Clinical trial NCT05110495
Conditions: Prostate Cancer
Sponsor: University of Oxford
Start date: 2021-12-17; Completion date: 2023-05-27
Enrollment: 27 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The WINGMEN trial aims to understand how a hormone-like protein called insulin-like growth factor (IGF) helps prostate cancers grow and become aggressive. IGF is required for normal development, and also helps cancers grow and spread. Men with high blood IGF are at increased risk of developing prostate cancer, and tall men are more likely to get aggressive prostate cancer. The WINGMEN trial will recruit 30 men with prostate cancer who have been offered an operation to remove the prostate. Most men have to wait 4-5 weeks between a decision to have prostate removal surgery, and actually having the operation. In this 4-5 week window we will offer treatment with a new IGF-blocker drug called xentuzumab. The drug is provided by Boehringer Ingelheim and the trial is funded by Prostate Cancer UK.

Xentuzumab will be given as an outpatient by once weekly intravenous infusion (drip) in the Early Phase Clinical Trials Unit, Oxford Cancer Centre, Churchill Hospital. In other trials, xentuzumab is being tested in patients with advanced cancer, and is proving to be well-tolerated. After the 4-week treatment, WINGMEN trial patients will have routine prostate removal surgery. Samples of blood and prostate cancer that are surplus to diagnostic need will be taken from the diagnostic prostate biopsy (pre-xentuzumab) and the cancer removed at surgery (after xentuzumab) for research tests. These samples will be compared to measure how effectively xentuzumab reduces signs of tumour growth, and identify which genes and proteins are switched on or off by xentuzumab, and which may therefore be important in helping IGF promote prostate cancer growth. The information we get from the WINGMEN trial may help us to improve treatment of men with prostate cancer, with the long-term aim of reducing the risk of aggressive prostate cancer

Detailed description:

Arms: arm 1: All patients will be allocated to receive Xentuzumab
Interventions: intervention 1: Xentuzumab
Intervention descriptions: intervention 1: The study IMP is xentuzumab, a humanised IgG1 monoclonal antibody that neutralises the IGF ligands to inhibit activation of IGF-1R and INSR-A, suppressing IGF-mediated proliferation, invasion and therapy resistance

Protocol documents:
Prot_000.pdf: 
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WINGMEN Protocol
Full title: Windows trial of INsulin-like Growth factor neutralising antibody 
Xentuzumab in MEN scheduled for radical prostatectomy
Short title: IGF inhibition with xentuzumab prior to radical prostatectomy
Protocol Version & date: 
 Version 2.0_21Nov2022
Protocol Number: 
OCTO_084 
EudraCT Number: 
2018-000204-42 
Ethics Reference number: 
21/SC/0170 
IRAS Project ID: 
242236 
Name of Registry: 
ClinicalTrials.gov Identifier NCT05110495
Registered on 05Nov2021 
Sponsor:  
University of Oxford   
Funder:  
Prostate Cancer UK (Reference RIA16-ST2-024) 
Conflict of Interest statement 
Details of potential conflicts of interest  are given 
on page 3. 
Confidentiality Statement 
This document contains confidential information 
that must not be disclosed to anyone other than 
the Sponsor, the Trial Office, the Investigator Team, 
host NHS Trust(s), regulatory authorities, and 
members of the Research Ethics Committee unless 
authorised to do so.   


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Key trial contacts 
General Queries 
WINGMEN Trial Team 
Oncology Clinical Trials Office (OCTO) 
Email: octo-WINGMEN@oncology.ox.ac.uk 
Website: www.oncology.ox.ac.uk/research/oncology-clinical-trials-
office-octo 
Department of Oncology, The University of Oxford 
Old Road Campus Research Building 
Oxford OX3 7DQ, UK 
Patient Registration
To register a patient on the trial email the completed and scanned 
Registration Form to the WINGMEN Trial Office: octo-
WINGMEN@oncology.ox.ac.uk 
During office hours 
Clinical Queries should be directed to the Trial Manager at OCTO 
(contact details as above). 
Out of office hours 
Call the Oxford University Hospitals switchboard on Tel: 0300 304 
7777 and ask to call the WINGMEN Trial Clinical Coordinator. 
SAE Reporting 
Pharmacovigilance Office, OCTO 
Email: octo-safety@oncology.ox.ac.uk
Chief Investigator 
Dr Simon Lord 
Consultant Medical Oncologist, Oxford University Hospitals NHS 
Foundation Trust
Department of Oncology, The University of Oxford 
Old Road Campus Research Building, Oxford OX3 7DQ, UK 
Email: simon.lord@oncology.ox.ac.uk
Tel: 01865 227212 
Co-Investigators 
Professor Valentine Macaulay 
Mr Alastair Lamb 
Professor Clare Verrill 
Sponsor 
University of Oxford  
Research Governance, Ethics & Assurance Team 
Joint Research Office  
1st floor, Boundary Brook House 
Churchill Drive 
Oxford OX3 7GB 
Tel: 01865 572244 
Email: ctrg@admin.ox.ac.uk


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Trial Statistician 
Dr Simon Lord 
Consultant Medical Oncologist, Oxford University Hospitals NHS 
Foundation Trust
Department of Oncology, The University of Oxford 
Old Road Campus Research Building, Oxford OX3 7DQ, UK 
Email: simon.lord@oncology.ox.ac.uk
Tel: 01865 227212 
Protocol Authors and conflict of interest statement 
Professor Valentine Macaulay, Department of Oncology, University of Oxford 
Stephanie Levy, Portfolio Lead, OCTO 
Dr Sophie Betteridge, Trial Manager, OCTO 
Tim Coutts, Trial Manager, OCTO 
Dr Simon Lord, Early Phase Clinical Trials Unit, Oxford Cancer Centre 
Mr Alastair Lamb, Nuffield Department of Surgical Sciences, Oxford 
Professor Clare Verrill, Nuffield Department of Surgical Sciences and Department of Cellular 
Pathology, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford. 
Professor Macaulay is a Consultancy Board member for Boehringer Ingelheim. The other authors 
have no conflict of interest to declare. 


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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS .......................................................................................................................... 7
SUMMARY SCHEDULE OF EVENTS .................................................................................................... 9
STUDY FLOW CHART ............................................................................................................................ 10
1
INTRODUCTION ................................................................................................................. 13
1.1
BACKGROUND ........................................................................................................................ 13
1.2
INVESTIGATIONAL MEDICINAL PRODUCT USED IN THE STUDY ............................................................ 14
1.3
OTHER RESEARCH INTERVENTIONS .............................................................................................. 15
1.4
RATIONALE FOR THE STUDY ....................................................................................................... 15
2
TRIAL DESIGN .................................................................................................................... 18
2.1
DURATION OF PATIENT PARTICIPATION ........................................................................................ 19
2.2
POST-TRIAL CARE AND FOLLOW-UP ............................................................................................. 19
3
OBJECTIVES AND ENDPOINTS ........................................................................................... 19
4
PATIENT SELECTION .......................................................................................................... 20
ELIGIBILITY CRITERIA FOR ENTRY INTO THE  STUDY ........................................................................... 20
4.1 
20
EXCLUSION CRITERIA: ........................................................................................................................... 21
4.2
PROTOCOL DEVIATIONS AND WAIVERS TO ENTRY CRITERIA ............................................................... 21
4.3
RE-SCREENING IF PATIENT DOES NOT MEET INCLUSION/EXCLUSION CRITERIA FIRST TIME AROUND ............ 21
4.4
PATIENT REGISTRATION PROCEDURE ............................................................................................ 22
TRIAL ASSESSMENTS AND PROCEDURES ........................................................................................ 22
4.5 
22
4.6
INFORMED CONSENT ................................................................................................................ 22
4.7
PRE-DOSING EVALUATIONS ........................................................................................................ 23
4.8
EVALUATIONS DURING THE STUDY ............................................................................................... 24
4.9
END OF STUDY (EOS) EVALUATIONS AT 6 WEEKS AFTER SURGERY (± 7 DAYS) ...................................... 26
4.10
EVALUATIONS ON EARLY WITHDRAWAL ........................................................................................ 27
5
EARLY PATIENT WITHDRAWAL ......................................................................................... 27
5.1
PATIENT EVALUABILITY AND REPLACEMENT ................................................................................... 27
6
SAMPLES FOR LABORATORY ANALYSIS ........................................................................... 28
6.1
SAMPLES TO BE ANALYSED ......................................................................................................... 28
6.2
LABELLING AND CONFIDENTIALITY OF SAMPLES SENT ....................................................................... 29
6.3
CLINICAL REPORTING OF EXPLORATORY RESEARCH ASSAY RESULTS ..................................................... 29
6.4
TRIAL SAMPLE RETENTION AT END OF STUDY ................................................................................. 29
6.5
WITHDRAWAL OF CONSENT FOR SAMPLE COLLECTION AND/OR RETENTION ......................................... 29
7
INVESTIGATIONAL MEDICINAL PRODUCT (IMP) ............................................................. 29
7.1
NAME OF IMP ....................................................................................................................... 29
7.2
TREATMENT DOSE ................................................................................................................... 30
7.3
DURATION OF TREATMENT ........................................................................................................ 30
7.4
MANAGEMENT OF DRUG ADMINISTRATION ................................................................................... 30
7.5
SPECIAL PRECAUTIONS .............................................................................................................. 30
7.6
DOSE MODIFICATION ................................................................................................................ 30


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7.7
COMPLIANCE .......................................................................................................................... 31
7.8
MANAGEMENT OF OVERDOSE .................................................................................................... 31
8
OTHER TREATMENTS (NON-IMPs) ................................................................................... 31
8.1
SUPPORT MEDICATION ............................................................................................................. 31
8.2
CONCOMITANT MEDICATION AND NON-DRUG THERAPIES ................................................................ 31
8.3
PROHIBITED THERAPIES ............................................................................................................. 31
8.4
DRUG INTERACTIONS/ POTENTIAL DRUG INTERACTIONS ................................................................. 32
8.5
POST-TRIAL TREATMENT .......................................................................................................... 32
9
DRUG MANAGEMENT ....................................................................................................... 32
9.1
DRUG SUPPLIES ....................................................................................................................... 32
9.2
DRUG ORDERING ..................................................................................................................... 32
9.3
IMP RECEIPT ......................................................................................................................... 32
9.4
HANDLING AND STORAGE .......................................................................................................... 32
9.5
LABELLING ............................................................................................................................. 33
9.6
DOSING DISPENSING ................................................................................................................ 33
9.7
DRUG ACCOUNTABILITY ............................................................................................................ 33
9.8
DRUG RETURNS FROM PATIENTS ................................................................................................. 33
9.9
DRUG DESTRUCTION ................................................................................................................ 33
9.10
OCCUPATIONAL SAFETY ............................................................................................................ 33
10
SAFETY REPORTING .......................................................................................................... 34
10.1
ADVERSE EVENT DEFINITIONS .................................................................................................... 34
10.2
CLINICAL LABORATORY ABNORMALITIES AND OTHER ABNORMAL ASSESSMENTS AS AES AND SAES ........... 36
10.3
DETERMINING ADVERSE EVENT CAUSALITY .................................................................................... 36
10.4
REFERENCE SAFETY INFORMATION (RSI) FOR ASSESSMENT OF EXPECTEDNESS ...................................... 37
10.5
SUSPECTED UNEXPECTED SERIOUS ADVERSE DRUG REACTIONS (SUSARS) ......................................... 37
10.6
EXPEDITED REPORTING OF SAES ................................................................................................. 37
10.7
FOLLOW-UP OF SERIOUS ADVERSE EVENTS ................................................................................... 38
10.8
REPORTING ADVERSE EVENTS ON THE CRF................................................................................... 38
10.9
EVENTS EXEMPT FROM BEING REPORTED AS AE/SAES .................................................................... 39
10.10 INFORMING INVESTIGATORS OF NEW SAFETY INFORMATION ............................................................. 39
10.11 DEVELOPMENT SAFETY UPDATE REPORTS .................................................................................... 39
11
PREGNANCY ...................................................................................................................... 40
12
DEFINING THE END OF TRIAL ............................................................................................ 40
13
STATISTICAL CONSIDERATIONS ........................................................................................ 40
SAMPLE SIZE AND POWER .......................................................................................................... 40
13.1 
40
14
STATISTICAL ANALYSIS PLAN ............................................................................................ 40
14.1
INCLUSION IN ANALYSIS ............................................................................................................. 41
14.2
SUBGROUP ANALYSIS ................................................................................................................ 41
14.3
INTERIM ANALYSES .................................................................................................................. 41
14.4
PROCEDURES FOR REPORTING ANY DEVIATION(S) FROM THE ORIGINAL STATISTICAL PLAN ....................... 41
14.5
FINAL ANALYSIS ....................................................................................................................... 41
15
TRIAL COMMITTEES .......................................................................................................... 41


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15.1
TRIAL MANAGEMENT GROUP (TMG) ......................................................................................... 41
15.2
DATA AND SAFETY MONITORING ................................................................................................ 41
15.3
TRIAL STEERING COMMITTEE ..................................................................................................... 41
16
DATA MANAGEMENT ....................................................................................................... 42
SOURCE DATA ........................................................................................................................ 42
16.1 
42
16.2
DATABASE CONSIDERATIONS ...................................................................................................... 45
16.3
CASE REPORTS FORMS (CRFS) ................................................................................................... 45
16.4
ACCOUNTING FOR MISSING, UNUSED, OR SPURIOUS DATA. .............................................................. 45
17
CLINICAL STUDY REPORT .................................................................................................. 45
18
STUDY SITE MANAGEMENT .............................................................................................. 46
18.1
STUDY SITE RESPONSIBILITIES ..................................................................................................... 46
18.2
STUDY SITE SET UP AND ACTIVATION ............................................................................................ 46
18.3
STUDY DOCUMENTATION .......................................................................................................... 46
19
REGULATORY AND ETHICAL CONSIDERATIONS ............................................................... 46
19.1
ETHICAL CONDUCT OF THE TRIAL AND ETHICS APPROVAL .................................................................. 46
19.2
REGULATORY AUTHORITY APPROVAL ........................................................................................... 46
19.3
NHS RESEARCH GOVERNANCE................................................................................................... 46
19.4
PROTOCOL AMENDMENTS ......................................................................................................... 47
19.5
URGENT SAFETY MEASURES ....................................................................................................... 47
19.6
TEMPORARY HALT ................................................................................................................... 47
19.7
SERIOUS BREACHES.................................................................................................................. 48
19.8
TRIAL REPORTS ....................................................................................................................... 48
20
EXPENSES AND BENEFITS .................................................................................................. 48
21
QUALITY ASSURANCE ....................................................................................................... 49
21.1
RISK ASSESSMENT .................................................................................................................... 49
21.2
MONITORING ......................................................................................................................... 49
21.3
AUDIT AND REGULATORY INSPECTION ......................................................................................... 49
22
RECORDS RETENTION & ARCHIVING ................................................................................ 49
23
PATIENT CONFIDENTIALITY .............................................................................................. 50
24
STUDY FUNDING ............................................................................................................... 50
25
SPONSORSHIP AND INDEMNITY ...................................................................................... 51
25.1
SPONSORSHIP ......................................................................................................................... 51
25.2
INDEMNITY ............................................................................................................................ 51
25.3
CONTRACTS/AGREEMENTS ........................................................................................................ 51
26
PUBLICATION POLICY ........................................................................................................ 51
27
REFERENCES ...................................................................................................................... 51
APPENDIX 1: ECOG PERFORMANCE SCALE ....................................................................................... 55
APPENDIX 2:  COCKROFT & GAULT FORMULA ................................................................................. 56
APPENDIX 3:  AMENDMENT HISTORY .............................................................................................. 57


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PROTOCOL SYNOPSIS 
Full Title of study: 
Windows trial of INsulin-like Growth factor neutralising antibody 
Xentuzumab in MEN scheduled for radical prostatectomy 
Short Title: 
IGF inhibition with xentuzumab prior to radical prostatectomy 
Trial Acronym: 
WINGMEN 
Clinical Phase: 
Phase 0 
Study Design: 
Open label, ‘window of opportunity’ study 
Number of Centres 
Single centre 
Objectives 
Endpoints 
Primary Endpoint: 
Assess the amount of IGF pathway 
inhibition induced by xentuzumab  
Phospho-IGF-1R and phospho-AKT (or 
downstream target) 
immunohistochemistry on tissue from 
biopsy and prostatectomy 
Secondary 
Endpoints: 
1. Feasibility of treatment in pre-
operative setting 
2. Assess safety and tolerability of 
xentuzumab administered in the pre-
prostatectomy setting 
1. Number of patients whose radical 
prostatectomy is performed on schedule 
after 3 doses of xentuzumab (patients 
can receive up to 10 doses of 
xentuzumab if surgery is delayed) 
2. Treatment-related adverse events 
scored using CTCAE v5.0
Tertiary/exploratory 
Endpoints 
1. Assess change in PSA following 
administration of xentuzumab in the 
pre-prostatectomy setting 
2. Assess changes in tissue markers 
following administration of xentuzumab 
in the pre-prostatectomy setting 
3. Assess changes in circulating markers 
following administration of xentuzumab 
in the pre-prostatectomy setting 
4. Correlate changes in IGF-1R 
expression, IGF axis activity with 
baseline and post-treatment cancer 
profile, which may include PTEN status 
by IHC, tumour mutation status,  
transcriptional, immune and phospho-
proteomic profile 
1. Change in serum PSA 
2. Changes by IHC and/or 
immunofluorescence on FFPE tissues in 
tissue markers e.g. Ki67 index, IGF-1R, 
RRM2, CD31, immune markers PD-L1, 
CD4, CD8, FoxP3 
3. Changes in circulating markers of 
response to IGF blockade e.g. IGF-1, 
insulin, IGFBPs, serum IGF bioactivity, 
metabolomic profile, PBMC 
immunoprofilingTumour profiling eg by 
gene mutation panel, IHC for PTEN, FISH 
for TMPRSS2-ERG, transcriptional and 
phospho-proteomic profile, 
quantification of immune cell 
infiltration.
Planned enrolment: 
20-30 patients 
Target Population: 
Men with localised biopsy proven prostate adenocarcinoma, scheduled 
to be treated by radical prostatectomy. 
Investigational 
Medicinal 
Product(s) 
Name of drug 
Formulation, dose, route of 
administration 
Xentuzumab 
Solution for infusion, 1000mg 
weekly, IV 
Dates for planned 
trial period 
Aug 2021- Apr 2023 
Treatment Duration 
3.5-4 weeks (may be  3-10 weeks if standard of care surgery is 
early/delayed unexpectedly) 
Follow-up duration 
6 weeks from date of surgery 


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End of study 
Last Patient Last Visit 


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SUMMARY SCHEDULE OF EVENTS 
Initial 
approach
Consent 
and 
screen
(day –7 to 0)b
Day 
1 
Day 
8  
Day 
15 
Day 
22c
Day 29
(participants 
with surgery 
delayed beyond 
day 29 only) 
Day 36
( and subsequent 
weeks in 
participants with 
surgery delayed 
only) maximum 10 
doses
Day before 
surgery  
(& Early 
withdrawal) 
Surgery
(day 24-42 
unless 
surgery has 
been 
delayed) 
End of study visit 
(6 weeks after surgery 
+/- 7 days)
Demographic details
X
Patient Information sheet
X
Consent
X
Medical history 
X
Concomitant medications
X
X
X
X
XC
X
X
X
X
Symptoms/Adverse events
X
X
X
X
XC
X
X
X
X
Height
X
Weight
X
X
X
Physical examination
X
X
X
X
X
ECOG performance status
X
X
X
X
Vital signs (pulse, BP, temperature)
X
X
X
X
XC
X
X
X
X
Haematology & biochemistry a
X
Xb
X
X
X
X
X
X
X
Blood PSA, insulin, HbA1c, IGF-1
X
Xb
X
X
X
ECG
X
X
X
Retrieval of surplus tissue from 
diagnostic biopsy for research 
X
Research blood sample(s)
X
X
X
Xentuzumab infusion
X
X
X
XC
X
X
Radical prostatectomy with tissue 
collection
X 
a Haematology: Hb, white blood cells (WBC) with differential count (neutrophils and lymphocytes) and platelets   Biochemistry: sodium, potassium, calcium, phosphate, urea, creatinine, total 
protein, albumin, bilirubin, alkaline phosphatase (alk phos), AST and ALT, LDH and glucose.Patients will have had appropriate standard of care imaging assessments, usually MRI staging, and 
prostate biopsy, prior to being considered for the trial  nb. The red X correspond to research activities 
b  Same day visit results are not required before treatment 
c Visit not required  if only 3 treatments are to be given


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Study Flow Chart 
a Blood PSA, insulin, HbA1, IGF-1 taken
b Research blood sample(s) taken 
c Visit not required  if only 3 treatments are to be given*Assessment pre-surgery can take place up to 3 days prior to surgery  
D=Day  OP= Outpatients
Assessment day before surgeryab*
If surgery delayed up to 10 doses of  
xentuzumab can be administered, 
final dose must be within 6 days of 
surgery
D 1ab, 8, 15a, 22c: 1000mg xentuzumab IV weekly 
x4
Ineligible
Eligible
D-7 to D-1: Consent and screena
Approach, discuss, offer PIS
Active surveillance
Urology OP: management options discussed 
with patient by Urology team
Urology MDT: identify men with localised  prostate adenocarcinoma, with cancer 
content of diagnostic biopsy sufficient to provide > 2 tumour-containing sections, 
surplus to diagnostic need, for IHC for primary endpoint analysis
Surgery
Radiotherapy
D23-D42  Robotic or open Radical prostatectomy, tumour sampling for research b
D42 Post surgery: End of study visita


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Abbreviations 
ADR 
Adverse drug reaction 
AE 
Adverse Event 
AESI 
Adverse events of special interest 
AKT 
Protein Kinase B 
ANC 
Absolute Neutrophil Count 
ALT 
Alanine Transaminase 
AR 
Androgen receptor 
AST 
Aspartate Transaminase 
BCT 
Blood collection tubes 
BrCa 
Breast Cancer 
CD4 
Immune marker 
CD8 
Immune marker 
CDK 4/6 
Immune marker 
CI 
Chief Investigator 
CRF 
Case Report form 
CRPC 
Castrate Resistant Prostate Cancer 
CTC 
Circulating tumour cells 
CTCAE 
Common Terminology Criteria for Adverse Events 
ctDNA 
Circulating Tumour DNA 
D 
Day 
dATP 
Deoxyadenosine triphosphate 
DLT 
Dose Limiting toxicity 
DSMC 
Data and Safety Monitoring Committee 
EGFR 
epidermal growth factor receptor 
EoS 
End of Study 
ES 
Ewing Sarcoma 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EDTA 
Ethylenediaminetetraacetic acid 
FFPE 
Formalin-fixed paraffin-embedded 
FOXP3 
Forkhead box P3 (Immune protein) 
GFR 
Glomerular Filtration Rate 
Hb 
Haemoglobin 
HbA1c 
Glycosylated Haemoglobin 
HR 
Hazard Ratio 
HR+ 
Hormone Receptor positive 
HRA 
Health Research authority 
IB 
Investigator Brochure 
IC 
Informed consent 
IEPTOC 
Independent Early Phase Trials Oversight Committee 
IGF 
Insulin-like Growth Factor 
IGF-1R 
Type 1 insulin-like Growth Factor Receptor 
IGFBP 
Insulin-like Growth Factor Binding Protein 
IHC 
Immunohistochemistry 
IMP 
Investigational Medicinal Product 


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INSR-A 
Insulin receptor isoform A 
INSR-B 
Insulin receptor isoform B 
IUD 
Intrauterine device 
IV 
Intravenous 
KG 
Kilogram 
LATP 
Local Anaesthetic Transperineal biopsy 
LRP 
Laparoscopic radical prostatectomy 
LDH 
Lactate Dehydrogenase 
LPLV 
last visit of the last patient undergoing the trial 
MA 
Marketing Authorisation 
MDT 
Multidisciplinary Team 
MHRA 
Medicines and Healthcare products regulatory agency 
MRI 
Magnetic Resonance Imaging 
MTD 
Maximal tolerated dose 
n 
Number 
NCI 
National Cancer institute 
NE 
Neuroendocrine  
NPC 
Nasopharyngeal carcinoma 
OCTO 
Oncology Clinical Trials Office 
OP 
Outpatients 
PBMCs 
Peripheral blood mononuclear cells 
PD-L1 
Programmed death-ligand 1 
PFS 
Progression free survival 
PI 
Principal Investigator 
PIS 
Patient Information sheet 
PR 
Partial Remission 
ProMPT 
Prostate Cancer mechanisms of response to treatment 
PSA 
Prostate Specific Antigen 
PTEN 
Phosphatase and tensin homolog
R & D 
Research and Development 
RARP 
Robot-assisted radical prostatectomy 
REC 
Research ethics committee 
RNA 
Ribonucleic Acid 
RNR 
Ribonucleotide reductase 
RP 
Radical Prostatectomy 
RRM2 
Regulatory subunit of ribonucleotide reductase 
RSI 
Reference safety information  
SAR 
Serious Adverse Reaction 
SD 
Standard deviation 
SPC 
Summary of Product Characteristics 
SUSAR 
Suspected Unexpected Serious Adverse Drug Reaction 
TKI 
Tyrosine kinase inhibitor 
TMG 
Trial management group 
TRANSLATE 
A randomised controlled trial of TRANSrectal biopsy versus Local 
Anaesthetic Transperineal biopsy Evaluation (TRANSLATE) of potential 
clinically significant prostate cancer 


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TRUS 
Transrectal Ultrasound Biopsy 
ULN 
Upper limit of normal 
WBC 
White Blood Cells 
1
INTRODUCTION 
1.1
Background  
Prostate cancer is the commonest cancer in men, and is diagnosed in 1 in 8 men in the UK, with over 
47,000 men diagnosed annually. Men aged 50 and over, black men and those with a family history 
of prostate cancer are most at risk.  Of men newly-diagnosed with prostate adenocarcinoma, ~55% 
present with localised (stage T1-T3) disease (1). Under current standard of care, and depending on 
stage and grade, these patients are offered a choice of active surveillance or radical treatment with 
radiotherapy or prostatectomy. Radical radiotherapy is delivered with androgen deprivation 
therapy via external beam or brachytherapy via an implanted radiation source (2).  Radical 
prostatectomy (RP) may be via an open operation, or more often now as laparoscopic (LRP) or robot-
assisted radical prostatectomy (RARP). These 3 approaches appear to generate similar outcomes 
although with shorter hospital stays and reduced blood transfusion requirement after LRP and RARP 
(3). Radical radiotherapy and RP have side effects that can impair quality of life, including erectile 
dysfunction, urinary incontinence and bowel symptoms.    
Patients on active surveillance are monitored with PSA testing, digital rectal examination and MRI, 
and are offered radical treatment for rising PSA, upstaging on imaging or Gleason score progression 
(to 4+3 or greater) on biopsy (4). In the large randomised ProtecT study of mainly low/intermediate 
risk disease, the incidence of prostate cancer-specific deaths was low (~1%) and similar between 
treatments, although twice as many men on active surveillance developed disease progression and 
metastatic disease compared with the RP and radiotherapy groups (5).  Of men assigned to active 
surveillance, ~25-30% require radical treatment within 3 years, and over half by 10 years (4,5). The 
conversion rate to active treatment may be reduced by incorporation of multi-parametric MRI (6). 
While some prostate cancers are indolent and do not threaten life, many are aggressive, and despite 
treatment, deaths due to prostate cancer remain high. In a survey of >50,000 men diagnosed with 
prostate cancer in the UK between 1997 and 2006, 49.8% died of prostate cancer (1).  New data 
indicate that prostate cancer kills more men in the UK (11,819 per year) than the number of women 
killed 
by 
breast 
cancer 
(https://prostatecanceruk.org/about-us/news-and-views/2018/2/). 
Therefore, there is a clear need for new treatments, particularly approaches to  prevent progression 
of small indolent prostate tumours to aggressive life-threatening cancers. This could potentially 
enable more patients to remain safely on active surveillance, avoiding radical treatment. If effective 
in the active surveillance setting, such approaches may have potential as preventive measures in 
high risk men.  
Insulin-like growth factors (IGFs) -1 and -2 activate type 1 IGF receptors (IGF-1Rs) to promote tumour 
growth, metastasis and treatment resistance (7). We have identified IGF-1R upregulation in primary 
and metastatic prostate cancer, showed that IGF-1R associates with radioresistance in prostate 
cancer cells and clinical cancers, and reported that IGF-1R translocates to the nucleus, upregulating 
genes that contribute to tumour cell survival and motility (8-13). IGFs cross-talk with androgen 
receptor (AR) signaling, and mediate resistance to endocrine therapy in prostate cancer (14,15). 
These properties make the IGF axis an attractive treatment target. However, trials of IGF-1R 
inhibitory drugs had mixed or negative results, likely due to co-inhibition of the metabolic insulin 
receptor (INSR-B) causing dose-limiting hyperglycaemia, and compensatory signaling via IGF-2-


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mediated activation of variant insulin receptor, INSR-A (16). These problems have been 
circumvented by antibodies that block the IGF ligands without perturbing insulin actions (17). Dr 
Macaulay is Oxford Principal Investigator for the BI 836845 trial of IGF neutralising antibody 
xentuzumab (BI 835845) with enzalutamide in advanced prostate cancer (NCT02204072).  
In addition to contributing to advanced disease, IGFs also have an important role at earlier stages in 
the natural history of cancer. Subjects with rare conditions causing low circulating IGF-1 are almost 
completely protected from cancer and diabetes (18-20). Conversely, people with high circulating 
IGF-1 are at increased risk of cancer. This has been shown most robustly for prostate cancer: men 
with IGF-1 levels in the highest vs lowest quintiles have ~1.4 fold-increased prostate cancer risk (21). 
IGFs are also implicated in the link between height and aggressive, lethal prostate cancer (22). There 
is compelling preclinical and clinical evidence that IGF-1 is not just an associated factor, but 
causative (20,23), although the molecular basis of this association is not understood.  
The WINGMEN trial will explore links between IGF-1 and prostate cancer progression. This is a Phase 
0 study of IGF antibody xentuzumab in men with prostate cancer in the 3-4-week window prior to 
radical prostatectomy.  The trial will test the feasibility of recruiting men with early prostate cancer, 
the tolerability of xentuzumab in the pre-operative setting, and will provide pre- and post- 
treatment samples for assessment of circulating and tissue markers of prostate cancer progression.  
If effective at downregulating mediators of high IGF-1, this approach has potential to be tested for 
its ability to reduce the need for radical treatment in men with small cancers on active surveillance. 
The long-term aims are to prevent prostate cancer progression, identify biomarkers to predict who 
will benefit from IGF blockade, and identify key mediators that may be targets for risk reduction. 
1.2
Investigational Medicinal Product used in the study  
The study IMP is xentuzumab, a humanised IgG1 monoclonal antibody that neutralises the IGF 
ligands to inhibit activation of IGF-1R and INSR-A, suppressing IGF-mediated proliferation, invasion 
and therapy resistance. Xentuzumab binds IGF-1 and IGF-2 with very high affinity (0.07 and 0.8 
nmol/L respectively), with no detectable binding to insulin, and IC50 values for inhibition of IGF-1R 
phosphorylation in response to IGF-1 of 0.6 nmol/L and IGF-2 of 7.5 nmol/L (24). The antibody cross-
reacts with murine IGFs, allowing preclinical in vivo assessment and revealing anticancer activity in 
rodent models in combination with rapamycin (24,25). Xentuzumab currently has no marketing 
authorisation, but in Phase I trials showed evidence of clinical activity with 2 confirmed partial 
responses at 800 and 1050 mg by weekly intravenous infusion, and 12/48 patients (25%) with 
confirmed stable disease. At doses of up to 1800 mg xentuxumab was well-tolerated, with no 
evidence of drug-related hyperglycaemia, and the maximum tolerated dose was not reached. Based 
on a terminal half-life of ~6 days and ability to inhibit circulating IGF bioactivity, the dose of 1000 
mg weekly was selected for Phase II evaluation (26,27).  
Xentuzumab is being evaluated in Phase Ib/II trials in EGFR-mutant non-small cell lung cancer with 
afatinib (NCT02191891), prostate cancer with enzalutamide (NCT02204072) and oestrogen 
receptor/progesterone receptor positive (ER+/PR+), HER2 negative breast cancer with everolimus 
and exemestane (NCT02123823). The latter trial reported activity in patients with predominant 
bone metastases (28), which may reflect preclinical evidence that tumour cells are primed for bone 
metastasis by high IGF-1 secretion by stromal components of the primary tumour, suggesting that 
bone metastases may reflect IGF dependency (29,30). These results have prompted a further Phase 
II trial of xentuzumab with everolimus and exemestane in breast cancer patients with non-visceral 
disease (NCT03659136). Xentuzumab is also being tested in patients with lung, breast and other 
solid tumours with CDK4/6 inhibitor abemaciclib (NCT03099174). Initial outcomes of the 


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randomised Phase II component of the xentuzumab trial in prostate cancer (31) are discussed 
below. 
In light of evidence linking IGF bioactivity with risk and progression of early cancer, WINGMEN is a 
phase 0 window of opportunity study in men with localised prostate cancer.  Xentuzumab will be 
delivered intravenously at the recommended phase II dose of 1,000 mg/week, administered weekly 
over 3.5 - 4 weeks on days 1, 8, 15 and 22.  This duration has been selected based on three criteria. 
Firstly, 3 weeks depletion of hepatic IGF-1 supply was shown to modify immune cell phenotypes 
towards an anti-tumour profile and inhibit metastatic tumour growth in vivo (32,33). Secondly, our 
preclinical data show that xentuzumab has significant  anti-tumour activity in vivo following 3 weeks’ 
treatment of tumour-bearing mice (30). Thirdly, the current interval between informing patients of 
their cancer diagnosis and their suitability for surgery and their date of radical prostatectomy is ~5 
weeks (personal communication from Professor Hamdy, Nuffield Professor of Surgical Sciences, and 
Mr Ben Wright, Operational Service Manager, Renal, Transplant and Urology, Surgery and Oncology 
Division, Oxford University Hospitals NHS Foundation Trust). Therefore, allowing 2-3 days for 
discussion, consent and screening, this will enable 4 doses of xentuzumab to be administered within 
a 3.5 – 4 week treatment window, without altering the standard of care surgery dates for trial 
participants. In the event that a participant’s surgery date is earlier than day 29, 3 treatments is 
sufficient. Equally, if it is later than day 29 a 5th dose of xentuzumab will be given on day 29. In the 
unlikely event that the participants surgery is further delayed patients can receive up to 10 doses of 
xentuzumab, the radical prostatectomy surgery must take place within 6 days of the final dose. 
Participants on the WINGMEN study can have a maximum of 10 doses of Xentuzumab. 
1.3
Other research interventions  
There are no other research interventions.  The surgery received by participants is standard of care. 
1.4
Rationale for the study 
Non-clinical  
Xentuzumab inhibits proliferation of human cancer cells in vitro, and increases anti-proliferative 
effects of exemestane in aromatase overexpressing breast cancer cells, of enzalutamide in prostate 
cancer cells, and everolimus and rapamycin in Ewing Sarcoma (ES) cells; the combination effects 
were also demonstrated in vivo in ES and prostate cancer xenografts (24) (Xentuzumab IB v11). 
Xentuzumab also enhances anti-proliferative effects of CDK4/6 inhibitor abemaciclib in breast, 
pancreatic and non-small cell lung cancer cells (34) (Xentuzumab IB v11). Xentuzumab has 
comparable affinities for human, rodent and Cynomolgus IGFs, allowing characterization of 
pharmacodynamic properties and toxicity in vivo. After dosing of mice, the majority of serum IGF-1 
was bound to xentuzumab, suggesting preferential complex formation over binding to IGFBPs, with 
increased circulating IGF-1 and GH, consistent with compensation for IGF blockade at the pituitary 
level (25). After repeated intravenous dosing of rats and Cynomolgus monkeys at up to ~32 mg/kg 
human equivalent dose, xentuzumab toxicity included weight loss and increase in blood glucose up 
to but not beyond the upper limit of normal. In rats only, there were dose-related changes in liver 
function, reduction in reticulocyte, lymphocyte and neutrophil counts, reduction in femoral and 
tibial trabecular bone, and atrophic changes in the incisors, spleen, thymus, adrenal cortex, ovaries 
and seminal vesicles (Xentuzumab IB v11). In young (7-8 weeks) rats, xentuzumab induced growth 
retardation with reduction in weight gain and tail length (Xentuzumab IB v11). 
This trial is underpinned by three recent preclinical findings from our group. Firstly, on the basis that 
effects of IGF-1 are likely to be mediated via its principal receptor, IGF-1R, we studied IGF-1R 
expression in men undergoing radical prostatectomy who were recruited into the ProMPT study 


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(NCT00967889, PI Prof Hamdy). We found that high serum IGF-1 associated with IGF-1R up-
regulation in malignant but not benign prostatic epithelium, and a trend to association with 
increased nuclear IGF-1R (Aleksic, Macaulay, unpublished). These data represent the first tissue-
level changes associated with circulating IGF-1, and suggest that IGF-1 influences the malignant 
epithelium of small cancers to drive their progression. Supporting a link between epithelial IGF-1R 
and cancer risk, investigation of the protective effects of pregnancy on breast cancer risk found 
prolonged post-partum Igf1r hypermethylation in murine mammary epithelium (35).  
Secondly, we showed that IGFs regulate expression of RRM2, the regulatory subunit of 
ribonucleotide reductase (RNR), consistent with reports that RRM2 is a component of a 
transcriptional signature induced by IGF-1 in breast cancer cells (36). RNR is the rate-limiting step 
for dNTP production, and when we treat cancer cells with IGF-1, RRM2 is upregulated, leading to 2-
3-fold increase in intracellular dATP and dTTP. Conversely, IGF-1R depletion or IGF inhibition with 
xentuzumab results in significant reduction in RRM2 expression and dATP supply, delaying 
replication fork progression and inducing replication stress (30). This new finding may contribute to 
the association of high serum IGF-1 with risk of developing cancer, given the dNTP pool imbalance 
we identify in IGF-treated cancer cells (30). Balanced dNTP supply is required for the fidelity of DNA 
replication and genome stability, and dNTP imbalance of the scale we identify upon manipulation 
of IGF signalling has been shown to be mutagenic in other models (37-39). Therefore, we predict 
that tumours arising in a high IGF-1 environment will harbour increased mutational load.   
Finally, we are investigating whether IGF-1 also promotes cancer progression by influencing 
metabolism and components of the tumour microenvironment. Our recent data show that IGF-1 
upregulates immune checkpoint PD-L1 in human prostate cancer cells (Nandakumar and Macaulay, 
unpublished), consistent with reported upregulation of PD-L1 by EGFR activation (40). Indeed, there 
is evidence that IGFs have profound effects on metabolism, tumour vascularization and components 
of the immune system, promoting the function of immunosuppressive FoxP3+ T regulatory cells 
(Tregs) and cytokines (41-43).  In a murine model, liver-specific IGF-1 depletion for 3 weeks 
downregulated IGF-1R and suppressed pro-tumorigenic profiles of tumour-infiltrating neutrophils 
and hepatic stellate cells, inhibiting growth of induced liver metastases (32). Taken together with 
effects of IGF-1 on RRM2 and dNTP supply that we report (30), we speculate that a high IGF 
environment influences expression of RRM2 and other pro-mutagenic mediators while suppressing 
the ability to mount an effective anti-tumour immune response. Investigating this hypothesis will 
be the focus of this trial. We propose to test this hypothesis by analysing the effect of IGF blockade 
on tumour and circulating markers in men with early prostate cancer.  
Clinical 
Table 1 summarises completed and ongoing xentuzumab trials, and toxicities reported in Phase I 
trials. The drug is well-tolerated and an MTD was not determined in Phase I studies 1280.1 and 
1280.2 (26,27). A relevant biological dose of 1000 mg weekly was selected for Phase Ib/II studies 
based on preclinical and clinical safety data, and anti-tumour activity in studies 1280.1, 1280.2 and 
1280.15. Dose selection was also informed by PK/PD data: plasma IGF bioactivity was suppressed 
down to the detection limits of the assay by xentuzumab 450 mg weekly, and dose-dependent 
increase in total plasma IGF-1 was found to plateau at ~1000 mg weekly (Xentuzumab IB v11).  
Outcomes of the randomised Phase II trials in breast cancer (1280.4, NCT02123823; (28) and 
prostate cancer (1280.8, NCT02204072; (31) have been recently reported (Table 1). The prostate 
cancer data are of particular relevance here. In 1280.8, patients with disease progression post 
abiraterone and docetaxel were randomised to xentuzumab plus enzalutamide vs enzalutamide 
alone. The most frequent adverse events (AEs) in the xentuzumab plus enzalutamide vs 
enzalutamide alone arms were: fatigue (67% v 49%); decreased appetite (56% v 54%), weight 


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reduction (37% v 12%), anaemia (33% v 44%), and back pain (30% v 37%) (31). Therefore, 
xentuzumab was generally well-tolerated in this population with advanced disease, although AEs in 
excess in the xentuzumab plus enzalutamide arm were fatigue and weight reduction.  
In this Phase II trial there was no overall benefit from addition of xentuzumab, although patients in 
the enzalutamide arm had more favourable baseline performance status and Gleason score. After 
post-hoc adjustment for these imbalances there was still no significant benefit from addition of 
xentuzumab in the overall population (HR 0.86, 95% confidence intervals 0.47 – 1.55, p=0.6113). 
Subgroup analysis suggested benefit from xentuzumab in patients whose tumours contained high 
IGF1 mRNA (HR 0.48 95% CI 0.20 – 1.16) but not low IGF1 (HR 4.44, 95% CI 1.20 – 16.48; interaction 
p=0.0123), albeit in a small (n=25) sample (31). There was also a trend to benefit in patients whose 
tumours contained moderate/high PTEN on immunohistochemistry (p=0.1352; Hussain, de Bono, 
unpublished). Outcomes have not yet been reported for the non-randomised Phase Ib component, 
in which xentuzumab was added to enzalutamide on PSA progression.   
Table 1: Clinical studies of xentuzumab 
Trial/Ref. 
Phase 
Disease type or 
indication 
No. of 
pts 
Main 
Toxicities 
Outcome 
1280.1 
NCT01403974 
(26) 
Phase I 
Solid tumours 
62 
Lymphocyte decrease, 
no 
hyperglycaemia, 
MTD not reached 
Weekly 10-1800 mg. Two PRs (NPC at 
800 mg; primitive NE tumour 1050 mg) 
12 pts (25%) had SD.  
1280.2 
NCT01317420 
(27) 
Phase I 
Solid tumours 
64 
Grade 1-2 abdominal 
pain, constipation, 
fatigue, reduced 
appetite, nausea, 
lethargy. No DLTs, 
MTD not reached. 
Three-weekly 10-3600mg. Four patients 
had SD; no objective responses. 
1280.15 
NCT02145741 
Phase I 
Solid tumours 
21 
 
Weekly 750-1400mg. 
1280.4 
NCT02123823 
(28) 
Phase 
Ib/II 
HR+ 
BrCa 
+ 
everolimus 
+ 
exemestane 
(Xe+Ev+Ex) vs  
Ev+Ex alone. 
163 
AEs similar between 
arms 
Xen+Ev+Ex 
v 
Ev+Ex: diarrhoea (44 v 
33%), mucositis (39 v 
32%), rash (34 v 33%), 
stomatitis (34 v 38%); 
most grade 1/2. 
Median PFS: Xen+Ev+Ex v Ev+Ex, 7.3 v 5.6 
months (HR 0.97, p=0.91). In pts without 
visceral metastases Xen+Ev +Ex had 
favourable PFS v Ev+Ex (HR 0.21, 
p=0.0141). 
1280.8 
NCT02204072 
(31) 
Phase 
Ib/II 
CRPC 
with 
enzalutamide 
(Xe+En) 
vs 
En 
alone. 
120 
AEs in Xe+En vs En: 
fatigue 67% v 49%; 
reduced appetite 56% 
v 54%; weight loss 37% 
v 12%; anaemia 33% v 
44%; back pain 30% v 
37%. 
Median PFS Xe+En 3.6m v En 6.2m (HR 
1.22, p=0.48). PSA response 21% v 19%; 
max PSA decline -20 v -9 μg/L; max CTC 
count decline -52% v -35%; CTC response 
16% v 11%. Favourable PFS with high 
tumour IGF1 mRNA (HR 0.48), not low 
IGF1 (HR 4.44; interaction p=0.0123). 
1280.16 
NCT02191891 
Phase 
Ib/II 
NSCLC 
with 
mutant 
EGFR, 
progression post-
TKI, plus afatinib 
32 
 
Recruitment completed, results not yet 
available. 
1280.18 
NCT03099174 
Phase I 
Solid 
tumours, 
breast 
cancer, 
NSCLC, 
plus 
abemaciclib 
148  
 
Ongoing 
1280-0022  
NCT03659136 
Phase II 
HR+ BrCa. non-
visceral disease 
80  
 
Ongoing 


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MTD, maximal tolerated dose; PR, partial response; SD, stable disease; DLT, dose-limiting toxicity; MTD, maximum 
tolerated dose; HR+, hormone receptor positive; AE, adverse event; PFS, progression-free survival; BrCa, breast 
cancer; CRPC, castrate resistant prostate cancer; NPC, nasopharyngeal carcinoma; NE, neuroendocrine; HR, hazard 
ratio; CI, confidence intervals; CTC, circulating tumour cells, EGFR, epidermal growth factor receptor; TKI, tyrosine 
kinase inhibitor. Source: (26-28,31), Xentuzumab IB v11. 
Covid-19 Risk/Benefit Balance
Cancer remains a fatal disease that continues to kill far more patients daily than COVID-19. The need 
to identify better treatments through clinical research is not affected by the presence of the 
pandemic. Pausing such research for months, if not years, until the pandemic subsides will likely 
result in more deaths as improvements in care are delayed. Nevertheless we have put in place 
significant mitigations. The COVID-19 risk for potential patients has been minimised as much as 
possible. The WINGMEN recruitment site, Churchill Hospital, is nominally COVID-19 free, and 
infected or potentially infected patients are treated at a geographically distinct site (the John 
Radcliffe Hospital). The following procedures have also been put in place at site: 

All patients (in and outpatients) are screened upon entry to the Churchill site 

Human traffic at the Churchill site is minimal with face to face appointments avoided and 
staff working from home, whenever possible. 

Face masks/social distancing/level 1 PPE for patient examinations and other protective 
measures are mandatory for staff at the Churchill site 
Furthermore, this trial requires only 6 extra patient visits: screening, 4 treatment visits (unless 
surgery is unexpectedly delayed) and one visit after completion of treatment and before surgery, 
for post-treatment blood tests. The post-treatment End-of-Study trial assessment will be held on 
the same day as the routine 6-week post-operative assessment, and so will not involve an extra 
hospital visit. There is no evidence that treatment with an IGF inhibitory drug will cause patients to 
be immunosuppressed. Indeed, given experimental evidence that IGFs themselves can suppress the 
immune system, it is possible that treatment with xentuzumab could enhance immune responses. 
Therefore , we accept that extra hospital visits may confer additional COVID risk, but the treatment 
itself should not increase this risk. 
Covid 19 Vaccination Considerations 
There is no contraindication to having a COVID-19 vaccination before, during or after the study and 
participants will be encouraged to do so.
2
TRIAL DESIGN 
This is an open label, ‘window of opportunity’ study investigating whether xentuzumab inhibits IGF 
signalling and proliferation in patients with localised prostate cancer scheduled for radical 
prostatectomy. The study is a Phase 0 trial because of the window of opportunity design where 
treatment-naïve patients are exposed to agent for a very short period of time, and the endpoints 
are related not to disease outcome but rather to provide a within-patient comparison to quantify 
IGF axis inhibition and identify mediators of high IGF supply that promote cancer progression. Thirty 
participants will be recruited at a single trial centre (Oxford University Hospitals NHS Foundation 
Trust).  


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Following successful completion of screening, participants will receive 4 weekly intravenous doses 
of xentuzumab prior to their standard of care prostatectomy, at which samples will be collected for 
comparison with the participant’s diagnostic biopsy.  Participants whose surgery is early, may 
receive only 3 doses, equally if surgery is delayed participants can receive up to 10 xentuzumab 
doses, patients must receive their prostatectomy within 6 days of their final dose of xentuzumab to 
be evaluable.  Refer to the schedule of events and flow chart for details of the study visits and 
procedures. 
2.1
Duration of patient participation 
Participants will be in the study for approximately 12 weeks (if surgery is not delayed) from start of 
screening to the last follow-up protocol visit 6 weeks after surgery.
2.2
Post-trial care and follow-up 
Following radical prostatectomy an end of study visit will be completed and patients will receive 
standard care.   
3
OBJECTIVES AND ENDPOINTS
Primary Objective 
Endpoints/ Outcome measures 
Time point(s) of evaluation of this 
end point  
Assess the amount of IGF pathway 
blockade induced by xentuzumab  
Phospho-IGF-1R and phospho-AKT 
(or downstream target) 
immunohistochemistry  
Baseline diagnostic biopsy vs. 
tissues from standard of care 
surgery after xentuzumab. Tissue 
will be formalin fixed and analysis 
will take place in batches. 
Secondary Objectives 
Endpoints 
Assess feasibility of treatment in 
the pre-prostatectomy setting 
Number of patients whose radical 
prostatectomy is performed on 
schedule after 3 doses of 
xentuzumab. 
Date of surgery  
Assess safety and tolerability of 
xentuzumab administered in the 
pre-prostatectomy setting  
Treatment-related adverse events 
scored using CTCAE v5.0 
AEs reported from study entry to 
end of study visit  
Tertiary/Exploratory Objectives 
Endpoints 
Assess change in PSA following 
administration of xentuzumab in 
the pre-prostatectomy setting 
Change in serum PSA 
Baseline, day 15, day 29 (if 
completed), on day before surgery 
and at end of study visit 
Assess changes in tissue markers 
following administration of 
xentuzumab in the pre-
prostatectomy setting 
Changes by IHC and/or 
immunofluorescence on FFPE 
tissues in tissue markers e.g. Ki67 
index, IGF-1R, RRM2, CD31, 
immune markers PD-L1, CD4, CD8, 
FoxP3.   
Baseline diagnostic biopsy vs. 
tissues from standard of care 
surgery after xentuzumab 
treatment 
Assess changes in circulating 
markers following administration 
of xentuzumab in the pre-
prostatectomy setting
Changes in circulating markers of 
response to IGF blockade e.g. IGF-1, 
insulin, IGFBPs, serum IGF 
bioactivity, metabolomic profile, 
PBMC immunoprofiling 
Baseline samples vs. samples taken 
prior to standard of care surgery 
after xentuzumab treatment 
Correlate changes in IGF-1R 
expression, IGF axis activity with 
baseline and post-treatment cancer 
Tumour mutation profiling by IHC 
for PTEN and gene mutation panel. 
Tissues from standard of care 
surgery after xentuzumab 
treatment 


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profile, which may include PTEN 
status by IHC, tumour mutation 
status,  transcriptional, immune 
and phospho-proteomic profile 
Tumour profiling eg by gene 
mutation panel, IHC for PTEN, FISH 
for TMPRSS2-ERG, transcriptional 
and phospho-proteomic profile, 
quantification of immune cell 
infiltration.Phospho-proteomic 
profiling of index tumour 
Tissue samples taken at standard 
of care surgery after xentuzumab 
treatment, with matched historical 
controls 
4
PATIENT SELECTION 
Written informed consent must be obtained before any study specific procedures are performed. 
The Investigator will determine patient eligibility based on the following criteria. Men with localised 
prostate adenocarcinoma who are due to undergo  a radical prostatectomy will be identified 
through information provided from the medical records at the weekly Urology Multi-Disciplinary 
Team (MDT) meeting. An additional check will be made at the MDT to assess the tumour content of 
the diagnostic biopsy, to ensure that patients are approached only if they have sufficient diagnostic 
biopsy material, surplus to diagnostic need, for the primary endpoint analysis.  
Patients in this study may be co-enrolled on the TRANSLATE diagnostic trial comparing Local 
Anaesthetic Transperineal biopsy (LATP) to Transrectal Ultrasound (TRUS) biopsy of the 
prostate.  TRANSLATE has a 4-month follow up period and would therefore overlap with the 
WINGMEN trial.  Men will be approached about the TRANSLATE trial before their diagnostic biopsy; 
those who are subsequently found to be suitable for radical prostatectomy surgery will be 
approached about the WINGMEN study.  Follow-up data collection for men co-enrolled to the 
TRANSLATE trial would continue; patients co-enrolled in the TRANSLATE trial would still receive 
questionnaires to complete (relating to Health-Related Quality of Life, symptom, and biopsy-related 
outcomes) at 7 days, 35 days and 4 months post-biopsy, to complete their post-biopsy follow 
up.  This should not be too burdensome for the patients, and would not compromise recruitment 
to the WINGMEN study. 
4.1
Eligibility criteria for entry into the  study 
Inclusion criteria:  
A patient will be eligible for inclusion in this study if all of the following criteria apply. 
1. Men with prostate adenocarcinoma confirmed on prostate biopsy and with sufficient 
cancer-containing biopsy tissue surplus to diagnostic need to provide 2 sections for 
primary endpoint analysis. 
2. Scheduled for open or robotic radical prostatectomy 
3. Age ≥ 18 years 
4. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 (Appendix 1) 
5. The patient is willing and able to comply with the protocol scheduled follow-up visits and 
examinations for the duration of the study 
6. Participant is willing and able to give informed consent. 
7. Participants whose partner is of child bearing potential must be willing to ensure that they 
or their partner use effective contraception during the trial and for 70 days thereafter. 
8. Adequate haematologic, renal and hepatic function, defined as follows: 
Laboratory Test 
Value required 
Haemoglobin (Hb) 
≥90g/L 


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White Blood Count (WBC) 
>2.5 x 109/L 
Absolute Neutrophil Count (ANC) 
≥ 1.5 x109/L  
Platelet count 
≥ 100 x 109/L 
AST, ALT, and alkaline phosphatase 
≤ 2.5 x upper limit of normal 
eGFR*  
≥30ml/min 
*eGFR calculated by Cockcroft & Gault formula, see appendix 2 
Exclusion criteria:
A patient will not be eligible for the trial if any of the following apply: 
1. Treated with systemic corticosteroids, insulin, metformin, other oral hypoglycemic agent, 
or anti-androgens in the 28 days prior to first dose of study drug 
2. Diabetes mellitus 
3. Previous prostate radiotherapy 
4. Current or previous treatment with xentuzumab or other IGF or GH -modifying therapy 
5. Patients who are known to be serologically positive for Hepatitis B, Hepatitis C or HIV 
6. Treatment with any other investigational agent, or treatment in another interventional 
clinical trial within 28 days prior to enrolment 
7. Other psychological, social or medical condition, physical examination finding or a 
laboratory abnormality that the Investigator considers would make the patient a poor 
trial candidate or could interfere with protocol compliance or the interpretation of trial 
results. 
4.2
Protocol deviations and waivers to entry criteria 
A trial related deviation is a departure from the ethically approved trial protocol or other trial 
document or process (e.g. consent process or IMP administration) or from Good Clinical Practice 
(GCP) or any applicable regulatory requirements.  
Protocol adherence is a fundamental part of the conduct of a clinical study.  Changes to the 
approved protocol need prior approval unless for urgent safety reasons. 
Investigators must contact OCTO to obtain guidance and/or clarification as necessary if unsure 
whether the patient satisfies all the entry criteria and to clarify matters of clinical discretion.  OCTO 
will contact the chief investigator or clinical coordinators as necessary.  Investigators should not 
request a protocol waiver to enter a patient who does not satisfy the selection criteria.  
The investigator must document and explain any deviations/violations from the approved protocol. 
The investigator should promptly report any important violations that might impact patient safety, 
data integrity or be a possible serious breach (see 19.7 below) to the trial office.  
4.3
Re-screening if patient does not meet inclusion/exclusion criteria first time around  
If a patient does not meet the inclusion/exclusion criteria initially he can be re-screened, provided 
it is still possible to complete re-screening and study treatment before the patient’s standard of care 
prostatectomy.  


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4.4
Patient registration procedure 
Potential participants will be identified from patients referred to the Oxford University Hospitals 
Urology MDT for the management of localised  prostate adenocarcinoma, and will be given a 
recruitment flyer.  Patients opting for surgical management will be considered for the trial with an 
initial approach made to the patient by the patients clinical care team.   
Following the initial approach and confirmation of interest in the study, patients will be informed of 
the aims of the trial, and will be given a Patient Information Sheet (PIS) and have the opportunity to 
ask questions.  Patients who express interest will be contacted e.g. by telephone approximately 24 
hours later by a member of the clinical care team and if still interested will be scheduled to attend 
to provide written informed consent and conduct screening procedures. If potential participants do 
not meet the screening criteria they will not be able to continue on the study and this will be 
communicated to them. 
A screening log must be kept of all patients considered for the trial including any that are 
subsequently excluded; the reason for exclusion must be recorded on this form. A copy of the 
screening log should be sent to the trial office on request, but without patient identifiers. The 
original must be retained on site. 
Before entering a patient onto the study the Principal Investigator or designee will confirm 
eligibility. If in any doubt the Chief Investigator must be consulted before entering the patient. 
Details of the query and outcome of the decision must be documented on the registration/ 
eligibility checklist. 
On completion of consent and screen procedures (i.e. before first xentuzumab treatment), site 
staff will complete the trial registration form and email this to the trial office to confirm the 
patient’s eligibility:         octo-WINGMEN@oncology.ox.ac.uk 
The trial office will check the information provided and register the patient on the trial.  The 
patient’s trial number will then be confirmed by return email to the trial site staff.   
4.5
Trial assessments and procedures 
Please refer to the Schedule of Events given at the front of this protocol.  Details of all protocol 
evaluations and investigations must be recorded in the patient’s medical record for extraction onto 
the CRF.  All study visits will take approximately 2-3 hours, comfort breaks will be provided during 
this time. 
4.6
Informed consent 
Potential participants will be given a current, approved version of the Patient Information Sheet and 
consent form. They will also receive clear verbal information about the study detailing no less than: 
the nature of the study; the implications and constraints of the protocol; the known side effects and 
any risks involved in taking part.  It will be explained that they will be free to withdraw from the 
study at any time, for any reason, without prejudice to future care, and with no obligation to give a 
reason for withdrawal. They will have at least 24 hours to consider the information provided and 
the opportunity to question the Investigator, their GP or other independent parties before deciding 
whether to participate. 


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The Investigator who obtains consent must be suitably qualified and experienced. All delegates 
must be authorised by the Principal Investigator to obtain consent.  The Investigator is responsible 
for ensuring that the trial consent procedures comply with current applicable GCP Regulatory and 
ethical requirements. Informed consent discussions and outcomes must be well documented in 
the medical record. The Investigator must be satisfied that the patient has made an informed 
decision before taking consent.  The patient and the Investigator must personally sign and date 
the current approved version of the informed consent form in each other’s presence. A copy of 
the information and signed consent form will be given to the participant. When completed 4 
copies of the consent form are required: 1 for the patient; 1 for Investigator Site File and 1 
(original) to be kept in the patient’s medical notes (at the discretion of the treating hospital) and 1 
for the Biobank.
Contraceptive/ Pregnancy counselling 
All participants must be advised on the need to use reliable methods of contraception during the 
study. The advice should include:  
(1) The acceptable methods, required for trial subjects with premenopausal female partners, 
include: condom plus spermicide for the participating male plus another acceptable form of 
birth control for female partners e.g. female sterilization, implants, injectables, combined 
oral contraceptives, some intrauterine devices (IUDs). Abstinence is an acceptable method 
only when this is in line with the preferred and usual lifestyle of the subject.  
(2) These precautions should be continued for minimum 3 months after the last dose of study 
drug.  
(3) That any pregnancy in female partners of male trial subjects occurring within 70 days of the 
last administration of study drug should be notified by the trial participant to the study team. 
The outcome (spontaneous miscarriage, elective termination, normal birth or congenital 
abnormality) will be reported and followed up even if the participant is discontinued from 
the study.  
4.7
Pre-dosing evaluations  
The following screening and eligibility assessments must be performed/obtained within the 7 days
before the patient receives the first study dose, except where indicated otherwise below.  

Written informed consent  

Demographic details (age, sex, smoking status and self-reported race/ethnicity) 

Medical History: to include current symptoms, cancer history, prior cancer therapies and 
procedures, reproductive status, smoking history, and clinically significant disease history 
and concomitant diseases  

Concomitant medications 

Physical examination, which should be symptom driven and include general appearance, 
examination of cardiovascular system, chest and abdomen.  Any abnormality identified at 
baseline should be recorded 

Height, weight, ECOG performance status (to confirm eligibility) (Appendix 1) 

Vital signs: systolic /diastolic blood pressure (BP), pulse rate and temperature 

Haematology: Hb, white blood cells (WBC) with differential count (neutrophils and 
lymphocytes) and platelets 

Biochemistry: sodium, potassium, calcium, phosphate, urea, creatinine, total protein, 
albumin, bilirubin, alkaline phosphatase (alk phos), AST and ALT, LDH and glucose  

Blood PSA, insulin, HbA1c and IGF-1 


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
Electrocardiogram (ECG) to confirm fitness for treatment 

Presence of prostate adenocarcinoma on prostate biopsy* 

Confirm availability of surplus tissue from diagnostic biopsy  
*Standard of care imaging assessments need not be completed in the 7 day screening period. 
4.8
Evaluations during the study 
Evaluations on day 1   
On the day the first dose of xentuzumab is given: 

Current symptoms, assessment for adverse events 

Concomitant medications 

Physical examination as detailed in 5.2. 

Vital signs: BP, pulse, temperature 

Haematology: Hb, WBC with differential count (neutrophils and lymphocytes) and platelets 

Biochemistry: sodium, potassium, calcium, phosphate, urea, creatinine, total protein, 
albumin, bilirubin, alkaline phosphatase (alk phos), AST and ALT, LDH and glucose  

Blood PSA, insulin, HbA1c, IGF-1 

Research blood samples  

Xentuzumab infusion: to commence after blood has been taken for the above assessments. 
Xentuzumab infusion can then be started without waiting for the day 1 blood results, 
provided the screening blood tests were taken within the 7 days pre-cycle 1. The infusion is 
to be administered over 1 hour  (with up to 15 minutes extra if needed for staff time to end 
infusion). Record time of starting and completing infusion. Patient to be monitored during 
the infusion and for one hour after the end of infusion. Grade 1 to 2 infusion reactions will 
be managed by reducing the infusion rate to 2 hours. For symptomatic treatment of infusion 
reactions hydrocortisone, antihistamines such as chlorphenamine, an antipyretic/analgesic, 
and/or a bronchodilator may be administered. Severe reactions require immediate and 
permanent discontinuation of xentuzumab infusion. 
Evaluations on day 8 ( +/- 1 days)

Assessment for adverse events  

Concomitant medications 

Vital signs: BP, pulse, temperature 

Haematology: Hb, WBC with differential count (neutrophils and lymphocytes) and platelets 

Biochemistry: sodium, potassium, calcium, phosphate, urea, creatinine, total protein, 
albumin, bilirubin, alkaline phosphatase (alk phos), AST and ALT, LDH and glucose  

Xentuzumab infusion: administered over 1 hour  (may be slowed to 2 hours if required due 
to infusion reaction, with up to 15 minutes extra if needed for staff time to end infusion).  
Monitor patient during infusion and for at least 15 minutes after end of infusion as is 
standard practice.  Record time of starting and completing infusion. At clinical discretion 
patient may then leave if there are no symptoms of infusion reaction, or continue to monitor 
as appropriate. 
Evaluations on day 15 ( +/- 1 days)

Assessment for adverse events  

Concomitant medications 

Vital signs: BP, pulse, temperature 

Weight 


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
Physical examination as detailed in 5.2. 

ECOG performance status 

Haematology: Hb, WBC with differential count (neutrophils and lymphocytes) and platelets 

Biochemistry: sodium, potassium, calcium, phosphate, urea, creatinine, total protein, 
albumin, bilirubin, alkaline phosphatase (alk phos), AST and ALT, LDH and glucose  

Blood PSA, insulin, HbA1c, IGF-1 

ECG 

Xentuzumab infusion: administered over 1 hour (may be slowed to 2 hours if required due 
to infusion reaction, with up to 15 minutes extra if needed for staff time to end infusion).  
Monitor patient during infusion and for at least 15 minutes after end of infusion as is 
standard practice.  Record time of starting and completing infusion. At clinical discretion 
patient may then leave if there are no symptoms of infusion reaction, or continue to monitor 
as appropriate. 
Evaluations on day 22 ( +/- 1 days) It is acceptable for this visit to be missed for participants whos 
surgery takes place within 6 days of the 3rd dose

Assessment for adverse events  

Concomitant medications 

Vital signs: BP, pulse, temperature 

Haematology: Hb, WBC with differential count (neutrophils and lymphocytes) and platelets 

Biochemistry: sodium, potassium, calcium, phosphate, urea, creatinine, total protein, 
albumin, bilirubin, alkaline phosphatase (alk phos), AST and ALT, LDH and glucose  

Xentuzumab infusion: administered over 1 hour (may be slowed to 2 hours if required due 
to infusion reaction, with up to 15 minutes extra if needed for staff time to end infusion).  
Monitor patient during infusion and for at least 15 minutes after end of infusion.  Record 
time of starting and completing infusion. At clinical discretion patient may then leave if there 
are no symptoms of infusion reaction, or continue to monitor as appropriate. 
Evaluations on day 29 (+/- 1 days, participants whose surgery is taking place after day 29 only)  

Assessment for adverse events  

Concomitant medications 

Vital signs: BP, pulse, temperature 

Haematology: Hb, WBC with differential count (neutrophils and lymphocytes) and platelets 

Biochemistry: sodium, potassium, calcium, phosphate, urea, creatinine, total protein, 
albumin, bilirubin, alkaline phosphatase (alk phos), AST and ALT, LDH and glucose  

Xentuzumab infusion: administered over 1 hour ( may be slowed to 2 hours if required due 
to infusion reaction, with up to 15 minutes extra if needed for staff time to end infusion).  
Monitor patient during infusion and for at least 15 minutes after end of infusion.  Record 
time of starting and completing infusion. At clinical discretion patient may then leave if there 
are no symptoms of infusion reaction, or continue to monitor as appropriate. 
Evaluations on day 36 (+/- 1 days, participants whose surgery is taking place after day 36 only) - 
Where prostatectomy is unexpectedly delayed beyond day 36, patients will continue to be dosed 
with weekly xentuzumab to within 6 days of surgery, up to a maximum of 10 doses in total 

Assessment for adverse events  

Concomitant medications 

Vital signs: BP, pulse, temperature 


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
Haematology: Hb, WBC with differential count (neutrophils and lymphocytes) and platelets 

Biochemistry: sodium, potassium, calcium, phosphate, urea, creatinine, total protein, 
albumin, bilirubin, alkaline phosphatase (alk phos), AST and ALT, LDH and glucose  

Xentuzumab infusion: administered over 1 hour (may be slowed to 2 hours if required due 
to infusion reaction, with up to 15 minutes extra if needed for staff time to end infusion).  
Monitor patient during infusion and for at least 15 minutes after end of infusion.  Record 
time of starting and completing infusion. At clinical discretion patient may then leave if there 
are no symptoms of infusion reaction, or continue to monitor as appropriate. 
Evaluations 1-3 days before surgery (Day 23 - Day 41), non-fasting 

Assessment for adverse events  

Concomitant medications 

Vital signs: BP, pulse, temperature 

Weight  

ECOG performance status 

Physical examination as detailed in 5.2. 

ECG to confirm fitness for surgery 

Haematology: Hb, white blood cells (WBC) with differential count (neutrophils and 
lymphocytes) and platelets 

Biochemistry: sodium, potassium, calcium, phosphate, urea, creatinine, total protein, 
albumin, bilirubin, alkaline phosphatase (alk phos), AST and ALT, LDH, glucose. 

Blood PSA, insulin, HbA1c & IGF-1 

Research blood samples, NB take blood same time of day (±3 hr) as Day 1 sample. 
Day of surgery (day 24 – 42 unless surgery has been delayed)   
Standard of care radical prostatectomy with collection of research tissue samples:  

Core biopsies (2-3) taken in theatre from radical prostatectomy for immediate fixation. 

Fresh frozen punch biopsy from index tumourprocessed fresh or stored as listed in section 
6.1 for later analysis.
4.9
End of Study (EoS) evaluations at 6 weeks after surgery (± 7 days) 

Assessment for adverse events  

Concomitant medications 

Vital signs: BP, pulse, temperature 

ECOG performance status 

Physical examination as detailed in 5.2

Haematology: Hb, WBC with differential count (neutrophils and lymphocytes) and platelets 

Biochemistry: sodium, potassium, calcium, phosphate, urea, creatinine, total protein, 
albumin, bilirubin, alkaline phosphatase (alk phos), AST and ALT, LDH, glucose.  

Blood PSA, insulin, HbA1c and IGF-1 
Follow-up evaluations 
There is no long-term follow-up as part of the trial.  Further follow-up for trial purposes will only be 
completed if a participant has an ongoing drug-related AE that is related to trial participation at the 
end of study visit, or if participant’s female partner has become pregnant. Participants will 
otherwise be followed-up post the end of study visit as per standard care post-prostatectomy.  


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4.10
Evaluations on early withdrawal 
Patients who withdraw before starting treatment will have no further trial evaluations. Where 
possible, patients who have had at least one xentuzumab infusion and withdraw early will 
complete all evaluations listed for the day before surgery visit. The evaluations listed in the day 
before surgery visit should be completed as soon as possible from the point of withdrawal, unless 
the day before surgery visit has already been performed. This is irrespective of whether the 
participant is due to receive surgery or not. This is not applicable for those who withdraw consent.
5
EARLY PATIENT WITHDRAWAL 
Treatment Withdrawal 
During the course of the trial, a patient may withdraw early from treatment.  This may happen for 
a number of reasons, including: 

Unacceptable toxicity e.g. severe infusion reaction 

AE/SAEs requiring discontinuation 

Loss to follow-up 

Significant protocol deviation or inability to comply with trial procedures 

Clinical decision 

Patient decision 
When the patient stops treatment early, the ‘End of Treatment’ Form needs to be completed, and 
any other relevant CRFs (example SAE Form).  The reason for withdrawing from treatment early 
should be clearly documented in the medical records.  
Participants who are withdrawn from treatment should complete the same evaluations that are 
listed in the ‘day before surgery’ visit. This includes collection of research samples if the patient 
agrees. 
Consent Withdrawal 
Consent withdrawal means that a patient wishes to withdraw from the study altogether.  Under 
these circumstances, the site needs to document all relevant discussions in the patient notes and 
notify the Trial Office, which will allow the office to mark all future CRFs as not applicable. Under 
these conditions, investigators are still responsible to follow up any SAEs till resolution. 
5.1
Patient evaluability and replacement 
The trial will be assessed on a modified intention-to-treat basis.  Patients who are not evaluable for 
the primary endpoint may be replaced at the TMGs discretion, this includes: 

Patients who receive fewer than 3 doses of xentuzumab e.g. due to early withdrawal 

Patients who for any reason do not have their planned standard of care prostatectomy 

Patients whose prostatectomy reveals predominantly neuroendocrine/small cell cancer 

Patients from whom diagnostic biopsy or surgical specimens were not taken or were of 
insufficient quantity or quality for analysis. 

Patients who do not receive their planned standard of care prostatectomy within 6 days of 
their final dose of xentuzumab. 


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If patients miss a dose(s) for unavoidable reasons (e.g. participants with covid infection or unable to 
attend for treatment in the scheduled visit window) they can remain on the trial provided they 
resume weekly dosing with the final dose of xentuzumab within 6 days of surgery. 
All participants who receive one or more doses of xentuzumab will be evaluable for safety analysis.   
As noted above, patients withdrawing early after one or more doses of xentuzumab, irrespective 
of their stage in the trial, will undergo evaluations on the day before surgery.  
6
SAMPLES FOR LABORATORY ANALYSIS 
6.1
Samples to be analysed  
Diagnostic Laboratories 
Samples for haematology and biochemistry analysis including analysis of PSA, HbA1c, insulin and 
IGF-1 will be labelled with standard patient identifiers and sent to the local hospital diagnostic 
laboratory. Results will be processed in the standard way and entered into the routine hospital 
reporting system. Samples will be stored, held, reported and subsequently destroyed in accordance 
with standard local laboratory practice. 
Pathology  
The routine diagnostic biopsies and routine prostatectomy tissue will be labelled, processed for 
routine haematoxylin and eosin (H&E staining) and reported according to local hospital protocols.  
Cores from the diagnostic biopsy that are surplus to diagnostic need and research samples from the 
prostatectomy will be sent for analysis in a central laboratory as per guidance in the following 
section. 
Sample handling 
Please refer to the sample handling manual for assay/sample handling and storage. 
Blood samples 
Blood samples will be obtained from trial subjects by suitably delegated site staff (as detailed in 
section 5).  
•Samples for analysis in the clinical Haematology and Biochemistry Laboratories will be sent as 
routine samples.  
•Blood (25ml) for research analysis will be taken into EDTA or heparin tubes to obtain plasma and 
PBMCs, serum collection tubes for serum, and into blood collection tubes (BCT) to collect ctDNA 
and PBMCs. Blood will be processed to plasma, serum PBMCs,circulating tumour DNA (ctDNA) and 
genomic DNA (gDNA) as detailed in the Sample Handling manual. 
Tissue samples 
Research cores will be taken in theatre from the prostatectomy for rapid fixation to ensure 
comparability between the biopsy and prostatectomy and avoid artefacts due to slow fixation of 
large prostatectomy sample (risk of degradation of phospho-signals), this material is used forIHC. 
The main prostatectomy sample will be transported fresh to cut-up at the John Radcliffe Hospital.  
Fresh punch research biopsies will be taken from the tumour and benign area(s) in the radical 
prostatectomy specimen. These samples may be processed fresh or stored for example by 
cryopreservation in CS10 medium or snap frozen in liquid nitrogen or dry ice/ethanol. Similarly 
stored and processed punch biopsies from non-WINGMEN trial radical prostatectomies (e.g. other 
biobanked samples where appropriate consent has been provided) will serve as controls. 


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This will be carried out by suitably delegated staff, further detail on sample handling and storage 
can be found in the WINGMEN sample handing manual. 
Formalin-fixed paraffin-embedded (FFPE) tissue blocks from diagnostic prostate biopsies, in-theatre 
cores and radical prostatectomies will be selected for tumour content by Professor Clare Verrill or 
other Pathologist, using H&E stained sections (section 7.1 above) as a guide. Blocks will be selected 
to enable comparison of tumour present in the biopsy with the index tumour in the prostatectomy. 
Tissue samples will be analysed as per detailed in the WINGMEN sample handling manual.  
Samples for biobanking 
Participants in this trial will be invited to permit the collection and long term retention of the study 
samples for use in possible other future research linked to trial data. Consent to participate in the 
Biobank is optional and not a requirement of participation in the main study. 
6.2
Labelling and confidentiality of samples sent 
All research samples sent to analytical Laboratories will be labelled with the trial code, trial patient 
number and date taken.  Should a laboratory receive any samples carrying unique patient identifiers 
the recipient must immediately obliterate this information and re-label. 
6.3
Clinical reporting of exploratory research assay results 
The results of the WINGMEN trial research assays are exploratory and are not intended to influence 
the individual patients’ medical care. Findings will not be reported routinely to the responsible 
clinician except in the event that the result might be beneficial to the patient’s clinical management 
e.g. if tumour mutation profiling reveals a clinically relevant actionable mutation. 
6.4
Trial sample retention at end of study 
The Chief Investigator has overall responsibility for custodianship of the trial samples. Laboratories 
are instructed to retain any surplus samples pending instruction from the Chief Investigator on use, 
storage or destruction.  It is possible that new or alternative assays may be of future scientific 
interest. At the end of the research study any surplus samples may be retained for use in other 
projects that have received ethical approval or transferred to a licensed tissue bank, in accordance 
with applicable host institution policies and the Human Tissue Act (HTA) requirements.  
6.5
Withdrawal of consent for sample collection and/or retention 
A patient may withdraw consent to provide samples for research at any time without giving a 
reason. The Investigator must ensure that their wishes are recorded in the medical record and will 
inform the Trial Office accordingly. The investigator should discuss with patients the valuable use of 
samples that have already been provided and under circumstances where these samples have 
already been processed and anonymised, it would not be possible to destroy such samples. 
7
INVESTIGATIONAL MEDICINAL PRODUCT (IMP)  
7.1
Name of IMP 
The unlicensed IMP used in the trial is xentuzumab.  Trial specific stock of xentuzumab is 
provided by Boehringer Ingelheim Ltd. 


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7.2
Treatment dose 
Treatment doses will be given weekly and will consist of 1000 mg of xentuzumab delivered 
intravenously over 1 hour (+15 minutes optional).   
7.3
Duration of treatment 
Patients should receive 4 weekly doses of xentuzumab on days 1, 8, 15 and 22, prior to 
prostatectomy. In the event that surgery takes place later than day 29 a 5th dose should be 
administered on day 29. If surgery is further delayed up to 10 doses in total can be 
administered. In the event that surgery takes place prior to day 22, it is acceptable for patients 
to have only 3 doses. The final dose of xentuzumab should be within 6 days of the scheduled 
prostatectomy. A maximum of 10 doses of xentuzumab can be given. 
7.4
Management of drug administration 
Xentuzumab is administered as an intravenous infusion over 1 hour (+15 minutes optional) 
after dilution in isotonic sodium chloride solution (0.9%). 
Patients should be monitored during and after the infusion for any sign of an infusion-related 
reaction, such as chest tightness, shortness of breath, flushing, tremor or rash.  Patients must 
be monitored for 1 hour after the first infusion but at the clinician’s discretion may be 
monitored for less than an hour after subsequent infusions as is standard practice, provided 
no symptoms of an infusion reaction have been observed. 
In the event of an infusion reaction appropriate therapy should be initiated (e.g. 
corticosteroids/antihistamines) as per standard local policy.  For mild to moderate infusion 
reactions a slower infusion rate and prophylactic antihistamines may be indicated for future 
infusions, refer to further guidance in section 7.6.  Severe infusion reactions require 
immediate and permanent discontinuation of infusion.  
If patients miss a dose(s) for unavoidable reasons (e.g. participants with covid infection or 
unable to attend for treatment in the scheduled visit window) they can remain on the trial 
provided they resume weekly dosing with the final dose of xentuzumab within 6 days of 
surgery. 
7.5
Special precautions 
In common with other monoclonal antibodies xentuzumab may cause an infusion reaction in 
a minority of patients and this may be severe.  Xentuzumab should be given under close 
supervision of medically qualified staff and with availability of resuscitation facilities. 
7.6
Dose modification  
All doses of xentuzumab will be 1000mg with no dose reduction.  In the event that a patient 
experiences unacceptable toxicity at this dose, the patient should be withdrawn from further 
treatment. 
Infusion reactions 
In the event of mild to moderate infusion reaction a slower infusion rate may be used, the 
infusion duration doubled from 1 to 2 hours.  Treatment with an antihistamine/corticosteroid 
may also be given, per standard local policy. Severe infusion reactions require immediate and 
permanent discontinuation of infusion.  


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Management of other toxicities
Patients with advanced cancer treated with xentuzumab in previous trials have experienced 
drug-related adverse events including decreased appetite, nausea, diarrhoea, constipation, 
fatigue, reduced weight, infusion-related reaction, reduced WBC and hyperglycaemia. The 
majority of drug-related AEs have been of grade 1-2 (Xentuzumab Investigator Brochure). 
Refer to the current xentuzumab IB for guidance on management and give symptomatic 
treatment as appropriate. In the event of unacceptable toxicity, the patient should be 
withdrawn from further treatment. 
7.7
Compliance 
All doses of xentuzumab will be delivered intravenously at the research site.  Site staff will 
document compliance with the protocol specified treatment schedule. 
7.8
Management of overdose 
In the case of xentuzumab overdose the patient should be monitored for evidence of toxicity 
and standard supportive treatment provided based on any signs or symptoms experienced.  
Administration of a dose of study drug exceeding that permitted by the trial protocol should 
be notified to the trial office.  Any toxicity resulting from administration of an overdose of 
study drug should also be reported as an adverse event/ serious adverse event (as 
appropriate) as per reporting processes detailed in section 10. 
8
OTHER TREATMENTS (NON-IMPs) 
8.1
Support medication 
Local policy may be followed for anti-emetics and for antihistamines/corticosteroids in the 
event of an infusion reaction. 
8.2
Concomitant medication and non-drug therapies 
Concomitant medication may be given as medically indicated.  All patients will be asked to provide 
a complete list of prescription and over-the-counter medications that have been taken within the 
previous 4 weeks prior to the first treatment visit.  They must also inform the Investigator about any 
new medication started while on the trial. 
Details must be recorded in the medical record and the appropriate CRF including indication, doses, 
frequency and start/stop dates) of concomitant medication taken during the trial until the 
completion of the off-study visit. 
8.3
Prohibited therapies 
Patients should not be prescribed any other anti-cancer or investigational therapies while 
participating in this study. In addition, the following are prohibited: 

Systemic corticosteroids (unless required for treatment of an infusion reaction) 

Insulin, metformin or other oral hypoglycemic agents (unless indicated to manage an 
adverse reaction of altered glucose metabolism) 

Anti-androgens 


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8.4
Drug Interactions/ Potential Drug Interactions 
There are currently no known clinically significant drug interactions for xentuzumab.  However, as 
the IMP is relatively new interactions may exist that are as yet unknown.  Investigators should 
refer to the current Investigator Brochure for the latest information on drug interactions.   
8.5
Post-Trial Treatment 
There will be no provision of the IMP beyond the trial treatment period.  
9
DRUG MANAGEMENT 
9.1
Drug supplies 
Xentuzumab is supplied as liquid formulation containing xentuzumab 10 mg/mL in 20 ml in 
individually boxed vials (200 mg xentuzumab/vial). The excipients are L-Histidine/L-Histidine 
hydrochloride monohydrate, mannitol, sucrose, polysorbate 20, and water for injection. 
Xentuzumab will be supplied free of charge by Boehringer Ingelheim KG and QP released to 
Almac who will do a second QP release to site pharmacy.   
Any required supportive medication is to be sourced and funded locally. 
9.2
Drug ordering 
The initial supply of xentuzumab will be supplied direct to site via temperature-controlled 
shipment by Almac, once Boehringer Ingelheim are informed by the Trial Office that all 
required approvals are in place. Subsequent supplies will be ordered by the Trial Office in 
batches. The ordering process will be described in detail in the WINGMEN pharmacy manual. 
OCTO will closely monitor the use of supplies and ensure that adequate supplies are in place 
prior to each patient being recruited.  Close communication will be maintained between 
Trial team and the pharmacy to ensure that recruitment and treatment are managed 
appropriately. 
9.3
IMP Receipt 
A copy of each delivery note and temperature monitoring form should be scanned and 
emailed as a PDF attachment to Boehringer Ingelheim Clinical Trials Supply Unit (CTSU) & the 
OCTO Trials Office (octo-wingmen@oncology.ox.ac.uk). The original should be kept in the 
Pharmacy File. If supplies are damaged on arrival contact the Trial Office. Damaged supplies 
should be destroyed on site and a Drug Destruction Log completed. 
9.4
Handling and storage 
Xentuzumab is supplied as a liquid formulation at 10 mg/mL in 20 mL single use vials, which 
contain 200 mg of xentuzumab per vial. Unopened vials of xentuzumab should be kept in the 
original outer carton and refrigerated at 2-8oC in a safe, secure refrigerator. Do not freeze.  
The investigator or an authorised designee will ensure that xentuzumab is stored in a secured 
area, under recommended storage conditions and in accordance with applicable regulatory 
requirements. 


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9.5
Labelling  
The supplied xentuzumab vials will have been labelled by Boehringer Ingelheim KG for clinical 
trial use as per the requirements of Eudralex Volume 4: Annex 13 ‘Investigational Medicinal 
Products’ of the European Union guide to Good Manufacturing Practice (GMP). 
Site pharmacies are permitted to add additional labels to the IMP at site as per standard local 
procedures (e.g. addition of patient identifiers) providing the original label is not obscured.
9.6
Dosing dispensing 
Xentuzumab should be prepared in site pharmacy for administration using aseptic technique, 
by dilution in 0.9% sodium chloride in an infusion bag. Diluted solutions can be stored at room 
temperature (25ºC) for up to 6 hours before administration. Infusion bags containing 
xentuzumab diluted solutions may also be stored up to 24 hours at 2-8ºC, provided that the 
solution was prepared under controlled, aseptic conditions, followed by a maximum of 6 hours 
at room temperature (25ºC) before administration. Prior to use and after dilution, the vials 
and infusion bag should be inspected for particulate matter or discolouration. If either of these 
changes is detected, xentuzumab solutions should not be used
9.7
Drug accountability 
Drug accountability is the responsibility of the site pharmacist listed on the trial delegation 
log.  Full drug accountability records must be maintained for xentuzumab.  The site pharmacy 
may amend the Drug Accountability Logs provided by the trial office or use their own 
documentation if it captures all the information requested on the Drug Accountability Logs 
and has been approved by the Trial Office in advance. 
Copies of completed accountability logs must be supplied to the trial office on request. 
9.8
Drug returns from patients 
There is no requirement to collect patient returns (this is not applicable as all treatment 
doses will be delivered at the trial site). 
9.9
Drug destruction 
Disposal of xentuzumab will be according to the table below. 
The original Drug Destruction logs should be placed in the Pharmacy File and a copy scanned 
and emailed to octo-wingmen@oncology.ox.ac.uk. 
Used / partially used vials 
Disposal at site according to local hospital policy. 
Expired drug 
Disposal at site according to local hospital policy. 
Documented on Drug Destruction Log. 
Drug left unused  
Once authorised to do so, any unused drug should be 
disposed of at site according to local hospital policy. A 
Drug Destruction Log should be completed. 
9.10
Occupational safety 
The product is not expected to pose an occupational safety risk to site staff under normal 
conditions of use and administration. 


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10 SAFETY REPORTING 
The Investigator will monitor each patient for clinical and laboratory evidence of adverse events on 
a routine basis throughout the study. Should an Investigator become aware of any study drug 
related SAEs following this period these must also be reported as stated below. Adverse event 
monitoring starts from the time the patient consents to the study until they complete the trial. All 
reportable AEs will be followed to a satisfactory conclusion. Any reportable drug-related AEs that 
are unresolved at the end of treatment visit are to be followed up by the Investigator until resolution 
or stabilisation. 
All AEs reported to the trial office will be processed according to internal SOPs. The trial office may 
request additional information for any AE as judged necessary. De-identified safety data will be 
made available to Boehringer Ingelheim to facilitate pharmacovigiliance monitoring of xentuzumab.
10.1
  Adverse Event Definitions 
An Adverse Event or experience (AE) is any untoward medical occurrence in a study subject 
temporally associated with the administration of an investigational medicinal product (IMP) or a 
comparator product, whether or not considered related to the IMP or a comparator product. An AE 
can therefore be any unfavourable and unintended sign, symptom, disease (new or exacerbated) 
and /or significant abnormal laboratory or physiological observation temporally associated with the 
use of a medicinal product. For marketed medicinal products, this also includes failure to produce 
expected benefits (i.e. lack of efficacy), abuse or misuse. 
A Serious Adverse Event (SAE) is any AE, regardless of dose, causality or expectedness, that: 
Results in death 
Is life-threatening  
This refers to an event in which the subject was at risk of 
death at the time of the event.  It does not refer to an 
event, which hypothetically might have caused death, if 
it were more severe. 

Requires in-patient 
hospitalisation  
or prolongs existing inpatient 
hospitalisation  
In general, hospitalisation signifies that the subject has 
been admitted (usually involving at least an overnight 
stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate 
in the physician’s office or out-patient setting.  
Complications that occur during hospitalisation are AEs.  
If a complication prolongs hospitalisation or fulfils any 
other serious criteria, the event is serious.  When in 
doubt as to whether hospitalisation occurred or was 
necessary, the AE should be considered serious. 

Results in persistent or 
significant incapacity or 
disability 
This means a substantial disruption of a person’s ability 
to conduct normal life functions.  It does not include 


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experiences of relatively minor medical significance or 
accidental trauma (e.g. sprained ankle), which do not 
constitute a substantial disruption. 

Is a congenital anomaly or 
birth defect 

Is any other medically 
important event 
Defined as an event that may jeopardise the patient or 
may require intervention to prevent one of the 
outcomes listed above. Any new primary cancer must be 
reported as an SAE regardless of the discontinuation of 
study medication up until the end of study visit. 
Adverse events of special interest (AESIs) 
The term AESI relates to any specific AE that has been identified by Boehringer Ingelheim at the 
WINGMEN project level as being of particular concern for prospective safety monitoring and safety 
assessment within this trial AESI need to be reported to the OCTO safety team via the same method 
and within the same timeframe that applies to SAE reporting. 
The following are considered as AESIs in the WINGMEN study : 
Hepatic injury 
A hepatic injury is defined by the following alterations of hepatic laboratory parameters: 
For patients with normal ALT and AST levels at baseline: 
An elevation of AST (Aspartate Aminotransferase) and/or ALT (Alanine Aminotransferase) ≥3 
fold ULN combined with an elevation of total bilirubin ≥2 fold ULN measured in the same 
blood sample, or in samples drawn within 30 days of each other, or ALT and/or AST 
elevations ≥10 fold ULN. 
Patients with abnormal liver function tests must have their abnormalities and the etiology 
documented in detail as baseline conditions. Every effort should be made to explain possible 
deteriorations of baseline conditions. These lab findings constitute a hepatic injury alert and the 
patients showing these lab abnormalities need to be followed up. 
In case of clinical symptoms of hepatic injury (icterus, unexplained encephalopathy, unexplained 
coagulopathy, right upper quadrant abdominal pain, etc.) without lab results (ALT, AST, total 
bilirubin) available, the investigator should make sure these parameters are analysed, if necessary 
in an unscheduled blood test. 
An Adverse Drug Reaction (ADR) is an AE which is considered to be causally related to any dose of 
the IMP.  This means that a causal relationship between the IMP and the AE is at least a reasonable 
possibility, i.e., the relationship cannot be ruled out. 
An Unexpected Drug Reaction is an adverse drug reaction, the nature or severity of which, is not 
consistent with applicable product information (referring to information in SPC or IB).
A Suspected Unexpected Serious Adverse Drug Reaction (SUSAR) is a serious adverse drug 
reaction, the nature or severity of which is not consistent with the applicable product information 


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(e.g. Investigator’s Brochure for an unapproved investigational product or SPC for an approved 
product). 
10.2
  Clinical laboratory abnormalities and other abnormal assessments as AEs and SAEs 
Abnormal laboratory findings (e.g., clinical chemistry, haematology, urinalysis) or other abnormal 
assessments (e.g., ECGs, X-rays and scans) that are judged by the investigator as clinically significant 
will be recorded as AEs or SAEs if they meet the definitions given above. By definition, all Grade 3 
or 4 laboratory abnormalities should usually be reported as SAEs.  However, if a lab result is 
categorised as CTCAE grade 3 or 4 but did not fulfil the safety reporting criteria for an SAE (e.g. 
asymptomatic, not life threatening, no intervention required) it is the clinician’s decision whether 
to report the event.  If the event is not reported the reason why should be documented in the 
patient notes. 
Clinically significant abnormal laboratory findings or other abnormal assessments that are detected 
during the study or are present at baseline and significantly worsen following the start of the study 
will be reported as AEs or SAEs.  However, clinically significant abnormal laboratory findings or other 
abnormal assessments that are associated with the disease being studied, unless judged by the 
investigator as more severe than expected for the patient’s condition, or that are present or 
detected at the start of the study and do not worsen, will not be reported as AEs or SAEs.  
The investigator will exercise his or her medical and scientific judgment in deciding whether an 
abnormal laboratory finding or other abnormal assessment is clinically significant.  
10.3
  Determining adverse event causality 
A Serious Adverse Reaction (SAR) is a SAE that may be related to trial treatment. The assessment 
of “relatedness” must be determined by a medically qualified individual and is primarily the 
responsibility of the PI at site or agreed designee. SAEs that will be considered related will include 
any SAE that is documented as possibly, probably or definitely related to protocol treatment. The 
assessment of relatedness is made using the Table below. 
The Investigator must endeavour to obtain sufficient information to confirm the causality of the 
adverse event (i.e. relation to surgery, study drug, background treatment, other illness, progressive 
malignancy etc) and give their opinion of the causal relationship between each AE and study drug.  
This may require instituting supplementary investigations of significant AEs based on their clinical 
judgement of the likely causative factors and/or include seeking a further specialist opinion. 
Classification 
Relationship 
Definition 
Drug-related 
Definitely 
related 
Starts within a time related to the study drug 
administration and
No obvious alternative medical explanation. 
Probably 
related 
Starts within a time related to the study drug 
administration and
Cannot be reasonably explained by known 
characteristics of the patient’s clinical state.  
Possibly related 
Starts within a time related to the study drug 
administration and


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A causal relationship between the study drug and 
the adverse event is at least a reasonable 
possibility.  
Not drug 
related 
Probably not 
related 
The time association or the patient’s clinical state is 
such that the study drug is not likely to have had an 
association with the observed effect.  
Definitely not 
related 
The AE is definitely not associated with the study 
drug administered.  
10.4
  Reference safety information (RSI) for assessment of expectedness 
The reference safety information (RSI) for the trial is section 7.6.2 of the xentuzumab IB and lists all 
the expected side effects associated with the use of xentuzumab.  The assessment of expectedness 
of reported SAEs will be made by the PI or an appropriately trained member of the site staff. A copy 
of the current OCTO, CI and MHRA approved version of the RSI document must be held in the Site 
File for reference. Any change or update to the RSI during the trial will be made via substantial 
amendment.  
At the time of writing the only expected SAR for xentuzumab is infusion related reaction.  Serious 
infusion reactions have been experienced by 3 out of 368 patients receiving xentuzumab in blinded 
clinical trials.  A further 11 patients experienced non-serious infusion reactions. 
10.5
  Suspected Unexpected Serious Adverse Drug Reactions (SUSARs) 
All SUSARS must be reported to the responsible Authority and main REC by the Trial Office within 
the required timelines: 

Fatal or life threatening SUSARs will be reported within 7 days of the Trial Office receiving 
the initial report. Any additional information will be reported within 8 days of sending the 
first report. 

All other SUSARs will be reported within 15 days of the Trial Office receiving the initial report 
In addition, other safety issues qualify for expedited reporting where they might materially alter the 
current risk assessment of an IMP or be sufficient to change IMP administration or the overall 
conduct of the trial.  
10.6
Expedited reporting of SAEs 
The following SAE reporting requirements apply regardless of the Investigator’s assessment of the 
causality or expectedness of the SAE.  All SAEs should be reported on the trial SAE report form (see 
SAE report form and completion guidelines). 
If a Serious Adverse Event occurs that requires reporting, a Serious Adverse Event reporting form 
should be completed and scanned and emailed as a PDF attachment within 24 hours of becoming 
aware of the event to: 
Pharmacovigilance Office, OCTO 
Email: octo-safety@oncology.ox.ac.uk


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If the SAE has not been reported within the specified timeframe, a reason for lateness must be 
provided when sending the SAE Report Form. Investigators should also adhere to their local Trust 
policy for incident and SAE reporting in research. 
10.7
Follow-up of Serious Adverse Events 
A follow-up report must be completed when the SAE resolves, is unlikely to change, or when 
additional information becomes available. If the SAE is a suspected SUSAR then follow up 
information must be provided as requested by the trial office. 
If new or amended information on a reported SAE becomes available, the Investigator should report 
this on a new SAE form using the completion guidelines.  If using the original form to notify further 
information, you must initial and date all new or amended information so that all changes are clearly 
identified.  
SAEs that are considered to be definitely unrelated to the trial intervention will not be followed up 
and monitored, unless Boehringer Ingelheim KG assess the de-identified SAE differently based on 
previous company experience with the drug. In this unusual scenario Boehringer Ingelheim KG may 
request some further information in order to make their assessment.  
OCTO will collaborate with the reporting site in order to obtain additional information.  However,  
Boehringer Ingelheim KG may not override the assessment of causality given by the reporting 
investigator or the nominated clinician who reviews each event.  Boehringer Ingelheim KG’s    
assessment will not be included in the TMF. 
10.8
Reporting Adverse Events on the CRF 
All AEs, including Serious AEs must be recorded on the case report forms (CRF) for that patient 
(unless otherwise specified in section 10.9). The information provided will include date of onset, 
event diagnosis (if known) or sign/symptom, severity, time course, duration and outcome and 
relationship of the AE to study drug.  Any concomitant medications or other any therapy used to 
treat the event must be listed. The Investigator will provide an “other” cause for serious AEs 
considered to be unrelated to the study drug.  Sites should ensure data entered into the CRF is 
consistent with the SAE report information where applicable. 
Each separate AE episode must be recorded. For example, if an AE resolves completely or resolves 
to baseline and then recurs or worsens again, this must be recorded as a separate AE. For AEs to be 
considered intermittent, the events must be of similar nature and severity. 
AEs may be spontaneously reported by the patient and/or in response to an open question from 
study personnel or revealed by observation, physical examination, or other diagnostic procedures. 
Any clinically relevant deterioration in laboratory assessments or other clinical finding is considered 
an AE. 
AEs which are serious must be reported to OCTO from the time of consent up to and including  the 
Day of the  End of Study visit. Any SAE that occurs at any time after completion of medication 
treatment or after the designated follow-up period that the sponsor-investigator and/or sub-
investigator consider to be related to any study drug must be reported to OCTO.  


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Terms and Grading of Events 
All adverse events and toxicities must be graded according to the NCI Common Terminology Criteria 
for adverse events (NCI-CTCAE) Version 5.0.   
10.9
Events exempt from being reported as AE/SAEs 
Progression of underlying disease 
As this is a short duration window of opportunity study in a population with localised disease 
suitable for radical prostatectomy, patients are unlikely to experience disease progression while on 
study.  However, in the event of disease progression and resultant death this will be captured on 
the CRF. Adverse events including hospitalisation that are clearly consistent with disease 
progression will not be reported as individual AE/SAEs. Clinical symptoms of progression will only 
be reported as adverse events if the symptom cannot be determined as exclusively due to the 
progression of the underlying malignancy, or does not fit the expected pattern of progression for 
the disease under study. 
Every effort should be made to document the objective progression of underlying malignancy.  In 
some cases, the determination of clinical progression may be based on symptomatic deterioration. 
For example, progression may be evident from clinical symptoms, but is not supported by tumour 
measurements, or disease progression is so evident that the investigator may elect not to perform 
further disease assessments.  
Death on study 
Death due to disease under study is to be recorded on the Death CRF form providing the death is 
not unexpected or if a causal relationship suspected. The investigator must clearly state whether 
the death was expected or unexpected and whether a causal relationship to the study IMP or other 
protocol treatment intervention is suspected.  
Elective admissions and supportive care 
Elective admissions to hospital for patient convenience or for planned procedures or investigations 
or treatment as specified in this protocol and standard supportive care are not SAEs, and do not 
require SAE reporting.  Hospital admission for prostatectomy is considered standard for this patient 
group and should not be reported as an SAE.  However, if an elective admission is prolonged due to 
an event that meets the criteria for a serious adverse event this should be reported as an SAE. 
10.10 Informing Investigators of new safety information 
The Trial Office or the Chief Investigator will ensure that all investigators are kept informed in a 
timely manner, as new safety profile information becomes available. Investigators are responsible 
for briefing their study team and onward transmission to their R&D office as appropriate. 
10.11 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, 
HRA (where required), Host NHS Trust and Sponsor.  
For assessment of SARs in the DSUR, the RSI that was approved at the start of the safety reporting 
period will be used. When there has been approved changes to the RSI by substantial amendment 
during the reporting period,  the RSI used for the DSUR will differ to the RSI used to assess 
expectedness at the time of SAR occurrence for SARs which require expedited reporting.  


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11 PREGNANCY  
All participants in this trial will be male.  In the event that the partner of a participant becomes 
pregnant during trial participation this will require expedited reporting. A pregnancy form should 
be completed and scanned and emailed to the trial office within the same timelines as an SAE. All 
reported pregnancies should be followed and the outcome reported using the same form. If the 
outcome of the pregnancy meets any of the criteria for seriousness, it must also be reported as an 
SAE. Examples of pregnancy outcomes that are SAEs include reports of: 

congenital anomalies or developmental delay, in the foetus or the child. 

foetal death and spontaneous abortion.      

suspected adverse reactions in the neonate that are classified as serious 
12 DEFINING THE END OF TRIAL  
For this study the end of the trial is defined as “The last visit of the last patient undergoing the trial 
(LPLV)”. The study will be stopped when the stated number of patients to be recruited is reached 
and all participants have reached their final study visit. 
The sponsor and the Chief Investigator reserve the right to terminate the study earlier at any time. 
In terminating the study, they must ensure that adequate consideration is given to the protection 
of the participants’ best interests. 
13 STATISTICAL CONSIDERATIONS  
13.1
Sample size and power
In a preclinical prostate cancer model, xentuzumab suppressed IGF-1R phosphorylation (pIGF-1R) 
with an effect size of 0.68 (G*Power v3.1). Using Wilcoxon signed rank test, matched pairs, 2-tailed), 
recruitment of 20 patients (20 matched pre/post-treatment pairs) will be significant with 80% 
power, alpha = 0.05. Using a one-tailed test based on the hypothesis that xentuzumab will reduce 
pIGF-1R, we will need 16 patients, 16 matched pairs of tissue. We will recruit 20-30 patients in case 
some prostate biopsies are inadequate or unsuitable for translational studies. 
14 STATISTICAL ANALYSIS PLAN 
Change in phospho-AKT (or downstream target) and phospho-IGF-1R immunoreactive score before 
and after treatment will be assessed using the Wilcoxon matched pairs signed rank test.  Changes 
in PSA and other IHC markers including Ki67 index, IGF-1R, RRM2, CD31 and immune markers CD4, 
CD8, PD-L1, FoxP3 will be assessed using a paired samples t-test or a Wilcoxon matched pairs signed 
rank test if normality assumptions are not satisfied. 
The severity of adverse events (AE) will be graded using the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0.  Adverse events will be 
summarised; highest grade per patient AE summaries will be presented, according to whether the 
AEs are considered treatment-related or not, and over time.   
A detailed statistical analysis plan will be written and will be finalised before any analysis is 
undertaken.  The analysis plan will be written in accordance with current Standard Operating 
Procedures. 


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14.1
Inclusion in analysis 
Patients with both pre- and post-treatment data will be included in the analysis, regardless of 
whether or not they completed xentuzumab treatment.  All patients will be included in the safety 
analysis. 
14.2
Subgroup analysis 
The Phase II trial of xentuzumab with enzalutamide in men with metastatic prostate cancer 
suggested benefit from xentuzumab in patients whose tumours contained high IGF1 mRNA (31), 
with a trend to benefit in patients whose tumours contained moderate/high PTEN by 
immunohistochemistry (Hussain, de Bono, unpublished). It has also been reported that relatively 
high serum IGF-1 associates with benefit from IGF axis inhibition (reviewed in (16). Therefore, we 
will analyse changes in tumour and circulating markers in: 

Men whose tumours contain moderate/high PTEN vs low/negative PTEN by IHC; 

Men with baseline serum IGF-1 values above the median vs below the median; 

Men whose tumours contain IGF1 mRNA above the median vs below the median, if we are 
able to perform transcriptomic profiling on baseline prostate biopsy material (section 7.2). 
14.3
Interim Analyses 
There will be no interim analysis or early stopping rules.
14.4
Procedures for reporting any deviation(s) from the original statistical plan 
Any deviation(s) from the original statistical plan will be documented and described and justified 
in the final study report.
14.5
Final analysis 
Based upon projected accrual rates, this trial is expected to complete recruitment within 24 months 
of opening to recruitment.  Final analysis will begin after all patients have reached the end of study 
(or prematurely withdrawn) and when central laboratory assay results required for primary, 
secondary and tertiary/exploratory objectives are available for analysis.   
15 TRIAL COMMITTEES 
15.1
Trial Management Group (TMG) 
The Chief Investigator will chair a TMG responsible for overseeing the successful conduct and 
publication of the trial.  The TMG will include the Chief Investigator, Co- Investigators, Trial Manager, 
Trial Statistician and others as required.  TMG membership and decision making procedures will be 
documented in the TMG charter.  
15.2
Data and Safety Monitoring 
There is no Data and Safety Monitoring Committee (DSMC). An independent Trial Steering 
Committee (IEPTOC) will be in place to monitor the safety and progress of the trial.  
15.3
Trial Steering Committee 
The Independent Early Phase Trials Oversight Committee (IEPTOC) will fulfil the role of Trial Steering 
Committee.  IEPTOC is an existing committee which provides oversight of several trials managed by 
the Oncology Clinical Trials Office and includes independent external committee members.  IEPTOC 
will provide overall supervision of the safe and effective conduct of the trial according to its charter. 


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At least annually it will review trial progress against agreed milestones, adherence to protocol, 
patient safety and consider new information.  
16 DATA MANAGEMENT 
The data management aspects of the study are summarised here with details fully described in the 
Data Management Plan.  See section on patient confidentiality for information on management of 
personal data. 
16.1  Source Data
Source documents are where data are first recorded, and from which participants’ CRF data are 
obtained. These include, but are not limited to, hospital records which could be electronic or paper 
(from which medical history and previous and concurrent medication may be summarised into the 
CRF), clinical and office charts, laboratory and pharmacy records, diaries, microfiches, 
radiographsand correspondence.


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Primary Objective
Endpoint
Data required
CRF data
Non-CRF
Source data
Source data location
Assess the amount of IGF 
pathway blockade induced by 
xentuzumab 
Phospho-IGF-1R and 
phospho-AKT (or 
downstream target) 
immunohistochemistry 
IHC Sample analysis 
Results 
No 
Yes 
Central laboratory 
records/ data files/ 
meta data 
Central Laboratory- Oxford 
University 
Secondary Objectives
Endpoints
Data required
CRF data1
Non-CRF2
Source data
Source data location
Assess feasibility of treatment 
in the pre-prostatectomy 
setting 
Number of patients whose 
radical prostatectomy is 
performed on schedule 
after 3 doses of 
xentuzumab. 
Metrics from 
treatment data 
Yes 
No 
Patient notes 
Patient notes 
Assess safety and tolerability of 
xentuzumab administered in 
the pre-prostatectomy setting 
Treatment-related 
adverse events scored 
using CTCAE v5.0 
Adverse events 
Yes 
No 
Patient notes 
Patient notes 
Tertiary/ Exploratory 
Objectives
Endpoints
Data required
CRF data1
Non-CRF2
Source data
Source data location
Assess change in PSA following 
administration of xentuzumab 
in the pre-prostatectomy 
setting 
Change in serum PSA 
Sample analysis 
results 
No 
Yes- Results from 
sample analysis 
Central laboratory 
records/ data files/ 
meta data 
Central Laboratory- Oxford 
University 
Assess changes in tissue 
markers following 
administration of xentuzumab 
in the pre-prostatectomy 
setting 
Changes by IHC and/or 
immunofluorescence on 
FFPE tissues in tissue 
markers e.g. Ki67 index, 
IGF-1R, RRM2, CD31, 
immune markers PD-L1, 
CD4, CD8, FoxP3.   
IHC Results 
Multiplex 
immunofluorescence 
(mIF) 
No 
Yes- Results from 
IHC and mIF 
analysis 
Central laboratory 
records/ data files/ 
meta data 
Central Laboratory- Oxford 
University 


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Assess changes in circulating 
markers following 
administration of 
xentuzumab in the pre-
prostatectomy setting 
Changes in circulating 
markers of response to 
IGF blockade e.g. IGF-1, 
insulin, IGFBPs, serum 
IGF bioactivity, 
metabolomic profile, 
PBMC immunoprofiling
Sample analysis 
results 
No 
Yes 
Central laboratory 
records/ data files/ 
meta data 
Central Laboratory- Oxford 
University 
Correlate changes in IGF-1R 
expression, IGF axis activity 
with baseline and post-
treatment cancer profile, 
which may include PTEN 
status by IHC, tumour 
mutation status,  
transcriptional, immune and 
phospho-proteomic profile
Tumour profiling eg by 
gene mutation panel, 
IHC for PTEN, FISH for 
TMPRSS2-ERG, 
transcriptional and 
phospho-proteomic 
profile, quantification of 
immune cell infiltration.
Sample analysis 
results
No 
Yes 
Central laboratory 
records/ data files/ 
meta data 
Central Laboratory- Oxford 
University 
CRF data: captured in OpenClinica eCRF. Database held on server hosted by Oxford University; Non-CRF Data: For data that are not being collected in 
OpenClinica CRFs, it is necessary to have quality control at every step: database validated, restricted access, version control, audit trail, evidence of 
training and qualification or supervision by trained and qualified person. 


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16.2
 Database considerations 
Data management will be performed via a web-based, bespoke trial database (OpenClinica). 
OpenClinica is a dedicated and validated clinical trials database designed for electronic data capture. 
See: http://www.openclinica.org.  The trial office will provide sites with instructions and a video link 
for training purposes.  
The participants will be identified by a unique trial specific number which will be provided once the 
patient has been registered on the study, and year of birth.  The name and any other identifying 
detail will NOT be included in any trial data electronic file. 
16.3
Case reports forms (CRFs) 
The Investigator and study site staff will ensure that data collected on each subject is recorded in 
the CRF as accurately and completely as possible.   All appropriate laboratory data, summary reports 
and Investigator observations will be transcribed into the CRFs from the relevant source data held 
in the site medical record(s). CRFs entries will not contain any source data (unless otherwise 
specified in the completion instructions provided by the trial office). It is important to ensure that: 

the relevant CRFs are completed. 

all CRF data are verifiable in the source documentation or the discrepancies must be 
explained.  

CRF sections are completed in a timely fashion, as close to the visit or event being recorded 
as possible. 

Data queries are resolved and documented by authorised study staff in a timely fashion. The 
reason for the change or correction should be given where appropriate. 

As much data as possible is entered and cleaned in preparation for each study database lock 
point. 
Note: ‘in a timely fashion’ means within no more than 10 working days of the initial event and within
28 days of receipt of a data query unless otherwise specified. 
The above considerations also apply to patients who are withdrawn early. If a patient withdraws 
from the study, the reason must be noted on the appropriate form and the patient must be 
followed-up as per protocol.  
16.4
Accounting for missing, unused, or spurious data. 
The statistical analysis plan will describe the procedure for accounting for missing, unused or 
spurious data. 
17 CLINICAL STUDY REPORT  
All clinical data will be presented at the end of the study as data listings. These will be checked to 
confirm the lists accurately represents the data collected during the course of the study.  The trial 
data will then be locked and a final data listing produced. The clinical study report will be based on 
the final data listings. The locked trial data may then be used for analysis and publication.  


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18 STUDY SITE MANAGEMENT 
18.1
Study site responsibilities 
The Principal Investigator (the PI or lead clinician for the study site) has overall responsibility for 
conduct of the study, but may delegate responsibility where appropriate to suitably experienced 
and trained members of the study site team.  All members of the study site team must complete 
the delegation log provided prior to undertaking any study duties.  The PI must counter sign and 
date each entry in a timely manner, authorising staff to take on the delegated responsibilities.  
18.2
Study site set up and activation 
The Principal Investigator leading the investigational study site is responsible for providing all 
required core documentation.  Mandatory Site Training organised by the trial office must be 
completed before the site can be activated.  The Trial Office will check to confirm that the site has 
all the required study information/documentation and is ready to recruit.  The site will then be 
notified once they are activated on the trial database and able to enter patients. 
18.3
Study documentation 
The trial office will provide an Investigator File and Pharmacy File to each investigational site 
containing the documents needed to initiate and conduct the study.  The trial office must review 
and approve any local changes made to any study documentation including patient information and 
consent forms prior to use. Additional documentation generated during the course of the trial, 
including relevant communications must be retained in the site files as necessary to reconstruct the 
conduct of the trial. 
19 REGULATORY AND ETHICAL CONSIDERATIONS 
The Sponsor and Investigators will ensure that this protocol will be conducted in compliance with 
the UK Clinical Trials Regulations1 and the applicable policies of the sponsoring organisation. 
Together, these implement the ethical principles of the Declaration of Helsinki (1996) and the 
regulatory requirements for clinical trials of an investigational medicinal product under the 
European Union Clinical Trials Directive. 
19.1
Ethical conduct of the trial and ethics approval 
The protocol, patient information sheet, consent form and any other information that will be 
presented to potential trial patients (e.g. advertisements or information that supports or 
supplements the informed consent) will be reviewed and approved by an appropriately constituted, 
independent Research Ethics Committee (REC). Principal Investigators will be approved by the REC 
and HRA. 
19.2
Regulatory Authority approval 
This study will be conducted under a UK Medicines and Healthcare Products Regulatory Agency 
(MHRA) Clinical Trials Authorisation (CTA). Approval to conduct the study will be obtained from the 
Responsible Authority prior to initiating the study.  
19.3
NHS Research Governance 
Investigators are responsible for ensuring they obtain local Trust management agreement to 
conduct the trial in accordance with local arrangements and policies. 
1 The Medicines for Human Use (Clinical Trials) Regulations (S.I. 2004/1031) and any subsequent amendments to it. 


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19.4
Protocol amendments 
Amendments are changes made to the research following initial approval. A ‘substantial 
amendment’ is an amendment to the terms of the Responsible Authority application (if applicable), 
the REC application, or to the protocol or any other supporting documentation, that is likely to affect 
to a significant degree: 

the safety or physical or mental integrity of the subjects of the trial; 

the scientific value of the trial; 

the conduct or management of the trial; or 

the quality or safety of the investigational medicinal product(s) used in the trial. 
Non-substantial amendments are those where the change(s) involve only minor logistical or 
administrative aspects of the study. 
All amendments will be generated and managed according to the trial office standard operating 
procedures to ensure compliance with applicable regulation and other requirements. Written 
confirmation of all applicable REC, HRA, regulatory and local approvals must be in place prior to 
implementation by Investigators. The only exceptions are for changes necessary to eliminate an 
immediate hazard to study patients (see below). 
It is the Investigator’s responsibility to update patients (or their authorised representatives, if 
applicable) whenever new information (in nature or severity) becomes available that might affect 
the patient’s willingness to continue in the trial.  The Investigator must ensure this is documented 
in the patient’s medical notes and the patient is re-consented if appropriate. 
19.5
Urgent safety measures 
The sponsor or Investigator may take appropriate urgent safety measures to protect trial 
participants from any immediate hazard to their health or safety. Urgent safety measures may be 
taken without prior authorisation. The trial may continue with the urgent safety measures in place.
The Investigator must inform the trial office IMMEDIATELY if the study site initiates an urgent 
safety measure:
The notification must include: 

Date of the urgent safety measure; 

Who took the decision; and 

Why the action was taken. 
The Investigator will provide any other information that may be required to enable the trial office 
to report and manage the urgent safety measure in accordance with the current regulatory and 
ethical requirements for expedited reporting and close out. The Trial office will follow written 
procedures to implement the changes accordingly.    
19.6
Temporary halt 
The sponsor and Investigators reserve the right to place recruitment to this protocol on hold for short 
periods for administrative reasons or to declare a temporary halt. A temporary halt is defined a formal 
decision to: 

interrupt the treatment of subjects already in the trial for safety reasons; 

stop recruitment on safety grounds; or 


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
stop recruitment for any other reason(s) considered to meet the substantial amendment 
criteria, including possible impact on the feasibility of completing the trial in a timely 
manner. 
The trial office will report the temporary halt via an expedited substantial amendment procedure. 
The trial may not restart after a temporary halt until a further substantial amendment to re-open is 
in place.  If it is decided not to restart the trial this will be reported as an early termination. 
19.7
Serious Breaches 
The Medicines for Human Use (Clinical Trials) Regulations require the Sponsor to notify any "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:  

the safety or physical or mental integrity of the subjects of the trial; or 

the scientific value of the trial” 
Investigators must notify the Trials Office immediately if any serious breach is suspected.  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 relevant NHS host 
organisation within seven calendar days. 
19.8
Trial Reports 
This protocol will comply with all current applicable Regulatory Authority, Research Ethics 
Committee and Sponsor reporting requirements.  
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, HRA 
(where required), Host NHS Trust and Sponsor.  
For assessment of SARs in the DSUR, the RSI that was approved at the start of the safety reporting 
period will be used. Where changes to the RSI have been approved by substantial amendment 
during the reporting period, the RSI used for the next DSUR will differ from the RSI used to assess 
expectedness for SARs on or after the date the amendment is approved.  
The trial office will determine which reports need to be circulated to Principal Investigators and 
other interested parties. Study sites are responsible for forwarding trial reports they receive to their 
local Trust as required. 
20 EXPENSES AND BENEFITS 
Reasonable travel expenses for any visits additional to normal care will be reimbursed on production 
of receipts or a mileage allowance provided as appropriate. 


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21 QUALITY ASSURANCE 
21.1
Risk assessment  
A risk assessment and a monitoring plan will be prepared before the study opens and will be 
reviewed throughout the study if necessary in the light of significant changes while the study is 
ongoing or in response to outcomes from monitoring activities.  Monitoring plans will be amended 
as appropriate.
21.2
Monitoring 
Regular monitoring will be performed according to the monitoring plan. Data will be evaluated for 
compliance with the protocol, completeness and accuracy. The investigator and institutions 
involved in the study will permit study-related monitoring and provide direct on-site access to all 
study records and facilities if required. They will provide adequate time and space for the 
completion of monitoring activities. 
Study sites will be monitored centrally by checking incoming data for compliance with the protocol, 
consistency, completeness and timing.  The case report data will be validated using appropriate set 
criteria, range and verification checks.  The study site must resolve all data queries in a timely 
manner.   All queries relating to key outcome and safety data and any requiring further clarification 
will be referred back to the study site for resolution. For other non-critical data items, OCTO staff 
may resolve data queries centrally providing the correct answer is clear. Such changes will be clearly 
identified in the CRF and the study site informed. 
Study sites will also be monitored remotely and/or by site visit as necessary to ensure their proper 
conduct of the trial.  OCTO staff will be in regular contact with site personnel to check on progress 
and deal with any queries that they may have. Monitoring reports will be sent to the site in a timely 
fashion.  The Investigator is expected to action any points highlighted through monitoring and must 
ensure that corrective and preventative measures are put into place as necessary to achieve 
satisfactory compliance. 
Sites will provide copies of the participant screening log to the trial office on request for remote 
monitoring purposes.  This must not include patient personal identifiers.   
21.3
Audit and Regulatory Inspection 
All aspects of the study conduct may be subject to internal or external quality assurance audit to 
ensure compliance with the protocol, GCP requirements and other applicable regulation or 
standards. It may also be subject to a regulatory inspection. Such audits or inspections may occur at 
any time during or after the completion of the study. Investigators and their host Institution(s) 
should understand that it is necessary to allow auditors/inspectors direct access to all relevant 
documents, study facilities and to allocate their time and the time of their staff to facilitate the audit 
or inspection visit. Anyone receiving notification of a Regulatory Inspection that will (or is likely to) 
involve this trial must inform the Trial Office without delay. 
22 RECORDS RETENTION & ARCHIVING 
During the clinical trial and after trial closure the Investigator must maintain adequate and accurate 
records to enable the conduct of a clinical trial and the quality of the research data to be evaluated 


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and verified.  All essential documents must be stored in such a way that ensures that they are readily 
available, upon request for the minimum period required by national legislation or for longer if 
needed.  The medical files of trial subjects must be retained in accordance with applicable national 
legislation and the host institution policy. 
Retention and storage of laboratory records for clinical trial samples must also follow these 
guidelines.  Retention and storage of central laboratory records supporting PK or PD endpoints and 
the disposition of samples donated via the trial must also comply with applicable legislation and 
Sponsor requirements. 
It is the University of Oxford’s policy to store data for a minimum of 5 years. Investigators may not 
archive or destroy study essential documents or samples without written instruction from the trial 
office. If there is a possibility that the research results will be used to apply for marketing 
authorisation, the research data will be archived for 15 years minimum. Copies of research data 
held by sites will be stored at site according to local policies. Data held at the University of Oxford 
will be stored electronically on a secure backed-up database, according to the policies of OCTO and 
the University of Oxford. 
23 PATIENT CONFIDENTIALITY 
The study will comply with the UK General Data Protection Regulation (UK-GDPR) and Data 
Protection Act 2018, which require data to be de-identified as soon as it is practical to do so. 
Personal data recorded on all documents will be regarded as confidential. 
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 and consent form, where participant’s year or birth will be recorded.  During 
participant registration, participant initials may be transferred from site to the randomisation 
system as a validation check in this process.  Participant initials do not form part of the trial dataset.
All documents will be stored securely and only accessible by study staff and authorised personnel. 
The study staff will safeguard the privacy of participants’ personal data. 
Patients consent forms will be retained for the life of the sample when patients have consented for 
study samples to be used beyond this study, to meet HTA traceability requirements. 
The Investigator site must maintain the patient’s anonymity in all communications and reports 
related to the research. The Investigator site team must keep a separate log of enrolled patients’ 
personal identification details as necessary to enable them to be tracked. These documents must 
be retained securely, in strict confidence. They form part of the Investigator Site File and are not to 
be released externally. 
24 STUDY FUNDING 
The WINGMEN trial is funded by Prostate Cancer UK (Reference RIA16-ST2-024).  The Oncology 
Clinical Trials Office is also supported by Cancer Research UK core funding.  Boehringer Ingelheim 
Ltd are providing xentuzumab free of charge to support the study. This study is further supported 
via the University of Oxford core clinical and research infrastructure.  
This trial is on the NIHR portfolio. Local research network support should be available to support 
entry of participants into this trial.   


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25 SPONSORSHIP AND INDEMNITY 
25.1
Sponsorship 
The Sponsor will provide written confirmation of Sponsorship and authorise the trial 
commencement once satisfied that all arrangements and approvals for the proper conduct of the 
trial are in place. A separate study delegation agreement, setting out the responsibilities of the Chief 
Investigator and Sponsor will be put in place between the parties.  
25.2
Indemnity 
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 
that is provided. 
25.3
Contracts/Agreements 
This trial is subject to the Sponsor’s policy requiring that written contracts/agreements are agreed 
formally by the participating bodies as appropriate.  A Clinical Trial Agreement (CTA) will be placed 
between the Sponsor and participating organisations prior to site activation.  The Sponsor will also 
set up written agreements with any other external third parties involved in the conduct of the trial 
as appropriate.  
26 PUBLICATION POLICY 
The sponsor will retain ownership of all data arising from the trial.  The intention is to publish this 
research in a specialist peer reviewed scientific journal on completion of the study.  The results may 
also be presented at scientific meetings and/or used for a thesis. The Investigators will be involved 
in reviewing drafts of the manuscripts, abstracts, press releases and any other publications arising 
from the trial and retain final editorial control. Authors will acknowledge that the study was 
Sponsored by and performed with the support of the Sponsor and other funding bodies as 
appropriate. 
Prior to the recruitment of the first participant, the trial will have been registered on a publicly 
accessible database.  Results will be uploaded to the European Clinical Trial (EudraCT) Database 
within 12 months of the end of trial declaration by the CI or their delegate.  Where the trial has 
been registered on multiple public platforms, the trial information will be kept up to date during 
the trial, and the CI or their delegate will upload results to all those public registries within 12 
months of the end of the trial declaration.  
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regulatory T cells and suppresses autoimmune disease. EMBO Mol Med 6, 1423-1435 
44. 
Rao, SR, Alham, NK, Upton, E, et al. (2020) Detailed Molecular and Immune Marker 
Profiling of Archival Prostate Cancer Samples Reveals an Inverse Association between 
TMPRSS2:ERG Fusion Status and Immune Cell Infiltration. J Mol Diagn 22, 652-669 
45. 
Charlton, P, O’Reilly, D, Philippou, Y, et al. (2020) 350 - A pilot transcriptomic analysis of 
archival prostate biopsy samples and response to radical radiotherapy. Eur Urol Open Science
19, e580 


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APPENDIX 1: ECOG PERFORMANCE SCALE 
Activity Performance Description 
Score 
Fully active, able to carry out all on all pre-disease performance without restriction. 
0 
Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature, e.g. light housework, office work. 
1 
Ambulatory and capable of all self-care, but unable to carry out any work activities.  
Up and about more than 50% of waking hours.  
2 
Capable of only limited self-care.  Confined to bed or chair more than 50% of waking 
hours.  
3 
Completely disabled. Cannot carry out any self-care. Totally confined to bed or chair.
4 


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APPENDIX 2:  COCKROFT & GAULT FORMULA 
GFR for males  
=  
 
1.23 x [140-age] x weight (kg) 
Serum creatinine (μmol/l) 


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APPENDIX 3:  AMENDMENT HISTORY 
Amendment No.
Protocol 
Version 
No. 
Date issued
Author(s) 
of 
changes 
Details of Changes made
Initial 
1.0
30Apr2021
002
2.0
TBC
Valentine 
Macaulay, Simon 
Lord, Tim Coutts 

Improved consistency of 
wording for tertiary 
objectives and endpoints 
throughout the document 

Added new power 
calculation 

Added that participants will 
be evaluable for the primary 
endpoint after receiving 3 
cycles of xentuzumab, to 
allow recruitment of 
participants with a shorter 
window between 
diagnosis/treatment 
decision and surgery. 

Added allowance for dose 
delay/omission 

+15 minute window added 
to dose duration. 

Added explanation that Day 
1 treatment can be based 
on blood results from 
during the screening period 
(within 7 days prior to day 
1). 

Punch biopsies taken from 
the prostatectomy will be 
processed fresh or stored in 
a biobank where patients 
have consented to this 

Additional Research Blood 
samples added 

Exclusion criteria #1 
changed to specify that 
systemic corticosteroids are 
excluded, also changed 
under prohibited therapies 

Protocol now consistently 
refers to CTCAE v5.0 as the 
criteria for grading adverse 
events 

Minor changes to tertiary 
endpoint wording, tertiary 


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endpoints now read 
consistently throughout 
protocol 

Addition of recruitment 
flyer for potential 
participants.  

Minor changes to protocol 
layout and formatting, 
OCTO contact details, CI 
contact detail.  

Removed planned 
recruitment period from 
protocol synopsis. 

Removed SAE reporting 
telephone number.  

Wording added to COVID 
risk/benefit (end of section 
1) to give the correct 
number of additional visits 
(in line with the rest of 
protocol and PIS) 

Clarified timeframe for 
screening bloods in Day 1 
evaluations description on 
page 24. 

All references to 
CTRG/Clinical Trials, 
Research & Governance 
changed to RGEA/Research 
Governance, Ethics & 
Assurance in line with 
sponsor office name change 

SAP_001.pdf: 
______________________________________          
SAP Version No: 1.0 
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Date: 24Jun2024 
Effective Date 19Mar2021  
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Page 1 of 23
Windows trial of INsulin-like Growth factor neutralising antibody 
Xentuzumab in MEN scheduled for radical prostatectomy
Statistical Analysis Plan 
Version 1.0_24Jun2024 
Linked to SAP - Data definitions and Tables 
Version 1.0_24Jun2024 
Based on Protocol version 2.0_21Nov2022
Trial registration: ClinicalTrials.gov NCT05110495 
Oxford Clinical Trials Research Unit (OCTRU) 


Windows trial of INsulin-like Growth factor neutralising 
antibody Xentuzumab in MEN scheduled for radical prostatectomy  
Funded by: Prostate Cancer UK   
ClinicalTrials.gov Registration Number: NCT05110495 
______________________________________    
SAP Version No: 1.0 
OCTRU-OST-001_V4.0_05Mar2021 
Date: 24Jun2024 
Effective Date 19Mar2021  
SAP Author: See section 1.1 
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CONTENTS 
1
INTRODUCTION ............................................................................................................................... 4
1.1 
KEY PERSONNEL .......................................................................................................................... 4 
1.2 
CHANGES FROM PREVIOUS VERSION OF SAP ..................................................................................... 5 
2
BACKGROUND AND OBJECTIVES ....................................................................................................... 6
3
STUDY METHODS ............................................................................................................................. 7
3.1 
TRIAL DESIGN/FRAMEWORK .......................................................................................................... 7 
3.2 
SAMPLE SIZE .............................................................................................................................. 7 
3.3 
STATISTICAL INTERIM ANALYSIS, DATA REVIEW AND STOPPING GUIDELINES ............................................ 8 
3.4 
TIMING OF FINAL ANALYSIS ........................................................................................................... 9 
3.4.1 
Primary endpoint ........................................................................................................... 9 
3.4.2 
Secondary endpoints ..................................................................................................... 9 
3.4.3 
Research/tertiary endpoints .......................................................................................... 9 
3.4.4 
Final integration of translational research data .......................................................... 10 
3.5 
BLINDED ANALYSIS ..................................................................................................................... 10 
3.6 
STATISTICAL ANALYSIS OUTLINE ................................................................................................... 10 
4
STATISTICAL PRINCIPLES................................................................................................................. 11
4.1 
STATISTICAL SIGNIFICANCE AND MULTIPLE TESTING ......................................................................... 11 
4.1.1 
Primary endpoint analysis ............................................................................................ 11 
4.1.2 
Secondary endpoints ................................................................................................... 11 
4.1.3 
Research/translational endpoints producing single values ......................................... 11 
4.1.4 
Metabolomics .............................................................................................................. 12 
4.1.5 
RNA-seq ........................................................................................................................ 12 
4.1.6 
RPPA data ..................................................................................................................... 13 
4.2 
DEFINITION OF ANALYSIS POPULATIONS ......................................................................................... 13 
5
TRIAL POPULATION AND DESCRIPTIVE ANALYSES ........................................................................... 13
5.1 
REPRESENTATIVENESS OF STUDY SAMPLE AND PATIENT THROUGHPUT ................................................ 13 
5.1.1 
Representativeness of study sample ........................................................................... 13 
5.1.2 
Patient Throughput ...................................................................................................... 13 
5.2 
WITHDRAWAL FROM TREATMENT AND/OR FOLLOW-UP .................................................................... 13 
5.3 
BASELINE CHARACTERISTICS ........................................................................................................ 13 
5.4 
UNBLINDING ............................................................................................................................ 14 
5.5 
TREATMENT COMPLIANCE WITH DETAILS OF INTERVENTION .............................................................. 14 
5.6 
RELIABILITY .............................................................................................................................. 14 
5.6.1 
Primary endpoint markers ........................................................................................... 14 
5.6.2 
Secondary endpoints ................................................................................................... 14 
5.6.3 
Research/tertiary endpoints ........................................................................................ 14 
6
ANALYSIS ....................................................................................................................................... 15
6.1 
OUTCOME DEFINITIONS.............................................................................................................. 16 
6.2 
ANALYSIS METHODS .................................................................................................................. 16 
6.3 
SENSITIVITY ANALYSIS ................................................................................................................ 17 


Windows trial of INsulin-like Growth factor neutralising 
antibody Xentuzumab in MEN scheduled for radical prostatectomy  
Funded by: Prostate Cancer UK   
ClinicalTrials.gov Registration Number: NCT05110495 
______________________________________    
SAP Version No: 1.0 
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Effective Date 19Mar2021  
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Page 3 of 23
6.4 
PRE-SPECIFIED SUBGROUP ANALYSIS ............................................................................................. 18 
6.5 
SUPPLEMENTARY/ ADDITIONAL ANALYSES AND OUTCOMES .............................................................. 18 
6.6 
HARMS ................................................................................................................................... 18 
6.7 
HEALTH ECONOMICS AND COST EFFECTIVENESS (WHERE APPLICABLE) ................................................. 19 
7
VALIDATION OF THE PRIMARY ANALYSIS ........................................................................................ 19
8
SPECIFICATION OF STATISTICAL PACKAGES ..................................................................................... 19
9
PUBLICATION ................................................................................................................................. 19
10
REFERENCES .................................................................................................................................. 20
APPENDIX: GLOSSARY OF ABBREVIATIONS ............................................................................................. 22


Windows trial of INsulin-like Growth factor neutralising 
antibody Xentuzumab in MEN scheduled for radical prostatectomy  
Funded by: Prostate Cancer UK   
ClinicalTrials.gov Registration Number: NCT05110495 
______________________________________    
SAP Version No: 1.0 
OCTRU-OST-001_V4.0_05Mar2021 
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1
INTRODUCTION 
This document details the proposed data presentation and analysis for the main paper(s) and final study 
reports from the WINGMEN Phase 0 Windows trial of INsulin-like Growth factor neutralising antibody 
Xentuzumab in MEN scheduled for radical prostatectomy. The results reported in these papers should follow 
the strategy set out here. Subsequent analyses of a more exploratory nature will not be bound by this strategy, 
though they are expected to follow the broad principles laid down here. The principles are not intended to 
curtail exploratory analysis (for example, to decide cut-points for categorisation of continuous variables), nor 
to prohibit accepted practices (for example, data transformation prior to analysis), but they are intended to 
establish the rules that will be followed, as closely as possible, when analysing and reporting the trial. This 
document follows published guidelines regarding the content of statistical analysis plans for clinical trial [1]. 
The analysis strategy will be available on request when the principal papers are submitted for publication in a 
journal. Suggestions for subsequent analyses by journal editors or referees, will be considered carefully, and 
carried out as far as possible in line with the principles of this analysis strategy. If reported, the analyses will 
be marked as post-hoc; the source of the suggestion will be acknowledged, and the reader will be advised to 
rely on the pre-specified analysis for the interpretation of the results.  
Any deviations from the statistical analysis plan will be described and justified in the final report of the trial. 
The analysis should be carried out by an identified, appropriately qualified and experienced statistician, who 
should ensure the integrity of the data during their processing. Examples of such procedures include quality 
control and evaluation procedures. 
Integral to this Statistical Analysis Plan (SAP) is the SAP – Data Definitions and Tables document which will 
include full detailed descriptions of all key outcomes, including their definition, generation and how they will 
be reported at the end of the study. These two documents should be read in tandem. 
1.1
Key personnel 
List of key people involved in the drafting and reviewing this SAP, together with their role in the trial and their 
contact details.
Author(s) (Trial statisticians)  
Dr Fiona Hartley (fiona.hartley@nds.ox.ac.uk)  
Dr Simon Lord (simon.lord@oncology.ox.ac.uk)
Dr Valentine Macaulay (valentine.macaulay@nds.ox.ac.uk) 
Dr Alessandro Barberis (alessandro.barberis@nds.ox.ac.uk) 
Reviewers (Trial Manager, DSMC, TSC, Statistician as appropriate)  
Tim Coutts (timothy.coutts@oncology.ox.ac.uk) 
Dr Alessandro Barberis (alessandro.barberis@nds.ox.ac.uk)
Approver (Senior Statistician, Chief Investigator)  
Dr Simon Lord (simon.lord@oncology.ox.ac.uk)


Windows trial of INsulin-like Growth factor neutralising 
antibody Xentuzumab in MEN scheduled for radical prostatectomy  
Funded by: Prostate Cancer UK   
ClinicalTrials.gov Registration Number: NCT05110495 
______________________________________    
SAP Version No: 1.0 
OCTRU-OST-001_V4.0_05Mar2021 
Date: 24Jun2024 
Effective Date 19Mar2021  
SAP Author: See section 1.1 
Page 5 of 23
1.2
Changes from previous version of SAP 
A summary of key changes from earlier versions of SAP, with particular relevance to protocol changes that 
have an impact on the design, definition, sample size, data quality/collection and analysis of the outcomes will 
be provided. Include protocol version number and date. 
Version number
Issue date 
Author of 
this issue 
Protocol Version & Issue 
date 
Significant 
changes 
from 
previous version, with reasons 
V1.0_24Jun2024
See section 
1.1 
Protocol_2.0_21Nov2022
Not applicable as this is the 1st issue
Add to or delete as required


Windows trial of INsulin-like Growth factor neutralising 
antibody Xentuzumab in MEN scheduled for radical prostatectomy  
Funded by: Prostate Cancer UK   
ClinicalTrials.gov Registration Number: NCT05110495 
______________________________________    
SAP Version No: 1.0 
OCTRU-OST-001_V4.0_05Mar2021 
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2
BACKGROUND AND OBJECTIVES 
WINGMEN is a windows trial of IGF blockade pre-prostatectomy. The aim is to identify key IGF-regulated 
genes/proteins that mediate effects of high serum IGF-1 in driving prostate cancer risk and progression.
The estimand for the primary objective (including the analysis of the primary outcome) is described in Table 
1. This trial is unusual in that it lacks a control arm. Patients serve as their own control through collection of 
samples before xentuzumab treatment. This affects the way intercurrent events are handled. 
Table 1: Estimand-to-analysis table template 
Primary Objective:  Assess the amount of IGF pathway inhibition induced by xentuzumab 
Estimand: The amount of IGF-1 blockade induced by xentuzumab measured through automated 
immunohistochemistry (IHC) analysis of IGF-1 receptor activation (phospho-IGF-1R) and downstream 
activation marker phospho-S6.  
Treatment: Xentuzumab infusion (1000mg), once weekly for a minimum of 4 weeks 
Estimand 
Analysis 
Target population 
Men ≥ 18 years old with prostate cancer who 
are scheduled for radical prostatectomy.  
Analysis set 
All participants who meet trial eligibility criteria and initiate 
treatment.  
Variable 
H-Score or % of positively stained cells for 
phospho-IGF-1R 
and 
phospho-S6 
as 
measured by IHC. 
Outcome measure 
Statistical significance of the difference between IGF1 axis 
activity in PRE treatment and POST treatment samples.
All participants who have sufficient material in the 
diagnostic 
(PRE-treatment) 
and 
in 
theatre 
(POST-
treatment) biopsy cores for IHC analysis will be included, 
provided intercurrent events have not affected their ability 
to meet trial eligibility criteria. 
Handling of intercurrent events 
Intercurrent events which prevent the 
patient from having in theatre (POST-
treatment) biopsy cores available for IHC 
analysis after at least 4 doses of xentuzumab 
will preclude the patient from analysis of the 
primary endpoint. This does not fall under the 
Handling of missing data 
Missing data will not be imputed. Patients whose samples 
are not sufficient to provide a score at baseline and after 
treatment will be excluded from the primary endpoint 
analysis. For other endpoints/analyses, Chief Investigator 
Sensitivity analysis: NA, data will not be imputed. 


Windows trial of INsulin-like Growth factor neutralising 
antibody Xentuzumab in MEN scheduled for radical prostatectomy  
Funded by: Prostate Cancer UK   
ClinicalTrials.gov Registration Number: NCT05110495 
______________________________________    
SAP Version No: 1.0 
OCTRU-OST-001_V4.0_05Mar2021 
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Page 7 of 23
typical handling of intercurrent events due to 
the single arm design of this trial. 
Intercurrent events that do not prevent the 
patient from having in theatre (POST-
treatment) biopsy cores available for IHC 
analysis, and would not affect the patient’s 
trial eligibility, will be assessed by the Chief 
Investigator. 
Population-level summary measure 
Statistical significance of the difference 
between IGF1 axis activity in PRE and POST 
treatment samples.
Analysis approach 
PRE/POST HALO scores will be analysed using a paired t-
test, or, if the paired differences do not follow a normal 
distribution, the Wilcoxon matched pairs signed rank test. 
Sensitivity analyses: Data will be tested for normal 
distribution and the appropriate test chosen accordingly 
(i.e. there is no assumption of normality). The appropriate 
sample size for 80% power was calculated as in Section 1.4.
1Strategies defined in E9 (R1) include treatment policy, while on treatment, principal stratum and hypothetical 
3
STUDY METHODS 
3.1
Trial Design/framework 
This is a phase 0 ‘window of opportunity’ study testing whether IGF neutralising antibody xentuzumab blocks 
IGF signalling and markers of aggressive tumour growth in men with localised prostate cancer scheduled for 
radical prostatectomy. Three factors influenced the trial design, and in particular the absence of a control arm. 
Firstly, trial design was informed by views of patients scheduled for prostatectomy. Men showing interest in 
the trial expressed the view that they would be less likely to participate in a trial randomising between 
treatment and control arms, because if they did take part, given the inconvenience of assessments and 
additional blood tests, they would want to receive the treatment. Other factors included the increased cost to 
Prostate Cancer UK of adding a control arm, doubling the trial size and cost, and the fact that the strength of 
a pre-operative windows study is the intra-patient pre/post treatment comparison. 
3.2
Sample Size 
Details of the sample size for primary outcomes and any co-primary or key secondary outcomes (if applicable), 
including treatment effect, power, levels of statistical significance (one-tailed or two-tailed), clinical relevance 
and justification.  
Trial size calculations were initially based on analysis of phospho-AKT immunohistochemistry in tumours of 
mice following 3 weeks treatment with xentuzumab (Figure 6G in [2]). Compared with control treatment, the 
reduction in phospho-AKT signal induced by xentuzumab indicates an effect size of 2.35. In anticipation of a 
reduced effect in a heterogeneous clinical population, calculations are based on a more conservative estimate 
of an effect size of 0.6. Recruitment of 24 patients, giving 24 matched pairs of tissue (diagnostic biopsy and in-
theatre biopsy), will enable reduction in phospho-AKT (or downstream target) (measured by H-Score or 


Windows trial of INsulin-like Growth factor neutralising 
antibody Xentuzumab in MEN scheduled for radical prostatectomy  
Funded by: Prostate Cancer UK   
ClinicalTrials.gov Registration Number: NCT05110495 
______________________________________    
SAP Version No: 1.0 
OCTRU-OST-001_V4.0_05Mar2021 
Date: 24Jun2024 
Effective Date 19Mar2021  
SAP Author: See section 1.1 
Page 8 of 23
percentage of positively stained cells) to be significant at the 5% level with 80% power. We will recruit 30 
patients in case some prostate biopsies are inadequate or unsuitable for translational studies. 
These calculations were checked against preliminary clinical data suggesting association of high serum IGF-1 
with increased IGF-1R content of malignant but not benign prostatic epithelium in a radical prostatectomy 
cohort of 139 patients with T1-T3a prostate cancer (Table 2). Supporting the proposed sample size calculated 
above, recruitment of 25 patients will enable a 2-point reduction in IGF-1R (measured by H-Score or 
percentage of positively stained cells) to be significant at the 5% level with 80% power (with within-person 
standard deviation of 3.5). Simulations from clinical data indicate that weekly dosing of 1000mg xentuzumab 
reduces mean free IGF-1 by >90% and mean free IGF-2 by 64% relative to pre-treatment. This suggests that 
the proposed intervention will have a biological effect at least as great as the difference in circulating IGF-1 
levels in the radical prostatectomy cohort. 
Sample size calculations were repeated in October 2022 based on newly acquired preclinical data quantifying 
the amount of IGF axis pathway inhibition achieved by xentuzumab. This equates to the WINGMEN trial 
primary endpoint: the amount of IGF axis pathway inhibition. In a preclinical prostate cancer model, 
xentuzumab suppressed IGF-1R phosphorylation (pIGF-1R) with an effect size of 0.68 (G*Power v3.1). Using 
Wilcoxon signed rank test (matched pairs, 2-tailed), recruitment of 20 patients (20 matched pre/post-
treatment pairs) will be significant at the 5% level with 80% power. Using a one-tailed test, based on the 
hypothesis that xentuzumab will reduce pIGF-1R, we will need 16 patients (16 matched pairs of tissue). 
Therefore, we aimed to recruit 20-30 patients in case some prostate biopsies are inadequate or unsuitable for 
translational studies. 
Table 2. Serum IGF-1 associates with IGF-1R immunoreactive score in malignant prostate epithelium. 
Immunoreactive scores (calculated as described in [3] were divided by the median values. IGF-1R scores were generally 
higher in malignant epithelium, consistent with our earlier report of IGF-1R overexpression in prostate cancer [4], hence 
cut point of 14 in malignant epithelium vs 10 in benign epithelium. NB Two samples had no benign epithelium in the 
scored sections (Aleksic, Verrill, Macaulay, unpublished). 
3.3
Statistical Interim Analysis, Data Review and Stopping guidelines 
State if there is a Data and Safety Monitoring Committee referencing the trial DSMC Charter (OCTRU GEN-011) 
for full details, but include the planned timing of meetings and of any formal comparative interim analysis. The 
latter should be outlined in the protocol and should be included here either in full, or summarised here with 
cross-reference to the full details in a separate document such as the DSMC_Report_Template (OCTRU 
Template OST-005, OCTRU SOP STATS-004 Interim Analysis).  
If no DSMC is reviewing accruing data, state this together with justification. 
The roles of the Trial Steering Committee and DSMC will be fulfilled by the Independent Early Phase Trial 
Oversight Committee (IEPTOC). The IEPTOC (at least 3 members including an independent chair) will provide 
overall supervision of the safe and effective conduct of the study according to its terms of reference. At least 
annually it will review study progress against agreed milestones, adherence to protocol, patient safety and 
consider new information. The IEPTOC has the authority to recommend study closure where appropriate. 
n 
Median serum 
IGF-1 nmol/l 
n 
Median serum 
IGF-1 nmol/l 
p value 
Benign epithelium 
IGF-1R score ≤ 10 
77 
16.54 
IGF-1R score > 10 
60 
16.68 
p=0.871 
Malignant epithelium
IGF-1R score ≤ 14
79 
15.58 
IGF-1R score > 14 
60 
17.07 
p=0.038 


Windows trial of INsulin-like Growth factor neutralising 
antibody Xentuzumab in MEN scheduled for radical prostatectomy  
Funded by: Prostate Cancer UK   
ClinicalTrials.gov Registration Number: NCT05110495 
______________________________________    
SAP Version No: 1.0 
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Page 9 of 23
3.4
Timing of Final Analysis 
Provide details of the final analysis time-points – clarifying if the outcomes will all be assessed at the same time 
or are there different time-points for analysis, for example short term and long-term outcomes, or dose 
escalation and dose expansion phase.  
To assess feasibility of tissue processing, two trial cases identified by Professor Clare Verrill, Consultant 
Prostate Pathologist, will be selected to check the tissue analysis pipeline. Sections of formalin-fixed paraffin-
embedded (FFPE) diagnostic (PRE) and in theatre (POST) biopsy cores will be cut for primary endpoint 
immunohistochemistry (IHC) (2 sections), multiplex immunofluorescence (mIF, 1 section), RNA extraction (3 
sections) and up to 4 additional sections depending on tumour content of diagnostic biopsies, which must not 
be cut to exhaustion. 
Outcomes will be assessed at different time points as follows: 
3.4.1
Primary endpoint  
The primary endpoint, the amount of IGF axis pathway inhibition, will be assessed by batch analysis using 
automated IHC for phospho-IGF-1R and downstream marker phospho-S6. Multiple rounds of validation have 
confirmed that the selected antibodies are stable, providing reproducible signal in multiple prostate samples 
and analytical runs. Analysis of freshly cut paired sections of diagnostic biopsy and in-theatre prostate biopsy 
cores from a non-trial subject confirmed that the selected phospho-epitopes are stable between these two 
time-points. The paired diagnostic (PRE-treatment) and in theatre (POST-treatment) biopsy cores of the two 
trial patients identified above will be analysed in the same staining run, alongside a negative IHC control. If the 
results are satisfactory, sections will be cut from the remaining PRE/POST biopsy core pairs and freshly stained 
for phospho-IGF-1R and phospho-S6. Again, each pair of tissues will be analysed in the same staining run, 
alongside a negative control. 
3.4.2
Secondary endpoints  
Feasibility of recruitment and safety data will be accrued in real time, the latter during trial treatment and up 
to and including the End of Study visit. These data will be analysed after data lock. 
3.4.3
Research/tertiary endpoints 
There are several tertiary and exploratory endpoints for which data will be collected in this trial. 

IGF-1, IGFBP3, insulin and PSA levels will be collected on a per patient basis in real time and analysed 
after data lock. 

Serum IGF bioactivity will be batch analysed by phospho-IGF-1R ELISA after data lock, ensuring pairs 
of PRE/POST serum samples from individual subjects are analysed in the same batch. 

For metabolomics profiling, samples of sodium heparin plasma will be molecular weight filtered then 
transferred on ice to the McCullagh laboratory in a single batch on completion of recruitment. Pairs 
of PRE/POST plasma will be analysed by mass spectrometry in the same analytical run. 

PBMC immunophenotyping will be done by mass cytometry (CyTOF) using 36 markers of diverse 
immune cell classes and their functional states. We will use non-trial samples to test the viability of 
cryopreserved cells post-thawing and to determine the number PBMC cells required for acquisition to 
identify low frequency but functionally important immune subsets. Pairs of PRE/POST PBMCs from 
individual subjects will be barcoded with a CD45 based approach, allowing all samples to be batch 
analysed in a single run. This significantly reduced batch effects).  


Windows trial of INsulin-like Growth factor neutralising 
antibody Xentuzumab in MEN scheduled for radical prostatectomy  
Funded by: Prostate Cancer UK   
ClinicalTrials.gov Registration Number: NCT05110495 
______________________________________    
SAP Version No: 1.0 
OCTRU-OST-001_V4.0_05Mar2021 
Date: 24Jun2024 
Effective Date 19Mar2021  
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
ctDNA: currently there are no funds to sequence these samples. Opportunities will be explored to 
perform this analysis in collaboration, for example using a next generation sequencing assay that 
identifies prostate-cancer relevant genomic alterations as in [5]. 

Exploratory IHC markers (see WINGMEN_DataDefinitions&Tables Section 5.2.1) will be batch analysed 
as for primary endpoint markers (Section 3.4.1 above) after completion of primary endpoint IHC. 

RNA will be extracted from unstained FFPE sections of diagnostic biopsy and in-theatre prostate biopsy 
cores, initially using freshly cut sections of the two first trial patients identified in Section 3.4, for 
transcriptional profiling. RNA will be stored in a designated -80oC freezer. If RNA yield and quality are 
sufficient for sequencing, RNA will be extracted from FFPE sections of the remaining cases and stored 
at -80oC as above. If RNA yield is insufficient, we will re-review each biopsy with Prof Clare Verrill to 
decide whether we can cut additional sections from some/all of the cases. RNA will be sent on dry ice 
to Azenta for quality control and sequening as described in WINGMEN_DataDefinitions&Tables 
Section 5.2.2. Final analysis will be performed when RNA-seq data have been accrued from all 
evaluable trial subjects (i.e. those with sufficient tumour in the diagnostic biopsy to allow within 
patient comparison with RNA extracted from prostate cancer cores post-xentuzumab). 

Mutation panel screening and TPMRSS2-ERG FISH will be performed on sections of radical 
prostatectomies as single batches after the samples from the last patient have been collected. 

Phospho-proteomic profiling: fresh frozen punch biopsies taken from unfixed prostatectomies are 
stored in the Oxford Radcliffe Biobank. Given that we have no matched pre-treatment fresh frozen 
biopsies, we plan to hold analysis of these samples until the other endpoint analyses have been 
completed. If sufficient funds remain, and if we can access fresh biopsies from Gleason-matched 
prostatectomies in non-trial patients, we will analyse tumour lysates by Reverse Phase Protein Array 
(e.g. Institute of Genetics and Cancer in Edinburgh: www.ed.ac.uk/cancer-centre/facilities/htpu-
microarray-services/reverse-phase-protein-arrays). The analysis will be performed in a single batch 
after samples from the last patient have been collected. 
3.4.4
Final integration of translational research data  
Final data integration will be performed when all results have been obtained from the primary, secondary and 
research/tertiary endpoint markers, as described in WINGMEN_DataDefinitions&Tables Section 5.3. Set-up of 
a private cBioPortal will allow us to study associations and correlations between different data types. 
Exploratory analyses will be conducted using the cBioPortal and followed up using independent analyses 
where relevant. Recruitment was completed by Q1 2023 and the study is funded until April 2025 to allow time 
for analysis of these datasets. 
3.5
Blinded analysis 
There will be no blinding for treatment: all trial subjects will be treated with xentuzumab. Research staff of 
the Translational Histopathology Lab will be blinded. Macaulay lab members will not be blinded as to whether 
the samples are PRE or POST xentuzumab. 
3.6
Statistical Analysis Outline 
Statistical analysis will follow the principles and consensus criteria set out in [1], including the minimum set 
of items that should be addressed and excluding items not relevant to this trial design (e.g. procedures for 
performing randomisation). The statistical tests that will be used are described in detail in Section 4. 


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4
STATISTICAL PRINCIPLES 
4.1
Statistical Significance and Multiple Testing 
If the analysis is under a conventional (statistical hypothesis testing approach), state the level of statistical 
significance and the confidence intervals to be reported. Acknowledgement of the issue of multiple testing (if 
applicable), together with the rationale of the intention to formally or informally adjust for multiplicity. If no 
adjustment planned this will be stated. State which outcomes will be adjusted for multiplicity (if applicable). 
Initial analysis will assess variables for normal distribution using the Shapiro-Wilk test. All tests will be 2-
tailed and p≤0.05 will be accepted as statistically significant. 
4.1.1
Primary endpoint analysis 
PRE/POST FFPE tissue biopsy sections stained for phospho-IGF-1R and phospho-S6 will be scanned and 
analysed on the HALO platform. This is a deep-learning convolutional neural network that generates H-Scores, 
representing the sum of the % tissues staining 0 (negative), 1+, 2+ and 3+ to generate a score range of 0-300.
If the staining intensity is not sufficient to define a scoring range for H-Scores, percentage of positively stained 
cells will be used as output instead. To assess the significance of differences before and after xentuzumab, the 
PRE/POST HALO scores will be analysed using a paired t-test, or, if the paired differences do not follow a 
normal distribution, the Wilcoxon matched pairs signed rank test. Phospho-IGF-1R staining patterns will also 
be assessed by Prof Clare Verrill, to semi-quantitatively score signal in the plasma membrane, cytoplasm and 
nucleus. Existing data from our group suggest that nuclear IGF-1R associates with higher stage prostate cancer 
[3] . 
4.1.2
Secondary endpoints 
The feasibility of treatment in a pre-operative setting will be assessed as the number (percent) of patients whose 
radical prostatectomy was performed on schedule after 4 doses of xentuzumab. Any reasons for delay post-4 cycles 
will be tabulated. 
The safety and tolerability of xentuzumab administered in the pre-prostatectomy setting will be examined through 
treatment-related adverse events scored using NCI-CTCAE v5.0. These results will be tabulated.
4.1.3
Research/translational endpoints producing single values 
Exploratory analyses will be conducted using various statistical tests as appropriate for the data type. These 
include, but are not limited to, the following. 
For endpoints which produce a single value PRE/POST xentuzumab (e.g. circulating biomarkers such as insulin, 
PSA, PMBC immunotypes; IGF bioactivity; exploratory tissue biomarkers) paired t-tests or Wilcoxon rank sum 
tests will be used to assess the significance of differences pre and post treatment. Which test will be used will 
be determined by the results of the Shapiro-Wilk test for normal distribution. For unpaired data, either 
unpaired t-tests or the Mann-Whitney U test will be used, again depending on results of the Shapiro-Wilk test 
for normal distribution. These results will be presented and analysed as for primary endpoint markers and as 
shown in WINGMEN_DataDefinitions&Tables Section 5. Results will be displayed as either the mean (and 
standard deviation), or median (with lower and upper quartiles). 
Relationships between many of these variables may be assessed for correlation. The Pearson correlation 
coefficient r will be used where two sets of raw data show a linear relationship with one another. If the 


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relationship is monotonic (i.e. non-linear) the Spearman’s rank test (correlation coefficient ρ) will be used to 
analyse correlation between ranked data. 
We had planned to assess changes in on-study serum IGF-1, previously reported to rise in patients on 
xentuzumab reflecting hypothalamic-pituitary axis response to blockade of pituitary IGF-1R [6]. However, on-
treatment serum IGF-1 values fell in WINGMEN trial subjects, and we found this was due to interference by 
xentuzumab in the IGF-1R assay used in the Biochemistry laboratory of the John Radcliffe Hospital. 
Other research endpoints (e.g. RNA-seq, metabolomics) will generate larger datasets and will be handled using 
the methods described below. 
4.1.4
Metabolomics 
Metabolomics profiles will be analysed in the laboratory of Prof James McCullagh (Department of Chemistry, 
Oxford 
University) 
using 
statistical 
methods 
described 
in 
[6] 
and 
presented 
as 
in 
WINGMEN_DataDefinitions&Tables Figure 4. In brief, univariate statistical analysis will be used to identify 
significantly deregulated metabolites (defined by ≥2 fold-change and false discovery rate (FDR) adjusted p-
value <0.05). Unsupervised multivariate statistical analysis will include principal component analysis (PCA) to 
visualise global metabolic profiles and identify outliers. Supervised multivariate statistical analysis will be used 
to model important compound features that differentiate PRE and POST xentuzumab samples, and pathway 
analysis will use MetaboAnalyst, based on the Kyoto Encyclopedia of Genes and Genomes (KEGG) metabolite 
library specific to Homo sapiens.  
4.1.5
RNA-seq 
RNA-seq data will be analysed by Dr Fiona Hartley and Dr Alessandro Barberis, Macaulay lab bioinformaticians. 
Analyses will use R Statistical Software and the RStudio integrated development environment. A matrix of 
gene 
counts 
containing 
all 
samples 
will 
be 
generated 
by 
the 
process(es) 
described 
in 
WINGMEN_DataDefinitions&Tables Section 5.2.2. Genes with low counts will be filtered using the 
filterByExpression function in the edgeR R package [8]. Differential expression analysis will be completed using 
widely used software packages such as DESeq2, edgeR, and limma [9, 8, 10]. All packages correct for the effect 
of library size. DESeq2 models genes using a negative binomial generalised linear model and tests the null 
hypothesis that there is no differential expression across the two sample groups using a Wald test. edgeR also 
tests for differential expression by fitting a negative binomial model and uses the exact test to identify 
differentially expressed genes. Limma fits a gene-wise linear model and uses moderated t--statistics to 
perform hypothesis testing. The p-values are corrected for multiple testing using the Benjamini-Hochberg (BH) 
method to produce an adjusted p-value. Results will be considered significant at adjusted p-value ≤0.05, 
meaning that the proportion of false positives expected amongst the differentially expressed genes is 5%. If 
the signal from differential expression analysis is not strong, an adjusted p-value ≤0.1 may be used. An 
unfiltered list of ranked genes will be used for gene set enrichment analysis (GSEA) to identify pathways that 
are activated or suppressed by xentuzumab [9]. The primary database that will be used for GSEA is the Gene 
Ontology (GO) terms for Biological Processes (BP) [10] and the analysis will be run using the clusterProfiler R 
package with BH multiple test correction. Depending on results of other analyses (e.g. PBMC 
immunoprofiling), we may manually select relevant pathways (e.g. immune pathways) from Gene Ontology 
Biological Processes  [10], KEGG [11, 12], BioCarta [13] , WikiPathways  [14], Reactome [15], and Hallmarks 
MSigDB [16]. Results of GSEA analysis will be considered significant at an adjusted p-value ≤0.05 or, if the 
expression signal is low, ≤0.1. 


Windows trial of INsulin-like Growth factor neutralising 
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4.1.6
RPPA data 
Normally distributed unpaired RPPA data (WINGMEN_DataDefinitions&Tables Section 5.2.4 and Figure 9) will 
be analysed for the most significantly deregulated proteins using the methods described in Section 4.1.3. 
4.2
Definition of Analysis Populations  
See WINGMEN_DataDefinitions&Tables Section 3. 
5
TRIAL POPULATION AND DESCRIPTIVE ANALYSES 
Summary of flow of trial participants through the trial and baseline stratification, demographic and clinical 
characteristics of each group. 
5.1
Representativeness of Study Sample and Patient Throughput 
5.1.1
Representativeness of study sample 
Subjects recruited to this trial will be fit (performance status 0-1) and thus representative of men scheduled 
for radical prostatectomy. For inclusion, the patient must have sufficient tumour in the diagnostic biopsy to 
provide at least 2 tissue sections for primary endpoint assessment. This criterion will be fulfilled for the 
majority of men whose prostate cancer is suitable for treatment by radical surgery. Exclusion criteria include: 
• Treatment with systemic corticosteroids, insulin, metformin, other oral hypoglycaemic agent, or anti-
androgens in the 28 days prior to first dose of study drug 
• Diabetes mellitus 
• Previous prostate radiotherapy 
• Current or previous treatment with xentuzumab or other IGF or GH -modifying therapy 
• Patients who are known to be serologically positive for Hepatitis B, Hepatitis C or HIV 
• Treatment with any other investigational agent, or treatment in another interventional clinical trial 
within 28 days prior to enrolment 
• Other psychological, social or medical condition, physical examination finding, or laboratory 
abnormality that the Investigator considers would make the patient a poor trial candidate or could 
interfere with protocol compliance or the interpretation of trial results. 
5.1.2
Patient Throughput 
See WINGMEN_DataDefinitions&Tables Section 4.2, Table 5, and Appendix 1: CONSORT Flow Diagram. The 
CONSORT flowchart will provide an overview, but additional expansion of reasons and timing of withdrawals 
from the study may be required. 
5.2
Withdrawal from Treatment and/or follow-up 
This information will be included in WINGMEN_DataDefinitions&Tables Section 4.2, Table 5, and Appendix 1: 
CONSORT Flow Diagram. No statistical tests will be used here. If patients withdraw early, their research blood 
and tissue samples will still be used for analysis if the patient gives consent. 
5.3
Baseline Characteristics 
Trial subjects’ baseline characteristics will be tabulated as in WINGMEN_DataDefinitions&Tables Section 4.1 
and Table 4. There will be no stratification by treatment group. Numbers (with percentages) for binary and 
categorical variables and mean (and standard deviation), or median (with lower and upper quartiles) for 
continuous variables will be presented. There will be no tests of statistical significance nor confidence intervals 
for differences between randomised groups on any baseline variable. 


Windows trial of INsulin-like Growth factor neutralising 
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Funded by: Prostate Cancer UK   
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5.4
Unblinding 
Not applicable: all trial subjects will receive the investigational medicinal product (IMP). 
5.5
Treatment Compliance with Details of Intervention 
The intervention being assessed in this trial is the IMP xentuzumab (Boehringer Ingelheim), an insulin-like 
growth factor (IGF) neutralising antibody. The drug is administered by intravenous infusion over one hour, 
once weekly for 4 weeks prior to standard of care radical prostatectomy. Trial subjects whose surgery is 
delayed will continue to receive weekly xentuzumab for up to 10 cycles in total. The final dose must be given 
within 6 days of surgery.  
Compliance and adherence to the protocol will be assessed by: 
• Ability to attend for trial treatment on a weekly basis ± 1 day of scheduled treatment visits. Incidence 
of delayed cycles and reasons for delay will be recorded as in WINGMEN_DataDefinitions&Tables
Section 4.2 and Table 5. 
• Ability and agreement to provide samples of blood and tissue for research. 
• Attendance for a post-xentuzumab blood sample (1-3 days before surgery) at the same time of day 
and interval after last meal (± 2-3 hr) as the pre-xentuzumab blood sample. This is important for 
consistency of metabolomic profiling. 
5.6
Reliability 
Note: This section should detail how the reliability of any variables, particularly outcomes, will be checked, for 
example those derived from raw data. Calculations performed by a computer program may be checked by hand 
calculations or confirmed by comparison with other measures.  This also applies to calculations made to replace 
missing data. 
Note: In the case of different assessors recording data, specify how inter-rater reliability will be assessed and 
any steps taken in analysis to allow for variations. 
5.6.1
Primary endpoint markers 
Staff of the Translational Histopathology Lab (THL) have assessed and optimised the primary endpoint markers 
phospho-IGF-1R and phospho-S6 by IHC using control cell samples generated in the Macaulay lab and tissue 
samples including tissue microarrays, prostatectomy sections, and prostate biopsies. The results are 
summarised in the THL Validation Report and confirm stable antibody performance over triplicate 
independent staining runs. Tests were also carried out to check stability of phospho-IGF-1R and phospho-S6 
epitopes by comparing the intensity and distribution of endpoint marker signal in diagnostic biopsy and in-
theatre core of a non-trial patient. An example is shown in WINGMEN_DataDefinitions&Tables Figure 1. 
5.6.2
Secondary endpoints 
Feasibility of treatment in the pre-operative setting, and safety and tolerability of xentuzumab administered 
in the pre-prostatectomy setting, will use standard clinical metrics including safety data assessed according to 
NCI-CTCAE v5.0.  
5.6.3
Research/tertiary endpoints 
Tertiary endpoints will be assessed in the Macaulay lab, Translational Histopathology Lab, the McCullagh 
Research Chemistry lab, and the Azenta Sequencing Facility using tested, standardised protocols.  


Windows trial of INsulin-like Growth factor neutralising 
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5.6.3.1
Tissue endpoints  
The reliability of research/tertiary IHC (e.g. Ki67, IGF-1R, RRM2, CD31) and TMPRSS2-ERG FISH will be checked 
by including positive and negative controls in each staining run. The signal will be quantified using HALO 
(WINGMEN_DataDefinitions&Tables Sections 4.3.1, 5.2.1 and 5.2.3) and reviewed with trial pathologist Prof 
Clare Verrill to check: staining of controls (e.g. cell pellets as shown in WINGMEN_DataDefinitions&Tables 
Figure 1A), technical quality of tissue staining, and whether pathological appearances are accurately 
represented by the HALO data. 
5.6.3.2
Circulating endpoints  
Paired PRE/POST serum samples will be tested for IGF bioactivity using a validated protocol obtained from 
Boehringer Ingelheim and used to assess the effect of xentuzumab in the Boehringer Ingelheim-sponsored 
Phase I trials [6]. Paired samples will be tested in the same assay run, and each assay will include a dose 
response of recombinant IGF-1, and the results in serum samples expressed as IGF-1 equivalents. 
5.6.3.3
PBMCs 
Immunoprofiling of peripheral blood mononuclear cells (PBMCs) will be performed either by flow cytometry 
or CyTOF. The latter will use Standardised Operating Procedures developed and validated by David Aherne 
(Research Associate and CyTOF Facility manager, Kennedy Institute of Rheumatology). 
5.6.3.4
RNA-seq data  
RNA derived from the FFPE-extracted tissue sections will undergo a series of quality checks. First the RNA 
quantity and purity will be tested in the Macaulay lab. On receipt at Azenta, RNA quantity will be rechecked, 
and the RNA integrity number (RIN) measured by TapeStation (Agilent). Azenta Standard Operating 
Procedures (SOPs) undergo regular review and all instruments are regularly calibrated and maintained, with 
records recorded in calibration and maintenance logs. Reagent and materials (including lot numbers) are 
tracked, laboratory staff are trained to the level required for clinical research, and IT systems are regularly 
maintained and backed up. The data will be analysed and cross-checked by two bioinformaticians in the 
Macaulay group, and the analysis will include checks on the expression of specific ‘indicator’ genes known to 
be IGF-regulated. 
5.6.3.5
Metabolomics 
Metabolomic profiles will be assessed on paired PRE/POST sodium heparin plasma using methods described 
in [7]. 
6
ANALYSIS 
Statistical methods to be used to compare groups for primary and secondary outcomes and methods for point 
and interval estimation.  Include methods for additional analyses, such as adjusted analyses and subgroup 
analyses, together with which populations will be analysed.  
Note: It may be appropriate to list the outcome definitions, analysis methods, missing data and sensitivity 
analyses separately for each primary and secondary outcome to be analysed. 
Section 4 above describes the methods that will be used to assess statistical significance of differences in 
endpoint marker signal between samples taken pre- and post- xentuzumab. 
The primary endpoint will be assessed by HALO analysis of 2 immunohistochemical (IHC) markers: phospho-
IGF-1R and phospho-S6 (see WINGMEN_DataDefinitions&Tables Figure 1 and Appendix 2). The scanned IHC 
images will be quantified using HALO by DPhil student Jinseon (Selena) Kim (Macaulay lab), and HALO data 


Windows trial of INsulin-like Growth factor neutralising 
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will be reviewed with trial pathologist Prof Clare Verrill as described in Section 5.6 above. Depending on the 
results of this assessment, we may use mean percentage change in one or both markers to quantify the 
amount of IGF axis inhibition. This measure will be used in correlation analyses with research/tertiary 
endpoints 
in 
both 
the 
entire 
population 
and 
in 
pre-defined 
subgroups 
as 
described 
in 
WINGMEN_DataDefinitions&Tables Section 5.3 and 5.3.1. 
6.1
Outcome Definitions 
Provide a simple list of all primary and secondary outcomes, together with time-points at which they are 
collected, with full details of definitions, and how these outcome variables will be generated and reported as 
provided in SAP - Data Definitions and Tables which should be cross-referenced.  
Objectives
Endpoints
Primary endpoint
Assess the amount of IGF pathway 
inhibition induced by xentuzumab  
Phospho-IGF-1R and phospho-S6
immunohistochemistry on tissue from 
biopsy and prostatectomy  
Secondary endpoints
1. Feasibility of treatment in pre-
operative setting 
2. Assess safety and tolerability of 
xentuzumab administered in the pre-
prostatectomy setting 
1. Number of patients whose radical 
prostatectomy is performed within 7 
days of the 4th dose of xentuzumab 
(patients can receive up to 10 doses of 
xentuzumab if surgery is delayed) 
2. Treatment-related adverse events 
scored using NCI-CTCAE v5.0  
Tertiary/exploratory
endpoints 
1. Assess change in PSA following 
administration of xentuzumab in the 
pre-prostatectomy setting 
2. Assess changes in tissue markers 
following administration of 
xentuzumab in the pre-prostatectomy 
setting 
3. Assess changes in circulating 
markers following administration of 
xentuzumab in the pre-prostatectomy 
setting 
4. Correlate changes in IGF-1R 
expression, IGF axis activity with 
cancer profile which may include 
mutation analysis, gene expression 
and phosphoproteomic profile 
1. Change in serum PSA
2. Changes by IHC on FFPE tissues in 
tissue markers (e.g. Ki67 index, IGF-1R, 
RRM2, CD31, immune markers: PD-L1, 
CD4, CD8, FoxP3) 
3. Changes in circulating markers of 
endocrine response to IGF blockade 
(e.g. IGF-1, insulin, IGFBPs, circulating 
IGF bioactivity, plasma metabolomic 
profile) 
4. Tumour profiling (e.g. gene 
mutation panel, IHC for PTEN, FISH for 
TMPRSS2-ERG, transcriptional and 
phospho-proteomic profile of index 
tumour) 
Table 3. Definition of WINGMEN outcomes. 
6.2
Analysis Methods 
For each primary and secondary outcome, describe what analysis methods will be used and how treatment 
effects will be presented (e.g. tabular and graphically- Cross-reference to the SAP – Data definitions and 
Tables). Detail which analysis population will be analysed. Detail any adjustment for covariates. Describe any 
methods to be used to check statistical assumptions and detail alternative methods if the assumptions do not 
hold, e.g. normality, proportional hazards. Where multiple analyses are planned, clearly distinguish which 
analysis will be the principal analysis, on which the outcome of the trial will be assessed, and which will be 


Windows trial of INsulin-like Growth factor neutralising 
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Funded by: Prostate Cancer UK   
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supporting analyses to aid interpretation. Details of sensitivity analyses and multiple imputation should be 
detailed either under each key outcome analysis where applicable or in separate sections (5.3 and 5.4) 
The primary endpoint (i.e. the amount of IGF pathway inhibition induced by xentuzumab)s will be presented 
as in WINGMEN_DataDefinitions&Tables Section 4.3.1, Figure 1, and Table 6 and analysed as described in 
Section 4 above. 
The trial will be assessed on a modified intention-to-treat basis. Patients who are not evaluable for the primary 
endpoint may be replaced at the discretion of the Trial Management Group; including: 
• Patients who receive fewer than 3 doses of xentuzumab (e.g. due to early withdrawal). 
• Patients who for any reason do not have their planned standard of care prostatectomy. 
• Patients whose prostatectomy reveals predominantly neuroendocrine/small cell cancer. 
• Patients from whom diagnostic biopsy or surgical specimens were not taken or were of insufficient 
quantity or quality for analysis. 
• Patients who do not receive their planned standard of care prostatectomy within 6 days of their final 
dose of xentuzumab. 
All participants who receive one or more doses of xentuzumab will be evaluable for safety analysis, and 
patients withdrawing early after one or more doses of xentuzumab, irrespective of their stage in the trial, will 
undergo evaluations on the day before surgery. 
The secondary outcomes relate to safety and feasibility of treatment and will be presented as described in 
Section 4.1.2 and WINGMEN_DataDefinitions&Tables Section 4.3.2 and Tables 7 and 8. The data will be 
tabulated and statistical analyses will not be conducted on these results. 
In a recent study testing the feasibility of RNA extraction and RNA-seq on FFPE diagnostic prostate biopsies, 
19/20 cases were found to provide RNA of sufficient quantity and quality for 3’RNA-seq [7]. The plan to recruit 
30 patients to this trial reflects recognition that not all cases may have sufficient tumour tissue in the 
diagnostic biopsy to provide sections for RNA extraction and research IHC markers. Reasons for unsuitability 
of 
research 
blood 
and 
tumour 
samples 
are 
described 
in 
the 
legend 
to 
Table 
5 
in 
WINGMEN_DataDefinitions&Tables.
The completeness of data required for primary and secondary outcomes is described, detailing methods to limit 
the possibility of missing data and methods for dealing with missing data when it occurs. 
A description of methods utilised for dealing with missing, spurious (outliers) and unused data during statistical 
analysis including the assumption for and type of missing data (Missing Completely At Random, Missing At 
Random, Missing Not At random).  If multiple imputation is to be used the methods should be specified, 
including the imputation method, variables used and number of imputations generated. If multiple Imputation 
is to be used if appropriate, please clarify what appropriate means, e.g. Multiple imputation will be used if >5% 
(or >10%) of data is missing, otherwise complete (or available) case analysis will be undertaken. Methods for 
handling withdrawals and protocol deviations will be documented. State if no missing data adjustment will be 
used. Where multiple imputation is utilised the methods used to test the validity of the different assumptions 
will be described, either here or under the sensitivity analyses section.
6.3
Sensitivity Analysis 
Describe any analysis utilised to check the robustness of the results. This may include repeating the primary 
analysis for different patient populations. Any sensitivity analyses checking the robustness of the results 
against the missing data assumptions should be included here or in the missing data section.


Windows trial of INsulin-like Growth factor neutralising 
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Funded by: Prostate Cancer UK   
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Primary endpoint analysis of phospho-IGF-1R and phospho-AKT or S6 IHC will be performed in parallel with 
controls as in WINGMEN_DataDefinitions&Tables Figure 1 and will require 2x 4 µm FFPE sections. Prof Clare 
Verrill advises that it is usually possible to cut maximum ~24 4-5 µm sections from a prostate biopsy, so the 
majority of trial subjects will have additional material if there are technical issues with initial analysis. Method 
optimisation indicates that IHC is capable of detecting changes in phospho-S6 phosphorylation comparable to 
changes detected on western blot of parallel whole cell extracts (see in WINGMEN_DataDefinitions&Tables 
Figure 1) 
Similarly, the planned blood sample collection will provide sufficient serum and sodium heparin plasma to 
repeat assays for IGF bioactivity and metabolomic profiling if there are technical issues with initial assays. Both 
assays on circulating biomarkers will use controls in the form of recombinant IGF-1 and metabolite controls 
respectively. The lower detection limit for phospho-IGF-1R ELISA is 2 nmol/l IGF-1 equivalents, with 
approximately linear detection up to 20 nmol/l (WINGMEN_DataDefinitions&Tables Figure 3).
6.4
Pre-specified Subgroup Analysis 
Describe any pre-specified subgroups for analysis, together with the justification for their relevance and 
importance, which outcomes they will be analysed for (it may just be the primary outcome), and include 
methods of analysis (reporting is dealt with in the SAP – Data Definitions and Tables document). It is 
recommended that subgroup-treatment interaction methods are used with presentation using forest plots. 
Subgroups are usually pre-specified in the protocol, but additional subgroup analyses may be added to the SAP 
prior to the final data lock following the blinded analysis or publication of other trials/research. Clearly specify 
if this analysis will be descriptive or if statistical testing will be undertaken. 
Subgroup analysis will be performed to assess correlation of specific phenotypes/genotypes with response to 
IGF axis blockade, as described in WINGMEN_DataDefinitions&Tables Section 5.3.1. 
6.5
Supplementary/ Additional Analyses and Outcomes 
Describe any supplementary/additional statistical analyses for primary or secondary outcomes required (if not 
already detailed elsewhere), e.g. complier-average causal effect analysis. 
Describe any outcomes and analyses pre-specified as exploratory in the protocol. Include detailed definition 
and analysis methodology or if not being undertaken by the statistician clearly state this and signpost to 
separate documents where these are detailed together with who will perform these 
There will be no supplementary analyses of primary or secondary endpoints. The exploratory research/tertiary 
endpoints 
will 
be 
subject 
to 
detailed 
analysis 
as 
described 
in 
Section 
4 
above 
and 
WINGMEN_DataDefinitions&Tables Section 5. 
6.6
Harms  
Provide sufficient detail on summarising safety data, e.g. information on severity, expectedness, and causality; 
details of how adverse events are coded or categorised; how adverse event data will be analysed, e.g. incident 
case analysis, intervention emergent analysis.  Will adverse events/complications also be recorded, 
summarised and analysed – full details for reporting should be specified in the SAP – Data Definitions and 
Tables document.
Potential harms include potential for drug toxicity and delay to standard of care surgery. Both will be captured 
as secondary endpoints and will be defined as described in WINGMEN_DataDefinitions&Tables Section 2.2 
and Table 2.  
There is a risk of COVID-19 exposure and infection from trial-specific hospital attendances, but measures have 
been put in place to minimise this risk as far as possible. The WINGMEN recruitment site, Churchill Hospital, is 


Windows trial of INsulin-like Growth factor neutralising 
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Funded by: Prostate Cancer UK   
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nominally COVID-19 free, and infected or potentially infected patients are treated at a geographically distinct 
site (John Radcliffe Hospital). The following procedures have also been put in place on site:  
• All patients (in and outpatients) are screened upon entry to the Churchill site. 
• Human traffic at the Churchill site is minimal, with face to face appointments avoided and staff working 
from home whenever possible.  
• Face masks/social distancing/level 1 PPE for patient examinations and other protective measures are 
mandatory for staff at the Churchill site  
Furthermore, this trial requires only 5 extra patients visits: screening and 4 treatment visits (unless surgery is 
unexpectedly delayed). The post-treatment End-of-Study trial assessment will be held on the same day as the 
routine 6-week post-operative assessment, and so will not involve an extra hospital visit. There is no evidence 
that treatment with an IGF inhibitory drug will cause patients to be immunosuppressed. Indeed, given 
experimental evidence that IGFs themselves can suppress the immune system [19, 20, 21], it is possible that 
treatment with xentuzumab could enhance immune responses. Therefore, we accept that extra hospital visits 
may confer additional COVID-19 risk, but the treatment itself should not increase this risk. There is no 
contraindication to having a COVID-19 vaccination before, during or after the study, and participants will be 
encouraged to do so if not already fully vaccinated. 
6.7
Health Economics and Cost Effectiveness (where applicable) 
NA - this not a planned objective of the trial. 
7
VALIDATION OF THE PRIMARY ANALYSIS 
To validate the primary outcome and key secondary outcomes a statistician not involved in the trial will 
independently repeat the analyses detailed in this SAP using different statistical software (if possible). The 
results will be compared and any unresolved discrepancies will be reported in the Statistical Report (See 
OCTRU SOP STATS-005 Statistical Report). Primary and secondary outcomes are defined and tabulated in 
Section 6.1. 
8
SPECIFICATION OF STATISTICAL PACKAGES 
All analysis will be carried out using appropriate validated statistical software such as GraphPad Prism, STATA, 
SAS, SPLUS or R. The relevant package and version number will be recorded in the Statistical Report. 
Specialised analyses of metabolomic and RNA-seq data will be performed as outlined in Section 4.1.4 and 
4.1.5. 
9
PUBLICATION 
A statement of CTU involvement will be included in any publication of the SAP. For example: This study was 
conducted as part of the portfolio of trials in the registered UKCRC Oxford Clinical Trials Research Unit (OCTRU) 
at the University of Oxford. It followed their Standard Operating Procedures ensuring compliance with the 
principles of Good Clinical Practice and the Declaration of Helsinki and any applicable regulatory requirements. 
The trial results will be reported in an appropriate journal once analysis is complete. 


Windows trial of INsulin-like Growth factor neutralising 
antibody Xentuzumab in MEN scheduled for radical prostatectomy  
Funded by: Prostate Cancer UK   
ClinicalTrials.gov Registration Number: NCT05110495 
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Reference to Data Management Plan 
Reference to Trial Master File and Statistical Trial Master File 
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50, 2005.  


Windows trial of INsulin-like Growth factor neutralising 
antibody Xentuzumab in MEN scheduled for radical prostatectomy  
Funded by: Prostate Cancer UK   
ClinicalTrials.gov Registration Number: NCT05110495 
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Windows trial of INsulin-like Growth factor neutralising 
antibody Xentuzumab in MEN scheduled for radical prostatectomy  
Funded by: Prostate Cancer UK   
ClinicalTrials.gov Registration Number: NCT05110495 
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APPENDIX: GLOSSARY OF ABBREVIATIONS  
AKT 
 
Protein kinase B 
BH 
 
Benjamini-Hochberg 
BP 
 
Biological processes 
CI 
 
Chief investigator 
CONSORT 
Consolidated Standards of Reporting Trails 
ctDNA
Circulating tumour DNA 
CyTOF  
Cytometry by time of flight 
DSMC  
Data and Safety Monitoring Committee  
ELISA 
 
Enzyme linked immunosorbent assay 
FDR 
 
False discovery rate 
FFPE 
 
Formalin-fixed paraffin-embedded 
FISH 
 
Fluorescence in situ hybridisation 
GO 
 
Gene ontology 
GSEA 
 
Gene set enrichment analysis 
IEPTOC  
Independent Early Phase Trial Oversight Committee 
IGF-1 
 
Insulin-like growth factor 1 
IGF-2 
 
Insulin-like growth factor 2 
IGF-1R  
IGF-1 receptor 
IGFBP3  
IGF binding protein 3 
IHC 
 
Immunohistochemistry 
IMP 
 
Investigational medicinal product 
KEGG  
Kyoto Encyclopedia of Genes and Genomes 
mIF 
 
Multiplex immunofluorescence 
NCI-CTCAE 
National Cancer Institute - Common Terminology Criteria for Adverse Events 
OCTRU  
Oxford Clinical Trials Research Unit 
PCA 
 
Principal component analysis 
pIGF-1R 
Phosphorylated IGF-1R 
PMBC  
Peripheral blood mononuclear cells 
POST 
 
Post xentuzumab treatment timepoint 
PRE 
 
Pre xentuzumab treatment timepoint 
PSA 
 
Prostate-specific antigen 


Windows trial of INsulin-like Growth factor neutralising 
antibody Xentuzumab in MEN scheduled for radical prostatectomy  
Funded by: Prostate Cancer UK   
ClinicalTrials.gov Registration Number: NCT05110495 
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SAP Version No: 1.0 
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RIN 
 
RNA integrity number 
RNA 
 
Ribonucleic acid 
RPPA 
 
Reverse-phase protein array 
SAP 
 
Statistical analysis plan 
SOP 
 
Standard operating procedure 
THL 
 
Translational Histopathology Lab 
TSC 
 
Trial Steering Committee 
WINGMEN 
Windows trial of INsulin-like Growth factor neutralising antibody Xentuzumab in MEN