Conditions: Biliary Tract Cancer
Keywords: Adenocarcinoma Ampullary Antineoplastic Agents Biliary Tract Cancer Chemotherapy Cholangiocarcinoma Cisplatin Digestive System Neoplasms Distal Bile Duct Extrahepatic First-line Chemotherapy Gallbladder Gastrointestinal Gemcitabine Hepatobiliary Intrahepatic Locally advanced Metastatic Neoplasm NUC-1031 ProTides Untreated
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 773
Healthy volunteers: no

Brief summary:
NuTide:121 compares NUC-1031 with gemcitabine, both in combination with cisplatin, in patients with previously untreated advanced biliary tract cancer.

The primary hypotheses are:

* The combination of NUC-1031 plus cisplatin prolongs overall survival compared to the gemcitabine plus cisplatin standard of care
* The combination of NUC-1031 plus cisplatin increases overall response rate compared to the gemcitabine plus cisplatin standard of care

Detailed description:

Arms:
arm 1: 725 mg/m\^2 NUC-1031 administered in combination with 25 mg/m\^2 cisplatin on Days 1 and 8 of a 21-day cycle arm 2: 1000 mg/m\^2 gemcitabine administered in combination with 25 mg/m\^2 cisplatin on Days 1 and 8 of a 21-day cycle

Interventions: intervention 1: NUC-1031 intervention 2: Gemcitabine intervention 3: Cisplatin
Intervention descriptions: intervention 1: IV infusion in 500 mL of 0.9% sterile saline for injection given over 30 minutes intervention 2: IV infusion in 250 mL of 0.9% sterile saline for injection given in accordance with the package insert intervention 3: IV in accordance with local institutional practice for biliary tract cancer, including the use of an appropriate hydration protocol

Protocol document:
Prot_000.pdf: 
 
 
 
CLINICAL STUDY PROTOCOL 
A Phase III Open-Label, Multi-Centre, Randomised Study Comparing 
NUC-1031 plus Cisplatin to Gemcitabine plus Cisplatin in Patients with 
Previously Untreated Locally Advanced or Metastatic Biliary Tract Cancer 
 
IMP: 
NUC-1031  
Protocol Number: 
NuTide:121 
Protocol Version, Date: 
Version 4.0, 18 December 2020 
Development Phase: 
III 
IND Number: 
139058 
EudraCT Number: 
NCT Number: 
2019-001025-28 
NCT04163900 
Sponsor: 
NuCana plc 
3 Lochside Way 
Edinburgh, EH12 9DT, UK 
Telephone: +44 (0)131 357 1111 
Email: NuTide121@nucana.com 
Approval: 
 
 
Dr Elisabeth Oelmann  
SVP, Clinical & Medical 
Development  
NuCana plc 
 
 
Date 
Medical Monitor: 
Dr Ettore Mari, MD 
IQVIA RDS Italy 
Via Fabio Filzi, 29, 20124 Milan, Italy 
Telephone: +39 02 2317 0756 
Email: ettore.mari@iqvia.com 
CONFIDENTIALITY STATEMENT 
This confidential document is the property of NuCana plc. No unpublished information 
contained herein may be disclosed without prior written approval from NuCana.  
Access to this document must be restricted to relevant parties.  
18. December 2020


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PRINCIPAL INVESTIGATOR AGREEMENT AND SIGNATURE 
 
A Phase III Open-Label, Multi-Centre, Randomised Study Comparing 
NUC-1031 plus Cisplatin to Gemcitabine plus Cisplatin in Patients with 
Previously Untreated Locally Advanced or Metastatic Biliary Tract Cancer 
 
Protocol Number: 
NuTide:121 
Protocol Version, Date: 
Version 4.0, 18 Dec 2020 
IMPs: 
NUC-1031 
Development Phase: 
III 
Sponsor: 
NuCana plc 
IND Number: 
139058 
EudraCT Number: 
2019-001025-28 
 
This study will be conducted in compliance with the clinical study protocol (and amendments), 
International Conference on Harmonisation guidelines for current Good Clinical Practice 
(ICH-GCP) and applicable regulatory requirements. Compliance with ICH-GCP standards 
provides assurance that the rights, safety, and wellbeing of study patients are protected, consistent 
with the principles that have their origin in the Declaration of Helsinki. 
 
• I agree to implement and conduct this clinical study diligently and in strict compliance with 
the protocol, good clinical practices, and all applicable national, federal and local laws and/or 
regulations. 
• I agree that this clinical protocol will not be modified by me or any member of my staff. 
• I certify that neither I nor any member of my staff has been disqualified or debarred by the US 
Food and Drug Administration (FDA), European Medicines Agency (EMA) or other 
regulatory bodies for clinical investigations or any other purpose. 
• I understand that this protocol and the accompanying clinical Investigator’s Brochure contains 
trade secrets and/or commercial information that are privileged and/or confidential and may 
not be disclosed unless disclosure is required by national, federal or local laws and/or 
regulations. 
 
 
Principal Investigator’s signature 
 
Date (dd-mmm-yyyy) 
Principal Investigator’s name (printed)  
 
 


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TABLE OF CONTENTS 
LIST OF FIGURES .................................................................................................................................... 7 
LIST OF TABLES ...................................................................................................................................... 7 
PROTOCOL SYNOPSIS ........................................................................................................................... 8 
SUMMARY SCHEDULE OF EVENTS ................................................................................................. 18 
ABBREVIATIONS ................................................................................................................................... 21 
1 
INTRODUCTION AND STUDY RATIONALE ............................................................................. 24 
1.1 
Biliary Tract Cancer ........................................................................................................................ 24 
1.2 
Treatment Options for Locally Advanced or Metastatic BTC ........................................................ 24 
1.3 
Gemcitabine with cisplatin in BTC ................................................................................................. 24 
1.3.1 Gemcitabine Resistance ................................................................................................................... 25 
1.4 
NUC-1031 ....................................................................................................................................... 25 
1.4.1 Non Clinical Data ............................................................................................................................ 25 
1.4.2 Clinical Data .................................................................................................................................... 26 
1.4.3 Pharmacokinetics ............................................................................................................................. 29 
1.5 
NuTide:121 Study Rationale ........................................................................................................... 30 
2 
STUDY OBJECTIVES AND ENDPOINTS .................................................................................... 30 
2.1 
Primary Objectives .......................................................................................................................... 30 
2.2 
Secondary Objectives ...................................................................................................................... 30 
2.3 
Tertiary Objectives .......................................................................................................................... 31 
2.4 
Primary Endpoints ........................................................................................................................... 31 
2.5 
Secondary Endpoints ....................................................................................................................... 31 
2.5.1 Key Secondary Endpoint ................................................................................................................. 31 
2.5.2 Other Secondary Endpoints ............................................................................................................. 31 
2.6 
Tertiary Endpoints ........................................................................................................................... 32 
3 
INVESTIGATIONAL PLAN ............................................................................................................ 32 
3.1 
Overall Study Design ....................................................................................................................... 32 
3.2 
Rationale for the Doses Selected ..................................................................................................... 32 
3.2.1 Arm A (NUC-1031 + cisplatin) ....................................................................................................... 32 
3.2.2 Arm B (gemcitabine + cisplatin) ..................................................................................................... 33 
3.3 
Study Treatment .............................................................................................................................. 35 
3.4 
Patient Selection and Study Centres ................................................................................................ 35 
3.5 
Robust QT Sub-study ...................................................................................................................... 35 
3.6 
Duration of Patient Participation and Post-Study Care ................................................................... 36 
3.7 
End of Study .................................................................................................................................... 36 
4 
PATIENT SELECTION .................................................................................................................... 37 
4.1 
Inclusion Criteria ............................................................................................................................. 37 
4.2 
Exclusion Criteria ............................................................................................................................ 38 
4.3 
Waivers to Entry Criteria ................................................................................................................. 39 
4.4 
Study Completion ............................................................................................................................ 39 
5 
STUDY ASSESSMENTS AND PROCEDURES ............................................................................. 40 


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5.1 
Informed Consent ............................................................................................................................ 40 
5.2 
Informed Consent for Collection of Archival Tumour Tissue Specimen, Robust QT Sub-study, and 
Follow-up of Pregnancy in Partners ............................................................................................................ 40 
5.3 
Screening Assessments .................................................................................................................... 41 
5.4 
Re-Screening Patients Who Fail Inclusion/Exclusion Criteria ........................................................ 42 
5.5 
Robust QT Sub-study ...................................................................................................................... 43 
5.6 
Evaluations to Be Performed During the Study .............................................................................. 44 
5.6.1 Each Cycle, Day 1 ........................................................................................................................... 44 
5.6.2 Each Cycle, Day 8 ........................................................................................................................... 45 
5.6.3 End of Treatment Visit .................................................................................................................... 46 
5.6.4 Follow-Up ........................................................................................................................................ 47 
6 
PATIENT WITHDRAWAL .............................................................................................................. 47 
6.1 
End of Treatment ............................................................................................................................. 47 
6.2 
Follow-Up After Treatment Discontinuation .................................................................................. 48 
6.3 
Consent Withdrawal ........................................................................................................................ 49 
6.4 
Patient Replacement ........................................................................................................................ 49 
7 
SAMPLES FOR LABORATORY ANALYSIS ............................................................................... 49 
7.1 
Clinical Laboratory Tests ................................................................................................................ 49 
7.2 
Pharmacokinetics ............................................................................................................................. 49 
7.3 
Collection of Archived Tumour Specimen ...................................................................................... 50 
7.4 
Labeling and Confidentiality of Biological Samples ....................................................................... 50 
8 
STUDY MEDICINAL PRODUCTS ................................................................................................. 50 
8.1 
NUC-1031 ....................................................................................................................................... 50 
8.1.1 NUC-1031 Supplies and Study Drug Packaging ............................................................................. 50 
8.1.2 NUC-1031 and Diluent Solution Handling and Storage ................................................................. 51 
8.1.3 NUC-1031 Preparation .................................................................................................................... 51 
8.2 
Cisplatin ........................................................................................................................................... 51 
8.3 
Gemcitabine ..................................................................................................................................... 51 
8.4 
Treatment Administration ................................................................................................................ 51 
8.4.1 Arm A (NUC-1031 in combination with cisplatin) ......................................................................... 52 
8.4.2 Arm B (gemcitabine in combination with cisplatin) ....................................................................... 52 
8.5 
Randomisation ................................................................................................................................. 52 
8.6 
Drug Destruction ............................................................................................................................. 53 
8.7 
Drug Accountability ........................................................................................................................ 53 
8.8 
Management of Overdose and Medication Errors ........................................................................... 53 
8.8.1 NUC-1031 ....................................................................................................................................... 53 
8.8.2 Cisplatin ........................................................................................................................................... 54 
8.8.3 Gemcitabine ..................................................................................................................................... 54 
8.9 
Interaction with Other Drugs ........................................................................................................... 54 
9 
MANAGEMENT OF TOXICITY .................................................................................................... 54 
9.1 
Criteria for Continuation of Treatment Post-Cycle 1 ...................................................................... 54 
9.2 
Criteria for Day 8 Dosing ................................................................................................................ 55 
9.3 
Dose Modifications .......................................................................................................................... 55 
9.3.1 Haematological Toxicity – Dose Adjustment .................................................................................. 56 


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9.3.2 Non-Haematological Toxicity – Dose Adjustment ......................................................................... 56 
9.3.3 Management of Nausea and Vomiting ............................................................................................ 58 
9.3.4 Management of Pulmonary Toxicity ............................................................................................... 58 
9.3.5 Management of Diarrhoea ............................................................................................................... 59 
9.3.6 Management of Infusion-Related Reactions ................................................................................... 59 
10 OTHER TREATMENTS (NON-IMP) ............................................................................................. 60 
10.1 
Support Medication ......................................................................................................................... 60 
10.2 
Haematopoietic Growth Factor Support .......................................................................................... 60 
10.3 
Concomitant Medication and Non-Drug Therapies......................................................................... 60 
10.3.1 Prohibited Therapies ........................................................................................................................ 60 
10.3.2 Therapies to be Used with Caution .................................................................................................. 61 
10.3.3 Biliary Stenting ................................................................................................................................ 62 
10.4 
Contraception Methods .................................................................................................................... 62 
10.5 
Fertility ............................................................................................................................................ 63 
11 TUMOUR RESPONSE ASSESSMENTS ........................................................................................ 63 
11.1 
Tumour Measurements and Assessment of Disease Response ....................................................... 63 
11.2 
Blinded Independent Central Review .............................................................................................. 65 
12 SAFETY ASSESSMENT AND REPORTING ................................................................................ 65 
12.1 
Definitions ....................................................................................................................................... 65 
12.2 
Adverse Event Reporting ................................................................................................................. 66 
12.3 
Assessment of Causality .................................................................................................................. 67 
12.4 
Assessment of Severity .................................................................................................................... 67 
12.5 
SAE Reporting ................................................................................................................................. 68 
12.6 
Expedited Reporting of SAEs .......................................................................................................... 69 
12.7 
SUSAR Reporting ........................................................................................................................... 69 
12.8 
Terms and Grading of Events .......................................................................................................... 69 
12.9 
Pregnancy ........................................................................................................................................ 70 
12.10 Events Exempt from Being Reported as AE/SAEs ......................................................................... 70 
12.10.1 Progression of Underlying Disease ................................................................................................ 70 
12.10.2 Death on Study Attributed to Malignancy ..................................................................................... 70 
12.10.3 Elective Admissions and Supportive Care ..................................................................................... 70 
12.11 Electrocardiograms .......................................................................................................................... 71 
12.11.1 Standard ECG Monitoring ............................................................................................................. 71 
12.11.2 Robust QT Sub-study ..................................................................................................................... 71 
12.12 Abnormal Laboratory Test Result Values ....................................................................................... 71 
12.13 Abnormal Vital Sign Values ............................................................................................................ 72 
12.14 Informing Investigators of New Safety Information ....................................................................... 72 
12.15 Reference Safety Information (RSI) for Assessment of Expectedness ........................................... 73 
12.16 Independent Data Monitoring Committee (IDMC) ......................................................................... 73 
13 STATISTICAL CONSIDERATIONS .............................................................................................. 74 
13.1 
Analysis Populations ....................................................................................................................... 74 
13.1.1 Intention-to-Treat (ITT) Population ................................................................................................ 74 
13.1.2 Intention-to-Treat with Measurable Disease at Baseline (ITTMD) Population .............................. 75 
13.1.3 Modified Intention-to-Treat (MITT) Population ............................................................................. 75 


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13.1.4 Safety Population ............................................................................................................................. 75 
13.1.5 Primary Analysis Populations ......................................................................................................... 75 
13.2 
Patient Disposition ........................................................................................................................... 75 
13.3 
Demographics and Baseline Characteristics .................................................................................... 75 
13.4 
Primary Efficacy Endpoints ............................................................................................................. 75 
13.4.1 Overall Survival ............................................................................................................................... 76 
13.4.2 ORR ................................................................................................................................................. 78 
13.5 
Secondary Efficacy Endpoints ......................................................................................................... 81 
13.5.1 Progression-Free Survival ............................................................................................................... 81 
13.5.2 Duration of Response ...................................................................................................................... 83 
13.5.3 18-Month and 12-Month Survival ................................................................................................... 84 
13.5.4 Disease Control Rate ....................................................................................................................... 84 
13.6 
Patient-Reported Outcomes ............................................................................................................. 84 
13.6.1 EORTC-QLQ-C30 with the QLQ-BIL21 Module .......................................................................... 84 
13.6.2 EuroQoL Health Questionnaire Instrument (EQ-5D-5L) ................................................................ 86 
13.7 
Health Economics ............................................................................................................................ 87 
13.8 
Pharmacokinetics ............................................................................................................................. 87 
13.8.1 Sparse Pharmacokinetic Sub-study .................................................................................................. 87 
13.9 
Safety Endpoints .............................................................................................................................. 87 
13.9.1 Adverse Events ................................................................................................................................ 87 
13.9.2 Laboratory Test Results ................................................................................................................... 88 
13.9.3 Other Safety Endpoints .................................................................................................................... 88 
13.9.4 Exposure .......................................................................................................................................... 88 
13.10 Interim Analyses .............................................................................................................................. 89 
13.10.1 Type 1 Error Control across the Interim Analyses and across the Multiple Endpoints ................. 90 
13.10.2 Interim Analysis for Futility .......................................................................................................... 93 
13.11 Sample Size and Power Calculation ................................................................................................ 93 
13.12 Subgroup Analyses .......................................................................................................................... 94 
13.13 Changes to the Planned Statistical Methods .................................................................................... 95 
14 PATIENT DATA HANDLING AND CONFIDENTIALITY ........................................................ 95 
14.1 
Case Report Forms .......................................................................................................................... 95 
14.2 
Monitoring of the Study .................................................................................................................. 95 
14.3 
Patient Confidentiality ..................................................................................................................... 96 
15 ETHICAL, REGULATORY AND RISK CONSIDERATIONS ................................................... 96 
15.1 
Good Clinical Practice Compliance ................................................................................................. 96 
15.2 
Institutional Review Boards/ Ethics Committees ............................................................................ 96 
15.3 
Regulatory Authority Approval ....................................................................................................... 96 
15.4 
Risk Management Considerations ................................................................................................... 96 
15.5 
Protocol Amendments ..................................................................................................................... 97 
15.6 
Protocol Deviations ......................................................................................................................... 97 
15.7 
Serious Breaches .............................................................................................................................. 97 
15.8 
Study Reporting Requirements ........................................................................................................ 98 
15.9 
Financial Disclosure ........................................................................................................................ 98 
15.10 Investigator Documentation............................................................................................................. 98 


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15.11 Study Records Retention ................................................................................................................. 98 
15.12 Audit and Regulatory Inspection ..................................................................................................... 98 
16 PUBLICATION POLICY ................................................................................................................. 99 
16.1 
Communication of Results by NuCana ........................................................................................... 99 
16.2 
Publication ....................................................................................................................................... 99 
17 REFERENCES ................................................................................................................................. 100 
18 APPENDICES .................................................................................................................................. 103 
Appendix 1: EORTC QLQ-C30 with QLQ-BIL21 Module ..................................................................... 103 
Appendix 2: EQ-5D-5 Questionnaire ....................................................................................................... 106 
Appendix 3: Concomitant medications that may prolong QTc interval ................................................... 108 
Appendix 4: Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 .............................. 111 
Appendix 5: ECOG Performance Scale .................................................................................................... 120 
 


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LIST OF FIGURES 
Figure 1 
Best response to treatment with NUC-1031 in combination with cisplatin in 
efficacy evaluable patients (ABC-08 study) ........................................................ 28 
Figure 2 
NuTide:121 study schema ................................................................................... 34 
Figure 3 
Type 1 error recycling between the two primary endpoints and the key secondary 
endpoint ............................................................................................................... 90 
 
LIST OF TABLES 
Table 1 
PK sampling schedule .......................................................................................... 50 
Table 2  
Drug administration schedule in Arm A and Arm B ........................................... 52 
Table 3 
Dose adjustments within a cycle (Day 8) based on ANC and platelet counts ..... 55 
Table 4 
Dose modification guidelines .............................................................................. 56 
Table 5 
Dose adjustment for non-haematological toxicities ............................................. 57 
Table 6 
Pharmacovigilance contact details ....................................................................... 68 
Table 7 
Censoring scheme used in the primary analysis of PFS ...................................... 82 
Table 8 
QLQ-C30 domain minimal clinically important differences (MCIDs) ............... 85 
Table 9 
QLQ-BIL21 domain minimal clinically important differences (MCIDs) ........... 86 
Table 10 
Analyses planned, primary endpoints evaluated, approximate timing, and drivers 
of timing .............................................................................................................. 89 
Table 11 
Efficacy boundaries and properties for ORR ....................................................... 91 
Table 12 
Efficacy boundaries and properties for OS .......................................................... 92 
 


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 PROTOCOL SYNOPSIS 
Study Title 
A Phase III open-label, multi-centre, randomised study comparing 
NUC-1031 plus cisplatin to gemcitabine plus cisplatin in patients with 
previously untreated locally advanced or metastatic biliary tract cancer 
Protocol Number 
NuTide:121 
IND Number 
139058 
EudraCT Number 
2019-001025-28 
Phase 
III 
Objectives 
Primary Objectives 
• Overall survival (OS) 
• Objective response rate (ORR) based on blinded independent central 
review (BICR) in patients with measurable disease at baseline 
Secondary Objectives 
• Progression-free survival (PFS) based on BICR 
• Duration of response (DoR) based on BICR 
• 18- and 12-month survival 
• Disease control rate (DCR) 
• Safety 
• Pharmacokinetics (PK) of NUC-1031 
• Patient-reported quality of life (QoL) 
Tertiary Objectives 
• Health economics 
• Assessment of tumour cell characteristics that may further an 
understanding of the mechanism(s) through which the clinical 
activity of NUC-1031 is achieved 
Study Design 
This is an open-label, randomised study of NUC-1031 in combination 
with cisplatin (Arm A) compared to gemcitabine in combination with 
cisplatin (Arm B), administered on Days 1 and 8 of 21-day cycles, in 
previously untreated patients with locally advanced or metastatic biliary 
tract cancer (BTC). 
Objective disease assessment will be performed by radiologic evaluation 
and assessed according to Response Evaluation Criteria in Solid 
Tumours (RECIST) v1.1 criteria. All known or suspected disease sites 
must be assessed at baseline by either computed tomography (CT), 
magnetic resonance imaging (MRI) or positron emission tomography 
CT (PET-CT) scan. For each patient, the same radiological method used 
at baseline must be used for disease assessment throughout the duration 
of the patient’s participation in the study. 
Tumour measurements and disease response assessments are to be 
performed every 9 weeks (±7 days) (approximating three cycles) from 
C1D1 until disease progression. If the patient stops study treatment for 


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reasons other than radiologically confirmed progressive disease (PD), 
tumour measurements and disease response assessments should 
continue at least every 12 weeks (±14 days) thereafter until PD is 
radiologically confirmed (regardless of whether any subsequent 
anti-cancer medication has been prescribed), consent withdrawal, lost to 
follow up, or death, whichever occurs first. 
Treatment and study continuation decisions based on radiologic 
assessments will be made by the treating Investigator. However, primary 
analyses of data will use BICR assessment of radiologic evaluation, with 
Investigator assessment serving as a secondary analysis.  
Study Centres 
This study will be conducted at approximately 130 sites across North 
America, Europe, and Asia-Pacific. 
Endpoints 
Primary Endpoints 
• OS, defined as the time from randomisation to the time of death from 
any cause 
• ORR, defined as the percentage of patients achieving a confirmed 
complete or partial response to treatment as assessed by BICR 
according to RECIST v1.1 criteria. This will be assessed only in 
patients with measurable disease at baseline. 
Key Secondary Endpoint 
• PFS, based on BICR according to RECIST v1.1 criteria, defined as 
the time from randomisation to the first observation of objective 
tumour progression or death from any cause. For patients with 
non-measurable disease at baseline, refer to the protocol criteria for 
disease progression. 
Other Secondary Endpoints 
Efficacy 
• DoR, as assessed by BICR, defined as the time from initial clinical 
response (partial response [PR] or complete response [CR] that is 
subsequently confirmed) to the first observation of tumour 
progression or death from any cause 
• 18-month survival 
• 12-month survival 
• DCR, based on BICR according to RECIST v1.1 criteria, defined as 
the percentage of patients demonstrating a Best Overall Response 
(BOR) of CR, PR, or stable disease (SD) 
Safety 
Safety and tolerability will be assessed by evaluation of the following: 
• Treatment-emergent AEs (TEAEs), including TEAEs by severity 
grade using Common Terminology Criteria for Adverse Events 
(CTCAE) v5.0 
• Serious TEAEs (SAEs) 
• Deaths due to TEAEs 


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• Treatment discontinuations due to TEAEs 
• Clinically significant changes in laboratory parameters 
• Changes in Eastern Cooperative Oncology Group (ECOG) status, 
physical exam, electrocardiogram (ECG) and vital signs 
A sub-study will be carried out to assess the effect of the NUC-1031 + 
cisplatin combination on cardiac repolarisation in a subset of patients.  
Pharmacokinetics of NUC-1031 
Sparse PK sampling will be taken on Cycle 1 Day 1 at the end of 
infusion, 2 hours after the end of infusion, and 6 hours after the end of 
infusion, to capture Ctrough and Cmax plasma levels.  
Patient-Reported Quality of Life 
Patient-reported quality of life will be assessed using the European 
Organisation for Research and Treatment (EORTC) Quality of Life 
Questionnaire (QLQ-C30) with the QLQ-BIL21 module and the 5-level 
EuroQol five-dimension scale (EQ-5D-5L). 
Tertiary Endpoints 
Health Economics 
Health economics will be assessed through collection of core health 
resource use information, using case report forms (CRFs) to capture 
procedure codes, days in hospital, and outpatient visits. Health outcomes 
will be quantified using quality-adjusted life years (QALYs) and a 
cost-utility analysis will be conducted by creating incremental 
cost-utility ratios for each of the treatment groups.  
Tumour Cell Characteristics 
Phenotypic, genotypic, and/or pharmacodynamic characteristics of 
archival tumour samples that may further delineate the mechanism(s) 
through which NUC-1031 acts. 
Study Population 
 
Patients 
with 
histologically- 
or 
cytologically-proven 
biliary 
adenocarcinoma, 
including 
cholangiocarcinoma 
(intra- 
and 
extra-hepatic biliary ducts), gallbladder or ampullary cancer, that is not 
amenable to surgical resection and who have had no prior systemic 
chemotherapy for treatment of locally advanced or metastatic disease 
are eligible.  
Patients with measurable or non-measurable disease are eligible for 
study participation in accordance with predefined randomisation strata. 
In accordance with local standards of care as appropriate, patients may 
have received prior low-dose chemotherapy in the adjuvant setting 
and/or radiotherapy with or without radio-sensitising low-dose 
chemotherapy for localised disease if completed at least 6 months prior 
to randomisation. Patients must have adequate biliary drainage without 
evidence of biliary obstruction. Patients whose disease is characterised 
as combined or mixed hepatocellular/cholangiocarcinoma are not 
eligible for this study. 


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Study Treatment 
Patients will be randomised to receive either: 
• NUC-1031 plus cisplatin (Arm A), or 
• Gemcitabine plus cisplatin (Arm B) 
In Arm A, cisplatin will be administered by intravenous (IV) infusion at 
25 mg/m2 in accordance with local institutional practice for BTC 
followed by IV infusion of NUC-1031 at 725 mg/m2 over 30 minutes on 
Days 1 and 8 of each 21-day cycle. 
In Arm B, cisplatin will be administered by IV infusion at 25 mg/m2 in 
accordance with local institutional practice for BTC followed by IV 
infusion of gemcitabine at 1000 mg/m2 in accordance with its package 
insert on Days 1 and 8 of each 21-day cycle. 
Inclusion Criteria 
 
1. Written informed consent and authorisation to use and disclose 
health information. 
2. Ability to comprehend and willingness to comply with the 
requirements of this protocol, including the QoL questionnaires. 
3. Female or male patients aged ≥18 years. 
4. Histologically- or cytologically-confirmed adenocarcinoma of the 
biliary tract (including gallbladder, intra and extra-hepatic biliary 
ducts and ampullary cancers) that is locally advanced, unresectable 
or metastatic (AJCC edition 8, 2018). Patients with measurable (as 
per RECIST v1.1 criteria) or non-measurable disease are permitted.  
5. Life expectancy ≥16 weeks. 
6. ECOG performance status 0 or 1. 
7. Adequate biliary drainage with no evidence of ongoing infection. If 
applicable, treatable and clinically-relevant biliary duct obstruction 
has been relieved by internal endoscopic drainage/stenting at least 
2 weeks previously or by palliative bypass surgery or percutaneous 
drainage prior to study treatment, and the patient has no active or 
suspected uncontrolled infection. Patients fitted with a biliary stent 
should be clinically stable and free of signs of infection for ≥2 weeks 
prior to study treatment. Patients with improving biliary function 
who meet all other inclusion criteria may be re-tested during the 
screening window. 
8. Adequate bone marrow, hepatic, and renal function, as evidenced 
by: 
• Absolute 
neutrophil 
count 
(ANC) 
≥1,500/μL 
without 
colony-stimulating factor support 
• Platelet count ≥100,000/μL 
• Haemoglobin ≥9 g/dL without need for haematopoietic growth 
factor or transfusion support in prior 2 weeks 
• Total bilirubin <2 × upper limit of normal (ULN); does not apply to 
patients with Gilbert's syndrome. Consistent with inclusion 
criterion 7, patients whose whole bilirubin and biliary function is 
recovering may be re-tested during the screening period. 


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• Alanine aminotransferase (ALT) and/or aspartate aminotransferase 
(AST) <5 × ULN 
• Creatinine clearance ≥45 mL/min actual or calculated by the 
Cockcroft-Gault method 
• International normalised ratio (INR) <1.5 and activated partial 
thromboplastin time (aPTT) <1.5 × ULN; does not apply to patients 
on an anti-coagulant with stable dose 28 days prior to first dose. 
9. QTc interval <450 msec (males) or <470 msec (females), in the 
absence of bundle branch block. In the presence of bundle branch 
block with consequent QTc prolongation, patients may be enrolled 
based on a careful risk-benefit assessment. 
10. Human Immunodeficiency Virus-infected patients who are healthy 
and 
have 
a 
low 
risk 
of 
Acquired 
Immunodeficiency 
Syndrome-related outcomes may be included in this study. 
11. Female patients of child-bearing potential (i.e., all women except 
those who are post-menopausal for ≥1 year or who have a history of 
hysterectomy or surgical sterilisation) must have a negative 
pregnancy test within 3 days prior to the first study drug 
administration. All patients of child-bearing potential must agree to 
practice true abstinence or to use two highly effective forms of 
contraception, one of which must be a barrier method of 
contraception, from the time of screening until 6 months after the 
last dose of study medication. 
12. Male patients with a female partner must either have had a successful 
vasectomy or they and their female partner meet the criteria above 
(not of childbearing potential or practicing highly effective 
contraceptive methods). 
Exclusion Criteria 
1. Combined or mixed hepatocellular/cholangiocarcinoma. 
2. Prior systemic therapy for advanced or metastatic biliary tract 
cancer. However, prior chemotherapy in the adjuvant setting or 
low-dose chemotherapy given in conjunction with radiotherapy in 
the adjuvant setting and completed at least 6 months prior to 
enrolment is permitted. The following prior interventions are 
allowed provided the patient has fully recovered: 
• Surgery: non-curative resection with macroscopic residual disease 
or palliative bypass surgery. Patients who have previously 
undergone curative surgery must now have evidence of 
non-resectable disease requiring systemic chemotherapy.  
• Radiotherapy: prior radiotherapy (with or without radio-sensitising 
low-dose chemotherapy) for localised disease and there is now clear 
evidence of disease progression requiring systemic chemotherapy. 
• Photodynamic therapy: prior photodynamic therapy for localised 
disease with no evidence of metastatic disease or for localised 
disease to relieve biliary obstruction in the presence of metastatic 
disease provided there is now clear evidence of disease progression 
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• Palliative radiotherapy: palliative radiotherapy provided that all 
adverse events have resolved and the patient has measurable disease 
outside the field of radiation. 
3. Prior treatment with or known hypersensitivity to NUC-1031, 
gemcitabine, cisplatin or other platinum-based agents or history of 
allergic reactions attributed to any parenteral excipients (e.g., 
dimethylacetamide [DMA], Cremophor EL, Polysorbate 80, Solutol 
HS 15). 
4. Symptomatic central nervous system or leptomeningeal metastases. 
5. History of other malignancies, except adequately treated 
non-melanoma skin cancer, curatively treated in situ cancer of the 
cervix, surgically excised or potentially curatively treated ductal 
carcinoma in situ of the breast, or low grade prostate cancer or 
patients after prostatectomy not requiring treatment. Patients with 
previous invasive cancers are eligible if treatment was completed 
more than 3 years prior to initiating the current study treatment, and 
the patient has had no evidence or recurrence since then. 
6. Concurrent serious (as deemed by the Investigator) medical 
conditions, including, but not limited to, New York Heart 
Association class III or IV congestive heart failure, history of 
congenital prolonged QT syndrome, uncontrolled infection, active 
hepatitis B or C, or other co-morbid conditions that in the opinion of 
the Investigator would impair study participation or cooperation. 
7. Congenital or acquired immunodeficiency (e.g., serious active 
infection with HIV). As per inclusion criterion 10, patients with HIV 
who are healthy and have a low risk of AIDS related outcomes are 
eligible.  
8. Other acute or chronic medical, neurological, or psychiatric 
condition or laboratory abnormality that may increase the risk 
associated with study participation or investigational product 
administration or may interfere with the interpretation of study 
results and, in the judgment of the Investigator, would make the 
patient inappropriate for entry into this study. 
9. Prior exposure to another investigational agent within 28 days prior 
to randomisation. 
10. Major surgery within 28 days prior to randomisation; patient must 
have completely recovered from any prior surgical or other 
procedures. 
11. Pregnant or breastfeeding. 
12. Residual toxicities from prior treatments or procedures which have 
not regressed to Grade ≤1 severity (CTCAE v5.0), except for 
alopecia or Grade ≤2 peripheral neuropathy. 
13. Concomitant use of drugs at doses known to cause clinically relevant 
prolongation of QT/QTc interval. 
14. Administration of a live vaccination within 28 days prior to 
randomisation. 


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15. Ongoing or recent (≤6 months) hepatorenal syndrome. 
Study Duration Per 
Patient 
Patients will continue to receive study treatment until radiographic 
documentation of progressive disease, evidence of unacceptable 
treatment-related AEs despite optimal medical management and/or dose 
modification, or withdrawal of consent. A patient who is receiving 
clinical benefit but experiencing toxicity related to the cisplatin 
component may continue on study receiving single agent NUC-1031 
(Arm A) or gemcitabine (Arm B). 
Patient 
Randomisation 
Patients will be randomised 1:1 with the following 4 stratification 
factors: 
• Measurable disease at baseline (yes, no) as determined by BICR 
• Metastatic disease at baseline (yes, no) 
• Tumour 
location 
(gallbladder, 
intra-hepatic, 
extra-hepatic/ 
ampullary) 
• Region (Asia, non-Asia) 
The number of patients with non-measurable disease at baseline as 
determined by BICR will be capped at 82 (due to statistical requirements 
of ORR analysis). 
Sample Size and 
Statistical 
Considerations 
Analysis Populations 
The intention-to-treat (ITT) population will consist of all patients who 
are randomised, regardless of whether any study medication was 
received, and patients will be summarised on the basis of the treatment 
group to which they were randomised. The ITT population with 
measurable disease at baseline (ITTMD) will consist of the ITT 
population patients randomised to the stratum corresponding to having 
measurable disease at baseline (as assessed by BICR). The ITT 
population will be the primary analysis population for OS and PFS; the 
ITTMD will be the primary analysis population for evaluating ORR; and 
DoR will be analysed in the subset of ITTMD patients who have 
confirmed response. 
All safety endpoints will be analysed using the Safety population which 
will consist of all patients who are randomised and receive any study 
medication, within which patients will be summarised on the basis of 
the actual study medication received. 
Primary Analysis for the Primary Endpoints 
OS and ORR are the dual primary endpoints. The study would be viewed 
as positive (in terms of the primary efficacy endpoints) if statistical 
significance is obtained on either of the two primary endpoints.  
Duration of OS is defined as the time from randomisation to the time of 
death due to any cause. For patients who are alive at the time of a data 
cut-off or are permanently lost to follow-up, duration of OS will be 
censored at the date at which they were last known to be alive. 
The primary analysis of OS will be a stratified log-rank test. A stratified 
Cox proportional hazards model (including only a term for treatment) 


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with Efron's method of handling ties will also be used to estimate the 
hazard ratio for OS and its associated confidence interval (CI).  
The Kaplan-Meier method will be used to estimate the survival curves, 
and the median survival time will be estimated for each treatment group, 
together with its CI using the Brookmeyer and Crowley method. 
Estimates of the 25th and 75th percentiles will also be derived together 
with their corresponding CIs. 
Subgroup analyses for OS will be carried out for each of the 
randomisation stratification factors as well as for other important 
factors. 
ORR will be determined using RECIST 1.1, as assessed by BICR. 
Timepoint response categorisation (into CR, PR, SD, PD, or Not 
Evaluable [NE]) will be carried out in accordance with Table 1 from 
Appendix 4 of the protocol. Confirmation after at least 28 days is 
required for CR or PR, and BOR will be determined from BICR 
timepoint assessments, using the rules given in Table 3 of Appendix 4 
of the protocol. In patients who discontinue treatment without 
progression, timepoint responses will still be considered in the 
calculation of BOR up until the time that the patient receives a 
subsequent anti-cancer therapy. ORR based on BICR assessment will 
then be calculated as the proportion of patients with BOR of CR or PR. 
The primary analysis of ORR will be based on the stratified 
Cochran-Mantel-Haenszel (CMH) test. The corresponding odds ratio 
and its confidence interval will be derived. Counts for patients with a 
BOR of CR, PR, SD, PD, or NE, based on BICR assessment, will each 
also be presented. Clopper-Pearson exact 95% two-sided CIs for ORR 
will be provided separately by treatment group. 
Subgroup analyses of ORR based on BICR assessment will be provided 
by primary tumour site (gallbladder, intra-hepatic, extrahepatic, 
ampullary) and by stage of disease (locally advanced, metastatic). 
Additional secondary analyses of ORR will be carried out based on 
Investigator assessment of response. 
Interim Analyses and Type 1 Error Control 
Three interim efficacy analyses are planned in addition to the final 
analysis. 
• The first interim analysis will evaluate the ORR primary endpoint. 
It will be performed 28 weeks after 418 patients in the measurable 
disease stratum have been randomised. At this interim a futility 
analysis will also be conducted based on OS. 
• The second interim analysis will evaluate the ORR and OS primary 
endpoints. It will be the final analysis for ORR and the first interim 
analysis (for demonstration of efficacy) on OS. It will be performed 
28 weeks after 644 patients in the measurable disease stratum have 
been randomised. It is estimated that approximately 425 deaths 
(67%) will be observed by this time. 


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• The third interim analysis will evaluate the OS primary endpoint for 
which it will be the second interim analysis (for demonstration of 
efficacy). It will take place after 541 deaths (85%) have been 
observed. 
• The final analysis will evaluate the OS primary endpoint. It will take 
place after 637 deaths (100%) have been observed, and is expected 
to occur approximately 48.0 months after the first patient is 
randomised. 
PFS will be tested only at the second interim analysis, at which time it 
is estimated that approximately 534 patients will have had a progression 
or death. 
The Maurer & Bretz method will be used to provide strong control of 
Type 1 error across the two primary endpoints and the key secondary 
endpoint, as well as across the interim analyses. Within this graphical 
procedure, initially α=0.005 one-sided will be allocated to ORR, 
α=0.020 one-sided will be allocated to OS, and α=0 will be allocated to 
PFS. If ORR obtains statistical significance at Interim Analysis 1 or 
Interim Analysis 2 then OS will be able to be tested using an overall 
α=0.025 one-sided. In addition, under this graphical procedure, if OS 
obtains statistical significance then ORR will be able to be tested using 
an overall α=0.017 one-sided, and PFS will be able to be tested using an 
overall α=0.008 one-sided. If both ORR and OS or both PFS and OS 
have then obtained statistical significance, the remaining endpoint (PFS 
or ORR) will be tested using an overall α=0.025 one-sided. 
For each primary endpoint a Lan-DeMets O'Brien-Fleming-like 
α-spending function will be used to control the Type 1 error across the 
multiple looks. 
Sample Size and Power 
For OS a hazard ratio of 0.76 has been assumed. With 3 looks (at 67%, 
85%, and 100% of the required number of events), an overall α=0.020 
one-sided, and 1:1 randomisation, then a total of 637 OS events gives 
over 90% power. 
A thirty-month duration of enrolment is assumed with gradual ramp-up 
over the first 12 months. OS events are assumed to follow an exponential 
distribution, and a 11.7-month median has been assumed for the control 
arm as seen in the gemcitabine in combination with cisplatin arm in the 
ABC-02 trial. The hazard ratio of 0.76 then gives a median of 
approximately 15.4 months in the NUC-1031 in combination with 
cisplatin arm. A total of 811 patients would result in the last of the 
637 events occurring at approximately 48 months. To allow for 2% of 
patients being lost to follow-up for OS, a total of 828 patients will be 
randomised. 
For ORR a 19% rate is assumed for the control arm. The derivation of 
this rate from the gemcitabine in combination with cisplatin arms within 
ABC-02, BT-22, and ABC-03 (allowing now for the requirement of 
confirmation, based on PS 0 or 1 patients only, including all randomised 


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patients in the denominator, excluding patients with non-measurable 
disease at baseline, and adjusting for use of BICR rather than 
Investigator assessment) is provided in an appendix to the SAP. For the 
NUC-1031 in combination with cisplatin arm a 31% ORR is assumed, 
which gives an assumed true odds ratio of 1.92. 
With 2 looks for ORR (at 65% and 100%), and with an overall α=0.005 
one-sided then a total of 644 patients with measurable disease at baseline 
(together with 418 at the interim analysis) gives 80% power. The two 
looks will take place 28 weeks (corresponding to three scheduled 
post-baseline radiographic scans plus a one week visit window) after the 
last of these required numbers of patients have been randomised. The 
number of randomised patients in the stratum for non-measurable 
disease at baseline is capped at 82 patients (~10%), which therefore 
gives at least 746 randomised patients in the measurable disease at 
baseline stratum. 


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SUMMARY SCHEDULE OF EVENTS 
Study 
assessments 
Screening 
Cycle 1 
Additional cycles 
End of 
treatment 
Long-term 
follow-up 
Day  
-21 to 0 
Day 1 
Day 8 
(±1 day) 
Day 1  
(±3 days) 
Day 8 
(±1 day) 
30 days after 
last dose 
(±3 days) 
Every 12 
weeks 
(±14 days) 
Informed consent 
X 
 
 
 
 
 
 
Inclusion/exclusion 
X 
 
 
 
 
 
 
Randomisation 
 
X1 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
Physical examination2 
X 
X10 
 
X 
 
X 
 
ECOG status 
X 
X10 
 
X 
 
X 
 
Vital signs, height, weight3 
X 
X 
X 
X 
X 
X 
 
12-lead ECG4 
X 
X4 
X4 
X4 
X4 
X4 
 
Holter ECG5 (QT sub-study) 
 
X 
X 
X 
X 
 
 
Pregnancy test6 
X 
X10 
 
X 
 
X 
 
Haematology and serum 
chemistry7 
X 
X10 
X 
X 
X 
X 
 
Coagulation profile7 
X 
X 
X 
X 
X 
X 
 
Radiologic tumour 
assessment8 
X8 
Every 9 weeks (±7 days) from C1D1 until 
disease progression 
 
X11 
PK sampling (Arm A)9 
 
X 
 
 
 
 
 
Cisplatin administration 
 
X 
X 
X 
X 
 
 
NUC-1031 or gemcitabine 
administration 
 
X 
X 
X 
X 
 
 
Concomitant medications 
 
X (ongoing) 
 
Adverse events  
(NCI CTCAE v5.0) 
X 
X (ongoing) 
 
Patient-reported QoL 
assessment12 
X 
X10 
 
X 
 
X 
 
Health economics13 
X 
X10 
 
X 
 
X 
 
Survival and treatment 
status 
 
 
 
 
 
 
X14 
Collection of archival 
tumour specimen 
X 
(may be collected at any time) 
 


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1. 
Randomisation takes place up to 1 working day prior to administration of study treatment 
on C1D1. 
2. 
After the screening period, the physical examination may be completed by a qualified 
designee. 
3. 
Vital signs include respiration rate, pulse, temperature and blood pressure, and must be 
taken after the patient has been seated or in supine position for 5 minutes. Weight should 
be recorded at baseline, Day 1 of every cycle and at the end-of-study visit. Documentation 
of height at baseline only is sufficient. 
4. 
Standard 12-lead ECG measurements must be obtained at screening and prior to dosing on 
Day 1 in all cycles. ECG measurements should also be taken prior to dosing and within 
30 minutes (±5 minutes) post-infusion on C1D1, C1D8, C2D1 and C2D8. 
The ECGs should be performed in triplicate (keeping the leads in place and patient supine 
for 5 minutes prior to and during readings) and reviewed by the Investigator or a qualified 
designee. The QTc interval should be calculated for each ECG using the Fridericia formula 
and averaged.  
5. 
At a subset of sites, a subset of 74 patients (approximately 37 in each treatment group) will 
participate in a ‘robust QT sub-study’. Patients must be supine for at least 5 minutes prior 
to, and during, the ECG read timepoints detailed below: 
ECG timepoint 
C1D1 
C1D8 
C2D1 
C2D8 
60 minutes pre-infusion 
 
X 
X 
X 
45 minutes pre-infusion 
X 
 
 
 
30 minutes pre-infusion 
X 
 
 
 
15 minutes pre-infusion 
X 
 
 
 
End of infusion 
X 
X 
X 
X 
10 minutes post-infusion 
X 
X 
X 
X 
30 minutes post-infusion 
X 
X 
X 
X 
60 minutes post-infusion 
X 
X 
X 
X 
2 hours post-infusion 
X 
X 
X 
X 
24 hours (±30 minutes) 
post-infusion 
X 
 
 
 
 
6. 
Serum or urine pregnancy testing is acceptable (women of childbearing potential only). 
7. 
Haematology, serum chemistry and coagulation assessments may be performed up to 
3 days prior to scheduled timepoint and must be completed prior to initiation of a new 
treatment cycle. Haematology parameters include WBC count, differential WBC count, 
RBC count, haemoglobin, haematocrit, and platelets. Chemistry parameters include 
sodium, potassium, magnesium, urea or blood urea nitrogen, creatinine, glucose, 


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phosphate, total protein, albumin, adjusted calcium, total bilirubin, bicarbonate, chloride, 
uric acid, alkaline phosphatase, AST, ALT, and LDH. 
8. 
Radiologic disease assessment (by CT, MRI, or PET-CT) will be performed at Screening 
and every 9 weeks (±7 days) from C1D1 until disease progression. Confirmatory scans 
should be performed at least 28 days and not more than 42 days after initial assessment of 
response. If a patient is found to have a response at the confirmatory scan which has 
improved from PR to CR, then the improved response must also be confirmed within a 
further 28-42 day window. Imaging completed prior to informed consent for routine 
clinical practice purposes can be used as the Screening radiologic disease assessment 
provided it was performed as per RECIST v1.1 criteria and within 28 days of 
randomisation. For each patient, the same imaging modality for disease assessment used at 
baseline should be used for the duration of the patient’s participation. Additional 
anatomical areas, other than chest, abdomen, and pelvis, should be assessed by CT scan, 
MRI, or PET-CT in case of suspicion of presence of metastases based on signs, symptoms, 
biochemical results and/or as standard of care imaging of patients (i.e., non-study related). 
A recently-biopsied lesion should not be designated as target lesions for the purposes of 
RECIST v1.1 criteria. 
9. 
Collection of blood for PK analysis will be performed in patients in Arm A only. 
A total of 3 blood samples will be collected on C1D1 only: 
(i) end of infusion (within 10 minutes) 
(ii)  2 hours after end of infusion (±30 minutes) 
(iii) 6 hours after end of infusion (±30 minutes) 
10. 
Does not need to be repeated if screening assessment was performed within 3 days of 
C1D1. 
11. 
Patients withdrawing from study treatment with no radiological evidence of disease 
progression will undergo radiologic disease assessment at least every 12 weeks (±14 days) 
until disease progression (regardless of whether any subsequent anti-cancer medication has 
been prescribed), consent withdrawal, lost to follow up, or death, whichever occurs first. 
Patients who stop treatment following an unconfirmed response should also still have a 
confirmatory scan within the pre-specified 28- to 42-day window, if the scan can take place 
prior to the patient starting any subsequent anti-cancer therapies.  
12. 
QoL will be assessed using the European Organisation for Research and Treatment 
(EORTC) Quality of Life Questionnaire (QLQ-C30) with the QLQ-BIL21 module and the 
5-level EuroQol five-dimension scale (EQ-5D-5L).  
Patient-reported QoL data should also be collected at the time of withdrawal from the 
study. 
13. 
Health economics will be assessed through collection of core health resource use 
information, using case report forms (CRFs) to capture procedure codes, days in hospital, 
and outpatient visits.  
14. 
Survival and initiation of new treatments will be assessed every 12 weeks (±14 days) until 
death. Survival status will also be requested prior to IDMC reviews, prior to each interim 
analysis, and prior to the final analysis. 


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ABBREVIATIONS 
ADR 
Adverse drug reaction 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
aPTT 
Activated partial thromboplastin time 
ASCO 
American Society for Clinical Oncology 
AST 
Aspartate aminotransferase 
AUC 
Area under the plasma concentration-time curve 
AUC0-t 
AUC from time zero to the last measurable concentration 
AUC0-24 
AUC from time zero to 24 hours 
BICR 
Blinded independent central review 
BOR 
Best overall response 
BSA 
Body surface area 
BTC 
Biliary tract cancer 
BUN 
Blood urea nitrogen 
CA19-9 
Carbohydrate antigen 19-9 
CFR 
Code of Federal Regulations 
CHW 
Cui, Hung, and Wang 
CI 
Confidence interval 
Cmax 
Maximum concentration 
CMH 
Cochran-Mantel-Haenszel 
CNAR 
Censoring not at random 
CR 
Complete Response 
CRF 
Case report form  
CRO 
Clinical Research Organisation 
CSR 
Clinical study report 
CT  
Computed tomography 
DCR 
Disease control rate 
dFdCTP 
Di-fluoro-deoxycytidine triphosphate 
dFdU 
Di-fluoro-deoxyuridine 
DMA 
Dimethylacetamide 
DoR 
Duration of response 
DSUR 
Development safety update report 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EORTC 
European Organisation for Research and Treatment of Cancer Quality of Life 
Questionnaire 
EQ-5D-5L 
5-level EuroQol five-dimension scale 
EudraCT 
European Clinical Trials Database 
FDA 
(US) Food and Drug Administration  
FIH 
First-in-human 
G-CSF 
Granulocyte colony stimulating factor 
GFR 
Glomerular filtration rate 
IB 
Investigator’s Brochure 


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ICF 
Informed consent form 
ICH-GCP 
International Conference on Harmonisation - Good Clinical Practice 
IDMC 
Independent Data Monitoring Committee 
IHC 
Intrahepatic cholangiocarcinoma 
IMP 
Investigational medicinal product 
INR 
International normalised ratio 
IRB/EC 
Institutional review board/ ethics committee 
ITT 
Intention-to-treat 
ITTMD 
Intention-to-treat with measurable disease at baseline 
IV 
Intravenous 
IxRS 
Interactive voice- or web-based response system 
LDH 
Lactate dehydrogenase 
MCID 
Minimal clinically important difference 
MedDRA 
Medical Dictionary for Regulatory Activities 
MITT 
Modified intention-to-treat 
MRI 
Magnetic resonance imaging 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NE 
Not Evaluable 
NM28 
Number of patients randomised in the measurable disease stratum with the 
opportunity for ≥28 weeks of follow-up 
ORR 
Objective Response Rate 
OS 
Overall Survival 
OS12 
Proportion of patients alive at 12 months 
OS18 
Proportion of patients alive at 18 months 
PBMC 
Peripheral blood mononuclear cell 
PD 
Progressive Disease 
PES 
Polyethersulfone 
PET 
Positron emission tomography 
PFS 
Progression-Free Survival 
PK 
Pharmacokinetics 
PR 
Partial Response 
PRES 
Posterior reversible encephalopathy syndrome 
PV 
Pharmacovigilance 
PVC 
Polyvinylchloride 
PVDF 
Polyvinylidene fluoride 
QALY 
Quality-adjusted life year 
QLQ-BIL21 
EORTC questionnaire module for patients with cholangiocarcinoma and 
gallbladder cancer 
QLQ-C30 
EORTC questionnaire to assess the quality of life of cancer patients 
QoL 
Quality of life 
RBC 
Red blood cells 
RECIST 
Response Evaluation Criteria in Solid Tumours (version 1.1) 
RMST 
Restricted man survival time 
RPSFT 
Rank-preserving structural failure time 
RP2D 
Recommended Phase II Dose 
RSI 
Reference Safety Information 
SAE 
Serious adverse event 


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SAP 
Statistical analysis plan 
SD 
Stable Disease  
SOC 
Standard of care 
SUSAR 
Suspected unexpected serious adverse reaction 
TEAE 
Treatment-emergent adverse event 
TMG 
Trial management group 
ULN 
Upper limit of normal 
WBC 
White blood cell 


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1 
INTRODUCTION AND STUDY RATIONALE 
1.1 
Biliary Tract Cancer 
Biliary tract cancer (BTC) encompasses a group of rare, highly fatal malignancies of the biliary 
system originating from the epithelium of the intra- and extra-hepatic biliary ducts, the gallbladder, 
and the cystic duct. Malignancies arising in the biliary tract include cholangiocarcinomas, 
gallbladder cancers, and carcinomas of the ampulla of Vater. These are most commonly identified 
histologically as adenocarcinomas (Sohal et al, 2016) and have the same underlying 
pathophysiology (Hennedige et al, 2014). Similar to pancreatic cancer, BTC is associated with the 
development of a dense stroma that contributes to a complex tumour microenvironment. This 
stroma not only promotes cancer development and progression but also confers resistance to 
chemotherapy treatment (Gentilini et al, 2018). 
BTC is most prevalent in patients between 50 and 70 years of age, with a higher incidence in males 
for cholangiocarcinoma and ampullary carcinomas, and in females for gallbladder cancers. 
Although >90% of BTCs are adenocarcinomas, additional histological subtypes such as squamous, 
neuroendocrine tumours, lymphomas or sarcomas (Gourgiotis et al, 2008; Gatto & Alvaro, 2010) 
are also observed. BTC is usually advanced at the time of diagnosis (Hennedige et al, 2014) and 
progresses quickly, leading to cachexia and inanition with a consequent rapid decline in 
performance status (Harrington et al, 2018). Without treatment, patients with advanced BTC have 
a short survival time of just 3-4 months (Patel, 2011). The prognosis of patients diagnosed with 
locally advanced or metastatic BTC is poor and is dictated primarily by factors such as tumour 
size, lymph node invasion and vascular invasion. The 5-year survival rates for stage III and IV are 
10% and 0%, respectively (AJCC, 2010). Thus, new therapies are urgently required within this 
area of unmet medical need. 
1.2 
Treatment Options for Locally Advanced or Metastatic BTC 
Despite a relatively low incidence, BTC is aggressive and associated with a high mortality rate.  
These cancers are generally diagnosed in advanced stages when surgical resection is not feasible 
and palliative chemotherapy is the only treatment available. Surgical resection is possible in only 
a limited number of patients, most of whom experience recurrence (Ghidini et al, 2019). The most 
effective chemotherapy drugs for the treatment of BTC are gemcitabine, platinum agents and 
fluoropyrimidines (NCCN, 2019; Eckel & Schmid, 2007; Tsavaris et al, 2004). Furthermore, 
double-agent chemotherapy in the first-line setting has shown improvement in Objective Response 
Rate (ORR), Overall Survival (OS) and quality of life (QoL) compared with single-agent therapy 
(Eckel & Schmid, 2007; Ciombor & Goff, 2013). 
1.3 
Gemcitabine with cisplatin in BTC 
There is no approved therapy for the treatment of BTC, but the combination of gemcitabine with 
cisplatin has been established as the standard of care (SOC; gemcitabine 1000 mg/m2 and cisplatin 
25 mg/m2 administered by IV infusion on Days 1 and 8 every 21 days) on the basis of clinical 
studies. European Society for Medical Oncology (ESMO) clinical practice guidelines identify the 
combination of gemcitabine with cisplatin as the SOC for first-line therapy of patients with locally 
advanced or metastatic disease (Valle et al, 2016). Furthermore, the combination of gemcitabine 
and cisplatin is recognised by the NCCN as a Category 1 recommendation for the first-line 
treatment of patients with BTC (NCCN, 2019). 
 


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There have been only three published randomised studies evaluating the clinical activity of 
gemcitabine in combination with cisplatin at the SOC regimen in the first-line setting of BTC 
(Okusaka et al, 2010; Valle et al, 2010; Valle et al, 2015). The reported ORR (based on 
unconfirmed responses) from these studies ranged from 18.5–26.1%. These studies each used a 
different definition of the population of patients from which ORR (based on unconfirmed 
responses) was calculated, and when adjustments are made to allow for this, the ORR results from 
these three studies were still similar. The median OS across the three studies was consistent, 
ranging from 11.2–11.9 months. 
1.3.1 Gemcitabine Resistance 
Gemcitabine is associated with key cancer resistance mechanisms, which may result in limited 
efficacy in patients with BTC. These resistance mechanisms include: 
• Inefficient uptake into cells requiring active membrane transporters, which limits the ability of 
gemcitabine to reach its site of action (Achiwa et al, 2004) 
• Poor intracellular conversion via intracellular kinases to the active di- and tri-phosphates forms 
(Kroep et al, 1998) 
• Metabolism via deamination in the plasma and intracellularly prior to being phosphorylated, 
thus rendering the drug inactive (Kroep et al, 1998) 
1.4 
NUC-1031 
NUC-1031 is a new chemical entity resulting from the phosphoramidate transformation of 
gemcitabine. NUC-1031 is synthesised as a pre-activated molecule bearing one protected 
phosphate group, termed the phosphoramidate motif, imparting several potential advantages over 
gemcitabine (Slusarczyk et al, 2014): 
• NUC-1031 is more efficiently taken up by cells as it does not rely on nucleoside transporters 
to cross the cellular membrane, due to its lipophilicity 
• NUC-1031 presents the cell with an already partially activated (monophosphate) form of the 
nucleoside, thereby obviating the need for the rate-limiting initial kinase activation 
• NUC-1031 is protected from enzymatic breakdown (especially by deaminases and 
phosphorylases) resulting in greater stability and a reduction in the generation of potentially 
toxic metabolites. 
1.4.1 Non Clinical Data 
NUC-1031 has shown in vitro efficacy against a range of cancer cell lines, including biliary tract, 
pancreatic,  bladder, prostate, breast, non-small cell lung and colon. The in vitro studies showed a 
consistent increase in cytotoxicity of NUC-1031 compared to gemcitabine controls (half-maximal 
effective concentration values for NUC-1031 showed 1.3 to 343-fold improvement over 
gemcitabine). 
In vivo, NUC-1031 has also demonstrated greater efficacy across a range of xenograft studies 
compared to gemcitabine. In all of the studies reported, NUC-1031 was more effective than 
gemcitabine at an equimolar dose. The increased effectiveness was in some cases related to 
improved tolerance to NUC-1031 allowing a higher dose to be administered. Where equivalent 
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Toxicology findings for NUC-1031 are consistent with the cytotoxic mechanism of action and are 
qualitatively similar to those reported for gemcitabine. Dose range finding, four-week toxicity, and 
thirteen-week toxicity studies have shown that NUC-1031 has an acceptable safety profile when 
administered once-weekly up to 12 mg/kg/day. The main findings included evidence of 
gastrointestinal mucosal irritation, suppression of the haematopoietic system, lymphoid atrophy 
and thymic atrophy, as well as minimal effects in the testes of male dogs. Data from genotoxicity 
studies suggest that NUC-1031 is only weakly genotoxic and significantly less so than 
gemcitabine. Further non clinical data can be found in the NUC-1031 Investigator’s Brochure (IB). 
1.4.2 Clinical Data 
Four clinical studies with NUC-1031 have been completed, including the first-in-human (FIH) 
study in 68 patients with advanced solid tumours receiving NUC-1031 as a single agent (PRO-001; 
NCT01621854), a study in 25 patients with recurrent ovarian cancer receiving NUC-1031 in 
combination with carboplatin (PRO-002; NCT02303912), a study in 21 patients with locally 
advanced or metastatic BTC receiving NUC-1031 in combination with cisplatin (ABC-08; 
NCT02351765), and a study in 51 patients with platinum-resistant ovarian cancer (PRO-105; 
NCT03146663; pending final study report). Data from these completed studies are summarised 
below in Sections 1.4.2.1, 1.4.2.2, and 1.4.2.3. 
There is one ongoing NUC-1031 study in metastatic pancreatic carcinoma (ACELARATE; 
ISRCTN 16765355). Available clinical data from ACELARATE can be found in the NUC-1031 
IB.  
1.4.2.1 PRO-001: First-in-Human Study in Advanced Solid Tumours 
The FIH Phase I study recruited 68 patients with advanced solid tumours (Blagden et al, 2018). 
Single-agent NUC-1031 at doses ranging from 375 mg/m2 to 1,000 mg/m2 was shown to be 
well-tolerated with 8 dose-limiting toxicities (4 events of Grade 3 alanine aminotransferase [ALT] 
elevations, 2 events of Grade 4 thrombocytopaenia, and 1 event each of Grade 4 neutropaenia and 
posterior reversible encephalopathy syndrome) observed in 4 patients at doses of 725 mg/m2 and 
above. Patients received a median of 3 cycles of NUC-1031 (range <1-19 cycles). Best Overall 
Response (BOR), assessed by RECIST v1.1, demonstrated that 5 patients achieved a PR and 
33 patients achieved Stable Disease (SD), resulting in a Disease Control Rate (DCR) of 78% 
(38/49 evaluable patients). The Progression-Free Survival (PFS) ranged from 1 to 25 months; 
however, the study design did not incorporate follow-up visits after the end of treatment and so 
the actual PFS may have been longer. 
A total of 18 patients with gynaecological cancer (11 ovarian cancer, 3 endometrial cancer, and 
2 each of cervical cancer and fallopian tube cancer) were treated on the PRO-001 study, of whom 
14 were evaluable for response, defined as having received ≥2 cycles and a post-treatment 
objective disease assessment. In this subset, two patients achieved a PR and a further 11 patients 
achieved SD, resulting in a DCR of 93%. The PFS ranged from 1.6 to 11.3 months, although is 
likely to be an underestimate. 
1.4.2.2 PRO-002: NUC-1031 Combination with Carboplatin in Recurrent Ovarian Cancer 
Data from the gynaecological cancer subset of patients in the PRO-001 study formed the basis for 
a completed Phase Ib dose escalation study of NUC-1031 in combination with carboplatin in 
patients with recurrent ovarian cancer (PRO-002; Blagden et al, 2017). 
Escalating doses of NUC-1031 from 500 mg/m2 to 750 mg/m2 on Days 1 and 8 were combined 
with carboplatin at an area under the curve (AUC) of 4 or 5 on Day 1 of 21-day cycles. Patients 


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could receive a maximum of 6 cycles of treatment. A total of 25 patients were enrolled and most 
completed all 6 cycles of chemotherapy. The tolerability of the combination was good and there 
were no unexpected adverse events (AEs). Of the 25 patients recruited, 23 were evaluable for 
response, defined as having received ≥1 cycle of treatment and having undergone a post-treatment 
objective disease assessment. In this population, 1 patient experienced confirmed CR, 8 patients 
experienced PR (4 confirmed), and 13 patients had SD. The DCR was 96% and the ORR was 39% 
in the evaluable patient population. 
1.4.2.3 ABC-08: NUC-1031 Combination with Cisplatin in BTC 
Study Design 
ABC-08 is a recently completed open-label, Phase Ib study of NUC-1031 in combination with 
cisplatin in patients with previously untreated locally advanced or metastatic BTC (McNamara et 
al, 2020). The study explored NUC-1031 administered at 625 mg/m2 (Cohort 1 and Expansion 
Cohort) or 725 mg/m2 (Cohort 2) in combination with cisplatin at 25 mg/m2, on Days 1 and 8 of 
21-day cycles. The starting dose was 625 mg/m2, with dose escalation evaluated in a traditional 
3+3 design.  
The purpose of this study was to provide proof-of-concept for the efficacy and safety of NUC-1031 
in combination with cisplatin and to determine the dose to carry forward into further clinical 
development in the treatment of patients with advanced/metastatic BTC. 
The primary objectives were to assess the safety and determine the recommended Phase II dose 
(RP2D) of NUC-1031 in combination with cisplatin in patients with advanced BTC. The 
secondary objectives were to assess the anti-tumour activity and to explore the pharmacokinetic 
(PK) profile of the combination. 
Patients enrolled in the study were males or females aged ≥18 years with non-resectable or 
recurrent/metastatic histologically- or cytologically-verified cholangiocarcinoma, gallbladder, or 
ampullary carcinoma who had not received prior systemic therapy and who had an Eastern 
Cooperative Oncology Group (ECOG) performance status of 0-1 and a life expectancy of 
>3 months.  
Patient Disposition 
A total of 21 patients were enrolled across Cohort 1 (625 mg/m2, n=8), Cohort 2 (725 mg/m2, n=6), 
and the Expansion Cohort (625 mg/m2, n=7) forming the ITT population. Across all cohorts, the 
median age was 61 years (range 47–78 years) and all patients were Caucasian. Thirteen male and 
eight female patients with the following subtypes of BTC were included: 7 hilar, 5 distal bile duct, 
5 intrahepatic, 2 ampullary, and 2 gallbladder. The majority of patients (n=17) had metastatic 
disease.  
Safety Results 
Patients in the 625 mg/m2 cohorts received a median of 6 cycles (range 1-12 cycles) and patients 
in the 725 mg/m2 cohort received a median of 7.5 cycles (range 1-14 cycles) of study treatment. 
The combination was well-tolerated, with no unexpected events and no patients discontinuing due 
to toxicities. The most frequently reported Grade 3/4 treatment-emergent AEs (TEAEs) included 
increased gamma-glutamyltransferase (48%), fatigue (19%), neutropaenia (19%), increased ALT 
(14%), decreased white blood cells (14%), and thrombus (14%). This is similar to the safety profile 
reported for gemcitabine in this patient population.  


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Efficacy Results 
Of the 21 patients in the ITT population, 5 patients did not meet the criteria for inclusion in the 
efficacy evaluable population (patients with measurable disease who received at least one cycle of 
study treatment and had at least one follow-up radiographic scan); thus, 16 patients were efficacy 
evaluable. In the efficacy evaluable population, an ORR (based on unconfirmed responses) of 44% 
was achieved (1 CR and 6 PRs). In addition, 6 patients had SD, resulting in a DCR of 81% (13 of 
16 patients). One further patient, who was initially assessed as having measurable disease at 
baseline, acheived a PR with a 67% reduction in the volume of target lesions based on Investigator 
assessment. However, the baseline target lesion was subsequently reclassified as non-measurable 
by the Sponsor resulting in the exclusion of the patient from the evaluable population. 
Furthermore, one patient with SD, whose tumour was initially considered unsuitable for surgical 
resection, became eligible for complete resection following treatment with NUC-1031 in 
combination with cisplatin and underwent surgery that resulted in complete removal of the tumour. 
The relative changes in tumour measurements per best response to treatment in the efficacy 
evaluable patients are shown in Figure 1. Ten of the 16 evaluable patients had tumour shrinkage 
and all five BTC subtypes were sensitive to NUC-1031 in combination with cisplatin. 
 
Figure 1 
Best response to treatment with NUC-1031 in combination with cisplatin in 
efficacy evaluable patients (ABC-08 study) 
Abbreviations: AMP=ampullary; DBD=distal bile duct; GB=gallbladder; IHC=intrahepatic. 
The cholangiocarcinoma grouping includes DBD, hilar, and IHC. The dashed lines at 20% and -30% represent the cut-offs for 
progressive disease and partial response, respectively, according to RECIST v1.1. 


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In the ITT population (n=21), 1 patient had a CR and 6 patients had PRs, resulting in an ORR 
(based on unconfirmed responses) of 33%. In addition, 9 patients had SD, resulting in a DCR of 
76%.  
The encouraging response rate observed in this study, although in a small number of patients, 
compares favourably with the 18.5–26.1% response rates in efficacy evaluable populations 
observed in prior studies with the standard of care gemcitabine and cisplatin regimen. This 
improvement in ORR suggested that the combination of NUC-1031 and cisplatin may represent a 
more effective therapeutic regimen for patients with locally advanced or metastatic BTC, thereby 
addressing a critical unmet medical need.  
1.4.3 Pharmacokinetics 
The disposition of NUC­1031 and its metabolites in plasma, peripheral blood mononuclear cells 
(PBMCs), and urine following intravenous (IV) administration of NUC-1031 was investigated in 
the PRO-001 study (Blagden et al, 2018).  
• After NUC-1031 administration over the dose range of 375 to 1,000 mg/m2, NUC-1031 plasma 
concentrations and key exposure parameters (AUC0-t and maximum concentration [Cmax]) 
increased with increasing dose in an approximately dose proportional manner 
• The predominant intracellular metabolite generated was di-fluoro-deoxycytidine triphosphate 
(dFdCTP), both in terms of concentration and key intracellular exposure parameters. 
Compared to published gemcitabine literature (Grunewald et al, 1990; Abbruzzese et al, 1991; 
Grunewald et al, 1992; Cattel et al, 2006; Peters et al, 2007), on an equimolar basis: 
o The median intracellular dFdCTP Cmax in PBMCs following NUC-1031 administration 
was 217-times higher than that observed with gemcitabine 
o The median intracellular dFdCTP AUC0-24 in PBMCs following NUC-1031 
administration was 139-times higher than that observed with gemcitabine 
o NUC-1031 administration resulted in intracellular dFdCTP concentrations throughout 
the following 24-hour period that were higher than that which is observed at the Cmax 
2-hour time point after gemcitabine administration 
• The predominant analyte found in excreted urine was di-fluoro-deoxyuridine (dFdU); urinary 
excretion of NUC-1031 and di-fluoro-deoxycytidine was minimal 
The findings of the PRO-001 PK analyses are consistent with the clinical data, where NUC-1031 
doses of 500 mg/m2 and above demonstrated marked anti-tumour activity. 
A comparison of the PK parameters from the ABC-08 study of NUC-1031 in combination with 
cisplatin (25 mg/m2) in patients with BTC or the PRO-002 study of NUC-1031 in combination 
with carboplatin (AUC 4-5) in patients with recurrent ovarian cancer with those generated during 
monotherapy (PRO-001 study) indicate that the combination with either cisplatin or carboplatin 
does not alter the PK profile of NUC-1031.  


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1.5 
NuTide:121 Study Rationale 
Gemcitabine in combination with cisplatin prolongs the survival of patients with advanced BTC 
over gemcitabine alone, as demonstrated in the ABC-02 study (Valle et al, 2010). Efficacy was 
similar across the main subgroups in this study, including intra- and extra-hepatic 
cholangiocarcinoma and gallbladder cancer, as well as in Western and Asian patient populations, 
as demonstrated in a second study with identical design conducted in Japan (Okusaka et al, 2010; 
Valle et al, 2014).  
Gemcitabine in combination with cisplatin has been established as the SOC for the first-line 
treatment of patients with BTC and is recognised by the National Comprehensive Cancer Network 
(NCCN) as a Category 1 recommendation for this patient group (NCCN, 2019). However, median 
survival time is very modest at less than 1 year. NUC-1031 is a new chemical entity resulting from 
the phosphoramidate transformation of gemcitabine, specifically designed to bypass the inherent 
or acquired cancer cell resistance pathways that severely limit the efficacy of gemcitabine and add 
to its toxicity. The combination of NUC-1031 and a platinum agent appears from our clinical 
studies to be very effective. The clinical activity of NUC-1031 in combination with cisplatin in 
patients with locally advanced or metastatic BTC was evaluated as first-line therapy in the ABC-08 
study (McNamara et al, 2020). The observed improvement in ORR indicates that NUC-1031 in 
combination with cisplatin may represent a more effective first-line treatment for patients with 
locally advanced or metastatic BTC than gemcitabine in combination with cisplatin, thus 
addressing a significant unmet medical need. 
On the basis of regulatory feedback and review of the ABC-08 data, NuCana designed the 
NuTide:121 study. Given that BTC is a rare disease for which there is currently no approved 
therapy, progression to a Phase III pivotal study on the foundation of promising Phase Ib data is 
justified in this indication in which new therapies are urgently required. NUC-1031 in combination 
with cisplatin has the potential to prolong survival over the SOC regimen as it is designed to 
overcome the key cancer resistance mechanisms associated with gemcitabine. 
NuTide:121 is a 1:1 randomised study designed to compare NUC-1031/cisplatin (Arm A) to the 
gemcitabine/cisplatin SOC (Arm B) and is designed to detect a clinically meaningful improvement 
in ORR and OS. 
2 
STUDY OBJECTIVES AND ENDPOINTS 
2.1 
Primary Objectives 
• OS 
• ORR based on blinded independent central review (BICR) in patients with measurable disease 
at baseline 
2.2 
Secondary Objectives 
• PFS based on BICR 
• Duration of response (DoR) based on BICR 
• 18- and 12-month survival 
• DCR based on BICR 
• Safety 
• PK of NUC-1031 


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• Patient-reported QoL 
2.3 
Tertiary Objectives 
• Health economics  
• Assessment of archival tumour sample characteristics that may further an understanding of the 
mechanism(s) through which the clinical activity of NUC-1031 is achieved 
2.4 
Primary Endpoints 
• OS, defined as the time from randomisation to the time of death from any cause 
• ORR, defined as the percentage of patients achieving a confirmed complete or partial response 
to treatment as assessed by BICR according to RECIST v1.1 criteria. This will be assessed 
only in patients with measurable disease at baseline. 
2.5 
Secondary Endpoints 
2.5.1 Key Secondary Endpoint 
• PFS, based on BICR according to RECIST v1.1 criteria, defined as the time from 
randomisation to the first observation of objective tumour progression or death from any cause. 
For patients with non-measurable disease at baseline, refer to the protocol criteria for disease 
progression (Section 11). 
2.5.2 Other Secondary Endpoints 
Efficacy 
• DoR, as assessed by BICR, defined as the time from initial clinical response (PR or CR that is 
subsequently confirmed) to the first observation of tumour progression or death from any cause 
• 18-month survival 
• 12-month survival 
• DCR, based on BICR according to RECIST v1.1 criteria, defined as the percentage of patients 
demonstrating a BOR of CR, PR, or SD 
Objective disease assessment will be performed radiologically and assessed according to RECIST 
v1.1 criteria. Treatment and study continuation decisions based on radiologic assessments will be 
made by the treating Investigator.  
Safety 
Safety and tolerability will be assessed by evaluation of the following: 
• TEAEs, including TEAEs by severity grade using Common Terminology Criteria for Adverse 
Events (CTCAE) v5.0 
• Serious TEAEs (SAEs) 
• Deaths due to TEAEs 
• Treatment discontinuations due to TEAEs 
• Clinically significant changes in laboratory parameters 
• Changes in ECOG status, physical exam, electrocardiogram (ECG) and vital signs 
A sub-study will be carried out to assess the effect of the NUC-1031 + cisplatin combination on 
cardiac repolarisation in a subset of patients.  


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Pharmacokinetics of NUC-1031 
Sparse PK sampling will be taken on Cycle 1 Day 1 at the end of infusion, 2 hours after the end of 
infusion, and 6 hours after the end of infusion, to capture Ctrough and Cmax plasma levels. See 
Section 7.2 for PK sampling details. 
Patient-Reported QoL 
Patient-reported QoL will be assessed using the European Organisation for Research and 
Treatment (EORTC) QoL Questionnaire (QLQ-C30) with the QLQ-BIL21 module (Appendix 1) 
and the 5-level EuroQol five-dimension scale (EQ-5D-5L; Appendix 2). 
2.6 
Tertiary Endpoints 
Health economics 
Health economics will be assessed through collection of core health resource use information, 
using case report forms (CRFs) to capture procedure codes, days in hospital, and outpatient visits. 
Health outcomes will be quantified using quality-adjusted life years (QALYs) and a cost-utility 
analysis will be conducted by creating incremental cost-utility ratios for each of the treatment 
groups. 
Biomarkers 
Phenotypic, genotypic, and/or pharmacodynamic characteristics of the tumour cell that may further 
delineate the mechanism(s) through which NUC-1031 acts. 
3 
INVESTIGATIONAL PLAN 
3.1 
Overall Study Design 
NuTide:121 is an open-label, randomised Phase III study of NUC-1031 in combination with 
cisplatin (Arm A) compared to gemcitabine in combination with cisplatin (Arm B), administered 
on Days 1 and 8 of 21-day cycles, in previously untreated patients with locally advanced or 
metastatic BTC (Figure 2). A total of 828 patients will be randomised in a 1:1 ratio to Arm A or 
Arm B, and may continue to receive study treatment until radiographic documentation of disease 
progression, evidence of unacceptable treatment-related AEs despite optimal medical management 
and/or dose modification, or withdrawal of consent. 
The study will continue until 637 deaths have occurred, unless the results for OS meet the 
pre-specified criterion at an interim analysis to stop for early demonstration of efficacy, or unless 
terminated early on the recommendation of the Independent Data Monitoring Committee (IDMC). 
The aim of this study is to compare the clinical activity and tolerability of NUC-1031 administered 
with cisplatin against the current SOC (gemcitabine in combination with cisplatin) in patients with 
locally advanced or metastatic BTC. 
3.2 
Rationale for the Doses Selected 
3.2.1 Arm A (NUC-1031 + cisplatin) 
Patients will receive NUC-1031 at a dose of 725 mg/m2 and cisplatin at a dose of 25 mg/m2 on 
Days 1 and 8 of 21-day cycles. The proposed dose of, and dosing schedule for, NUC-1031 are 
derived predominantly from clinical data in study ABC-08, supported by Phase I and non clinical 
data. 


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In study ABC-08, NUC-1031 at doses of 625 mg/m2 or 725 mg/m2 and cisplatin at a dose of 
25 mg/m2 were administered on Days 1 and 8 of 21-day cycles (McNamara et al, 2020). The dose 
of NUC-1031 in Cohort 1 of study ABC-08 was 625 mg/m2. After expansion of the cohort to 
6 patients, the Trial Management Group (TMG) recommended that the dose should increase to 
725 mg/m2. Following review of clinical and PK data, the TMG determined the dose of NUC-1031 
for further study as 725 mg/m2 as patients were able to maintain a higher treatment intensity for 
longer at this dose. Thus, patients in the 725 mg/m2 dose group received cumulatively more 
NUC-1031 and cisplatin when compared to patients in the 625 mg/m2 dose group, suggesting that 
the combination is not only tolerable at this dose but also potentially therapeutically advantageous 
compared to the lower dose. In addition, there was no discernible difference between the two dose 
groups in safety or PK. The dose selection is further supported by Phase I data from completed 
studies and Phase III data from an ongoing study in pancreatic cancer. 
Single agent NUC-1031 was evaluated in the first-in-human dose escalation study, PRO-001, in 
solid tumours up to doses of 1000 mg/m2. In this study, one patient in the 725 mg/m2 group 
experienced 2 occurrences of Grade 3 reversible alanine aminotransferase (ALT) elevations, one 
patient in the 750 mg/m2 group experienced a reversible Grade 4 thrombocytopaenia, one patient 
in the 1000 mg/m2 group experienced 2 occurrences of Grade 3 reversible ALT elevations, and 
another patient in the 1000 mg/m2 group experienced reversible Grade 4 thrombocytopaenia, 
neutropaenia and posterior reversible encephalopathy syndrome (PRES). However, no patients in 
either the 825 or 900 mg/m2 cohorts experienced dose-limiting toxicity (DLT). Expansion cohorts 
at doses of 825 and 900 mg/m2 enrolled 12 and 9 patients, respectively. 
NUC-1031 in combination with carboplatin was evaluated in a Phase Ib study, PRO-002, in 
patients with recurrent ovarian cancer. In this study, NUC-1031 was administered at doses up to 
750 mg/m2 on Days 1 and 8 of 21-day cycles in combination with carboplatin at AUC4 or 5. The 
combination was well tolerated, and most treatment-emergent adverse events (TEAEs) resolved 
allowing patients to continue treatment. 
NUC-1031 is also currently being evaluated in a Phase III study, ACELARATE, in patients with 
advanced pancreatic cancer who are not considered suitable for combination chemotherapy. In this 
study, NUC-1031 is being administered at a dose of 825 mg/m2 on Days 1, 8, and 15 of 28-day 
cycles. The NUC-1031 dose selected for the NuTide:121 study is 725 mg/m2 on Days 1 and 8 of 
21-day cycles, i.e., 3 doses per month at 725 mg/m2 (2175 mg/m2/month), which is lower than the 
dosing regimen already shown to have an acceptable tolerability profile in the pancreatic cancer 
study (2475 mg/m2 per month). 
Taking all available data into consideration, and after discussion with Investigators in the ABC-08 
study and the Chief Investigator for this study, a NUC-1031 dose of 725 mg/m2 was identified as 
offering patients the best opportunity for clinical benefit. 
3.2.2 Arm B (gemcitabine + cisplatin) 
The established SOC regimen will be administered in Arm B, with 1000 mg/m2 gemcitabine 
administered in combination with 25 mg/m2 cisplatin on Days 1 and 8 of 21-day cycles. Treatment 
will continue until radiographic documentation of objective disease progression, unacceptable 
treatment-related AEs, or other requirement to discontinue treatment. 


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Figure 2 
NuTide:121 study schema 
*Patients who stop treatment with no evidence of disease progression as defined by RECIST v1.1 criteria will continue 
to receive scans at least every 12 weeks (±14 days) until radiographic disease progression in order to determine 
duration of overall response and PFS. 
* 


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3.3 
Study Treatment 
Patients who have signed the informed consent and are eligible will be randomised on C1D1 in a 
1:1 ratio to receive treatment in Arm A (cisplatin at 25 mg/m2 followed by NUC-1031 at 
725 mg/m2) or Arm B (cisplatin at 25 mg/m2 followed by gemcitabine at 1000 mg/m2) on Days 1 
and 8 of a 21-day cycle. 
The randomisation process is detailed in Section 8.5 of this protocol. Criteria for inter-cycle and 
intra-cycle dose delay and dose modification are specified in Section 9 of this protocol. The reasons 
for dose delay or dose modification must be captured as AEs in the patient medical record and 
noted on the case report form (CRF). 
3.4 
Patient Selection and Study Centres 
Patients will be randomised in this study from approximately 130 sites in North America, Europe, 
and Asia Pacific. Patients are eligible for the study if all of the inclusion criteria are met and none 
of the exclusion criteria apply.  
Eligible patients will have histologically- or cytologically-proven biliary adenocarcinoma, 
including cholangiocarcinoma (intra- and extra-hepatic biliary ducts), gallbladder or ampullary 
cancer, that is not amenable to surgical resection (please refer to AJCC edition 8, 2018) and will 
have had no prior systemic chemotherapy for treatment of locally advanced or metastatic disease.  
Patients with measurable or non-measurable disease are eligible for study participation in 
accordance with predefined randomisation strata; however, non-measurable disease is limited to 
82 patients (due to statistical requirements of ORR analysis). Determination of measurable or 
non-measurable disease status will be based on BICR assessment. 
In accordance with local standards of care as appropriate, patients may have received prior 
chemotherapy in the adjuvant setting and/or radiotherapy with or without radio-sensitising 
low-dose chemotherapy for localised disease if completed at least 6 months prior to randomisation. 
Patients must have adequate biliary drainage without evidence of biliary obstruction. Patients with 
disease characterised as combined or mixed hepatocellular/ cholangiocarcinoma are not eligible 
for this study. 
3.5 
Robust QT Sub-study 
A sub-study will be carried out to assess any potential effects of the NUC-1031 + cisplatin 
combination on cardiac repolarisation. 
Holter ECG monitoring will be implemented in a subset of patients at a subset of sites to collect 
QT/QTc data to allow a primary analysis of the QT effect of NUC-1031 in combination with 
cisplatin relative to the effect of gemcitabine in combination with cisplatin, based on a by-time 
point analysis. A total of 74 patients (approximately 37 patients in each treatment group) will be 
enrolled and will have Holter ECGs conducted through the first 2 cycles of treatment. See 
Section 5.5 for details of ECG read timepoints. 
ECGs will be centrally evaluated and measured in a blinded manner. A by-time central tendency 
analysis will be used as the primary analysis for assessing QTc in the sub-study.  Further to this, 
all ECG parameters will be statistically analysed and described, including categorical outlier 
analysis for QT/QTc outliers as well as HR, PR and QRS which will be outlined in a separate QT 
Statistical Analysis Plan. Refer to Sections 5.5 and 12.11 for further details. 


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3.6 
Duration of Patient Participation and Post-Study Care 
Patients will continue to receive study treatment until radiographic documentation of objective 
progressive disease, evidence of unacceptable treatment-related AEs despite optimal medical 
management and/or dose modification, or withdrawal of consent. Reasons for treatment 
discontinuation must be captured in the patient medical record and on the Treatment 
Discontinuation page of the CRF. 
A patient who is receiving clinical benefit but experiencing toxicity related to the cisplatin 
component may continue on study receiving single agent NUC-1031 (Arm A) or gemcitabine 
(Arm B). 
If a patient discontinues treatment without radiological evidence of disease progression, they 
should continue to undergo tumour assessment at least every 12 weeks (±14 days) until such time 
as progression can be documented. Patients who stop treatment following an unconfirmed response 
should also still have a confirmatory scan within the 28- to 42-day window, if the scan can take 
place prior to the patient starting any subsequent anti-cancer therapies. 
Following discontinuation of study treatment, patients will receive treatment in accordance with 
local standard of care. 
3.7 
End of Study 
The end of study date is defined as the time when 637 deaths have occurred, unless the results for 
OS meet the pre-specified criterion at an interim analysis to stop for early demonstration of 
efficacy, or unless the study is terminated early on safety grounds on the recommendation of the 
IDMC. 
Patients who are still receiving benefit from study treatment at the end of study date, or in the event 
of early termination of the study, may continue study treatment at the discretion of the Investigator 
and in accordance with local regulations until disease progression or until the drug becomes 
commercially available and accessible locally. A patient will be eligible to receive study drug after 
study completion if the following conditions are met: 
• There is evidence of continued clinical benefit for the patient and the patient consents to 
continue with treatment 
• There are no appropriate alternative treatment options available to the patient or a change 
in treatment would pose a risk to the patient 
• The patient and his/her doctor comply with and satisfy any legal or regulatory 
requirements for continuation of study treatment 
A patient will not be eligible to receive study drug after study completion if any of the following 
conditions are met: 
• The Sponsor has discontinued development of the study drug or data suggest that the 
study drug is not effective for locally advanced or metastatic BTC 
• The Sponsor has reasonable safety concerns regarding the study drug as treatment for 
locally advanced or metastatic BTC 
• Provision of study drug is not permitted under the laws and regulations of the patient’s 
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4 
PATIENT SELECTION 
4.1 
Inclusion Criteria 
To be enrolled in this study, patients must meet all of the following criteria during the Screening 
period: 
1. Written informed consent and authorisation to use and disclose health information. 
2. Ability to comprehend and willingness to comply with the requirements of this protocol, 
including the QoL questionnaires. 
3. Female or male patients aged ≥18 years. 
4. Histologically- or cytologically-confirmed adenocarcinoma of the biliary tract (including 
gallbladder, intra and extra-hepatic biliary ducts and ampullary cancers) that is locally 
advanced, unresectable or metastatic (AJCC edition 8, 2018). Patients with measurable (as per 
RECIST v1.1 criteria) or non-measurable disease are permitted.  
5. Life expectancy ≥16 weeks. 
6. ECOG performance status 0 or 1. 
7. Adequate biliary drainage with no evidence of ongoing infection. If applicable, treatable and 
clinically-relevant biliary duct obstruction has been relieved by internal endoscopic 
drainage/stenting at least 2 weeks previously or by palliative bypass surgery or percutaneous 
drainage prior to study treatment, and the patient has no active or suspected uncontrolled 
infection. Patients fitted with a biliary stent should be clinically stable and free of signs of 
infection for ≥2 weeks prior to study treatment. Patients with improving biliary function who 
meet all other inclusion criteria may be re-tested during the screening window.   
8. Adequate bone marrow, hepatic, and renal function, as evidenced by: 
• Absolute neutrophil count (ANC) ≥1,500/μL without colony-stimulating factor support. 
• Platelet count ≥100,000/μL. 
• Haemoglobin ≥9 g/dL without need for haematopoietic growth factor or transfusion support in 
prior 2 weeks. 
• Total bilirubin <2 × upper limit of normal (ULN); does not apply to patients with Gilbert's 
syndrome. Consistent with inclusion criterion 7, patients whose whole bilirubin and biliary 
function is recovering may be re-tested during the screening period. 
• ALT and/or AST <5 × ULN 
• Creatinine clearance ≥45 mL/min actual or calculated by the Cockcroft-Gault method. 
• International normalised ratio (INR) <1.5 and activated partial thromboplastin time (aPTT) 
<1.5 × ULN; does not apply to patients on an anti-coagulant with stable dose 28 days prior to 
first dose. 
9. QTc interval <450 msec (males) or <470 msec (females), in the absence of bundle branch 
block. In the presence of bundle branch block with consequent QTc prolongation, patients may 
be enrolled based on a careful risk-benefit assessment.  
10. Human Immunodeficiency Virus (HIV)-infected patients who are healthy and have a low risk 
of Acquired Immune Deficiency Syndrome-(AIDS) related outcomes may be included in this 
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11. Female patients of child-bearing potential (i.e., all women except those who are 
post-menopausal for ≥1 year or who have a history of hysterectomy or surgical sterilisation) 
must have a negative pregnancy test within 3 days prior to the first study drug administration. 
All patients of child-bearing potential must agree to practice true abstinence or to use two 
highly effective forms of contraception, one of which must be a barrier method of 
contraception, from the time of screening until 6 months after the last dose of study medication. 
12. Male patients with a female partner must either have had a successful vasectomy or they and 
their female partner meet the criteria above (not of childbearing potential or practicing highly 
effective contraceptive methods). 
4.2 
Exclusion Criteria 
Patients who meet any of the following criteria at Screening will be excluded from the study: 
1. Combined or mixed hepatocellular/cholangiocarcinoma. 
2. Prior systemic therapy for advanced or metastatic biliary tract cancer. However, prior 
chemotherapy in the adjuvant setting or low-dose chemotherapy given in conjunction with 
radiotherapy in the adjuvant setting and completed at least 6 months prior to enrolment is 
permitted. The following prior interventions are allowed provided the patient has fully 
recovered:  
• Surgery: non-curative resection with macroscopic residual disease or palliative bypass surgery. 
Patients who have previously undergone curative surgery must now have evidence of 
non-resectable disease requiring systemic chemotherapy.  
• Radiotherapy: prior radiotherapy (with or without radio-sensitising low-dose chemotherapy) 
for localised disease and there is now clear evidence of disease progression requiring systemic 
chemotherapy. 
• Photodynamic therapy: prior photodynamic therapy for localised disease with no evidence of 
metastatic disease or for localised disease to relieve biliary obstruction in the presence of 
metastatic disease provided there is now clear evidence of disease progression requiring 
systemic chemotherapy. 
• Palliative radiotherapy: palliative radiotherapy provided that all AEs have resolved and the 
patient has measurable disease outside the field of radiation. 
 
3. Prior treatment with or known hypersensitivity to NUC-1031, gemcitabine, cisplatin or other 
platinum-based agents or history of allergic reactions attributed to any parenteral excipients 
(e.g., dimethylacetamide [DMA], Cremophor EL, Polysorbate 80, Solutol HS 15). 
4. Symptomatic central nervous system or leptomeningeal metastases. 
5. History of other malignancies, except adequately treated non-melanoma skin cancer, curatively 
treated in situ cancer of the cervix, surgically excised or potentially curatively treated ductal 
carcinoma in situ of the breast, or low grade prostate cancer or patients after prostatectomy not 
requiring treatment. Patients with previous invasive cancers are eligible if treatment was 
completed more than 3 years prior to initiating the current study treatment, and the patient has 
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6. Concurrent serious (as deemed by the Investigator) medical conditions, including, but not 
limited to, New York Heart Association class III or IV congestive heart failure, history of 
congenital prolonged QT syndrome, uncontrolled infection, active hepatitis B or C, or other 
co-morbid conditions that in the opinion of the Investigator would impair study participation 
or cooperation. 
7. Congenital or acquired immunodeficiency (e.g., serious active infection with HIV). As per 
inclusion criterion 10, patients with HIV who are healthy and have a low risk of AIDS-related 
outcomes are eligible. 
8. Other acute or chronic medical, neurological, or psychiatric condition or laboratory 
abnormality that may increase the risk associated with study participation or investigational 
product administration or may interfere with the interpretation of study results and, in the 
judgment of the Investigator, would make the patient inappropriate for entry into this study. 
9. Prior exposure to another investigational agent within 28 days prior to randomisation. 
10. Major surgery within 28 days prior to randomisation; patient must have completely recovered 
from any prior surgical or other procedures. 
11. Pregnant or breastfeeding. 
12. Residual toxicities from prior treatments or procedures which have not regressed to Grade ≤1 
severity (CTCAE v5.0), except for alopecia or ≤Grade 2 peripheral neuropathy. 
13. Concomitant use of drugs at doses known to cause clinically relevant prolongation of QT/QTc 
interval (see Appendix 3). 
14. Administration of a live vaccination within 28 days prior to randomisation. 
15. Ongoing or recent (≤6 months) hepatorenal syndrome. 
4.3 
Waivers to Entry Criteria 
The Investigator at each study site is responsible for ensuring the accuracy and completeness of 
all research records, the accountability of study drug, and the conduct of clinical and laboratory 
evaluations as outlined in the protocol. 
Waivers will not be granted for a patient who does not satisfy the eligibility criteria. Investigators 
who are unsure whether the patient satisfies all the entry criteria and wish to clarify matters of 
clinical discretion must contact the Medical Monitor who will consult NuCana before responding 
to the enquiry. 
4.4 
Study Completion 
The study will continue until 637 deaths have occurred, unless the results for OS meet the 
pre-specified criterion at an interim analysis to stop for early demonstration of efficacy, or unless 
the study is terminated early on the recommendation of the IDMC after the interim analysis. 
Patients who are still receiving benefit from study treatment at the end of study date, or in the event 
of early termination of the study, may continue study treatment at the discretion of the Investigator 
in accordance with local regulations until disease progression or until the drug becomes 
commercially available and accessible locally.  
An AE present at the time of study withdrawal should continue to be assessed for up to 30 days 
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These measures should ensure that sufficient information is available to enable assessment of the 
primary endpoints and other critical secondary endpoints including safety. When the criterion for 
the interim analysis or final analysis to take place is reached, there will be a data cut-off. In the 
weeks subsequent to this, a date for database lock will be assigned, and any outstanding queries 
concerning data elements will be resolved prior to this.  
Data from all procedures and assessments must be recorded in the patient’s medical record for 
extraction into the CRF. Please refer to the Summary Schedule of Events for further details. 
5 
STUDY ASSESSMENTS AND PROCEDURES 
5.1 
Informed Consent 
Potential patients will be given the current approved version of the study information sheet and 
informed consent form (ICF). 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 designee who obtains consent must be suitably qualified and experienced. All 
designees must be authorised by the Investigator to obtain consent. The Investigator is responsible 
for ensuring that the study consent procedures comply with International Council for 
Harmonisation Good Clinical Practice (ICH-GCP) and any other additional local regulatory 
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 ICF in each other’s presence. 
A copy of the study information and signed ICF will be given to the patient. The original signed 
form will be retained at the study site, with copies held in both the medical record and Investigator 
Site File. Written informed consent for participation in the study must be obtained prior to 
performing any study-specific screening tests or evaluations. 
If new safety information results in significant changes in the risk/benefit assessment, the patient 
information sheet and associated consent form would be reviewed and updated if necessary. If the 
patient information sheet and consent form is updated with new safety information, all patients 
(including those already being treated) would be informed of the new information, given a copy 
of the revised documents, and asked to re-consent to continue in the study. 
5.2 
Informed Consent for Collection of Archival Tumour Tissue Specimen, Robust QT 
Sub-study, and Follow-up of Pregnancy in Partners 
During the process described in Section 5.1, patients will also be asked to consent separately to 
the submission of an archival tumour tissue specimen and participation in the robust QT sub-study 
(at participating sites only; see Section 3.5 for details of the sub-study). In addition, should the 
female partner of a male patient become pregnant during his participation in the study, she will be 
asked to sign a pregnant partners ICF. If the partner agrees, she will be followed up until she gives 
birth and the health of the baby will be followed up until 6 months of age.  


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The submission of an archival tumour tissue specimen, generally from diagnosis or resection, is 
requested to allow for future analyses directed at further understanding and/or confirming the 
mechanism(s) of action of NUC-1031. The lack of an available archival tissue specimen, or the 
refusal to consent to submission of a specimen, will not preclude an eligible patient from the study.  
In the event that the archival tumour tissue specimen was only recently obtained, the biopsied 
lesion should not be designated a target lesion for the purposes of RECIST v1.1 criteria unless 
sufficient time has elapsed that the lesion has fully recovered. 
If a primary cancer specimen is unavailable, a specimen from a metastatic site is acceptable. Where 
local regulations prohibit submission of blocks of tumour tissue, a predetermined number of slides 
of representative tumour tissue may be substituted in response to this request. 
For slide preparation, storage conditions and shipment instructions, please refer to the 
accompanying Tumour Tissue Laboratory Manual. 
Shipment of archival samples can occur at anytime during the study treatment or follow-up 
periods, as long as the patient does not withdraw consent. 
5.3 
Screening Assessments 
All screening activities must be performed within 21 days prior to C1D1. A Screening Log must 
be kept of all patients considered for the study (i.e., all patients screened, including any that are 
subsequently excluded). The reason for exclusion must be recorded on this form. A copy of the 
Screening Log must be retained on site and provided to the Clinical Research Organisation (CRO) 
upon request, but without patient identifiers. 
Standard of care assessments that were completed prior to informed consent but are within the 
screening window may be used for screening assessments and do not have to be repeated. Imaging 
completed prior to informed consent for routine clinical practice purposes is acceptable provided 
it was performed as per RECIST v1.1 criteria and within 28 days of randomisation. All 
protocol-required assessments that are not deemed standard of care should not be performed prior 
to written informed consent. 
Screening assessments of consented patients will be comprised of the following: 
• Provision of written informed consent 
• Eligibility confirmation, including histological or cytological diagnosis of adenocarcinoma of 
the biliary tract (please refer to AJCC edition 8, 2018) 
• Interactive voice- or web-based response system (IxRS) registration 
• Recording of demographic data 
• Assessment of medical and surgical history and prior medications 
• Routine physical examination 
• ECOG performance status 
• Assessment of vital signs, including measurement of pulse rate, respiratory rate, blood pressure 
and temperature, after the patient has been seated or in the supine position for 5 minutes 
• Measurement of height and weight 


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• 12-lead ECG should be performed in triplicate (keeping the leads in place and patient supine 
for 5 minutes prior to and during readings) and reviewed by the Investigator or a qualified 
designee for safety and quality. The QTc interval should be calculated for each ECG using the 
Fridericia formula and averaged. Management of QT/QTc prolongation should be performed 
in accordance with institutional standard of care at the discretion of the treating physician. 
Digital and certified paper copies should be stored as part of the study documents in the event 
they need to be used in a future analysis. 
• Blood samples drawn for: 
o Haematology: white blood cell (WBC) count, differential WBC count, red blood cell 
(RBC) count, haemoglobin, haematocrit and platelets 
o Coagulation parameters: PT/INR and aPTT 
o Chemistry: sodium, potassium, magnesium, urea or blood urea nitrogen (BUN), 
creatinine, glucose, phosphate, total protein, albumin, adjusted calcium, total bilirubin, 
bicarbonate, chloride, uric acid, alkaline phosphatase, AST, ALT and lactate 
dehydrogenase (LDH) 
o Pregnancy testing: For women of childbearing potential, serum or urine pregnancy must 
be performed within 3 days prior to C1D1 
• Tumour imaging (computed tomography [CT], magnetic resonance imaging [MRI] and/or 
positron emission tomography CT (PET-CT) of thorax, abdomen and pelvis). Additional 
anatomical areas, other than chest, abdomen, and pelvis, should be assessed by CT scan, MRI, 
or PET-CT in case of suspicion of presence of metastases based on signs, symptoms, 
biochemical results and/or as standard of care imaging of patients (i.e., non-study related). A 
recently-biopsied lesion should not be designated as target lesions for the purposes of RECIST 
v1.1 criteria 
• Assessment of patient-reported QoL using EORTC QLQ-C30 with the QLQ-BIL21 module 
(Appendix 1) and the EQ-5D-5L (Appendix 2) 
• Assessment of health economics through collection of core health resource use information, 
using case report forms (CRFs) on days in hospital and outpatient visits 
• Collection of archival tissue specimen (may occur at any time during study participation) 
Carbohydrate antigen 19-9 (CA19-9) will not be measured as part of the study but may be 
measured as part of standard of care for the patient. 
5.4 
Re-Screening Patients Who Fail Inclusion/Exclusion Criteria 
If a patient does not meet the inclusion criteria upon first assessment because of residual toxicity 
from prior therapy or because of laboratory abnormalities, the patient can be reassessed as needed 
during the 21 day screening period. Patients who fail at re-screening are ineligible and may not be 
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5.5 
Robust QT Sub-study 
Holter ECG monitoring will be implemented at a subset of sites to collect QT/QTc data for a total 
of 74 patients (approximately 37 patients in each treatment group) during the first 2 cycles of 
treatment to allow robust analysis of ECG parameters, including QT/QTc analysis.  
A centralised ECG vendor will provide standardised and calibrated Holter ECG equipment to these 
sites along with training on correct lead positioning, machine use, and transmission of the digital 
Holter ECG data in real time to the centralised vendor on an ongoing basis. The Holter recording 
will be reviewed to ensure quality and, if required, issues flagged for purposes of retraining as 
needed. 
ECGs will be taken using a continuous Holter device on Day 1 and Day 8 of Cycle 1 and 2, with 
readouts at the following timepoints: 
ECG timepoint 
C1D1 
C1D8 
C2D1 
C2D8 
60 minutes pre-infusion 
 
X 
X 
X 
45 minutes pre-infusion 
X 
 
 
 
30 minutes pre-infusion 
X 
 
 
 
15 minutes pre-infusion 
X 
 
 
 
End of infusion 
X 
X 
X 
X 
10 minutes post-infusion 
X 
X 
X 
X 
30 minutes post-infusion 
X 
X 
X 
X 
60 minutes post-infusion 
X 
X 
X 
X 
2 hours post-infusion 
X 
X 
X 
X 
24 hours (±30 minutes) 
post-infusion 
X 
 
 
 
Holter devices must be fitted at least 15 minutes prior to the first reading and patients must remain 
supine for 5 minutes before, and during, each timepoint. 
ECGs will be centrally evaluated and measured in a blinded manner. A by-time central tendency 
analysis will be used as the primary analysis for assessing QTc in the sub-study.  Further to this, 
all ECG parameters will be statistically analysed and described, including categorical outlier 
analysis for QT/QTc outliers as well as HR, PR and QRS which will be outlined in a separate QT 
Statistical Analysis Plan. 


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5.6 
Evaluations to Be Performed During the Study 
During the treatment period, the assessments detailed in the sections below and summarised in the 
Summary Schedule of Events will be performed. 
5.6.1 Each Cycle, Day 1 
All procedures are to be completed prior to dosing, except for post-infusion PK sampling in 
participating patients. Holter ECG (where applicable), safety ECG, and PK (Arm A only) must be 
completed in that order. Safety laboratory assessments, physical examination, and patient-reported 
QoL assessments may be performed up to 3 days prior to Day 1 of each cycle. 
• Routine physical examination (may be completed by a qualified designee) 
• ECOG performance status 
• Assessment of vital signs, including measurement of pulse rate, respiratory rate, blood pressure 
and temperature, after the patient has been seated or in the supine position for 5 minutes 
• Measurement of weight 
• For sites participating in the robust QT sub-study, a continuous ECG assessment will be carried 
out using Holter monitors provided by an ECG vendor. Holter monitors must be fitted at least 
15 minutes prior to the first reading.  
o On Cycle 1 Day 1, the Holter monitor will be started 45 minutes before the start of 
infusion and should run until at least 2 hours after end of infusion and may continue to 
run until 24 hours after the end of infusion to capture the 24-hour timepoint or may be 
stopped after the 2-hour timepoint and the patient may be discharged but must return for 
the 24-hour timepoint where the Holter monitor would be reattached and run for at least 
30 minutes to capture the 24-hour timepoint. Patients should remain supine for 5 minutes 
before, and during, the following timepoints to ensure appropriate reads are available: 
45, 30 and 15 minutes before the start of infusion, at the end of infusion, and at 10, 30, 
60, 120 minutes, and 24 hours following the end of infusion on Cycle 1 Day 1. 
o On Cycle 2 Day 1, the Holter monitor will be started at a timepoint within 60 minutes 
before the start of infusion and should run until at least 2 hours after end of infusion.  
Patients should remain supine for 5 minutes before, and during, the following timepoints 
to ensure appropriate reads are available: within 60 minutes before the start of infusion, 
at the end of infusion, and at 10, 30, 60, and 120 minutes following the end of infusion 
on Cycle 2 Day 1. The Holter monitoring should be stopped and data transmitted as per 
the central ECG manual. Holter ECGs will be recorded on Day 1 and Day 8 of Cycles 1 
and 2 only. 
• 12-lead ECGs should be performed prior to beginning treatment, within 30 minutes 
(±5 minutes) post-infusion on C1D1 and C2D1 only, and prior to initiation of treatment on 
Day 1 in subsequent cycles. The ECGs should be performed in triplicate (keeping the leads in 
place and patient supine for 5 minutes prior to and during readings) and reviewed by the 
Investigator or a qualified designee for safety and quality. The QTc interval should be 
calculated for each ECG using the Fridericia formula and averaged. Management of QT/QTc 
prolongation should be performed in accordance with institutional standard of care at the 
discretion of the treating physician. Digital and/or certified paper copies should be retained at 
site and stored as part of the study documents in the event they need to be used in a future 
analysis. 


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• Blood samples drawn for: 
o Haematology: WBC count, differential WBC count, RBC count, haemoglobin, 
haematocrit and platelets 
o Chemistry: sodium, potassium, magnesium, urea or BUN, creatinine, glucose, 
bicarbonate, chloride, uric acid, phosphate, total protein, albumin, adjusted calcium, total 
bilirubin, alkaline phosphatase, AST, ALT and LDH 
o Coagulation parameters: PT/INR and aPTT 
o Pregnancy testing (serum or urine; for women of childbearing potential) 
• Cycle 1 Day 1 only - Blood samples collected for PK assessment (Arm A only). A total of 
3 blood samples are collected: (i) end of infusion, (ii) 2 hours after the end of infusion, and (iii) 
6 hours after the end of infusion 
• Assessment of patient-reported QoL using EORTC QLQ-C30 with the QLQ-BIL21 module 
(Appendix 1) and the EQ-5D-5L (Appendix 2) 
• Assessment of health economics through collection of core health resource use information, 
using case report forms (CRFs) on days in hospital and outpatient visits  
• IV administration of cisplatin followed by NUC-1031 (Arm A) or gemcitabine (Arm B) 
• Recording of concomitant medications 
• AE recording and causality assessments 
5.6.2 Each Cycle, Day 8 
All procedures to be completed prior to dosing, except for post-infusion PK sampling. Holter ECG 
(where applicable) should be completed before safety ECG. 
• Assessment of vital signs, including measurement of pulse rate, respiratory rate, blood pressure 
and temperature, after the patient has been seated or in the supine position for 5 minutes 
• For sites participating in the robust QT sub-study, a continuous ECG assessment will be carried 
out using Holter monitors provided by an ECG vendor. Holter monitors must be fitted at least 
15 minutes prior to the first reading. The Holter monitor will be started at a timepoint within 
60 minutes prior to infusion and should run until 2 hours after the end of infusion. Patients 
should remain supine for 5 minutes before, and during, the following timepoints to ensure 
appropriate reads are available: within 60 minutes before the start of infusion, end of infusion, 
and at 10, 30, 60, and 120 minutes following the end of infusion. The Holter monitoring should 
be stopped and data transmitted as per the central ECG manual. Holter ECGs will be recorded 
on Day 1 and Day 8 of Cycles 1 and 2 only. 
• 12-lead ECGs should be performed prior to beginning treatment, within 30 minutes 
(±5 minutes) post-infusion on C1D8 and C2D8, and prior to initiation of treatment on Day 1 
in subsequent cycles. The ECGs should be performed in triplicate (keeping the leads in place 
and patient supine for 5 minutes prior to and during readings) and reviewed by the Investigator 
or a qualified designee for safety and quality. The QTc interval should be calculated for each 
ECG using the Fridericia formula and averaged. Management of QT/QTc prolongation should 
be performed in accordance with institutional standard of care at the discretion of the treating 
physician. Digital and/or certified paper copies should be retained at site and stored as part of 
the study documents in the event they need to be used in a future analysis. 


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• Blood samples drawn for: 
o Haematology: WBC count, differential WBC count, RBC count, haemoglobin, 
haematocrit and platelets 
o Chemistry: sodium, potassium, magnesium, urea or BUN, creatinine, glucose, 
bicarbonate, chloride, uric acid, phosphate, total protein, albumin, adjusted calcium, total 
bilirubin, alkaline phosphatase, AST, ALT and LDH 
o Coagulation parameters: PT/INR and aPTT 
• IV administration of cisplatin followed by NUC-1031 (Arm A) or gemcitabine (Arm B). 
• Recording of concomitant medications 
• AE recording and causality assessment 
5.6.3 End of Treatment Visit 
The End of Treatment visit should occur within 30 days (±3 days) of the last administration of 
study treatment. The assessments should be performed upon discontinuation due to radiographic 
disease progression or early treatment discontinuation for other reasons (e.g., withdrawal of 
consent). 
• Routine physical examination (may be completed by a qualified designee) 
• ECOG performance status 
• Assessment of vital signs, including measurement of pulse rate, respiratory rate, blood pressure 
and temperature, after the patient has been seated or in the supine position for 5 minutes 
• 12-lead ECGs should be performed at the end of treatment visit. The ECGs should be 
performed in triplicate (keeping the leads in place and patient supine for 5 minutes prior to and 
during readings) and reviewed by the Investigator or a qualified designee for safety and quality. 
The QTc interval should be calculated for each ECG using the Fridericia formula and averaged. 
Management of QT/QTc prolongation should be performed in accordance with institutional 
standard of care at the discretion of the treating physician. Digital and/or certified paper copies 
should be retained at site and stored as part of the study documents in the event they need to 
be used in a future analysis. 
• Blood samples drawn for: 
o Haematology: WBC count, differential WBC count, RBC count, haemoglobin, 
haematocrit and platelets 
o Coagulation parameters: PT/INR and aPTT 
o Chemistry: sodium, potassium, magnesium, creatinine, glucose, chloride, phosphate, 
albumin, adjusted calcium, total bilirubin, alkaline phosphatase, AST, ALT and LDH 
o Pregnancy testing (serum or urine; for women of childbearing potential) 
• Assessment of patient-reported QoL using EORTC QLQ-C30 with the QLQ-BIL21 module 
(Appendix 1) and the EQ-5D-5L (Appendix 2).  Patient-reported QoL data should also be 
collected at the time of withdrawal from the study. 
• Assessment of health economics through collection of core health resource use information, 
using case report forms (CRFs) on days in hospital and outpatient visits 


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• Recording of concomitant medications 
• AE recording and causality assessment 
5.6.4 Follow-Up 
Patients who stop treatment with no evidence of disease progression as defined by RECIST v1.1 
criteria will continue to receive scans at regular intervals (at least every 12 weeks [±14 days]) until 
radiographic disease progression (regardless of whether any subsequent anti-cancer medication 
has been prescribed), consent withdrawal, lost to follow up or death, whichever occurs first, in 
order to determine duration of overall response and PFS. Patients who stop treatment following an 
unconfirmed response should still have a confirmatory scan within the 28- to 42-day window, if 
the scan can take place prior to the patient starting any subsequent anti-cancer therapy. If a patient 
is found to have a response at the confirmatory scan which has improved from PR to CR, then the 
improved response must also be confirmed within a further 28- to 42-day window, if the scan can 
take place prior to the patient starting any subsequent anti-cancer therapy. 
To ensure current and complete data on ORR for each of the first two interim analyses, in the 
6 weeks prior to the scheduled data cut-off date any patients with an unconfirmed response (with 
no earlier confirmed response) based on Investigator assessment (with no earlier confirmed 
response) will be identified. For such patients, Investigators will be reminded to schedule the 
confirmatory radiographic scan as soon after 28 days as possible, provided that the patient has not 
stopped treatment and started any subsequent anti-cancer therapy.  
Patient survival and initiation of new treatments (along with response to these new treatments) will 
be assessed approximately every 12 weeks (±14 days) until death, in order to determine duration 
of OS. To ensure current and complete survival data at the time of database locks, updated survival 
status may be requested prior to but not limited to IDMC review, interim analyses, and the final 
analysis. 
6 
PATIENT WITHDRAWAL 
6.1 
End of Treatment 
Study treatment is to be continued until one of the following occurs: 
• Progressive Disease (PD) as defined by RECIST v1.1 criteria. Patients should not discontinue 
treatment because of raised tumour marker levels or other clinical signs of PD until PD has 
been confirmed by RECIST v1.1 criteria. 
• Unmanageable toxicity defined as an AE that is considered by the Investigator to warrant 
permanent discontinuation of study treatment including the following: 
o AE resulting in a dosing delay of more than 21 days in starting the next cycle, unless the 
patient is receiving clinical benefit 
o Clinically significant drug-related AE that recurs despite dose reduction in two 
consecutive cycles. Patients may continue to receive treatment if the Principal 
Investigator and Medical Monitor agree that the patient is receiving a clinical benefit and 
the toxicity is manageable, reversible or transient. 
• Radiologically-confirmed pneumonitis 
• Radiologically-confirmed posterior reversible encephalopathy syndrome (PRES) 


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• Lack of further clinical benefit or unfavourable risk/benefit profile as judged by the 
Investigator in consultation with the medical monitor 
• Inter-current illness that prevents further administration of study treatment 
• Patient withdraws consent from further treatment or for further data collection 
o If the patient withdraws consent for further treatment, follow-up visits should continue 
o If the patient withdraws consent for further treatment and data collection, then no 
additional study visits or data collection should occur 
• Patient requires use of a prohibited concomitant medication or therapy 
• Pregnancy 
• Changes in the patient’s condition, which in the opinion of the Investigator and in consultation 
with the medical monitor, make the patient unsuitable for further treatment with study drugs 
• Lost to follow-up 
• NuCana request 
All study procedures outlined for the End of Treatment visit are to be completed within 30 days 
(±3 days) of the last dose of study drug. The primary reason for study drug discontinuation is to 
be recorded in the CRF. 
6.2 
Follow-Up After Treatment Discontinuation 
Patients in either treatment group who have documented disease progression defined by RECIST 
v1.1 criteria while receiving study medication will discontinue treatment but will enter the 
follow-up period. Treatment should not be discontinued because of raised tumour marker levels or 
other clinical signs of PD until disease status has been assessed by objective measures and PD has 
been determined by RECIST v1.1 criteria. 
Patients in either treatment group who stop treatment with no evidence of disease progression will 
enter the follow-up period and should attend clinic at least every 12 weeks (±14 days) for follow-up 
scans, assessments, and information regarding subsequent anti-cancer medications prescribed. 
This follow-up for both treatment groups should continue (regardless of whether any subsequent 
anti-cancer medication has been prescribed) until radiographic disease progression or death. 
Patients in either treatment group who no longer attend clinic every 12 weeks should continue to 
be followed for progression status (unless progression has already been documented), for details 
on any new anti-cancer treatments, and for survival status. If a patient in either treatment group 
becomes uncontactable, then the Investigator should follow up on their status by other means (such 
as GP contact, next of kin contact), in line with patient consent. Patients who stop treatment 
following an unconfirmed response should also still have a confirmatory scan within the 28- to 
42-day window, if the scan can take place prior to the patient starting any subsequent anti-cancer 
therapies. If a patient is found to have a response at the confirmatory scan which has improved 
from PR to CR, then the improved response must also be confirmed within a further 28- to 42-day 
window, provided that they have not yet started subsequent anti-cancer therapy. 


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6.3 
Consent Withdrawal 
Patients will be informed that they have the right to withdraw from the study at any time for any 
reason, without prejudice to their medical care.  
Due to the importance of collection of survival data, if a patient wishes to discontinue from the 
study, and withdraw consent for further visits and participation, it should be confirmed with them 
whether they agree for the Investigator to follow up on their status by other means (such as GP 
contact, next of kin contact) or if they truly wish to withdraw so that no further data is collected 
on their status. Confirmation of this will be recorded in source data at site. 
Consent withdrawal means that a patient has expressed a wish to withdraw from the study 
altogether. Under these circumstances, the site personnel should document all relevant discussions 
in the patient notes and mark all future CRF pages as not applicable. Under these conditions, 
Investigators are still responsible to follow up any SAEs until resolution. 
6.4 
Patient Replacement 
Patients that are randomised but not treated will not be replaced. Section 13.1 provides details on 
patient populations to be used for analysis of all efficacy and safety endpoints. 
7 
SAMPLES FOR LABORATORY ANALYSIS 
7.1 
Clinical Laboratory Tests 
All clinical laboratory testing will be performed at local sites. A pregnancy test will be performed 
in women of child-bearing potential at the Screening and follow-up visits. Laboratory tests may 
be performed either on the day of a treatment visit, or during the 3 days prior to a treatment visit. 
Samples will be analysed for the following parameters: 
• Haematology: WBC count, differential WBC count, RBC count, haemoglobin, haematocrit 
and platelets 
• Coagulation parameters: PT/INR and aPTT 
• Chemistry: sodium, potassium, magnesium, urea or BUN, creatinine, glucose, phosphate, total 
protein, albumin, adjusted calcium, total bilirubin, bicarbonate, chloride, uric acid, alkaline 
phosphatase, AST, ALT and LDH 
Clinically-significant abnormal laboratory results will be recorded as AEs, see Section 12.2 for 
further information. 
CA19-9 will not be measured as part of the study but may be measured as part of standard of care 
for the patient. 
7.2 
Pharmacokinetics 
Blood samples for PK analyses will be collected. Blood sampling will be performed for patients 
in Arm A. The PK sampling scheme is designed to allow for application of a population PK model 
in order to estimate exposure (e.g., AUC, Cmax, Cmin) to NUC-1031, dFdC and dFdU. 
Blood samples will be collected on Cycle 1 Day 1 only at the timepoints described in Table 1. 


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Table 1 
PK sampling schedule  
Sample 1 
T0 – end of infusion (within 10 minutes) 
Sample 2 
T1 – 2 hours after the end of infusion (± 30 minutes) 
Sample 3 
T2 – 6 hours after the end of infusion (± 30 minutes) 
Standard PK parameters for each compound of interest will be derived from the measured plasma 
concentrations using a population PK model derived from Phase I data. The results of the PK 
analyses will be reported separately. The PK samples will be processed and analysed at a central 
laboratory. Please refer to the Guidelines for Pharmacokinetic Sample Management for details 
regarding PK sample collection, processing, storage and shipment. 
7.3 
Collection of Archived Tumour Specimen 
Specific instructions on the collection and shipment of tissue samples will be provided in the 
Tumour Tissue Laboratory Manual.  
Tissue samples may be stored for a maximum timeframe in accordance with local regulations 
following the last patient’s last visit for the study at a facility selected by NuCana to enable further 
analysis of biomarkers. 
7.4 
Labeling and Confidentiality of Biological Samples 
All biological samples sent to analytical laboratories will be labelled with the study number, patient 
number and date/time taken. Sample labels must not contain any personally identifiable 
information. 
8 
STUDY MEDICINAL PRODUCTS 
8.1 
NUC-1031  
NUC-1031 for injection is an investigational medicinal product presented as a sterile solution in 
clear glass vials at a concentration of 250 mg/mL formulated in DMA and normal saline in the 
ratio of 80:20. NUC-1031 for injection is not administered directly to patients, but must be diluted 
into saline to generate a NUC-1031 saline-based formulation. 
NUC-1031 saline-based formulation for infusion is prepared by mixing NUC-1031 for injection 
with a Diluent Solution and subsequent withdrawal of the required dose for addition to the saline 
infusion bag. 
8.1.1 NUC-1031 Supplies and Study Drug Packaging  
NUC-1031 for injection is manufactured by NuCana plc and supplied to the pharmacy of the 
investigative clinical site and will be supplied as a 7 mL fill volume in 10 mL clear glass vials. 
The vials are packaged in a labelled cardboard outer carton, each containing 6 vials. 
The Diluent Solution is manufactured by NuCana plc and supplied to the pharmacy of the 
investigative site and will be supplied as a 10 mL volume in clear glass 20 mL vials. The Diluent 
Solution is comprised of 20% DMA, 40% Kolliphor ELP and 40% Tween 80. The Diluent Solution 
vials are packaged in labelled cardboard outer carton, each containing 3 vials. 


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8.1.2 NUC-1031 and Diluent Solution Handling and Storage 
NUC-1031 for injection and Diluent Solution must be stored in an appropriately secure 
Investigational Pharmacy at all times until dispensed for administration to patients on protocol. 
NUC-1031 must be stored between 2-8°C (36-46°F) in a temperature-monitored refrigerated unit. 
The Diluent Solution must be stored at room temperature (15-25°C/59-77°F). Only adequately 
trained pharmacy staff are permitted to handle NUC-1031 for injection and the Diluent Solution. 
The study medication should not be removed from the pharmacy except for the purposes of 
dispensing to the patient for this protocol. 
If NUC-1031 for injection or the Diluent Solution contacts the skin or the mucous membranes, it 
should be washed immediately and thoroughly.  
Due to known issues regarding DMA and its compatibility with polycarbonate, polyvinylchloride 
(PVC), polyvinylidene fluoride (PVDF) and polyethersulfone (PES), do not use syringes or 
syringe filters made of these materials in the preparation of the NUC-1031 saline-based 
formulation. 
For additional information on study drug handling including dispensing directions, please refer to 
the NUC-1031 Pharmacy Manual.  
8.1.3 NUC-1031 Preparation 
As with other cytotoxic substances, applicable local procedures should be used in the preparation 
and administration of NUC-1031. Please refer to the administration guidance in the current version 
of the Pharmacy Manual and Administration Guidelines document for information on the 
preparation of NUC-1031. 
8.2 
Cisplatin 
Cisplatin is commercially available and may be centrally provided by NuCana or sourced locally 
by investigative sites in accordance with local regulatory requirements. Descriptive information 
for cisplatin can be found in the package insert and should be stored as detailed on the product 
label and according to manufacturer’s instructions. Further information can be found in the 
Pharmacy Manual. 
For administration, any device containing aluminium that may come in contact with cisplatin 
(sets for IV infusion, needles, catheters, syringes) must be avoided. 
8.3 
Gemcitabine 
Gemcitabine is commercially available and may be centrally provided by NuCana or sourced 
locally by investigative sites in accordance with local regulatory requirements. Descriptive 
information for gemcitabine can be found in the package insert and should be stored as detailed on 
the product label and according to manufacturer’s instructions. Further information can be found 
in the Pharmacy Manual.  
8.4 
Treatment Administration 
All study drugs will be administered to each patient based on their body surface area (BSA) at 
baseline. If a patient’s weight increases or decreases by ≥10% during the course of the study, the 
doses of the drugs should be recalculated. The Dubois & Dubois BSA calculation is the preferred 
method, however other standard calculations can also be used. Sites should document the method 
used in the electronic CRF (eCRF). 


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Dubois & Dubois BSA calculation: 
BSA (m2) = 0.007184 × Height (cm)0.725 × Weight (kg)0.425 
 
The drug administration schedule in Arm A and Arm B is shown in Table 2. Dose adjustments or 
dose delays are to be implemented within or between cycles based on drug related toxicities. The 
dose modification scheme to be employed is detailed in Section 9 of this protocol. 
Table 2  
Drug administration schedule in Arm A and Arm B 
Arm 
Agent 
Dose 
Route 
Schedule 
Duration 
A 
NUC-1031 
725 mg/m2 
IV 
D1 and D8 of 
each 21-day 
cycle 
Until 
radiographic 
disease 
progression or 
unmanageable 
toxicity 
Cisplatin 
25 mg/m2 
IV 
B 
Gemcitabine 
1000 mg/m2 
IV 
Cisplatin 
25 mg/m2 
IV 
8.4.1 Arm A (NUC-1031 in combination with cisplatin) 
Patients in Arm A will receive cisplatin by IV infusion at 25 mg/m2 followed by IV infusion of 
NUC-1031 saline-based formulation at 725 mg/m2 on Days 1 and 8 of each 21-day cycle.  
Cisplatin should be administered in accordance with local institutional practice for BTC, including 
the use of an appropriate hydration protocol. 
Cisplatin administration is then followed by NUC-1031 (725 mg/m2) administered by IV infusion 
in 500 mL of 0.9% sterile saline for injection given over 30 minutes. The administration time may 
be increased to 60 minutes and then to 2 hours, if required.  
Please refer to the current Pharmacy Manual and Administration Guidelines for further 
information on NUC-1031 preparation and administration. 
8.4.2 Arm B (gemcitabine in combination with cisplatin) 
Patients in Arm B will receive cisplatin by IV infusion at 25 mg/m2 followed by IV infusion of 
gemcitabine at 1000 mg/m2 on Days 1 and 8 of each 21-day cycle.  
Cisplatin should be administered in accordance with local institutional practice for BTC, including 
the use of an appropriate hydration protocol.   
Cisplatin administration is then followed by gemcitabine (1000 mg/m2) administered by IV 
infusion in accordance with the package insert. 
8.5 
Randomisation 
Patients may be randomised up to 1 working day prior to C1D1 using an independent IxRS system. 
At this time, the Investigator will enter into the IxRS system their site information, metastatic 
disease at baseline (yes, no), and the primary tumour location (gallbladder, intra-hepatic, 
extra-hepatic or ampullary). The BICR will have already entered into the IxRS system whether the 
patient has measurable disease at baseline (yes, no).  The IxRS will then indicate to which 
treatment group the patient has been randomised and the study site will obtain the patient’s 
identification number from the IxRS. 


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The randomisation will be in a 1:1 ratio to receive treatment in Arm A (NUC-1031 plus cisplatin) 
or Arm B (gemcitabine plus cisplatin). Randomisation will be stratified by the following 4 factors: 
• Measurable disease at baseline (yes, no) as determined by BICR 
• Metastatic disease at baseline (yes, no) 
• Tumour location (gallbladder, intra-hepatic, extra-hepatic/ampullary) 
• Region (Asia, non-Asia) 
The number of patients with non-measurable disease at baseline as determined by BICR is capped 
at 82 (due to statistical requirements of ORR analysis). 
8.6 
Drug Destruction  
Used vials should be destroyed in accordance with local procedures and documented in the drug 
accountability and drug destruction log. Where this is not possible due to local regulations, used 
vials should be stored on site and returned to NuCana/vendor for destruction. A copy of the 
disposal certificates should be kept in the study file.  
8.7 
Drug Accountability 
The US Food and Drug Administration (FDA) and other regulatory authorities require accounting 
of all study drug received by each study site. Records of drug disposition required include the date 
received by the site, date administered, quantity administered, and the patient to whom study drug 
was administered. The Investigator is responsible for the accountability of all used and unused 
study drug containers and used and unused study drug. Each study site is to use a study drug 
accountability log to document study drug disposition. All items on this form are to be completed 
in full. 
The Investigator identification number and patient initials (as allowed by local regulations) and 
identification number are to be recorded on each study drug accountability log. Each time study 
personnel dispense study drug for a patient, he or she is to record the date dispensed, amount of 
study drug dispensed, lot number, and the dispenser’s initials. Study personnel are to monitor the 
inventory of clinical supplies and maintain a count of all used and unused study drug. NuCana’s 
designated site monitor will review study drug accountability records and remaining drug supplies 
during routine monitoring visits. 
8.8 
Management of Overdose and Medication Errors 
Overdoses and errors for all study drugs should be recorded as follows: 
1. If an overdose/error occurs in the course of the study, site personnel must inform the 
Investigator and monitor immediately upon discovery of the event. An overdose/error will 
be recorded on the treatment CRF page and any associated AEs/SAEs will be recorded as 
the AE diagnosis/symptoms on the relevant AE/SAE page in the CRF. An overdose/error 
with no associated symptoms is only reported on the treatment CRF. 
2. All overdoses/errors should be tracked as a deviation. 
8.8.1 NUC-1031 
The dose of NUC-1031 for administration on this protocol is 725 mg/m2. In the Phase I 
first-in-human study, the highest dose studied was 1,000 mg/m2. Should a substantial overdose or 
medication error occur, there is no known antidote. Any patient who inadvertently receives a dose 
of NUC-1031 higher than intended should be monitored closely, managed with appropriate 
supportive care, including transfusion and haematopoietic growth factors as needed, until 
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8.8.2 Cisplatin 
In case of overdose (>200 mg/m2) or medication error, direct effects on the respiratory centre are 
possible, which might result in life threatening respiratory disorders and acid base equilibrium 
disturbance due to passage of the blood brain barrier. 
An acute overdose of cisplatin may result in renal failure, liver failure, deafness, ocular toxicity 
(including detachment of the retina), significant myelosuppression, untreatable nausea and 
vomiting and/or neuritis. An overdose may be fatal. 
There is no specific antidote in the event of an overdose of cisplatin. Even if haemodialysis is 
initiated 4 hours after the overdose, it has little effect on the elimination of cisplatin from the body 
following a strong and rapid fixation of cisplatin to proteins. 
Treatment in the event of an overdose or error consists of general support measures. Efficient 
hydration and osmotic diuresis can aid in reduction of toxicity, provided this is applied 
immediately after overdose.   
8.8.3 Gemcitabine 
There is no known antidote for overdose of gemcitabine. Doses as high at 5700 mg/m2 have been 
administered by IV infusion over 30-minutes every 2 weeks with clinically acceptable toxicity. In 
the event of suspected overdose or medication error, the patient should be monitored with 
appropriate blood counts and receive supportive therapy, as necessary.  
8.9 
Interaction with Other Drugs 
NUC-1031 is not a substrate for, nor is metabolised by, Cytochrome P450 enzymes. Patients 
receiving NUC-1031 should be carefully managed for potential drug interactions according to 
local practice.  
Interactions between cisplatin, gemcitabine, and any concomitant medications should be checked 
with the respective package inserts in accordance with local practice. Local practice and guidelines 
should be followed for the management of any potential cisplatin or gemcitabine/concomitant 
medication interactions. 
9 
MANAGEMENT OF TOXICITY 
9.1 
Criteria for Continuation of Treatment Post-Cycle 1 
Patients must meet all of the following criteria prior to receiving study treatment on 
commencement of subsequent cycles (Day 1). Laboratory results may be assessed within 24 hours 
of the first scheduled dose. 
• ANC ≥1000/μL: use of short-acting granulocyte colony stimulating factor (G-CSF) is 
permitted after Cycle 1 but must be stopped in advance of the start of a cycle to allow 
stabilisation of neutrophil count (at least 5 days for short-acting growth factors). Growth factors 
should only be used as per American Society for Clinical Oncology (ASCO) guidelines. 
• Haemoglobin ≥8 g/dL (transfusions are permitted) 
• Platelet count ≥100,000/μL (without platelet transfusions) 
• No evidence of disease progression (based on radiographic assessment) 
• Recovery from all clinically significant toxicities to ≤Grade 2 or to baseline grade 


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If the above criteria are not met for Day 1 of a cycle, dosing with study treatment should be delayed 
by 1 week and then lab parameters re-evaluated. If the delay is >21 days, the patient must be 
withdrawn from treatment, unless the patient is receiving a clinical benefit.  
9.2 
Criteria for Day 8 Dosing 
On Day 8 of a cycle, patients should be dosed according to the criteria in Table 3. If the below 
criteria are not met for Day 8 of a cycle, or a patient is already at dose level -2, dosing with study 
treatment should be delayed for up to 6 days and then lab parameters re-evaluated. 
Table 3 
Dose adjustments within a cycle (Day 8) based on ANC and platelet counts 
ANC 
(/μL) 
 
Platelets 
(/μL) 
NUC-1031 
Dose 
Management 
Gemcitabine 
Dose 
Management 
Cisplatin Dose 
Management 
≥1000 
AND 
≥100,000 
No dose change 
No dose change 
No dose change 
500 - 
<1000 
AND/OR 
50,000 - 
<100,000 
 Reduce 1 dose 
level 
 Reduce 1 dose 
level 
No dose change 
<500 
AND/OR 
<50,000 
Hold*§ 
Hold*§ 
Hold*§ 
ANC=absolute neutrophil count. 
*The dose of NUC-1031 or gemcitabine will be re-escalated to full dose upon recovery of haematological 
toxicity despite a previous Day 8 dose reduction in order to maintain the dose intensity of therapy. 
§When held, treatment must not be reinstated within a cycle until the ANC reaches ≥500/µL and the platelet 
count reaches ≥50,000/µL. 
 
If there is a 1-week delay of Day 8 of a cycle, then omit and restart with Day 1 of the next cycle 
(provided Day 1 re-treatment criteria are met).  
Patients must also meet the following criteria prior to receiving treatment on Day 8 of all cycles: 
• Recovery from all clinically significant toxicities to ≤Grade 2 or to baseline grade 
• No evidence of disease progression (based on radiographic assessment) 
9.3 
Dose Modifications 
Dose modifications for gemcitabine and cisplatin should be performed in accordance with their 
package inserts. For NUC-1031, the proposed Level-1 reduction takes the dose to one that was 
well tolerated in the Phase I study (PRO-001), and which is expected to provide appropriate 
mitigation of AEs.  
Adverse events may be managed by dose delays and/or dose reductions according to the clinical 
situation. Advice on how to modify dosing for haematological and non-haematological toxicities 
is given in Table 4.  
Only one dose reduction is permitted within a cycle. This may be a temporary dose reduction, in 
which case the next cycle can revert to the starting dose of the previous cycle so long as the patient 
meets the criteria for doing so, or it may be a permanent dose reduction (based on the Investigator’s 
judgement) which would apply to all subsequent cycles. Over the whole dosing period, each 
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which treatment will be discontinued. The lowest dose of NUC-1031 which may be administered 
is 425 mg/m2 and the lowest dose of gemcitabine which may be administered is 500 mg/m2. 
Cisplatin can be dose reduced 25% before discontinuation. 
It is expected that some patients will interrupt or discontinue cisplatin but continue on NUC-1031 
or gemcitabine until progression. Patients may not proceed on cisplatin alone. 
Table 4 
Dose modification guidelines 
Dose Level 
NUC-1031 Dose 
Gemcitabine Dose 
Cisplatin Dose 
Starting 
725 mg/m2 
1000 mg/m2 
25 mg/m2 
Dose Level -1 
575 mg/m2 
750 mg/m2 
19 mg/m2 
Dose Level -2 
425 mg/m2 
500 mg/m2 
Omit 
Treatment between cycles can be delayed for up to 21 days in order for patients to meet the 
re-treatment criteria before starting their next cycle. Patients who do not meet these requirements 
after this additional time will not be allowed to receive further cycles of study treatment, unless 
the patient is receiving clinical benefit.  
Should a patient experience multiple toxicities, dose adjustments will be based on the most severe 
toxicity. 
9.3.1 Haematological Toxicity – Dose Adjustment  
Study treatment administration should be given according to the ANC and platelet count on the 
day of dosing. On Day 1 of each 21-day cycle, if the ANC is ≥1000/µL and the platelet count is 
≥100,000/µL, then study treatment should be given at full dose unless the patient has previously 
been permanently dose-reduced. 
On Day 1 of each 21-day cycle, if the ANC is 500/µL to 1000/µL and the platelet count is 
50,000/µL to <100,000/µL without evidence of bleeding, then study treatment should be given at 
a reduced dose unless the patient has received 2 prior dose reductions. 
Within a cycle, should patients experience neutropaenia or thrombocytopaenia, dosing on Day 8 
should be adjusted per Table 3. 
If there is a 1-week delay of Day 8 of a cycle, then omit Day 8 of that cycle and proceed with 
Day 1 of the next cycle (provided Day 1 re-treatment criteria are met).  
9.3.2 Non-Haematological Toxicity – Dose Adjustment  
Dose adjustment should be performed according to Table 5. No dose reductions or modifications 
are required for Grade 1-2 fatigue, nausea/vomiting, diarrhoea, oedema, or any grade alopecia. If 
dose omission is required, treatment should be delayed until the toxicity has resolved to ≤Grade 2. 
If this occurs, subsequent doses should be permanently reduced, without re-escalation. For 
significant pulmonary complications (e.g., pneumonitis and acute respiratory distress syndrome), 
study treatment should be stopped. 


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Table 5 
Dose adjustment for non-haematological toxicities 
Toxicity 
NUC-1031 / gemcitabine  
dose management 
Cisplatin  
dose management 
GFR <45 mL/min* 
No dose change 
Hold cisplatin** 
Grade 3 or 4 
fatigue*** 
Reduce 1 dose level. Stop treatment if it 
persists despite 2 dose reductions. 
Reduce dose by 25%. Stop treatment if it 
persists despite dose reduction. 
Grade 3 or 4 
nausea/vomiting*** 
Ensure optimal use of antiemetics and bowel routine (according to local policy). Delay 
until recovery to ≤Grade 2 then reassess. If better optimised, proceed without dose 
reduction. If Investigator feels optimisation was in place during Grade 3 or 4 episode, wait 
until recovery to ≤Grade 2 and dose-reduce cisplatin. If no improvement after reducing 
cisplatin it should be omitted and Investigator may consider reducing NUC-1031 or 
gemcitabine dose by 1 dose level. For further episodes of Grade 3 or 4, supportive care 
measures should be revisited. If nausea/vomiting persists despite dose reductions and after 
optimal anti-emetics or dose reduction, stop treatment. 
≥Grade 3 ALT/AST 
documented in prior 
cycle but recovered to 
<5 × ULN for Day 1 
of next cycle 
No dose change 
No dose change 
Hy’s Law (see 
Section 12.12) 
(ALT or AST >8 × 
ULN; ALT or AST 
>5 × ULN for more 
than 2 weeks; ALT or 
AST >3 × ULN with 
total bilirubin >2 × 
ULN; ALT or AST 
>3 × ULN and INR 
>1.5) 
If liver dysfunction is due to drug-related toxicity consider discontinuation of treatment 
or, if patient is deriving benefit in the opinion of Investigator, consider holding treatment 
until values are <3 x ULN for AST and/or ALT and <2 x ULN for total bilirubin, then 
restart treatment at a reduced dose (as per Table 4). Laboratory values must be closely 
monitored and study treatment must be discontinued if patients meets criteria for a second 
time despite dose reduction. 
See Section 10.3.3 for instructions if liver dysfunction is due to underlying biliary issues. 
Grade 3 peripheral 
neuropathy 
No dose change 
Hold cisplatin until recovery to ≤Grade 2, 
then reduce dose by 25%. If Grade 3 
recurs, discontinue cisplatin. 
Grade 4 peripheral 
neuropathy 
No dose change 
Stop treatment 
Grade 3 or 4 oedema 
Dipstick urine test for protein followed by 
full 24-hour urinary protein estimation if 
result ≥1+. Delay until recovery to ≤Grade 
2 (with use of appropriate diuretics), then 
reduce 1 dose level. If recurs after dose 
modification and use of appropriate 
diuretics, stop treatment. 
No dose change, but delay to restart with 
NUC-1031 or gemcitabine 
Tinnitus 
No dose change 
No dose change if full recovery between 
cycles. Omit if no recovery between 
cycles. 
Grade 2 to 4 
pulmonary toxicity 
(including ARDS and 
pneumonitis) 
Stop treatment. 
Supportive therapy (high dose steroids) should be initiated immediately. 


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Toxicity 
NUC-1031 / gemcitabine  
dose management 
Cisplatin  
dose management 
Grade 3-4 pulmonary 
oedema 
Stop treatment and initiate supportive care. 
Note: in the case of mild exacerbation of pre-existing pulmonary oedema by IV 
chemotherapy or fluids (Grade 1-2), interrupt study treatment to adjust supportive care 
measures and resume treatment at Investigator’s discretion when returned to baseline 
condition.    
Radiologically 
confirmed posterior 
reversible 
encephalopathy 
syndrome  
Stop treatment 
Stop treatment 
Febrile neutropaenia 
during previous cycle 
Reduce 1 dose level 
No dose change 
Haemolytic uremic 
syndrome  
Stop treatment 
Stop treatment 
Capillary leak 
syndrome 
Stop treatment 
Stop treatment 
Anaphylactoid 
reactions 
Stop treatment 
Stop treatment 
ALT=alanine aminotransferase; AST=aspartate aminotransferase; GFR=glomerular filtration rate; ULN=upper limit of normal. 
*Repeat the creatinine clearance assessment ensuring the patient is adequately hydrated. Proceed with cisplatin if repeat reading is ≥45 
mL/min, otherwise hold until recovery of renal function. 
**If the Investigator wishes to continue cisplatin after the recovery period with persistent GFR >30 mL/min (i.e., at next assessment of 
GFR on Day 1 of subsequent cycle), the dose of cisplatin can be reduced by 25%. If GFR <30 mL/min, discontinue cisplatin.  
***If the delay is >21 days (from scheduled Day 1) for non-haematological toxicity, the patient should be withdrawn from treatment 
unless receiving clinical benefit, support for the toxicity was not optimally managed, and/or the Investigator feels it is in the patient’s 
best interest to continue. 
9.3.3 Management of Nausea and Vomiting 
• 
Consider anti-emetic medications. Examples of anti-emetic medications include granisetron, 
palonosetron, dexamethasone, metoclopramide, domperidone, cyclizine 
• 
Maintain adequate hydration including use of IV fluids if indicated 
• 
Supplement electrolytes, particularly potassium and magnesium, to recommended levels 
• 
Discontinue any concomitant medications that could contribute to nausea and vomiting 
• 
Rule out other potential aetiologies (for example, gastrointestinal tract obstruction) 
• 
Consider prophylactic anti-emetic medications (per ASCO guidelines for chemotherapy 
regimens of moderate emetic risk) prior to next dose of study drug. 
9.3.4 Management of Pulmonary Toxicity 
Dyspnoea has been reported to occur in approximately 25% of patients treated with gemcitabine, 
whereas serious pulmonary toxicities are much less common, occurring in approximately 0.3% of 
patients. If pneumonitis is suspected or confirmed, immediately discontinue NUC-1031 or 
gemcitabine and refer to specialist respiratory physician for assessment. Normally, this is treated 
with inhaled or oral steroids. NUC-1031 or gemcitabine should not be re-initiated in a participant 


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who has developed radiologically-confirmed pneumonitis, even if symptoms have resolved after 
appropriate management. 
9.3.5 Management of Diarrhoea 
• All available anti-diarrhoeal medications including loperamide and opiate preparations should 
be considered for treatment 
• Maintain adequate hydration, including use of IV fluids if indicated 
• Supplement electrolytes, particularly potassium and magnesium, to recommended levels to 
minimise risk of related AEs 
• Avoid oral supplementation of electrolytes since the diarrhoea could be exacerbated in some 
cases 
• Rule out other potential causes including infectious aetiologies for diarrhoea 
• Discontinue any concomitant medications that could exacerbate diarrhoea. 
9.3.6 Management of Infusion-Related Reactions 
Symptoms of infusion-related reactions include pyrexia, chills, flushing, hypotension, dyspnoea, 
wheezing, back pain, abdominal pain, and urticaria. Symptoms should be managed according to 
the following guidelines: 
NCI-CTCAE Grade 
Treatment Modification 
Grade 1 (mild) 
Mild transient reaction; infusion interruption not 
indicated; intervention not indicated 
Decrease the infusion rate by 50% and monitor 
closely for any worsening 
Grade 2 (moderate) 
Therapy or infusion interruption indicated but 
responds promptly to symptomatic treatment (e.g., 
antihistamines, NSAIDs, narcotics, IV fluids); 
prophylactic medications indicated for 24 hours 
Temporarily discontinue infusion 
Resume infusion at 50% of previous rate once 
infusion-related reaction has resolved or decreased to 
at least Grade 1 in severity, and monitor closely for 
any worsening 
Grade 3 or Grade 4 (severe or life-threatening) 
Grade 3: Prolonged (e.g., not rapidly responsive to 
symptomatic medication and/or brief interruption of 
infusion); recurrence of symptoms following initial 
improvement; hospitalisation indicated for clinical 
sequelae 
Grade 4: Life-threatening consequences; urgent 
intervention indicated 
Stop the infusion immediately and disconnect 
infusion tubing from the patient 
Patients have to be withdrawn immediately from 
treatment and must not receive any further treatment 
 
IV=intravenous; 
NCI-CTCAE=National 
Cancer 
Institute-Common 
Terminology 
Criteria 
for 
Adverse 
Event; 
NSAIDs=nonsteroidal anti-inflammatory drugs 
 
 


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10 OTHER TREATMENTS (NON-IMP) 
All prescription and non-prescription medications and therapies, including pharmacologic doses 
of vitamins, herbal medicines, or other non-traditional medicines, taken from 28 days prior to the 
first dose of study treatment through the End of Treatment Visit must be recorded in the CRF. 
All prior anti-cancer therapies from initial diagnosis up until enrolment must be recorded in the 
CRF, regardless of time taken prior to first dose. 
Should a patient discontinue study treatment, information on subsequent anti-cancer therapies, 
along with response to these therapies, must be recorded in the CRF. 
10.1 
Support Medication 
Patients may receive standard prophylactic and support medications so long as they are not listed 
as a prohibited therapy in Section 10.3.1. All such medications must be recorded in the CRF. 
10.2 
Haematopoietic Growth Factor Support 
The Investigator may prescribe G-CSF as treatment for Grade 3 or higher neutropaenia according 
to local protocols and as prophylaxis after the first event of Grade 3 neutropaenia or for any febrile 
neutropenic episode in order to enable the patient to continue on study. All haematopoietic growth 
factors used from 30 days prior to date of consent until 30 days after administration of last dose of 
study drug must be recorded in the CRF. Any blood or platelet transfusions should also be recorded 
in the CRF. 
10.3 
Concomitant Medication and Non-Drug Therapies 
Concomitant medication may be given as medically indicated. All concomitant medication and 
non-drug therapies used from 30 days prior to date of consent until 30 days after administration of 
last dose of study drug must be recorded in the CRF.  
10.3.1 Prohibited Therapies 
Refer to the cisplatin and gemcitabine package inserts for information regarding drug interactions. 
Use of the following therapies is prohibited during the study: 
• Cytotoxic chemotherapy, for diseases other than indicated in this protocol 
• Radiotherapy (palliative radiotherapy to a non-target lesion is allowed)  
• Immunotherapy including immunosuppressive therapy 
• Radioimmunotherapy  
• Hormone therapy (other than contraceptives, hormone-replacement therapy, or megestrol 
acetate) 
• Biologic agents intended for the treatment of BTC (other than haematopoietic growth factors, 
which are allowed if clinically indicated and used in accordance with instructions provided in 
the package inserts) 
• Any therapies intended for the treatment of BTC, whether approved by local regulatory 
authorities or investigational 
• Any drugs at doses known to cause clinically-relevant prolongation of QT/QTc interval (see 
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• Anti-convulsant treatment with phenytoin 
• Live vaccines (must also be avoided for six weeks after last study drug dose administration) 
10.3.2 Therapies to be Used with Caution  
The following medications and/or treatments are permitted with caution and should be monitored 
during the study: 
• Drugs that are known substrates of either CYP3A, CYP1A2, P-gp, BCRP, MATE1 or OCT2:  
In vitro studies are being conducted to assess the drug-drug interaction potential of NUC-1031.  
Although it is not anticipated that NUC-1031 will cause drug-drug interactions, there may be the 
possible risk of perpetrating drug-drug interactions through CYP3A inhibition, CYP3A induction 
(some transporters such as P-gp might also be co-induced), CYP1A2 repression, or inhibition of 
several transporters (P-gp, BCRP, MATE1, OCT2). The clinical impact of these in vitro 
observations is not known and patients who are taking concurrent drugs that are known substrates 
of either CYP3A, CYP1A2, P-gp, BCRP, MATE1 or OCT2 should be carefully monitored. A list 
of such drugs can be consulted in: 
• Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana 
University School of Medicine (2007) (http://medicine.iupui.edu/clinpharm/ddis/) 
• http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugIntera
ctionsLabeling/ucm093664.htm 
The following therapies are to be used with caution when given concomitantly with cisplatin 
during the study: 
• Anti-hypertensive agents containing furosemide, hydralazine, diazoxide, and propranolol  
• Nephrotoxic agents (e.g., cephalosporins, aminoglycosides, amphotericin B, or contrast media) 
• Ototoxic agents (e.g., aminoglycosides or loop diuretics) 
• Anti-histamines, buclizine, cyclizine, loxapine, meclozone, phenothiazines, thioxanthenes, or 
trimethobenzamines 
• Anti-convulsive agents 
• Oral anti-coagulants 
• Agents whose elimination is primarily through the renal pathway (e.g., bleomycin or 
methotrexate) 
• Ifosfamide 
• Paclitaxel 
• Pyroxidine and altretamine  
• Bleomycin and vinblastine  
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10.3.3 Biliary Stenting 
In the event of the development of obstructive jaundice or other adverse medical condition thought 
to be due to or historically associated with biliary tract obstruction, including but not limited to 
pain, pruritus, hepatocellular dysfunction, biliary cirrhosis, and cholangitis, appropriate measures 
will be undertaken to diagnose (e.g., by ultrasound and/or CT scan) and relieve the obstruction 
(e.g., 
by 
endoscopic 
retrograde 
cholangiopancreatography/ 
percutaneous 
transhepatic 
cholangiography +/- stent insertion/drainage). Patients do not need to be taken off study treatment 
permanently if this occurs.  
Chemotherapy may be deferred until the liver function tests have improved to pre-treatment 
eligibility levels (total bilirubin <2 × ULN; ALT and/or AST <5 × ULN) and/or other associated 
medical issues have resolved to the point that the treating physician feels, in keeping with standard 
of care, it is appropriate to resume treatment. Re-initiation of study treatment should be considered 
to be Day 1 of the next cycle.  
Dose delays for biliary tract obstruction and/or stent placement or replacement are considered 
separately from dose adjustments for treatment-related AEs. 
If complications as a result of plastic stenting are deemed to be the cause of the obstruction or 
other adverse medical condition, consider replacement of the plastic stent with a metal stent. Stent 
replacement is permitted and patients are permitted a treatment-free interval as necessary to 
recover from this procedure, at the Investigator’s discretion. 
10.4 Contraception Methods 
If patients are not infertile or post-menopausal, they must agree to: 
• True abstinence (when this is in line with the preferred and usual lifestyle of the patient) during 
the entire participation in the study and for 6 months post-last dose of study medication or 
• Use two forms of contraception, one of which must be a barrier method and one must be a 
highly effective form (less than 1% failure rate if used consistently and correctly) 
True abstinence is defined as refraining from heterosexual intercourse during the entire study 
period and for 6 months after the last dose of study medication; periodic abstinence (such as 
calendar, ovulation, symptothermal, and post-ovulation methods) and withdrawal are not 
acceptable methods of contraception. 
Acceptable barrier methods (which may not be considered highly effective): 
• Male or female condom, with or without spermicide 
• Cap, diaphragm or sponge with spermicide 
Highly effective forms of contraception include: 
• Oral, intravaginal or transdermal combined (oestrogen- and progestogen-containing) hormonal 
contraception associated with inhibition of ovulation 
• Oral, injectable, or implantable progestogen-only hormonal contraception associated with 
inhibition of ovulation 
• Surgical sterilisation (bilateral occlusion, vasectomised partner) 


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• Intrauterine device or intrauterine hormone-releasing system 
These forms of contraception must be used from the time of signing consent, throughout the 
treatment period, and for 6 months following the last study drug administration. Oral or injectable 
contraceptive agents cannot be the sole method of contraception. Patients of childbearing potential 
must have a negative pregnancy test within 3 days prior to the first study drug administration. 
Patients of childbearing potential must also refrain from donating sperm or eggs from the time of 
first study drug administration until 6 months after the last study drug administration.  
10.5 Fertility 
In accordance with the cisplatin package insert, genetic consultation is recommended if the patient 
wishes to have children after ending treatment. Since treatment with cisplatin may cause 
irreversible infertility, it is recommended that patients, who wish to become parents in the future, 
ask for advice regarding cryo-conservation of their sperm or eggs prior to treatment. Due to the 
poor prognosis of patients with a diagnosis of advanced BTC, Investigator’s discretion should be 
used before conversations concerning this subject matter are broached. 
11 TUMOUR RESPONSE ASSESSMENTS 
Many of the primary and secondary efficacy endpoints (including ORR, PFS, DoR, and DCR) are 
based on assessment of tumour response to treatment (see Section 13 for further details).  
Objective disease assessment will be performed by radiologic evaluation and assessed according 
to RECIST v1.1 criteria (as described in detail for this study in Appendix 4). Treatment and study 
continuation decisions based on radiologic assessments will be made by the treating Investigator. 
However, primary analyses of data will use BICR assessment of radiologic evaluation using 
blinded double reads with adjudication (see Section 11.2), and secondary analyses will be carried 
out based on Investigator assessment. 
11.1 
Tumour Measurements and Assessment of Disease Response 
Patients with measurable disease at baseline (as assessed by BICR) must have at least one lesion 
that can be accurately assessed at baseline by CT, MRI, or PET-CT, and which is suitable for 
repeated assessment in order to be considered evaluable for response. All known or suspected 
disease sites must be assessed at baseline by either CT, MRI or PET-CT scan. For each patient, 
the same radiological method used at baseline must be used for disease assessment throughout the 
duration of the patient’s participation in the study. Additional anatomical areas, other than chest, 
abdomen, and pelvis, should be assessed by CT scan, MRI, or PET-CT in case of suspicion of 
presence of metastases based on signs, symptoms, biochemical results and/or as standard of care 
imaging of patients (i.e., non-study related).  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). 
Disease must be measured according to RECIST v1.1 criteria, with target and non-target lesions 
identified, measured and followed throughout the study, as well as new lesions identified 
(Appendix 4). Biopsied lesions must not be designated as target lesions for the purposes of 
RECIST v1.1 criteria, unless sufficient time has elapsed that the lesion has fully recovered. 


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Whenever possible, the same qualified physicians will interpret the radiologic assessments to 
reduce variability. Radiographic images will be maintained at the study centre, and Investigator’s 
findings will be filed in the patient’s source documents. 
In addition, digital copies of all radiographic images will be collected and stored in a central 
radiologic facility in order to allow for a blinded independent assessment of the radiographic 
imaging results. Instructions for the collection, and submission of images are provided in a separate 
Imaging Manual. 
Tumour measurements and disease response assessments are to be performed every 9 weeks 
(±7 days) (approximating three cycles) from C1D1 until radiographic disease progression. If the 
patient stops study treatment for reasons other than radiologically-confirmed PD, tumour 
measurements and disease response assessments should continue at least every 12 weeks (±14 
days) thereafter until PD is radiologically observed.  
Objective disease assessment is also to be performed any time disease progression is suspected. 
Patients should not discontinue study treatment because of raised tumour marker levels or other 
clinical signs of PD until PD has been confirmed radiographically by RECIST v1.1 criteria. 
All responses (CRs and PRs) must be confirmed by repeated imaging more than 28 days but less 
than 42 days after initial documentation. If a patient is found to have a response at the confirmatory 
scan which has improved from PR to CR, then the improved response must also be confirmed 
within a further 28-42 day window. 
Patients who stop treatment following an unconfirmed response should also still have a 
confirmatory scan within the 28- to 42-day window, if the scan can take place prior to the patient 
starting any subsequent anti-cancer therapies. If a patient is found to have a response at the 
confirmatory scan which has improved from PR to CR, then the improved response must also be 
confirmed within a further 28-42 day window, if the scan can take place prior to the patient starting 
any subsequent anti-cancer therapy. 
In the case of SD, measurements must have met the SD criteria at least once after C1D1 at a 
minimum of 8 weeks later (i.e., allowing for the 8-10 week time window for the first scheduled 
scan at Week 9). 
Assessment of progression for the purposes of measuring PFS in patients with non-measurable 
disease will be performed according to RECIST v1.1 recommendations (Eisenhauer et al, 2009). 
Unequivocal progression of non-measurable disease is defined as an increase in overall disease 
burden that is comparable in magnitude to the increase that would be required to declare PD for 
measurable disease, i.e., an increase in tumour burden representing an additional 73% increase in 
volume (which is equivalent to a 20% increase in diameter in a measurable lesion). Examples 
include an increase in a pleural effusion from ‘trace’ to ‘large’, an increase in lymphangitic disease 
from localised to widespread, or an increase sufficient to require a change in therapy. If 
unequivocal progression is observed, the patient should be considered to have had overall PD at 
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11.2 
Blinded Independent Central Review 
The BICR of all radiological imaging data will be carried out using RECIST v1.1. All radiological 
scans at baseline (prior to randomisation) will be provided to the BICR for their determination of 
whether or not the patient has measurable disease at baseline. This will be used for determining 
whether the patient is randomised to the measurable disease at baseline stratum or to the 
non-measurable disease at baseline stratum. 
All radiological scans for all patients at baseline and post-baseline (including scans from 
unscheduled visits, or visit outside of windows) will be provided to the BICR. The imaging scans 
will be reviewed by 2 independent radiologists and assessed using RECIST v1.1 criteria; in the 
case that both radiologists do not agree, a third independent radiologist will provide adjudication. 
Results of these independent reviews will not be communicated to Investigators, and all patient 
treatment decisions will continue to be made by the Investigators at the site. To ensure that the 
BICR do not become unblinded the following information will not be provided to the BICR when 
radiographic data is transmitted: the treatment group (or any data that might unblind the treatment 
group); assessments made by the Investigator, situational specific descriptions of the scans 
including whether scans are confirmatory or end of treatment; the total number of exams for a 
patient (to exclude progression bias); the results of assessments of other reviewers participating in 
the review process (except during adjudication); and any clinical data that may influence the 
independent reviewers. Further details of the BICR are documented in a separate BICR Charter. 
Please refer to the NuTide:121 Imaging Manual for details on submission and review of images. 
12 SAFETY ASSESSMENT AND REPORTING 
12.1 
Definitions 
The Investigator is responsible for reporting all AEs that are observed or reported during the study, 
regardless of their relationship to study drug or their clinical significance. 
An AE is defined as any untoward medical occurrence in a patient enrolled into this study 
regardless of its causal relationship to study drug. Patients or their legally authorised 
representatives will be instructed to contact the Investigator or Sub-Investigator at any time after 
signing the ICF if any symptoms develop. 
A Treatment Emergent AE (TEAE) is defined as any event not present before exposure to study 
drug or any event already present that worsens in severity after exposure to study drug. 
A Serious AE (SAE) is defined as any event that fulfils one or more of the following criteria: 
• Results in death 
• Is immediately life-threatening 
• Requires inpatient hospitalisation or prolongation of existing hospitalisation 
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly/birth defect 
• Is a significant medical event in the Investigator's judgment (e.g., may jeopardise the patient 
or may require medical/surgical intervention to prevent one of the outcomes listed above) 
Disease progression and disease-related death will not be considered an AE or SAE. 


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An Adverse Drug Reaction (ADR) is an AE, which is considered to be causally related to any 
dose of study drug. This means that a causal relationship between study drug and the AE is at least 
a reasonable possibility, i.e., the relationship cannot be ruled out. 
An Unexpected Drug Reaction is an ADR, the nature or severity of which, is not consistent with 
applicable product information (referring to information in IB, see RSI). 
A Suspected Unexpected Serious Adverse Reaction (SUSAR) is a serious ADR, the nature or 
severity of which is not consistent with the applicable product information (e.g., IB for an 
unapproved IMP). 
Important medical events that may not result in death, be life threatening, or require hospitalisation 
may be considered an SAE when, based upon appropriate medical judgment, they may jeopardise 
the patient and may require medical or surgical intervention to prevent one of the outcomes listed 
in this definition. Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias, convulsions that do not 
result in inpatient hospitalisation, or the development of drug dependency or drug abuse. Please 
consult Section 12.5 for the specific mechanism by which SAEs are to be reported. 
12.2 
Adverse Event Reporting 
At every study visit, patients will be asked nondirective questions to elicit any medically related 
changes in their well-being. They will also be asked if they have been hospitalised, had any 
accidents, used any new medications, or changed concomitant medication regimens (both 
prescription and over-the-counter medications). In addition to patient observations, AEs will be 
documented from any data collected on the CRF or other documents that are relevant to patient 
safety. Any allergic reaction to the agents administered as study drug treatment must be reported 
as an AE. 
All AEs that occur from date of consent through 30 days after the last dose of study drug must be 
reported in detail on the AE CRF. Disease progression in the medical opinion of the physician 
and/or disease-related morbidity and mortality as a study endpoint will not be considered an AE 
or SAE but should be captured on the Death CRF. Information to be collected for each AE includes 
onset date, type of event, aetiology, Investigator-specified assessment of severity and relationship 
to study drug, seriousness, any required treatment or evaluations, outcome and date of resolution. 
AEs resulting from concurrent illnesses, reactions to concurrent illnesses, reactions to concurrent 
medications, or progression of disease states must also be reported. All AEs will be followed for 
30 days after the patient’s last dose, or until resolution, whichever comes first. 
Pre-existing conditions (present before the start of the AE collection period) are considered 
concurrent medical conditions and should not be recorded as AEs. However, if the patient 
experiences a worsening or complication of such a concurrent condition, the worsening or 
complication should be recorded as an AE. Pre-existing AEs that worsen should be followed until 
30 days after the patient’s last dose or resolution to the AE level present at study entry. 
Investigators should ensure that the AE term recorded captures the change in the condition (e.g., 
“worsening of [condition]”). 
Insufficient clinical response, efficacy, or pharmacological action should NOT be recorded as an 
AE. The Investigator must make the distinction between exacerbation of pre-existing illness and 
lack of therapeutic efficacy. PD is NOT an AE; however, some sequelae of PD (i.e., pain, 
neurologic impairment) may be reported as AEs (generally not related to study drug). 


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Abnormal laboratory values or test results constitute AEs only if they induce clinical signs or 
symptoms, are considered clinically significant, require therapy or further diagnosis beyond repeat 
testing for confirmation, or (if not associated with clinical signs or symptoms) they remain at levels 
consistent with severe abnormalities despite appropriate medical intervention. It is requested that 
when reporting AEs for which potentially redundant NCI CTCAE terms exist, the Investigator 
utilises the more clinically-oriented terminology (for example, ‘anaemia’ is preferable to 
‘haemoglobin decreased’). 
It is also requested that in the setting of an allergic reaction or suspected allergic reaction 
considered by the Investigator to be related to NUC-1031, that the Investigator reports both the 
specific symptoms associated with the reaction (i.e., ‘urticaria’, ‘dyspnoea’) and also reports the 
appropriate term indicating the allergic reaction (‘allergic reaction’ or ‘anaphylaxis’ if appropriate 
[Immune System Disorders; CTCAE v5.0]). 
12.3 
Assessment of Causality 
The Investigator’s assessment of an AE's relationship to study drug is part of the documentation 
process, but it is not a factor in determining what is or is not recorded on the CRF in the study. If 
there is any doubt as to whether a clinical observation is an AE, the event should be recorded. 
The relationship of an AE to study drug should be classified using the following guidelines: 
Definitely Related: There is clear evidence to suggest a causal relationship and other possible 
contributing factors can be ruled out. 
Probably Related: There is evidence to suggest a causal relationship and the influence of other 
factors is unlikely. 
Possibly Related: There is some evidence to suggest a causal relationship (e.g., because the event 
occurs within a reasonable time after administration of the study drug). However, the influence of 
other factors may have contributed to the event (e.g., the patient’s clinical condition, other 
concomitant treatments). 
Unlikely Related: There is little evidence to suggest a causal relationship (e.g., the event did not 
occur within a reasonable time after administration of the study drug). There is another reasonable 
explanation for the event (e.g., the patient’s clinical condition, other concomitant treatments). 
Not Related: There is no evidence of any causal relationship. N.B. An alternative cause for the 
AE should be given. 
12.4 
Assessment of Severity 
The severity of each AE is to be assessed by the Investigator according to NCI CTCAE, v5.0. If 
the AE is not included in the NCI CTCAE, then the Investigator is to determine the intensity of 
the AE according to the following criteria: 
Mild (Grade 1):  
AE that disappears or is easily tolerated on continuation of study 
drug 
Moderate (Grade 2):  
AE sufficiently discomforting to cause interference with usual 
daily activities 
Severe (Grade 3):  
AE that is incapacitating, with inability to work or perform daily 
activities 


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Life-Threatening (Grade 4):  
AE that is potentially life-threatening* 
Death (Grade 5):  
Death related to AE 
*If a life-threatening (Grade 4) AE is immediately life-threatening, the event is, by definition, 
serious and is to be reported as described in Sections 12.6 and 12.7. 
12.5 
SAE Reporting 
Any AE considered serious by the Investigator or sub-Investigator or that meets the seriousness 
criteria that occurs from the date of consent through 30 days after last study drug dose must be 
reported to the CRO pharmacovigilance (PV) department within 24 hours from the time study site 
personnel first learn about the event. 
The SAE report will be completed using the eCRF. Contact details for safety reporting issues are 
provided in Table 6. 
Table 6 
Pharmacovigilance contact details 
Email 
PHV_NUC1031@iqvia.com 
If the patient is hospitalised because of or during the course of an SAE, then a copy of the hospital 
discharge summary (if available) should be sent to the CRO PV department, using the contact 
details listed above, as soon as it becomes available. Withdrawal from the study and all therapeutic 
measures will be performed at the discretion of the Investigator or sub-Investigator. 
NuCana, or the CRO PV department, will notify appropriate regulatory authorities of any 
unexpected, fatal, or life-threatening experience that is determined to be related to the use of the 
study drug. Refer to Section 12.7 for more details. 
The Investigator or sub-Investigator is responsible for informing their Institutional Review Board 
(IRB)/Ethics Committee (EC). Copies of SAE correspondence between all Investigators or 
sub-Investigators, governing authorities, IRB/ECs, and NuCana must be submitted to the CRO PV 
department for filing. 
A patient experiencing one or more SAE will receive treatment and follow-up evaluations by the 
Investigator or sub-Investigator or will be referred to another appropriate physician for treatment 
and follow-up. All SAEs must be followed to resolution or, if resolution is unlikely, to stabilisation. 
Expected outcomes in patients with BTC include disease-related mortality and morbidity, which 
will not be reported as expedited Investigational New Drug safety reports, unless there is a serious 
and unexpected event with evidence of a causal relationship between study drug and the event. As 
appropriate and based on the frequency of occurrence, SAEs in the study will be reported to the 
FDA, and other regulatory authorities as applicable, at an appropriate interval, such as inclusion 
in the periodic update IND annual report.  
The following SAEs should not be reported in an expedited manner because they are anticipated 
to occur in the BTC study population receiving standard of care treatment at some frequency 
independent of study drug exposure: 
• Progression of disease 
• Death as a consequence of the underlying malignancy 


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• Morbidity as a consequence of the underlying malignancy 
• Any hospital admission which is due to sepsis or other medical event as a result of biliary tract 
obstruction or cholangitis 
• Any hospital admission which is due to obstructive jaundice or other medical event as a result 
of biliary stent blockage 
12.6 
Expedited Reporting of SAEs 
The SAE reporting requirements apply regardless of the Investigator’s assessment of the causality 
or expectedness of the SAE. If an SAE occurs that requires reporting, the SAE CRF page should 
be completed within 24 hours of Investigator awareness to the CRO PV contact details provided 
above (or paper SAE form completed and faxed or emailed if the CRF is not available). 
If the SAE has not been reported within the specified timeframe, a reason for the delay must be 
provided when sending the SAE Report Form. SAEs that are fatal or life-threatening must be 
notified immediately. For all SAEs, the Investigator is obliged to pursue and provide all required 
information in accordance with the timelines provided above. 
12.7 
SUSAR Reporting 
All SUSARs must be reported to the responsible Regulatory Authorities and IRBs/ECs within the 
required timelines: 
• Fatal or life threatening SUSARs will be reported within 7 days of receipt. Any additional 
information will be reported within 8 days of sending the first report 
• All other SUSARs will be reported within 15 days of receipt 
In addition, other safety issues qualify for expedited reporting where they might materially alter 
the current risk assessment of study drug or be sufficient to change study drug administration or 
the overall conduct of the study. 
NuCana, or CRO PV, will notify appropriate regulatory authorities by telephone or fax 
transmission of any fatal, or life-threatening experience that is determined to be related to the use 
of the study drug (expedited report) as soon as possible but no later than 7 calendar days after the 
initial receipt of the information. Initial notification will be followed by a written report within 
15 calendar days. 
For unexpected events associated with the use of the study drug which are not fatal or life 
threatening, NuCana or CRO PV will notify the regulatory authorities as soon as possible, but no 
later than 15 days of the initial receipt of information. 
The IRB/EC will be informed in line with local regulations. Copies of SAE correspondence with 
all Investigators or Sub-Investigators, regulatory authorities, IRBs/ECs and NuCana must be 
submitted to CRO PV for filing. 
12.8 
Terms and Grading of Events 
All AEs and toxicities must be graded according to NCI CTCAE v5.0. 


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12.9 
Pregnancy 
A patient who becomes pregnant should be withdrawn from study treatment immediately. 
Pregnancies (in a patient or partner) occurring during study treatment, and up to 6 months after the 
end of study treatment, require expedited reporting. Should the female partner of a male patient 
become pregnant during his participation in the study, she will be asked to consent to follow-up of 
the pregnancy until birth and the health of the baby up until 6 months of age. A Pregnancy 
Notification Report should be completed and submitted to the CRO PV department within the 
same timelines and using the same contact details as an SAE. All reported pregnancies should be 
followed up and the outcome reported using the Pregnancy Follow-up Report. If the outcome of 
the pregnancy meets any of the criteria for seriousness, it must also be reported as an SAE.  
Examples of pregnancy outcomes that are SAEs include reports of: 
• Congenital anomalies or developmental delay, in the foetus or the child 
• Foetal death and spontaneous abortion 
• Suspected adverse reactions in the neonate that are classified as serious. 
12.10 
Events Exempt from Being Reported as AE/SAEs 
12.10.1 Progression of Underlying Disease 
Disease progression will be captured on the CRF. AEs including hospitalisation that are clearly 
consistent with disease progression will not be reported as individual AE/SAEs. Clinical symptoms 
of disease progression will only be reported as AEs 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 BTC. 
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. 
12.10.2 Death on Study Attributed to Malignancy  
Death due to disease under study, BTC, is to be recorded on the Death CRF form, provided that 
the death is not unexpected and no causal relationship with study drugs or other 
protocol-prescribed treatment intervention is suspected. The Investigator must clearly state 
whether the death was expected or unexpected and whether a causal relationship to study drug or 
other protocol treatment intervention is suspected. 
12.10.3 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 
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12.11 
Electrocardiograms 
12.11.1 Standard ECG Monitoring 
ECG parameters will be described at each timepoint. The site will be required to review ECGs as 
a safety check. This will be done immediately by a qualified Investigator or cardiologist at the 
study site, who will record their overall assessment as either normal, abnormal but not clinically 
significant, or abnormal clinically significant. ECG assessments may be retained for review 
centrally, where results will be provided to the study site and retained as source data. 
12.11.2 Robust QT Sub-study 
Intensive ECG monitoring will be implemented at a subset of sites to collect QT/QTc data for 
74 patients (approximately 37 patients in each treatment group) during the first 2 cycles of 
treatment to allow robust analysis of ECG parameters.  
ECGs will be centrally evaluated and measured in a blinded manner. A by-time central tendency 
analysis will be used as the primary analysis for assessing QTc in the sub-study.  Further to this, 
all ECG parameters will be statistically analysed and described, including categorical outlier 
analysis for QT/QTc outliers as well as HR, PR and QRS which will be outlined in a separate QT 
Statistical Analysis Plan. 
12.12 
Abnormal Laboratory Test Result Values 
The Investigator will identify and record clinically significant laboratory test results. Not every 
laboratory test result abnormality qualifies as an AE; however, a laboratory test result must be 
reported as an AE if it meets any of the following criteria: 
• Is accompanied by clinical symptoms 
• Results in a change in study treatment (e.g., dosage modification, treatment interruption, or 
treatment discontinuation) 
• Results in a medical intervention (e.g., potassium supplementation for hypokalaemia) or a 
change in concomitant therapy 
• Is clinically significant in the Investigator’s judgement 
It is the Investigator’s responsibility to review all laboratory test result findings. Medical and 
scientific judgement should be exercised in deciding whether an isolated laboratory test result 
abnormality should be classified as an AE.  
If a clinically significant laboratory test result abnormality is a sign of a disease or syndrome (e.g., 
alkaline phosphatase and bilirubin 5 × ULN associated with cholestasis), the diagnosis (i.e., 
cholestasis) should be recorded only on the AE eCRF. 
If a clinically significant laboratory test result abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the AE eCRF, along with a descriptor indicating 
whether the test result is above or below the normal range (e.g., “elevated potassium,” as opposed 
to “abnormal potassium”). If the laboratory test result abnormality can be characterised by a 
precise clinical term per standard definitions, the clinical term should be recorded as the AE. For 
example, an elevated serum potassium level of 7.0 mEq/L should be recorded as “hyperkalemia.”  
Cases of potential drug-induced liver injury that include an elevated ALT or AST in combination 
with either an elevated bilirubin or INR must be recorded (FDA, 2009).  


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These cases are defined by Hy’s law if they meet one of the following criteria: 
• Treatment-emergent ALT or AST >8 × ULN 
• Treatment-emergent ALT or AST >5 × ULN for more than 2 weeks 
• Treatment-emergent ALT or AST >3 × ULN with total bilirubin >2 × ULN  
• Treatment-emergent ALT or AST >3 × ULN and INR >1.5 
And none of the following criteria: 
• No initial finding of cholestasis (elevated serum ALP) 
• No other reason can be found to explain the increases in ALT/AST and bilirubin or INR, such 
as viral hepatitis A, B, or C; pre-existing or acute liver disease; biliary duct obstruction; or 
another drug capable of causing the observed injury 
For patients meeting Hy’s law criteria due to drug-related toxicity, consider discontinuation of 
treatment or, if the patient is deriving benefit in the opinion of Investigator, consider holding 
treatment until values are <3 × ULN for AST and/or ALT and <2 × ULN for total bilirubin, then 
restart treatment at a reduced dose (as per Table 4). Laboratory values must be closely monitored 
and study treatment must be discontinued if patients meets criteria for a second time despite dose 
reduction.  
Patients meeting Hy’s law criteria with clear progression of liver metastases must discontinue 
study treatment; however, they will continue to be assessed for safety.  
Refer to Section 10.3.3 for instructions on handling patients who meet Hy’s law criteria due to 
underlying biliary issues.  
12.13 
Abnormal Vital Sign Values 
The Investigator will identify and record clinically significant vital sign results.  
Not every vital sign abnormality qualifies as an AE; however, a vital sign result must be reported 
as an AE if it meets any of the following criteria: 
• Is accompanied by clinical symptoms 
• Results in a change in study treatment (e.g., dosage modification, treatment interruption, or 
treatment discontinuation) 
• Results in a medical intervention or a change in concomitant therapy 
• Is clinically significant in the Investigator’s judgement 
It is the Investigator’s responsibility to review all vital sign result findings. Medical and scientific 
judgement should be exercised in deciding whether an isolated vital sign value abnormality should 
be classified as an AE.  
If a clinically significant vital sign value abnormality is a sign of a disease or syndrome (e.g., high 
blood pressure), the diagnosis (i.e., hypertension) should be recorded only on the AE eCRF. 
12.14 
Informing Investigators of New Safety Information 
NuCana will ensure that all Investigators are kept informed, in a timely manner, as new safety 
information becomes available. Investigators are responsible for briefing their study team as 
appropriate. 


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12.15 
Reference Safety Information (RSI) for Assessment of Expectedness 
The IB supplied by NuCana for NUC-1031 contains a defined table, which will act as the 
NUC-1031 reference safety information (RSI) for the study. Only the IB version with current 
regulatory and IRB/EC approval for use in the study should be used to assess SAE reports to 
identify SUSARs. 
• Significant Changes to the RSI: If patient safety or the risk/benefit assessment has changed 
or new expected reactions have been added, then approval of the updated IB by applicable 
Regulatory Authorities and IRBs/ECs will be sought. If new expected reactions have been 
added to the IB or events have downgraded to ‘expected’, a justification for the changes will 
be included in the amendment request. Changes to the IB that impact on patient safety or alter 
the risk/benefit assessment may require changes to the study documentation such as the ICF. 
NuCana will identify any such required changes and ensure ICF revisions are made and 
approved by applicable Regulatory Authorities and IRBs/ECs, and patients re-consented as 
applicable. Significant updates to the IB shall be attached to the development safety update 
report (DSUR) (once approved by applicable Regulatory Authorities and IRBs/ECs); however, 
the IB in effect at the start of the DSUR reporting period serves at the RSI during the reporting 
period. 
• Non-Significant Changes to the RSI: If changes to the IB are minor and do not include 
new/removed expected reactions, do not impact on patient safety or alter the benefit/risk 
assessment, then sites will not receive the updated IB until the end of the DSUR reporting 
period and this decision will be made by NuCana. 
If the non-significant updated IB is to be implemented in the new DSUR reporting period, then 
Regulatory Authority and IRB/EC should be informed of the intention to implement the updated 
IB after the DSUR reporting period ends. The updated IB will be attached to the DSUR. If new 
expected reactions have been added to the IB or events have downgraded to ‘expected’, then the 
updated IB must receive approval before it is implemented. The IB will be sent to the study sites 
with a covering letter documenting the changes. This will be circulated after the DSUR has been 
submitted at the start of the new DSUR reporting period. 
The approved SmPCs (section 4.8) for cisplatin and gemcitabine will serve as their respective 
RSIs, which are also summarised in the appendix section of the NUC-1031 IB. 
12.16 
Independent Data Monitoring Committee (IDMC) 
An IDMC will review the safety, dosing intensity, and clinical activity data from the study. The 
IDMC is an independent expert advisory group commissioned and charged with the responsibility 
of evaluating cumulative safety and efficacy data as well as other clinical study data at regular 
intervals.  Actions of the IDMC will be governed by an IDMC charter and the data to be reviewed 
will be outlined within an IDMC Statistical Analysis Plan. Members of the IDMC will include:  
• Independent therapeutic experts in BTC with relevant clinical study experience 
• Independent biostatistician 
The IDMC will meet at the following timepoints to review the clinical safety and efficacy data: 
• The IDMC will review the safety data from approximately the first 50 randomised patients 
who have completed one cycle (approximately 25 patients in each treatment group) 


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• The IDMC will meet at least every 6 months thereafter to review safety data 
• Additional reviews of the safety data may be requested by the IDMC or by the Sponsor at 
additional points during the study 
In addition, the IDMC will review efficacy and safety data as follows: 
• Interim Analysis 1 with a data cut-off 28 weeks after 418 patients have been randomised to the 
"measurable disease at baseline" stratum. This will assess ORR for demonstration of efficacy, 
and assess OS for futility 
• Interim Analysis 2 with a data cut-off 28 weeks after 644 patients have been randomised to the 
"measurable disease at baseline" stratum. This will assess ORR for demonstration of efficacy 
(ORR Final Analysis), and will also assess OS for efficacy (OS Interim Analysis 1), based on 
approximately 425 OS events 
• Interim Analysis 3 after 541 OS events have occurred, which will assess OS for efficacy (OS 
Interim Analysis 2) 
BTC is a highly complex and variable disease, with malignancies occurring along any part of the 
biliary tract from the ampulla of Vater to the smallest intrahepatic ductules and the gallbladder. 
Multiple imaging modalities are used to assess different forms of BTC. However, BTC is a rare 
disease and so experience in radiologic assessment of BTC will be critical to assessment of many 
of the proposed endpoints in this study.  
Following reviews of safety, futility, and/or efficacy, the IDMC will recommend whether the study 
should continue unchanged, be stopped, or be modified in any way. Once the IDMC has reached 
a recommendation, a report will be provided to NuCana. This report will include the 
recommendation together with any proposed amendments to the protocol. The final decision to 
modify or stop the study will be made by NuCana. 
The NuTide:121 IDMC charter contains details on the IDMC members and their responsibilities. 
13 STATISTICAL CONSIDERATIONS 
Full details of the planned analyses will be provided in a separate Statistical Analysis Plan (SAP) 
which will be finalised prior to the start of randomisation. The statistical principles applied in the 
design and planned analyses of this study are consistent with ICH E9 and FDA Guidance for 
Industry: Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics (2018). 
13.1 
Analysis Populations 
The following sections define the populations that will be used for statistical analyses. 
13.1.1  Intention-to-Treat (ITT) Population 
The ITT population will consist of all patients who are randomised, regardless of whether any 
study medication was received. Patients will be summarised on the basis of the treatment group to 
which they were randomised. 


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13.1.2  Intention-to-Treat with Measurable Disease at Baseline (ITTMD) Population 
The ITTMD population will consist of all patients who are randomised to the stratum 
corresponding to having measurable disease at baseline (as assessed by BICR), regardless of 
whether any study medication was received. Patients will be summarised on the basis of the 
treatment group to which they were randomised. 
13.1.3  Modified Intention-to-Treat (MITT) Population 
The MITT population will consist of all patients who are randomised and received any study 
medication. Patients will be summarised on the basis of the treatment group to which they were 
randomised. 
13.1.4 Safety Population 
The Safety population will consist of all patients who are randomised and receive any study 
medication. Patients will be summarised on the basis of the actual study medication received, i.e., 
NUC-1031 in combination with cisplatin (Arm A), or gemcitabine in combination with cisplatin 
(Arm B). Any patients receiving study medication from both arms will be summarised under 
Arm A. 
13.1.5  Primary Analysis Populations 
The ITTMD will be the primary analysis population for evaluating ORR and DCR. DoR will be 
analysed in the subset of ITTMD patients who have confirmed response. For evaluating all other 
efficacy endpoints, the primary analysis population will be the ITT population. The MITT 
population will be used only for a secondary analysis of the OS primary endpoint. The Safety 
population will be the primary analysis population for evaluating all safety endpoints. 
13.2 
Patient Disposition 
For the ITT population, counts and percentages will be provided by treatment group for each of 
the following: treated or untreated; treatment ongoing or treatment ended; primary reason for end 
of treatment; and whether the patient discontinued the study overall and by reason. For each 
treatment group, the number of patients in each analysis population will be summarised. Major 
protocol deviations (as defined in a separate Protocol Deviation Management Plan) will also be 
summarised by reason and overall. 
13.3 
Demographics and Baseline Characteristics 
Demographic and baseline characteristics will be summarised by treatment group for the ITT, 
ITTMD, and Safety populations. Full details on the variables summarised are provided within the 
SAP. 
13.4 
Primary Efficacy Endpoints 
This study has OS and ORR as dual primary endpoints. The study will be viewed as positive (in 
terms of the primary efficacy endpoints) if statistical significance is obtained on either of the two 
primary endpoints. The control of Type 1 error by the Maurer & Bretz (2013) method across the 
two primary endpoints and the key secondary endpoint (PFS), as well as across the interim 
analyses, is described in Section 13.10.1. 


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13.4.1  Overall Survival 
13.4.1.1 Definition of Overall Survival 
Duration of OS is defined as the time from randomisation to the time of death due to any cause. 
For patients who are alive at the time of a data cut-off or are permanently lost to follow-up, duration 
of OS will be censored at the date at which they were last known to be alive. 
The date at which the patient is last known to be alive is defined as the latest date of: (i) last site 
visit; (ii) last date at which the patient had a radiographic scan; and (iii) last date at which the 
patient, the study investigator, their other physicians, or a family member confirmed that the 
patient was alive. 
13.4.1.2 Primary Analysis for Overall Survival 
The primary analysis of OS will be performed using the ITT population. As described further in 
Section 13.10 and summarised there in Table 10 and Table 12, OS will be assessed for 
demonstration of efficacy on 3 occasions, i.e., after approximately 425 OS events (67%), after 
541 OS events (85%), and after 637 OS events (100%). At each of these 3 looks, the treatment 
effect for OS will be assessed by the stratified log-rank test. The one-sided p-value will be 
compared with the critical values as derived in Section 13.10.1 to determine if statistical 
significance has been obtained at that time.  
The stratification factors to be included within the stratified log-rank test are defined by a rule 
given in the SAP. This rule starts with the design's four stratification factors and successively 
eliminates factors (as needed) in a pre-defined manner, so that for both treatment groups combined 
there is no combination of the stratification factors with less than 10 OS events. For each 
stratification factor, the values from the IxRS at randomisation will be used, even if it is 
subsequently found that these values were incorrect for one or more patient. The rule will be 
implemented at Interim Analysis 2 which is the first look at which OS determination of efficacy 
is to be made. The same resultant set of stratification factors will also be used (without change) for 
all analyses of OS at Interim Analysis 2, Interim Analysis 3 and at the Final Analysis. It will also 
be used for the analysis of PFS. 
A stratified Cox proportional hazards model with Efron's method of handling ties will be used to 
estimate the hazard ratio for OS. The model will include a term for treatment and the same set of 
stratification factors as used within the stratified log-rank test. The 100(1-2α)% two-sided 
confidence interval (CI) for the hazard ratio will also be derived where "α" is the "Critical p-value 
(1-sided)" for OS derived as described in Section 13.10.1 and illustrated in Table 12.  
The non-parametric Kaplan-Meier method will also be used to estimate the survival curves, within 
which Greenwood's formula will be used to derive the standard error. The number of patients at 
risk at the start of each month after randomisation will also be displayed. The median survival time 
will be estimated for each treatment group, together with its CI using the Brookmeyer & Crowley 
(1982) method. Estimates of the 25th and 75th percentiles will also be derived together with their 
corresponding CIs. 


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13.4.1.3 Secondary and Supportive Analyses for Overall Survival 
A secondary analysis of OS based on a stratified Cox proportional hazards model will be carried 
out in the same manner as described in Section 13.4.1.2, but with terms for treatment and ECOG 
status at baseline (0 or 1), as well as including terms for any of the design stratification factors 
which (based on the rule given within the SAP) are not able to be included as analysis stratification 
factors. 
Subgroup analyses of OS for each of the randomisation stratification factors as well as for other 
important factors will be provided as described in Section 13.12. 
The analyses of OS described in Section 13.4.1.2 will also be carried out based on the MITT 
population (which is the subset of the ITT population including only those patients that received 
any study medication), and these analyses will be viewed as supportive. 
The methods described in Section 13.4.1.2 assume censoring is at random. Since censoring may 
depend upon progression, and progression is expected to be affected by treatment group, it is 
possible that censoring may be informative, i.e., may vary systematically between treatment 
groups. Therefore, methods which assume censoring not at random (CNAR) will be used to assess 
the robustness of the inference from the primary analysis for OS. 
To allow straightforward comparison with the planned Cox proportional hazards regression 
analysis, multiple imputation of time to event using the Cox model will be used to implement the 
CNAR analyses (Lipkovich et al, 2016). Full details of the methodology and its assumptions are 
presented in the paper cited. The analysis will use the SAS macro publicly available at 
missingdata.org.uk. Refer to the SAP for further information.  
A tipping point approach will be used. For all patients censored in the primary analysis of OS for 
whom a progression has occurred, irrespective of treatment group, this analysis will as a first step 
assume censoring at random but will then impose a multiple of the estimated hazard of death – say 
delta – before imputing censored times to event. In a tipping point analysis, the quantity delta is 
successively increased in a sequence of analyses, i.e., the assumption about post-censoring hazard 
is made more severe. Note that the patients thus censored not at random in the tipping point 
approach would be only those patients who are censored in the primary analysis (excluding 
patients administratively censored due to reaching the data cut-off date) and who progressed at 
any time whether the progression occurred while on study treatment, or if it occurred after 
discontinuing study treatment, and even if it occurred after starting another cancer treatment. 
Depending upon the patterns of censoring there may be a delta large enough such that inference 
made by the primary analysis no longer holds – this would be the “tipping point”. If the “tipping 
point” delta exists and is judged unrealistically high, then this provides evidence to help assess the 
robustness of inference from the primary analysis to the assumption of censoring at random. 
The Restricted Mean Survival Time (RMST) method at 12 months and 18 months may also be 
conducted for OS to account for any possible non-proportional hazards and to estimate the absolute 
benefit of experimental treatment. 


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13.4.1.4 Additional Sensitivity Analyses for Overall Survival as a Result of the COVID-19 
Pandemic 
All analyses for Overall Survival in Sections 13.4.1.2 and 13.4.1.3 are based on all-cause mortality, 
i.e., include OS events with cause of death not reported as COVID-19 as well as OS events with 
COVID-19 cause of death.  All analyses in those two sections also include all OS events regardless 
of whether or not the patient discontinued treatment due to a COVID-19 infection. 
A first set of COVID-19-related sensitivity analyses for OS will be carried out using each method 
described in Section 13.4.1.2, but where in each case patients with COVID-19 recorded as the 
cause of death will be censored at their date of death. Frequencies and percentages based on the 
ITT population will also be derived for each treatment group separately for: (i) OS with cause of 
death related to reasons other than COVID-19; and (ii) OS with cause of death reported as 
COVID-19. 
A second set of COVID-19-related sensitivity analyses for OS will be carried out using each 
method described in Section 13.4.1.2, but where patients discontinuing treatment due to a 
COVID-19 infection will be censored at the date of such treatment discontinuation. Any patients 
that did not discontinue treatment due to a COVID-19 infection but who died with COVID-19 as 
cause of death will be censored at their date of death. Frequencies and percentages based on the 
ITT population will also be derived for each treatment group separately for: (i) OS with cause of 
death related to reasons other than COVID-19 in patients who did not discontinue treatment due 
to a COVID-19 infection; and (ii) all other deaths. 
In addition to the sensitivity analyses for OS described above, further sensitivity analyses for OS 
may ultimately be needed once the nature and extent of the direct and indirect impact of COVID-19 
becomes clearer, and such additional analyses will then be described within the SAP. 
13.4.2  ORR 
13.4.2.1 Derivation of Best Overall Response 
Radiographic disease assessment will be made by BICR using RECIST v1.1 for all randomised 
patients. For all scheduled and unscheduled visits at which radiographic scans take place, these 
scans will be reviewed by two independent radiologists, each of whom will record all details as 
described within Appendix 4. The two radiologists will independently derive each timepoint 
response categorisation (into CR, PR, SD, PD, or NE) in accordance with Table 1 from 
Appendix 4, i.e., the response obtained overall at each visit by assessing target lesions, non-target 
lesions, and new lesions. The BICR Charter describes the process by which the reviewer who made 
what is regarded as the "definitive assessment" is identified in the case that adjudication is required. 
All statistical analyses based on BICR assessment will, for a given patient, be based only on the 
independent reviewer who provided this "definitive assessment". 
Then, based on the timepoint response categorisations made by this independent reviewer, the Best 
Overall Response (BOR) from BICR will be derived programmatically using the rules given in 
Table 3 from Appendix 4, taking into account: 
(i) 
Confirmation after at least 28 days is required for CR or PR; 


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(ii)  
For classification as SD, the radiographic assessment on which this is based must have met 
 
the SD criteria at least once after C1D1 at a minimum of 8 weeks later (i.e., allowing for 
 
the earlier possible time from the 8-10 week window for the first scheduled scan); 
(iii) 
In patients who discontinue treatment without progression, timepoint responses will be 
 
considered in the calculation of BOR only up until the time that the patient receives a 
 
subsequent anti-cancer therapy; and 
(iv)  
The rules given in Appendix 3 of the SAP for when patients have one or more intermediate 
 
visits with timepoint responses of NE. 
 
From the Investigator's review of the imaging scans, their recorded tumour response data will be 
used to programmatically determine each patient's timepoint response categorisation (into CR, PR, 
SD, PD, or NE) in accordance with Table 1 from Appendix 4 for patients in the ITTMD population, 
or categorisation (into CR, non-CR/non-PD, PD, or NE) in accordance with Table 2 from 
Appendix 4 for patients randomised to the non-measurable disease at baseline stratum.  The BOR 
will then be derived programmatically using the rules given in Table 3 from Appendix 4, taking 
into account (i)-(iv) above. 
Note: The Independent reviewer's timepoint response categorisation is used prior to 
programmatically deriving BOR based on BICR assessment. However, for BOR based on 
Investigator assessment, the timepoint response is also derived programmatically. 
13.4.2.2 Primary Analysis for ORR 
All analyses of ORR will be based only on patients randomised to the stratum corresponding to 
having measurable disease at baseline. As described further in Section 13.10 and summarised there 
in Table 10 and Table 11, ORR will be assessed for demonstration of efficacy on 2 occasions, 
which are scheduled to take place 28 weeks after 418 patients in this stratum and 28 weeks after 
644 patients in this stratum have been randomised. This minimum period of follow-up allows for 
three scheduled post-baseline radiographic scans plus a one week visit window. Let NM28 denote 
the actual number of patients in the ITTMD population that were randomised ≥28 weeks before 
the data cut-off for a given interim analysis.   
The primary analysis of ORR at a given look will be performed based on the NM28 patients in the 
ITTMD population (randomized ≥28 weeks before the data cut-off), where ORR is then defined 
as the proportion of the NM28 patients within the treatment group that have BOR of CR or PR based 
on BICR assessment. 
Note: At the time of the data cut-off for each of the two interim analyses at which ORR is 
assessed, there will be some of the NM28 patients who have an unconfirmed response based 
on Investigator assessment at their most recent radiographic scan (with no earlier 
confirmed response based on Investigator assessment) but who have not yet had their 
confirmatory radiographic scan. The date of the latest unconfirmed response over all such 
patients will be determined. Radiographic assessments (by BICR and by the Investigator) 
from those confirmatory scans which are scheduled to take place within at most 6 weeks 
after this date will be included at the interim analyses only in the calculation of counts with 
confirmed CR, counts with confirmed PR, and in ORR. 


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At each of these two looks, the odds ratio for ORR will be assessed by the stratified 
Cochran-Mantel-Haenszel (CMH) test. The one-sided p-value will then be compared with the 
critical values as derived in Section 13.10.1 to determine if statistical significance has been 
obtained at that time for ORR. The stratification factors to be included within the stratified CMH 
test are defined for ORR by a rule given in the SAP. This rule starts with the design's following 
three stratification factors: metastatic disease (yes, no), primary tumour location (gallbladder, 
intra-hepatic, extra-hepatic/ampullary), and region (Asia, non-Asia). It successively eliminates 
factors (as needed) in a pre-defined manner, so that for both treatment groups combined there is 
no combination of the stratification factors with less than 10 patients. Measurable disease (yes/no) 
will not be used because all ITTMD patients were randomised to the measurable disease at baseline 
stratum. Here, for these three factors the values from the IxRS at randomisation will be used, even 
if it is subsequently found that these values were incorrect for one or more patient. The rule will 
be implemented on the NM28 patients at Interim Analysis 1, which is the first look at which ORR 
determination of efficacy is to be made. The same resultant set of stratification factors will also be 
used (without change) for analysis of ORR at Interim Analysis 2. 
The 100(1-2α)% two-sided CI for the odds ratio will also be derived where "α" is the "Critical p-
value (1-sided)" for ORR derived as in Section 13.10.1 and summarised in Table 11.  
Counts for patients with a BOR of CR, PR, SD, PD, or NE, based on BICR assessment, will also 
be presented by treatment group for the NM28 patients.  
Clopper-Pearson exact 95% two-sided CIs for ORR based on BICR assessment will be provided 
separately by treatment group (Clopper & Pearson, 1934). 
13.4.2.3 Secondary and Supportive Analyses for ORR 
Let NM denote the total number of patients in the ITTMD population that were randomised before 
the data cut-off for a given interim analysis (regardless of how long beforehand they were 
randomised). As a supportive analysis, the CMH test as described in Section 13.4.2.2 will also be 
carried out for ORR using BICR assessment, based on the NM patients. Counts for patients with a 
BOR of CR, PR, SD, PD, or NE, based on BICR assessment, will also be presented by treatment 
group for the NM patients. 
Counts will also be provided by treatment group for the number out of the NM patients in the 
ITTMD population that have tumour resection. Counts will also be provided separately by the 
number of such patients that: (i) previously had a confirmed PR; or (ii) did not previously have a 
confirmed PR. 
A secondary analysis of ORR will also be provided in terms of the difference in proportions based 
on BICR assessment. This estimate of the difference in ORRs and corresponding 100(1-2α)% 
two-sided CI will be calculated for the NM28 patients in the ITTMD population using CMH 
methodology and adjusted for the same three stratification factors. 
Subgroup analyses of ORR based on BICR assessment will be provided as described in 
Section 13.12. 
The analyses of ORR based on BICR assessment as described in Section 13.4.2.2 will also be 
carried out based on the subset of the NM28 patients in the ITTMD population that received any 
treatment, and these analyses will be viewed as supportive. 


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Additional secondary analyses of ORR will be based on Investigator assessment of response. All 
analyses described for BICR assessment (except for the subgroup analyses) will also be conducted 
based on Investigator assessment. In addition, a concordance analysis will be performed in which, 
separately for each treatment group, the categories (PR/CR or SD/PD/NE) of BOR for BICR 
assessment will be presented cross-classified with the corresponding categories based on 
Investigator assessment. 
13.4.2.4 Additional Sensitivity Analyses for ORR as a Result of the COVID-19 Pandemic 
For ORR, additional sensitivity analyses that account for the impact of COVID-19 will be 
described in a future protocol amendment, with further details provided in the SAP, once the nature 
and extent of the impact becomes clearer. Potential impacts of COVID-19 on ORR include death 
due to COVID-19 prior to response, treatment discontinuation or interruption due to COVID-19, 
delayed or missing regular scheduled radiographic scans, and delayed or missing confirmatory 
radiographic scans (following a PR or CR). For radiographic scans, these delays could be directly 
related to COVID-19 such as resulting from the patient's COVID-19 infection, or the delays could 
be indirectly related to COVID-19 such as caused by regional lockdowns (or by other logistical 
reasons). These sensitivity analyses will clearly specify whether only the direct impact of 
COVID-19 is to be taken into account, or whether the indirect impact of COVID-19 will also be 
taken into account. 
13.5 
Secondary Efficacy Endpoints 
13.5.1  Progression-Free Survival 
PFS will be calculated as the time from randomisation until objective disease progression or death 
from any cause, whichever occurs earlier. PFS based on BICR assessment is the single key 
secondary efficacy parameter. 
Progression will be based on radiographic assessments only, and whether or not a patient has a 
progression will be determined for each scheduled visit and for any unscheduled visits. For patients 
with target lesions at baseline (and so having measurable disease at baseline), whether or not a 
patient has PD at a timepoint will be determined on the basis of the guidelines provided in Table 1 
of Appendix 4. For patients with no target lesions at baseline (and so having non-measurable 
disease at baseline), whether or not a patient has PD at a timepoint will be determined on the basis 
of the guidelines provided in Table 2 of Appendix 4, where "unequivocal PD" will be determined 
as described in Section 11. For the primary analysis of PFS, the censoring scheme described in 
Table 7 will be used. 
The SAP provides details on what constitutes an ‘adequate tumour assessment’ and provides 
further details on the handling of cases where data are partially missing from adequate tumour 
assessment visits. 
The rules within Table 7 are consistent with European Medicines Agency (EMA) Appendix 1 to 
the guideline on the evaluation of anti-cancer medicinal products in man (2012). The rules in 
Table 7 are also fully consistent with the rules given in Table C2 from FDA Guidance for Industry: 
Clinical Trial Endpoints for the approval of non-small cell lung cancer drugs and biologics (2015). 
The primary analysis of PFS will be performed using the ITT population. As described further in 
Section 13.10.1, PFS will be assessed for demonstration of efficacy only at Interim Analysis 2, at 
which time approximately 534 PFS events are projected to have occurred. PFS will be assessed by 


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the stratified log-rank test, with the same set of stratification factors as identified for use with OS. 
If statistical significance is obtained for both ORR and OS (see Section 13.10.1) then PFS will be 
tested at the 2.5% one-sided significance level. A stratified Cox proportional hazards model with 
Efron's method of handling ties will be used to estimate the hazard ratio for PFS, in which the 
model only includes the term for treatment. The 95% two-sided CI for the hazard ratio will also 
be derived for PFS from this model. If instead statistical significance is obtained for OS but not 
for ORR (see Section 13.10.1), then the above testing will be carried out at the 0.8% one sided 
significance level and the CI for the hazard ratio will be 98.4% two-sided. 
Table 7 
Censoring scheme used in the primary analysis of PFS 
Case Situation 
Date of Progression or Censoring 
Outcome 
1 
Incomplete or no baseline tumour 
assessments 
Randomisation 
Censored 
2 
Progression documented between 
scheduled visits 
Earliest time at which progression can be 
declared: 
• Date of first progression assessment 
showing new lesion (if progression is 
based on new lesion); or 
• Date of first radiological assessment 
of target lesions showing a 
predefined increase in the sum of the 
target lesion measurements 
Progressed 
3 
No progression 
Date of last progression assessment with 
no 
documented progression 
Censored 
4 
Treatment discontinuation for 
undocumented progression 
Date of last progression assessment with 
no 
documented progression 
Censored 
5 
Death or progression after treatment 
discontinuation for toxicity or other non-
progression related reason 
Date of progression or death, whichever 
occurs first 
Progressed 
6 
Death or progression after new anti-
cancer treatment started 
Date of progression or death, whichever 
occurs first 
Progressed 
7 
Death before first scheduled PD 
assessment 
Date of death 
Progressed 
8 
Death after adequate progression 
assessment visit or death after one 
missed visit (where in either situation 
there is no previous documentation of 
progression) 
Date of death 
Progressed 
9 
Death or progression after more than one 
missed visit 
Date of progression or death, whichever 
occurs first 
Progressed 


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Note: Missed visit includes visits that were completely missed or visits that did not have an adequate tumour 
assessment (ATA), and "progression assessment" in the above censoring rules only refers to visits with ATA. 
The Kaplan-Meier method will also be used to estimate the survival curves for PFS in each 
treatment group, within which Greenwood's formula will be used to derive the standard error. The 
number of patients at risk at the start of each month will also be displayed. The median will be 
estimated for each treatment group, together with its CI using the Brookmeyer & Crowley (1982) 
method. Estimates of the 25th and 75th percentiles will also be derived together with their 
corresponding CIs. 
The first sensitivity analysis of PFS will follow the primary analysis except for the following 
change to Case 6: 
• Patients with new anti-cancer treatment started (with no prior documented progression) 
will be censored at the date of their last progression assessment (prior to starting new 
anti-cancer treatment). 
The second sensitivity analysis of PFS, which is fully consistent with Table C1 from FDA 
Guidance for Industry: Clinical Trial Endpoints for the approval of non-small cell lung cancer 
drugs and biologics (2015), will follow the rules from the first sensitivity analysis but will also 
make the following changes to Cases 5 and 9: 
• Patients with treatment discontinuation (for toxicity or for another non-progression-related 
reason) and no documented prior progression will be censored at the date of the last 
progression assessment (prior to treatment discontinuation). 
• Patients that die or progress after more than one missed visit will be censored. The date of 
censoring will be the date of last progression assessment with documented 
non-progression, or date of randomisation if all post-baseline progression assessments 
were missed. 
Note: In the second sensitivity analysis, any patient who meets the conditions for both Case 5 
and Case 6 will be censored at the earliest of the two possible censoring dates. 
Supportive analyses of PFS based on Investigator assessment will also be carried out using each 
of the three sets of censoring rules defined above. 
In case the proportional hazards assumption is not valid, supportive analyses using the RMST 
method may be conducted for PFS to account for a possible non-proportional hazards effect. 
For PFS, additional sensitivity analyses that account for the impact of COVID-19 will be described 
in a future protocol amendment, with further details provided in the SAP, once the nature and 
extent of the impact becomes clearer. 
13.5.2 Duration of Response 
DoR as determined by BICR, using RECIST v1.1 criteria, is defined as the time from the first 
occurrence of a confirmed objective response to the time of disease progression, or death due to 
any cause, whichever occurs first. The time of progression or death, and censoring, will each be 
based on the rules used for the primary analysis of PFS as described in Section 13.5.1. 
DoR will be summarised for the subgroup of patients in the ITTMD population with confirmed 
response using the Kaplan-Meier method and will also be displayed graphically. The median event 


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time will be estimated for each treatment group, together with its CI using the Brookmeyer & 
Crowley (1982) method. Estimates of the 25th and 75th percentiles will also be derived together 
with their corresponding CIs. 
In addition, DoR based on Investigator assessment will be summarised in the same way, and this 
will be considered a supportive analysis. 
13.5.3 18-Month and 12-Month Survival 
The proportion of patients alive at 18 months (OS18) will be defined as the Kaplan-Meier estimate 
of OS at 18 months. For each treatment group the 95% CI will also be derived using Greenwood's 
method. A comparison between treatment groups for OS18 will also be carried out using the 
method described in Klein et al (2007). 
The proportion of patients alive at 12 months (OS12) will be analysed in the same way as OS18. 
13.5.4 Disease Control Rate 
DCR is the proportion of the NM28 (defined in Section 13.4.2.2) patients within the treatment group 
that have a BOR of CR, PR, or SD. The primary analysis of DCR is based on BICR assessment 
and a supportive analysis will also be conducted based on Investigator assessment. 
13.6 
Patient-Reported Outcomes 
QoL will be assessed using the EORTC-QLQ-C30 with the QLQ-BIL21 module (Appendix 1) and 
the EQ-5D-5L (Appendix 2). 
The ECOG performance status scale will be used to assess patients’ ability to perform daily living 
tasks and their range of basic physical ability. A copy of the ECOG scale is provided in 
Appendix 5. 
Patient Reported Outcomes will be collected using electronic tablets provided to the patients 
during the study visits to facilitate accurate and timely capture of the QoL data. Missing data points 
will be queried and centralised compliance monitoring will identify any trends in errors or missing 
data to allow retraining intervention, should this be required.   
13.6.1 EORTC-QLQ-C30 with the QLQ-BIL21 Module 
The EORTC QLQ-C30 is a self-administered cancer-specific questionnaire with multi-
dimensional scales. It consists of both multi-item scales and single-item measures, including five 
functional domains, a global QoL domain, three symptom domains, and six single symptom 
measures. Scoring of the EORTC QLQ-C30 data will be completed following the procedures 
recommended by the EORTC Study Group on Quality of Life. For each domain or single-item 
measure, a linear transformation will be applied to standardise the raw score to range between 0 
and 100. QoL data will be analysed to test for clinically meaningful differences between the two 
treatment groups. Questionnaire compliance rates will be ascertained for each treatment group at 
each measurement timepoint. Mean baseline scores for each subscale and summary scores will be 
calculated. 
The principal QoL analysis will be based on Kaplan-Meier estimates and log-rank tests on time to 
definitive QoL deterioration, as measured by the EORTC QLQ-C30 physical function and global 
QoL scores, in each treatment group. The event of interest is the time to a definitive QoL 
deterioration, which is defined as the minimum time where two consecutive post-baseline visits 


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have a 5-point or greater deterioration from baseline scores by subtracting baseline scores for each 
individual from his/her own scores. The 5-point change has been reported to represent “a little’ 
change in QLQ-C30 (Osoba et al, 1998; Cocks et al, 2012). It has been shown that this is a degree 
of change that is perceptible to patients (Osoba et al, 1998). A minimal change approach is being 
taken by using a 5-point decrement in physical functioning so that any perceptible change could 
be captured, but a more definite change may be a 10-point decrement. Indeed, Raman et al (2018) 
have reported asymmetries between improved and worsened states of physical functioning, with 
worsening requiring roughly a three-fold difference in numeric score compared with the improved 
state (see Table 8). 
Secondary QoL analyses will include analyses of the domains of the QLQ-C30 in which patients 
are categorised as either improved, stable, or worsened (Raman et al, 2018), as described in 
Table 8.  
Table 8 
QLQ-C30 domain minimal clinically important differences (MCIDs) 
Domain 
Improved 
Worsened 
Physical functioning 
≥5 
<-15 
Role functioning 
≥12 
<24 
Emotional functioning 
≥8 
<18 
Cognitive functioning 
≥5 
<14 
Social functioning 
≥8 
<20 
Fatigue 
<-13 
≥19 
Pain 
<9 
≥21 
Nausea & vomiting 
≥-4 
≥9 
Appetite 
<9 
≥19 
The domain specific minimal clinically important difference (MCID) changes will be used to 
classify patients as improved, stable, or worsened.  As an example, using Table 8, patients with 
≥5-point change in Physical Functioning will be classified as improved. If their score is between 
+5 and -15, then they will be classified as stable.  If their score has <-15 change, then they will be 
classified as worsening.   
The Pain domain of the QLQ-C30 will also be summarised relative to changes in analgesic use.  
Patients’ use of analgesics will be categorised into 2-categories (Increased or Stable) relative to 
their baseline use.  Change in actual pain medication will be defined as (Increased/Stable) where 
a change (increase) is defined as a doubling of the dose of the same medication OR a switch to a 
more potent medication. 
The EORTC QLQ-BIL21 is a validated disease-specific module for measuring QoL in patients 
with cholangiocarcinoma and cancer of the gallbladder that is designed to be used with EORTC 
QLQ-C30. The QLQ-BIL21 is self-administered and consists of 21 questions: 3 single-item 
assessments relating to treatment side-effects, difficulties with drainage bags/tubes, and concerns 


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regarding weight loss, in addition to 18 items grouped into 5 scales: eating symptoms (4 items), 
jaundice symptoms (3 items), tiredness (3 items), pain symptoms (4 items), and anxiety symptoms 
(4 items). Using an anchor-based approach, Kaupp-Roberts et al (2016) have reported meaningful 
changes in each of the domains of the QLQ-BIL21, as shown in Table 9. 
Table 9 
QLQ-BIL21 domain minimal clinically important differences (MCIDs) 
QLQ-BIL21 Domain 
Difference 
Eating 
18 
Jaundice 
7 
Tiredness 
22 
Pain 
15 
Anxiety 
14 
Treatment side effects 
16 
Drains 
18 
Weight loss 
1 
Analysis of QLQ-BIL21 will be carried out in a similar manner as QLQ-C30, using the domain 
specific MCIDs shown in Table 9. 
Perceived weight loss is an important indicator of patient well-being and is captured by the 
QLQ-BIL21.  Actual weight patient change from baseline will also be summarised with weight 
loss defined as a negative change from baseline of 5% or greater. 
13.6.2 EuroQoL Health Questionnaire Instrument (EQ-5D-5L) 
The EQ-5D-5L questionnaire will also be administered as a part of this study to assess 
health-related QoL. EQ-5D is an international, validated, standardised, generic questionnaire for 
describing and valuing health-related QoL (Rabin & de Charro, 2001). EQ-5D was developed by 
the EuroQol group in order to provide a simple, generic measure of health for clinical and 
economic appraisal. This instrument generates a preference-based health-state utility score 
(EQ-5D utility index) and an overall health state score based on a visual analogue scale (EQ-5D 
VAS). 
EQ-5D is designed for self-completion by respondents and is ideally suited for use in clinics and 
face to face interviews. It is cognitively undemanding, taking only a few minutes to complete. 
Instructions to respondents are included in the questionnaire. The most recent version of the 
EQ-5D is the EQ-5D-5L, which was developed to improve the instrument’s sensitivity and to 
reduce ceiling effects. The number of dimensions (mobility, self-care, usual activities, 
pain/discomfort, anxiety/depression) has not changed; however, the new version includes 5 levels 
of severity in each of the existing dimensions in place of three (EuroQol Group, 2015).  


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13.7 
Health Economics 
Health economics will be assessed through collection of core health resource use information, 
using CRFs to capture inpatient procedure codes, total number of days in hospital and outpatient 
visits. Data collected on concomitant medication will also be used in this economic analysis. For 
the economic modelling, costs will be imputed on the basis of representative country unit costs at 
the point of analysis using standard fee schedules. Health outcomes will be quantified using 
QALYs. Quality adjustments will be based on patients’ responses to the EQ-5D-5L health status 
measure which will be administered at baseline, before each cycle of therapy, and each point of 
follow up as part of the QoL questionnaire. Finally, a cost-utility analysis will be conducted by 
creating incremental cost-utility ratios for each of the treatment groups. 
13.8 
Pharmacokinetics 
13.8.1 Sparse Pharmacokinetic Sub-study 
Sparse PK sampling will be performed and individual exposure to NUC-1031 and dFdU will be 
estimated using a population PK model. Summary statistics of the observed concentrations will be 
reported. 
A detailed description of the planned PK analyses is provided in the separate PK analysis plan. 
13.9 
Safety Endpoints 
All safety analyses will be performed using all patients in the Safety population. No formal 
statistical comparison between the two treatments groups is planned. 
13.9.1 Adverse Events 
AEs will be coded using Medical Dictionary for Regulatory Activities (MedDRA) v20.0 (or 
higher), and will also be graded according to NCI CTCAE v5.0 (or higher). TEAEs will be defined 
as those AEs that either start after initiation of study medication (and up to 30 days after the last 
dose of study medication), or which are present at the time the time of starting study medication, 
but subsequently increase in severity.  
The overall incidences of TEAEs, CTCAE Grade 3 or higher TEAEs, SAEs, TEAEs leading to 
study medication discontinuation, TEAEs leading to reduction in dose of study medication, TEAEs 
leading to interruption of study medication, and TEAEs leading to death will be produced. The 
following additional summaries in terms of incidences and percentages will be provided: (i) 
TEAEs by system organ class and preferred term; (ii) CTCAE Grade 3 or higher TEAEs by 
preferred term; and (iii) SAEs by preferred term. Incidence tables will also be provided for TEAEs 
by severity (based on individual CTCAE grades), and TEAEs by relationship to study medication. 
Listings will be provided for SAEs, TEAEs leading to study medication discontinuation, TEAEs 
leading to reduction in dose of any study medication, and TEAEs leading to death. 
The overall incidence of patients with a confirmed case of COVID-19 will be derived and a 
corresponding listing will be provided. The overall incidence of patients discontinuing study 
treatment due to COVID-19 will also be derived and a corresponding listing will be provided. 
In addition, listings will be provided of those patients with any impact of COVID-19 on study 
treatment, on a study endpoint, or on the assessment of a study endpoint. This will include, but is 
not limited to: (i) patients delaying, interrupting, or discontinuing treatment due to the patient's 
confirmed or suspected COVID-19 infection; (ii) patients delaying, interrupting, or discontinuing 
treatment due to a COVID-19-related indirect reason; (iii) patients who missed or delayed one or 


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more (regularly scheduled  or confirmatory) radiographic scan due to the patient's confirmed or 
suspected COVID-19 infection; (iv) patients who missed or delayed one or more (regularly 
scheduled  or confirmatory) radiographic scan due to a COVID-19-related indirect reason; (v) 
patients taking a concomitant medication for a COVID-19 infection; and (vi) patients with a 
COVID-19 cause of death. 
13.9.2 Laboratory Test Results 
Laboratory results will be classified according to NCI CTCAE v5.0 (or higher). Incidence tables 
will be provided for laboratory parameters reported as TEAEs in which patient counts (and 
percentages) are given for each CTCAE grade separately (based on worst grade), for Grades 3-4 
combined (based on worst grade), and for Grades 1-4 combined. Shift tables from baseline to each 
scheduled study visit will be produced for each laboratory parameter using NCI CTCAE grade. 
Laboratory test results that are classified as clinically significant in the opinion of the Investigator 
will be summarised in terms of incidence, as well as provided in listing form. Full listings of all 
results for laboratory parameters will also be provided. 
13.9.3 Other Safety Endpoints 
Vital sign results that are classified as clinically significant in the opinion of the Investigator will 
be summarised in terms of incidence, as well as provided in listing form. Full listings of all results 
for vital sign parameters (blood pressure, heart rate, respiratory rate, and temperature) and body 
weight will also be provided.  
Incidence tables will be provided for each vital sign parameter reported as a TEAE in which patient 
counts (and percentages) are given for each CTCAE grade separately (based on worst grade), for 
Grades 3-4 combined (based on worst grade), and for Grades 1-4 combined. 
The vital signs test results will also be summarised by treatment group using descriptive statistics 
for actual values and for changes from baseline by scheduled visit. 
ECOG performance status (see Appendix 5), and physical examination findings by visit will each 
also be listed. 
The incidence of clinically significant changes in ECG parameters will be summarised. Shift tables 
based on the Investigator's overall ECG assessment (normal, abnormal not clinically significant, 
abnormal clinically significant) will also be provided. In addition, all ECG results will be provided 
in listing form. 
13.9.4 Exposure 
The following will be summarised for the Safety population by treatment group: number of 
infusions received, number of cycles received, number of infusions delayed, and number of 
infusions missed. This information will also be provided separately for the NUC-1031 or 
gemcitabine component and for the cisplatin component of treatment, where in addition the total 
dose given during the study and the relative dose intensity will also be summarised. 


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13.10 
Interim Analyses 
Three interim efficacy analyses are planned in addition to the final analysis. 
• The first interim analysis (Interim Analysis 1) will evaluate the ORR primary endpoint. It will 
be performed 28 weeks after 418 patients in the measurable disease stratum have been 
randomised. At this interim, a futility analysis will also be conducted for OS and it is estimated 
that approximately 258 deaths will be observed by this time. 
• The second interim analysis (Interim Analysis 2) will evaluate the ORR and OS primary 
endpoints. It will be the final analysis for ORR and the first interim analysis (for demonstration 
of efficacy) on OS. It will be performed 28 weeks after 644 patients in the measurable disease 
stratum have been randomised. It is estimated that approximately 425 deaths will be observed 
by this time. 
• The third interim analysis (Interim Analysis 3) will evaluate the OS primary endpoint for which 
it will be the second interim analysis (for demonstration of efficacy). It will take place after 
541 deaths have been observed. 
• The final analysis will evaluate the OS primary endpoint. It will take place after 637 deaths 
have been observed, and is expected to occur approximately 48.0 months after the first patient 
is randomised. 
PFS, the key secondary endpoint, will also be assessed at Interim Analysis 2 and approximately 
534 patients are expected to have a PFS event at this time.  
A summary of the planned analyses for demonstration of efficacy, with timings and primary 
endpoints to be evaluated, is given in Table 10. 
Table 10 
Analyses planned, primary endpoints evaluated, approximate timing, and 
drivers of timing 
Analysis 
Primary Endpoints 
Assessed for 
Demonstration of Efficacy 
Approximate 
Time 
(months) 
Driver of Timing 
Interim Analysis 1 
ORR 
~25.51,2 
NM28 = 418 patients 
Interim Analysis 2 
ORR, OS 
~33.11,2 
NM28 = 644 patients (~4251,3 
OS events expected at this 
time) 
Interim Analysis 3 
OS 
~40.01,3 
541 OS events 
Final Analysis 
OS 
~48.01,3 
637 OS events 


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NM28 = Number of patients randomised in the measurable disease stratum with the opportunity for ≥28 weeks of 
follow-up. 
1. Approximate times for all 4 looks and approximate number of OS events at Interim Analysis 2 assume a 
30-month duration of enrolment with gradual ramp-up (as described in the SAP) over the first 12 months, and a 
constant rate of enrolment for the next 18 months.  
2. Approximate times for the first 2 looks also assume that the percentage of patients with non-measurable disease 
at baseline is exactly 10%. 
3. Approximate times for the last 2 looks and the approximate number of OS events at Interim Analysis 2 further 
assume that:  
 
(i) 
OS events follow an exponential distribution with a 11.7-month median for the control arm (Arm 
 
 
B) as well as a median of 11.7/0.76 months in Arm A;  
 
(ii)  
The rate of discontinuation of treatment and the rate of discontinuation from the study (for Arm 
 
 
A and for Arm B) are both comparable to the rates seen in the gemcitabine plus cisplatin arm of 
 
 
ABC-02; and  
 
(iii) 
A total of 2% of patients will be lost to follow-up for OS. 
Note: PFS, the key secondary endpoint will also be assessed at Interim Analysis 2. 
 
If ORR crosses its efficacy boundary at Interim Analysis 1, and provided that a further assessment 
of ORR is not required by regulators, then the driver of timing for Interim Analysis 2 will instead 
be the occurrence of 425 OS events. 
13.10.1 Type 1 Error Control across the Interim Analyses and across the Multiple Endpoints 
The Maurer & Bretz method is used to provide strong control of Type 1 error across the two 
primary endpoints and the key secondary endpoint, as well as across the interim analyses (Maurer 
& Bretz, 2013). Figure 3 shows the initial one-sided α allocated to each of these three endpoints, 
and the arrows indicate how α is recycled between the endpoints. 
 
Figure 3 
Type 1 error recycling between the two primary endpoints and the key 
secondary endpoint 
 
Further details are provided below for each of the primary endpoints and for the key secondary 
endpoint. 
 


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ORR 
ORR will be tested using an overall α=0.005 one-sided initially. If the null hypothesis for OS is 
rejected (at Interim Analysis 2, Interim Analysis 3, or at the Final Analysis), then ORR can be 
tested using an overall α=0.017 one-sided. If, in addition, the null hypothesis for PFS is rejected 
(at Interim Analysis 2), then ORR can be tested using an overall α=0.025 one-sided. The 
Lan-DeMets O'Brien-Fleming-like α-spending function (Lan & DeMets, 1983) will be used to 
control the Type 1 error across the two looks for ORR, and Table 11 gives the bounds and 
boundary properties for ORR testing. 
If ORR has not already obtained statistical significance (using the overall α=0.005 one-sided) at 
either Interim Analysis 1 or Interim Analysis 2, then if the null hypothesis for OS is rejected (at 
Interim Analysis 2, Interim Analysis 3, or at the Final Analysis), but the null hypothesis for PFS 
is not rejected (at Interim Analysis 2), then the p-value for ORR at Interim Analysis 2 can be 
compared to the updated alpha value of 0.0160 one-sided (from the α=0.017 one-sided column in 
Table 11) to determine statistical significance for the ORR primary endpoint. However, if the null 
hypothesis for OS and the null hypothesis for PFS are both rejected, then the p-value for ORR at 
Interim Analysis 2 can be compared to the updated alpha value 0.0233 one-sided (from the α=0.025 
one-sided column in Table 11) to determine statistical significance for the ORR primary endpoint. 
Table 11, including the required critical values, will be updated using the actual numbers of 
patients (in the stratum corresponding to measurable disease at baseline who have the opportunity 
for ≥28 weeks of follow-up), if these differ from those given. 
Table 11 
Efficacy boundaries and properties for ORR 
Analysis 
Value 
α=0.005 (1-sided) α=0.017 (1-sided) α=0.025 (1-sided) 
Interim 
Analysis 1: 
65% 
 
NM28 = 4181 
 
 
Critical p-value (1-sided) 
0.0005 
0.0031 
0.0054 
Cumulative α (1-sided) 
0.0005 
0.0031 
0.0054 
Odds Ratio at boundary2
 
~2.11 
~1.88 
~1.80 
Difference in proportions at 
boundary2 
~14.1% 
~11.6% 
~10.7% 
Cumulative Power3 
29.6% 
50.7% 
58.3% 
Interim 
Analysis 2: 
100% 
 
NM28: 6441 
 
 
Critical p-value (1-sided) 
0.0048 
0.0160 
0.0233 
Cumulative α (1-sided) 
0.0050 
0.0170 
0.0250 
Odds Ratio at boundary2
 
~1.63 
~1.50 
~1.46 
Difference in proportions at 
boundary2 
~8.6% 
~7.1% 
~6.5% 
Cumulative Power3 
80.0% 
90.2% 
92.6% 
1. 
NM28 denotes the number of patients in the stratum corresponding to measurable disease at baseline who have the  
 
opportunity for ≥28 weeks of follow-up. 
2.  
The approximate odds ratio and approximate difference in proportions at the boundary assume that ORR=19% is 
observed in the control arm. 
3.  
The cumulative power is based on assumed true proportions of 31% vs. 19%. 
 


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OS 
OS will be tested using an overall α=0.020 one-sided. If the null hypothesis for ORR is rejected 
(at either Interim Analysis 1 or Interim Analysis 2), then OS can be tested using an overall α=0.025 
one-sided. The Lan-DeMets O'Brien-Fleming-like α-spending function (Lan & DeMets, 1983) is 
used to control the Type 1 error across the three looks for OS, and Table 12 gives the bounds and 
boundary properties for OS testing. 
Table 12, including the required critical values, will be updated using the actual number of OS 
events if these differ from the counts given. 
Table 12 
Efficacy boundaries and properties for OS 
Analysis 
Value 
α=0.020 
(1-sided) 
α=0.025 
(1-sided) 
Interim Analysis 2: 67% 
 
N ~ 828 
 
~ 425 OS events 
 
 
Z-statistic 
2.6198 
2.5082 
Critical p-value (1-sided) 
0.0044 
0.0061 
Cumulative α (1-sided) 
0.0044 
0.0061 
Hazard Ratio at boundary1 
~ 0.776 
~ 0.784 
Difference in medians at 
boundary (months)1,2 
~ 3.39 
~ 3.22 
Cumulative Power3 
58.3% 
62.6% 
Interim Analysis 3: 85% 
 
N = 828 
 
541 OS events 
 
 
Z-statistic 
2.3164 
2.2204 
Critical p-value (1-sided) 
0.0103 
0.0132 
Cumulative α (1-sided) 
0.0116 
0.0150 
Hazard Ratio at boundary1 
~ 0.819 
~ 0.826 
Difference in medians at 
boundary (months)1,2 
~ 2.58 
~ 2.46 
Cumulative Power3 
81.4% 
83.8% 
 Final Analysis: 100% 
 
 N = 828 
 
 637 OS events 
 
  
Z-statistic 
2.1366 
2.0490 
Critical p-value (1-sided) 
0.0163 
0.0202 
Cumulative α (1-sided) 
0.0200 
0.0250 
Hazard Ratio at boundary1 
~ 0.844 
~ 0.850 
Difference in medians at 
boundary (months)1,2 
~ 2.16 
~ 2.06 
Cumulative Power3 
90.9% 
92.2% 
1. 
The approximate hazard ratio and the approximate difference in medians at the boundary assumes proportional hazards. 
2.  
The approximate difference in medians at the boundary also assumes an 11.7 month observed control arm median. 
3.  
Cumulative power is based on an assumed true hazard ratio of 0.76. These power values allow for the possibility that 
 
the study could stop for futility at Interim Analysis 1. 
 


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PFS 
If the null hypothesis for ORR (at Interim Analysis 1 or Interim Analysis 2) and the null hypothesis 
for OS (at Interim Analysis 2, Interim Analysis 3, or at the Final Analysis) are both rejected using 
the Maurer & Bretz procedure then PFS can be tested at the α=0.025 one-sided significance level. 
However, if only the null hypothesis for OS is rejected then PFS can be tested at the α=0.008 
one-sided significance level.  
PFS will be analysed at Interim Analysis 2 only, at which point 534 patients are expected to have 
had a PFS event. This number of patients with a PFS event is based on a control median of 
7.6 months, a hazard ratio of 0.74, a 30-month duration of enrolment with gradual ramp-up (as 
described in the SAP) over the first 12 months, and a constant rate of enrolment for the next 
18 months. 
13.10.2 Interim Analysis for Futility 
At Interim Analysis 1, a futility analysis will take place based on the OS endpoint. A total of 
approximately 258 OS events are expected to have occurred, which represents approximately 41% 
of the required number (637) of OS events. The futility boundary is Z1 ≤ZFUT, where Z1 is derived 
from a log-rank test stratified by primary tumour location (gallbladder, intra-hepatic, 
extra-hepatic/ampullary) and extent of disease (locally advanced, metastatic), where ZFUT = 0.0. 
This boundary can be viewed as corresponding to an effect size favouring the control arm. 
Kaplan-Meier plots will be produced for OS at Interim Analysis 1 to determine if there is any 
evidence of delayed onset of efficacy. The IDMC will indicate whether or not they recommend 
stopping the trial for futility, and such a recommendation to stop for futility should be made only 
if the futility boundary is crossed and there is no indication of delayed onset of OS efficacy. 
The futility boundary is non-binding and so it is ignored in all calculations of Type 1 error. 
However, for OS power calculations the impact of the futility boundary is taken into account. 
The time of Interim Analysis 1 is based on ORR and the exact number of OS events may differ 
from 258. If the number of OS events at Interim Analysis 1 is ≤248 then ZFUT will be re-calculated 
using a method described in the SAP. 
13.11 
Sample Size and Power Calculation 
For OS a hazard ratio of 0.76 has been assumed. With 3 looks (at 67%, 85%, and 100% of the 
required number of OS events as described in Table 12), use of the Lan-DeMets O'Brien-Fleming-
like α-spending function (Lan & DeMets, 1983), an overall α=0.020 one-sided, and 1:1 
randomisation, then a total of 637 OS events gives 90.9% power (after allowing for the small 
power loss from having the futility boundary). Initially, α=0.020 one-sided is assigned to OS and 
α=0.005 one-sided is assigned to ORR. 
A thirty-month duration of enrolment is assumed with gradual ramp-up over the first 12 months 
(as described in the SAP). OS events are assumed to follow an exponential distribution, and a 
11.7 month median has been assumed for the control arm as seen in the gemcitabine in 
combination with cisplatin arm in the ABC-02 trial (Valle et al, 2010). The hazard ratio of 0.76 
then gives a median of approximately 15.4 months in the NUC-1031 in combination with cisplatin 
arm (Arm A). If the rate of discontinuation of treatment and the rate of discontinuation from the 
study (for Arm A and for Arm B) are both assumed to be comparable to the gemcitabine in 
combination with cisplatin arm from ABC-02, then 811 patients would result in the last of the 
637 events occurring at approximately 48 months. It is also assumed that 2% of patients will be 


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lost to follow-up for OS (with unknown status of dead/alive) and so 828 patients will be 
randomised. 
If the study has not stopped with demonstration of efficacy then a power reassessment will be 
carried out at Interim Analysis 3, which is scheduled to occur after 541 OS events. This power 
reassessment will use the CHW method (Cui et al, 1999), which guarantees that the maximum 
experimentwise Type 1 error will still be controlled at the required level. The SAP provides 
additional details on the procedure that will be used to implement the CHW method, including 
details on the maximum increase in number of OS events. 
For ORR, a 19% rate is assumed for the control arm. The derivation of this rate from the 
gemcitabine in combination with cisplatin arms within ABC-02, BT-22, and ABC-03 studies 
(allowing now for the requirement of confirmation, based on patients with performance status 0 or 
1 only, including all randomised patients in the denominator, excluding patients with 
non-measurable disease at baseline, and adjusting for use of BICR rather than Investigator 
assessment) is provided in Appendix 1 of the SAP. For the NUC-1031 in combination with 
cisplatin arm (Arm A) a 31% ORR is assumed, which gives an assumed true odds ratio of 1.92. 
With 2 looks for ORR (at 65% and 100% as described in Table 11), use of the Lan-DeMets 
O'Brien-Fleming-like α-spending function (Lan & DeMets, 1983), and with an overall α=0.005 
one-sided, then a total of 644 patients with measurable disease at baseline (together with 418 at 
the interim analysis) gives 80% power. The two looks will take place 28 weeks (corresponding to 
three scheduled post-baseline radiographic scans plus a one week visit window) after the last of 
these required numbers of patients have been randomised. The number of randomised patients in 
the stratum for non-measurable disease at baseline is capped at 82 patients (~10%), which therefore 
gives at least 746 randomised patients in the measurable disease at baseline stratum. 
13.12 
Subgroup Analyses 
For OS, numbers of events by treatment group, together with hazard ratios (derived from an 
unstratified Cox proportional hazards model with a single term for treatment within the model) 
will be provided separately for each of the following subgroups: 
• Primary tumour site: gallbladder, intra-hepatic, extra-hepatic, ampullary 
• Stage of disease at baseline: metastatic disease, locally advanced disease 
• ECOG Performance Status (at baseline): 0, 1 
• Region: Asia, Non-Asia (with non-Asia also subdivided and provided separately for North 
America/Western Europe/Australasia combined, and for Central/Eastern Europe/Rest of the 
World combined) 
• Gender: Male, Female 
• Age (at baseline): <65, ≥65 
• Measurable disease at baseline: yes, no 
For ORR, analyses in terms of estimates (of ORR, as well as counts for CR and for PR) by 
treatment group, together with odds ratios, difference in proportions of patients with ORR will be 
given for each of the following subgroups: 
• Primary tumour site: gallbladder, intra-hepatic, extra-hepatic, ampullary 


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• Stage of disease at baseline: metastatic disease, locally advanced disease 
For OS as well as for ORR, the statistical methods to derive CIs for the individual subgroups are 
provided within the SAP. 
Additional power calculations are provided in the SAP for subgroup analyses. 
13.13 
Changes to the Planned Statistical Methods 
Any changes to the planned statistical methods from those specified in the final SAP will be 
documented in the clinical study report (CSR). 
14 PATIENT DATA HANDLING AND CONFIDENTIALITY 
14.1 
Case Report Forms 
As part of the responsibilities assumed by participating in the study, the Investigator or 
Sub-Investigator agrees to maintain adequate case histories for the patients enrolled as part of the 
research under this protocol. The Investigator agrees to maintain accurate CRFs and source 
documentation as part of the case histories. These source documents include, but are not limited 
to, laboratory reports and objective disease assessment scans. 
An eCRF will be used, please refer to the CRF Completion Guidelines for further information. 
The Investigator must review each completed eCRF in a timely manner. The Investigator will be 
required to review and electronically sign and date the CRFs once the patient’s data is complete. 
14.2 
Monitoring of the Study 
Monitoring and auditing procedures developed by NuCana or designee will be followed, in order 
to comply with ICH-GCP guidelines. Before a study centre can enter a patient into the study, a 
representative of NuCana or designee will visit the study centre to: 
• Determine the adequacy of the facilities 
• Discuss with the Investigator(s) and other personnel their responsibilities with regard to 
protocol adherence, and the responsibilities of NuCana or its representatives. This will be 
documented in a Clinical Study Agreement between NuCana and the Investigator. 
During the study, representatives from NuCana and/or its designee will have regular contacts with 
the study centre, for the following: 
• Provide information and support to the Investigators 
• Confirm that facilities remain acceptable 
• Confirm that the investigational team is adhering to the protocol, that data are being accurately 
recorded in the source documents and eCRFs, and that drug accountability checks are being 
performed 
• Perform source data verification. This includes a comparison of the data in the eCRFs with the 
patient’s medical records at the hospital or practice, and other records relevant to the study. 
This will require direct access to all original records for each patient (e.g., charts or records) 
• Record and report protocol deviations 
• Confirm AEs and SAEs have been identified and properly documented in the eCRFs and 
confirm any SAEs have been forwarded to NuCana or designee, and those SAEs that met 
criteria for reporting have been forwarded to the IRB/EC. 


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The monitor will be available between visits if the Investigator or other staff needs information or 
advice. Note, during the COVID-19 pandemic, remote visits may replace on-site visits for as short 
a period of time as possible. 
14.3 
Patient Confidentiality 
Personal data recorded on all documents will be regarded as highly confidential. To preserve each 
patient’s anonymity, only the patient study number, initials and date of birth, as appropriate to 
country regulations, will be recorded on the eCRFs. 
The Investigative site must maintain the patient’s anonymity in all communications and reports 
related to the research. The Investigator site team must keep a separate log of enrolled patients’ 
personal identification details as necessary to enable them to be tracked. These documents must 
be retained securely, in strict confidence. They form part of the Investigator Site File and are not 
to be released externally. 
15 ETHICAL, REGULATORY AND RISK CONSIDERATIONS 
15.1 
Good Clinical Practice Compliance 
NuCana, designees, Investigators, and any third party to whom aspects of the study management 
or monitoring have been delegated will undertake their assigned roles for this study in compliance 
with ICH-GCP, US 21 Code of Federal Regulations (CFR) 11, 21 CFR 50, 21 CFR 54, 
21 CFR 56, 21 CFR 312 and all other applicable regulations. 
15.2 
Institutional Review Boards/ Ethics Committees 
The applicable IRBs/ECs will review all appropriate study documentation in order to safeguard 
the rights, safety, and wellbeing of the patients. 
The final study protocol and ICF must be approved in writing by the applicable IRBs/ECs for each 
site. Written IRB/EC approval must be received by the appointed CRO before a study centre can 
enrol any patients into the study. In addition, the IRB/EC must approve all advertising used to 
recruit patients for the study. 
In some countries, the protocol (and associated documents, including amendments) must be 
re-approved by the IRB/ECs annually, as local regulations require. Progress reports will be 
provided to the IRB/EC according to local regulations and guidelines. 
15.3 
Regulatory Authority Approval 
Authorisation to conduct the study will be obtained from the applicable Regulatory Authorities 
prior to initiating the study in each participating country. 
15.4 
Risk Management Considerations 
This study will enrol patients with advanced or metastatic BTC, a disease for which there are 
currently no approved therapies. Given the limited treatment options and poor prognosis, this 
patient population is considered appropriate for enrolment to a Phase III study of chemotherapy 
combination treatment. The sites that have been selected for participation in this study have 
experience in treating this patient population and in conducting Phase III clinical studies.  
As described in Section 3.2, the dose and schedule of NUC-1031 has been appropriately 
determined from the ongoing ABC-08 study, in which the combination of NUC-1031 and cisplatin 
has been well-tolerated in patients with advanced or metastatic BTC.  


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To ensure patient safety, the IDMC will review the safety, dosing intensity and clinical activity 
data during the study. As described in Section 12.16, an initial safety check will be performed after 
the first 50 patients have been randomised (approximately 25 in each treatment group) and a futility 
analysis will be performed after approximately 258 OS events have occurred to ensure patients are 
not exposed to sub-optimal therapies. In addition, dose modification criteria and suggested 
management procedures for drug-related toxicities are provided in Section 9. 
ECGs are being routinely monitored throughout the study for any acute cardiac effects (see 
Summary Schedule of Events). As outlined in Section 3.5, a robust QT analysis is being conducted 
as part of a sub-study in 74 patients (approximately 37 each arm) to assess any potential effect of 
the NUC-1031 + cisplatin combination on the QT interval. 
Patient safety will be monitored closely on an ongoing basis through recording and reporting of 
AEs, routine laboratory tests, and physical examination/vital signs monitoring. Procedures for 
safety reporting are clearly outlined in Section 12 and post-study follow-up of patients is described 
in Section 4.4.  
15.5 
Protocol Amendments 
All protocol amendments (and amendments to related study documentation) will be approved, in 
line with local regulations, by the applicable IRBs/ECs and Regulatory Authorities prior to 
implementation.  
15.6 
Protocol Deviations 
The Investigator, or designee, must document and explain in the patient’s source documentation 
any deviation from the approved protocol. 
A deviation from the protocol is an unintended and/or unanticipated departure from the procedures 
and/or processes approved by NuCana and the IRB/EC and agreed to by the Investigator or 
Sub-Investigator. Deviations usually have an impact on individual patients or a small group of 
patients and do not involve inclusion/exclusion or primary endpoint criteria. Deviations will be 
tracked by the CRO along with the corrective and preventative actions by responsible party.  
A major protocol deviation (sometimes referred to as a protocol violation) occurs when there is 
nonadherence to the protocol that results in a significant, additional risk to the patient, when the 
patient has failed to adhere to significant protocol requirements, or when there is nonadherence to 
the FDA or other applicable ICH-GCP guidelines. 
The clinical monitor will document protocol deviations throughout the course of monitoring visits. 
The monitor will notify the Investigators during a visit and in writing of all deviations. The IRB/EC 
should be notified of all protocol deviations in a timely manner. 
15.7 
Serious Breaches 
A serious breach is defined as a breach of ICH-GCP or the study protocol which is likely to effect 
to a significant degree the:  
• Safety or physical or mental integrity of the patients of the study; or 
• Scientific value of the study 
Investigators will notify NuCana or its designee within one working day if any serious breach of 
ICH-GCP or the protocol is suspected. Upon confirmation of a serious breach, NuCana or its 
designee will notify the applicable Regulatory Authorities. Typically, serious breach notifications 


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should be made within seven days of NuCana or its designee becoming aware; however, this 
timeline may differ as specified by applicable local regulatory requirements. 
15.8 
Study Reporting Requirements 
The Investigator agrees to submit progress reports to their IRB/EC as appropriate. The Investigator 
also agrees to provide NuCana with an adequate report shortly after completion of their 
participation in the study. 
15.9 
Financial Disclosure 
The Investigators and Sub-Investigators are required to provide financial disclosure information 
to allow NuCana to submit the complete and accurate certification or disclosure statements 
required under 21 CFR 54. In addition, the Investigator and Sub-Investigators must provide 
NuCana with a commitment to update this information promptly if any relevant changes occur 
during the course of the investigation and for one year after study completion. 
Neither NuCana nor the designated CRO is financially responsible for further testing and/or 
treatment of any medical condition, which may be detected during the screening process. In 
addition, in the absence of specific arrangements, neither NuCana nor the designated CRO is 
financially responsible for further treatment of the patient’s disease. 
15.10 
Investigator Documentation 
Before beginning the study, each investigative site will have all applicable essential documents 
available, in accordance with ICH-GCP section 8.2. 
15.11 
Study Records Retention 
Essential documents should be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing applications 
in an ICH region, or at least 2 years have elapsed since the formal discontinuation of NUC-1031 
clinical development. These documents should be retained for a longer period, however, if required 
by the applicable regulatory requirements or by an agreement with NuCana. It is the responsibility 
of NuCana to inform the Investigator or Sub-Investigator or institution as to when these documents 
no longer need to be retained. 
If the Investigator becomes unable for any reason to continue to retain study records for the 
required period, NuCana should be prospectively notified. The study records must be transferred 
to a designee acceptable to NuCana, such as another Investigator, another institution, or to an 
independent third party arranged by NuCana. The Investigator must obtain written permission 
from NuCana before disposing of any records, even if retention requirements have been met. 
Retention and storage of central laboratory records supporting PK and ECG endpoints and the 
disposition of samples donated via the study must also comply with applicable legislation. 
15.12 
Audit and Regulatory Inspection 
The Investigator, Sub-Investigators, and institutions involved in the study will permit study-related 
monitoring, audits, IRB/EC review, and regulatory inspection(s) by providing direct access to all 
study records. In the event of an audit, the Investigator or Sub-Investigator agrees to allow NuCana, 
representatives of NuCana, the FDA, or other regulatory agency access to all study records. 
The Investigator should promptly notify NuCana and the designated CRO of any audits scheduled 
by any regulatory authorities and promptly forward copies of any audit reports received to NuCana.  


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16 PUBLICATION POLICY 
An ICH E3-compliant CSR will be generated based on the final data listings of this study. The 
final CSR will be submitted to Regulatory Authorities and IRBs/ECs in accordance with the 
stipulated timelines. 
16.1 
Communication of Results by NuCana 
NuCana shall publicly disclose study results. Mechanisms for publicly disclosing study results 
include posting on ClinicalTrials.gov, the European Clinical Trials Database (EudraCT) and/or 
other applicable public registries in accordance with local laws and regulations. 
Final study results will be submitted to ClinicalTrials.gov within one year of the primary 
completion date, which is defined as ‘the date that the final patient was examined or received an 
intervention for the purposes of final collection of data for the primary outcome, whether the 
clinical study concluded according to the pre-specified protocol or was terminated’. Final study 
results will be posted to EudraCT within one year of the end of study date, as defined in this 
protocol. 
16.2 
Publication  
Investigators may not publish or disclose results until the study is completed. In addition, 
Investigators shall acknowledge that, due to the limited patient numbers in their individual group, 
the data generated from their individual participation in the study and evaluation of individual 
results, may not be sufficient from which to draw any meaningful scientific conclusion. 
Authorship rights will generally be allocated to Investigators in order of greatest contribution of 
evaluable patients to the study. NuCana may form a publication committee to evaluate and give 
approval of any submission for publication or presentation. 
The proposed publication (manuscript, abstract or poster) or presentation will be provided to 
NuCana by the Investigator for review and comment at least 60 days prior to the planned 
submission. The Investigator understands and agrees that participation in the study may involve a 
commitment to publish the study results in a cooperative publication with other Investigators. No 
publication of confidential information shall be made without NuCana’s prior written approval. 
The Investigator agrees, upon NuCana’s request, to delete any confidential information that may 
impact intellectual property protection from the proposed publication. 
Investigators will comply with recognised ethical publications and authorship standards, including 
Section II of the ‘Recommendations for the conduct, reporting, editing, and publication of 
scholarly work in medical journals’ (ICMJE, 2018). 


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18 APPENDICES 
Appendix 1: EORTC QLQ-C30 with QLQ-BIL21 Module 
 


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Appendix 2: EQ-5D-5 Questionnaire 
 
 


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Appendix 3: Concomitant medications that may prolong QTc interval 
Medications with a known risk of torsade de pointes (i.e., significant evidence they cause QT 
prolongation and are associated with a risk of causing torsade de pointes) are listed below. 
Appendix 3. Table 1. Drugs known to prolong QT/QTc interval 
Generic Name 
Brand Names (Partial List) 
Aclarubicin (only on non-US market) 
Aclacin®, Aclacinomycine®, Aclacinon®, Aclaplastin®, 
Jaclacin® 
Amiodarone 
Cordarone®, Pacerone®, Nexterone® 
Anagrelide 
Agrylin®, Xagrid® 
Arsenic trioxide 
Trisenox® 
Astemizole (removed from US 
market) 
Hismanal® 
Azithromycin 
Zithromax®, Zmax® 
Bepridil (removed from US market) 
Vascor® 
Chloroquine 
Aralen® 
Chlorpromazine 
Thorazine®, Largactil®, Megaphen® 
Chlorprothixene 
Truxal® 
Cilostazol 
Pletal® 
Ciprofloxacin 
Cipro®, Cipro-XR®, Neofloxin® 
Cisapride (removed from US market) 
Propulsid® 
Citalopram 
Celexa®, Cipramil® 
Clarithromycin 
Biaxin®, Prevpac® 
Cocaine 
Cocaine 
Disopyramide 
Norpace® 
Dofetilide 
Tikosyn® 
Domperidone (only on non-US 
market) 
Motilium®, Motillium®, Motinorm Costi®, Nomit® 
Donepezil 
Aricept® 
Dronedarone 
Multaq® 
Droperidol 
Inapsine®, Droleptan®, Dridol®, Xomolix® 
Erythromycin 
E.E.S.®, Robimycin®, EMycin®, Erymax®, Ery-Tab®, Eryc 
Ranbaxy®, Erypar®, Eryped®, Erythrocin Stearate Filmtab®, 
Erythrocot®, E-Base®, Erythroped®, Ilosone®, MY-E®, 
Pediamycin®, Zineryt®, Abboticin®, Abboticin-ES®, Erycin®, 
PCE Dispertab®, Stiemycine®, Acnasol®, Tiloryth® 
Escitalopram 
Cipralex®, Lexapro®, Nexito®, Anxiset-E® (India), Exodus® 
(Brazil), Esto® (Israel), Seroplex®, Elicea®, Lexamil®, Lexam®, 
Entact® (Greece), Losita® (Bangladesh), Reposil® (Chile), 
Animaxen® (Colombia), Esitalo® (Australia), Lexamil® (South 
Africa) 
Flecainide 
Tambocor®, Almarytm®, Apocard®, Ecrinal®, Flécaine® 
Fluconazole 
Diflucan®, Trican® 


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Generic Name 
Brand Names (Partial List) 
Gatifloxacin (removed from US 
market) 
Tequin® 
Grepafloxacin (removed from US 
market) 
Raxar® 
Halofantrine (only on non-US 
market) 
Halfan® 
Haloperidol 
Haldol® (US & UK), Aloperidin®, Bioperidolo®, Brotopon®, 
Dozic®, Duraperidol® (Germany), Einalon S®, Eukystol®, 
Halosten®, Keselan®, Linton®, Peluces®, Serenace®, Serenase®, 
Sigaperidol® 
Hydroquinidine (Dihydroquinidine) 
(only on non-US market) 
Serecor 
Hydroxychloroquine 
Plaquenil®, Quineprox® 
Ibogaine (only on non-US market) 
None 
Ibutilide 
Corvert® 
Levofloxacin 
Levaquin®, Tavanic® 
Levomepromazine 
(Methotrimeprazine) (only on non-
US market) 
Nosinan®, Nozinan®, Levoprome® 
Levomethadyl acetate (removed from 
US market) 
Orlaam® 
Levosulpiride (only on non-US 
market) 
Lesuride®, Levazeo®, Enliva® (with rabeprazole) 
Mesoridazine (removed from US 
market) 
Serentil® 
Methadone 
Dolophine®, Symoron®, Amidone®, Methadose®, Physeptone®, 
Heptadon® 
Moxifloxacin 
Avelox®, Avalox®, Avelon® 
Nifekalant (only on non-US market) 
Shinbit® 
Ondansetron 
Zofran®, Anset®, Ondemet®, Zuplenz®, Emetron®, Ondavell®, 
Emeset®, Ondisolv®, Setronax® 
Oxaliplatin 
Eloxatin® 
Papaverine HCl 
None 
Pentamidine 
Pentam® 
Pimozide 
Orap® 
Probucol (removed from US market) 
Lorelco® 
Procainamide 
Pronestyl®, Procan® 
Propofol 
Diprivan®, Propoven® 
Quinidine 
Quinaglute®, Duraquin®, Quinact®, Quinidex®, Cin-Quin®, 
Quinora® 
Roxithromycin (only on non-US 
market) 
Rulide®, Xthrocin®, Roxl-150®, Roxo®, Surlid®, Rulide®, 
Biaxsig®, Roxar®, Roximycinv®, Roxomycin®, Rulid®, 
Tirabicin®, Coroxin®  
Sevoflurane 
Ulane®, Sojourn® 
Sotalol 
Betapace®, Sotalex®, Sotacor® 


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Generic Name 
Brand Names (Partial List) 
Sparfloxacin (removed from US 
market) 
Zagam® 
Sulpiride (only on non-US market) 
Dogmatil®, Dolmatil®, Eglonyl®, Espiride®, Modal®, Sulpor® 
Sultopride (only on Non-US market) 
Barnetil®, Barnotil®, Topral® 
Terfenadine (removed from US 
market) 
Seldane® 
Terlipressin (only on non-US market) Teripress®, Glypressin®, Terlipin®, Remestyp®, Tresil®, 
Teriss® and others  
Terodiline (only on non-US market) 
Micturin®, Mictrol® (not bethanechol) 
Thioridazine 
Mellaril®, Novoridazine®, Thioril® 
Vandetanib 
Caprelsa® 
If clinically relevant or urgent medical intervention is required with a drug known to prolong the 
QT/QTc interval, study treatment must be paused and options for re-starting the study drugs 
should be discussed with the Medical Monitor.
Note: Medicines on the above list are reviewed on an ongoing basis to assure that the available 
evidence supports their continued placement on this list. The list changes regularly and we 
recommend checking the website at crediblemeds.org for the most up-to-date information. There 
may be many additional brand names that are not listed on this table.  
Disclaimer and Waiver: The information presented is intended solely for the purpose 
of providing general information about health-related matters. It is not intended for any other 
purpose, including but not limited to medical advice and/or treatment, nor is it intended to 
substitute for the users’ relationships with their own health care providers. To that extent, by use 
of this website and the information it contains, the user affirms the understanding of the 
purpose and releases AZCERT, Inc. from any claims arising out of his/her use of the website 
and its lists. The absence of drugs from these lists should not be considered an indication that 
they are free of risk of QT prolongation or torsades de pointes. Many medicines have not been 
tested for this risk in patients, especially those with congenital long QT syndrome. 
Woosley, RL and Romero, KA, www.Crediblemeds.org, QT drugs List, AZCERT, Inc. 
1822 Innovation Park Dr., Oro Valley, AZ 85755, USA.  
https://www.crediblemeds.org/#sthash.vzyRSgay.dpuf. Accessed 11 October 2020. 


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Appendix 4: Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 
The following paragraphs provide a detailed description of the implementation of RECIST criteria 
(v1.1; Eisenhauer et al, 2009), with slight modifications and additional clarifying text to highlight 
what is required for this study.  
 
MEASURABILITY OF TUMOUR AT BASELINE DEFINITIONS 
At baseline, tumour lesions/lymph nodes will be categorised measurable or non-measurable as 
follows. 
a. 
Measurable Tumour Lesions 
Tumour Lesions. Tumour lesions must be accurately measured in at least one dimension (longest 
diameter in the plane of measurement is to be recorded) with a minimum size of: 
• 10 mm by computed tomography (CT) or magnetic resolution imaging (MRI) scan (CT/MRI 
scan slice thickness/interval no greater than 5 mm) 
• 10-mm caliper measurement by clinical examination (lesions that cannot be accurately 
measured with calipers should be recorded as non-measurable) 
 
Malignant Lymph Nodes. To be considered pathologically enlarged and measurable, a lymph 
node must be ≥15 mm in the short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis will 
be measured and followed. See also notes below on “Baseline Documentation of Target and Non-
Target Lesions” for information on lymph node measurement. 
 
b. 
Non-Measurable Tumour Lesions 
Non-measurable tumour lesions encompass small lesions (longest diameter <10 mm or 
pathological lymph nodes with ≥10 to <15 mm short axis), as well as trulynon-measurable lesions. 
Lesions considered truly non-measurable include leptomeningeal disease, ascites, pleural or 
pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, 
peritoneal spread, and abdominal masses/abdominal organomegaly identified by physical 
examination that is not measurable by reproducible imaging techniques. 
 
c. 
Special Considerations Regarding Lesion Measurability 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require particular 
comment, as outlined below. 
Bone lesions: 
• Bone scan, positron emission tomography (PET) scan, or plain films are not considered 
adequate imaging techniques to measure bone lesions. However, these techniques can be used 
to confirm the presence or disappearance of bone lesions 
• Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, that 
can be evaluated by cross-sectional imaging techniques such as CT or MRI can be considered 


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measurable lesions if the soft tissue component meets the definition of measurability described 
above 
• Blastic bone lesions are non-measurable 
Cystic lesions: 
• Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts 
• Cystic lesions thought to represent cystic metastases can be considered measurable lesions if 
they meet the definition of measurability described above. However, if non-cystic lesions are 
present in the same patient, these are preferred for selection as target lesions 
Lesions with prior local treatment: 
• 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. 
 
TARGET LESIONS: SPECIFICATIONS BY METHODS OF MEASUREMENTS 
a. 
Measurement of Lesions 
All measurements should be recorded in metric notation, using calipers if clinically assessed. All 
baseline evaluations should be performed as close as possible to the treatment start and never more 
than 21 days before the beginning of the treatment. 
b. 
Method of Assessment 
The same method of assessment and the same technique should be used to characterise each 
identified and reported lesion at baseline and during study. Imaging-based evaluation (CT scan, 
MRI, or PET-CT) should always be used in this study. 
Clinical Lesions. Clinical lesions will be considered measurable only when they are superficial 
and ≥10 mm in diameter as assessed using calipers (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 
suggested. 
Chest X-Ray. Chest X-ray should not be used in assessment of lesion size or for detecting new 
lesions. If, however, a new lesion is detected by X-ray then it should be confirmed by CT scan, 
MRI, or PET-CT. 
CT, MRI, PET-CT. 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 
on the basis of 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 and PET-CT are also acceptable. 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). 
If prior to enrolment it is known that a patient is unable to undergo CT scans with IV contrast 
because of allergy or renal insufficiency, the decision as to whether a non-contrast CT scan or MRI 


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scan (without IV contrast) will be used to evaluate the patient at baseline and during the study 
should be guided by the tumour type under investigation and the anatomic location of the disease. 
For patients who develop contraindications to contrast after a baseline contrast CT scan is done, 
the decision as to whether non-contrast CT or MRI (enhanced or non-enhanced) scan will be 
performed should also be based on the tumour type and the anatomic location of the disease and 
should be optimised to allow for comparison with the prior studies if possible. 
Each case should be discussed with the radiologist to determine if substitution of these other 
approaches is possible and, if not, the patient should be considered not evaluable from that point 
forward. Care must be taken in measurement of target lesions on a different modality and 
interpretation of non-target disease or new lesions since the same lesion may appear to have a 
different size using a new modality. 
Ultrasound. Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement. 
Endoscopy, Laparoscopy, Tumour Markers, Cytology, Histology. The utilisation of these 
techniques for objective tumour evaluation cannot generally be advised. 
 
TUMOUR RESPONSE EVALUATION 
ASSESSMENT OF OVERALL TUMOUR BURDEN AND MEASURABLE DISEASE 
To assess objective response or future progression, it is necessary to estimate the overall tumour 
burden at baseline and to use this as a comparator for subsequent measurements. Measurable 
disease is defined by the presence of at least one measurable lesion, as detailed above. 
BASELINE DOCUMENTATION OF TARGET AND NON-TARGET LESIONS 
When more than one measurable lesion is present at baseline, all lesions up to a maximum of five 
lesions total (and a maximum of two lesions per organ) representative of all involved organs should 
be identified as target lesions and will be recorded and measured at baseline. This means in 
instances where patients have only one or two organ sites involved, a maximum of two lesions 
(one site) and four lesions (two sites), respectively, will be recorded. Other lesions (albeit 
measurable) in those organs will be recorded as non-target lesions (even if the size is >10 mm by 
CT, MRI, or PET-CT scan). 
Target lesions should be selected on the basis of their size (lesions with the longest diameter) and 
be representative of all involved organs but, additionally, should lend themselves to reproducible 
repeated measurements. It may be the case that, on occasion, the largest lesion does not lend itself 
to reproducible measurement, in which circumstance the next largest lesion that can be measured 
reproducibly should be selected. 
Lymph nodes merit special mention since they are normal anatomical structures that may be visible 
by imaging even if not involved by tumour. As noted above, pathological nodes that are defined 
as measurable and may be identified as target lesions must meet the criterion of a short axis of ≥15 
mm by CT scan. Only the short axis of these nodes will contribute to the baseline sum. The short 
axis of the node is the diameter normally used by radiologists to judge if a node is involved by 
solid tumour. Nodal size is normally reported as two dimensions in the plane in which the image 
is obtained (for CT scan, this is almost always the axial plane; for MRI scan the plane of acquisition 
may be axial, sagittal, or coronal). The smaller of these measures is the short axis. For example, 


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an abdominal node that is reported as being 20 mm x 30 mm has a short axis of 20 mm and qualifies 
as a malignant, measurable node. In this example, 20 mm should be recorded as the node 
measurement. All other pathological nodes (those with short axis ≥10 mm but <15 mm) should be 
considered non-target lesions. Nodes that have a short axis <10 mm are considered 
non-pathological and should not be recorded or followed. 
Lesions irradiated within 3 weeks prior to Cycle 1 Day 1 may not be counted as target lesions. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum of diameters. If lymph nodes are to be 
included in the sum, then, as noted above, only the short axis is added into the sum. The baseline 
sum of diameters will be used as a reference to further characterise any objective tumour regression 
in the measurable dimension of the disease. 
All other lesions (or sites of disease), including pathological lymph nodes, should be identified as 
non-target lesions and should also be recorded at baseline. Measurements are not required and 
these lesions should be followed as “present,” “absent,” or in rare cases “unequivocal progression.” 
In addition, it is possible to record multiple non-target lesions involving the same organ as a single 
item on the CRF (e.g., “multiple enlarged pelvic lymph nodes” or “multiple liver metastases”). 
 
RESPONSE CRITERIA 
a. 
Evaluation of Target Lesions 
This section provides the definitions of the criteria used to determine objective tumour response 
for target lesions. 
• Complete response (CR): disappearance of all target lesions 
o Any pathological lymph nodes (whether target or non-target) must have reduction 
in short axis to <10 mm 
• Partial response (PR): at least a 30% decrease in the sum of diameters of target lesions, 
taking as reference the baseline sum of diameters 
• Progressive disease (PD): at least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (nadir), including baseline 
o In addition to the relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm 
o The appearance of one or more new lesions is also considered progression. 
• Stable disease (SD): neither sufficient shrinkage (compared to baseline) to qualify for PR 
nor sufficient increase (taking as reference the smallest sum of diameters while on study) 
to qualify for PD 
 
b. 
Special Notes on the Assessment of Target Lesions 
Lymph Nodes. Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded (measured in the same anatomical plane as the baseline examination), even 
if the nodes regress to <10 mm on study. This means that when lymph nodes are included as target 
lesions, the sum of lesions may not be zero even if CR criteria are met since a normal lymph node 
is defined as having a short axis <10 mm. 


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Target Lesions That Become Too Small to Measure. While on study, all lesions (nodal and 
non-nodal) recorded at baseline should have their actual measurements recorded at each 
subsequent evaluation, even when very small (e.g., 2 mm). However, sometimes lesions or lymph 
nodes that are recorded as target lesions at baseline become so faint on CT scan that the radiologist 
may not feel comfortable assigning an exact measure and may report them as being too small to 
measure.  
When this occurs, it is important that a value be recorded on the CRF as follows: 
 
• 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 and BML (below measurable limit) should be ticked. 
(Note: It is less likely that this rule will be used for lymph nodes since they usually have a 
definable size when normal and are frequently surrounded by fat such as in the 
retroperitoneum; however, if a lymph node is believed to be present and is faintly seen but 
too small to measure, a default value of 5 mm should be assigned in this circumstance as 
well and BML should also be ticked). 
 
To reiterate, however, if the radiologist is able to provide an actual measure, that should be 
recorded, even if it is below 5 mm, and, in that case, BML should not be ticked. 
Lesions That Split or Coalesce on Treatment. When non-nodal lesions fragment, the longest 
diameters of the fragmented portions should be added together to calculate the target lesion sum. 
Similarly, as lesions coalesce, a plane between them may be maintained that would aid in obtaining 
maximal diameter measurements of each individual lesion. If the lesions have truly coalesced such 
that they are no longer separable, the vector of the longest diameter in this instance should be the 
maximal longest diameter for the coalesced lesion. 
 
c. 
Evaluation of Non-Target Lesions 
This section provides the definitions of the criteria used to determine the tumour response for the 
group of non-target lesions. Although some non-target lesions may actually be measurable, they 
need not be measured and, instead, should be assessed only qualitatively at the timepoints specified 
in the protocol. 
• CR: disappearance of all non-target lesions  
o All lymph nodes must be non-pathological in size (<10 mm short axis) 
• Non-CR/Non-PD: persistence of one or more non-target lesion(s)  
• PD: unequivocal progression of existing non-target lesions 
o The appearance of one or more new lesions is also considered progression 
 
d. 
Special Notes on Assessment of Progression of Non-Target Disease 
When the Patient Also Has Measurable Disease. In this setting, to achieve unequivocal 
progression on the basis of the non-target disease, there must be an overall level of substantial 


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worsening in non-target disease in a magnitude that, even in the presence of SD or PR in target 
disease, the overall tumour burden has increased sufficiently to merit discontinuation of therapy. 
A modest increase in the size of one or more non-target lesions is usually not sufficient to qualify 
for unequivocal progression status. The designation of overall progression solely on the basis of 
change in non-target disease in the face of SD or PR of target disease will therefore be extremely 
rare. 
When the Patient Has Only Non-Measurable Disease. The same general concepts apply here as 
noted above; however, in this instance, there is no measurable disease assessment to factor into 
the interpretation of an increase in non-measurable disease burden. Because worsening in 
non-target disease cannot be easily quantified (by definition: if all lesions are truly 
non--measurable), a useful test that can be applied when assessing patients for unequivocal 
progression is to consider if the increase in overall disease burden based on the change in 
non-measurable disease is comparable in magnitude to the increase that would be required to 
declare PD for measurable disease; that is, an increase in tumour burden representing an additional 
73% increase in volume (which is equivalent to a 20% increase in diameter in a measurable lesion). 
Examples include an increase in a pleural effusion from “trace” to “large” or an increase in 
lymphangitic disease from localised to widespread or may be described in protocols as “sufficient 
to require a change in therapy.” If unequivocal progression is seen, the patient should be considered 
to have had overall PD at that point. Although it would be ideal to have objective criteria to apply 
to non-measurable disease, the very nature of that disease makes it impossible to do so; therefore, 
the increase must be substantial. 
 
e. 
New Lesions 
The appearance of new malignant lesions denotes disease progression; therefore, some comments 
on detection of new lesions are important. There are no specific criteria for the identification of 
new radiographic lesions; however, the finding of a new lesion should be unequivocal, that is, not 
attributable to differences in scanning technique, change in imaging modality, or findings thought 
to represent something other than tumour (for example, some “new” bone lesions may be simply 
healing or flare of preexisting lesions). This is particularly important when the patient’s baseline 
lesions show PR or CR. For example, necrosis of a liver lesion may be reported on a CT scan 
report as a “new” cystic lesion, which it is not. 
A lesion identified during the study in an anatomical location that was not scanned at baseline is 
considered a new lesion and will indicate disease progression. 
If a new lesion is equivocal, for example because of its small size, continued therapy and follow-up 
evaluation will clarify if it represents truly new disease. If repeat scans confirm there is definitely 
a new lesion, then progression should be declared using the date of the initial scan. 
 
 
 


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EVALUATION OF RESPONSE 
a. 
Timepoint Response (Overall Response) 
It is assumed that at each protocol-specified timepoint, a response assessment occurs. Table 1 
provides a summary of the overall response status calculation at each timepoint for patients who 
have measurable disease at baseline. 
When patients have non-measurable (therefore non-target) disease only, Table 2 is to be used. 
 
Table 1 
Timepoint response: patients with target lesions (with or without non-target 
lesions) 
Target  
Lesions 
Non-Target  
Lesions 
New  
Lesions 
Overall  
Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all 
evaluated 
No 
PR 
SD 
Non-PD or not all 
evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or no 
PD 
Any 
PD 
Yes or no 
PD 
Any 
Any 
Yes 
PD 
CR = complete response; NE = not evaluable; PD = progressive disease; PR = partial response; SD = stable disease. 
 
Table 2 
Timepoint response: patients with non-target lesions only 
Non-Target  
Lesions 
New  
Lesions 
Overall  
Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD a 
Not all evaluated 
No 
NE 
Unequivocal PD 
Yes or no 
PD 
Any 
Yes 
PD 
CR = complete response; NE = not evaluable; PD = progressive disease. 
a “Non-CR/non-PD” is preferred over “stable disease” for non-target disease since stable disease is increasingly 
used as an endpoint for assessment of efficacy in some studies; thus, assigning “stable disease” when no lesions  
can be measured is not advised. 
 
 


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b. 
Missing Assessments and Not-Evaluable Designation 
When no imaging/measurement is done at all at a particular timepoint, the patient is not evaluable 
at that timepoint. If only a subset of lesion measurements are made at an assessment, usually the 
case is also considered not evaluable at that timepoint, unless a convincing argument can be made 
that the contribution of the individual missing lesion(s) would not change the assigned timepoint 
response. This would be most likely to happen in the case of PD. For example, if a patient had a 
baseline sum of 50 mm with three measured lesions and, during the study, only two lesions were 
assessed, but those gave a sum of 80 mm; the patient will have achieved PD status, regardless of 
the contribution of the missing lesion. 
If one or more target lesions were not assessed either because the scan was not done or the scan 
could not be assessed because of poor image quality or obstructed view, the response for target 
lesions should be “unable to assess” since the patient is not evaluable. Similarly, if one or more 
non-target lesions are not assessed, the response for non-target lesions should be “unable to assess” 
except where there is clear progression. Overall response would be “unable to assess” if either the 
target response or the non-target response is “unable to assess,” except where this is clear evidence 
of progression as this equates with the case being not evaluable at that timepoint. 
Table 3 
Best overall response allowing for the requirement of confirmation for PR and CR 
Overall Response at  
First Response Timepoint 
Overall Response  
at Subsequent Timepoint 
Best  
Overall Response 
CR 
CR 
CR 
CR 
PR 
SD, PD, or PRa 
CR 
SD 
SD, provided minimum duration 
 
 
for SD was met; otherwise, PD 
CR 
PD 
SD, provided minimum duration 
 
 
for SD was met; otherwise, PD 
CR 
NE 
SD, provided minimum duration 
 
 
for SD was met; otherwise, NE 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD, provided minimum duration 
 
 
for SD was met; otherwise, PD 
PR 
NE 
SD, provided minimum duration 
 
 
for SD was met; otherwise, NE 
NE 
NE 
NE 
CR = complete response; NE = not evaluable; PD = progressive disease; PR = partial response; SD = stable disease. 
a If a CR is truly met at the first timepoint, any disease seen at a subsequent timepoint, even disease meeting PR 
criteria relative to baseline, qualifies as PD at that point (since disease must have reappeared after CR). Best 
response would depend on whether the minimum duration for SD was met. However, sometimes CR may be 
claimed when subsequent scans suggest small lesions were likely still present and in fact the patient had PR, not 
CR, at the first timepoint. Under these circumstances, the original CR should be changed to PR and the best 
response is PR. Note: For a BOR of SD, the timepoint on which this is based must be at least 8 weeks after C1D1. 


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c. 
Special Notes on Response Assessment 
When nodal disease is included in the sum of target lesions and the nodes decrease to “normal” 
size (<10 mm), they may still have a measurement reported on scans. This measurement should be 
recorded even though the nodes are normal in order not to overstate progression should it be based 
on increase in size of the nodes. As noted earlier, this means that patients with CR may not have a 
total sum of “zero” on the CRF. 
Patients with a global deterioration of health status requiring discontinuation of treatment without 
objective evidence of disease progression at that time should be reported as “symptomatic 
deterioration.” Every effort should be made to document objective progression after 
discontinuation of treatment. Symptomatic deterioration is not a descriptor of an objective 
response; it is a reason for stopping study therapy. The objective response status of such patients 
is to be determined by evaluation of target and non-target disease as shown in Table 1-Table 3. 
For equivocal findings of progression (e.g., very small and uncertain new lesions; cystic changes 
or necrosis in existing lesions), treatment may continue until the next scheduled assessment unless 
there are other indications for discontinuation, such as AEs or co-morbidities. If at the next 
scheduled assessment progression is confirmed, the date of progression should be the earlier date 
when progression was suspected. 
If a patient undergoes an excisional biopsy or other appropriate approach (e.g., multiple passes 
with large core needle) of a new lesion or an existing solitary progressive lesion that following 
serial sectioning and pathological examination reveals no evidence of malignancy 
(e.g., inflammatory cells, fibrosis, etc.), then the new lesion or solitary progressive lesion will not 
constitute disease progression. 
The present study is one in which patients with advanced disease are eligible (i.e., primary disease 
still or partially present), the primary tumour should also be captured as a target or non-target 
lesion, as appropriate. This is to avoid an incorrect assessment of CR if the primary tumour is still 
present but not evaluated as a target or non-target lesion. 
 
 


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Appendix 5: ECOG Performance Scale 
 
Activity Performance Description 
Score 
Fully active, able to carry out all on all pre-disease performance 
without restriction. 
0 
 
 
Restricted in physically strenuous activity but ambulatory and able to 
carry out work of a light or sedentary nature, e.g., light housework, 
office work. 
1 
 
 
Ambulatory and capable of all self-care, but unable to carry out any 
work activities.  
Up and about more than 50% of waking hours.  
2 
 
 
Capable of only limited self-care. Confined to bed or chair more than 
50% of waking hours.  
3 
 
 
Completely disabled. Cannot carry out any self-care. Totally confined 
to bed or chair. 
4 
 
 
Dead 
5 
 
 

SAP_001.pdf: 
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STATISTICAL ANALYSIS PLAN 
 
 
 
A Phase III Open-Label, Multi-Centre, Randomised Study 
Comparing NUC-1031 plus Cisplatin to Gemcitabine plus 
Cisplatin in Patients with Previously Untreated Locally 
Advanced or Metastatic Biliary Tract Cancer 
 
 
 
 
 
 
PROTOCOL NUMBER: 
NuTide:121 
 
PROTOCOL VERSION: 
 
Version 4.0, 18 December 2020 
 
STUDY DRUG: 
 
 
NUC-1031 in combination with cisplatin 
 
SAP VERSION: 
 
 
Version 6.0, 25 February 2022 
 
 
IND NUMBER: 
 
 
139058 
 
EUDRACT NUMBER: 
 
2019-001025-28 
 
SPONSOR:  
 
 
NuCana plc 
 
 
 
 
3 Lochside Way 
 
 
 
 
Edinburgh, EH12 9DT 
 
 
 
 
UK 
 
 
 
 
 
 
CONFIDENTIALITY STATEMENT 
This confidential document is the property of NuCana plc. No unpublished information contained 
herein may be disclosed without prior written approval from NuCana. 
Access to this document must be restricted to relevant parties. 
 


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REVISION HISTORY 
Version Number 
Date 
Reason for Revision 
1 
11 March 2019 
N/A 
2 
31 July 2019 
Update of study design details in line with protocol 
update 
Addition of a modified intention-to-treat analysis 
population 
Update of visit window conventions  
Addition of a definition for ‘date at which patient is last 
known to be alive’ for the purposes of OS 
Update of analysis details for OS, ORR, PFS, and DCR  
Update of details for the interim analysis for power 
reassessment  
Update of analysis details for patient-report QoL  
Addition of subgroup analysis details 
Addition of Hy’s law definition 
3 
21 November 2019 
Clarification of the procedure for follow-up of patients 
who discontinue without disease progression 
Update of details for stratification factors used in the 
primary analysis of ORR  
Update of PFS analysis details 
Update of details for the interim analysis for futility  
4 
05 February 2021 
Update of secondary and supportive analyses for OS 
Update to Hy’s law criteria to align with FDA guidance  
Update of analyses for disposition, OS, ORR, PFS, 
DoR, and AEs, as well as for the futility analysis, to 
cover additions or modifications that are needed due to 
the COVID-19 pandemic 
5 
15 December 2021 
Additional details on supportive analyses of OS and 
PFS 
Clarifications provided on analysis populations for 
which data collected prior to randomisation will be 
summarised 


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Additional details provided explicitly on the (SAS 
default) variance estimators to be used for analyses of 
ORR 
Inclusion of explicit details on how, under the CHW 
method for power re-assessment (Cui et al, 1999), the 
test statistic for OS needs to be calculated for the final 
analysis if under the procedure the new required number 
of events is increased 
Inclusion of additional safety analyses for SAEs and 
Deaths. Further clarifications on COVID-19 related 
safety summaries 
6 
25 February 2022 
Inclusion of additional supportive analyses for OS, 
ORR, and PFS in which those patients taking particular 
treatment prior to randomisation are excluded. 
Inclusion of additional sensitivity analyses for OS, 
ORR, and PFS in which stratification factors are 
derived using particular information recorded by the 
investigator at the Screening Visit 
Updated the description of the ECG sub-study to align 
with that sub-study's latest SAP. 
 




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Table of Contents 
Revision History ....................................................................................................................... 2 
1 
ADMINISTRATIVE STRUCTURE AND VERSION HISTORY ............................... 13 
2 
STUDY DESCRIPTION ............................................................................................... 14 
2.1 
Study Design .................................................................................................................. 14 
2.2 
Study Treatment ............................................................................................................. 15 
2.3 
Study Objectives and Endpoints .................................................................................... 16 
2.3.1 Primary Objectives ......................................................................................................... 16 
2.3.2 Secondary Objectives ..................................................................................................... 16 
2.3.3 Tertiary Objectives ......................................................................................................... 16 
2.3.4 Primary Endpoints ......................................................................................................... 16 
2.3.5 Secondary Endpoints ..................................................................................................... 16 
2.3.5.1 
Key Secondary Endpoint ...................................................................................... 16 
2.3.5.2 
Other Secondary Endpoints .................................................................................. 17 
2.3.6 Tertiary Endpoints ......................................................................................................... 18 
2.4 Power and Sample Size Justification ............................................................................. 18 
2.5 Randomisation ............................................................................................................... 19 
3 
ANALYSIS POPULATIONS ....................................................................................... 19 
3.1 
Intention-to-Treat (ITT) Population ............................................................................... 19 
3.2 
Intention-to-Treat with Measurable Disease at Baseline (ITTMD) Population ............ 19 
3.3 
Modified Intention-to-Treat (MITT) Population ........................................................... 20 
3.4 
Safety Population ........................................................................................................... 20 
3.5 
Primary Analysis Populations ........................................................................................ 20 
4 
GENERAL CONVENTIONS ....................................................................................... 20 


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4.1 
Definition of Baseline .................................................................................................... 20 
4.2 
Definition of Study Day ................................................................................................. 21 
4.3 
Visit Windows ............................................................................................................... 21 
4.4 
Handling of Missing Data .............................................................................................. 21 
4.4.1 Imputation of Partial Dates ............................................................................................ 21 
4.4.2 Imputation Rules for Laboratory Values Outside of the Quantification Range ............ 22 
4.5 
Safety Observation Period ............................................................................................. 22 
4.6 
Definition of Prior and Concomitant Medications ......................................................... 22 
4.7 
Software ......................................................................................................................... 22 
4.8 
Changes to Planned Analyses ........................................................................................ 22 
5 
STUDY POPULATION SUMMARIES ....................................................................... 23 
5.1 
Disposition ..................................................................................................................... 23 
5.2 
Demographic and Baseline Characteristics.................................................................... 23 
5.3 
Medical History ............................................................................................................. 25 
5.4 
Cancer History and Current Disease Status ................................................................... 25 
5.5 
Randomisation Strata compared with Baseline Current Disease Status ........................ 25 
6 
TREATMENTS AND MEDICATIONS ....................................................................... 26 
6.1 
Prior Anti-Cancer and Radiation Therapy ..................................................................... 26 
6.2 
Prior Medications, Concomitant Medications, Prohibited Medications and Prohibited 
Procedures ...................................................................................................................... 26 
6.3 
Non-Protocol Anti-Cancer Therapy (NPACT) .............................................................. 27 
6.4 
Study Treatment Exposure and Study Treatment Modifications ................................... 27 
6.5 
Post-randomisation Surgery/Procedure, including Biliary Stenting .............................. 28 
7 
EFFICACY ANALYSES .............................................................................................. 28 
7.1 
Primary Efficacy Endpoints ........................................................................................... 28 


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7.1.1 Overall Survival ............................................................................................................. 28 
7.1.1.1 
Definition of Overall Survival .............................................................................. 28 
7.1.1.2 
Primary Analysis of Overall Survival ................................................................... 28 
7.1.1.3 
Secondary, Supportive, and Sensitivity Analyses of Overall Survival ................. 29 
7.1.1.4 
Additional Sensitivity Analyses for Overall Survival as a Result of the COVID-
19 Pandemic ................................................................................................................... 31 
7.1.2 Objective Response Rate ............................................................................................... 31 
7.1.2.1 
Derivation of Best Overall Response .................................................................... 31 
7.1.2.2 
Primary Analysis of Objective Response Rate ..................................................... 32 
7.1.2.3 
Secondary, Supportive, and Sensitivity Analyses of Objective Response Rate ... 33 
7.1.2.4 
Additional Sensitivity Analyses for ORR as a Result of the COVID-19 Pandemic
 
35 
7.2 
Key Secondary Efficacy Endpoint ................................................................................. 35 
7.2.1 Progression-Free Survival (PFS) ................................................................................... 35 
7.3 
Interim Analyses ............................................................................................................ 39 
7.3.1 Determination of Efficacy at the Interim Analyses ....................................................... 39 
7.3.2 Interim Analysis for Assessment of Futility .................................................................. 40 
7.3.3 Interim Analysis for Power Re-Assessment .................................................................. 41 
7.4 
Control of Type 1 Error ................................................................................................. 42 
7.5 
Additional Secondary Efficacy Endpoints ..................................................................... 46 
7.5.1 Duration of Response ..................................................................................................... 46 
7.5.2 18-Month and 12-Month Survival ................................................................................. 46 
7.5.3 Disease Control Rate ...................................................................................................... 46 
7.6 
Patient-Reported Quality of Life ................................................................................... 46 
7.6.1 EORTC-QLQ-C30 with the QLQ-BIL21 module ......................................................... 46 


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7.6.2 EuroQoL Health questionnaire instrument (EQ-5D-5L) ............................................... 48 
7.7 
Health Economics .......................................................................................................... 49 
7.8 
Pharmacokinetics ........................................................................................................... 49 
7.9 
Efficacy Analyses by Subgroups ................................................................................... 49 
8 
SAFETY SUMMARIES ................................................................................................ 50 
8.1 
Adverse Events, Serious Adverse Events, and Deaths .................................................. 50 
8.1.1 Treatment-Emergent COVID-19 Adverse Events, Including their Impact on the Study
 
52 
8.2 
Laboratory Parameters ................................................................................................... 53 
8.3 
Vital Signs ...................................................................................................................... 54 
8.4 
ECOG Performance Status ............................................................................................ 54 
8.5 
Electrocardiogram .......................................................................................................... 55 
9 
REFERENCES .............................................................................................................. 56 
Appendix 1: Derivation of the Objective Response Rate Assumed for the Control Arm ...... 58 
Appendix 2: Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1............ 62 
Appendix 3: Determination of Best Overall Response in Patients having Intermediate 
Timepoint Responses of NE .......................................................................................... 71 
Appendix 4: Power Calculations for Subgroup Analyses of ORR ......................................... 73 
 
 


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List of Tables 
Table 1 
Censoring scheme used in the Primary Analysis of PFS ........................................................... 37 
Table 2: 
Analyses Planned, Primary Endpoints Evaluated, Approximate Timing, and Drivers of Timing
 
40 
Table 3: 
Efficacy boundaries and properties for ORR ............................................................................. 44 
Table 4: 
Efficacy boundaries and properties for OS ................................................................................ 45 
Table 5: 
QLQ-C30 domain minimal clinically important differences (MCIDs) ..................................... 47 
Table 6: 
QLQ-BIL21 domain minimal clinically important differences (MCIDs) ................................. 48 
 
List of Figures 
Figure 1: 
Type 1 error recycling between the two primary endpoints, and the key secondary 
endpoint 
43 


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LIST OF ABBREVIATIONS 
 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
ATA 
Adequate tumour assessment 
ATC 
Anatomical therapeutic chemical 
BICR 
Blinded independent central review 
BOR 
Best overall response 
BMI 
Body mass index 
BTC 
Biliary tract cancer 
C1D1 
Cycle 1 Day 1 
CHW 
Cui, Hung, Wang 
CI 
Confidence interval 
CMH 
Cochran-Mantel-Haenszel 
CNAR 
Censoring not at random 
CR 
Complete response 
CT 
Computed tomography 
CTCAE 
Common terminology criteria for adverse events 
DATELUR 
Date of the latest unconfirmed response 
DCR 
Disease control rate 
DILI 
Drug-induced liver injury 
DoR 
Duration of response 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EMA 
European Medicines Agency 
EORTC 
European Organisation for Research and Treatment of Cancer  
eCRF 
Electronic case report form 
EQ-5D-5L 
5-level EuroQol five-dimension scale 
FDA 
Food and Drug Administration 
HR 
Hazard ratio 
ICH 
International Council for Harmonisation 
IDMC 
Independent Data Monitoring Committee 


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INR 
International Normalised Ratio 
ITT 
Intention-to-treat 
ITTMD 
Intention-to-treat with measurable disease at baseline 
ITTMD28 
Subset of the ITTMD population consisting of patients randomized ≥28 weeks 
prior to the data cut-off 
IxRS 
Interactive voice or web-based response system 
LLQ 
Lower limit of quantitation 
MCID 
Minimal clinically important difference 
MedDRA 
Medical Dictionary for Regulatory Activities 
MITT 
Modified intention-to-treat 
MRI 
Magnetic resonance imaging 
NCI 
National Cancer Institute 
NE 
Not evaluable 
NM28 
Number of patients randomised in the measurable disease stratum with the 
opportunity for ≥28 weeks of follow-up 
NPACT 
Non-protocol anti-cancer treatment 
ORR 
Objective response rate 
OS 
Overall survival 
OS12 
Proportion of patients alive at 12 months 
OS18 
Proportion of patients alive at 18 months 
PD 
Progressive disease 
PET 
Positron emission tomography 
PFS 
Progression-free survival 
PK 
Pharmacokinetic 
PR 
Partial response 
PS 
Performance status 
QALY 
Quality-adjusted life-year 
QLQ-BIL21 
EORTC questionnaire module for patients with cholangiocarcinoma and 
gallbladder cancer 
QLQ-C30 
EORTC questionnaire to assess the quality of life cancer patients 
QoL 
Quality of life 
RDI 
Relative dose intensity 
RECIST 
Response Evaluation Criteria in Solid Tumours (version 1.1) 
RMST 
Restricted mean survival time 


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SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Stable Disease 
SOC 
System organ class 
TE 
Treatment-emergent 
TEAE 
Treatment-emergent adverse event 
ULQ 
Upper limit of quantitation 
VAS 
Visual analogue scale 
WBC 
White blood cell 
WHO-DD 
World Health Organisation drug dictionary 


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1 
ADMINISTRATIVE STRUCTURE AND VERSION HISTORY 
 
This study is being conducted under the sponsorship of NuCana plc.  
Statistical programming and analyses are being conducted under contract by IQVIA.  
This version of the NuTide:121 Statistical Analysis Plan (SAP) is based on Version 4.0 of the 
NuTide:121 protocol, dated 18 December 2020. 
 
 


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2 
STUDY DESCRIPTION 
2.1 
Study Design 
This is an open-label, randomised Phase III study of NUC-1031 in combination with cisplatin 
(Arm A) compared to gemcitabine in combination with cisplatin (Arm B), administered on Days 1 
and 8 of 21-day cycles, in previously untreated patients with locally advanced or metastatic biliary 
tract cancer (BTC). A total of 828 patients will be randomised in a 1:1 ratio to Arm A or Arm B, 
and may continue to receive study treatment until documentation of disease progression, evidence 
of unacceptable treatment-related adverse events (AEs) despite optimal medical management 
and/or dose modification, or withdrawal of consent. 
Patients will be recruited from approximately 130 sites in North America, Europe, and Asia Pacific 
(Asia and Australasia). Patients are eligible to participate in the study if all of the inclusion criteria 
are met and none of the exclusion criteria apply.  
Eligible patients must have histologically- or cytologically-proven biliary adenocarcinoma, 
including cholangiocarcinoma (intra- and extra-hepatic biliary ducts), gallbladder or ampullary 
cancer, that is not amenable to surgical resection and will have had no prior systemic chemotherapy 
for treatment of locally advanced or metastatic disease. Patients with measurable or 
non-measurable disease are eligible for study participation in accordance with predefined 
randomisation strata; however, non-measurable disease is limited to 82 patients. All screening 
activities must be performed within 21 days prior to Cycle 1 Day 1 (C1D1), including the baseline 
radiographic assessment which must also be conducted within 21 days prior to C1D1.  
In accordance with local standards of care as appropriate, patients may have received prior 
chemotherapy in the adjuvant setting and/or radiotherapy with or without radio-sensitising low-
dose chemotherapy for localised disease if completed at least 6 months prior to randomisation. 
Patients must have adequate biliary drainage without evidence of biliary obstruction. Patients with 
disease characterised as combined or mixed hepatocellular/cholangiocarcinoma are not eligible for 
this study. 
Objective disease assessment will be performed by radiologic evaluation and assessed according 
to Response Evaluation Criteria in Solid Tumours (RECIST) v1.1 criteria. All known or suspected 
disease sites must be assessed at baseline by either computed tomography (CT), magnetic 
resonance imaging (MRI) or positron emission tomography-CT (PET-CT) scan. For each patient, 
the same radiological method, including the use or not of contrast, used at baseline must be used 
for disease assessment throughout the duration of the patient’s participation in the study. 
Tumour measurements and disease response assessments are to be performed every 9 weeks 
(±7 days) (approximating three cycles) from C1D1 until disease progression. Responses (Complete 
Response [CR] or Partial Response [PR]) are scheduled to be confirmed at least 28 days and not 
more than 42 days after the first observation of response.  If a patient is found to have a response 
at the confirmatory scan which has improved from PR to CR, then the improved response must 
also be confirmed within a further 28-42 day window. 
Treatment and study continuation decisions based on radiologic assessments will be made by the 
treating Investigator. Independent radiologic disease assessments will be performed through a 
Blinded Independent Central Review (BICR). In addition, assessment of measurable or 
non-measurable disease as baseline for the purposes of determining the appropriate randomisation 


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stratum as well as for use in determining whether the 82 patient limit on non-measurable patients 
has been reached will be based on BICR assessment. Further details on BICR are described in 
Section 11.2 of the Study Protocol and in the separate BICR charter. 
Patients in either treatment group who stop treatment with no evidence of disease progression as 
defined by RECIST v1.1 criteria will continue to receive scans at regular intervals (at least every 
12 weeks [±14 days]) until disease progression in order to determine duration of overall response 
and progression-free survival (PFS). This follow-up for both treatment groups should continue 
(regardless of whether any subsequent anti-cancer medication has been prescribed) until disease 
progression, or death. Patients in either treatment group who no longer attend clinic every 12 weeks 
should continue to be followed for progression status (unless progression has already been 
documented), for details on any new anti-cancer treatments, and for survival status. Patients who 
stop treatment following an unconfirmed response should still have a confirmatory scan within the 
28- to 42-day window, provided that they have not yet started subsequent anti-cancer therapy. If a 
patient is found to have a response at the confirmatory scan which has improved from PR to CR, 
then the improved response must also be confirmed within a further 28- to 42-day window, 
provided that they have not yet started subsequent anti-cancer therapy. 
Survival and initiation of new treatments will be assessed approximately every 12 weeks 
(±14 days) until death. To ensure current and complete survival data at the time of database locks, 
updated survival status may be requested prior to but not limited to Independent Data Monitoring 
Committee (IDMC) review, interim analyses, and the final analysis. 
The study will continue until 637 deaths have occurred, unless the results for overall survival (OS) 
meet the pre-specified criterion at an interim analysis to stop for early demonstration of efficacy 
(as described in Sections 7.3.1 and 7.4), or unless terminated early on the recommendation of the 
IDMC. 
The study design, schedule of the visits, assessments and conduct are further described within the 
Study Protocol. 
Robust electrocardiogram (ECG) monitoring will be implemented in a subset of patients at a subset 
of sites to collect QT/QTc data to allow a primary analysis of the QT effect of NUC-1031 in 
combination with cisplatin relative to the effect of gemcitabine in combination with cisplatin, based 
on a by-time point analysis.  A total of 64 patients (approximately 32 patients in each treatment 
group) will be enrolled and will have standard 12-lead ECG monitoring conducted during the first 
2 cycles of treatment.  This will constitute a sub-study and will be reported separately in accordance 
with a separate SAP. 
2.2 
Study Treatment 
Eligible consenting patients will be randomised on C1D1 in a 1:1 ratio to receive treatment in 
Arm A (cisplatin at 25 mg/m2 followed by NUC-1031 at 725 mg/m2) or Arm B (cisplatin at 
25 mg/m2 followed by gemcitabine at 1000 mg/m2) on Days 1 and 8 of 21-day cycles. 
Criteria for inter-cycle and intra-cycle dose delay and dose modification are specified in the 
protocol. The reasons for dose delay or dose modification must be captured as AEs in the patient 
medical record and noted on the electronic case report form (eCRF). 


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Patients may continue to receive study treatment until documentation of objective progressive 
disease (PD), evidence of unacceptable treatment-related AEs despite optimal medical 
management and/or dose modification, or withdrawal of consent. Reasons for treatment 
discontinuation must be captured in the patient medical record and on the Treatment 
Discontinuation page of the eCRF. 
A patient who is receiving clinical benefit but experiencing toxicity related to the cisplatin 
component may continue on study receiving single agent NUC-1031 (Arm A) or gemcitabine 
(Arm B). 
2.3 
Study Objectives and Endpoints 
2.3.1 
Primary Objectives 
• OS 
• 
Objective response rate (ORR) based on BICR in patients with measurable disease at 
baseline 
2.3.2 
Secondary Objectives 
• PFS based on BICR 
• Duration of response (DoR) based on BICR 
• 18- and 12-month survival 
• Disease Control Rate (DCR) based on BICR 
• Safety 
• Pharmacokinetics (PK) of NUC-1031 
• Patient-reported Quality of Life (QoL) 
2.3.3 
Tertiary Objectives 
• Health economics  
• Assessment of archival tumour sample characteristics that may further an understanding of 
the mechanism(s) through which the clinical activity of NUC-1031 is achieved 
2.3.4 
Primary Endpoints 
• OS, defined as the time from randomisation to the time of death from any cause 
• ORR, defined as the percentage of patients achieving a confirmed complete or partial 
response to treatment as assessed by BICR according to RECIST v1.1 criteria.  This will 
be assessed only in patients with measurable disease at baseline. 
2.3.5 
Secondary Endpoints 
2.3.5.1 Key Secondary Endpoint 
• PFS, based on BICR according to RECIST v1.1 criteria, defined as the time from 
randomisation to the first observation of objective tumour progression or death from any 
cause 


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2.3.5.2 Other Secondary Endpoints 
Efficacy 
• DoR, as assessed by BICR, defined as the time from initial clinical response (PR or CR that 
is subsequently confirmed) to the first observation of tumour progression or death from any 
cause 
• 18-month survival 
• 12-month survival 
• DCR, based on BICR according to RECIST v1.1 criteria, defined as the percentage of 
patients demonstrating a Best Overall Response (BOR) of CR, PR, or Stable Disease (SD) 
Objective disease assessment will be performed radiologically and assessed according to RECIST 
v1.1 criteria. 
Safety 
Safety and tolerability will be assessed by evaluation of the following: 
• Treatment-emergent AEs (TEAEs), including TEAEs by severity grade using Common 
Terminology Criteria for Adverse Events (CTCAE) version 5.0 (or higher) 
• Serious TEAEs (SAEs) 
• Deaths due to TEAEs 
• Treatment discontinuations due to TEAEs 
• Clinically-significant changes in laboratory parameters 
• Changes in Eastern Cooperative Oncology Group (ECOG) status, Physical Exam, ECGs 
and Vital Signs 
A sub-study will be carried out to assess the effect of the NUC-1031 + cisplatin combination on 
cardiac repolarisation in a subset of patients.  
Pharmacokinetics of NUC-1031 
Sparse PK sampling will be taken on Cycle 1 Day 1 at the end of infusion, 2 hours after the end of 
infusion, and 6 hours after the end of infusion, to capture Ctrough and Cmax plasma levels. 
Patient-Reported QoL 
Patient-reported QoL will be assessed using the European Organisation for Research and Treatment 
(EORTC) QoL Questionnaire (QLQ-C30) with the QLQ-BIL21 module, and the 5-level EuroQoL 
five-dimension scale (EQ-5D-5L). 


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2.3.6 
Tertiary Endpoints 
Health economics 
Health economics will be assessed through collection of core health resource use information, using 
case report forms (eCRFs) to capture procedure codes, days in hospital, and outpatient visits. 
Health outcomes will be quantified using quality-adjusted life years (QALYs) and a cost-utility 
analysis will be conducted by creating incremental cost-utility ratios for each of the treatment 
groups. 
Biomarkers 
Phenotypic, genotypic, and/or pharmacodynamic characteristics of the tumour cell that may further 
delineate the mechanism(s) through which NUC-1031 acts. 
2.4 
Power and Sample Size Justification 
For OS, a hazard ratio (HR) of 0.76 has been assumed. With 3 looks (at 67%, 85%, and 100% of 
the required number of OS events as described in Table 4 within Section 7.4), use of the 
Lan-DeMets O'Brien-Fleming-like α-spending function (Lan & DeMets, 1983), an overall α=0.020 
one-sided, and 1:1 randomisation, then a total of 637 OS events gives 90.9% power (after allowing 
for the small power loss from having the futility boundary). As described in Section 7.4, initially 
α=0.020 one-sided is assigned to OS and α=0.005 one-sided is assigned to ORR. 
A thirty-month duration of enrolment is assumed with gradual ramp-up in enrolment rate over the 
first 12 months. OS events are assumed to follow an exponential distribution, and a 11.7-month OS 
median has been assumed for the control arm as seen in the gemcitabine in combination with 
cisplatin arm from the ABC-02 study (Valle et al, 2010). The HR of 0.76 then gives a median OS 
of approximately 15.4 months in the NUC-1031 in combination with cisplatin arm. If the rate of 
discontinuation of treatment and the rate of discontinuation from the study are both assumed to be 
comparable to the gemcitabine in combination with cisplatin arm from ABC-02, then 811 patients 
would result in the last of the 637 events occurring at approximately 48 months. It is also assumed 
that 2% of patients will be lost to follow-up for OS (with unknown status of dead/alive) and so 
828 patients will be randomised. 
The gradual ramp-up in enrolment assumes the following percentages of patients are randomised 
in each of the first 12 months: 0.16%, 0.23%, 0.55%, 1.10%, 1.84%, 2.52%, 3.16%, 3.52%, 3.74%, 
3.81%, 3.87%, and 3.90%. Then, for Months 13-30 enrolment is assumed to continue at a constant 
rate of 3.98% of patients per month. 
The target number of OS events at the final analysis may be increased based on the effect size at 
Interim Analysis 3 using the Cui, Hung, & Wang (CHW) method (Cui et al, 1999). Further details 
are provided in Section 7.3.3. 
For ORR, a 19% rate is assumed for the control arm. The derivation of this rate from the 
gemcitabine in combination with cisplatin arms within ABC-02 (Valle et al, 2010), BT-22 
(Okusaka et al, 2010), and ABC-03 (Valle et al, 2015) (allowing now for the requirement of 
confirmation, based on Performance Status (PS) 0 or 1 patients only, including all randomised 
patients in the denominator, excluding patients with non-measurable disease at baseline, and 
adjusting for use of BICR rather than Investigator assessment) is provided in Appendix 1. For the 
NUC-1031 in combination with cisplatin arm, a 31% ORR is assumed, which gives an assumed 
true odds ratio of 1.92. 


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With 2 looks for ORR (at 65% and 100% as described in Table 3 within Section 7.4), use of the 
Lan-DeMets O'Brien-Fleming-like α-spending function (Lan & DeMets, 1983), and with an overall 
α=0.005 one-sided, then a total of 644 patients with measurable disease at baseline (together with 
418 at the interim analysis) gives 80% power. The two looks will take place 28 weeks 
(corresponding to three scheduled post-baseline radiographic scans plus a one week visit window) 
after the last of these required numbers of patients have been randomised. 
Additional power calculations for subgroup analyses are summarised in Section 7.9. 
2.5 
Randomisation 
This is a randomised, open-label, controlled study of NUC-1031 in combination with cisplatin 
versus gemcitabine in combination with cisplatin. 
Patients will be randomised by an independent interactive voice or web-based response system 
(IxRS). The IxRS will receive information prior to C1D1 for each patient on whether or not the 
patient has measurable disease at baseline as determined by BICR, where that determination will 
have been made as described in the Imaging Review Charter.  At C1D1, the Investigator will enter 
into the IxRS their site information, whether the patient has metastatic disease (yes or no), and the 
primary tumour location (gallbladder, intra-hepatic, extra-hepatic or ampullary).  The IxRS will 
then indicate to which treatment group the patient has been randomised, and the study site will also 
obtain the patient’s identification number from the IxRS. 
The randomisation will be in a 1:1 ratio to receive treatment in Arm A (NUC-1031 plus cisplatin) 
or Arm B (gemcitabine plus cisplatin). Randomisation will be stratified by the following 4 factors: 
• Measurable disease at baseline (yes, no) as determined by BICR 
• Metastatic disease (yes, no) 
• Tumour location (gallbladder, intra-hepatic, extra-hepatic/ampullary) 
• Region (Asia, non-Asia) 
 
The number of patients with non-measurable disease at baseline as determined by BICR is capped 
at 82. 
3 
ANALYSIS POPULATIONS 
3.1 
Intention-to-Treat (ITT) Population 
The ITT population will consist of all patients who are randomised, regardless of whether any study 
medication was received.  Patients will be summarised on the basis of the treatment group to which 
they were randomised. 
3.2 
Intention-to-Treat with Measurable Disease at Baseline (ITTMD) Population 
The ITTMD population will consist of all patients who are randomised to the stratum 
corresponding to having measurable disease at baseline (as assessed by BICR), regardless of 
whether any study medication was received.  Patients will be summarised on the basis of the 
treatment group to which they were randomised. 
The sub-population of the ITTMD population consisting of patients randomised ≥ 28 weeks before 
the data cut-off will be denoted by the ITTMD28 population. 


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3.3 
Modified Intention-to-Treat (MITT) Population 
The MITT population will consist of all patients who are randomised and received any study 
medication. Patients will be summarised on the basis of the treatment group to which they were 
randomised. 
3.4 
Safety Population 
The Safety population will consist of all patients who are randomised and receive any study 
medication. Patients will be summarised on the basis of the actual study medication received, i.e., 
NUC-1031 in combination with cisplatin (Arm A), or gemcitabine in combination with cisplatin 
(Arm B). Any patients receiving study medication from both arms will be summarised under 
Arm A. 
3.5 
Primary Analysis Populations 
The ITTMD28 will be the primary analysis population for evaluating ORR and DCR. DoR will be 
analysed in the subset of ITTMD28 patients who have confirmed response. For evaluating all other 
efficacy endpoints, the primary analysis population will be the ITT population. The MITT 
population will be used only for a secondary analysis of the OS primary endpoint. The Safety 
population will be the primary analysis population for evaluating all safety endpoints. 
4 
GENERAL CONVENTIONS 
The statistical principles applied in the design and planned analyses of this study are consistent 
with International Council for Harmonisation (ICH) E9 and Food and Drug Administration (FDA) 
Guidance for Industry: Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics 
(2018). 
Continuous data will be summarised using descriptive statistics (number of observations, mean, 
standard deviation, median, 25th and 75th percentiles, minimum, and maximum). Frequencies and 
percentages will be used for summarising categorical (discrete) data. 
P-values will be presented as two-sided in all cases. In addition, p-values for the primary analyses 
of OS, ORR, and PFS will also be presented as one-sided for consistency with the method for type 
1 error control described in Section 7.4. 
Confidence intervals (CIs), where presented, will be provided at the 95% level, with the exception 
of certain analyses of the primary efficacy endpoints and the key secondary endpoint (as described 
in Section 7.1 and Section 7.2.1). 
A month is operationally defined to be 30.4375 days (=365.25/12). 
All summaries will be presented by treatment group unless otherwise specified. 
4.1 
Definition of Baseline 
In general, for efficacy endpoints the last observed measurement prior to randomisation will be 
considered the baseline measurement.  
For safety endpoints the last observation before first dose of study treatment will be considered the 
baseline measurement unless otherwise specified. For assessments on the day of first dose where 
time is not captured, a nominal pre-dose indicator, if available, will serve as sufficient evidence 
that the assessment occurred prior to first dose. 


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Assessments on the day of first dose where neither time nor a nominal pre-dose indicator are 
captured will be considered prior to first dose if such procedures are required by the protocol to be 
conducted before first dose. 
4.2 
Definition of Study Day 
For the purpose of efficacy data summaries, study day is defined with respect to the randomisation 
date. For visits (or events) that occur on or after randomisation, study day is defined as (date of 
visit [event] – date of randomisation + 1). For visits (or events) that occur prior to randomisation, 
study day is defined as (date of visit [event] – date of randomisation). 
For the purpose of safety data summary, Day 1 is defined as the date of first dose of study treatment 
(referred to in the protocol as C1D1). For visits (or events) that occur on or after first dose, dose 
day is defined as (date of visit [event] – date of first dose of study treatment + 1). For visits (or 
events) that occur prior to first dose, dose day is defined as (date of visit [event] – date of first dose 
of study treatment).   
Data listings for safety will include day number in numerical format and in CxDy format (referring 
to Cycle x Day y). 
4.3 
Visit Windows 
The planned analyses do not require the calculation of visit windows. 
4.4 
Handling of Missing Data 
In general, other than for partial dates, missing data will not be imputed and will be treated as 
missing with the exceptions specified for certain efficacy variables. 
4.4.1 Imputation of Partial Dates 
Concomitant medication and adverse events start dates 
• If the date is completely missing or if year is missing, then do not impute 
• If (year is present and month and day are missing) or (year and day are present and month 
is missing), impute as January 1st 
• If year and month are present and day is missing, impute day as first day of the month 
Concomitant medication and adverse events end dates 
• If the date is completely missing or if year is missing, then do not impute 
• If (year is present and month and day are missing) or (year and day are present and 
month is missing), impute as December 31st, unless this is after the date of death in 
which case date of death will be used instead 
• If year and month are present and day is missing, impute day as last day of the month, 
unless this is after the date of death in which case date of death will be used instead 
In addition, for AEs and concomitant medications if, for a partial start date, the start date could 
(when also considering the end date) potentially be on the first study medication date, the start 
date will be imputed with the first study medication date to assume a “worst case” scenario; e.g., 
AE from UNK-Feb-2014 to 23-Mar-2014 with first study medication date 21-Feb-2014, then the 
AE start date will be imputed to 21-Feb-2014. 


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4.4.2 Imputation Rules for Laboratory Values Outside of the Quantification Range 
Lab values below the lower limit of quantification (LLQ) that are reported as “<LLQ” or “≤LLQ” 
in the database will be imputed by LLQ × 0.99 for analysis purposes. The original value will be 
listed. 
Lab values above the upper level of quantification (ULQ) that are reported as “>ULQ” or “≥ULQ” 
in the database will be imputed by ULQ × 1.01 for analysis purposes. The original value will be 
listed. 
4.5 
Safety Observation Period 
The safety observation period is defined as time from first dose date of study treatment to the 
earlier of: the date of the decision to permanently discontinue study treatment +30 days, or date 
patient withdrew consent, or date of death, or data cut-off date. 
Generally, only the safety data (including AEs, laboratory results, vital signs, ECG, ECOG PS, 
concomitant medications, etc) reported during the safety observation period will be analysed and 
summarised, unless otherwise specified in this plan. 
4.6 
Definition of Prior and Concomitant Medications 
For the purpose of inclusion in summary tables, incomplete medication or radiation start and stop 
dates will be imputed as detailed in Section 4.4. Based on imputed start and stop dates: 
• Prior medications/radiation therapies are defined as medications or radiation therapies with 
a start date occurring before the date of first dose of study treatment 
• Concomitant medications/radiation therapies are defined as medications or radiation 
therapies that are already being taken or received on the date of first dose day, or which 
start after the date of first dose day where this start date is before the end of safety 
observation period 
Medications that have a start date before the date of the first dose of study treatment and that have 
a stop date after the date of the first day of study treatment will be included under both prior 
medications/radiation therapies and concomitant medications/radiation therapies. 
4.7 
Software 
All analyses will be conducted using SAS Version 9.4 or higher. 
4.8 
Changes to Planned Analyses 
Version 3 of this SAP was finalised prior to randomising the first patient, version 5 of this SAP 
was finalised prior to the data cut-off for the first interim analysis, and version 6 of this SAP was 
finalised prior to the IDMC meeting for the first interim analysis. None of the changes to the SAP 
made in versions 4, 5, or 6 (after randomising the first patient) were substantive, because these do 
not change the primary analyses of OS, ORR, or PFS, and no changes were made to methods of 
type 1 error control or to interim analysis boundaries. However, any future changes to the analyses 
described in the protocol or in approved versions of this plan that are substantive will be fully 
documented in an addendum to this plan that will also be approved by the Sponsor prior to 
conducting the analyses. Any such substantive changes will also be documented in the clinical 
study report. 


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5 
STUDY POPULATION SUMMARIES 
5.1 
Disposition 
The number of patients screened will be summarised; for screen failures, counts for the reasons 
why they were not randomised will also be provided. 
For the ITT population, counts and percentages will be provided by treatment group for each of the 
following: treated or untreated; treatment ongoing or treatment ended; primary reason for end of 
treatment as recorded on the eCRF; and whether the patient discontinued the study overall together 
with by primary reason for discontinuation from the study as recorded on the eCRF. For patients 
with withdrew consent as the primary reason for discontinuation from the study, separate counts 
will also be provided for the subset who withdraw consent to be followed for survival status, and 
the subset who agreed to continue to be followed for survival status only. 
For the ITT population, counts and percentages will also be provided for patients randomised 
before approval of a COVID-19 vaccine in their country, and for patients randomised after approval 
of a COVID-19 vaccine in their country. Appendix 5 provide details on the date that a COVID-19 
vaccine was first approved for emergency use for each country that randomized patients in the 
NuTide:121 trial. 
For each treatment group, the number of patients in each analysis population will be summarised.  
Summaries will be provided of any patients randomised that did not satisfy one or more inclusion 
criterion or who were randomised but satisfied one or more exclusion criterion. 
Major protocol deviations will be defined in a separate "Protocol Deviation Management Plan". 
They will be summarised by reason and overall. 
5.2 
Demographic and Baseline Characteristics 
For demographic and background characteristics at baseline summary statistics will be provided 
for continuous variables and counts with percentages will be provided for categorical variables.  
These analyses will be presented for patients in the ITT, ITTMD28, and Safety populations. 
5.2.1 
Demographic Characteristics 
• Age (continuous) 
• Age category 1 
o <65 years 
o ≥65 years 
• Age category 2 
o <65 years 
o 65 to <75 years 
o 75 to <85 years 
o ≥85 years 
• Sex 
o Male 
o Female 


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o Not reported 
• Ethnicity 
o Hispanic or Latino 
o Not Hispanic or Latino 
o Not reported 
• Race 
o American Indian or Alaska Native 
o Asian 
o Black or African American 
o Native Hawaiian or Other Pacific Islander 
o White 
o Not reported 
o Other 
• Geographic Region 
o Asia 
o Non-Asia 
 North America (Canada/USA) 
 Europe 
 Western Europe 
 Central/Eastern Europe 
 Australia/New Zealand 
 Rest of World 
 
5.2.2 Background Characteristics 
• Height in metres 
• Weight in kg 
• Body mass index (BMI) in kg/m2, calculated as (weight in kg) / (Height in m)2 - 
continuous 
• BMI category 
o < 25 kg/m2 
o 25 - < 30 kg/m2 
o ≥ 30 kg/m2 
• Smoking history 
o Current 
o Former 
o Never 


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5.3 
Medical History 
General medical history data will be coded per Medical Dictionary for Regulatory Authorities 
(MedDRA) version 20.0 (or higher), and summarised for the ITT population. 
5.4 
Cancer History and Current Disease Status 
For the ITT population as well as for the ITTMD28 and Safety populations, cancer history and 
current disease characteristics data collected related to cancer history will be summarised 
categorically or with descriptive statistics as appropriate. The following summaries are planned: 
• Diagnosis of BTC by histology or cytology (yes, no) 
• Time in years to randomisation since diagnosis of BTC as identified by histology or 
cytology 
• Primary tumour location (gallbladder, intra-hepatic, extra-hepatic, ampullary) 
• Extent of Disease (locally advanced, metastatic) 
• Measurable Disease (yes, no) 
o As assessed by the Investigator 
o As assessed by BICR 
• Number of target lesions as identified by the Investigator 
o Overall 
o By organ site 
• Number of target lesions as identified by BICR 
o Overall 
o By organ site 
• ECOG PS (0, 1, missing) 
5.5 
Randomisation Strata compared with Baseline Current Disease Status 
For the ITT population the occurrence of any cases of mis-stratifications in the randomisation will 
be summarised by:  
• Comparing primary tumour location (gallbladder, intra-hepatic, extra-hepatic/ampullary) 
as recorded on the eCRF with primary tumour location as used for stratification within the 
IxRS 
• Comparing extent of disease (locally advanced, metastatic) as recorded on the eCRF with 
extent of disease as used for stratification within the IxRS 
• Comparing measurable disease (yes, no) as assessed by BICR with measurable disease (yes, 
no) as used for stratification within the IxRS 
Patient counts, separately by treatment group, will also be provided for the complete 
cross-classification of the four stratification factors as used within the IxRS. 


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6 
TREATMENTS AND MEDICATIONS 
6.1 
Prior Anti-Cancer and Radiation Therapy 
Prior anti-cancer therapies will be coded per World Health Organisation drug dictionary 
(WHO-DD). 
The following will be summarised categorically or with descriptive statistics as appropriate for all 
patients in the ITT, ITTMD28, and Safety populations: 
• Prior adjuvant chemotherapy or low dose adjuvant chemotherapy with radiotherapy 
completed at least 6 months prior to study enrolment (yes, no) 
• Prior surgery for BTC (yes and completely resected, yes and incompletely resected, no) 
• Prior surgery for BTC with subsequent evidence of non-resectable disease that requires 
 systemic chemotherapy (yes, no) 
• Prior radiotherapy for local BTC disease with subsequent evidence of non-resectable 
 disease that requires systemic chemotherapy (yes, no) 
• Prior photodynamic therapy for local BTC disease with subsequent evidence of disease 
 progression that requires systemic chemotherapy (yes, no) 
• Prior photodynamic therapy for localised disease to relieve biliary obstruction with 
 subsequent evidence of disease progression that requires systemic chemotherapy (yes, no) 
• Prior surgery to implant a biliary stent (yes, no) 
• Stent currently in place (yes, no) 
• Type of stent (plastic, metal) 
• Length of time that stent has been in place (months) 
All prior non-radiation anti-cancer agents will be summarised categorically by Anatomical 
Therapeutic Chemical (ATC) Class Text and WHO-DD base substance preferred name by 
treatment group. Listing of these prior non-radiation anti-cancer agents will also be provided.  
6.2 
Prior Medications, Concomitant Medications, Prohibited Medications and 
Prohibited Procedures 
6.2.1  Prior and Concomitant Medications 
Medications recorded on the eCRFs will be coded using WHO-DD. Prior medications and 
concomitant medications will each be summarised by treatment group in the Safety population by 
ATC and WHO-DD base substance preferred name. 
6.2.2 Prohibited Medications and Prohibited Procedures 
An incidence table and a listing-type table will be provided for those Safety population patients 
who took prohibited medications. In addition, a listing-type table be be provided for Safety 
population patients who underwent prohibited procedures after randomisation. 
An IQVIA clinician will review all concomitant medication and procedure records via an Excel 
extract from the database. This regular review will be on a case-by-case basis and should a 
medication meet any of the prohibited criteria detailed in section 10.3.1 or appendix 3 of the study 
protocol, this will be indicated via a Prohibited Medication flag (Yes/No) that the clinician will 
add to the Excel file. This prohibited medication flag will be incorporated during the production 


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of the SDTM datasets, by importing and then merging this external Excel file with the respective 
raw data panels. 
Note: Post-randomisation procedures allowed by the protocol are summarized within Section 6.5. 
6.3 
Non-Protocol Anti-Cancer Therapy (NPACT) 
NPACT will be summarised for the ITT, ITTMD28, and Safety populations by ATC Class Text 
and WHO-DD base substance preferred name. This will include: 
• NPACT given in the period from the time of initial dosing of study medication on C1D1 
until the day of last dosing of study medication 
• Anti-cancer medications taken after the day of last dosing of study medication (subsequent 
anti-cancer medications) 
The date of first starting (where applicable) any subsequent anti-cancer medication will be listed 
for all patients in the ITT population.  
6.4 
Study Treatment Exposure and Study Treatment Modifications 
Study treatment exposure will be summarised categorically or with descriptive statistics, as 
appropriate, in the Safety population and in the ITTMD28 population. The following will be 
derived for each patient and summarised by treatment group: 
• Number of treatment cycles received overall and separately by: 
o Treatment cycles with cisplatin infused and NUC-1031 (Arm A) or gemcitabine 
(Arm B) infused on each day of the cycle on which infusions are received 
o Treatment cycles with NUC-1031 (Arm A) or gemcitabine (Arm B) infused on each 
day on which infusions are received, but with no cisplatin infusion during the cycle 
o Treatment cycles with NUC-1031 (Arm A) or gemcitabine (Arm B) infused on each 
of the two days (within the cycle) on which infusions are received, but with cisplatin 
infusion given on only one out of those two days 
• Number of days with infusions received overall and separately by: 
o Number of days with infusion received containing cisplatin (Arm A and Arm B) and 
infusion also received containing NUC-1031 (Arm A), or containing gemcitabine 
(Arm B) 
o Number of days with infusion received containing NUC-1031 (Arm A) or containing 
gemcitabine (Arm B), but on which day no infusion of cisplatin was given 
• Number of infusions delayed separately by: 
o Number of cisplatin infusions delayed 
o Number of NUC-1031 (Arm A) or gemcitabine (Arm B) infusions delayed 
• Total dose given during the study 
o Total dose given during the study of NUC-1031 (Arm A), or gemcitabine (Arm B) 
o Total dose of cisplatin given during the study 
• Relative dose intensity (RDI) 
o RDI for NUC-1031 (Arm A), or gemcitabine (Arm B) 
o RDI for cisplatin 


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RDI is calculated as 100% × (d/D), where d is the actual cumulative dose delivered up to the actual 
last day of dosing and D is the intended cumulative dose to be delivered up to the actual last day 
of dosing. 
Treatment modifications (interruptions, temporary modifications, permanent reductions) in study 
drug dosing due to AE/toxicity will be summarised in the Safety population. In this summary 
patients will be included in the counts for each treatment modification that applies. Counts will 
also be given for patients with none of these treatment modifications. Such modifications will be 
summarised separately for: (i) the cisplatin component; (ii) the NUC-1031 (Arm A) or gemcitabine 
(Arm B) component; and (iii) for either component of the treatment regimen. In addition, 
permanent discontinuations of cisplatin (where the patient continues on NUC-1031 [Arm A] or 
gemcitabine [Arm B]) will also be summarised. 
6.5 
Post-randomisation Surgery/Procedure, including Biliary Stenting 
Post-randomisation surgery/procedures that impacted the tumour lesion (Yes, No, Unknown) will 
be summarised by treatment group for patients in the ITT and ITTMD28 populations. 
7 
EFFICACY ANALYSES 
7.1 
Primary Efficacy Endpoints 
7.1.1 Overall Survival 
7.1.1.1 Definition of Overall Survival 
Duration of OS is defined as the time from randomisation to the time of death due to any cause. 
For patients who are alive at the time of a data cut-off or are permanently lost to follow-up, duration 
of OS will be censored at the date at which they were last known to be alive. 
The date at which the patient is last known to be alive is defined as the latest date of: (i) last site 
visit; (ii) last date at which the patient had a radiographic scan; and (iii) last date at which the 
patient, the study investigator, their other physicians, or a family member confirmed that the patient 
was alive. 
When expressed in months: 
OS = (earliest date of death or censoring – date of randomisation + 1) × [12/365.25] 
7.1.1.2 Primary Analysis of Overall Survival 
The primary analysis of OS will be performed using the ITT population. As described further in 
Section 7.3.1 (with summary in Table 2) as well as in Section 7.4 (as illustrated there in Table 4), 
OS will be assessed for demonstration of efficacy on 3 occasions, i.e., after approximately 425 OS 
events (67%), after 541 OS events (85%), and after 637 OS events (100%). At each of these 3 looks 
the treatment effect for OS will be assessed by the stratified log-rank test. The one-sided p-value 
will be compared with the critical values as derived in Section 7.4 (and illustrated in Table 4) to 
determine if statistical significance has been obtained at that time.  
To determine the stratification factors (primary tumour location, extent of disease, measurable 
disease at baseline, and region) to be included within the stratified log-rank test the following rule 
is used: consider the 24 combinations of the stratification factor levels (as used within the IxRS at 
randomisation), i.e., primary tumour location (gallbladder, intra-hepatic, extra-hepatic/ampullary), 
extent of disease (locally advanced, metastatic), measurable disease at baseline (yes, no), and 


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region (Asia, non-Asia). If for any of the 24 combinations (cells) there are less than 10 OS events, 
then the factor (when considered separately) that has the category which contains the smallest 
number of OS events will be removed from the stratified analysis. The removal of stratification 
factors will continue until all cells contain at least 10 OS events. The rule will be implemented at 
Interim Analysis 2 which is the first look at which OS determination of efficacy is to be made. The 
same resultant set of stratification factors will also be used (without change) for analyses of OS at 
Interim Analysis 3 and at the Final Analysis. It will also be used for the analysis of PFS. 
A stratified Cox proportional hazards model with Efron's method of handling ties will be used to 
estimate the HR for OS. The model will include a term for treatment and the same set of 
stratification factors as used within the stratified log-rank test. The 100 (1-2α) % two-sided CI for 
the HR will also be derived where "α" is the "Critical p-value (1-sided)" for OS derived as described 
in Section 7.4 and illustrated there in Table 4. 
Overall counts of deaths will also be summarized together with counts for censored patients 
subdivided into those still in survival follow-up, patients who are lost to follow up, and patients 
who have withdrawn consent to continue to be followed for survival status. The non-parametric 
Kaplan-Meier method will also be used to estimate the survival curves, within which Greenwood's 
formula will be used to derive the standard error. The number of patients at risk at the start of each 
3-month timepoint after randomisation will also be displayed. The median survival time will be 
estimated for each treatment group, together with its 95% CI using the Brookmeyer & Crowley 
(1982) method. Estimates of the 25th and 75th percentiles will also be derived together with their 
corresponding CIs. 
7.1.1.3 Secondary, Supportive, and Sensitivity Analyses of Overall Survival 
A secondary analysis of OS based on a stratified Cox proportional hazards model will be carried 
out in the same manner as described in Section 7.1.1.2, but with terms for treatment and ECOG 
status at baseline (0 or 1), as well as including terms for any of the design stratification factors 
which (based on the rule given above) are not able to be included as analysis stratification factors. 
Subgroup analyses of OS for each of the randomisation stratification factors as well as for other 
important factors will be provided as described in Section 7.9. 
The analyses of OS described in Section 7.1.1.2 will also be carried out based on the MITT 
population (which is the subset of the ITT population including only those patients that received 
any study medication), and these analyses will be viewed as supportive. 
In addition, the analyses described in Section 7.1.1.2 will be carried out on a subset of the ITT 
population which excludes those patients for whom either of the following conditions related to 
particular prior treatment were identified at Screening: (i) Prior treatment with NUC-1031, 
gemcitabine, cisplatin, or other platinum-based agents (Condition 1); or (ii) Prior systemic therapy 
for advanced or metastatic biliary tract cancer other than as allowed in the adjuvant setting as 
specified in the Protocol's wording of exclusion criterion 2 (Condition 2).  These analyses will also 
be viewed as supportive. 
Sensitivity analyses for the stratified log-rank test and for the stratified Cox proportional hazards 
model will be carried out for OS based on the ITT population, as described in Section 7.1.1.2 , but 
where the stratification factors (for primary tumour location and for extent of disease) are derived 
using information recorded by the investigator at the Screening Visit (rather than using the 
information that the investigator entered into the IxRS at randomisation). To determine the 


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stratification factors to be used in the stratified log-rank test and in the stratified Cox proportional 
hazards model an analogous procedure to that described in Section 7.1.1.2 will be used but now 
starting with the 24 combinations of: (i) primary tumour location as recorded by the investigator at 
the Screening Visit; (ii) extent of disease as recorded by the investigator at the Screening Visit; (iii) 
measurable disease (yes, no) at baseline as entered by the BICR into the IxRS; and (iv) Region. 
The methods described in Section 7.1.1.2 assume censoring is at random. Since censoring may 
depend upon progression, and progression is expected to be affected by treatment group, it is 
possible that censoring may be informative, i.e., may vary systematically between treatment 
groups. Therefore, methods which assume censoring not at random (CNAR) will be used to assess 
the robustness of the inference from the primary analysis for OS. 
To allow straightforward comparison with the planned Cox proportional hazards regression 
analysis, multiple imputation of time to event using the Cox model will be used to implement the 
CNAR analyses (Lipkovich et al, 2016). Full details of the methodology and its assumptions are 
presented in the paper cited. The analysis will use the SAS macro publicly available at 
missingdata.org.uk under the “DIA working group” tab, at the “Imputation approaches” option 
under “Multiple imputation for time to event data under Kaplan-Meier, Cox or piecewise-
exponential frameworks – SAS macros”, downloadable as Package_Release_V3 Final.zip.  
A tipping point approach will be used. For all patients censored in the primary analysis of OS for 
whom a progression has occurred, irrespective of treatment group, this analysis will as a first step 
assume censoring at random but will then impose a multiple of the estimated hazard of death – say 
delta – before imputing censored times to event. In a tipping point analysis, the quantity delta is 
successively increased in a sequence of analyses, i.e., the assumption about post-censoring hazard 
is made more severe. Note that the patients thus CNAR in the tipping point approach would be 
only those patients who are censored in the primary analysis (excluding patients administratively 
censored due to reaching the data cut-off date) and who progressed at any time whether the 
progression occurred while on study treatment, or if it occurred after discontinuing study treatment, 
and even if it occurred after starting another cancer treatment. Depending upon the patterns of 
censoring there may be a delta  large enough such that inference made by the primary analysis no 
longer holds – this would be the “tipping point”. If the “tipping point” delta exists and is judged 
unrealistically high, then this provides evidence to help assess the robustness of inference from the 
primary analysis to the assumption of censoring at random. 
The Restricted Mean Survival Time (RMST) method may also be conducted for OS to account for 
any possible non-proportional hazards and to estimate the absolute benefit of experimental 
treatment. Here RMST would be evaluated at: (i) the minimum of the maximum observed event 
time of each arm (minimax event time); (ii) 24 months; (iii) 18 months; and (iv) 12 months. 
Treatment groups would then be compared in each case using the SAS RMSTREG procedure (SAS 
Institute Inc. 2020). In addition to a term for treatment the model will include covariables (as 
CLASS variables) corresponding to the variables that are identified as stratification factors in the 
primary analysis of OS by the method described in Section 7.1.1.2. 


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7.1.1.4 Additional Sensitivity Analyses for Overall Survival as a Result of the COVID-19 
Pandemic 
All analyses for Overall Survival in Sections 7.1.1.2 and 7.1.1.3 are based on all-cause mortality, 
i.e., include OS events with cause of death not reported as COVID-19 as well as OS events with 
COVID-19 cause of death.  All analyses in those two sections also include all OS events regardless 
of whether or not the patient discontinued treatment due to a COVID-19 infection. 
A first set of COVID-19-related sensitivity analyses for OS will be carried out using each method 
described in Section 7.1.1.2, but where in each case, patients with COVID-19 recorded as the cause 
of death will be censored at their date of death. Frequencies and percentages based on the ITT 
population will also be derived for each treatment group separately for: (i) OS with cause of death 
related to reasons other than COVID-19; and (ii) OS with cause of death reported as COVID-19.  
Note: As the eCRF does not include a category of COVID-19 as the primary cause of death the 
identification of such cases is carried out using the following two-stage process: (i) cases 
that are potentially COVID-19 deaths are found by first searching the primary cause of 
death on the death details page of the eCRF for the text 'COVID', 'VIRUS', 'CORONA', or 
'19'; and then (ii) all cases found by the search in (i) will be manually reviewed to identify 
cases where 'COVID-19' is the primary cause of death. 
A second set of COVID-19-related sensitivity analyses for OS will be carried out using each 
method described in Section 7.1.1.2, but where patients discontinuing treatment due to a 
COVID-19 infection will be censored at the date of such treatment discontinuation. Any patients 
that did not discontinue treatment due to a COVID-19 infection but who died with COVID-19 
cause of death will be censored at their date of death.  Frequencies and percentages based on the 
ITT population will also be derived for each treatment group separately for: (i) OS with cause of 
death related to reasons other than COVID-19 in patients who did not discontinue treatment due to 
a COVID-19 infection; and (ii) all other deaths. 
While these two sets of analyses include all statistical methods described within Section 7.1.1.2, 
greater emphasis will be placed here on the estimated hazard ratios rather than on statistical 
significance. This is because the power will be lower than originally planned because fewer OS 
events will be able to be included in these analyses. 
In addition to the sensitivity analyses for OS described above, further sensitivity analyses for OS 
may ultimately be needed once the nature and extent of the direct and indirect impact of COVID-19 
becomes clearer, and such additional analyses will then be described within future versions of this 
SAP. 
7.1.2 Objective Response Rate 
7.1.2.1 Derivation of Best Overall Response 
Radiographic disease assessment will be made by BICR using RECIST v1.1 for all randomised 
patients. A detailed description of how RECIST v1.1 is implemented within the current study is 
given in Appendix 2. For all scheduled and unscheduled visits at which radiographic scans take 
place, these scans will be reviewed by two independent radiologists, each of whom will record all 
details as described within Appendix 2. The two radiologists will independently derive each 
timepoint response categorisation (into CR, PR, SD, PD, or Not Evaluable [NE]) in accordance 
with Appendix 2 Table 1,  i.e., the response obtained overall at each visit by assessing target lesions, 
non-target lesions, and new lesions. The BICR Charter describes the process by which the reviewer 


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who made what is regarded as the "definitive assessment" is identified in the case that adjudication 
is required. All statistical analyses based on BICR assessment will, for a given patient, be based 
only on the independent reviewer who provided this "definitive assessment". 
Then based on the timepoint response categorisations made by this independent reviewer the BOR 
from BICR will be derived programmatically using the rules given in Appendix 2 Table 3, taking 
into account:  
(i)  Confirmation after at least 28 days is required for CR or PR; 
(ii)  For classification as SD, the radiographic assessment on which this is based must have met 
the SD criteria at least once after C1D1 at a minimum of 8 weeks later (i.e., allowing for the 
earliest possible time from the 8-10 week window for the first scheduled scan);  
(iii) In patients who discontinue treatment without progression, timepoint responses will be 
considered in the calculation of BOR only up until the time that the patient receives a 
subsequent anti-cancer therapy; and 
(iv)  The rules given in Appendix 3 for when patients have one or more intermediate visits with 
timepoint responses of NE. 
From the investigator's review of the imaging scans their recorded tumour response data will be 
used to programmatically determine each patient's timepoint response categorisation (into CR, PR, 
SD, PD, or NE) in accordance with Appendix 2 Table 1 for patients in the ITTMD population, or 
categorisation (into CR, non-CR/non-PD, PD, or NE) in accordance with Appendix 2 Table 2 from 
for patients randomised to the non-measurable disease at baseline stratum.  The BOR will then be 
derived programmatically using the rules given in Appendix 2 Table 3, taking into account (i)-(iv) 
above. 
Note: The independent reviewer's timepoint response categorisation is used prior to 
programmatically deriving BOR based on BICR assessment. However, for BOR based on 
investigator assessment the timepoint response is also derived programmatically. 
7.1.2.2 Primary Analysis of Objective Response Rate 
All analyses of ORR will be based only on patients randomised to the stratum corresponding to 
having measurable disease at baseline. As described further in Section 7.3.1 and summarised there 
in Table 2, ORR will be assessed for demonstration of efficacy on two occasions which are 
scheduled to take place 28 weeks after 418 patients in this stratum, and 28 weeks after 644 patients 
in this stratum have been randomised. This minimum period of follow-up allows for three 
scheduled post-baseline radiographic scans plus a one-week visit-window. Let NM28 denote the 
actual number of patients in the ITTMD population that were randomised ≥28 weeks before the 
data cut-off for a given interim analysis, i.e., NM28 denotes the number of patients in the ITTMD28 
population.   
The primary analysis of ORR at a given look will be performed based on the NM28 patients in the 
ITTMD28 population, where ORR is then defined as the proportion of the NM28 patients within the 
treatment group that have BOR of CR or PR based on BICR assessment. 
Note: For the first interim analysis all patients randomised on the day that the 418th patient in this 
stratum is randomized will be included in the ITTMD28 population. Likewise, for the 
second interim analysis all patients randomised on the day that the 644th patient in this 
stratum is randomized will be included in the ITTMD28 population. 


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Note: At the time of the data cut-off for each of the two interim analyses at which ORR is assessed, 
there will be some of the NM28 patients who have an unconfirmed response based on 
investigator assessment at their most recent radiographic scan (with no earlier confirmed 
response based on investigator assessment) but who have not yet had their confirmatory 
radiographic scan. The date of the latest unconfirmed response over all such patients 
(DATELUR) will be determined. Radiographic assessments (by BICR and by the 
investigator) from those confirmatory scans which are scheduled to take place within at 
most 6 weeks after DATELUR will be included at the interim analyses only in the calculation 
of counts with confirmed CR, counts with confirmed PR, and in ORR. 
At each of these two looks, the odds ratio for ORR will be assessed by the stratified 
Cochran-Mantel-Haenszel (CMH) test. The one-sided p-value will then be compared with the 
critical values as derived in Section 7.4 and illustrated in Table 3 to determine if statistical 
significance has been obtained at that time for ORR.  
Measurable disease (yes/no) will not be used as a stratification factor for the CMH test because all 
ITTMD patients will be randomised to the measurable disease at baseline stratum. To determine 
the remaining stratification factors (primary tumour location, extent of disease, and region) to be 
included within the stratified CMH test the following rule is used: consider the 12 combinations of 
the stratification factor levels (as used within the IxRS at randomisation), i.e., primary tumour 
location (gallbladder, intra-hepatic, extra-hepatic/ampullary), extent of disease (locally advanced, 
metastatic), and region (Asia, non-Asia). If for any of the 12 combinations (cells) there are less 
than 10 patients, then the factor (when considered separately) that has the category which contains 
the smallest number of patients will be removed from the stratified analysis. The removal of 
stratification factors will continue until all cells contain at least 10 patients. The rule will be 
implemented on the NM28 patients at Interim Analysis 1 which is the first look at which ORR 
determination of efficacy is to be made. The same resultant set of stratification factors will also be 
used (without change) for analysis of ORR at Interim Analysis 2. 
Note:  In analyses of ORR the values from the IxRS at randomisation will be used for the 
stratification factors, even if it is subsequently found that these values were incorrect for 
one or more patient.  
The Mantel-Haenszel estimate of the common odds ratio will be derived, together with the 100 (1-
2α) % two-sided CI for the odds ratio, using the Robins et al (1986) variance estimate,  where "α" 
is the "Critical p-value (1-sided)" for ORR derived as in Section 7.4 and illustrated there in Table 3.   
Counts for patients with a BOR of CR, PR, SD, PD, or NE, based on BICR assessment, will also 
be presented by treatment group for the NM28 patients.  
Clopper-Pearson exact 95% two-sided CIs for ORR based on BICR assessment will be provided 
separately by treatment group (Clopper & Pearson, 1934). 
7.1.2.3 Secondary, Supportive, and Sensitivity Analyses of Objective Response Rate 
Let NM denote the total number of patients in the ITTMD population that were randomised before 
the data cut-off for a given interim analysis (regardless of how long beforehand they were 
randomised). As a supportive analysis, the CMH test as described in Section 7.1.2.2 will also be 
carried out for ORR using BICR assessment, based on the NM patients. Counts for patients with a 
BOR of CR, PR, SD, PD, or NE, based on BICR assessment, will also be presented by treatment 
group for the NM patients. 


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Counts will also be provided by treatment group for the number out of the NM patients in the 
ITTMD population that have tumour resection. Counts will also be provided separately by the 
number of such patients that: (i) previously had a confirmed PR; or (ii) did not previously have a 
confirmed PR. 
A secondary analysis of ORR will also be provided in terms of the difference in proportions based 
on BICR assessment. This estimate of the difference in ORRs will be based on Mantel-Haenszel 
weights (using the same stratification factors derived using the methodology described in Section 
7.1.2.2). The p-value and the corresponding 100 (1-2α) % two-sided CI will be calculated for the 
NM28 patients in the ITTMD population using the Sato variance estimator (Sato, 1989). 
Subgroup analyses of ORR based on BICR assessment will be provided as described in Section 7.9. 
The analyses of ORR based on BICR assessment as described in Section 7.1.2.2 will also be carried 
out based on the subset of the NM28 patients in the ITTMD population patients that received any 
treatment, and these analyses will be viewed as supportive. 
In addition, the analyses of ORR based on BICR assessment as described in Section 7.1.2.2 will 
also be carried out on the subset of the ITTMD28 population which excludes those patients for 
whom Condition 1 or Condition 2 (related to particular prior treatment, as defined in Section 
7.1.1.3) applies. These analyses will be viewed as supportive. 
Sensitivity analyses for the stratified CMH test will be carried out for ORR based on the ITTMD28 
population, as described in Section 7.1.2.2, but where the stratification factors (for primary tumour 
location and for extent of disease) are derived using information recorded by the investigator at the 
Screening Visit (rather than using the information that the investigator entered into the IxRS at 
randomisation). To determine the stratification factors to be used in the stratified CMH test an 
analogous procedure to that described in Section 7.1.2.2 will be used but now starting with the 12 
combinations of:  (i) primary tumour location as recorded by the investigator at the Screening Visit; 
(ii) extent of disease as recorded by the investigator at the Screening Visit; and (iii) Region. 
To provide a more detailed understanding of anti-tumour activity, the maximum tumour reduction 
since baseline in target lesions will be derived for the subset of those NM28 patients from the ITTMD 
population who have baseline and at least one post-baseline measure. The maximum percentage 
tumour reduction from baseline in target lesions for each group will be displayed graphically using 
waterfall plots. For each patient, data from time points after the first date of any of the censoring 
outcomes defined for the primary analysis of PFS as described in Section 7.2.1.2 will be excluded 
from the waterfall plots. 
Further supportive analyses of ORR will be carried out based on Investigator assessment of 
response, within which CR, PR, SD, PD, NE, and then BOR will all be determined 
programmatically. All analyses described for BICR assessment (except for the subgroup analyses) 
will also be conducted based on Investigator assessment.  
In addition, a concordance analysis will be performed in which separately for each treatment group 
the categories (PR/CR or SD/PD/NE) of BOR for BICR assessment will be presented 
cross-classified with the corresponding categories based on Investigator assessment. For this 
concordance analysis, only those ITTMD28 population patients that are considered by the 
Investigator as having measurable disease at baseline will be included, i.e., the analysis will be 
based on patients considered by both the BICR and the Investigator to have measurable disease at 
baseline. 


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7.1.2.4 Additional Sensitivity Analyses for ORR as a Result of the COVID-19 Pandemic 
For ORR, additional sensitivity analyses that account for the impact of COVID-19 will be 
described in a future version of this SAP, once the nature and extent of the impact becomes clearer.  
The focus of the additional sensitivity analyses will be on effect sizes (e.g., in terms of odds ratios) 
rather than on statistical significance because the power will be lower than originally planned as 
fewer patients will be able to be included in these analyses. 
Potential impacts of COVID-19 on ORR include death due to COVID-19 prior to response, 
treatment discontinuation or interruption due to COVID-19, delayed or missing regular scheduled 
radiographic scans, and delayed or missing confirmatory radiographic scans (following a PR or 
CR). For radiographic scans these delays could be directly related to COVID-19, such as resulting 
from the patient's COVID-19 infection, or the delays could be indirectly related to COVID-19, 
such as caused by regional lockdowns (or by other logistical reasons). These sensitivity analyses 
will clearly specify whether only the direct impact of COVID-19 is to be taken into account, or 
whether the indirect impact of COVID-19 will also be taken into account. 
7.2 
Key Secondary Efficacy Endpoint 
7.2.1 Progression-Free Survival (PFS) 
7.2.1.1 Definition of Progression-Free Survival 
PFS will be calculated as the time from randomisation until objective disease progression or death 
from any cause, whichever occurs earlier. PFS based on BICR assessment is the single key 
secondary efficacy parameter. 
Progression will be based on radiographic assessments only, and whether or not a patient has a 
progression will be determined for each scheduled visit and for any unscheduled visits. For patients 
with target lesions at baseline (and so having measurable disease at baseline), whether or not a 
patient has PD at a timepoint will be determined by Appendix 2 Table 1. For patients with no target 
lesions at baseline (and so having non-measurable disease at baseline), whether or not a patient has 
PD at a timepoint will be determined by Appendix 2 Table 2, where "unequivocal PD" is defined 
as an increase in overall disease burden that is comparable in magnitude to the increase that would 
be required to declare PD for measurable disease, i.e., an increase in tumour burden representing 
an additional 73% increase in volume (which is equivalent to a 20% increase in diameter in a 
measurable lesion). Examples include an increase in a pleural effusion from ‘trace’ to ‘large’, an 
increase in lymphangitic disease from localised to widespread, or an increase sufficient to require 
a change in therapy. 
7.2.1.2 Analyses for Progression-Free Survival 
For all analyses of PFS, the recorded date of radiographic progression is the date of the tumour 
assessment visit at which progression is declared. If multiple scan dates are associated with a 
tumour assessment visit, the earliest assessment date within the set will be chosen as the 
progression date. 
Only adequate tumour assessments (ATAs) will be considered in the determination of radiographic 
progression and censoring dates. Here ATA is defined as one that results in a time point assignment 
of: response (complete or partial), SD/(non-CR, non-PD), or progression. For the primary analysis 
of PFS, the censoring scheme described in Table 1 will be used. 


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The rules within Table 1 are consistent with European Medicines Agency (EMA) Appendix 1 to 
the guideline on the evaluation of anti-cancer medicinal products in man (2012). The rules in 
Table 1 are also fully consistent with the rules given in Table C2 from FDA Guidance for Industry: 
Clinical Trial Endpoints for the approval of non-small cell lung cancer drugs and biologics (2015). 
The primary analysis of PFS will be performed using the ITT population. As described further in 
Section 7.4, PFS will be assessed for demonstration of efficacy only at Interim Analysis 2, at which 
time approximately 534 PFS events are projected to have occurred. PFS will be assessed by the 
stratified log-rank test, with the same set of stratification factors as identified for use with OS. If 
statistical significance is obtained for both ORR and OS (see Section 7.4) then PFS will be tested, 
at the 2.5% one-sided significance level. A stratified Cox proportional hazards model with Efron's 
method of handling ties will be used to estimate the HR for PFS, in which the model only includes 
the term for treatment. The 95% two-sided CI for the HR will also be derived for PFS from this 
model. If instead statistical significance is obtained for OS but not for ORR (see Section 7.4) then 
the above testing will be carried out at the 0.8% one sided significance level and the CI for the HR 
will be 98.4% two-sided. 
 
 


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Table 1 
Censoring scheme used in the Primary Analysis of PFS 
Case Situation 
Date of Progression or Censoring 
Outcome 
1 
Incomplete or no baseline 
tumour assessments 
Randomisation 
Censored 
2 
Progression documented 
between scheduled visits 
 Earliest time at which progression can be 
declared: 
• Date of first progression assessment 
showing new lesion (if progression is based 
on new lesion); or 
• Date of first radiological assessment of 
target lesions showing a predefined increase 
in the sum of the target lesion 
measurements 
Progressed 
3 
No progression 
Date of last progression assessment with no 
documented progression 
Censored 
4 
Treatment discontinuation 
for undocumented 
progression 
Date of last progression assessment with no 
documented progression 
Censored 
5 
Death or Progression after 
treatment discontinuation 
for toxicity or other non-
progression related reason 
Date of progression or death, whichever occurs 
first 
Progressed 
6 
Death or Progression after 
new anti-cancer treatment 
started 
Date of progression or death, whichever occurs 
first 
Progressed 
7 
Death before first scheduled 
PD assessment 
Date of death 
Progressed 
8 
Death after adequate 
progression assessment visit 
or death after one missed 
visit (where in either 
situation there is no previous 
documentation of 
progression) 
Date of death 
Progressed 
9 
Death or progression after 
more than one missed visit 
Date of progression or death, whichever occurs 
first 
Progressed 
Note: Missed visit includes visits that were completely missed or visits that did not have an adequate tumour
assessment (ATA), and "progression assessment" in the above censoring rules only refers to visits with ATA. 
 


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Overall counts of patients with a PFS event will be provided together with counts for RECIST 
progression, and counts for death in the absence of progression. For RECIST progression separate 
counts will also be given for progression based on target lesions, non-target lesions, and new 
lesions, where for patients who have progression from multiple sources, the earliest source of 
progression is presented. If the earliest progression event occurs from multiple sources then the 
progression events will be categorized using the precedence ordering: Target lesions, non-target 
lesions, new lesions. Counts will also be provided for censored patients subdivided into those 
progression-free at the time of analysis, patients who are lost to follow up, and patients who have 
withdrawn consent. For patients who have multiple censoring reasons the earliest of such 
censorings will be used. 
The Kaplan-Meier method will also be used to estimate the survival curves for PFS in each 
treatment group, within which Greenwood's formula will be used to derive the standard error. The 
number of patients at risk at the start of each 3-month timepoint will also be displayed. The median 
will be estimated for each treatment group, together with its CI using the Brookmeyer & Crowley 
(1982) method. Estimates of the 25th and 75th percentiles will also be derived together with their 
corresponding CIs. 
Supportive analyses will also be carried out for each of the analyses of PFS described above (using 
the censoring scheme as defined for the primary analysis) based on the subset of the ITT population 
which excludes those patients for whom Condition 1 or Condition 2 (related to particular prior 
treatment, as defined in Section 7.1.1.3) applies. 
The first sensitivity analysis of PFS will follow the primary analysis except for the following 
change to Case 6: 
• Patients with new anti-cancer treatment started (with no prior documented progression) will 
be censored at the date of their last progression assessment (prior to starting new anti-cancer 
treatment). 
The second sensitivity analysis of PFS, which is fully consistent with Table C1 from FDA 
Guidance for Industry: Clinical Trial Endpoints for the approval of non-small cell lung cancer drugs 
and biologics (2015) will follow the rules from the first sensitivity analysis but will also make the 
following changes to Cases 5 and 9: 
• Patients with treatment discontinuation (for toxicity, or for another non-progression-related 
reason) and no documented prior progression will be censored at the date of the last 
progression assessment (prior to treatment discontinuation)  
• Patients that die or progress after more than one missed visit will be censored. The date of 
censoring will be the date of last progression assessment with documented non-progression, 
or date of randomisation if all post-baseline progression assessments were missed. 
 
Note: In the second sensitivity analysis any patient who meets the conditions for both Case 5 and 
Case 6 will be censored at the earliest of the two possible censoring dates. 
Supportive analyses of PFS based on Investigator assessment will also be carried out using each of 
the three sets of censoring rules defined above. 


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Additional sensitivity analyses based on the stratified log-rank test and based on the stratified Cox 
proportional hazards model will be carried out for PFS (using the censoring scheme as defined for 
the primary analysis), but where, as described for OS in Section 7.1.1.3, the stratification factors 
(for primary tumour location and for extent of disease) are derived using information recorded by 
the investigator at the Screening Visit (rather than using the information that the investigator 
entered into the IxRS at randomisation). The stratification factors to be used in the stratified log-
rank test and in the stratified Cox proportional hazards model will be the same set as identified for 
the corresponding analysis of OS in Section 7.1.1.3. 
In case the proportional hazards assumption is not valid supportive analyses using the RMST 
method may be conducted for PFS to account for a possible non-proportional hazards effect. Here 
RMST would be evaluated at: (i) the minimum of the maximum observed event time of each arm 
(minimax event time); (ii) 18 months; and (iii) 12 months. Treatment groups would then be 
compared in each case using the SAS RMSTREG procedure (SAS Institute Inc. 2020). In addition 
to a term for treatment the model will include covariables (as CLASS variables) corresponding to 
the variables that are identified as stratification factors by the method described in Section 7.1.1.2. 
For PFS based on BICR assessment, a sensitivity analysis will be carried out for the ITT population 
based on Table 1, but where patients with a COVID-19 cause of death and with no prior progression 
will be censored at their time of death. Additional sensitivity analyses of PFS based on BICR 
assessment may be needed once the nature and extent of the direct and indirect impact of 
COVID-19 becomes clearer, and such additional analyses will be described within a future version 
of this SAP. 
7.3 
Interim Analyses 
7.3.1 Determination of Efficacy at the Interim Analyses 
Three interim efficacy analyses are planned in addition to the final analysis: 
• The first interim analysis (Interim Analysis 1) will evaluate the ORR primary endpoint. It 
will be performed 28 weeks after 418 patients in the measurable disease stratum have been 
randomised 
• The second interim analysis (Interim Analysis 2) will evaluate the ORR and OS primary 
endpoints. It will be the final analysis for ORR and the first interim analysis (for 
demonstration of efficacy) for OS. It will be performed 28 weeks after 644 patients in the 
measurable disease stratum have been randomised. It is estimated that approximately 
425 deaths will be observed by this time. 
• The third interim analysis (Interim Analysis 3) will evaluate the OS primary endpoint for 
which it will be the second interim analysis (for demonstration of efficacy) and it will take 
place after 541 deaths have been observed. 
• The final analysis will evaluate the OS primary endpoint. It will take place after 637 deaths 
have been observed, and is expected to occur approximately 48.0 months after the first 
patient is randomised 
PFS, the key secondary endpoint will also be assessed at Interim Analysis 2 and approximately 
534 patients are expected to have a PFS event at this time. 
The assessment of futility at Interim Analysis 1 is described in Section 7.3.2, and the power 
re-assessment at Interim Analysis 3 is described in Section 7.3.3. 


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A summary of the planned analyses for demonstration of efficacy, with timings, and primary 
endpoints to be evaluated, is given in Table 2. 
If ORR crosses its efficacy boundary at Interim Analysis 1, and provided that a further assessment 
of ORR is not required by regulators, then the driver of timing for Interim Analysis 2 will instead 
be the occurrence of 425 OS events. 
Table 2: 
Analyses Planned, Primary Endpoints Evaluated, Approximate Timing, and 
Drivers of Timing 
Analysis 
Primary Endpoints 
Assessed for 
Demonstration of Efficacy 
Approximate 
Time 
(months) 
Driver of Timing 
Interim Analysis 1 
ORR 
~25.51,2 
NM28 = 418 patients 
Interim Analysis 2 
ORR, OS 
~33.11,2 
NM28 = 644 patients (~425 OS1,3 
events expected at this time) 
Interim Analysis 3 
OS 
~40.01,3 
541 OS events 
Final Analysis 
OS 
~48.01,3 
637 OS events 
1. Approximate times for all 4 looks and approximate number of OS events at Interim Analysis 2 assume a 30-month duration 
of enrolment with gradual ramp-up (as described in Section 2.4) over the first 12 months, and a constant rate of enrolment for 
the next 18 months.  
2. Approximate times for the first 2 looks also assume that the percentage of patients with non-measurable disease at baseline is 
exactly 10%. 
3. Approximate times for the last 2 looks and the approximate number of OS events at Interim Analysis 2 further assume that: 
(i) OS events follow an exponential distribution with a 11.7-month median for the control arm (Arm B) as well as a median of 
11.7/0.76 months  in Arm A; (ii) The rate of discontinuation of treatment and the rate of discontinuation from the study (for Arm 
A and for Arm B) are both comparable to the rates seen in the gemcitabine plus cisplatin arm of ABC-02; and (iii) A total of 2% 
of patients will be lost to follow-up for OS. 
Note: PFS, the key secondary endpoint, will also be assessed at Interim Analysis 2. 
Abbreviations: NM28=Number of patients randomised in the measurable disease stratum with the opportunity for ≥28 weeks of 
follow-up; ORR=objective response rate; OS=overall survival. 
 
7.3.2 Interim Analysis for Assessment of Futility 
At Interim Analysis 1, a futility analysis will take place based on the OS endpoint. A total of 
approximately 258 OS events are expected to have occurred, which represents approximately 41% 
of the required number (637) of OS events. The futility boundary is Z1 < ZFUT, where Z1 is derived 
from a log-rank test stratified by primary tumour location (gallbladder, intra-hepatic, 
extra-hepatic/ampullary) and extent of disease (locally advanced, metastatic), where ZFUT = 0.0. 
This boundary can be viewed as corresponding to an effect size favouring the control arm. Kaplan-
Meier plots will be produced for OS at Interim Analysis 1 to determine if there is any evidence of 
delayed onset of efficacy. The value of Z1 from this stratified log-rank test as well as Kaplan-Meier 
plots will also be derived for the two additional types of sensitivity analyses that are described in 
Section 7.1.1.4. These two sensitivity analyses have been included with the aim of at least partially 
taking account of the COVID-19 pandemic on OS. The IDMC will indicate whether or not they 
recommend stopping the study for futility. Such a recommendation to stop for futility should be 
made only if the futility boundary is crossed, there is no indication of delayed onset of OS efficacy, 
and these findings also apply in the COVID-19-related sensitivity analyses. 
The futility boundary is non-binding and so it is ignored in all calculations of Type 1 error. 
However, for OS power calculations, the impact of the futility boundary is taken into account. 


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The time of Interim Analysis 1 is based on ORR and the exact number of OS events may differ 
from 258.  If the number of OS events at Interim Analysis 1 is ≤ 248 then ZFUT will be re-calculated 
as follows: 
Let d1 denote the observed number of OS events at Interim Analysis 1, and similarly let d2, d3, and 
d4 denote the planned number of OS events at looks 2-4 as given in Table 2, i.e., d2 = 425, d3 = 541, 
and d4 = 637. If Zi, i = 1, 2, 3, 4 denotes the test statistic from a log-rank test conducted on the di 
OS events, then Zi ~ N (Δ[di/4]0.5, 1), ρZi,Zj = [di/dj]0.5 for i<j, and the canonical joint distribution 
holds (Jennison & Turnbull, 2000). Multiple simulated datasets with this distribution, for a 
specified Δ=log (HR), can be generated using the SAS SIMNORMAL procedure (SAS Institute, 
Inc, 2020). 
If the observed number of OS events at Interim Analysis 1 is ≤ 248 then the revised value of ZFUT 
will be calculated (by consideration of successively smaller values, starting from ZFUT = 0) so as 
to give a maximal power loss of at most 1% for all of Med1 = 14.0, 14.1, 14.2, 14.3, or 14.4, where 
Med1 represents a value of the OS median for the NUC-1031 in combination with cisplatin 
treatment group, and where then Δ = log (Med1/11.7). The power loss will be equal to the 
proportion of simulated datasets for which [Z1 < ZFUT] and [Zi ≥ Z1-αi for one or more of i = 2, 3, or 
4], where Z1-αi are the critical z-statistic values from the overall α = 0.025 (one-sided) column of 
Table 4. Here the specific values of Med1 have been found (by consideration of many possible 
values for d1) to provide a range that contains the value of Δ with largest power loss. 
7.3.3 Interim Analysis for Power Re-Assessment 
If the study has not crossed the efficacy boundary for OS (at Interim Analysis 2 or at Interim 
Analysis 3) then a power reassessment will be carried out at Interim Analysis 3 which is scheduled 
to occur after 541 OS events, and projected to take place 40.0 months after the start of 
randomisation (see Table 2 in Section 7.3.1), i.e., projected to occur 10 months after the end of 
enrolment. This power reassessment will use the CHW method (Cui et al, 1999), which guarantees 
that the maximum experimentwise Type 1 error will still be controlled at the required level. 
This power reassessment will be carried out by an independent unblinded statistician (who is not a 
member of the IDMC), and a charter (the Power Reassessment Charter) will describe the full 
procedure. The IQVIA Biostatistician in support of the IDMC process will provide the value of Z3 
(the z-statistic for OS at Interim Analysis 3) to this independent unblinded statistician. The rule is 
deterministic and this independent unblinded statistician will provide the new required number of 
OS events only to NuCana. No information will be provided to NuCana except for the new required 
number of OS events. 
The specific details on the algorithm to be used will be pre-specified only in the Power 
Reassessment Charter. However, the general form of the algorithm is as follows: 
 
If ZA < Z3 < ZB then the target number of OS events at the final analysis is increased to 701, 
 
otherwise the target number of OS events at the final analysis remains at 637. 
The interval (ZA , ZB) could be viewed as being analogous to a "promising zone", and is chosen on 
the basis of maximizing overall power with the aim of increasing the required number of events to 
701 (which is a 10% increase) when 637 events would be projected to have a high chance of just 
failing to obtain statistical significance. By definition, the value ZB will be lower than the value (as 
given in Table 4 within Section 7.4) required for statistical significance at Interim Analysis 3. 


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The Power Reassessment Charter itself (including the values ZA and ZB) will be shared with the 
sponsor, but will not be shared with the IDMC. However, after the power reassessment the sponsor 
will only be told the new required number of OS events, and so the sponsor will not be able to 
back-calculate the effect size at Interim Analysis 3 because this new required number of events can 
only take two possible values (637 or 701). 
Let Z3 denote the z-statistic for the primary analysis of OS calculated at Interim Analysis 3 which 
is based on an observed d3 (~541) events. Also let Z4 denote the corresponding z-statistic at the 
final analysis if the power re-assessment rule described above determines that the target number of 
OS events at the final analysis is to remain at 637. In addition, let Z4U denote a z-statistic (based on 
sufficient statistics) that could be derived if the power re-assessment rule instead determines that 
the target number of OS events at the final analysis is to be 701, and let 
*
4
d  be the observed number 
of events (~701) at the final analysis. Under the CHW method (Cui et al, 1999) if there is no 
increase in the target number of events then Z4 is still used at the final analysis, but if there is an 
increase in the target number of events then instead at the final analysis Z4CHW is used where 
 
 
*
3
3
4
3
34
637
637
637
CHW
d
d
Z
Z
Z
−
=
+
 
 and where                               
*
*
3
4
34
4
3
*
*
4
3
4
3
U
d
d
Z
Z
Z
d
d
d
d
=
−
−
−
 
 
is the incremental z-statistic corresponding to the additional 
*
4
3
d
d
−
 OS events. 
Note: If the final analysis under the CHW procedure is based on Z4CHW then the α value will be 
derived as described in Section 7.4 and illustrated in Table 4 but still using d4 = 637. 
If the required number of OS events remains at 637 then as stated in Table 4 within Section 7.4 the 
difference in medians at the boundary would be 2.16 months if OS is tested at an overall α=0.020 
one-sided, and would be 2.06 months if OS is tested at an overall α=0.025 one-sided. If the required 
number of OS events is increased to 701 under the power reassessment procedure then (under the 
same assumptions as given in footnotes 1 and 2 of Table 4) the difference in medians at the 
boundary would be 2.05 months if OS is tested at an overall α=0.020 one-sided, and would be 
1.96 months if OS is tested at an overall α=0.025 one-sided, i.e., the difference in medians at the 
boundary would then only be reduced by approximately 0.1 months (~3 days) if the required 
number of OS events is increased from 637 to 701. 
7.4 
Control of Type 1 Error 
The Maurer & Bretz method is used to provide strong control of Type 1 error across the two 
primary endpoints and the key secondary endpoint, as well as across the interim analyses (Maurer 
& Bretz, 2013). Figure 1 shows the initial one-sided α allocated to each of the two primary 
endpoints, and the arrows indicate how α is recycled between the endpoints. 
 
 


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Figure 1: 
Type 1 error recycling between the two primary endpoints, and the key 
secondary endpoint 
 
Further details are provided below for each of the primary endpoints and for the key secondary 
endpoint. 
ORR 
ORR will be tested using an overall α=0.005 one-sided initially. If the null hypothesis for OS is 
rejected (at Interim Analysis 2, Interim Analysis 3, or at the Final Analysis) then ORR can be tested 
using an overall α=0.017 one-sided. If in addition the null hypothesis for PFS is rejected (at Interim 
Analysis 2), then ORR can be tested using an overall α=0.025 one-sided. The Lan-DeMets O'Brien-
Fleming-like α-spending function (Lan & DeMets, 1983) will be used to control the Type 1 error 
across the two looks for ORR, and Table 3 gives the bounds and boundary properties for ORR 
testing. The critical values for this α-spending function are derived using the SAS SEQDESIGN 
procedure with the ERRFUNCOBF design method (SAS Institute, Inc, 2020). 
If ORR has not already obtained statistical significance (using the overall α=0.005 one-sided) at 
either Interim Analysis 1 or Interim Analysis 2, then if the null hypothesis for OS is rejected (at 
Interim Analysis 2, Interim Analysis 3, or at the Final Analysis), but the null hypothesis for PFS is 
not rejected (at Interim Analysis 2) then the p-value for ORR at Interim Analysis 2 can be compared 
to the updated alpha value of 0.0160 one-sided (from the α=0.017 1-sided column in Table 3) to 
determine statistical significance for the ORR primary endpoint. However, if the null hypothesis 
for OS and the null hypothesis for PFS are both rejected then the p-value for ORR at Interim 
Analysis 2 can be compared to the updated alpha value 0.0233 one-sided (from the α=0.025 1-sided 
column in Table 3) to determine statistical significance for the ORR primary endpoint. 
The table below, including the required critical values, will be updated using the actual numbers 
of patients (in the stratum corresponding to measurable disease at baseline who have the 
opportunity for ≥28 weeks of follow-up), if these differ from those given in Table 3. 


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Table 3: 
Efficacy boundaries and properties for ORR 
Analysis 
Value 
α=0.005 (1-sided) α=0.017 (1-sided) α=0.025 (1-sided) 
Interim Analysis 1: 
65% 
 
NM28 = 4181 
 
 
Critical p-value (1-sided) 
0.0005 
0.0031 
0.0054 
Cumulative α (1-sided) 
0.0005 
0.0031 
0.0054 
Odds Ratio at boundary2
 
~ 2.11 
~1.88 
~ 1.80 
Difference in proportions 
at boundary2 
~ 14.1% 
~11.6% 
~ 10.7% 
Cumulative Power3 
29.6% 
50.7% 
58.3% 
Interim Analysis 2: 
100% 
 
NM28: 6441 
 
 
Critical p-value (1-sided) 
0.0048 
0.0160 
0.0233 
Cumulative α (1-sided) 
0.0050 
0.0170 
0.0250 
Odds Ratio at boundary2
 
~ 1.63 
~1.50 
~ 1.46 
Difference in proportions 
at boundary2 
~ 8.6% 
~7.1% 
~ 6.5% 
Cumulative Power3 
80.0% 
90.2% 
92.6% 
1. NM28 denotes the number of patients in the stratum corresponding to measurable disease at baseline who have the opportunity 
for ≥28 weeks of follow-up. 
2. The approximate odds ratio and approximate difference in proportions at the boundary assume that ORR=19% is observed in  
the control arm. 
3. The cumulative power is based on assumed true proportions of 31% vs. 19%. 
 
OS 
OS will be tested using an overall α=0.020 one-sided. If the null hypothesis for ORR is rejected (at 
either Interim Analysis 1 or Interim Analysis 2) then OS can be tested using an overall α=0.025 
one-sided. The Lan-DeMets O'Brien-Fleming-like α-spending function (Lan & DeMets, 1983) is 
used to control the Type 1 error across the three looks for OS, and Table 4 gives the bounds and 
boundary properties for OS testing. The critical values for this α-spending function are derived 
using the SAS SEQDESIGN procedure with the ERRFUNCOBF design method (SAS Institute, 
Inc, 2020). 
Table 4, including the required critical values, will be updated using the actual number of OS events 
if these differ from the counts given in the table.  


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Table 4: 
Efficacy boundaries and properties for OS 
Analysis 
Value 
α=0.020 
(1-sided) 
α=0.025 
(1-sided) 
Interim Analysis 2: 67% 
 
N ~ 828 
 
~ 425 OS events 
 
 
Z-statistic 
2.6198 
2.5082 
Critical p-value (1-sided) 
0.0044 
0.0061 
Cumulative α (1-sided) 
0.0044 
0.0061 
HR at boundary1 
~ 0.776 
~ 0.784 
Difference in medians at 
boundary (months)1,2 
~ 3.39 
~ 3.22 
Cumulative Power3 
58.3% 
62.6% 
Interim Analysis 3: 85% 
 
N = 828 
 
541 OS events 
 
 
Z-statistic 
2.3164 
2.2204 
Critical p-value (1-sided) 
0.0103 
0.0132 
Cumulative α (1-sided) 
0.0116 
0.0150 
HR at boundary1 
~ 0.819 
~ 0.826 
Difference in medians at 
boundary (months)1,2 
~ 2.58 
~ 2.46 
Cumulative Power3 
81.4% 
83.8% 
Final Analysis: 100% 
N = 828 
637 OS events 
 
Z-statistic 
2.1366 
2.0490 
Critical p-value (1-sided) 
0.0163 
0.0202 
Cumulative α (1-sided) 
0.0200 
0.0250 
HR at boundary1 
~ 0.844 
~ 0.850 
Difference in medians at 
boundary (months)1,2 
~ 2.16 
~ 2.06 
Cumulative Power3 
90.9% 
92.2% 
1. The approximate HR and the approximate difference in medians at the boundary assumes proportional hazards. 
2. The approximate difference in medians at the boundary also assumes an 11.7 month observed control arm median. 
3. Cumulative power is based on an assumed true HR of 0.76. These power values allow for the possibility that the study could 
stop for futility at Interim Analysis 1. 
Abbreviations: HR=hazard ratio; OS=overall survival. 
 
PFS 
If the null hypothesis for ORR (at Interim Analysis 1 or Interim Analysis 2) and the null hypothesis 
for OS (at Interim Analysis 2, Interim Analysis 3, or at the Final Analysis) are both rejected using 
the Maurer & Bretz procedure, then PFS can be tested at the α=0.025 one-sided significance level. 
However, if only the null hypothesis for OS is rejected then PFS can be tested at the α=0.008 
one-sided significance level. 
PFS will be analysed at Interim Analysis 2 only, at which point 534 patients are expected to have 
had a PFS event. This number of patients with a PFS event is based on a control median of 
7.6 months, a HR of 0.74, 30-month duration of enrolment with gradual ramp-up over the first 
12 months, and a constant rate of enrolment for the next 18 months. 


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7.5 
Additional Secondary Efficacy Endpoints 
7.5.1 Duration of Response 
DoR as determined by BICR, using RECIST v1.1 criteria, is defined as the time from the first 
occurrence of a confirmed objective response to the time of disease progression, or death due to 
any cause, whichever occurs first. The time of progression or death, and censoring, will each be 
based on the rules used for the primary analysis of PFS as described in Section 7.2.1.2. 
DoR will be summarised, for the subgroup of patients in the ITTMD28 population with confirmed 
response, using the Kaplan-Meier method and will also be displayed graphically.  The median 
event time will be estimated for each treatment group, together with its CI using the Brookmeyer 
& Crowley (1982) method. Estimates of the 25th and 75th percentiles will also be derived together 
with their corresponding CIs. 
In addition, DoR based on Investigator assessment will be summarised in the same way, and this 
will be considered a supportive analysis. 
For DoR, a sensitivity analysis will be carried out using the rules for the time of disease progression, 
death, and censoring as used for the primary analysis of PFS described in Section 7.2.1.2, except 
that patients with a COVID-19 cause of death and with no prior progression will be censored at 
their time of death. Additional sensitivity analyses of DoR may be needed once the nature and 
extent of the direct and indirect impact of COVID-19 becomes clearer, and such additional analyses 
will be described within a future version of this SAP. 
7.5.2 18-Month and 12-Month Survival 
The proportion of patients alive at 18 months (OS18) will be defined as the Kaplan-Meier estimate 
of OS at 18 months. For each treatment group, the 95% CI will also be derived using Greenwood's 
method.  A comparison between treatment groups for OS18 will also be carried out using the 
method described in Klein et al (2007). 
The proportion of patients alive at 12 months (OS12) will be analysed in the same way as OS18. 
7.5.3 Disease Control Rate 
DCR is the proportion of the NM28 (defined in Section 7.1.2.2) patients within the treatment group 
that have BOR of CR, PR, or SD. The primary analysis of DCR is based on BICR assessment and 
a supportive analysis will also be conducted based on Investigator assessment. 
7.6 
Patient-Reported Quality of Life 
Patient-reported QoL will be assessed using the EORTC-QLQ-C30 with the QLQ-BIL21 module 
and the EQ-5D-5L. 
The ECOG PS scale (for which the planned analyses are described in Section 8.4) will be used to 
assess patients’ ability to perform daily living tasks and their range of basic physical ability. 
7.6.1 EORTC-QLQ-C30 with the QLQ-BIL21 module 
The EORTC QLQ-C30 is a self-administered cancer-specific questionnaire with multi-dimensional 
scales. It consists of both multi-item scales and single-item measures, including five functional 
domains, a global QoL domain, three symptom domains, and six single symptom measures. 
Scoring of the EORTC QLQ-C30 data will be completed following the procedures recommended 
by the EORTC Study Group on Quality of Life. For each domain or single-item measure, a linear 


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transformation will be applied to standardise the raw score to range between 0 and 100. QoL data 
will be analysed to test for clinically meaningful differences between the two treatment groups. 
Questionnaire compliance rates will be ascertained for each treatment group at each measurement 
timepoint. Mean baseline scores for each subscale and summary scores will be calculated. Listings 
will also be provided which where applicable specify the reasons for each patient why the whole 
EORTC QLQ-C30 questionnaire was not completed at any scheduled visit, and where applicable 
also provide reasons why data for any of the 30 specific items is missing. 
The principal QoL analysis will be based on Kaplan-Meier estimates and log-rank tests on time to 
definitive QoL deterioration, as measured by the EORTC QLQ-C30 physical function and global 
QoL scores, in each treatment group. The event of interest is the time to a definitive QoL 
deterioration, which is defined as the minimum time where two consecutive post-baseline visits 
have a 5-point or greater deterioration from baseline scores by subtracting baseline scores for each 
individual from his/her own scores. The 5-point change has been reported to represent “a little’ 
change in QLQ-C30 (Osoba et al, 1998, Cocks et al, 2012). It has been shown that this is a degree 
of change that is perceptible to patients (Osoba et al, 1998). A minimal change approach is being 
taken by using a 5-point decrement in physical functioning so that any perceptible change could be 
captured, but a more definite change may be a 10-point decrement. Indeed, Raman et al (2018) 
have reported asymmetries between improved and worsened states of physical functioning, with 
worsening requiring roughly a three-fold difference in numeric score compared with the improved 
state (see Table 5). 
Secondary QoL analyses will include analyses of the domains of the QLQ-C30 in which patients 
are categorised as either improved, stable, or worsened (Raman et al, 2018), as described in Table 5.  
Table 5: 
QLQ-C30 domain minimal clinically important differences (MCIDs) 
Domain 
Improved 
Worsened 
Physical functioning 
≥5 
<-15 
Role functioning 
≥12 
<24 
Emotional functioning 
≥8 
<18 
Cognitive functioning 
≥5 
<14 
Social functioning 
≥8 
<20 
Fatigue 
<-13 
≥19 
Pain 
<9 
≥21 
Nausea & vomiting 
≥-4 
≥9 
Appetite 
<9 
≥19 
The domain specific minimal clinically important difference (MCID) changes will be used to 
classify patients as improved, stable, or worsened.  As an example, using Table 5, patients with 
≥5-point change in Physical Functioning will be classified as improved. If their score is between 
+5 and -15, then they will be classified as stable.  If their score has <-15 change, then they will be 
classified as worsening.   


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The Pain domain of the QLQ-C30 will also be summarised relative to changes in analgesic use.  
Patients’ use of analgesics will be categorised into 2-categories (Increased or Stable) relative to 
their baseline use.  Change in actual pain medication will be defined as (Increased/Stable) where a 
change (Increase) is defined as a doubling of the dose of the same medication OR a switch to a 
more potent medication. 
The EORTC QLQ-BIL21 is a validated disease-specific module for measuring QoL in patients 
with cholangiocarcinoma and cancer of the gallbladder that is designed to be used with EORTC 
QLQ-C30. The QLQ-BIL21 is self-administered and consists of 21 questions: 3 single-item 
assessments relating to treatment side-effects, difficulties with drainage bags/tubes, and concerns 
regarding weight loss, in addition to 18 items grouped into 5 scales: eating symptoms (4 items), 
jaundice symptoms (3 items), tiredness (3 items), pain symptoms (4 items), and anxiety symptoms 
(4 items). Using an anchor-based approach, Kaupp-Roberts et al (2016) have reported meaningful 
changes in each of the domains of the QLQ-BIL21, as shown in Table 6. 
Table 6: 
QLQ-BIL21 domain minimal clinically important differences (MCIDs) 
QLQ-BIL21 Domain 
Difference 
Eating 
18 
Jaundice 
7 
Tiredness 
22 
Pain 
15 
Anxiety 
14 
Treatment side effects 
16 
Drains 
18 
Weight loss 
1 
Analysis of QLQ-BIL21 will be carried out in a similar manner as QLQ-C30, using the domain 
specific MCIDs shown in Table 6. Listings will also be provided which where applicable specify 
the reasons for each patient why the whole EORTC QLQ-BIL21 questionnaire was not completed 
at any scheduled visit, and where applicable also provide reasons why data for any of the 21 specific 
items is missing. 
Perceived weight loss is an important indicator of patient well-being and is captured by the 
QLQ-BIL21.  Actual weight patient change from baseline will also be summarised with weight 
loss defined as a negative change from baseline of 5% or greater. 
7.6.2 EuroQoL Health questionnaire instrument (EQ-5D-5L) 
The EQ-5D-5L questionnaire will also be administered as a part of this study to assess 
health-related QoL. EQ-5D is an international, validated, standardised, generic questionnaire for 
describing and valuing health-related QoL (Rabin & de Charro, 2001). EQ-5D was developed by 
the EuroQol group in order to provide a simple, generic measure of health for clinical and economic 
appraisal. This instrument generates a preference-based health-state utility score (EQ-5D utility 
index) and an overall health state score based on a visual analogue scale (EQ-5D VAS). 


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EQ-5D is designed for self-completion by respondents and is ideally suited for use in clinics and 
face to face interviews. It is cognitively undemanding, taking only a few minutes to complete. 
Instructions to respondents are included in the questionnaire. The most recent version of the EQ-5D 
is the EQ-5D-5L, which was developed to improve the instrument’s sensitivity and to reduce 
ceiling effects. The number of dimensions (mobility, self-care, usual activities, pain/discomfort, 
anxiety/depression) has not changed; however, the new version includes 5 levels of severity in each 
of the existing dimensions in place of three (EuroQol Group, 2015). 
7.7 
Health Economics 
Health economics will be assessed through collection of core health resource use information, using 
eCRFs to capture inpatient procedure codes, total number of days in hospital and outpatient visits. 
Data collected on concomitant medication will also be used in this economic analysis. For the 
economic modelling, costs will be imputed on the basis of representative country unit costs at the 
point of analysis using standard fee schedules. Health outcomes will be quantified using QALYs. 
Quality adjustments will be based on patients’ responses to the EQ-5D-5L health status measure 
which will be administered at baseline, before each cycle of therapy, and each point of follow up 
as part of the QoL questionnaire. Finally, a cost-utility analysis will be conducted by creating 
incremental cost-utility ratios for each of the treatment groups. 
7.8 
Pharmacokinetics 
PK analyses are outside the scope of this SAP. A separate PK analysis plan and report will be 
provided. 
7.9 
Efficacy Analyses by Subgroups 
For OS numbers of events by treatment group in the ITT population, together with HRs (derived 
from an unstratified Cox proportional hazards model with a single term for treatment within the 
model) will be provided separately for each of the following subgroups: 
• Primary tumour site: gallbladder, intra-hepatic, extra-hepatic, ampullary 
• Stage of Disease: Metastatic disease, Locally advanced disease 
• ECOG PS (at baseline): 0, 1 
• Region: Asia, Non-Asia (with non-Asia also subdivided and provided separately for North 
America/Western Europe/Australasia combined, and for Central/Eastern Europe/Rest of 
the World combined) 
• Gender: Male, Female 
• Age (at baseline): <65, ≥65 
• Measurable disease at baseline: Yes, No (based on BICR) 
The study is powered on the basis of the overall treatment effect and is not designed to have high 
power for separate subgroup analyses of the primary endpoints. However, for OS 95% and 80% 
two-sided CIs (derived from an unstratified Cox proportional hazards model with a single term for 
treatment within the model) will be provided separately for each of the above subgroups. 
For ORR analyses in terms of estimates (of ORR, as well as counts for CR and for PR) by treatment 
group in the ITTMD28 population, together with odds ratios and difference in proportions of 
subjects with ORR, each calculated from raw counts, will be given for each of the following 
subgroups: 


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• Primary tumour site: gallbladder, intra-hepatic, extra-hepatic, ampullary 
• Stage of Disease: Metastatic disease, Locally advanced disease 
The odds ratio for ORR will have 95% and 80% two-sided CIs derived using the Baptista-Pike 
mid-p method (Fagerland et al, 2015). For the difference in proportions of patients with ORR 95% 
and 80% two-sided CIs will be derived using the Newcombe method without continuity correction 
(Newcombe, 1998, method 10). 
Power calculations for subgroup analyses of ORR are provided in Appendix 4, for overall 
subgroup sizes of 20, 30, 40, or 50 across multiple sets of possible ORR values. Based on these 
calculations a rationale is provided there for the proposal that 20 patients in total be viewed as 
sufficient for an adequate assessment of ORR within a subgroup.  
8 
SAFETY SUMMARIES 
All safety analyses will be performed using all patients in the Safety population. No formal 
statistical comparison between the two treatments groups is planned. 
Only results with assessment dates through the end of the safety observation period (see 
Section 4.5) will be included in any safety analyses, unless otherwise specified. For AE listing-
type tables and for the AE data listing, those events within the safety observation period which 
started or increased in severity after initiating NPACT will be flagged. Similarly, for other safety 
listing-type tables or data listings, values recorded within the safety observation period after 
initiating NPACT will be flagged. 
An IDMC will monitor safety during the study on a regular basis. The committee will operate 
independently from the Sponsor and the clinical Investigators. Refer to Section 12.16 of the Study 
Protocol and the separate IDMC charter for further details. 
8.1 
Adverse Events, Serious Adverse Events, and Deaths 
Adverse event terms recorded on the eCRF will be mapped to preferred terms and system organ 
class (SOC) using MedDRA version 20.0 (or higher). The severity of AEs will be measured by 
CTCAE version 5.0 (or higher) guidelines, and for those AEs not included in CTCAE the severity 
will be categorised as described in Section 12.4 of the Study Protocol.  
SAEs will be defined as described in Section 12.1 of the Study Protocol. The relationship of an 
AE to study medication is categorised as described in Section 12.3 of the Protocol. 
Events (including patient deaths) exempt from being reported as AEs or SAEs follow the rules as 
described in Protocol Section 12.10. 
A TEAE is defined as any event with an onset date on or after initiation of study medication (and 
up to 30 days after the last dose of study medication), or which are present at the time of starting 
study medication, but which subsequently increase in severity. 
For the purpose of calculating treatment emergence and inclusion in summary tables, incomplete 
onset dates will be imputed as detailed in Section 4.4. 
An overall summary of AEs will be provided with the number and percentage of patients who 
experienced the following types of events during the safety observation period (unless otherwise 
noted) in each treatment group: 


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• Patients with any TEAE 
• Patients with a Definitely or Probably Related TEAE 
• Patients with a Serious TEAE 
• Patients with a Serious Definitely or Probably Related TEAE 
• Patients with a Worst-Grade 3 or 4 TEAE 
• Patients with a Worst-Grade 3 or 4 Definitely or Probably Related TEAE 
• Patients with a Worst-Grade 4 TEAE 
• Patients with a Worst-Grade 4 Definitely or Probably Related TEAE 
• Patients with a Grade 5 TEAE 
• Patients with a Grade 5 Definitely or Probably Related TEAE 
• Patients with a TEAE leading to Treatment Discontinuation of both components (cisplatin 
and NUC-1031 [Arm A], cisplatin and gemcitabine [Arm B]) of study medication 
• Patients with a TEAE leading to Treatment Discontinuation of the cisplatin component of 
study medication 
• Patients with a TEAE leading to Dose Reduction of either component (cisplatin or NUC-1031 
[Arm A], cisplatin or gemcitabine [Arm B]) of study medication 
• Patients with a TEAE leading to Dose Reduction of the cisplatin component of study 
medication 
• Patients with a TEAE leading to Dose Reduction of the NUC-1031 (Arm A) or gemcitabine 
(Arm B) component of study medication 
• Patients with a TEAE leading to Interruption of either component (cisplatin or NUC-1031 
[Arm A], cisplatin or gemcitabine [Arm B]) of study medication 
The following additional summaries in terms of incidences and percentages will be provided:  
• TEAEs by SOC and preferred term (all CTCAE Grades) 
• TEAEs by SOC and preferred term, separately by worst severity (CTCAE Grade 1/2, 3, 4, 
or 5) 
• TEAEs by SOC and preferred term, separately by strongest relationship 
• TEAEs CTCAE Grades 3 or higher by SOC and preferred term, separately by strongest 
relationship 
• Deaths due to all causes by primary cause of death (Progressive disease, SAE, COVID-19, 
Drug-induced liver injury (DILI), and Unknown). 
• TEAEs of CTCAE Grade 5 (deaths) by SOC and preferred term 
• Serious TEAEs by SOC and preferred term 
• Serious TEAEs by SOC and preferred term, separately by worst severity (CTCAE Grade 
1/2, 3, 4, or 5) 
• Serious TEAEs by SOC and preferred term, separately by strongest relationship 
• TEAEs leading to Treatment Discontinuation by SOC and preferred term 
• TEAEs leading to Dose Reduction by SOC and preferred term 


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• TEAEs leading to Interruption of Study Medication by SOC and preferred term 
Listing-type tables will also be provided for SAEs, TEAEs leading to study medication 
discontinuation (of cisplatin alone or of both components of study medication), TEAEs leading to 
reduction in dose of study medication (reduction for both components of study medication, 
reduction for cisplatin alone, or reduction for NUC-1031 [Arm A] or gemcitabine [Arm B] alone), 
TEAEs leading to interruption of either component of study medication, TEAEs leading to death, 
and deaths due to all causes. 
Note: The eCRF does not include a category of COVID-19 as the primary cause of death and 
Section 7.1.1.4 describes the process by which cases where 'COVID-19' is the primary 
cause of death will be identified. The eCRF also did not include a category of DILI as the 
primary cause of death and so here also the identification of such cases is carried out in a 
two-stage process: (i) searching the primary cause of death on the death details page of the 
eCRF for the text term "LIVER' or for text terms starting with 'HEPAT'; and then (ii) 
carrying out a manual review to identify those cases from (i) where DILI is the primary 
cause of death. Analyses will then use DILI or COVID-19 (as applicable) as the primary 
cause of death in place of the the reason recorded on the eCRF. For the analyses of safety 
data (but not for the sensitivity analyses of OS described in section 7.1.1.4) if any patients 
have both DILI and COVID-19 identified in the way described above as the primary cause 
of death then DILI will take precedence over COVID-19. 
8.1.1 Treatment-Emergent COVID-19 Adverse Events, Including their Impact on the 
Study  
The overall incidence of patients with a confirmed case of treatment-emergent (TE) COVID-19 
will be derived and a corresponding listing will be provided. In addition, the overall incidence of 
patients with a confirmed case of TE COVID-19 will be presented by severity. The overall 
incidence of patients discontinuing study treatment due to TE COVID-19 will also be derived and 
a corresponding listing will be provided. In addition, a listing from the death details page of the 
eCRF will be provided for patients with COVID-19 as the primary cause of death. 
Note: The procedure for identifying patients with COVID-19 as the primary cause of death is 
described in Section 7.1.1.4. For identifying COVID-19 AEs the following two-stage 
procedure will be carried out: (i) cases that are potentially COVID-19 AEs are found by 
first searching AE preferred terms and high level terms for the text 'COVID', 'VIRUS', 
'CORONA', or '19'; and then (ii) all cases found by the search in (i) will be manually 
reviewed to identify cases where 'COVID-19' is an AE. 
Listings will also be provided for:  
(i)  
Patients delaying, interrupting, or discontinuing treatment due to the patient's confirmed or 
suspected COVID-19 infection; and 
 (ii)  
Patients taking a concomitant medication for a COVID-19 infection.   
Additional analyses of the impact of COVID-19 on the study may ultimately be needed once the 
nature and extent of the direct or indirect impact of COVID-19 becomes clearer, and such 
additional analyses will then be described within a future version of this SAP. 


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8.2 
Laboratory Parameters 
All clinical laboratory testing will be performed at local sites.  Laboratory tests may be performed 
either on the day of a treatment visit, or during the 3 days prior to a treatment visit. 
Samples will be analysed for the following parameters: 
• Haematology: white blood cell (WBC) count, differential WBC count, red blood cell count, 
haemoglobin, haematocrit and platelets 
• Coagulation parameters: prothrombin time/international normalised ratio and activated 
partial thromboplastin time  
• Chemistry: sodium, potassium, magnesium, urea or blood urea nitrogen, creatinine, 
glucose, phosphate, total protein, albumin, adjusted calcium, total bilirubin, bicarbonate, 
chloride, uric acid, alkaline phosphatase, aspartate aminotransferase (AST), alanine 
aminotransferase (ALT) and lactate dehydrogenase 
The investigator will identify and record clinically significant laboratory test results. The 
investigator will also record laboratory test results as an AE if it meets any of the four criteria as 
specified in Section 12.12 of the Protocol. Estimated glomerular filtration rate will also be derived 
at each applicable visit using the Cockroft-Gault formula (Cockroft & Gault, 1976). 
All laboratory data parameters and visits will include flags for values above or below laboratory 
reference ranges. Toxicity grades will be assigned programmatically by applying the National 
Cancer Institute (NCI) CTCAE version 5.0 (or higher) guidelines. Only results with assessment 
dates through the end of the safety observation period will be included in summary tables. 
Laboratory summaries will be presented in SI units. Continuous laboratory test results will be 
summarised by treatment group using descriptive statistics for actual values and for changes from 
baseline by scheduled visit. Box-Whiskers plots may also be presented at each scheduled visit (with 
visits shown on x-axis) for some laboratory parameters. For continuous laboratory test results 
which are below or above the quantification level, the imputed values as described in Section 4.4 
will be used for deriving the grade and then summarised. 
Laboratory test results that are identified by the investigator as being clinically significant will be 
summarised in terms of incidence and in listing form. 
Incidence tables will be provided for each laboratory parameter reported as a TEAE in which 
patient counts (and percentages) are given for each CTCAE grade separately (based on worst 
grade), for Grades 3-4 combined (based on worst grade), and for Grades 1-4 combined.  For 
laboratory parameters which have CTCAE grades for both low and high, the summaries will be 
produced separately and labelled by the name of the condition, e.g., sodium will be summarised as 
hyponatraemia and hypernatremia. 
Shift tables from baseline to each scheduled study visit will be produced for each laboratory 
parameter using individual NCI CTCAE grades. Corresponding shift tables will also be produced 
from baseline to worst value recorded at a post-baseline visit. 
Shift tables will also be provided based on reference ranges. 
Additional summaries will also be provided for ALT, AST, alkaline phosphatase, total bilirubin, 
neutrophils, haemoglobin, and platelets. 


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Cases of potential drug-induced liver injury are defined by the stopping criteria defined in the FDA 
DILI guidance document (FDA Guidance for Industry: Drug-induced liver injury: premarketing 
clinical evaluation, 2009) if they meet any of the following four criteria: 
1. Treatment-emergent ALT or AST >8 x ULN 
2. Treatment-emergent ALT or AST >5 x ULN for more than 2 weeks 
3. Treatment-emergent ALT or AST >3 x ULN with total bilirubin >2 x ULN  
4. Treatment-emergent ALT or AST >3 x ULN and International Normalised Ratio (INR) >1.5 
Patients, who meet any of the criteria above and any of the following criteria might potentially 
meet criteria for Hy’s law: 
• No initial finding of cholestasis (elevated serum ALP) 
• No other reason can be found to explain the increases in ALT/AST and bilirubin or INR, 
such as viral hepatitis A, B, or C; pre-existing or acute liver disease; biliary duct obstruction 
or another drug capable of causing the observed injury 
For any possible Hy's law cases, patient profiles for all liver function tests will also be produced. 
For each of criteria 1-4, counts will be provided for patients meeting the criterion based on ALT 
but not AST, based on AST but not ALT, based on both ALT and AST, or based on either AST or 
ALT. Counts will also be provided for patients meeting any of criteria 1-4. 
Laboratory parameters will also be summarised in listing form within which the CTCAE grade will 
be indicated, and flags will be included for those values above or below the reference range. 
8.3 
Vital Signs 
The following vital signs will be summarised: 
• Systolic blood pressure (mmHg) 
• Diastolic blood pressure (mmHg) 
• Pulse rate (bpm) 
• Weight (kg) 
The investigator will identify and record clinically significant vital sign results. The investigator 
will also record vital sign results as an AE if it meets any of the four criteria as specified in 
Section 12.13 of the Protocol. 
Vital sign results that are identified by the investigator as being clinically significant will be 
summarised in terms of incidence and in listing form. 
The vital signs test results will also be summarised by treatment group using descriptive statistics 
for actual values and for changes from baseline by scheduled visit. 
8.4 
ECOG Performance Status 
For the purpose of evaluating safety, ECOG will be summarised in terms of shift from baseline 
for, at minimum, the worst value recorded after the initiation of study treatment. 
Frequencies of ECOG worsening of ≥ +1 and +2 change from baseline to worst value after first 
dose will also be summarised. 


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8.5 
Electrocardiogram 
Standard 12-lead ECG measurements will be obtained at screening and prior to dosing on Day 1 
of all cycles. In addition, ECG measurements will be taken within 30 minutes post-infusion on 
C1D1, C1D8, C2D1, and C2D8. ECG readings should be performed in triplicate. The QTc interval 
will be calculated using the Fredericia formula and averaged. 
Only results with assessment dates through the end of the safety observation period (see 
Section 4.5) will be considered for summaries. The following categorical summaries based on the 
patients' worst value will be presented: 
• number of patients with triplicate average QTc >450 msec (for male patients only) 
• number of patients with triplicate average QTc >480 msec (separately by gender and for 
both genders combined) 
• number of patients with triplicate average QTc >500 msec (separately by gender and for 
both genders combined) 
• number of patients with increase in triplicate average QTc from baseline of >60 msec 
(separately by gender and for both genders combined) 
• number of patients with increase in triplicate average QTc from baseline of >30 msec 
(separately by gender and for both genders combined)  
Separate shift tables will also be produced for male patients for QTc comparing the baseline 
value to the patient's worst value using each of the 450, 480, and 500 msec cut-points. Similar 
shift tables will be produced for female patients using the 480 and 500 msec cut-points. 
Shift tables will be produced from baseline to the patient's worst value based on Investigator's 
overall assessment (normal, abnormal not clinically significant, abnormal clinically 
significant). 
QTc (using the Fredericia formula), QT interval, PR interval, RR interval, QRS interval, and 
heart rate will also be summarised (on the basis of triplicate averages) in terms of absolute 
values and change from baseline values. 
ECG findings and ECG values will also be provided in listings. 
The analyses to be carried out on the data from the robust QT sub-study will be summarised in a 
separate SAP. 


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9 
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Appendix 1: Derivation of the Objective Response Rate Assumed for the Control Arm 
The control arm of the NuTide:121 study is gemcitabine at a dose of 1000 mg/m2 in combination 
with cisplatin at a dose of 25 mg/m2, each given on Days 1 and 8 of 21-day cycles. 
An extensive Medline search was undertaken to identify randomised studies in patients with 
previously untreated advanced BTC which included an arm for gemcitabine in combination with 
cisplatin administered on the schedule to be used in NuTide:121. 
A total of three such randomised studies in patients with advanced BTC using the reference 
regimen were identified, which are briefly summarised below and which form the basis for 
derivation of the value assumed for ORR in the control arm as used within the power and sample 
size justification section of this SAP (Section 2.4). 
ABC-02 
Valle et al, 2010 reported on the results from the ABC-02 study in which patients with previously 
untreated advanced BTC were randomised to gemcitabine in combination with cisplatin or to 
single-agent gemcitabine. The earlier Valle et al, 2009 publication reported on the ABC-01 study 
(with the same arms as in ABC-02), but that study will not be considered further here because it 
was expanded into the ABC-02 study, and the ABC-02 study publication includes all patients 
already reported in ABC-01. 
BT-22 
Okusaka et al, 2010 reported on the BT-22 study in patients with previously untreated advanced 
BTC within which gemcitabine in combination with cisplatin was compared to single-agent 
gemcitabine.  
ABC-03 
Valle et al, 2015 reported on the ABC-03 study in which patients with previously untreated 
advanced BTC were randomised to gemcitabine in combination with cisplatin or gemcitabine in 
combination with cisplatin plus cediranib. 
In the NuTide:121 study, the primary analysis population for ORR will be the ITTMD population, 
which consists of all patients randomised with measurable disease at baseline (as assessed by 
BICR). The denominator for the primary ORR analysis will consist of all patients in the ITTMD 
population. The numerator for the primary ORR analysis in NuTide:121 will consist of all patients 
with PR or CR with confirmation at least 28 days later, and will be based on BICR assessment. 
As regards the denominator, only the ABC-03 study derived this in the way that will be used in the 
NuTide:121 study. Furthermore, ABC-02 and BT-22 did not report the numbers of patients that 
had measurable disease at baseline. 
Also, for the numerator part of the calculation, none of these three reference studies required 
confirmation of response (CR or PR) and results in each case were based on Investigator 
assessment and not BICR.  Thus, the three reference studies reported unconfirmed responses based 
on Investigator assessment. 
Therefore, to derive an estimate of ORR for the control arm to use in sample size calculations for 
the NuTide:121 study, it has been necessary to start with the count data as reported in these three 
reference publications. 


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Note: ABC-03 and BT-22 only enrolled patients with ECOG PS of 0 or 1, whereas ABC-02 
enrolled patients with ECOG PS of 0, 1 or 2. However, Professor Valle (personal communication, 
2018) has provided ABC-02 results related to ORR calculation for the subset of patients with 
ECOG PS of 0 or 1. The count data for these three studies are summarised below in Appendix 1 
Table 1. 
Appendix 1 Table 1: Gemcitabine in combination with cisplatin – reported counts from 
ABC-02, BT-22 and ABC-03 studies 
Number of Patients 
ABC-02 
(PS 0, 1 or 2) 
ABC-02 
(PS 0 or 1 only) 
BT-22 
ABC-03 
Randomised 
204 
177 
42 
62 
Randomised and treated 
200 
NS 
41 
60 
Measurable disease at baseline 
NS 
31 
NS 
54 
Evaluable at baseline and 
Evaluable post-baseline 
161 
146 
37 
50 
    CR 
1 
1 
0 
0 
    PR 
41 
38 
8 
10 
    SD 
89 
84 
20 
25 
    PD 
30 
23 
9 
15 
    NE post-baseline 
NS 
NS 
NS 
4 
Abbreviations: CR=complete response; NE=not evaluable; NS=not specified; PD=progressive disease; PR=partial 
response; PS=performance status; SD=stable disease. 
The calculation of ORR for use in the control arm within the sample size section of the SAP is 
carried out in the following stages in turn: 
• Estimation of the number of patients in ABC-02 and BT-22 that had measurable disease at 
baseline 
• Derivation of pooled and meta-analysis-based estimates of ORR in all randomised patients 
with measurable disease at baseline, but still based on Investigator assessment and without 
the requirement for confirmation of response 
• Adjustment of the estimate to allow for the requirement for confirmation of response 
• Further adjustment of the estimate to allow for assessment needing to be BICR-based 
(rather than based on Investigator assessment) 
Estimation of the number of patients in ABC-02 and BT-22 that had measurable disease at 
baseline 
Appendix 1 Table 1 above shows that 8/62 patients in the gemcitabine/cisplatin arm from ABC-03 
had non-measurable disease at baseline, and the Valle et al, 2015 paper also reported that the 
gemcitabine/cisplatin/cediranib arm from that same study had 3/62 with non-measurable disease at 
baseline. Therefore, at baseline 11/124 (8.9%) patients had non-measurable disease at baseline in 
ABC-03.  


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The number of patients with non-measurable disease at baseline is not provided in either ABC-02 
or BT-22, but this can be estimated as 8.9% of the patients randomised in the gemcitabine/cisplatin 
arm, i.e., for ABC-02 (PS 0/1 only) we then obtain 15.25 (=177 × 0.089) with non-measurable 
disease at baseline, and for BT-22 we obtain 3.74 (=42 × 0.089) with non-measurable disease at 
baseline.  This then gives revised counts as in Appendix 1 Table 2 below: 
Appendix 1 Table 2: Gemcitabine in combination with cisplatin – counts from ABC-02, 
BT-22 and ABC-03 studies with estimates for number of patients with 
measurable disease at baseline in ABC-02 and BT-22 
 Number of Patients 
ABC-02 
(PS 0 or 1) 
BT-22 
ABC-03 
Randomised 
177 
42 
62 
Non-measurable disease at baseline 
15.75# 
3.74# 
8 
Measurable disease at baseline 
146 + 15.25# 
37 + 1.26# 
50 + 4 
    CR 
1 
0 
0 
    PR 
38 
8 
10 
    SD 
84 
20 
25 
    PD 
23 
9 
15 
    NE 
15.25# 
1.26# 
4 
ORR based on Investigator Assessment 
with No Requirement for Confirmation, 
but now based on all randomised patients 
with measurable disease at baseline 
24.19% 
20.91% 
18.50% 
(39/161.25) 
(8/38.26) 
(10/54) 
#=imputed values based on an assumed 8.9% being non-measurable at Baseline. 
Abbreviations: CR=complete response; NE=not evaluable (post-baseline); ORR=objective response rate; 
PD=progressive disease; PR=partial response; PS=performance status; SD=stable disease. 
 
 
Pooled and Meta-Analysis-based Estimates of ORR in all Randomised Patients with 
Measurable Disease at Baseline, but based on Investigator Assessment Without the 
Requirement for Confirmation of Response 
A pooled estimate of ORR of 22.48% (57/253.51) is then obtained, based on the counts in 
Appendix 1 Table 2 above, for ORR based on Investigator assessment without the requirement for 
confirmation. A formal fixed-effects meta-analysis of the above estimates was also conducted and 
gave an overall estimate of 22.29%, with p=0.351 for Cochran's Q-statistic.  
This 22.29% represents the best estimate of ORR based on Investigator assessment without a 
requirement for confirmation, i.e., it is now based on the denominator that will be used in 
NuTide:121, but it does not yet use the appropriate numerator, i.e., it does not yet allow for the 
requirement for confirmation of response and it is still based on Investigator assessments (rather 
than based on BICR assessments). 


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Adjustment to Allow for the Requirement of Confirmation of Response 
Bogaerts et al (2009) assessed the use of RECIST v1.1 criteria in 16 previous studies in solid 
tumours with a total of 6,512 patients and considered initially responding (CR or PR) patients who 
had a follow-up evaluation (or a progression) within eight weeks. They found that 1,858 out of 
2,207 initial responders (84.2%) had confirmed responses.  
With application of this multiplier of 0.842 to allow for the requirement for confirmation, the 
unconfirmed ORR estimate of 22.29% in randomised patients with measurable disease at baseline 
would be decreased to approximately 18.77%. 
Further Adjustment to Allow for BICR Rather than Investigator Assessment of Response 
There are no published randomised studies in patients with BTC which report results for ORR 
based on BICR assessment. However, five recent papers reporting on large randomised studies in 
particular solid tumours were identified for which results were given for ORR assessed by BICR 
and ORR based on Investigator assessment, with confirmation required in each case. These studies 
(which were in renal cell carcinoma or in non-small cell lung cancer) included a total of 
2469 randomised patients. After simple pooling of the BICR-based ORR results from these studies 
and simple pooling of the corresponding ORR results based on Investigator assessment, a ratio of 
1.034 was derived for BICR-based ORR divided by ORR based on Investigator assessment. 
If this multiplier is applied to the 18.77% estimate, then we obtain 19.41% (= 1.034 x 18.77%).  
Then, after rounding to the nearest integer percentage we obtain 19% as an estimate for ORR based 
on all randomised patients with measurable disease at baseline, allowing for the requirement for 
confirmation, and adjusting for the need for BICR.   
This 19% value is then used for sample size calculation related to ORR within Section 2.4 of the 
SAP. 


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Appendix 2: Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 
This appendix is identical to Appendix 4 from the Study Protocol. 
The following paragraphs provide a detailed description of the implementation of RECIST criteria 
(v1.1; Eisenhauer et al, 2009), with slight modifications and additional clarifying text to highlight 
what is required for this study.  
MEASURABILITY OF TUMOUR AT BASELINE DEFINITIONS 
At baseline, tumour lesions/lymph nodes will be categorised as measurable or non-measurable as 
follows. 
a. 
Measurable Tumour Lesions 
Tumour Lesions. Tumour lesions must be accurately measured in at least one dimension (longest 
diameter in the plane of measurement is to be recorded) with a minimum size of: 
• 10 mm by CT or MRI scan (CT/MRI scan slice thickness/interval no greater than 5 mm) 
• 10 mm calliper measurement by clinical examination (lesions that cannot be accurately 
measured with callipers should be recorded as non-measurable) 
Malignant Lymph Nodes. To be considered pathologically enlarged and measurable, a lymph 
node must be ≥15 mm in the short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis will 
be measured and followed. See also notes below on “Baseline Documentation of Target and Non-
Target Lesions” for information on lymph node measurement. 
b. 
Non-Measurable Tumour Lesions 
Non-measurable tumour lesions encompass small lesions (longest diameter <10 mm or 
pathological lymph nodes with ≥10 to <15 mm short axis), as well as truly non-measurable lesions. 
Lesions considered truly non-measurable include leptomeningeal disease, ascites, pleural or 
pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, 
peritoneal spread, and abdominal masses/abdominal organomegaly identified by physical 
examination that is not measurable by reproducible imaging techniques. 
c. 
Special Considerations Regarding Lesion Measurability 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require particular 
comment, as outlined below. 
Bone lesions: 
• Bone scan, PET scan, or plain films are not considered adequate imaging techniques to 
measure bone lesions. However, these techniques can be used to confirm the presence or 
disappearance of bone lesions. 
• Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, 
that can be evaluated by cross-sectional imaging techniques such as CT or MRI can be 
considered measurable lesions if the soft tissue component meets the definition of 
measurability described above. 
• Blastic bone lesions are non-measurable. 
 


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Cystic lesions: 
• Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. 
• Cystic lesions thought to represent cystic metastases can be considered measurable lesions 
if they meet the definition of measurability described above. However, if non-cystic lesions 
are present in the same patient, these are preferred for selection as target lesions. 
Lesions with prior local treatment: 
• 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. 
 
TARGET LESIONS: SPECIFICATIONS BY METHODS OF MEASUREMENTS 
a. 
Measurement of Lesions 
All measurements should be recorded in metric notation, using callipers if clinically assessed. All 
baseline evaluations should be performed as close as possible to the treatment start and never more 
than 14 days before the beginning of the treatment. 
 
b. 
Method of Assessment 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during study. Imaging-based evaluation (CT scan, 
MRI, or PET-CT) should always be used in this study. 
Clinical Lesions. Clinical lesions will be considered measurable only when they are superficial 
and ≥10 mm in diameter 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 
suggested. 
Chest X-Ray. Chest X-ray should not be used in assessment of lesion size or for detecting new 
lesions. If, however, a new lesion is detected by X-ray then it should be confirmed by CT scan, 
MRI, or PET-CT. 
CT, MRI, PET-CT. 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 
on the basis of 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 and PET-CT are also acceptable. 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). 
If prior to enrolment it is known that a patient is unable to undergo CT scans with IV contrast 
because of allergy or renal insufficiency, the decision as to whether a non-contrast CT scan or MRI 
scan (without IV contrast) will be used to evaluate the patient at baseline and during the study 
should be guided by the tumour type under investigation and the anatomic location of the disease. 


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For patients who develop contraindications to contrast after a baseline contrast CT scan is done, 
the decision as to whether non-contrast CT or MRI (enhanced or non-enhanced) scan will be 
performed should also be based on the tumour type and the anatomic location of the disease and 
should be optimised to allow for comparison with the prior studies if possible. 
Each case should be discussed with the radiologist to determine if substitution of these other 
approaches is possible and, if not, the patient should be considered not evaluable from that point 
forward. Care must be taken in measurement of target lesions on a different modality and 
interpretation of non-target disease or new lesions since the same lesion may appear to have a 
different size using a new modality. 
Ultrasound. Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement. 
Endoscopy, Laparoscopy, Tumour Markers, Cytology, Histology. The utilisation of these 
techniques for objective tumour evaluation cannot generally be advised. 
TUMOUR RESPONSE EVALUATION 
ASSESSMENT OF OVERALL TUMOUR BURDEN AND MEASURABLE DISEASE 
To assess objective response or future progression, it is necessary to estimate the overall tumour 
burden at baseline and to use this as a comparator for subsequent measurements. Measurable 
disease is defined by the presence of at least one measurable lesion, as detailed above. 
BASELINE DOCUMENTATION OF TARGET AND NON-TARGET LESIONS 
When more than one measurable lesion is present at baseline, all lesions up to a maximum of five 
lesions total (and a maximum of two lesions per organ) representative of all involved organs should 
be identified as target lesions and will be recorded and measured at baseline. This means in 
instances where patients have only one or two organ sites involved, a maximum of two lesions (one 
site) and four lesions (two sites), respectively, will be recorded. Other lesions (albeit measurable) 
in those organs will be recorded as non-target lesions (even if the size is >10 mm by CT, MRI, or 
PET-CT scan). 
Target lesions should be selected on the basis of their size (lesions with the longest diameter) and 
be representative of all involved organs but, additionally, should lend themselves to reproducible 
repeated measurements. It may be the case that, on occasion, the largest lesion does not lend itself 
to reproducible measurement, in which circumstance the next largest lesion that can be measured 
reproducibly should be selected. 
Lymph nodes merit special mention since they are normal anatomical structures that may be visible 
by imaging even if not involved by tumour. As noted above, pathological nodes that are defined as 
measurable and may be identified as target lesions must meet the criterion of a short axis of ≥15 mm 
by CT scan. Only the short axis of these nodes will contribute to the baseline sum. The short axis 
of the node is the diameter normally used by radiologists to judge if a node is involved by solid 
tumour. Nodal size is normally reported as two dimensions in the plane in which the image is 
obtained (for CT scan, this is almost always the axial plane; for MRI scan the plane of acquisition 
may be axial, sagittal, or coronal). The smaller of these measures is the short axis. For example, an 
abdominal node that is reported as being 20 mm x 30 mm has a short axis of 20 mm and qualifies 
as a malignant, measurable node. In this example, 20 mm should be recorded as the node 
measurement. All other pathological nodes (those with short axis ≥10 mm but <15 mm) should be 


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considered non-target lesions. Nodes that have a short axis <10 mm are considered non-
pathological and should not be recorded or followed. 
Lesions irradiated within 3 weeks prior to C1D1 may not be counted as target lesions. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum of diameters. If lymph nodes are to be 
included in the sum, then, as noted above, only the short axis is added into the sum. The baseline 
sum of diameters will be used as a reference to further characterize any objective tumour regression 
in the measurable dimension of the disease. 
All other lesions (or sites of disease), including pathological lymph nodes, should be identified as 
non-target lesions and should also be recorded at baseline. Measurements are not required and these 
lesions should be followed as “present,” “absent,” or in rare cases “unequivocal progression.” 
In addition, it is possible to record multiple non-target lesions involving the same organ as a single 
item on the eCRF (e.g., “multiple enlarged pelvic lymph nodes” or “multiple liver metastases”). 
RESPONSE CRITERIA 
a. 
Evaluation of Target Lesions 
This section provides the definitions of the criteria used to determine objective tumour response 
for target lesions. 
• Complete response (CR): disappearance of all target lesions 
o Any pathological lymph nodes (whether target or non-target) must have reduction in 
short axis to <10 mm 
• Partial response (PR): at least a 30% decrease in the sum of diameters of target lesions, 
taking as reference the baseline sum of diameters 
• Progressive disease (PD): at least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (nadir), including baseline 
o In addition to the relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm 
o The appearance of one or more new lesions is also considered progression. 
• Stable disease (SD): neither sufficient shrinkage (compared to baseline) to qualify for PR 
nor sufficient increase (taking as reference the smallest sum of diameters while on study) 
to qualify for PD 
b. 
Special Notes on the Assessment of Target Lesions 
Lymph Nodes. Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded (measured in the same anatomical plane as the baseline examination), even 
if the nodes regress to <10 mm on study. This means that when lymph nodes are included as target 
lesions, the sum of lesions may not be zero even if CR criteria are met since a normal lymph node 
is defined as having a short axis <10 mm. 
Target Lesions That Become Too Small to Measure. While on study, all lesions (nodal and 
non-nodal) recorded at baseline should have their actual measurements recorded at each subsequent 
evaluation, even when very small (e.g., 2 mm). However, sometimes lesions or lymph nodes that 


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are recorded as target lesions at baseline become so faint on CT scan that the radiologist may not 
feel comfortable assigning an exact measure and may report them as being too small to measure.  
When this occurs, it is important that a value be recorded on the eCRF as follows: 
• 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 and BML (below measurable limit) should be ticked. 
(Note:  It is less likely that this rule will be used for lymph nodes since they usually have a 
definable size when normal and are frequently surrounded by fat such as in the 
retroperitoneum; however, if a lymph node is believed to be present and is faintly seen but 
too small to measure, a default value of 5 mm should be assigned in this circumstance as 
well and BML should also be ticked). 
To reiterate, however, if the radiologist is able to provide an actual measure, that should be 
recorded, even if it is below 5 mm, and, in that case, BML should not be ticked. 
Lesions That Split or Coalesce on Treatment. When non-nodal lesions fragment, the longest 
diameters of the fragmented portions should be added together to calculate the target lesion sum. 
Similarly, as lesions coalesce, a plane between them may be maintained that would aid in obtaining 
maximal diameter measurements of each individual lesion. If the lesions have truly coalesced such 
that they are no longer separable, the vector of the longest diameter in this instance should be the 
maximal longest diameter for the coalesced lesion. 
c. 
Evaluation of Non-Target Lesions 
This section provides the definitions of the criteria used to determine the tumour response for the 
group of non-target lesions. Although some non-target lesions may actually be measurable, they 
need not be measured and, instead, should be assessed only qualitatively at the timepoints specified 
in the protocol. 
• CR: disappearance of all non-target lesions  
o All lymph nodes must be non-pathological in size (<10 mm short axis) 
• Non-CR/Non-PD: persistence of one or more non-target lesion(s)  
• PD: unequivocal progression of existing non-target lesions 
o The appearance of one or more new lesions is also considered progression 
d. 
Special Notes on Assessment of Progression of Non-Target Disease 
When the Patient Also Has Measurable Disease. In this setting, to achieve unequivocal 
progression on the basis of the non-target disease, there must be an overall level of substantial 
worsening in non-target disease in a magnitude that, even in the presence of SD or PR in target 
disease, the overall tumour burden has increased sufficiently to merit discontinuation of therapy. 
A modest increase in the size of one or more non-target lesions is usually not sufficient to qualify 
for unequivocal progression status. The designation of overall progression solely on the basis of 
change in non-target disease in the face of SD or PR of target disease will therefore be extremely 
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When the Patient Has Only Non-Measurable Disease. The same general concepts apply here as 
noted above; however, in this instance, there is no measurable disease assessment to factor into the 
interpretation of an increase in non-measurable disease burden. Because worsening in non-target 
disease cannot be easily quantified (by definition: if all lesions are truly non--measurable), a useful 
test that can be applied when assessing patients for unequivocal progression is to consider if the 
increase in overall disease burden based on the change in non-measurable disease is comparable in 
magnitude to the increase that would be required to declare PD for measurable disease; that is, an 
increase in tumour burden representing an additional 73% increase in volume (which is equivalent 
to a 20% increase in diameter in a measurable lesion). Examples include an increase in a pleural 
effusion from “trace” to “large” or an increase in lymphangitic disease from localised to widespread 
or may be described in protocols as “sufficient to require a change in therapy.” If unequivocal 
progression is seen, the patient should be considered to have had overall PD at that point. Although 
it would be ideal to have objective criteria to apply to non-measurable disease, the very nature of 
that disease makes it impossible to do so; therefore, the increase must be substantial. 
e. 
New Lesions 
The appearance of new malignant lesions denotes disease progression; therefore, some comments 
on detection of new lesions are important. There are no specific criteria for the identification of 
new radiographic lesions; however, the finding of a new lesion should be unequivocal, that is, not 
attributable to differences in scanning technique, change in imaging modality, or findings thought 
to represent something other than tumour (for example, some “new” bone lesions may be simply 
healing or flare of pre-existing lesions). This is particularly important when the patient’s baseline 
lesions show PR or CR. For example, necrosis of a liver lesion may be reported on a CT scan report 
as a “new” cystic lesion, which it is not. 
A lesion identified during the study in an anatomical location that was not scanned at baseline is 
considered a new lesion and will indicate disease progression. 
If a new lesion is equivocal, for example because of its small size, continued therapy and follow-
up evaluation will clarify if it represents truly new disease. If repeat scans confirm there is definitely 
a new lesion, then progression should be declared using the date of the initial scan. 
EVALUATION OF RESPONSE 
a. 
Timepoint Response (Overall Response) 
It is assumed that at each protocol-specified timepoint, a response assessment occurs. Appendix 2 
Table 1 provides a summary of the overall response status calculation at each timepoint for patients 
who have measurable disease at baseline. 
When patients have non-measurable (therefore non-target) disease only, Appendix 2 Table 2 is to 
be used. 


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Appendix 2 Table 1: Timepoint response: patients with target lesions (with or without 
non-target lesions) 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or no 
PD 
Any 
PD 
Yes or no 
PD 
Any 
Any 
Yes 
PD 
Abbreviations: CR = complete response; NE = not evaluable; PD = progressive disease; PR = partial response; SD = 
stable disease. 
 
Appendix 2 Table 2: Timepoint response: patients with non-target lesions only 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PDa 
Not all evaluated 
No 
NE 
Unequivocal PD 
Yes or no 
PD 
Any 
Yes 
PD 
a “Non-CR/non-PD” is preferred over “stable disease” for non-target disease since stable disease is increasingly  
used as an endpoint for assessment of efficacy in some studies; thus, assigning “stable disease” when no lesions  
can be measured is not advised.  
Abbreviations: CR = complete response; NE = not evaluable; PD = progressive disease. 
 
b. 
Missing Assessments and Not-Evaluable Designation 
When no imaging/measurement is done at all at a particular timepoint, the patient is not evaluable 
at that timepoint. If only a subset of lesion measurements are made at an assessment, usually the 
case is also considered not evaluable at that timepoint, unless a convincing argument can be made 
that the contribution of the individual missing lesion(s) would not change the assigned timepoint 
response. This would be most likely to happen in the case of PD. For example, if a patient had a 
baseline sum of 50 mm with three measured lesions and, during the study, only two lesions were 
assessed, but those gave a sum of 80 mm; the patient will have achieved PD status, regardless of 
the contribution of the missing lesion. 


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If one or more target lesions were not assessed either because the scan was not done or the scan 
could not be assessed because of poor image quality or obstructed view, the response for target 
lesions should be “unable to assess” since the patient is not evaluable. Similarly, if one or more 
non-target lesions are not assessed, the response for non-target lesions should be “unable to assess” 
except where there is clear progression. Overall response would be “unable to assess” if either the 
target response or the non-target response is “unable to assess,” except where this is clear evidence 
of progression as this equates with the case being not evaluable at that timepoint. 
Appendix 2 Table 3: Best overall response allowing for the requirement of confirmation for 
PR and CR 
Overall Response at First 
Timepoint 
Overall Response at 
Subsequent Timepoint 
 
Best Overall Response 
CR 
CR 
CR 
CR 
PR 
SD, PD, or PR a 
CR 
SD 
SD, provided minimum duration 
for SD was met; otherwise, PD 
CR 
PD 
SD, provided minimum duration 
for SD was met; otherwise, PD 
CR 
NE 
SD, provided minimum duration 
for SD was met; otherwise, NE 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD, provided minimum duration 
for SD was met; otherwise, PD 
PR 
NE 
SD, provided minimum duration 
for SD was met; otherwise, NE 
NE 
NE 
NE 
a If a CR is truly met at the first timepoint, any disease seen at a subsequent timepoint, even disease meeting PR 
criteria relative to baseline, qualifies as PD at that point (since disease must have reappeared after CR). Best 
response would depend on whether the minimum duration for SD was met. However, sometimes CR may be 
claimed when subsequent scans suggest small lesions were likely still present and in fact the patient had PR,  
not CR, at the first timepoint. Under these circumstances, the original CR should be changed to PR and the best 
response is PR.  
Note: For a best overall response of SD the timepoint on which this is based must be at least 8 weeks after C1D1. 
Abbreviations: CR = complete response; NE = not evaluable; PD = progressive disease; PR = partial response; SD = 
stable disease. 
 


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c. 
Special Notes on Response Assessment 
When nodal disease is included in the sum of target lesions and the nodes decrease to “normal” 
size (<10 mm), they may still have a measurement reported on scans. This measurement should be 
recorded even though the nodes are normal in order not to overstate progression should it be based 
on increase in size of the nodes. As noted earlier, this means that patients with CR may not have a 
total sum of “zero” on the eCRF. 
Patients with a global deterioration of health status requiring discontinuation of treatment without 
objective evidence of disease progression at that time should be reported as “symptomatic 
deterioration.” Every effort should be made to document objective progression after 
discontinuation of treatment. Symptomatic deterioration is not a descriptor of an objective 
response; it is a reason for stopping study therapy. The objective response status of such patients 
is to be determined by evaluation of target and non-target disease as shown in Appendix 2 Table 1-
Table 3. 
For equivocal findings of progression (e.g., very small and uncertain new lesions; cystic changes 
or necrosis in existing lesions), treatment may continue until the next scheduled assessment. If at 
the next scheduled assessment progression is confirmed, the date of progression should be the 
earlier date when progression was suspected. 
If a patient undergoes an excisional biopsy or other appropriate approach (e.g., multiple passes 
with large core needle) of a new lesion or an existing solitary progressive lesion that following 
serial sectioning and pathological examination reveals no evidence of malignancy 
(e.g., inflammatory cells, fibrosis, etc), then the new lesion or solitary progressive lesion will not 
constitute disease progression. 
The present study is one in which patients with advanced disease are eligible (i.e., primary disease 
still or partially present), the primary tumour should also be captured as a target or non-target 
lesion, as appropriate. This is to avoid an incorrect assessment of CR if the primary tumour is still 
present but not evaluated as a target or non-target lesion. 


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Appendix 3: Determination of Best Overall Response in Patients having Intermediate 
Timepoint Responses of NE 
Appendix 2 Table 3 describes the rules for determination of BOR allowing for the requirement of 
confirmation for PR and CR. However, as noted in section 4.4.4 of Eisenhauer et al (2009), when 
confirmation of response is required it is necessary to define how missing data/assessments will be 
addressed in determination of response. 
Appendix 3 here provides rules for defining BOR when patients have a timepoint response of PR 
or CR, followed by one or more intermediate visits with timepoint responses of NE, and then 
followed by a timepoint response of PR or CR (at least 28 days after the previous PR or CR). 
The first case of this type is 
1) 
CR timepoint response, followed by one or more NE timepoints responses, followed by 
CR timepoint response - BOR = CR 
For Case 1 above where BOR is classified as CR, this also requires that the timepoint responses 
with NE either had no imaging assessment in all cases, or if one or more assessments with NE did 
have imaging undertaken then all of the following were satisfied at each such timepoint:  
(i)  
any subset of target and non-target lesions that were assessed are found to have 
disappeared;  
(ii)  
any lymph nodes assessed have short axis <10 mm; and  
(iii)  no new lesions were identified 
The rule above for Case 1 patients would take precedence over the BOR classification given in 
Appendix 2 Table 3, e.g., if the first CR timepoint response was immediately preceded by a PR 
timepoint response (giving a sequence of PR-CR-NE-CR) then Appendix 2 Table 3 would have 
classified such a patient as having BOR = PR, but the rule above re-classifies such a patient as 
having BOR = CR. 
The next cases considered here are: 
2) 
PR timepoint response, followed by one or more NE timepoints responses, followed by 
PR timepoint response - BOR = PR 
3) 
PR timepoint response, followed by one or more NE timepoints responses, followed by 
CR timepoint response - BOR = PR 
For Cases 2 and 3 where BOR is classified as PR, this also requires that the timepoint responses 
with NE either had no imaging assessment in all cases, or if one or more assessments with NE did 
have imaging undertaken then all of the following were satisfied at each such timepoint:  
(iv)  the subset of target lesions that were assessed have a sum of diameters such that if all 
of the non-lymph node target lesions not assessed had a zero value, and the lymph node 
target lesions not assessed had a 10 cm value, then it would still be possible to 
demonstrate at least a 30% decrease relative to baseline;  
(v)  
any non-target lesions are non-PD; and  
(vi)  no new lesions were identified 


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For Case 3 if the CR timepoint response is followed by a further CR then the BOR classification 
given in Appendix 2 Table 3 takes precedence over the rule given above, e.g., a sequence of 
PR-NE-CR-CR would be classified as BOR = PR above, but Appendix 2 Table 3 would have 
classified such a patient as having BOR = CR and the CR takes precedence over PR in calculation 
of BOR. 
The remaining case considered here is: 
4) 
CR timepoint response, followed by one or more NE timepoints responses, followed by 
PR timepoint response - BOR would use the rules for CR followed by PR as given in 
Appendix 2 Table 3 to classify as PR, SD, or PD, but the additional conditions (iv)-(vi) 
above would need to be satisfied for assessments with NE in order for the BOR to be 
classified as PR 
 


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Appendix 4: Power Calculations for Subgroup Analyses of ORR 
Section 7.9 indicates that confidence intervals will be provided for ORR by primary tumour site 
(gallbladder, intra-hepatic, extra-hepatic, ampullary) and by stage of disease (metastatic disease, 
locally advanced disease). Estimates of ORR (as well as counts for CR and for PR) by treatment 
group, together with odds ratios and difference in proportions of subjects with ORR will be given 
for these subgroups. In addition, the odds ratio for ORR will have 95% and 80% two-sided CIs 
derived using the Baptista-Pike mid-p method (Fagerland et al, 2015). For the difference in 
proportions of patients with ORR, 95% and 80% two-sided CIs will also be derived using the 
Newcombe method without continuity correction (Newcombe, 1998, method 10). 
This appendix provides details on power and other related calculations for subgroup sizes of 20, 
30, 40, and 50 (corresponding to 10, 15, 20, and 25 per arm). Appendix 4 Table 1 below identifies 
the 9 cases in which power calculations have been derived, where θ1 represents the true ORR in 
Arm A and θ2 represents the true ORR in Arm B.  
Appendix 4 Table 1: Sets of Parameters values for which Power Calculations have been 
Derived 
Case 
θ1 
θ2 
θ1 - θ2 
Odds Ratio 
1 
0.28 
0.17 
0.11 
1.90 
2 
0.34 
0.17 
0.17 
2.52 
3 
0.39 
0.17 
0.22 
3.12 
4 
0.31 
0.19 
0.12 
1.92 
5 
0.37 
0.19 
0.18 
2.50 
6 
0.42 
0.19 
0.23 
3.09 
7 
0.34 
0.21 
0.13 
1.94 
8 
0.40 
0.21 
0.19 
2.51 
9 
0.45 
0.21 
0.24 
3.08 
Case 4 represents the parameter values assumed for the overall sample size calculations where the 
corresponding odds ratio is 1.92 and the corresponding difference in proportions is 0.12. Cases 1 
and 7 correspond to approximately the same odds ratio as case 4 but assume slightly lower (Case 
1) and slightly higher (Case 7) values for the true ORR in Arm B. Only small differences in the 
assumed ORR for Arm B are considered because the value for θ2 was derived (as described in 
Appendix 1) from past data on approximately 250 patients.  
For Arm A, in addition to values of θ1 which correspond to an odds ratio of approximately 1.92 
(Cases 1, 4, 7), values which correspond to odds ratios of approximately 2.5 (Cases 2, 5, 8) and 
approximately 3.1 (Cases 3, 6, 9) are considered. As described in Protocol Section 1.4.3, in the 
ABC-08 study 7/14 (50%) of patients from the ITT population had a response (BOR of CR or PR). 
Confirmation of response was not required in ABC-08, but if (as described in Appendix 1 of the 
SAP) the 0.842 multiplier obtained from Bogaerts et al (2009) was applied then an approximation 
to a confirmed response rate would be 42.1%. If a response rate in Arm A was 42.1% compared to 
a response rate of 19% in Arm B, then this would give an odds ratio of 3.1. Therefore, in Appendix 
4 Table 1 above an odds ratio of 3.1 has been considered together with a value that is midway 
between 1.9 and 3.1. 


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Three further cases have been considered where Δ = θ1 - θ2 = 0 (and so where the odds ratio = 1), 
i.e., with common assumed true ORRs of 0.17 (Case 10), 0.19 (Case 11), and 0.21 (Case 12).  
Calculations in Appendix 4 Table 2 and Table 3 below have all been derived based on exact 
binomial probabilities. For subgroups with relatively small sample sizes any confidence intervals 
will necessarily be relatively wide. Appendix 4 Table 2 provides tail probabilities for the observed 
odds ratio using cut-points of 1.5, 1.75, and 1.9, where the latter is approximately equal to the odds 
ratio assumed in the overall sample size calculation. 
Appendix 4 Table 2: Probabilities that the Observed Odds Ratio is Greater than Particular 
Cut-Points, With Subgroup Sample Sizes in the Range 20-50 
n per 
arm 
Total n 
Case 
P (ORhat > 1.5) 
P (ORhat > 1.75) 
P (ORhat > 1.9) 
10 
20 
1 
62.3% 
51.7% 
51.7% 
10 
20 
2 
72.8% 
61.6% 
61.6% 
10 
20 
3 
79.8% 
69.3% 
69.3% 
10 
20 
4 
63.5% 
51.5% 
51.5% 
10 
20 
5 
73.3% 
61.4% 
61.4% 
10 
20 
6 
79.9% 
69.3% 
69.3% 
10 
20 
7 
64.3% 
51.6% 
51.6% 
10 
20 
8 
73.5% 
61.7% 
61.7% 
10 
20 
9 
79.8% 
69.6% 
69.6% 
10 
20 
10 (Δ=0) 
37.9% 
32.3% 
32.3% 
10 
20 
11 (Δ=0) 
38.4% 
31.3% 
31.3% 
10 
20 
12 (Δ=0) 
38.7% 
30.1% 
30.1% 
15 
30 
1 
60.3% 
54.6% 
52.8% 
15 
30 
2 
71.9% 
67.7% 
65.0% 
15 
30 
3 
80.1% 
76.8% 
73.8% 
15 
30 
4 
60.4% 
55.5% 
52.8% 
15 
30 
5 
72.1% 
68.1% 
64.6% 
15 
30 
6 
80.4% 
76.9% 
73.3% 
15 
30 
7 
60.9% 
56.5% 
52.8% 
15 
30 
8 
72.7% 
68.5% 
64.4% 
15 
30 
9 
81.0% 
76.9% 
73.1% 
15 
30 
10 (Δ=0) 
35.6% 
29.1% 
28.8% 
15 
30 
11 (Δ=0) 
34.4% 
28.2% 
27.6% 
15 
30 
12 (Δ=0) 
33.1% 
27.5% 
26.5% 
20 
40 
1 
62.8% 
54.4% 
49.8% 
20 
40 
2 
76.8% 
68.6% 
65.1% 
20 
40 
3 
85.7% 
78.6% 
76.3% 
20 
40 
4 
64.2% 
54.8% 
50.9% 
20 
40 
5 
77.8% 
68.9% 
66.2% 
20 
40 
6 
86.3% 
79.0% 
77.0% 


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n per 
arm 
Total n 
Case 
P (ORhat > 1.5) 
P (ORhat > 1.75) 
P (ORhat > 1.9) 
20 
40 
7 
65.8% 
55.5% 
52.4% 
20 
40 
8 
78.9% 
69.7% 
67.3% 
20 
40 
9 
86.9% 
79.8% 
77.7% 
20 
40 
10 (Δ=0) 
32.8% 
26.4% 
23.3% 
20 
40 
11 (Δ=0) 
31.6% 
25.3% 
21.7% 
20 
40 
12 (Δ=0) 
30.8% 
24.2% 
20.7% 
25 
50 
1 
64.2% 
56.4% 
49.8% 
25 
50 
2 
78.4% 
72.2% 
66.1% 
25 
50 
3 
86.9% 
82.5% 
77.7% 
25 
50 
4 
64.6% 
57.1% 
50.3% 
25 
50 
5 
78.4% 
72.5% 
66.6% 
25 
50 
6 
87.0% 
82.4% 
78.2% 
25 
50 
7 
65.1% 
57.9% 
51.2% 
25 
50 
8 
78.7% 
72.7% 
67.6% 
25 
50 
9 
87.3% 
82.5% 
79.2% 
25 
50 
10 (Δ=0) 
30.8% 
24.7% 
20.5% 
25 
50 
11 (Δ=0) 
29.8% 
23.6% 
19.2% 
25 
50 
12 (Δ=0) 
28.9% 
22.6% 
18.2% 
 
It can be seen that with 10 patients per arm in Cases 3, 6, and 9 (which each have an assumed true 
odds ratio of 3.1) an observed odds ratio greater than 1.9 is obtained 69%-70% of the time but 
when the true odds ratio is 1.0 (Cases 10-12) an observed odds ratio greater than 1.9 is obtained 
approximately 30%-32% of the time. With increasing sample size these probabilities of obtaining 
an observed odds ratio greater than 1.9 for Cases 3, 6, and 9 compared with Cases 10-12 become: 
(i) 73%-74% vs. 27%-29% for 15 patients per arm; (ii) 76%-78% vs. 21%-23% for 20 patients per 
arm; and (iii) 78%-79% vs. 18%-21% for 25 patients per arm. 
Even though confidence intervals will necessarily be wide for subgroups with relatively small 
sample sizes, in Table 3 the following power values have been derived in relation to 80% CIs: 
 
• The probability that the lower limit of the 80% Newcombe CI for the difference in proportions 
is greater than zero; and 
• The probability that the lower limit of the 80% Gart CI for the odds ratio is greater than 1.0. 
 
As indicated in Section 7.9, CIs for the subgroup analyses of ORR for this study will be derived 
using the Baptista-Pike mid-p method for the odds ratio and by the Newcombe method (without 
continuity correction) for the difference in proportions. For the power calculations given below the 
Newcombe method has been used for the difference in proportions, but the Gart method 


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(Agresti, 2013) which is a modified Wald CI whereby 0.5 is added to each of the four cell counts, 
has been used for simplicity for the odds ratio.  
Note:  The Gart method was found by Fagerland et al, 2015 to be somewhat conservative 
(although less conservative than for unmodified Wald based CIs) for small sample sizes. 
For Cases 10-12 (which each have a true assumed odds ratio of 1.0) the Type 1 Error ranged 
from 6.5% to 8.7% for the 4 sample sizes considered, i.e., lower than the nominal 10% 
expected for 80% two-sided CIs. Therefore, it would be expected that the power values 
given in Table 3 would also be lower than the power from the less conservative Baptista-
Pike mid-p method that will actually be used in the subgroup analyses for the odds ratio. 
It can be seen from Table 3 that for Cases 3, 6, and 9 the power from the Newcombe 80% two-
sided CI is: (i) 46%-49% with 10 patients per arm; (ii) 55%-56% with 15 patients per arm; (iii) 
63%-67% with 20 patients per arm; and (iv) 68%-70% for 25 patients per arm. Corresponding 
power values from the Gart 80% CI for the odds ratio were 1%-5% lower than the values obtained 
from the Newcombe method (for difference in proportions), but as noted above the Gart method is 
conservative and so will in general underestimate the power that would be obtained from the 
Baptista-Pike mid-p method based CIs for odds ratios that will be used in the actual subgroup 
analyses.  
In summary, with 10 patients per arm (20 patients in total within the subgroup) when the true odds 
ratio for ORR is approximately 3.1 (which was derived on the basis of data from ABC-08) the 
power from Newcombe 80% two-sided CIs is 46%-49%, the probability that the observed odds 
ratio will be greater than 1.9 (the value assumed in the studies overall power calculation for ORR) 
is 69%-70%, and the probability that the observed odds ratio will be greater than 1.5 is 80%. 
Therefore, it is proposed that 20 patients in total be viewed as sufficient for an adequate assessment 
of ORR within a subgroup. 
 
 
 


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Appendix 4 Table 3: Power Values for the Newcombe CI for the Difference in Proportions, 
and for the Gart CI for the Odds Ratio, with Subgroup Sample Sizes in 
the Range 20-50 
n per arm 
Total n 
Case 
P (Newc. 80% CI > 0) 
P (Gart 80% CI > 1) 
10 
20 
1 
26.2% 
21.8% 
10 
20 
2 
36.7% 
32.7% 
10 
20 
3 
46.2% 
42.3% 
10 
20 
4 
27.5% 
23.9% 
10 
20 
5 
38.1% 
34.5% 
10 
20 
6 
47.7% 
43.6% 
10 
20 
7 
29.0% 
25.7% 
10 
20 
8 
39.8% 
35.8% 
10 
20 
9 
49.3% 
44.5% 
15 
30 
1 
31.9% 
26.0% 
15 
30 
2 
44.7% 
38.6% 
15 
30 
3 
55.3% 
50.0% 
15 
30 
4 
32.7% 
27.2% 
15 
30 
5 
45.1% 
39.9% 
15 
30 
6 
55.6% 
51.4% 
15 
30 
7 
33.4% 
28.6% 
15 
30 
8 
45.6% 
41.5% 
15 
30 
9 
56.1% 
53.1% 
20 
40 
1 
32.7% 
30.3% 
20 
40 
2 
49.5% 
46.8% 
20 
40 
3 
63.3% 
60.1% 
20 
40 
4 
35.1% 
32.7% 
20 
40 
5 
51.8% 
48.4% 
20 
40 
6 
65.1% 
60.9% 
20 
40 
7 
37.7% 
34.6% 
20 
40 
8 
54.1% 
49.5% 
20 
40 
9 
66.8% 
61.5% 
25 
50 
1 
37.1% 
33.4% 
25 
50 
2 
54.7% 
51.0% 
25 
50 
3 
68.2% 
65.4% 
25 
50 
4 
38.5% 
35.1% 
25 
50 
5 
55.6% 
52.6% 
25 
50 
6 
68.9% 
66.9% 
25 
50 
7 
39.9% 
36.9% 
25 
50 
8 
56.7% 
54.6% 
25 
50 
9 
70.0% 
68.8% 
 


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Appendix 5: Dates that a COVID-19 Vaccine Was First Approved in those Countries Which 
Randomized Patients in the NuTide:121 Trial 
Country 
Date that a COVID-19 Vaccine was first 
approved1 
Australia 
25-Jan-21 
Canada 
23-Dec-20 
Czech Republic 
21-Dec-20 
France 
21-Dec-20 
Germany 
21-Dec-20 
Hungary 
21-Dec-20 
Italy 
21-Dec-20 
Russia 
11Aug-20 
South Korea 
10-Feb-21 
Spain 
21-Dec-20 
Taiwan 
6-May-21 
Turkey 
14-Jan-21 
Ukraine 
22-Feb-21 
United Kingdom 
2-Dec-20 
United States 
11-Dec-20 
1 Date corresponds to when a COVID-19 was first approved in the country even if this was just 
under an Emergency Use Authorisation (or equivalent).