A Phase Ib/II Open Label Study to Assess the Safety and Pharmacokinetics of NUC-3373, a Nucleotide Analogue, Given in Combination With Standard Agents Used in Colorectal Cancer Treatment
Phase: PHASE1
Conditions: Colorectal Cancer, Colorectal Neoplasms, Colorectal Carcinoma, Colorectal Tumors, Neoplasms, Colorectal
Sponsor: NuCana plc

 
 
 
 
 
 
 
CLINICAL STUDY PROTOCOL 
 
 
A Phase Ib/II open label study to assess the safety and pharmacokinetics of 
NUC-3373, a nucleotide analogue, given in combination with standard 
agents used in colorectal cancer treatment 
 
 
IMP 
NUC-3373 
Protocol Number 
NuTide:302 
Protocol Version, Date 
Version 4.2, 10 August 2022 
Development Phase 
Ib/II 
IND Number 
135275 
EudraCT Number 
2017-002062-53 
NCT Number 
NCT03428958 
Sponsor: 
NuCana plc 
3 Lochside Way 
Edinburgh, EH12 9DT, UK 
Telephone: +44 (0)131 357 1111 
Email: nutide302@nucana.com 
Approval: 
 
 
Dr Elisabeth Oelmann, MD 
PhD  
SVP, Clinical & Medical 
Development  
 
 
Date 
Medical Monitor: 
Dr Peter Langecker, MD PhD 
Executive Medical Director, Global Oncology 
Clinipace 
Tel: +1 919 578 5100 
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 No unpublished information 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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PRINCIPAL INVESTIGATOR AGREEMENT  
AND SIGNATURE 
 
 
A Phase Ib/II open label study to assess the safety and pharmacokinetics of 
NUC-3373, a nucleotide analogue, given in combination with standard 
agents used in colorectal cancer treatment 
 
Protocol Number 
NuTide:302 
Protocol Version, Date 
Version 4.2, 10 Aug 2022 
IMP 
NUC-3373 
Development Phase 
Ib/II 
Sponsor 
NuCana plc 
IND Number 
135275 
EudraCT Number 
2017-002062-53 
NCT Number 
NCT03428958 
 
 
This study will be conducted in compliance with the clinical study protocol (and amendments), 
International Council for 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. 
 
 
 
 
Principal Investigator’s signature 
 
 
 
 
Date (dd-mmm-yyyy) 
Principal Investigator’s name (printed)  
 
 
 
 

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TABLE OF CONTENTS  
CLINICAL STUDY PROTOCOL ............................................................................ 0 
TABLE OF CONTENTS ........................................................................................... 2 
LIST OF FIGURES .................................................................................................... 8 
LIST OF TABLES ...................................................................................................... 8 
PROTOCOL SYNOPSIS.............................................................................................. 9 
OVERALL STUDY DESIGN .................................................................................... 28 
SUMMARY SCHEDULE OF EVENTS: ARM 1A AND ARM 1B ......................... 29 
SUMMARY SCHEDULE OF EVENTS: ARM 1C AND ARM 1D ......................... 33 
SUMMARY SCHEDULE OF EVENTS: PART 2 (ALL ARMS) ............................ 37 
SUMMARY SCHEDULE OF EVENTS: PART 3 .................................................... 41 
SUMMARY SCHEDULE OF EVENTS: PK SUB-STUDY (PART 2 ARM 2B; 
CYCLE 1 AND CYCLE 2 DAYS 1 AND 2) .......................................... 45 
ABBREVIATIONS .................................................................................................... 49 
1. 
INTRODUCTION AND STUDY RATIONALE ................................... 52 
1.1. 
Treatment Options for Recurrent Colorectal Cancer ............................... 52 
1.2. 
5-FU in Colorectal Cancer ....................................................................... 52 
1.2.1 
Adjuvant Treatment ................................................................................. 52 
1.2.2 
Treatment for Metastatic Disease ............................................................ 52 
1.3. 
Limitations of 5-FU Treatment ................................................................ 53 
1.3.1 
Susceptibility to Breakdown .................................................................... 53 
1.3.2 
Requirement of Activation ...................................................................... 55 
1.3.3 
Dosing Administration Challenges .......................................................... 55 
1.4. 
NUC-3373 ................................................................................................ 55 
1.4.1 
Non Clinical Data .................................................................................... 56 
1.5. 
Clinical Data ............................................................................................ 57 
1.6. 
Pharmacokinetics ..................................................................................... 59 
1.6.1 
Plasma Levels .......................................................................................... 59 
1.6.2 
Intracellular Levels .................................................................................. 59 
1.7. 
Study Rationale ........................................................................................ 59 
2. 
STUDY OBJECTIVES AND ENDPOINTS ........................................... 62 
2.1. 
Primary Objectives .................................................................................. 62 
2.2. 
Secondary Objectives .............................................................................. 62 
2.3. 
Exploratory Objectives ............................................................................ 62 
2.4. 
Primary Endpoints ................................................................................... 63 

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2.5. 
Secondary Endpoints ............................................................................... 63 
2.5.1 
Safety (Phase Ib and Phase II) ................................................................. 63 
2.5.2 
Pharmacokinetics (Phase Ib and Phase II) ............................................... 63 
2.5.3 
Efficacy Endpoints (Phase Ib) ................................................................. 64 
2.6. 
Exploratory Endpoints (Phase Ib and Phase II) ....................................... 64 
3. 
INVESTIGATIONAL PLAN .................................................................. 65 
3.1. 
Overall Study Design ............................................................................... 65 
3.1.1 
Part 1 ........................................................................................................ 67 
3.1.2 
Part 2 ........................................................................................................ 68 
3.1.3 
Part 3 ........................................................................................................ 70 
3.1.4 
PK Sub-study ........................................................................................... 71 
3.2. 
Rationale for the NUC-3373 Dose Selected ............................................ 71 
3.3. 
Study Treatment ....................................................................................... 72 
3.4. 
Dose Escalation Guidelines ..................................................................... 78 
3.4.1 
Definition of Dose-Limiting Toxicity ..................................................... 78 
3.5 
Duration of Patient Participation ............................................................. 79 
3.6 
Study Completion .................................................................................... 79 
4 
PATIENT SELECTION .......................................................................... 80 
4.1 
Inclusion Criteria ..................................................................................... 80 
4.2 
Exclusion Criteria .................................................................................... 83 
4.3 
Waivers to Entry Criteria ......................................................................... 85 
5 
STUDY ASSESSMENTS AND PROCEDURES................................... 86 
5.1 
Informed Consent .................................................................................... 86 
5.1.1 
Informed Consent for Tumour Tissue Collection .................................... 86 
5.2 
Patient Registration and Screening Procedures ....................................... 86 
5.3 
Screening Assessments ............................................................................ 87 
5.4 
Re-Screening Patients who Fail Screening .............................................. 88 
5.5 
Evaluations to be Performed during the Study ........................................ 88 
5.5.1 
Cycle 0 (Arm 1a and Arm 1b) ................................................................. 89 
5.5.2 
Each cycle, Day 1 .................................................................................... 90 
5.5.3 
Cycle 1 ONLY – Days 1, 2 & 3, and Days 15 & 16 ............................... 91 
5.5.4 
Cycle 1 ONLY – Day 8 (or Day 15) ........................................................ 92 
5.5.5 
Cycle 3 – Days 1 & 15 (C3D1 & C3D15; all cohorts) ............................ 92 
5.5.6 
Each cycle, Day 8 (Q1W dosing cohorts only) ....................................... 92 
5.5.7 
Each cycle, Day 15 (all cohorts) .............................................................. 93 

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5.5.8 
Each cycle, Day 22 (Q1W cohorts only) ................................................. 94 
5.5.9 
PK sub-study (Part 2, Arm 2b): Cycle 1 and Cycle 2 D1/D2 ONLY ...... 96 
5.5.10 
Every 8 weeks (±7 days) from Cycle 1 Day 1 until disease progression, 
initiation of a new treatment or death ...................................................... 97 
5.5.11 
End of Treatment Visit ............................................................................ 98 
5.5.12 
Long-Term Follow-Up ............................................................................ 99 
6 
PATIENT WITHDRAWAL .................................................................. 100 
6.1 
End of Treatment ................................................................................... 100 
6.2 
Consent Withdrawal .............................................................................. 101 
6.3 
Patient Evaluability and Replacement ................................................... 101 
7 
SAMPLES FOR LABORATORY ANALYSIS ................................... 102 
7.1 
Clinical Laboratory Tests ...................................................................... 102 
7.2 
Pharmacokinetics ................................................................................... 102 
7.2.1 
PK Sub-study ......................................................................................... 104 
7.3 
Pharmacodynamics (Part 1 only) ........................................................... 106 
7.4 
Exploratory Biomarkers ......................................................................... 106 
7.5 
Tumour Tissue Sample Submission ...................................................... 106 
7.6 
Labelling and Confidentiality of Biological Samples............................ 106 
7.7 
Withdrawal of Consent for Biological Sample Collection or Retention
 ............................................................................................................... 107 
8 
INVESTIGATIONAL MEDICINAL PRODUCTS .............................. 108 
8.1 
NUC-3373 .............................................................................................. 108 
8.1.1 
NUC-3373 Description .......................................................................... 108 
8.1.2 
NUC-3373 Supplies and Study Drug Packaging ................................... 108 
8.1.3 
Handling and Storage of NUC-3373 ..................................................... 108 
8.1.4 
Preparation of NUC-3373 ...................................................................... 108 
8.1.5 
NUC-3373 Administration .................................................................... 108 
8.2 
Other IMPs (Agents to be used in Combination with NUC-3373)........ 109 
8.3 
Administration of NUC-3373 and other IMPs ...................................... 109 
8.3.1 
Part 1 ...................................................................................................... 109 
8.3.2 
Part 2 ...................................................................................................... 111 
8.3.3 
Part 3 ...................................................................................................... 113 
8.4 
NUC-3373 Drug Destruction ................................................................. 116 
8.5 
NUC-3373 Study Drug Accountability ................................................. 116 
8.6 
Management of Overdose of NUC-3373 ............................................... 117 
9 
DOSE MODIFICATIONS .................................................................... 118 

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9.1 
Criteria for Continuation of Treatment .................................................. 119 
9.2 
Dose Modifications (Dose Delays and Dose Reductions) ..................... 119 
9.3 
Suggested Management of Toxicity ...................................................... 121 
9.3.1 
Nausea and Vomiting ............................................................................ 121 
9.3.2 
Diarrhoea ............................................................................................... 121 
9.3.3 
Mucositis ................................................................................................ 122 
9.3.4 
Palmar-Plantar Erythrodysesthaesia (hand-foot syndrome) .................. 122 
9.3.5 
Dermatologic Toxicity ........................................................................... 122 
9.3.6 
Infusion Reactions ................................................................................. 123 
9.3.7 
Ocular Toxicity ...................................................................................... 123 
9.3.8 
Fatigue ................................................................................................... 123 
9.3.9 
Combination Therapies .......................................................................... 123 
9.3.9.1 
Oxaliplatin ............................................................................................. 123 
9.3.9.2 
Irinotecan ............................................................................................... 124 
9.3.9.3 
Bevacizumab .......................................................................................... 124 
9.3.9.4 
EGFR inhibitors ..................................................................................... 124 
10 
OTHER TREATMENTS (NON-IMP) .................................................. 126 
10.1 
Support Medication ............................................................................... 126 
10.2 
Haematopoietic Growth Factor Support ................................................ 126 
10.3 
Concomitant Medications ...................................................................... 126 
10.3.1 
Contraception Methods .......................................................................... 126 
10.3.2 
Prohibited Therapy ................................................................................ 127 
10.3.3 
Therapy to be Used with Caution .......................................................... 127 
10.3.4 
COVID-19 Vaccinations ....................................................................... 128 
11 
TUMOUR RESPONSE ASSESSMENTS ............................................ 129 
11.1 
Tumour Measurements and Assessment of Disease Response ............. 129 
12 
SAFETY REPORTING ......................................................................... 130 
12.1 
Definitions ............................................................................................. 130 
12.2 
Adverse Event Reporting ....................................................................... 131 
12.3 
Assessment of Causality to Study Drug(s) ............................................ 132 
12.4 
Assessment of Severity .......................................................................... 132 
12.5 
SAE Reporting ....................................................................................... 133 
12.6 
Expedited Reporting of SAEs ................................................................ 134 
12.7 
SUSAR Reporting ................................................................................. 134 
12.8 
Terms and Grading of Adverse Events and Toxicities .......................... 134 

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12.9 
Pregnancy .............................................................................................. 134 
12.10 
Events Exempt from being Reported as AE/SAEs ................................ 135 
12.10.1 
Progression of Underlying Disease ....................................................... 135 
12.10.2 
Death on Study Attributed to Malignancy ............................................. 135 
12.10.3 
Elective Admissions and Supportive Care ............................................ 135 
12.11 
Informing Investigators of New Safety Information ............................. 135 
12.12 
Reference Safety Information (RSI) for Assessment of Expectedness . 135 
12.13 
Data Safety Monitoring Committee (DSMC) ........................................ 136 
13 
STATISTICAL CONSIDERATIONS .................................................. 137 
13.1 
Sample Sizes .......................................................................................... 137 
13.2 
Missing, Unused and Spurious Data ...................................................... 137 
13.3 
Analysis Populations ............................................................................. 137 
13.3.1 
Safety Population ................................................................................... 137 
13.3.2 
Full Analysis Set .................................................................................... 138 
13.3.3 
Evaluable for Response Set ................................................................... 138 
13.3.4 
PK Analysis Set ..................................................................................... 138 
13.4 
Patient Disposition ................................................................................. 138 
13.5 
Statistical Methods ................................................................................. 139 
13.5.1 
Demographics and Baseline Data .......................................................... 139 
13.5.2 
Concomitant Medications ...................................................................... 139 
13.5.3 
Extent of Exposure ................................................................................ 139 
13.5.4 
Safety Analysis ...................................................................................... 139 
13.5.5 
Efficacy Analysis ................................................................................... 142 
13.5.6 
Pharmacodynamic Endpoints (Part 1 only) ........................................... 144 
13.5.7 
Primary and Interim Analyses ............................................................... 145 
13.5.8 
Changes to the Planned Statistical Methods .......................................... 145 
14 
PATIENT DATA HANDLING AND CONFIDENTIALITY .............. 146 
14.1 
Case Report Forms ................................................................................ 146 
14.2 
Monitoring of the Study ......................................................................... 146 
14.3 
Patient Confidentiality ........................................................................... 147 
15 
ETHICAL AND REGULATORY CONSIDERATIONS ..................... 148 
15.1 
Good Clinical Practice Compliance ....................................................... 148 
15.2 
Institutional Review Boards/ Ethics Committees .................................. 148 
15.3 
Regulatory Authority Approval ............................................................. 148 
15.4 
Protocol Amendments ........................................................................... 148 

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15.5 
Protocol Violations and Deviations ....................................................... 148 
15.6 
Serious Breaches .................................................................................... 149 
15.7 
Study Reporting Requirements .............................................................. 149 
15.8 
Financial disclosure ............................................................................... 149 
15.9 
Investigator Documentation ................................................................... 149 
15.10 
Study Records Retention ....................................................................... 149 
15.11 
Audit and Regulatory Inspection ........................................................... 150 
16 
PUBLICATION POLICY ..................................................................... 151 
16.1 
Communication of Results by Sponsor ................................................. 151 
16.2 
Publication by Investigators .................................................................. 151 
17 
REFERENCES ...................................................................................... 152 
18 
APPENDICES ....................................................................................... 155 
APPENDIX 1. RESPONSE EVALUATION CRITERIA IN SOLID TUMOURS 
(RECIST) VERSION 1.1 ....................................................................... 155 
APPENDIX 2. ECOG PERFORMANCE SCALE ................................................ 160 
APPENDIX 3. CONCOMITANT MEDICATIONS THAT MAY PROLONG QTC 
INTERVAL ........................................................................................... 161 
APPENDIX 4. MANAGEMENT GUIDE FOR DIARRHOEA ........................... 164 
 
 
 

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LIST OF FIGURES 
Figure 1 
NuTide:302 study schema ....................................................................... 65 
Figure 2 
NuTide:302 Part 1 study schema ............................................................. 67 
Figure 3 
NuTide:302 Part 2 study schema ............................................................. 68 
Figure 4 
NuTide:302 Part 3 study schema ............................................................. 70 
Figure 5 
PK sub-study schema ............................................................................. 104 
Figure 6 
PK sub-study blood sampling schema ................................................... 105 
  
LIST OF TABLES 
Table 1 
NuTide:301 dose escalation, treatment schedule, and enrolment ............ 58 
Table 2 
NUC-3373 safety profile (Part 1 of NuTide:302) .................................... 61 
Table 3 
Patient populations ................................................................................... 66 
Table 4 
Part 2 expansion phase treatment arms .................................................... 69 
Table 5 
Part 3 treatment arms ............................................................................... 70 
Table 6 
Anticipated dose levels of NUC-3373 to be evaluated in Part 1 ............. 73 
Table 7 
Study treatment in Arm 2a ....................................................................... 74 
Table 8 
Anticipated dose levels of agents to be evaluated in Arm 2a .................. 74 
Table 9 
Study treatment in Arm 2b ...................................................................... 75 
Table 10 
Anticipated dose levels of NUC-3373 to be evaluated in Arm 2b .......... 75 
Table 11 
Study treatment in Arm 2c ....................................................................... 75 
Table 12 
Study treatment in Arm 2d ...................................................................... 76 
Table 13 
Study treatment in PK sub-study ............................................................. 77 
Table 14 
Dose escalation guidance rules ................................................................ 78 
Table 15 
PK sampling schedule (Main study) ...................................................... 103 
Table 16 
PD sampling schedule (Part 1 only) ...................................................... 106 
Table 17 
NUC-3373 infusion duration guidance .................................................. 109 
Table 18 
Dose reduction guidelines for Part 1, Arms 1a and 1b .......................... 118 
Table 19 
Dose reduction guidelines for Part 1, Arm 1c and 1d ............................ 118 
Table 20 
Dose reduction guidelines for Part 2 and Part 3 .................................... 119 
Table 21 
Dose modifications for Cycle 2 onwards and for non-DLT toxicities 
within Cycle 1 ........................................................................................ 120 
Table 22 
Dose modification guidelines for severe acneiform rash....................... 122 
Table 23 
Intensity of adverse events not included in CTCAE.............................. 132 
Table 24 
Pharmacovigilance contact details ......................................................... 133 

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 PROTOCOL SYNOPSIS 
Study  
Title 
A Phase Ib/II open label study to assess the safety and pharmacokinetics 
of NUC-3373, a nucleotide analogue, given in combination with standard 
agents used in colorectal cancer treatment 
Protocol 
Number 
NuTide:302 
IND 
Number 
135275 
EudraCT 
Number 
2017-002062-53 
NCT 
Number 
NCT03428958 
Phase 
Ib/II 
Objectives 
This study consists of two phases (Phase Ib and Phase II) and includes three 
study parts (Parts 1, 2 and 3) with several treatment arms within each part. 
Phase Ib includes Part 1 (Arms 1a-1d) and Part 2 (Arms 2a-2d) and Phase II 
includes Part 3 (Arms 3a-3g). 
Primary Objectives 
Phase Ib 
• To identify a recommended dose and schedule for NUC-3373 when 
combined with other agents commonly used in treatment of advanced 
colorectal cancer (CRC), including: 
o leucovorin (LV) 
o oxaliplatin 
o oxaliplatin and vascular endothelial growth factor (VEGF) 
pathway inhibitors (bevacizumab) 
o oxaliplatin and epidermal growth factor receptor (EGFR) 
inhibitors (cetuximab or panitumumab) 
o irinotecan 
o irinotecan and VEGF pathway inhibitors (bevacizumab) 
o irinotecan and EGFR inhibitors (cetuximab or panitumumab)  
Phase II 
To explore the anti-cancer activity of NUC-3373 when combined with other 
agents commonly used in the treatment of advanced CRC using Response 
Evaluation in Solid Tumours (RECIST) v1.1 criteria. 
Secondary Objectives 
• To assess the safety and tolerability of each NUC-3373-containing 
regimen (Phase Ib and Phase II) 
• To assess the pharmacokinetics (PK) of NUC-3373, oxaliplatin, 
irinotecan and their metabolites in each NUC-3373-containing regimen 
(Phase Ib and Phase II) 
• To make a preliminary assessment of the anti-tumour activity of 
NUC-3373 alone and in each NUC-3373-containing regimen (Phase Ib 
only) 
• To conduct a within-patient and a between-patient analysis of the effect 
of LV when added to NUC-3373 on intracellular pharmacodynamic 

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(PD) parameters and haematological parameters and use this 
information to determine if the addition of LV to NUC-3373-
containing regimens is required for clinical activity (Part 1 Arm 1a and 
Arm 1b only) 
Exploratory Objectives 
• To explore predictive biomarkers of biological activity and possible 
relationships between PK and PD effects (Phase Ib and Phase II) 
• Depending on emerging data, to potentially conduct a within-patient 
analysis of the effect of combining NUC-3373 with irinotecan on the 
plasma PK parameters of both NUC-3373 and irinotecan (Part 2 
Arm 2b sub-study only) 
Study 
Design 
This is a three-part, open label, Phase Ib/II study of NUC-3373 administered 
by intravenous (IV) infusion (weekly [Q1W] or fortnightly [Q2W]), either as 
monotherapy or as part of various combinations with agents commonly used 
to treat patients with advanced CRC (LV, oxaliplatin, irinotecan, 
bevacizumab, cetuximab, and panitumumab). Phase Ib includes Part 1 
(Arms 1a-1d) and Part 2 (Arms 2a-2d) and Phase II includes Part 3 
(Arms 3a-3g). 
Patients may continue treatment until radiological disease progression or 
unacceptable toxicity despite optimal medical management or dose or 
schedule modification, or withdrawal of consent. All patients will be followed 
up until withdrawal of consent, lost to follow-up, death or the overall end of 
study has been reached (defined in Section 3.6), whichever occurs first.  
Part 1 
Part 1 determined that NUC-3373 should be administered with LV (Arms 1a, 
1b and 1c) and will further assess the safety and tolerability of NUC-3373 + 
LV on a Q1W schedule (Arm 1d). 
Part 2 
Part 2 will assess the safety and tolerability of different doses of Q1W 
NUC-3373 + LV when administered in combination with either oxaliplatin 
(NUFOX) or irinotecan (NUFIRI). 
Part 3 
Part 3 will assess the safety and efficacy of Q1W NUFOX and NUFIRI 
regimens administered in combination with bevacizumab (Q2W arms may 
also be opened). NUFOX and NUFIRI regimens may also be administered in 
combination with cetuximab or panitumumab, depending on emerging data. In 
addition, Q1W NUC-3373 + LV in combination with bevacizumab may be 
assessed in patients qualifying for maintenance therapy.  
Different patient populations will be included in the study as follows: 
 
 
 
 

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Patient Population 
Criteria 
Study 
Phase/Part 
≥3rd-line patients  
Received ≥2 prior lines of therapy for 
locally advanced or metastatic disease, one 
must include a fluoropyrimidine plus 
oxaliplatin, the other must include a 
fluoropyrimidine plus irinotecan. 
Phase Ib 
Part 1  
Part 2 (dose 
escalation) 
Combination 
chemotherapy 
ineligible patients 
Considered unable to receive combination 
chemotherapy for locally advanced or 
metastatic disease and may have received 
1 prior line of fluoropyrimidine-containing 
therapy. 
Phase Ib 
Part 1 
2nd-/3rd-line patients  
Received at least 1, but no more than 2, 
prior lines of fluoropyrimidine-containing 
therapy combined with oxaliplatin and/or 
irinotecan 
for 
locally 
advanced 
or 
metastatic 
disease. 
3rd-line 
patients 
enrolled to Arms 2c and 2d should have 
received prior bevacizumab treatment, 
unless ineligible or unless bevacizumab 
was not standard of care according to 
relevant 
region-specific 
treatment 
recommendations. 
Phase Ib 
Part 2 
(expansion) 
Rapid progressors 
(on prior fluoropyrimidine 
therapy) 
Received 
≤2 
prior 
lines 
of 
fluoropyrimidine-containing 
therapy 
combined 
with 
oxaliplatin 
and/or 
irinotecan 
for 
locally 
advanced 
or 
metastatic 
disease 
and 
progressed 
≤3 months 
of 
starting 
the 
last 
fluoropyrimidine-containing regimen.  
To be 
determined. 
Cohorts of 
rapid 
progressors 
may be 
opened 
depending on 
emerging 
data. 
2nd-line patients 
Received 1 prior line of fluoropyrimidine-
containing 
therapy 
combined 
with 
oxaliplatin and/or irinotecan for locally 
advanced or metastatic disease. 
Phase II 
Part 3 
Maintenance 
patients 
Received ≥12 weeks of 1st-line standard of 
care therapy for locally advanced or 
metastatic disease, achieved at least stable 
disease and are eligible for maintenance 
therapy. 
Phase II 
Part 3 
Previous 
treatment 
with 
triplet 
chemotherapy-based 
regimens 
is 
permitted 
(i.e., FOLFOXIRI), as long as any toxicities from the previous regimen still allow repeated 
treatment with oxaliplatin or irinotecan. 
If positive efficacy signals are observed in any of the patient populations 
included in Parts 1, 2 or 3 of the study, expansion cohorts may be opened to 
further assess efficacy in approximately 20 patients per cohort.  
A Q2W schedule may be explored at any time, depending on emergent safety, 
efficacy and PK data. 

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Part 1  
Part 1 determined that NUC-3373 should be administered with LV (Arms 1a, 
1b and 1c) and will further assess the safety and tolerability of NUC-3373 + 
LV (Arm 1d) in patients with advanced or metastatic CRC.  Initially, ≥3rd-line 
patients were randomised via block randomisation to two parallel arms, each 
receiving NUC-3373 Q2W either with LV (Arm 1a) or without LV (Arm 1b). 
Upon completion of the Q2W dose administration arms, a third arm of 
≥3rd-line patients was enrolled to a Q1W administration schedule of NUC-
3373 (1500 and 2500 mg/m2) plus LV (Arm 1c). Arms 1a, 1b, and 1c are now 
complete. Following this, approximately 10 combination chemotherapy 
ineligible patients will be enrolled to a Q1W administration schedule of 
NUC-3373 plus LV (Arm 1d). 
In Arm 1a, patients received a single dose of NUC-3373 at 1500 mg/m2. This 
visit was considered Cycle 0, Day 1 (C0D1) for the purposes of the study visits.  
The initial dose was followed by a 2-week washout period, during which safety 
and PK/PD were monitored. The next dose of NUC-3373 was given in 
combination with LV at 400 mg/m2.  This visit was considered Cycle 1, Day 1 
(C1D1) for the purposes of the study visits. All subsequent doses of NUC-3373 
were given Q2W in combination with LV in 28-day cycles. In Arm 1b, patients 
received a single dose of NUC-3373 at 1500 mg/m2 in combination with LV 
at 400 mg/m2. This visit was considered C0D1 for the purposes of the study 
visits.  The initial combination dose was followed by a 2-week washout period 
during which safety and PK/PD were monitored. The next dose of NUC-3373 
was given without any LV. This visit was considered C1D1 for the purposes 
of the study visits. All subsequent doses of NUC-3373 were given Q2W 
without LV in 28-day cycles. 
In Arm 1c, patients received NUC-3373 Q1W at either 1500 mg/m2 or 
2500 mg/m2 in combination with LV Q1W at 400 mg/m2.  NUC-3373 and LV 
were administered on Days 1, 8, 15 and 22 of 28-day cycles.  
The dose of NUC-3373 selected from Arm 1c for further exploration was 
2500 mg/m2 in combination with LV at 400 mg/m2.  
In Arm 1d, a cohort of approximately 10 combination chemotherapy ineligible 
patients will receive NUC-3373 at 2500 mg/m2 in combination with LV at 
400 mg/m2. NUC-3373 and LV will be administered on Days 1, 8, 15 and 22 
of 28-day cycles. 
All patients in Part 1 (Arms 1a, 1b, and 1c) were monitored for dose-limiting 
toxicities (DLTs) up to Day 28 of Cycle 1.   
If the dose of NUC-3373 was not tolerable or was sub-optimal, alternate dose 
levels as described in the table below may have been explored.  
Anticipated dose levels to be assessed in Part 1 
Dose 
Level* 
≥3rd-line patients 
NUC-3373 dose (mg/m2)  
Days 1 and 15 
Arms 1a and 1b 
NUC-3373 dose (mg/m2)  
Days 1, 8, 15 and 22 
Arm 1c 
-1 
1000 
1250 
1 
1500 
1500 

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2 
2000 
1750 
3 
2500 
2000 
4 
3000 
2250 
*Additional dose levels could be explored if necessary 
If cohorts at additional doses were opened, these were to utilise a modified 3+3 
design in which a fourth patient may have been added to each initial 3-patient 
cohort to account for a patient that became unevaluable for DLT evaluation 
for any reason other than safety. There was to be a 7-day observation period 
between treatment of the first patient and treatment of subsequent patients in a 
cohort. Once a minimum of 3 patients in each of Arms 1a, 1b and 1c had 
completed the 28-day DLT evaluation period all available safety data, PK and 
PD data were evaluated to establish the tolerability of NUC-3373 ± LV 
administered in each dose administration schedule.   
In addition to the assessment of safety, tolerability, PK and PD, a radiologic 
assessment of disease will be performed at 8-week intervals and evaluated 
using Response Evaluation Criteria in Solid Tumours (RECIST) v1.1 to gain 
a preliminary assessment of clinical activity.  
Part 2 
Data from Part 1 of the study showed that LV did not impact the safety or PK 
of NUC-3373; therefore, the decision was made that LV should be 
administered at 400 mg/m2 on each day of NUC-3373 administration in all 
parts of the study. 
Part 2 of the study consists of a dose escalation phase using a modified 3 + 3 
design, which may be followed by an expansion phase. The dose escalation 
phase will assess the safety and tolerability of different doses of NUC-3373 + 
LV when administered in combination with either oxaliplatin (NUFOX) or 
irinotecan (NUFIRI) in a Q1W schedule in ≥3rd-line patients. Oxaliplatin and 
irinotecan will be given at standard doses and schedules. In the expansion 
phase, cohorts of 2nd-/3rd-line patients may be enrolled to assess Q1W 
schedules of the NUFOX and NUFIRI regimens selected in the dose escalation 
phase.  
The dose escalation group of patients will receive NUC-3373 + LV to assess 
the safety and tolerability of different doses of NUC-3373 + LV administered 
in combination with oxaliplatin (Arm 2a) or irinotecan (Arm 2b).   
In Arm 2a, ≥3rd-line patients will receive NUC-3373 + LV on Days 1, 8, 15 
and 22 and oxaliplatin on Days 1 and 15 of 28-day cycles.  
In Arm 2b, ≥3rd-line patients will receive NUC-3373 + LV on Days 1, 8, 15 
and 22 and irinotecan on Days 1 and 15 of 28-day cycles.  
The starting dose of NUC-3373 will be 1500 mg/m2 and the dose levels to be 
evaluated are described in the table below. Based on a clinical study of 
NUC-3373 (NuTide:301, EudraCT 2015-002250-13, NCT02723240), 
alternate and/or additional dose levels may be considered and implemented 
upon recommendation of the Data Safety Monitoring Committee (DSMC).   
 

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Anticipated dose levels to be assessed in Part 2 – Q1W cohorts 
Dose Level* 
NUC-3373 dose (mg/m2) 
Days 1, 8, 15 and 22 
Arm 2a and Arm 2b 
Oxaliplatin dose 
(mg/m2)** 
Arm 2a 
Irinotecan dose 
(mg/m2)** 
Arm 2b 
-1 
1250 
85 
180 
1 
1500 
85 
180 
2 
1750 
85 
180 
3 
2000 
85 
180 
4 
2250 
85 
180 
* Additional dose levels may be explored if necessary 
** Alternative dose levels of oxaliplatin and irinotecan may be explored based on PK analyses 
and safety observations 
 
The decision on which arm to enrol a patient to, Arm 2a or Arm 2b, will be 
made by the treating physician and will take into account the patient’s clinical 
condition and any therapies that have previously been administered for 
treatment of CRC.   
Patients will be enrolled into cohorts following a modified 3+3 design, in 
which a fourth patient may be enrolled in each initial 3-patient cohort as 
described above. The initial patient in each cohort will complete a 7-day 
observation period before subsequent patients are enrolled. All patients in 
Arms 2a & 2b will be monitored for DLTs up to Day 28 of Cycle 1. Dose 
escalation or de-escalation decisions will be based on DSMC review once 
three patients have completed the first 28-day cycle.  
The recommended dose of NUC-3373 + LV in combination with oxaliplatin 
(Arm 2a) or irinotecan (Arm 2b) will be determined separately, and may be 
different.  
Once the dose escalation groups have been completed, the DSMC will review 
the available safety, clinical activity and PK/PD data to determine the 
recommended dose of NUC-3373 + LV when given in combination with either 
oxaliplatin or irinotecan. If safety concerns arise, additional cohorts assessing 
alternative doses of oxaliplatin and irinotecan may be opened with agreement 
from the DSMC.   
Expansion cohorts may be enrolled to Part 2 to further assess the safety, 
tolerability and preliminary efficacy of the Q1W NUFOX and NUFIRI 
regimens, using the dose of NUC-3373 selected in the dose escalation phase. 
NUFOX and NUFIRI regimens will be administered as described in the table 
below.   
Arm 
Treatment 
Number of patients 
2c  
NUC-3373 + LV Q1W, oxaliplatin Q2W 
(NUFOX) 
~10 2nd-/3rd-line patients  
2d 
NUC-3373 + LV Q1W, irinotecan Q2W 
(NUFIRI) 
~10 2nd-/3rd-line patients 

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Part 3 
Following determination of the recommended NUFOX and NUFIRI regimens 
in the Part 2 dose escalation phase, Part 3 will open. The Part 2 expansion 
phase may open in parallel.  
In Part 3, the safety and efficacy of the NUFOX and NUFIRI regimens in 
combination with bevacizumab will be evaluated. Q1W bevacizumab-
containing arms will be opened first and will be evaluated in 2nd-line patients. 
Following this, Q2W arms and/or cetuximab combination arms may be 
opened, depending on emerging data. In addition, the safety and efficacy of 
NUC-3373 + LV in combination with bevacizumab may be evaluated in 
patients qualifying for maintenance therapy.   
The treatment for each arm is described in the table below.  The choice of arm 
to which an eligible patient should be enrolled will be at the Investigator’s 
discretion, taking into account the patient’s clinical condition and therapies 
that have previously been administered.   
Dose groups to be assessed in Part 3 
Arm 
Treatment 
Number of patients 
3a  
NUFOX (NUC-3373 + LV Q1W) + 
bevacizumab 
~10 2nd-line patients 
3b 
NUFOX (NUC-3373 + LV Q2W) + 
bevacizumab  
~10 2nd-line patients 
3c 
NUFIRI (NUC-3373 + LV Q1W) + 
bevacizumab 
~10 2nd-line patients 
3d 
NUFIRI (NUC-3373 + LV Q2W) + 
bevacizumab 
~10 2nd-line patients 
3e 
NUC-3373 + LV Q1W + bevacizumab 
~10 maintenance patients 
3f 
NUFOX (NUC-3373 + LV Q1W or Q2W) 
+ cetuximab 
~10 2nd-line patients 
3g 
NUFIRI (NUC-3373 + LV Q1W or Q2W) 
+ cetuximab 
~10 2nd-line patients 
Bevacizumab and cetuximab should be used in accordance with standard local 
practice. 
Panitumumab combination arms may also be opened (~10 2nd-line patients), 
depending on emerging data. 
Cohorts of rapid progressors may also be opened (~10 patients), depending on 
emerging data.  
PK Sub-study 
A PK sub-study may be conducted during Part 2 if emerging data suggest it 
would be beneficial to evaluate the PK relationship between NUC-3373, LV 
and irinotecan. If conducted, an additional 8 patients would be enrolled in the 
NUFIRI Q1W cohort (Arm 2b). In Cycle 1 of the sub-study, irinotecan and 
LV will be administered concurrently on Day 1. On Day 8, NUC-3373 and LV 

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will be administered sequentially. On Day 15, 4 patients (Group A) will first 
be administered irinotecan concurrently with LV, followed by NUC-3373. The 
remaining 4 patients (Group B) will first be administered NUC-3373, followed 
by irinotecan concurrently with LV. On Day 22, NUC-3373 and LV will be 
administered sequentially. On Cycle 2 Day 1 (29 days after the start of 
treatment), the infusion sequence will be reversed in a cross-over fashion 
whereby patients in Group A will first be administered NUC-3373, followed 
by irinotecan concurrently with LV and patients in Group B will first be 
administered irinotecan concurrently with LV, followed by NUC-3373. 
 
C1D1 
C1D8 
C1D15 
C1D22 
C2D1 
Group A 
Irinotecan + 
LV 
LV  
NUC-3373 
Irinotecan + 
LV  
NUC-3373 
LV  
NUC-3373 
NUC-3373 
 
Irinotecan + 
LV 
Group B 
Irinotecan + 
LV 
LV  
NUC-3373 
NUC-3373 
 
Irinotecan + 
LV 
LV > NUC-
3373 
Irinotecan + 
LV  
NUC-3373 
Plasma samples will be collected for PK analysis on Cycle 1 Day 1, Cycle 1 
Day 8, Cycle 1 Day 15, Cycle 1 Day 22 and Cycle 2 Day 1.  In addition, Holter 
ECG assessments will be performed on Cycle 1 Day 8 and Cycle 1 Day 22 
during infusion and up to 24 hours post-infusion. Following this, patients will 
continue on the treatment schedule outlined for Arm 2b.  
Study 
Centres 
This study will be conducted at approximately 15 sites in the United States, 
United Kingdom and European Union. 
Endpoints 
Primary Endpoints 
Phase Ib 
To identify a recommended dose and schedule for NUC-3373 when combined 
with LV and other agents routinely used in the treatment of patients with 
advanced CRC. 
Phase II 
Objective disease assessment by radiographic imaging will be performed 
every 8 weeks and analysed using RECIST v1.1 criteria. Anti-tumour activity 
will be assessed on the basis of: 
• Percentage change from baseline in tumour size 
• Objective Response Rate (ORR) 
• Disease Control Rate (DCR) 
• Duration of Response (DoR) 
• Duration of Stable Disease (DoSD) 
• Progression-Free Survival (PFS) 
• Overall Survival (OS) rate at 6 and 12 months 

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Secondary Endpoints 
Safety (Phase Ib and Phase II) 
• Treatment-emergent 
adverse 
events 
(TEAEs; 
per 
Common 
Terminology Criteria for Adverse Events [CTCAE] v5.0) 
• Clinically-significant laboratory changes (per CTCAE v5.0) 
• Changes in physical exam, vital signs and serial electrocardiograms 
(ECGs) 
Pharmacokinetics (Phase Ib and Phase II) 
The PK of NUC-3373, oxaliplatin, irinotecan and their metabolites will be 
assessed, including: 
• Concentration at end of NUC-3373 infusion (Cinf) 
• Maximum concentration (Cmax) 
• Area under the curve (AUC) 
• Half-life (t1/2) 
• Volume of distribution (Vd) 
• Clearance (CL) 
 
The analytes measured may include, but are not limited to: 
• In plasma: NUC-3373, oxaliplatin, irinotecan and their metabolites 
• In peripheral blood mononuclear cells (PBMCs): NUC-3373, 
fluorodeoxyuridine 
monophosphate 
(FUDR-MP), 
FBAL, 
5-fluorouridine 
triphosphate 
(5-FUTP), 
deoxythymidine 
monophosphate (dTMP), deoxyuridine monophosphate (dUMP) 
(Part 1 only) 
Efficacy (Phase Ib) 
Objective disease assessment by radiographic imaging will be performed 
every 8 weeks and analysed using RECIST v1.1 criteria.  Anti-tumour activity 
will be assessed on the basis of: 
• Percentage change from baseline in tumour size 
• ORR 
• DCR 
• DoR 
• DoSD 
• PFS 
• OS rate at 6 and 12 months 
Exploratory Endpoints (Phase Ib and Phase II) 
• Pre-treatment and on-treatment measurements of PD markers in 
PBMCs (Part 1 only) 
• Exploration of predictive biomarkers such as gene expression and/or 
genetic alternations in blood and tumour (e.g., genetic alterations in 
genes involved in PK exposure, PD effects, safety and efficacy)  
• DNA/RNA and protein analysis of pre- and on-treatment tumour 
samples, including but not limited to KRAS and BRAF 
• Potential sub-study to evaluate the PK relationship between NUC-
3373, LV and irinotecan (Part 2 Arm 2b sub-study only) 
The PK of NUC-3373, LV and irinotecan will be assessed, including 
Cinf, Cmax, AUC, t1/2, Vd, CL 

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The analytes measured in plasma will include, but are not limited to: 
o NUC-3373, 5-FU, and FBAL 
o LV and 5-methyl-THF 
o Irinotecan, SN-38, SN-38 glucuronide, APC and NPC 
Study 
Population 
Patients with histologically or cytologically confirmed CRC that is locally 
advanced or metastatic and radiologically-measurable; Eastern Cooperative 
Oncology Group (ECOG) performance status 0-1; adequate haematologic, 
renal and hepatic function. 
Study 
Treatment 
The sections below provide suggested administration times and order for each 
of the combination agents; however, each administration in Parts 1, 2 and 3 of 
the study may be modified based on emerging safety and PK data (in line with 
local guidelines/relevant Prescribing Information) with agreement from the 
DSMC.   
It is suggested that NUC-3373 at 1500 mg/m2 is infused over 120 minutes. The 
infusion duration for lower and higher doses of NUC-3373 should be adjusted 
relative to the 1500 mg/m2 dose (e.g., a 25% increase in dose requires an 
approximately 25% increase in infusion duration). 
Phase Ib 
Part 1 (≥3rd-line and combination chemotherapy ineligible patients) 
Arm 1a (≥3rd-line patients) 
NUC-3373 was administered by IV infusion at 1500 mg/m2 over 120 minutes 
followed by a 14-day washout period. Thereafter, on Days 1 and 15 of 28-day 
cycles, LV was administered by IV infusion at 400 mg/m2 over 120 minutes, 
followed by NUC-3373 administration by IV infusion at the cohort-prescribed 
dose level.   
Arm 1b (≥3rd-line patients) 
LV was administered at 400 mg/m2 by IV infusion over 120 minutes, followed 
by NUC-3373 infusion at 1500 mg/m2 over 120 minutes. LV was not 
administered again in Arm 1b. After a 14-day washout period, NUC-3373 was 
administered on Days 1 and 15 of 28-day cycles by IV infusion at the 
cohort-prescribed dose level.   
Arm 1c (≥3rd-line patients) 
On Days 1, 8, 15 and 22 of 28-day cycles, LV was administered by IV infusion 
at 400 mg/m2 over 120 minutes, followed by NUC-3373 administration by IV 
infusion at the cohort-prescribed dose level.  
Arm 1d (combination chemotherapy ineligible patients) 
On Days 1, 8, 15 and 22 of 28-day cycles, LV will be administered by IV 
infusion at 400 mg/m2 over 120 minutes, followed by NUC-3373 
administration by IV infusion at 2500 mg/m2 over 200 minutes. 
Part 2 Dose Escalation (≥3rd-line patients) 
In the NUFOX and NUFIRI dose escalation cohorts, patients will receive 
NUC-3373 + LV Q1W combined with the standard dose and schedule of 
oxaliplatin and irinotecan.  

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For patients experiencing toxicity related to NUC-3373 in the NUFOX and 
NUFIRI cohorts, initially the NUC-3373 dose modification guidelines in 
Section 9 should be followed. The doses of oxaliplatin and irinotecan may be 
adjusted (through agreement with the DSMC) based on, but not limited to, 
safety and PK data generated in patients receiving treatment with NUFOX and 
NUFIRI regimens. If oxaliplatin or irinotecan-related adverse events are 
observed, dose de-escalation should be performed as per the respective 
Prescribing Information or standard local practice, or alternate doses may be 
explored, with approval from the DSMC. The modified dose of oxaliplatin or 
irinotecan (in combination with NUC-3373) will be assessed in approximately 
6 evaluable patients in each arm. 
The order of administration of each of the agents in Part 2 may be modified 
with approval from the DSMC, so that NUC-3373 + LV is infused first 
followed by either oxaliplatin (Arms 2a and 2c) or irinotecan (Arms 2b and 
2d). Alternate infusion parameters may be implemented with approval from 
the DSMC.  
Arm 2a 
NUC-3373 + LV will be administered Q1W and oxaliplatin will be 
administered Q2W in 28-day cycles, as outlined in the table below. 
Infusion order 
Infusion 
duration 
D1 
D8 
D15 
D22 
LV (400 mg/m2)a 
120 minsa 
X 
X 
X 
X 
Oxaliplatin (85 mg/m2)a 
X 
 
X 
 
NUC-3373  
(cohort prescribed dose level) 
120 minsb 
X 
X 
X 
X 
aLV and oxaliplatin to be administered concurrently  
bSuggested duration, refer to Pharmacy Manual 
Arm 2b 
NUC-3373 + LV will be administered Q1W and irinotecan will be 
administered Q2W in 28-day cycles, as outlined in the table below. 
Infusion ordera 
Infusion 
duration 
D1 
D8 
D15 
D22 
LV (400 mg/m2)b 
120 minsc 
X 
X 
X 
X 
Irinotecan (180 mg/m2)b   
X 
 
X 
 
NUC-3373  
(cohort prescribed dose level) 
120 minsd 
X 
X 
X 
X 
aThe infusion order may change as a result of emerging PK or safety data (refer to the PK 
Manual for further information) 
bLV and irinotecan to be administered concurrently  
cThe infusion duration for irinotecan may be changed to 90 mins based on emerging data 
dSuggested duration, refer to Pharmacy Manual 

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Part 2 Dose Expansion (2nd-/3rd-line patients) 
Following completion of Arms 2a and 2b, expansion cohorts may be initiated 
in 2nd-/3rd-line patients at the selected dose levels established in the dose 
escalation phase. The NUFOX and NUFIRI regimens will be administered in 
separate arms of the study (Arm 2c for NUFOX and Arm 2d for NUFIRI). 
Arm 2c 
NUC-3373 + LV will be administered Q1W and oxaliplatin will be 
administered Q2W in 28-day cycles, as outlined in the table below. 
Infusion order 
Infusion 
duration 
D1 
D8 
D15 
D22 
LV (400 mg/m2)a 
120 minsa 
X 
X 
X 
X 
Oxaliplatin (85 mg/m2)a,b 
X 
 
X 
 
NUC-3373  
(dose selected in Arm 2a) 
120 minsc 
X 
X 
X 
X 
aLV and oxaliplatin to be administered concurrently 
bThe oxaliplatin dose may be reduced based on observations in Arm 2a  
cSuggested duration, refer to Pharmacy Manual 
Arm 2d 
NUC-3373 + LV will be administered Q1W and irinotecan will be 
administered Q2W in 28-day cycles, as outlined in the table below. 
Infusion ordera 
Infusion 
duration 
D1 
D8 
D15 
D22 
LV (400 mg/m2)b 
120 minsc 
X 
X 
X 
X 
Irinotecan (180 mg/m2)b 
X 
 
X 
 
NUC-3373 
(dose selected in Arm 2b) 
120 minsd 
X 
X 
X 
X 
aThe infusion order may change as a result of emerging PK or safety data (refer to the PK 
Manual for further information) 
bLV and irinotecan to be administered concurrently  
cThe infusion duration for irinotecan may be changed to 90 mins based on emerging data 
dSuggested duration, refer to Pharmacy Manual 
 
Phase II 
Part 3 (2nd-line patients and maintenance patients) 
In Part 3, 2nd-line patients will receive the NUFOX and NUFIRI regimens 
selected in Part 2 in combination with bevacizumab. Q1W bevacizumab-
containing arms will be opened first. Following this, Q2W and/or cetuximab 
combination arms may be opened, depending on emerging data. In addition, 
patients qualifying for maintenance therapy may receive NUC-3373 + LV in 
combination with bevacizumab. 

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Arm 3a (2nd-line patients) 
NUC-3373, LV and oxaliplatin at dose levels used in Arm 2a will be combined 
with bevacizumab. NUC-3373 and LV will be administered Q1W and 
oxaliplatin and bevacizumab will be administered Q2W. 
Arm 3b (2nd-line patients) 
NUC-3373, LV and oxaliplatin at dose levels used in Arm 2a will be combined 
with bevacizumab. NUC-3373, LV, oxaliplatin and bevacizumab will be 
administered Q2W.  
Arm 3c (2nd-line patients) 
NUC-3373, LV and irinotecan at dose levels used in Arm 2b will be combined 
with bevacizumab. NUC-3373 and LV will be administered Q1W and 
irinotecan and bevacizumab will be administered Q2W.   
Arm 3d (2nd-line patients) 
NUC-3373, LV and irinotecan at dose levels used in Arm 2b will be combined 
with bevacizumab. NUC-3373, LV, irinotecan and bevacizumab will be 
administered Q2W.  
Arm 3e (Maintenance patients) 
NUC-3373 (2500 mg/m2 Q1W) + LV (400 mg/m2 Q1W) will be combined 
with bevacizumab (5 mg/kg Q2W). 
Arm 3f (2nd-line patients) 
NUC-3373, LV and oxaliplatin at dose levels used in Arm 2a may be 
administered in subsequent cetuximab cohorts. NUC-3373 + LV may be 
administered Q1W or Q2W, oxaliplatin will be administered Q2W and 
cetuximab will be administered Q1W.     
Arm 3g (2nd-line patients) 
NUC-3373, LV and irinotecan at dose levels used in Arm 2b may be 
administered in subsequent cetuximab cohorts. NUC-3373 + LV may be 
administered Q1W or Q2W, irinotecan will be administered Q2W and 
cetuximab will be administered Q1W.      
In all bevacizumab-containing arms, NUC-3373 dose adjustments may occur 
depending on emerging data.  
Panitumumab combination arms may also be opened (~10 2nd-line patients), 
depending on emerging data. 
Cohorts of rapid progressors may also be opened (~10 patients), depending on 
emerging data.  
In all parts of the study, patients may continue on study until documentation 
of radiological disease progression or unacceptable toxicity. Guidelines for 
dose modifications and discontinuations of NUC-3373 are provided; dose and 
schedule modifications for the other agents (LV, oxaliplatin, irinotecan, 
bevacizumab, cetuximab, panitumumab) will be in accordance with their 
respective Prescribing Information or standard local practice, unless safety 
concerns emerge regarding dosing as determined by the DSMC. 

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PK sub-study (Arm 2b) 
Patients participating in the PK sub-study will receive NUC-3373, LV and 
irinotecan, as outlined in the table below. Following this, patients will continue 
on the treatment schedule outlined for Arm 2b.  
Infusion 
order 
Infusion 
duration 
C1D1 
C1D8 
C1D15c 
C1D22 
C2D1c 
(29 days 
after start of 
treatment) 
LVa 
120 
minsa 
X 
X 
X 
X 
X 
Irinotecana   90 minsa 
X 
 
X 
 
X 
NUC-3373 
120 
minsb 
 
X 
X 
X 
X 
aLV and irinotecan to be administered concurrently  
bSuggested duration, refer to Pharmacy Manual 
cPatients will be alternately assigned to two groups (Group A and Group B) for treatment 
on Cycle 1 Day 15 and Cycle 2 Day 1 (29 days after start of treatment) and will receive the 
study treatments in an order that has been pre-specified for each group (refer to Section 7.2.1 
for details). 
Patients enrolled in the PK sub-study will be considered evaluable for PK endpoints if they 
have received planned study treatment and had PK assessments up to at least C1D15. If 
patients discontinue study treatment or require dose modifications before C1D15, they will 
be considered non-evaluable and will be replaced.   
Sample 
Size 
Part 1:   
Up to 50 patients 
Part 2:   
Up to 65 patients 
Part 3:   
Up to 100 patients 
 
Total: Up to 215 patients.  
Inclusion 
Criteria 
 
All patients 
1. Provision of written informed consent 
2. Have histological confirmation of CRC with evidence of locally 
advanced/unresectable or metastatic disease 
3. Age ≥18 years 
4. Life expectancy of ≥12 weeks  
5. ECOG Performance status 0 or 1 
6. Measurable disease as defined by RECIST v1.1 
7. Known RAS and BRAF status. Patients with wild-type KRAS tumours 
who are to be enrolled to a cohort that does not contain an EGFR pathway 
inhibitor (Arms 2a, 2b, 2c, 2d, 3a, 3b, 3c, 3d and 3e) must have received 
prior treatment with an EGFR inhibitor, unless this was not standard of 
care according to relevant region-specific treatment recommendations. 
Patients with BRAF V600E mutant tumours should have received prior 
treatment with encorafenib in combination with an EGFR inhibitor, unless 
this was not standard of care according to relevant region-specific 
treatment recommendations 
8. Adequate bone marrow function as defined by: absolute neutrophil count 
≥1.5×109/L, platelet count ≥100×109/L (with no evidence of bleeding), and 
haemoglobin ≥9 g/dL 

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9. Adequate liver function, as defined by: serum total bilirubin ≤1.5×upper 
limit of normal (ULN), aspartate aminotransferase and alanine 
aminotransferase ≤2.5×ULN (or ≤5×ULN if liver metastases are present) 
10. Adequate renal function assessed as serum creatinine <1.5×ULN or 
glomerular filtration rate ≥50 mL/min. This criterion does not apply to the 
combination chemotherapy ineligible patient subgroup (Arm 1d); please 
refer to specific criteria for this subgroup below 
11. Serum albumin ≥3 g/dL 
12. For the cohort in which the patient will participate, there are no 
contra-indications to receiving the approved partner combination drugs 
13. Ability to comply with protocol requirements 
14. Female patients of child-bearing potential must have a negative serum 
pregnancy test within 7 days prior to the first study drug administration. 
This criterion does not apply to patients who have had a previous 
hysterectomy or bilateral oophorectomy.  Male patients and female 
patients of child-bearing potential must agree to practice true abstinence 
(defined in Section 10.3.1) or to use two highly effective forms of 
contraception, one of which must be a barrier method. These forms of 
contraception must be used from the time of signing consent, throughout 
the treatment period, and for 6 months following the last dose of any study 
medication. Oral or injectable contraceptive agents cannot be the sole 
method of contraception 
15. Patients must have been advised to take measures to avoid or minimise 
exposure to UV light for the duration of study participation and for a period 
of 4 weeks following the last dose of study medication 
16. For patients receiving oxaliplatin:  Male patients must have been offered 
advice on and/or sought counselling for conservation of sperm prior to the 
first dose of study medication 
In addition to meeting the criteria above for all patients, the following criteria 
must be met for each patient population: 
≥3rd-line patients 
1. Must have received at least two prior lines of therapy for locally advanced 
or metastatic CRC, including one fluoropyrimidine plus oxaliplatin 
containing regimen and one fluoropyrimidine plus irinotecan containing 
regimen. Previous treatment with standard of care chemotherapy regimens 
in combination with molecular targeted therapies (e.g., therapies including 
VEGF and EGFR pathway inhibitors and immuno-oncology agents) is 
permitted. Patients who have received FOLFOXIRI-based regimens in 1st- 
and/or 2nd-line settings may also be included  
2. Patients in Part 2 of the study who are to receive NUFOX regimens should 
be suitable for re-challenge with an oxaliplatin-based regimen  
3. Patients in Part 2 of the study who are to receive NUFIRI regimens 
should be suitable for re-challenge with an irinotecan-based regimen 

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2nd-/3rd-line patients 
1. Must have received at least one, but no more than two, prior lines of 
fluoropyrimidine-containing therapy in combination with oxaliplatin 
and/or irinotecan for locally advanced or metastatic CRC. Previous 
treatment with standard of care chemotherapy regimens in combination 
with molecular targeted therapies (e.g., therapies including VEGF and 
EGFR pathway inhibitors and immuno-oncology agents) is permitted. 
Patients who have received FOLFOXIRI-based regimens in 1st- and/or 
2nd-line settings may also be included. 3rd-line patients enrolled to Arms 2c 
and 2d must have received prior bevacizumab treatment, unless ineligible 
or unless bevacizumab was not standard of care according to relevant 
region-specific treatment recommendations  
2. Patients in Part 2 of the study who are to receive NUFOX regimens should 
be suitable for re-challenge with an oxaliplatin-based regimen  
3. Patients in Part 2 of the study who are to receive NUFIRI regimens 
should be suitable for re-challenge with an irinotecan-based regimen 
Combination chemotherapy ineligible patients 
1. Patients may have received one prior line of fluoropyrimidine-containing 
therapy for locally advanced or metastatic CRC   
2. Ineligible to receive combination therapy for locally advanced or 
metastatic CRC, as defined by the presence of one or more of the following 
criteria: 
a. Dependency for daily activities due to comorbidities (different to 
deterioration due to cancer) 
b. Previous history of three or more of the following comorbidities 
(controlled or uncontrolled by treatments): 
i. 
Congestive heart failure 
ii. 
Other chronic cardiovascular disease 
iii. 
Chronic obstructive pulmonary disease 
iv. 
Cerebrovascular disease 
v. 
Peripheral neuropathy  
vi. 
Chronic renal failure 
vii. 
Arterial hypertension 
viii. 
Diabetes mellitus 
ix. 
Systemic vasculitis 
x. 
Severe arthritis 
c. At least one of the following geriatric features: 
i. 
Age >75 years 
ii. 
Faecal or urinary incontinence  
iii. 
Spontaneous bone fractures 
iv. 
Mild or moderate dementia 
v. 
Frequent falls 
3. Creatinine clearance of >30 mL/min 
Rapid progressors  
1. Must have received no more than two prior lines of fluoropyrimidine-
containing therapy in combination with oxaliplatin and/or irinotecan for 
locally advanced or metastatic CRC. Previous treatment with standard of 

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care chemotherapy regimens in combination with molecular targeted 
therapies (e.g., therapies including VEGF and EGFR pathway inhibitors 
and immuno-oncology agents) is permitted. Patients who have received 
FOLFOXIRI-based regimens in 1st- and/or 2nd-line settings may also be 
included 
2. Must have had tumour progression ≤3 months of starting the last 
fluoropyrimidine-containing regimen 
3. Patients who are to receive NUFOX regimens should be suitable for re-
challenge with an oxaliplatin-based regimen  
4. Patients who are to receive NUFIRI regimens should be suitable for re-
challenge with an irinotecan-based regimen 
2nd-line patients 
1. Must have received one prior line of fluoropyrimidine-containing therapy 
in combination with oxaliplatin and/or irinotecan for locally advanced or 
metastatic CRC. Previous treatment with standard of care chemotherapy 
regimens in combination with molecular targeted therapies (e.g., therapies 
including VEGF and EGFR pathway inhibitors and immuno-oncology 
agents) is permitted. Previous treatment with triplet chemotherapy-based 
regimens is allowed (i.e., FOLFOXIRI) 
Maintenance patients 
1. Must have received at least 12 weeks of 1st-line standard of care therapy 
for locally advanced or metastatic CRC and achieved at least stable disease 
2. Eligible for maintenance therapy 
Exclusion 
Criteria: 
 
All patients 
1. Prior history of hypersensitivity or current contra-indications to 5-FU or 
capecitabine 
2. Prior history of hypersensitivity or current contra-indication to any of the 
combination agents required for the study arm to which the patient is 
assigned 
3. History of allergic reactions attributed to components of the NUC-3373 
drug product formulation (Kolliphor ELP, super refined polysorbate 80, 
dimethylacetamide [DMA]) 
4. Symptomatic central nervous system or leptomeningeal metastases 
5. Symptomatic ascites, ascites currently requiring drainage procedures or 
ascites requiring drainage over the prior 3 months 
6. Chemotherapy, radiotherapy (other than a short cycle of palliative 
radiotherapy [e.g., for bone pain*), immunotherapy, or exposure to another 
investigational agent within 28 days (or five times the half-life for a 
biological or molecular targeted agent or three times the half-life for an 
immunotherapy agent) of first administration of NUC-3373: 
a. For nitrosoureas and mitomycin C within 6 weeks of first 
administration of NUC-3373 
b. For hormone or biological therapy within 14 days of first 
administration of NUC-3373 
c. Corticosteroid treatment is allowed if not more than stable daily 
dosing of 10 mg prednisolone (or steroid equivalent) 

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* Palliative radiotherapy during participation in the study is permitted, but 
should not include a target lesion 
7. Residual toxicities from prior chemotherapy or radiotherapy which have 
not regressed to Grade ≤1 severity (CTCAE v5.0), except for alopecia.  In 
cohorts not containing oxaliplatin, residual Grade 2 neuropathy is allowed 
8. Patients who have a history of another malignancy diagnosed within the 
past 5 years, with the exception of adequately treated non-melanoma skin 
cancer curatively treated carcinoma in situ 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 there is no evidence of recurrence 
9. Presence of an active bacterial or viral infection (including SARS-CoV-2, 
Herpes Zoster or chicken pox), known Human Immunodeficiency Virus 
positive or known active hepatitis B or C 
10. Presence of any uncontrolled concurrent serious illness, medical condition 
or other medical history, including laboratory results, which, in the 
Investigator’s opinion, would be likely to interfere with the patient’s ability 
to participate in the study or with the interpretation of the results, including 
any of the following: 
a. Congestive heart failure (New York Heart Association Class III or 
Class IV) 
b. Myocardial infarction within 6 months of the first dose of study 
medication 
c. Unstable or poorly controlled angina pectoris 
d. Complete left bundle branch, bifascicular block or other clinically 
significant abnormal ECG finding 
e. History of or current risk factor for torsade de pointes (e.g., heart 
failure, hypokalaemia, or a family history of long QT syndrome) 
f. History of severe skin reactions 
g. History of severe ocular disorders 
h. Interstitial pneumonitis or pulmonary fibrosis 
11. Any condition (e.g., known or suspected poor compliance, psychological 
instability, geographical location, etc.) that, in the judgment of the 
Investigator, may affect the patient’s ability to sign the informed consent 
and undergo study procedures 
12. Currently pregnant, lactating or breastfeeding 
13. QTc interval >450 milliseconds for males and >470 milliseconds for 
females 
14. Required concomitant use of drugs known to prolong QT/QTc interval 
15. Required concomitant use of strong CYP3A4 inducers or strong CYP3A4 
inhibitors, or use of strong CYP3A4 inducers within 2 weeks of first 
receipt of study drug or use of strong CYP3A4 inhibitors within 1 week of 
first receipt of study drug (refer to Section 10.3.2) 
16. For patients receiving irinotecan: Use of strong UGT1A1 inhibitors within 
1 week of first receipt of study drug (refer to Section 10.3.3) 
17. Has received a live vaccination within four weeks of first planned dose of 
study medication 

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18. Known DPD or TYMP mutations associated with toxicity to 
fluoropyrimidines 
19. Use of warfarin and other types of long acting anti-coagulants (such as 
phenprocoumon and anti‑Xa inhibitors with a half‑life of >12 hours) is 
prohibited within 4 weeks of the first dose of study treatment. Patients 
requiring anti-coagulant treatment should switch to low molecular weight 
heparin or anti‑Xa inhibitors with a half‑life of ≤12 hours 
Patients receiving bevacizumab 
1. Patients with a history of haemoptysis (1/2 teaspoon or more of red blood) 
2. Wound healing complications or surgery within 28 days of starting 
bevacizumab (wound healing must have been fully completed before 
starting bevacizumab) 
3. Severe chronic wounds, ulcers or bone fracture 
4. Arterial thromboembolic events or haemorrhage within 6 months prior to 
study entry (except for tumour bleeding surgically treated by tumour 
resection) 
5. Bleeding diatheses or coagulopathy 
6. Receiving full-dose anti-coagulation treatment. Patients who have been on 
stable doses for at least 6 months and have tolerated prior bevacizumab 
treatment are eligible 
7. Uncontrolled hypertension 
8. Clinically significant coronary heart disease or myocardial infarction 
within the last 12 months or high risk of uncontrolled arrhythmia 
9. Severe proteinuria (nephrotic syndrome) 
10. Acute or subacute ileus, chronic inflammatory bowel disease or chronic 
diarrhoea 
11. Any contraindication present in the bevacizumab Prescribing Information 
Patients receiving cetuximab or panitumumab 
1. Clinically significant coronary heart disease or myocardial infarction 
within the last 12 months or high risk of uncontrolled arrhythmia 
2. Acute or subacute ileus, chronic inflammatory bowel disease or chronic 
diarrhoea 
3. Hypomagnesaemia or hypokalaemia not controlled by oral therapy 
4. Any contraindication present in the cetuximab or panitumumab 
Prescribing Information 
Patients participating in the PK sub-study (Arm 2b) 
1. Patients with the UGT1A1 *28/*28 genotype (homozygous poor UGT1A1 
metabolisers) 
Study 
Duration 
Per 
Patient 
Patients may continue to receive treatment in the absence of radiological 
disease progression or unacceptable toxicity that is not ameliorated by optimal 
medical or non-medical supportive or prophylactic care, or withdrawal of 
consent. All patients will be followed up until withdrawal of consent, lost to 
follow-up, death, or the overall end of study has been reached (defined in 
Section 3.6), whichever occurs first. 

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OVERALL STUDY DESIGN 
 
 
Abbreviations: Iri=irinotecan; LV=leucovorin; NUFIRI=NUC-3373 + LV + irinotecan; NUFOX=NUC-3373 + LV + oxaliplatin; Ox=oxaliplatin; Q1W=weekly; 
Q2W=fortnightly.

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SUMMARY SCHEDULE OF EVENTS: ARM 1a AND ARM 1b 
Study  
Assessments1 
Screening/ 
Baseline 
Cycle 
0* 
Cycle  
1** 
Additional  
Cycles** 
End of 
Treatment 
Follow-
up 
Visits16 
 
D1 
D1 
D2 
D3 
D8 
D15 
(±1) 
D16 
D1 
(±3) 
D15 
(±1) 
30 days 
post last 
dose  
(+7 days) 
Q8 wks 
(±7 
days) 
Informed consent 
(including 
pregnancy 
counselling) 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographic data 
X 
 
 
 
 
 
 
 
 
 
 
 
Previous medical 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
medication 
X 
X 
X 
 
 
 
X 
 
X 
X 
X 
 
Physical 
examination 
(including 
neurological) 
X 
X 
X 
 
 
 
X 
 
X 
X 
X 
 
Urinalysis 
X 
X 
X 
 
 
 
 
 
X 
 
X 
 
ECOG performance 
status 
X 
X 
X 
 
 
 
 
 
X 
 
X 
 
Vital signs  
(including weight)2 
X 
X 
X 
 
 
 
X 
 
X 
X 
X 
 
ECG3 
X 
X3 
X3 
 
 
 
X3 
 
X3 
X3 
X 
 
Pregnancy test4 
X 
X 
X 
 
 
 
 
 
X 
 
X 
 
FBC and chemistry5 
X 
X 
X 
 
 
 
X 
 
X 
X 
X 
 
Coagulation profile 
X 
X 
X 
 
 
 
 
 
 
 
X 
 
Tumour markers6 
X 
X 
X 
 
 
 
 
 
X 
 
X 
 
Radiologic tumour 
assessment  
(CT / MRI)7 
X 
 
 
 
 
 
 
 
Assessed 
every 8 
weeks from 
the start of 
Cycle 1 
 
X8 
Randomise to Arm  
1a or 1b 
 
X 
 
 
 
 
 
 
 
 
 
 
NUC-3373 
administration  
(all patients) 
 
X 
X 
 
 
 
X 
 
X 
X 
 
 
Leucovorin 
administration9 
 
X 
X 
 
 
 
X 
 
X 
X 
 
 
AEs/SAEs10 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X10 
PK blood sample11 
 
X 
X 
X 
X 
 
X 
X 
 
 
 
 
PD blood sample12 
 
X 
X 
 
 
 
X 
 
 
 
 
 
PGx blood sample13 
X 
 
 
 
 
 
 
 
X13 
 
 
 
Archived sample14 
X 
 
 
 
 
 
 
 
 
 
 
 
Tumour biopsy15 
X 
 
 
 
 
X 
 
 
 
 
 
 
* Cycle 0 duration is assumed to be 14 days including the washout period, subject to the patient 
completing the cycle and subsequently commencing Cycle 1 

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** Cycle 1 and all additional cycles thereafter are assumed to be 28 days in duration (excluding 
any allowances for visit window) subject to the patient completing the cycle in full 
1 
Assessments scheduled on days of dosing should be done prior to administration of all 
Investigational Medicinal Products (IMPs), unless otherwise specified. Lab 
assessments may be performed up to 72 hours prior to IMP administration.  
2 
Vital signs include respiration rate, pulse, temperature and blood pressure.  Height 
should be recorded at baseline only. Weight should be recorded at baseline, Day 1 of 
every cycle and at end of study visit. If a patient’s weight increases or decreases by 
≥10% during the study, the dose of ‘NUC-3373 for infusion’ should be recalculated. 
3 
Standard 12-lead ECG measurements will be performed prior to administration of all 
IMPs, at the indicated visits.  
Note: Additional ECG measurements must be taken at 30-60 minutes post 
administration of all IMPs at the C0D1, C1D1, C1D15, C3D1, and C3D15 visits.  
All 12-lead ECG measurements should be performed in triplicate (keeping the leads in 
place and the patient supine during readings) and reviewed by the Investigator or 
qualified designee for safety and quality.    
4 
Serum pregnancy assessment to be performed within 7 days of C0D1. Required only in 
women of childbearing potential.   
5 
Clinical chemistry (including hepatic panel) and haematology will be conducted every 
2 weeks throughout the study. In the event of neutropaenia (absolute neutrophil count 
[ANC] less than 0.5x109/L), thrombocytopaenia (platelet count less than 50x109/L), or 
≥Grade 2 clinical chemistry toxicity, these assessments will be conducted more 
frequently as clinically indicated until toxicity resolves to ≤Grade 1. 
6 
Collect a pre-dose blood sample for evaluation of carcinoembryonic antigen (CEA).  
7 
Computed tomography (CT)/magnetic resonance imaging (MRI) disease assessments 
will be performed at Screening (within 28 days prior to the first dose of IMP) and every 
8 weeks (±7 days) from Cycle 1 Day 1. Additional tests may be requested at the 
Investigator’s discretion. The same modality should be used throughout. 
8 
Patients withdrawing from study treatment with no radiological evidence of disease 
progression will remain in the study and receive scans every 8 weeks (±7 days) from 
C1D1 until disease progression, initiation of a new treatment for CRC or death in order 
to determine duration of overall response and progression-free survival (PFS).  
9 
Leucovorin is administered with all doses beginning at C1D1 in Arm 1a and once at 
C0D1 in Arm 1b. 
10 
After informed consent has been obtained, but prior to initiation of study drug, only 
adverse events (AEs) and serious adverse events (SAEs) caused by a protocol-mandated 
intervention will be reported.  Thereafter, all AEs occurring up to and including 30 days 
after the last dose of study drug has been administered must be reported in detail on the 
AE case report form (CRF). 
Note: SAE reporting is required until 30-days post the last dose of study medication.  
11 
Blood samples for PK measurements, based on a 2-hour and a 4-hour infusion duration 
of NUC-3373, will be drawn on C0D1, C1D1 (Samples 1-12) and C1D15 (Samples 1-
11) as follows:  

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Sample 
Number 
Sample Collection Time  
(NUC-3373 2-hour infusion) 
Sample Collection Time  
(NUC-3373 4-hour infusion) 
Sample Collection 
Window 
PRIOR TO NUC-3373 INFUSION 
1 
Pre-dose 
Up to 30 minutes prior  
to starting infusion 
DURING NUC-3373 INFUSION 
2 
T0 + 30 minutes 
T0 + 60 minutes 
+/- 5 minutes 
3 
T0 + 60 minutes 
T0 + 120 minutes 
4 
T0 + 120 minutes 
T0 + 240 minutes 
AFTER NUC-3373 INFUSION 
5 
T1 + 15 minutes 
+/- 5 minutes 
6 
T1 + 30 minutes 
7 
T1 + 60 minutes 
8 
T1 + 90 minutes 
9 
T1 + 120 minutes 
+/- 15 minutes 
10 
T1 + 240 minutes 
+ 4 hours / - 15 minutes 
11 
T1 + 24 hours 
+ 4 hours 
12* 
T1 + 48 hours 
• T0 = Start of NUC-3373 infusion 
• T1 = End of NUC-3373 infusion 
• Samples 2, 3, and 4 are triggered by the start time of the infusion and assume a 
2-hour or a 4-hour infusion duration. Collection times will be modified in 
alignment with infusion duration changes 
• Samples 5-12 are timed from the end of the infusion 
* Sample 12 is optional for C1D1. Sample 12 will not be taken for C1D15. 
12 
Blood samples for PD measurements will be drawn Pre-dose (sample to be drawn 
within 30 minutes prior to the first dose) and at 30 minutes (±5 mins) following the end 
of the NUC-3373 infusion, (i.e., T1+30 mins, where T1 = end of NUC-3373 infusion).  
Sample  
Number 
Sample  
Time  
Sample Collection  
Window 
PRIOR TO NUC-3373 INFUSION 
1 
Pre-dose 
Up to 30 minutes prior  
to starting infusion 
AFTER NUC-3373 INFUSION 
2 
T1 + 30 minutes 
+/- 5 minutes 
13 
Blood samples (optional) for mRNA analyses (e.g., PAX gene) will be drawn at 
baseline or pre-dose on C0D1 and again at C3D1.   
14 
Original diagnostic block will be recalled (where available). 

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15 
Fresh biopsy (optional) will be performed at Screening (maximum 14-days before the 
first dose) and on treatment on C1D8 or C1D15 at 3-6 hours after study treatment, in 
consenting patients. 
16 
During the COVID-19 pandemic, collection of follow-up data can be performed via a 
telephone call with the patient where possible (e.g., for data regarding concomitant 
medications, AEs, and quality of life [QoL]). The data collected and the follow-up 
schedule remain as per the schedule of events. Patients in follow-up who have not 
experienced radiological disease progression should continue to attend the clinic for 
planned radiologic scans; however, other follow-up data can be collected via telephone 
to limit patient visits. 
 
 

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SUMMARY SCHEDULE OF EVENTS: ARM 1c and ARM 1d 
Study  
Assessments1 
Screening/ 
Baseline 
Cycle  
1* 
Additional  
Cycles* 
End of 
Treatment 
Follow-up 
Visits18 
Days -28  
to 1 
D1 
D2 
D3 
D8 
(±1) 
D15 
(±1) D16 D22 
(±1) 
D1  
(±3) 
D8, 15, 
22 (±1) 
30 days post 
last dose  
(+7 days) 
Q8 wks 
(±7 days) 
Informed consent 
(including pregnancy 
counselling) 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographic data 
X 
 
 
 
 
 
 
 
 
 
 
 
Previous medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medication 
X 
X 
 
 
X 
X 
 
X 
X 
X 
X 
 
Physical examination 
(including neurological) 
X 
X 
 
 
X 
X 
 
X 
X 
X 
X 
 
Urinalysis 
X 
X 
 
 
 
 
 
 
X 
 
X 
 
ECOG performance status 
X 
X 
 
 
 
 
 
 
X 
 
X 
 
Vital signs  
(including weight)2 
X 
X 
 
 
X 
X 
 
X 
X 
X 
X 
 
Height2  
X 
 
 
 
 
 
 
 
 
 
 
 
ECG3 
X 
X3 
 
 
X3 
X3 
 
X3 
X3 
X3 
X 
 
Pregnancy test4 
X 
X 
 
 
 
 
 
 
X 
 
X 
 
FBC and chemistry5 
X 
X 
 
 
X 
X 
 
X 
X 
X 
X 
 
RAS/BRAF status testing 
X6 
 
 
 
 
 
 
 
 
 
 
 
Coagulation profile 
X 
X 
 
 
 
 
 
 
X 
 
X 
 
Tumour markers7 
X 
X 
 
 
 
 
 
 
X 
 
X 
 
Radiologic tumour 
assessment (CT / MRI)8 
X 
 
 
 
 
 
 
 
Assessed every 8 
weeks from the start 
of Cycle 1 
 
X9 
NUC-3373 administration  
(all patients) 
 
X 
 
 
X 
X 
 
X 
X 
X 
 
 
Leucovorin 
administration10 
 
X 
 
 
X 
X 
 
X 
X 
X 
 
 
AEs/SAEs11 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X11 
PK blood sample12 
 
X 
X 
X 
 
X 
X 
 
 
 
 
 
PK urine sample13 
 
X 
X 
X 
 
X 
X 
 
 
 
 
 
PGx blood sample14 
X14 
 
 
 
 
 
 
 
X14 
 
 
 
Archived sample15 
X 
 
 
 
 
 
 
 
 
 
 
 
Tumour biopsy16 
X 
 
 
 
X 
X 
 
 
 
 
 
 
Survival17 
Assessed every 3 months from the start of Cycle 1 
 
* Cycle 1 and all additional cycles thereafter are assumed to be 28 days in duration (excluding 
any allowances for visit window) subject to the patient completing the cycle in full 
 

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1. 
Assessments scheduled on days of dosing should be done prior to administration of all 
IMPs, unless otherwise specified. Lab assessments may be performed up to 72 hours 
prior to IMP administration.  
2. 
Vital signs include respiration rate, pulse, temperature and blood pressure. Height 
should be recorded at baseline only. Weight should be recorded at baseline, Day 1 of 
every cycle and at end of study visit.  If a patient’s weight increases or decreases by 
≥10% during the study, the dose of ‘NUC-3373 for infusion’ should be recalculated. 
3. 
Standard 12-lead ECG measurements will be performed prior to administration of all 
IMPs, at the indicated visits.  
Note: Additional ECG measurements must be taken at 30-60 minutes post 
administration of all IMPs at the C1D1, C1D15, C3D1, and C3D15 visits.  
All 12-lead ECG measurements should be performed in triplicate (keeping the leads in 
place and the patient supine during readings) and reviewed by the Investigator or 
qualified designee for safety and quality. 
4. 
Serum pregnancy assessment to be performed within 7 days of C1D1. Perform only in 
women of childbearing potential. 
5. 
Clinical chemistry (including hepatic panel) and haematology will be conducted every 
week throughout the study. In the event of neutropaenia (ANC less than 0.5x109/L), 
thrombocytopaenia (platelet count less than 50x109/L), or ≥Grade 2 clinical chemistry 
toxicity, these assessments will be conducted more frequently as clinically indicated 
until toxicity resolves to ≤Grade 1. 
6. 
If RAS/BRAF mutation status is unknown, perform genetic testing. 
7. 
Collect a pre-dose blood sample for evaluation of CEA. 
8. 
CT/MRI disease assessments will be performed at Screening (within 28 days prior to 
the first dose of IMP) and every 8 weeks (±7 days) from Cycle 1 Day 1. Additional 
tests may be requested at the Investigator’s discretion. The same modality should be 
used throughout. 
9. 
Patients withdrawing from study treatment with no radiological evidence of disease 
progression will remain in the study and receive scans every 8 weeks (±7 days) from 
C1D1 until disease progression, initiation of a new treatment for CRC or death in order 
to determine duration of overall response and PFS.  
10. 
Leucovorin is administered with all doses beginning at C1D1. 
11. 
After informed consent has been obtained, but prior to initiation of study drug, only 
AEs and serious adverse events caused by a protocol-mandated intervention will be 
reported.  Thereafter, all AEs occurring up to and including 30 days after the last dose 
of study drug has been administered must be reported in detail on the AE CRF. 
Note: SAE reporting is required until 30-days post the last dose of study medication.  
12. 
Blood samples for PK measurements, based on a 2-hour and a 4-hour infusion duration 
of NUC-3373, will be drawn on C1D1 (Samples 1-12) and C1D15 (Samples 1-11) as 
follows: 

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Sample 
Number 
Sample Collection Time  
(NUC-3373 2-hour infusion) 
Sample Collection Time  
(NUC-3373 4-hour infusion) 
Sample Collection 
Window 
PRIOR TO NUC-3373 INFUSION 
1 
Pre-dose 
Up to 30 minutes prior  
to starting infusion 
DURING NUC-3373 INFUSION 
2 
T0 + 30 minutes 
T0 + 60 minutes 
+/- 5 minutes 
3 
T0 + 60 minutes 
T0 + 120 minutes 
4 
T0 + 120 minutes 
T0 + 240 minutes 
AFTER NUC-3373 INFUSION 
5 
T1 + 15 minutes 
+/- 5 minutes 
6 
T1 + 30 minutes 
7 
T1 + 60 minutes 
8 
T1 + 90 minutes 
9 
T1 + 120 minutes 
+/- 15 minutes 
10 
T1 + 240 minutes 
+ 4 hours / - 15 minutes 
11 
T1 + 24 hours 
+ 4 hours 
12* 
T1 + 48 hours 
• Sample 1, pre-dose should be collected prior to infusion of any IMPs 
• T0 = Start of NUC-3373 infusion 
• T1 = End of NUC-3373 infusion 
• Samples 2, 3, and 4 are triggered by the start time of the infusion and assume a 
2-hour or a 4-hour infusion duration. Collection times will be modified in 
alignment with infusion duration changes 
• Samples 5-12 are timed from the end of the infusion 
* Sample 12 is optional for C1D1. Sample 12 will not be taken for C1D15. 
13. 
Urine samples for PK analyses will be collected in Arm 1d only. Samples will be 
collected 0-8 hours and 8-24 hours from the start of NUC-3373 infusion. For patients 
who provide optional consent, urine collection will continue for 48 hours on C1D1 
only.  
14. 
Blood samples (optional) for mRNA analyses (e.g., PAX gene) will be drawn at 
baseline or pre-dose on C1D1 and again at C3D1. 
15. 
Original diagnostic block will be recalled (where available). 
16. 
Fresh biopsy (optional) will be performed at Screening (maximum 14-days before the 
first dose) and on treatment on C1D8 or C1D15 at 3-6 hours after study treatment, in 
consenting patients. If this is not possible, it may be obtained at any time after C1D15 
with agreement from the Medical Monitor. 
17. 
All patients will be followed up until withdrawal of consent, lost to follow-up, death, 
or the overall end of study has been reached (defined in Section 3.6), whichever occurs 
first. Survival follow-up may be performed via telephone call.  

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NuCana plc                                                             Confidential 
36
18. 
During the COVID-19 pandemic, collection of follow-up data can be performed via a 
telephone call with the patient where possible (e.g., for data regarding concomitant 
medications, AEs, and QoL). The data collected and the follow-up schedule remain as 
per the schedule of events. Patients in follow-up who have not experienced radiological 
disease progression should continue to attend the clinic for planned radiologic scans; 
however, other follow-up data can be collected via telephone to limit patient visits. 

NuTide:302                                                                                                                       Version 4.2, 10 Aug 2022 
Confidential                                                            NuCana plc 
37 
SUMMARY SCHEDULE OF EVENTS: PART 2 (ALL ARMS) 
Study  
Assessments1 
Screening 
Cycle  
1* 
Additional 
Cycles* 
End of 
Treatment 
Follow-
up 
Visits19 
Days -28  
to 1 
D1 
D2 
D3 
D8 
(±1) 
D15 
(±1) 
D16 
D22 
(±1) 
D1 
(±3) 
D8,1
5, 22 
(±1) 
30-days 
post last 
dose  
(+7 days) 
Q8 wks 
(±7 days) 
Informed consent 
(including pregnancy 
counselling) 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographic data 
X 
 
 
 
 
 
 
 
 
 
 
 
Previous medical 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
medication 
X 
X 
 
 
X 
X 
 
X 
X 
X 
X 
 
Physical examination 
(including 
neurological) 
X 
X 
 
 
X 
X 
 
X 
X 
X 
X 
 
Urinalysis 
X 
X 
 
 
 
 
 
 
X 
 
X 
 
ECOG performance 
status 
X 
X 
 
 
 
 
 
 
X 
 
X 
 
Vital signs 
(including weight)2 
X 
X 
 
 
X 
X 
 
X 
X 
X 
X 
 
Height2 
X 
 
 
 
 
 
 
 
 
 
 
 
ECG3 
X 
X3 
 
 
X3 
X3 
 
X3 
X3 
X3 
X 
 
Pregnancy test4 
X 
X 
 
 
 
 
 
 
X 
 
X 
 
FBC and chemistry5 
X 
X 
 
 
X 
X 
 
X 
X 
X 
X 
 
RAS/BRAF status 
testing 
X6 
 
 
 
 
 
 
 
 
 
 
 
Coagulation profile 
X 
X 
 
 
 
 
 
 
X 
 
X 
 
Tumour markers7 
X 
X 
 
 
 
 
 
 
X 
 
X 
 
Radiologic tumour 
assessment  
(CT / MRI)8 
X 
 
 
 
 
 
 
 
Assessed 
every 8 weeks 
from the start 
of Cycle 1 
 
X9 
NUC-3373 (+LV) 
administration 
 
X 
 
 
X 
X 
 
X 
X 
X 
 
 
Combination agent 
administration based 
on arm 10 
 
X 
 
 
 
X 
 
 
X 
X11 
 
 
AEs/SAEs12 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X12 
PK blood sample(s)13  
 
X 
X 
X 
 
X 
X 
 
 
 
 
 
PGx blood sample14 
X14 
 
 
 
 
 
 
 
X14 
 
 
 
Archived sample15 
X 
 
 
 
 
 
 
 
 
 
 
 
Tumour biopsy16 
X 
 
 
 
X 
X 
 
 
 
 
 
 
Survival17 
Assessed every 3 months from the start of Cycle 1 
* Cycle 1 and all additional cycles thereafter are assumed to be 28 days in duration (excluding 
any allowances for visit window) subject to the patient completing the cycle in full 

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NuCana plc                                                             Confidential 
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1. 
Assessments scheduled on days of dosing should be done prior to administration of all 
IMPs, unless otherwise specified. Lab assessments may be performed up to 72 hours 
prior to IMP administration.  
2. 
Vital signs include respiration rate, pulse, temperature and blood pressure. Height 
should be recorded at baseline only. Weight should be recorded at baseline, Day 1 of 
every cycle and at end of study visit.  If a patient’s weight increases or decreases by 
≥10% during the study, the dose of ‘NUC-3373 for infusion’ should be recalculated. 
3. 
Standard 12-lead ECG measurements will be performed prior to administration of all 
IMPs, at the indicated visits.  
Note: Additional ECG measurements must be taken at 30-60 minutes post 
administration of all IMPs at the C1D1, C1D15, C3D1, and C3D15 visits.  
All 12-lead ECG measurements should be performed in triplicate (keeping the leads in 
place and the patient supine during readings) and reviewed by the Investigator or 
qualified designee for safety and quality. 
4. 
Serum pregnancy assessment to be performed within 7 days of C1D1. Perform only in 
women of childbearing potential. 
5. 
Clinical chemistry (including hepatic panel) and haematology will be conducted every 
week throughout the study. In the event of neutropaenia (ANC less than 0.5x109/L), 
thrombocytopaenia (platelet count less than 50109/L), or ≥Grade 2 clinical chemistry 
toxicity, these assessments will be conducted more frequently as clinically indicated 
until toxicity resolves to ≤Grade 1.  
6. 
If RAS/BRAF mutation status is unknown, perform genetic testing. 
7. 
Collect a pre-dose blood sample for evaluation of CEA. 
8. 
CT/MRI disease assessments will be performed at Screening (within 28 days prior to 
the first dose of IMP) and every 8 weeks (±7 days) from Cycle 1 Day 1. Additional 
tests may be requested at the Investigator’s discretion. The same modality should be 
used throughout.  
9. 
Patients withdrawing from study treatment with no radiological evidence of disease 
progression will remain in the study and receive scans every 8 weeks (±7 days) from 
C1D1 until disease progression, initiation of a new treatment for CRC, or death in order 
to determine duration of overall response and PFS.  
10. 
IV administration of combination agents as follows:  
Arms 
Cycle 1 Day 1 and beyond 
Arm 2a & Arm 2c 
Days 1, 8, 15, 22: NUC-3373 + LV  
Days 1 & 15: oxaliplatin 
Arm 2b & Arm 2d 
Days 1, 8, 15, 22: NUC-3373 + LV  
Days 1 & 15: irinotecan 
11. 
Combination agent administration on Day 15 of additional cycles only (Q2W schedule). 

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Confidential                                                            NuCana plc 
39 
12. 
After informed consent has been obtained, but prior to initiation of study drug, only 
AEs and serious adverse events caused by a protocol-mandated intervention will be 
reported.  Thereafter, all AEs occurring up to and including 30 days after the last dose 
of study drug has been administered must be reported in detail on the AE CRF. 
Note: SAE reporting is required until 30 days post the last dose of study medication.  
13. 
Blood samples for PK measurements, based on a 2-hour and a 4-hour infusion duration 
of NUC-3373, will be drawn on C1D1 (Samples 1-12) and C1D15 (Samples 1-11) as 
follows: 
Sample 
Number 
Sample Collection Time  
(NUC-3373 2-hour infusion) 
Sample Collection Time  
(NUC-3373 4-hour infusion) 
Sample Collection 
Window 
PRIOR TO NUC-3373 INFUSION 
1 
Pre-dose 
Up to 30 minutes prior  
to starting infusion 
DURING NUC-3373 INFUSION 
2 
T0 + 30 minutes 
T0 + 60 minutes 
+/- 5 minutes 
3 
T0 + 60 minutes 
T0 + 120 minutes 
4 
T0 + 120 minutes 
T0 + 240 minutes 
AFTER NUC-3373 INFUSION 
5 
T1 + 15 minutes 
+/- 5 minutes 
6 
T1 + 30 minutes 
7 
T1 + 60 minutes 
8 
T1 + 90 minutes 
9 
T1 + 120 minutes 
+/- 15 minutes 
10 
T1 + 240 minutes 
+ 4 hours / - 15 minutes 
11 
T1 + 24 hours 
+ 4 hours 
12* 
T1 + 48 hours 
• Sample 1, pre-dose should be collected prior to infusion of any IMPs 
• T0 = Start of NUC-3373 infusion 
• T1 = End of NUC-3373 infusion 
• Samples 2, 3, and 4 are triggered by the start time of the infusion and assume a 
2-hour or a 4-hour infusion duration. Collection times will be modified in 
alignment with infusion duration changes 
• Samples 5-12 are timed from the end of the infusion 
* Sample 12 is optional for C1D1. Sample 12 will not be taken for C1D15. 
14. 
Blood samples (optional) for mRNA analyses (e.g., PAX gene) will be drawn at 
baseline or pre-dose on C1D1 and again at C3D1. 
15. 
Original diagnostic block will be recalled (where available). 
16. 
Fresh biopsy (optional) will be performed at Screening (maximum 14 days before the 
first dose) and on treatment on C1D8 or C1D15 at 3-6 hours after study treatment, in 
consenting patients. If this is not possible, it may be obtained at any time after C1D15 
with agreement from the Medical Monitor. 

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NuCana plc                                                             Confidential 
40
17. 
All patients will be followed up until withdrawal of consent, lost to follow-up, death, 
or the overall end of study has been reached (defined in Section 3.6), whichever occurs 
first. Survival follow-up may be performed via telephone call.  
18. 
During the COVID-19 pandemic, collection of follow-up data can be performed via a 
telephone call with the patient where possible (e.g., for data regarding concomitant 
medications, AEs, and QoL). The data collected and the follow-up schedule remain as 
per the schedule of events. Patients in follow-up who have not experienced radiological 
disease progression should continue to attend the clinic for planned radiologic scans; 
however, other follow-up data can be collected via telephone to limit patient visits. 

NuTide:302                                                                                                                       Version 4.2, 10 Aug 2022 
Confidential                                                            NuCana plc 
41 
SUMMARY SCHEDULE OF EVENTS: PART 3 
Study  
Assessments1 
Screening 
Cycle 1* 
Additional Cycles* 
End of 
Treatment 
Follow-up 
Visits18 
Days  
-28 to 1 
D1 
D2 
D3 
D8 
(±1)** 
D15 
(±1) 
D16 
D22 
(±1)** 
D1 (±3) 
D8,15, 22 
(±1)** 
30-days post 
last dose (+7 
days) 
Q8 wks 
(±7 days) 
Informed consent 
(including pregnancy 
counselling) 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/ 
exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographic data 
X 
 
 
 
 
 
 
 
 
 
 
 
Previous medical 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
medication 
X 
X 
 
 
X 
X 
 
X 
X 
X 
X 
 
Physical examination 
(including 
neurological) 
X 
X 
 
 
X 
X 
 
X 
X 
X 
X 
 
Urinalysis 
X 
X 
 
 
 
 
 
 
X 
 
X 
 
ECOG performance 
status 
X 
X 
 
 
 
 
 
 
X 
 
X 
 
Vital signs  
(including weight)2 
X 
X 
 
 
X 
X 
 
X 
X 
X 
X 
 
Height2 
X 
 
 
 
 
 
 
 
 
 
 
 
ECG3 
X 
X3 
 
 
X3 
X3 
 
X3 
X3 
X3 
X 
 
Pregnancy test4 
X 
X 
 
 
 
 
 
 
X 
 
X 
 
FBC and chemistry5 
X 
X 
 
 
X 
X 
 
X 
X 
X 
X 
 
RAS/BRAF status 
testing  
X6 
 
 
 
 
 
 
 
 
 
 
 
Coagulation profile 
X 
X 
 
 
 
 
 
 
X 
 
X 
 
Tumour markers7 
X 
X 
 
 
 
 
 
 
X 
 
X 
 
Radiologic tumour 
assessment (CT/MRI)8 
X 
 
 
 
 
 
 
 
Assessed every 8 weeks 
from the start of Cycle 1 
 
X9 
NUC-3373 (+LV) 
administration 
 
X 
 
 
X** 
X 
 
X** 
X 
X** 
 
 
Combination agent 
administration10  
 
X 
 
 
X*** 
X 
 
X*** 
X 
X*** 
 
 
AEs/SAEs11 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X11 
PK blood sample(s)12  
 
X 
X 
X 
 
X 
X 
 
 
 
 
 
PK urine sample (Arm 
3e)13 
 
X 
X 
X 
 
X 
X 
 
 
 
 
 
PGx blood sample14 
X14 
 
 
 
 
 
 
 
X14 
 
 
 
Archived sample15 
X 
 
 
 
 
 
 
 
 
 
 
 
Tumour biopsy16 
X 
 
 
 
X 
X 
 
 
 
 
 
 
Survival17 
Assessed every 3 months from the start of Cycle 1 
 
* Cycle 1 and all additional cycles thereafter are assumed to be 28 days in duration (excluding 
any allowances for visit window) subject to the patient completing the cycle in full 
** Day 8 and Day 22 will only be completed in the Q1W NUC-3373 + LV cohorts (Arms 3a, 
3c, 3e, 3f and 3g) 
*** Day 8 and Day 22 will only be completed in arms containing cetuximab (Arms 3f and 3g), 
depending on the chosen schedule 
 

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NuCana plc                                                             Confidential 
42
1. 
Assessments scheduled on days of dosing should be done prior to administration of all 
IMPs, unless otherwise specified. Lab assessments may be performed up to 72 hours 
prior to IMP administration.  
2. 
Vital signs include respiration rate, pulse, temperature and blood pressure. Height 
should be recorded at baseline only. Weight should be recorded at baseline, Day 1 of 
every cycle and at end of study visit.  If a patient’s weight increases or decreases by 
≥10% during the study, the dose of ‘NUC-3373 for infusion’ should be recalculated. 
3. 
Standard 12-lead ECG measurements will be performed prior to administration of all 
IMPs, at the indicated visits.  
Note: Additional ECG measurements must be taken at 30-60 minutes post 
administration of all IMPs at the C1D1, C1D15, C2D1, C2D15, C3D1, and C3D15 
visits.  
All 12-lead ECG measurements should be performed in triplicate (keeping the leads in 
place and the patient supine during readings) and reviewed by the Investigator or 
qualified designee for safety and quality 
4. 
Serum pregnancy assessment to be performed within 7 days of C1D1. Perform only in 
women of childbearing potential. 
5. 
Clinical chemistry (including hepatic panel) and haematology will be conducted every 
week for patients on Q1W schedules and every 2 weeks for patients on Q2W schedules 
throughout the study. In the event of neutropaenia (ANC less than 0.5x109/L), 
thrombocytopaenia (platelet count less than 50x109/L), or ≥Grade 2 clinical chemistry 
toxicity, these assessments will be conducted more frequently as clinically indicated 
until toxicity resolves to ≤Grade 1. 
6. 
If RAS/BRAF mutation status is unknown, perform genetic testing. 
7. 
Collect a pre-dose blood sample for evaluation of CEA. 
8. 
CT/MRI disease assessments will be performed at Screening (within 28 days prior to 
the first dose of IMP) and every 8 weeks (±7 days) from Cycle 1 Day 1. Additional 
tests may be requested at the Investigator’s discretion. The same modality should be 
used throughout.  
9. 
Patients withdrawing from study treatment with no radiological evidence of disease 
progression will remain in the study and receive scans every 8 weeks (±7 days) from 
C1D1 until disease progression, initiation of a new treatment for CRC, or death in order 
to determine duration of overall response and PFS.  
10. 
IV administration of combination agents as follows:  
Arm 
Cycle 1 Day 1 and beyond 
Arm 3a 
NUFOX + bevacizumab 
Days 1, 8, 15, 22: NUC-3373 + LV  
Days 1 & 15: oxaliplatin  
Arm 3b 
NUFOX + bevacizumab 
Days 1 & 15: NUC-3373 + LV + oxaliplatin  

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Confidential                                                            NuCana plc 
43 
11. 
After informed consent has been obtained, but prior to initiation of study drug, only 
AEs and serious adverse events caused by a protocol-mandated intervention will be 
reported.  Thereafter, all AEs occurring up to and including 30 days after the last dose 
of study drug has been administered must be reported in detail on the AE CRF.  
Note: SAE reporting is required until 30-days post the last dose of study medication.  
12. 
Blood samples for PK measurements, based on a 2-hour and a 4-hour infusion duration, 
will be drawn on C1D1 (Samples 1-12) and C1D15 (Samples 1-11) as follows as 
follows: 
Sample 
Number 
Sample Collection Time  
(NUC-3373 2-hour infusion) 
Sample Collection Time  
(NUC-3373 4-hour infusion) 
Sample Collection 
Window 
PRIOR TO NUC-3373 INFUSION 
1 
Pre-dose 
Up to 30 minutes prior  
to starting infusion 
DURING NUC-3373 INFUSION 
2 
T0 + 30 minutes 
T0 + 60 minutes 
+/- 5 minutes 
3 
T0 + 60 minutes 
T0 + 120 minutes 
4 
T0 + 120 minutes 
T0 + 240 minutes 
AFTER NUC-3373 INFUSION 
5 
T1 + 15 minutes 
+/- 5 minutes 
6 
T1 + 30 minutes 
7 
T1 + 60 minutes 
8 
T1 + 90 minutes 
9 
T1 + 120 minutes 
+/- 15 minutes 
10 
T1 + 240 minutes 
+ 4 hours / - 15 minutes 
11 
T1 + 24 hours 
+ 4 hours 
12* 
T1 + 48 hours 
• Sample 1, pre-dose should be collected prior to infusion of any IMPs 
Arm 3c 
NUFIRI + bevacizumab 
Days 1, 8, 15, 22: NUC-3373 + LV 
Days 1 & 15: irinotecan 
Arm 3d 
NUFIRI + bevacizumab 
Days 1 & 15: NUC-3373 + LV + irinotecan 
Arm 3e 
NUC-3373 + LV + bevacizumab 
Days 1, 8, 15, 22: NUC-3373 + LV  
Arm 3f 
NUFOX + cetuximab 
Q1W or Q2W 
Arm 3g 
NUFIRI + cetuximab 
Q1W or Q2W 
Bevacizumab and cetuximab should be administered in accordance with standard local practice. 
 

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NuCana plc                                                             Confidential 
44
• T0 = Start of NUC-3373 infusion 
• T1 = End of NUC-3373 infusion 
• Samples 2, 3, and 4 are triggered by the start time of the infusion and assume a 
2-hour or a 4-hour infusion duration. Collection times will be modified in 
alignment with infusion duration changes 
• Sample 6-12 are timed from the end of the infusion 
* Sample 12 is optional for C1D1. Sample 12 will not be taken for C1D15. 
13. 
Urine samples for PK analyses will be collected in Arm 3e only. Samples will be 
collected 0-8 hours and 8-24 hours from the start of NUC-3373 infusion. For patients 
who provide optional consent, urine collection will continue for 48 hours on C1D1 
only.  
14. 
Blood samples (optional) for mRNA analyses (e.g., PAX gene) will be drawn at 
baseline or pre-dose on C1D1 and again at C3D1. 
15. 
Original diagnostic block will be recalled (where available). 
16. 
Fresh biopsy (optional) will be performed at Screening (maximum 14 days before the 
first dose) and on treatment on C1D8 or C1D15 at 3-6 hours after study treatment, in 
consenting patients. If this is not possible, it may be obtained at any time after C1D15 
with agreement from the Medical Monitor.  
17. 
All patients will be followed up until withdrawal of consent, lost to follow-up, death, 
or the overall end of study has been reached (defined in Section 3.6), whichever occurs 
first. Survival follow-up may be performed via telephone call.  
18. 
During the COVID-19 pandemic, collection of follow-up data can be performed via a 
telephone call with the patient where possible (e.g., for data regarding concomitant 
medications, AEs, and QoL). The data collected and the follow-up schedule remain as 
per the schedule of events. Patients in follow-up who have not experienced radiological 
disease progression should continue to attend the clinic for planned radiologic scans; 
however, other follow-up data can be collected via telephone to limit patient visits. 
 
 

NuTide:302                                                                                                                       Version 4.2, 10 Aug 2022 
Confidential                                                            NuCana plc 
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SUMMARY SCHEDULE OF EVENTS: PK SUB-STUDY (PART 2 
ARM 2B; CYCLE 1 AND CYCLE 2 DAYS 1 AND 2) 
Study  
Assessments1 
Screening 
Cycle 1 
Cycle 2 
Days -28  
to 1 
D1 
D2 
D8 
D9 
D15 
D16 
D22 
D23 
D1 
D2 
Informed consent 
(including 
pregnancy 
counselling) 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
 
 
 
 
 
 
 
 
 
 
Demographic data 
X 
 
 
 
 
 
 
 
 
 
 
Previous medical 
history 
X 
 
 
 
 
 
 
 
 
 
 
Concomitant 
medication 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
Physical 
examination 
(including 
neurological) 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
Urinalysis 
X 
X 
 
 
 
 
 
 
 
X 
 
ECOG performance 
status 
X 
X 
 
 
 
 
 
 
 
X 
 
Vital signs 
(including weight)2 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
Height2 
X 
 
 
 
 
 
 
 
 
 
 
Safety ECG3 
X 
X3 
 
X3 
 
X3 
 
X3 
 
X3 
 
Holter ECG4 
 
 
 
X4 
X4 
 
 
X4 
X4 
 
 
Pregnancy test5 
X 
X 
 
 
 
 
 
 
 
X 
 
FBC and chemistry6 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
RAS/BRAF status 
testing 
X7 
 
 
 
 
 
 
 
 
 
 
Coagulation profile 
X 
X 
 
 
 
 
 
 
 
X 
 
Tumour markers8 
X 
X 
 
 
 
 
 
 
 
X 
 
Radiologic tumour 
assessment  
(CT / MRI)9 
X 
 
 
 
 
 
 
 
 
 
 
Genotyping blood 
sample10 
X 
 
 
 
 
 
 
 
 
 
 
NUC-3373 
administration11 
 
 
 
X 
 
X 
 
X 
 
X 
 
LV 
administration11 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Irinotecan 
administration11 
 
X 
 
 
 
X 
 
 
 
X 
 
AEs/SAEs12 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PK blood sample13  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PGx blood sample14 
X 
 
 
 
 
 
 
 
 
 
 
Archived sample15 
X 
 
 
 
 
 
 
 
 
 
 
Tumour biopsy16 
X 
 
 
X 
 
X 
 
 
 
 
 
 

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NuCana plc                                                             Confidential 
46
The rows in bold font are the only rows that are different from the main Part 2 Summary 
Schedule of Events, and only apply to Cycle 1 and Day 1/2 of Cycle 2. Following this, 
patients in the PK sub-study will continue with the main schedule for Part 2 (Arm 2b). 
 
1. 
Assessments scheduled on days of dosing should be done prior to administration of all 
IMPs, unless otherwise specified. Lab assessments may be performed up to 72 hours 
prior to IMP administration.  
2. 
Vital signs include respiration rate, pulse, temperature and blood pressure. Height 
should be recorded at baseline only. Weight should be recorded at baseline, Day 1 of 
every cycle and at end of study visit.  If a patient’s weight increases or decreases by 
≥10% during the study, the dose of ‘NUC-3373 for infusion’ should be recalculated. 
3. 
Standard 12-lead ECG measurements will be performed prior to administration of all 
IMPs, at the indicated visits.  Note: Additional ECG measurements must be taken at 
30-60 minutes post administration of all IMPs at the C1D1, C1D15, C3D1, and C3D15 
visits.  
All 12-lead ECG measurements should be performed in triplicate (keeping the leads in 
place and the patient supine during readings) and reviewed by the Investigator or 
qualified designee for safety and quality. 
4. 
Holter ECG measurements will be performed on C1D8 and C1D22, with continuous 
readings taken over 24 hours, starting from 30 minutes prior to the start of infusion (see 
footnote 13). Patients must be supine for 30 minutes prior to the start of infusion and 
for at least 5 minutes prior to, and during, the other timepoints where PK draws are 
taken (as outlined in footnote 13). 
All Holter ECG data should be transmitted for blinded central review. 
5. 
Serum pregnancy assessment to be performed within 7 days of C1D1. Perform only in 
women of childbearing potential. 
6. 
Clinical chemistry (including hepatic panel) and haematology will be conducted every 
week throughout the study. In the event of neutropaenia (ANC less than 0.5x109/L), 
thrombocytopaenia (platelet count less than 50x109/L), or ≥Grade 2 clinical chemistry 
toxicity, these assessments will be conducted more frequently as clinically indicated 
until toxicity resolves to ≤Grade 1.  
7. 
If RAS/BRAF mutation status is unknown, perform genetic testing. 
8. 
Collect a pre-dose blood sample for evaluation of CEA. 
9. 
CT/MRI disease assessments will be performed at Screening (within 28 days prior to 
the first dose of IMP) and every 8 weeks (±7 days) from Cycle 1 Day 1. Additional 
tests may be requested at the Investigator’s discretion. The same modality should be 
used throughout.  
10. 
Genotyping to be performed for each patient using genomic DNA from white blood 
cells isolated from a 3 mL sample of whole blood taken during screening. The genomic 
DNA will be analysed using pharmacogenomic protocols specific for individual 
genotypes for drug metabolising enzymes and drug transporters, e.g., TATA box 
polymorphism 
of 
the 
UGT1A1 
promoter 
region 
and 
NR1I2-rs10934498 
polymorphism, prior to admission to the sub-study. Genotyping is not required for 
patients who have a known UGT1A1 status from prior testing.  

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Confidential                                                            NuCana plc 
47 
11. 
LV is administered on Days 1, 8, 15 & 22 of Cycle 1 and Day 1 of Cycle 2 (29 days 
after start of treatment); irinotecan is administered on Days 1 & 15 of Cycle 1 and Day 
1 of Cycle 2 (29 days after start of treatment); NUC-3373 is administered on Days 8, 
15 & 22 of Cycle 1 and Day 1 of Cycle 2 (29 days after start of treatment). Patients will 
be alternately assigned to two groups (Group A and Group B) for treatment on Cycle 1 
Day 15 and Cycle 2 Day 1 and will receive the study treatments in an order that has 
been pre-specified for each group (refer to Section 7.2.1 for details). Following this, 
patients in the PK sub-study will continue to receive study treatment as outlined for 
Arm 2b. Patients enrolled in the PK sub-study will be considered evaluable for PK 
endpoints if they have received planned study treatment and had PK assessments up to 
at least C1D15. If patients discontinue study treatment or require dose modifications 
before C1D15, they will be considered non-evaluable and will be replaced.  
12. 
After informed consent has been obtained, but prior to initiation of study drug, only 
AEs and serious adverse events caused by a protocol-mandated intervention will be 
reported.  Thereafter, all AEs occurring up to and including 30 days after the last dose 
of study drug has been administered must be reported in detail on the AE CRF. 
Note: SAE reporting is required until 30 days post the last dose of study medication.  
13. 
PK sub-study blood samples for analysis of irinotecan, NUC-3373 and their metabolites 
will be drawn for patients assigned to Group A and Group B as follows (sample 
collection times may be adjusted based on emerging data): 
Group A 
  
  
  
Timepoints (min post-first infusion) 
 
 
Pre-
dose*
60 mins 
(+/- 5 mins)
120 mins 
(+/- 5 mins)
150 mins 
(+/- 5 mins)
180 mins 
(+/- 5 mins)
250 mins 
(+/- 5 mins)
280 mins 
(+/- 5 mins)
300 mins 
(+/- 5 mins)
360 mins 
(+/- 15 mins)
480 mins 
(+/- 15 mins)
24 hours 
(+/- 2 hours)
C1D1 
Infusion
 
Irinotecan + LV  
 
 
 
 
 
PK Draw
X
X
X
 
X
X
 
X
X
X
X
C1D8 
Infusion
 
LV
NUC-3373
 
 
 
 
 
PK Draw
X
 
 
 
X
X
X
X
X
X
X
C1D15 
Infusion
 
Irinotecan + LV
NUC-3373
 
 
 
 
 
PK Draw
X
X
X
 
X
X
X
X
X
X
X
C1D22 
Infusion
 
LV
NUC-3373
 
 
 
 
 
PK Draw
X
 
 
 
X
X
X
X
X
X
X
C2D1 
Infusion
 
NUC-3373
Irinotecan + LV
 
 
 
PK Draw
X
X
X
X
X
X
 
X
X
X
X
*Pre-dose = up to 30 minutes prior to the administration of irinotecan + LV (C1D1, C1D15) or NUC-3373 (C1D8, C1D22, C2D1) 
Group B 
  
  
  
Timepoints (min post-first infusion) 
 
 
Pre-
dose*
60 mins 
(+/- 5 mins)
120 mins 
(+/- 5 mins)
150 mins 
(+/- 5 mins)
180 mins 
(+/- 5 mins)
250 mins 
(+/- 5 mins)
280 mins 
(+/- 5 mins)
300 mins 
(+/- 5 mins)
360 mins 
(+/- 15 mins)
480 mins 
(+/- 15 mins)
24 hours 
(+/- 2 hours)
C1D1 
Infusion
 
Irinotecan + LV  
 
 
 
 
 
PK Draw
X
X
X
 
X
X
 
X
X
X
X
C1D8 
Infusion
 
LV
NUC-3373
 
 
 
 
 
PK Draw
X
 
 
 
X
X
X
X
X
X
X
C1D15 
Infusion
 
NUC-3373
Irinotecan + LV
 
 
 
 
 
PK Draw
X
X
X
X
X
X
 
X
X
X
X
C1D22 
Infusion
 
LV
NUC-3373
 
 
 
 
 
PK Draw
X
 
 
 
X
X
X
X
X
X
X
C2D1 
Infusion
 
Irinotecan + LV
NUC-3373
 
 
 
PK Draw
X
X
X
 
X
X
X
X
X
X
X
*Pre-dose = up to 30 minutes prior to the administration of irinotecan + LV (C1D1, C2D1) or NUC-3373 (C1D8, C1D15, C1D22) 
The exact time each PK sample is taken must be recorded. 

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Note that for C1D8 and C1D22 when the patient is wearing the Holter monitor, 
the patient must be supine for 30 minutes prior to the start of infusion and for at 
least 5 minutes prior to, and during, the other timepoints when PK draws are 
taken (see footnote 4). 
14. 
Blood samples (optional) for mRNA analyses (e.g., PAX gene) will be drawn at 
baseline or pre-dose on C1D1 and again at C3D1. 
15. 
Original diagnostic block will be recalled (where available). 
16. 
Fresh biopsy (optional) will be performed at Screening (maximum 14 days before the 
first dose) and on treatment on C1D8 or C1D15 at 3-6 hours after study treatment, in 
consenting patients. If this is not possible, it may be obtained at any time after C1D15 
with agreement from the Medical Monitor. 

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ABBREVIATIONS 
5-FU
5-fluorouracil
5-FUTP
5-fluorouridine triphosphate
5-methyl-THF
5-methyltetrahydofolate
ADR
Adverse drug reaction
AE
Adverse event
ALT
Alanine aminotransferase
ANC
Absolute neutrophil count
APC
Irinotecan metabolite (7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-
piperidino]-carbonyloxycamptothecin)
aPTT 
Activated partial thromboplastin time
AST 
Aspartate aminotransferase
AUC 
Area under the curve
AUC0-24 
Area under the plasma concentration-time curve from time zero to 24 hours
BRAF 
Proto-oncogene protein B-raf gene
BSA 
Body surface area
CAPIRI 
Capecitabine + irinotecan
CAPOX 
Capecitabine + oxaliplatin
CEA 
Carcinoembryonic antigen
CFR 
Code of Federal Regulations
Cinf 
Concentration at the end of infusion
CL 
Apparent clearance
Cmax 
Maximum plasma concentration; peak plasma concentration
COVID-19 
Coronavirus Disease 2019
CR 
Complete response
CRC 
Colorectal cancer
CRF 
Case report form
CRO 
Clinical Research Organisation
CSR 
Clinical study report
CT 
Computed tomography
CTCAE 
Common Terminology Criteria for Adverse Events
CYP3A4 
Cytochrome P450 3A4
DCR 
Disease control rate
DLT 
Dose-limiting toxicity
DMA 
Dimethylacetamide
DNA 
Deoxyribonucleic acid
DoR 
Duration of response
DoSD 
Duration of stable disease
DPD 
Dihydropyrimidine dehydrogenase
DSMC 
Data Safety Monitoring Committee
DSUR 
Development safety update report
dTMP 
Deoxythymidine monophosphate
dUMP 
Deoxyuridine monophosphate
EC50 
Half-maximal effective concentration
ECG 
Electrocardiogram
ECOG 
Eastern Cooperative Oncology Group
eCRF 
Electronic Case Report Form
EFR 
Evaluable for response

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EGFR 
Epidermal growth factor receptor 
EMA 
European Medicines Agency 
EoT 
End of treatment 
EudraCT 
European Clinical Trials Database 
FAS 
Full analysis set 
FBAL 
α-fluoro-β-alanine 
FDA 
(US) Food and Drug Administration  
FOLFIRI 
5-FU + LV + irinotecan 
FOLFOX 
5-FU + LV + oxaliplatin 
FOLFOXIRI 
5-FU + LV + oxaliplatin + irinotecan 
FUDR 
Floxuridine; (5-fluorodeoxyuridine) 
FUDR-MP 
Fluorodeoxyuridine-monophosphate 
G-CSF 
Granulocyte colony stimulating factor 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH-GCP 
International Council for Harmonisation - Good Clinical Practice 
IMP 
Investigational medicinal product 
IND 
Investigational New Drug 
INR 
International normalised ratio 
IRB/EC 
Institutional review board/ ethics committee 
IV 
Intravenous(ly) 
KRAS 
Gene that codes for the KRAS protein 
L 
Litre 
LDH 
Lactate dehydrogenase 
LV 
Leucovorin 
m2 
Meter2 
MedDRA 
Medical Dictionary for Regulatory Activities 
Mg 
Milligram 
µM 
Micromolar 
Ml 
Millilitre 
mM 
Millimolar 
MRI 
Magnetic resonance imaging 
MTD 
Maximum tolerated dose 
NE 
Not evaluable 
NPC 
Irinotecan metabolite (7-ethyl-10-(4-amino-1-piperidino)-
carbonyloxycamptothecin) 
NUFIRI 
NUC-3373 + LV + irinotecan 
NUFOX 
NUC-3373 + LV + oxaliplatin 
OPRT 
Orotate Phosphoribosyl Transferase 
ORR 
Objective Response Rate 
OS 
Overall survival 
PBMC 
Peripheral blood mononuclear cell 
PD 
Progressive Disease or Pharmacodynamics 
PFS 
Progression-Free Survival 
PGx 
Pharmacogenomics 
PK 
Pharmacokinetics 
PR 
Partial Response 
PT 
Prothrombin time 
Q1W 
Weekly 

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Q2W 
Fortnightly  
QoL 
Quality of life 
QT/QTc 
QT interval / Corrected QT interval  
RECIST 
Response Evaluation Criteria In Solid Tumours (version 1.1) 
RBC 
Red blood cell 
RNA 
Ribonucleic acid 
RP2D 
Recommended Phase II dose 
RSI 
Reference Safety Information 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Stable Disease  
SmPC 
Summary of Product Characteristics 
SN-38 
Irinotecan metabolite (7-ethyl-10-hydroxycamptothecin) 
SOC 
System Organ Class 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
t1/2 
Terminal half-life 
TK 
Thymidine kinase 
TP 
Thymidine phosphorylase 
TS 
Thymidylate synthase 
TEAE 
Treatment-emergent adverse event 
UGT1A1 
UDP glucuronosyltransferase 1A1 
ULN 
Upper limit of normal 
Vd 
Volume of distribution 
VEGF 
Vascular endothelial growth factor 
VEGFR 
Vascular endothelial growth factor receptor 
WBC 
White blood cell 
WHO DD 
World Health Organisation Drug Dictionary 
 

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1. 
INTRODUCTION AND STUDY RATIONALE 
1.1. 
Treatment Options for Recurrent Colorectal Cancer 
Colorectal cancer (CRC) is the third most common cancer in males and the second most 
common in females, accounting for 10% of all cancers. The incidence worldwide is 
approximately 1.8 million new cases per year with a 5-year survival rate of 10% for patients 
diagnosed with metastatic disease (De Falco et al, 2020). In the United States, there are 
approximately 1.5 million people living with CRC and approximately 148,000 new cases of 
CRC and 53,000 deaths due to the disease are expected in 2020. Worldwide, there were an 
estimated 881,000 deaths due to CRC in 2018, and the global burden is expected to increase to 
more than 2.2 million new cases and 1.1 million deaths annually by 2030. 
Most systemic therapies for CRC include the pyrimidine analogue 5-fluorouracil (5-FU), either 
as monotherapy or in combination with another chemotherapeutic, typically oxaliplatin or 
irinotecan.  Both alone and in combination, 5-FU is the single most effective compound against 
these tumours.  Nevertheless, despite being the standard of care, the effectiveness of 5-FU as a 
single-agent is modest. 
1.2. 
5-FU in Colorectal Cancer 
1.2.1 Adjuvant Treatment 
5-FU has been the mainstay of adjuvant treatment for high-risk Stage II or Stage III colon 
cancer for several decades.  Adjuvant chemotherapy with a 5-FU-based regimen has been 
shown to improve overall survival (OS) by 7% (5% for those with Stage II and 10% with 
Stage III cancer; Ragnhammar et al, 2001).  In the adjuvant setting, 5-FU is given with 
leucovorin (LV) or combined with LV and oxaliplatin (FOLFOX).  The oral 5-FU prodrug 
capecitabine (Xeloda) can be used instead of 5-FU, either as monotherapy or in combination 
with oxaliplatin (CAPOX). 
1.2.2 Treatment for Metastatic Disease 
5-FU is an essential component of chemotherapy for CRC in the metastatic setting, as part of 
FOLFOX (5-FU, LV and oxaliplatin), FOLFIRI (5-FU, LV and irinotecan), FOLFOXIRI 
(5-FU, LV, oxaliplatin and irinotecan), CAPOX (capecitabine and oxaliplatin) or CAPIRI 
(capecitabine and irinotecan).  The use of 5-FU in these combinations, and the addition of 
targeted therapies, such as a vascular endothelial growth factor (VEGF) inhibitor, vascular 
endothelial growth factor receptor (VEGFR) inhibitor or an epidermal growth factor receptor 
(EGFR) inhibitor, has seen the median survival from CRC increase to 24 months (compared to 
12 months with 5-FU alone) (Ikoma et al, 2017).   
The standard of care for 1st-line metastatic patients is either a FOLFOX-based or 
FOLFIRI-based regimen, usually in combination with the VEGF inhibitor bevacizumab. 
Following progression, most patients receive 2nd-line FOLFIRI-based or FOLFOX-based 
regimens, with or without bevacizumab. A Phase III study investigating the sequence of 
FOLFOX and FOLFIRI regimens as 1st- and 2nd-line therapy for patients with advanced CRC 
demonstrated no significant difference in median OS between the FOLFIRI followed by 
FOLFOX6 (20.4 months) and FOLFOX6 followed by FOLFIRI (21.5 months) regimens (Lee 
& Sun, 2016).  

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In the 2nd-line, anti-VEGF therapy with bevacizumab was shown to improve outcomes when 
combined with FOLFOX compared to FOLFOX alone, with significant differences in median 
OS (12.9 months vs 10.8 months), median progression-free survival (PFS) (7.3 months vs 
4.7 months), and objective response rate (ORR) (22.7% vs 8.6%) (Giantonio et al, 2007). 
Furthermore, it has been shown that continuation of bevacizumab in combination with 
chemotherapy in 2nd-line treatment resulted in improved OS when compared to 2nd-line 
chemotherapy alone (median OS: 11.2 months vs 9.8 months) (Bennouna et al, 2013). 
1.3. 
Limitations of 5-FU Treatment 
First introduced in 1957, 5-FU is still widely used for the treatment of many cancers, including 
colorectal, breast, stomach, head and neck, and pancreatic cancers.  Approximately 
500,000 patients in North America receive 5-FU each year.  Two other drugs have been 
approved 
that 
generate 
the 
same 
active 
anti-cancer 
metabolite 
as 
5-FU: 
fluorodeoxyuridine/floxuridine, marketed as FUDR®, and capecitabine, marketed as Xeloda®.  
Like 5-FU, both of these drugs are pro-drugs which must be converted to an active anti-cancer 
metabolite, fluorodeoxyuridine-monophosphate (FUDR-MP) inside the cancer cell in order to 
exert their primary cytotoxic activity.  Capecitabine is a derivative of 5-FU containing a 
chemical modification of the nucleoside ring, which allows oral dosing. 
FUDR-MP binds to and inhibits thymidylate synthase (TS), a critical enzyme in de novo 
nucleotide synthesis and cell survival (Longley et al, 2003).  TS is required to convert uridine, 
specifically 
deoxyuridine 
monophosphate, 
or 
dUMP, 
to 
thymidine, 
specifically 
deoxythymidine monophosphate, or dTMP, one of the four nucleotides that comprise DNA.  
The inhibition of TS results in an imbalance in the ratio of the nucleotides dUMP and dTMP, 
disrupting DNA synthesis and repair, which ultimately leads to cancer cell death. Due to 
multiple limitations, 5-FU is not efficiently converted to the active anti-cancer metabolite, 
FUDR-MP, and is often co-administered with LV in an attempt to enhance its binding to TS 
and subsequent anti-cancer activity. 
Key cancer resistance mechanisms impacting breakdown and activation of 5-FU have been 
associated with a poor prognosis to treatment (Longley et al, 2003; Longley & Johnston, 2005). 
1.3.1 Susceptibility to Breakdown 
More than 85% of administered 5-FU is degraded by the enzyme dihydropyrimidine 
dehydrogenase (DPD) in the liver, therefore most of the drug is catabolised before it has an 
opportunity to enter cancer cells, become activated and exert any therapeutic effect (Diasio & 
Harris, 1989).  DPD is also present in other tissues, such as the gastrointestinal tract (Pizzorno 
et al, 2003), and in tumour cells, resulting in additional 5-FU catabolism.  
In an analysis of more than 60 human cancer cell lines, a highly significant inverse correlation 
between DPD expression and activity and response to 5-FU was demonstrated (Beck et al, 
1994; Scherf et al, 2000).  The overexpression of DPD in a number of different cancer cells 
has been shown to confer resistance to 5-FU (Takebe et al, 2001).  Furthermore, high levels of 
DPD were associated with a poorer response to 5-FU in tumour xenograft studies (Ishikawa et 
al, 1999).  
In patients, DPD activity has been found to be elevated in hepatocellular carcinomas that are 
inherently resistant to fluoropyrimidine-based therapy (Jiang et al, 1997) and DPD levels were 
found to predict resistance to 5-FU in patients with CRC (Diasio et al, 1999; Etienne et al, 
1995).  High transcription of DPD mRNA in colorectal tumours has been shown to correlate 
with resistance to 5-FU, potentially caused by more DPD-mediated catabolism of 5-FU in these 

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tumours (Salonga et al, 2000).  Moreover, a significantly shorter OS (4.9 vs 13.1 months) has 
been observed among patients with CRC receiving 5-FU treatment whose DPD levels were 
high compared to patients with low DPD expression (Salonga et al, 2000). The catabolism of 
5-FU by DPD is subject to marked circadian variations, leading to increased breakdown of 
5-FU at certain times throughout the day with consequent reductions in 5-FU efficacy during 
these times.  Clinical protocols have attempted to overcome these challenges by altering the 
5-FU infusion rate on a circadian schedule, necessitating an increased infusion rate in the early 
morning (Pizzorno et al, 2003).  
In addition to the reduced efficacy, 5-FU catabolism by DPD results in the generation of toxic 
by products, such as α-fluoro-β-alanine (FBAL), which has been associated with off-target 
toxicity including hand foot syndrome, which is also known as chemotherapy-induced acral 
erythema or palmar plantar erythrodysesthesia. This well-established cutaneous toxicity occurs 
in 25-75% of patients treated with 5-FU (Meta Analysis Group in Cancer, 1998; Hansen et al, 
1996; Chiara et al, 1997; Chau et al, 2005; Kwakman et al, 2020) and  is characterised by 
erythema, dysesthesia, pain, cracking, and desquamation on the palms of the hands and the 
soles of the feet (Nikolaou et al, 2016).  Hand foot syndrome can be debilitating and 
significantly affects quality of life, often necessitating 5-FU dose modifications or treatment 
discontinuation.  Additional off-target toxicities associated with 5-FU by-products 
(predominantly FBAL and its breakdown products fluoroacetate and F-citrate) include 
cardiotoxicity and neurotoxicity, both of which are known to be dose limiting (Yamashita et 
al, 2004; Jensen & Sorensen, 2006; Deboever et al, 2013).  Moreover, there is evidence 
indicating that these 5-FU catabolites interfere with the anti-cancer efficacy of 5-FU (Spector 
et al, 1995).  Therefore, circumventing DPD-mediated degradation is anticipated to 
significantly improve the safety and efficacy of fluoropyrimidines. 
Although high levels of DPD have a clear impact on efficacy and safety, 5-FU and related 
agents are also associated with risk of severe or fatal toxicities in patients who are 
DPD-deficient.  Partial DPD deficiency is carried in an estimated 2-5% of the Caucasian and 
Asian populations, and in 8% of African-Americans.  These patients are unable to effectively 
breakdown 5-FU through the catabolic DPD pathway, leading to prolonged exposure to toxic 
levels of 5-FU metabolites with resultant adverse events (AEs), including mucositis, 
granulocytopaenia, neuropathy, and even death (Baek et al, 2006).  Techniques are available 
for the detection of this autosomal dominant condition (Mattison et al, 2004; Innocenti, 2014; 
Henricks et al, 2018) and testing is becoming more widely used in clinical practice.  
5-FU is also phosphorylated to 5-fluorouridine triphosphate (5-FUTP), which is known to be 
partially responsible for 5-FU-associated off-target toxicity through incorporation into RNA in 
healthy cells (Brutcher et al, 2018).  Indeed, 5-FUTP is thought to be the primary mediator 
underlying diarrhoea, a key dose-limiting toxicity (DLT), in patients treated with 5-FU (Adjei, 
1999). Fluoropyrimidines are also susceptible to enzymatic hydrolysis by thymidine 
phosphorylase (TP), which is commonly overexpressed in tumours (Longley et al, 2003; 
Bronckaers et al, 2009) or introduced by mycoplasma infection (Huang et al, 2001) and 
interferes with chemo-sensitivity (Jetté et al, 2008). 
Overall, the by-products FBAL and 5-FUTP produced during metabolism of 5-FU are 
associated with significant off-target toxicities that limit the clinical utility of 5-FU. 

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1.3.2 Requirement of Activation 
5-FU needs to be processed by a series of enzymes in cancer cells to generate the primary active 
anti-cancer metabolite, FUDR-MP, which binds to and inhibits TS. The inhibition of TS results 
in an imbalance in the ratio of the nucleotides dUMP and dTMP, disrupting DNA synthesis 
and repair, which ultimately leads to cancer cell death (Longley et al, 2003). 
The levels of two key enzymes in the 5-FU activation pathway have been shown to correlate 
with treatment efficacy. Orotate phosphoribosyltransferase (OPRT) converts 5-FU to 
fluorouridine monophosphate, an intermediate in the formation of FUDR-MP. Low levels of 
OPRT in tumour cells is associated with resistance to 5-FU (Tsutani et al, 2008). In patients 
with CRC receiving 5-FU based chemotherapy, low levels of OPRT is associated with 
significantly worse OS rates (Komori et al, 2013).  In addition, TP converts 5-FU to FUDR, 
which is then further processed to FUDR-MP by thymidine kinase (TK). It has been shown 
that TK deficiency in human cancer cells diminishes the activity of 5-FU (Vande Voorde et al, 
2011).  It has been observed that expression of TP correlates with response to 5-FU therapy 
(Panczyk, 2014).  Higher TP levels theoretically should correlate to greater sensitivity to 5-FU 
due to increase in the concentration of FUDR-MP.  However, studies have shown mixed results 
regarding response to 5-FU-based chemotherapy and level of TP expression.  Low TP 
expression in one study correlated with improved OS in patients with metastatic CRC treated 
with adjuvant 5-FU (Soong et al, 2008; Salonga et al, 2000).  A more recent study in patients 
with mCRC demonstrated longer time to progression with high TP expression (Lindskog et al, 
2014).  Further studies are needed to establish a definitive link between TP expression and 
5-FU sensitivity. 
1.3.3 Dosing Administration Challenges 
5-FU is associated with significant dosing administration challenges due to poor 
pharmacokinetic (PK) properties.  The plasma half-life (t1/2) of 5-FU is very short at 8 to 
14 minutes; consequently, prolonged infusion times over 46 hours are required to allow uptake 
and activation of the pro-drug to generate therapeutic levels of FUDR-MP, whilst also 
attempting to minimise maximum concentration (Cmax) levels of toxic by-products.  This 
dosing regimen and the substantial off-target toxicities are burdensome for providers, 
inconveniences patients, and contributes additional costs to the healthcare system. 
1.4. 
NUC-3373 
NUC-3373 is specifically designed to overcome the key resistance mechanisms that limit the 
clinical utility of 5-FU, thereby potentially improving the efficacy and safety profile, whilst 
also reducing the dosing administration burdens associated with 5-FU (McGuigan et al, 2011; 
Vande Voorde et al, 2011). NUC-3373 generates the same active intracellular anti-cancer 
metabolite, FUDR-MP, as 5-FU, but at significantly higher concentrations. 
NUC-3373 is a pre-activated and protected form of FUDR-MP. The addition of the protective 
phosphoramidate group changes the structural characteristics of NUC-3373 such that it is not 
a substrate for, and is therefore resistant to enzymatic breakdown by, DPD. This confers the 
advantage of reduced exposure to by-products and associated off-target toxicities, such as hand 
foot syndrome.    
In addition, NUC-3373 generates much lower levels of FUTP compared to 5-FU, and the 
incidence of Grade 3 or higher toxicities associated with off-target incorporation of this 
molecule into the RNA of normal cells has been low in clinical studies to date.   

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The chemical structure also alters the lipophilicity of the molecule, enabling NUC-3373 to 
enter cancer cells without the need for nucleobase transporters.   
Finally, as NUC-3373 contains the active anti-cancer metabolite, there is no need for enzymatic 
conversion to FUDR and subsequent phosphorylation, thus overcoming major rate limiting 
cancer resistance pathways associated with 5-FU.   
Together, these unique properties are expected to result in enhanced drug systemic exposure 
and a reduction in the release of toxic by-products.  Once inside the cancer cell, the protective 
group is cleaved off with release of significantly higher levels of the active anti-cancer 
metabolite FUDR-MP.  This results in enhanced interaction with, and inhibition of, the target 
enzyme TS, driving an imbalance in the dUMP:dTMP ratio with subsequent disruption of DNA 
synthesis and repair and, ultimately, cancer cell death. 
Refer to the NUC-3373 IB for current information on mechanisms of action as well as the latest 
non clinical and clinical data.  
1.4.1 Non Clinical Data 
NUC-3373 has consistently demonstrated greater activity than 5-FU across a range of 
non-clinical studies. 
• In vitro cytotoxic activity of NUC-3373 and 5-FU was examined across a range of human 
tumour cell lines, including the colorectal cell lines HT29, SW620 and Colo205.  The 
half-maximal effective concentration (EC50) data from the majority of cell lines tested 
demonstrated that NUC-3373 has up to 330-times greater activity than 5-FU. 
• The ability of NUC-3373, FUDR and 5-FU to generate the active intracellular metabolite, 
FUDR-MP, was examined in HT29 human colorectal cells. NUC-3373 and 5-FU were 
added to HT29 cells at a concentration of 50 µM for 24 hours. FUDR-MP was quantified 
using ultra-performance liquid chromatography coupled to tandem mass spectrometry. 
NUC-3373 generated 366-times the amount of intracellular FUDR-MP compared with 
5-FU. 
• Over half of CRC cases are infected by mycoplasma (Huang et al, 2001).  
Mycoplasma-encoded TP reduces the activity of several chemotherapeutic agents (Liekens 
et al, 2009), including 5-FU.  In cancer cell lines, mycoplasma infection decreases 5-FU 
activity by up to 100-times (Jetté et el, 2008).  Non clinical studies have shown that 
NUC-3373 is resistant to TP-mediated degradation, whereas FUDR is significantly broken 
down, and that in human glioblastoma U87 cells chronically infected by mycoplasma 
hyorhinis, FUDR markedly lost its cytotoxic activity 429-fold, whereas NUC-3373 activity 
was unaffected (Vande Voorde et al, 2011). 
• An in vitro study investigating the effect of DPD activity on the intracellular concentrations 
of NUC-3373 was conducted in cell lysate from pooled CRC cell lines (SW620, HCT116 
and HT29). NUC-3373 was not susceptible to DPD-mediated degradation unlike 5-FU, 
which was rapidly catabolised by DPD. 
• The cytotoxicity of NUC-3373 and FUDR were compared in CEM wild type and 
TK-deficient CEM human leukaemia cells (McGuigan et al, 2011).  NUC-3373 activity 
was largely independent of TK with less than a 5-fold decrease in EC50 values in 
TK-deficient cells, whereas FUDR loses activity was decreased by more than 136-fold. 

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In xenograft studies examining the effect of NUC-3373 and 5-FU on the growth of HT29 
human colorectal tumour cell line, NUC-3373 showed significant reduction in tumour volume 
compared to 5-FU.   NUC-3373 showed a statistically significant increase in tumour doubling 
time when compared with the control group, whereas 5-FU did not. 
A formal good laboratory practice repeat dose study has been conducted to assess the toxicity 
and toxicokinetic profile of NUC-3373 in the Beagle dog. NUC-3373 was administered 
intravenously (IV) to dogs at 1, 4 and 8 mg/kg/day once daily for 5 days/week for 4 consecutive 
weeks.  Doses greater than 4 mg/kg/day induced weight loss as the most significant side effect 
as well as histopathological changes in testes, epididymides and gall bladder. These findings 
showed full reversibility after a 2-week treatment-free period, except for testes and 
epididymides that were recovering but were thought to take longer to fully recover. 
Based on the results of this study, the highest non-severely toxic dose was considered to be 
8 mg/kg/day.  These results compare favourably with the reported toxicity of 5-FU in Beagle 
dogs following single bolus IV administration (Sayre et al, 2012) 
More details on the toxicology, pharmacology and toxicokinetics can be found in the 
NUC-3373 Investigator’s Brochure (IB). 
1.5. 
Clinical Data 
NuTide:301 was a first-in-human dose escalation study in patients with advanced solid tumours 
(EudraCT 2015-002250-13, NCT02723240) which enrolled patients across three investigative 
sites in the UK. The study had a two-part dose escalation and expansion design which evaluated 
safety, PK, pharmacodynamic (PD) and anti-tumour activity, in addition to establishing the 
maximum tolerated dose (MTD), recommended Phase II dose (RP2D) and schedule of 
single-agent IV NUC-3373.   
Enrolment has completed and the final results are being collated and analysed. In Part 1, 
NUC-3373 was administered on a weekly (Q1W) schedule on Days 1, 8, 15 and 22 of a 28-day 
cycle.  In Part 2, NUC-3373 was administered as a fortnightly (Q2W) infusion on Days 1 and 
15 of a 28-day cycle.   
A total of 59 patients received NUC-3373 in the study.  The dosing schedule is summarised in 
Table 1. 
All patients received NUC-3373 by IV infusion over time periods ranging from 30 minutes to 
4 hours. Considering that NUC-3373 is 5-times the equimolar weight of 5-FU, the starting dose 
of 125 mg/m2 NUC-3373 equates to approximately 25 mg/m2 5-FU; thus, micro-doses of 
NUC-3373 were given in the early stages of the study.  
This heavily pre-treated patient population (median of 3 prior lines of chemotherapy; range 
0-11 lines) had a variety of primary tumour types, with CRC representing approximately half 
of the cases. 
Promising signs of activity have been observed, with at least 10 patients staying on study 
treatment for at least 4 months and 3 of these patients achieving prolonged stable disease (SD) 
lasting more than nine months.  A 70-year-old male patient with CRC had received 6 prior lines 
of therapy, including 5 prior lines of 5-FU-based therapy (progressed within 2 months on 3rd-
line treatment with CapOx, progressed within 8 months on 4th-line treatment with FOLFIRI, 
progressed within 3 months on 5th-line treatment with trifluridine-tipiracil). This patient 
received 1500 mg/m2 NUC-3373 Q1W and achieved SD for 9 months before choosing to 
suspend treatment to go on vacation.  

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A 60-year-old female patient with cholangiocarcinoma who had progressed within 6 months 
of her 1st-line of therapy (gemcitabine in combination with cisplatin) achieved SD for 
11 months during treatment with 1125 mg/m2 NUC-3373 Q1W.  
A 55-year-old male patient with basal cell carcinoma had received 2 prior lines of therapy and 
had progressed within 3 months of the most previous treatment (paclitaxel in combination with 
carboplatin). This patient received NUC-3373 at 1500 mg/m2 every 2 weeks and achieved SD 
for 10 months. 
Table 1 
NuTide:301 dose escalation, treatment schedule, and enrolment 
Group 
Dosing Schedule 
Number of Patients 
Cohort 1 
NUC-3373 IV infusion 125 mg/m2 
On days 1, 8, 15, 22 of a 28-day cycle 
3 
Cohort 2 
NUC-3373 IV infusion 250 mg/m2 
On days 1, 8, 15, 22 of a 28-day cycle 
6 
Cohort 3 
NUC-3373 IV infusion 500 mg/m2 
On days 1, 8, 15, 22 of a 28-day cycle 
8 
Cohort 4 
NUC-3373 IV infusion 750 mg/m2 
On days 1, 8, 15, 22 of a 28-day cycle 
4 
Cohort 5a 
NUC-3373 IV infusion 1125 mg/m2 
On days 1, 8, 15, 22 of a 28-day cycle 
3 
Cohort 6a 
NUC-3373 IV infusion 1500 mg/m2 
On days 1, 8, 15, 22 of a 28-day cycle 
3 
Cohort 5b 
NUC-3373 IV infusion 1500 mg/m2 
On days 1 and 15 of a 28-day cycle 
4 
Cohort 6b 
NUC-3373 IV infusion 1875 mg/m2 
On days 1 and 15 of a 28-day cycle 
6 
Cohort 7a 
NUC-3373 IV infusion 1875 mg/m2 
On days 1, 8, 15, 22 of a 28-day cycle 
6 
Cohort 7b 
NUC-3373 IV infusion 2500 mg/m2 
On days 1 and 15 of a 28-day cycle 
6 
Cohort 8a 
NUC-3373 IV infusion 2500 mg/m2  
On Days 1, 8, 15, 22 of a 28-day cycle 
6 
Cohort 9a 
NUC-3373 IV infusion 3250 mg/m2  
On Days 1, 8, 15, 22 of a 28-day cycle 
4 
TOTAL 
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NUC-3373 was well tolerated at doses up to and including 2500 mg/m2. The most common 
treatment-emergent adverse events (TEAEs) considered related to NUC-3373 were fatigue 
(46%), nausea (36%), diarrhoea (31%), infusion reactions (most commonly described as a 
feeling of flushing; 29%), transaminases increased (19%), vomiting (15%), and anaemia 
(15%). The majority of events were Grade 1/2, with Grade 3 treatment-related events reported 
in only 7 patients (4 patients with transaminases increased and 1 patient each with fatigue, 
shingles and hypotension). None of the reported events appeared to be dose-related.  

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Twenty-nine serious adverse events (SAEs) were reported in 22 patients.  Most of these SAEs 
resolved and only two were considered by the Investigator to be unexpected.  Six of the SAEs 
were judged by the Investigator to be definitely, probably or possibly related to NUC-3373 
(chest pain, transaminases increased, infusion reaction, shingles, PRES and pyrexia).  
Four patients experienced DLTs; 1 out of 8 patients in the 500 mg/m2 Q1W cohort, 1 out of 6 
patients in the 1875 mg/m2 Q1W cohort and 2 out of 4 patients in the 3250 mg/m2 Q1W cohort. 
In the 500 mg/m2 and 1875 mg/m2 Q1W cohort, DLTs of Grade 3 transaminases increased 
were reported. In the 3250 mg/m2 Q1W cohort, DLTs of Grade 2 headache and Grade 3 
transient hypotension (decreased blood pressure for <5 minutes) were reported. Based on this, 
the MTD for single-agent NUC-3373 was determined to be 2500 mg/m2 Q1W. 
1.6. 
Pharmacokinetics 
Plasma and intracellular (PBMC) PK analyses have been conducted on 45 patients recruited to 
the NuTide:301 (range: 125 to 3250 mg/m2) and NuTide:302 (1500 mg/m2) studies.  The PK 
profile of NUC-3373 compares favourably to that of 5-FU. 
1.6.1 Plasma Levels 
A fully validated bioanalytical liquid chromatography mass spectrometry method was used to 
calculate PK parameters for NUC-3373 and its metabolites, FUDR and FBAL, over a dose 
range of 500-2500 mg/m2. A dose-proportional increase in the NUC-3373 AUC was observed 
over the dose range. Over the range studied, NUC-3373 had a mean elimination half-life of 
5-10 hours (vs 8-14 minutes for 5-FU). The volume of distribution and the clearance of 
NUC-3373 at the 1500 mg/m2 dose (n=20) was 198 L and 28.5 L/h, respectively.  
The mean Cmax and AUC values for NUC-3373 at the MTD (2500 mg/m2) were found to be 
41.7 µg/mL and 222.2 µg•h/mL.  Cmax and AUC values for FUDR and FBAL were 0.3 µg/mL 
and 1.3 µg•h/mL and 3.4 µg/mL and 34.1 µg•h/mL, respectively. No accumulation was 
observed for NUC-3373 or its circulating metabolites (FUDR and FBAL) between Day 1 and 
Day 15. M. 
1.6.2 Intracellular Levels 
A dose-proportional increase in the intracellular AUC for the active anti-cancer metabolite 
FUDR-MP was observed over a dose range of 125-2500 mg/m2 in PBMCs. The Cmax and Tmax 
of intracellular FUDR-MP was influenced by the time of infusion. In the 1500 mg/m2 cohort, 
the mean intracellular Cmax and AUC0‐24 of FUDR‐MP were 11.7 pmol/million cells and 
95.6 pmol/million cells/h, respectively. In the 2500 mg/m2 cohort, the mean intracellular Cmax 
and AUC0‐24 of FUDR‐MP were 23.0 pmol/million cells and 135.5 pmol/million cells/h, 
respectively.  The half-life of intracellular FUDR-MP was calculated to be 10-14 hours. A 
positive linear relationship was observed between intracellular FUDR‐MP and dUMP levels. 
The toxic metabolites FBAL and FUTP were undetectable intracellularly at the dose levels 
tested.I. 
1.7. 
Study Rationale 
NUC-3373 is a pre-activated (monophosphorylated) and protected form of the active anti-
cancer agent FUDR-MP. The addition of the phosphoramidate group to the FUDR-MP protects 
NUC-3373 against inactivation by enzymatic breakdown, resulting in greater stability, and 
reduces the release of potentially toxic metabolites. 
NUC-3373 is lipophilic and can enter cancer cells without the need for nucleobase transporters. 
It is synthesised as the monophosphate and, as such, has already by-passed the activation steps 

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dependent on the enzymes OPRT and TK.  NUC-3373 is resistant to degradation by DPD and 
to intracellular metabolic breakdown by TP.  As a result, NUC-3373 is anticipated to rapidly 
generate high concentrations of the active metabolite FUDR-MP intracellularly and efficiently 
inhibit TS to confer therapeutic benefits. 
NUC-3373 has shown the ability to generate high levels of FUDR-MP and markedly inhibit 
tumour cell growth in non clinical studies.  In particular, the degree of tumour regression with 
NUC-3373 is greater than with 5-FU in human CRC xenograft models.  Toxicology results 
compare favourably with the reported toxicity of 5-FU in Beagle dogs following single bolus 
IV administration (Sayre et al, 2012).  The first-in-human Phase I clinical study, NuTide:301, 
has confirmed the potential for NUC-3373 to generate high intracellular levels of the active 
agent FUDR-MP. NUC-3373 has been well-tolerated in 59 patients at doses up to and including 
2500 mg/m2 and has shown encouraging signs of anti-cancer activity.   
Together these data demonstrate the potential for NUC-3373 to overcome the known resistance 
mechanisms associated with 5-FU and potentially to offer a more effective treatment option 
for patients with CRC.   
The addition of LV potentiates the anti-cancer activity of infusional 5-FU by prolonging the 
intracellular half-life and increasing intracellular levels of FUDR-MP, as well as stabilising the 
complex it makes with TS. Because it improves the clinical efficacy of 5-FU, LV has become 
an integral part of infusional 5-FU based regimens.  
Additionally, 5-FU is commonly used in combination with oxaliplatin (comprising the 
FOLFOX regimen) and irinotecan (comprising the FOLFIRI regimen); these regimens are 
often combined with agents that target the VEGF (e.g., bevacizumab) and EGFR (e.g., 
cetuximab) pathways.  In order to maximise clinical benefit for patients, it is important to study 
NUC-3373 in combination with these agents and regimens that are routinely used in, and 
considered standard of care for, patients with advanced CRC.  Thus, the goal for Part 1 of this 
study is to evaluate the safety and benefit of combining LV with NUC-3373. Parts 2 and 3 of 
this study will then be undertaken to establish safe and effective regimens of NUC-3373 
combinations with the long-term goal of improving upon the activity of 5-FU and establishing 
more effective treatments for patients with CRC. 
Patients who are considered ineligible for combination chemotherapy regimens and patients 
who have rapidly progressed on prior fluoropyrimidine-based therapies also have limited 
treatment options. Combination chemotherapy ineligible patients are generally frail with a 
poorer performance status and, therefore, require more tolerable therapies. Given the 
favourable risk/benefit profile observed with NUC-3373, these patients could be good 
candidates for treatment with NUC-3373 + LV. Rapid progressors are unlikely to receive 
benefit from treatment with further lines of 5-FU based regimens. On the other hand, owing to 
its advantageous PK profile and ability to generate much higher levels of the active anti-cancer 
metabolite, NUC-3373 may overcome 5-FU resistance mechanisms. Indeed, NUC-3373 has 
shown anti-cancer activity in patients who have relapsed on, or are refractory to, prior treatment 
with a fluoropyrimidine, thus offering a potential treatment option for these patients.   
The current standard of care for the 1st-line and 2nd-line treatment of patients with advanced or 
metastatic CRC is FOLFOX, FOLFIRI or FOLFOXIRI in combination with VEGF inhibitors 
or EGFR inhibitors. During the patient’s treatment journey, components of the 1st-line regimen 
(e.g., oxaliplatin or irinotecan) will be either paused and re-instated, or switched to introduce a 
new combination agent, for the 2nd-line regimen. Some patients may receive maintenance 
therapy with a fluoropyrimidine ± bevacizumab. Data in the 2nd-line setting show that 
following irinotecan-based 1st-line treatment (e.g., FOLFIRI), FOLFOX is generally the best 

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option, and the combination of FOLFOX plus bevacizumab appears to be superior to FOLFOX 
alone. Alternatively, following FOLFOX failure in the 1st-line, irinotecan and FOLFIRI are the 
most appropriate options for 2nd-line treatment. Interim data from Part 1 of NuTide:302 show 
that NUC-3373 has promising anti-tumour activity, including tumour shrinkage and 
encouraging rates of prolonged disease stabilisation beyond 3 months (11/38 patients) in 
heavily pre-treated patients (3-11 prior lines of treatment for metastatic disease) in whom 
disease stabilisation is difficult to achieve. Furthermore, NUC-3373 has a favourable 
tolerability profile compared to either 5-FU or capecitabine (Table 2) and offers an attractive 
administration schedule with a short (2-4 hours) Q1W or Q2W infusion, instead of the 
prolonged infusion (46 hours) required for 5-FU. These data suggest that NUC-3373 might be 
an attractive option to replace 5-FU in the current standard of care FOLFOX and FOLFIRI 
regimens in the 2nd-line setting. Addition of targeted agents to these combinations offers an 
additional potential advantage for tumour control in this setting, justifying the evaluation of 
NUFOX and NUFIRI regimens in combination with bevacizumab or cetuximab in 
NuTide:302. 
Table 2 
NUC-3373 safety profile (Part 1 of NuTide:302) 
 
 
Depending on response to combination therapies in the 1st-line metastatic setting in CRC, 
maintenance therapies offer patients a break from intensive combination treatments while 
maintaining tumour control. The goal of maintenance therapy is to maximise quality of life 
(QoL) by minimising toxicities and delivering superior efficacy in order to delay the initiation 
of a new intensive combination regimen. Based on the favourable safety and tolerability profile 
observed to date, and the more convenient administration schedule, NUC-3373 may offer a 
good maintenance therapy option for patients. Bevacizumab as single agent or in combination 
with a fluoropyrimidine has shown good efficacy in this setting (single agent activity of disease 
stabilisation between 5-10 months, depending on the study; Ma et al, 2019); thus, the 
combination of NUC-3373 and bevacizumab could provide an additional option for delaying 
the initiation of 2nd-line therapy.  
 

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2. 
 STUDY OBJECTIVES AND ENDPOINTS 
This study consists of two phases (Phase Ib and Phase II) and includes three study parts (Parts 1, 
2 and 3) with several treatment arms within each part. Phase Ib includes Part 1 (Arms 1a-1d) 
and Part 2 (Arms 2a-2d) and Phase II includes Part 3 (Arms 3a-3g). 
2.1. 
Primary Objectives 
Phase Ib 
The primary objective is to identify a recommended dose and schedule for NUC-3373 when 
combined with other agents commonly used in treatment of advanced CRC, including: 
• LV  
• oxaliplatin 
• oxaliplatin and VEGF pathway inhibitors (bevacizumab) 
• oxaliplatin and EGFR inhibitors (cetuximab or panitumumab)  
• irinotecan  
• irinotecan and VEGF pathway inhibitors (bevacizumab) 
• irinotecan and EGFR inhibitors (cetuximab or panitumumab) 
Phase II 
To explore the anti-cancer activity of NUC-3373 when combined with other agents commonly 
used in the treatment of advanced CRC using Response Evaluation in Solid Tumours (RECIST) 
v1.1 criteria. 
2.2. 
Secondary Objectives 
The secondary objectives are: 
• To assess the safety and tolerability of each NUC-3373-containing regimen 
(Phase Ib and Phase II) 
• To assess the PK of NUC-3373, oxaliplatin, irinotecan and their metabolites in each 
NUC-3373-containig regimen (Phase Ib and Phase II) 
• To make a preliminary assessment of the anti-tumour activity of NUC-3373 alone 
and in each NUC-3373-containig regimen (Phase Ib only) 
• To conduct a within-patient and between-patient analysis of the effect of LV when 
added to NUC-3373 on intracellular PD parameters and haematological parameters 
and use this information to determine if the addition of LV to NUC-3373-containing 
regimens is required for clinical activity (Part 1 Arm 1a and Arm 1b only) 
2.3. 
Exploratory Objectives 
• To explore predictive biomarkers of biological activity and possible relationships 
between PK and PD effects (Phase Ib and Phase II) 
• Depending on emerging data, to potentially conduct a within-patient analysis of the 
effect of combining NUC-3373 with irinotecan on the plasma PK parameters of 
both NUC-3373 and irinotecan (Part 2 Arm 2b sub-study only) 

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2.4. 
Primary Endpoints 
Phase Ib 
To identify a recommended dose and schedule for NUC-3373 when combined with LV and 
other agents routinely used in the treatment of patients with advanced CRC 
Phase II 
Objective disease assessment by radiographic imaging will be performed every 8 weeks and 
analysed using RECIST v1.1 criteria. Anti-tumour activity will be assessed on the basis of: 
• Percentage change from baseline in tumour size 
• Objective Response Rate (ORR) 
• Disease Control Rate (DCR) 
• Duration of Response (DoR) 
• Duration of Stable Disease (DoSD) 
• Progression-Free Survival (PFS) 
• Overall Survival (OS) rate at 6 and 12 months 
2.5. 
Secondary Endpoints 
2.5.1 Safety (Phase Ib and Phase II) 
• TEAEs (per Common Terminology Criteria for Adverse Events [CTCAE] v5.0) 
• Clinically-significant laboratory changes (per CTCAE v5.0) 
• Changes in physical exam, vital signs and serial electrocardiograms (ECGs) 
2.5.2 Pharmacokinetics (Phase Ib and Phase II) 
The PK of NUC-3373, oxaliplatin, irinotecan and their metabolites will be assessed, including: 
• Concentration at end of NUC-3373 infusion (Cinf) 
• Maximum concentration (Cmax) 
• AUC 
• t1/2 
• Volume of distribution (Vd) 
• Clearance (CL) 
The analytes measured will include, but are not limited to: 
• In plasma:  NUC-3373, oxaliplatin, irinotecan and their metabolites 
• In peripheral blood mononuclear cells (PBMCs):  NUC-3373, FUDR-MP, FBAL, 
5-FUTP, dTMP, dUMP (Part 1 only) 

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2.5.3 Efficacy Endpoints (Phase Ib) 
Objective disease assessment by radiographic imaging will be performed every 8 weeks and 
analysed using Response Evaluation Criteria in Solid Tumours (RECIST) v1.1 criteria 
(Appendix 1).  Anti-tumour activity will be assessed on the basis of: 
• Percentage change from baseline in tumour size 
• ORR 
• DCR 
• DoR 
• DoSD 
• PFS 
• OS rate at 6 and 12 months 
2.6. 
Exploratory Endpoints (Phase Ib and Phase II) 
• Pre-treatment and on-treatment measurements of PD markers in PMBCs (Part 1 
only) 
• Exploration of predictive biomarkers such as gene expression and/or genetic 
alternations in blood and tumour (e.g., genetic alterations in genes involved in PK 
exposure, PD effects, safety and efficacy)  
• DNA/RNA and protein analysis of pre- and on-treatment tumour samples, including 
but not limited to KRAS and BRAF 
• Potential sub-study to evaluate the PK relationship between NUC-3373, LV and 
irinotecan (Part 2 Arm 2b sub-study only) 
The PK of NUC-3373, LV and irinotecan will be assessed, including Cinf, Cmax, 
AUC, t1/2, Vd, CL 
The analytes measured in plasma will include, but are not limited to: 
o NUC-3373, 5-FU, and FBAL  
o LV and 5-methyl-THF 
o Irinotecan, SN-38, SN-38 glucuronide, APC and NPC 

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3. 
INVESTIGATIONAL PLAN 
3.1. 
Overall Study Design 
This is a three-part, Phase Ib/II study of NUC-3373 administered by IV infusion (Q1W or 
Q2W), either as monotherapy or as part of various combinations with LV, oxaliplatin, 
irinotecan, VEGF inhibitors and EGFR inhibitors. (Figure 1). Phase Ib includes Part 1 
(Arms 1a-1d) and Part 2 (Arms 2a-2d) and Phase II includes Part 3 (Arms 3a-3g). The opening 
and timing of study arms will depend on emerging data.  
For VEGF inhibitors, the preferred treatment option is Avastin; however, biosimilars may be 
used after discussion with the Sponsor. For EGFR inhibitors, the preferred treatment options 
are Erbitux (cetuximab) or Vectibix (panitumumab); however, if biosimilars become available, 
their use may be discussed with the Sponsor.     
Patients may continue treatment until radiological disease progression or unacceptable toxicity 
despite optimal medical management or dose or schedule modification, or withdrawal of 
consent. All patients will be followed up until withdrawal of consent, lost to follow-up, death, 
or the overall end of study has been reached (defined in Section 3.6), whichever occurs first. 
 
Abbreviations: Iri=irinotecan; LV=leucovorin; NUFIRI=NUC-3373 + LV + irinotecan; NUFOX=NUC-3373 + LV + oxaliplatin; Ox=oxaliplatin; Q1W=weekly; 
Q2W=fortnightly 
Figure 1 
NuTide:302 study schema 

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Part 1 determined that NUC-3373 should be administered with LV (Arms 1a, 1b and 1c) and 
will further assess the safety and tolerability of NUC-3373 + LV on a Q1W schedule (Arm 1d).  
Part 2 will assess the safety and tolerability of different doses of Q1W NUC-3373 + LV when 
administered in combination with either oxaliplatin (NUFOX) or irinotecan (NUFIRI).  
Part 3 will assess the safety and efficacy of Q1W NUFOX and NUFIRI regimens administered 
in combination with bevacizumab (Q2W arms may also be opened). NUFOX and NUFIRI 
regimens may also be administered in combination with cetuximab or panitumumab, 
depending on emerging data. In addition, Q1W NUC-3373 + LV in combination with 
bevacizumab may be assessed in patients qualifying for maintenance therapy.  
A Q2W schedule may be explored at any time, depending on emergent safety, efficacy and PK 
data. 
It is anticipated that approximately 215 patients with advanced or metastatic radiologically-
measurable CRC may be required in this study.  Additional patients may be enrolled in all parts 
of the study to replace patients who withdraw prior to completing Cycle 0 (where relevant) and 
the initial 28-day safety evaluation period in Cycle 1. Additionally, if the Data Safety 
Monitoring Committee (DSMC) determine that an increased number of patients are required 
to evaluate alternate doses within a study part, enrolment in a cohort may be expanded. If 
positive efficacy signals are observed in any of the patient populations included in Parts 1, 2 or 
3 of the study, expansion cohorts may be opened to further assess efficacy in approximately 
20 patients per cohort.  
The patient populations outlined in Table 3 will be included in the study. 
Table 3 
Patient populations 
Patient Population 
Criteria 
Study 
Phase/Part 
≥3rd-line patients  
Received ≥2 prior lines of therapy for locally 
advanced or metastatic disease, one must include a 
fluoropyrimidine plus oxaliplatin, the other must 
include a fluoropyrimidine plus irinotecan. 
Phase Ib 
Part 1  
Part 2 (dose 
escalation) 
Combination 
chemotherapy ineligible 
patients 
Considered 
unable 
to 
receive 
combination 
chemotherapy for locally advanced or metastatic 
disease and may have received 1 prior line of 
fluoropyrimidine-containing therapy. 
Phase Ib  
Part 1 
2nd-/3rd-line patients  
Received at least 1, but no more than 2, prior lines 
of fluoropyrimidine-containing therapy combined 
with oxaliplatin and/or irinotecan for locally 
advanced or metastatic disease. 3rd-line patients 
enrolled to Arms 2c and 2d should have received 
prior bevacizumab treatment, unless ineligible or 
unless bevacizumab was not standard of care 
according to relevant region-specific treatment 
recommendations. 
Phase Ib 
Part 2 
(expansion) 
Rapid progressors 
(on prior fluoropyrimidine 
therapy) 
Received ≤2 prior lines of fluoropyrimidine-
containing therapy combined with oxaliplatin and/or 
irinotecan for locally advanced or metastatic disease 
and progressed ≤3 months of starting the last 
fluoropyrimidine-containing regimen. 
To be 
determined. 
Cohorts of rapid 
progressors may 
be opened 

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depending on 
emerging data 
2nd-line patients 
Received 1 prior line of fluoropyrimidine-
containing therapy combined with oxaliplatin and/or 
irinotecan for locally advanced or metastatic 
disease. 
Phase II 
Part 3 
Maintenance patients 
Received ≥12 weeks of 1st-line standard of care 
therapy for locally advanced or metastatic disease, 
achieved at least stable disease and are eligible for 
maintenance therapy. 
Phase II 
Part 3 
Previous treatment with triplet chemotherapy-based regimens is permitted (i.e., FOLFOXIRI), as long as any 
toxicities from the previous regimen still allow repeated treatment with oxaliplatin or irinotecan. 
 
3.1.1 Part 1  
Part 1 determined that NUC-3373 should be administered with LV (Arms 1a, 1b and 1c) and 
will further assess the safety and tolerability of NUC-3373 + LV (Arm 1d) in patients with 
advanced or metastatic CRC (Figure 2).  Initially, ≥3rd-line patients were randomised via block 
randomisation to two parallel arms, each receiving NUC-3373 Q2W either with LV (Arm 1a) 
or without LV (Arm 1b). Upon completion of the Q2W dose administration arms, a third arm 
of ≥3rd-line patients was enrolled to a Q1W administration schedule of NUC-3373 plus LV 
(Arm 1c). Arms 1a, 1b, and 1c are now complete. Following this, approximately 
10 combination chemotherapy ineligible patients will be enrolled to a Q1W administration 
schedule of NUC-3373 plus LV (Arm 1d). 
 
Figure 2 
NuTide:302 Part 1 study schema 
In Arm 1a, an initial arm of up to 6 evaluable patients were to receive a single dose of 
NUC-3373 at 1500 mg/m2.  This visit was considered Cycle 0, Day 1 (C0D1) for the purposes 
of the study visits.  The initial dose was followed by a 2-week washout period, during which 
safety and PK/PD were monitored. The next dose of NUC-3373 was given in combination with 
LV at 400 mg/m2.  This visit was considered Cycle 1, Day 1 (C1D1) for the purposes of the 
study visits. All subsequent doses of NUC-3373 were given Q2W in combination with LV in 
28-day cycles. A total of 10 patients were finally enrolled in Arm 1a to obtain 6 evaluable 
patients. 
In Arm 1b, an initial arm of up to 6 evaluable patients were to receive a single dose of 
NUC-3373 at 1500 mg/m2 in combination with LV at 400 mg/m2.  This visit was considered 
C0D1 for the purposes of the study visits. The initial combination dose was followed by a 
2-week washout period during which safety and PK/PD were monitored. The next dose of 
NUC-3373 was given without any LV.  This visit was considered C1D1 for the purposes of the 
study visits.  All subsequent doses of NUC-3373 were given Q2W without LV in 28-day cycles. 
A total of 11 patients were finally enrolled in Arm 1b to obtain 6 evaluable patients. 

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In Arm 1c, two initial cohorts of up to 12 evaluable patients each were to receive NUC-3373 
Q1W at either 1500 mg/m2 or 2500 mg/m2 in combination with LV Q1W at 400 mg/m2.  
NUC-3373 and LV were administered on Days 1, 8, 15 and 22 of 28-day cycles. A total of 
17 patients were finally enrolled in Arm 1c to obtain 6 evaluable patients per cohort. 
The dose of NUC-3373 selected from Arm 1c for further exploration was 2500 mg/m2 in 
combination with LV at 400 mg/m2.  
In Arm 1d, a cohort of approximately 10 combination chemotherapy ineligible patients will 
receive NUC-3373 at 2500 mg/m2 in combination with LV at 400 mg/m2.  NUC-3373 and LV 
will be administered on Days 1, 8, 15 and 22 of 28-day cycles. 
All patients in Part 1 (Arms 1a, 1b and 1c) were monitored for DLTs up to Day 28 of Cycle 1.   
If the dose of NUC-3373 was not tolerable or was sub-optimal, alternate dose levels (as 
described in Table 6) may have been explored. If cohorts at additional doses were opened, these 
were to utilise a modified 3+3 design in which a fourth patient may have been added to each 
initial 3-patient cohort to account for a patient that became unevaluable for DLT evaluation for 
any reason other than safety.  There was to be a 7-day observation period between treatment of 
the first patient and treatment of subsequent patients in a cohort.  
Once a minimum of 3 patients in each of Arms 1a, 1b and 1c had completed the 28-day DLT 
evaluation period all available safety, PK and PD data were evaluated to establish the 
tolerability of NUC-3373 ± LV administered in each dose administration schedule.   
Patients who completed the DLT period may have been switched from a Q1W to a Q2W 
schedule if they experienced drug-related toxicity (other than fatigue) that would otherwise 
have led to treatment discontinuation. In addition, patients who completed the DLT period may 
have moved from a Q2W to a Q1W schedule. The decision to switch schedules was to be 
discussed with and approved by the Sponsor on an individual patient basis.   
In addition to the assessment of safety, tolerability, PK and PD, a radiologic assessment of 
disease will be performed at 8-week intervals and evaluated using RECIST v1.1 to gain a 
preliminary assessment of clinical activity. 
3.1.2 Part 2 
Findings from Part 1 of the study showed that LV did not impact the safety or PK of NUC-3373; 
therefore, the decision was made that LV should be administered at 400 mg/m2 on each day of 
NUC-3373 administration in all parts of the study. 
Part 2 of the study consists of a dose escalation phase using a modified 3 + 3 design, which 
may be followed by an expansion phase (Figure 3). The dose escalation phase will assess the 
safety and tolerability of different doses of NUC-3373 + LV when administered in combination 
with either oxaliplatin (NUFOX) or irinotecan (NUFIRI) in a Q1W schedule in ≥3rd-line 
patients. Oxaliplatin and irinotecan will be given at standard doses and schedules. In the 
expansion phase, cohorts of 2nd-/3rd-line patients may be enrolled to assess Q1W schedules of 
the NUFOX and NUFIRI regimens selected in the dose escalation phase.  
 
Figure 3 
NuTide:302 Part 2 study schema 

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The dose escalation group of patients will receive NUC-3373 + LV to assess the safety and 
tolerability of different doses of NUC-3373 + LV administered in combination with oxaliplatin 
(Arm 2a) or irinotecan (Arm 2b).   
In Arm 2a, ≥3rd-line patients will receive NUC-3373 + LV on Days 1, 8, 15 and 22 and 
oxaliplatin on Days 1 and 15 of 28-day cycles.  
In Arm 2b, ≥3rd-line patients will receive NUC-3373 + LV on Days 1, 8, 15 and 22 and 
irinotecan on Days 1 and 15 of 28-day cycles.  
The starting dose of NUC-3373 will be 1500 mg/m2 and the dose levels to be evaluated are 
described in Table 7 and Table 8. Based on a clinical study of NUC-3373 (NuTide:301, 
EudraCT 2015-002250-13, NCT02723240), alternate and/or additional dose levels may be 
considered and implemented upon recommendation of the DSMC.   
The decision on which arm to enrol a patient to, Arm 2a or Arm 2b, will be made by the treating 
physician and will take into account the patient’s clinical condition and any therapies that have 
previously been administered for treatment of CRC.   
Patients will be enrolled into cohorts following a modified 3+3 design, in which a fourth patient 
may be enrolled in each initial 3-patient cohort as described above. The initial patient in each 
cohort will complete a 7-day observation period before subsequent patients are enrolled. All 
patients Arms 2a & 2b will be monitored for DLTs up to day 28 of Cycle 1.  Dose escalation 
or de-escalation decisions will be based on DSMC review once three patients have completed 
the first 28-day cycle.  
The recommended dose of NUC-3373 + LV in combination with oxaliplatin (Arm 2a) or 
irinotecan (Arm 2b) will be determined separately, and may be different.  
Patients who have completed the DLT period may be switched from a Q1W to a Q2W schedule 
if they experience drug-related toxicity (other than fatigue) that would otherwise lead to 
treatment discontinuation. In addition, patients who have completed the DLT period may move 
from a Q2W to a Q1W schedule. The decision to switch schedules must be discussed with and 
approved by the Sponsor on an individual patient basis.   
Once the dose escalation groups have been completed, the DSMC will review the available 
safety, clinical activity and PK data to determine the recommended dose of NUC-3373 + LV 
when given in combination with oxaliplatin or irinotecan. If safety concerns arise, additional 
cohorts assessing alternative doses of oxaliplatin and irinotecan may be opened with agreement 
from the DSMC.   
The MTD for NUFIRI has been established in Arm 2b and was determined to be 1500 mg/m2 
NUC-3373 + 400 mg/m2 LV + 180 mg/m2 irinotecan.   
Expansion cohorts may be enrolled to Part 2 to further assess the safety, tolerability and 
preliminary efficacy of the Q1W NUFOX and NUFIRI regimens, using the dose of NUC-3373 
selected in the dose escalation phase. NUFOX and NUFIRI regimens will be administered as 
described in Table 4.  
Table 4 
Part 2 expansion phase treatment arms 
Arm 
Treatment 
Number of patients 
2c  
NUC-3373 + LV Q1W, oxaliplatin Q2W (NUFOX) 
~10 2nd-/3rd-line patients  
2d 
NUC-3373 + LV Q1W, irinotecan Q2W (NUFIRI) 
~10 2nd-/3rd-line patients  

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3.1.3 Part 3 
Following determination of the recommended NUFOX and NUFIRI regimens in the Part 2 
dose escalation phase, Part 3 will open. The Part 2 expansion phase may open in parallel. 
In Part 3, 2nd-line patients will receive the NUFOX and NUFIRI regimens selected in Part 2 in 
combination with bevacizumab (Figure 4). Q1W bevacizumab-containing arms will be opened 
first. Following this, Q2W arms and/or cetuximab combination arms may be opened, 
depending on emerging data. In addition, patients qualifying for maintenance therapy may 
receive NUC-3373 + LV in combination with bevacizumab.  
 
Figure 4 
NuTide:302 Part 3 study schema 
The treatment for each arm is described in Table 5. The choice of arm to which an eligible 
patient should be enrolled will be at the Investigator’s discretion, taking into account the 
patient’s clinical condition and therapies that have previously been administered.  
Table 5 
Part 3 treatment arms 
Arm 
Treatment 
Number of patients 
3a  
NUFOX (NUC-3373 + LV Q1W) + bevacizumab 
~10 2nd-line patients 
3b 
NUFOX (NUC-3373 + LV Q2W) + bevacizumab  
~10 2nd-line patients 
3c 
NUFIRI (NUC-3373 + LV Q1W) + bevacizumab 
~10 2nd-line patients 
3d 
NUFIRI (NUC-3373 + LV Q2W) + bevacizumab 
~10 2nd-line patients 
3e 
NUC-3373 + LV Q1W + bevacizumab 
~10 maintenance patients 
3f 
NUFOX (NUC-3373 + LV Q1W or Q2W) + 
cetuximab 
~10 2nd-line patients 
3g 
NUFIRI (NUC-3373 + LV Q1W or Q2W) + 
cetuximab 
~10 2nd-line patients 
Bevacizumab and cetuximab should be used in accordance with standard local practice. 
Panitumumab combination arms may also be opened (~10 2nd-line patients), depending on 
emerging data. 
Cohorts of rapid progressors may also be opened (~10 patients), depending on emerging data.  

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3.1.4 PK Sub-study 
A PK sub-study may be conducted during Part 2 if emerging data suggest it would be beneficial 
to evaluate the PK relationship between NUC-3373, LV and irinotecan. If conducted, an 
additional 8 patients would be enrolled in the NUFIRI Q1W cohort (Arm 2b). Inclusion into 
this sub-study will also involve individual patient genotyping for drug metabolising enzymes 
and drug transporters to predict irinotecan-related toxicities. Genotyping will be performed for 
each patient using genomic DNA from white blood cells isolated from whole blood samples 
taken during screening. The genomic DNA will be analysed using pharmacogenomic protocols 
specific for individual genotypes for drug metabolising enzymes and drug transporters, e.g., 
TATA box polymorphism of the UGT1A1 promoter region and NR1I2-rs10934498 
polymorphism, prior to admission to this sub-study. Genotyping is not required for patients 
who have a known UGT1A1 status from prior testing. 
In Cycle 1 of the sub-study, irinotecan and LV will be administered concurrently on Day 1. On 
Day 8, NUC-3373 and LV will be administered sequentially. On Day 15, 4 patients (Group A) 
will first be administered irinotecan concurrently with LV, followed by NUC-3373. The 
remaining 4 patients (Group B) will first be administered NUC-3373, followed by irinotecan 
concurrently with LV. On Day 22, NUC-3373 and LV will be administered sequentially. On 
Cycle 2 Day 1, the infusion sequence will be reversed in a cross-over fashion whereby patients 
in Group A will first be administered NUC-3373, followed by irinotecan concurrently with LV 
and patients in Group B will first be administered irinotecan concurrently with LV, followed 
by NUC-3373. Patients will be alternately assigned to Group A or Group B. The doses of 
NUC-3373 and irinotecan used in the sub-study will be the recommended doses determined in 
Arm 2b.  
 
C1D1 
C1D8 
C1D15 
C1D22 
C2D1 
Group A 
Irinotecan + LV 
LV  NUC-
3373 
Irinotecan + LV 
 NUC-3373 
LV  NUC-
3373 
NUC-3373  
Irinotecan + LV 
Group B 
Irinotecan + LV 
LV  NUC-
3373 
NUC-3373  
Irinotecan + LV 
LV > NUC-
3373 
Irinotecan + LV 
 NUC-3373 
Blood samples will be collected for plasma PK analysis on Cycle 1 Day 1, Cycle 1 Day 8, 
Cycle 1 Day 15, Cycle 1 Day 22, and Cycle 2 Day 1. In addition, Holter ECG assessments will 
be performed on Cycle 1 Day 8 and Cycle 1 Day 22 during infusion and up to 24 hours post-
infusion. 
Patients enrolled in the PK sub-study will be considered evaluable for PK endpoints if they 
have received planned study treatment and had PK assessments up to at least C1D15. If patients 
discontinue study treatment or require dose modifications before C1D15, they will be 
considered non-evaluable and will be replaced.  Following this, patients will continue on the 
treatment schedule outlined for Arm 2b.  
3.2. 
Rationale for the NUC-3373 Dose Selected 
The safety of NUC-3373 as a single agent at doses ranging from 125 to 3250 mg/m2 
administered on Days 1, 8, 15 and 22 of a 28-day schedule has been studied in the NuTide:301 
study as described in Section 1.5. This study also included a Q2W schedule and doses of 1500 
to 2500 mg/m2 administered on Days 1 and 15 of a 28-day schedule have been evaluated. 
Enrolment to this study has completed and the final results are being collated and analysed. 
Four patients experienced DLTs. In the 500 mg/m2 Q1W and 1875 mg/m2 Q1W cohorts, DLTs 

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of Grade 3 transaminases increased were reported. In the 3250 mg/m2 Q1W cohort, two DLTs 
were reported, one DLT of Grade 2 headache and one DLT of Grade 3 transient hypotension 
(drop in blood pressure for <5 minutes). Based on these findings, the MTD for single-agent 
NUC-3373 was determined to be 2500 mg/m2 Q1W. The DSMC for the NuTide:301 study has 
determined that NUC-3373 as evaluated to date is safe and well-tolerated in patients with 
advanced solid malignancies.  Based on safety data from the NuTide:301 study and because 
the 1500 mg/m2 dose has been shown to be safe when administered on Days 1 and 15 (Q2W) 
and when administered more frequently on Days 1, 8, 15 and 22 (Q1W), this dose was selected 
for all arms of Part 1.  
For Part 2, NUC-3373 + LV will be given in combination with oxaliplatin and irinotecan at 
doses standardly used in the FOLFOX and FOLFIRI regimens.  The initial dose of NUC-3373 
to be administered on a Q1W basis with oxaliplatin or irinotecan in Arm 2a and Arm 2b was 
determined on the basis of safety data collected in Part 1 (see Section 3.4) and additional data 
collected in NuTide:301.   
For Part 3, the NUC-3373 dose + LV with oxaliplatin selected as the NUFOX regimen and the 
NUC-3373 dose + LV with irinotecan selected as the NUFIRI regimen in Part 2 will be 
administered in combination with bevacizumab or cetuximab. For patients in the maintenance 
cohort, the NUC-3373 dose + LV selected in Part 1 (2500 mg/m2) will be administered in 
combination with bevacizumab. 
3.3. 
Study Treatment 
This is a three-part, multi-cohort combination chemotherapy study.  Study treatments given in 
each arm are described below. Patients may continue to receive NUC-3373 and the 
combination agent(s) until documentation of radiological disease progression using RECIST 
v1.1 or unacceptable toxicity.  Treatment cycles are 28 days in duration.  
Protocol-specific guidelines for NUC-3373 dosage and administration are provided in detail in 
Section 8.3. Guidelines for protocol-specific dose modifications and discontinuations of 
NUC-3373 are provided in Section 9. For patients experiencing toxicity related to NUC-3373 
in NUFOX and NUFIRI cohorts, initially the NUC-3373 dose modification guidelines in 
Section 9 should be followed. Schedule modifications for the other agents (LV, oxaliplatin, 
irinotecan, VEGF pathway inhibitors, EGFR inhibitors) will be in accordance with their 
Respective Prescribing Information or standard local practice, unless safety concerns emerge 
regarding dosing as determined by the DSMC.   
The sections below provide suggested administration times and order for each of the 
combination agents; however, each administration in Parts 1, 2 and 3 of the study may be 
modified based on emerging safety and PK data (in line with local guidelines/relevant 
Prescribing Information) with agreement from the DSMC.  
It is suggested that NUC-3373 at 1500 mg/m2 is infused over 120 minutes. The infusion 
duration for lower and higher doses of NUC-3373 should be adjusted relative to the 
1500 mg/m2 dose (e.g., a 25% increase in dose requires an approximately 25% increase in 
infusion duration). 

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3.3.1 Part 1 (≥3rd-line and combination chemotherapy ineligible patients) 
3.3.1.1 Arm 1a (≥3rd-line patients) 
NUC-3373 was administered by IV infusion at 1500 mg/m2 over 120 minutes followed by a 
14-day washout period. Thereafter, on Days 1 and 15 of 28-day cycles, LV was administered 
by IV infusion at 400 mg/m2 over 120 minutes, followed by NUC-3373 administration by IV 
infusion at the cohort-prescribed dose level.  
3.3.1.2 Arm 1b (≥3rd-line patients) 
On Day 1, LV was administered by IV infusion at 400 mg/m2 over 120 minutes, followed by 
NUC-3373 infusion at 1500 mg/m2 over 120 minutes.  LV was not administered again in 
Arm 1b.  After a 14-day washout period, NUC-3373 was administered on Days 1 and 15 of 
28-day cycles by IV infusion at the cohort-prescribed dose level.   
3.3.1.3 Arm 1c (≥3rd-line patients) 
On Days 1, 8, 15 and 22 of 28-day cycles, LV was administered by IV infusion at 400 mg/m2 
over 120 minutes, followed by NUC-3373 administration by IV infusion at the 
cohort-prescribed dose level.   
3.3.1.4 Arm 1d (combination chemotherapy ineligible patients) 
On Days 1, 8, 15 and 22 of 28-day cycles, LV will be administered by IV infusion at 400 mg/m2 
over 120 minutes, followed by NUC-3373 administration by IV infusion at 2500 mg/m2 over 
200 minutes. 
3.3.1.5 NUC-3373 Dosing for Part 1 
It was anticipated that 1500 mg/m2 would be the starting dose for all arms in Part 1 and is noted 
as Dose Level 1 in Table 6.  Other dose levels as described in Table 6 may have been evaluated 
if recommended by the DSMC.  
If cohorts at additional dose levels were opened, these were to utilise a modified 3+3 design in 
which a fourth patient may have been added to each initial 3-patient cohort to account for a 
patient that became unevaluable for DLT evaluation for any reason other than safety. There 
was to be a 7-day observation period between treatment of the first patient and treatment of 
subsequent patients in a cohort.  
Table 6 
Anticipated dose levels of NUC-3373 to be evaluated in Part 1 
 
≥3rd-line patients 
Dose 
Level* 
NUC-3373 dose (mg/m2)  
Days 1 and 15 
Arms 1a and 1b 
NUC-3373 dose (mg/m2)  
Days 1, 8, 15 and 22 
Arm 1c 
 -1 
1000 
1250 
1 
1500 
1500 
2 
2000 
1750 
3 
2500 
2000 
4 
3000 
2250 
* Additional dose levels could be explored if necessary 
 

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3.3.2 Part 2  
The order of administration of each of the agents in Part 2 may be modified with approval from 
the DSMC, so that NUC-3373 + LV is infused first followed by either oxaliplatin (Arms 2a 
and 2c) or irinotecan (Arms 2b and 2d). Alternate infusion parameters may be implemented 
with approval from the DSMC. 
3.3.2.1 Dose Escalation (≥3rd-line patients) 
In the NUFOX and NUFIRI dose escalation cohorts, patients will receive NUC-3373 + LV 
Q1W combined with the standard dose and schedule of oxaliplatin and irinotecan. 
Arm 2a 
NUC-3373 + LV will be administered Q1W and oxaliplatin will be administered Q2W in 
28-day cycles, as outlined in Table 7. 
Table 7 
Study treatment in Arm 2a 
Infusion order 
Infusion duration 
D1 
D8 
D15 
D22 
LV (400 mg/m2)a 
120 minsa 
X 
X 
X 
X 
Oxaliplatin (85 mg/m2)a 
X 
 
X 
 
NUC-3373 (cohort prescribed dose level) 
120 minsb 
X 
X 
X 
X 
aLV and oxaliplatin to be administered concurrently  
bSuggested duration, refer to Pharmacy Manual 
 It is anticipated that 1500 mg/m2 will be the starting dose in the first dose administration cohort 
for Arm 2a and is noted as ‘Dose Level 1’ in Table 8.  The starting dose will not be higher than 
the MTD established in Part 1c. Based on a clinical study of NUC-3373 (NuTide:301, EudraCT 
2015-002250-13, NCT02723240), alternate and/or additional dose levels may be considered 
and implemented upon recommendation of the DSMC.   
Table 8 
Anticipated dose levels of agents to be evaluated in Arm 2a 
Dose Level* 
NUC-3373 (mg/m2) 
Days 1, 8, 15 and 22 
Leucovorin (mg/m2) 
Days 1, 8, 15 and 22 
Oxaliplatin (mg/m2)** 
Days 1 and 15 
-1 
1250 
400 
85 
1 
1500 
400 
85 
2 
1750 
400 
85 
3 
2000 
400 
85 
4 
2250 
400 
85 
* Additional dose levels may be explored if necessary 
** Alternative dose levels of oxaliplatin may be explored based on PK analyses and safety observations 
Arm 2b 
NUC-3373 + LV will be administered Q1W and irinotecan will be administered Q2W in 
28-day cycles, as outlined in Table 9. 

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Table 9 
Study treatment in Arm 2b 
Infusion ordera 
Infusion duration 
D1 
D8 
D15 
D22 
LV (400 mg/m2)b 
120 minsc 
X 
X 
X 
X 
Irinotecan (180 mg/m2)b   
X 
 
X 
 
NUC-3373 (cohort prescribed dose level) 
120 minsd 
X 
X 
X 
X 
aThe infusion order may change as a result of emerging PK or safety data (refer to the PK Manual for further 
information) 
bLV and irinotecan to be administered concurrently  
cThe infusion duration for irinotecan may be changed to 90 mins based on emerging data 
dSuggested duration, refer to Pharmacy Manual 
It is anticipated that 1500 mg/m2 will be the starting dose in the first dose administration cohort 
for Arm 2b and is noted as Dose Level 1 in Table 10.  The starting dose will not be higher than 
the MTD established in Part 1c. Based on a clinical study of NUC-3373 (NuTide:301, EudraCT 
2015-002250-13, NCT02723240), alternate and/or additional dose levels may be considered 
and implemented upon recommendation of the DSMC.   
Table 10 
Anticipated dose levels of NUC-3373 to be evaluated in Arm 2b 
Dose Level* 
NUC-3373 (mg/m2) 
Days 1, 8, 15 and 22 
Leucovorin (mg/m2) 
Days 1, 8, 15 and 22 
Irinotecan (mg/m2)** 
Days 1 and 15 
-1 
1250 
400 
180 
1 
1500 
400 
180 
2 
1750 
400 
180 
3 
2000 
400 
180 
4 
2250 
400 
180 
* Additional dose levels may be explored if necessary 
** Alternative dose levels of irinotecan may be explored based on PK analyses and safety observations 
The MTD for NUFIRI has been established in Arm 2b and was determined to be 1500 mg/m2 
NUC-3373 + 400 mg/m2 LV + 180 mg/m2 irinotecan.   
3.3.2.2 Dose Expansion (2nd-/3rd-line patients) 
Following completion of Arms 2a and 2b, expansion cohorts may be initiated at the selected 
dose levels established in the dose escalation phase. The NUFOX and NUFIRI regimens will 
be administered in separate arms of the study (Arm 2c for NUFOX and Arm 2d for NUFIRI). 
Arm 2c 
NUC-3373 + LV will be administered Q1W and oxaliplatin will be administered Q2W in 
28-day cycles, as outlined in Table 11. 
Table 11 
Study treatment in Arm 2c 
Infusion order 
Infusion duration 
D1 
D8 
D15 
D22 
LV (400 mg/m2)a 
120 minsa 
X 
X 
X 
X 
Oxaliplatin (85 mg/m2)a,b 
X 
 
X 
 
NUC-3373 (dose selected in Arm 2a) 
120 minsc 
X 
X 
X 
X 

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aLV and oxaliplatin to be administered concurrently  
bThe oxaliplatin dose may be reduced based on observations in Arm 2a  
cSuggested duration, refer to Pharmacy Manual 
 Arm 2d   
NUC-3373 + LV will be administered Q1W and irinotecan will be administered Q2W in 
28-day cycles, as outlined in Table 12. 
Table 12 
Study treatment in Arm 2d 
Infusion ordera 
Infusion duration 
D1 
D8 
D15 
D22 
LV (400 mg/m2)b 
120 minsc 
X 
X 
X 
X 
Irinotecan (180 mg/m2)b 
X 
 
X 
 
NUC-3373 (1500 mg/m2) 
120 minsd 
X 
X 
X 
X 
aThe infusion order may change as a result of emerging PK or safety data (refer to the PK/PD Manual for 
further information) 
bLV and irinotecan to be administered concurrently  
cThe infusion duration for irinotecan may be changed to 90 mins based on emerging data 
dSuggested duration, refer to pharmacy manual 
For patients experiencing toxicity related to NUC-3373 in the NUFOX and NUFIRI cohorts, 
initially the NUC-3373 dose modification guidelines in Section 9 should be followed. The 
doses of oxaliplatin and irinotecan may be adjusted (through agreement with the DSMC) based 
on, but not limited to, safety and PK data generated in patients receiving treatment with 
NUFOX and NUFIRI regimens. If oxaliplatin or irinotecan-related AEs are observed, dose 
de-escalation should be performed as per the respective Prescribing Information or standard 
local practice. The modified dose of oxaliplatin or irinotecan (in combination with NUC-3373) 
will be assessed in approximately 6 evaluable patients in each arm. 
3.3.3 Part 3 (2nd-line patients and maintenance patients) 
 In Part 3, 2nd-line patients will receive the NUFOX and NUFIRI regimens selected in Part 2 
in combination with bevacizumab. Q1W bevacizumab-containing arms will be opened first. 
Following this, Q2W arms and/or cetuximab combination arms may be opened, depending on 
emerging data. In addition, patients qualifying for maintenance therapy may receive NUC-3373 
in combination with bevacizumab. 
Refer to Section 8.3.3 for detailed guidance on administration of each study drug.  
3.3.3.1 Arm 3a (2nd-line patients) 
NUC-3373, LV and oxaliplatin at dose levels used in Arm 2a will be combined with 
bevacizumab. NUC-3373 and LV will be administered Q1W and oxaliplatin and bevacizumab 
will be administered Q2W.    
3.3.3.2 Arm 3b (2nd-line patients) 
NUC-3373, LV and oxaliplatin at dose levels used in Arm 2a will be combined with 
bevacizumab. NUC-3373, LV, oxaliplatin and bevacizumab will be administered Q2W.    

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3.3.3.3 Arm 3c (2nd-line patients) 
NUC-3373, LV and irinotecan at dose levels used in Arm 2b will be combined with 
bevacizumab. NUC-3373 and LV will be administered Q1W and irinotecan and bevacizumab 
will be administered Q2W.    
3.3.3.4 Arm 3d (2nd-line patients) 
NUC-3373, LV and irinotecan at dose levels used in Arm 2b will be combined with 
bevacizumab. NUC-3373, LV, irinotecan and bevacizumab will be administered Q2W.  
3.3.3.5 Arm 3e (Maintenance patients) 
NUC-3373 (2500 mg/m2 Q1W) + LV (400 mg/m2 Q1W) will be combined with bevacizumab 
and bevacizumab (5 mg/kg Q2W). 
Arm 3f (2nd-line patients) 
NUC-3373, LV and oxaliplatin at dose levels used in Arm 2a may be administered in 
subsequent cetuximab cohorts. NUC-3373 + LV may be administered Q1W or Q2W, 
oxaliplatin will be administered Q2W and cetuximab will be administered Q1W 
3.3.3.6 Arm 3g (2nd-line patients) 
NUC-3373, LV and irinotecan at dose levels used in Arm 2b may be administered in 
subsequent cetuximab cohorts. NUC-3373 + LV may be administered Q1W or Q2W, 
irinotecan will be administered Q2W and cetuximab will be administered Q1W.  
In all bevacizumab-containing arms, NUC-3373 dose adjustments may occur depending on 
emerging data. 
Panitumumab combination arms may also be opened (~10 2nd-line patients), depending on 
emerging data. 
Cohorts of rapid progressors may also be opened (~10 patients), depending on emerging data. 
3.3.4 PK sub-study 
Patients participating in the PK sub-study will receive NUC-3373, LV and irinotecan, as 
outlined in Table 13. 
Table 13 
Study treatment in PK sub-study 
Infusion order 
Infusion duration 
C1D1 
C1D8 
C1D15c 
C1D22 
C2D1c 
(29 days 
after start 
of 
treatment) 
LVa 
120 minsa 
X 
X 
X 
X 
X 
Irinotecana,   
90 minsa 
X 
 
X 
 
X 
NUC-3373 
120 minsb 
 
X 
X 
X 
X 
aLV and irinotecan to be administered concurrently  
bSuggested duration, refer to Pharmacy Manual 
cPatients will be alternately assigned to two groups (Group A and Group B) for treatment on Cycle 1 Day 15 
and Cycle 2 Day 1 (29 days after the start of treatment) and will receive the study treatments in an order that 
has been pre-specified for each group (refer to Section 7.2.1 for details) 
Patients enrolled in the PK sub-study will be considered evaluable for PK endpoints if they have received 
planned study treatment and had PK assessments up to at least C1D15. If patients discontinue study treatment 
or require dose modifications before C1D15, they will be considered non-evaluable and will be replaced.   

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Following this, patients will continue on the treatment schedule outlined for Arm 2b. 
3.4. 
Dose Escalation Guidelines 
In those arms in which dose escalation is considered (Arm 1a, Arm 1b, Arm 1c, Arm 2a, and 
Arm 2b), dose escalation decisions will be made according to the dose escalation guidance 
rules in Table 14 when 3 patients in a dosing cohort have completed the 28-day DLT evaluation 
period or been discontinued due to documentation of a DLT prior to completing the initial 
28-day DLT evaluation period cycle.  To be evaluable for DLT, a patient must have received 
NUC-3373 and any assigned combination agent(s) in accordance with the arm to which the 
patient is assigned, have completed the 28-day safety evaluation requirements, and must have 
- 
Either received 75% or more of the specified dose of each agent during the DLT 
evaluation period 
or 
- 
experienced a DLT in the assessment period 
Dose escalation decisions will occur based on review of available safety information obtained 
during the 28-day DLT period, including AEs (regardless of causality), laboratory safety data, 
vital signs and ECG data.  Emerging safety data for patients who continue treatment beyond 
Cycle 1 will also be reviewed.  
Table 14 
Dose escalation guidance rules 
Number of Patients with 
DLT at a Given Dose Level 
Escalation Decision Rule 
0 out of 3 patients (0 out of 4 
in modified 3+3) 
Dose is tolerable 
≥1 out of 3 patients 
Expand cohort, if needed, to include 6 patients. 
• If only 1 out of 6 has DLT, dose is tolerable  
• If ≥ 2 have DLTs, dose is not tolerable and lower 
dose cohort should be explored 
≥2 out of 3-6 patients 
This dose level will be declared a non-tolerated dose and 
a lower dose cohort should be explored 
In the case of a tolerable dose being established, either alone or in combination, the DSMC will 
decide whether to explore a higher dose level or whether this dose is the recommended dose of 
NUC-3373 for the combination.   
At least 6 patients are required for the dose to be declared as the MTD; therefore, additional 
patients may need to be enrolled. 
Patients who withdraw from study treatment prior to the end of Cycle 1, due to a DLT, will not 
be replaced. Patients who withdraw for other reasons may be replaced.  
3.4.1 Definition of Dose-Limiting Toxicity 
DLT is defined as any of the following occurring during the first 28-day treatment cycle that 
are not due to CRC or to a known concurrent medical condition and are judged as clinically 
significant and related to study treatment. 
• Grade 4 neutropaenia (absolute neutrophil count [ANC] <0.5x109/L) that persists 
for more than 7 days 

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• Febrile neutropaenia (ANC <1000/mm3 with a single temperature of >38.3°C 
[101°F] or a sustained temperature of ≥38°C [100.4°F] for >1 hour) 
• Grade 3 thrombocytopaenia (platelets <50.0x109/L) with bleeding complications 
requiring platelet transfusions or that persists for more than 7 days  
• Grade 4 thrombocytopaenia 
• Grade 4 anaemia unexplained by underlying disease 
• Grade 5 haematological toxicity 
• Grade 4 diarrhoea or vomiting that persists despite optimal medical management 
• Grade 3 or greater aspartate aminotransferase (AST)/alanine aminotransferase 
(ALT) elevation (exceptions may be made for transient [<7 days] Grade 3 
elevations of AST/ALT in the presence of known liver metastases and without 
evidence of other hepatic injury, if agreed by the treating physician and the DSMC) 
•  Grade 2 or greater AST/ALT elevation and Grade 2 or greater bilirubin elevation 
(exceptions may be made for transient [<7 days] elevations of AST/ALT and 
bilirubin in the presence of known liver metastases without evidence of other 
hepatic injury, if agreed upon by the treating physician and the DSMC) 
• Any prolonged toxicity that does not resolve to ≤ Grade 1 or baseline within 21 days 
of dose interruption 
• Any other non-haematological toxicity Grade ≥3 except for: 
- 
Alopecia  
- 
Grade 3 nausea, vomiting, or diarrhoea events that resolve within 72 hours with 
anti-emetic or anti-diarrhoeal therapy 
3.5 Duration of Patient Participation 
Patients may continue to receive NUC-3373 in accordance with the dosing regimen (schedule 
and specific combination) to which they were assigned until the occurrence of radiological 
disease progression by RECIST v1.1 or unmanageable drug-related AEs despite optimal 
medical management or dose or schedule modification. Patients may also decline treatment at 
any time for any reason, or they may meet any of the other reasons for treatment withdrawal 
defined in Section 6.1. Reasons for treatment discontinuation must be captured in the patient 
medical record and on the Treatment Discontinuation page of the case report form (CRF). 
Should a patient discontinue treatment without radiological evidence of disease progression, 
the patient should continue to undergo tumour assessment every 8 weeks from Cycle 1 Day 1 
until such time as progression can be documented, a new treatment is initiated, or death. 
All patients will be followed up until withdrawal of consent, lost to follow-up, death, or the 
overall end of study has been reached (defined in Section 3.6), whichever occurs first. 
3.6 Study Completion 
The study will be considered complete when all evaluable patients in opened arms have 
exhibited radiological disease progression or 12 months have elapsed since the final patient 
was enrolled (whichever occurs first, unless the study is terminated early on the 
recommendation of the DSMC or decision of the Sponsor), and it is determined that no further 
arms should be opened based on emerging data.   

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4 
PATIENT SELECTION 
4.1  
Inclusion Criteria 
To be enrolled in this study, patients must meet the following criteria during the Screening 
period: 
All patients 
1. Provision of written informed consent 
2. Have histological confirmation of CRC with evidence of locally advanced/unresectable 
or metastatic disease 
3. Age ≥18 years 
4. Life expectancy of ≥12 weeks  
5. Eastern Cooperative Oncology Group (ECOG) Performance status 0 or 1 
6. Measurable disease as defined by RECIST v1.1 
7. Known RAS and BRAF status. Patients with wild-type KRAS tumours who are to be 
enrolled to a cohort that does not contain an EGFR pathway inhibitor (Arms 2a, 2b, 2c, 
2d, 3a, 3b, 3c, 3d and 3e) must have received prior treatment with an EGFR 
inhibitor, unless this was not standard of care according to relevant region-specific 
treatment recommendations. Patients with BRAF V600E mutant tumours should have 
received prior treatment with encorafenib in combination with an EGFR 
inhibitor, unless this was not standard of care according to relevant region-specific 
treatment recommendations 
8. Adequate bone marrow function as defined by: ANC ≥1.5×109/L, platelet count 
≥100×109/L (with no evidence of bleeding), and haemoglobin ≥9 g/dL 
9. Adequate liver function, as defined by: serum total bilirubin ≤1.5×upper limit of normal 
(ULN), AST and ALT ≤2.5×ULN (or ≤5×ULN if liver metastases are present) 
10. Adequate renal function assessed as serum creatinine <1.5×ULN or glomerular 
filtration rate ≥50 mL/min. This criterion does not apply to the combination 
chemotherapy ineligible patient subgroup (Arm 1d); please refer to specific criteria for 
this subgroup below 
11. Serum albumin ≥3 g/dL 
12. For the cohort in which the patient will participate, there are no contra-indications to 
receiving the approved partner combination drugs 
13. Ability to comply with protocol requirements 
14. Female patients of child-bearing potential must have a negative serum pregnancy test 
within 7 days prior to the first study drug administration. This criterion does not apply 
to patients who have had a previous hysterectomy or bilateral oophorectomy.  Male 
patients and female patients of child-bearing potential must agree to practice true 
abstinence (defined in Section 10.3.1) or to use two highly effective forms of 
contraception, one of which must be a barrier method. These forms of contraception 
must be used from the time of signing consent, throughout the treatment period, and for 
6 months following the last dose of any study medication. Oral or injectable 
contraceptive agents cannot be the sole method of contraception 

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15. Patients must have been advised to take measures to avoid or minimise exposure to UV 
light for the duration of study participation and for a period of 4 weeks following the 
last dose of study medication 
16. For patients receiving oxaliplatin:  Male patients must have been offered advice on 
and/or sought counselling for conservation of sperm prior to the first dose of study 
medication 
In addition to meeting the criteria above for all patients, the following criteria must be met for 
each patient population: 
≥3rd-line patients 
1. Must have received at least two prior lines of therapy for locally advanced or metastatic 
CRC, including one fluoropyrimidine plus oxaliplatin containing regimen and one 
fluoropyrimidine plus irinotecan containing regimen. Previous treatment with standard 
of care chemotherapy regimens in combination with molecular targeted therapies (e.g., 
therapies including VEGF and EGFR pathway inhibitors and immuno-oncology agents) 
is permitted. Patients who have received FOLFOXIRI-based regimens in 1st- and/or 
2nd-line settings may also be included 
2. Patients in Part 2 of the study who are to receive NUFOX regimens should be suitable 
for re-challenge with an oxaliplatin-based regimen  
3. Patients in Part 2 of the study who are to receive NUFIRI regimens should be suitable 
for re-challenge with an irinotecan-based regimen 
2nd-/3rd-line patients 
1. Must have received at least one, but no more of two, prior lines of fluoropyrimidine-
containing therapy in combination with oxaliplatin and/or irinotecan for locally 
advanced or metastatic CRC. Previous treatment with standard of care chemotherapy 
regimens in combination with molecular targeted therapies (e.g., therapies including 
VEGF and EGFR pathway inhibitors and immuno-oncology agents) is permitted. 
Patients who have received FOLFOXIRI-based regimens in 1st- and/or 2nd-line settings 
may also be included. 3rd-line patients enrolled to Arms 2c and 2d must have received 
prior bevacizumab treatment, unless ineligible or unless bevacizumab was not standard 
of care according to relevant region-specific treatment recommendations 
2. Patients in Part 2 of the study who are to receive NUFOX regimens should be suitable 
for re-challenge with an oxaliplatin-based regimen  
3. Patients in Part 2 of the study who are to receive NUFIRI regimens should be suitable 
for re-challenge with an irinotecan-based regimen 
Combination chemotherapy ineligible patients 
1. Patients may have received one prior line of fluoropyrimidine-containing therapy for 
locally advanced or metastatic CRC   
2. Ineligible to receive combination therapy for locally advanced or metastatic CRC, as 
defined by the presence of one or more of the following criteria: 
a. Dependency for daily activities due to comorbidities (different to deterioration due 
to cancer) 
b. Previous history of three or more of the following comorbidities (controlled or 
uncontrolled by treatments): 

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i. 
Congestive heart failure 
ii. 
Other chronic cardiovascular disease 
iii. 
Chronic obstructive pulmonary disease 
iv. 
Cerebrovascular disease 
v. 
Peripheral neuropathy  
vi. 
Chronic renal failure 
vii. 
Arterial hypertension 
viii. 
Diabetes mellitus 
ix. 
Systemic vasculitis 
x. 
Severe arthritis 
c. At least one of the following geriatric features: 
i. 
Age >75 years 
ii. 
Faecal or urinary incontinence  
iii. 
Spontaneous bone fractures 
iv. 
Mild or moderate dementia 
v. 
Frequent falls 
3. Creatinine clearance of >30 mL/min 
Rapid progressors  
1. Must have received no more than two prior lines of fluoropyrimidine-containing 
therapy in combination with oxaliplatin and/or irinotecan for locally advanced or 
metastatic CRC. Previous treatment with standard of care chemotherapy regimens in 
combination with molecular targeted therapies (e.g., therapies including VEGF and 
EGFR pathway inhibitors and immuno-oncology agents) is permitted. Patients who 
have received FOLFOXIRI- based regimens in 1st- and/or 2nd-line settings may also 
be included 
2. Must have had tumour progression ≤3 months of starting the last fluoropyrimidine-
containing regimen 
3. Patients who are to receive NUFOX regimens should be suitable for re-challenge with 
an oxaliplatin-based regimen  
4. Patients who are to receive NUFIRI regimens should be suitable for re-challenge with 
an irinotecan-based regimen 
2nd-line patients 
1. Must have received one prior line of fluoropyrimidine-containing therapy in 
combination with oxaliplatin and/or irinotecan for locally advanced or metastatic CRC. 
Previous treatment with standard of care chemotherapy regimens in combination with 
molecular targeted therapies (e.g., therapies including VEGF and EGFR pathway 
inhibitors and immuno-oncology agents) is permitted. Previous treatment with triplet 
chemotherapy-based regimens is allowed (i.e., FOLFOXIRI) 
Maintenance patients 
1. Must have received at least 12 weeks of 1st-line standard of care therapy for locally 
advanced or metastatic CRC and achieved at least stable disease 
2. Eligible for maintenance therapy 

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4.2 
Exclusion Criteria 
Potential patients who meet any of the following criteria at Screening will be excluded from 
the study: 
All patients 
1. Prior history of hypersensitivity or current contra-indications to 5-FU or capecitabine  
2. Prior history of hypersensitivity or current contra-indication to any of the combination 
agents required for the study arm to which the patient is assigned  
3. History of allergic reactions attributed to components of the NUC-3373 drug product 
formulation (Kolliphor ELP, super refined polysorbate 80, dimethylacetamide [DMA]) 
4. Symptomatic central nervous system or leptomeningeal metastases 
5. Symptomatic ascites, ascites currently requiring drainage procedures or ascites 
requiring drainage over the prior 3 months 
6. Chemotherapy, radiotherapy (other than a short cycle of palliative radiotherapy [e.g., 
for bone pain]*), immunotherapy or exposure to another investigational agent within 
28 days (or five times the half-life for a biological or molecular targeted agent or three 
times the half-life for an immunotherapy agent) of first administration of NUC-3373: 
• For nitrosoureas and mitomycin C, within 6 weeks of first administration of 
NUC-3373 
• For hormone or biological therapy, within 14 days of first administration of 
NUC-3373 
• Corticosteroid treatment is allowed if not more than stable daily dosing of 10 mg 
prednisolone (or steroid equivalent) 
* Palliative radiotherapy during participation in the study is permitted, but should not 
include a target lesion 
7. Residual toxicities from prior chemotherapy or radiotherapy which have not regressed 
to Grade ≤1 severity (CTCAE v5.0), except for alopecia. In cohorts not containing 
oxaliplatin, residual Grade 2 neuropathy is allowed  
8. Patients who have a history of another malignancy diagnosed within the past 5 years, 
with the exception of adequately treated non-melanoma skin cancer, curatively treated 
carcinoma in situ 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 there is no evidence of recurrence 
9. Presence of an active bacterial or viral infection (including SARS-CoV-2, Herpes 
Zoster or chicken pox), known Human Immunodeficiency Virus positive or known 
active hepatitis B or C 
10. Presence of any uncontrolled concurrent serious illness, medical condition or other 
medical history, including laboratory results, which, in the Investigator’s opinion, 
would be likely to interfere with the patient’s ability to participate in the study or with 
the interpretation of the results, including any of the following: 

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a. Congestive heart failure (New York Heart Association Class III or Class IV) 
b. Myocardial infarction within 6 months of the first dose of study medication  
c. Unstable or poorly controlled angina pectoris 
d. Complete left bundle branch, bifascicular block or other clinically significant 
abnormal ECG finding 
e. History of or current risk factor for torsades de pointes (e.g., heart failure, 
hypokalaemia, or a family history of long QT syndrome)   
f. History of severe skin reactions 
g. History of severe ocular disorders 
h. Interstitial pneumonitis or pulmonary fibrosis 
11. Any condition (e.g., known or suspected poor compliance, psychological instability, 
geographical location, etc.) that, in the judgment of the Investigator, may affect the 
patient’s ability to sign the informed consent and undergo study procedures 
12. Currently pregnant, lactating or breastfeeding 
13. QTc interval >450 milliseconds for males and >470 milliseconds for females 
14. Required concomitant use of drugs known to prolong QT/QTc interval 
15. Required concomitant use of strong CYP3A4 inducers or strong CYP3A4 inhibitors, 
or use of strong CYP3A4 inducers within 2 weeks of first receipt of study drug or use 
of strong CYP3A4 inhibitors within 1 week of first receipt of study drug (refer to 
Section 10.3.2) 
16. For patients receiving irinotecan: Use of strong UGT1A1 inhibitors within 1 week of 
first receipt of study drug (refer to Section 10.3.3)  
17. Has received a live vaccination within four weeks of first planned dose of study 
medication 
18. Known DPD or TYMP mutations associated with toxicity to fluoropyrimidines 
19. Use of warfarin and other types of long acting anti-coagulants (such as phenprocoumon 
and anti‑Xa inhibitors with a half‑life of >12 hours) is prohibited within 4 weeks of the 
first dose of study treatment. Patients requiring anti-coagulant treatment should switch 
to low molecular weight heparin or anti‑Xa inhibitors with a half‑life of ≤12 hours 
Patients receiving bevacizumab 
1. Patients with a history of haemoptysis (1/2 teaspoon or more of red blood) 
2. Wound healing complications or surgery within 28 days of starting bevacizumab 
(wound healing must have been fully completed before starting bevacizumab) 
3. Severe chronic wounds, ulcers or bone fracture 
4. Arterial thromboembolic events or haemorrhage within 6 months prior to study entry 
(except for tumour bleeding surgically treated by tumour resection) 
5. Bleeding diatheses or coagulopathy 
6. Receiving full-dose anti-coagulation treatment. Patients who have been on stable doses 
for at least 6 months and have tolerated prior bevacizumab treatment are eligible 
7. Uncontrolled hypertension 
8. Clinically significant coronary heart disease or myocardial infarction within the last 
12 months or high risk of uncontrolled arrhythmia  

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9. Severe proteinuria (nephrotic syndrome) 
10. Acute or subacute ileus, chronic inflammatory bowel disease or chronic diarrhoea  
11. Any contraindication present in the bevacizumab Prescribing Information 
Patients receiving cetuximab or panitumumab 
1. Clinically significant coronary heart disease or myocardial infarction within the last 
12 months or high risk of uncontrolled arrhythmia  
2.  Acute or subacute ileus, chronic inflammatory bowel disease or chronic diarrhea 
3. Hypomagnesaemia or hypokalaemia not controlled by oral therapy 
4. Any contraindication present in the cetuximab or panitumumab Prescribing Information 
Patients participating in the PK sub-study (Arm 2b) 
1. Patients with the UGT1A1 *28/*28 genotype (homozygous poor UGT1A1 
metabolisers) 
4.3 
Waivers to Entry Criteria 
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 the 
Sponsor before responding to the enquiry. 

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5 
STUDY ASSESSMENTS AND PROCEDURES 
Data from all procedures and assessments must be recorded in the patient’s medical record for 
extraction into the CRF. Refer to the Summary Schedule of Events for further details. 
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 or 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 or authorised designee who 
obtains consent 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. 
5.1.1 
Informed Consent for Tumour Tissue Collection 
This study will evaluate biomarkers to potentially identify patients that are likely to respond to 
NUC-3373 or patients who may be resistant to NUC-3373. An optional fresh biopsy of tumour 
tissue is requested during screening and on treatment at either C1D8 or C1D15 for participation 
in this study. If this is not possible, it may be obtained at any time after C1D15 with agreement 
from the Medical Monitor. Patients who do not have easily accessible tumour for biopsy should 
not be put at undue risk for sample collection. Biopsied lesions should not be designated as 
target lesions for the purposes of RECIST v1.1. In addition, patients will be requested to 
consent to providing archival tumour tissue from the time of diagnosis, if available.  
For sampling procedures, storage conditions and shipment instructions, please refer to the 
accompanying Tumour Tissue Laboratory Manual. 
5.2 
Patient Registration and Screening Procedures 
All screening activities must be performed within 28 days of randomisation or first 
protocol-prescribed treatment. A Screening Log must be kept of all patients considered for the 
study (i.e., all those that are included for screening and 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. 

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5.3 
Screening Assessments 
Screening assessments of consented patients will comprise the following: 
• Provision of written informed consent 
• Eligibility confirmation, including histological diagnosis of mCRC, with evidence 
of disease recurrence 
• Recording of demographic data 
• Assessment of medical and surgical history, including prior therapy for CRC 
• Recording of concomitant medication 
• Routine physical examination (including neurological exam), including vital signs. 
Vital signs include measurement of pulse rate, respiratory rate, blood pressure and 
temperature, after the patient has been seated or in the supine position for 5 minutes 
• Height and weight 
• Baseline assessment of symptoms  
• ECOG performance status 
• 12-lead ECG  
o The 12-lead ECGs should be performed in triplicate (keeping the leads in place 
and patient supine during readings) and reviewed by the Investigator or a 
qualified designee for safety and quality 
o 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 
o Digital and 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: white blood cell (WBC) count, differential WBC count, red 
blood cell count (RBC), haemoglobin, haematocrit and platelets 
o Coagulation parameters: prothrombin time/international normalised ratio 
(PT/INR) and activated partial thromboplastin time (aPTT) 
o Chemistry: sodium, potassium, magnesium, urea, 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 pregnancy must 
be performed within 7 days of first dose 
o RAS/BRAF mutation status testing, if unknown  
o Tumour markers (carcinoembryonic antigen [CEA]) 

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o PK sub-study only: genotyping for drug metabolising enzymes and drug 
transporters. Genotyping is not required for patients who have a known 
UGT1A1 status from prior testing.   
• Urinalysis: pH, specific gravity, ketones, leukocytes, protein, glucose, bilirubin, 
urobilirubin and occult blood. Dipstick testing is acceptable 
• Tumour imaging (computed tomography [CT] or magnetic resonance imaging 
[MRI] of thorax, abdomen and pelvis) – performed within 28 days prior to first dose 
of IMP. A recent previously obtained image may be used if obtained within 28 days 
prior to first dose of IMP and images collected meet protocol requirements.  
Biopsied lesions should not be designated as target lesions for the purposes of 
RECIST v1.1  
• Advise the patient to take measures to avoid or minimise exposure to UV light for 
the duration of study participation and for a period of 4 weeks following the last 
dose of study medication 
• For patients receiving oxaliplatin:  Male patients must have been advised on and/or 
sought counselling for conservation of sperm prior to the first dose of study 
medication 
• Patient registration 
• Obtain an archival tumour tissue block, if available 
• For consenting patients with an accessible tumour that is not a target lesion for the 
purposes of the study, obtain a fresh tumour specimen. Patients should not be put at 
undue risk for collection of tumour samples. For sampling procedures, storage 
conditions, and shipment instructions, see the Laboratory Manual 
• Blood samples (optional) for mRNA analyses (e.g., PAX gene) – Refer to 
Section 7.4 for more details 
5.4 
Re-Screening Patients who Fail Screening 
If a patient does not meet the inclusion/exclusion criteria upon first assessment, the patient can 
be re-screened within 14 days of screen failure confirmation being determined.  Patients who 
fail at re-screening are ineligible and may not be re-screened. 
All Screening assessments that result in a patient failing the initial screening process must be 
repeated and confirmed as meeting the inclusion criteria for the study in advance of C0D1 
(Arms 1a and 1b) or C1D1 of all other parts of the study.  During the re-screening process, any 
Screening assessment that will be greater than 28 days from the date taken to C0D1 (Arms 1a 
and 1b) or C1D1 of all other parts of the study must also be repeated. 
5.5 
Evaluations to be Performed during the Study 
Patients participating in the PK sub-study in Part 2 will have the assessments detailed in Section 
5.5.9 during Cycle 1 and on Days 1 and 2 of Cycle 2. Following this, patients in the sub-study 
will continue with the normal assessments described for patients in Arm 2b (Sections 5.5.2 to 
5.5.8).  

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5.5.1 Cycle 0 (Arm 1a and Arm 1b) 
All procedures to be completed prior to dosing except treatment and collection of on-treatment 
and post-treatment blood samples.   
• Recording of new or changes to concomitant medication 
• Routine physical examination (including neurological examination), including vital 
signs. Vital signs include measurement of pulse rate, respiratory rate, blood pressure 
and temperature, after the patient has been seated or in the supine position for 
5 minutes 
• Weight 
• ECOG performance status 
• 12-lead ECGs should be performed prior to infusion of all IMPs  
o At Cycle 0 Day 1 the 12-lead ECGs should also be performed at 30-60 minutes 
post-infusion of NUC-3373  
o The ECGs should be performed in triplicate (keeping the leads in place and 
patient supine during readings) and reviewed by the Investigator or a qualified 
designee for safety and quality 
o 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 
o Digital and 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, haemoglobin, 
haematocrit and platelets 
o Coagulation parameters: PT/INR and aPTT 
o Chemistry: sodium, potassium, magnesium, urea, creatinine, glucose, 
bicarbonate, chloride, uric acid, phosphate, total protein, albumin, adjusted 
calcium, total bilirubin, alkaline phosphatase, AST, ALT and LDH 
o Tumour markers (CEA) 
• Urinalysis: pH, specific gravity, ketones, leukocytes, protein, glucose, bilirubin, 
urobilirubin and occult blood. Dipstick testing is acceptable 
• Urine pregnancy test for women of child-bearing potential. If any urine test result 
is positive, patient dosing will be postponed until the result is confirmed by a serum 
pregnancy test. Any patient with a positive serum test will not be allowed to receive 
any study treatment 
• IV administration of NUC-3373 ± LV: 
o Arm 1a: NUC-3373 only 
o Arm1b: LV + NUC-3373  
• AE recording and causality assessment 

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• Blood samples for PK measurements - Refer to Section 7.2 for more details 
• Part 1 only: Blood samples for PD measurements - Refer to Section 7.3 for more 
details 
• Blood samples (optional) for mRNA analyses (e.g., PAX gene) if not taken at 
Baseline/Screening – Refer to Section 7.4 for more details 
5.5.2 Each cycle, Day 1 
All procedures to be completed prior to dosing except study drug administration and applicable 
PK samples. 
• Recording of new or changes to concomitant medication. 
• Routine physical examination (including neurological examination), including vital 
signs. Vital signs include measurement of pulse rate, respiratory rate, blood pressure 
and temperature, after the patient has been seated or in the supine position for 
5 minutes 
• Weight 
• ECOG performance status 
• 12-lead ECGs should be performed prior to infusion of all IMPs 
o At Cycle 1 Day 1, Cycle 2 Day 1 (Part 3 only) and Cycle 3 Day 1 the 12-lead 
ECGs should also be performed at 30-60 minutes post-infusion of NUC-3373  
o The ECGs should be performed in triplicate (keeping the leads in place and 
patient supine during readings) and reviewed by the Investigator or a qualified 
designee for safety and quality 
o 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 
o Digital and 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, haemoglobin, 
haematocrit and platelets 
o Coagulation parameters: PT/INR and aPTT* 
* Do not repeat for patients enrolled into Arms 1a and 1b 
o Chemistry: sodium, potassium, magnesium, urea, creatinine, glucose, 
bicarbonate, chloride, uric acid, phosphate, total protein, albumin, adjusted 
calcium, total bilirubin, alkaline phosphatase, AST, ALT and LDH 
o Tumour markers (CEA) 
• Urinalysis: pH, specific gravity, ketones, leukocytes, protein, glucose, bilirubin, 
urobilirubin and occult blood. Dipstick testing is acceptable 

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• Urine pregnancy test for women of child-bearing potential. If any urine test result 
is positive, patient dosing will be postponed until the result is confirmed by a serum 
pregnancy test. Any patient with a positive serum test will not be allowed to receive 
any study treatment 
• IV administration of study drug: 
o Arm 1a: NUC-3373 + LV 
o Arm 1b: NUC-3373 alone 
o Arm 1c: NUC-3373 + LV 
o Arm 1d: NUC-3373 + LV 
 
o Arm 2a: NUC-3373 + LV + oxaliplatin 
o Arm 2b: NUC-3373 + LV + irinotecan 
o Arm 2c: NUC-3373 + LV + oxaliplatin 
o Arm 2d: NUC-3373 + LV + irinotecan 
 
o Arm 3a: NUC-3373 + LV + oxaliplatin + bevacizumab 
o Arm 3b: NUC-3373 + LV + oxaliplatin + bevacizumab 
o Arm 3c: NUC-3373 + LV + irinotecan + bevacizumab 
o Arm 3d: NUC-3373 + LV + irinotecan + bevacizumab 
o Arm 3e: NUC-3373 + LV + bevacizumab 
o Arm 3f: NUC-3373 + LV + oxaliplatin + cetuximab 
o Arm 3g: NUC-3373 + LV + irinotecan + cetuximab 
• AE recording and causality assessment. 
5.5.3 Cycle 1 ONLY – Days 1, 2 & 3, and Days 15 & 16  
• Blood samples for PK measurements - Refer to Section 7.2 for more details 
• Arms 1d and 3e only: Urine samples for PK measurements - Refer to Section 7.2 
for more details 
o 0-8 and 8-24* hour or 48-hour urine collection starting from the beginning of 
NUC-3373 infusion (to be collected in 3-6 patients in each arm). For patients 
who provide optional consent, urine collection will continue for 48 hours on 
C1D1 only.  
*Patient to be provided with sample collection kit so they can continue to collect 
urine samples at home. The samples will then be brought back when the patient 
attends for the Day 2 or Day 16 (24 hours) or Day 3 (48 hours) blood samples. For 
logistical reasons (e.g., if the patient lives far away) it may be necessary for the 
patient to stay overnight.  
• Part 1 only: Blood samples for PD measurements (Days 1 and 15 only) - Refer to 
Section 7.3 for more details 

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• Blood samples (optional) for mRNA analyses (e.g., PAX gene) if not taken at 
Baseline/Screening – at Day 1 only in Cycle 1 (Cycle 0 Day 1 in Arms 1a and 1b) 
- Refer to Section 7.4 for more details 
5.5.4 Cycle 1 ONLY – Day 8 (or Day 15) 
• For consenting patients with an accessible tumour that is not a target lesion for the 
purposes of the study, obtain an optional fresh tumour specimen 3-6 hours after 
study drug treatment. Patients should not be put at undue risk for collection of 
tumour samples. For sampling procedures, storage conditions, and shipment 
instructions, see the Laboratory Manual 
5.5.5 Cycle 3 – Days 1 & 15 (C3D1 & C3D15; all cohorts) 
• Blood samples (optional) for mRNA analyses (e.g., PAX gene) – at Day 1 only in 
Cycle 3 - Refer to Section 7.4 for more details 
5.5.6 Each cycle, Day 8 (Q1W dosing cohorts only) 
All procedures to be completed prior to dosing: 
• Recording of new or changes to concomitant medications 
• Routine physical examination (including neurological examination), including vital 
signs. Vital signs include 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 will be performed prior to infusion of all IMPs at all relevant visits  
o The ECGs should be performed in triplicate (keeping the leads in place and 
patient supine during readings) and reviewed by the Investigator or a qualified 
designee for safety and quality 
o 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 
o Digital and 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, haemoglobin, 
haematocrit and platelets 
o Chemistry: sodium, potassium, magnesium, urea, creatinine, glucose, 
bicarbonate, chloride, uric acid, phosphate, total protein, albumin, adjusted 
calcium, total bilirubin, alkaline phosphatase, AST, ALT and LDH 
• IV administration of study drug: 
o Arm 1c: NUC-3373 + LV 
o Arm 1d: NUC-3373 + LV 
 

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o Arm 2a: NUC-3373 + LV 
o Arm 2b: NUC-3373 + LV 
o Arm 2c: NUC-3373 + LV 
o Arm 2d: NUC-3373 + LV 
 
o Arm 3a: NUC-3373 + LV 
o Arm 3c: NUC-3373 + LV 
o Arm 3e: NUC-3373 + LV 
o Arm 3f: NUC-3373 + LV + cetuximab (if administered Q1W) 
o Arm 3g: NUC-3373 + LV + cetuximab (if administered Q1W) 
• AE recording and causality assessment 
5.5.7 Each cycle, Day 15 (all cohorts) 
All procedures to be completed prior to dosing except study drug administration and applicable 
PK samples. 
• Recording of new or changes to concomitant medications 
• Routine physical examination (including neurological examination), including vital 
signs. Vital signs include 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 prior to infusion of all IMPs at all visits.  
o At Cycle 1 Day 15, Cycle 2 Day 15 (Part 3 only) and Cycle 3 Day 15 the 12-lead 
ECGs should be performed at 30-60 minutes post-infusion of NUC-3373.  
o The ECGs should be performed in triplicate (keeping the leads in place and 
patient supine during readings) and reviewed by the Investigator or a qualified 
designee for safety and quality 
o 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  
o Digital and 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 
o Note: Section 5.5.6 above, Cycle 3 Day 15 requires triplicate ECG 
measurements at 30-60 minute post dose, in addition to pre-infusion ECG 
measurements 
• Blood samples drawn for: 
o Haematology: WBC count, differential WBC count, RBC, haemoglobin, 
haematocrit and platelets 

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o Chemistry: sodium, potassium, magnesium, urea, creatinine, glucose, 
bicarbonate, chloride, uric acid, phosphate, total protein, albumin, adjusted 
calcium, total bilirubin, alkaline phosphatase, AST, ALT and LDH 
• IV administration of study drug: 
o Arm 1a: NUC-3373 + LV 
o Arm 1b: NUC-3373 alone 
o Arm 1c: NUC-3373 + LV 
o Arm 1d: NUC-3373 + LV 
 
o Arm 2a: NUC-3373 + LV + oxaliplatin 
o Arm 2b: NUC-3373 + LV + irinotecan 
o Arm 2c: NUC-3373 + LV + oxaliplatin 
o Arm 2d: NUC-3373 + LV + irinotecan 
 
o Arm 3a: NUC-3373 + LV + oxaliplatin + bevacizumab 
o Arm 3b: NUC-3373 + LV + oxaliplatin + bevacizumab 
o Arm 3c: NUC-3373 + LV + irinotecan + bevacizumab 
o Arm 3d: NUC-3373 + LV + irinotecan + bevacizumab 
o Arm 3e: NUC-3373 + LV + bevacizumab 
o Arm 3f: NUC-3373 + LV + oxaliplatin + cetuximab 
o Arm 3g: NUC-3373 + LV + irinotecan + cetuximab 
• AE recording and causality assessment 
• Blood samples for PK measurements (Cycle 1 only) - Refer to Section 7.2 for more 
details 
• Part 1 only: Blood samples for PD measurements (Cycle 1 only) - Refer to 
Section 7.3 for more details 
5.5.8 Each cycle, Day 22 (Q1W cohorts only)  
All procedures to be completed prior to dosing with study drug: 
• Recording of new or changes to concomitant medications 
• Routine physical examination (including neurological examination), including vital 
signs. Vital signs include 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 prior to infusion of all IMPs at all relevant visits 
o The ECGs should be performed in triplicate (keeping the leads in place and 
patient supine during readings) and reviewed by the Investigator or a 
qualified designee for safety and quality 

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o 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 
o Digital and 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, haemoglobin, 
haematocrit and platelets 
o Chemistry: sodium, potassium, magnesium, urea, creatinine, glucose, 
bicarbonate, chloride, uric acid, phosphate, total protein, albumin, adjusted 
calcium, total bilirubin, alkaline phosphatase, AST, ALT and LDH 
• IV administration of study drug: 
o Arm 1c: NUC-3373 + LV 
o Arm 1d: NUC-3373 + LV 
 
o Arm 2a: NUC-3373 + LV 
o Arm 2b: NUC-3373 + LV 
o Arm 2c: NUC-3373 + LV 
o Arm 2d: NUC-3373 + LV 
 
o Arm 3a: NUC-3373 + LV 
o Arm 3c: NUC-3373 + LV  
o Arm 3e: NUC-3373 + LV 
o Arm 3f: NUC-3373 + LV + cetuximab (if administered Q1W) 
o Arm 3g: NUC-3373 + LV + cetuximab (if administered Q1W) 
• AE recording and causality assessment 

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5.5.9 PK sub-study (Part 2, Arm 2b): Cycle 1 and Cycle 2 D1/D2 ONLY 
Patients participating in the PK sub-study in Part 2 will have the assessments detailed in this 
section during Cycle 1 and on Days 1 and 2 of Cycle 2. Following this, patients in the sub-study 
will continue with the normal assessments described for patients in Arm 2b (Sections 5.5.2 to 
5.5.8).  
• Recording of new or changes to concomitant medications (C1D1, C1D8, C1D15, 
C1D22 and C2D1) 
• Routine physical examination (including neurological examination), including vital 
signs. Vital signs include measurement of pulse rate, respiratory rate, blood pressure 
and temperature, after the patient has been seated or in the supine position for 
5 minutes (C1D1, C1D8, C1D15, C1D22 and C2D1) 
• Urinalysis: pH, specific gravity, ketones, leukocytes, protein, glucose, bilirubin, 
urobilirubin and occult blood. Dipstick testing is acceptable (C1D1 and C2D1) 
• Urine pregnancy test for women of child-bearing potential. If any urine test result 
is positive, patient dosing will be postponed until the result is confirmed by a serum 
pregnancy test. Any patient with a positive serum test will not be allowed to receive 
any study treatment (C1D1 and C2D1) 
• ECOG performance status (C1D1 and C2D1) 
• Standard 12-lead ECGs should be performed prior to infusion of all IMPs on C1D1, 
C1D8, C1D15, C1D22 and C2D1. 12-lead ECGs should also be performed at 30-
60 minutes post-administration of all IMPs on C1D1 and C1D15 
o The ECGs should be performed in triplicate (keeping the leads in place and 
patient supine during readings) and reviewed by the Investigator or a 
qualified designee for safety and quality 
o 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 
o Digital and 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 
• Holter ECGs should be performed on C1D8 and C1D22, with continuous readings 
taken over 24 hours, starting from 30 minutes prior to the start of infusion 
o Patients must remain supine for 30 minutes prior to the start of infusion and for 
at least 5 minutes before, and during, the other PK draw timepoints (see 
Section 7.2.1)  
o The ECG data should be transmitted for blinded central review 
• Blood samples drawn for: 
o Haematology: WBC count, differential WBC count, RBC, haemoglobin, 
haematocrit and platelets (C1D1, C1D8, C1D15, C1D22 and C2D1) 
o Chemistry: sodium, potassium, magnesium, urea, creatinine, glucose, 
bicarbonate, chloride, uric acid, phosphate, total protein, albumin, adjusted 

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calcium, total bilirubin, alkaline phosphatase, AST, ALT and LDH (C1D1, 
C1D8, C1D15, C1D22 and C2D1) 
o Coagulation parameters: PT/INR and aPTT (C1D1 and C2D1) 
o Tumour markers (CEA) (C1D1 and C2D1) 
• IV administration of study treatment as follows: 
o Cycle 1 Day 1: LV + irinotecan 
o Cycle 1 Day 8: LV + NUC-3373 
o Cycle 1 Day 15: LV + irinotecan + NUC-3373* 
o Cycle 1 Day 22: LV + NUC-3373 
o Cycle 2 Day 1: LV + NUC-3373 + irinotecan* 
*Patients will be alternately assigned to two groups (Group A and Group B) for 
treatment on Cycle 1 Day 15 and Cycle 2 Day 1 and will receive the study 
treatments in an order that has been pre-specified for each group (refer to Section 
7.2.1 for details). 
• Blood samples for PK measurements will be collected as follows: 
o Cycle 1 Day 1 & Day 2  
o Cycle 1 Day 8 & Day 9  
o Cycle 1 Day 15 & Day 16  
o Cycle 1 Day 22 & Day 23  
o Cycle 2 Day 1 & Day 2  
o Note that for C1D8 and C1D22 when the patient is wearing the Holter monitor, 
the patient must be supine for 30 minutes prior to the start of infusion and for at 
least 5 minutes prior to, and during, the other timepoints when PK draws are 
taken 
The exact time that each PK sample is taken must be recorded 
Refer to Section 7.2.1 for more details. 
• AE recording and causality assessment (C1D1, C1D2, C1D8, C1D9, C1D15, 
C1D16, C1D22, C1D23, C2D1 and C2D2) 
• For consenting patients with an accessible tumour that is not a target lesion for the 
purposes of the study, obtain an optional fresh tumour specimen 3-6 hours after 
study drug treatment on C1D8 or C1D15. Patients should not be put at undue risk 
for collection of tumour samples. For sampling procedures, storage conditions, and 
shipment instructions, see the Laboratory Manual 
5.5.10 Every 8 weeks (±7 days) from Cycle 1 Day 1 until disease progression, initiation 
of a new treatment or death  
• Tumour imaging (CT, or MRI of thorax, abdomen and pelvis) 

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5.5.11 End of Treatment Visit 
The assessments to be performed on discontinuation due to radiological disease progression or 
early treatment discontinuation for other reasons (e.g., withdrawal of consent) are summarised 
below. The End of Treatment (EoT) visit should occur within a minimum of 30 days to a 
maximum of 37 days following the last administration of any study medication. During the 
EoT visit, the following items will be assessed: 
• Recording of new or changes to concomitant medication 
• Routine physical examination (including neurological examination), including vital 
signs. Vital signs include measurement of pulse rate, respiratory rate, blood pressure 
and temperature, after the patient has been seated or in the supine position for 
5 minutes, and temperature 
• Weight 
• ECOG performance status 
• 12-lead ECG  
o The 12-lead ECGs should be performed in triplicate (keeping the leads in place 
and patient supine during readings) and reviewed by the Investigator or a 
qualified designee for safety and quality  
o 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 
o Digital and 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, haemoglobin, 
haematocrit and platelets 
o Coagulation parameters: PT/INR and aPTT 
o Chemistry: sodium, potassium, magnesium, urea, creatinine, glucose, 
bicarbonate, chloride, uric acid, phosphate, total protein, albumin, adjusted 
calcium, total bilirubin, alkaline phosphatase, AST, ALT and LDH 
o Pregnancy testing for women of child-bearing potential 
o Tumour markers CEA 
• Urinalysis: pH, specific gravity, ketones, leukocytes, protein, glucose, bilirubin, 
urobilirubin and occult blood. Dipstick testing is acceptable 
• AE recording and causality assessment 

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5.5.12 Long-Term Follow-Up 
Patients who stop treatment with no evidence of radiological disease progression as defined by 
RECIST v1.1 criteria will continue to receive scans at regular intervals (every 8 weeks 
[±7 days] from C1D1) until disease progression, initiation of a new treatment for CRC, or death 
(whichever comes first) to determine duration of overall response and PFS. 
All patients will be followed up until withdrawal of consent, lost to follow-up, death, or the 
overall end of study has been reached (defined in Section 3.6), whichever occurs first. 
During the COVID-19 pandemic, collection of follow-up data can be performed via a telephone 
call with the patient where possible (e.g., for data regarding concomitant medications, AEs, 
and QoL). The data collected and the follow-up schedule remain as per the schedule of events. 
Patients in follow-up who have not experienced radiological disease progression should 
continue to attend the clinic for planned radiologic scans; however, other follow-up data can 
be collected via telephone to limit patient visits. 

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6 
 PATIENT WITHDRAWAL 
6.1 
End of Treatment 
Patients may continue on study until one of the following occurs: 
• Progressive Disease as defined by RECIST v1.1 criteria. Patients should not 
discontinue NUC-3373 due to clinical signs of progressive disease until it has been 
confirmed by RECIST v1.1 
• Unmanageable toxicity defined as an AE that is considered by the Investigator to 
warrant permanent discontinuation of NUC-3373 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 treatment-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 
• Lack of further clinical benefit or unfavourable risk/benefit profile as judged by the 
Investigator 
• Inter-current illness that prevents further administration of NUC-3373 
• 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, make 
the patient unsuitable for any further treatment under the protocol; note that at the 
Investigator’s discretion, the patient may discontinue treatment with an agent in the 
prescribed combination, other than NUC-3373, without requiring discontinuation 
from the study 
• Patient non-compliance 
• Lost to follow-up 
• Patient withdrawal of consent 
• Sponsor request 
All study procedures outlined for the EoT visit are to be completed 30 days (+7 days) after the 
last dose of study drug. The primary reason for study drug discontinuation is to be recorded in 
the CRF. 

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6.2 
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.  
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. 
6.3 
Patient Evaluability and Replacement 
Enrolment in the dose escalation arms will continue until there are at least 3 (or 6 in the case 
that an arm or dosing cohort is expanded on the basis of an earlier DLT) patients evaluable for 
DLT in each arm or dose cohort within an arm.    
All patients who receive at least one dose of NUC-3373 are considered evaluable for safety 
analysis.  
All patients with measurable disease who undergo at least two cycles of treatment, receive at 
least 75% of planned treatment in that two-cycle period, and undergo a post-treatment objective 
disease assessment will be considered evaluable for response assessment. 
Patients enrolled in the PK sub-study will be considered evaluable for PK endpoints if they 
have received planned study treatment and had PK assessments up to at least C1D15. If patients 
discontinue study treatment or require dose modifications before C1D15, they will be 
considered non-evaluable and will be replaced.  
 

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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 visit. Laboratory tests may be 
performed either on the day of a treatment visit (prior to study drug administration) or during 
the three days prior to a treatment visit. 
7.2 
Pharmacokinetics 
The PK schedule is designed to explore the relationship between the pharmacokinetics of 
NUC-3373, safety, pharmacodynamics and clinical activity. The full set of mandatory PK 
samples must be collected from a minimum of four patients per arm. 
Blood samples will be collected at the following visits:  
• C0D1, C0D2 and C0D3* (Arms 1a and 1b only) 
• Parts 1, 2 and 3: C1D1, C1D2 and C1D3* 
• Parts 1, 2 and 3: C1D15 and C1D16  
* Optional 48-hour PK sample 
PK endpoints will include assessments of, but are not limited to: 
• In plasma: NUC-3373, 5-FU, 5-FUDR, FBAL 
• Part 1 only: In PBMCs: NUC-3373, FUDR-MP, FBAL, 5-FUTP, dTMP, and 
dUMP 
The PK sampling schedule, based on an NUC-3373 infusion duration of 2 hours and 4 hours, 
is summarised in Table 15. 
Collection times for the ‘During NUC-3373 Infusion’ PK samples (Samples 2-4) should be 
adjusted proportionally to the NUC-3373 dose and infusion duration, where Sample 2 is 
collected a quarter of the way through the infusion, Sample 3 halfway through the infusion and 
Sample 4 at the end of the infusion.  

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Table 15 
PK sampling schedule (Main study) 
Sample 
Number 
Sample Collection Time  
(NUC-3373 2-hour infusion) 
Sample Collection Time  
(NUC-3373 4-hour infusion) 
Sample Collection 
Window 
PRIOR TO NUC-3373 INFUSION 
1 
Pre-dose 
Up to 30 minutes prior  
to starting infusion 
DURING NUC-3373 INFUSION 
2 
T0 + 30 minutes 
T0 + 60 minutes 
+/- 5 minutes 
3 
T0 + 60 minutes 
T0 + 120 minutes 
4 
T0 + 120 minutes 
T0 + 240 minutes 
AFTER NUC-3373 INFUSION 
5 
T1 + 15 minutes 
+/- 5 minutes 
6 
T1 + 30 minutes 
7 
T1 + 60 minutes 
8 
T1 + 90 minutes 
9 
T1 + 120 minutes 
+/- 15 minutes 
10 
T1 + 240 minutes 
+ 4 hours / - 15 minutes 
11 
T1 + 24 hours 
+ 4 hours 
12* 
T1 + 48 hours 
• 
T0 = Start of NUC-3373 infusion 
• 
T1 = End of NUC-3373 infusion 
• 
Sample 1, Pre-dose should be collected prior to infusion of all IMPs 
• 
Samples 2, 3, and 4 are triggered by the start time of the infusion and assume a 2-hour or a 4-hour infusion 
duration. Collection times will be modified in alignment with infusion duration changes 
* Sample 12 = Optional 48-hour PK sample 
Urine samples will be collected in Arms 1d and 3e only at the following visits:  
• C1D1, C1D2 and C1D3* 
• C1D15 and C1D16 
* Optional 48-hour urine PK sample 
All urine passed over the first 24 hours after the administration of NUC-3373 on C1D1 and 
C1D15 will be collected on each PK study day. Urine from hour 0 to 8 will be collected in a 
separate container to urine collected between hour 8 and 24. Patients who consent to the 
48-hour PK time point will be asked to collect their urine between hour 24 and 48.  
Patients are to be provided with a sample collection kit so they can continue to collect urine 
samples at home. The samples will then be brought back when the patient attends for the Day 2 
or Day 16 (24 hours) or Day 3 (48 hours) blood samples. For logistical reasons (e.g., if the 
patient lives far away) it may be necessary for the patient to stay overnight.  
Standard PK parameters for each compound of interest will then be derived from the measured 
plasma, PBMC (Part 1 only), and urine concentrations. The PK samples will be processed and 
analysed at a central laboratory. Please refer to the PK Laboratory Manual for details regarding 
PK sample collection, processing and shipping.  

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7.2.1 PK Sub-study 
A PK sub-study may be conducted during Part 2 if emerging data suggest it would be beneficial 
to evaluate the PK relationship between NUC-3373, LV and irinotecan (Figure 5). If 
conducted, an additional 8 patients would be enrolled in the NUFIRI Q1W cohort (Arm 2b). 
Inclusion into this sub-study will also involve individual patient genotyping for drug 
metabolising enzymes and drug transporters to predict irinotecan-related toxicities. Genotyping 
will be performed for each patient using genomic DNA from white blood cells isolated from 
whole blood samples taken during screening. The genomic DNA will be analysed using 
pharmacogenomic protocols specific for individual genotypes for drug metabolising enzymes 
and drug transporters, e.g., TATA box polymorphism of the UGT1A1 promoter region and 
NR1I2-rs10934498 polymorphism, prior to admission to this sub-study (Deyme et al, 2021). 
Genotyping is not required for patients who have a known UGT1A1 status from prior testing.   
 
 
Figure 5 
PK sub-study schema 
 
In Cycle 1 of the sub-study, irinotecan and LV will be administered concurrently on Day 1. On 
Day 8, NUC-3373 and LV will be administered sequentially. On Day 15, 4 patients (Group A) 
will first be administered irinotecan concurrently with LV, followed by NUC-3373. Prior to 
the start of NUC-3373 infusion on Day 15 the 2-hour post-start of irinotecan/LV infusion PK 
sample should be taken, which will also serve as the pre-infusion sample for NUC-3373 PK 
for Group A. The remaining 4 patients (Group B) will first be administered NUC-3373, 
followed by irinotecan concurrently with LV. On Day 15, the 2-hour post-start of NUC-3373 
infusion PK sample should be taken, which will also serve as the pre-infusion sample for 
irinotecan PK for Group B.  
On Day 22, NUC-3373 and LV will be administered sequentially. On Cycle 2 Day 1, the 
infusion sequence will be reversed in a cross-over fashion whereby patients in Group A will 
first be administered NUC-3373, followed by irinotecan concurrently with LV and patients in 
Group B will be first be administered irinotecan concurrently with LV, followed by NUC-3373. 
Prior to the start of irinotecan/LV infusion on Cycle 2 Day 1 the 2-hour post-start of NUC-3373 
PK sample should be taken, which will also serve as the pre-infusion sample for irinotecan PK 
for Group A. Prior to the start of NUC-3373 infusion on Cycle 2 Day 1 the 2-hour post-start of 
irinotecan/LV PK sample should be taken, which will also serve as the pre-infusion sample for 
NUC-3373 PK for Group B. Patients will be alternately assigned to Group A or Group B.  
C1D15
C1D22
C2D1
C1D1
C1D8
Group A
n=4
Group B
n=4
Irino
LV
90 min
NUC
-3373
LV
120 min
NUC
-3373
Irino
LV
NUC
-3373
Irino
LV
NUC
-3373
LV
NUC
-3373
Irino
LV
NUC
-3373
LV
NUC
-3373
LV
Irino
LV
NUC
-3373
Irino
LV
120 min
120 min
120 min
120 min
120 min
120 min
120 min
120 min
120 min
120 min
120 min
120 min
90 min
120 min
90 min
120 min
90 min
120 min
90 min
120 min
90 min
120 min

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Patients enrolled in the PK sub-study will be considered evaluable for PK endpoints if they 
have received planned study treatment and had PK assessments up to at least C1D15. If patients 
discontinue study treatment or require dose modifications before C1D15, they will be 
considered non-evaluable and will be replaced.  
Holter ECG measurements will be performed on C1D8 and C1D22 for patients in the PK 
sub-study, with continuous readings taken over 24 hours, starting from 30 minutes prior to the 
start of infusion. Patients must be supine for 30 minutes prior to the start of infusion and for at 
least 5 minutes prior to, and during, the other timepoints where PK draws are taken (as outlined 
in Figure 6). All Holter ECG data should be transmitted for blinded central review. 
Plasma samples will be collected for PK analysis on Cycle 1 Day 1, Cycle 1 Day 8, Cycle 1 
Day 15, Cycle 1 Day 22, and Cycle 2 Day 1, as detailed in Figure 6.  
The exact time that each PK sample is taken must be recorded. 
Following this, patients will continue on the treatment schedule outlined for Arm 2b.  
Group A 
  
  
  
Timepoints (min post-first infusion) 
 
 
Pre-
dose*
60 mins 
(+/- 5 mins)
120 mins 
(+/- 5 mins)
150 mins 
(+/- 5 mins)
180 mins 
(+/- 5 mins)
250 mins 
(+/- 5 mins)
280 mins 
(+/- 5 mins)
300 mins 
(+/- 5 mins)
360 mins 
(+/- 15 mins)
480 mins 
(+/- 15 mins)
24 hours 
(+/- 2 hours)
C1D1 
Infusion
Irinotecan + LV
 
 
 
 
PK Draw
X
X
X
 
X
X
 
X
X
X
X
C1D8 
Infusion
 
LV
NUC-3373
 
 
 
 
 
PK Draw
X
 
 
 
X
X
X
X
X
X
X
C1D15 
Infusion
Irinotecan + LV
NUC-3373
 
 
 
 
 
PK Draw
X
X
X
 
X
X
X
X
X
X
X
C1D22 
Infusion
 
LV
NUC-3373
 
 
 
 
 
PK Draw
X
 
 
 
X
X
X
X
X
X
X
C2D1 
Infusion
NUC-3373
Irinotecan + LV
 
 
 
PK Draw
X
X
X
X
X
X
 
X
X
X
X
*Pre-dose = up to 30 minutes prior to the administration of irinotecan + LV (C1D1, C1D15) or NUC-3373 (C1D8, C1D22, C2D1) 
Group B 
  
  
  
Timepoints (min post-first infusion) 
 
 
Pre-
dose*
60 mins 
(+/- 5 mins)
120 mins 
(+/- 5 mins)
150 mins 
(+/- 5 mins)
180 mins 
(+/- 5 mins)
250 mins 
(+/- 5 mins)
280 mins 
(+/- 5 mins)
300 mins 
(+/- 5 mins)
360 mins 
(+/- 15 mins)
480 mins 
(+/- 15 mins)
24 hours 
(+/- 2 hours)
C1D1 
Infusion
Irinotecan + LV
 
 
 
 
PK Draw
X
X
X
 
X
X
 
X
X
X
X
C1D8 
Infusion
 
LV
NUC-3373
 
 
 
 
 
PK Draw
X
 
 
 
X
X
X
X
X
X
X
C1D15 
Infusion
NUC-3373
Irinotecan + LV
 
 
 
 
 
PK Draw
X
X
X
X
X
X
 
X
X
X
X
C1D22 
Infusion
 
LV
NUC-3373
 
 
 
 
 
PK Draw
X
 
 
 
X
X
X
X
X
X
X
C2D1 
Infusion
Irinotecan + LV
NUC-3373
 
 
 
PK Draw
X
X
X
 
X
X
X
X
X
X
X
*Pre-dose = up to 30 minutes prior to the administration of irinotecan + LV (C1D1, C2D1) or NUC-3373 (C1D8, C1D15, C1D22) 
Figure 6 
PK sub-study blood sampling schema 
PK endpoints will include plasma assessments of (but are not limited to): 
• NUC-3373, FUDR, NUC-3373 alanine phosphate intermediate  
• Irinotecan, SN-38, SN-38 glucuronide, APC and NPC  

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Standard PK parameters for each compound of interest will then be derived from the measured 
plasma concentrations. The PK samples will be processed and analysed at a central laboratory. 
Please refer to the PK Laboratory Manual for details regarding PK sample collection, 
processing and shipping.  
7.3 
Pharmacodynamics (Part 1 only) 
The PD schedule is designed to explore the relationship between NUC-3373 
pharmacodynamics and clinical activity.  
Blood samples will be collected at the following visits:  
• C0D1 (Arms 1a and 1b only) 
• C1D1 and C1D15 
PD endpoints will include assessments of: 
• Part 1 only: In PBMCs: TS - total, bound and unbound 
The PD sampling schedule is summarised in Table 16. 
Table 16 
PD sampling schedule (Part 1 only) 
Sample Number 
Sample Time  
Sample Collection Window 
PRIOR TO NUC-3373 INFUSION 
1 
Pre-dose 
Up to 30 minutes prior  
to starting infusion 
AFTER NUC-3373 INFUSION 
2 
T1 + 30 minutes 
+/- 5 minutes 
• 
Sample 1, Pre-dose should be collected prior to infusion of all IMPs 
• 
T1 = End of NUC-3373 infusion 
7.4 
Exploratory Biomarkers 
Blood samples (optional) will be collected for mRNA analyses (e.g., PAX gene) at baseline or 
C1D1 pre-dose and at C3D1. 
7.5 
Tumour Tissue Sample Submission 
Tissue specimens will be collected from patients enrolled in the study for exploration of 
pharmacodynamic biomarkers of biological activity and possible relationships between PK 
exposure, PD effects, safety and efficacy. An archival specimen will be collected from 
consenting patients for whom an archival tissue exists; the specimen may be collected at any 
time during the study. An optional fresh tissue specimen also will be collected during the 
screening period and on treatment on C1D8 or C1D15 3-6 hours after study drug infusion in 
consenting patients. The fresh tissue specimen should not be taken from a lesion to be 
designated a target lesion for the purposes of the study. Specific instructions on the collection 
and shipment of tissue samples will be provided in the Tumour Tissue Laboratory Manual.  
7.6 
Labelling and Confidentiality of Biological Samples 
All biological samples (including blood, PBMC and tumour tissue) sent to analytical 
laboratories will be labelled with the study code, patient study number and date/time taken. 
Samples labels must not contain any unique patient identifiers.  

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7.7 
Withdrawal of Consent for Biological Sample Collection or Retention 
A patient may withdraw consent to provide samples or allow their samples to be used for 
research at any time without giving a reason. The Investigator must ensure that their wishes are 
recorded in the medical record and CRF. The clinical research associate should be informed 
accordingly. The Investigator should discuss with patients the valuable use of samples that 
have already been provided and under circumstances where these samples have already been 
processed and anonymised, it would not be possible to destroy such samples. 

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8 
INVESTIGATIONAL MEDICINAL PRODUCTS 
8.1 
NUC-3373 
8.1.1 NUC-3373 Description 
The Drug Product is called ‘NUC-3373 for infusion’ and is presented as a single-dose sterile 
liquid formulation for IV injection of NUC-3373 in a clear glass vial. 
8.1.2 NUC-3373 Supplies and Study Drug Packaging  
‘NUC-3373 for infusion’ will be supplied to the pharmacy of the investigative clinical site in 
10 mL clear glass vials. The vials are packaged in a labelled cardboard outer carton. 
NUC-3373 saline-based formulation is prepared by withdrawing the required volume of 
‘NUC-3373 for infusion’ from the vial and adding it directly to the saline infusion bag. Please 
refer to the dose preparation guidance in the current version of the Pharmacy Manual and the 
Administration Guidelines for further information on the preparation of NUC-3373 
saline-based formulations.  
8.1.3 Handling and Storage of NUC-3373 
‘NUC-3373 for infusion’ must be stored in an appropriately secure investigational pharmacy 
at all times until dispensed for administration to patients on protocol. ‘NUC-3373 for infusion’ 
must be stored between 2-8°C (36-46°F) in a temperature-monitored refrigerated unit. Only 
adequately trained pharmacy staff are permitted to handle ‘NUC-3373 for infusion’. The study 
medication should not be removed from the pharmacy except for the purposes of dispensing to 
the patient for this protocol. Study drug that has been quarantined for any reason must not be 
dispensed or administered to patients. 
If ‘NUC-3373 for infusion’ contacts the skin or the mucous membranes, it should be washed 
immediately and thoroughly. Please refer to the guidance in the current version of the Pharmacy 
Manual for further information on the preparation of NUC-3373 saline-based formulations.  
8.1.4 Preparation of NUC-3373 
As with other cytotoxic substances, applicable local procedures should be used in the 
preparation and administration of ‘NUC-3373 for infusion’. Please refer to the administration 
guidance in the current version of the Pharmacy Manual and Administration Guidelines for 
further information on the preparation of NUC-3373 saline-based formulation. 
Due to known issues regarding DMA and compatibility with polycarbonate, do not use 
polycarbonate syringes or polycarbonate filter needles to withdraw ‘NUC-3373 for infusion’. 
8.1.5 NUC-3373 Administration 
‘NUC-3373 for infusion’ will be administered to each patient based on body surface area (BSA; 
calculated form patient’s height and weight) at baseline and/or height at baseline and weight at 
Day 1 of each cycle based on local standard operating practises. If a patient’s weight increases 
or decreases by ≥10% during the course of the study, the dose of ‘NUC-3373 for infusion’ 
should be re-calculated. 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 case report form (eCRF). 

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Dubois & Dubois BSA calculation: 
BSA (m2) = 0.007184 × Height (cm)0.725 × Weight (kg)0.425 
The duration of infusion of NUC-3373 saline-based formulations should align with the 
guidance provided in Table 17.  Should a decision on dose modification be taken that increases 
or reduces the dose of ‘NUC-3373 for infusion’ administered to the patient, the duration of the 
infusion should also be checked and adjusted in accordance with the guidance provided. 
It is suggested that NUC-3373 at 1500 mg/m2 is infused over 120 minutes. The infusion 
duration for lower and higher doses of NUC-3373 should be adjusted relative to the 
1500 mg/m2 dose (e.g., a 25% increase in dose requires an approximately 25% increase in 
infusion duration), as shown in Table 17. 
Table 17 
NUC-3373 infusion duration guidance 
Dose of NUC-3373 
Minimum Infusion Duration* 
1125 mg/m2 (-25%) 
90 minutes 
1500 mg/m2 
120 minutes 
1875 mg/m2 (+25%) 
150 minutes 
2000 mg/m2 (+33%) 
160 minutes 
2250 mg/m2 (+50%) 
180 minutes 
2500 mg/m2 (+67%) 
200 minutes 
*  - 5 to +15 minute window will be permitted on all infusion durations   
 
8.2 Other IMPs (Agents to be used in Combination with NUC-3373) 
All of the agents to be used in combination with NUC-3373 in the different arms of this study 
are commercially available and should be sourced locally by the Investigative sites. Descriptive 
information for these agents can be found in the package inserts.  These agents should be stored 
according to the manufacturer’s instructions.  Further information can be found in the 
pharmacy manual.  
For VEGF inhibitors, the preferred treatment option is Avastin; however, biosimilars may be 
used after discussion with the Sponsor. For EGFR inhibitors, the preferred treatment options 
are Erbitux (cetuximab) or Vectibix (panitumumab); however, if biosimilars become available, 
their use may be discussed with the Sponsor.     
8.3    Administration of NUC-3373 and other IMPs 
The sections below provide suggested administration times and order for each of the 
combination agents; however, each administration in Parts 1, 2, and 3 of the study may be 
modified based on emerging safety and PK data (in line with local guidelines/relevant 
Prescribing Information) with agreement from the DSMC. 
8.3.1 Part 1 
A total of 21 eligible and consenting ≥3rd-line patients were randomised to either Arm 1a or 
Arm 1b and a further 17 patients were enrolled to each of two dosing cohorts in Arm 1c. 
Arms 1a, 1b, and 1c are now complete. Following this, approximately 10 combination 
chemotherapy ineligible patients will be enrolled to a Q1W administration schedule of 
NUC-3373 plus LV (Arm 1d). Dose adjustments or dose delays are to be implemented within 

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or between cycles based on drug-related toxicities. The dose modification scheme to be 
employed is detailed in Section 9 of this protocol. 
Arm 1a: SINGLE DOSE NUC-3373 / LV + NUC-3373 COMBINATION  
At C0D1:  
• NUC-3373 IV over 120 minutes at an initial dose of 1500 mg/m2  
NUC-3373 monotherapy was given once followed by a 2-week washout period.  
At C1D1 and beyond:  
• LV 400 mg/m2 IV (or equivalent levo-leucovorin) over 120 minutes prior to each 
NUC-3373 infusion on Days 1 and 15 of each 28-day treatment cycle 
• NUC-3373 IV over 120 minutes at an initial dose of 1500 mg/m2 on Days 1 and 
15 of each 28-day treatment cycle 
Arm 1b: SINGLE DOSE NUC-3373 + LV / NUC-3373 MONOTHERAPY  
At C0D1:  
• LV 400 mg/m2 IV (or equivalent levo-leucovorin) over 120 minutes prior to 
NUC-3373 infusion   
• NUC-3373 IV over 120 minutes at an initial dose of 1500 mg/m2  
NUC-3373 + LV was given once followed by a 2-week washout period.  
At C1D1 and beyond:  
• NUC-3373 IV over 120 minutes at an initial dose of 1500 mg/m2 on Days 1 and 
15 of each 28-day treatment cycle 
Arm 1c: NUC-3373 + LV COMBINATION  
At C1D1 and beyond:  
• LV 400 mg/m2 IV (or equivalent levo-leucovorin) over 120 minutes prior to each 
NUC-3373 infusion on Days 1, 8, 15 and 22 of each 28-day treatment cycle 
• NUC-3373 by IV over 120 minutes at an initial dose of 1500 mg/m2 on Days 1, 8, 
15 and 22 of each 28-day treatment cycle 
Starting doses for subsequent cohorts will be determined during the study by the DSMC. 
Arm 1d: NUC-3373 + LV (combination chemotherapy ineligible patients) 
At C1D1 and beyond:  
• LV 400 mg/m2 IV (or equivalent levo-leucovorin) over 120 minutes prior to each 
NUC-3373 infusion on Days 1, 8, 15 and 22 of each 28-day treatment cycle 
• NUC-3373 IV over 200 minutes at a dose of 2500 mg/m2 on Days 1, 8, 15 and 22 
of each 28-day treatment cycle 

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8.3.2 Part 2 
Eligible consenting patients in Part 2 will receive one of the combinations listed below, as 
determined by the Investigator and number of patients enrolled per cohort. Patients will 
continue to receive NUC-3373 + the combination drug(s) until the occurrence of radiological 
disease progression using RECIST v1.1 or unmanageable drug-related AEs despite dose 
modification. Guidelines for dose modifications and discontinuations due to AEs will be 
provided. 
The order of administration of each of the agents in Part 2 may be modified with approval from 
the DSMC, so that NUC-3373 + LV is infused first followed by either oxaliplatin (Arms 2a 
and 2c) or irinotecan (Arms 2b and 2d). Alternate infusion parameters may be implemented 
with approval from the DSMC.  
Arm 2a: NUFOX Dose Escalation Q1W (≥3rd-line patients) 
C1D1 and beyond: 
• LV 400 mg/m2 IV (or equivalent levo-leucovorin) over 120 minutes prior to 
NUC-3373 infusion 
• Oxaliplatin 85 mg/m2 IV over 120 minutes prior to NUC-3373 infusion  
• NUC-3373 IV over 120 minutes at the combination dose as determined at the 
DSMC meeting for Part 1 
NUC-3373 + LV is given on Days 1, 8, 15 and 22 in each 28-day treatment cycle (Q1W). 
Oxaliplatin is given on Days 1 and 15 in each 28-day treatment cycle (Q2W), as per the 
Prescribing Information.  
Arm 2b: NUFIRI Dose Escalation Q1W (≥3rd-line patients) 
C1D1 and beyond: 
• LV 400 mg/m2 IV (or equivalent levo-leucovorin) over 120 minutes prior to 
NUC-3373 infusion 
• Irinotecan 180 mg/m2 IV over 120 minutes prior to NUC-3373 infusion  
• NUC-3373 IV over 120 minutes at the combination dose as determined at the 
DSMC meeting for Part 1 
NUC-3373 + LV is given on Days 1, 8, 15 and 22 in each 28-day treatment cycle (Q1W). 
Irinotecan is given on Days 1 and 15 in each 28-day treatment cycle (Q2W), as per the 
Prescribing Information.  
The MTD for NUFIRI has been established in Arm 2b and was determined to be 1500 mg/m2 
NUC-3373 + 400 mg/m2 LV + 180 mg/m2 irinotecan.   

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PK sub-study (Arm 2b): NUFIRI Q1W  
C1D1: 
• LV (400 mg/m2 IV; or equivalent levo-leucovorin) over 120 minutes concurrently 
with irinotecan (180 mg/m2 IV) over 90 minutes  
C1D8: 
• LV (400 mg/m2 IV; or equivalent levo-leucovorin) over 120 minutes  
• NUC-3373 (1500 mg/m2 IV) over 120 minutes 
C1D15 (Arm A): 
• LV (400 mg/m2 IV; or equivalent levo-leucovorin) over 120 minutes concurrently 
with irinotecan (180 mg/m2 IV) over 90 minutes  
• NUC-3373 (1500 mg/m2 IV) over 120 minutes 
C1D15 (Arm B): 
• NUC-3373 (1500 mg/m2 IV) over 120 minutes 
• LV (400 mg/m2 IV; or equivalent levo-leucovorin) over 120 minutes concurrently 
with irinotecan (180 mg/m2 IV) over 90 minutes  
C1D22: 
• LV (400 mg/m2 IV; or equivalent levo-leucovorin) over 120 minutes  
• NUC-3373 (1500 mg/m2 IV) over 120 minutes 
C2D1 (Arm A): 
• NUC-3373 (1500 mg/m2 IV) over 120 minutes 
• LV (400 mg/m2 IV; or equivalent levo-leucovorin) over 120 minutes concurrently 
with irinotecan (180 mg/m2 IV) over 90 minutes  
C2D1 (Arm B): 
• LV (400 mg/m2 IV; or equivalent levo-leucovorin) over 120 minutes concurrently 
with irinotecan (180 mg/m2 IV) over 90 minutes  
• NUC-3373 (1500 mg/m2 IV) over 120 minutes 
 
Arm 2c: NUFOX Dose Expansion Q1W (2nd-/3rd-line patients) 
C1D1 and beyond: 
• LV 400 mg/m2 IV (or equivalent levo-leucovorin) over 120 minutes prior to 
NUC-3373 infusion (concurrently with oxaliplatin) 
• Oxaliplatin 85 mg/m2 IV over 120 minutes prior to NUC-3373 infusion 
(concurrently with LV) 
• NUC-3373 IV at the combination dose as determined at the DSMC meeting for 
Part 2 dose escalation 
NUC-3373 + LV is given on Days 1, 8, 15 and 22 in each 28-day treatment cycle (Q1W). 
Oxaliplatin is given on Days 1 and 15 in each 28-day treatment cycle (Q2W), as per the 
Prescribing Information.  

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Arm 2d: NUFIRI Dose Expansion Q1W (2nd-/3rd-line patients) 
C1D1 and beyond: 
• LV 400 mg/m2 IV (or equivalent levo-leucovorin) over 120 minutes prior to 
NUC-3373 infusion (concurrently with irinotecan) 
• Irinotecan 180 mg/m2 IV over 120 minutes prior to NUC-3373 infusion 
(concurrently with LV) 
• NUC-3373 1500 mg/m2 IV over 120 minutes 
NUC-3373 + LV is given on Days 1, 8, 15 and 22 in each 28-day treatment cycle (Q1W). 
Irinotecan is given on Days 1 and 15 in each 28-day treatment cycle (Q2W), as per the 
Prescribing Information.  
Guidance on combination agent infusion time and order has been provided above; however, in 
all instance’s combination agents may be administered in accordance with local and national 
guidelines for FOLFOX and FOLFIRI regimens. 
For patients experiencing toxicity related to NUC-3373 in the NUFOX and NUFIRI cohorts, 
initially the NUC-3373 dose modification guidelines in Section 9 should be followed. The 
doses of oxaliplatin and irinotecan may be adjusted (through agreement with the DSMC) based 
on, but not limited to, safety and PK data generated in patients receiving treatment with 
NUFOX and NUFIRI regimens. If oxaliplatin or irinotecan-related AEs are observed, dose 
de-escalation should be performed as per the respective Prescribing Information or standard 
local practice. The modified dose of oxaliplatin or irinotecan (in combination with NUC-3373) 
will be assessed in approximately 6 evaluable patients in each arm. 
8.3.3 Part 3 
In Part 3, 2nd-line patients will receive the NUFOX and NUFIRI regimens selected in Part 2 in 
combination with bevacizumab. Q1W bevacizumab-containing cohorts will be opened first. 
Following this, Q2W arms and/or cetuximab combination cohorts may be opened, depending 
on emerging data. In addition, patients qualifying for maintenance therapy may receive 
NUC-3373 + LV in combination with bevacizumab. 
Eligible consenting patients in Part 3 will receive one of the combinations listed below, as 
determined by the Investigator and number of patients enrolled per cohort. Patients will 
continue to receive treatment until the occurrence of radiological disease progression using 
RECIST v1.1 or unmanageable drug-related AEs despite dose modification. Guidelines for 
dose modifications and discontinuations due to AEs will be provided. 
Alternate infusion parameters may be implemented with approval from the DSMC.  
Arm 3a: NUFOX + bevacizumab Q1W (2nd-line patients) 
C1D1 and beyond: 
• Bevacizumab 5 mg/kg: 
o 90 minutes for the first dose 
o 60 minutes for the second dose (if first dose is tolerated) 
o 30 minutes for subsequent doses (if second dose is tolerated) 
• LV 400 mg/m2 IV (or equivalent levo-leucovorin) over 120 minutes prior to 
NUC-3373 infusion (concurrently with oxaliplatin) 

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• Oxaliplatin 85 mg/m2 IV over 120 minutes prior to NUC-3373 infusion 
(concurrently with LV) 
• NUC-3373 IV at the combination dose and infusion duration determined at the 
DSMC meeting for Part 2 dose escalation 
NUC-3373 and LV are given on Days 1, 8, 15 and 22 in each 28-day treatment cycle (Q1W). 
Oxaliplatin and bevacizumab are given on Days 1 and 15 in each 28-day treatment cycle 
(Q2W), as per the respective Prescribing Information.  
Arm 3b: NUFOX + bevacizumab Q2W (2nd-line patients) 
C1D1 and beyond: 
• Bevacizumab 5 mg/kg: 
o 90 minutes for the first dose 
o 60 minutes for the second dose (if first dose is tolerated) 
o 30 minutes for subsequent doses (if second dose is tolerated) 
• LV 400 mg/m2 IV (or equivalent levo-leucovorin) over 120 minutes prior to 
NUC-3373 infusion (concurrently with oxaliplatin) 
• Oxaliplatin 85 mg/m2 IV over 120 minutes prior to NUC-3373 infusion 
(concurrently with LV)  
• NUC-3373 IV at the combination dose and infusion duration determined at the 
DSMC meeting for Part 2 dose escalation 
NUC-3373, LV, oxaliplatin and bevacizumab are given on Days 1 and 15 in each 28-day 
treatment cycle (Q2W).  
Arm 3c: NUFIRI + bevacizumab Q1W (2nd-line patients) 
C1D1 and beyond: 
• Bevacizumab 5 mg/kg: 
o 90 minutes for the first dose 
o 60 minutes for the second dose (if first dose is tolerated) 
o 30 minutes for subsequent doses (if second dose is tolerated) 
• LV 400 mg/m2 IV (or equivalent levo-leucovorin) over 120 minutes prior to 
NUC-3373 infusion (concurrently with irinotecan) 
• Irinotecan 180 mg/m2 IV over 120 minutes prior to NUC-3373 infusion 
(concurrently with LV) 
• NUC-3373 1500 mg/m2 IV over 120 minutes 
NUC-3373 and LV are given on Days 1, 8, 15 and 22 in each 28-day treatment cycle (Q1W). 
Irinotecan and bevacizumab are given on Days 1 and 15 in each 28-day treatment cycle (Q2W), 
as per the respective Prescribing Information.  

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Arm 3d: NUFIRI + bevacizumab Q2W (2nd-line patients) 
C1D1 and beyond: 
• Bevacizumab 5 mg/kg: 
o 90 minutes for the first dose 
o 60 minutes for the second dose (if first dose is tolerated) 
o 30 minutes for subsequent doses (if second dose is tolerated) 
• LV 400 mg/m2 IV (or equivalent levo-leucovorin) over 120 minutes prior to 
NUC-3373 infusion (concurrently with irinotecan) 
• Irinotecan 180 mg/m2 IV over 120 minutes prior to NUC-3373 infusion 
(concurrently with LV) 
• NUC-3373 1500 mg/m2 IV over 120 minutes 
NUC-3373, LV, irinotecan and bevacizumab are given on Days 1 and 15 in each 28-day 
treatment cycle (Q2W).  
Arm 3e: NUC-3373 + bevacizumab Q1W (Maintenance patients) 
C1D1 and beyond: 
• Bevacizumab 5 mg/kg: 
o 90 minutes for the first dose 
o 60 minutes for the second dose (if first dose is tolerated) 
o 30 minutes for subsequent doses (if second dose is tolerated) 
• LV 400 mg/m2 IV (or equivalent levo-leucovorin) over 120 minutes prior to 
NUC-3373 infusion 
• NUC-3373 2500 mg/m2 IV over 200 minutes  
NUC-3373 and LV are given on Days 1, 8, 15 and 22 in each 28-day treatment cycle (Q1W). 
Bevacizumab is given on Days 1 and 15 in each 28-day treatment cycle (Q2W), as per the 
Prescribing Information.  
Arm 3f: NUFOX + cetuximab Q1W or Q2W (2nd-line patients) 
C1D1 and beyond: 
• Cetuximab infusion to be completed 1 hour prior to NUFOX infusions: 
o First dose: 400 mg/m2 IV over 120 minutes 
o Subsequent doses: 250 mg/m2 IV over 60 minutes 
• LV 400 mg/m2 IV (or equivalent levo-leucovorin) over 120 minutes prior to 
NUC-3373 infusion (concurrently with oxaliplatin) 
• Oxaliplatin 85 mg/m2 IV over 120 minutes prior to NUC-3373 infusion 
(concurrently with LV) 
• NUC-3373 IV at the combination dose and infusion duration determined at the 
DSMC meeting for Part 2 dose escalation 
The NUC-3373 + LV administration schedule may be Q1W or Q2W, depending on emerging 
data.  

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Oxaliplatin is given on Days 1 and 15 in each 28-day treatment cycle (Q2W) and cetuximab is 
given on Days 1, 8, 15 and 22 in each 28-day treatment cycle (Q1W), as per the respective 
Prescribing Information.  
Arm 3g: NUFIRI + cetuximab Q1W or Q2W (2nd-line patients) 
C1D1 and beyond: 
• Cetuximab infusion to be completed 1 hour prior to NUFIRI infusions: 
o First dose: 400 mg/m2 IV over 120 minutes 
o Subsequent doses: 250 mg/m2 IV over 60 minutes 
• LV 400 mg/m2 IV (or equivalent levo-leucovorin) over 120 minutes prior to 
NUC-3373 infusion (concurrently with irinotecan) 
• Irinotecan 180 mg/m2 IV over 120 minutes prior to NUC-3373 infusion 
(concurrently with LV) 
• NUC-3373 1500 mg/m2 IV over 120 minutes 
The NUC-3373 + LV administration schedule may be Q1W or Q2W, depending on emerging 
data.  
Irinotecan is given on Days 1 and 15 in each 28-day treatment cycle (Q2W) and cetuximab is 
given on Days 1, 8, 15 and 22 in each 28-day treatment cycle (Q1W), as per the respective 
Prescribing Information.  
In all bevacizumab-containing arms, NUC-3373 dose adjustments may occur depending on 
emerging data. 
Guidance on combination agent infusion time has been provided above; however, in all 
instance’s combination agents may be administered in accordance with local and national 
guidelines. 
Panitumumab combination arms may also be opened (~10 2nd-line patients), depending on 
emerging data. 
Cohorts of rapid progressors may also be opened (~10 patients), depending on emerging data. 
8.4    NUC-3373 Drug Destruction 
Used vials of NUC-3373 should be destroyed in accordance with local procedures and 
documented in the drug accountability and drug destruction log.  A copy of the disposal 
certificates should be kept in the study file. 
8.5  
NUC-3373 Study Drug Accountability 
The US Food and Drug Administration (FDA) and other applicable regulatory authorities 
require accounting of all study drug received by each study centre. Records of drug disposition 
required include the date received by the centre, 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 unused study drug. Each study 
centre 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 

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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. The Sponsor’s designated site monitor will review study drug accountability records and 
remaining drug supplies during routine monitoring visits. 
8.6   
Management of Overdose of NUC-3373 
The initial dose of NUC-3373 intended for use on this protocol is 1500 mg/m2.  In the Phase I, 
first-in-human study, the highest dose studied at the time of writing this protocol has been 
3250 mg/m2. Should a substantial overdose occur, there is no known antidote.  
In the event of a substantial overdose of any of the agents used in the prescribed combinations 
(LV, oxaliplatin, irinotecan, bevacizumab, cetuximab, panitumumab), the management should 
follow guidance in the Prescribing Information or standard local practice. 
Any patient who inadvertently receives a dose of any agent in this study higher than intended 
should be monitored closely, managed with appropriate supportive care, including transfusion 
and haematopoietic growth factors as needed, until recovery. Such overdoses should be 
recorded as follows: 
1. If an overdose occurs in the course of the study, site personnel must inform the 
Investigator and monitor immediately upon discovery of the event. An overdose 
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 with no associated symptoms is only reported on the treatment CRF. 
2. All overdoses should be tracked as a violation. 

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9 
DOSE MODIFICATIONS 
Adverse events may be managed by dose delays and/or dose reductions according to the 
clinical situation. For patients experiencing toxicity related to NUC-3373 in NUFOX and 
NUFIRI cohorts, initially the NUC-3373 dose modification guidelines should be followed. 
Note that for patients in the PK sub-study, any dose modifications required prior to C1D15 will 
make the patient non-evaluable for the sub-study analysis. Such patients will be replaced.   
Advice on how to modify NUC-3373 dosing for haematological and non-haematological 
toxicities in Part 1 is given in Table 18 and Table 19 and in Part 2 and Part 3 is given in Table 
20.   
NUC-3373 dose reductions may be temporary, in which case the next cycle can revert to the 
starting dose of the previous cycle, or permanent, which would apply to all subsequent cycles. 
Over the whole dosing period, each patient may have a maximum of 2 permanent dose 
reductions, after which treatment with NUC-3373 will be discontinued and the patient will be 
removed from study.  
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 
NUC-3373 and will be withdrawn from the study, unless the patient is receiving clinical benefit 
in the opinion of the Investigator. 
In the case of the agents given in combination with NUC-3373 and in patients receiving clinical 
benefit, AEs attributed to the combination agents may be managed by dose adjustment, holds 
or discontinuation of the agent in accordance with standard clinical practice.  For example, a 
patient assigned to the NUFOX regimen who is receiving clinical benefit and who experiences 
neuropathy that is judged as related to the oxaliplatin may undergo an oxaliplatin treatment-free 
interval at the discretion of the Investigator. However, treatment with NUC-3373 must be 
continued for the patient to remain on treatment for the purposes of this protocol.  
Table 18 
Dose reduction guidelines for Part 1, Arms 1a and 1b 
Reduction 
NUC-3373 
Days 1 and 15 every 28 days 
LV 
Day 1 and 15 
1 
75% of starting dose1 
100% of starting dose2 
2 
50% of starting dose1 
100% of starting dose2 
1  Two dose reductions allowed 
2   LV dose should be maintained but may be reduced at the discretion of the Investigator, with 
confirmation from the Medical Monitor and Sponsor 
 
Table 19 
Dose reduction guidelines for Part 1, Arm 1c and 1d 
Reduction 
NUC-3373 
Days 1, 8, 15 and 22 every 28 days 
LV 
Days 1, 8, 15 and 22 every 28 days 
1 
75% of starting dose1 
100% of starting dose2 
2 
50% of starting dose1 
100% of starting dose2 
1  Two dose reductions allowed 

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2  LV dose should be maintained but may be reduced at the discretion of the Investigator, with 
confirmation from the Medical Monitor and Sponsor 
 
Table 20 
Dose reduction guidelines for Part 2 and Part 3 
Reduction 
NUC-3373 
LV 
Combination agent 
1 
75% of Starting Dose1 
100% of starting dose2 
Per Prescribing 
Information3 
2 
50% of Starting Dose1 
100% of starting dose2 
Per Prescribing 
Information3 
1 Two dose reductions allowed. Minimum 25% reduction per reduction 
2 LV dose should be maintained but may be reduced in accordance with label 
3 Doses of combination agents should be reduced in accordance with Prescribing Information 
or standard local practice 
9.1 
Criteria for Continuation of Treatment 
Patients must meet ALL of the following criteria prior to receiving a dose of study treatment: 
• ANC ≥1.5×109/L (growth factor support permitted after Cycle 1) 
• Platelet count ≥75×109/L without platelet transfusion (platelet transfusion permitted 
after Cycle 1) 
• No evidence of disease progression (based on radiographic assessment) 
• Recovery from all clinically significant toxicities to ≤Grade 2 or to baseline grade 
present at study entry  
Administration of study drug should be held until all of the re-treatment criteria are met. Any 
missed dose(s) should not be made up if treatment delay exceeds 24 hours. If treatment delay 
is <24 hours, subsequent scheduled dose(s) may be administered. If a DLT occurs during a 
cycle, doses of study drug will be withheld for the remainder of the cycle and subsequent cycles 
will be administered at the previously tested next lower dose level. 
9.2 
Dose Modifications (Dose Delays and Dose Reductions)  
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 unless receiving clinical benefit in the 
opinion of the Investigator.  Patients who fail to meet these requirements after this additional 
time will not be allowed to receive further cycles of therapy within the study, unless they are 
receiving clinical benefit in the opinion of the Investigator. If a patient experiences multiple 
toxicities, dose adjustments will be based on the most severe toxicity. A patient who 
experiences a toxicity meeting the definition of DLT (during any cycle) but whose toxicity 
recovers within 21 days may be dose reduced to the next lower dose level. If a patient 
experiences a sub-DLT toxicity, they may be dose reduced at the Investigators discretion. Any 
patient who experiences one or more recurrent, clinically significant toxicities after the initial 
dose reduction may have one further dose reduction. Patients who continue to experience 
clinically significant toxicity despite two dose reductions will either be discontinued from study 
treatment or may be switched to a Q2W schedule, if the timecourse of the toxicity indicates 
that a different schedule may improve tolerability.  A patient receiving clinical benefit will not 
require discontinuation and treatment guidelines for such patient will be decided in discussion 

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with the Investigator, Medical Monitor and Sponsor based on all data currently available for 
NUC-3373 at the time.  
Patients who have completed the DLT period may be switched from a Q1W to a Q2W schedule 
if they experience drug-related toxicity (other than fatigue) that would otherwise lead to 
treatment discontinuation. In addition, patients who have completed the DLT period may move 
from a Q2W to a Q1W schedule. The decision to switch schedules must be discussed with and 
approved by the Sponsor on an individual patient basis.   
General guidance for dose modifications of NUC-3373 is provided in Table 21. 
Table 21 
Dose modifications for Cycle 2 onwards and for non-DLT toxicities within 
Cycle 1  
Toxicity Grade 
Recommended immediate action 
with NUC-3373 
Recommendation for dose modification of 
NUC-3373 at start of a new cycle 
Mucositis 
Grade 2 
No immediate action 
Continue current dose level with appropriate 
mouth care. 
Grade 3 or 4 
Hold  
If resolved to ≤Grade 2 within 14 days reduce by 
1 dose level. If mucositis has not resolved to 
≤Grade 2 within 14 days, permanently stop 
treatment. 
Febrile neutropaenia 
Grade 3 or 4 
Hold  
If neutropaenia resolved to ≤Grade 1, reduce by 1 
dose level. If not resolved to ≤Grade 1 within 14 
days, permanently stop treatment. 
Neutropaenia 
Grade 2  
Hold only if starting a new cycle 
[delay of max 14 days allowed until 
ANC≥1.5 x 109/L]. If within a cycle, 
no immediate action required. 
If study drug held at the start of new cycle, 
continue current dose level once neutropaenia 
resolved to ≤Grade 1 (ANC≥1.5 x 109/L). 
Grade 3 or 4  
Hold, consider growth factor 
support.  
If held at the start of new cycle continue at the 
next lower dose level if neutropaenia resolved to 
≤Grade 1 within 14 days.  
If study drug held within a cycle, if neutropaenia 
resolved ≤Grade 2 within 14 days, continue at 
next lower dose level.  
If neutropaenia has not resolved to ≤Grade 2 
within 14 days, permanently stop treatment. 
Thrombocytopaenia 
Grade 2  
Hold if starting or within a cycle 
[delay of max 14 days allowed until 
platelets ≤ Grade 1]  
If held at the start or within cycle continue at 
the next lower dose level if thrombocytopaenia 
resolved to ≤Grade 1 within 14 days.  
If thrombocytopaenia has not resolved to ≤Grade 
1 within 14 days, permanently stop treatment. 

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Toxicity Grade 
Recommended immediate action 
with NUC-3373 
Recommendation for dose modification of 
NUC-3373 at start of a new cycle 
Grade 3 or 4  
Hold 
and 
follow 
treatment 
guidelines 
When thrombocytopaenia resolved to ≤Grade 1, 
continue current study at the next lower dose 
level. 
If thrombocytopaenia has not resolved to ≤Grade 
1 within 14 days, permanently stop treatment.  
Diarrhoea 
Grade 2 
Hold if starting or within a cycle 
[delay of max 14 days allowed until 
platelets ≤Grade 1]  
Refer to Appendix 4 
Grade 3 or 4  
Hold 
and 
follow 
treatment 
guidelines 
Refer to Appendix 4 
9.3 
Suggested Management of Toxicity 
9.3.1 Nausea and Vomiting 
• Consider anti-emetic medications, e.g., granisetron, dexamethasone, cyclizine  
• Maintain adequate hydration, including use of intravenous 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 (e.g., gastrointestinal tract obstruction) 
• Consider prophylactic anti-emetic medications per ASCO guidelines for 
chemotherapy regimens of moderate emetic risk prior to next scheduled treatment 
9.3.2 Diarrhoea 
• All available anti-diarrhoeal medications, including loperamide and opium 
preparations etc, should be considered for treatment 
• Maintain adequate hydration, including use of intravenous fluids if indicated 
• Supplement electrolytes, particularly potassium and magnesium, to recommended 
levels 
• Avoid oral supplementation of electrolytes since diarrhoea could be exacerbated in 
some cases 
• Rule out other potential causes, including infectious aetiologies 
• Discontinue any concomitant medications that could exacerbate diarrhoea 
• Avoid the use of diuretics and laxatives 
• Refer to Appendix 4 for further guidance 

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9.3.3 Mucositis 
• Encourage good oral hygiene, including cleaning teeth after each meal and at 
bedtime, using soft-bristled toothbrush 
• Rinse mouth using chlorhexidine (or similar) mouthwash after brushing teeth, after 
mealtimes and in the evenings 
• Careful dental flossing once daily; avoid visits to dental hygienist during treatment 
• Dentures cleaned after each meal and soaked overnight in cleaning solution 
• Avoidance of spicy, rough or crunchy foods 
• Manage pain from mucositis with benzydamine mouthwash (Difflam), systemic 
analgesics such as dispersible paracetamol or aspirin 
• For ulcers, local analgesia including Mucaine equivalent 10 mL qds, lidocaine 1% 
gel, topical Bonjela up to every 3 hours, buccal hydrocortisone (2.5 mg) tablets 4x 
daily or orabase ointments 
• Sucralfate suspension 5 mL qds rinsed around the mouth 
• For patients with Grade 3/4 mucositis, use low dose opiates; consider rinsing with 
Gelcair oral gel (15 mL sachets) 
9.3.4 Palmar-Plantar Erythrodysesthaesia (hand-foot syndrome) 
• For Grade 1 or above, consider starting pyridoxine 50 mg tds 
9.3.5 Dermatologic Toxicity 
Severe acneiform rash can occur with exposure to an EGFR inhibitor.  Recommended dose 
modifications for severe (CTCAE v5.0 Grade 3 or 4) acneiform rash are specified in Table 22.  
Table 22 
Dose modification guidelines for severe acneiform rash 
Occurrence 
Action with EGFR 
inhibitor 
Outcome 
Action 
First 
Delay treatment 1-2 weeks 
Improvement 
Continue at standard dose 
No improvement 
Discontinue 
Second 
Delay treatment 1-2 weeks 
Improvement 
Continue at 80% of the dose 
No improvement 
Discontinue 
Third 
Delay treatment 1-2 weeks 
Improvement 
Continue at 60% of the dose 
No improvement 
Discontinue 
Fourth 
Discontinue 
In general, patients should be treated as per local standards of care for EGFR inhibitor-related rash.  
However, the following guidance should also be considered: 

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Application of a skin moisturiser and a broad-spectrum sunscreen of SPF ≥30 when going outside is 
recommended in all patients, since the rash is accompanied by dry skin and may be aggravated by sun 
exposure. 
Prevention of acneiform rash caused by EGFR inhibitors should include topical corticosteroids (e.g., 
hydrocortisone 2.5%, alclometasone) and oral antibiotics (e.g., minocycline, doxycycline, or antibiotics 
covering skin flora) twice daily for at least the first 6 weeks.  
For occurrence of rash while on therapy, a dermatologist should be consulted. Potential treatment options 
include:  
In patients who have already developed Grade 1/2 rash: topical corticosteroids (e.g., hydrocortisone 
2.5%, alclometasone) and oral antibiotics (e.g., minocycline, doxycycline, or antibiotics covering skin 
flora) twice daily for at least 4 weeks is recommended.  
In cases where secondary infections are suspected: a bacterial swab culture should be performed in 
order to institute oral antibiotic therapy based on sensitivities. 
9.3.6 Infusion Reactions 
Infusion reactions may occur with any of the study drugs. Infusion reactions should be managed 
as follows:  
• 
Reduce infusion rate by 50% in patients experiencing a mild or moderate (Grade 1 
or 2) infusion reaction for the duration of that infusion 
• 
Terminate the infusion in patients experiencing severe infusion reactions. 
Depending on the severity and/or persistence of the reaction, permanently 
discontinue the combination agent.  
9.3.7 Ocular Toxicity 
Patients presenting with signs or symptoms suggestive of eye disorders such as acute or 
worsening eye inflammation, lacrimation, light sensitivity, blurred vision, eye pain and/or red 
eye should be referred promptly to an ophthalmology specialist for evaluation.  
9.3.8 Fatigue 
Fatigue is an expected AE for patients with heavily pre-treated advanced cancer who will be 
enrolled to this study.  As clinical benefit is most likely to be realised only with continued 
treatment, best efforts that include supportive care and carefully considered dose reductions of 
all or some of the agents within a treatment regimen can be considered.  Changes in dose for 
any agent should be discussed with the medical monitor prior to implementation. 
9.3.9 Combination Therapies 
Patients receiving treatment with combination therapies in Parts 2 and 3 of the study should be 
managed as outlined in the sections below.  
9.3.9.1 Oxaliplatin  
Serious and fatal hypersensitivity reactions, including anaphylaxis, can occur with oxaliplatin 
within minutes of administration and during any cycle of treatment. Oxaliplatin should be 
discontinued in patients who experience severe hypersensitivity reactions which are not 
manageable with dose reductions, infusion time adjustments and prophylactic treatment with 
steroids and histamine receptor antagonists.  

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For patients experiencing oxaliplatin-related toxicities in NUFOX cohorts, the dose of 
oxaliplatin may be adjusted (through agreement with the DSMC) based on safety events.  
If oxaliplatin-related AEs are observed, dose de-escalation should be performed as per the 
Prescribing Information or standard local practice.  
For a complete overview of oxaliplatin-related AEs, refer to the Prescribing Information.  
9.3.9.2 Irinotecan 
Early and late diarrhoea can occur with irinotecan. Early diarrhoea may be accompanied by 
cholinergic symptoms, which may be prevented or ameliorated by atropine. Late diarrhoea can 
be life-threatening and should be treated promptly with loperamide. Patients with diarrhoea 
must be monitored and given fluid and electrolytes as needed. Antibiotic therapy should be 
initiated if patients develop ileus, fever or severe neutropaenia.   
For patients experiencing irinotecan-related toxicities in the NUFIRI cohorts, the dose of 
irinotecan may be adjusted (through agreement with the DSMC) based on safety events.  
If irinotecan-related AEs are observed, dose de-escalation should be performed as per the 
Prescribing Information or standard local practice.  
For a complete overview of irinotecan-related AEs, refer to the Prescribing Information.  
9.3.9.3 Bevacizumab 
Infusion reactions reported across clinical studies and post-marketing experience include 
hypertension, hypertensive crises associated with neurologic signs and symptoms, wheezing, 
oxygen desaturation, Grade 3 hypersensitivity, chest pain, headaches, rigors, and diaphoresis. 
Discontinue bevacizumab in patients who develop a severe infusion reaction and administer 
appropriate medical therapy (e.g., epinephrine, corticosteroids, intravenous antihistamines, 
bronchodilators and/or oxygen). 
The incidence of severe hypertension is increased in patients receiving bevacizumab as 
compared to patients receiving chemotherapy alone. Across clinical studies, the incidence of 
Grade 3-4 hypertension ranged from 5% to 18%. Monitor blood pressure every two to three 
weeks during treatment with bevacizumab. Treat with appropriate anti-hypertensive therapy 
and monitor blood pressure regularly. 
Bevacizumab treatment must be discontinued in patients with gastrointestinal perforations or 
wound healing complications requiring medical intervention.  
For patients undergoing elective surgery, bevacizumab must be withheld for at least 28 days 
prior to the surgery and must not be administered for at least 28 days following surgery and 
until the wound is fully healed.  
Bevacizumab should be discontinued in patients with Grade 3-4 haemorrhage.  
If bevacizumab-related AEs are observed, dose de-escalation should be performed as per the 
Prescribing Information or standard local practice. 
For a complete overview of bevacizumab-related AEs, refer to the Prescribing Information.  
9.3.9.4 EGFR inhibitors 
EGFR inhibitors can cause serious and fatal infusion reactions and must be discontinued in 
patients who experience serious infusion reactions.  

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Cardiopulmonary arrest or sudden death have occurred in patients receiving EGFR inhibitors 
with radiation therapy or with platinum-based therapy and fluorouracil and extra caution needs 
to be applied, especially in patients with pre-existing heart conditions. Patients receiving EGFR 
inhibitors must be monitored for serum electrolytes, including magnesium, potassium, and 
calcium, during and after administration.  
If EGFR inhibitor-related AEs are observed, dose de-escalation should be performed as per the 
Prescribing Information or standard local practice. 
For a complete overview of EGFR inhibitor-related AEs, refer to the cetuximab or 
panitumumab Prescribing Information.  
9.5 
Schedule Modification 
For patients having received treatment for at least 4 cycles at a NUC-3373 dose level 
subsequently determined to be below the recommended dose, the Investigator may, after 
discussion with the Medical Monitor and Sponsor, consider an increase in the dose of 
NUC-3373.  If the dose level is increased and found to be not as well tolerated as the previous 
lower dose level, the NUC-3373 dose level may be reduced back to the previous level and not 
considered one of the maximum of two dose reductions allowed per patient. Best efforts should 
be given to maintaining a patient receiving clinical benefit on study. 

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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 30 days 
prior to the first dose of NUC-3373 through the EoT Visit must be recorded in the CRF. All 
prior anti-cancer therapies from initial diagnosis up until enrolment must be recorded in the 
CRF. 
10.1 
Support Medication 
Patients may receive prophylactic medical treatment at the Investigator’s discretion to 
prevent AEs common to the administration of anti-cancer agents including, but not restricted 
to, anaphylaxis, nausea and vomiting. All support medications must be recorded in the CRF. 
Support medications should be administered according to the Prescribing Information or 
standard local practice for the relevant combination agents. The following support medications 
are recommended: anti-emetics (palonosetron, granisetron, aprepitant, dexamethasone, 
metoclopramide, domperidone, cyclizine); anti-histamines; atropine (e.g., for irinotecan-
containing regimens); sunscreen of ≥SPF 30; topical corticosteroids (e.g., hydrocortisone 2.5%, 
alclometasone); and oral antibiotics (e.g., minocycline, doxycycline, or antibiotics covering 
skin flora) for cetuximab-containing regimens.  
10.2 
Haematopoietic Growth Factor Support 
The prophylactic use of haematopoietic growth factors (e.g., G-CSF) is not permitted in the 
first cycle in patients being evaluated for DLT. However, the Investigator may include 
haematopoietic growth factor support according to local protocols and as prophylaxis after any 
febrile neutropaenic episode in order to enable the patient to continue on study after completion 
of Cycle 1.  All haematopoietic growth factors used from 30 days prior to date of consent until 
30 days after administration of last dose of NUC-3373 must be recorded in the CRF. Any blood 
and platelet transfusions should also be recorded in the CRF. 
10.3 
Concomitant Medications 
May be given as medically indicated unless prohibited as outlined in Section 10.3.2.  All 
concomitant medications used from 30 days prior to date of consent until 30 days after 
administration of last administration of NUC-3373 must be recorded in the CRF. 
10.3.1 Contraception Methods 
As defined below, male patients and female 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. 
• True abstinence is defined as refraining from sexual intercourse. True abstinence is only 
acceptable if this practice is in line with the patient’s preference and usual lifestyle. 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods), 
declaration of abstinence for the duration of exposure to the investigational drug, and 
withdrawal are not acceptable methods of contraception.  
• Surgical sterilisation (males) 
• Intrauterine device or intrauterine system 
• Oral contraception plus a barrier method 

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• Double-barrier method (e.g., male condom or a diaphragm plus a vaginal spermicidal 
cream) 
These forms of contraception must be used from the time of signing consent, throughout the 
treatment period, and for 6 months following the last dose of any study medication. Oral or 
injectable contraceptive agents cannot be the sole method of contraception. Female patients of 
childbearing potential must have a negative pregnancy test within seven days prior to the first 
study drug administration. Female patients are considered to be of child-bearing potential 
unless they are post-menopausal (12 months of amenorrhea) or surgically sterile.  
10.3.2 Prohibited Therapy  
Except as included in the specific arms and dosing regimens of this study, use of the following 
therapies is prohibited at any dose during the study: 
• Other cytotoxic chemotherapy 
• Radiotherapy, excluding a short cycle of palliative radiotherapy (e.g., for bone pain) 
• Immunotherapy including immunosuppressive therapy 
• Radioimmunotherapy 
• Hormone therapy (other than contraceptives, hormone-replacement therapy, or 
megestrol acetate) 
• Other biologic agents intended for the treatment of CRC (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 CRC, whether approved by local regulatory 
authorities or investigational 
• Drugs that are known to prolong QTc interval (refer to Appendix 3) 
• Strong inducers of CYP3A4, including but not limited to phenytoin, phenobarbital, 
carbamazepine, rifampin, rifabutin or St. John’s wort 
• Strong inhibitors of CYP3A4, including but not limited to ketoconazole, 
clarithromycin, indinavir, itraconazole, lopinavir, nefazodone, nelfinavir, ritonavir, 
saquinavir, or atazanavir 
• Live vaccines (must also be avoided for six weeks after last dose of study medication) 
• Diuretics and laxatives should be avoided in patients experiencing treatment-related 
diarrhoea and cholinergic reactions 
• Patients in bevacizumab-containing arms should not receive full-dose anti-coagulation 
therapy, with the exception of patients who have been on stable doses for at least 6 
months and have tolerated prior bevacizumab treatment 
10.3.3 Therapy to be Used with Caution 
The following warnings and precautions regarding concomitant medications apply to 
irinotecan containing dose combinations: 
• Strong inhibitors of UGT1A1, including but not limited to ketoconazole, indinavir, 
itraconazole, lopinavir, nelfinavir, ritonavir, saquinavir, atazanavir, or gemfibrozil, 
should not be administered with irinotecan.  Strong inhibitors of UGT1A1 should be 
discontinued at least 1 week prior to starting irinotecan.  Do not administer strong 

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inhibitors of UGT1A1 with irinotecan unless there are no other therapeutic alternatives.  
Please contact the Medical Monitor before concomitant administration of strong 
UGT1A1 inhibitors and irinotecan 
• Interaction between irinotecan and neuromuscular blocking agents cannot be ruled out. 
Irinotecan has anti-cholinesterase activity, which may prolong the neuromuscular 
blocking effects of suxamethonium and the neuromuscular blockade of non-
depolarising drugs may be antagonised.  Caution should be used when using 
neuromuscular blocking agents with irinotecan 
For patients in all parts and arms of the study, warfarin and other types of long acting 
anti-coagulants (such as phenprocoumon and anti‑Xa inhibitors with a half‑life of >12 hours) 
is prohibited within 4 weeks of the first dose of study treatment.  Patients requiring anti-
coagulant treatment should switch to low molecular weight heparin or anti‑Xa inhibitors with 
a half‑life of ≤12 hours. 
Refer to the NUC-3373 IB for current information on potential drug interactions.  
10.3.4 COVID-19 Vaccinations  
A risk assessment performed in accordance with MHRA guidance ‘Managing clinical trials 
during COVID-19’ (MHRA, 2021) concluded that a COVID-19 vaccine given to a study 
patient is considered a simple concomitant medication. 
No action is required in relation to COVID-19 vaccination timing with respect to administration 
of NUC-3373 and the other combination agents used in this study. 

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11 
TUMOUR RESPONSE ASSESSMENTS 
11.1 
Tumour Measurements and Assessment of Disease Response 
Patients must have at least one lesion that can be accurately assessed at baseline by CT or MRI 
and which is suitable for repeated assessment in order to be eligible for this study. All known 
or suspected disease sites must be assessed at baseline by either CT or MRI scan. The same 
radiological method used at baseline must be used to follow lesions throughout the study. 
Disease status must be assessed according to RECIST v1.1 criteria, with target and non-target 
lesions identified, measured and followed throughout the study (Appendix 1).  Biopsied lesions 
should not be designated as target lesions for the purposes of RECIST v1.1 and a target lesion 
should not be biopsied during the study unless medically necessary. 
Whenever possible, the same qualified physician will interpret results to reduce variability. 
Radiographic images will be maintained at the study centre and Investigator’s assessments will 
be filed in the patient’s source documents. 
Tumour measurements and disease response assessments are to be performed every 8 weeks 
(±7 days) from Cycle 1 Day 1. If the patient stops study treatment for reasons other than 
radiologically-confirmed progressive disease, tumour measurements and disease response 
assessments should continue every 8 weeks (±7 days) from Cycle 1 Day 1 until progressive 
disease is radiologically confirmed. 
Tumour measurements and disease response assessments should be performed any time disease 
progression is suspected.  Patients should not discontinue treatment because of clinical signs 
of progression until it has been radiologically confirmed by radiologic assessment. 
Complete responses (CRs) and partial responses (PRs) must be confirmed by repeated images 
at least 4 weeks after initial documentation. 
In the case of SD, measurements must have met the SD criteria at least once after study entry 
at a minimum interval of not less than 7 weeks after the start of study treatment. 

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12 
SAFETY REPORTING 
This study evaluates NUC-3373 in combination with a variety of agents commonly used in 
treatment of advanced CRC, including LV, oxaliplatin, irinotecan, bevacizumab, cetuximab, 
and panitumumab. In considering safety assessments and reporting, it is anticipated that some 
safety findings may be attributable to a specific agent in a combination regimen, while others 
may not be attributable to a specific agent.  In this section, the term “study drug(s)” refers to 
any of the agents administered to the patient in the arm of the study to which he/she was 
enrolled. 
12.1 
Definitions 
The Investigator is responsible for reporting all AEs that are observed or reported during the 
study, regardless of relationship to study drug(s) or 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(s). 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 TEAE is defined as any event not present before exposure to study drug(s) or any event 
already present that worsens in either intensity or frequency after exposure to study drug(s). 
A SAE is defined as any event that: 
• 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. 
An adverse drug reaction (ADR) is an AE which is considered to be causally related to any 
dose of study drug(s).  This means that a causal relationship between study drug(s) 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.  For NUC-3373, please refer to the IB Reference Safety 
Information (RSI).  For the other agents used in combination with NUC-3373, please refer to 
the applicable Summary of Product Characteristics (SmPC), which serve as their 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). 
An important medical event that may not result in death, be life-threatening, or require 
hospitalisation may be considered an SAE when, based upon appropriate medical judgment, it 
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 

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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. 
After informed consent has been obtained, but prior to initiation of study drug, only AEs and 
SAEs caused by a protocol-mandated intervention will be reported.  Thereafter, all AEs 
occurring up to and including 30 days after the last dose of study drug has been administered 
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 grade or 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. Progressive disease is NOT an AE; however, some sequelae 
of progressive disease (i.e., pain, neurologic impairment) may be reported as AEs (generally 
not related to study drug(s)). 
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) remain at 
levels consistent with severe abnormalities despite appropriate medical intervention. It is 
requested that when reporting AEs for which potentially redundant CTCAE terms exist, the 
Investigator uses 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 study drug(s), the Investigator reports both the 
specific symptoms associated with the reaction (i.e., ‘urticaria’, ‘dyspnoea’) and also report the 

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appropriate term indicating the allergic reaction (‘allergic reaction’ or ‘anaphylaxis’ if 
appropriate [Immune System Disorders; CTCAE v5.0]). 
12.3 
Assessment of Causality to Study Drug(s) 
The Investigator’s assessment of an AE's relationship to study drug(s) is part of the 
documentation process, but it is not a factor in determining what is or is not reported in the 
study. If there is any doubt as to whether a clinical observation is an AE, the event should be 
reported. 
The relationship of an AE to study drug(s) in this study 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 CTCAE, v5.0. If the 
AE is not included in the CTCAE, then the Investigator should determine the intensity of the 
AE according to the criteria described in Table 23. 
Table 23 
Intensity of adverse events not included in CTCAE 
Intensity 
Criteria 
Mild (Grade 1) 
AE that disappears or is easily tolerated on continuation of study 
drug 
Moderate (Grade 2) 
AE is sufficiently discomforting to cause interference with usual 
work activities 
Severe (Grade 3) 
AE that is incapacitating, with inability to work or perform daily 
activities 
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. 

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12.5  SAE Reporting 
Any AE considered serious by the Investigator or sub-Investigator or that meets the seriousness 
criteria and that occurs from first administration of study drug(s) through 30 days after last 
administration of a study drug must be reported to the Sponsor within 24 hours from the time 
study site personnel first learn about the event. The SAE report should be entered directly in 
the EDC. If the EDC is unavailable. The SAE report may be completed and emailed or faxed 
using the contact details in Table 24. 
Table 24 
Pharmacovigilance contact details 
Email 
Nucana@primevigilance.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 provided in an SAE follow-up report in 
the EDC or, if needed, using the contact details listed in Table 24 as soon as it becomes 
available.  
NuCana 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(s).  Refer 
to Section 12.7 for more details. 
The Investigator or sub-Investigator is responsible for informing the relevant institutional 
review board/ethics committee (IRB/EC).  Copies of SAE correspondence with all 
Investigators or sub-Investigators, governing authorities, ethics committees, and the Sponsor 
(or sponsor designee) must be submitted for filing. 
A patient experiencing one or more SAEs 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. 
Study endpoints in patients with cancer, including CRC, include disease-related mortality and 
morbidity; as study endpoints, these will not be reported as expedited Investigational New Drug 
(IND) safety reports, unless there is a serious and unexpected event with evidence of a causal 
relationship between study drug(s) and the event. As appropriate and based on the frequency 
of occurrence, SAEs in the study will be reported to the relevant regulatory authorities at an 
appropriate interval, such as inclusion in the development safety update report.  
The following SAEs will not be reported individually in an expedited manner because they are 
anticipated to occur in the CRC 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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12.6  Expedited Reporting of SAEs 
The following SAE reporting requirements apply regardless of the Investigator’s assessment 
of the causality or expectedness of the SAE. If an SAE occurs that requires reporting, an SAE 
Report Form should be completed in the EDC and communicated within 24 hours of 
Investigator awareness using the contact details provided in Table 24. 
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 NUC-3373 or be sufficient to change NUC-3373 
administration or the overall conduct of the study. 
The Sponsor will notify appropriate regulatory authorities of any fatal or life-threatening 
experience that is determined to be related to the use of the study drug(s) (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(s) which are not fatal or life 
threatening, the Sponsor will notify the regulatory authorities as soon as possible and no later 
than 15 days of the initial receipt of information.  
The Investigator is responsible for informing the IRB/EC.  Copies of SAE correspondence with 
all Investigators or Sub-Investigators, regulatory authorities, IRBs/ECs and the Sponsor must 
be submitted for filing. 
12.8  Terms and Grading of Adverse Events and Toxicities 
All AEs and toxicities must be graded according to CTCAE v5.0. 
12.9  Pregnancy 
A woman who becomes pregnant during the course of the study should be withdrawn from 
study treatment immediately. Pregnancy occurring in a patient or partner during the study 
require expedited reporting. A Pregnancy Notification Report should be completed and 
submitted to the Sponsor using the contact information provided in Table 24 and within the 
same timelines as an SAE. All reported pregnancies should be followed 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 

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12.10 Events Exempt from being Reported as AE/SAEs 
12.10.1  Progression of Underlying Disease 
Disease progression and resultant death 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 progression of the underlying 
malignancy or does not fit the expected pattern of progression for the disease under study. 
Every effort should be made to document the objective progression of underlying malignancy. 
In some cases, the determination of clinical progression may be based on symptomatic 
deterioration. For example, progression may be evident from clinical symptoms but is not 
supported by tumour measurements. Or 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 is to be recorded on the Death CRF form, provided that the 
death is not unexpected and no causal relationship is suspected. The Investigator must clearly 
state whether the death was expected or unexpected and whether a causal relationship to 
NUC-3373 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 require SAE reporting.  
12.11 Informing Investigators of New Safety Information 
The sponsor will ensure that all Investigators are informed in a timely manner of new safety 
information regarding NUC-3373 that becomes available. Investigators are responsible for 
briefing their study team as appropriate. 
12.12 Reference Safety Information (RSI) for Assessment of Expectedness 
12.12.1    NUC-3373 
The Investigator Brochure (IB) supplied by NuCana for NUC-3373 contains the NUC-3373 
RSI for this study.  Only the IB version with current regulatory and IRB/EC approval for use 
in the study will 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 been down-graded 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 study documentation, such as the ICF. The sponsor will identify any 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.  

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• Non-Significant Changes to the IB: 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. 
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. 
12.11.2  Other Agents to be Used in Combination with NUC-3373 
The SmPC of each individual agent intended to be administered in conjunction with NUC-3373 
in this study will serve as their own RSI.  Representative SmPCs for each agent are provided 
in the NUC-3373 IB (Section 8.1) for ease of reference.  
12.13 Data Safety Monitoring Committee (DSMC) 
The DSMC will review ongoing and cumulative safety, dosing intensity, PK, PD and clinical 
activity data from each cohort.  In all cohorts, the DSMC will determine if the dose 
levels/schedules are safe and tolerable and if an arm should be expanded, if other dose 
levels/schedules should be explored, or if the cohort should be stopped.   
The DSMC will review all data in accordance with the European Medicines Agency (EMA) 
guideline on strategies to identify and mitigate risks for first-in-human and early clinical trials 
with investigational medicinal products (EMEA/CHMP/SWP/28367/07 Rev. 1, EMA 01 Feb 
2018). 
Members of the DSMC will include (at a minimum):  
• Chief Investigators from US and Europe  
• Medical Monitors 
• Sponsor’s Medical Director 
• Sponsor’s study management staff  

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13 
STATISTICAL CONSIDERATIONS 
A Statistical Analysis Plan (SAP) will be finalised before database lock and conduct of the 
final analysis is undertaken. Only the main features of the planned statistical analysis are 
included below. 
All statistical analyses will be performed using SAS®, Version 9.3 or higher.  
Unless specified otherwise, all data from each study part will be presented separately in the 
tables, figures and listings.  Furthermore, for Parts 2 and 3, data for each cohort will be 
presented separately. 
The study database will be locked prior to the primary analyses for inclusion in the clinical 
study report (CSR). However, interim data will be made available to the DSMC to assist with 
the identification of DLTs and enable dose escalation decisions whilst the study is ongoing. 
13.1 
Sample Sizes 
The study is not formally powered, but has been designed to estimate the safety and tolerability 
of NUC-3373 when given with the combination agents described in Section 3.3. For the dose 
escalation phases, a modified 3+3 design has been selected to enable an assessment of safety 
and tolerability, whilst limiting the number of patients exposed to experimental treatment and 
procedures. 
13.2 
Missing, Unused and Spurious Data 
In general, missing data will remain missing and will not be included in data summaries.   
Exceptions are described below.  
Missing baseline data (safety data) 
If a baseline value is not available and a screening value is available for the same parameter, 
then the last screening value will be used as baseline.  This value will also be used for 
calculations of changes from baseline. Unless otherwise defined, baseline will be defined as 
C0D1 for Part 1 Arm 1a & 1b, or C1D1 for all other cohorts. 
13.3 
Analysis Populations 
The analysis populations defined for this study are detailed below. In addition, and as deemed 
warranted by the data, efficacy may also be assessed in sub-populations as defined by the 
sponsor.  Subgroup analyses will assess consistency of treatment effect across potential or 
expected prognostic factors or biomarkers.  Analyses will not be performed if there are too few 
events available for a meaningful analysis of a particular sub-group. 
13.3.1 Safety Population 
For each part of the study, the Safety Population includes all patients in that part of the study 
who received at least 1 dose of NUC-3373 and will be the primary analysis set for the 
assessment of safety and tolerability in the study.  
For the purpose of data summaries, patients will be included in the Safety Population according 
to the treatment cohort and dose level initially received, regardless of any subsequent dose 
adjustments. 

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13.3.2 Full Analysis Set 
For all study parts and cohorts, the Full Analysis Set (FAS) is based on the intention-to-treat 
principles and includes all patients who received at least one dose of NUC-3373. Patients will 
be included in the FAS based on the dose of NUC-3373 initially received, regardless of any 
subsequent dose adjustments. 
The FAS will be used to assess PFS and the PD markers. 
13.3.3 Evaluable for Response Set 
The Evaluable for Response (EFR) set is defined as a subset of the FAS with measurable 
disease at baseline and who have undergone at least two cycles of treatment, received at least 
75% of planned treatment over the two cycles, and undergone a post-treatment objective 
disease assessment.  
The EFR set will be the primary analysis set used to assess tumour size, ORR, DCR, DoR and 
DoSD in all study parts. 
13.3.4 PK Analysis Set 
The PK Population contains all patients who received NUC-3373 as per protocol (i.e., intended 
dose) and provided at least one usable PK profile. All PK data will be analysed according to 
treatment received.   
This population will comprise all data from patients who received study treatment as per 
protocol (i.e., intended dose) and did not violate or deviate from the protocol and planned 
dosing regimen in ways that would significantly affect the PK analyses (for example skipping 
doses, or taking reduced doses or taking concomitant medications with the potential to cause a 
drug-drug interaction) during the PK sampling period. Patients who did deviate from the 
planned dosing regimen may still provide some data for inclusion in the PK set if they have at 
least one usable PK profile. The population and decisions regarding which profiles are usable 
will be defined by the study team, pharmacokineticist and statistician prior to any analyses 
being performed. 
13.4 
Patient Disposition 
The disposition of patients will be summarised presenting the number of patients enrolled, the 
number of patients treated, the number of patients for whom the study drug was discontinued 
with the reasons for discontinuation, and the number of patients who discontinued participation 
in the study.  
The number and percentage of patients included in each analysis population (as defined in 
Section 13.3) will be presented. 
Patients with major protocol deviations or other significant deviations as defined in the SAP 
will be listed and summarised by dose cohort and study.  

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13.5 
Statistical Methods 
13.5.1 Demographics and Baseline Data 
Demographic and baseline disease characteristic data will be presented based on the FAS.  
Baseline demographic and background data, including, but not limited to age, gender, weight, 
height, race, ethnicity and ECOG status will be listed and summarised using appropriate 
descriptive statistics. 
Baseline disease characteristics including, but not limited to, primary diagnosis, primary 
tumour location and disease status at baseline will also be listed and summarised using 
appropriate descriptive statistics. 
Relevant medical history and prior treatment for CRC, including, but not limited to systemic 
therapies, radiation and surgeries, will be listed and summarised using appropriate descriptive 
statistics. Full details will be provided in the SAP. 
13.5.2 Concomitant Medications 
Concomitant medications, coded using World Health Organisation Drug Dictionary (WHO 
DD) by WHO DD anatomical, therapeutic, chemical class and preferred term will be listed.  
Summaries may be produced for concomitant medications of specific interest, as determined 
by the study team physician, for example use of haematopoietic growth factors and 
transfusions. 
13.5.3 Extent of Exposure 
Descriptive statistics for patients treated, including the number of infusions received, total dose 
given, and infusions delayed or missed, will be presented. 
To understand the impact of dose reductions on the intended dosing regimen, dose intensity 
will also be listed and summarised. Dose intensity will be defined in the SAP. 
13.5.4 Safety Analysis 
Safety analyses in addition to those described in the following subsections may be determined 
at any time without prejudice in order to most clearly enumerate rates of toxicities and to define 
further the safety profile of NUC-3373 and/or any of the proposed combinations. 
13.5.4.1 
Adverse Events 
AEs will be considered treatment-emergent (TEAE) if they start on or after the time of the first 
dose of study treatment and up to 30 days after the last dose of study treatment. AEs will be 
summarised by Medical Dictionary for Regulatory Activities (MedDRA)™, Version 18.1 (or 
higher), System Organ Class (SOC) and preferred term. The severity of AEs will also be 
summarised by CTCAE v5.0 (or higher), Grade. Non-treatment-emergent AEs will be included 
in the patient listings and flagged as such but will not be included in the summary tables. Where 
an AE date is partial or missing, and it is unclear whether the AE is treatment-emergent, the 
AE will be assumed to be treatment-emergent. 

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The following summaries will be produced by dose cohort for all TEAEs: 
• An overview table of the incidence of TEAEs, Grade 3+ TEAEs, SAEs, treatment-
related TEAEs, TEAEs leading to treatment discontinuation, TEAEs leading to 
treatment interruption, and TEAEs leading to death, by dose and overall for each 
combination 
• Summary of TEAEs by SOC and preferred term: Both the number and percentage 
of patients in each category (patient-level summary) and the number of episodes 
(episode-level summary) 
• Summary of treatment-related TEAEs by SOC and preferred term 
• Summary of TEAEs occurring in at least 10% of patients, sorted in descending 
order of frequency (i.e., most frequent event shown first). The order of frequency 
will be determined by the most frequent preferred term across all cohorts. 
• Summary of CTCAE Grade 3 and above TEAEs by preferred term 
• Summary of TEAEs leading to NUC-3373 interruptions by SOC and preferred term 
• Summary of TEAEs leading to treatment discontinuation by SOC and preferred 
term for each study treatment 
• Summary of TEAEs by SOC, preferred term and maximum severity 
• Summary of TEAEs by SOC, preferred term and worst-case relationship attribution  
• Summary of SAEs by SOC and preferred term 
• Summary of SAEs by preferred term sorted in descending order of frequency 
Additionally, the following will be listed: 
• All AEs, listed with date of onset, study day, dose at onset, treatment status at onset 
(pre-treatment, ongoing or post-treatment) and Investigator’s assessment of severity 
and relationship to study drug. 
• AEs with outcome of death along with the date of onset, study day, dose at onset, 
treatment status at onset (pre-treatment, ongoing or post-treatment) and 
Investigator’s assessment of severity and relationship to study drug 
• All SAEs along with the date of onset, study day, dose at onset, treatment status at 
onset (pre-treatment, ongoing or post-treatment), date of resolution (if SAE is 
resolved), Investigator’s assessment of severity and relationship to study drug(s) 
• AEs leading to discontinuation of study medication, listed along with the date of 
onset, study day, dose at onset, treatment status at onset (pre-treatment, ongoing or 
post-treatment) and Investigator’s assessment of severity and relationship to study 
drug 
• AEs leading to treatment interruptions, listed along with the date of onset, study 
day, dose at onset, treatment status at onset (pre-treatment, ongoing or post-
treatment) and Investigator’s assessment of severity and relationship to study drug 
If an AE is reported more than once during the study period the greatest severity and the 
worst-case attribution will be presented in summary tables. Any AEs commencing >30 days 
after discontinuation of study treatment will not be included in the tabulations of AE data 

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13.5.4.2 
Laboratory Parameters 
Clinical laboratory data (actual and change from baseline) for continuous parameters at each 
scheduled assessment will be summarised using descriptive statistics including number of 
observations, mean, standard deviation, interquartile range (for overall only), minimum, 
median and maximum values. For categorical laboratory assessments, shift from baseline will 
be summarised using frequency and proportion at each scheduled assessment time. 
Additionally, data may be displayed graphically. Full details will be provided in the SAP. 
All clinical laboratory data for individual patients will be listed. 
13.5.4.3 
Vital Signs 
Actual values at baseline and each scheduled visit and change from baseline at each post-
baseline scheduled visit of vital signs (including pulse, respiration, systolic and diastolic blood 
pressure, oral temperature, and weight) will be summarised with descriptive statistics by dose 
cohort and time point. All data will also be listed.  
13.5.4.4 
ECOG Performance Status 
ECOG performance status will be summarised and listed. The ECOG Performance Scale is 
provided in Appendix 2. 
13.5.4.5 
Physical Examination 
Listings will be provided for physical examination parameters.  
13.5.4.6 
ECGs 
13.5.4.6.1 Safety ECGs 
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. ECG assessments may be retained for review centrally, where results will be 
provided to the study site and retained as source data. 
The triplicate values at each timepoint for a patient will be averaged, and the average value will 
be used in the summaries. Actual values at baseline and each scheduled visit and change from 
baseline at each post-baseline scheduled visit in ECG endpoints will be summarised with 
descriptive statistics by dose cohort and time point. Additionally, abnormal results will be 
summarised with frequencies and percentages by clinical significance, treatment group, and 
time point. All ECG data will be displayed in a data listing. 
13.5.4.6.2 Holter ECGs (PK sub-study) 
Holter ECG monitoring will be implemented for patients in the PK sub-study (Arm 2b) to 
collect QT/QTc data to allow robust analysis of ECG parameters. Holter monitoring will be 
performed on C1D8 and C1D22, when patients receive NUC-3373 + LV only.  
ECGs will be centrally evaluated. The analysis of ECG parameters for QT/QTc evaluation will 
be outlined in a separate QT SAP.  
 
 

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13.5.4.7 
Pharmacokinetics 
The PK of single and multiple-dose NUC-3373 will be assessed, including: 
• Cmax 
• AUC 
• t1/2 
• Vd 
• CL 
PK of the following will be measured, but are not limited to: 
• In plasma: NUC-3373, 5-FU, 5-FUDR, FBAL 
• Part 1 only: In PBMCs: NUC-3373, FUDR-MP, FBAL, 5-FUTP, dTMP and 
dUMP 
All above PK parameters will be analysed in the PK population. 
13.5.4.8 
Exploratory Endpoints 
Genomic, transcriptomic and proteomic biomarkers of biological activity will be analysed in a 
pre-treatment tumour sample and pre- and on-treatment blood and PBMC (Part 1 only) samples 
from patients in the intention-to-treat population.  The SAP will specify candidate biomarkers 
where known as well as the exploratory nature of the biomarker studies to be conducted and 
exploration of possible relationships, if evident, of relationships between PK exposure, PD 
effects, safety and clinical activity. 
13.5.5 Efficacy Analysis 
The primary efficacy endpoints and methods of analysis are defined below: 
13.5.5.1 
Change from Baseline in Tumour Size  
The percentage change from baseline in tumour size at 8-week intervals (%ΔTStimepooint) will 
be defined as follows: 
• Baseline tumour size (TSbaseline): sum of longest diameters of target lesions at 
baseline 
• On-study TS (TStimepoint): sum of longest diameters of target lesions at a post-
treatment disease assessment timepoint 
 
%∆TS𝑡𝑖𝑚𝑒𝑝𝑜𝑖𝑛𝑡= TS𝑡𝑖𝑚𝑒𝑝𝑜𝑖𝑛𝑡− TS𝑏𝑎𝑠𝑒𝑙𝑖𝑛𝑒
TS𝑏𝑎𝑠𝑒𝑙𝑖𝑛𝑒
 ×  100 
 
The best percentage change from baseline in tumour size (%ΔTSbest) across all timepoints will 
be calculated and presented using waterfall plots.  
The %ΔTSbest will be defined as follows:  
• Baseline tumour size (TSbaseline): sum of longest diameters of target lesions at 
baseline 

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• Best TS (TSbest):  smallest sum of longest diameters of target lesions observed at 
any timepoint, regardless of whether the assessment was scheduled or unscheduled, 
after first dose and prior to disease progression 
 
%∆𝑇𝑆𝑏𝑒𝑠𝑡= TS𝑏𝑒𝑠𝑡− TS𝑏𝑎𝑠𝑒𝑙𝑖𝑛𝑒
TS𝑏𝑎𝑠𝑒𝑙𝑖𝑛𝑒
 ×  100 
 
If a patient with measurable disease has no evaluable post-dose target lesion data, then they 
will be excluded from the waterfall plot of %ΔTSbest.  
Tumour size (%ΔTSWk8 and %ΔTSbest) will be presented graphically using waterfall plots for 
presenting each patient’s percentage change in tumour size as a separate bar with the bars 
ordered from the largest increase to the largest decrease.  Reference lines at the +20% and –
30% change in tumour size levels will be added to the plots, which correspond with the 
definitions of disease progression and PR, respectively.   
13.5.5.2 
Objective Response Rate (ORR) 
ORR is defined as the number of patients achieving a confirmed response (CR or PR), defined 
in accordance with RECIST v1.1 (see Appendix 1). The number and percentage of patients in 
each RECIST v1.1 response category (CR, PR, SD, progressive disease or not evaluable [NE]), 
as well as the ORR will be presented.  
All data will be listed. 
13.5.5.3 
Disease Control Rate (DCR) 
DCR is defined as the number of patients achieving confirmed response (CR and PR) or SD as 
a best overall response.  
DCR may be summarised if there are a number of patients achieving SD or response. 
13.5.5.4 
Duration of Response (DoR) 
DoR is defined for the subset of the EFR population categorised as responders for the 
assessment of ORR. DoR is defined as the time, in days, from the time measurement criteria 
are first met for CR or PR (whichever is first recorded) until the first date that recurrent or 
progressive disease is objectively documented (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started). Only responses that were later 
confirmed, will be considered when calculating the DoR. For patients who were lost to follow-
up without progression or reached the time point of analysis without a known record of death 
or progression, the DoR will be censored at the date of last tumour assessment. 
DoR will be listed, and may be summarised if there are sufficient responders. 
13.5.5.5 
Duration of Stable Disease (SD) 
SD is defined for the subset of the EFR population categorised as having neither sufficient 
shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease. Duration 
of SD is defined as the time, in days, from the time measurement criteria are first met for SD 
until the first date that recurrent or progressive disease is objectively documented (taking as 
reference for progressive disease the smallest measurements recorded since the treatment 
started). For patients who were lost to follow-up without progression or reached the time point 

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of analysis without a known record of death or progression, the duration of SD will be censored 
at the date of last tumour assessment. 
Duration of SD will be listed, and may be summarised if there are sufficient responders. 
13.5.5.6 
Progression-Free Survival (PFS) 
PFS is defined as the time from first dose of study treatment until the date of objective disease 
progression or death (by any cause in the absence of disease progression) regardless of whether 
the patient withdraws from study therapy prior to progression. Patients who start another 
anti-cancer therapy prior to progression will be censored at the date of the last available 
RECIST v1.1 assessment.  
Patients who have not experienced disease progression or died at the time of analysis will be 
censored at the time of the latest date of assessment from their last evaluable RECIST v1.1 
assessment.   
The PFS time will always be derived based on the scan/assessment dates rather than visit dates 
and the following rules will be applied: 
• Date of disease progression will be determined based on the earliest of the dates of the 
component that triggered the disease progression, i.e., if both the target lesions and the 
non-target lesions indicate disease progression but were scanned on different days, the 
earlier of the 2 dates would be applied   
• When censoring a patient for PFS the patient will be censored at the latest of the dates 
contributing to a particular overall visit assessment 
PFS will be presented using all available data up until the earlier of progression and starting 
subsequent therapy, or last evaluable RECIST v1.1 assessment in the absence of progression.  
The number of overall censored patients, number of patients with events and Kaplan-Meier 
estimates median time will be provided. In addition, the results will be presented graphically 
in Kaplan-Meier plots.  
13.5.5.7 
Overall Survival (OS) 
OS is defined as the time from Screening to the time of death due to any cause. For patients 
who are alive at the time of analysis, 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. 
The number of overall censored patients, number of patients with events and Kaplan-Meier 
estimates with 95% confidence intervals will be presented. 
13.5.6 Pharmacodynamic Endpoints (Part 1 only) 
Baseline and post-dose PBMC marker data will be analysed using a paired t test. Full details 
will be provided in the SAP. 
Boxplots for the change from baseline over time in neutrophils, platelets, and lymphocytes will 
also be produced. 
Full details of all planned analyses of PD endpoints will be provided in the SAP. 

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13.5.7 Primary and Interim Analyses   
The analysis of safety for a cohort will take place when all of the enrolled patients have 
completed one treatment cycle or have withdrawn from treatment. At least 3 evaluable patients 
are required for the analysis. The efficacy analysis of % change in tumour size will take place 
when all patients in a given cohort have undergone at least 2 imaging assessments for 
evaluation of percentage change in tumour size by RECIST v1.1 or have withdrawn from 
treatment. To enable the DSMC to make dose escalation decisions, safety and tolerability data 
will be reviewed on an ongoing basis. There will be no formal requirements for a database lock 
to support these ongoing reviews. Upon review of the safety and tolerability data from each 
cohort by the DSMC, additional patients may be added to a cohort to further evaluate the safety 
profile of the combination.  
13.5.8 Changes to the Planned Statistical Methods 
Planned statistical analyses will be documented in the final SAP before database lock. Any 
changes to the planned statistical methods will be documented in the CSR.  

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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 laboratory reports 
and MRI or CT scans. 
An eCRF will be used, please refer to the eCRF 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 the Sponsor 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 the Sponsor 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 the Sponsor or its 
representatives. This will be documented in a Clinical Study Agreement between 
the Sponsor and the Investigator 
During the study, a monitor from the Sponsor or appointed CRO 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. clinic charts) 
• Record and report any protocol deviations not previously sent to the Sponsor 
• Confirm AEs and SAEs have been properly documented in the eCRFs and confirm 
any SAEs have been forwarded to the Sponsor or designee, and those SAEs that 
met criteria for reporting have been forwarded to the IRB/EC 
The monitor will be available between visits if the Investigator or other staff needs information 
or guidance.  
Note: during the COVID-19 pandemic, remote visits may replace on-site visits for as short a 
period of time as possible. 

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14.3 
 Patient Confidentiality 
Personal data recorded on all documents will be regarded as highly confidential. To preserve 
each patient’s anonymity, only their patient study number and date of birth (or other identified 
as appropriate to country regulations and agreed with the Sponsor) will be recorded on the 
eCRFs.  
The Investigator site must maintain the patient’s anonymity in all communications and reports 
related to the research.  The Investigator site team must keep a separate log of enrolled patients’ 
personal identification details as necessary to enable them to be tracked.   These documents 
must be retained securely, in strict confidence. They form part of the Investigator Site File and 
are not to be released externally.  

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15 
ETHICAL AND REGULATORY CONSIDERATIONS 
15.1 
Good Clinical Practice Compliance 
The Sponsor, 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 to safeguard the 
rights, safety, and well being 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 Sponsor or 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 the US, 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 
Protocol Amendments 
All protocol amendments (and amendments to related study documentation) will be approved 
by the applicable IRBs/ECs and Regulatory Authorities prior to implementation. 
15.5 
Protocol Violations and 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 the Sponsor 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/ or primary endpoint criteria. Deviations 
will be tracked by the CRO along with the corrective and preventative actions by responsible 
party.  
A protocol violation occurs when there is nonadherence to the protocol that results in a 
significant, additional risk to the patient, when the patient or Investigator has failed to adhere 
to significant protocol requirements (e.g., inclusion/ criteria and the patient was enrolled 
without prior Sponsor approval), or when there is nonadherence to the FDA or other applicable 
ICH-GCP guidelines. 
The clinical monitor will document protocol violations and deviations throughout the course 
of monitoring visits. The monitor will notify the Investigators during a visit and in writing of 
all violations and deviations. The IRB/EC should be notified of all protocol violations and 
deviations in a timely manner. 

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15.6 
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 the CRO within one working day if any serious breach of ICH-GCP 
or the protocol is suspected. Upon confirmation of a serious breach, the CRO will notify the 
applicable Regulatory Authorities. Typically, serious breach notifications should be made 
within seven days of the CRO becoming aware; however, this timeline may differ as specified 
by applicable local regulatory requirements. 
15.7 
Study Reporting Requirements 
The Investigator agrees to submit progress reports to their IRB/EC as appropriate. The 
Investigator also agrees to provide the Sponsor with an adequate report shortly after completion 
of their participation in the study. 
15.8  Financial disclosure 
The Investigators and Sub-Investigators are required to provide financial disclosure 
information to allow the sponsor to submit the complete and accurate certification or disclosure 
statements required under 21 CFR 54. In addition, the Investigator and Sub-Investigators must 
provide the sponsor with a commitment to update this information promptly if any relevant 
changes occur during the investigation and for one year after study completion. 
Neither the sponsor nor the CRO is financially responsible for further testing/treatment of any 
medical condition which may be detected during the screening process. In addition, in the 
absence of specific arrangements, neither the sponsor nor the CRO is financially responsible 
for further treatment of the patient’s disease. 
15.9  Investigator Documentation 
Before beginning the study, each investigative site will have all applicable essential documents 
available, in accordance with ICH-GCP section 8.2. 
15.10 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-3373 clinical development. These documents should be retained for a 
longer period, however, if required by the applicable regulatory requirements or by an 
agreement with the sponsor. It is the responsibility of the sponsor 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, the sponsor should be prospectively notified. The study records must be 
transferred to a designee acceptable to the sponsor, such as another Investigator, another 
institution, or to an independent third party arranged by the sponsor. The Investigator must 
obtain written permission from the sponsor before disposing of any records, even if retention 
requirements have been met. Retention and storage of central laboratory records supporting PK 

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endpoints and the disposition of samples donated via the study must also comply with 
applicable legislation. 
15.11  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 the sponsor representatives of the sponsor, the FDA, or other regulatory agency 
access to all study records. 
The Investigator should promptly notify the sponsor and the appointed CRO of any audits 
scheduled by any regulatory authorities and promptly forward copies of any audit reports 
received to the sponsor.  

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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 Sponsor 
The sponsor shall publicly disclose study results through posting on ClinicalTrials.gov, the 
European Clinical Trials Database (EudraCT) and any other applicable public registries in 
accordance with local laws and regulations. 
Final study results may 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 may be posted to EudraCT within one year of the end of study. 
 
16.2 
Publication by Investigators 
Investigators may not publish or disclose results until the study is completed. In addition, 
Investigators shall acknowledge that, due to the limited patient population in its treatment 
group, the data generated from its individual participation in the study and evaluation of its 
individual results, may not be sufficient from which to draw any meaningful scientific 
conclusion. 
The sponsor will provide authorship rights to Investigators in order of greatest contribution of 
evaluable patients to the study. Publication of study results may also be described in the 
agreement between the sponsor and each Institution. In addition, the Sponsor may form a 
publication committee to evaluate and give final approval of publication submission. 
The proposed publication (manuscript, abstract or poster) or presentation will be provided to 
the sponsor 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 the sponsor’s prior written 
approval.  
The Investigator agrees, upon sponsor’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 (http://www.icmje.org/icmje-recommendations.pdf). 
 
 

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17 
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18 APPENDICES 
APPENDIX 1. RESPONSE EVALUATION CRITERIA IN SOLID 
TUMOURS (RECIST) VERSION 1.1 
The following paragraphs are a quick reference to the RECIST criteria (v1.1). The complete 
criteria are available at http://www.eortc.be/RECIST and are included in the published RECIST 
document: 
Eisenhauer et al. New response evaluation criteria in solid tumours: revised RECIST guideline 
(version 1.1). Eur J Cancer 2009; 45: 228–247. 
 
Measurability of Tumour Lesions at Baseline – Definitions 
Measurable disease – the presence of at least one measurable lesion. If the measurable disease 
is restricted to a solitary lesion, its neoplastic nature should be confirmed by 
cytology/histology. 
Measurable lesions – tumour lesions that can be accurately measured in at least one dimension 
(longest diameter to be recorded) as ≥20 mm with chest x-ray, and as ≥10 mm with CT scan or 
clinical examination [using callipers]. Bone lesions are considered measurable only if assessed 
by CT scan and have an identifiable soft tissue component that meets these requirements (soft 
tissue component ≥10 mm by CT scan). Malignant lymph nodes must be ≥15 mm in the short 
axis to be considered measurable; only the short axis will be measured and followed. All 
tumour measurements must be recorded in millimetres (or decimal fractions of centimetres) by 
use of a ruler or callipers. Tumour lesions situated in a previously irradiated area, or in an area 
subjected to other loco-regional therapy, are usually not considered measurable unless there 
has been demonstrated progression in the lesion. 
Non-measurable lesions – all other lesions (or sites of disease), including small lesions are 
considered non-measurable disease. Bone lesions without a measurable soft tissue component, 
leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonis, 
inflammatory breast disease, lymphangitic involvement of lung or skin and abdominal masses 
followed by clinical examination are all non-measurable. Nodes that have a short axis <10 mm 
at baseline are considered non-pathological and should not be recorded or followed. 
Target lesions – when more than one measurable tumour lesion or malignant lymph node is 
present at baseline all lesions up to a maximum of 5 lesions total (and a maximum of 2 lesions 
per organ) representative of all involved organs should be identified as target lesions and will 
be recorded and measured at baseline. Target lesions should be selected on the basis of their 
size (lesions with the longest diameter), be representative of all involved organs, but in addition 
should be those that lend themselves to reproducible repeated measurements. Note that 
pathological nodes must meet the criterion of a short axis of ≥15 mm by CT scan and only the 
short axis of these nodes will contribute to the baseline sum.  
At baseline, the sum of the target lesions (longest diameter of tumour lesions plus short axis of 
lymph nodes: overall maximum of 5) is to be calculated and recorded. 
Non-target lesions – all non-measurable lesions (or sites of disease) including pathological 
nodes (those with short axis ≥10 mm but <15 mm), plus any measurable lesions over and above 
those listed as target lesions are considered non-target lesions. Measurements are not required 
but these lesions should be noted at baseline and should be followed as “present” or “absent”. 

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All baseline evaluations should be performed as closely as possible to the beginning of 
treatment and never more than 4 weeks before the beginning of the treatment. 
Methods of Measurements 
The same method of assessment and the same technique should be used to characterise each 
identified and reported lesion at baseline and during follow-up. Assessments should be 
identified on a calendar schedule and should not be affected by delays in therapy, which may 
be treatment arm dependent. While on study, all target lesions recorded at baseline should have 
their actual measurements recorded on the CRF at each subsequent evaluation, even when very 
small (e.g., 2 mm). If it is the opinion of the radiologist that the lesion has likely disappeared, 
the measurement should be recorded as 0 mm. If the lesion is believed to be present and is 
faintly seen but too small to measure, a default value of 5 mm should be assigned. For lesions 
which fragment/split add together the longest diameters of the fragmented portions; for lesions 
which coalesce, measure the maximal longest diameter for the “merged lesion”. 
Clinical lesions – clinical lesions will only be considered measurable when they are superficial 
and ≥10 mm as assessed using callipers (e.g., skin nodules). For the case of skin lesions, 
documentation by colour photography including a ruler to estimate the size of the lesion is 
recommended. If feasible, imaging is preferred. 
Chest X-ray – chest CT is preferred over chest X-ray, particularly when progression is an 
important endpoint, since CT is more sensitive than X-ray, particularly in identifying new 
lesions. However, lesions ≥20 mm on chest X-ray may be considered measurable if they are 
clearly defined and surrounded by aerated lung. 
CT, MRI – CT is the best currently available and reproducible method to measure lesions 
selected for response assessment. This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT slice thickness is 5 mm or less. When CT scans have 
slice thickness greater than 5 mm, the minimum size for a measurable lesion should be twice 
the slice thickness. MRI is also acceptable in certain situations (e.g., for body scans). While 
PET scans are not considered adequate to measure lesions, PET-CT scans may be used 
providing that the measures are obtained from the CT scan and the CT scan is of identical 
diagnostic quality to a diagnostic CT (with IV and oral contrast). 
Ultrasound – ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement. If new lesions are identified by ultrasound in the course of the study, 
confirmation by CT should be obtained. 
Endoscopy, Laparoscopy – the utilisation of these techniques for objective tumour evaluation 
is not advised. However, they can be useful to confirm complete pathological response when 
biopsies are obtained or to determine relapse in studies where recurrence following complete 
response or surgical resection is an endpoint. 
Tumour markers – tumour markers alone cannot be used to assess objective tumour response. 
If markers are initially above the upper normal limit, however, they must normalise for a patient 
to be considered in complete response. 
Cytology, Histology – these techniques can be used to differentiate between PR and CR in rare 
cases if required by protocol (for example, residual lesions in tumour types such as germ cell 
tumours, where known residual benign tumours can remain). When effusions are known to be 
a potential adverse effect of treatment (e.g. with certain taxane compounds or angiogenesis 
inhibitors), the cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumour has met criteria for response or stable 
disease is advised to differentiate between response or stable disease and progressive disease. 

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Tumour Response Evaluation 
All patients will have their BEST RESPONSE from the start of study treatment until the end 
of treatment classified as outlined below. Complete or PRs may be claimed only if the criteria 
for each are met at a subsequent time point at least 4 weeks later. Refer to the Appendix 1, 
Tables 1 and 2 below. 
Complete Response (CR) – disappearance of all target and non-target lesions and 
normalisation of tumour markers. Pathological lymph nodes must have short axis measures 
<10 mm (Note: continue to record the measurement even if <10 mm and considered CR). 
Tumour markers must have normalised. Residual lesions (other than nodes <10 mm) thought 
to be non-malignant should be further investigated (by cytology or PET scans) before CR can 
be accepted.  
Partial Response (PR) – at least a 30% decrease in the sum of measures (longest diameter for 
tumour lesions and short axis measure for nodes) of target lesions, taking as reference the 
baseline sum of diameters. Non-target lesions must be non-PD.  
Stable Disease (SD) – neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD taking as reference the smallest sum of diameters on study. 
Progressive Disease (PD) – at least a 20% increase in the sum of diameters of measured lesions 
taking as references the smallest sum of diameters recorded on study (including baseline) AND 
an absolute increase of ≥5 mm. Appearance of new lesions will also constitute PD (including 
lesions in previously unassessed areas). In exceptional circumstances, unequivocal progression 
of non-target disease may be accepted as evidence of disease progression, where the overall 
tumour burden has increased sufficiently to merit discontinuation of treatment, for example 
where the tumour burden appears to have increased by at least 73% in volume (which is the 
increase in volume when all dimensions of a single lesion increase by 20%). Modest increases 
in the size of one or more non-target lesions are NOT considered unequivocal progression. If 
the evidence of PD is equivocal (target or non-target), treatment may continue until the next 
assessment, but on further documentation, the earlier date must be used. 
 
 

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Appendix 1.  Table 1.  Integration of Target, Non-Target and New Lesions into Response 
Assessment 
Target 
Lesions 
Non-Target Lesions 
New 
Lesions 
Overall 
Response 
Best Response for this 
Category Also Requires 
Patients with target lesions ± non-target lesions 
CR 
CR 
No 
CR 
Normalisation of tumour 
markers 
All tumour nodes <10 mm 
Documented at least once 
≥4 weeks from baseline 
CR 
Non-CR/Non-PD 
No 
PR 
Documented at least once 
≥4 weeks from baseline 
CR 
Not all evaluated 
No 
PR 
PR 
Non-PD/ not all evaluated 
No 
PR 
SD 
Non-PD/ not all evaluated 
No 
SD 
 
Not all 
evaluated 
Non-PD 
No 
NE 
 
PD 
Any 
Any 
PD 
 
Any 
PD 
Any 
PD 
 
Any 
Any 
Yes 
PD 
 
Note: Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression (or evidence of unequivocal disease progression) 
at that time should be reported as “symptomatic deterioration”. This is a reason for stopping therapy, 
but is NOT objective PD. Every effort should be made to document the objective progression even 
after discontinuation of treatment. 
 
Complete or partial responses may be claimed only if the criteria for each are met at a 
subsequent time point at least 4 weeks later. The best overall response can be interpreted from 
Appendix 1 Table 2 on the next page. 
 
 

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Appendix 1.  Table 2.  Response Assessment after Subsequent Scan 
Response: First 
Time Point 
Subsequent 
Time Point 
BEST Overall Response 
Also Requires 
CR 
CR 
CR 
Normalisation of tumour 
markers. All tumour nodes 
<10 mm. 
CR 
PR 
SD, PD or PR (see comment*) 
 
CR 
SD 
SD provided minimum criteria for SD 
duration met, otherwise, PD 
 
CR 
PD 
SD provided minimum criteria for SD 
duration met, otherwise, PD 
 
CR 
NE 
SD provided minimum criteria for SD 
duration met, otherwise NE 
 
PR 
CR 
PR 
 
PR 
PR 
PR 
 
PR 
SD 
SD 
 
PR 
PD 
SD provided minimum criteria for SD 
duration met, otherwise, PD 
 
PR 
NE 
SD provided minimum criteria for SD 
duration met, otherwise NE 
 
NE 
NE 
NE 
 
* may consider PR providing initial “CR” likely PR on subsequent review – then original CR should be 
corrected. Recurrence of lesion after true CR is PD.  
 
Frequency of Tumour Re-Evaluation 
Tumours should be assessed at the end of every 2nd cycle. 
Date of Progression 
This is defined as the first day when the RECIST (v1.1) criteria for PD are met. 
Reporting of Tumour Response 
All patients included in the study must be assessed for response to treatment, even if there is a 
major protocol treatment deviation or if they are ineligible, or not followed/re-evaluated. Each 
patient will be assigned one of the following categories: complete response, partial response, 
stable disease, progressive disease, early death from malignant disease, early death from 
toxicity, early death from other cause or unknown (not assessable, insufficient data). 
‘Early death’ is defined as any death occurring before the first per protocol time point of tumour 
re-evaluation. The responsible Investigator will decide if the cause of death is malignant 
disease, toxicity or other cause. Patients for whom response is not confirmed will be classified 
as "unknown", unless they meet the criteria for stable disease (or the criteria for partial response 
in case of an unconfirmed complete response). Patients’ response will also be classified as 
"unknown" if insufficient data were collected to allow evaluation per these criteria. 

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APPENDIX 2. 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 
 
 
 

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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 market) 
Hismanal® 
Azithromycin 
Zithromax®, Zmax® 
Bepridil  
Vascor® 
Cesium chloride 
Energy catalyst  
Chloroquine 
Aralen® 
Chlorpromazine 
Thorazine®, Largactil®, Megaphen® 
Chlorprothixene (only on non-US 
market) 
Truxal® 
Cilostazol 
Pletal® 
Ciprofloxacin 
Cipro®, Cipro-XR®, Neofloxin® 
Cisapride (removed from 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® 
Gatifloxacin (removed from US 
market) 
Tequin® 

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Generic Name 
Brand Names (Partial List) 
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® 
Hydoquinidine (Dihydroquinidine) 
(only on non-US market) 
Serecor® 
Hydroxychloroquine  
Plaquenil®, Quineprox® 
Ibogaine (only on non-US market) 
None 
Ibutilide 
Corvert® 
Levofloxacin 
Levaquin®, Tavanic® 
Levomepromazine (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) 
Meglumine antimoniate (only on non-
US market) 
Glucantime® 
Mesoridazine (removed from US 
market) 
Serentil® 
Methadone 
Dolophine®, Symoron®, Amidone®, Methadose®, Physeptone®, 
Heptadon® 
Mobocertinib 
Exkivity® 
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 (intra-coronary) 
None 
Pentamidine 
Pentam® 
Pimozide 
Orap® 
Probucol (removed from 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®  
Sertindole (only on non-US market) 
Serdolect®, Serlect® 
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® 
* Except as included in the specific arms and dosing regimens of this study. 
Note: Medicines on this 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.  
 
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. 
 
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, [Accessed August 
2022], AZCERT, Inc. 1822 Innovation Park Dr., Oro Valley, AZ  85755, USA. 
See more at: https://www.crediblemeds.org/#sthash.vzyRSgay.dpuf  
  
 
 

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APPENDIX 4. MANAGEMENT GUIDE FOR DIARRHOEA 
Patients receiving 5-FU are at risk for developing diarrhoea.  This side effect often leads to 
delay in treatment, dose reduction or discontinuation of treatment.  There is a small but 
significant mortality associated with chemotherapy-induced diarrhoea (CID), especially when 
it occurs concomitantly with mucositis and neutropaenia. 
Classification  
Chemotherapy-induced diarrhoea is graded using the NCI criteria (Appendix 4 Table 1) which 
grades diarrhoea on a scale of 0 (normal) to 4 (severe) according to the number of loose 
stools/days, presence of nocturnal stools, incontinence, cramping and blood in stools. 
Appendix 4 Table 1.  NCI criteria for assessment of chemotherapy-induced diarrhoea 
Criteria 
GRADE 
0 
1 
2 
3 
4 
Number of 
stools per day 
Normal 
2–3 
4-6 
7-9 
>10 
Symptom 
- 
- 
Nocturnal stools Incontinence 
Bloody stool 
- 
- 
Moderate 
cramping 
Severe 
cramping 
Need for 
parenteral fluid 
 
Management 
CID can be a serious complication and requires prompt assessment. The steps in this 
assessment are as follows: 
1. Rule out other or concomitant causes of diarrhoea 
Other causes of diarrhoea must be ruled out.  These include medications (e.g. stool softeners, 
laxatives, antacids, etc), infection by C. difficile or Candida species, partial bowel obstruction, 
malabsorption, faecal impaction, acute radiation reaction and surgery (short bowel syndrome).   
Diets high in fibre or lactose may aggravate diarrhoea. 
 
2. Dietary modifications during diarrohea 
Mild diarrhoea may be managed with diet to decrease the frequency of stools.  Patients should 
be advised to increase intake of clear fluids (e.g., water, sports drinks, broth, gelatin, clear 
juices, decaffeinated tea, caffeine-free soft drinks).  A BRAT (banana, rice, apples, toast) diet 
can be helpful. 
 
3. Medications 
• Loperamide 
Loperamide is indicated for Grade 1 diarrhoea that persists for more than 12-24 hours 
or for moderate diarrhoea (Grade 2).  The standard dose of loperamide is 4 mg followed 
by 2 mg every 4 hours or after each unformed stool (maximum dose 16 mg/day).    This 
dose may be increased in patients with mild to moderate diarrhoea (Grade 1 or 2) that  

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• persists for more than 24 hours.   The dose is 4 mg to start, followed by 2 mg every 2 
hours (or 4 mg every 4 hours at night to allow sleep). Loperamide should be continued 
for 12 hours following resolution of the diarrhoea and re-establishment of a normal diet. 
High-dose loperamide (4 mg followed by 2 mg every 2 hours) is also recommended at 
the onset of any diarrhoea in patients receiving irinotecan chemotherapy. 
• Atrophine-diphenoxylate  
At the discretion of the treating physician, it may be useful to add atropine- 
diphenoxylate 1 to 2 tablets, every 6-8 hours, to loperamide therapy for Grade 1 or 2 
diarrhoea.  It should not be expected that this would be sufficient for the management 
of Grade 3 or 4 diarrhoea. 
 
• Octreotide 
For Grades 1 and 2 diarrhoea lasting more than 24 hours despite high-dose loperamide 
+ atrophine-diphenoxylate, octreotide 100-150 mcg SC TID may be considered.  For 
Grades 3 and 4 diarrhoea, octreotide 150 mcg SC TID is indicated; these patients 
usually require hospitalisation. If there is no improvement in the diarrhoea after 24 
hours, the dose of octreotide should be increased to 300-500 mcg SC TID. The duration 
of octreotide therapy should be individualised, but can be discontinued 24 hours after 
the end of diarrhoea and re-establishment of a normal diet. Alternatively, octreotide 
may be administered via a syringe driver with infusion over 24 hours of 600 mcg 
octreotide. If not controlled each day, increase the dose to 1200 mcg, then 1800 mcg, 
then 2400 mcg, but not beyond this daily dose. If diarrhoea is controlled, then octreotide 
can be de-escalated. 
 
• Antibiotics 
In the presence of concomitant neutropaenia (granulocytes <1×106/L), antibiotics (e.g., 
ciprofloxacin 500 mg BID) should be considered until resolution of diarrhoea and 
recovery of the granulocyte counts. In addition, oral antibiotics (minocycline, 
doxycycline, or antibiotics covering skin flora) should be given to prevent or treat 
EGFR inhibitor-related rash. 
 
Avoid the use of diuretics, laxatives and other agents know to exacerbate diarrhoea.