Conditions: Intermediate Risk Prostate Cancer Castration-resistant Prostate Cancer
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 23
Healthy volunteers: no

Brief summary:
This is a clinical trial of a new treatment for prostate cancer that is a type of vaccine that could be a new way to treat cancer. A vaccine that could alert the immune system to the presence of cancer cells in the body may enable the immune system to target and kill those cells effectively. This vaccine is intended to work by making the immune system kill cells that have a special protein (called 5T4) that is present on the surface of cancer cells. The vaccine is made up of two recombinant viruses ("ChAdOx1"- chimpanzee adenovirus Ox1 and "MVA" - modified vaccinia Ankara) that have been designed to produce the 5T4 protein and have been modified so that they are weakened and cannot reproduce themselves within the body like normal viruses. Once injected into the body, these viruses make the 5T4 protein and help the body's immune system to learn to target this protein and destroy cancer cells.

This vaccine will be used in combination with the immunotherapy drug called nivolumab which is an anti-PD-1 (Programmed Death protein-1) monoclonal antibody. This is a molecule that releases the brakes on the immune system and helps the immune system to kill cancer cells more efficiently. Nivolumab as a monotherapy was approved for treatment of several tumour types but not for the prostate cancer.

This study will evaluate the safety and efficacy of ChAdOx1-MVA 5T4 vaccine in combination with nivolumab in low and intermediate risk prostate cancer patients who have elected to have their prostate removed and in patients with advanced metastatic prostate cancer.

Detailed description:
The purpose of this study was to evaluate the safety and efficacy of a combination of two new vaccines (ChAdOx1.5T4 and MVA.5T4) with a monoclonal antibody (PD-1 mAb, also known as Nivolumab and Opdivo®) against Prostate Cancer.

A vaccine that alerts the immune system to the presence of cancer cells in the body may enable the immune system to target and kill those cells effectively. This vaccine is intended to work by making the immune system kill cells that have a special protein (called 5T4) that is present on the surface of cancer cells. The use of two different forms of the vaccine has been shown to generate a more effective immune response.

ChAdOx1.5T4 consists of a virus (ChAdOx1), which is a weakened version of a chimpanzee adenovirus that has been genetically altered so that it is impossible for it to grow in humans. Modified Vaccinia virus Ankara (MVA) is licensed as third-generation vaccine against smallpox and serves as a potent vector system for development of new candidate vaccines against infectious diseases and cancer.

To both viruses we have added genes that make the 5T4 protein that is present in prostate cancer cells and which is essential to the cancer. By vaccinating, we are hoping to make the body recognise and develop an immune response to these proteins that will neutralise the effects of the cancer in human cells and therefore prevent the infection responsible for the disease.

Nivolumab (PD-1 mAb) is an immune checkpoint inhibitor. Immune checkpoints are a normal part of the immune system. Their role is to prevent an immune response from being so strong that it destroys healthy cells in the body. Immune checkpoints engage when proteins on the surface of immune cells called T cells recognize and bind to partner proteins on other cells, such as some tumour cells. These proteins are called immune checkpoint proteins. When the checkpoint and partner proteins bind together, they send an "off" signal to the T cells. This can prevent the immune system from destroying the cancer. Immunotherapy drugs called immune checkpoint inhibitors work by blocking checkpoint proteins from binding with their partner proteins. This prevents the "off" signal from being sent, allowing the T cells to kill the cancer cells. Nivolumab as a monotherapy has been approved for treatment of several tumour types but not currently for prostate cancer.

The intent was to have two cohorts of participants: Group 1 were patients who had been diagnosed with low- or intermediate-risk non-metastatic prostate adenocarcinoma and who were scheduled for radical prostatectomy; Group 2 comprised patients with metastatic castration resistant prostate cancer (mCRPC) with evidence of progression on anti-androgens.

Unfortunately, it proved impossible to recruit participants into Group 1, so the trial proceeded with just Group 2.

It was planned that the results would be measured by a composite response rate defined as one of the following:

* reduction of circulating tumour DNA of ≥50%
* serum PSA decrease of ≥50%

However, the analysis to measure the circulating tumour DNA (ctDNA) was not done for any of the participants due to the trial ending prematurely because of the COVID-19 pandemic in 2020.

The trial and the follow-up of participants was severely hampered by the Covid-19 pandemic.

In this study, we have shown that the candidate 5TA vaccines given were safe and well-tolerated. No serious adverse reactions occurred during the follow-up period. Most adverse events reported were mild or moderate in severity and all resolved spontaneously. The profile of adverse events reported in this trial is similar to other ChAdOx1 vectored vaccines.

Arms:
arm 1: ChAdOx1.5T4 on week 0 followed by booster injection of MVA.5T4 and nivolumab infusion on week 1. Patients will undergo radical prostatectomy on week 6. arm 2: ChAdOx1.5T4 on week 0 followed by booster injections of MVA.5T4 on week 4, ChAdOx1.5T4 on week 12 and MVA.5T4 on week 16. Nivolumab infusions are to be administered on week 4, 8 and 12.

Interventions: intervention 1: ChAdOx1-MVA 5T4 vaccine intervention 2: Nivolumab Infusion [Opdivo]
Intervention descriptions: intervention 1: ChAdOx1.5T4 will be administered intramuscularly in an extremity (e.g. thigh) at a dose of 2.5 x10\^10 virus particles followed by MVA.5T4 administered via the same route at the dose of 2x10\^8 plaque forming units intervention 2: Nivolumab is to be administered as a flat dose of 480 mg over approximately 60-minutes via IV infusion

Protocol document:
Prot_000.pdf: 
ADVANCE_v6.0                                                          21st August 2019                                                    Page 1 of 86 
UNIVERSITY OF OXFORD 
Phase I/II open label non-randomised safety and efficacy study of the viral vectored ChAd-
MVA 5T4 vaccine in combination with PD-1 checkpoint blockade in low- or intermediate-risk 
localized or locally advanced prostate cancer and advanced metastatic prostate cancer
Study short title: 
VAccination in early and ADvanced prostate caNCEr (ADVANCE) 
Study Code: ADVANCE 
Protocol Version: 6.0
21st August 2019 
Chief Investigator: Dr. Mark Tuthill 
Oxford Cancer and Haematology Centre, Oxford University Hospitals NHS Foundation Trust 
Lead Investigator: Prof. Freddie Hamdy 
Nuffield Department of Surgical Sciences, Oxford University Hospitals NHS Foundation Trust 
Sponsor: University of Oxford 
REC Number: 8/NE/0004 
EudraCT Number: 2017-001992-22 
This document contains confidential information that must not be disclosed to anyone other than 
the Sponsor, the Investigator Team, and members of the Independent Ethics Committee. This 
information cannot be used for any purpose other than the evaluation or conduct of the clinical 
investigation without the prior written consent of Professor Freddie Hamdy and Dr Mark Tuthill. 


ADVANCE_v6.0                                                          21st August 2019                                                    Page 2 of 86 
STATEMENT OF COMPLIANCE  
The trial will be conducted in compliance with the protocol, International Conference on 
Harmonisation Good Clinical Practice Guideline E6 (R1) (ICH-GCP) and the applicable regulatory 
requirements.    
Signatures 
“I have read this protocol and agree to abide by all provisions set forth therein.  
I agree to comply with the principles of the International Conference on Harmonisation Tripartite 
Guideline on Good Clinical Practice.”  
Prof. Freddie Hamdy  
-------------------------------------           ------------------------------------                --------------------------------  
Lead Investigator                               Investigator’s signature                       Date   
Dr. Mark Tuthill 
-------------------------------------           ------------------------------------                --------------------------------  
Chief Investigator                               Investigator’s signature                       Date   
Prof. Adrian Hill  
-------------------------------------           ------------------------------------                --------------------------------  
Lead Investigator                               Investigator’s signature                       Date   
Assoc. Prof. Andrew Protheroe  
-------------------------------------           ------------------------------------                --------------------------------  
Principal Investigator                         Investigator’s signature                   Date
Prof. Peter Hoskin 
-------------------------------------           ------------------------------------                --------------------------------  
Principal Investigator                         Investigator’s signature                   Date 


ADVANCE_v6.0                                                          21st August 2019                                                    Page 3 of 86 
CONFLICT OF INTEREST 
Adrian Hill is a co-founder of, share holder in and consultant to Vaccitech Ltd who have a commercial 
interest in the results of this trial and are providing limited co-funding support. Mark Tuthill is a 
consultant to Vaccitech Ltd.  


ADVANCE_v6.0                                                          21st August 2019                                                    Page 4 of 86 
MODIFICATION HISTORY  
Version
Date
Modifications
Authors
1.0
       17.11.2017 
N/A
     Irina Redchenko
     Lucy Carter 
2.0 
17.04.2018 
Trial centres: University Hospital of Wales 
(Cardiff) was replaced by the Christie NHS 
Foundation Trust.  
1.Synopsis was modified to reflect changes in 
the dosing regimens, follow up duration for RP 
patients, and clarification of primary and 
secondary endpoint for metastatic prostate 
cancer patients 
2.2. Rationale for the study design was 
modified to reflect changes in the vaccine and 
immune checkpoint inhibitor dose and dosing 
regimens 
2.5. Previous clinical experience with ChAdOx1-
MVA 5T4 vaccine section was modified to 
reflect an update VANCE01 study progress  
3. OBJECTIVES section was modified to reflect 
clarification of the primary and secondary 
objectives for metastatic prostate cancer 
patients 
4.2. Investigational products section was 
modified to reflect introduction of the new 
batch of MVA.5T4 manufactured by IDT 
4.2.2 Anti-Programmed Death Receptor-1 (PD-
1) antibody - nivolumab (Opdivo®) section was 
modified to reflect changes in the Opdivo dose 
and dosing regimen  
Irina Redchenko 


ADVANCE_v6.0                                                          21st August 2019                                                    Page 5 of 86 
4.3. Allocation to study groups and dosing 
regime section was modified to reflect changes 
in the dosing regimens of the vaccines and 
Opdivo  
4.4. Duration of study section was modified to 
reflect the change in the follow-up of early 
stage prostate cancer patients from 12 months 
to 6 months:  
4.6.2 Surgery delay section was modified to 
reflect a reduction in the delay to 6 weeks 
instead of 2 months  
4.6.4 Risks associated with checkpoint inhibitor 
therapy section was modified to reflect 
reduced number Opdivo doses for early stage 
prostate cancer patients 
6.1. Study visits section was modified to reflect 
changes in the dosing regimens  
7. Assessment of scientific objectives section 
was modified to reflect clarification of the 
primary, secondary and exploratory endpoint 
for metastatic prostate cancer patients  
Appendix 1:  Schedule of attendance and study 
procedures was modified to reflect changes in 
the dosing regimens 
3.0
03.09.18
Trial centres: Leeds, Sheffield and Surrey 
removed as sites along with local PIs. New 
trial centre, University College London, and 
the PI are added. 
Andrew Protheroe is identified as PI at the 
Oxford Cancer and Haematology Centre
trial centre. 
1.Synopsis was modified to reflect changes in 
the study design to remove the control no  
vaccine arm and randomisation, and reduce 
follow up duration for mCRPC patients. 
2. Background and rationale section was 
modified to incorparet recent update on the 
Irina Redchenko 
Adrian Hill 
Mark Tuthill 
Ian Poulton 


ADVANCE_v6.0                                                          21st August 2019                                                    Page 6 of 86 
efficacy of anti-PD1 therapy in mCRPC, an 
update on VANCE01 progress and a  
modification to ADVANCE study.  
4.2.2 Anti-Programmed Death Receptor-1 
(PD-1) antibody - nivolumab (Opdivo®) section 
was modified to indicate a supplier pf Opdivo 
for ADVANCE study. 
4.3. Allocation to study groups and dosing 
regime section was modified to reflect 
changes to the study design.
4.4. Duration of study section was modified to 
reflect the change in the follow-up of mCRPC 
patients from 48 months to 12 months. 
4.6.4 Risk associated with exposure to ionising 
radiation added. 
5.3. Inclusion and Exclusion Criteria section 
was modified to include additional 
requirements  
5.7. Interim monitoring and study stopping 
rules section was added 
6.1. Study visits section was modified to reflect 
a requirement for on-sudy biopsy and the 
changes to the study design. 
6.2. Additional study procedures section was 
modified to reflect changes in participating 
clinical trial centres, to clarify the sample 
collection process and to add the details of 
radiological assessment for mCRPC. 
8.7. Data and Safety Monitoring Committee 
section was modified to clarify composition of 
DSMC. 
9.1. Sample size section was modified to reflect 
changes to the study design. 


ADVANCE_v6.0                                                          21st August 2019                                                    Page 7 of 86 
Appendix 1:  Schedule of attendance and study 
procedures was modified to reflect changes to 
the study design. 
4.0
19.11.18
Appendix 1:  Schedule of attendance and study 
procedures was modified to reflect changes in 
blood volumes and timepoints for sample 
collection for Group 2 
Irina Redchenko 
5.0
15.02.19
London and Lausanne trial centres were 
removed due to their withdrawal from the 
study. 
Irina Redchenko 
5.3. Inclusion and Exclusion Criteria:
Treatment with abiraterone and 
enzalutamedie will be discontinued after 
enrolment to the study because of potential 
risk of liver toxicities. 
The criterion for on-study tumour biopsy was 
moved from the criteria for all participants to 
the criteria for metatstatic patients only. 
6.1. Telephone communications:
A window for a telephone call after study 
treatment was changed from 2 days to 2+3 
days for logistical reasons. 
12.7. Participant Confidentiality 
The wording has been modified to comply with 
the General Data Protection Regulation 2018 
Appendix 1:  Schedule of attendance and 
study procedures was modified to reflect the 
following changes. A blood samples for HLA 
typing will be collected at visit 2 instead of visit 
3 for logistaical reasons.  
Blood samples for ctDNA quantification will be 
collected at weeks 0, 4, 8, 12 and 24 instead of 
weeks 0, 24 and 48. Blood samples for CTC 
quantification will be collected at weeks 0, 8, 
and 24 instead of weeks 0, 24 and 48. 
6.0
21.08.19
Key roles and general information:
PI at the Manchester change – Prof Gillessen 
replaced by Prof Hoskin 
Irina Redchenko 


ADVANCE_v6.0                                                          21st August 2019                                                    Page 8 of 86 
Details of the Study Medical Monitor added.
8.5. Reporting procedures  
SAEs will be reported to the study medical 
monitor, not to local safety monitor. 
8.7. Data and Safety Monitoring Committee
Responsibilities of the members of the data and 
safety monitoring committee (DSMC) have 
been clarified. 


ADVANCE_v6.0                                                          21st August 2019                                                    Page 9 of 86 
CONTENTS   
STATEMENT OF COMPLIANCE .................................................................................................................................. 2
Key roles and general information: .......................................................................................................................... 7
PI at the Manchester change – Prof Gillessen replaced by Prof Hoskin ................................................................... 7
Details of the Study Medical Monitor added. ........................................................................................................... 8
8.5. Reporting procedures .................................................................................................................................... 8
CONTENTS ................................................................................................................................................................ 9
KEY ROLES AND GENERAL INFORMATION ............................................................................................................. 12
ABBREVIATIONS ..................................................................................................................................................... 15
1. SYNOPSIS ............................................................................................................................................................ 17
2. BACKGROUND AND RATIONALE ........................................................................................................................ 19
2.1. The need for a new vaccine against prostate cancer .................................................................................. 19
2.2. Rationale for the study design .................................................................................................................... 21
2.3. Pre-clinical studies involving ChAdOx1-MVA 5T4 vaccine as a monotherapy and in combination with PD-
1 ......................................................................................................................................................................... 29
2.4. Previous clinical experience with MVA.5T4 vaccine ................................................................................... 35
2.5. Previous clinical experience with ChAdOx1-MVA 5T4 vaccine ................................................................... 36
2.6. Previous clinical experience with PD-1 blockade in prostate cancer .......................................................... 38
3. OBJECTIVES ......................................................................................................................................................... 39
4. STUDY DESIGN .................................................................................................................................................... 40
4.1. Study overview ............................................................................................................................................ 40
4.2. Investigational products .............................................................................................................................. 41
4.3. Allocation to study groups and dosing regime ........................................................................................... 43
4.4. Duration of study ........................................................................................................................................ 44
4.5. Definition of the Start and End of the Study ............................................................................................... 45
4.6. Potential risks to participants ..................................................................................................................... 45
4.7. Potential benefits to participants ............................................................................................................... 49
5. RECRUITMENT AND WITHDRAWAL OF STUDY SUBJECTS .................................................................................. 50
5.1. Selection of Participants ............................................................................................................................. 50
5.2. Informed consent ........................................................................................................................................ 51
5.3. Inclusion and Exclusion Criteria .................................................................................................................. 51
5.4. Concurrent therapies .................................................................................................................................. 54
5.5. Delay and discontinuation cirteria .............................................................................................................. 55


ADVANCE_v6.0                                                          21st August 2019                                                    Page 10 of 86 
5.6. Withdrawal criteria ..................................................................................................................................... 56
5.7. Interim monitoring and study stopping rules ............................................................................................. 57
6. TREATMENT OF STUDY SUBJECTS ...................................................................................................................... 57
6.1. Study visits................................................................................................................................................... 57
6.2. Additional study procedures ....................................................................................................................... 61
7. ASSESSMENT OF SCIENTIFIC OBJECTIVES........................................................................................................... 63
7.1. Primary endpoints and outcome measures ................................................................................................ 63
7.2. Secondary endpoints and outcome measures ............................................................................................ 64
7.3. Other endpoints and outcome measures ................................................................................................... 65
8. SAFETY ASSESSMENT.......................................................................................................................................... 66
8.1. Specification, timing and recording of safety parameters .......................................................................... 66
8.2. Assessment of Adverse Events .................................................................................................................... 66
8.3. Causality assessment .................................................................................................................................. 68
8.4. Severity assessment .................................................................................................................................... 69
8.5. Reporting procedures ................................................................................................................................. 70
8.6. Procedures to be followed in the event of abnormal findings ................................................................... 71
8.7. Data and Safety Monitoring Committee ..................................................................................................... 71
8.8. Development Safety Update Reports ......................................................................................................... 72
9. STATISTICS .......................................................................................................................................................... 72
9.1. Sample size .................................................................................................................................................. 72
9.2. Analysis ........................................................................................................................................................ 73
10. DATA HANDLING AND RECORD KEEPING......................................................................................................... 73
10.1. Data Handling ............................................................................................................................................ 73
10.2. Record Keeping and Access to Data .......................................................................................................... 73
10.3. Source Data and Case Report Forms (CRFs) .............................................................................................. 74
10.4. Data Protection ......................................................................................................................................... 74
11. QUALITY CONTROL AND QUALITY ASSURANCE PROCEDURES ........................................................................ 74
12. ETHICAL AND REGULATORY CONSIDERATIONS ............................................................................................... 75
12.1.Good Clinical Practice ................................................................................................................................ 75
12.2. Ethical Review ........................................................................................................................................... 76
12.3. Informed Consent ..................................................................................................................................... 76
12.4 . Surgery delay ............................................................................................................................................ 76
12.5. Approvals .................................................................................................................................................. 76
12.6. Reporting ................................................................................................................................................... 76
12.7. Participant Confidentiality ........................................................................................................................ 76


ADVANCE_v6.0                                                          21st August 2019                                                    Page 11 of 86 
13. FINANCE AND INSURANCE ............................................................................................................................... 77
13.1. Financing ................................................................................................................................................... 77
13.2 Insurance .................................................................................................................................................... 77
13.3. Compensation ........................................................................................................................................... 77
14. PUBLICATION POLICY ....................................................................................................................................... 77
APPENDIX 1:  SCHEDULE OF ATTENDANCE AND STUDY PROCEDURES ................................................................. 78
APPENDIX 2: SEVERITY GRADING FOR IMPORTANT IMMUNE-MEDIATED AEs ..................................................... 82
REFERENCES ........................................................................................................................................................... 84


ADVANCE_v6.0                                                          21st August 2019                                                    Page 12 of 86 
KEY ROLES AND GENERAL INFORMATION  
Trial Centres  
Centre for Clinical Vaccinology and  
Tropical Medicine   
Churchill Hospital  
Old Road, Headington   
Oxford, OX3 7LJ, UK  
Department of Oncology  
Churchill Hospital  
Oxford University Hospitals NHS Foundation Trust  
Old Road, Headington, Oxford, OX3 7LE, UK  
Department of Urology 
Churchill Hospital  
Oxford University Hospitals NHS Foundation Trust  
Old Road, Headington, Oxford, OX3 7LE, UK  
Department of Oncology 
The Christie NHS Foundation Trust 
Wilmslow Road 
Manchester  
M20 4BX 
Chief Investigator 
 
Dr Mark Tuthill 
Oxford Cancer and Haematology Centre 
Churchill Hospital  
Oxford University Hospitals NHS Foundation Trust  
Old Road  
Oxford, OX3 7LE, UK  
Tel: 01865 227042 
Fax: 01865 235982 
Email: mark.tuthill@oncology.ox.ac.uk 
Lead Investigator 
   
  
 Professor Freddie Hamdy  
Nuffield Department of Surgical Sciences 
University of Oxford  
John Radcliffe Hospital   
Oxford University Hospitals NHS Foundation Trust  


ADVANCE_v6.0                                                          21st August 2019                                                    Page 13 of 86 
Headley Way  
Oxford, OX3 9DU, UK  
Tel: 01865 221297  
Fax: 01865 765063  
Email: freddie.hamdy@nds.ox.ac.uk
Lead Investigator   
Professor Adrian VS Hill  
                                                        Centre for Clinical Vaccinology  
                                                        and Tropical Medicine   
Churchill Hospital   
Old Road, Headington  
Oxford, OX3 7LJ, UK  
Tel: 01865 857417  
Fax: 01865 857471  
Email: adrian.hill@ndm.ox.ac.uk  
Principal Investigator   
                          Associate Professor Andrew Protheroe  
Oxford Cancer and Haematology Centre 
Churchill Hospital  
Oxford University Hospitals NHS Foundation Trust  
Old Road  
Oxford, OX3 7LE, UK  
Tel: 01865 372300 
Fax: 01865 235982 
Email: andrew.protheroe@oncology.ox.ac.uk 
Principal Investigator
Professor Peter Hoskin
Department of Oncology 
The Christie NHS Foundation Trust 
Wilmslow Road 
Manchester, M20 4BX 
Tel: 0161 302 3242
Email: peterhoskin@nhs.net


ADVANCE_v6.0                                                          21st August 2019                                                    Page 14 of 86 
Co-Investigators 
                         
RJ Bryant 
SF Brewster    
C Verrill   
 
           R McPherson  
G Attard 
Study Medical Monitor                                      Professor Simon Crabb 
Cancer Sciences Unit 
University of Southampton Faculty of Medicine 
Southampton, SO16 6Y 
Tel.: +44 (0)23 8120 517 
S.J.Crabb@southampton.ac.uk 
Chair of Data and Safety  
Monitoring Committee           
Dr Miranda Payne  
Oncology Department 
Churchill Hospital  
Oxford University Hospitals NHS Foundation Trust  
Old Road  
Oxford, OX3 7LE, UK  
Tel: 01865 235272 
Sponsor
University of Oxford  
Named contact: Heather House,  
Clinical Trials and Research Governance  
                          Boundary Brook House  
                          Churchill Drive,  
Headington, Oxford OX3 7LQ   
Phone: 01865 572224  
Email: ctrg@admin.ox.ac.uk 


ADVANCE_v6.0                                                          21st August 2019                                                    Page 15 of 86 
ABBREVIATIONS 
AE 
 
Adverse event   
ALP
 Alkaline Phosphatase 
ALT 
 
 Alanine aminotransferase  
AST
 Aspartate Aminotransferase 
CCVTM 
 Clinical Centre for Vaccinology and Tropical Medicine  
CBF 
 
 Clinical Biomanufacturing Facility  
ChAdOx1 
 Chimpanzee Adenovirus Ox1  
CMI 
 
 Cell-mediated immunity  
CPI 
 
Checkpoint inhibitor 
CRF 
 
 Case report form  
CTC 
 
Circulating tumour cell 
ctDNA  
Circulating tumour DNA 
CTL 
 
 Cytotoxic T lymphocytes  
DSMC  
 Data and Safety monitoring committee  
ELISA  
 Enzyme-linked immunosorbent assay  
ELISPOT 
 Enzyme-linked immunospot  
ENZ 
 
 Enzalutamide 
FBC 
 
 Full blood count  
GCP 
 
 Good Clinical Practice  
GMP  
 Good Manufacturing Practice  
HBsAg  
 Hepatitis B Surface Antigen   
HBV 
 
Hepatitis B virus  
HCV 
 
 Hepatitis C Virus  
HIV 
 
 Human Immunodeficiency Virus  
HLA 
 
 Human leukocyte antigen  
IB 
 
Investigator’s Brochure 
ICS 
 
 Intracellular cytokine staining  
IFN-γ  
 Interferon-gamma  
i.m. 
 
 Intramuscularly  
IMP 
 
 Investigational Medicinal Product  
IRB 
 
Independent Review Board  
i.p. 
 
 Intraperitoneally   
i.v. 
 
 Intravenously 
LDH
 Lactate dehydrogenase 
LFT 
Liver function test  
LSM 
 
Local safety monitor 
mAb 
 
Monoclonal antibody  
mCRC  
 Metastatic colorectal cancer 
mCRPC 
 Metastatic castration resistant prostate cancer  
MDT  
 Multidisciplinary team 
MHRA
 Medicines and Healthcare products Regulatory Agency  


ADVANCE_v6.0                                                          21st August 2019                                                    Page 16 of 86 
MVA  
Modified Vaccinia virus Ankara
NHS 
 
National Health Service
OS 
 
Overall survival
PAP 
 
 Prostatic acid phosphatase 
PBMC  
Peripheral blood mononuclear cells  
PCa
 Prostate Cancer 
PCR 
 
Polymerase chain reaction 
PD-1  
 Programmed Death-1 
PFS 
 
Progression-free survival
Pfu 
 
Plaque forming units 
PD-L1  
 Programmed Death-1 ligand 
PSA 
 
Prostate specific antigen 
REC 
 
 Research Ethics Committee  
RP 
 
radical prostatectomy  
SAE 
 
Serious adverse event  
SFC 
 
Spot-forming cell 
SmPC  
 Summary of Product Characteristics  
SOP 
 
Standard Operating Procedures  
STEAP1 
Six transmembrane anigen of the prostate 
SUSAR  
Suspected unexpected serious adverse reaction  
TAA 
 
Tumour-associated antigen  
Vp 
 
Virus particles 


ADVANCE_v6.0                                             21st August 2019                                                    Page 17 of 86 
1. SYNOPSIS 
Trial Title 
Phase I/II open label non-randomised safety and efficacy study of the 
viral vectored ChAd-MVA 5T4 vaccine in combination with PD-1 
checkpoint blockade in low- or intermediate-risk localised or locally 
advanced prostate cancer and advanced metastatic prostate cancer  
Trial identifier 
ADVANCE  
Trial Centres 
Centre for Clinical Vaccinology and Tropical Medicine  
Churchill Hospital, Old Road, Headington  
Oxford OX3 7LJ, UK  
Urology Department   
Churchill Hospital  
Oxford University Hospitals NHS Foundation Trust  
Old Road, Headington, Oxford, OX3 7LE, UK  
Oncology Department   
Churchill Hospital  
Oxford University Hospitals NHS Foundation Trust  
Old Road, Headington, Oxford, OX3 7LE, UK  
Department of Oncology 
The Christie NHS Foundation Trust 
Wilmslow Road 
Manchester 
M20 4BX, UK 
Clinical Phase 
Phase I/II  
Trial Design 
Open label, non-randomised   
Trial Population 
Men aged 18 years and over, diagnosed with low- or intermediate-risk 
localised or locally advanced prostate cancer scheduled for radical 
prostatectomy (RP), or diagnosed with metastatic prostate cancer 
Planned Sample Size  
36 subjects 
Group 1: 12 subjects per group 
Group 2: 24 subjects per group 
Group 1:   Low- or Intermediate-risk localised or locally advanced 
prostate cancer patients scheduled for RP 
ChAd-MVA 5T4 vaccine (one cycle) plus 1 dose of anti-PD-1 mAb 
(nivolumab) 


ADVANCE_v6.0                                             21st August 2019                                                    Page 18 of 86 
Group 2:   Metastatic prostate cancer patients progressing on the 
second generation anti-androgens (e.g. abiraterone or enzalutamide) 
 ChAd-MVA 5T4 vaccine (two cycles) plus 3 doses of anti-PD-1 mAb 
(nivolumab) 
Follow up Duration 
6 months for surgery patients and 12  months for metastatic patients 
Planned Study Period  
Approximately 2 years 
Co-primary Objectives 
Low- or intermediate-risk localised or locally advanced prostate cancer 
patients: 

To assess safety of the viral vectored ChAd-MVA 5T4 vaccine 
when administered in combination with anti-PD-1  mAb  

To determine whether ChAd-MVA 5T4 vaccine in combination 
with anti-PD-1 will impact on the serum level of PSA  
Metastatic prostate cancer patients 

To assess safety of the viral vectored ChAd-MVA 5T4 vaccine 
when administered in combination with anti-PD-1  mAb  

To assess efficacy of the viral vectored ChAd-MVA 5T4 vaccine 
when administered in combination with anti-PD-1 mAb as 
measured by composite response rate defined as one of the 
following: 
- reduction of circulating tumour DNA  
- serum PSA decrease
Secondary Objectives 
Low- or intermediate-risk localised or locally advanced prostate cancer 
patients: 

To assess the magnitude of immune responses in the periphery 
generated by ChAd-MVA 5T4 vaccine in combination with anti-
PD-1 mAb 

To assess immune cell subsets in the prostate secondary to 
treatment 
Metastatic prostate cancer patients 

To assess the magnitude of immune responses in the periphery 
generated by ChAd-MVA 5T4 vaccine in combination with anti-
PD-1 mAb 
• 
To evaluate radiographic progression-free survival at 6 and 12 
months post enrolment
• 
To evaluate overall survival at 6 and 12 months post enrolment 
Investigational Products ChAdOx1.5T4  
MVA.5T4  
PD-1 mAb (nivolumab) 


ADVANCE_v6.0                                             21st August 2019                                                    Page 19 of 86 
Forms 
ChAdOx1.5T4                        liquid  
MVA.5T4                                liquid  
PD-1 mAb (nivolumab)        liquid 
Doses 
ChAdOx1.5T4                    2.5 x 1010 vp  
MVA.5T4                            2.0 x 108 pfu  
PD-1 mAb (nivolumab)    480mg 
Route 
ChAdOx1.5T4 and MVA.5T4: Intramuscular (i.m.) injection in a thigh  
PD-1 mAb (nivolumab):          Intravenous (i.v.) infusion 
2. BACKGROUND AND RATIONALE  
2.1. The need for a new vaccine against prostate cancer  
Prostate cancer is the most common non-skin cancer in men and the second leading cause of 
cancer-related death in the Western world, including the UK. At present, prostate cancer is most 
often diagnosed at a clinically localised disease stage following blood testing for prostate-
specific antigen (PSA). However, approximately one third of men treated with surgery or 
radiotherapy for clinically localised prostate cancer will experience recurrence of the disease. If 
the disease progresses to metastatic castration-resistant prostate cancer (mCRPC), the 
treatment options are limited and mainly palliative. Second generation anti-androgen agents 
(i.e. abiraterone and enzalutamide) have recently been approved by the FDA for treatment of 
mCRPC. However, resistance to these drugs often ensues,  with the disease becoming lethal.  
There is a substantial body of evidence that immune responses can control and eradicate cancer. 
Numerous studies have demonstrated an increase in spontaneous and carcinogen-induced 
cancers in immunocompromised mice1. Epidemiological studies show that there is an increasing 
risk of cancer among people treated with immuno-suppressants following transplantion2. It is 
now accepted that immune responses can be directed to antigens expressed in tumours 
(tumour-associated antigens, or TAAs) which can lead to long-term tumour control or destroy 
tumours.   
Over the last decade, cancer immunotherapy has been evolving as a viable option for treatment 
of advanced stage prostate cancer patients. The first and to date only one therapeutic cancer 
vaccine, Provenge, has been approved by the FDA, and is indicated for an asymptomatic or 
minimally symptomatic metastatic castration resistant prostate cancer3. This immunotherapy 
targets one of the prostate-associated TAAs – prostatic acid phosphatase (PAP). The treatment 
entails three rounds of leukapheresis per patient, in vitro stimulation of the cells shipped to a 
centralized manufacturing facility and re-infusion of the cells. The vaccine has shown statistically 
significant though modest efficacy in clinical trials, increasing overall survival in treated patients 
by four months. However, no effect on time to tumour progression compared to placebo group 
has been observed, and the induced T cell responses appeared to be rather weak4. Additionally, 


ADVANCE_v6.0                                             21st August 2019                                                    Page 20 of 86 
there are substantial cost implications for this individualised immunotherapy in that the vaccine 
is custom-made and currently the treatment costs over $90,000 per patient. Given the high price 
for a modest effectiveness, Provenge is unlikely to be cost-effective, in particular because
individually tailored approaches are logistically impractical on a population basis.   
Another clinically advanced vaccine, PROSTVAC, was until recently in a Phase III clinical trial 
(NCT01322490). This vaccine comprises two recombinant viral vectors, replication competent 
vaccinia- and fowlpox viruses, each encoding a transgene for PSA. The treatment consists of a 
priming injection with vaccinia vector followed by 6 boosting injections with the fowlpox vector. 
In a prospective randomized, double-blind, placebo-controlled phase II study in patients with 
metastatic prostate cancer, men in the PROSTVAC group had a significant increase in median 
overall survival (8.5 months) compared to the control group. However, there was no antibody 
response to PSA, and T cell immune responses were very modest5. Recently, it was announced 
that no significant efficacy was observed in the phase III trial. Taken together, the available data 
on immunogenicity of prostate cancer vaccines indicate the need for more effective vaccine 
capable of eliciting sustained immune responses of high magnitude which can promote tumour 
control and lead to anti-tumour responses.  
The efficacy of  immunotherapy may be best at the early stages of prostate cancer, when cancer 
cell deposits are comparatively few and small, and are more accessible to the cytotoxic T cells 
(CTL), which are the major players in anti-tumour protection. If an effective prostate cancer 
vaccine is administered before or soon after radical treatment with curative intent to patients 
without clinical evidence of metastatic disease, but who could later develop recurrence because 
of undetected micrometastases, there would be a minimal tumour burden for the CTLs to 
destroy and, therefore, the treatment may be more likely to be curative.  
A new class of anti-cancer drugs termed immune checkpoint inhibitors (CPIs) has recently 
emerged. These belong to a category of antigen non-specific immunotherapies, in contrast to 
Provenge and PROSTVAC. The immune system is capable of recognising and eliminating cancer 
but it is held in check by inhibitory receptors and ligands. These immune checkpoint pathways, 
which normally maintain self-tolerance and down-regulate immune responses to pathogens to 
limit collateral tissue damage, can be co-opted by cancer to evade immune destruction. The 
novel drugs are the molecules that interrupt these immune checkpoint pathways and thus 
unleash anti-tumour immunity. The monoclonal antibodies (mAbs) against CTLA-4 (Cytotoxic T-
lymphocyte–associated antigen 4),  PD-1 (Programmed Death-1) and PD-L1 (Programmed Death 
Ligand-1) are the first drugs having entered the clinic as immunotherapies, and they have been 
licenced for advanced melanoma, lung, bladder, kidney cancers and other cancer types6,7.  
It is noteworthy that cancer types with the highest response rate to PD-1 blockade are the ones 
with the highest mutational load. Mutated proteins can give rise to neoantigens that are likely 
to be recognized by the host immune system and generate a spontaneous anti-tumour immune 


ADVANCE_v6.0                                             21st August 2019                                                    Page 21 of 86 
response. Prostate cancer is known to have a relatively low mutational burden and this may, at 
least in part, explain the observation that checkpoint inhibitors have shown limited clinical 
benefit in prostate cancer to date8,9. However, the data from the ongoing KEYNOTE-199 study 
(NCT02787005) reported (by de Bono et al.) at the ASCO annual meeting in June 2018 (abstract 
number 5007) demostrate that anti PD-1 therapy had clinical activity in 11% of 258 metatstatic 
castration-resistant prostate cancer patients. These drugs are even more likely to be clinically 
effective in prostate cancer if they are delivered in combination with an immunogenic vaccine, 
thus circumventing the need for tumour-specific neoepitopes in order to induce spontaneous 
anti-tumour immune responses.  
2.2. Rationale for the study design  
Heterologous ChAdOx1-MVA prime boost regime  
ADVANCE will investigate a vaccination regime comprising a simian adenovirus ChAdOx1 as a 
priming agent and an MVA vector as a boosting vaccine. Both viral vectors will encode the same 
antigen, the TAA 5T4. Previous studies have shown that heterologous prime-boost regimens 
(rather than homologous prime-boost regimes) employing different genetic vaccine vectors are 
better means to induce potent T cell responses in nonhuman primates and humans10-12. 
Adenovirus vectors have attracted considerable attention as potential viral vectors for genetic 
vaccination given their favourable safety profile and potent transduction efficiency following 
intramuscular injection. However, the neutralising antibody response against adenoviral capsid 
proteins following adenovirus vectors injection limits the success of vaccination protocols based 
on multiple administrations of the same adenoviral serotype. This has lead to the consideration 
of simian adenoviruses, which are not known to cause pathology or illness in humans and to 
which the prevalence of antibodies is low. There is already considerable clinical experience with 
this vector expressing influenza 13 and tuberculosis antigens.
A therpauetic vaccine in the form of MVA.5T4 viral vector was originally developed by Oxford 
BioMedica Ltd under a trade name of TroVax® as a homologous prime boost vaccination regime 
and to date has been administered to over 600 cancer patients14-16 (details in section 2.4). More 
recently Oxford has developed a new MVA.5T4 vector with the same transgene insert, but 
expressed from a different likely more potent poxvirus promoter. 
The ChAdOx1-MVA 5T4 vaccination regime has undergone the first clinical testing as a prostate 
cancer vaccine in the VANCE01 study, which was completed in May 2018 (NCT02390063). 
Preliminary data analysis from low- and intermediate-risk localised prostate cancer patients 
enrolled in this study to date have demonstrated that the vaccine has a good safety profile and 
elicits substantial T cell immunogenicity (section 2.5). 


ADVANCE_v6.0                                             21st August 2019                                                    Page 22 of 86 
Selection of the 5T4 antigen as a prostate cancer vaccine transgene 
The vaccine transgene, 5T4 antigen, is a transmembrane glycoprotein of 72 kDa normally 
expressed on the embryonic tissue but also on various malignant tumour cells, whereas tissue 
from all essential organs are negative for 5T4 expression. Weak to moderate staining was 
observed in some specialized epithelia; however, this staining was weak compared to the 
human placenta positive control.  
The 5T4 antigen plays a vital role in the multiple biological and pathological processes including 
massive cellular migration during embryogenesis, cell invasion associated with implantation, 
and neoplastic metastasis in the progression of tumour genesis. Expression of 5T4 decreases 
cell-substratum attachment and increases cellular motility17. The 5T4 antigen is expressed in a 
wide spectrum of human solid malignancies including prostate cancer, and high expression of 
5T4 is associated with poor prognosis18. Significant expression of 5T4 has been detected in the 
majority of primary prostate cancers (16/19, 84%) studied. In addition, although access to 
biopsy material from metastatic prostate cancer is limited, three samples confirmed as PSA 
positive were also positive for 5T4 expression, whereas expression of this protein is not evident 
in normal prostate tissues (screen of three donors) but is present at low levels in benign 
prostatic hyperplasia (BPH). 5T4 antigen expression in BPH contrasts with that identified in 
prostatic carcinomas; expression is generally diffuse and at low level with localisation to basal 
epithelial cells, whereas in primary prostate cancer samples expression is generally high and 
does not show any apparent polarization. These data indicate that 5T4 antigen is not expressed 
in normal prostatic epithelia, but is expressed at low levels in non-malignant hyperplasia and 
at high levels in prostate cancer. These observations support the hypothesis that 5T4 
expression increases in association of malignant epithelial progression and suggest that the 
5T4 antigen is a promising target for prostate cancer immunotherapy.   
PD-1 checkpoint blockade in prostate cancer
The clinical activity of PD-1 checkpoint monotherapy has been confirmed in a number of 
malignancies, including melanoma, kidney, lung, urothelial, head and neck cancer and Hodgkin’s 
lymphoma. This approach may also be advantageous for targeting prostate cancer, a disease for 
which anti-tumour vaccines have demonstrated clinical benefit, and yet PD-1 pathway inhibitors 
alone or in combination with vaccines have not been studied extensively. 
The main two reasons for prostate cancer being left out from the list of suitable targets for PD-1 
axis inhibition are reported prostate tumour negativity for PD-L1 expression and low tumour 
mutational load resulting in a limited number of potentially immunogenic neoantigens. The latter 
issue could be circumvented if checkpoint blockers are co-administered with a vaccine delivering 
a specific antigen for an immune attack rather than relying on spontaneous immune responses 
to neoantigens. 


ADVANCE_v6.0                                             21st August 2019                                                    Page 23 of 86 
Regarding prostate cancer and PD-L1 expression, there are several arguments in support of anti-
PD1 treatment in prostate cancer settings. The full activity spectrum of PD-1 pathway-blocking 
drugs is not yet known. Although PD-L1 presence appears to enrich for response to anti-PD1/L1 
therapy, it has been documented that patients with PD-L1 negative tumours can also respond to 
treatment, and in urogenital cancers (such as bladder carcinoma and renal cell carcinoma), 
patients with both PD-L1 positive and negative tumours responded at the same rate19. Efficacy of 
PD1 therapy in PD-L1 negative tumours may be attributed to several factors. Firstly, the 
immunohistochemistry assays for detecting PD-L1 expression in tumours are still under 
development, and some methods and antibodies used in these assays may be more sensitive and 
specific than others. Also, there may be differences in definition of positivity (tumour cells only 
or expression on other cells in the various studies)20.  
Technical aspects aside, given the focal nature of PD-L1 expression within many tumours and 
information about intra-tumoural genetic heterogeneity21, if small needle biopsies are screened, 
a false-negative evaluation could potentially ensue. Also, PD-L1 expression is likely to fluctuate 
over time in response to changes in tumour microenvironment, e.g. PD-L1 is up-regulated on 
tumour cells following IFNγ secretion by vaccine-induced T cells. All of these factors may lead to 
a poor correlation between PD-L1 expression levels at any one time point and response to 
therapy. 
Consideration also has to be given to the PD-L1 expression on various immune cell types in 
addition to tumour cells. IFNγ has been demonstrated to induce the up-regulation of PD-L1 by 
many cell types including myeloid-derived cells, regulatory Tcells and endothelial cells22-24. Other 
cytokines including IL-2, IL-7, IL-15 and IL-21 have also been shown to up-regulate PD-L1 
expression by various cell types25. Moreover, a significantly increased number of PD-L1/2-positive
dendritic cells and a high frequency of PD-1 positive T cells have recently been detected in blood 
samples of prostate cancer patients progressing on enzalutamide compared to treatment-naïve 
patients or those responding to treatment26. 
With further development and validation of PD-L1 antibodies for immunohistochemistry, the new 
data have recently emerged regarding PD-L1 expression on primary prostate tumours. The PD-L1 
expression was reported in prostate tumour epithelial cells in 92% of cases27. More importantly, 
expression of the PD-L1 was not only highly prevalent in primary prostate cancer cells but was 
also an independent indicator of biochemical recurrence, suggesting a biologic relevance in 
primary tumors and potential clinical benefit for hormone-naïve prostate cancer28. 
Based on all of this information, prostate cancer patients may derive clinical benefit from PD-1 
blockade in combination with the ChAdOx-MVA vaccine. Despite the apparent negative PD-L1 
expression status of prostate tumours, there are some clinical trials evaluating the effect of anti-
PD-1 mAbs in the advanced prostate cancer stage setting (NCT02312557, NCT00730639, 
NCT01968109) and some of these studies are testing the efficacy of anti-PD-1 mAbs in 
combination with vaccines (NCT02325557, NCT0142096). 


ADVANCE_v6.0                                             21st August 2019                                                    Page 24 of 86 
Encouragingly, the first meaningful evidence of PD-1 clinical activity in advanced metastatic 
prostate cancer has recently emerged. Graff and colleagues enrolled 27 men with mCRPC 
progressing on the androgen receptor antagonist enzalutamide (ENZ) and treated them with anti-
PD-1 mAb pembrolizumab. Five of the 27 treated patients demonstrated a strong response to the 
treatment, with a 99% PSA  reduction and observed shrinkage of measurable tumour lesions 
(ESMO 2017). 
A large multi-centre international trial, KEYNOTE-199, to evaluate pembrolizumab as a 
monotherapy in 370 patients with metastatic castration resistant prostate cancer previously 
treated 
with 
docetaxel-based 
chemotherapy 
is 
currently 
ongoing 
(NCT02787005).  
Groundbreaking preliminary results from 258 patients already recruited to the trial were reported 
by De Bono and colleagues at the ASCO annual meeting in June 2018 (J Clin Oncol 36, 2018 (suppl; 
abstr 5007). It was demonstrated that pembrolizumab has antitumour activity in both PD-L1 
positive and PD-L1 negative patients with mCRPC, as shown in the figure below. Across all 
cohorts, disease control rate lasting ≥6 months was 11% in both RECIST-measurable and non-
measurable disease.  
Metastatic castration-resistant prostate cancer is genetically heterogeneous and includes DNA 
repair defective subtypes. DNA repair defects were suggested to be associated with 
pembrolizumab anti-tumour activity in this study. These data support further evaluation of anti 
PD-1 therapy in mCRPC and, in particular, in combination with vaccines that would provide a 
tumour-associated antigen as an alternative to naturally occurring mutated antigens.  


ADVANCE_v6.0                                             21st August 2019                                                    Page 25 of 86 
In ADVANCE, we are targeting a 25% or greater response rate to the vaccine in combination with 
PD-1 blockade in mCRPC patients. The sample size of 24 patients in Group 2 will require that 6 
out of 24 treated patients will have complete response, partial response or stable disease. The 
patient cohorts recruited to the KEYNOTE-199 study will serve as a control group for ADVANCE 
and 11% overall response rate to PD-1 blockade as a monohterapy will be compared with the 
response rate to the vaccine in combination with anti-PD-1 treatment in the ADVANCE patients. 
If six of 24 treated patients do respond as described the would be a significantly (P,0.05, two-
tailed) higher rate than in the KEYNOTE-199 series and suggest added value to use of the viral 
vectors, supporting their assessment in a future larger scale trial.  
Route of injection 
The choice of the intramuscular route for ChAdOx1 vector is based on the assumption that no 
co-infection of natural human adenovirus could occur at this site. Furthermore, there is a large 
body of data from human clinical trials using replication defective Ad5- and Ad6-based HIV 
vaccines injected intramuscularly showing an excellent safety profile, no viral shedding, and high 
levels of immunogenicity. MVA.5T4 will also be given by the intramuscular route following data 
from A. Hill showing enhanced immunogenicity and less local reactivity (study VAC033) when 
MVA vectors are administered via the intramuscular compared to subcutaneous route.   
Change From Baseline in Sum of <br />Target Lesions, Cohorts 1+2 
Presented By Johann De Bono at 2018 ASCO Annual Meeting 


ADVANCE_v6.0                                             21st August 2019                                                    Page 26 of 86 
Anti-PD-1 monoclonal antibody will be administered by intravenous infusion as per the SmPC. 
Vaccine and immune checkpoint inhibitor dose 
In this study ChAdOx1.5T4 and MVA.5T4 vaccines are administered in a single injection at the 
dose of 2.5x1010 vp and 2x108 pfu respectively. Low- or intermediate-risk prostate cancer 
patients will receive one cycle of ChAd and MVA immunisation with the vaccines given one week 
apart. Metastatic prostate cancer patients will receive two cycles of ChAd-MVA immunisations 
with the vaccines given four weeks apart. This is intended to boost the elicited immune response 
and to maintain the pool of antigen-specific memory T cells. The interval between the cycles will 
be approximately 2 months. In the recently compelted phase I trial there was similar 
immunogenicity with intervals between the ChAd and MVA vector administration of 1 and 4 
weeks. The 1 week interval is likely to be preferred by low and intermediate risk patients as this 
reduces time to surgery. 
PD-1 mAb (nivolumab, Opdivo®) is administered intravenously at a uniform dose of 480mg per 
infusion.  Low- or intermediate-risk prostate cancer patients will receive one intravenous 
infusion of nivolumab concomitantly with MVA.5T4 vaccine (i.e. on the same day as the vaccine).  
Metastatic prostate cancer patients will receive three intravenous infusion of nivolumab four 
week apart, with the first dose given concomitantly with the first MVA.5T4 vaccine.  
The dosing regimens for each arm are shown in the diagram below. 


ADVANCE_v6.0                                             21st August 2019                                                    Page 27 of 86 
Selection of the study patient cohort  
Low- or intermediate-risk localised or locally advanced prostate cancer patients undergoing RP. 
One trial cohort in this study will comprise patients who have been diagnosed with low- or 
intermediate-risk non-metastatic prostate adenocarcinoma and who are scheduled for radical 
prostatectomy. Surgery is one of the standard treatment options for localised or locally advanced 
prostate cancer. This patient cohort has been chosen for the study for a number of reasons. 
Firstly, these patients are likely to benefit from immunotherapy that may prevent relapse after 
primary treatment for localised or locally advanced prostate cancer. Their immune system has 
not been compromised by either immunosuppressive drugs or the immunosuppressive effects 
arising from a significant tumour burden, and therefore, these men are more likely to mount a 
tumour-specific immune response following vaccination, and therein benefit from a vaccine that  
induces long-lasting prevention of tumour recurrence via induction of immune memory. 
Importantly, this patient population has been shown to mount 5T4-specific immune responses 
following ChAdOx1-MVA 5T4 vaccination as a monotherapy in the VANCE01 study. In the current 
study, we will investigate the possibility that a combination of the vaccine with anti-PD-1 mAb 
will result in stronger immunity and / or enhanced clinical benefit compared to the vaccine as a 
single agent tested in VANCE01. 
MVA
ChAd
0
1
Screening
Group 1 dosing regimen
Group 2 dosing regimen
MVA
ChAd
0
4
Screening
ChAd
MVA
8
12
16
v
weeks
weeks
v


ADVANCE_v6.0                                             21st August 2019                                                    Page 28 of 86 
This trial design will allow a rapid assessment of the vaccine’s immunological effect, and not only 
in circulation but, more importantly, in samples from a surgical specimen. Tissue from the whole 
prostate following surgical removal will be studied using immunohistochemistry to investigate 
the impact of vaccination on the tumour characteristics, including the number of CD8+ and CD4+ 
T cells and Gleason grading, by comparing these post-treatment surgical samples against baseline 
pre-treatment diagnostic biopsy samples. In addition, the specificity of tumour-infiltrating 
lymphocytes in the prostate will be compared against that of those in the blood, to investigate if 
T cells are enriched for those targeting the 5T4 antigen (if a fresh surgical specimen is available).   
Metastatic prostate cancer patients 
A second trial cohort in this study will comprise patients with metastatic castration resistant 
prostate cancer (mCRPC) with evidence of progression on anti-androgens. In the CRPC setting, 
the primary successful therapeutic target remains the androgen receptor. Intensive research into 
androgen receptor resistance mechanisms has enabled effective new treatments - androgen 
synthesis pathway targeting agents, such as abiraterone, and direct inhibitors of the androgen 
receptor, such as enzalutamide (ENZ). All patients with CRPC will ultimately succumb to the 
disease in the absence of a competing cause of mortality. The majority of prostate cancer vaccine 
monotherapies have to date been tested in this patient cohort and have demonstrated significant 
but only modest survival benefit.  
Whilst CRCP patients have shown resistance to immune checkpoint blockade29-31 until recently, 
there are several lines of evidence to indicate that metastatic patients who are resistant to the 
second generation anti-androgens (particularly enzalutamide), can be particularly susceptible to 
immunotherapies. In one case study, a durable complete PSA response was reported in a patient 
progressing on ENZ following treatment with Provenge32. More recently, in a small trial of ten 
mCRPC patients progressing on ENZ and treated with anti-PD-1 mAb, three patients experienced 
rapid PSA reduction to ≤ 0.2 ng/ml33. Although the mechanisms behind efficacy of the vaccine and 
checkpoint blockade in ENZ-resistant patients remain to be elucidated, there are considerable 
data showing that androgen-ablation may augment an anti-tumor immune response.  
Second generation anti-androgen therapy represents a more potent form of androgen 
suppression and may therefore be associated with previously under-appreciated immune 
modulatory effects. Interestingly, patients progressing on ENZ had significantly increased PD-L1/2 
positive dendritic cells in blood compared to treatment-naïve or those responding to treatment26. 
These data would be consistent with the notion that responses to immunotherapy might be more 
common in men progressing on enzalutamide and potentially abiraterone and thus provide a 
rationale for selecting this patient cohort for this trial.  
Early evidence of vaccine efficacy in combination with PD-1 blockade compared to PD-1 
inhibition on its own will be assessed by novel genomic analysis methods, in addition to 


ADVANCE_v6.0                                             21st August 2019                                                    Page 29 of 86 
established efficacy endpoints such PSA reduction, progression-free survival (PFS) and overall 
survival (OS). Circulating tumour DNA (ctDNA) and circulating tumour cells (CTCs) quantification 
will be performed at baseline and following the immunotherapy course to monitor tumour 
burden secondary to intervention.  
2.3. Pre-clinical studies involving ChAdOx1-MVA 5T4 vaccine as a monotherapy 
and in combination with PD-1  
ChAdOx1.5T4 -MVA.5T4 prime boost vaccination regime as a monotherapy  
The ChAdOx1.5T4 vaccine has shown robust immunogenicity in mouse studies. A summary of 
representative data is described below. The ChAdOx1.5T4 vaccine has been used most 
commonly in a heterologous prime-boost regimen with MVA.5T4. In a typical experiment, 6-8 
week old C57BL/6 mice were primed with ChAdOx1.5T4 on day 0 and boosted with MVA.5T4 
four weeks later on day 28. All vaccines were delivered intramuscularly.  The dose of adenovirus 
was 5 x 109 vp and the dose of MVA was 1 x 107 pfu. Anti-5T4 cellular immune responses were 
assessed two weeks after the prime on day 14 and one week after the boost on day 35 by an 
IFNγ ELISPOT assay performed on PBMCs (Figure 1). An IFN-γ ELISPOT assay was also performed 
on the splenocytes 2 weeks after the MVA boost (Figure 2). The dissection of the responses to 
the individual 5T4 peptide pools demonstrated a broad specificity of the induced immune 
responses (Figure 3). In conclusion, the ChAdOx1-MVA 5T4 prime-boost vaccination regime is 
immunogenic in a mouse model.


ADVANCE_v6.0                                             21st August 2019                                                    Page 30 of 86 


ADVANCE_v6.0                                             21st August 2019                                                    Page 31 of 86 
Immunopotency of the clinical grade ChAdOx1.5T4 batch  
The immunopotency assay was performed to compare a pre-clinical stock of the vaccine with 
the clinical grade ChAdOx1.5T4 vaccine manufactured by the Oxford Clinical Biomanufacturing 
Facility (CBF).   
Two groups of 6-8 week old C57BL/6 male mice were vaccinated intramuscularly with 5 x 109 vp 
of the pre-clinical stock of ChAdOx1.5T4 vaccine and 5 x 109 vp of the clinical grade vaccine. For 
additional information, two sets of 5 mice were vaccinated with 5 x 108 vp and 5 x 107 vp per 
mouse. Thirteen days later the mice were sacrificed and the spleens harvested for an ex-vivo 
IFNγ ELISPOT assay. This assay demonstrated that ChAdOx1.5T4 elicited a strong cellular 
immune response, with all mice responding, at all three doses tested (Figure 4). The assay 
showed equivalent immunopotency of the pre-clinical stock and clinical grade vaccines (Figure 
5).  


ADVANCE_v6.0                                             21st August 2019                                                    Page 32 of 86 
Safety of the clinical grade ChAdOx1.5T4 batch 
A GLP repeat dose toxicity study of the ChAdOx1.5T4 vaccine has been performed at the 
Huntingdon Life Sciences test facilities. The objective of this study was to investigate the potential 
toxicity of ChAdOx1.5T4 to BALB/c mice when administered by intra-muscular injection on 2 
occasions with a 14 day interval followed by a 13 day observational period. One group comprising 
ten male and ten female mice have received 55 µL of ChAdOx1.5T4 (1 x 10^10 vp) into the right 
hind limb on Day 1 and Day 15. The control group consisting of five male and five female mice 
have received phosphate buffered saline (PBS), at the same volume-dose as the treated group. 
During the study, clinical conditions, body weight, food consumption, haematology (peripheral 
blood), blood chemistry, organ weight, macropathology and histpathology investigations were 
undertaken. 
There was no effect of treatment on bodyweight gain or food consumption. There was no effect 
of treatment on blood chemistry parameters. Haematological examination on Day 28 revealed 
slightly higher group mean neutrophil and lymphocyte counts for treated males and females 
when compared with control males.  This resulted in a slightly higher group mean total white 
blood cell count for treated animals. Values for other parameters, some of which attained a level 
of statistical significance were considered to be within the expected ranges for mice of this age 
and strain. There was no effect of treatment on blood chemistry parameters. 
There were no unscheduled deaths during the study. There were no clinical findings and no 
reaction to treatment at the dose site during the course of the study. It was concluded that 
treatment with ChAdOx1.5T4 was well tolerated and was not associated with any adverse 
effects. 
Figure 5. Immunopotency of ChAdOx1.5T4 pre-clinical
Stock and clinical batch at 5 x 10^9 vp dose
Preclinical stock
Clinical batch
0
100
200
300
SFU/106 Splenocytes


ADVANCE_v6.0                                             21st August 2019                                                    Page 33 of 86 
ChAdOx1.5T4 -MVA.5T4 prime boost vaccination regime in combination with anti-PD-1 
monoclonal antibody  
Previously, we have shown that the ChAdOx1-MVA vaccine encoding the prostate-associated 
antigen STEAP1 in combination with PD-1 blockade enhances efficacy and significantly improves 
survival of mice in the TRAMP-C1 subcutaneous tumour model34. Further research has been 
conducted to assess the immunogenicity and tumour protective efficacy of ChAdOx1-MVA 5T4 
vaccine as a single agent and in combination with checkpoint blocking antibodies. First, we have 
demonstrated that the vaccine alone mediated complete protection against challenge with the 
B16 tumour cell line expressing 5T4 antigen in a prophylactic setting. However, in a therapeutic 
setting the tumour progression has been modestly delayed, so we have evaluated whether the 
vaccine efficacy can be improved by a combination with anti PD-1 mAb35. In a typical experiment, 
C57BL/6 mice were challenged with B16.h5T4 cells and primed with ChAdOx1.h5T4 or MVA.h5T4 
vectors, or were left untreated (naïve mice). One week after, mice received MVA.h5T4 boost and 
PD-1 or isotype control antibodies intraperitoneally (i.p.). A comparative efficacy of the vaccine 
and PD-1 blockade as monotherapies and their combinations is shown in Figure 6 A,B. Firstly, 
blockade of PD-1 on its own offered just marginally better  survival over isotype control mAb. As 
expected, ChAdOx1-MVA vaccine on its own delayed tumour progression to some extent. 
Notably, the administration of this vaccine in combination with anti-PD-1 was significantly more 
effective at suppressing tumour growth and prolonging survival of challenged mice than 
ChAdOx1-MVA vaccination used as monotherapy. In comparison, B16.h5T4 challenged mice 
prime-boosted with the MVA.5T4 vector, succumbed to tumours at the same time as naïve 
controls. Importantly, the analysis of IFNγ responses in PBMCs isolated from the different groups 
demonstrated no effect of anti PD-1 therapy on the magnitude of h5T4-specific T cell responses 
in circulation, suggesting that anti PD-1 antibodies  are acting at the tumour site (Figure 6C).  
5
10
15
20
0
50
100
150
200
250
300
350
400
Days post tumour challenge
Tumour volume, mm3
Naive+IgG
CM h5T4+IgG
CM h5T4+aPD-1
MM h5T4+IgG
MM h5T4+aPD-1
Naive+aPD-1
A


ADVANCE_v6.0                                             21st August 2019                                                    Page 34 of 86 
Figure 6. Heterologous ChAdOx1-MVA h5T4 vaccination regime in combination with anti PD-1 
therapy significantly improves survival in B16.h5T4 melanoma tumour model compared with 
homologous MVA h5T4 vaccination combined to anti PD-1 therapy 
C57BL/6 mice were challenged subcutaneously with 0.5x106 B16.h5T4 cells and immunised 
intramuscularly with 107 IU of ChAdOx1.h5T4 or 106 pfu of MVA.h5T4. One week later, mice were 
boosted with 106 pfu of MVA.h5T4 with PD-1 antibody or isotype control antibody. Naïve control 
mice were challenged and given only antibodies (IgG or PD-1) at the timepoint for boosting 
immunisation. Tumour size was measured three times per week and volumes were calculated as 
described above. Representative data of two biological replicate experiments are shown. (A) 
Tumour growth kinetics for each group expressed by mean tumour volume ± SEM. (B) Kaplan-
Meyer survival curves of the different groups of mice. (C) Graph shows representative data of ex 
vivo blood ELIspot performed after prime-boost immunisations in the different groups of mice. 
Bars represent median spot forming cells (SFC) per 106 PBMCs.
0
5
10
15
20
25
0
20
40
60
80
100
Days post tumour challenge
Percent survival
Naive+IgG
Naive+aPD-1
CM h5T4+IgG
CM h5T4+aPD-1
MM h5T4+IgG
MM h5T4+aPD-1
p=0.017
p=0.013
p=0.016
p=0.008
B
Naive+aPD-1
CM h5T4+IgG
CM h5T4+aPD-1
MM h5T4+IgG
MM h5T4+aPD-1
0
200
400
600
800
1000
SFC/106 PBMCs
C


ADVANCE_v6.0                                             21st August 2019                                                    Page 35 of 86 
2.4. Previous clinical experience with MVA.5T4 vaccine  
An MVA vector expressing the 5T4 antigen has been developed by Oxford BioMedica Ltd under 
the trade name of TroVax®. TroVax® has been administered to over 600 cancer patients. 12 
studies of TroVax® in colorectal, renal and prostate cancer have been completed to date, and 
few serious adverse events have been attributed to TroVax® by investigators or the sponsor. 
Mild transient injection site reactions were reported in the majority of subjects together with 
mild transient pyrexia.  No other notable, common or serious adverse events have been 
reported in studies using TroVax® as a single agent in heavily pre-treated subjects or in studies 
combining TroVax® with chemotherapy, interferon-α and IL-215,36-41.  
Single agent studies  
A single agent study (TV1) was conducted in 22 mCRC patients in objective response or stable 
disease (SD) 2.5 months after the end of first line chemotherapy. Four dose levels and two 
routes of administration (i.m. or i.d.) were tested in this study. TroVax® was well tolerated at 
all dose levels with a similar safety profile at each dose level. The highest dose level tested was 
6.83 x 108 pfu. The safety profile was comparable to the usual safety profile of a vaccine. The 
main AEs considered to be related to TroVax®, all Grade 1, were injection site erythema and 
injection site reaction. Sixteen out of 17 patients evaluable for immune response had a cellular 
or humoral immune response. No radiological objective response was reported.  
A second single agent study (TV-CR-UK) was conducted in 20 patients with resectable liver 
metastases of colorectal cancer. Patients received two injections before and after surgery. Two 
additional injections were administered in case of immune response. Sixteen out of 19 
evaluable patients for immune response had a 5T4 cellular or humoral immune response prior 
to surgery. All 16 patients who completed four TroVax® injections and underwent surgery had 
a 5T4 cellular or humoral immune response after the surgery. Overall, taking into account 
immune response before and after surgery, 18 out of 19 evaluable patients had a 5T4 cellular 
or humoral immune response. The most common AE considered related to TroVax® was Grade 
1-2 injection site reaction.  
Combination studies  
In colorectal cancer 
Two Phase II combination studies were conducted in colorectal cancer (TV2-cr-ch-Oxaliplatin 
and TV2-cr-ch-Irinotecan studies). Chemotherapy did not abrogate the immune response to 
TroVax®. In both studies, the safety profile of TroVax® was similar to the safety profile reported 
in the single agent study. The safety profile of chemotherapy in combination with TroVax® was 
similar to the safety profile of chemotherapy alone.  


ADVANCE_v6.0                                             21st August 2019                                                    Page 36 of 86 
In advanced renal cell cancer 
Four Phase II and 1 Phase III studies were initiated in advanced renal clear cell cancer. One Phase 
II study assessed TroVax® in combination with interleukin-2 high dose (IL-2 HD) (TV2 Renal), 1 
Phase II study of TroVax® in combination with IL-2 low dose (IL-2 LD) (TV-B2-001-05); 1 Phase 
I/II feasibility study of TroVax® with IFN-α (TV2-003-06); and 1 Phase II study of TroVax® with or 
without IFN-α (TV2-002-06).  
A randomized Phase III double blind study was initiated in 2006 (TV3-001-06). This study 
compared TroVax® to placebo combined to standard of care (IL-2, IFN-α, sunitinib) in first line 
advanced (locally advanced or metastatic) renal clear cell cancer. The primary endpoint was 
overall survival; however, following the fourth interim review by the data safety monitoring 
board, the study was judged to be futile and was terminated early.   
In hormone refractory prostate cancer 
Three randomized Phase II studies were initiated in hormone refractory prostate cancer; one 
study evaluated TroVax® either alone or in combination with granulocyte macrophage-colony 
stimulating factor (GM-CSF) (TV-PHPRC-001-06), one study evaluated TroVax® plus docetaxel 
and docetaxel alone (PCa-07-101) but was stopped prematurely due to the termination of the 
TRIST study, and the third study (TV2-001-09) compared TroVax® plus docetaxel and docetaxel 
alone, but was also stopped prematurely owing to slow recruitment.  
Overall conclusions from TroVax clinical studies  
The administration of TroVax® is safe with mild to moderate vaccine reactions, chills, pyrexia, 
arthralgia and myalgia being the only adverse events of note. The safety profile of TroVax® is 
similar to that of a vaccine containing an attenuated vaccinia virus. The vector (MVA) has been 
widely used and no complications were reported when it was administered to over 120,000 
subjects, including subjects at risk from vaccine complication. The safety profile of TroVax® 
allows combination with chemotherapy without increase in treatment toxicity and does not 
abrogate the immune response.  
2.5. Previous clinical experience with ChAdOx1-MVA 5T4 vaccine  
VANCE01 was the first phase I clinical trial to assess the safety and immunogenicity of ChAdOx1-
MVA 5T4 vaccine. VANCE01 began in Oxford in June 2015 (NCT02390063) and completed in May 
2018. It compares ChAd-MVA vaccination to MVA alone, with and without low dose 
cyclophosphamide in low- and intermediate-risk localised prostate cancer.  
An initial clinical assessment of the vaccine has shown it to be both safe and immunogenic for 
cellular and antibody responses to the 5T4 protein. The study design and further details of this 


ADVANCE_v6.0                                             21st August 2019                                                    Page 37 of 86 
trial are given below.  
To date, 40 patients have been enrolled and 39 of these have completed the vaccination course 
comprising either a standard immunisation protocol of 3 immunisations given at 4 week intervals 
or an accelerated protocol of 2 immunisations given at a 1 week interval.   
The majority of adverse events were mild in nature and the interim clinical safety review was 
satisfactory. Both ChAdOx1.5T4 and MVA.5T4 vaccines have been well tolerated in both the 
standard prime-boost and the accelerated prime-boost vaccination regimes. Systemic 
reactogenicity appears most pronounced following the accelerated vaccination regime after the 
MVA.5T4 boost, but all symptomatic manifestations have been self-limiting and quickly resolving. 
Derangements in clinical haematology and biochemistry have all been mild and transient in 
nature. No additional safety findings are apparent following vaccination in combination with low 
dose cyclophosphamide.  There has been one serious adverse event (SAE) which was deemed 
unlikely to be related to the investigational medicinal products employed in this study. 
Overall, ChAdOx1-MVA 5T4 vaccine was safe and well tolerated. An initial assessment of 
immunogenicity is very encouraging given that 5T4 is a self-antigen against which an 
immunological tolerance is likely to exist. More than 60% of the patients in VANCE01 have 
mounted cellular 5T4 specific responses that are readily detectable ex vivo. A summary of the 
cellular immune responses observed to date are shown in Figure 7. Of note, the elicited immune 
responses were comparable between the standard 4 week vaccination regime and the 
accelerated 1 week immunisation schedule, but CTX pre-condtioning has not improved vaccine 
immunogenicity. Therefore, in ADVANCE study CTX will not be administered and a 2 week interval 
between ChAdOx1.5T4 prime and MVA.5T4 boost will be deployed in order to minimise surgery 
Randomised, open label trial
48 
patients 
ChAdOx1 
MVA 
MVA 
MVA 
MVA 
MVA 
CTX+ 
CTX- 
CTX- 
CTX+ 
n=4 
n=4 
n=4 
n=4 
Immunisations  
4 weeks apart 
ChAdOx1 
MVA 
CTX+ 
CTX- 
n=8 
n=8 
ChAdOx1 
MVA 
CTX+ 
CTX- 
n=8 
n=8 
Immunisations  
1 week apart 
Radical prostatectomy 
Active surveillance 


ADVANCE_v6.0                                             21st August 2019                                                    Page 38 of 86 
delay for intermediate-risk prostate cancer patients and at the same time to allow sufficient time 
for the immune cells to mediate their effect on the target organ. 
Figure 7. Summary of 5T4-specific cellular immune responses. Each dot represents the 
magnitude of the largest response at any post vaccination time point for each responding subject.  
2.6. Previous clinical experience with PD-1 blockade in prostate cancer  
PD-1 blockade as a monotherapy  
Results to date examining  PD-1 blockade alone have suggested little role for these treatments as 
monotherapy for patients with prostate cancer. Clinical efficacy of PD-1 therapy (nivolumab) in 
mCRPC has been assessed in two independent phase 1 trials. Despite evidence showing that CD8 
T cells infiltrating prostate tumours express PD-1, no objective responses to single-agent PD-1 
blockade were reported in the 25 patients with prostate cancer who were treated in both of these 
trials8,9. 
More recently, however, an unexpected clinical activity of PD-1 blockade was seen in mCRPC 
patients progressing on ENZ33. Patients with evidence of progression on enzalutamide were 
treated with anti-PD-1 mAb (pembrolizumab) 200 mg IV every 3 weeks for 4 doses. Anti-PD-1 
mAb was added to standard dose of enzalutamide. Three of the first ten patients enrolled in this 
ongoing phase II trial experienced rapid PSA reductions to ≤ 0.2 ng/ml. Two of these three 
patients had measurable disease upon study entry and both of these patients achieved a partial 
response. A phase II trial is currently underway that more thoroughly examines the antitumor 
efficacy of PD-1 blockade in patients with mCRPC (NCT02312557). 
As mentioned earlier, a large multi-centre international trial, KEYNOTE-199, evaluating 
pembrolizumab as a monotherapy in 370 patients with metastatic castration resistant prostate 
cancer is currently ongoing (NCT02787005). Preliminary results from 258 patients already 
10
100
1000
10000
SFC/106 PBMCs


ADVANCE_v6.0                                             21st August 2019                                                    Page 39 of 86 
recruited to the trail were reported by De Bono and colleagues at the ASCO annual meeting in 
June 2018 and showed that pembrolizumab had antitumour activity in 11% of both PD-L1 positive 
and PD-L1 negative patients with mCRPC.  
PD-1 blockade in combination with vaccines  
It remains to be determined whether PD-1 blockade will be more effective in patients with 
prostate cancer when used in combination with other treatments. To address this question,
several trials are currently underway to the assess clinical activity of PD-1 in combination with 
vaccines. 
In one trial, mCRPC patients are treated with anti-PD-1 (pembrolizumab) in combination with 
plasmid DNA vaccine (pTVG-HP) encoding prostatic acid phosphatase (PAP). This pilot phase I 
study will recruit 32 patients who will be randomized to two arms to receive 6 doses of the vaccine 
and four infusions of anti-PD-1 either concurrently or sequentially (NCT02499835). 
In the second trial, anti-PD-1 mAb (nivolumab) is administered in combination with PROSTVAC 
vaccine. Three doses of nivolumab (240mg per dose) are administered at the same time as the 
booster vaccinations given 3 weeks apart. This study is recruiting cancer patients who are surgical 
candidates for radical prostatectomy and the experimental treatment is given as a  neoadjuvant 
prior to surgery (NCT02933255). 
Data collection for both studies is ongoing and the final results are not expected within the next 
couple of years. 
3. OBJECTIVES   
Primary objectives  
Low- or intermediate-risk PCa patients:

To assess safety of the viral vectored ChAd-MVA 5T4 vaccine when administered in 
combination with anti-PD-1  mAb  

To determine whether ChAd-MVA 5T4 vaccine in combination with anti-PD-1 will impact 
on the level of PSA in the blood 
Metastatic PCa patients:

To assess safety of the viral vectored ChAd-MVA 5T4 vaccine when administered in 
combination with anti-PD-1  mAb  

To assess efficacy of the viral vectored ChAd-MVA 5T4 vaccine when administered in 
combination with anti-PD-1 mAb as measured by composite response rate defined as 
one of the following: 


ADVANCE_v6.0                                             21st August 2019                                                    Page 40 of 86 
- reduction of circulating tumour DNA of ≥50% 
- serum PSA decrease of ≥50% 
Secondary objectives 
Low- or intermediate-risk PCa patients:

To assess the magnitude of immune responses in the periphery generated by ChAd-MVA 
5T4 vaccine in combination with anti-PD-1 mAb 

To assess immune cell subsets in the prostate secondary to treatment 
Metastatic PCa patients: 
• 
To assess the magnitude of immune responses in the periphery generated by ChAd-MVA 
5T4 vaccine in combination with anti-PD-1 mAbTo evaluate radiographic progression-
free survival at 6 months and one year post enrollment
• 
To evaluate overall survival at 6 months and one year post enrollment 
Exploratory objectives 

To investigate whether ChAd-MVA 5T4 vaccine in combination with checkpoint blockers 
will lead to up-regulation of PD-L1 expression in the primary tumour or metastatic lesion  

To determine whether ChAd-MVA 5T4 vaccine in combination with PD-1 mAb will impact 
on the level of PSA-related kallikreins in the blood 

To assess biochemical (PSA) response rates according to PCWG2 criteria 

To assess whether ChAd-MVA 5T4 vaccine administered in combination with anti-PD-1 
mAb will lead to reduction of circulating tumour cells   

To evaluate phenotypic and functional profile of immune cells in the blood secondary to 
treatment 

To evaluate immunologic antigen spreading to other prostate-associated antigens 
secondary to treatment 
4. STUDY DESIGN  
4.1. Study overview  
This is a phase I/II open label non-randomised study to determine the safety and immunogenicity 
of the viral vectored ChAd-MVA.5T4 vaccines in combination with anti-PD-1 checkpoint blockade 
in low- or intermediate-risk localised or locally advanced prostate cancer and in metastatic 
prostate cancer.  
This is an adaptive design study. A number of modifications to the protocol may be implemented 
on review of interim safety and efficacy data, following evaluation by the trial’s independent data 


ADVANCE_v6.0                                             21st August 2019                                                    Page 41 of 86 
and safety monitoring committee. One of the possible modifications may include sample size re-
calculation. Subjects with low- or intermediate-risk disease and metastatic prostate cancer 
enrolled to the study will be evaluated for markers of treatment efficacy using the primary study 
endpoints  (i.e. circulating tumour DNA and PSA kinetics) and vaccine-specific and non-specific 
immune responses. In the event that interim analysis indicates an early efficacy signal among a 
particular population of study participants, a sample size re-calculation may be undertaken and 
recruitment targets adjusted to provide enhanced power on efficacy analyses. Sample size re-
calculation and group size adjustments will be made with the oversight of the study independent 
data and safety monitoring committee and subject to satisfactory interim safety profile of the 
groups involved. Additionally, if the patients demonstrate a clinical response to the study 
treatment, the number of vaccinations and/or nivolumab infusions can be increased. 
Any changes to the study design will constitute a substantial amendment and, therefore, will be 
reviewed and approved by the Sponsor, REC/HRA, and MHRA (if appropriate) prior to 
implementation.  
4.2. Investigational products  
The investigational products to be used in this study are: 
• 
ChAdOx1.5T4   
• 
MVA.5T4  
• 
Nivolumab (anti-PD-1 monoclonal antibody) 
4.2.1 Vaccine formulation, storage and accountability  
ChAdOx1.5T4  
ChAdOx1.5T4 vaccine is is an unlicensed medicinal product manufactured by by the University 
of Oxford Clinical Biomanufacturing Facility (CBF), Churchill Hospital, Oxford. It is formulated in 
formulation buffer at a nominal concentration of 1.1x1011 vp/mL. The formulation buffer 
consists of 10mM Histidine, 7.5% sucrose, 35mM NaCI, 1mM MgCl2, 0.1% PS80, 0.1mM EDTA, 
0.5% EtOH, pH 6.6. The fill volume is 0.5-1.0 mL. The dose of ChAdOx1.5T4 to be used in this 
study is 2.5x1010 vp. It is manufactured, labelled and released under Good Manufacturing 
Practice conditions to the clinical sites by the CBF. All movements of the study vaccine between 
the CBF and the clinical sites will be documented. The vaccine is supplied as liquid in glass vials 
and is stored at -80C in a locked, alarmed, temperature monitored freezer prior to release to 
the clinical sites. Following shipment to sites, the vaccine is stored as above, however, short-
term storage for up to 3 months at 2-8C is acceptable if required, based on the manufacturer’s 
stability data to date. 
MVA.5T4  
MVA.5T4 vaccine is an unlicensed medicinal product that has not been administered to humans 
before. VANCE01 trial has made use of the biologically equivalent MVA.5T4 vaccine supplied by 
Oxford BioMedica (manufactured by Baxter), trade name TroVax®. The new batch of MVA.5T4 


ADVANCE_v6.0                                             21st August 2019                                                    Page 42 of 86 
vaccine expresses the 5T4 antigen under control of the different poxvirus promoter. It has been 
manufactured under Good Manufacturing Practice conditions by IDT Biologika GmbH, Germany. 
MVA.5T4 is supplied as a frozen liquid formulation in 10mM Tris buffer 140 mM NaCl, pH 7.7 in 
2.0 mL clear glass vials. The formulation titre is 2x109 pfu/ml, the final drug product titre is 1x109
pfu/ml. The fill volume is 0.55 mL. Further details relating to batch manufacture can be found in 
the MVA.5T4 IMPD. 
To ensure consistency with the VANCE01 clinical trial and all previous University of Oxford trials 
using MVA vectored vaccines, the dose to be used in this study will be 2x108 pfu. The vaccine 
will be labelled and released under Good Manufacturing Practice conditions to the clinical sites 
by the CBF. All movements of the study vaccine between the CBF and the clinical sites will be 
documented. At CBF it is stored at -80C in a locked, alarmed, temperature monitored freezer 
prior to release to the clinical sites. Following shipment to sites, the vaccine is stored as above. 
 Minimising environmental contamination with Genetically Modified Organisms (GMO)  
In order to minimise dissemination of the recombinant virus into the environment, the 
inoculation site will be covered with a dressing after immunisation. This should absorb any 
virus that may leak out through the needle track. The dressing will be removed from the 
injection site after 60 minutes (± 15 minutes) and will be disposed of as GMO waste by 
autoclaving as well as unused/expired vaccine vials, in accordance with the relevant Standard 
Operating Procedure (SOP) and current standard UK practice.  
Checkpoint inhibitor formulation, storage and accountability 
4.2.2 Anti-Programmed Death Receptor-1 (PD-1) antibody - nivolumab (Opdivo®) 
Nivolumab (Opdivo®) is a human immunoglobulin G4 (IgG4) monoclonal antibody directed 
against programmed death-1 (PD-1) receptor. It is a licenced pharmaceutical product 
manufactured and marketed by Bristol Myers Squibb Pharmaceutical Limited. It holds a UK 
licence for the treatment of unresectable or metastatic advanced melanoma as monotherapy or 
in combination with ipilimumab, and is also licensed for the treatment of locally advanced or 
metastatic non-small cell lung cancer after prior chemotherapy, and as monotherapy of advanced 
renal cell carcinoma. Comprehensive pharmaceutical information for nivolumab is contained in 
the manufacturer’s Summary of Product Characteristics (SmPC). Briefly, nivolumab is a clear to 
opalescent, colourless to pale yellow solution of pH 6.0 and osmolality of 340 mOsm/kg supplied 
as a 10 mg/mL sterile concentrate for solution for intravenous infusion. Nivolumab (Opdivo®) will 
be purchased by the host institution for use in the trial and stored at 2°-8°C in the clinical trials 
pharmacy until expiry date stated in the SmPC. It will be dispensed for use in ADVANCE from the 
pharmacy following receipt of a trial-specific prescription and labelled according to the Medicine 
for Human Use (Clinical Trials) Regulation 2004. All movements of nivolumab between the host 
institution pharmacy and the clinical sites will be documented.  


ADVANCE_v6.0                                             21st August 2019                                                    Page 43 of 86 
The recommended dose of nivolumab for current licenced indications is 3 mg/kg administered 
intravenously every 2 weeks or a flat dose of 480 mg adnministered intravenously every 4 weeks. 
The new dose of 480 mg 4-weekly was approved by FDA in March 2018 
(https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/125554s048s049s050s051s052s
061s062s064s065s066lbl.pdf).  
Therefore, this study will make use of a uniform intravenous dose of nivolumab 480mg per 
infusion, administered on one or three occasions only, at an interval of 4 weeks apart.  
Nivolumab (Opdivo®) for this study will be supplied by a commercial company, Vaccitech Ltd., 
that will have access to the study results. 
4.2.3 Administration of study drugs   
All study drugs will be administered in the clinical research facility or oncology treatment suite of 
the respective study centres where trained personel, resuscitation equipment and emergency 
drugs are immediately available. Vital signs will be measured before and after administration of 
all investigational products. The doctor/nurse will wear gloves and eye protection. Patients will 
remain in the unit for 1 hour (+/- 15 min) for observation after each vaccination and 30 min (+/- 
15 min) for observation after each checkpoint inhibitor treatment. 
ChAdOx1.5T4 and MVA.5T4 vaccines 
The vaccines will be allowed to thaw to room temperature and will be administered by 
intramuscular injection within 1 hour of removal from the freezer. The preferred site for 
vaccination is the vastus lateralis muscle of the thigh but the deltoid muscle of the arm is an 
acceptable alternative. It is advised to use a different thigh (arm) for each of the two MVA.5T4 
immunisations. 
Immune checkpoint inhibitor nivolumab (Opdivo®) 
Nivolumab 480mg, will be prepared from 10mg/ml concentrate, diluted into sodium chloride 9 
mg/mL (0.9%) solution for injection and administered intravenously in a volume of 100ml to a 
final concentration of 4.8mg/ml. Preparation and handling will adopt strict aseptic technique. In 
line with the manufacturer’s instructions, nivolumab will be administered intravenously over a 
period of 60 minutes using a volumetric pump, an infusion set and an in-line, sterile, non-
pyrogenic, low protein binding filter of pore size of 0.2μm to 1.2μm. After administration the line 
will be flushed with sodium chloride 9 mg/mL (0.9%) solution for injection. 
4.3. Allocation to study groups and dosing regime  
The 36 subjects will be recruited to the study: 12 patients with low- or intermediate-risk prostate 
cancer (Group 1) and 24 patients with metastatic prostate cancer (Group 2). 


ADVANCE_v6.0                                             21st August 2019                                                    Page 44 of 86 
Group 1: Low- or intermediate-risk localised or locally advanced prostate cancer patients 
scheduled to undergo radical prostatectomy 
12 subjects will be treated with ChAd-MVA.5T4 vaccination plus 1 dose of the anti-PD-1 
monoclonal antibody Nivolumab  
Week 0: 
ChAdOx1.5T4  
2.5 x 1010 vp  intramuscular injection 
Week 1: 
MVA.5T4 
 
2 x 108 pfu
intramuscular injection  
Nivolumab 
 
480mg  
intravenous infusion  
Group 2: Metastatic prostate cancer patients with disease progression on anti-androgen 
therapy with either enzalutamide or abiraterone 
24 subjects will be treated with ChAd-MVA.5T4 vaccination plus 3 doses of the anti-PD-1 
monoclonal antibody Nivolumab  
Week 0: 
ChAdOx1.5T4  
2.5 x 1010 vp  intramuscular injection 
Week 4: 
MVA.5T4 
 
2 x 108 pfu      intramuscular injection 
Nivolumab 
 
480mg  
intravenous infusion  
Week 8: 
Nivolumab 
 
480mg  
intravenous infusion 
Week 12: 
 
ChAdOx1.5T4  
2.5 x 1010 vp  intramuscular injection 
Nivolumab 
 
480mg  
intravenous infusion 
Week 16: 
 
MVA.5T4 
 
2 x 108pfu
intramuscular injection 
Compliance with Dosing Regimen  
Administration of all vaccines and checkpoint inhibitor therapies will be undertaken by a 
delegated research nurse or investigator in the clinical research facility or oncology treatment 
suite of the respective study centres. All study treatments will be recorded in the CRF and the 
relevant accountability log by the research nurse or investigator. There are no self-
administered investigational products involved in this study.
4.4. Duration of study  
Subjects undergoing radical prostatectomy will all be followed up for a total duration of 6 
months from enrolment. Planned follow up for participants with metastatic prostate cancer is 
12 months from enrolment.  


ADVANCE_v6.0                                             21st August 2019                                                    Page 45 of 86 
4.5. Definition of the Start and End of the Study  
The start of the study is defined as the date of the first administration of a study drug. The end 
of the study is three months after the last visit of the last subject to allow for sample analysis.  
4.6. Potential risks to participants 
Risks to participants in this Phase II study can be divided as follows: 
4.6.1 Phlebotomy   
The volume of blood drawn over the study period (up to 616ml) should not compromise patients, 
as during any one normal blood donation a total volume of 470ml can be drawn and the 
procedure is allowed for up to 3 times a year according to the NHS regulations.  
Local reactions to vaccine, venepuncture or intravenous cannulation  
Mild tenderness, bruising, light-headedness or, rarely, syncope, may result from venepuncture. 
Vaccine-related side effects are believed to be related more to the vectors used rather than the 
specific insert. 
4.6.2 Surgery delay  
Surgery is expected to take place at least 4 weeks post nivolumab infusion. The risk associated 
with postponing surgery for low and intermediate risk prostate cancer by a maximum of 
approximately 6 weeks is difficult to accurately quantify but the researchers consider it to be 
very small for men with this type of prostate cancer. Indeed, many men with low- and 
intermediate-risk prostate cancer do not need any immediate treatment at all, and some choose 
“active surveillance” and potentially delay treatment for many years (or can avoid treatment 
altogether) in order to avoid treatment-related side effects and potential “over-treatment” of 
clinically insignificant forms of prostate cancer, rather than undergo immediate treatment with 
surgery or radiotherapy. Patients with high-risk prostate cancer, where the effect of a 6-week 
delay might be significant, will not be included in this study. Seventeen studies have investigated 
the effect of delaying surgery for low and intermediate risk prostate cancer42. None of these 
studies reported lower chance of cure for patients with low risk cancer if surgery delayed for up 
to several years. Many patients with low risk prostate cancer do not need any treatment at all, 
but may still opt for surgery rather than active surveillance. One of these studies reported higher 
risk of recurrence if surgery for intermediate risk cancer was delayed for more than 9 months, 
but in the other 16 studies no significant negative effect was found among men who had delayed 
surgery42. Patients with high-risk prostate cancer, on the other hand, should be treated without 
delay and are therefore not eligible for the ADVANCE study. In summary, the researchers 
therefore believe that a 6-week delay of surgery for men in this study, all of whom have been 
diagnosed with low or intermediate risk prostate cancer, in order for them to receive their 
vaccinations poses very little risk with regards a change in the potential of the surgery to cure 
them of their prostate cancer.  All patients will have a mpMRI scan before enrolment that will 
minimize the risk of any patient with a high-risk cancer being misclassified as low or intermediate 
risk.   


ADVANCE_v6.0                                             21st August 2019                                                    Page 46 of 86 
4.6.3 Risks associated with study vaccinations 
Vaccination may precipitate a local inflammatory reaction. This may include swelling, tenderness 
or erythema. Systemic reactions that could potentially occur following immunisation with a 
recombinant ChAdOx1 and MVA vaccines include constitutional manifestations resembling flu 
such as fever, headache, rash, malaise, fatigue, anorexia, arthralgia, and myalgia. These are 
typically self-limiting over a period of 48-72 hours following ChAd-MVA.5T4 monotherapy. 
Allergic and hypersensitivity reactions to the vaccine are a reasonable expectation. Severe 
hypersensitivity reactions to the vaccine are rare and should be managed in accordance with 
Advanced Life Support algorithms. Immunological sequaelae following any immunisation are 
recognised but rare. These are however associated with checkpoint inhibitor therapy as discussed 
below. 
4.6.4 Risks associated with checkpoint inhibitor therapy 
Extravascular infiltration 
In the event of inadvertent infiltration into the extravascular compartment subjects may 
experience localised irritation and discomfort, including swelling and erythema. However, 
nivolumab (Opdivo®) is a non-vesicant drug and therefore does not confer risk of extravasation 
tissue necrosis. No specific neutralising or dispersal interventions are indicated.  The potential for 
extravascular infiltration will be minimised by careful selection of the cannulation site and close 
monitoring of the subject during the infusion. At the earliest appearance of extravascular 
infiltration the infusion will be stopped, the device removed and the site cared for according to 
local guidance. 
Infusion reaction 
At the time of licencing the overall incidence of hypersensitivity/infusion reactions associated 
with nivolumab monotherapy was 5.0%. The majority of infusion reactions are mild in severity 
and are evident within 2 hours of the infusion. Hypersensitivity reactions may manifest as: 
• 
Flushing or itching or rash 
• 
Nausea or vomiting 
• 
Fever or chills 
• 
Dyspnoea, wheeze or chest discomfort 
• 
Hypotension and changes to vital signs 
All infusion reactions will be graded and recorded as adverse events according to NCI CTCAE v4.0 
criteria and managed in line with established site-specific treatment algorithms.  All treatments 
will be undertaken by oncology nurses experienced in the management of intravenous therapies 
and take place in a treatment facility with access to resuscitation equipment and a medical 
emergency / resuscitation team. Severe infusion reactions and anaphylaxis will be managed 
according to Advanced Life Support protocols. 


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General side effects 
The most frequent side effects of immune checkpoint inhibitor therapy are fatigue, decreased 
appetite and nausea which each affect between 20 and 50% of cancer patients receiving 
continuous checkpoint inhibitor treatment in recent Phase III clinical trials. There is limited data 
on the side effects of short term immune checkpoint inhibitors. 
Immune mediated toxicity 
Checkpoint inhibitor treatment is associated with immune-mediated adverse reactions which 
may affect any organ system. Current data on the incidence of immune-related toxicities are 
derived from a number of large phase III clinical trials administering weeks to months of 
continuous checkpoint inhibitor therapy until disease progression, loss of clinical benefit or 
unacceptable toxicity, in a range of non-prostate tumour types. This study, however, will make 
use of a restricted course of treatment limited to 3 infusions 4 weeks apart for metastatic PCa 
patients and only 1 infusion for low- or intermediate- risk PCa patients . The incidence and 
severity of immune-mediated toxicities following a limited course of 3 infusions four weeks apart 
is not publically available. However, immune-mediated adverse events may occur at any time 
from the onset of therapy or after completion of treatment and may not be dose-dependent. 
Most immune-related adverse reactions, however, are low in severity and resolve with 
appropriate management, though fatal cases have been reported.  
The frequency and median time to onset for the major immune mediated toxicities from pooled 
phase III datasets are shown in Table 1. These data relate to continuous therapy regimes with 
repeat nivolumab infusions at 2 week intervals. The incidence of toxicities grade 3 or above is 
<2% for all organ systems. Importantly, more than 50% of immune-mediated toxicities develop 
after several weeks of continuous treatment, therefore the frequency and risk of treatment-
related adverse events following a restricted course of 3 infusions in this study is anticipated to 
be considerably lower than during licenced clinical use.  
Table 1.  Immune mediated adverse events after continuous monotherapy with Nivolumab 
Immune-mediated toxicity 
Frequency  (%) * 
Median (range) time 
to onset (months) 
Corresponding 
number of doses at 
median time of 
onset ** 
Any severity 
Grade 3 or 
above 
Rash 
25.6 
0.9 
1.4 months( 0.0-
113.7)  
3 
Diarrhoea / Colitis 
12.6 
1.3 
1.4 months (0.0-20.9) 
3 
Pneumonitis 
3.0 
0.8 
3.3 months (0.0-19.6) 
7 
Liver dysfunction/ 
Hepatitis  
6.4 
1.8 
1.9 months (0.0-10.4) 
4 
Renal dysfunction 
2.7 
0.5 
2.3 months (0.0-18.2) 
5 
Endocrinopathy 
Thyroid disorders
8.5 
<0.1 
2.8 months (0.0-14.0) 
6 


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Adrenal insufficiency
Pituitary disorders 
0.4 
0.4 
0.2 
0.2 
* From pooled dataset n = 2227 (CA209066, CA209037, CA209067 trials) nivolumab 3mg/kg   
    across tumour types 
** Based on standard licenced dosing interval of 2 weeks 
Participants will be under continuous monitoring for checkpoint inhibitor toxicity.  Established 
consensus treatment algorithms for investigation and management are in place and will be 
adopted according to site-specific clinical practice. All participants will be counselled on 
recognition and early reporting of potential treatment toxicities. The major immune-mediated 
toxicities associated with continuous use of nivolumab are: 
Dermatological  
Rash is the most common immune-related toxicity associated with anti-PD-1 therapy. The most 
frequent manifestation is with maculopapular rash, however, other presentations including 
urticarial dermatitis, vitiligo, lichenoid or psoriatic lesions are also possible. The majority of cases 
are grade 1 in severity. Isolated cases of Stevens-Johnson Syndrome and toxic epidermal 
necrolysis have been observed.  
Diarrhoea  
This presentation incorporates a spectrum of pathology ranging from increased stool frequency 
to active inflammation of the bowel (colitis) manifesting as abdominal pain, profuse diarrhoea, 
rectal bleeding and radiographic changes. The majority of cases are grade 1 or 2 in severity. 
Evaluation of diarrhoea and/or abdominal pain must include assessment for alternative 
aetiologies, in particular infective enteritis, constipation or obstruction and overflow. 
Respiratory 
Pneumonitis, or diffuse lung inflammation may present with shortness of breath, cough or chest 
pain. The major differential diagnoses include bacterial pneumonia and pulmonary embolism.  
The majority of cases are grade 1 or 2 in severity. 
Hepatic and hepatobiliary  
Immune-mediated liver toxicity may manifest with asymptomatic abnormalities in liver 
transaminases or total bilirubin during monitoring blood tests. Clinically apparent pancreatitis has 
been reported in ≤1% of patients across clinical trials of continuous monotherapy in multiple 
tumour types. Laboratory abnormalities or subclinical disorders  with elevation in serum amylase 
and lipase occur more frequently and may not warrant active intervention. Any suspected 
presentation requires detailed work up to exclude alternative aetiologies such as metabolic or 
obstructive liver / hepatobiliary pathologies.  


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Endocrine  
Immune-mediated endocrinopathy may include thyroiditis with or without deranged thyroid 
function, adrenal insufficiency, diabetes mellitus or pituitary dysfunction. Presentation may 
involve non-specific symptoms including fatigue, anorexia, dehydration or headache and requires 
clinicians to retain a high index of suspicion. Endocrinopathy may require short or long term 
hormone replacement. 
Renal dysfunction 
Treatment-associated renal dysfunction manifesting as rise in serum creatinine with or without 
active urinary sediment may represent immune mediated or interstititial  nephritis. However, 
careful attention and investigation are required to exclude alternative causes of renal 
impairment, including alternative nephrotoxic agents, pre-renal mechanisms and obstructive 
uropathy, particularly among participants with significant pelvic or retroperitoneal disease.     
Other immune-mediated toxicities 
Immune-mediated toxicity may rarely affect outher organ systems. Immune-mediated 
neurological toxicity, including peripheral neuropathy, uveitis and ocular disorders, 
demyelination and myasthenic syndrome have, together been reported in <1% in cancer patients 
treated with continuous checkpoint inhibitor monotherapy in phase III clinical trials. 
Haematological disturbances including neutropaenia and thrombocytopaenia may occur.   
4.6.5 Risks associated with exposure to ionising radiation (CT scan and bone scan) 
Exposure to ionising radiation carries a risk of deleterious effect, in this case induction of excess 
cancers in the exposed population.  However, it should be noted that  risks relating to cancer 
induction may not be expressed for many years, and are therefore of reduced significance in some 
patient groups, e.g. those where life expectancy is reduced, or the elderly. In some such groups 
the cancer induction risk is unlikely to be expressed during the remaining years of life. 
4.7. Potential benefits to participants    
Additional medical care 
Through the schedule of study visit and investigations, including study-specific MRI scans and 
contact with health professionals, participants in this study will benefit from enhanced level of 
medical care. This enhanced level of care may facilitate the early diagnosis and management of 
any disease related complications and/or comorbid conditions should they occur.  
Potential anti-tumour activity 
Among the population of men with prostate cancer in this study there is as yet no proven clinical 
benefit from the therapies under investigation. However, checkpoint inhibitor drugs have 
demonstrated anti-tumour efficacy and clinically significant benefits as single agent therapies in 
phase III trials against multiple non-prostatic malignancies, including melanoma, non small cell 


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lung cancer, bladder cancer and renal cell carcinoma. Moreover, results of a small phase II study 
of anti-PD-1 antibody treatment in metastatic prostate cancer indicate that a short course of 
checkpoint inhibitor monotherapy can elicit significant anti-tumour activity and a measurable 
clinical benefit among some patients.   
In addition, among men with localised low- and intermediate-risk prostate cancer ChAd-MVA 5T4 
vaccination has been shown to elicit immunological responses which are compatible with anti-
tumour activity against prostate cancer cells. This effectly forms the basis for the ADVANCE study 
and supports the possibility that combined checkpoint inhibitor therapy and ChAd-MVA 5T4 
vaccination might induce enhanced anti-cancer immunity. Such an affect could potentially reduce 
the patients’ risk of recurrence after surgery for localised and locally advanced prostate cancer 
and delay, slow or prevent disease progression in patients with metastatic disease. 
5. RECRUITMENT AND WITHDRAWAL OF STUDY SUBJECTS  
5.1. Selection of Participants  
Participants will be recruited into either of two cohorts within the study - subjects with operable 
localised or locally advanced prostate cancer who are planned to undergo radical prostatectomy, 
or subjects with metastatic prostate cancer who demonstrate disease progression on therapy 
with second generation anti-androgens (enzalutamide or abiraterone). 
Radical prostatectomy group 
The subjects recruited will be men over the age of 18 years,  diagnosed with low- or intermediate-
risk localised or locally advanced prostate cancer and deemed operable and fit to undergo radical 
prostatectomy by the treating consultant urological surgeon.  The number of subjects newly 
diagnosed with low- and intermediate-risk prostate cancer and selecting radical prostatectomy 
as their treatment option at the Oxford Churchill Hospital is approximately 5 per month. At the 
point when the decision has been made to offer radical prostatectomy as one of the potential 
treatment options, the trial will be introduced to the patient by the existing medical care team 
during their routine clinic visit, the PIS will be given and permission will be sought for the research 
team to approach them.  
Metastatic prostate cancer groups 
Subjects recruited will be men  over the age of 18 with a diagnosis of prostate cancer, metastatic 
to one or more distant sites, who have demonstrated disease progression following anti-
androgen treatment with either enzalutamide or abiraterone as a standard of care.  Subjects will 
be identified in the outpatient setting by the existing medical care team during their routine clinic 
visit, the PIS will be given and permission sought for the research team to approach them. The 
number of metastatic prostate cancer patients demonstrating evidence of disease  progression 
on enzalutamide is approximately 2 per month at the Oxford Churchill Hospital.


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5.2. Informed consent  
All patients will sign and date the informed consent form before any study-specific 
procedures are performed. The information sheet will be made available to the patient 
at least 24 hours prior to the screening visit. The patient will be fully informed of all 
aspects of the trial, the potential risks and their obligations. The following general 
principles will be emphasised:  
•
Participation in the study is entirely voluntary  
•
Refusal to participate involves no penalty or loss of medical benefits  
•
The patient may withdraw from the study at any time  
•
The patient is free to ask questions at any time to allow him or her to understand the 
purpose of the study and the procedures involved  
•
The study involves research of an investigational vaccine and checkpoint inhibitor 
•
The study involves delaying the patient’s surgery by approximately 2 months  
•
There may be no direct benefit for participating  
The aims of the study and all tests to be carried out will be explained. The patient will be given 
the opportunity to ask about details of the study, and will then have time to consider whether 
or not to participate. If they do decide to participate, they will sign and date the consent form, 
which will also be signed and dated by the investigator. One copy will be given to the 
partiicpant, one copy will be placed in the study file, and the original will be placed in their 
medical notes.  
5.3. Inclusion and Exclusion Criteria  
Inclusion Criteria  - Radical Prostatectomy groups 
The participant must satisfy all the following criteria to be eligible for the study:
-
Histologically confirmed adenocarcinoma of the prostate  
-
Clinically localised or locally advanced disease deemed operable by the treating 
consultant urological surgeon  i.e.:
•
Gleason score ≤ 7  
•
Local tumour stage ≤T3c and deemed operable    
•
No evidence of metastases (Nx/N0 and Mx/M0)  
•
No evidence of high grade Gleason 5 disease 
•
PSA ≤ 20 ng/ml  
-
Scheduled for and considered fit for radical prostatectomy
-
Absence of any indication to perform urgent surgery that would not allow completion  
of the study interventions prior to radical prostatectomy  


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Inclusion Criteria -  Metastatic prostate cancer groups 
The participant must satisfy all the following criteria to be eligible for the study:
-
Histologically confirmed adenocarcinoma of the prostate cancer. Note, any Gleason 
grade or primary tumour staging at diagnosis is permitted. 
-
Evidence of at least one distant metastasis based on MRI, CT, PET or bone scintigraphy. 
-
Established on and suitable to continue with androgen deprivation therapy (ADT) using 
any luteinizing hormone releasing hormone (LHRH) agonist. LHRH agonist therapy may 
include goserelin (Zoladex®), leuprorelin acetate (Prostap®) or any other licenced 
product in this class.  
-
On treatment with anti-androgen therapy using either abiraterone (Zytiga®) or 
enzalutamide (Xtandi®) and demonstrating evidence of disease progression at the time 
of enrolment, defined according Prostate Cancer Working Group 3 Criteria as either: 
•
PSA progression as defined by a minimum of 3 rising PSA levels with an interval 
of ≥1 week between each assessment where the PSA value at screening should 
be ≥2 ng/mL or; 
•
progressive nodal or visceral disease or; 
•
progressive bone metastases  
Upon enrolment in the study, the treatment with abiraterone or enzalutamide will be 
discontinued. 
-
An archival specimen of tumour tissue should be available; if not, an on-study fresh 
tumour biopsy must be obtained prior to the first study treatment. 
-
Patients who have recieved chemotherapy following progression on androgen-
targeting therapies are eligibile 
-
Satisfactory functional status defined as Eastern Cooperative Oncology Group (ECOG) 
Performance Status ≤ 1 
Inclusion Criteria – All participants  
All participants must satisfy all the following criteria to be eligible for the study:  
-
Males aged over 18 years   
-
Any antineoplastic therapy, including Radium-223 and limited field radiotherapy must 
have been completed a minimum of 28 days prior to enrolment. 
-
Systemic antimicrobial therapy, for any indication, must have been completed a 
minimum of 7 days prior to enrolment.Baseline laboratory parameters obtained no 
more than 28 days prior to administration of the first study drug must meet the 
following criteria: 


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Laboratory Index 
Eligibility threshold 
Haematology 
Haemoglobin 
≥ 80 g/L 
White cell count 
≥ 2.0 x109/L  
Neutrophils 
≥ 1.5 x109/L  * 
Lymphocytes 
≥ 0.5 x109/L 
Platelets 
≥ 100 x109/L 
Clinical Biochemistry 
Renal  
Creatinine Clearance 
≥ 40 ml/min by Cockcroft Gault formulation 
Hepatobiliary 
Total Bilirubin 
≤ 1.5 ULN 
ALT 
≤ 1.5 ULN 
Amylase 
≤ 1.5 ULN 
* unless established as stable, benign ethnic neutropaenia
-
On enrolment, the subject, or the subjects partner, must agree to continuously practice 
a reliable form of contraception during treatment and for a minimum of 5 months 
following the final administered dose of nivolumab (Opdivo®). Reliable forms of 
contraception are: 
•
Male sterilisation (Vasectomy) 
•
Barrier methods of contraception (condom with or without spermicide) 
•
Established use of oral, injected or implanted hormonal contraceptives. 
•
Placement of an intrauterine device (IUD) or intrauterine system (IUS). 
•
Female sterilisation (Tubal occlusion) or Total abdominal hysterectomy 
•
Complete abstinence when this is in line with the preferred and usual 
lifestyle of the subject. Periodic abstinence, natural family planning and 
withdrawal are not acceptable methods of contraception. 
-
Subject is able and willing in the Investigator’s opinion to comply with all study 
requirements  
-
Subject is able to provide written informed consent  
Exclusion Criteria – All participants  
The patient may not enter the study if any of the following apply:  
-
Any prior diagnosis or clinical suspicion of autoimmune disease including, but not 
limited to, systemic lupus erythematosus, inflammatory bowel disease, vasculitis, 
Grave’s disease and type I diabetes mellitus. Note, subjects with known pre-existing 
clinically silent positive autoantibodies should not be included (although these will not 
be assayed at screening unless indicated) 
-
History of allergic disease or reaction likely to be exacerbated by any component of the 
vaccine, e.g. egg products 


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-
Other prior malignancy with an estimated ≥ 30% chance of relapse within 2 years.
Allowed recent cancers include (but are not limited to) non-melanomatous skin cancer 
and superficial bladder cancer  
-
Participation in another research study involving an investigational product or 
investigational surgical procedure in the 30 days preceding enrolment, or planned use 
during the study period  
-
Any prior exposure to checkpoint inhibitor drugs including anti-PD-1, anti-PD-L1, or anti-
CTLA-4 monoclonal antibodies or any prior treatment with investigational vaccines  
-
Administration of immunoglobulins and/or any blood products within the one month 
preceding the planned administration of the study drugs  
-
Seropositive for hepatitis B surface antigen (HBsAg) 
-
Seropositive for hepatitis C virus (antibodies to HCV)  
-
Any confirmed or suspected immunocompromised state, including but not limited to, 
asplenia, HIV infection, a history of atypical, recurrent or severe infections, or, regular 
use (> 14 days) of systemic immunosuppressant medication within the past 6 months 
(except that lower dosage of prednisolone (< 11 mg per day) are allowable) 
-
Any history of hereditary angioedema, acquired angioedema, or idiopathic angioedema 
-
History of anaphylaxis in relation to vaccination or any clinically significant allergic 
disease likely to be exacerbated by any component of the vaccine or checkpoint 
inhibitor preparations, as listed in the Investigator’s Brochure and SmPC 
-
Confirmed or suspected recreational drug use or harmful drinking in the last 5 years 
-
History of a serious psychiatric condition or other circumstances that may be associated 
with impaired mental capacity  
-
Evidence of significant clinical disorder or laboratory finding which in the opinion of the 
investigating physician increases the level of risk to the patient, limits the ability of the 
patient to participate in the study or impairs interpretation of the study data  
Exclusion Criteria – Metastatic prostate cancer groups 
The patient may not enter the metastatic prostate cancer arm of the study if:  
-
The treating oncologist or urological cancer MDT estimates a subject’s life expectancy 
to be ≤ 6 months 
-
Any active, previously treated, or suspected intracranial or leptomeningeal metastases. 
5.4. Concurrent therapies 
All concomitant medications and interventions at enrolment and during follow up must be 
recorded in the study CRF.   


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Permitted treatments 
There are no restrictions on the use of the following therapies: 
-
Treatment with alpha blockers (e.g. doxazosin, tamsulosin or terazosin) or 
anticholinergic preparations (e.g. oxybutynin)) for relief of lower urinary tract 
symptoms. 
-
Non-systemic corticosteroids (i.e. topical, ocular, inhaled, intranasal, and intra-articular 
preparations) for non-autoimmune disorders are permitted throughout the study.  
-
Palliative (limited-field) radiotherapy for control of pain metastatic bone pain is 
permitted, as clinically indicated, throughout the study.  
Restricted Treatments 
The following therapies and interventions are restricted during the study:  
-
Systemic corticosteroids are permitted when in conjunction with abiraterone therapy at 
a dose ≤ 10mg oral prednisolone daily (or equivalent).   
-
Systemic corticosteroids >10mg oral prednisolone daily (or equivalent) are permitted in 
the management of immune-related checkpoint inhibitor toxicity only, according to site-
specific treatment algorithms. 
-
Non-investigational vaccines for the prevention of seasonal or travel-associated 
infections should be undertaken before enrolment wherever possible. Vaccines within 
the first 6 months of study therapy should be approved by the Investigators in view of the 
potentially elevated risk of autoimmune reactivity. 
5.5. Delay and discontinuation cirteria 
Discontinuation rules 
Treatment with study vaccines and checkpoint inhibitors should be permanently discontinued 
under the following circumstances: 
-
On withdrawal of informed consent i.e. the subjects request to discontinue 
-
Any immune-related checkpoint inhibitor toxicity ≥ Grade 3 in severity in the following 
organ systems: 
o
Dermatological 
o
Gastrointestinal, hepatic or hepatobiliary 
o
Respiratory 
o
Renal 
o
Endocrine 
o
Neurological (apart from headache) 
o
Haematological 
-
Any infusion reaction of ≥ Grade 3 severity  


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-
Any significant clinical disorder, laboratory finding or adverse event, in the judgment of 
the Investigator makes it unsuitable for the participant to continue study treatment. 
Dose delay criteria 
Treatment with study vaccine and / or checkpoint inhibitor should be delayed under the following 
circumstances: 
-
If the subject has a temperature of > 37.5 °C. 
-
Any immune-related checkpoint inhibitor toxicity of < Grade 3 in severity, until symptoms 
have resolved and management with corticosteroids (if indicated) is complete  
-
Any grade 2 electrolyte disturbance (i.e. abnormalities in serum sodium, potassium, 
calcium or magnesium), until appropriate correction / replacement has been initiated 
-
Any significant clinical disorder, laboratory finding, adverse event or intercurrent illness 
which in the judgment of the Investigator makes it unsuitable for the participant to 
proceed with treatment. 
5.6. Withdrawal criteria  
Subjects may be withdrawn from the study early:  
-
By withdrawing voluntarily  
-
On the decision of the Investigator  
-
On the advice of the local safety monitor (LSM)  
The Investigator may withdraw the subject for any of the following reasons:  
-
Any adverse event which results in inability to comply with study procedures  
-
Ineligibility either arising during the study or retrospectively (having been overlooked 
at screening)  
-
Evidence of significant change in disease status such that an alternative care pathway 
becomes indicated, for example the requirement for salvage radiotherapy following 
prostatectomy or transition to palliative care in participants with metastatic disease.  
-
Significant protocol deviation  
-
Subject non-compliance with study requirements  
-
Loss to follow up (applies to a subject who does not return for protocol study visits, is 
not reachable by telephone or other means of communication and/or is not able to be 
located).  
The reason for withdrawal will be recorded in the CRF. If the subject is withdrawn due to an 
AE, the Investigator will arrange for appropriate specialist management or follow up visits or 


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telephone calls until the AE has resolved or stabilised.  Withdrawn participants will not be 
replaced. 
If a subject withdraws from the study, data and blood samples collected before their 
withdrawal from the trial will be used/stored unless the subject specifically requests 
otherwise. 
5.7. Interim monitoring and study stopping rules 
An independent Data and Safety Monitoring Committee (DSMC) will be appointed to review the 
accumulating data and provide advice on whether the accumulating data from the trial justify 
continuing recruitment of further patients or further follow-up (see also section 8.7). The first 
review will take place after the first 6 patients (3 patients with intermediate risk disease and 3 
metastatic patinets) complete the study treatment and have reached the 24-week timepoint for 
efficacy assessment, unless there is a need to convene the Committee earlier due to the safety 
concerns. If a decision is made to continue the study, the DSMC will advise on the frequency of 
future reviews of the data on the basis of accrual and event rates. 
6. TREATMENT OF STUDY SUBJECTS   
6.1. Study visits  
The study visits and administration of investigational therapies will be undertaken by an 
adequately qualified and trained member of the team of investigators. Each visit is assigned a 
time point and a window period, within which the visit will be conducted. These can be found 
in the schedule of attendances (Appendix 1).  
Screening visit 
All potential participants will have a screening visit, which may take place up to 4 weeks prior 
to the first study procedure. Informed consent will be taken at screening prior to any study- 
specific procedures being carried out, as described in section 5.2. If consent is obtained, the 
screening procedures indicated in the schedule of attendances will be undertaken. A baseline 
medical history, physical examination and assessment of performance status will be 
performed. Vital signs will be recorded and urinalysis will be performed. Inclusion and 
exclusion criteria will be checked. Blood will be drawn for clinical haematology and 
biochemistry, HIV, Hepatitis B and Hepatitis C serology, PSA, exploratory biochemistry and 
ctDNA. Subjects will be counseled by one of the investigators prior to HIV, Hepatitis B and 
Hepatitis C testing.   
Potential subjects will be informed that blood samples, as well as the surgical specimens from 
radical prostatectomy and archival biopsy samples that are collected as standard of care or 
newly obtained on-study tumour biopsy samples will be used for research purposes. They will 
be informed that after study investigations are completed, any surplus samples of blood (and/or 
surgical or biopsy material) may be stored for possible future ethically approved research, 


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including for example exploratory immunology,  and genotypic testing of genetic 
polymorphisms potentially relevant to vaccine immunogenicity. Subjects will be able to decide 
if they permit such future use of any unused or surplus samples. If a subject elects not to permit 
this, all of that subject’s leftover samples will be discarded at the end of the study to meet Good 
Clinical Practice (GCP) and regulatory requirements.  
The eligibility of the subject will be reviewed at the end of the screening visit and again when 
all results from the screening visit have been considered. If eligible, a week 0 enrolment visit 
will then be scheduled.   
Subsequent Visits  
At each subsequent study visit the ongoing eligibility of the volunteer will be reviewed. Vital 
signs will be recorded, urinalysis performed, ECOG performance status assessed and if 
necessary, a medical history and physical examination may be undertaken to determine any 
relevant interval changes in the participants health. In the event of new clinical or laboratory 
findings, study procedures involving administration of investigational vaccines or intravenous 
checkpoint inhibitors may be postponed according to criteria in Section 5.5. All blood tests 
should be taken prior to administration of any study therapies. 
Group 1   
Day 0: Enrolment, ChAdOx1.5T4 priming vaccination visit   
Subjects will not be considered enrolled in the study until they have received the first study 
vaccination with ChAdOx1.5T4 on Day 0. Prior to vaccination, blood tests will be taken as 
detailed in the schedule of attendances (Appendix 1). Following intramuscular administration 
of the ChAdOx1.5T4 vaccine, the injection site will be covered with a sterile dressing and the 
patient will stay under observation, in case of immediate adverse events. Observations will be 
taken 60±15 min after vaccination and the sterile dressing removed and injection site 
inspected. A diary card, oral thermometer and tape measure will be given to each participant 
to solicit the following adverse events:  
-
Localised adverse events 
o
Diameter of redness at vaccination site 
o
Diameter of swelling at vaccination site 
o
Pain, warmth and erythema at the vaccination site 
-
Systemic adverse events 
o
Recorded temperature and pyrexial episodes 
o
Feverishness 
o
Headaches 
o
Fatigue 
o
Nausea 
o
Generalised muscle aches 


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o
Generalised joint aches 
Day 7: MVA.5T4 boost vaccination visit and first checkpoint inhibitor therapy  
-
Prior to Day 7 study vaccination and checkpoint inhibitor therapy, the subject’s 
diary card entries will be reviewed and any adverse events assessed. Blood tests will 
be taken as detailed in the schedule of attendances (Appendix 1). The MVA.5T4 vaccine 
will be administered intramuscularly and the injection site(s) will be covered with a 
sterile dressing. The participants will remain under observation and vital signs 
repeated 60±15 min after vaccination when the sterile dressing will be removed 
removed and injection site inspected. Participants will then undergo intravenous 
cannulation and intravenous infusion of nivolumab. The infusion will preferably 
commence a minimum of 60 minutes following administration of the MVA.5T4 vaccine, 
but if operationally required simply on the same day as immunisation. Participants will 
remain in the department for a further 30±15 minutes on completion of the infusion 
and vital signs repeated prior to departure. At the conclusion of this visit, the 
intravenous canula will be removed. 
Participants will be provided with an alert card, in line with the manufacturer’s 
guidance, outlining the ‘red flag’ symptoms of immune-mediated checkpoint inhibitor 
toxicity and emergency contact details for the study medical team. An oral 
thermometer (if necessary) and new diary card will be given to each participant. In 
addition to the local and systemic AEs listed above, checkpoint inhibitor associated AEs 
will also be solicited in the following organ systems: 
-
Respiratory 
-
Dermatological 
-
Gastrointestinal 
-
Urological
Group 2 
Day 0: Enrolment, ChAdOx1.5T4 priming vaccination visit   
Subjects will not be considered enrolled in the study until they have received the first study 
vaccination with ChAdOx1.5T4 on Day 0. Prior to vaccination, blood tests will be taken as 
detailed in the schedule of attendances (Appendix 1). Following intramuscular administration 
of the ChAdOx1.5T4 vaccine, the injection site will be covered with a sterile dressing and the 
patient will stay under observation, in case of immediate adverse events. Observations will be 
taken 60±15 min after vaccination and the sterile dressing removed and injection site inspected. 
A diary card, oral thermometer and tape measure will be given to each participant to solicit the 
following adverse events:  
-
Localised adverse events 
o
Diameter of redness at vaccination site 
o
Diameter of swelling at vaccination site 


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o
Pain, warmth and erythema at the vaccination site 
-
Systemic adverse events 
o
Recorded temperature and pyrexial episodes 
o
Feverishness 
o
Headaches 
o
Fatigue 
o
Nausea 
o
Generalised muscle aches 
o
Generalised joint aches 
Week 4: MVA.5T4 boost vaccination visit and first checkpoint inhibitor therapy  
Prior to Week 4 study vaccination and checkpoint inhibitor therapy, the subject’s diary card 
entries will be reviewed and any adverse events assessed. Blood tests will be taken as detailed 
in the schedule of attendances (Appendix 1). The MVA.5T4 vaccine will be administered 
intramuscularly and the injection site(s) will be covered with a sterile dressing. The participants 
will remain under observation and vital signs repeated 60±15 min after vaccination when the 
sterile dressing will be removed removed and injection site inspected. Participants will then 
undergo intravenous cannulation and intravenous infusion of nivolumab. The infusion will 
preferably commence a minimum of 60 minutes following administration of the MVA.5T4 
vaccine, but if operationally required simply on the same day as immunisation. Participants will 
remain in the department for a further 30±15  minutes on completion of the infusion and vital 
signs repeated prior to departure. At the conclusion of this visit, the intravenous canula will be 
removed and participants will be provided with an alert card, in line with the manufacturer’s 
guidance, outlining the ‘red flag’ symptoms of immune-mediated checkpoint inhibitor toxicity 
and emergency contact details for the study medical team. In addition to the local and systemic 
AEs listed above, checkpoint inhibitor associated AEs will also be solicited in the following organ 
systems: 
-
Respiratory 
-
Dermatological 
-
Gastrointestinal 
-
Urological 
Week 8: Second checkpoint inhibitor therapy 
Prior to Week 8, blood tests will be taken as detailed in the schedule of attendances (Appendix 
1). The results of clinical haematology and biochemistry (excluding serum PSA and thyroid 
function tests) taken either on arrival or within the preceding 48 hours will be reviewed prior to 
proceding with checkpoint inhibitor therapy. Participants will undergo intravenous cannulation 
and intravenous infusion of nivolumab following the same administration and monitoring plan 
as on Week 4.  


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Week 12: Second cycle of ChAd-MVA immunisation – ChAdOx1.5T4 boost and third 
checkpoint inhibitor therapy 
Prior to week 12, the subject’s diary card entries will be reviewed and any adverse events 
assessed. Blood tests will be taken as detailed in the schedule of attendances (Appendix 1).The 
results of clinical haematology and biochemistry (excluding serum PSA and thyroid function 
tests) taken either on arrival or within the preceding 48 hours will be reviewed prior to 
administration of vaccine. Then the patients will undergo ChAdOx1.5T4 vaccination and 
nivolumab infusion, following the same administration and monitoring plan as on Week 4. 
Week 16: Second cycle of ChAd-MVA immunisation – MVA.5T4 boost  
Prior to week 16, the subject’s diary card entries will be reviewed and any adverse events 
assessed. Blood tests will be taken as detailed in the schedule of attendances (Appendix 1).The 
results of clinical haematology and biochemistry (excluding serum PSA and thyroid function 
tests) taken either on arrival or within the preceding 48 hours will be reviewed prior to 
administration of vaccine. Then the patients will undergo MVA.5T4 vaccination, following the 
same administration and monitoring plan as on Day 0. 
All remaining visits – groups 1 and 2 
At all remaining follow up visits, blood tests will be taken as detailed in the schedule of 
attendances (Appendix 1). Vital signs will be recorded, urinalysis performed, ECOG performance 
status assessed and if necessary, a medical history and physical examination may be undertaken 
to determine any relevant interval changes in the participants health. Subjects are 
recommended to carry their clinical trial alert card, outlining the ‘red flag’ symptoms of 
immune-mediated checkpoint inhibitor toxicity and emergency contact details for the study 
medical team, for a minimum of 6 months after treatment on study.  
Telephone communications   
Patients will be telephoned by a research nurses on day 2-5 (48-120 hours) following 
vaccination and/or checkpoint inhibitor therapy to enquire about adverse events and provide 
further advice regarding completion of the diary card.  
6.2. Additional study procedures  
The procedures to be included in each visit are documented in the schedule of attendances in 
Appendix 1. Additional procedures or laboratory tests may be performed at the discretion of 
the Investigators, for example in the investigation of potential diease complications or 
treatment toxicities.   


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Observations  
Vital signs measurements performed on each study visit are, heart rate, blood pressure, oxygen 
saturations and temperature. Weight and height will additionally be recorded at the screening 
visit. Vital sign measurements outside the normal range or deviating from the individual’s 
baseline recording will be repeated, clinically evaluated and acted upon as guided by the study 
nursing and/or medical team.  
Sample collection  
Blood and urine will be collected for the following laboratory tests and processed at the 
Oxford University Hospitals NHS Foundation Trust and the Christie Hospital NHS 
Foundation Trust through an accredited NHS pathology service and disposed of after 
analysis .The following tests will be undertaken:  
• 
Haematology: Full Blood Count and differential  
• 
Biochemistry: Sodium, potassium, urea, creatinine, albumin, liver function tests (total 
bilirubin, ALT, ALP), calcium, magnesium, serum amylase, LDH 
• 
Serum glucose 
• 
PSA blood test
• 
Diagnostic serology: Hepatitis B surface antigen (HBsAg), Hepatitis C Antibody (HCV Ab), 
and HIV (HIV Ab).  
• 
Thyroid Function Tests: Total triiodothyronine (T3) or free T3c, free thyroxine (T4) and 
thyroid stimulating hormone (TSH) 
• 
Clinical immunology: Human Leukocyte Antigen (HLA) typing   
• 
Urinalysis for blood, protein and glucose using dipstick tests 
Unprescribed blood tests – at the discretion of the local PI to maintain the welfare of the 
participant
Prostate tumour tissue will be collected and processed at the Oxford University Hospitals NHS 
Foundation Trust and the Christie Hospital NHS Foundation Trust, through an accredited NHS 
pathology service as standard of care. This tissue will be made available for 
immunohistochemistry performed at the research laboratories (Oxford).  
Research blood will be collected for the following assays performed at the research laboratories 
(Oxford University and University College London) or a central contract laboratory:  
• 
Exploratory Immunology: Ex vivo ELISPOT assays for interferon gamma; ELISA assays for 
antibody responses; flow cytometry assays, immunohistochemistry 
• 
Exploratory Biochemistry: Four kallikrein peptidases blood test  
• 
Circulating tumour DNA (ctDNA) and circulating tumour cell (CTC) quantification assays 
Other tests, e.g. immunological assays including ELISPOT assays for other cytokines, T cell epitope 
mapping, RNA and DNA sequencing or other methods of analysis of genetic polymorphism 


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potentially relevant to the investigational products may also be performed at the discretion of 
the investigators.  
Multi-parametric Magnetic resonance imaging (mpMRI) – Group 1  
Participants in group 1 who are planned to undergo radical prostatectomy will undergo an 
mpMRI of the prostate and pelvis prior to enrolment on the study  as part of standard care in 
the prostate cancer diagnostic pathway. The subjects who had  a pelvic / prostate mpMRI of 
adequate quality before screening and enrolment will have a repeat on-study mpMRI to 
evaluate any post-treatment radiolographic change in the prostate. The on-study mpMRI should 
take place prior to radical prostatectomy and a minimum of 7 days after final study checkpoint 
inhibitor therapy, i.e. on or after study week 4 +7 days. Participants, whose pre-enrolment 
pelvis/prostate mpMRI is, in the opinion of the reporting radiologist, of low diagnostic value (for 
example, images are significantly degraded by artefact or post-biopsy haemorrhage), are not 
required to undergo a repeat on-study mpMRI as the baseline scan will not provide adequate 
comparator for post-treatment changes. Conventional three-planar MRI including T1 and T2 
weighted DCE-MRI and diffusion-weighted sequences will be performed on a 1.5 T magnet. 
Areas of signal abnormality suspicious for malignancy within the prostate will be graded 
according to PIRADS criteria. Local T-stage disease identified on scans will be reported as per 
European consensus on prostate MRI43. The procedure will be performed at the Oxford 
University Hospitals NHS Foundation Trust a nd the Christie Hospital NHS Foundation Trust 
clinical sites.  
Tumour Assement by CT scan, bone scintigraphy, MR scan – Group 2  
Radiological tumour assessments will be performed at baseline (28 day sceening period), at 6 
months and 12 months. The assessments will include a CT scan of chest, abdomen and pelvis 
and bone imaging, e.g. bone scans or body MRI. CT and MR imaging will be performed with 
contrast unless this is  contraindicated for medical reasons.  
The response to treatment in patients with measurable disease will be evaluated per Response 
Evaluation Criteria In Solid Tumours 1.1 (RECIST 1.1) and per immune-related response criteria 
(iRECIST).  
7. ASSESSMENT OF SCIENTIFIC OBJECTIVES  
7.1. Primary endpoints and outcome measures  
• 
Incidence of adverse events, using the National Cancer Common Terminology Criteria 
(version 4) up to 12 months following completion of the study treatment. Adverse events 


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will be summarized by type and severity in tabular format. Fisher's exact test will be used 
to compare adverse events rates between study arms. 
• 
Composite response rate for metatstatic PCa patients defined as one of the following: 
A. PSA response rate: 
 - 24-week PSA response rate: Patients who achieve at least a 50% reduction in PSA  at   
   24  weeks compared to baseline.  
 - Maximal PSA response rate: Patients who achieve at least a 50% reduction in PSA  at   
   any time compared to baseline. 
B. Reduction of circulating tumor DNA following study treatment:   
- 24-week ctDNA response rate: Patients who achieve at least a 50% reduction in ctDNA  
at 24 weeks compared to baseline.  
- Maximal ctDNA response rate: patients who achieve at least a 50% reduction in ctDNA 
at any time compared to baseline.  
Changes in ctDNA from pre-treatment (date of screening/randomization) to post-
treatment assessments at any time will be evaluated using a paired t-test. ctDNA will be 
quantified by digital PCR. Changes in ctDNA will be summarized in terms of means and 
standard deviations.  
• 
For low- and intermediate-risk PCa patients, serum PSA kinetics secondary to study 
treatment as measured by rate of change before radical prostatectomy. Serum PSA levels 
will be measured by a standard clinical laboratory test at baseline and at pre-defined 
timepoints following study treatment as detailed in Appendix 1.  
7.2. Secondary endpoints and outcome measures  

Development or increase in anti-5T4 cellular responses following study treatment two 
weeks post last vaccination and at any time-point on the study. Measurement of T cell 
responses will be done by IFNγ ELISPOT assay to measure T cell responses to tumour and 
control antigens. Descriptive statistical analysis will be conducted. Immune profile of the 
prostate (low- or intermediate-risk PCa patients only). Tumour-infiltrating immune cells in 
surgical specimens and pre-treatment archival diagnostic needle prostate biopsies will be 
compared. Immune cell density, phenotype and function and will be assessed by 
immunohistochemistry and digital image analysis of formalin fixed paraffin-embedded 
tumour tissue samples using a panel of cell surface and intracellular markers. Descriptive 
statistical analysis will be conducted. 

Radiographic progression-free survival rate as measured by MRI, CT scans or bone 
scintigraphy (metastatic PCa patients only). Fisher's exact test will be used to compare  6 
and 12-month progression-free survival rates between study arms. In order to evaluate 
progression-free rate as a function of baseline time point, analysis will be conducted using 


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two different baseline values: date of randomization and one months post last study 
treatment. 

Overall survival will be assessed for each arm 6 and 12 months post enrolment using the 
Kaplan-Meier method and log-rank test for statistical significance (metastatic PCa 
patients only).  
7.3. Other endpoints and outcome measures  
The following exploratory analyses will be performed based on initial immunogenicity assessment 
and sample availability: 

Detailed analysis of cognate CD4+/CD8+ T cell function and memory phenotype may also 
be performed by multi-colour flow cytometry to simultaneously analyse surface markers 
and  intracellular production of other cytokines (e.g. IL-2, IFNγ, TNFα). Frequencies of 5T4-
specific immune responses will be summarised in tabular format for each study arm and 
for overall combined study. Descriptive statistical analysis will be conducted, and the 
continuous variables will be summarised using mean, standard deviation, median, 
minimum and maximum. Fisher’s exact test will be used to compare the 5T4-specific T 
cell response rates between study arms. 

Up-regulation of PD-L1 expression in a primary tumour or metastatic lesion(s) following 
study treatment. Density of PD-L1 positive immune cells and epithelial cells will be 
assessed by immunohistochemistry and digital image analysis of matched tumour tissue 
specimens before and after study treatment. PD-L1 expression levels will be summarised 
in terms of means, standard deviations and ranges for each study arm.  

PSA related kallikreins level change secondary to study treatment. The level of kallikreins 
in the blood will be measured by a 4 kallikrein peptidases test45. Descriptive statistical 
analysis will be conducted. 

Change in number of circulating tumour cells secondary to study treatment may be 
assessed by CellSearch or Adnatest44. 

Immunologic antigen spreading to other prostate associated antigens following study 
treatment (metastatic PCa patients only). The detection of antigen spread to other 
prostate associated antigens and the identification of specific antigens recognized will be 
analyzed descriptively by IFNγ ELISPOT assay or ELISA. 
Additional assays may include but are not limited to:  
• 
Treatment-induced cellular immune responses characterized by cultured ELISPOT assay  
• 
Treatment-induced cellular immune responses characterized by T cell receptor 
sequencing 
• 
Flow cytometry analysis of immune cells isolated from the blood and surgical specimens 


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• 
Measurement of anti-5T4 serum antibody levels by ELISA (using plasma from preparation 
of above PBMC sample)  
• 
Profiles of gene expression in the blood and surgical specimens by RNA analysis   
• 
DNA or RNA sequencing of blood and tumour specimens for identification of tumour-
specific somatic mutations 
8. SAFETY ASSESSMENT  
8.1. Specification, timing and recording of safety parameters  
At regular intervals (specified in section 6.1), the subjects will be assessed for the following 
safety parameters:   
• 
General physical examination and vital signs   
• 
Full blood count   
• 
Urea and electrolytes   
• 
Liver function tests   
• 
Kidney function tests  
The above will be recorded in the patients’ case report form (CRF) by the relevant clinician or 
their nominee.  
Reports of recorded events, along with a narrative from the Chief Investigator, will be submitted 
to the Safety Monitoring Committee after every 6 completed patients.  
8.2. Assessment of Adverse Events  
Adverse Event (AE) 
An AE is any untoward medical occurrence in a volunteer, which may occur during or after 
administration of an Investigational Medicinal Product (IMP) and does not necessarily have a 
causal relationship with the intervention. An AE can therefore be any unfavourable and 
unintended sign (including an abnormal laboratory finding), symptom or disease temporally 
associated with the study intervention, whether or not considered related to the study 
intervention.  
Adverse Drug Reaction (ADR) 
An AR is any untoward or unintended response to an IMP. This means that a causal relationship 
between the IMP and an AE is at least a reasonable possibility, i.e., the relationship cannot be 
ruled out. All cases judged by the reporting medical Investigator as having a reasonable 
suspected causal relationship to an IMP (i.e. possibly, probably or definitely related to an IMP) 
will qualify as adverse reactions.  


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Unexpected Adverse Reaction (UAR) 
An adverse reaction the nature and severity of which is not consistent with the product 
information set out in:  
• 
the summary of product characteristics (SmPC) for products with a marketing 
authorisation, i.e. nivolumab.  
• 
the Investigator's Brochure (IB) for any other investigational product, i.e. 
ChAdOx1.5T4, MVA.5T4 
Serious Adverse Event (SAE)  
An SAE is an AE that results in any of the following outcomes, whether or not considered related 
to the vaccine:  
• 
Death (apart from death where prostate cancer is certified as the underlying cause)  
• 
Life-threatening event (i.e., the volunteer was, in the view of the Investigators, at 
immediate risk of death from the event that occurred). This does not include an AE that,  
if it occurred in a more serious form, might have caused death  
• 
Persistent or significant disability or incapacity (i.e. substantial disruption of one’s ability 
to carry out normal life functions)  
• 
Hospitalisation, regardless of length of stay, even if it is a precautionary measure for 
continued observation or prolongation of existing hospitalisation 
• 
An important medical event (that may not cause death, be life threatening, or require 
hospitalization) that may, based upon appropriate medical judgment, jeopardize the 
participant and/or require medical or surgical intervention to prevent one of the 
outcomes listed above. Examples of such medical events include allergic reaction 
requiring intensive treatment in an emergency room or clinic, blood dyscrasias, or 
convulsions that do not result in inpatient hospitalization.  
• 
Congenital anomaly or birth defect  
 Serious Adverse Reaction (SAR) 
An adverse event (expected or unexpected) that is both serious and, in the opinion of the 
reporting Investigator or Sponsors, believed to be possibly, probably or definitely due to an IMP 
or any other study treatments, based on the information provided. 


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Suspected Unexpected Serious Adverse Reaction (SUSAR)  
A serious adverse reaction, the nature and severity of which is not consistent with the 
information about the medicinal product in question set out in the IB or SmPC.
8.3. Causality assessment  
For every AE, an assessment of the relationship of the event to the administration of the study 
treatments will be undertaken by the CI-delegated clinician. An intervention-related AE refers 
to an AE for which there is a probable or definite relationship to administration of a vaccine or 
checkpoint inhibitor. Adverse events are considered unrelated if they fall into the category of 
no relationship or unlikely relationship. An interpretation of the causal relationship of the 
intervention to the AE in question will be made, based on the type of event; the relationship of 
the event to the time of vaccine or checkpoint inhibitor administration; and the known biology 
of the vaccine and checkpoint inhibitor therapy (Table 2). Alternative causes of the AE, such as 
the natural history of pre-existing medical conditions, concomitant therapy, other risk factors 
and the temporal relationship of the event to study treatments will be considered and 
investigated.  
Table 2. Guidelines for assessing the relationship of vaccine administration to an AE  
0 
No 
Relationship
No temporal relationship to study product and
Alternate aetiology (clinical state, environmental or other interventions); and
Does not follow known pattern of response to study product  
1 
Unlikely 
relationship
Unlikely temporal relationship to study product; and
Alternative aetiology likely (clinical state, environmental or other 
interventions); and
Does not follow known typical or plausible pattern of response to the vaccine  
2 
Possible
Reasonable temporal relationship to study product; or
Event not readily produced by clinical state, environmental or other 
interventions; or
Similar pattern of response to that seen with other vaccines  
3 
Probable
Reasonable temporal relationship to study product; and
Event not readily produced by clinical state, environment, or other 
interventions or
Known pattern of response seen with other vaccines  
4 
Definite
Reasonable temporal relationship to study product; and
Event not readily produced by clinical state, environment, or other 
interventions; and
Known pattern of response seen with other vaccines  


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8.4. Severity assessment  
The severity of adverse events will be assessed according to the NIH Common Terminology 
Criteria for Adverse Events version 4.0. The generic severity scale is shown in Table 3.  NIH CTCAE 
v4.0 severity scales specific to selected important immune mediated checkpoint inhibitor 
toxicities are included in Appendix 2. 
Table 3. Generic scale for assessing the severity of AEs (CTCAE v4, NIH NCI)  
Grade 
Description 
Definition 
1 
Mild 
Asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated.
2 
Moderate 
Minimal, local or noninvasive intervention indicated; limiting age-appropriate 
instrumental ADL*.  
3 
Severe 
Medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self care ADL**.  
4 
Life-threatening 
Urgent intervention indicated
5 
Death  
Death related to AE 
*Activities of Daily Living (ADL). Instrumental ADL refer to preparing meals, shopping for   
groceries or clothes, using the telephone, managing money, etc. 
**Self care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden. 
Participants will be asked to record their temperature on a daily basis, as well as the size of 
any swelling or redness at the vaccination site and the symptoms that can be associated with 
checkpoint inhibitor therapy. For these solicited AEs participants will be instructed on self 
assessment of symptom severity based on the NIH CTCAE criteria above. The measured local 
reaction and daily temperature recording will be numerically graded in severity  according to 
Table 4:  
Table 4. Scale for assessing the severity of solicited AEs with numerical values  
Adverse Event
Grade
Intensity
Erythema at 
injection site 
1 
≥3 - ≤50 mm 
2 
>50 - ≤100 mm 
3 
>100 mm 
Swelling at 
injection site 
1 
>1 - ≤20 mm 
2 
>20 - ≤50 mm 
3 
>50 mm 
Fever (oral) 
1 
37.6°C - 38.0°C 
2 
38.1°C – 39.0°C 
3 
>39.0°C 
Physical observations taken at rest will be graded according to criteria in Table 4 and acted upon 
based on clinical context and prior history of  the individual.  


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Grade 1 
(mild) * 
Grade 2 
(moderate) ** 
Grade 3 
(severe) *** 
Tachycardia (bpm) 
101 – 115 
116 – 130 
>130 or 
Bradycardia (bpm) 
50 – 54 
40 – 49 
<40 
Systolic hypertension (mmHg) 
141 - 159 
160 – 179 
≥180 
Diastolic hypertension (mmHg) 
91 - 99 
100 – 109 
≥110 
Systolic hypotension (mmHg) 
85 – 89 
80 – 84 or 
<80 or 
8.5. Reporting procedures  
Reporting Procedures for All Adverse Events  
After an eligible participant is enroled onto the study on receipt of the first study procedure, 
all AEs occurred within 28 days of study treatment and only grade 3 AEs outside this time 
window will be reported in the study case report forms (CRF), whether or not attributed to 
study procedures. AEs may be observed by the Investigators or reported by the participant 
either spontaneously or during diary card monitoring. All AEs that result in a subject’s 
withdrawal from the study will be followed up, with their consent until a satisfactory 
resolution occurs, or until a non-study related causality is assigned.  
Reporting Procedures for Serious Adverse Events  
All serious adverse events (SAEs) occurring after an eligible participant is enrolled onto the 
study on receipt of the first study intervention, will be reported throughout the trial period. 
All SAEs will be documented accurately and notification deadlines respected. SAEs will be 
reported on an SAE Report Form to the Sponsor or the Sponsor’s delegated representative  
(Chief Investigator) and the Study  Medical Monitor (SMM), according to the relevant SOP 
within 24 hours of the Investigator becoming aware of them. SAEs will not normally be 
reported immediately to the ethical committee(s) and MHRA unless there is a clinically 
important increase in occurrence rate, an unexpected outcome, or a new event that is likely 
to affect safety of trial volunteers, in the opinion of the Chief Investigator and/or SMM. In 
addition to the expedited reporting above, the Investigator shall include all SAEs in the annual 
Development Safety Update Report (DSUR) report. Any updates to relevant information 
concerning the SAE that becomes available after the SAE initial report has been sent 
(outcome, precise history, results of investigations, copy of hospital report, etc) will be 
forwarded in a timely manner using the SAE Update Report Form. For all deaths, any available 
post-mortem reports and relevant medical reports will be made available for reporting to the 
relevant authorities. The Sponsor, or a medically qualified investigator delegated by the 


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Sponsor, is responsible for commencing, maintaining and completing the SAE Sponsor Report 
Form. The anonymity of subjects shall be respected when forwarding this information.  
Expectedness 
Expectedness will be determined according to the Investigators’ Brochure (ChAOx1.5T4 and 
MVA.5T4 vaccines) or the SmPC (nivolumab).  
Reporting Procedures for SUSARs  
The Chief Investigator will report all SUSARs to the MHRA and ethical committee(s) within 
required timelines (15 days for all SUSARs, unless life threatening in which case 7 days, with a 
final report within a further 8 days (total 15). The Chief Investigator will also inform all 
Investigators concerned of relevant information about SUSARs that could adversely affect the 
safety of participants. All SUSARs and deaths occurring during the study will be reported to 
the Sponsor. 
8.6. Procedures to be followed in the event of abnormal findings  
Abnormal clinical findings from medical history, examination, urinalysis or blood tests at any 
point in the study will be assessed as to their clinical significance. If a test is deemed clinically 
significant, it may be repeated, to ensure it is not a single occurrence and further diagnostic 
investigations carried out to determine any underlying pathology. If a result or finding is 
persistent or clinically significant, the subject will be informed and appropriate medical care 
arranged as appropriate and with the permission of the subject. Decisions to exclude the 
subject from enrolling in the trial or to withdraw a subject from the trial will be at the 
discretion of the Investigators, following procedures for adverse events as described above.  
8.7. Data and Safety Monitoring Committee  
A Data and Safety Monitoring Committee (DSMC) will be appointed to provide real-time safety 
oversight. It will consist of a consultant oncologist, a consultant physican with experience of 
vectored vaccine trials, a further member with statistical expertise and up to two further 
members with trial expertise, all of them independent of the study. The DSMC will review all 
SAEs at the meetings that will be convened following each interim safety report and a narrative 
from the Chief Investigator at the timepoints as below:  
An interim safety report of all recorded events, along with a narrative from the Chief 
Investigator, will be submitted to the Data and Safety Monitoring Committee for review after 
the first 6 patients (3 patients with intermediate risk disease and 3 metastatic patients) 
complete the study treatment and have reached the 24-week timepoint for efficacy assessment. 
An updated report to the Data and Safety Monitoring Committee, covering all enrolled 
participants to date will then be triggered when every 6th subsequent  participant has reached  
24-week timepoint for efficacy assessment.   
The DSCM has the power to terminate the study if deemed necessary following a study-related 
SAE.  


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The DSMC chair  will be notified of SAEs if deemed possibly, probably or definitely related to 
study-related interventions within 24 hours of the investigators’ being aware of their 
occurrence.  
The chair of the DSMC will be contacted for advice and independent review in the following 
situations:  
• 
Following any SAE deemed to be possibly, probably, or definitely related to the study 
vaccine. 
• 
Any other situation where the Investigator feels independent advice or review is 
important.  
8.8. Development Safety Update Reports  
The CI will submit (in addition to the expedited reporting above) DSURs once a year throughout 
the clinical trial, or on request, to the Competent Authority (MHRA in the UK), Ethics Committee, 
Host NHS Trust and Sponsor.  
9. STATISTICS  
9.1. Sample size  
This is a non-randomised multi-centre phase I/II study. The trial will be open label; given the 
objective nature of the measurements, this is unlikely to introduce significant bias in assessing 
key outcomes. Study ID will be assigned to participants in the order in which they are enrolled in 
the trial. The correspondence between the subject study ID and the treatment number/arm 
allocation will be noted down in the CRF and subsequently entered in the OpenClinica system. 
The total number of subjects enrolled  to the study will be 36: 12 subjects with low- or 
intermediate-risk localised or locally advanced prostate cancer and 24 subjects with metastatic 
disease.  
In this adaptive design study, the sample size of each patient cohort is chosen to allow an initial 
descriptive report of the safety of the vaccine in combination with checkpoint blockade. In this 
study, we are targeting a 25% response rate to the vaccine in combination with PD-1 blockade in 
mCRPC patients. The sample size of 24 patients in Group 2 will require that 6 out of 24 treated 
patients will have a complete response, partial response or stable disease. The patient cohorts 
recruited to the KEYNOTE-199 study will serve as a control group for ADVANCE and 11% overall 
response rate to PD-1 blockade as a monotherapy will be compared with the response rate to 
the vaccine in combination with anti-PD-1 treatment in the ADVANCE patients. 
The 12 patients in the surgical group will be compared for response rate to the 26 surgical 
subjects treated with the same vectored vaccines but no anti-PD1 in the VANCE trial. None of 
the 26 patients in VANCE showed a significant reduction in PSA levels during that trial. The 


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sample size of 12 is chosen to allow an initial descriptive comparison of response rates with and 
without anti-PD1 to help power any potential future trial. 
9.2. Analysis  
A detailed statistical analysis plan (SAP) will be prepared and finalised with the study statistician 
before the first interim data analysis. 
Data analysis of the following endpoints: safety, efficacy and immunogenicity will be assessed as 
detailed in Section 7. Safety data will be presented according to frequency, severity and duration 
of adverse events. Efficacy analysis will be primarily based on evaluation of ctDNA reduction, PSA 
response rate, radiographic progression-free and overall survival between metastaic PCa study 
arms. Immunogenicity will consist of descriptive analysis of cellular and humoral immune 
responses to the vaccine transgene in the circulation, focusing on the magnitude and qualities of 
T cell responses. 
Exploratory analyses may also include, but are not limited to, the analyses described below:  
Factors predictive of treatment benefit: baseline demographic, tumour status, haematological or 
immunological variables may be included as interactions with treatment in logistic, longitudinal 
or proportional hazards models of efficacy endpoints in order to assess their value as factors 
predictive of treatment benefit.  
Factors predictive of immune response: baseline demographic, tumour status, haematological or 
immunological variables may be included as explanatory variables in models of qualitative and 
quantitative immunological endpoints in order to assess their value as factors predictive of 
immune response.  
10. DATA HANDLING AND RECORD KEEPING  
10.1. Data Handling  
The Chief Investigator will have overall responsibility for receiving, entering, cleaning, querying, 
analysing and storing all data that accrues from the study, but these tasks may be delegated to 
other Investigators. The data will be entered into the participants’ CRFs which will be in a paper 
and/or electronic format using the OpenClinica™ database. This includes safety data, laboratory 
data (both clinical and immunological) and outcome data. Data are entered in a web browser 
on PCs and then transferred to the OpenClinica Database by encrypted (https) transfer. 
Electronic data will be stored on secure servers which are outsourced by OpenClinica™. 
10.2. Record Keeping and Access to Data  
The Investigators will maintain appropriate medical and research records for this trial, in 
compliance with the requirements of the Medicines for Human Use (Clinical Trial) Regulations 
2004, ICH E6 GCP and regulatory and institutional requirements for the protection of 
confidentiality of participants. Participants will only be referred to by their ID number on all 
study data. The Principal Investigator, co-investigators and clinical research nurses will have 


ADVANCE_v6.0                                             21st August 2019                                                    Page 74 of 86 
access to records. The Investigators will permit authorized representatives of the sponsor, 
relevant NHS Trust, and regulatory agencies to examine (and when required by applicable law, 
to copy) clinical records for the purposes of quality assurance reviews, audits and evaluation of 
the study safety and progress. All source data and subject CRFs in paper and electronic form will 
be stored securely at the clinical sites in locked cupboards and secure servers respectively, and 
anonymised prior to archiving. The study data will be stored for a minimum of 10 years after 
publication or public release. 
10.3. Source Data and Case Report Forms (CRFs)  
All protocol required information will be collected in CRFs designed by the Investigators. All 
source documents will be filed in the patient medical records at the relevant site. Source 
documents are original documents, data, and records from which the subject’s CRF data are 
obtained. For this study, these will include, but are not limited to, subject consent form, blood 
results, clinician response letters, laboratory records, diary cards and alert cards. In the majority 
of cases, CRF entries will be considered source data where the CRF is the site of the original 
recording.  
10.4. Data Protection  
The study protocol, documentation, data and all other information generated will be held in 
strict confidence. No information concerning the study or the data will be released to any 
unauthorized third party, without prior written approval of the sponsor.  
11. QUALITY CONTROL AND QUALITY ASSURANCE PROCEDURES  
Investigator procedures 
Approved SOPs will be used at all clinical and laboratory sites.  
Monitoring  
Regular Monitoring will be performed according to ICH Good Clinical Practice (GCP). Data will 
be evaluated for compliance with the protocol and accuracy in relation to source documents. 
Following written standard operating procedures, the monitors will verify that the clinical trial 
is conducted and data are generated, documented and reported in compliance with the 
protocol, GCP and the applicable regulatory requirements. The investigator sites will provide 
direct access to all trial related source data/documents and reports for the purpose of 
monitoring and auditing by the sponsor and inspection by local and regulatory authorities  
Modification to protocol  
No substantial amendments to this protocol will be made without consultation with, and 
agreement of, the Sponsor.  Any substantial amendments to the trial that appear necessary 
during the course of the trial must be discussed by the Investigator and Sponsor concurrently. 
If agreement is reached concerning the need for a substantial amendment, it will be produced 


ADVANCE_v6.0                                             21st August 2019                                                    Page 75 of 86 
in writing by the Chief Investigator and will be made a formal part of the protocol following 
ethical and regulatory approval.  
A non-substantial amendment is one that modifies administrative and logistical aspects of a 
protocol but does not affect the subjects’ safety, the objectives of the trial and its progress. A 
non-substantial amendment does not require ethical or regulatory approval.  
Protocol deviation   
Any deviations from the protocol will be documented in a protocol deviation form and filed in 
the trial master file.   
Audit & inspection   
The sponsor may carry out audit to ensure compliance with the protocol, GCP and appropriate 
regulations.  GCP inspections may also be undertaken by the MHRA to ensure compliance with 
protocol and the Medicines for Human Use (Clinical Trials) Regulations 2004. The sponsor will 
assist in any inspections and will formally respond to the MHRA as part of the inspection 
procedure.  
Serious Breaches
The Medicines for Human Use (Clinical Trials) Regulations contain a requirement for the 
notification of "serious breaches" to the MHRA within 7 days of the sponsor becoming aware of 
the breach.   
A serious breach is defined as “A breach of GCP or the trial protocol which is likely to effect to a 
significant degree –   
(a) the safety or physical or mental integrity of the subjects of the trial; or 
(b) the scientific value of the trial”. 
In the event that a serious breach is suspected, the sponsor must be contacted within 1 working 
day. In collaboration with the CI, the serious breach will be reviewed by the Sponsor and, if 
appropriate, the Sponsor will report it to the REC committee, Regulatory Authority and the NHS 
host organisation within 7 calendar days.  
Trial Progress 
The progress of the trial will be overseen by the Chief Investigator or a nominated person.  
12. ETHICAL AND REGULATORY CONSIDERATIONS  
12.1.Good Clinical Practice  
This trial will be conducted in accordance with the principles of the Declaration of Helsinki as 
agreed by the World Medical Association General Assembly (2013), ICH Good Clinical Practice 


ADVANCE_v6.0                                             21st August 2019                                                    Page 76 of 86 
(GCP), the requirements of the Medicines for Human Use (Clinical Trial) Regulations 2004, and 
local regulatory requirements.
12.2. Ethical Review  
A copy of the protocol, proposed informed consent form and other written subject 
information will be submitted to an independent EC for written approval. The Investigators 
will submit and, where necessary, obtain approval from the EC for all subsequent substantial 
amendments to the protocol and informed consent document (and previously approved by 
the sponsor). The Investigators will notify serious deviations from the protocol or SAEs 
occurring at the site to the Sponsor and will notify the EC of these in accordance with local 
procedures.  
12.3. Informed Consent  
Written informed consent will be obtained at screening as detailed in section 5.2.  
12.4 . Surgery delay  
The risk associated with postponing surgery by approximately 6 weeks is considered very small 
as detailed in section 4.6.2. The investigators will discuss this issue with the potential 
participants in detail. The patients who require an operation without delay are not eligible for 
this study.     
12.5. Approvals  
The protocol and related documents will be submitted to the Sponsor, an appropriate Research 
Ethics Committee (REC), the Health Research Authority (HRA) and host institution(s) for 
approval and the Medicines and Healthcare products Regulatory Agency (MHRA) for Clinical 
Trial Authorisation.  
 The Investigator will submit and, where necessary, obtain approval from the above parties for 
all substantial amendments to the original approved documents.  
12.6. Reporting  
The CI shall submit an Annual Progress report to the REC Committee, host organisation and 
Sponsor.  In addition, an End of Study notification and final report will be submitted to the same 
parties.  
12.7. Participant Confidentiality  
The study will comply with the General Data Protection Regulation (GDPR) and Data Protection 
Act 2018, which require data to be de-identified as soon as it is practical to do so. The processing 
of the personal data of participants will be minimised by making use of a unique participant study 
number only on all study documents and any electronic database(s), with the exception of the 
CRF, where participant initials may be added.  All documents will be stored securely and only 


ADVANCE_v6.0                                             21st August 2019                                                    Page 77 of 86 
accessible by study staff and authorised personnel. The study staff will safeguard the privacy of
participants’ personal data. 
13. FINANCE AND INSURANCE  
13.1. Financing  
The study will be funded by the IMPROVE EC FP7 grant.  
13.2 Insurance  
The University of Oxford is the research sponsor of the trial. The University has a specialist 
insurance policy in place which would operate in the event of any participant suffering harm as 
a result of their involvement in the research (Newline Underwriting Management Ltd, at Lloyd’s 
of London).  NHS indemnity operates in respect of the clinical treatment which is provided. 
Research undertaken in Switzerland will have separate insurance arrangements. 
13.3. Compensation  
Subjects will be compensated for their time and for the inconvenience caused by procedures. 
The amount of compensation will be stated in the subject’s information sheet. If subjects 
withdraw without completing the study then they are entitled to receive a pro-rata amount of 
compensation. If subjects need to have additional visits (e.g. for repeats of safety bloods) then 
additional compensation can be given. Where participants incur higher travel costs due to 
additional unanticipated visits then appropriate compensation will be provided.  
14. PUBLICATION POLICY  
The Investigators will be involved in reviewing drafts of the manuscripts, abstracts, press 
releases and any other publications arising from the study.  Authors will acknowledge that the 
study was funded by the EC FP7 grant. Authorship will be determined in accordance with the 
ICMJE guidelines and other contributors will be acknowledged.  


ADVANCE_v6.0                                             21st August 2019                                                    Page 78 of 86 
APPENDIX 1:  SCHEDULE OF ATTENDANCE AND STUDY PROCEDURES    
Group 1: Participants scheduled for Radical Prostatectomy 
Visit/Telephone Call Number
S 
V1 
T1 
V2 
T2 
V3 
V4 
V5 
V6 
Time from enrolment (weeks +days)  
≤ -4 
0 
0+2 
1 
1+2 
2 
5 
≥5 
16 
24 
Window (days) *
0
=3 
+3 
+3 
+3 
±7 
+14 
±7 
±7 
Informed consent
X
Review of inclusion criteria 
X
X
Review of exclusion criteria
X 
X
X 
X
X
X
X
Medical history
X
(X)
(X)
(X)
(X)
 
(X)
(X)
Physical examination
X
Targeted physical examination 
(X)
(X)
(X)
(X)
 
(X)
(X)
Retrieval of archival diagnostic biopsy 
f
h
t d f
X** 
 
Fresh biopsy (if required) 
X** 
 
Telephone call 
X
X
Recording vital signs
X
X
X
X
X
X
X
ECOG Status 
X
X
X
ChAdOx1.5T4 vaccination
X 
 
MVA.5T4 vaccination
X 
Nivolumab infusion
X 
Radical Prostatectomy (mpMRI – optional) 
X 
Assessment & recording of adverse events
X
X
X
X
X
X
X
X
Patient alert card provided 
X
Diary card provided
A
C
Diary card returned
X
X
Haematology1
2
2
2
2
2
2
2
Biochemistry1
4
4
4
4
4
4
4
Serum glucose1
2
2
2
2
2
2
2
Thyroid function tests1,2
2
2 
2
2
PSA1
5 
5
5
5
5
5
5
Urinalysis
X
X
X
X
X
X
X
HBVsAg, HIV &HCV Ab1
5
Human leukocyte antigen typing (ml)
5
Exploratory immunology (ml)
50
50
50
50
 
50
50
Exploratory biochemistry (ml)
2
2
2
2
2
2


ADVANCE_v6.0                                             21st August 2019                                                    Page 79 of 86 
Total blood volume per visit (ml)1
20
70
65
65 
67
 
67
67
Cumulative blood volume  ≈ 421ml1
* Window is based on preceeding IMP administration 
** Window is  –28 days 
1 Volume can vary by site according to local practices 
2 Total triiodothyronine (T3) or free T3c, free thyroxine (T4) and thyroid stimulating hormone (TSH)


ADVANCE_v6.0                                             21st August 2019                                                    Page 80 of 86 
Group 2: Participants with Metastatic Prostate Cancer 
Table of events (part 1 of 2) 
Visit/Telephone Call Number 
S 
V1 
T1 
V2 
V3 
T2 
V4 
V5 
T3 
V6 
Time from enrolment (weeks+days) 
≤ -4 
0 
0+2 
2 
4 
4+2 
5 
8 
8+2 
9 
Window (days)*
+3 
±2 
±2 
+3 
+3 
±2 
+3 
+3 
Informed consent 
X 
Review of inclusion/exclusion criteria 
X 
X 
 
(X) 
X 
(X) 
X 
(X) 
Medical history 
X 
(X) 
 
(X) 
(X) 
(X) 
(X) 
(X) 
Physical examination (if required) 
X 
(X) 
 
(X) 
(X) 
(X) 
(X) 
(X) 
Retrieval of archival diagnostic 
biopsy
X1
Fresh biopsy (if required)
X1
Telephone Call 
X 
X 
X 
Recording vital signs 
X 
X 
X 
X 
X 
X 
X 
ECOG Status 
X 
X 
X 
ChAdOx1.5T4 vaccination 
X 
 
 
MVA.5T4 vaccination 
X 
Nivolumab infusion 
X 
X 
Assessment & recording of adverse 
events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Radiological assessment (bone 
scintigraphy, CT scan,  MR scan) 
X1
Patient alert card provided 
X 
Diary card provided 
B 
C 
D 
Diary card returned 
X 
X 
Haematology2
2 
2 
2 
2 
2 
2 
2 
Biochemistry2
4 
4 
4 
4 
4 
4 
4 
Serum glucose2
2 
2 
2 
2 
2 
2 
2 
Thyroid function tests2-3
2 
2 
2 
PSA1
5 
5 
5 
5 
5 
5 
5 
Urinalysis 
X 
X 
X 
X 
X 
X 
X 
HBVsAg, HIV &HCV Ab1
5 
Human leukocyte antigen typing (ml) 
5 
Exploratory immunology (ml) 
30 
 
40 
40 
40 
CTC (ml) 
8 
8 
ctDNA  (ml) 
8 
8 
  8 


ADVANCE_v6.0                                             21st August 2019                                                    Page 81 of 86 
* Window is based on preceeding IMP administration 
1  Window is  –28 days 
2 Volume can vary by site according to local practices 
3 Total triiodothyronine (T3) or free T3c, free thyroxine (T4) and thyroid stimulating hormone (TSH) 
Group 2: Participants with Metastatic Prostate Cancer
Table of events (part 2 of 2) 
Total blood volume per visit (ml)2
20 
61 
58 
21 
53 
31 
53 
Visit/Telephone Call Number 
V7 
T4 
V8 
V9 
T5 
V10 
V11 
V12 
V13 
Time from enrolment (weeks+days)  
12 
12+2
13 
16 
16+2
17 
24 
36 
48 
Window (days)*
±7 
+3 
+3 
±2 
+3 
+3 
±7 
±14 
±14 
Informed consent 
Review of inclusion/exclusion criteria  
X 
(X) 
X 
(X) 
(X) 
(X) 
(X) 
Medical history 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
Physical examination (if required) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
Telephone Call 
X 
X 
Recording vital signs 
X 
X 
X 
X 
X 
X 
X 
ECOG Status  
X 
X 
X 
X 
X 
ChAdOx1.5T4 vaccination 
X 
 
MVA.5T4 vaccination 
X 
Nivolumab infusion 
X 
 
Assessment & recording of adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Radiological assessment (bone 
scintigraphy, CT  MR scan) 
X 
X 
Diary card provided 
C 
B 
Diary card returned 
X 
X 
X 
Haematology1
2 
2 
2 
2 
2 
2 
2 
Biochemistry1
4 
4 
4 
4 
4 
4 
4 
Serum glucose1
2 
2 
2 
2 
2 
2 
2 
Thyroid function tests1, 2
2 
2 
2 
2 
2 
PSA1
5 
5 
5 
5 
5 
5 
5 
Urinalysis 
X 
X 
X 
X 
X 
X 
X 
Exploratory immunology (ml) 
40 
40 
30 
40 
40 
CTC (ml) 
8 
ctDNA  (ml)   
8 
8 
Total blood volume per visit (ml)1
23 
53 
15 
53 
61 
55 
55 


ADVANCE_v6.0                                             21st August 2019                                                    Page 82 of 86 
* Window is based on preceeding IMP administration 
1 Volume can vary by site according to local practices 
2 Total triiodothyronine (T3) or free T3c, free thyroxine (T4) and thyroid stimulating hormone (TSH)
APPENDIX 2: SEVERITY GRADING FOR IMPORTANT IMMUNE-MEDIATED AEs 
Adverse Event 
 Grade
         1 
          2 
        3 
        4 
Rash 
Cutaneous disorder composite of erythema or lesions of maculopapular, 
pruritic, pustular or other character 
Lesions covering 
<10% BSA 
Symptomatic or 
asymptomatic 
Lesions covering 
10-30% BSA 
Symptomatic or 
asymptomatic 
Limiting 
instrumental 
ADLs 
Lesions covering 
> 30% BSA 
Symptomatic or 
asymptomatic 
Exfoliative, 
ulcerated or 
bullous 
Localised 
superinfection 
Life-threatening 
consequences; 
urgent 
intervention 
indicated 
Hepatitis or 
Transaminitis 
Disorder characterised by deranged liver function tests or inflammation of 
the liver 
Asymptomatic 
ALT or AST ≤ 2.5 
x ULN 
Total bilirubin ≤ 
1.5 x ULN 
Symptomatic 
ALT or AST > 
2.5x ULN and ≤ 
5x ULN 
Total bilirubin ≤ 
3x ULN 
Symptomatic 
ALT or AST > 5x 
ULN 
Total Bilirubin > 
3x ULN 
Decompensated 
liver function 
(e.g., ascites, 
oedema 
coagulopathy, 
encephalopathy) 
Diarrhoea and 
Colitis 
Disorder frequent and watery bowel movements and/or inflammation of 
the colon 
Increase of less 
than four stools 
per day over 
baseline;  
Increase of four 
to six stools per 
day over 
baseline;  
Abdominal pain 
Increase of 
seven or more 
stools per day 
over baseline; 
incontinence; 
hospitalization 
Life-threatening 
consequences; 
urgent 
intervention 
indicated 
Cumulative blood volume = 612ml1


ADVANCE_v6.0                                             21st August 2019                                                    Page 83 of 86 
Blood or mucus 
per rectum  
indicated; 
limiting self-care 
activities of daily 
living 
Ileus  
Fever 
Peritonism 
Pneumonitis 
Disorder characterized by inflammation focally or diffusely affecting the 
lung parenchyma 
Asymptomatic; 
clinical or 
diagnostic 
observations 
only; 
intervention not 
indicated 
Symptomatic; 
medical 
intervention 
indicated; 
limiting 
instrumental 
ADL 
Severe 
symptoms; 
limiting self care 
ADLs;  
oxygen 
indicated 
Life-threatening 
respiratory 
compromise; 
urgent 
intervention 
indicated (e.g., 
tracheotomy or 
intubation) 
Nephritis / 
Renal 
dysfunction  
Disorder characterised by immune mediated acute kidney injury 
[urological 
causes of acute 
kidney injury 
must be 
excluded] 
Asymptomatic 
Serum 
creatinine > ULN 
and ≤ 1.5 
baseline 
1+ proteinuria; 
urinary protein 
<1.0 g/24 hrs 
Serum 
creatinine > 
1.5x baseline 
and ≤ 3x 
baseline 
Active urinary 
sediment 
2+ proteinuria; 
urinary 
protein 1.0 - 3.4 
g/24 hrs; 
Serum 
creatinine > 3x 
baseline and ≤ 
6x baseline 
Active urinary 
sediment 
3+ proteinuria; 
urinary protein 
>=3.5 
g/24 hrs; 
Serum creatinine 
> 6 x baseline 


ADVANCE_v6.0                                             21st August 2019                                                    Page 84 of 86 
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