SOTO Study: Prospective Study to Correlate the Treatment Sensitivity of Patient-derived Organoids With Clinical Outcomes in Head and Neck Squamous Cell Carcinoma (HNSCC) Patients
Conditions: Head and Neck Squamous Cell Carcinoma, Head and Neck Cancer
Sponsor: Guy's and St Thomas' NHS Foundation Trust

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1 Protocol details 
1.1 Title 
SOTO study: Prospective study to correlate the treatment Sensitivity of 
patient-derived Organoids with Treatment Outcomes in head and neck 
cancer patients 
Short title - SOTO: treatment Sensitivity of Organoids to predict Treatment 
Outcome 
1.2 Names (titles), roles and contact details of: 
Sponsor 
Name of Sponsoring Organisation: King’s College London 
Name of Sponsor Representative: Prof. Reza Razavi, Vice President and  
Address: Room 5.31, James Clerk Maxwell Building 
57 Waterloo Road, 
London SE1 8WA 
Email: reza.razavi@kcl.ac.uk 
 
Name of Co-Sponsoring Organisation: Guy’s and St. Thomas Foundation NHS trust 
Name of Co-Sponsor Representative: Rachel Fay 
Address: Guy's & St Thomas' NHS Foundation Trust 
R&D Department, 16th floor, Tower Wing, Guy's Hospital 
Great Maze Pond, 
London SE1 9RT 
Email: R&D@gstt.nhs.uk  
 
Chief Investigator  
Name: Dr. Anthony Kong 
Address: Comprehensive Cancer Centre 
King’s College London, Guy’s Campus 
Room 2.36b New Hunt’s House, London SE1 1UL 
Telephone: 0207-848-8302 
E-mail: Anthony.kong@kcl.ac.uk; Anthony.kong@gstt.nhs.uk 
 
Name and address of co-investigators  
Name: Ms. Caroline Murphy 
Address: King’s Clinical Trial Unit 
Research Management and Innovation Directorate 
KCTU 
             
 

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Telephone: 020 7848 0532 
E-mail: caroline.murphy@kcl.ac.uk 
Clinical fellow: Dr. Ifigenia Vasiliadou 
Address: Comprehensive Cancer Centre 
King’s College London, Guy’s Campus 
Room 2.36 New Hunt’s House, London SE1 1UL 
E-mail: ifigenia.vasiliadou@nhs.net; ifigenia.1.vasiliadou@kcl.ac.uk 
 
Name: Dr. Teresa Guerrero Urbano 
Address: Clinical oncology and radiotherapy 
Guy’s Cancer Centre 
Guy’s Hospital 
Great Maze Pond, 
London, SE1 9RT 
Email: teresa.guerrerourbano@gstt.nhs.uk 
 
Name: Dr. Lisette Collins 
Address: Head and neck pathology 
Floor 4 Tower Wing 
Guy’s Hospital 
Great Maze Pond 
London, SE1 9RT 
Email: lisette.collins@gstt.nhs.uk 
Name: Mr. Jean-Pierre Jeannon 
Address: ENT department 
Guy’s Hospital 
Great Maze Pond 
London, SE1 9RT 
Email: jean-Pierre.Jeannon@gstt.nhs.uk  
 
Name: Dr. Steve Connor 
Address: Head and neck radiology 
Guy’s Hospital 
Great Maze Pond 
London, SE1 9RT 
Email: steve.connor@gstt.nhs.uk  
Name: Prof. Tony Ng 
Address: Comprehensive Cancer Centre 
King’s College London, Guy’s Campus 
New Hunt’s House, London SE1 1UL 
Email: tony.ng@kcl.ac.uk 
Laboratories 
Name: Dr. Abul Azad  
Postdoctoral research fellow 
Address: Dr. Anthony Kong’s Lab 
Comprehensive Cancer Centre 
King’s College London, Guy’s Campus 

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Room 2.36 New Hunt’s House, London SE1 1UL 
Telephone: 0207-848-8302 
Email: Anthony.kong@kcl.ac.uk; abul.azad.@kcl.ac.uk 
 
Name: Rhonda Henley-Smith 
Address: Head and neck pathology 
Floor 4 Tower Wing 
Guy’s Hospital 
Great Maze Pond 
London, SE1 9RT 
Telephone:  
Email: Rhonda.Henley-Smith@gstt.nhs.uk 
 
1.3 Protocol details 
Sponsor’s/Protocol number: 305689 
Protocol Version number 1.0 
Date: 14/03/2022 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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2 Signature Page 
The Chief Investigator and the R&D (sponsor office) have discussed this protocol. The investigators 
agree to perform the investigations and to abide by this protocol  
The investigator agrees to conduct the trial in compliance with the approved protocol, EU GCP, the 
UK Data Protection Act (1998), the Trust Information Governance Policy (or other local equivalent), 
the Research Governance Framework (2005’ 2nd Edition; as amended), the Sponsor’s SOPs, and 
other regulatory requirements as amended. 
Chief investigator 
[Insert name of CI] 
 
 
 
Signature 
Date 
Sponsor Representative 
R&D to Add  
 
 
GSTFT 
Signature 
Date 
 
 
 

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3 Contents Page 
1 
Protocol details ............................................................................................................................... 1 
1.1 
Title ......................................................................................................................................... 1 
1.2 
Names (titles), roles and contact details of: ........................................................................... 1 
1.3 
Protocol details ....................................................................................................................... 3 
2 
Signature Page ................................................................................................................................ 4 
3 
Contents Page ................................................................................................................................. 5 
4 
List of Abbreviations and Definitions .............................................................................................. 7 
5 
Summary/Synopsis .......................................................................................................................... 8 
6 
Introduction .................................................................................................................................. 10 
7 
Trial objectives and purpose ......................................................................................................... 11 
8 
Study design & Flowchart ............................................................................................................. 12 
8.1 
Study Design.......................................................................................................................... 12 
8.2 
Treatment visits .................................................................................................................... 15 
9 
Subject selection ........................................................................................................................... 15 
9.1 
Subject inclusion criteria ....................................................................................................... 15 
9.2 
Subject exclusion criteria ...................................................................................................... 15 
10 
Study procedures ...................................................................................................................... 15 
10.1 
Subject recruitment .............................................................................................................. 15 
10.2 
Screening Procedures ........................................................................................................... 18 
10.3 
Schedule of assessments for each visit ................................................................................. 18 
10.4 
Follow up Procedures ........................................................................................................... 18 
10.5 
End of Study Definition ......................................................................................................... 18 
11 
Laboratories .............................................................................................................................. 19 
11.1 
Data Recording/Reporting .................................................................................................... 19 
11.2 
Sample Receipt/Chain of Custody/Accountability ................................................................ 19 
11.3 
Sample Transfer to sites outside the Organisation ............................................................... 19 

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12 
Assessment of Safety ................................................................................................................ 19 
12.1 
Ethics Reporting .................................................................................................................... 20 
12.2 
Ethics & Regulatory Approvals .............................................................................................. 20 
13 
Compliance and withdrawal ..................................................................................................... 20 
13.1 
Subject compliance ............................................................................................................... 20 
13.2 
Withdrawal / dropout of subjects ......................................................................................... 20 
13.3 
Protocol Compliance ............................................................................................................. 20 
14 
Data ........................................................................................................................................... 20 
14.1 
Data management ................................................................................................................ 20 
15 
Statistical considerations .......................................................................................................... 21 
16 
Ethical considerations ............................................................................................................... 21 
16.1 
Research Ethics Committee (REC) review & reports ............................................................ 21 
16.2 
Peer review ........................................................................................................................... 21 
16.3 
Regulatory Compliance ......................................................................................................... 22 
17 
Financing and Insurance ........................................................................................................... 22 
18 
Reporting and dissemination .................................................................................................... 22 
 
 

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4 List of Abbreviations and Definitions 
(Delete as appropriate) 
AE 
 
 
Adverse Event  
 
 
AR 
 
 
Adverse Reaction 
ASR 
 
 
Annual Safety Report 
CA 
 
 
Competent Authority 
CI 
 
 
Chief Investigator 
CRF 
 
 
Case Report Form 
CRO 
 
 
Contract Research Organisation 
DMC 
 
 
Data Monitoring Committee 
EC 
 
 
European Commission 
GAfREC  
 
Governance Arrangements for NHS Research Ethics Committees 
ICF 
 
 
Informed Consent Form 
MA 
 
 
Marketing Authorisation 
MS 
 
 
Member State 
Main REC 
 
Main Research Ethics Committee 
NHS R&D 
 
National Health Service Research & Development   
PI 
 
 
Principal Investigator 
QA 
 
 
Quality Assurance 
QC 
 
 
Quality Control 
Participant 
 
An individual who takes part in a clinical trial 
REC 
 
 
Research Ethics Committee 
SAE 
 
 
Serious Adverse Event 
SDV 
 
 
Source Document Verification 
SOP 
 
 
Standard Operating Procedure  
SSA 
 
 
Site Specific Assessment 
TMG 
 
 
Trial Management Group 
TSC 
 
 
Trial Steering Committee 

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5 Summary/Synopsis 
 
Trial Title 
Prospective study to correlate the treatment sensitivity of 
patient-derived organoids with clinical outcomes in head 
and neck squamous cell carcinoma (HNSCC) patients 
Internal ref. no. (or short title) 
SOTO: treatment Sensitivity of Organoids to predict 
Treatment Outcome in head and neck cancer patients 
Protocol Version number and Date 
Version 1.1 14th March 2022 
Study Phase if not mentioned in title 
NA. It is an observation study 
IRAS Number 
305689 
REC Reference 
22/NW/0023                          
Study Duration 
1 year of recruitment followed by standard of care follow-up 
for 5 years 
Sponsor name 
King’s College London  
Guy’s and St. Thomas Foundation NHS trust (co-sponsor) 
Chief Investigator 
Dr. Anthony Kong 
Funder 
Guy’s and St Thomas’ (GSTT) charity via a generous 
philanthropic donation from Charles Wilson and Rowena 
Olegario 
Medical condition or disease under 
investigation 
Head and neck squamous cell carcinoma (HNSCC) 
 
Objectives 
Endpoints 
Primary 
 
To assess the success rate of 
generating organoids from 
tissues in patients with HNSCC 
Rates of successful 
organoid cultures 
Secondary 
 
1) To assess the sensitivity of 
radiotherapy, cisplatin 
chemotherapy or cetuximab or 
their combination in PDOs  
 
 
2) To correlate the treatment 
sensitivities of PDOs above with 
the treatment outcome 
The ability of these 
treatment(s) to decrease 
tumour growth and kill 
the organoids ex-vivo 
(number and size of alive 
organoids after 
treatments) 
 
To correlate the IC50 
doses and dose response 

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undergoing primary surgery 
and adjuvant radiotherapy +/- 
concurrent platinum 
chemotherapy (Cohort 1) 
 
3) To correlate the treatment 
sensitivities of PDOs above with 
the treatment outcome of 
patients undergoing primary 
radiotherapy +/- platinum 
chemotherapy (Cohort 2) 
 
4) To correlate the sensitivities 
of platinum chemotherapy 
and/or cetuximab of PDOs or 
anti-PD1 with the treatment 
outcome of recurrent or 
metastatic HNSCC patients 
(Cohort 3) 
curves above with the 
recurrence rates and 
disease-free survival of 
patients  
 
The ability of the 
organoids to predict 
complete metabolic 
response and treatment 
outcome of patients  
 
 
The ability of the 
organoids to predict 
response to the same 
systemic treatments that 
the patients are receiving 
systemic treatments 
Number of Subjects/Patients 
20 patients for year 1 pilot study 
Study Type 
Observational 
Main Inclusion Criteria 
- Patients with head and neck squamous cell carcinoma 
undergoing curative treatment (primary surgery or 
radiotherapy) or presenting with recurrent or metastatic 
cancers  
- Age  > 18 years old 
Statistical Methodology and Analysis 
This is a prospective study with a one-year pilot study aiming 
to recruit 20 patients, which is the realistic target for year 1. 
The results from year 1 will be used to estimate the sample 
size for future prospective observation study 
Human Tissue Samples (if 
applicable) 
We will generate organoids from fresh tumour tissues and 
normal tissue when applicable and also stored unused 
biological samples in head and neck biobank for future 
translational research 
Data collected/storage (if 
applicable) 
Patients’ demographics, smoking and alcohol history, 
tumour characteristics, treatment details and responses, 
recurrences and survivals will be obtained from clinical 

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record and recorded on paper Case Report Forms (CRFs).  
6 Introduction 
 
Background 
Head and neck cancers are a group of heterogeneous diseases and the most common histology 
being squamous cell carcinoma (1). Head and neck squamous cell carcinomas (HNSCC) tend to be 
associated with smoking and alcohol intake although there has been increasing incidence of 
oropharyngeal cancer due to HPV infection (2). Localized HNSCCs are usually treated with combined 
treatment modalities including surgery, radiotherapy and chemotherapy. HPV positive oropharygeal 
patients respond better to chemoradiation compared to HPV negative, tobacco-induced 
oropharyngeal cancer patients (2). These patients also have better 3-year rates of overall survival 
(82.4%, vs. 57.1%) compared with patients with HPV-negative tumours (3). Apart from HPV status, 
there is no accurate way of predicting which patients will be cured from radical treatment although 
patients with tumours which are resistant to radiotherapy +/- platinum cisplatin chemotherapy tend 
to present with locoregional recurrence and have a poorer outcome. There is no easy way to test 
radiosensitivity and chemosensitivity of these tumours. There is a need, therefore, to develop an 
accurate test to evaluate the sensitivity ex-vivo so that we can predict which patients are likely to be 
resistant to radiotherapy or platinum chemotherapy and therefore more likely to relapse. If so, 
treatment interventions such as radiation dose escalation, use of radiosensitising agents and/or 
other treatment strategies could be implemented. 
 
Rationale of the study 
Up to 50% of HNSCC patients may recur and the prognosis of these patients is less than one year. 
The first-line treatment for these patients is a platinum-based chemotherapy with cetuximab (4), 
which is toxic and only benefit a small number of patients. Although immunotherapy has shown 
great promise in recurrent or metastatic HNSCC as first-line or second-line treatments, only around 
15-20% patients respond to these therapies with durable responses (5-6). There is therefore a need 
to ensure more effective radical curative treatment to prevent recurrences and to develop more 
effective targeted therapies for recurrent/metastatic HNSCC patients based on their genomic 
profiles.  
 
Previously most of the preclinical models were largely based on immortalized cancer cell lines and 
xenografts studies from transformed cell lines. These techniques have been important in elucidating 
the mechanisms of late-stage tumour development as well as studying drug resistance. However, 
large-scale drug screens of transformed cell line panels have resulted in a high failure rate of 
preclinical compounds in clinical trials, which demonstrates the limitations of using these existing 
preclinical models based on transformed cell models. To this end, living biobanks consisting of 
tumour organoids, which facilitates the integration of genomic data with drug screening of patients’ 
tumour samples to identify effective therapeutic regimens, have been established in a few tumour 
types including colorectal cancers, gastric cancers, liver cancers, breast cancers and more recently 
head and neck squamous cell carcinomas (7-10). The use of organoids in conjunction with genomic 
analysis from patient-derived tumour samples has the potential to stratify and identify effective 

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cancer therapies for individual patients by (a) comparing the response of individual tumours to 
specific drugs in order to provide personalized recommendations to manage patient care; (b) 
assessing how tumours respond and develop resistance to in order to further understand the 
mechanisms; (c) determining the next drug treatment option when standard clinical options are not 
available or not considered effective; (d) creating a database of drug sensitivity to tumour genetics 
to recommend potential therapeutic strategies. 
 
In this study, we aim to assess whether PDOs can be used to predict treatment sensitivity in HNSCC 
patients. 
 
7 Trial objectives and purpose 
 
Overall aim  
This study aims to generate patient-derived organoids (PDOs) from patients’ tumour samples and to 
collect preliminary data on the ability of PDOs to predict patients’ treatment response and whether 
their radiosensitivity and chemosensitivity can be correlated with their survival outcome. 
 
Patient’s cohorts 
We will have three cohorts of HNSCC patients undergoing standard of care treatments:  
1) Surgically resectable disease, followed by adjuvant radiotherapy +/- chemotherapy 
2) Primary radiotherapy +/- concurrent chemotherapy  
3) Recurrent or metastatic HNSCC undergoing platinum based chemotherapy +/- cetuximab 
 
Primary objective 
To assess the percentage of successful generated organoids from tissues in head and neck cancer 
patients 
Secondary and exploratory objectives 
Secondary objectives:  
1) To assess the sensitivity of radiotherapy, platinum (cisplatin and/or carboplatin) chemotherapy or 
cetuximab or their combination in PDOs  
2) To correlate the treatment sensitivities of PDOs above with the treatment outcome of patients 
undergoing primary surgery and adjuvant radiotherapy +/- concurrent platinum chemotherapy 
(cohort 1) 
3) To correlate the treatment sensitivities of PDOs above with the treatment outcome of patients 
undergoing primary radiotherapy +/- platinum chemotherapy (cohort 2) 
4) To correlate the sensitivities of platinum chemotherapy and/or cetuximab or immunotherapy of 
PDOs with the treatment outcome of recurrent or metastatic HNSCC patients (cohort 3) 
 
Exploratory objectives:  
1) To correlate the treatment sensitivities of PDOs with the detection rates of plasma ctDNA (all 
cohorts)  

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2) To assess and correlate the histopathological, genomic and transcriptomic features of patients’ 
samples with PDOs 
3) To assess the sensitivities of PDOs to various targeted therapies based on their genomic profiles 
4) Collection of archival tissues, blood samples (whole or processed for ctDNA and PBMC), saliva (for 
ctDNA), urine or stool samples for other translational research  
8 Study design & Flowchart 
8.1 Study Design 
This is a prospective observation study to generate patient-derived organoids from patients’ samples 
to assess treatment response and to correlate with patients’ treatment outcomes. We would first do 
a pilot study during year 1 to establish the pathways required and to assess the success rate in 
generating patient-derived organoids. During this time, we will also assess the willingness of patients 
to participate in the study, as well as that of clinicians to help recruitment. In addition, the time 
required to generate HNSCC organoids and to assess treatment response in order to correlate with 
patients’ outcome will be evaluated during year 1. 
Primary endpoint and outcome 
Primary endpoint 
The percentage of successful organoid samples generated from the tumour samples obtained 
 
Primary outcome 
The ability to generate organoid cultures successfully from tumour samples 
 
Secondary endpoint and outcomes 
Secondary endpoints 
1) To determine the IC50 doses and dose response curves of radiotherapy, cisplatin or carboplatin 
chemotherapy and their combination of PDOs  
2) To correlate the IC50 doses and dose response curves above with the recurrence rates and 
disease-free survival of patients  
3) To correlate IC50 doses and dose response curves above with the complete metabolic response 
(PET-CT) and residual disease or salvage neck dissection   
4) To correlate IC50 doses/dose response curves above with the objective response rates of patients 
undergoing same systemic treatment 
 
Secondary outcomes 
1) The ability of these treatment(s) to decrease tumour growth and kill the organoids ex-vivo 
(number and size of alive organoids after treatments) 
2) The ability of the PDOs to predict recurrences and survival outcome of these patients based on 
the radiosensitivity and chemosensitivity of the PDOs  
3) The ability of the organoids to predict complete metabolic response and treatment outcome of 
patients 
4) The ability of the organoids to predict response to the same systemic treatments that the patients 
are receiving systemic treatments 
 
Exploratory endpoints and outcomes  

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Exploratory endpoints 
1) To correlate the IC50 doses/dose response curves with plasma ctDNA before and after treatment 
2) Immunohistochemistry (IHC) staining, exome sequencing and RNA sequencing of PDOs and 
patients’ samples 
3) The IC50 doses of various targeted therapies based on actionable genetic mutations 
4) To conduct further translational research using the patients’ samples 
Exploratory outcomes 
1) The ability of the PDOs to predict minimal residual disease and persistent disease  
2) The ability of the PDOs to recapitulate the histopathological and genomic features of human 
samples 
3) The ability of the PDOs to predict responses to various targeted therapies based on genomic 
profiles 
4) The ability of the PDOs to facilitate high quality translational research that will help to predict 
treatment response and bring benefit to patients 
 
Table of endpoints/measures and outcomes 
Objectives  
Endpoints/Measures  
Outcomes  
PRIMARY 
1) Compliance and acceptability 
of tissue sampling for the 
generation of organoids in head 
and neck cancer patients 
2) Ability to generate organoids 
from patients’ tissues 
Percentage of approached 
participants who consent to 
taking part 
Percentage of individuals 
whose successful organoid 
samples are obtained 
Rates of participants who 
agree to have samples taken 
to generate PDOs  
Rates of successful organoid 
cultures 
SECONDARY 
1) To assess the sensitivity of 
radiotherapy, cisplatin 
chemotherapy or cetuximab or 
their combination in PDOs  
2) To correlate the treatment 
sensitivities of PDOs above with 
the treatment outcome of 
patients undergoing primary 
surgery and adjuvant 
radiotherapy +/- concurrent 
platinum chemotherapy (Cohort 
1) 
Determine IC50 doses and 
dose response curves of 
radiotherapy, cisplatin 
chemotherapy and their 
combination of PDOs  
To correlate the IC50 doses 
and dose response curves 
above with the recurrence 
rates and disease-free 
survival of patients  
Correlating IC50 doses and 
The ability of these 
treatment(s) to decrease 
tumour growth and kill the 
organoids ex-vivo measured 
by the number and size of 
alive organoids after 
treatments. 
The ability of the PDOs to 
predict recurrences and 
survival outcome of these 
patients based on the 
radiosensitivity and 
chemosensitivity of the PDOs  
The ability of the organoids to 

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3) To correlate the treatment 
sensitivities of PDOs above with 
the treatment outcome of 
patients undergoing primary 
radiotherapy +/- platinum 
chemotherapy (Cohort 2) 
4) To correlate the sensitivities of 
platinum chemotherapy and/or 
cetuximab or immunotherapy of 
PDOs with the treatment 
outcome of recurrent or 
metastatic HNSCC patients 
(Cohort 3) 
dose response curves above 
with the complete metabolic 
response (PET-CT) and 
residual disease or salvage 
neck dissection   
Correlating IC50 doses/dose 
response curves above with 
the objective response rates 
of patients undergoing same 
systemic treatment 
predict complete metabolic 
response and treatment 
outcome of patients  
The ability of the organoids to 
predict response to the same 
systemic treatments that the 
patients are receiving 
systemic treatments 
EXPLORATORY 
1) To correlate the treatment 
sensitivities of PDOs with the 
detection rates of plasma ctDNA 
(all cohorts)  
2) To assess and correlate the 
histopathological, genomic and 
transcriptomic features of 
patients’ samples with PDOs 
3) To assess the sensitivities of 
PDOs to various targeted 
therapies based on their genomic
profiles 
4) Collection of archival tissues, 
blood (whole or processed for 
ctDNA and PBMC) +/-  saliva (for 
ctDNA) as well as mouth 
swab/stool samples for other 
translational research  
To correlate the IC50 
doses/dose response curves 
with plasma ctDNA before and 
after treatment 
IHC staining, exome 
sequencing and RNA 
sequencing of PDOs and 
patients’ samples 
The IC50 doses of various 
targeted therapies based on 
actionable genetic mutations 
To conduct various 
translational research 
including TMB, PDL1 test, co-
culturing of PDOs with PBMC 
to assess immunotherapy 
response 
The ability of the PDOs to 
predict minimal residual 
disease and persistent disease 
The ability of the PDOs to 
recapitulate the histo-
pathological and genomic 
features of human samples 
The ability of the PDOs to 
predict responses to various 
targeted therapies based on 
genomic profiles 
The ability of the PDOs to 
facilitate high quality 
translational research that 
will help to predict treatment 
response and bring benefit to 
patients 
 

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8.2 Treatment visits 
This is an observation study and the patients will continue their clinical visits and follow-up for 5 
years as per normal standard of care.  We will obtain the treatment outcome from medical records 
of patients. 
 
9 Subject selection 
This will be a single centre study performed at King’s College London and Guy’s and St Thomas’ NHS 
foundation trust. 
We will have several cohorts of HNSCC patients undergoing standard of care treatments, which we 
plan to include: 
1) 10 patients with surgically resectable locally advanced disease, followed by adjuvant 
radiotherapy +/- chemotherapy 
2)  5 primary radiotherapy +/- concurrent chemotherapy  
3)  5 recurrent or metastatic HNSCC undergoing platinum based chemotherapy +/- cetuximab or 
immunotherapy. 
9.1 Subject inclusion criteria 
1) Patients with head and neck squamous cell carcinoma (including oral cavity, oropharynx, 
paranasal sinuses, hypopharynx or larynx) undergoing curative treatment (primary surgery or 
radiotherapy) or presenting with recurrent or metastatic cancers  
2)  Age  > 18 years old 
In addition, there are specific criteria for the three cohorts: 
• 
Cohort 1:  
Patients with surgically resectable locally advanced disease who will likely to undergo adjuvant 
radiotherapy +/- concurrent chemotherapy 
• 
Cohort 2: 
Patients suitable for primary radical radiotherapy +/- concurrent chemotherapy who agree to 
have additional research biopsy 
• 
Cohort 3: 
Patients with recurrent or metastatic disease who agree to have additional research biopsy 
9.2 Subject exclusion criteria  
1) Patients unable to give informed consent e.g. mental disability or vulnerable adults 
10 Study procedures 
10.1 Subject recruitment 
Method of recruitment 
The potential participants will be identified from MDT, surgical and oncology clinics and the initial 
approach to the potential participants will only be made by the direct care team members including 
those from surgical, oncology and radiology teams. HNSCC patients suspected to have primary or 

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recurrent HNSCC will be asked to consent to an additional research biopsy while undergoing an 
Examination Under Anaethesia (EUA) or biopsy or transoral robotic resection or biopsy as standard 
of care. This additional research biopsy will be used to generate PDOs in the lab. For those surgical 
resectable patients, we may ask for additional resected sample once adequate sample have been 
obtained for routine diagnostic purposes. For these patients, the resectable samples will be used to 
obtain more PDOs regardless of whether the biopsy samples were successful in generating PDOs. 
Moreover, for the surgical patients we will request specimens from the normal surrounding resected 
tissue to create normal tissue organoids to be used as the control. Once the PDOs are successfully 
generated in the lab, they will be tested for sensitivities to various treatments including 
radiotherapy, cisplatin/carboplatin and their combination for those organoids generated from 
HNSCC patients undergoing curative radical treatment and also platinum based chemotherapy +/- 
cetuximab or immunotherapy for those organoids generated from recurrent or metastatic HNSCC 
patients.  
 
When the PDOs contain sufficient cells, these cells will be treated with increasing doses of 
radiotherapy and/or cisplatin chemotherapy and/or cetuximab in order to determine the IC50 and to 
obtain dose-response curves of these organoids to the treatments. In particular, we will treat the 
PDOs with the same treatments that the HNSCC patients receive in order to correlate the responses 
to radiotherapy and/or platinum chemotherapy +/- cetuximab or immunotherapy (co-cultured with 
immune cells). Successfully generated tumour organoids will be stored in the lab and can be used for 
future research.  
 
The response of these HNSCC-PDOs will be compared to the actual tumour response to these 
treatments in these HNSCC patients: 
 
1) Cohort 1: surgically resectable locally advanced disease 
The tumours of these patients would have been surgically resected and so the responses of these 
organoids to radiotherapy and chemotherapy cannot be directly assessed. Most of these patients 
may then undergo adjuvant radiotherapy +/- concurrent chemotherapy. It is anticipated that the 
radiosensitivity and platinum chemosensitivity may correlate with the outcome of these patients. 
We will therefore assess whether those PDOs with lower IC50 would have longer disease-free 
survivals. If PDOs could be derived from both biopsy and resected samples from these patients, we 
will compare the differences in responses of these PDOs generated from either biopsy or resected 
samples. We will use the normal tissue organoids from the periphery of the surgical specimen to 
confirm that response to the treatments is tumour specific.  
 
2) Cohort 2: Primary radiotherapy +/- platinum chemotherapy 
We will culture HNSCC-PDOs and treat with irradiation and the same platinum chemotherapy drugs 
(cisplatin or carboplatin) as the corresponding patient. A few of these patients may undergo 
neoadjuvant chemotherapy before definitive chemoradiation. In this case, we will assess the 
responses and sensitivities of these organoids to the same chemotherapy drugs, usually docetaxel, 
cisplatin and 5FU (TPF). For patients undergoing primary radiotherapy with or without concurrent 
chemoradiation, PET-CT scan is done at 3 months after the completion of treatment to assess 
metabolic response. We will correlate the treatment sensitivity of PDOs as determined by the IC50 
and dose-response curves with the complete metabolic responses by PET-CT scan and the rates of 
residual disease as well as salvage neck dissection. 
 
3)Cohort 3: recurrent or metastatic HNSCC 
The first-line treatment for the recurrent or metastatic HNSCC patients had been platinum-based 
chemotherapy +/- 5FU chemotherapy with or without cetuximab (oral cavity SCC only). 

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Pembrolizumab monotherapy is now approved as a first-line treatment for HNSCC patients with 
PDL1 positive (Combine pathology score CPS  1) tumours in the UK. Patients with PDL1 negative 
tumours or those with rapidly progressing disease will continue to receive platinum based 
chemotherapy as first-line treatment. We will correlate the treatment sensitivities of PDOs to these 
drugs with the radiological responses from the HNSCC patients. In addition, we are currently running 
an EORTC study (AK is the UK chief PI) where HNSCC patients previously treated with platinum-based 
chemotherapy will be allocated to be treated with different targeted therapies or immunotherapy 
based on potential biomarkers and molecular alterations of their tumours (NCT03088059, 
UPSTREAM study). We will record whether the assessment of the genetic profiles of these PDOs may 
help to enrol these patients in the UPSTREAM study eventually. 
 
Payment  
The participants will not be paid for this study since patients will not be required to have additional 
visits other than their standard of care visits. 
 
Consent  
This observation study will be opened at Guy’s and St Thomas’ NHS foundation trust only. The 
Principal Investigator (PI) retains overall responsibility for the conduct of research at participating 
site(s) with delegation of duties to appropriate clinical sub-investigators (e.g. clinical fellow), which 
includes the taking of informed consent of participants at their site with the processes below:  
• 
Checking the inclusion and the exclusion criteria  
• 
A discussion with the potential participant about the research including the nature and 
objectives of this study and possible risks associated with their participation 
• 
Patient information leaflet and consent form will be given to patients, usually at least 24 
hours before consent although it can be on the same day for this observation study if 
required 
• 
Potential participants will be given the opportunity to ask questions 
• 
Assessment of the mental capacity for the participants to consent will be performed by 
either the PI or the appropriate clinical sub-investigators  
 
The principal investigator will ensure that any person delegated the responsibility to participate in 
the informed consent process is duly authorised, trained and competent to participate according to 
the ethically approved protocol, principles of Good Clinical Practice (GCP) and Declaration of 
Helsinki. 
 
Translational research: Participants will be asked to give generic consent for their samples, derived 
organoids and/or cell lines and linked data to be transferred and used in future research.  This 
includes the transfer and use of samples/data to KCL and its partners including the commercial 
sector and overseas organisations (including genetic research and whole genome sequencing). This 
will include the depositing of genetic and whole genome sequencing data in international 
repositories and participant-level data where it would not be possible to have data subsequently 
deleted. 
Based on this consent, archival tissue, blood, saliva, oral swab, urine and stool samples will be stored 
at Guy’s and St Thomas’ head and neck biobank beyond the ethics approval date of the project and 
stored under the custodial of Rhonda Hanley-Smith, biobank manager (HTA licence 12121; Licence 
Holder Cheryl Gillet). All material will be handled in accordance with the Human Tissue Act 2004 and 
other relevant legislation relating to the use of cell lines. Specific agreements will be put in place as 
required by the Sponsor including material transfer agreements where necessary.  

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Blood and other biological sample collection time points: We will ask patients to provide blood 
samples before (baseline) and at 3 months after the completion of their treatments. We may also 
request for up to additional 4 times during their treatment (e.g. at 3rd and 6th weeks of your 
radiotherapy) and follow-up (at 12 months after completion or at the event of recurrence), most 
likely at the same time that they are having blood tests as part of the standard procedures or 
occasionally as an additional procedure on each occasion, we will take up to 40ml of blood. We may 
also ask them to donate other samples such as saliva, oral swab, urine or faeces for future research 
at the same time points above. 
Withdrawal of consent: The right of a participant to refuse participation without giving reasons will 
be respected. The participant will remain free to withdraw at any time from the trial without giving 
reasons and without prejudicing his/her further treatment and will be provided with a contact point 
where he/she may obtain further information about the trial. Patients will be made aware of the 
terms and conditions around withdrawal. If a patient withdraws from the study, the research team 
can retain any tissue samples, DNA/RNA samples and organoids/cell lines that have been created up 
until the time of the patient’s withdrawal if the patient agrees. Any unused samples taken for 
research purpose can be destroyed if patients request to do so. Any demographic and medical 
information already provided or results from tests already performed on their samples will continue 
to be used in the study, however no further data or sample collection will be performed.  
10.2 Screening Procedures  
Potential eligible patients will be identified from surgical and/or oncology clinics and/or multi-
disciplinary meetings. These patients will be checked to see whether they will meet inclusion criteria. 
No extra screening investigations are needed for this study since this is an observation study. 
Patients will undergo routine standard of care investigations and treatments apart from consenting 
to this study and for their samples to be used for translational research during their routine standard 
of care procedures. 
10.3 Schedule of assessments for each visit  
Patients will undergo assessments as per normal standard of care and the schedule will not be 
changed due to this study. 
10.4 Follow up Procedures 
The follow-up procedures will be as per normal standard of care for 5 years and the schedule will not 
be changed due to this study. We will obtain relevant clinical information from the medical records. 
10.5 End of Study Definition  
The patient recruitment for the initial pilot study will be one year from the commencement of the 
study at Guy’s Hospital. We will assess whether the endpoints and outcomes are met at the end of 
the pilot study but the patients will be followed up for their long-term treatment outcome and 
survival as per normal standard of care. We will continue to obtain relevant information on patients’ 
treatment and survival outcome from patients’ medical records. The end of the study definition for 
the pilot study (year 1) is the end of 12 months’ period after the commencement of the study 
regardless of the number of patients recruited. We will submit the protocol for a major amendment 
towards the end of year 1 so that SOTO study will continue as a prospective observation study for up 
to additional 4 years of recruitment if further funding is obtained. If no further funding is obtained 

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by the end of year 1, we will end the patient recruitment and the study. We will analyse all data and 
produce the final study report at the end of second year. 
The criteria for progression beyond year 1 pilot study are set as below: 
1) More than 50% of the approached participants will consent to taking part in SOTO study  
2) At least 30% of the tissue samples will be successfully used to generate organoids 
3) Further funding is obtained to continue beyond year 1 
11 Laboratories  
The fresh tissue samples will be provided by the head and neck biobank at Guy’s Hospital to be 
processed for organoids within 72 hours at Dr. Kong’s laboratory at Kings College London and the blood 
samples will be processed according to standard laboratory SOP at Dr. Kong’s laboratory at Kings 
College London. Plasma and saliva samples will also be processed to assess ctDNA in the future. The 
additional biological samples including oral swab, urine or stool samples if obtained will be stored at 
Guy’s Hospital head and neck biobank under the custodial of Rhonda Hanley-Smith, biobank manager 
(HTA licence is 12121; the Licence Holder is Cheryl Gillet). Further details on the sample collection, 
processing, storage and analysis will be provided in the laboratory manual. 
11.1 Data Recording/Reporting  
All staff that would directly deal with the human tissues or blood will undertake HTA training.  
11.2 Sample Receipt/Chain of Custody/Accountability  
Handling of the samples upon arrival at the laboratory needs to be documented. Upon receipt of the 
samples, the laboratory should ensure that the physical integrity of these samples have not been 
compromised in transit. If it has, it is important that the study teams, as well as the sponsor, are 
informed of this. Upon receipt of samples laboratory staff should ensure that all samples are 
accounted as per the labeling. All samples received should be logged in an accountability log.  
11.3 Sample Transfer to sites outside the Organisation 
Individual informed consent will be obtained from the patients to specify whether they would agree 
for their samples to be transferred to collaborating third parties including overseas and commercial 
laboratories on behalf of KCL.  This may include but not be limited to validation of research results. 
The patient samples and derived organoids (with linked data) may be shared with collaborating 
laboratories, nationally or internationally, for the purposes of facilitating the research aims.  Specific 
agreements will be put in place as required by the Sponsor including material transfer agreements 
where necessary. Any commercialisation of the results of this study will be specified in contractual 
arrangements between parties where necessary and participants will be informed that they would 
not benefit financially. 
12  Assessment of Safety 
This is an observation study and the patients participated in this study will undergo routine 
treatments and the safety of the treatments will be assessed as per standard of care. 

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12.1  Ethics Reporting 
No serious adverse events are expected to occur following the tissue sampling involved in this study, 
as they will be done during standard care procedures. Participants will be followed-up by their 
treating clinicians as per normal practice.   
12.2 Ethics & Regulatory Approvals 
Study protocol and other documentation will be submitted to the North West - Greater 
Manchester South Research Ethics Committee for ethical approval.  
 
13 Compliance and withdrawal 
13.1 Subject compliance 
We will monitor the percentage of approached participants who consent to taking part in the study 
during the first year of recruitment. 
13.2 Withdrawal / dropout of subjects 
We will monitor the percentage of participants who withdraw consent from the study after taking 
part. Since the primary outcome is the rate of successful generated organoids and will not be 
affected by the dropouts of subjects, we will not need to recruit more participants to back fill those 
who may have withdrawn or dropped out once the fresh tissues are obtained from patients 
following consent. 
13.3 Protocol Compliance  
The patients will undergo routine treatments as per standard of care. We will monitor whether we 
will miss the blood samples from patients during specific time points. 
14 Data 
14.1 Data management 
As this is an observation study, we will collect data from patients that are already available in the 
hospital record on patients’ demographics, smoking and alcohol history, tumour characteristics 
including HPV status, proposed treatment plans. The patients’ treatment details, treatment 
responses, recurrences and survivals will also be obtained from clinical record. They will be recorded 
on paper Case Report Forms (CRFs). Participant files and paper CRFs will be identified using a 
Participant Identification Number. Personal information will not be stored on CRFs. Screening and 
enrolment logs will be maintained by the research team. For enrolled participants, identifiable 
patient data will be stored in an Excel file for the purposes of gathering follow-up data. This file will 
password protected and stored on the KCL secured network, whereby access is only granted by the 
PI to named individuals.  Paper CRFs, consent forms and the Trial Master File will be stored in locked 
filing cabinets within the Oral Clinical Research Unit (KCL, Guy’s Hospital, London, UK).  Data 
generated from laboratory processes related to the generation of PDOs and subsequent testing will 

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be kept in the research laboratory. These data will be identified with the PIN and no personal data 
will be used in the lab records.  
 
Data linkage 
If the participating patients have come from or will move to different health care providers, we will 
attempt to get either available archival tissues and/or data from the relevant health care providers 
after sending them the relevant patients’ consent forms. We may also go to the central national 
databases with a patient’s NHS number to get clinical data if necessary. 
15 Statistical considerations 
The first year of recruitment will serve as a pilot study for this observation study and no formal 
power calculation is performed for year 1. The number of patients chosen for each cohort is the 
expected number of patients that we anticipate to recruit within 12 months based on the number of 
HNSCC patients that we treat at Guy’s. We expect more than 50% of the approached participants 
will consent to taking part in SOTO study and at least 30% of the tissue samples will be successfully 
used to generate organoids. A successful pilot study in year 1 will be defined as one that meets the 
pre-defined expectation. The data from year 1 pilot study will be used to calculate the sample size 
required to extend the observation study beyond year 1, which will be submitted as a major 
amendment. 
16 Ethical considerations 
16.1 Research Ethics Committee (REC) review & reports 
Before the start of the trial, approval will be sought from an NHS REC for the trial protocol, informed 
consent forms, patient information sheet, and GP information letters.   
Any amendments to the protocol or study documents will be reviewed by the Sponsor, sent to the 
REC for review and approvals. No changes will be implemented until approval has been received 
from the REC and approved by the Trust R&D department, if required.   
All correspondence with the REC will be retained in the Trial Master File.  
An annual progress report (APR) will be submitted to the REC within 30 days of the anniversary date 
on which the favourable opinion was given, and annually until the trial is declared ended. The Chief 
Investigator’s will approve the annual report which will be submitted by the CI or delegate. 
The Chief Investigator will notify the REC of the end of the trial within 90 days of the end of the 
study. If the trial is ended prematurely, the Chief Investigator will notify the REC, including the 
reasons for the premature termination. 
Within one year after the end of the trial, the Chief Investigator will submit a final report with the 
results, including any publications/abstracts, to the REC. 
16.2 Peer review 
This study has been previously peer reviewed when an application for was submitted to the GSTT 
charity for the funding of this study. 

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16.3 Regulatory Compliance  
The trial will not commence until a Favourable REC opinion is obtained along with HRA approval and 
confirmation of capacity and capability from the GSTT R&D department. 
All amendments to the protocol and study documents will be reviewed by the Sponsor and 
submitted for REC approval. Subsequently, documents and approvals will be sent to the Trust R&D 
department for confirmation of implementation.  
17 Financing and Insurance 
The study is co-sponsored by King’s College London and Guys and St Thomas’ NHS Foundation Trust. 
The sponsors will, at all times, maintain adequate insurance in relation to the study. King’s College 
London through its’ own professional indemnity (Clinical Trials) & no fault compensation and the 
Trust having a duty of care to patients via NHS indemnity cover, in respect of any claims arising as a 
result of negligence by its employees, brought by or on behalf of a study participant. 
18 Reporting and dissemination 
The results of this trial will be submitted for publication in peer-reviewed journals. The manuscripts 
will be prepared by the chief investigator and co-investigators. The authorship will be determined by 
mutual agreement. A copy of the publication will be provided to the participants if interested and 
requested.  

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References 
 
1. Haddad RI and Shin DM. Recent advances in head and neck cancer. N Engl J Med 2008;359:1143–
1154.  
2. Fakhry C et al. Improved survival of patients with human papillomavirus-positive head and neck 
squamous cell carcinoma in a prospective clinical trial. J Natl Cancer Inst 2008;100:261-269 
3. Ang KK et al. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J 
Med. 2010;363(1):24-35. 
Bonner J et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N 
Engl J Med. 2006;354(6):567-78. 
4. Vermoken JB et al. Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl 
J Med. 2008;359(11):1116-27.  
5. Ferris RL et al. Nivolumab for Recurrent Squamous-Cell Carcinoma of the Head and Neck. N Engl J 
Med. 2016;375(19):1856-1867. 
6. Burtness B et al. Pembrolizumab alone or with chemotherapy versus cetuximab with 
chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-
048): a randomised, open-label, phase 3 study. Lancet. 2019 Oct 31. pii: S0140-6736(19)32591-7. 
7. Vlachogiannis G et al. Patient-derived organoids model treatment response of metastatic 
gastrointestinal cancers. Science. 2018;359(6378):920-926. 
8. Pauli C et al. Personalized In Vitro and In Vivo Cancer Models to Guide Precision Medicine. Cancer 
Discov. 2017 May;7(5):462-477. 
9. Driehuis E et al. Oral Mucosal Organoids as a Potential Platform for Personalized Cancer Therapy. 
Cancer Discov. 2019;9(7):852-871. 
10. Schütte M et al. Molecular dissection of colorectal cancer in pre-clinical models identifies 
biomarkers predicting sensitivity to EGFR inhibitors. Nat Commun. 2017;8:14262.