Clinical trial NCT04648033
Conditions: Locally Advanced Non-Small Cell Lung Cancer
Sponsor: University of Oxford
Start date: 2020-12-07; Completion date: 2023-10-02
Enrollment: 21 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
This is a phase I, open-label trial that will utilise a Time To Event Continual Reassessment Method (TiTE-CRM) to determine the maximum tolerated dose (MTD) of atovaquone in combination with concurrent CRT in NSCLC. Twenty evaluable participants will be recruited at three centres.

Detailed description:
Twice daily oral atovaquone will be added to standard concurrent chemoradiotherapy (CRT): 66 Gy in 33 fractions, once daily, 5 days a week (Monday-Friday), with cisplatin (80 mg/m2 IV on days 1 and 22 of CRT) and vinorelbine (15 mg/m2 IV on days 1, 8, 22 and 29 of CRT). Whilst awaiting CRT to start, patients will receive two weeks (+/- 7 days) of oral atovaquone to ensure steady state is reached (after seven days). Patients will be allocated one of four dose levels: 450 mg, 600 mg, 675 mg or 750 mg (all doses PO BD). Atovaquone dose will be assigned as per the TiTE-CRM statistical model. The first two trial participants will receive 450 mg BD. In the absence of unacceptable toxicity, subsequent patients will be assigned doses up to and including 750 mg BD.

Hypoxia biomarker data will be collected at baseline (start of atovaquone run-in) and following two weeks (+/- 7 days) of atovaquone treatment. Atovaquone will then be continued without break for the duration of CRT, with the CRT schedule remaining constant for all patients at both centres. Assessment for Dose Limiting Toxicities (DLTs) will be from the first scheduled dose of atovaquone until three months after completion of CRT. The CT scan performed at the three-month follow up visit will be reviewed to collect tumour response data.

Arms: arm 1: Atovaquone:

* Taken during an initial run in period (2 weeks +/- 7 days), then continued during standard of care chemoradiotherapy.
* One of 4 dose levels is allocated to each patient by a TiTE-CRM statistical model which takes into account all toxicity data to date.
* Dose levels - 450 mg, 600 mg, 675 mg or 750 mg (all doses PO BD).
* Last dose atovaquone taken on the last day of radiotherapy.
* Total duration of atovaquone treatment is 59 days (+/- 7 days), unless stopped earlier for toxicity or any other reason.

Chemotherapy:

* 2 x 21-day cycles.
* 80 mg/m2 cisplatin on day 1 and 22 of chemoradiotherapy.
* 15 mg/m2 vinorelbine on days 1,8, 22 and 29 of chemoradiotherapy.

Radiotherapy:

* 66 Gy in 33 fractions.
* Delivered once daily, 5 days a week (Monday-Friday) for 6.5 weeks. arm 2: Atovaquone:

* Taken during an initial run in period (2 weeks +/- 7 days), then continued during standard of care chemoradiotherapy.
* One of 4 dose levels is allocated to each patient by a TiTE-CRM statistical model which takes into account all toxicity data to date.
* Dose levels - 450 mg, 600 mg, 675 mg or 750 mg (all doses PO BD).
* Last dose atovaquone taken on the last day of radiotherapy.
* Total duration of atovaquone treatment is 59 days (+/- 7 days), unless stopped earlier for toxicity or any other reason.

Chemotherapy:

* 2 x 21-day cycles.
* 80 mg/m2 cisplatin on day 1 and 22 of chemoradiotherapy.
* 15 mg/m2 vinorelbine on days 1,8, 22 and 29 of chemoradiotherapy.

Radiotherapy:

* 66 Gy in 33 fractions.
* Delivered once daily, 5 days a week (Monday-Friday) for 6.5 weeks. arm 3: Atovaquone:

* Taken during an initial run in period (2 weeks +/- 7 days), then continued during standard of care chemoradiotherapy.
* One of 4 dose levels is allocated to each patient by a TiTE-CRM statistical model which takes into account all toxicity data to date.
* Dose levels - 450 mg, 600 mg, 675 mg or 750 mg (all doses PO BD).
* Last dose atovaquone taken on the last day of radiotherapy.
* Total duration of atovaquone treatment is 59 days (+/- 7 days), unless stopped earlier for toxicity or any other reason.

Chemotherapy:

* 2 x 21-day cycles.
* 80 mg/m2 cisplatin on day 1 and 22 of chemoradiotherapy.
* 15 mg/m2 vinorelbine on days 1,8, 22 and 29 of chemoradiotherapy.

Radiotherapy:

* 66 Gy in 33 fractions.
* Delivered once daily, 5 days a week (Monday-Friday) for 6.5 weeks. arm 4: Atovaquone:

* Taken during an initial run in period (2 weeks +/- 7 days), then continued during standard of care chemoradiotherapy.
* One of 4 dose levels is allocated to each patient by a TiTE-CRM statistical model which takes into account all toxicity data to date.
* Dose levels - 450 mg, 600 mg, 675 mg or 750 mg (all doses PO BD).
* Last dose atovaquone taken on the last day of radiotherapy.
* Total duration of atovaquone treatment is 59 days (+/- 7 days), unless stopped earlier for toxicity or any other reason.

Chemotherapy:

* 2 x 21-day cycles.
* 80 mg/m2 cisplatin on day 1 and 22 of chemoradiotherapy.
* 15 mg/m2 vinorelbine on days 1,8, 22 and 29 of chemoradiotherapy.

Radiotherapy:

* 66 Gy in 33 fractions.
* Delivered once daily, 5 days a week (Monday-Friday) for 6.5 weeks.
Interventions: intervention 1: Atovaquone Oral Suspension intervention 2: Standard of care chemotherapy intervention 3: Standard of care radiotherapy
Intervention descriptions: intervention 1: Atovaquone, cisplatin and vinorelbine are all considered Investigational Medicinal Products (IMPs) in this trial due to the investigation of these drugs in a novel combination. Patients will be allocated one of four doses of atovaquone: 450 mg, 600 mg, 675 mg or 750 mg (all doses PO BD). intervention 2: Atovaquone, cisplatin and vinorelbine are all considered Investigational Medicinal Products (IMPs) in this trial due to the investigation of these drugs in a novel combination. Patients will receive two 21-day cycles of cisplatin and vinorelbine chemotherapy, comprising 80 mg/m2 cisplatin on days 1 \& 22 of their CRT treatment and 15 mg/m2 vinorelbine on days 1, 8, 22 \& 29. intervention 3: Thoracic radiotherapy will commence on day one of chemotherapy and be delivered in 66 Gy in 33 fractions, once daily, 5 days a week (Monday-Friday) for 6.5 weeks.

Protocol documents:
Prot_000.pdf: 
Full title: 
A Phase I Trial of the Hypoxia Modifier Atovaquone in Combination with Radical 
Concurrent Chemoradiotherapy in Locally Advanced Non-Small Cell Lung Cancer
Short title:
ARCADIAN: Atovaquone with Radical ChemorADIotherapy in locally Advanced NSCLC
Protocol Version & date: 
V2.0, 23Mar2020
Protocol Number: 
OCTO_088 
EudraCT Number: 
2019-002097-30 
IRAS ID: 
266541 
Sponsor:  
University of Oxford   
Funder:  
Cancer Research UK (Clinical Research Committee, award 
reference C34326/A27515) 
Conflict of Interest statement 
None of the protocol authors have declared a potential 
conflict of interest  
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, HRA, and members of the Research Ethics 
Committee unless authorised to do so.   


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Key trial contacts 
Chief Investigator 
Professor Geoff Higgins 
Consultant Clinical Oncologist and Clinician Scientist 
CRUK/MRC Oxford Institute for Radiation Oncology 
University of Oxford, Old Road Campus Research Building 
Oxford, OX3 7DQ 
01865 617355    
geoffrey.higgins@oncology.ox.ac.uk
Co-Investigator 
Dr Sorcha Campbell (Consultant Clinical Oncologist) 
Edinburgh Cancer Research Centre, Western General Hospital, Edinburgh 
Sorcha.Campbell@nhslothian.scot.nhs.uk
Co-Investigator 
Dr Stefan Symeonides (Senior Clinical Lecturer in Medical Oncology) 
Edinburgh Cancer Research Centre, Western General Hospital, Edinburgh 
Stefan.Symeonides@ed.ac.uk
Co-Investigator 
Dr Daniel McGowan (Senior Clinical Lecturer) 
Department of Oncology, University of Oxford 
daniel.mcgowan@oncology.ox.ac.uk
Co-Investigator 
Professor Francesca Buffa (Associate Professor, Computational Biology and 
Integrative Genomics) 
Department of Oncology, University of Oxford 
francesca.buffa@oncology.ox.ac.uk
Co-Investigator 
Dr Dilip Patel (Consultant Radiologist) 
Edinburgh Cancer Research Centre, Western General Hospital, Edinburgh 
dilip.patel@nhslothian.scot.nhs.uk
Co-Investigator 
Dr Ruth Macpherson (Radiology Consultant) 
Churchill Hospital, Oxford University Hospitals NHS Foundation Trust 
ruth.macpherson@ouh.nhs.uk
Co-Investigator 
Professor Fergus Gleeson (Radiology Consultant) 
Churchill Hospital, Oxford University Hospitals NHS Foundation Trust 
fergus.gleeson@oncology.ox.ac.uk
Oxford Clinical Trial Office (OCTO) 
ARCADIAN Trial Office 
Oncology Clinical Trials Office (OCTO)
Department of Oncology, The University of Oxford 
Old Road Campus Research Building 
Oxford OX3 7DQ 
01865 617018 
octo-ARCADIAN@oncology.ox.ac.uk
www.oncology.ox.ac.uk/about-us/overview/clinical-trials/oncology-clinical-
trials-office
Sponsor 
Ms Heather House 
University of Oxford Clinical Trials and Research Governance Team 
1st Floor, Boundary Brook House 
Churchill Drive, Headington, Oxford, OX3 7GB 
ctrg@admin.ox.ac.uk
Statistician 
Dr Jane Holmes 
Medical Statistician 
Centre for Statistics in Medicine  


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Nuffield Department of Orthopaedics Rheumatology and Musculoskeletal 
Sciences, Oxford, OX3 7LD 
jane.holmes@csm.ox.ac.uk
Statistician 
Ms Cathy Qi 
Medical Statistician 
Centre for Statistics in Medicine  
Nuffield Department of Orthopaedics Rheumatology and Musculoskeletal 
Sciences, Oxford, OX3 7LD 
cathy.qi@csm.ox.ac.uk
Trial Management Group 
Professor Geoff Higgins (Chief Investigator)  
Professor Sarah Blagden (ECMC Lead and Director of EPCTU) 
Dr Daniel McGowan (Co-Investigator) 
Dr Jane Holmes (Medical Statistician) 
Cathy Qi (Medical Statistician) 
Dr Ruth Harman (Trial Manager)
Trial oversight is provided by the Radiotherapy and Imaging Oversight Committee (RIOC) 
 RIOC Chairman
Professor Peter Hoskin 
Medical Monitor 
During office hours: Clinical Queries should be directed to the ARCADIAN Trial Office (details as above) for action. 
Out of office hours: call the Oxford University Hospitals switchboard on Tel: 0300 304 7777 and ask to call the 
ARCADIAN clinical trial emergency contact. 
Patient Registration: To register a patient on the trial please email the completed and scanned registration form to 
the ARCADIAN Trial Office: octo-ARCADIAN@oncology.ox.ac.uk.
Protocol Authors and conflict of interest statement 
Geoff Higgins*1
Michael Skwarski*2
Daniel McGowan*1
Helen Flight*1
Ruth Harman*1
Jane Holmes*3
Cathy Qi*3 
* The authors declare that there are no relationships/conditions/circumstances that present an actual or potential conflict of 
interest 
1 University of Oxford, Department of Oncology 
2 Oxford University Hospitals NHS Foundation Trust 
3 University of Oxford, Centre for Statistics in Medicine, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal 
Sciences (NDORMS) 


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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS ................................................................................................................................................. 7
SUMMARY SCHEDULE OF EVENTS .................................................................................................................................. 8
STUDY SCHEMA ............................................................................................................................................................ 10
ABBREVIATIONS ....................................................................................................................................................... 11
1
INTRODUCTION ..................................................................................................................................... 14
1.1
BACKGROUND .................................................................................................................................................... 14
1.2
INVESTIGATIONAL MEDICINAL PRODUCTS USED IN THE STUDY...................................................................................... 14
1.3
OTHER RESEARCH INTERVENTIONS .......................................................................................................................... 15
1.4
RATIONALE FOR THE STUDY ................................................................................................................................... 16
2
TRIAL DESIGN ......................................................................................................................................... 17
2.1
DURATION OF PATIENT PARTICIPATION .................................................................................................................... 18
2.2
POST-TRIAL CARE AND FOLLOW-UP......................................................................................................................... 18
3
OBJECTIVES AND ENDPOINTS ................................................................................................................ 18
4
PATIENT SELECTION ............................................................................................................................... 19
4.1
ELIGIBILITY CRITERIA FOR ENTRY INTO THE STUDY ....................................................................................................... 19
4.2
EXCLUSION CRITERIA: .......................................................................................................................................... 19
4.3
PROTOCOL DEVIATIONS AND WAIVERS TO ENTRY CRITERIA........................................................................................... 20
4.4
RE-SCREENING IF PATIENT DOES NOT MEET INCLUSION/EXCLUSION CRITERIA FIRST TIME ROUND ......................................... 20
4.5
PATIENT REGISTRATION PROCEDURE ....................................................................................................................... 20
5
TRIAL ASSESSMENTS AND PROCEDURES ................................................................................................ 21
5.1
DETAILED GUIDANCE FOR TRIAL ASSESSMENTS AND PROCEDURES ................................................................................. 21
5.1.1
INFORMED CONSENT ........................................................................................................................................... 21
5.1.2
CONTRACEPTIVE/PREGNANCY COUNSELLING ............................................................................................................ 21
5.1.3
MEDICAL HISTORY AND CONCOMITANT MEDICATIONS ................................................................................................ 21
5.2
PRE-DOSING EVALUATIONS (SCREENING AND BASELINE ............................................................................................... 22
5.3
EVALUATIONS DURING THE STUDY .......................................................................................................................... 23
5.4
END OF STUDY EVALUATIONS FOLLOWING COMPLETION OF CHEMORADIOTHERAPY TREATMENT ......................................... 24
6
EARLY PATIENT WITHDRAWAL .............................................................................................................. 24
6.1
PATIENT EVALUABILITY AND REPLACEMENT .............................................................................................................. 25
7
SAMPLES FOR LABORATORY ANALYSIS .................................................................................................. 25
7.1
SAMPLES TO BE ANALYSED IN LOCAL TRUST’S LABORATORIES ....................................................................................... 25
7.2
SAMPLES TO BE SENT TO AND ANALYSED IN A CENTRAL LABORATORY ............................................................................ 25
7.2.1
PHARMACOKINETIC ASSAYS ................................................................................................................................... 25
7.2.2
PLASMA HYPOXIA MARKER (MIR-210).................................................................................................................... 25
7.2.3
HYPOXIA METAGENE EXPRESSION ........................................................................................................................... 26
7.2.4
SUMMARY OF SAMPLES/ASSAYS TO BE TAKEN DURING THE STUDY ................................................................................ 26
7.3
LABELLING AND CONFIDENTIALITY OF SAMPLES SENT .................................................................................................. 26
7.4
CLINICAL REPORTING OF EXPLORATORY RESEARCH ASSAY RESULTS................................................................................. 26
7.5
TRIAL SAMPLE RETENTION AT END OF STUDY ............................................................................................................. 26
7.6
WITHDRAWAL OF CONSENT FOR SAMPLE COLLECTION AND/OR RETENTION .................................................................... 27
7.7
CORRELATIVE HYPOXIA BIOMARKER STUDIES ............................................................................................................. 27
8
INVESTIGATIONAL MEDICINAL PRODUCT (IMP) ..................................................................................... 27
8.1
TREATMENT DOSE ............................................................................................................................................... 27
8.2
DURATION OF TREATMENT ................................................................................................................................... 27
8.3
MANAGEMENT OF DRUG ADMINISTRATION .............................................................................................................. 28
8.4
SPECIAL PRECAUTIONS ......................................................................................................................................... 29
8.5
ACTUAL VERSUS IDEAL BODY WEIGHT ...................................................................................................................... 29
8.6
DOSE MODIFICATION ........................................................................................................................................... 29
8.7
CALCULATING AND RECALCULATING BSA/DOSES ....................................................................................................... 30
8.8
DOSE CAPPING AND DOSE BANDING ........................................................................................................................ 30
8.9
COMPLIANCE ..................................................................................................................................................... 30
8.10
MANAGEMENT OF OVERDOSE ............................................................................................................................... 31


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DOSE LIMITING TOXICITY ....................................................................................................................... 31
9.1
DEFINITION OF A DOSE LIMITING TOXICITY .............................................................................................................. 31
10
OTHER TREATMENTS (NON-IMPS) ......................................................................................................... 32
10.1
SUPPORT MEDICATION ......................................................................................................................................... 32
10.2
CONCOMITANT MEDICATION AND NON-DRUG THERAPIES ........................................................................................... 32
10.3
PROHIBITED THERAPIES AND (POTENTIAL) DRUG INTERACTIONS .................................................................................... 32
11
DRUG MANAGEMENT ............................................................................................................................ 33
11.1
DRUG SUPPLIES .................................................................................................................................................. 33
11.2
DRUG ORDERING AND RECEIPT .............................................................................................................................. 34
11.3
HANDLING AND STORAGE ..................................................................................................................................... 34
11.4
LABELLING ......................................................................................................................................................... 34
11.5
DOSING DISPENSING ............................................................................................................................................ 34
11.6
DRUG ACCOUNTABILITY........................................................................................................................................ 34
11.7
DRUG RETURNS FROM PATIENTS ............................................................................................................................ 34
11.8
DRUG DESTRUCTION ............................................................................................................................................ 34
11.9
OCCUPATIONAL SAFETY ........................................................................................................................................ 35
12
RADIOTHERAPY ..................................................................................................................................... 35
12.1
SIMULATION ...................................................................................................................................................... 35
12.2
PLANNING ......................................................................................................................................................... 35
12.3
TREATMENT DELIVERY .......................................................................................................................................... 35
12.4
MANAGEMENT OF UNSCHEDULED GAPS .................................................................................................................. 35
12.5
CHEMORADIOTHERAPY TOXICITY ............................................................................................................................ 36
12.6
RADIOTHERAPY QUALITY ASSURANCE ...................................................................................................................... 36
13
EVALUATION OF RESPONSE ................................................................................................................... 37
13.1
MEASUREMENT OF DISEASE FOR SOLID TUMOUR ....................................................................................................... 37
13.2
TUMOUR ASSESSMENT ......................................................................................................................................... 37
13.3
TUMOUR RESPONSE ............................................................................................................................................ 37
13.4
OTHER DEFINITIONS OF OUTCOME.......................................................................................................................... 38
14
SAFETY REPORTING ............................................................................................................................... 38
14.1
ADVERSE EVENT DEFINITIONS ............................................................................................................................... 38
14.2
CLINICAL LABORATORY ABNORMALITIES AND OTHER ABNORMAL ASSESSMENTS AS AES AND SAES ...................................... 39
14.3
DETERMINING ADVERSE EVENT CAUSALITY ............................................................................................................... 39
14.4
REFERENCE SAFETY INFORMATION (RSI) FOR ASSESSMENT OF EXPECTEDNESS ................................................................. 40
14.5
SUSPECTED UNEXPECTED SERIOUS ADVERSE DRUG REACTIONS (SUSARS) .................................................................... 40
14.6
EXPEDITED REPORTING OF SAES ............................................................................................................................ 41
14.7
FOLLOW-UP OF SERIOUS ADVERSE EVENTS .............................................................................................................. 41
14.8
REPORTING ADVERSE EVENTS ON THE CRF .............................................................................................................. 41
14.9
EVENTS EXEMPT FROM BEING REPORTED AS AE/ SAES............................................................................................... 41
14.10
INFORMING INVESTIGATORS OF NEW SAFETY INFORMATION ........................................................................................ 42
14.11
SUMMARY OF TRIAL SAFETY REPORTING REQUIREMENTS ............................................................................................. 42
15
PREGNANCY ........................................................................................................................................... 44
16
DEFINING THE END OF TRIAL ................................................................................................................. 44
17
STATISTICAL CONSIDERATIONS .............................................................................................................. 44
17.1
STUDY DESIGN .................................................................................................................................................... 44
17.2
THE TITE-CRM MODEL ....................................................................................................................................... 45
17.3
DOSE SELECTION DURING THE TRIAL ........................................................................................................................ 45
17.4
SAMPLE SIZE ...................................................................................................................................................... 45
17.5
MTD AND RPTD DEFINITION ................................................................................................................................ 46
17.6
STOPPING THE TRIAL ............................................................................................................................................ 46
18
STATISTICAL ANALYSIS PLAN.................................................................................................................. 46
18.1
INCLUSION IN ANALYSIS ........................................................................................................................................ 46
18.2
SUBGROUP ANALYSIS ........................................................................................................................................... 46
18.3
INTERIM ANALYSES ............................................................................................................................................. 46
18.4
PROCEDURES FOR REPORTING ANY DEVIATION(S) FROM THE ORIGINAL STATISTICAL PLAN .................................................. 46
18.5
FINAL ANALYSIS .................................................................................................................................................. 46


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TRIAL COMMITTEES ............................................................................................................................... 46
19.1
TRIAL MANAGEMENT GROUP (TMG) .................................................................................................................... 46
19.2
DATA AND SAFETY MONITORING ........................................................................................................................... 47
19.3
TRIAL STEERING COMMITTEE ................................................................................................................................ 47
20
DATA MANAGEMENT ............................................................................................................................ 47
20.1
DATABASE CONSIDERATIONS ................................................................................................................................. 47
20.2
CASE REPORT FORMS (CRFS) ................................................................................................................................ 47
20.3
IMPORTANCE OF RAPID DATA RETURN ..................................................................................................................... 48
20.4
ACCOUNTING FOR MISSING, UNUSED, OR SPURIOUS DATA. .......................................................................................... 48
21
CLINICAL STUDY REPORT ....................................................................................................................... 48
22
STUDY SITE MANAGEMENT ................................................................................................................... 48
22.1
STUDY SITE RESPONSIBILITIES ................................................................................................................................ 48
22.2
STUDY SITE SET UP AND ACTIVATION ....................................................................................................................... 48
22.3
STUDY DOCUMENTATION ..................................................................................................................................... 48
23
REGULATORY AND ETHICAL CONSIDERATIONS ...................................................................................... 48
23.1
ETHICS, HRA AND REGULATORY APPROVALS ............................................................................................................ 48
23.2
NHS RESEARCH GOVERNANCE .............................................................................................................................. 49
23.3
PROTOCOL AMENDMENTS .................................................................................................................................... 49
23.4
URGENT SAFETY MEASURES .................................................................................................................................. 49
23.5
TEMPORARY HALT ............................................................................................................................................... 49
23.6
SERIOUS BREACHES ............................................................................................................................................. 50
23.7
TRIAL REPORTS .................................................................................................................................................. 50
23.8
TRANSPARENCY IN RESEARCH ................................................................................................................................ 50
24
EXPENSES AND BENEFITS ....................................................................................................................... 50
25
QUALITY ASSURANCE ............................................................................................................................ 50
25.1
RISK ASSESSMENT ............................................................................................................................................... 50
25.2
MONITORING .................................................................................................................................................... 50
25.3
AUDIT AND REGULATORY INSPECTION ..................................................................................................................... 51
26
RECORDS RETENTION & ARCHIVING ...................................................................................................... 51
27
PATIENT CONFIDENTIALITY .................................................................................................................... 51
28
STUDY FUNDING .................................................................................................................................... 52
29
SPONSORSHIP AND INDEMNITY ............................................................................................................ 52
29.1
SPONSORSHIP .................................................................................................................................................... 52
29.2
INDEMNITY ........................................................................................................................................................ 52
29.3
CONTRACTS/AGREEMENTS ................................................................................................................................... 52
30
PUBLICATION POLICY ............................................................................................................................. 52
31
REFERENCES ........................................................................................................................................... 52
APPENDIX 1: ECOG PERFORMANCE SCALE ................................................................................................................ 54
APPENDIX 2: MEASUREMENT OF DISEASE - RECIST CRITERIA ................................................................................... 56
APPENDIX 3: AMENDMENT HISTORY ........................................................................................................................ 59


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PROTOCOL SYNOPSIS 
Full Title of study: 
A Phase I Trial of the Hypoxia Modifier Atovaquone in Combination with Radical 
Concurrent Chemoradiotherapy in Locally Advanced Non-Small Cell Lung Cancer 
Short Title: 
Atovaquone with Radical ChemorADIotherapy in locally Advanced NSCLC 
Trial Acronym: 
ARCADIAN 
Clinical Phase: 
Phase I 
Study Design: 
Single arm, open-label trial utilising Time To Event Continual Reassessment Method 
(TiTE-CRM) 
Objectives 
Endpoints 
Primary Endpoint: 
To determine the maximum tolerated 
dose (MTD), and therefore recommended 
phase II dose (RPTD), of atovaquone when 
combined with radical concurrent 
chemoradiotherapy in patients with non-
small cell lung cancer (NSCLC) 
The dose of atovaquone associated with no 
more than 48% dose limiting toxicity (DLT) 
rate (target toxicity level) 
Secondary Endpoints: 
To assess the safety and toxicity profile of 
atovaquone in combination with radical 
concurrent chemotherapy for NSCLC 
Adverse events graded per Common 
Terminology Criteria for Adverse Events 
(CTCAE) v4.03 
To confirm feasibility of measuring 
hypoxia metagene signature using 3’RNA-
Seq in diagnostic NSCLC samples 
Hypoxia metagene signature from 
diagnostic tissue using 3’RNA-Seq  
To assess agreement of FMISO PET-CT 
with plasma miR-210 level and tumour 
hypoxia gene expression pre-treatment 
with atovaquone 

Tumour hypoxic volume determined by 
FMISO PET-CT  

Plasma miR-210 level

Hypoxia metagene signature from 
diagnostic tissue using 3’RNA-Seq 
To assess agreement in changes in FMISO 
PET-CT and plasma miR-210 level 
following two weeks (+/- 7 days) of 
atovaquone  

Tumour hypoxic volume determined by 
FMISO PET-CT  

Plasma miR-210 level
To assess the tumour response rate at 
three months (13-15 weeks) following 
treatment 
Response to treatment assessed per 
Response Evaluation Criteria in Solid 
Tumours (RECIST) V1.1  
Exploratory Endpoint: 
To assess the relationship between 
plasma atovaquone levels and hypoxia 
response as measured by FMISO PET-CT 
and plasma miR-210 level 

Plasma atovaquone concentration  

Tumour hypoxic volume determined by 
FMISO PET-CT  

Plasma miR-210 level
Planned enrolment: 
20 evaluable participants 
Target Population: 
Patients with locally advanced Non-Small Cell Lung Cancer planned to be treated with 
concurrent chemoradiotherapy 
Investigational 
Medicinal Products 
Name of drug 
Formulation, dose, route of administration 
Atovaquone 
Suspension, oral, twice daily, dose to be 
allocated per TiTE-CRM: 450 mg, 600 mg, 
675 mg or 750 mg (all doses PO BD) 
Cisplatin 
80 mg/m2 IV on days 1 & 22 
Vinorelbine 
15 mg/m2 IV on days 1, 8, 22 & 29 
Other interventions: 
Thoracic radiotherapy: 66 Gy in 33 fractions, once daily, 5 days a week (Monday-Friday) 
Study duration: 
31 months (start of recruitment to close out) 
Treatment Duration 
Up to 9.5 weeks of atovaquone treatment, with concurrent chemoradiotherapy for 6.5 
of these weeks 
Follow-up duration 
Six months (26-28 weeks) post completion of chemoradiotherapy 
End of study 
Last Patient Last Visit 


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SUMMARY SCHEDULE OF EVENTS 
ATOVAQUONE RUN IN
CHEMORADIOTHERAPY 
FOLLOW UP 
                                                        Timing 
Procedure 
Screeninga
Week -2/-3
Week -1b
Week 1 
Week 2 
Week 3 
Week 4 
Week 5 
Week 6 
Week 7c
Week 10-13 
1 month (3-6 wks) 
post-CRT
Week 20-22 
3 months (13-15 wks) 
post-CRT 
Week 33-35 
6 months (26-28 wks) 
post-CRT
Day -21 to -8
Day -7 to -1
Day 1 to 7
Day 8 to 14
Day 15 to 21
Day 22 to 28
Day 29 to 35
Day 36 to 42
Day 43 to 49
Day 64 to 91
Day 134-154
Day 231-245 
Informed consent 
X 
Vital signs 
X 
Xd
X 
X 
X 
X 
X 
X 
X 
Height 
X 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
Physical exam 
X 
Xd
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG performance status 
X 
Xd
X 
X 
X 
X 
X 
X 
X 
X 
X 
Haematology & biochemistrye
X 
Xd
X 
X 
X 
X 
X 
X 
X 
Pregnancy test (WOCBP only) 
X 
X 
X 
X 
Medical history 
X 
Pulmonary function tests (FEV1 and TLCO) 
Xf
CT or PET-CT scang
Xh
Xi
Atovaquone dispensing 
X 
New bottle to be dispensed as required, each contains up to 21 days treatment 
Atovaquone treatment completionj
XXXXXXX 
XXXXXXX 
XXXXXXX
XXXXXXX 
XXXXXXX
XXXXXXX 
XXXXXXX
XXXXXXX 
XXXXXXX
XXXXXXX 
XXXXXXX
XXXXXXX 
XXXXXXX
XXXXXXX 
XXXXXXX
XXXXXXX 
XXX 
XXX 
Radiotherapy  
CT simulation and RT planning 
XXXXX 
XXXXX 
XXXXX 
XXXXX 
XXXXX 
XXXXX 
XXX 
Cisplatink
X 
X 
Vinorelbinel
X 
X 
X 
X 
Request diagnostic tissue for hypoxia 
metagene  
X 
PK blood sample 
X 
X 
Research blood samplefor hypoxia 
biomarkersm
X 
X 
FMISO PET-CT  
X 
X 
Atovaquone dosing compliance review 
X 
X 
X 
X 
X 
X 
X 
X 
AE assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
DLT assessment 
Xn
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Commencement of other cancer therapies0
X 
a  Eligibility tests and patient registration should be completed within two weeks of receiving a screening number (see section 4.5) 
b  The end of atovaquone run in appointment (including FMISO PET-CT scan) should be carried out as close to day 1 of CRT as possible (ideally Friday of week -1 with CRT commencing Monday of week 1, but within 
a maximum of one week prior to commencing CRT) 
c  The week 7 visit should ideally be held on the last day of RT  
d  Week -2/-3 assessments need not be repeated if screening tests have been carried out within 2 weeks of atovaquone dispensing visit 
e  Haematology & biochemistry (Haematology - haemoglobin, white blood cells with differential neutrophils and lymphocyte count and platelets; Biochemistry - sodium, potassium, calcium, phosphate, urea, 
creatinine, total protein, albumin, bilirubin, alkaline phosphatase, aspartate aminotransferase and/or alanine aminotransferase and lactate dehydrogenase; International Normalised Ratio). Tests will be carried 
out locally in site labs  


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f  Previously completed standard of care FEV1 & TLCO need not be repeated, provided this is within 90 days of informed consent date 
g  CT or PET-CT of brain/chest/abdomen or chest/abdomen/pelvis, as per local standard of care 
h  Previously completed standard of care PET-CT or CT scans need not be repeated provided this is within 60 days of informed consent date 
i  Patients prescribed Durvalumab may have their follow-up CT scan up to 17 weeks post-CRT (i.e. up to week 24) 
j   Atovaquone taken orally, twice daily, at dose selected per process defined in section 17.3 
k  Cisplatin (80 mg/m2 IV) administered on D1 & 22 
l  Vinorelbine (15 mg/m2 IV) administered on D1, 8, 22 & 29 
m miR-210 
n This visit falls within the DLT reporting period. However, DLTs will be retrospectively reported from the week -1 visit 
o E.g. Durvalumab, if clinically indicated 


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STUDY SCHEMA 


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ABBREVIATIONS 
FMISO   
18F-fluoromisonidazole 
3'RNA-seq 
3' RNA-sequencing 
ADR 
Adverse drug reaction 
AE 
Adverse Event 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
AP/PA 
Anterior posterior/posterior anterior 
AST 
Aspartate aminotransferase 
ATOM 
Atovaquone as Tumour HypOxia Modifier 
BD 
Twice daily 
BP 
Blood pressure  
BSA 
Body surface area 
C 
Celsius 
CAIX 
Carbonic Anhydrase IX (9) 
CBCT 
Cone Beam Computed Tomography 
cm 
Centimetre 
CR 
Complete response 
CRF 
Case Report Form 
CRT 
Chemoradiotherapy 
CT 
Computed Tomography 
CTA 
Clinical Trials Authorisation 
CTA 
Clinical Trials Agreement 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTV 
Clinical target volume 
DAHANCA 
Danish Head and Neck Cancer Group  
DLT 
Dose limiting toxicity 
Dmax
Maximum dose  
DRR 
Digitally reconstructed radiograph  
EBUS 
Endobronchial ultrasound 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
ELISA 
Enzyme-linked immunosorbent assay 
EU 
European Union 
FEV1 
Forced expiration volume 
FFPE 
Formalin-fixed paraffin-embedded  
g 
Gramme 
GCP 
Good Clinical Practice 
GDPR 
General Data Protection Regulation 
GP 
General practitioner  
GSK 
GlaxoSmithKline 
GTV 
Gross tumour volume  
Gy 
Gray (radiation dose unit) 
Hb 
Haemoglobin  
HCG 
Human chorionic gonadotropin 
HIV 
Human immunodeficiency virus 
HPLC 
High Performance Liquid Chromatography 
HRA 
Health Research Authority  
HTA 
Human Tissue Act 
HV 
Hypoxic volume 
IB 
Investigator brochure 
ICRU 
International Commission on Radiation Units and Measurements 
IGRT 
Image-guided radiation therapy 
IMP 
Investigational Medicinal Product 
IMRT 
Intensity modulated radiotherapy 
INR 
International normalised ratio (blood clotting test) 


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ISF 
Investigator site file 
ITV 
Internal target volume 
IUD 
Intrauterine device 
IV 
Intravenous 
kV-CBCT 
Kilo-voltage cone beam computed tomography 
L 
Litre 
LDH 
Lactate dehydrogenase 
LPLV 
Last visit of the last patient undergoing the trial 
m 
Metre 
MBq 
Megabecquerel (unit of radioactivity) 
mg 
Milligrammes 
MHRA 
Medicines and Healthcare Products Regulatory Authority 
miR-210 
A MicroRNA with altered expression in tumour tissue 
mL 
Millilitre 
MLC 
Multileaf collimator  
mm 
Millimetre 
MRC 
Medical Research Council  
MRI 
Magnetic Resonance Imaging 
MTD 
Maximum tolerated dose 
MV 
Megavoltage 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NE 
Not evaluated 
NHS 
National Health Service 
NIHR 
National Institute of Health Research  
nIMP 
Non-Investigational Medicinal Product 
NSCLC 
Non-small cell lung cancer 
OAR 
Organs at risk 
OCR 
Oxygen consumption rate 
OCTO 
Oncology Clinical Trials Office 
OCTRU 
Oxford Clinical Trials Research Unit 
OPD 
Outpatient Department 
PCP 
Pneumocystis pneumonia 
PD 
Pharmacodynamics 
PD 
Progressive disease 
PDPP 
Protocol decision point plan  
PET 
Positron Emission Tomography 
pg 
Picogrammes 
PI 
Principal Investigator 
PK 
Pharmacokinetics 
PO 
Administered orally 
PPI 
Proton pump inhibitor 
PR 
Partial response 
PRV 
Positioning reference volume  
PTV 
Planning target volume 
QA 
Quality assurance 
qRT-PCR 
Quantitative reverse transcription polymerase chain reaction  
R&D 
Research and development  
RA 
RapidArc 
REC 
Research Ethics Committee 
RECIST 
Response evaluation criteria in solid tumours  
RIOC 
Radiotherapy & Imaging Oversight Committee 
RPTD 
Recommended Phase Two Dose 
RSI 
Reference Safety Information 
RT 
Radiotherapy 
RT/LT 
Right/left 
RTOG 
Radiation Therapy Oncology Group 
RTP 
Radiation treatment planning 
RTTQA 
Radiotherapy trials quality assurance 


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SAE 
Serious Adverse Event 
SAR 
Serious Adverse Reaction 
SD 
Stable disease 
SDV 
Source data verification 
SmPC 
Summary of Product Characteristics 
SOC 
Standard of care 
SOP 
Standard operating procedure 
SUP/INF 
Superior/inferior  
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
SUV 
Standardised uptake value 
TBR 
Tumour to blood ratio 
TD5/5 
Tolerance dose yielding 5% risk of a particular outcome at 5 years 
TDS 
Three times daily 
TiTE-CRM 
Time To Event Continual Reassessment Method  
TLCO 
Transfer factor of the lung for carbon monoxide 
TMG 
Trial Management Group 
µmol 
Micromoles 
Vx
Lung volume receiving ≥X Gy of radiation 
VEGF 
Vascular Endothelial Growth Factor 
VMAT 
Volumetric modulated arc therapy 
WBC 
White blood cell(s) 
WOCBP 
Women of child bearing potential  


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1
INTRODUCTION 
1.1
Background  
Patient population 
Lung cancer is the leading cause of cancer death in the UK with non-small cell lung cancer (NSCLC) accounting for 
approximately 85% of cases [1]. A third of patients with NSCLC present with locally advanced (stage III) non-metastatic 
disease and treatment with concurrent chemoradiotherapy has become the standard of care for patients with good 
performance status. However, despite significant improvements in technical radiotherapy delivery, clinical outcomes 
for patients treated with 'curative intent' remain extremely poor with survival rates at five years largely unchanged at 
only 15% [2]. Suboptimal locoregional control contributes to these poor outcomes and therefore developing novel 
radiosensitisers for this purpose represents a significant unmet clinical need for this patient population. 
Tumour hypoxia and radiotherapy 
Many solid tumours, including NSCLC, are typically dependent upon an abnormal, poorly functioning vasculature for 
oxygen delivery [3]. Coupled with the high metabolic requirements of many tumours, this leads to an imbalance in 
oxygen supply and demand. The resulting hypoxic microenvironment is recognised as promoting an aggressive 
phenotype, including resistance to drug treatment, and increased metastatic potential [4]. Although tumour hypoxia is 
associated with adverse patient outcomes regardless of which treatment modality is used, the profound radiation 
resistance caused by tumour hypoxia leads to particularly poor outcomes for patients treated with radiotherapy or CRT 
[5]. There is therefore significant interest in developing effective hypoxia modifying therapies which can be safely 
combined with radiotherapy. 
Previous hypoxia modifying strategies aimed at overcoming hypoxia-induced radioresistance have primarily focused on 
improving the oxygen supply to tumours. These have unfortunately yielded only limited success and none are currently 
in widespread routine clinical use. The reasons for this are multifactorial and include poor trial design, absence of 
predictive therapeutic biomarkers and the use of sub-optimal hypoxia modifying agents [6]. In particular, the 
importance of appropriately selecting patients who will benefit from hypoxia targeted therapy has become well-
recognised. For example, it has been demonstrated retrospectively that the addition of nimorazole, an oxygen mimetic, 
to radiotherapy treatment in patients with head and neck cancer (DAHANCA 5) would have resulted in significantly 
greater clinical benefits (locoregional control and disease specific survival) if a hypoxia gene expression classifier had 
been used to select patients with hypoxic tumours [7]. In a separate study in this tumour site, patients with tumours 
classified as hypoxic using 18F-fluoromisonidazole (FMISO) PET-CT imaging had greater benefit from the addition of the 
hypoxia-activated cytotoxic agent tirapazamine when combined with chemoradiotherapy [8].  
Therefore, a paradigm shift in the approach to addressing tumour hypoxia in clinical studies is required to prevent 
further futile trials in this field, with the focus not only on developing deliverable and more efficacious agents, but also 
on using hypoxia biomarkers to enable appropriate patient selection for treatment.  
This study will be the first trial to combine atovaquone, a promising novel hypoxia modifier with radiation and aims to 
assess safety whilst developing candidate hypoxia biomarkers to further confirm efficacy and guide future hypoxia trial 
design. 
1.2
Investigational Medicinal Products used in the study  
Atovaquone 
Atovaquone has EU marketing authorisation and is indicated for acute treatment of mild to moderate Pneumocystis 
pneumonia (PCP). It is also used in combination with proguanil for malaria prophylaxis. The recommended oral (PO) 
dose for PCP is 750 mg (5 mL) twice a day (BD) for 21 days. 
In vitro studies have demonstrated that atovaquone at clinically relevant concentrations significantly reduces oxygen 
consumption in a number of tumour cell lines [9]. Subcutaneous murine tumour models have been used to confirm that 
oral atovaquone causes a significant reduction in tumour hypoxia. Our data suggests that atovaquone causes these 
effects by reducing oxidative phosphorylation in mitochondria. 
750 mg BD oral atovaquone has also been demonstrated to reduce tumour hypoxia in patients with NSCLC in the ATOM 
(Atovaquone as Tumour HypOxia Modifier) window-of-opportunity study (unpublished data). ATOM participants 
received 7-17 days treatment with atovaquone, shorter than the treatment duration for PCP, but sufficient for blood 
atovaquone levels to reach steady state.  


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Atovaquone was exceptionally well tolerated by ATOM participants with very few side effects reported. The ATOM trial 
protocol included an option to escalate atovaquone dose to 1000 mg BD if no effect on tumour hypoxia was seen at 750 
mg BD, however efficacy was seen at 750 mg and therefore the higher dose was not investigated. Higher dosing 
regimens [750 mg three times daily (n=8) and 1500 mg twice daily (n=8)] have been given safely in HIV infected 
volunteers [10]. 
Participants in the ATOM trial were awaiting surgery for NSCLC and received no concurrent chemotherapy or 
radiotherapy. In recognition that ARCADIAN will combine atovaquone with concurrent chemoradiotherapy (CRT), the 
first participants will receive a lower dose of atovaquone (450 mg BD). Pre-clinical data gives no indication that 
atovaquone will exacerbate the side effects of CRT, but such an effect cannot be conclusively ruled out. Escalation to 
doses of atovaquone up to and including 750 mg BD, if appropriate, will be guided by the Time-to-Event Continual 
Reassessment Method (TiTE-CRM) statistical model. 
ARCADIAN participants will receive two weeks (+/- 7 days) of treatment with atovaquone prior to commencing CRT. As 
demonstrated in the ATOM trial, seven days of treatment is sufficient to achieve a reduction in tumour hypoxia. Patients 
will not have their CRT delayed due to enrolment on the trial, as atovaquone run in will occur while patients are waiting 
for their standard of care CRT to begin. Atovaquone treatment will then continue concurrently with CRT, for a total 
duration of 59 days (+/- 7 days). 
Cisplatin and vinorelbine 
Concurrent CRT is the standard of care for patients with locally advanced NSCLC and good performance status. The CRT 
regime used is variable across the UK with variation in the type of chemotherapy (e.g. cisplatin and etoposide vs. 
cisplatin and vinorelbine) and the number of cycles of chemotherapy (two or four). Participants in the ARCADIAN trial 
will receive two cycles of cisplatin and vinorelbine. This has been selected due to being a widely accepted regimen in 
the UK, and one that is deliverable at the intended research sites. Vinorelbine has also been chosen in preference to 
etoposide as atovaquone has been found to increase plasma levels of etoposide and its metabolite when given for PCP 
prophylaxis to children undergoing treatment for acute lymphoblastic leukaemia. 
1.3
Other research interventions  
Radiotherapy 
Concurrent CRT is the standard of care for patients with locally advanced NSCLC and good performance status. There is 
variation in the radiotherapy regime used across the UK, with schedules delivered as standard of care including 55 Gy 
in 2.75 Gy fractions, 60 Gy in 2 Gy fractions and 66 Gy in 2 Gy fractions. Participants in the ARCADIAN trial will receive 
66 Gy in 33 fractions of 2 Gy. This is an established treatment regimen in the UK and deliverable at the intended research 
sites. 
FMISO PET-CT 
The most widely used method for measuring tumour hypoxia in the clinical setting is PET imaging with radiotracers 
which accumulate in hypoxic tissues, such as 18F-misonidazole (FMISO). This particular method has been shown to be 
more effective at detecting reoxygenation states than alternative techniques [11]. The imaging and reconstruction 
protocols on the scanners at Oxford and Edinburgh will be set up by the collaborating physicist to ensure high quality 
and comparable FMISO PET-CT data from both sites is obtained. Scan analysis will be conducted by a PET-CT consultant 
radiologist and physicist in Oxford with extensive experience in FMISO PET-CT using well-recognised tumour-to-blood 
parameters. In the event that FMISO is unavailable (e.g. due to failure in the manufacturing process), trial participants 
will continue in the study, but will not be required to undergo tumour hypoxia imaging. 
FMISO PET-CT technique: 
An activity of 370 MBq (+/- 10%) of FMISO will be injected and a 10-minute acquisition image obtained four hours post-
injection. CT will be performed for localisation and PET attenuation correction (a 4DCT technique will be used where 
possible). Tumour outlining will be performed by an experienced PET-CT radiologist and any metastases (nodal or 
extranodal) identified within the PET field of view also outlined and included in the analysis. A background mean 
standardised uptake value (SUVmean) should be obtained by outlining blood in the descending aorta. To determine the 
tumour hypoxic volume (HV), voxel-by-voxel SUVs will be divided by the background SUVmean to provide tumour-to-
blood ratio (TBR) values for each tumour voxel. Voxels with TBR ≥ 1.4 will be classified as hypoxic, consistent with 
previously published data [12]. Volumes of hypoxic voxels before and after atovaquone treatment will be compared 
and a ≥10% reduction in hypoxic volume (HV) will be defined as a response.  


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HV measurements will also be compared to plasma hypoxia marker data and hypoxia metagene signature data. 
Additional information can be found in the separate imaging guidelines document.  
1.4
Rationale for the study 
Non-clinical  
Mathematical modelling studies have suggested that reducing the oxygen demand of tumours is likely to be a more 
effective way of reducing tumour hypoxia than increasing oxygen delivery [13]. The novel concept of reprogramming 
tumour cell metabolism by reducing oxidative phosphorylation to decrease the oxygen consumption rate (OCR) has 
therefore developed rapidly  [14]. Recently, the commonly prescribed antimalarial drug atovaquone was demonstrated 
to cause a rapid reduction in OCR in multiple different tumour cell lines by reducing oxidative phosphorylation through 
inhibition of complex III of the electron transport chain [9]. Treatment with atovaquone led to the eradication of tumour 
hypoxia in 3D-spheroid and subcutaneous xenograft models, and caused a marked increase in tumour radiosensitivity 
in tumour regrowth delay models. The tumour radiosensitising effects of atovaquone appear to be entirely mediated 
through effects on hypoxia (a tumour-specific phenomenon) as it does not alter intrinsic cell radiosensitivity. Of note, 
atovaquone is also significantly more effective than the oxygen mimetic, nimorazole [9]. Collectively these data strongly 
support the hypothesis that adding atovaquone to chemoradiotherapy will improve outcomes without increasing 
normal tissue toxicity. Furthermore, as atovaquone is well-tolerated and inexpensive we feel it represents an ideal 
candidate to take forward into clinical testing as a novel radiosensitiser. 
Clinical 
Atovaquone as a hypoxia modifier clinical proof-of-concept: the ATOM trial 
To initiate clinical studies investigating whether atovaquone holds significant promise as a hypoxia modifying and thus 
radiosensitising drug, a window-of-opportunity clinical trial in patients with operable NSCLC – the ‘Atovaquone as 
Tumour HypOxia Modifier’ (ATOM) trial was completed in late 2018. The primary endpoint of this study utilised tumour 
hypoxia imaging to assess the effect of atovaquone treatment at the top licenced dose of 750 mg BD on tumour hypoxia. 
FMISO PET-CT scans were arranged at baseline and repeated following approximately 14 days of atovaquone treatment 
and the tumour HV compared. Tumour regions with a tumour-to-blood FMISO uptake ratio (TBR) ≥1.4 at four hours 
post-injection were defined as being hypoxic [12]. Of the 15 patients who received atovaquone treatment 11 patients 
(73%) were classed as responders (defined as 10% reduction in HV) with a median reduction in HV of 28% in these 
patients. Importantly, as expected from decades of clinical experience using atovaquone, we have observed no toxicity 
associated with atovaquone use during the ATOM study. 
Other compounds such as metformin have also previously been shown to reduce OCR and decrease hypoxia in pre-
clinical models [15]. However, to the best of our knowledge there is currently no clinical trial data confirming these 
effects. A recent study combining metformin with radical chemoradiotherapy in locally-advanced NSCLC did not show 
improvement in clinical outcomes [16]. Moreover, our pre-clinical data suggests that atovaquone causes a much greater 
reduction in tumour hypoxia than metformin does at clinically achievable concentrations [9]. Therefore, atovaquone is 
currently the best available compound to decrease tumour hypoxia by reducing OCR and this trial is well supported by 
both pre-clinical and now emerging clinical data.  
Combining atovaquone with chemoradiotherapy in NSCLC 
Patients will receive two weeks (+/- 7 days) of atovaquone to ensure stable plasma concentrations (achieved after seven 
days) and then continue treatment throughout CRT. Atovaquone dose will be assigned as per a TiTE-CRM statistical 
model. The first trial participants will receive 450 mg BD. In the absence of unacceptable toxicity, subsequent patients 
will be assigned doses up to and including 750 mg BD. 
If this study demonstrates that combining atovaquone with radical CRT for NSCLC is well tolerated and the 
recommended phase II dose (RPTD) is established, we plan to conduct further trials to investigate its effect on 
radiotherapy outcomes in this patient population. However, prior to embarking on large efficacy studies, it is important 
to establish a clear strategy for selection of patients with hypoxic tumours, and therefore patients who are likely to 
benefit from hypoxia modification with atovaquone by further developing candidate hypoxia biomarkers. It is well-
recognised that a lack of hypoxia-dependant patient selection in clinical studies has been responsible for numerous 
promising hypoxia modifying agents showing only modest clinical benefit and is one of the main reasons why currently 
no hypoxia treatments are in widespread clinical use. The need for the development and utilisation of hypoxia 
biomarkers for this purpose is now well-accepted in this field and is one of the important aims of this trial. In addition, 
such biomarkers would further evaluate hypoxia response to atovaquone, as well as other novel hypoxia modifiers, in 
future clinical studies. 


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ARCADIAN hypoxia biomarker strategy 
Currently, hypoxia PET-CT imaging with tracers such as FMISO are the most accepted and widely used technique in 
hypoxia clinical research. However, performing these scans in large studies is prohibitively expensive and associated 
with significant logistical challenges including limited availability of FMISO and significant impact on radiology 
department resources. Utilising FMISO PET-CT in large clinical trials, or subsequently integrating this imaging modality 
into clinical practice to guide clinical decision making, is therefore unlikely to be feasible. As a result, there is a clear 
need to establish alternative and clinically deliverable biomarkers. In this study we aim to utilise a previously described 
hypoxia biomarker, microRNA 210 (miR-210), and tumour tissue hypoxia metagene expression analysis, and assess their 
performance to detect hypoxia by comparing to FMISO PET-CT.  
More specifically, under hypoxic conditions miR-210 becomes highly upregulated in response to hypoxia-inducing 
factors [17]. It has been demonstrated that elevated serum levels of miR-210, as measured by quantitative reverse 
transcription polymerase chain reaction (qRT-PCR), are indicative of poor clinical outcomes in NSCLC [18]. Additionally, 
a previously validated hypoxia gene expression signature has been shown to be a prognostic biomarker in different 
tumour types [19]. In the ARCADIAN trial both these biomarkers will be investigated. 
Summary of ARCADIAN hypoxia biomarker aims: 

To confirm the feasibility of measuring the hypoxia metagene signature using RNA sequencing (3’RNA-seq) on 
diagnostic tissue in patients with NSCLC. 

To assess the agreement of plasma miR-210 levels and tumour hypoxia metagene with FMISO PET-CT to further 
support their use as measures of hypoxia in NSCLC and to develop a clear strategy for hypoxia-dependant selection 
of patients for future large efficacy studies. 

To assess agreement in the observed changes in plasma miR-210 levels and FMISO PET-CT following atovaquone 
treatment. This information will be crucial to not only further establish atovaquone as a hypoxia modifier, but 
provide important information to guide future trial design, in particular with regards to determining sample size. 
2
TRIAL DESIGN 
This is a phase I, single arm, open-label trial that will utilise a TiTE-CRM to determine the maximum tolerated dose (MTD) 
of atovaquone in combination with concurrent CRT in NSCLC. Twenty evaluable participants will be recruited at two 
centres. 
Twice daily oral atovaquone will be added to standard concurrent CRT: 66 Gy in 33 fractions, once daily, 5 days a week 
(Monday-Friday), with cisplatin (80 mg/m2 IV on days 1 and 22 of CRT) and vinorelbine (15 mg/m2 IV on days 1, 8, 22 
and 29 of CRT). Whilst awaiting CRT to start, patients will receive two weeks (+/- 7 days) of oral atovaquone to ensure 
steady state is reached (after seven days). Wherever possible, two weeks of atovaquone treatment should be 
administered prior to CRT, but in appreciation of the difficulty often experienced in radiotherapy scheduling and 
planning as well as treatment targets, a +/- 7 days window is permitted. In addition, hypoxia biomarker data will be 
collected at baseline (start of atovaquone run-in) and following two weeks (+/- 7 days) of atovaquone. Atovaquone will 
then be continued without break for the duration of CRT with the CRT schedule remaining constant for all patients at 
both centres. Assessment for DLTs will be from the first scheduled dose of atovaquone until three months after 
completion of CRT. CT scans performed at the three-month follow up visit will be reviewed to collect tumour response 
data. 
The trial will start at the lowest dose of atovaquone (450 mg BD). Two participants will receive this dose and escalation 
will only be considered when we have 12 weeks of safety data (a high-risk period of developing dose-limiting toxicity, 
DLT) for at least one participant at this dose level, thus preventing inappropriate early dose escalation. Following this 
initial safety run in, eligible patients will be continuously recruited and the TiTE-CRM will be used to recommend the 
dose of atovaquone for each patient, as detailed in section 17.3. 
Refer to the schedule of events and flow chart for details of the study visits and procedures. 


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2.1
Duration of patient participation 
Participants will be in the study for up to 38 weeks. This is composed of up to three weeks of treatment prior to 
initiation of CRT, 6.5 weeks of CRT and follow-up for six months (26-28 weeks) post CRT (see summary schedule of 
events).  
2.2
Post-trial care and follow-up 
Following the last study visit, patients will receive standard care.  
3
OBJECTIVES AND ENDPOINTS 
Primary Objective 
Endpoints/ Outcome measures 
Time point(s) of evaluation of 
this end point 

To determine the maximum 
tolerated dose (MTD), and 
therefore recommended phase II 
dose (RPTD), of atovaquone when 
combined with radical concurrent 
chemoradiotherapy in patients 
with non-small cell lung cancer 
(NSCLC) 

The dose of atovaquone 
associated with no more than 48% 
dose limiting toxicity (DLT) rate 
(target toxicity level) 

From week -2/-3 until three 
months post-completion of 
CRT 
Secondary Objectives 

To assess the safety and toxicity 
profile of atovaquone in 
combination with radical 
concurrent chemotherapy for 
NSCLC 

Adverse events graded per 
Common Terminology Criteria for 
Adverse Events (CTCAE) v4.03 
From screening/baseline until 
six months post completion 
of CRT 

To confirm feasibility of measuring 
hypoxia metagene signature using 
3’RNA-Seq in diagnostic NSCLC 
samples 

Hypoxia metagene signature from 
diagnostic tissue using 3’RNA-Seq  
At baseline 

To assess agreement of FMISO 
PET-CT with plasma miR-210 level 
and tumour hypoxia gene 
expression pre-treatment with 
atovaquone 

Tumour hypoxic volume 
determined by FMISO PET-CT  

Plasma miR-210 level 

Hypoxia metagene signature from 
diagnostic tissue using 3’RNA-Seq
Week -2/-3 (prior to 
atovaquone treatment) 

To assess agreement in changes in 
FMISO PET-CT and plasma miR-
210 level following two weeks (+/- 
7 days) of atovaquone  

Tumour hypoxic volume 
determined by FMISO PET-CT  

Plasma miR-210 level  
Week -2/-3 (prior to 
atovaquone treatment)  
Following two weeks (+/- 7 
days) of atovaquone 
treatment 

To assess the tumour response 
rate at three months following 
treatment 

Response to treatment assessed 
per Response Evaluation Criteria 
in Solid Tumours (RECIST) V1.1  
Three months post 
completion of CRT 
Exploratory Objectives 
To assess the relationship between 
plasma atovaquone levels and hypoxia 
response as measured by FMISO PET-
CT and plasma miR-210 level  

Plasma atovaquone concentration 

Tumour hypoxic volume 
determined by FMISO PET-CT  

Plasma miR-210 level  
Week -2/-3 (prior to 
atovaquone treatment)  
Following two weeks (+/- 7 
days) of atovaquone 
treatment 


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4
PATIENT SELECTION 
Patients will be identified in thoracic oncology clinics in Edinburgh and Oxford Cancer Centres (and referring clinics) and 
once the decision has been made to proceed with radical concurrent CRT, the trial will be discussed with patients and 
the patient information sheet provided. Patients will be given at least 24 hours to decide whether to participate and if 
interested, a consent and screening visit will be arranged. 
Written informed consent must be obtained before any study specific procedures are performed. The Investigator will 
determine patient eligibility based on the following criteria.  
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.
Histologically or cytologically confirmed diagnosis of locally advanced NSCLC and selected for treatment with 
full dose radical concurrent CRT  
2.
At least one measurable lesion greater than 2 cm maximal length in any direction on routine imaging (CT or 
PET-CT scan performed in the 60 days prior to consent) 
3.
Male or female, age  18 years 
4.
ECOG performance status 0 or 1 
5.
Adequate pulmonary function tests for thoracic radiotherapy (FEV1 and TLCO, >40% predicted) 
6.
Haematological and biochemical indices within the ranges shown below: 
Lab Test 
Value required 
Bilirubin 
≤1.5 x upper limit of normal (ULN) 
ALT and/or AST 
≤2.5 x ULN 
Creatinine clearance 
Calculated creatinine clearance (using 
Cockcroft-Gault or Wright formula) or 
measured* creatinine clearance ≥60 mL/min 
Absolute neutrophil count  
≥1.5x109/L 
Platelets  
≥100x109/L 
Haemoglobin  
≥90 g/L 
INR 
≤1.5 
* The radioisotope method of assessing glomerular filtration rate may be utilised if clinically indicated 
7.
The patient is willing and able to comply with the protocol scheduled follow-up visits and examinations for 
the duration of the study 
8.
Written (signed and dated) informed consent and be capable of co-operating with protocol 
4.2
Exclusion criteria: 
A patient will not be eligible for the trial if any of the following apply: 
1.
Pregnant or breast-feeding women, or women of childbearing potential unless effective methods of 
contraception are used 
2.
Previous systemic chemotherapy or biological therapy within 21 days of commencing atovaquone treatment 
3.
Treatment with any other investigational agent as part of a clinical trial within 28 days of study enrolment 
4.
Previous thoracic radiotherapy 
5.
Known previous adverse reaction to atovaquone or its excipients 
6.
Active hepatitis, gallbladder disease or pancreatitis 
7.
Impaired gastrointestinal function that may significantly alter absorption of atovaquone 
8.
Concurrent administration of warfarin in the 14 days prior to starting atovaquone 
9.
Concurrent administration of known electron transport chain inhibitors (e.g. metformin). A wash-out period 
prior to administration of atovaquone is required (e.g. 4 days for metformin). Refer to section 10.3 for further 
details. 
10.
An additional cancer diagnosis that the treating clinician feels may significantly impact planned CRT 
treatment tolerability or treatment outcome 
11.
Established diagnosis of pulmonary fibrosis 
12.
Established diagnosis of connective tissue disorder (e.g. scleroderma or systemic lupus erythematosus) 
13.
Cardiac morbidity such as angina, myocardial infarction in the previous six months, unstable angina or 
uncontrolled hypertension, left ventricular failure or severe valvular disease 


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14.
Other serious illness or medical conditions (such as major surgery in the four weeks prior to study entry or 
uncontrolled infection) 
15.
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 
16.
Patients who are known to be serologically positive for Hepatitis B, Hepatitis C or HIV (testing is not required 
as part of trial screening) 
4.3
Protocol deviations and waivers to entry criteria 
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 from the approved protocol. The Investigator should 
promptly report any important deviations that might impact patient safety, data integrity or be a possible serious breach 
(see 23.6 below) to the Trial Office. Deviations will be monitored, followed up and any corrective actions put into place 
as part of central monitoring activities (see the separate Central Monitoring Plan for details).   
4.4
Re-screening if patient does not meet inclusion/exclusion criteria first time round 
Patients failing the screening process are ineligible for the trial. Patients will not be rescreened unless imaging or lung 
function tests are not within the required timeframe. In these cases, imaging can be repeated and the patient 
reconsidered for the trial. 
4.5
Patient registration procedure 
Trial sites must contact OCTO to check the availability of a screening slot before giving out a patient information sheet. 
If a slot is available, OCTO will issue a screening number and the patient may then be approached to consider 
participation. The site should register the participant within two weeks of receiving the screening number or confirm 
that the patient has declined to participate/failed screening assessments. If more than two weeks are needed to 
complete registration the Trial Office should be contacted to agree an extension.  
Before entering a patient onto the trial, the Principal Investigator or designee will confirm eligibility. If in any doubt the 
Chief Investigator and Trial Office must be consulted before entering the patient. Protocol waivers should not be 
requested to enter patients who are not eligible.  
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 must be sent to the Trial Office on 
request, but without patient identifiers. The original log must be retained on site in the investigator site file (ISF). 
To register a patient:  
After checking patient eligibility, site staff will complete the trial Registration Form. Scan the Registration Form and 
email to: octo-ARCADIAN@oncology.ox.ac.uk.
The Trial Office will check the submitted form and register the patient on the trial. Confirmation of the patient’s trial 
number will be emailed to the PI & other relevant site contacts. Where possible the assigned dose of atovaquone will 
be communicated at the same time as trial number, or where further time is needed to complete dose assignment (as 
per process detailed in section 17.3 and the separate Protocol Decision Point Plan), dose will be confirmed by the Trial 
Office as soon as possible after registration.  


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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 case report form (CRF), with 
the exception of central laboratory assay results and analysis of research imaging.  
5.1
Detailed guidance for trial assessments and procedures 
5.1.1
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. 
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. The original signed form will be retained in the Investigator Site File, whilst a copy 
is to be filed in the medical record. If the Trust has a different policy to these terms and conditions, sites should discuss 
this at the stage of site activation before the trial is opened at the site. 
Patients will also be asked to consent to collect names and NHS numbers to allow flagging with NHS Digital (and 
Scottish equivalent) so that long term outcome data can be collected in future ethically-approved trials. This will be an 
optional question on the standard informed consent form.   
5.1.2  Contraceptive/pregnancy counselling 
All participants must be advised on the need to use reliable methods of contraception during the study. The advice 
should include:  

The acceptable methods, including: male or female sterilisation, implants, injectables, combined oral 
contraceptives, some intrauterine devices (IUDs), and abstinence. N.B. abstinence is only acceptable if 
refraining from heterosexual intercourse during the entire period of risk associated with the study drugs 
(periodic abstinence is unacceptable). The reliability of sexual abstinence needs to be evaluated in relation to 
the duration of the clinical trial and the preferred and usual lifestyle of the participant. 

The recommendation that a barrier method should be used in addition to another form of contraception. 

Both males and females should continue to take these precautions for a minimum six months after the last 
dose of the study drugs.  

That any pregnancy (also applies to female partners of male trial subjects) occurring within six months of the 
last administration of study drug should be notified by the trial participant to the study team. The pregnancy 
will be followed up and the outcome of all pregnancies (spontaneous miscarriage, elective termination, 
normal birth or congenital abnormality) will be reported, even if the participant is discontinued from the 
study.  
5.1.3  Medical history and concomitant medications
Medical history includes clinically significant diseases, surgeries, cancer history (including prior cancer therapies and 
procedures), reproductive status, smoking history, and all medications (e.g. prescription drugs, over-the-counter drugs, 
herbal or homeopathic remedies, nutritional supplements) used by the patient within four weeks prior to the first day 
of atovaquone run-in.  


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5.1.4
Physical examination 
A complete physical examination should be carried out at screening. This should include an evaluation of the head, and 
the cardiovascular, dermatological, respiratory, gastrointestinal, and neurological systems. Any abnormality identified 
at baseline should be recorded on the General Medical History and Baseline Conditions electronic case report form 
(eCRF). Height and weight should be measured and recorded in the eCRF.  
At subsequent visits (or as clinically indicated), limited, symptom-directed physical examinations should be performed 
if clinically indicated. Changes from baseline abnormalities should be recorded in patient notes. New or worsened 
clinically significant abnormalities should be recorded as adverse events on the Adverse Event eCRF. 
5.2
Pre-dosing evaluations (screening and baseline) 
Screening/baseline evaluations are to be conducted within two weeks prior to start of protocol therapy (except CT or 
PET-CT scanning, which must be within 60 days of informed consent and pulmonary function tests, which must be 
within 90 days of informed consent). In the event that the patient’s condition is deteriorating, laboratory evaluations 
should be repeated within 48 hours prior to initiation of trial therapy. 

Written informed consent  

Demographic details: age, sex, and self-reported race/ethnicity 

Medical History (as detailed in 5.1.3) 

Concomitant medications (as detailed in 5.1.3) 

Complete physical examination (as detailed in 5.1.4) 

Vital signs: systolic/diastolic blood pressure (BP), pulse rate, respiratory rate, oxygen saturation and 
temperature 

Pulmonary function tests for thoracic radiotherapy: FEV1 and TLCO (if standard of care tests have not been 
done in the 90 days prior to consent) 

Height, weight and body surface area (BSA) 

ECOG performance status 

Blood tests: 
o
Haematology - Hb, white blood cells (WBC) with differential count (neutrophils and lymphocytes) and 
platelets 
o
Biochemistry – sodium, potassium, calcium, phosphate, urea, creatinine, total protein, albumin, 
bilirubin, alkaline phosphatase (alk phos), aspartate aminotransferase (AST) and/or alanine 
aminotransferase (ALT) and lactate dehydrogenase (LDH) 
o
International Normalised Ratio (INR) 

Adverse event assessment (SAEs will be collected from the time a patient consents) 

Pregnancy test (females of childbearing potential only) - serum or urine Human Chorionic Gonadotropin 
(HCG) test to rule out pregnancy at study entry; results must be obtained and reviewed before the first dose 
of atovaquone is administered or any ionising imaging is performed. 

CT or PET-CT scan of brain/chest/abdomen or chest/abdomen/pelvis (if standard of care scan has not been 
done in the 60 days prior to consent)  

Radiotherapy planning (refer to detailed guidance in section 12) 
Results of standard of care tests or examinations performed before obtaining informed consent and before the start 
of trial treatment may be used; such tests do not need to be repeated for screening provided that they have been 
completed within the specified time window. 
All screening evaluations must be completed and reviewed to confirm that subjects meet all eligibility criteria. The 
patient should then be registered on the trial (as detailed in section 4.5) before the first dose of trial treatment.  


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5.3
Evaluations during the study 
5.3.1 Evaluations during week -2 or -3 (day 1 of atovaquone treatment) 
On the day the first dose of atovaquone is taken: 

Vital signs: systolic/diastolic blood pressure (BP), pulse rate, respiratory rate and temperature* 

Symptom-directed physical examination, if clinically indicated (as detailed in 5.1)* 

ECOG performance status* 

Blood tests: 
o
Haematology (as per screening bloods detailed in 5.2)* 
o
Biochemistry (as per screening bloods detailed in 5.2)* 
o
Atovaquone pharmacokinetics (PK)  
o
Plasma marker of hypoxia (miR-210) 

Adverse event assessment (SAEs will be collected from the time a patient consents) 

New or changes to existing medications 

FMISO PET-CT scan (as per detailed guidance provided in trial imaging manual) 

Request retrieval of archival diagnostic tumour sample for research purposes 

Dispense atovaquone and advise patient on dietary requirements
* Week -2/-3 assessments need not be repeated if screening tests have been carried out within 2 weeks of 
atovaquone dispensing visit. 
5.3.2 Evaluations during week -1 (following two weeks (+/- 7 days) of atovaquone treatment)  

Vital signs: systolic/diastolic blood pressure (BP), pulse rate, respiratory rate and temperature 

Weight 

Symptom-directed physical examination, if clinically indicated (as detailed in 5.1) 

ECOG performance status 

blood tests: 
o
Haematology (as per screening bloods detailed in 5.2) 
o
Biochemistry (as per screening bloods detailed in 5.2) 
o
Atovaquone pharmacokinetics (PK)  
o
Plasma marker of hypoxia (miR-210) 

Adverse events and DLTs since the previous assessment - clinician to identify clearly in medical notes any AE 
that is a DLT according to criteria for this protocol 

New or changes to existing medications 

FMISO PET-CT scan (as per detailed guidance provided in trial imaging manual) 

Review patient compliance with atovaquone dosing 

Dispense additional supply of atovaquone if this will be needed prior to next review (opened bottles may be 
used for up to 21 days) 
The week -1 visit (including FMISO PET-CT scan) should be carried out as close to day 1 of CRT as possible. Ideally on 
Friday of week -1 with CRT commencing Monday of week 1, but within a maximum of one week prior to commencing 
CRT. Following completion of the week -1 visit and atovaquone run-in patients will commence standard of care 
chemoradiotherapy in week 1. During chemoradiotherapy the following evaluations are required: 
5.3.3 Evaluations during week 1 

Adverse events and DLTs since the previous assessment 

New or changes to existing medications 

Review patient compliance with atovaquone dosing 

Dispense additional supply of atovaquone if this will be needed prior to next review (opened bottles may be 
used for up to 21 days) 
5.3.4 Evaluations during weeks 2, 3, 4, 5, 6 and 7: 
Once per week complete the following assessments: 

Vital signs: systolic/diastolic blood pressure (BP), pulse rate, respiratory rate and temperature 

Weight 

Symptom-directed physical examination, if clinically indicated (as detailed in 5.1) 

ECOG performance status 


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
Blood tests: 
o
Haematology (as per screening bloods detailed in 5.2) 
o
Biochemistry (as per screening bloods detailed in 5.2) 

Pregnancy test (weeks 2 and 6 only) 

Adverse events and DLTs since the previous assessment 

New or changes to existing medications 

Review patient compliance with atovaquone dosing 

Dispense additional supply of atovaquone if this will be needed prior to next review (opened bottles may be 
used for up to 21 days) 
5.4
End of study evaluations following completion of chemoradiotherapy treatment  
5.4.1 Evaluations during 1-month (week 10-13) follow up 

Symptom-directed physical examination, if clinically indicated (as detailed in 5.1) 

ECOG performance status 

Pregnancy test  

Adverse events and DLTs since the previous assessment 

New or changes to existing medications 
5.4.2 Evaluations during 3-month (week 20-22) follow up 

Symptom-directed physical examination, if clinically indicated (as detailed in 5.1) 

ECOG performance status 

Adverse events and DLTs since the previous assessment 

New or changes to existing medications 

CT scan 
5.4.3 Evaluations during 6-month (week 33-35) follow up 

Adverse events since the previous assessment 
Follow-up evaluations 
Following end of study evaluations patients will return to follow-up as per standard of care in the NHS.  
Patients may commence Durvalumab treatment after CRT is completed, even if they are still within the trial follow up 
window. Treatment with Durvalumab should be documented on the patient’s eCRF. Response rates and number of 
patients who have been prescribed Durvalumab will be reported in the final analysis.   
6
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 

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, the ‘End of Treatment’ Form needs to be completed, and any other relevant CRFs 
(example SAE Form) and the Trial Office notified within 24 hours. The reason for withdrawing from treatment early, 
should be clearly documented in the medical records.  
Patients who have stopped treatment early should continue to be invited to all follow-up visits and assessments, unless 
patient consent for follow-up is withdrawn. 


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Participants have the option to consent to NHS Digital follow-up. This will entail completion of a separate tracing sheet 
which will contain the participant’s name and NHS number, and will therefore be kept securely by the Trial Office. This 
will enable future ethically-approved trials to trace participants’ outcome data for long term follow up. 
Consent Withdrawal 
Consent withdrawal means that a patient has expressed a wish 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.  
Data and samples collected prior to participant consent withdrawal will be used for trial analysis. Participants who 
initially consented to be registered with NHS Digital or equivalent will remain on the system so that important long 
term follow up data can be requested from NHS Digital, unless the patient specifically requests that permission is 
withdrawn to do so.  
Under these conditions, Investigators are still responsible for following up any SAEs until resolution. 
6.1
Patient evaluability and replacement 
Patients will not be replaced since the TiTE-CRM uses all accumulated data. However, the TMG may decide to recruit 
an additional patient if drop-out occurs early in the treatment schedule for reasons other than a DLT. The dose allocated 
to the additional patient may not necessarily be the same, as this will be determined by the TiTE-CRM model, taking 
into account accumulated toxicity data at that time point. In the specific situation where one of the first two patients 
needs to be replaced, the dose allocated to the additional patient will be 450 mg bd, to ensure this dose level is 
evaluated before escalating to higher doses as per detailed process in section 17.3. 
All patients who receive at least one dose of atovaquone will be evaluable for the safety analysis. All patients who 
commence chemoradiotherapy treatment within the study will be evaluable for response. 
7
SAMPLES FOR LABORATORY ANALYSIS 
7.1
Samples to be analysed in local Trust’s laboratories 
Diagnostic Laboratories 
Samples for haematology and biochemistry analysis 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 pathology samples and additional research samples taken at diagnosis will also be labelled, 
processed and reported according to local hospital protocols. Where sufficient diagnostic material is available, tissue 
should also be submitted for central laboratory analysis, as detailed in the following sections and separate Sample 
Handling Manual.  
7.2
Samples to be sent to and analysed in a Central Laboratory 
During weeks -2/-3 and week -1, additional blood samples of approximately 25 mL will be taken in order to evaluate 
plasma atovaquone concentration and hypoxia biomarker levels.  
7.2.1
Pharmacokinetic assays  
For atovaquone PK studies, plasma will be retained and dispatched to a central laboratory for HPLC plasma 
atovaquone concentration measurement (refer to Sample Handling Manual for specific details).  
7.2.2
Plasma hypoxia marker (miR-210) 
For plasma hypoxia biomarker analysis, plasma will be retained and dispatched to a central laboratory for qRT-PCR 
measurement of miR-210 (refer to Sample Handling Manual for specific details). 


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7.2.3
Hypoxia metagene expression 
In cases with sufficient diagnostic tissue, a section of formalin-fixed paraffin-embedded (FFPE) tissue will be obtained 
and sent to a central laboratory for tumour tissue extraction and hypoxia metagene analysis using the 3’RNA-seq 
method. This is the optimal technique available to obtain such data from limited and low quality FFPE tissue samples, 
as is often the case in NSCLC.  
More specifically, a previously validated hypoxia gene expression signature will be measured using diagnostic biopsy 
FFPE samples. We will utilise 3’RNA-seq as it has clear advantages over alternative and now more dated sequencing 
and array techniques. 3’RNA-seq can accurately estimate gene expression even if applied to low quality or degraded 
samples and it requires only 100 pg total RNA input. This is an important consideration in our patient population, as 
diagnostic tissue can often be very scarce. Importantly, modern RNA-seq techniques are relatively inexpensive and 
when performed on already obtained diagnostic tissue can be easily incorporated into larger clinical studies, or 
potentially routine diagnostic work-up thereafter. 
We will not require patients to undergo additional tissue sampling in appreciation of the difficulty and often repeated 
attempts required to obtain sufficient diagnostic tissue in this patient population. Also, given the short time window 
to get patients on treatment and to start CRT, mandating additional tissue may result in a delay in treatment that we 
feel would be unacceptable. 
7.2.4
Summary of samples/assays to be taken during the study 
The full list of samples required for central laboratory analysis is as follows: 
Time Point 
Week -2 or -3 
Week -1 
Blood sample for PK analysis 
X 
X
Blood sample for plasma biomarker (miR210) 
X 
X 
Request diagnostic tissue sample for hypoxia metagene 
X 
Trial sites will be provided with a separate Sample Handling Manual with detailed arrangements for sample collection, 
immediate processing, labelling and shipment. Whenever possible, all blood samples will be taken at the same time as 
blood samples are taken prior to chemotherapy, therefore minimising discomfort and inconvenience to the patient. 
7.3
Labelling and confidentiality of samples sent 
All samples sent to central 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. 
7.4
Clinical reporting of exploratory research assay results 
The results of central laboratory research assays are exploratory and are not intended to influence the individual 
patient’s medical care. Findings will not be reported routinely to the responsible clinician except in the unlikely event 
that the result might be beneficial to the patient’s clinical management. 
7.5
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. Hence, any surplus study samples and 
study information may be transferred to a licensed tissue bank where they will be stored for use in any future ethically 
approved medical research. Patients are required to authorise these procedures by signing the consent form. This will 
identify them by name and/or patient study number, and will be sent to the tissue bank along with their samples. 
Patients can withdraw permission to use their samples in these ways at any time, without affecting their participation 
in the study. Banked samples will be managed in accordance with applicable host institution policies and the Human 
Tissue Act (HTA) requirements.  


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7.6
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, it would not be possible to destroy such samples. 
7.7
Correlative hypoxia biomarker studies  
Where possible, data from imaging and plasma hypoxia markers from the ARCADIAN trial will be combined with such 
data obtained from the ATOM trial to increase the patient sample size.  
8
INVESTIGATIONAL MEDICINAL PRODUCT (IMP)  
The trial is investigating the use of atovaquone suspension in combination with chemoradiotherapy. Atovaquone, 
cisplatin and vinorelbine are all considered Investigational Medicinal Products (IMPs) in this trial due to the 
investigation of these drugs being used in a novel combination. 
8.1
Treatment dose 
Atovaquone 
Atovaquone doses to be tested are listed in the table below. The dose received by each participant will be decided per 
the process detailed in section 17.3. All doses are given orally (PO) and twice daily (BD). 
Atovaquone dose level 
Atovaquone dose 
Level 1 (starting) 
450 mg PO BD 
Level 2 
600 mg PO BD 
Level 3 
675 mg PO BD 
Level 4 
750 mg PO BD 
Cisplatin and vinorelbine 
Two 21-day cycles of cisplatin and vinorelbine chemotherapy will be given concurrently during radiotherapy 
treatment, as follows: 
Chemotherapy agent 
Chemotherapy dose 
Timing of dose 
Cisplatin 
80 mg/m2
Days 1 & 22 
Vinorelbine 
15 mg/m2
Days 1, 8, 22 & 29 
It is acceptable for chemotherapy to commence up to two days after radiotherapy is started. Any delays to 
chemotherapy treatment during cycle one should result in a corresponding delay to cycle two (see section 8.3.2).   
8.2
Duration of treatment 
Atovaquone 
Patients will receive two weeks (+/- 7 days) of atovaquone prior to starting CRT, treatment will then continue 
concurrently with CRT. The last dose of atovaquone will be on the morning of the last fraction of radiotherapy. Total 
duration of atovaquone treatment will be 59 days (+/- 7 days), unless stopped earlier for toxicity or any other reason. 
Cisplatin and vinorelbine 
Patients will receive two 21-day cycles of cisplatin/vinorelbine as part of their CRT treatment. Chemotherapy will 
commence (along with RT) on day 1 in week 1, with the last dose of vinorelbine administered on day 29 (week 5). This 
will follow two weeks (+/- 7 days) of atovaquone treatment, which will be continued throughout CRT. Altogether, 
patients will receive chemotherapy on 4 days during the trial (unless omitting doses is clinically indicated). Details of 
chemotherapy treatment received will be recorded in the eCRF.   


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8.3
Management of drug administration  
Atovaquone 
Patients will be instructed to take atovaquone oral suspension twice daily with each dose self-administered using a 
provided syringe, preferably in the morning and evening, and at approximately the same time each day. The 
bioavailability of atovaquone is increased up to three-fold when administered with fat containing food. Patients will 
therefore be asked to take atovaquone with a meal, if possible one containing a high fat content (e.g. butter, whole 
milk, cheese, ice cream, eggs, etc.).  
If a patient misses a dose, the dose should be taken later, provided the patient remembers within four hours. If the 
patient does not remember within four hours, the missed dose should be omitted. Doses should not be doubled to 
make up for missed doses. If a patient vomits after taking the suspension, the dose should not be replaced. 
Cisplatin and vinorelbine 
Cisplatin and vinorelbine chemotherapy should be administered concurrently with radiotherapy, as detailed in section 
8.1.2. Cisplatin and vinorelbine will be supplied from hospital stock and administered according to local practice and 
SmPC guidelines. Dispensing labels must be completed for all patients, but trial-specific labelling of these 
chemotherapy drugs is not required. On days where chemotherapy is delayed for administrative reasons (for example, 
holidays or weather), this will not be considered a protocol deviation, provided the full planned dose of radiotherapy 
is administered. Omissions of cisplatin should be resumed as soon as possible. Single-day vinorelbine omissions due to 
holidays or weather, or for other clinically indicated reasons do not need to be reinstated.  
Days 1 & 22 
Pre-chemotherapy hydration 

1 L 0.9% sodium chloride infusion over 2 hours 
Pre-chemotherapy medications 

Dexamethasone  

Mannitol (if urine output <100 mL/hr) 

A 5-HT3 antagonist and NK1 antagonist may be given 
Chemotherapy 

Cisplatin – 80 mg/m2 infusion in 500 mL of 0.9% sodium chloride over 1 hour 

Vinorelbine – 15 mg/m2 supervised infusion in 50 mL of 0.9% sodium chloride over 5 minutes 
Post-chemotherapy hydration 

Cisplatin – 1 L 0.9% sodium chloride / 10 mmol magnesium sulphate / 20 mmol potassium chloride 
infusion over 2 hours 

Vinorelbine – 100 mL 0.9% sodium chloride infusion (first 3 minutes supervised at 600 mL/hr, then 
1000 mL/hr to finish) 
Take home drugs 

Dexamethasone 

Ciprofloxacin 

Movicol sachet

Cyclizine*
Days 8 & 29 
Chemotherapy 

Vinorelbine – 15 mg/m2 supervised infusion in 50 mL of 0.9% sodium chloride over 5 minutes 
Take home drugs 

Ciprofloxacin  
See section 10 for details of supportive medications.  
* Note that metaclopramide must NOT be given as an antiemetic, as it may alter plasma levels of atovaquone (see 
section 10 for further details). 
Patient monitoring and management of hypersensitivity and extravasation will be as per local hospital policy. 


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8.4
Special precautions  
Atovaquone 
Unopened bottles of atovaquone have a shelf life of 12 months when stored at room temperature (not exceeding 
25°C). If room temperature is expected to exceed this, bottles should be kept in a cool, dark location. Bottles may be 
refrigerated if necessary, but should never be placed in the freezer. Opened bottles of atovaquone suspension can be 
stored for up to 21 days at room temperature, but must be kept away from extremes of heat or moisture (so should 
not be kept, for example, in a bathroom). 
Cisplatin and vinorelbine 
Refer to cisplatin and vinorelbine SmPCs for special warnings and precautions for use.  
8.5
Actual versus ideal body weight  
Atovaquone 
Not applicable - atovaquone dose will not be adjusted for body weight. 
Cisplatin and vinorelbine 
Doses of cisplatin and vinorelbine will be calculated for each patient based on actual weight. The patient’s weight 
should be recorded prior to every chemoradiotherapy cycle to determine dose of chemotherapy. See section 8.7 for 
BSA calculation.  
8.6
Dose modification 
Atovaquone 
If chemotherapy is reduced or stopped, atovaquone should be continued. 
If RT is suspended for less than seven consecutive days for reasons other than toxicity, atovaquone treatment can also 
be suspended (at the clinician’s discretion), but restarted with RT.  
If RT is interrupted for less than seven days due to toxicity, atovaquone should be stopped when RT is discontinued 
and not restarted.  
Interruptions of RT of greater than seven days for toxicity reasons (related to IMPs, CRT or the combination thereof) 
are defined as DLTs, in which case atovaquone should be permanently discontinued.  
If a patient experiences toxicity that is thought to be directly related to atovaquone treatment and not controlled by 
supportive medication, then atovaquone should be discontinued, rather than the dose reduced, and it should not be 
restarted. Investigators are encouraged to discuss such decisions to discontinue atovaquone with the CI. See section 9 
for effects defined as dose limiting toxicities and reporting procedure.   
Single agent atovaquone treatment is not usually associated with significant side effects and as this drug has been 
prescribed for many years it has a well-established toxicity profile. It is not expected that addition of atovaquone to CRT 
will increase side effects, however this may occur and will be reported as part of the safety and DLT assessment, if 
applicable. 
Cisplatin and vinorelbine 
The following dose modification schedule is recommended for haematological and biochemical abnormalities on 
chemotherapy. As each patient’s clinical circumstances are unique, these are intended as a guide only. 
Haematology for cisplatin: 
ANC (x109/L) 
Platelets (x109/L) 
Chemotherapy dose 
1.5 
And 
100 
100% 
<1.5 
Or 
<100 
Delay one week and reassess 
<1.0 
– 
– 
Delay one week, give additional 
5 days antibiotics and reassess 


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Haematology for vinorelbine: 
ANC (x109/L) 
Platelets (x109/L) 
Chemotherapy dose 
1.5 
And 
100 
100% 
<1.5 
And 
<100 
Omit 
Febrile neutropenia  
Or 
Grade 4 haematological toxicity 
75% 
Renal dysfunction for cisplatin: 
Creatinine clearance (mL/min) 
Chemotherapy dose 
>60 
100% 
40-60 
62.5% 
<40 
Discontinue 
Oto- and neurotoxicity for cisplatin: 
Ototoxicity or neurotoxicity 
Chemotherapy dose 
< Grade 3 
100% 
 Grade 3 
Discontinue 
Hepatic dysfunction for vinorelbine: 
ALT 
Total bilirubin  
Chemotherapy dose 
<5 x ULN 
And 
<2 x ULN 
100% 
>5 x ULN 
And/or 
>2 x ULN 
70% 
If urea is more than 7.0 mmol/L or creatine clearance drops by 20%, discuss with Principal Investigator. Precede day 8 
& 29 vinorelbine with 500 mL 0.9% sodium chloride infusion. 
Add daily GCSF if patient has had:  

Previous chemotherapy 

Previous pneumonectomy 

Febrile neutropenia during previous chemotherapy cycle 

Chemotherapy delay of >7 days due to neutropenia  

Grade 4 neutropenia  
8.7
Calculating and recalculating BSA/doses 
Atovaquone 
Not applicable – atovaquone dose is not calculated according to body surface area (BSA).  
Cisplatin and vinorelbine 
BSA is calculated according to the DuBois and DuBois formula. If a patient’s weight changes by ≥ 10% from baseline 
(see section 8.5), then drug doses should be recalculated. If a patient’s weight changes by <10% the dose may be 
adjusted according to local policy/clinician’s discretion, but is not an absolute requirement.  
8.8
Dose capping and dose banding 
Atovaquone 
Not applicable – no doses are to be capped/banded. 
Cisplatin and vinorelbine 
No doses are to be capped.  
Dose banding can be applied according to local policy. The Trials Office will request each site to state up front whether 
or not dose banding will be used. 
8.9
Compliance 
Atovaquone 
Patients will be asked to report if they have any missed doses of atovaquone during their weekly clinic visits. Data 
should be recorded in the clinical record and entered into an eCRF in order to monitor compliance for dose decisions. 


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Patients should be asked to bring any unused/remaining trial medicines (empty, open or unopened) with them to 
each clinic visit.  At each visit, the patient’s supply of atovaquone should be checked and an additional bottle 
dispensed if needed prior to the next visit (after first opening, the suspension may only be stored for up to 21 days). 
The trial visits at which resupply is required will vary between participants, dependent on the duration of atovaquone 
treatment received prior to starting CRT. 
Accountability logs are required for atovaquone. Site staff will collect and measure patient returns which must be 
recorded on the drug accountability log. Accountability Logs should be returned to the Trial Office as requested.  
Cisplatin and vinorelbine 
Cisplatin and vinorelbine compliance will be monitored via the clinical record.  
8.10
Management of overdose 
Atovaquone 
There is no specific antidote for atovaquone, however several cases of overdose have been published – none of which 
resulted in life-threatening or fatal side effects  [20]. Patients experiencing toxicities upon mis-dosing or over-dosing 
will be treated at the discretion of the Investigator with adequate supportive care and followed until full recovery. 
Cisplatin and vinorelbine 
Refer to guidance provided in the SmPC documents for cisplatin and vinorelbine regarding recommendations 
following overdose.  
Administration of a dose of trial drug exceeding that permitted by the trial protocol should be notified to the Trial 
Office. Any toxicity resulting from administration of an overdose of trial drug should also be reported as an adverse 
event/serious adverse event (as appropriate) as per reporting processes detailed in section 14. 
9
DOSE LIMITING TOXICITY 
9.1
Definition of a Dose Limiting Toxicity 
All patients who have received at least one dose of atovaquone will be evaluable for DLTs.  
DLTs are defined as any of the following occurring between the start of trial treatment until three months post CRT, 
and assessed by the Principal Investigator as possibly, probably or definitely related to atovaquone and/or to 
chemoradiotherapy. If an event is believed to be possibly, probably or definitely related to treatment with 
Durvalumab rather than trial IMPs, it may be reported as an SAE rather than a DLT. 
DLTs will be defined as per NCI CTCAE v4.03 and include: 

Grade ≥4 absolute neutrophil count (ANC) (<0.5 x 109/L) for >7 days   

Grade ≥3 febrile neutropenia (fever of unknown origin without clinically or microbiologically documented 
infection) (ANC <1.0 x 109/L, fever ≥38.5°C) lasting >3 days  

Infection (documented clinically or microbiologically) with grade 3 or 4 neutropenia (ANC <1.0 x 109/L)  

Grade ≥3 thrombocytopenia (platelets <25 x 109/L)  

Clinically significant bleeding attributed to grade 3 thrombocytopenia or requiring platelet transfusion  

Grade ≥3 oesophagitis 

Grade ≥3 pneumonitis onset within 3 months of starting radiotherapy  

Grade ≥3 nausea or vomiting not controlled by optimal outpatient anti-emetic treatment for ≥5 days 

Grade ≥3 diarrhoea despite optimal outpatient anti-diarrhoeal medication use  

Any toxicity causing a delay of radiotherapy completion by greater than one week  

An elevation of ALT or AST >5 x ULN lasting 8 days or more  

A concurrent elevation of ALT or AST (>3 × ULN) and total bilirubin (>2 × ULN) in whom there is no evidence of 
biliary obstruction or other causes that can reasonably explain the concurrent elevation  

Other grade ≥3 effects thought to be clinically significant and directly related to the combination of atovaquone 
with chemoradiotherapy   


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Dose limiting toxicities must be reported within 24 hours of the site becoming aware using the SAE form (even if 
the event does not meet the definition of an SAE). Scan the form and email as an attachment to octo-
safety@oncology.ox.ac.uk.  
See section 14 for safety reporting procedures. 
DLTs will be processed to support dose decisions according to procedures detailed in Section 17 and the separate 
Protocol Decision Point Plan.  
10
OTHER TREATMENTS (NON-IMPS) 
10.1 Support medication 
Patients will be given the following medication as part of their CRT treatment:  
Days 1 & 22 (cisplatin & vinorelbine) 
Pre-chemotherapy medications 

Dexamethasone - 12 mg IV  

Mannitol (if urine output <100 mL/hr) - 10%, 500 mL IV over 30 minutes post-chemo A 5-HT3 
antagonist and aprepitant may be given, according to local policy (e.g. Akynzeo®) 
Take home drugs 

Dexamethasone - 4 mg BD for 3 days following cisplatin treatment 

Ciprofloxacin - 250 mg BD for 14 days following vinorelbine treatment 

Movicol sachet - 1-2 daily, 14 days following cisplatin treatment, then as needed 

Cyclizine* - 50 mg TDS for up to 5 days following cisplatin treatment, then as needed 
Days 8 & 29 (vinorelbine only) 
Take home drugs 

Ciprofloxacin - 250 mg BD for 14 days following vinorelbine treatment 
* It is important that nausea should be managed with antiemetic therapy other than metoclopramide, which may alter 
plasma levels of atovaquone.  
10.2 Concomitant medication and non-drug therapies 
Concomitant medication to treat diarrhoea such as loperamide given at a standard dose should be considered for grade 
1-2 diarrhoea along with oral hydration and dietetic measures. More severe diarrhoea should be treated appropriately 
at the Investigator’s discretion and may include IV fluid administration. Skin rash will be managed at the Investigator’s 
discretion and may include the use of anti-histamines and corticosteroids. 
Corticosteroids may be given to patients who have been prescribed Durvalumab to manage the side effects of immune-
mediated reactions.  
Other 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 four weeks prior to the first 
treatment visit. They must also inform the Investigator about any new medication started while in the trial. Details 
(including indication, doses, frequency and start/stop dates) of concomitant medication taken during the trial until the 
completion of the off-study visit must be recorded in the medical record and the appropriate CRF. 
10.3 Prohibited therapies and (potential) drug interactions 
Patients should not be prescribed other anti-cancer or investigational therapies while participating in this study (with 
the exception of Durvalumab, see Section 5.4). However, if there is evidence of disease progression on completion of 
CRT and there is clinical need to commence anti-cancer therapy, this should not be withheld and the CI should be 
informed.  
Concurrent administration of warfarin within the 14 days prior to starting atovaquone is prohibited.  


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Concurrent administration of known electron transport chain inhibitors is prohibited (due to possible alteration of 
hypoxia interpretation). Commonly used electron transport chain inhibitors include:  

Metformin 

Phenformin  

α-Tocopheryl succinate 

Arsenic trioxide 
Metformin must not be administered within four days before starting atovaquone. For other electron transport chain 
inhibitors, the length of wash-out period will be discussed and agreed by the trial team with reference to the available 
drug reference data. 
Concomitant administration with the following drugs is prohibited because they are known to reduce plasma 
concentrations of atovaquone: 

Rifampicin or rifabutin  

Metoclopramide (give an alternative antiemetic if required) 

Tetracycline  

Efavirenz or boosted protease-inhibitors  
Atovaquone can increase the levels of etoposide and its metabolite. Atovaquone has high plasma protein binding and 
should therefore be used in caution with other drugs with high protein binding and narrow therapeutic windows. 
Please refer to the Summary of Product Characteristics (SmPC) for atovaquone for further details. 
Drug 
Details 
Timescale (if applicable) 
Warfarin 
Atovaquone may increase plasma 
levels of warfarin 
Prohibited during trial and within 
14 days prior to starting 
atovaquone 
Metformin 
Electron transport inhibitors, possible 
alteration of hypoxia interpretation 
Prohibited during trial and within 4 
days prior to starting atovaquone 
Phenformin  
Contact trial team 
α-Tocopheryl succinate 
Contact trial team 
Arsenic trioxide 
Contact trial team 
Rifampicin or rifabutin  
Reduce plasma concentration of 
atovaquone 
Prohibited 
Metoclopramide  
Tetracycline  
Efavirenz 
Other boosted protease-inhibitors 
Etoposide 
Atovaquone can increase plasma levels 
of etoposide and its metabolite 
Prohibited 
Refer to the SmPCs for cisplatin and vinorelbine for details of drug interactions. 
11
DRUG MANAGEMENT 
11.1 Drug supplies 
Atovaquone (IMP) will be purchased by the site pharmacy as commercial stock. Any brand of 750 mg/5 mL oral 
suspension atovaquone may be procured, according to local policy. The arrangements for funding atovaquone will be 
detailed in the trial site agreement. 
Cisplatin and vinorelbine should be supplied from trial site’s own stock and funded locally.  
All supportive medication is to be sourced and funded locally. 


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11.2 Drug ordering and receipt 
The local Investigator and Pharmacy are responsible for liaising to ensure that commercial supplies of atovaquone, 
cisplatin and vinorelbine are held in stock as necessary to supply the recruited patients. 
11.3 Handling and storage 
Unopened bottles of atovaquone may be stored at controlled room temperature up to 25oC. Unopened containers 
have a shelf life of 12 months. After first opening, the suspension may be stored for up to 21 days. Patients who are 
continuing treatment with atovaquone must therefore be resupplied with a new bottle of atovaquone at intervals of 
21 days or less.  
11.4 Labelling  
The responsible Pharmacy will ensure that IMP supplies dispensed for trial use are appropriately labelled in accordance 
with all applicable regulatory requirements.  

Atovaquone – bottles that are given to patients should also be labelled with full information regarding the 
trial. These labels are included in the Pharmacy File provided by OCTO upon site activation. 

 Cisplatin & vinorelbine – chemotherapy drugs administered as standard of care will be labelled as per 
local practice and are not required to have trial specific labels.  
Emergency contact details will be supplied to the participant on the trial label.   
Local labels can be used as long as they contain exactly the same information as in the labels provided, and must be 
approved by OCTO prior to use. 
11.5 Dosing dispensing 
Atovaquone 
Atovaquone will be dispensed in a high-density polyethylene bottle with child resistant polypropylene closure, 
containing atovaquone suspension. A measuring syringe will be included. One bottle contains sufficient drug for up to 
21 days treatment for one patient at 750 mg per dose. Therefore, participants taking lower doses of atovaquone will 
have excess medication left after 21 days which must be returned to the clinical trial pharmacy for compliance 
monitoring and disposal.  
Cisplatin and vinorelbine 
Refer to the SmPCs for full prescribing information and details of drug reconstitution, administration and stability.
11.6 Drug accountability 
Drug accountability records must be maintained for atovaquone. Drug Accountability Logs are provided. Hospitals 
may amend the Drug Accountability Logs provided or use their own documentation if they capture all the information 
requested on the Drug Accountability Logs, but must be approved by OCTO prior to use.  
For cisplatin and vinorelbine, pharmacy records must detail; patient’s name/identifier, date and dose dispensed and 
batch number of drug. It is expected that pharmacy aseptic unit worksheets will be sufficient. 
11.7 Drug returns from patients 
Patient returns of atovaquone should be returned to the clinical trial pharmacy. End of treatment returns should be 
made on or following the last day of radiotherapy. Pharmacy staff will collect and measure patient returns using the 
weight of the returned bottle (minus bottle standard weight), converted to fluid in mL. Returns must be recorded in 
the patient’s Accountability Log and a scanned copy sent to the Trial Office as requested.  
11.8 Drug destruction 
Any patient returns of atovaquone should be disposed of at site according to local hospital policy, after first weighing 
returned bottles to document the volume of solution returned. A record of destruction should be kept as per local 
policy.  
Destruction of unused/expired cisplatin and vinorelbine is also per local hospital policy.  


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11.9 Occupational safety 
Atovaquone is not expected to pose an occupational safety risk to site staff under normal conditions of use and 
administration. 
Cisplatin and vinorelbine are cytotoxic and appropriate precautions should be taken during handling, as per local 
hospital policy.  
12
RADIOTHERAPY 
Patients registered for the trial will receive concurrent thoracic radiation therapy consisting of 66 Gy in 33 fractions, 
once daily, 5 days a week (Monday-Friday), prescribed according to the International Commission on Radiation Units 
and Measurements (ICRU) 83. Radiation treatment should ideally commence on a Monday, but delays of up to two days 
are acceptable. Prior to inclusion of any patient on this study, the radiation oncologist will evaluate the thoracic CT scan 
in order to ensure that the treatment volumes are unlikely to significantly exceed the specified normal tissue 
constraints. 
12.1 Simulation 
Patients should be positioned on a flat CT couch using appropriate immobilisation device (e.g. vac-bag, wingboard), 
preferably in the supine position with arms supported above their head. Simulation will consist of a free-breathing 
helical CT image for target and organs at risk (OAR) delineation and dosimetry planning, followed by a free-breathing 
4D-CT. The extent of the helical planning CT scan must be sufficient to include all potential organs at risk. As a guide, 
contiguous axial slices will be obtained from the upper cervical spine to the lower edge of the liver, taking care to include 
all lung parenchyma on the planning scan. Axial slices of 2.5 mm should be utilised, but up to 3 mm is permitted. The 
extent of the 4D-CT should be equivalent to the helical planning CT scan. In the absence of 4D-CT, fluoroscopy may be 
used to assess tumour motion. Intravenous contrast should be used for central tumours to differentiate disease from 
blood vessels or atelectasis. This will be specifically requested on the planning request form and given at the time of the 
planning scan.  
Please refer to the separate radiotherapy guidance document for details on volumes, margins, organ at risk 
constraints, plan optimisation and quality assurance to ensure that standard of care is consistent across sites.   
12.2 Planning  
6-10 MV photons will be used for planning using a forward-planned intensity modulated radiotherapy (IMRT) 
treatment plan. Where possible, this should utilise volumetric modulated arc therapy (VMAT), but static field is 
permissible. 
12.3
Treatment delivery 
Treatment requires a linac with CBCT capabilities for IMRT/VMAT delivery. Weekly clinical assessments are required 
during CRT. 
As a minimum, daily online CBCT should be performed for the first three days of treatment, and then at least weekly 
thereafter. Local procedure should be followed regarding set up queries.  
Additional imaging (at the treatment unit or in pre-treatment) can be used if there is any uncertainty regarding patient 
positioning.  
On days when both chemotherapy and radiation are administered, it is recommended that radiation should follow 
within 30 to 60 minutes of the completion of chemotherapy or post-cisplatin hydration. When this is not feasible for 
logistical reasons, radiotherapy may be delivered out with this window and may be prior to the administration of 
chemotherapy or post-cisplatin hydration. On days where chemotherapy is delayed for administrative reasons (for 
example, holidays or weather), this will not be considered a protocol deviation, provided the full planned dose of 
radiotherapy is administered.   
12.4
Management of unscheduled gaps 
ARCADIAN patients will be treated as RCR category 1 patients. Unscheduled gaps in radiotherapy should be limited to 
no more than 2 consecutive planned fractions, where possible. 


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Where delivery of radiotherapy is interrupted for reasons other than toxicity, RCR guidance on managing unscheduled 
interruptions should be followed:  

Where possible, patients should be transferred to a matched linear accelerator on the day of interruption 
Where this is not possible, clinicians should consider the following: 

Treating patients at weekends and on public holidays  

Treating patients twice daily, with a minimum of 6 hrs between therapies 

Using Biologically Equivalent Dose (BED) calculations to derive an alternative treatment schedule with an 
alternative number of fractions to complete the course in the planned time, but perhaps accepting a higher BED 
in normal tissues 

Treating patients with extra fractions where compensation cannot be achieved within the original planned time 
 Any toxicity resulting in delay in radiotherapy for greater than one week is considered a DLT (see section 9). 
12.5  Chemoradiotherapy toxicity 
The acute adverse events expected for chemoradiotherapy are summarised in the following table. This data is derived 
from the combined cohorts of the IDEAL-CRT trial [21]. This nonrandomised phase 1/2 trial enrolled stage II and III 
NSCLC patients, who received RT doses between 63 Gy and 73 Gy in 30 once-daily fractions over 40 days, concurrent 
with 2 cycles of cisplatin and vinorelbine. 
Toxicity* 
Rate (%) 
Oesophagitis (Grade <3) 
94 
Oesophagitis (Grade ≥3) 
6 
RT pneumonitis (Grade <3) 
97 
RT pneumonitis (Grade ≥3) 
4 
White blood cell decreased 
13 
Lymphocyte decreased 
11 
Neutrophil decreased 
15 
Lung infection 
22 
FEV decreased 
15 
Dyspnoea 
9 
Co-diffusing capacity decreased 
7 
Fatigue 
7 
Pulmonary embolism 
7 
Late radiation fibrosis 
6 
Nausea 
6 
Anorexia 
5 
Chest pain 
5 
Hearing impairment/reduction/loss 
5 
Vomiting 
5 
Febrile neutropenia 
4 
Diarrhoea 
2 
   *Data from IDEAL-CRT [21]. 
Radiation toxicity will be graded as per NCI CTCAE v4.03. The management of radiation side effects should be as per 
local protocol. The Investigators are advised to suspend the use of chemotherapy given with radiation if they believe 
that continuing chemotherapy administration will compromise delivery of full-dose radiation in an uninterrupted 
manner.  
12.6  Radiotherapy quality assurance 
The QA programme for the study will be co-ordinated by the National Radiotherapy Trials QA (RTTQA) Group. The details 
of the programme can be found on the RTTQA website, www.rttrialsqa.org.uk. In the first instance, any queries 
regarding radiotherapy quality assurance for ARCADIAN should be addressed to the national Radiotherapy Trials QA 
group (RTTQA) contact (rttrialsqa.enh-tr@nhs.net).  


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Pre-Trial QA Programme  
All Pre-Trial QA is completed prior to centre activation for the trial and consists of:  

Facility Questionnaire (FQ): General and trial specific questions on equipment, software, techniques and 
procedures to be used for the trial.  

Dosimetry Audit: Centres must have successfully completed the IMRT credentialing programme through the 
RTTQA group. 
On-trial QA Programme 
Real time review of all patients will be required for the first patient treated in each site and there will be timely 
retrospective review of radiotherapy for the rest of the patients. All images, outlines, plan and dose data (DICOM) should 
be submitted to the RTTQA contact who will co-ordinate review of the data to check protocol compliance as each patient 
is recruited. 
13
EVALUATION OF RESPONSE 
13.1 Measurement of disease for solid tumour 
For the secondary endpoint of tumour response rate, disease must be measured according to the RECIST V1.1 criteria, 
where applicable, given in Appendix 2. 
13.2 Tumour assessment 
A clinical and radiological evaluation of malignancy, as judged appropriate by the Investigator, and in line with the 
protocol, must be performed before starting the study treatment. The same methods that detect lesions at baseline 
will be used to follow these lesions throughout the study. To ensure compatibility, the radiological assessments used to 
assess response must be performed using identical techniques. Imaging-based evaluation is preferred to evaluation by 
clinical examination when both methods have been used to assess the anti-tumour effect of a treatment. 
Baseline evaluations 
These will include radiological measurements of the extent of disease by CT or PET-CT scan of brain/chest/abdomen or 
chest/abdomen/pelvis, with or without contrast as requested by the treating clinician. All areas of disease present must 
be mentioned (even if specific lesions are not going to be followed for response) and the measurements of all 
measurable lesions must be recorded on the scan reports. Any non-measurable lesions must be stated as being present. 
For clinical measurements, documentation by colour photography, including a ruler to estimate the size of the lesion is 
recommended to aid external independent review of responses (see separate Central Monitoring Plan for details).  
Evaluation after end of treatment 
Tumour assessment will be repeated three months after completion of CRT. All lesions measured at baseline must be 
measured at the subsequent disease assessment, and recorded on the scan report. All non-measurable lesions noted 
at baseline must be reported as present or absent. 
Investigators must ensure that their radiologists are aware of the requirement to follow up and measure every target 
lesion mentioned at baseline and comment on the non-target lesions in accordance with RECIST criteria. 
13.3 Tumour response 
All patients will have their response classified as complete response (CR), partial response (PR), early progression (EP) 
or “not evaluable” (NE), as measured from their baseline scan to their follow up scan at the end of treatment. See 
Appendix 2 for response category criteria.  
To be assigned a status of complete response (CR) or partial response (PR), changes in tumour measurements must be 
confirmed by two observations at least 4 weeks apart.  
To be assigned a status of stable disease (SD), tumour measurements must have met the SD criteria at least once, a 
minimum of six weeks after study treatment is started. 
Should rapid tumour progression occur before the completion of treatment, the patient will be classified as having early 
progression (EP). 


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Tumour response should be classified as “not evaluable” (NE), only when it is not possible to classify it under another 
response category (e.g., when baseline and/or follow-up assessment is not performed or not performed appropriately).  
The applicable overall response category for each visit that includes disease assessment must be recorded in the medical 
record for inclusion in the appropriate CRF in OpenClinica. 
13.4 Other definitions of outcome 
Toxic death:  
Any death to which drug toxicity is thought to have a major contribution. 
Early death:  
Death during the first three weeks of treatment that is not a toxic death. 
14
SAFETY REPORTING 
The Investigator will monitor each patient for clinical and laboratory evidence of adverse events on a routine basis 
throughout the study.  
Adverse event monitoring starts from the time the patient consents to the study until the patient’s last study visit (at 6 
months post-CRT). During this timeframe, all AEs which are serious must be reported to OCTO, as detailed in Section 
14.6. This includes SAEs occurring before patients are registered. Should an Investigator become aware of any study 
drug-related SAEs following this period, these must also be reported as stated below.  
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.  
14.1 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 experiences of relatively minor medical 
significance or accidental trauma (e.g. sprained ankle), which do not constitute 
a substantial disruption. 


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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. Pregnancies occurring within six months 
of the end of CRT must also be reviewed as to whether they meet SAE criteria 
(see section 15).  
Any event meets the definition of a DLT should be reported as an SAE (even 
if it doesn’t meet the definition of an SAE).
All dose-limiting toxicities should be notified to the Trial Office via the SAE expedited reporting system, even where the 
event does not meet the definition of an SAE as defined above (see section 14.6 for procedure). 
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 SmPC or Investigator’s Brochure, 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 (e.g. IB for an unapproved investigational 
product or SmPC for an approved product). 
14.2 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.  
electrocardiograms, 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 CTCAE Grade 3 or 4 laboratory abnormalities should 
usually be reported as SAEs. However, if a lab result is categorised as Grade 3 or 4 but did not fulfil the safety reporting 
criteria for an SAE (asymptomatic, not life threatening, no intervention), 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. 
If a laboratory abnormality is part of a diagnosis, the diagnosis should be reported as an AE/SAE. If possible, the 
laboratory abnormality should be recorded as a medical term and not simply as an abnormal laboratory result (e.g. 
record thrombocytopenia rather than decreased platelets). Discuss with clinician regarding significance. 
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.  
14.3 Determining adverse event causality 
A Serious Adverse Reaction (SAR) is a SAE that may be related to any IMP either on its own or in combination with RT. 
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. AEs that will be considered related will include any AE that is 
documented as possibly, probably or definitely related to protocol treatment. The assessment of relatedness is made 
using the following: 


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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

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 
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. 
14.4 Reference safety information (RSI) for assessment of expectedness 
The reference safety information (RSI) for the trial which lists all the expected side effects associated with trial treatment 
is: 

For atovaquone: section 4.8 of the SmPC for atovaquone.  

For cisplatin: section 4.8 of the SmPC for cisplatin. 

For vinorelbine: section 4.8 of the SmPC for vinorelbine. 
Please note that the list of expected side effects in the atovaquone SmPC are those listed for treatment of mild to 
moderate Pneumocystis pneumonia and in patients who are intolerant of co-trimoxazole therapy. It is therefore 
possible that in this study population other side effects may occur, or the patient might suffer a more severe reaction.  
Equally, the list of expected side effects in the SmPCs for cisplatin and vinorelbine are those listed for patients 
receiving standard chemoradiotherapy or chemotherapy alone. It is therefore possible that in this study population, 
where combination of atovaquone is used with standard chemoradiotherapy, other side effects may occur, or the 
patient might suffer a more severe reaction.   
A copy of the current approved version of the RSI documents must be held in the Investigator Site File for reference. 
The SmPCs used as RSI are the versions provided by OCTO (approved for use in this trial by the MHRA). It is not 
specified that any particular brand of cisplatin or vinorelbine must be prescribed, however irrespective of the brand 
prescribed, the RSI to be referenced is provided by OCTO. N.B. this may not be the latest SmPC version available 
online. Any change or update to the RSI during the trial will be made via a substantial amendment.  
Expected AEs due to chemoradiotherapy are listed in section 12.5. 
14.5 Suspected Unexpected Serious Adverse Drug Reactions (SUSARs) 
All SUSARS will 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 seven days of the Trial Office receiving the initial 
report. Any additional significant information will be reported within eight days of sending the first report. 

All other SUSARs will be reported within 15 days of the Trial Office receiving the initial report. Any additional, 
significant information must be reported within a further 15 days. 


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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.  
14.6 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 notified to the Trial Manager by phone or email and reported on the trial 
SAE report form (see SAE report form and completion guidelines). This should be completed, scanned and emailed 
within 24 hours of becoming aware of the event to: 
Pharmacovigilance Office, OCTO 
Email: octo-safety@oncology.ox.ac.uk
Tel no: 01865 617082 
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/Board policy for incident and SAE reporting in research. 
14.7 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.  
SAEs that are considered to be probably or definitely unrelated to any trial intervention will not be followed up and 
monitored. 
14.8 Reporting Adverse Events on the CRF 
All AEs, including Serious AEs must be recorded on the eCRF for registered patients, unless otherwise specified in section 
14.9. 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 any other 
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 eCRF 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. 
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 4.0 (currently up to Version 4.03). Toxicity grades should be recorded on the eCRF. These 
will be coded by OCTO to the MedDRA version current on the date of MHRA approval of the trial.  
14.9 Events exempt from being reported as AE/ SAEs 
Progression of underlying disease 
Disease progression and resultant death 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. 


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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, the 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 the following supportive care procedures are considered standard for this patient group and should not 
be reported as SAEs:

Non-emergency admission for feeding tube placement  

A visit to accident and emergency or other hospital department for less than 24 hours, that does not result in 
admission (unless considered an important medical or life-threatening event) 

Admissions as per protocol for a planned medical/surgical procedure 

Routine health assessment requiring admission for baseline/trending of health status  

Medical/surgical admission other than to remedy ill health and planned prior to entry into the study 

Admission encountered for another life circumstance that carries no bearing on health status and requires no 
medical/surgical intervention (e.g. lack of housing, economic inadequacy, caregiver respite, family 
circumstances, administrative reason) 

Admission for administration of anti-cancer therapy in the absence of any other SAEs  
14.10 Informing Investigators of new safety information 
Regular dose decision meetings will be held during which new safety information will be disseminated and discussed. 
Principal Investigators should attend such meetings, or send an appropriate representative.  
Principal Investigators are responsible for briefing their study team and onward transmission to their R&D office as 
appropriate. 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. 
14.11 Summary of trial safety reporting requirements 
Event 
DLT 
SAE 
AE/SAE 
AE/SAE defined as Dose limiting toxicity (DLT) 
Defined as per NCI CTCAE v4.03
Email SAE reporting 
form within 24 hours 
Report in 
AE CRF 
Non-
reportable 
Grade ≥4 absolute neutrophil count (ANC) (<0.5 x 109/L) for >7 days 
X 
X 
Grade ≥3 febrile neutropenia (fever of unknown origin without clinically or 
microbiologically documented infection) (ANC <1.0 x 109/L, fever ≥38.5°C) 
lasting >3 days 
X 
X 
Infection (documented clinically or microbiologically) with grade 3 or 4  
X 
X 


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neutropenia (ANC <1.0 x 109/L) 
Grade ≥3 thrombocytopenia (platelets <25 x 109/L) 
X 
X 
Clinically significant bleeding attributed to grade 3 thrombocytopenia or  
requiring platelet transfusion 
X 
X 
Grade ≥3 oesophagitis 
X 
X 
Grade ≥3 pneumonitis onset within 3 months of starting radiotherapy 
X 
X 
Grade ≥3 nausea or vomiting not controlled by optimal outpatient anti-emetic 
treatment for ≥5 days 
X 
X 
Grade ≥3 diarrhoea despite optimal outpatient anti-diarrhoeal medication use 
X 
X 
Any toxicity causing a delay of radiotherapy completion by greater than one 
week 
X 
X 
An elevation of ALT or AST >5 x ULN lasting 8 days or more 
X 
X 
A concurrent elevation of ALT or AST (>3 × ULN) and total bilirubin (>2 × ULN) in 
whom there is no evidence of biliary obstruction or other causes that can 
reasonably explain the concurrent elevation 
X 
X 
Other grade ≥3 effects thought to be clinically significant and directly related to 
the combination of atovaquone with chemoradiotherapy 
X 
X 
Medically important events in the context of this trial 
Email reporting form 
within 24 hours 
Report in 
AE CRF 
Non-
reportable 
Events believed to be possibly, probably or definitely related to treatment with 
Durvalumab rather than trial IMPs 
X 
X 
AE/SAEs, abnormal assessments and laboratory results 
Email reporting form 
within 24 hours 
Report in 
AE CRF 
Non-
reportable 
AE is life-threatening 
X 
X 
AE requires in-patient hospitalisation or prolongs existing inpatient 
hospitalisation 
X 
X 
AE results in persistent or significant incapacity or disability 
X 
X 
AE is a congenital anomaly or birth defect 
X 
X 
AE is any other medically important event 
X 
X 
All other grade ≥3 AEs, assessments, abnormal laboratory results, if clinically 
significant 
X 
X 
All other grade ≤2 AEs, assessments, abnormal laboratory results, if clinically 
significant 
X 
Grade ≥3 laboratory results not fulfilling safety reporting criteria 
X1
X1
Disease progression and death 
Email reporting form 
within 24 hours 
Report in 
AE CRF 
Non-
reportable 
Clinical symptoms, assessments or laboratory results associated with disease 
progression 
X 
Hospitalisation for disease progression 
X 
Non-emergency admission for feeding tube placement 
X 
A visit to accident and emergency or other hospital department for less than 24 
hours, that does not result in admission (unless considered an important 
medical or life-threatening event) 
X 
Admissions as per protocol for a planned medical/surgical procedure 
X 
Routine health assessment requiring admission for baseline/trending of health 
status 
X 
Medical/surgical admission other than to remedy ill health and planned prior to 
entry into the study 
X 
Admission encountered for another life circumstance that carries no bearing on 
health status and requires no medical/surgical intervention 
X 
Admission for administration of anti-cancer therapy in the absence of any other 
SAEs 
X 
Death 
X2
X3
1  If a lab result is categorised as Grade 3 or 4 but did not fulfil the safety reporting criteria for an SAE (asymptomatic, not life 
threatening, no intervention), 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. 
2  If death is possibly related directly to atovaquone or the combination of atovaquone + radiotherapy +/- chemotherapy. 
3  Providing the death is not unexpected or if a causal relationship is not suspected. The investigator must clearly state whether a 
causal relationship to atovaquone + radiotherapy +/- chemotherapy is suspected, and if so, whether the death was expected or 
unexpected. 


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15
PREGNANCY  
Pregnancies (in a participant or partner) occurring while participating in this trial require expedited reporting. A 
pregnancy form should be completed, 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 
Women who become pregnant should be withdrawn from trial treatment immediately. Any pregnancy occurring up to 
the patient’s last study visit (i.e. in the six months following CRT) should be reported by the participant to the Trial 
Office.   
16
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. 

The stated objectives of the study are achieved. 
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. 
17
STATISTICAL CONSIDERATIONS  
17.1 Study design 
This is a phase I, single arm, open label, two-centre study. The primary objective is to identify the MTD, and thus RPTD, 
of atovaquone when combined with concurrent CRT in NSCLC using a Bayesian TiTE-CRM design. 
The CRM is a model-based method for finding the maximum tolerated dose (MTD) under the defining monotonicity 
assumption which posits that toxicity increases monotonically with increasing dose, and that efficacy also increases with 
increasing dose. The objective is to find the dose with a probability of experiencing a Dose Limiting Toxicity (DLT) close 
to a pre-specified target toxicity level. The TiTE-CRM is a modified version of the CRM that allows late-onset toxicities 
to be accounted for without fully observing a patient before recruiting the next and is therefore particularly 
advantageous for radiotherapy trials where toxicities are often observed later than in studies using systemic therapy 
alone. A major advantage of the TiTE-CRM is the fact that it uses all current accumulated information to decide which 
dose to assign the next patient. A further advantage of this design is that it will be able to include partial information on 
patients who could not be formally evaluated for DLTs due to withdrawal, treatment discontinuation or death, that is 
unrelated to treatment within the DLT assessment period (from week-2/-3 to three months post-CRT). In addition, the 
method results in shorter study duration as it is not necessary for a patient to be observed for the full observation period 
before recruiting the next patient, and also more patients are treated close to the MTD. 
Toxicity will be scored according to NCI CTCAE v4.03 with DLT definition as stated in Section 9. The trial aims to identify 
the MTD which is the dose associated with no more than 48% DLT rate (target toxicity level). This is based on the fact 
that standard concurrent CRT for NSCLC is often associated with a significant Grade 3 toxicity rate. Average rates of 
Grade 3 oesophagitis are in the region of 25%, although reported rates are variable and can be as high as 48%.  
In addition, rates of Grade 3 pneumonitis as high as 32% have been reported and haematological toxicity when using 
platinum-doublet chemotherapy can also be significant in this patient population [22]. The atovaquone treatment 
schedule lasts for up to 9.5 weeks, with patients followed up at the end of the DLT assessment period (at three months 
post-CRT). An additional follow-up occurs a further three months later (at six months post-CRT), to provide a total trial 
observation window of up to 38 weeks. 


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17.2
The TiTE-CRM model  
A two-parameter Bayesian logistic model with weak priors will be used. The priors are calibrated to ensure the model 
provides sensible recommendations early in the trial. With this model we can obtain a distribution for the probability 
of DLT rate given a specific dose d based on all available data. This is a posterior probability distribution for dose d. We 
write P(T>0.48|Data, dose = d) to mean the posterior probability that the DLT rate is greater than 48% on dose d, given 
the data observed so far.  
At each dose decision (to assign a dose to the next patient), data for patients who have completed the DLT assessment 
period or experienced a DLT will contribute full information to this model. Only partial information is known for patients 
who are currently on trial, within the DLT assessment period, or have stopped treatment in the DLT assessment period 
for reasons other than a DLT. This partial information contributes to the model, weighted proportionally to the observed 
portion of their toxicity time window and treating them as not experiencing a DLT.   
17.3
Dose selection during the trial 
The trial will start at the lowest dose of atovaquone (Dose 1: 450 mg BD). Two participants will receive this dose and 
escalation will only be considered when we have at least 12 weeks of safety data (high risk period of developing DLT) 
for at least one participant at this dose level, thus preventing inappropriate early dose escalation. Following this initial 
safety run in, all eligible patients will be continuously recruited. The TiTE-CRM model will be fitted every time a new 
patient is registered to recommend the dose of atovaquone from the possible doses: 450 mg, 600 mg, 675 mg or 750 
mg. The dose recommended will be the dose with posterior mean DLT rate closest to the target toxicity level, subject 
to no dose skipping.  
In order to escalate to a higher dose of atovaquone, there must be at least one patient on the previous highest dose 
who fulfils the following criteria:   

Completed ≥1 full cycle of CRT (i.e. at least three weeks of RT) 

Received ≥50% the specified dose of cisplatin 

Taken ≥75% their allocated dose of atovaquone 

Not experienced a DLT 
The data provided to the model is binary (1 or 0 for experiencing a dose limiting toxicity or not) and thus information 
about severity of toxicities is not used. Whilst the model is carefully designed to make sensible decisions based on what 
the TMG would do in a certain situation, ultimately, the model and decision rules act as a guide. All dose 
recommendations made by the model will be reviewed by the TMG. The TMG will meet in person, teleconference, or 
via correspondence, and either approve the dose allocation recommendation or select a different dose on the basis of 
clinical review of the data. Additionally, since the window to observe toxicities is long, the TMG may opt to pause 
recruitment whilst on-trial patients complete their treatment. The trial will stop for safety if there is sufficient evidence 
to suggest that the lowest dose is too toxic. More specifically, we will consider dose level 1 to be too toxic if, given all 
the available data, there is a high probability that the DLT rate is greater than the target toxicity level of 48%. 
We considered a number of scenarios to ensure that the trial design was appropriate. For each scenario, 1000 
simulations were performed to assess and improve the model-based trial design. Full details of the simulated 
performance of the design under these scenarios are available in the Statistical Analysis Plan. 
Further detail of the dose selection process will be defined in a separate Protocol Decision Point Plan (PDPP). Data 
used to inform dose selection will include all relevant data points as defined in the PDPP entered on the trial database 
prior to performing a data extract for the purpose of running the TiTE-CRM model. The trial management team will 
work with trial sites to ensure data contained in the database is as complete and accurate as possible prior to each 
dose selection decision. However, due to the need to make timely decisions, data extracts may have missing data or 
include data that has not been fully cleaned. Source Data Verification (SDV) of data against the patient notes will only 
be completed where this is indicated by the trial risk assessment.  
17.4 Sample size  
The sample size will be 20 evaluable patients. 
The estimated accrual for this study is one patient per month and therefore the maximum patient accrual is expected 
to be completed within 20 months. Additional time is required to allow safety data collection to be collected to ensure 
all patients complete the DLT assessment window.  


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17.5 MTD and RPTD definition 
The MTD will be the final recommended dose after the trial has completed recruitment using all data accumulated in 
the trial. The MTD will constitute the recommended phase II dose (RPTD). 
17.6 Stopping the trial 
The trial will stop for safety if there is sufficient evidence that the lowest dose is too toxic (if P(T>0.48|dose = 1, current 
data) > 0.7).  
18
STATISTICAL ANALYSIS PLAN 
All patients who receive at least one dose of atovaquone, regardless of how much treatment received and follow-up 
completed, will contribute to analysis. It is therefore important that every effort is made to encourage patients, 
including those patients who do not receive/complete their allocated treatment, to attend for follow-up clinic visits to 
avoid bias in the analysis of the results. 
A detailed Statistical Analysis Plan will be available from the time the first patient is recruited and will be finalised before 
any analysis is undertaken. The analysis plan will be written in accordance with the current OCTRU standard operating 
procedures and will be finalised and agreed by the trial statistician and the CI. Sites must report any unintended 
deviations to OCTO according to the procedure outlined in site training.  
18.1 Inclusion in analysis 
All patients enrolled in the study and who received at least one dose of atovaquone will be accounted for and 
included in the analyses. The number of patients who were not evaluable, who died or withdrew before 
treatment began will be recorded. The distribution of follow-up time will be described and the number of patients lost 
to follow-up will be given. 
The analysis will include a description of patients who did not meet all the eligibility criteria, an assessment of 
protocol deviations, study drug accountability and other data that impact on the general conduct of the study.  
Baseline characteristics will be summarised for all enrolled patients. Patients who died or withdrew before treatment  
started or do not complete the required safety observations will be described and evaluated separately. Treatment-
related toxicity will be tabulated by type and grade of toxicity.  All patients will be evaluable for  
toxicity from the time of their first treatment. Adverse events will be summarised by the number of patients 
experiencing each type of event. The grades and causality will be reported.  
18.2 Subgroup analysis
No subgroup analysis is planned.  
18.3 Interim Analyses 
For each patient recruited after the initial two patients, the TiTE-CRM model will use all current available data to 
recommend the dose to assign the patient.   
18.4 Procedures for reporting any deviation(s) from the original statistical plan 
Any deviations from the original statistical plan will be described and justified in the final report.
18.5 Final analysis 
Based upon projected accrual rates, this trial is expected to complete recruitment within 20 months of opening to 
recruitment. Final analysis will be after all patients have either completed their six-month follow up visit, have 
experienced a DLT, or have withdrawn from the study.  
19
TRIAL COMMITTEES 
19.1 Trial Management Group (TMG) 
The Chief Investigator will chair a TMG responsible for overseeing the successful conduct and publication of the trial. 


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The TMG will include Chief Investigator, Co-Investigators, Clinical Trial Manager, Trial Statistician and others as required. 
The TMG will meet as necessary to discuss toxicity data and to decide on dose escalation. TMG membership and 
decision-making procedures will be documented in the TMG charter. 
19.2 Data and Safety Monitoring 
There is no independent Data and Safety Monitoring Committee (DSMC) for this trial. The Safety Review Committee 
(SRC) will be convened, as required, to review DLTs and dose escalation decisions made by the TMG. In the event of 
the TMG being unable to conclude on a dose recommendation, the SRC will meet to decide. The main outcomes will 
be analysed as stated in the analysis plan and will not be analysed as an interim analysis. The SRC will consist of: 
1. Trial Statistician 
2. OCTO trial management representative 
3. Either: 
a.  One Medical Oncologist and one Clinical Oncologist or 
b.  Two Clinical Oncologists 
The SRC Charter document for this trial will define the exact membership and who should be present for decisions to 
be made. Further internal or external experts may be consulted by the SRC, as necessary. Any PI can request an ad hoc 
SRC meeting at any time in order to facilitate the immediate communication of any emerging safety issues during the 
course of the trial.
19.3 Trial Steering Committee 
The Independent Radiotherapy and Imaging Oversight Committee (RIOC) will act as the TSC. The role of RIOC is to 
provide oversight for the trial on behalf of the Sponsor and Funders. RIOC will provide overall supervision of the safe 
and effective conduct of the trial, as further defined in the RIOC charter. At least annually, RIOC will review trial progress 
against agreed milestones, adherence to protocol, and patient safety, and consider new information. RIOC has the 
authority to recommend study closure where appropriate. Membership of RIOC includes PPI representation.  
20
DATA MANAGEMENT 
20.1 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 and/or code in any database.  The name and any 
other identifying detail will NOT be included in any trial data electronic file, except where patients have consented to 
NHS Digital flagging. In this case, patients will have their name and NHS number stored in a secure section of a digital 
database (RRAMP) for secure transfer to NHS Digital. 
20.2 Case report 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). CRF 
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:
1.
The relevant CRFs are completed. 
2.
All CRF data are verifiable in the source documentation or the discrepancies must be explained.  
3.
CRF sections are completed in a timely fashion, as close to the visit or event being recorded as possible. 
4.
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. 
5.
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 five working days of the initial event and within 14 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.  


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20.3 Importance of rapid data return 
Data analysis will be performed in real-time based on all relevant available data to best inform the atovaquone dose to 
allocate to the next patient. It will also provide safety monitoring. For these reasons, it is important that data is collected 
and made available on OpenClinica swiftly, no more than five working days of the initial event and within 14 days of 
receipt of a data query unless otherwise specified. 
In the event of data which is critical to a dose decision, the Trial Office may request that sites provide data in less 
than 5 working days.  
20.4 Accounting for missing, unused, or spurious data. 
The statistical analysis plan describes the procedure for accounting for missing, unused or spurious data. 
21
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.  
22
STUDY SITE MANAGEMENT 
22.1 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.  
22.2 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. 
22.3 Study documentation 
The Trial Office will provide an Investigator File, Pharmacy File and Radiology 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. 
23
REGULATORY AND ETHICAL CONSIDERATIONS 
The Sponsor and Investigators will ensure that this protocol will be conducted in compliance with the UK Clinical Trials 
Regulations [23], 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. 
23.1 Ethics, HRA and regulatory approvals 
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). HRA approval will also 
be obtained prior to initiating the study. 


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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.  
23.2 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. 
23.3 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. 
23.4 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.   
23.5 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: 
1.
Interrupt the treatment of subjects already in the trial for safety reasons; 
2.
Stop recruitment on safety grounds; or 
3.
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. 


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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. 
23.6 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:  
1. The safety or physical or mental integrity of the subjects of the trial; or 
2. The scientific value of the trial” 
In the event that a serious breach is suspected, the Trials Office must be contacted within one working day. In 
collaboration with the CI, the serious breach will be reviewed by the Trials Office and, if appropriate, the Trials Office 
will report it to the REC committee, Regulatory Authority and the relevant NHS host organisation within seven 
calendar days. 
23.7 Trial Reports 
This protocol will comply with all current applicable Regulatory Authority, Research Ethics Committee and Sponsor 
reporting requirements.  
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. 
23.8
Transparency in Research  
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.  
24
EXPENSES AND BENEFITS 
The Trial Office is unable to provide reimbursement for patients’ travel expenses incurred by participating in this trial. 
Sites should, where possible, use local funding arrangements to reimburse patients reasonable travel expenses for visits 
additional to normal care. Sites should provide clear information to patients on the funding available and any 
requirements (e.g. production of receipts). 
25
QUALITY ASSURANCE 
25.1 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. 
25.2 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 


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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 following participant information to the Trial Office on request for remote monitoring 
purposes. All patient personal identifiers must be obliterated from the information except where explicit consent for 
release of personal information has been obtained from the patient:  

Participant screening log  
25.3 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. 
26
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 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 and imaging data must also follow these guidelines. 
Retention and storage of central laboratory records supporting pharmacokinetic (PK) 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 five years. Investigators may not archive or 
destroy study essential documents or samples without written instruction from the Trial Office. 
27
PATIENT CONFIDENTIALITY 
The study will comply with the General Data Protection Regulation (GDPR) and Data Protection Act 2018, which 
require data to be de-identified as soon as it is practical to do so. The processing of the personal data of participants 
will be minimised by making use of a unique participant study number only on all study documents and any electronic 
database(s), with the exception of: 

The CRF, where participant initials and year of birth may be added 

The NHS Digital tracing form (if patients have consented to long term follow up) – where participant name 
and NHS number will be required 
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. 


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The Investigator site must maintain the patient’s anonymity in all other 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. 
28
STUDY FUNDING 
The ARCADIAN trial is funded by the Clinical Research Committee (Clinical Trial Awards) on behalf of Cancer Research 
UK (C34326/A27515). This trial is further supported via the University of Oxford Department of Oncology core clinical 
and research infrastructure underpinned by strategic research programme grant funds. As a Cancer Research UK funded 
trial, ARCADIAN is eligible for inclusion on the NIHR portfolio; local research network support should be available at 
each site taking part to support entry of participants into this trial (via the NIHR in England and in Scotland via NHS 
Research Scotland). 
29
SPONSORSHIP AND INDEMNITY 
29.1 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.  
29.2 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 which is provided.  
29.3 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. 
Ownership of intellectual property (IP) generated by employees of the University vests in the University. The University 
will ensure appropriate arrangements are in place as regards any new IP arising from the trial. 
30
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 trial. 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 trial was 
Sponsored by and performed with the support of the Sponsor and other funding bodies as appropriate. 
31
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Soeberg, H. You, T. Matsuda, M. Bielska-Lasota, H. Storm, T. C. Tucker, M. P. Coleman and and the CONCORD 
Working Group, "Global surveillance of cancer survival 1995–2009: analysis of individual data for 25 676 887 
patients from 279 population-based registries in 67 countries (CONCORD-2)," The Lancet, vol. 385, p. 977–1010, 
2015.  
[23] Department of Health and Social Care, The Medicines for Human Use (Clinical Trials) Regulations (S.I. 2004/1031) 
and any subsequent amendments, 2004.  
APPENDIX 1: ECOG PERFORMANCE SCALE 
Activity Performance Description 
Score 


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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: MEASUREMENT OF DISEASE - RECIST CRITERIA 
RESPONSE EVALUATION CRITERIA IN SOLID TUMOURS 
Objective tumour response and time of progression will be measured according to the RECIST (Response Evaluation 
Criteria In Solid Tumours) criteria (version 1.1).  
Response criteria are essentially based on a set of measurable lesions identified at baseline as target lesions, and – 
together with other lesions that are denoted as non-target lesions – followed until disease progression. 
The following paragraphs are a quick reference to the RECIST criteria (version 1.1). The complete criteria are included 
in the published RECIST document: 
Eisenhauer, EA, Therasse, P, Bogaerts, J, et al. New response evaluation criteria in solid tumours: revised RECIST 
guideline (version 1.1). Eur J Cancer 2009;45:228-247.  
And also available at: http://www.eortc.be/RECIST
B.1 
Measurability of tumour lesions at baseline 
B.1.1 
Definitions 

Measurable disease - the presence of at least one measurable lesion. If the measurable disease is restricted to 
a solitary lesion, its neoplastic nature should be confirmed by cytology/histology.  

Measurable lesions - tumour lesions that can be accurately measured in at least one dimension (longest 
diameter to be recorded) as ≥ 20 mm with chest x-ray, and as ≥ 10 mm with CT scan or clinical examination 
[using callipers]. Bone lesions are considered measurable only if assessed by CT scan and have an identifiable 
soft tissue component that meets these requirements (soft tissue component > 10 mm by CT scan). Malignant 
lymph nodes must be ≥ 15 mm in the short axis to be considered measurable; only the short axis will be 
measured and followed. All tumour measurements must be recorded in millimetres (or decimal fractions of 
centimetres) by use of a ruler or callipers. Tumour lesions situated in a previously irradiated area, or in an area 
subjected to other loco-regional therapy, are usually not considered measurable unless there has been 
demonstrated progression in the lesion.  

Non-measurable lesions - All other lesions (or sites of disease), including small lesions are considered non-
measurable disease. Bone lesions without a measurable soft tissue component, leptomeningeal disease, 
ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonis, inflammatory breast disease, lymphangitic 
involvement of lung or skin and abdominal masses followed by clinical examination are all non-measurable. 
Nodes that have a short axis <10 mm at baseline are considered non-pathological and should not be recorded 
or followed.  

Target Lesions. When more than one measurable tumour lesion or malignant lymph node is present at baseline 
all lesions up to a maximum of 5 lesions total (and a maximum of 2 lesions per organ) representative of all 
involved organs should be identified as target lesions and will be recorded and measured at baseline. Target 
lesions should be selected on the basis of their size (lesions with the longest diameter), be representative of 
all involved organs, but in addition should be those that lend themselves to reproducible repeated 
measurements. Note that pathological nodes must meet the criterion of a short axis of ≥ 15 mm by CT scan 
and only the short axis of these nodes will contribute to the baseline sum. At baseline, the sum of the target 
lesions (longest diameter of tumour lesions plus short axis of lymph nodes: overall maximum of 5) is to be 
calculated and recorded. 

Non-target Lesions. All non-measurable lesions (or sites of disease) including pathological nodes (those with 
short axis ≥ 10 mm but < 15 mm), plus any measurable lesions over and above those listed as target lesions are 
considered non-target lesions. Measurements are not required but these lesions should be noted at baseline 
and should be followed as “present” or “absent”. 
All baseline evaluations should be performed as closely as possible to the beginning of treatment and never more than 
4 weeks before the beginning of the treatment. 


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B.1.2 
Methods of measurements 
The same method of assessment and the same technique should be used to characterize each identified and reported 
lesion at baseline and during follow-up. Assessments should be identified on a calendar schedule and should not be 
affected by delays in therapy, which may be treatment arm dependent. While on study, all target lesions recorded at 
baseline should have their actual measurements recorded on the CRF at each subsequent evaluation, even when very 
small (e.g. 2 mm). If it is the opinion of the radiologist that the lesion has likely disappeared, the measurement should 
be recorded as 0 mm. If the lesion is believed to be present and is faintly seen but too small to measure, a default value 
of 5 mm should be assigned. For lesions which fragment/split add together the longest diameters of the fragmented 
portions; for lesions which coalesce, measure the maximal longest diameter for the “merged lesion”. 

Clinical Lesions. Clinical lesions will only be considered measurable when they are superficial and ≥ 10 mm as 
assessed using callipers (e.g. skin nodules). For the case of skin lesions, documentation by colour photography 
including a ruler to estimate the size of the lesion is recommended. If feasible, imaging is preferred. 

Chest X-ray. Chest CT is preferred over chest X-ray, particularly when progression is an important endpoint, 
since CT is more sensitive than X-ray, particularly in identifying new lesions. However, lesions > 20 mm on chest 
X-ray may be considered measurable if they are clearly defined and surrounded by aerated lung. 

CT, MRI. CT is the best currently available and reproducible method to measure lesions selected for response 
assessment. This guideline has defined measurability of lesions on CT scan based on the assumption that CT 
slice thickness is 5 mm or less. When CT scans have slice thickness greater than 5 mm, the minimum size for a 
measurable lesion should be twice the slice thickness. MRI is also acceptable in certain situations (e.g. for body 
scans). While PET scans are not considered adequate to measure lesions, PET-CT scans may be used providing 
that the measures are obtained from the CT scan and the CT scan is of identical diagnostic quality to a diagnostic 
CT (with IV and oral contrast). 

Ultrasound. Ultrasound is not useful in assessment of lesion size and should not be used as a method of 
measurement. If new lesions are identified by ultrasound in the course of the study, confirmation by CT should 
be obtained.  

Endoscopy, Laparoscopy. The utilization of these techniques for objective tumour evaluation is not advised. 
However, they can be useful to confirm complete pathological response when biopsies are obtained or to 
determine relapse in trials where recurrence following complete response or surgical resection is an endpoint. 

Tumour Markers. Tumour markers alone cannot be used to assess objective tumour response. If markers are 
initially above the upper normal limit, however, they must normalize for a patient to be considered in complete 
response.  

Cytology, Histology. These techniques can be used to differentiate between PR and CR in rare cases if required 
by protocol (for example, residual lesions in tumour types such as germ cell tumours, where known residual 
benign tumours can remain). When effusions are known to be a potential adverse effect of treatment (e.g. 
with certain taxane compounds or angiogenesis inhibitors), the cytological confirmation of the neoplastic origin 
of any effusion that appears or worsens during treatment when the measurable tumour has met criteria for 
response or stable disease is advised to differentiate between response or stable disease and progressive 
disease. 
B.2 
Tumour response evaluation 
All patients will have their BEST RESPONSE from the start of study treatment until the end of treatment classified as 
outlined below. Complete or partial responses may be claimed only if the criteria for each are met at a subsequent 
time point at least 4 weeks later. Refer to the table B1and table B2 below. 

Complete Response (CR): disappearance of all target and non-target lesions and normalization of tumour 
markers. Pathological lymph nodes must have short axis measures < 10 mm (Note: continue to record the 
measurement even if < 10 mm and considered CR). Tumour markers must have normalized. Residual lesions 
(other than nodes < 10 mm) thought to be non-malignant should be further investigated (by cytology or PET 
scans) before CR can be accepted.  

Partial Response (PR): at least a 30% decrease in the sum of measures (longest diameter for tumour lesions 
and short axis measure for nodes) of target lesions, taking as reference the baseline sum of diameters. Non-
target lesions must be non-PD.  

Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD 
taking as reference the smallest sum of diameters on study. 


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
Progressive Disease (PD): at least a 20% increase in the sum of diameters of measured lesions taking as 
references the smallest sum of diameters recorded on study (including baseline) AND an absolute increase of 
≥ 5 mm. Appearance of new lesions will also constitute PD (including lesions in previously unassessed areas). 
In exceptional circumstances, unequivocal progression of non-target disease may be accepted as evidence of 
disease progression, where the overall tumour burden has increased sufficiently to merit discontinuation of 
treatment, for example where the tumour burden appears to have increased by at least 73% in volume 
(which is the increase in volume when all dimensions of a single lesion increase by 20%). Modest increases in 
the size of one or more non-target lesions are NOT considered unequivocal progression. If the evidence of PD 
is equivocal (target or non-target), treatment may continue until the next assessment, but on further 
documentation, the earlier date must be used.
Table B1: Integration of target, non-target and new lesions into response assessment 
Target Lesions
Non-Target Lesions
New Lesions
Overall Response
Best Response for this category also requires
Patients with Target lesions ± non-target lesions
CR 
CR 
No 
CR 
Normalization of tumour markers
All tumour nodes < 10 mm 
Documented at least once ≥ 4 weeks from 
baseline 
CR
Non-CR/Non-PD
No
PR
Documented at least once ≥ 4 weeks from 
baseline 
CR
Not all evaluated
No
PR
PR
Non-PD/ not all evaluated
No
PR
SD
Non-PD/ not all evaluated
No
SD
Not all evaluated
Non-PD
No
NE
PD
Any
Any
PD
Any
PD
Any
PD
Any
Any
Yes
PD
Patients with non-target lesions ONLY
No Target 
CR 
No 
CR 
Normalization of tumour markers
All tumour nodes < 10 mm 
Documented at least once ≥ 4 weeks from 
baseline 
No Target
Non-CR/non-PD
No
Non-CR/ non-PD
No Target
Not all evaluated
No
NE
No Target
Unequivocal PD
Any
PD
No Target
Any
Yes
PD
Note: Patients with a global deterioration of health status requiring discontinuation of treatment without objective evidence of disease progression [or evidence of 
unequivocal disease progression] at that time should be reported as “symptomatic deterioration”. This is a reason for stopping therapy, but is NOT objective PD. Every 
effort should be made to document the objective progression even after discontinuation of treatment.
Complete or partial responses may be claimed only if the criteria for each are met at a subsequent time point at least 
four weeks later. The best overall response can be interpreted from Table B2. 
Table B2: Response assessment after subsequent scan 
Response: 
First time point 
Subsequent 
time point 
BEST overall response 
Also requires 
CR 
CR 
CR 
Normalization of tumour markers
All tumour nodes < 10 mm 
CR
PR
SD, PD or PR (see comment*)
CR
SD
SD provided minimum criteria for SD duration met, otherwise, PD
CR
PD
SD provided minimum criteria for SD duration met, otherwise, PD
CR
NE
SD provided minimum criteria for SD duration met, otherwise NE
PR
CR
PR
PR
PR
PR
PR
SD
SD
PR
PD
SD provided minimum criteria for SD duration met, otherwise PD
PR
NE
SD provided minimum criteria for SD duration met, otherwise NE
NE
NE
NE
* May consider PR providing initial “CR” likely PR on subsequent review – then original CR should be corrected. Recurrence of lesion after true CR is PD.


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B.2.1 
Frequency of tumour re-evaluation 
Response will only be evaluated at one timepoint.  
B.2.2 
Date of progression 
This is defined as the first day when the RECIST (version 1.1) criteria for PD are met.  
B.3 
Reporting of tumour response 
All patients included in the study must be assessed for response to treatment, even if there is a major protocol treatment 
deviation or if they are ineligible, or not followed/re-evaluated. Each patient will be assigned one of the following 
categories: complete response, partial response, stable disease, progressive disease, early death from malignant 
disease, early death from toxicity, early death from other cause or unknown (not assessable, insufficient data). 
Early death is defined as any death occurring before the first per protocol time point of tumour re-evaluation. The 
responsible Investigator will decide if the cause of death is malignant disease, toxicity or other cause. 
Patients for whom response is not confirmed will be classified as "unknown", unless they meet the criteria for stable 
disease (or the criteria for partial response in case of an unconfirmed complete response). Patients’ response will also 
be classified as "unknown" if insufficient data were collected to allow evaluation per these criteria. 
APPENDIX 3: AMENDMENT HISTORY 
Amendment 
No. 
Protocol 
Version 
No. 
Date issued
Details of Changes made
N/A
V1.0
30Jan2020
N/A - first version
N/A –
amended prior 
to approval.  
V2.0
23Mar2020
On request of MHRA during approval process: 
-
Reduction of dose limiting toxicity rate (target toxicity 
level) from 50% to 48%. 
-
Amendment of SAE reporting period to reflect AE 
reporting period (from consent to 6 months post-CRT).  

SAP_001.pdf: 
______________________________________          
SAP Version No: V1.0 
 
OCTRU-OST-001_V3.0_16Feb2018 
Date: 17Jun2021 
 
Effective Date 23Feb2018 
SAP Author: Cathy Qi 
Page 1 of 16 
 
 
 
 
Full title:  
A Phase I Trial of the Hypoxia Modifier Atovaquone in Combination with Radical 
Concurrent Chemoradiotherapy in Locally Advanced Non-Small Cell Lung Cancer 
Short title:  
Atovaquone with Radical ChemorADIotherapy in locally Advanced NSCLC 
 
Statistical Analysis Plan 
Version V1.0 – 17Jun2021 
 
Based on Protocol version V2.0 – 23Mar2020 
Trial registration: 2019-002097-30 
 
 
Role 
Name 
Title   
Author 
Cathy Qi 
Trial Statistician  
Reviewer 
Jane Holmes 
Senior Trial Statistician 
Approver  
Geoff Higgins  
Chief Investigator 
 
Oxford Clinical Trials Research Unit (OCTRU) 
Centre for Statistics in Medicine (CSM) 
 
 
                      
 
 


ARCADIAN: A Phase I Trial of the Hypoxia Modifier Atovaquone in Combination with Radical Concurrent Chemoradiotherapy in Locally Advanced Non-
Small Cell Lung Cancer. Funded by Cancer Research UK. EudraCT Number: 2019-002097-30. Protocol Number: OCTO_088 
______________________________________          
SAP Version No: V1.0 
 
OCTRU-OST-001_V3.0_16Feb2018 
Date: 17Jun2021 
 
Effective Date 23Feb2018 
SAP Author: Cathy Qi 
Page 2 of 16 
 
CONTENTS 
 
INTRODUCTION ............................................................................................................................... 3 
 
KEY PERSONNEL ...................................................................................................................................... 3 
 
CHANGES FROM PREVIOUS VERSION OF SAP ............................................................................................... 4 
 
BACKGROUND AND OBJECTIVES ....................................................................................................... 5 
 
BACKGROUND AND RATIONALE ................................................................................................................. 5 
 
OBJECTIVES ........................................................................................................................................... 5 
 
STUDY METHODS ............................................................................................................................. 6 
 
TRIAL DESIGN/FRAMEWORK ..................................................................................................................... 6 
 
RANDOMISATION AND BLINDING ............................................................................................................... 7 
 
SAMPLE SIZE .......................................................................................................................................... 7 
 
STATISTICAL INTERIM ANALYSIS, DATA REVIEW AND STOPPING GUIDELINES ..................................................... 7 
 
TIMING OF FINAL ANALYSIS ...................................................................................................................... 8 
 
BLINDED ANALYSIS .................................................................................................................................. 8 
 
STATISTICAL ANALYSIS OUTLINE ................................................................................................................ 9 
 
STATISTICAL PRINCIPLES................................................................................................................... 9 
 
STATISTICAL SIGNIFICANCE AND MULTIPLE TESTING ..................................................................................... 9 
 
DEFINITION OF ANALYSIS POPULATIONS ..................................................................................................... 9 
 
TRIAL POPULATION AND DESCRIPTIVE ANALYSES ............................................................................. 9 
 
REPRESENTATIVENESS OF STUDY SAMPLE AND PATIENT THROUGHPUT ............................................................ 9 
 
WITHDRAWAL FROM TREATMENT AND/OR FOLLOW-UP ................................................................................ 9 
 
BASELINE COMPARABILITY...................................................................................................................... 10 
 
UNBLINDING ........................................................................................................................................ 10 
 
DESCRIPTION OF COMPLIANCE WITH INTERVENTION ................................................................................... 10 
 
RELIABILITY .......................................................................................................................................... 10 
 
ANALYSIS ....................................................................................................................................... 10 
 
OUTCOME DEFINITIONS ......................................................................................................................... 10 
 
ANALYSIS METHODS ............................................................................................................................. 12 
 
MISSING DATA ..................................................................................................................................... 13 
 
SENSITIVITY ANALYSIS ............................................................................................................................ 13 
 
PRE-SPECIFIED SUBGROUP ANALYSIS ........................................................................................................ 14 
 
SUPPLEMENTARY/ ADDITIONAL ANALYSES AND OUTCOMES ........................................................................ 14 
 
HARMS ............................................................................................................................................... 14 
 
HEALTH ECONOMICS AND COST EFFECTIVENESS (WHERE APPLICABLE) ........................................................... 14 
 
META-ANALYSES (IF APPLICABLE) ............................................................................................................ 14 
 
VALIDATION OF THE PRIMARY ANALYSIS ........................................................................................ 14 
 
SPECIFICATION OF STATISTICAL PACKAGES ..................................................................................... 14 
 
REFERENCES .................................................................................................................................. 14 
 GLOSSARY OF ABBREVIATIONS ....................................................................................................... 15 
 APPENDIX 1 (SEPARATE DOCUMENT) ............................................................................................. 15 
 APPENDIX 2 (SEPARATE DOCUMENT) ............................................................................................. 15 
 APPENDIX 3 (SEPARATE DOCUMENT) ............................................................................................. 15 
 APPENDIX 4 ................................................................................................................................... 15 
 


ARCADIAN: A Phase I Trial of the Hypoxia Modifier Atovaquone in Combination with Radical Concurrent Chemoradiotherapy in Locally Advanced Non-
Small Cell Lung Cancer. Funded by Cancer Research UK. EudraCT Number: 2019-002097-30. Protocol Number: OCTO_088 
______________________________________          
SAP Version No: V1.0 
 
OCTRU-OST-001_V3.0_16Feb2018 
Date: 17Jun2021 
 
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SAP Author: Cathy Qi 
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 INTRODUCTION 
This document details the proposed data presentation and analysis for the main paper(s) and final study 
reports from the Cancer Research UK -funded multicentre single-arm trial of the hypoxia modifier 
atovaquone in combination with radical concurrent chemoradiotherapy in locally advanced non-small cell 
lung cancer (ARCADIAN).  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.  
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 source of the 
suggestion will be acknowledged. 
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. 
 Key personnel 
Trial statisticians 
Cathy Qi (Author)   
Email: cathy.qi@csm.ox.ac.uk 
Jane Holmes (Reviewer)  
Email: jane.holmes@csm.ox.ac.uk 
Medical Statisticians 
Centre for Statistics in Medicine 
University of Oxford 
Botnar Research Centre 
Windmill Road 
Oxford OX3 7LD 
 
Chief Investigator  
Geoff Higgins (Approver)  
Email: Geoffrey.Higgins@oncology.ox.ac.uk 
Consultant Clinical Oncologist and Clinician Scientist 
CRUK/MRC Oxford Institute for Radiation Oncology 
University of Oxford 
Old Road Campus Research Building 
Oxford OX3 7DQ 
Tel.: 01865 617355 
 
Trial management 
Ruth Harman (Trial manager)  
Email: octo-arcadian@oncology.ox.ac.uk 


ARCADIAN: A Phase I Trial of the Hypoxia Modifier Atovaquone in Combination with Radical Concurrent Chemoradiotherapy in Locally Advanced Non-
Small Cell Lung Cancer. Funded by Cancer Research UK. EudraCT Number: 2019-002097-30. Protocol Number: OCTO_088 
______________________________________          
SAP Version No: V1.0 
 
OCTRU-OST-001_V3.0_16Feb2018 
Date: 17Jun2021 
 
Effective Date 23Feb2018 
SAP Author: Cathy Qi 
Page 4 of 16 
 
Oncology Clinical Trials Office (OCTO) 
Department of Oncology 
University of Oxford 
Old Road Campus Research Building 
Oxford OX3 7DQ, UK 
 
 Changes from previous version of SAP 
The following table is 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.  
Version number 
Issue date 
Author of 
this issue 
Protocol Version & Issue 
date 
Significant changes from 
previous version together with 
reasons 
V1.0_17Jun2021 
CQ 
V2.0 – 23Mar2020 
Not applicable as this is the 1st 
issue 
 
 
 
 
 
 
 
 
 
 
 


ARCADIAN: A Phase I Trial of the Hypoxia Modifier Atovaquone in Combination with Radical Concurrent Chemoradiotherapy in Locally Advanced Non-
Small Cell Lung Cancer. Funded by Cancer Research UK. EudraCT Number: 2019-002097-30. Protocol Number: OCTO_088 
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SAP Author: Cathy Qi 
Page 5 of 16 
 
 BACKGROUND AND OBJECTIVES 
 Background and rationale 
The following table summarises the study protocol.  
Full Title of study: 
A Phase I Trial of the Hypoxia Modifier Atovaquone in Combination with Radical Concurrent 
Chemoradiotherapy in Locally Advanced Non-Small Cell Lung Cancer 
Short Title: 
Atovaquone with Radical ChemorADIotherapy in locally Advanced NSCLC 
Trial Acronym: 
ARCADIAN 
Clinical Phase: 
Phase I 
Study Design: 
Single arm, open-label trial utilising Time To Event Continual Reassessment Method (TiTE-CRM) 
Objectives and 
endpoints  
The primary objective is to determine the maximum tolerated dose (MTD), and therefore 
recommended phase II dose (RPTD), of atovaquone when combined with radical concurrent 
chemoradiotherapy. The full list of study objectives and endpoints is in Section 2.2.  
Planned enrolment: 
20 evaluable participants 
Target Population: 
Patients with locally advanced Non-Small Cell Lung Cancer planned to be treated with concurrent 
chemoradiotherapy 
Investigational 
Medicinal Products 
Name of drug 
Formulation, dose, route of administration 
Atovaquone 
 
Suspension, oral, twice daily, dose to be allocated per 
TiTE-CRM: 450 mg, 600 mg, 675 mg or 750 mg (all 
doses PO BD) 
Cisplatin 
80 mg/m2 IV on days 1 & 22 
Vinorelbine 
15 mg/m2 IV on days 1, 8, 22 & 29 
Other interventions: 
Thoracic radiotherapy: 66 Gy in 33 fractions, once daily, 5 days a week (Monday-Friday) 
Study duration: 
31 months (start of recruitment to close out) 
Treatment Duration 
Up to 9.5 weeks of atovaquone treatment, with concurrent chemoradiotherapy for 6.5 of these 
weeks 
Follow-up duration 
Six months (26-28 weeks) post completion of chemoradiotherapy 
End of study 
Last Patient Last Visit 
 
 Objectives 
The table below shows the full list of trial objectives and corresponding outcome measures. Objectives in grey 
will be not analysed by trial statisticians within CSM so are not covered by this SAP.  
Primary Objective 
Endpoints/ Outcome 
measures 
Time point(s) of evaluation 
of this end point  
Analysis population 
To determine the maximum 
tolerated dose (MTD), and 
therefore recommended 
phase II dose (RPTD), of 
atovaquone when combined 
with radical concurrent 
chemoradiotherapy in 
patients with non-small cell 
lung cancer (NSCLC) 
The dose of atovaquone 
associated with no more 
than 48% dose limiting 
toxicity (DLT) rate (target 
toxicity level) 
From week -2/-3 until three 
months post-completion of 
CRT 
All patients who have 
received at least one dose of 
atovaquone 
Secondary Objectives 
 
 
 
To assess the safety and 
toxicity profile of atovaquone 
in combination with radical 
Adverse events graded per 
Common Terminology 
Criteria for Adverse Events 
From screening/baseline until 
six months post completion of 
CRT 
All patients who have 
received at least one dose of 
atovaquone 


ARCADIAN: A Phase I Trial of the Hypoxia Modifier Atovaquone in Combination with Radical Concurrent Chemoradiotherapy in Locally Advanced Non-
Small Cell Lung Cancer. Funded by Cancer Research UK. EudraCT Number: 2019-002097-30. Protocol Number: OCTO_088 
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Page 6 of 16 
 
concurrent chemotherapy for 
NSCLC 
(CTCAE) v4.03 
To confirm feasibility of 
measuring hypoxia metagene 
signature using 3’RNA-Seq in 
diagnostic NSCLC samples 
Hypoxia metagene 
signature from diagnostic 
tissue using 3’RNA-Seq  
At baseline 
 
To assess pre-treatment 
agreement of: 
1. FMISO PET-CT with 
plasma miR-210 level 
2. FMISO PET-CT with 
tumour hypoxia gene 
expression  
▪ 
Tumour hypoxic 
volume determined 
by FMISO PET-CT  
▪ 
Plasma miR-210 level 
▪ 
Hypoxia metagene 
signature from 
diagnostic tissue using 
3’RNA-Seq 
Week -2/-3 (prior to 
atovaquone treatment) 
1. All patients with outcome 
measures from both the 
baseline FMISO PET-CT 
scan and the baseline 
blood sample 
 
To assess agreement in 
changes in FMISO PET-CT and 
plasma miR-210 level 
following two weeks (+/- 7 
days) of atovaquone  
▪ 
Tumour hypoxic 
volume determined 
by FMISO PET-CT  
▪ 
Plasma miR-210 level  
▪ 
Week -2/-3 (prior to 
atovaquone treatment)  
▪ 
Following two weeks (+/- 
7 days) of atovaquone 
treatment 
All patients with outcome 
measures from FMISO PET-CT 
scans and blood samples 
taken at both time points  
To assess the tumour 
response rate at three 
months following treatment 
Response to treatment 
assessed per Response 
Evaluation Criteria in Solid 
Tumours (RECIST) V1.1  
Three months post 
completion of CRT 
All patients who commence 
chemoradiotherapy 
treatment within the study  
Exploratory Objectives 
 
 
 
To assess the relationship 
between: 
1. plasma atovaquone levels 
and hypoxia response as 
measured by FMISO PET-
CT  
2. plasma atovaquone levels 
and plasma miR-210 level  
▪ 
Plasma atovaquone 
concentration  
▪ 
Tumour hypoxic 
volume determined 
by FMISO PET-CT  
▪ 
Plasma miR-210 level  
▪ 
Week -2/-3 (prior to 
atovaquone treatment)  
▪ 
Following two weeks (+/- 
7 days) of atovaquone 
treatment 
 
All patients with an outcome 
measure from the PK 
assessment and outcome 
measures from: 
1. blood samples taken at 
both time points 
2. FMISO PET-CT scans 
taken at both time points  
 
 STUDY METHODS 
 Trial Design/framework 
Arcadian is a single arm, open-label phase I dose escalation trial using the Time-To-Event Continual 
Reassessment Method (TiTE-CRM) i.e. a model-based approach to determine the maximum tolerated dose 
(MTD) of atovaquone in combination with concurrent CRT in patients with NSCLC. 
 
Patients will receive an oral suspension of atovaquone twice daily. The four atovaquone dose levels to be 
assessed in the TiTE-CRM is as follows: 
 
 
Dose level  
 
1 
450 mg 
2 
600 mg 
3 
675 mg 
4 
750 mg 
 
Patients will receive atovaquone alone for 1 to 3 weeks during a run-in period followed by 6.5 weeks of 
concurrent chemoradiotherapy (CRT). The 6.5 weeks of CRT consists of two cycles: Cisplatin (80 mg/m2 IV ) 


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on days 1 & 22, Vinorelbine (15 mg/m2 IV) on days 1, 8, 22 & 29 and thoracic radiotherapy: 66 Gy in 33 
fractions, once daily, 5 days a week (Monday-Friday). Therefore, the total treatment duration is expected to 
be up to 9.5 weeks.  
 
Patients will have follow-up visits at approximately 1, 3 and 6 months after completion of CRT.  
 
The TiTE-CRM will take into account toxicity from the start of the atovaquone run-in period to 12 weeks (84 
days) after completion of CRT, so the end of the toxicity assessment period will be approximately the time of 
the 3 months post-CRT visit.  
 
The figure below shows the study schema  
 
 
 Randomisation and Blinding 
This study is not randomised.  
 
 Sample Size 
The sample size will be 20 evaluable patients. Evaluable patients are patients enrolled in the study who 
received at least one dose of atovaquone.  
 Statistical Interim Analysis, Data Review and Stopping guidelines 
The TMG will meet following each interim analysis, and as necessary, to review toxicity data and decide on 
dose escalation.  
The first two participants recruited will receive the lowest dose of atovaquone (Dose 1: 450 mg BD). 
Subsequent eligible patients will be continuously recruited but no dose escalation will be considered until we 
have at least 12 weeks of safety data for one or both of the first two participants (or at least one participant 
on dose 1 if the first 2 are not evaluable). 
There will be an interim analysis each time a new patient is enrolled. At each interim analysis, the TiTE-CRM 
model will use all currently available data to recommend the dose to assign the new patient. This analysis 
will follow the methods for the primary analysis described in Section 6.2. All dose recommendations made 
by the model will be reviewed by the TMG. The TMG will either approve the dose allocation 
recommendation or select a lower dose on the basis of clinical review of the data.  
 
In order to escalate to a higher dose of atovaquone, there must be at least one patient on the previous 
highest dose who fulfils the following criteria:    


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• 
Completed ≥1 full cycle of CRT (i.e. at least three weeks of RT) 
• 
Received ≥50% the specified dose of cisplatin  
• 
Taken ≥75% their allocated dose of atovaquone  
• 
Not experienced a DLT  
 
The template for the first TMG dose decision report is given in Appendix 2. Changes may be made to this 
template as the trial progresses but note that the original template will not be updated as it refers only to 
the first dose decision meeting. 
 
The TMG will include the Chief Investigator, Co‐Investigators, Clinical Trial Manager, Trial Statistician and 
others as required. TMG membership and decision-making procedures will be documented in the TMG 
charter. 
 
There is no independent Data and Safety Monitoring Committee (DSMC) for this trial. The Safety Review 
Committee (SRC) will be convened, as required, to review DLTs and dose escalation decisions made by the 
TMG. In the event of the TMG being unable to conclude on a dose recommendation, the SRC will meet to 
decide. The SRC will consist of: 
 
1. Trial Statistician 
2. OCTO trial management representative 
3. Either: 
a.  One Medical Oncologist and one Clinical Oncologist or 
b.  Two Clinical Oncologists 
 
Additionally, since the window to observe toxicities is long, the TMG may opt to pause recruitment whilst 
on-trial patients complete their treatment. The trial will stop for safety (i.e. before reaching the maximum 
number of patients specified by the sample size) if there is sufficient evidence to suggest that the lowest 
dose is too toxic. More specifically, we will consider dose level 1 (450mg) to be too toxic if, given all the 
available data, there is more than 70% probability that the DLT rate is greater than the target toxicity level of 
48%.  
 
The SRC Charter document for this trial will define the exact membership and who should be present for 
decisions to be made. Further internal or external experts may be consulted by the SRC, as necessary. Any PI 
can request an ad hoc SRC meeting at any time in order to facilitate the immediate communication of any 
emerging safety issues during the course of the trial. 
 
The Independent Radiotherapy and Imaging Oversight Committee (RIOC) will act as the Trial Steering 
Committee (TSC). The role of RIOC is to provide oversight for the trial on behalf of the Sponsor and Funders. 
RIOC will provide overall supervision of the safe and effective conduct of the trial, as further defined in the 
RIOC charter. At least annually, RIOC will review trial progress against agreed milestones, adherence to 
protocol, and patient safety, and consider new information. RIOC has the authority to recommend study 
closure where appropriate. Membership of RIOC includes PPI representation.  
 Timing of Final Analysis 
Final analysis will take place after all enrolled patients have either completed their six-month follow up visit 
or have withdrawn from the study.  
 
 Blinded analysis 
This is not a blinded trial. 


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 Statistical Analysis Outline 
Section 18 (Statistical Analysis Plan) of the protocol includes the following:  
 
All patients enrolled in the study and who received at least one dose of atovaquone will be accounted for 
and included in the analyses. The number of patients who were not evaluable, who died or withdrew before 
treatment began will be recorded. The distribution of follow‐up time will be described, and the number of 
patients lost to follow‐up will be given. 
The analysis will include a description of patients who did not meet all the eligibility criteria, an assessment 
of protocol deviations, study drug accountability and other data that impact on the general conduct of the 
study.  
Baseline characteristics will be summarised for all enrolled patients. Patients who died or withdrew before 
treatment started or do not complete the required safety observations will be described and evaluated 
separately. Treatment-related toxicity will be tabulated by type and grade of toxicity. All patients will be 
evaluable for toxicity from time of the first treatment. Adverse events will be summarised by the number of 
patients experiencing each type of event. The grades and causality will be reported. 
 
 STATISTICAL PRINCIPLES 
 Statistical Significance and Multiple Testing 
There will be no statistical significance level defined for Arcadian as it is a dose-finding trial and dose 
recommendations will be based on the posterior probabilities calculated by the dose-toxicity model using all 
available data at each time.  
 Definition of Analysis Populations  
The analysis population for the primary and secondary safety analysis is all patients who have received at 
least one dose of atovaquone. See Section 2.2 for the definitions of the analysis populations for the other 
endpoints.  
 
Sensitivity analysis for the primary endpoint will be carried out including only patients who have received 
>75% of the full prescribed dose of atovaquone up to time of assessment. Patients who have had a DLT will 
be included irrespective of amount of atovaquone received.  
 
 TRIAL POPULATION AND DESCRIPTIVE ANALYSES 
 Representativeness of Study Sample and Patient Throughput 
The flow of participants through each stage of the trial, including numbers of participants assigned to a 
schedule, receiving intended treatment, completing the study protocol, and analysed for the primary outcome 
will be provided following CONSORT.  Protocol violations/deviations and information relating to the screening 
data including the number of ineligible patients entering the study, together with reasons will be reported. 
Information on number of participants screened, found to be ineligible (with reasons where available), refused 
to participate (with reasons where available) will also be included.  
A CONSORT diagram will be prepared, an example CONSORT diagram is given in Appendix 3 
 Withdrawal from treatment and/or follow-up 
Withdrawals/loss to follow-up together with reasons will be reported by atovaquone dose schedule. Also see 
Appendix 3.  


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 Baseline Comparability  
Baseline characteristics, including important demographic and clinical variables will be reported for all 
evaluable patients.  
Numbers (with percentages) for binary and categorical variables and means (and standard deviations), or 
medians (with lower and upper quartiles) for continuous variables will be presented.  
 Unblinding 
This trial is not blinded.  
 
 Description of Compliance with Intervention 
A summary of the total amount of atovaquone received and the total amount of CRT received will be 
presented by assigned atovaquone dose schedule. Further detail related to compliance to atovaquone and 
each CRT component will be presented descriptively in tables and graphs. Any withdrawals from treatment or 
consent will be presented. See tables and graphs in Appendix 3.  
 
 Reliability 
Safety and treatment compliance data will be regularly checked and cleaned, this may involve checking that 
data is complete e.g. not missing CTCAE grade and consistent across CRFs.  
Variables derived from raw data using a computer program may be checked by hand for 5% of patients 
randomly sampled. 
 
 ANALYSIS 
 Outcome Definitions 
Primary outcome 
To determine the maximum tolerated dose (MTD), and therefore recommended phase II dose (RPTD), of 
atovaquone when combined with radical concurrent chemoradiotherapy  
The outcome is the occurrence (yes/no) of a DLT within the DLT assessment period. For patients without a 
DLT, time observed within the DLT assessment period  will also be taken into account in the analysis. The total 
i.e. maximum duration of the DLT assessment period for each patient is the length of the atovaquone run-in 
period (1-3 weeks) which will be pre-specified before the patient starts treatment, plus the length of CRT 
treatment (6.5 weeks= 45 days) plus follow-up duration (12 weeks = 84 days). At final analysis, patients without 
a DLT will have completed the DLT period unless they withdrew early. The MTD will be the dose level with 
posterior mean DLT rate closest to the target toxicity level of 48% when the dose-toxicity model is updated 
for the final analysis.  
For the definition of a DLT, see Appendix 4. 
 
Secondary outcomes  
To assess the safety and toxicity profile of atovaquone in combination with radical concurrent 
chemotherapy  
Adverse events from the first dose of atovaquone to six months post completion of CRT will be presented (see 
Appendix 3). 
 


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To confirm feasibility of measuring hypoxia metagene signature using 3’RNA-Seq in diagnostic NSCLC 
samples 
 
To assess agreement of FMISO PET-CT with plasma miR-210 level and tumour hypoxia gene expression pre-
treatment with atovaquone 
Hypoxia assessed using the baseline FMISO PET-CT scan will be measured using tumour to blood ratio 
(TBRvolume) (ml). 
Plasma miR-210 level will be derived from the baseline blood sample. 
Baseline is at week -2/-3 prior to receiving the first dose of atovaquone.  
 
To assess agreement in changes in FMISO PET-CT and plasma miR-210 level following two weeks (+/- 7 days) 
of atovaquone 
Change in FMISO PET-CT will be the % change between TBRvolume (ml) derived from the baseline and pre-
CRT scans.  
Change in plasma miR-210 level will be the % change between miR-210 level derived from the baseline and 
pre-CRT blood samples. 
Baseline is at week -2/-3 prior to receiving the first dose of atovaquone and pre-CRT is at week -1 (two weeks 
(+/- 7 days) after starting atovaquone and prior to receiving any CRT.  
To assess the tumour response rate at three months following treatment 
Tumour response will be measured according to the RECIST V1.1 criteria, this endpoint will be the response 
taken at the assessment three months after the completion of CRT (at 13-15 weeks post-CRT).  
Response will be classified as complete response (CR), partial response (PR), stable disease (SD), progressive 
disease (PD) or “not evaluable” (NE), as measured from their baseline scan to three months post-CRT scan. 
See Appendix 2 of the protocol for response category criteria.  
 
The protocol states ‘To be assigned a status of complete response (CR) or partial response (PR), changes in 
tumour measurements must be confirmed by two observations at least 4 weeks apart.’ The Chief investigator 
has confirmed that it was never the intention for patients to receive a second scan to confirm CR/PR status, 
furthermore it is not standard of care and  it is not included in the MPE dose assessment or IRAS application, 
so it cannot be done with our current ethics so the disease response will only be taken at the three months 
post CRT visit. There is currently no plan to update the protocol to amend this minor error.  
 
To be assigned a status of stable disease (SD), tumour measurements must have met the SD criteria at least 
once, a minimum of six weeks after study treatment is started. 
 
Should rapid tumour progression occur before the completion of treatment, the patient will be classified as 
having early progression (EP). 
 
Tumour response should be classified as “not evaluable” (NE), only when it is not possible to classify it under 
another response category (e.g., when baseline and/or follow-up assessment is not performed or not 
performed appropriately).  
 
Exploratory outcomes 


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To assess the relationship between plasma atovaquone levels and hypoxia response as measured by 
FMISO PET-CT and plasma miR-210 level 
Plasma atovaquone levels (µM) will be derived from the pre-CRT blood samples.  
Hypoxia response will be measured using TBRvolume (ml) derived from the baseline and pre-CRT FMISO PET-
CT scans.  
Plasma miR-210 level will be derived from the baseline and pre-CRT blood samples. 
 
 Analysis Methods 
Primary analysis  
To determine the maximum tolerated dose (MTD), and therefore recommended phase II dose (RPTD), of atovaquone 
when combined with radical concurrent chemoradiotherapy  
All trial patients who received at least one dose of atovaquone will be included in the primary analysis. The 
same analysis is used during dose escalation as for the final analysis.  
The analysis will follow the TiTE-CRM. A two-parameter logistic model will be used to model the relationship 
between dose and toxicity i.e. the dose toxicity curve (DTC). Dose recommendations following the first two 
evaluable patients will be made using all current toxicity data as follows: 
▪ 
Data for patients who have completed the DLT assessment period or experienced a DLT will contribute 
full information to this model.  
▪ 
Data for patients who have not completed the DLT assessment period will contribute partial 
information to the model, weighted proportionally to the observed portion of their time window, and 
treating them as not experiencing a dose limiting toxicity. The weight function is defined in the 
equation below as 𝑤𝑗.  
There are 4 atovaquone doses which are coded x = 1:4. Assuming dose 1 is the reference dose, 𝑑∗, we have 
treated J patients with dose 𝑥𝑗, 𝑗= 1, …  𝐽, then we model the probability of a DLT occurring using the 
weighted likelihood given by 
𝐿(𝜃) = ∏[𝜃𝑥𝑗∗𝑤𝑗]
𝑦𝑗[(1 −𝜃𝑥𝑗) ∗𝑤𝑗]
1−𝑦𝑗
𝐽
𝑗=1
 
where  
𝑦𝑗={   1 𝑖𝑓 𝑑𝑙𝑡 𝑜𝑐𝑐𝑢𝑟𝑒𝑑 
  0 𝑖𝑓 𝑛𝑜 𝐷𝐿𝑇           
𝑔(𝜃𝑥𝑗) = 𝑙𝑜𝑔𝑖𝑡(𝜃𝑥𝑗) = log(𝛼) + 𝛽log (
𝑥𝑗
𝑑∗)   this is the unweighted two-parameter logistic model 
𝑤𝑗={
   1 𝑖𝑓 𝑦𝑗= 1          
 min (1,
𝑢𝑗
𝑇𝑗) 𝑖𝑓 𝑦𝑗= 0           
𝑢𝑗 = time patient j has been followed for and 𝑇𝑗 = total DLT window for patient j = pre-specified run-in time + 
45 days + 84 days (note: as patients are followed up in the trial beyond the DLT observation period, 𝑢𝑗 can 
exceed 𝑇𝑗 in which case the weight for patient j in the model will still be 1).  
Further detail on the chosen prior distributions for the parameters and simulation results is described in 
Appendix 1.  
See Neuenschwander, Branson and Gsponer (2008) and Cheung YK and Chappell R (2000) for descriptions of 
the model 


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Dose-escalation rules  
At each analysis the dose recommended by the toxicity model will be the dose with posterior mean DLT rate 
closest to the target toxicity level of 48%, subject to no dose skipping. However in order to escalate to the next 
dose, there must also be at least one patient on the previous highest dose fulfilling the following criteria:  
▪ 
Completed ≥1 full cycle of CRT (i.e. at least three weeks of RT) 
▪ 
Received ≥50% the specified dose of cisplatin 
▪ 
Taken ≥75% their allocated dose of atovaquone 
▪ 
Not experienced a DLT 
 
There is no restriction on dose de-escalation.  
Early stopping 
At each analysis, the TMG will be recommended to stop the trial early for safety if there is greater than 70% 
probability that the DLT rate at the lowest dose (dose 1) exceeds the target toxicity level of 48% i.e. if P(risk of 
DLT>0.48|dose = 1, current data) > 0.7, which would suggest the lowest dose is too toxic.  
 
Definition of MTD 
The MTD will be the final recommended dose after the trial has completed recruitment and all participants 
had completed the DLT window (or had a DLT/withdrawn) using all data accumulated in the trial. The MTD 
will constitute the RPTD. 
If the trial stops early for toxicity, the MTD will be assumed to be lower than dose 1 and the RPTD will not be 
established. 
 
Secondary and tertiary analyses 
There will be no formal analysis of the secondary or tertiary objectives. See template in Appendix 3 for tables 
and figures that will be presented.  
 
 Missing Data  
Primary outcome  
The trials team will be informed within 24 hrs if a DLT has been identified. Furthermore a dedicated CRF has 
been designed which captures only the data required for dose-escalation decisions including key treatment 
compliance data.  
Secondary and tertiary outcomes  
Every effort will be made for complete collection and recording of data. Any missing scans or missing blood 
sample collection will be presented with reasons for missingness. The number of available outcome measures  
for each secondary and tertiary endpoint i.e. TBRvolume values from the FMISO PET-CT scan, miR-210/PK 
atovaquone values from blood samples and the number of patients with treatment response from the 3 
months post-CRT CT/PET-CT scan will be presented.  
No data imputation is planned.  
 Sensitivity Analysis 
Sensitivity analysis on the primary outcome will be carried out: 
▪ 
On the sensitivity population defined in Section 4.2 at each interim analysis and for the final analysis 


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▪ 
On the primary analysis population but with a toxic scenario, i.e. assuming patients that currently 
have insufficient follow-up have a DLT, at each interim analysis 
The model and analysis method remain the same as described for the primary analysis.  
 
 Pre-specified Subgroup Analysis 
No subgroup analyses are planned. 
 
 Supplementary/ Additional Analyses and Outcomes 
There are no supplementary or additional analyses planned. 
 
 Harms  
This analysis will be based on the primary analysis population and will be presented as given in Appendix 3. 
 
 Health Economics and Cost Effectiveness (where applicable) 
There is no health economics and cost effectiveness analysis.   
 
 Meta-analyses (if applicable) 
No meta-analysis is planned 
 
 VALIDATION OF THE PRIMARY ANALYSIS 
Before the trial starts, code for generating dose decisions will be validated by creating a large dataset, and 
comparing results from analysis using standard logistic regression with the trial code. Although results will 
not be identical due to the differences between frequentist and Bayesian analyses, with fairly vague priors 
and a large dataset parameter estimates should be similar. Validation will be stored in the statistical eTMF. 
 
 SPECIFICATION OF STATISTICAL PACKAGES 
All analysis will be carried out using appropriate validated statistical software such as STATA, SAS, SPLUS or R. 
The relevant package and version number will be recorded in the Statistical report. 
Analysis for dose allocation decisions (i.e. TMG reports) and the primary analysis will be carried out using R 
and OpenBugs, the version number will be recorded in each TMG report. For these analyses, the R package 
checkpoint() will be used to install R packages as they were on a given date e.g. 13th January 2020 for future 
reproducibility. 
 
 REFERENCES 
Cheung YK, Chappell R. Sequential designs for phase I clinical trials with late-onset toxicities. Biometrics. 
2000 Dec;56(4):1177-82 
 
Neuenschwander, Branson and Gsponer (2008). Critical aspects of the Bayesian approach to phase I cancer 
trials. Stats in Med, 27:2420-2439  
 


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GLOSSARY OF ABBREVIATIONS 
CI 
 
Chief Investigator 
CRF 
 
Case Report Form 
CRT 
 
Chemoradiotherapy 
DLT 
 
Dose Limiting Toxicity 
DSMC  
Data and Safety Monitoring Committee  
MTD  
 
Maximum Tolerated Dose  
NSCLC   
Non-Small Cell Lung Cancer  
RIOC  
 
Radiotherapy and Imaging Oversight Committee  
RPTD   
Recommended Phase II Dose  
SAP 
 
Statistical Analysis Plan 
SRC 
 
Safety Review Committee  
TiTE-CRM  
Time-To-Event Continual Reassessment Method  
TMG 
 
Trial Management Group 
TSC 
 
Trial Steering Committee 
 
 
APPENDIX 1 (SEPARATE DOCUMENT)  
 
APPENDIX 2 (SEPARATE DOCUMENT) 
 
APPENDIX 3 (SEPARATE DOCUMENT) 
 
APPENDIX 4  
Definition of a Dose Limiting Toxicity  
DLTs are defined as any of the following occurring between the start of trial treatment until three months 
post CRT, and assessed by the Principal Investigator as possibly, probably or definitely related to atovaquone 
and/or to chemoradiotherapy. If an event is believed to be possibly, probably or definitely related to 
treatment with Durvalumab rather than trial IMPs, it may be reported as an SAE rather than a DLT. DLTs 
must be reported within 24 hours of the site becoming aware. 
DLTs will be defined as per NCI CTCAE v4.03 and include: 
 
▪ 
Grade ≥4 absolute neutrophil count (ANC) (<0.5 x 109/L) for >7 days   
▪ 
Grade ≥3 febrile neutropenia (fever of unknown origin without clinically or microbiologically documented 
infection) (ANC <1.0 x 109/L, fever ≥38.5°C) lasting >3 days  
▪ 
Infection (documented clinically or microbiologically) with grade 3 or 4 neutropenia (ANC <1.0 x 109/L)  
▪ 
Grade ≥3 thrombocytopenia (platelets <25 x 109/L)  
▪ 
Clinically significant bleeding attributed to grade 3 thrombocytopenia or requiring platelet transfusion  
▪ 
Grade ≥3 oesophagitis 
▪ 
Grade ≥3 pneumonitis onset within 3 months of starting radiotherapy  
▪ 
Grade ≥3 nausea or vomiting not controlled by optimal outpatient anti-emetic treatment for ≥5 days 
▪ 
Grade ≥3 diarrhoea despite optimal outpatient anti-diarrhoeal medication use  


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▪ 
Any toxicity causing a delay of radiotherapy completion by greater than one week  
▪ 
An elevation of ALT or AST >5 x ULN lasting 8 days or more  
▪ 
A concurrent elevation of ALT or AST (>3 × ULN) and total bilirubin (>2 × ULN) in whom there is no evidence 
of biliary obstruction or other causes that can reasonably explain the concurrent elevation  
▪ 
Other grade ≥3 effects thought to be clinically significant and directly related to the combination of 
atovaquone with chemoradiotherapy