other than durvalumab. For example, 
it is possible that you could develop an allergy to shellfish or IV contrast while taking 
durvalumab. These allergies may be severe and life threatening.
In addition to the possible risks identified in patients treated with durvalumab, other immune-
mediated side effects are possible that have not been observed and can result in inflammatory side 
effects in any organ or tissue.
Tremelimumab (Part B only)
Because Tremelimumab activates the immune system, the main side effects we are concerned 
about are auto-immune side-effects. Your study team will give you medicines to help lessen side 
effects if they occur. Many side effects go away with those medicines and others may go away 
soon after you stop the study drug. In some cases, side effects can be serious, long lasting, or may 
never go away. There are no known long-lasting side effects from Tremelimumab at this time. 
The following are side effects that have been associated with Tremelimumab and are common with 
combination therapy of Tremelimumab and Durvalumab:

Diarrhea

Rash that can result in severe and life-threatening symptoms

Pruritus (itching)

Fatigue

Nausea
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
Vomiting

Anorexia (loss of appetite)

Headache

Abdominal Pain

Auto-immune changes to the pituitary gland leading to hormonal changes.

Inflammation of the colon which can lead to abdominal pain and diarrhea with or without 
blood. If left untreated, this may lead to a tear in the wall of the intestine which can be 
serious and life threatening. 

Inflammation of the liver called hepatitis, that can be fatal. 

During or after drug infusion having fever, chills, change in blood pressure or difficulty in 
breathing which might be serious 

Allergic reactions, causing:
o
swelling of the face, lips and throat
o
difficulty in breathing which might be serious 
o
hives or nettle like rash
o
change in blood pressure

New allergies to previously exposed substances, other than Tremelimumab. For example, 
it is possible that you could develop an allergy to shellfish or IV contrast while taking 
Tremelimumab. These allergies may be severe and life threatening.
You should also not receive a live vaccination 30 days before receiving Tremelimumab and for 6 
months after receiving your last doses of Tremelimumab. Discuss any vaccinations you may need 
with your Study Doctor.
Tell your study doctor right away if you have any of these symptoms as it may need to be treated 
urgently.
Risks from Blood Collection 
Side effects of blood draws include pain and bruising in the area where the needle was placed, 
lightheadedness, and rarely, fainting. When large amounts of blood are collected, low red blood 
cell count (anemia) can develop.
Risks from CT scans
If contrast dye is used, there is a risk for allergic reaction to the dye. Participants might experience 
hives, itching, headache, difficulty breathing, increased heartrate and swelling. 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.
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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.
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 up to three CT guided biopsies (two mandatory and one optional). The amount of radiation 
exposure you will receive from these procedures is equal to approximately 10.1 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 33.7 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 1 out of 100 (1%) 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.
POTENTIAL BENEFITS OF PARTICIPATION
Are there benefits to taking part in this study? 
The aim of this study is to find out whether the experimental treatment causes your tumor to shrink. 
We do not know if you will receive personal, medical benefit from taking part in this study. There 
is no evidence that the experimental treatment benefits participants with your type of tumor. 
Potential benefits could include shrinking of your tumor or lessening of your symptoms, such as 
pain, that are caused by the cancer. Because there is not much information about the drug’s effect 
on your cancer, we do not know if you will benefit from taking part in this study, although the 
knowledge gained from this study may help others in the future who have cancer. 
ALTERNATIVE APPROACHES OR TREATMENTS
Instead of being in this study, you have these options:

Getting treatment or care for your cancer without being in a study

Taking part in another study
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
Getting comfort care, also called palliative care. This type of care helps reduce pain, 
tiredness, appetite problems and other problems caused by the cancer. It does not treat the 
cancer directly. Instead, it tries to improve how you feel. Comfort care tries to keep you as 
active and comfortable as possible.
Please talk to your doctor about these and other options.
STOPPING THERAPY
Your doctor may decide to stop your therapy for the following reasons:

if he/she believes that it is in your best interest

if your disease comes back during treatment

if you become pregnant

if you start another cancer therapy

if you receive a certain type drug (tumor necrosis factor inhibitor)

if you have side effects from the treatment that your doctor thinks are too severe

if new information shows that another treatment would be better for you

if the investigator decides to end the study
In this case, you will be informed of the reason therapy is being stopped.
You can stop taking part in the study at any time. However, if you decide to stop taking part in the 
study, we would like you to talk to the study doctor and your regular doctor first.
If you decide at any time to withdraw your consent to participate in the trial, we will not collect 
any additional medical information about you. However, according to FDA guidelines, 
information collected on you up to that point may still be provided to Medimmune/Astrazeneca 
and /or Sillajen Inc or designated representatives. If you withdraw your consent and leave the trial, 
any samples of yours that have been obtained for the study and stored at the NCI can be destroyed 
upon request. However, any samples and data generated from the samples that have already been 
distributed to other researchers or placed in the research databases cannot be recalled and 
destroyed. 
CONFLICT OF INTEREST
The National Institutes of Health (NIH) reviews NIH staff researchers at least yearly for conflicts 
of interest. This process is detailed in a Protocol Review Guide. You may ask your research team 
for a copy of the Protocol Review Guide or for more information. Members of the research team 
who do not work for NIH are expected to follow these guidelines but they do not need to report 
their personal finances to the NIH.
Members of the research team working on this study may have up to $15,000 of stock in the 
companies that make products used in this study. This is allowed under federal rules and is not a 
conflict of interest. 
IRB NUMBER: 17C0092
IRB APPROVAL DATE: 07/09/2020


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (2)
Version Date: 07/07/2020
Page 18 of 22
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
The National Institutes of Health and the research team for this study are using therapies developed 
by Medimmune/Astrazeneca and /or Sillajen Inc through a joint study with your researchers and 
the companies. The companies also provide financial support for this study. 
USE OF SPECIMENS AND DATA FOR FUTURE RESEARCH
To advance science, it is helpful for researchers to share information they get from studying human 
samples. They do this by putting it into one or more scientific databases, where it is stored along 
with information from other studies. A researcher who wants to study the information must apply 
to the database and be approved. Researchers use specimens and data stored in scientific databases 
to advance science and learn about health and disease. 
We plan to keep some of your specimens and data that we collect and use them for future research 
and share them with other researchers. We will not contact you to ask about each of these future 
uses. These specimens and data will be stripped of identifiers such as name, address or account 
number, so that they may be used for future research on any topic and shared broadly for research 
purposes. Your specimens and data will be used for research purposes only and will not benefit 
you. It is also possible that the stored specimens and data may never be used. Results of research 
done on your specimens and data will not be available to you or your doctor. It might help people 
who have cancer and other diseases in the future. 
In addition to the use and sharing of your specimens and data described above, we might remove 
any information from your specimens and data that can identify you such as name, address, or 
medical record number, and then use the specimens and 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 do not want your stored specimens and data used for future research, please contact us in 
writing and let us know that you do not want us to use your specimens and/or data. Then any 
specimens that have not already been used or shared will be destroyed and your data will not be 
used for future research. However, it may not be possible to withdraw or delete materials or data 
once they have been shared with other researchers.
Genomic Data Sharing
As part of this research study, we will put your genomic data in a large database for broad sharing 
with the research community. These databases are commonly called data repositories. The 
information in this database will include but is not limited to genetic information, race and 
ethnicity, and sex.  If your individual data are placed in one of these repositories, they will be 
labeled with a code and not with your name or other information that could be used to easily 
identify you, and only qualified researchers will be able to access them. These researchers must 
receive prior approval from individuals or committees with authority to determine whether these 
researchers can access the data.
Summary information about all of the participants included in this study (including you) is being 
placed in a database and will be available through open access. That means that  researchers and 
non-researchers will be able to access summary information about all the participants included in 
the study, or summary information combined from multiple studies, without applying for 
permission. The risk of anyone identifying you with this information is very low.
IRB NUMBER: 17C0092
IRB APPROVAL DATE: 07/09/2020


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (2)
Version Date: 07/07/2020
Page 19 of 22
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
NIH policies require that genomic data be placed in a repository for sharing. Therefore, we cannot 
offer you a choice of whether your data will be shared.  If you do not wish to have your data placed 
in a repository, you should not enroll in this study.
COMPENSATION, REIMBURSEMENT, AND PAYMENT
Will you receive compensation for participation in the study?
Some NIH Clinical Center studies offer compensation for participation in research. The amount 
of compensation, if any, is guided by NIH policies and guidelines.
You will not receive compensation for participation in this study. 
Will you receive reimbursement or direct payment by NIH as part of your participation?
Some NIH Clinical Center studies offer reimbursement or payment for travel, lodging or meals 
while participating in the research. The amount, if any, is guided by NIH policies and guidelines.
On this study, the NCI will cover the cost for some of your expenses.  Some of these costs may 
be paid directly by the NIH and some may be reimbursed after you have paid.  Someone will 
work with you to provide more information. 
Will taking part in this research study cost you anything? 
NIH does not bill health insurance companies or participants for any research or related clinical 
care that you receive at the NIH Clinical Center. 

If some tests and procedures performed outside the NIH Clinical Center, you 
may have to pay for these costs if they are not covered by your insurance 
company.

Medicines that are not part of the study treatment will not be provided or paid 
for by the NIH Clinical Center.

Once you have completed taking part in the study, medical care will no longer 
be provided by the NIH Clinical Center.  
CLINICAL TRIAL REGISTRATION AND RESULTS REPORTING
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this Web site at any time.
CONFIDENTIALITY PROTECTIONS PROVIDED IN THIS STUDY  
Will your medical information be kept private? 
We will do our best to make sure that the personal information in your medical record will be kept 
private.  However, we cannot guarantee total privacy.  Organizations that may look at and/or copy 
your medical records for research, quality assurance, and data analysis include:

The National Cancer Institute (NCI) 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
IRB NUMBER: 17C0092
IRB APPROVAL DATE: 07/09/2020


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (2)
Version Date: 07/07/2020
Page 20 of 22
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY

Qualified representatives from Medimmune/Astrazeneca, the pharmaceutical company 
who produces Durvalumab and Tremelimumab.

Qualified representatives from Sillajen Inc, the pharmaceutical company who produces the 
Pexa-Vec vaccine.
When results of an NIH research study are reported in medical journals or at scientific meetings, 
the people who take part are not named and identified.  In most cases, the NIH will not release any 
information about your research involvement without your written permission.  However, if you 
sign a release of information form, for example, for an insurance company, the NIH will give the 
insurance company information from your medical record.  This information might affect (either 
favorably or unfavorably) the willingness of the insurance company to sell you insurance.
If we share your specimens or data with other researchers, in most circumstances we will remove 
your identifiers before sharing your specimens or data. You should be aware that there is a slight 
possibility that someone could figure out the information is about you. 
Further, the information collected for this study is protected by NIH under a Certificate of 
Confidentiality and the Privacy Act. 
Certificate of Confidentiality
To help us protect your privacy, the NIH Intramural Program has received a Certificate of 
Confidentiality (Certificate). With this certificate, researchers may not release or use data or 
information about you except in certain circumstances.  
NIH researchers must not share information that may identify you in any federal, state, or local 
civil, criminal, administrative, legislative, or other proceedings, for example, if requested by a 
court.  
The Certificate does not protect your information when it:  
1. is disclosed to people connected with the research, for example, information may be used 
for auditing or program evaluation internally by the NIH; or 
2. is required to be disclosed by Federal, State, or local laws, for example, when information 
must be disclosed to meet the legal requirements of the federal Food and Drug 
Administration (FDA); 
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.
IRB NUMBER: 17C0092
IRB APPROVAL DATE: 07/09/2020


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (2)
Version Date: 07/07/2020
Page 21 of 22
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Privacy Act
The Federal Privacy Act generally protects the confidentiality of your NIH medical records we 
collect under the authority of the Public Health Service Act.  In some cases, the Privacy Act 
protections differ from the Certificate of Confidentiality.  For example, sometimes the Privacy Act 
allows release of information from your medical record without your permission, for example, if 
it is requested by Congress. Information may also be released for certain research purposes with 
due consideration and protection, to those engaged by the agency for research purposes, to certain 
federal and state agencies, for HIV partner notification, for infectious disease or abuse or neglect 
reporting, to tumor registries, for quality assessment and medical audits, or when the NIH is 
involved in a lawsuit.  However, NIH will only release information from your medical record if it 
is permitted by both the Certificate of Confidentiality and the Privacy Act.
POLICY REGARDING RESEARCH-RELATED INJURIES  
The NIH Clinical Center will provide short-term medical care for any injury resulting from your 
participation in research here. In general, no long-term medical care or financial compensation for 
research-related injuries will be provided by the NIH, the NIH Clinical Center, or the Federal 
Government. However, you have the right to pursue legal remedy if you believe that your injury 
justifies such action.
PROBLEMS OR QUESTIONS
If you have any problems or questions about this study, or about your rights as a research 
participant, or about any research-related injury, contact the Principal Investigator, 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: 17C0092
IRB APPROVAL DATE: 07/09/2020


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (2)
Version Date: 07/07/2020
Page 22 of 22
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Adult Research Participant: I have read the explanation about this study and have been given the opportunity 
to discuss it and to ask questions. I consent to participate in this study.
Signature of Research Participant
Print Name of Research Participant
Date
Legally Authorized Representative (LAR) for an Adult Unable to Consent: I have read the explanation 
about this study and have been given the opportunity to discuss it and to ask questions. I am legally authorized 
to make research decisions on behalf of the adult participant unable to consent and have the authority to provide 
consent to this study. As applicable, the information in the above consent was described to the adult participant 
unable to consent who agrees to participate in the study.
Signature of LAR
Print Name of LAR
Date
Investigator:
Signature of Investigator
Print Name of Investigator
Date
Witness to the oral short-form consent process only: This section is only required if you are doing the oral 
short-consent process and this English consent form has been approved by the IRB for use as the basis of 
translation.
Witness:
Signature of Witness*
Print Name of Witness
Date
*NIH ADMINISTRATIVE SECTION TO BE COMPLETED REGARDING THE USE OF AN 
INTERPRETER:
An interpreter, or other individual, who speaks English and the participant’s preferred language facilitated
the administration of informed consent and served as a witness. The investigator obtaining consent may not 
also serve as the witness.
An interpreter, or other individual, who speaks English and the participant’s preferred language facilitated
the administration of informed consent but did not serve as a witness. The name or ID code of the person 
providing interpretive support is:
.
IRB NUMBER: 17C0092
IRB APPROVAL DATE: 07/09/2020