Clinical trial NCT03146663
Conditions: Ovarian Cancer
Keywords: Platinum-resistant ovarian neoplasm antineoplastic agents ovarian diseases cancer of the ovary
Sponsor: NuCana plc
Start date: 2017-09-28; Completion date: 2019-12-31
Enrollment: 53 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study was designed to evaluate the effect of two dose levels of NUC-1031 (500 mg/m2 and 750mg/m2) in patients with ovarian cancer. The primary objective was to determine the anti-tumor activity of NUC-1031 at the selected dose level (500 mg/m2 or 750 mg/m2).

Detailed description:
A total of 53 patients were randomized, of whom 51 patients were treated in Part I of the study, 24 patients in the 500 mg/m2 arm and 27 patients in the 750 mg/m2 arm. Eligible, consenting patients received NUC-1031 by IV infusion on Days 1, 8, and 15 of each 28-day cycle. Patients continued to receive NUC-1031 until the occurrence of disease progression and underwent imaging every 8 weeks. After disease progression, patients were followed for overall survival.

Part II of the study was designed to select one of the treatment dose levels for further evaluation based on clinical and laboratory assessments of patients recruited in Part I. Despite promising efficacy and a good tolerability profile in Part I, it was decided not to initiate Part II as the pre-specified boundary for efficacy was uncertain to be met in this heavily pre-treated population with significant co-morbidities.

Arms: arm 1: NUC-1031 500 mg/m2 administered on Days 1, 8, and 15 of 28-day cycles arm 2: NUC-1031 750 mg/m2 administered on Days 1, 8, and 15 of 28-day cycles
Interventions: intervention 1: NUC-1031 500 mg intervention 2: NUC-1031 750mg
Intervention descriptions: intervention 1: NUC-1031 500 mg/m2 on Days 1, 8, and 15 of a 28-day cycle. intervention 2: NUC-1031 750 mg/m2 on Days 1, 8, and 15 of a 28-day cycle

Protocol documents:
Prot_000.pdf: 
 
 
CLINICAL STUDY PROTOCOL 
 
A Phase II Open-Label Study of NUC-1031 in Patients 
with Platinum-Resistant Ovarian Cancer 
 
NCT Number: 
NCT03146663 
Date: 
11 October 2017 


PRO-105 
 
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2 
 
 
CLINICAL STUDY PROTOCOL 
 
A Phase II Open-Label Study of NUC-1031 in Patients 
with Platinum-Resistant Ovarian Cancer 
 
IMP: 
NUC-1031 
Protocol #: 
PRO-105 
Protocol Version, Date: 
Version 2.5, 11 October 2017_FINAL 
Development Phase: 
II 
IND #: 
130348 
EudraCT #: 
2016-003287-39 
Sponsor: 
NuCana plc 
3 Lochside Way 
Edinburgh, EH12 9DT, UK 
Tel: +44 (0)131 357 1111 
Medical Monitor: 
Jaroslaw Jac, MD 
Chiltern International Inc 
4000 Centregreen Way, Suite 300 
Cary, North Carolina, 27513, USA 
Tel: +1 978 697 9099 
Email: Jaroslaw.Jac@Chiltern.com 
 
CONFIDENTIALITY STATEMENT 
This confidential document is the property of NuCana plc. No unpublished information 
contained herein may be disclosed without prior written approval from NuCana. Access 
to this document must be restricted to relevant parties.  
 


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PRINCIPAL INVESTIGATOR AGREEMENT AND 
SIGNATURE 
 
A Phase II Open-Label Study of NUC-1031 in Patients 
with Platinum-Resistant Ovarian Cancer 
 
Protocol #: 
PRO-105 
Protocol Version, Date: 
Version 2.5, 11 October 2017 
IMP: 
NUC-1031 
Development Phase: 
II 
Sponsor: 
NuCana plc 
IND #: 
130348 
EudraCT #: 
2016-003287-39 
 
This study will be conducted in compliance with the clinical study protocol (and amendments), 
International Conference on Harmonisation guidelines for current Good Clinical Practice 
(ICH-GCP) and applicable regulatory requirements. Compliance with ICH-GCP standards 
provides assurance that the rights, safety, and wellbeing of study patients are protected, 
consistent with the principles that have their origin in the Declaration of Helsinki. 
 
 
 
 
Principal Investigator’s signature 
 
 
 
 
Date (dd-Mmm-yyyy) 
Principal Investigator’s name (printed)  
 
 
 
 


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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS .............................................................................................................. 8 
SUMMARY SCHEDULE OF EVENTS .................................................................................... 12 
ABBREVIATIONS ...................................................................................................................... 15 
1 
INTRODUCTION AND STUDY RATIONALE ................................................................ 17 
1.1 
Treatment Options for Recurrent Ovarian Cancer ................................................................ 17 
1.2 
Treatment for Platinum-Resistant Ovarian Cancer ............................................................... 17 
1.3 
Gemcitabine in Ovarian Cancer ............................................................................................ 18 
1.3.1 Gemcitabine Resistance ...................................................................................................... 18 
1.4 
NUC-1031 ............................................................................................................................ 19 
1.4.1 Nonclinical Data ................................................................................................................. 19 
1.4.2 Clinical Data ....................................................................................................................... 19 
1.4.3 Pharmacokinetics ................................................................................................................ 20 
1.5 
Study Rationale..................................................................................................................... 21 
2 
STUDY OBJECTIVES AND ENDPOINTS ....................................................................... 21 
2.1 
Primary Objective ................................................................................................................. 22 
2.2 
Secondary Objectives ........................................................................................................... 22 
2.3 
Exploratory Objectives ......................................................................................................... 22 
2.4 
Primary Endpoint .................................................................................................................. 22 
2.5 
Secondary Endpoints ............................................................................................................ 23 
2.6 
Pharmacokinetics .................................................................................................................. 23 
2.7 
Exploratory Endpoints .......................................................................................................... 23 
3 
INVESTIGATIONAL PLAN ............................................................................................... 24 
3.1 
Overall Study Design ............................................................................................................ 24 
3.2 
Rationale for the NUC-1031 Dose Selected ......................................................................... 25 
3.3 
Study Treatment ................................................................................................................... 25 
3.4 
Duration of Patient Participation .......................................................................................... 25 
3.5 
Patient Selection and Study Centers ..................................................................................... 26 
4 
PATIENT SELECTION ....................................................................................................... 26 
4.1 
Inclusion Criteria .................................................................................................................. 26 
4.2 
Exclusion Criteria ................................................................................................................. 27 
4.3 
Waivers to Entry Criteria ...................................................................................................... 28 
4.4 
Study Completion ................................................................................................................. 28 
5 
STUDY ASSESSMENTS AND PROCEDURES ................................................................ 28 
5.1 
Informed Consent ................................................................................................................. 28 
5.1.1 Informed Consent for Tumor Tissue Collection ................................................................. 29 
5.2 
Patient Registration and Screening Procedures .................................................................... 29 
5.3 
Screening Assessments ......................................................................................................... 30 
5.4 
Re-Screening Patients Who Fail Inclusion/Exclusion Criteria ............................................. 31 


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5.5 
Evaluations to Be Performed During the Study ................................................................... 31 
5.5.1 Each Cycle, Day 1 .............................................................................................................. 31 
5.5.2 For Sites Collecting Optional Fresh Biopsy: Within 24 Hours of Cycle 1 Day 1 .............. 32 
5.5.3 For Sites Participating in PK Sample Collection: Cycles 1 & 3 – Days 1 & 2 .................. 32 
5.5.4 Each Cycle, Days 8 & 15 .................................................................................................... 32 
5.5.5 For Sites Participating in PK sample Collection: Cycle 1 Days 15 & 16 ........................... 33 
5.5.6 Every 8 Weeks (±7 days) from Cycle 1 Day 1 Until Disease Progression, Initiation of a New 
Treatment or Death ........................................................................................................................ 34 
5.5.7 End of Treatment Visit ....................................................................................................... 34 
5.5.8 Follow-Up ........................................................................................................................... 35 
6 
PATIENT WITHDRAWAL ................................................................................................. 35 
6.1 
End of Treatment .................................................................................................................. 35 
6.2 
Follow-Up After Treatment Discontinuation ....................................................................... 36 
6.3 
Consent Withdrawal ............................................................................................................. 36 
6.4 
Patient Evaluability and Replacement .................................................................................. 36 
7 
SAMPLES FOR LABORATORY ANALYSIS .................................................................. 36 
7.1 
Clinical Laboratory Tests ..................................................................................................... 36 
7.2 
Pharmacokinetics .................................................................................................................. 36 
7.3 
Tumor Tissue Biopsies ......................................................................................................... 37 
7.4 
Labeling and Confidentiality of Biological Samples ............................................................ 38 
7.5 
Withdrawal of Consent for Biological Sample Collection or Retention .............................. 38 
8 
INVESTIGATIONAL MEDICINAL PRODUCT .............................................................. 38 
8.1 
NUC-1031 Description ......................................................................................................... 38 
8.2 
NUC-1031 Supplies and Study Drug Packaging .................................................................. 38 
8.3 
Handling and Storage ........................................................................................................... 38 
8.4 
Preparation ............................................................................................................................ 39 
8.5 
Study Drug Dosage and Administration ............................................................................... 39 
8.6 
Drug Destruction .................................................................................................................. 39 
8.7 
Study Drug Accountability ................................................................................................... 39 
8.8 
Management of NUC-1031 Overdose .................................................................................. 40 
9 
DOSE MODIFICATIONS .................................................................................................... 40 
9.1 
Hematological Toxicity – Dose Adjustment ........................................................................ 40 
9.2 
Non-Hematological Toxicity – Dose Adjustment ................................................................ 42 
9.3 
Guidance for Dose Omissions .............................................................................................. 43 
10 OTHER TREATMENTS (NON-IMP) ................................................................................ 43 
10.1 
Support Medication ............................................................................................................ 43 
10.2 
Hematopoietic Growth Factor Support ............................................................................... 43 
10.3 
Concomitant Medication and Non-Drug Therapies............................................................ 43 
10.3.1 Contraception Methods ....................................................................................................... 44 
10.4 
Prohibited Therapy and Concomitant Medications ............................................................ 45 


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11 TUMOR RESPONSE ASSESSMENTS .............................................................................. 45 
11.1 
Tumor Measurements and Assessment of Disease Response ............................................ 45 
12 SAFETY REPORTING ........................................................................................................ 46 
12.1 
Definitions .......................................................................................................................... 46 
12.2 
Adverse Event Reporting .................................................................................................... 47 
12.3 
Assessment of Causality ..................................................................................................... 48 
12.4 
Assessment of Severity ....................................................................................................... 48 
12.5 
SAE Reporting .................................................................................................................... 49 
12.6 
Expedited Reporting of SAEs ............................................................................................. 49 
12.7 
SUSAR Reporting .............................................................................................................. 50 
12.8 
Terms and Grading of Events ............................................................................................. 50 
12.9 
Pregnancy ........................................................................................................................... 50 
12.10 Events Exempt from Being Reported as AE/SAEs ............................................................ 51 
12.10.1 Progression of Underlying Disease ................................................................................... 51 
12.10.2 Death on Study Attributed to Malignancy ........................................................................ 51 
12.10.3 Elective Admissions and Supportive Care ........................................................................ 51 
12.11 Informing Investigators of New Safety Information .......................................................... 51 
12.12 Reference Safety Information (RSI) for Assessment of Expectedness .............................. 52 
12.13 Data Safety Monitoring Committee (DSMC) ..................................................................... 52 
13 STATISTICAL CONSIDERATIONS ................................................................................. 53 
13.1 
Sample Size ........................................................................................................................ 53 
13.2 
Missing, Unused and Spurious Data ................................................................................... 53 
13.3 
Analysis Populations .......................................................................................................... 53 
13.4 
Patient Disposition .............................................................................................................. 54 
13.5 
Statistical Methods ............................................................................................................. 54 
13.5.1 Demographics and Baseline Data ....................................................................................... 54 
13.5.2 Concomitant Medications ................................................................................................... 54 
13.5.3 Extent of Exposure ............................................................................................................. 54 
13.5.4 Efficacy Analysis ................................................................................................................ 55 
13.5.5 PRO Analysis ..................................................................................................................... 56 
13.5.6 Safety Analysis ................................................................................................................... 56 
13.5.7 Primary Analysis and Interim Analyses ............................................................................. 58 
13.5.8 Changes to the Planned Statistical Methods ....................................................................... 58 
14 PATIENT DATA HANDLING AND CONFIDENTIALITY ........................................... 59 
14.1 
Case Report Forms ............................................................................................................. 59 
14.2 
Monitoring of the Study ..................................................................................................... 59 
14.3 
Patient Confidentiality ........................................................................................................ 59 
15 ETHICAL AND REGULATORY CONSIDERATIONS .................................................. 60 
15.1 
Good Clinical Practice Compliance .................................................................................... 60 
15.2 
Institutional Review Board/ Ethics Committees ................................................................. 60 


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15.3 
Regulatory Authority Approval .......................................................................................... 60 
15.4 
Protocol Amendments ........................................................................................................ 60 
15.5 
Protocol Violations and Deviations .................................................................................... 60 
15.6 
Serious Breaches ................................................................................................................. 61 
15.7 
Study Reporting Requirements ........................................................................................... 61 
15.8 
Financial Disclosure ........................................................................................................... 61 
15.9 
Investigator Documentation................................................................................................ 61 
15.10 Study Records Retention .................................................................................................... 62 
15.11 Audit and Regulatory Inspection ........................................................................................ 62 
16 PUBLICATION POLICY .................................................................................................... 62 
16.1 
Communication of Results by NuCana .............................................................................. 62 
16.2 
Publication by Investigators ............................................................................................... 62 
17 REFERENCES ...................................................................................................................... 64 
18 APPENDICES ....................................................................................................................... 66 
Appendix 1: Concomitant medications that may prolong QTc interval ........................................ 66 
Appendix 2: Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 ..................... 69 
Appendix 3: FOSI-18 Questionnaire ............................................................................................. 74 
Appendix 4: EQ-5D-5L Questionnaire .......................................................................................... 76 
Appendix 5: ECOG Performance Scale ......................................................................................... 78 
 
LIST OF FIGURES 
Figure 1 
PRO-105 Study Schema ............................................................................................... 24 
 
LIST OF TABLES 
Table 1 
PK sampling schedule ................................................................................................... 37 
Table 2 
Dose adjustments within a cycle (Days 8 and 15) based on ANC and platelet 
counts ........................................................................................................................... 41 
Table 3 
Dose adjustments for hematological toxicities (excluding toxicities relating to 
ANC and platelet counts) ............................................................................................. 42 
Table 4 
Dose adjustment for non-hematological toxicities ........................................................ 42 
Table 5 
Dose omission guidance ................................................................................................ 43 
Table 6 
Chiltern pharmacovigilance contact details ................................................................... 49 
 


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PROTOCOL SYNOPSIS 
Study Title: 
A Phase II Open-Label Study of NUC-1031 in Patients with Platinum-Resistant 
Ovarian Cancer 
Protocol #: 
PRO-105 
IND #: 
130348 
EudraCT #: 
2016-003287-39 
Phase: 
II 
Objectives: 
Primary Objective: 
• To assess the anti-tumor activity of NUC-1031 as measured by Objective 
Response Rate measured by RECIST at the selected dose level (500 mg/m2 
or 750 mg/m2). Primary assessment will be done by a blinded independent 
central reviewer (BICR). 
Secondary Objectives: 
• To assess additional measures of anti-tumor activity, including: 
o Change from baseline in tumor size. 
o Duration of Overall Response (per RECIST). 
o Progression-Free Survival (per RECIST). 
o Time to Disease Progression (per RECIST). 
o Disease Control Rate (CR+PR+SD, per RECIST). 
o Best GCIG Overall Response, combining the change in CA125 
from baseline with RECIST assessment (per GCIG criteria). 
o Overall Survival. 
• To further assess the safety profile of NUC-1031 administered over 
multiple cycles. 
• To explore relationships between NUC-1031 PK, pharmacodynamics and 
clinical activity. 
• To describe the effects of NUC-1031 on ovarian cancer symptoms.  
Exploratory Objectives: 
• To establish the expression of genomic, transcriptomic and proteomic 
biomarkers in PBMCs and tissue samples, which may help predict patients 
who derive additional benefit from NUC-1031. 
• To explore the impact of treatment and disease state on health state utility 
by EuroQoL five dimensions, five level (EQ-5D-5L). 
Study Design: 
This is a randomized, open-label two-part clinical study in up to 64 patients with 
platinum-resistant ovarian cancer.  
Patients will be randomized to NUC-1031 500 mg/m2 or 750 mg/m2 and will be 
evaluated in two parallel cohorts of up to 20 patients each in Part I of the study. 
The randomization will be stratified to ensure that key prognostic factors 
(including BRCA mutation status and number of prior lines of chemotherapy) are 
balanced between the 2 dose levels. On the basis of ongoing safety, dosing 
intensity, PK and clinical activity observed during Part I, one dose level will be 
selected for further evaluation in Part II of the study, where enrollment shall 
continue until a total of 44 evaluable patients are recruited at the selected dose. The 
study will be deemed complete when all patients have reached the progression free 
survival endpoint, or 24 months have elapsed since the final patient was enrolled 
(whichever occurs first). 
Study 
Centers: 
This study will be conducted at approximately 30 sites in the United States and 
Europe. 


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Endpoints: 
Primary Endpoint 
• Objective Response Rate (per RECIST) at the selected dose level 
(500 mg/m2 or 750 mg/m2), assessed by a BICR. 
Secondary Endpoints 
Efficacy 
• Change from baseline in tumor size. 
• Duration of Overall Response (per RECIST). 
• Progression-Free Survival (per RECIST). 
• Time to Disease Progression (per RECIST). 
• Disease Control Rate (CR+PR+SD, per RECIST). 
• Best GCIG Overall Response, combining the change in CA125 from 
baseline with RECIST assessment (per GCIG criteria). 
• Overall Survival. 
• Assessment of ovarian cancer symptoms using the FOSI-18 questionnaire. 
Safety 
• Treatment-emergent adverse events (per NCI CTCAE v4.03). 
• Clinically-significant laboratory parameters (per NCI CTCAE v4.03). 
• Changes in vital signs and serial ECGs. 
Pharmacokinetics 
PK sampling will be performed at a sub-set of sites specified by NuCana. 
The PK of single and multiple-dose NUC-1031 will be assessed, including: 
• Maximum concentration (Cmax). 
• Area under the curve (AUC). 
• Half-life (T1/2). 
• Volume of distribution (Vd). 
• Clearance (CL). 
PK of the following analytes will be measured: 
• In plasma/urine: NUC-1031, dFdC and dFdU. 
• In PBMCs: NUC-1031, dFdC, dFdCMP, dFdCDP, dFdCTP and dFdU.  
Exploratory Endpoints 
• Assessment of candidate genomic, transcriptomic and proteomic 
biomarkers of resistance/sensitivity to NUC-1031 in PBMCs and tissue 
samples. Examples of candidate markers include cytidine deaminase 
(CDA), deoxycytidine kinase (dCK), human equilibrative nucleoside 
transporter 1 (hENT1), ribonucleotide reductase M1 (RRM1) and RRM2. 
• Assessment of impact of treatment and disease state on health state utility 
by EuroQoL five dimensions, five level questionnaire (EQ-5D-5L). 
Study 
Population: 
Patients with platinum-resistant epithelial cancer of the ovary, fallopian tube or 
primary peritoneum (here termed ‘ovarian cancer’), who have been treated with 3 
or more prior chemotherapy regimens. 
Study 
Treatment: 
Eligible consenting patients will receive NUC-1031 by intravenous (IV) infusion 
over 30 minutes at a dose of 500 mg/m2 or 750 mg/m2 on days 1, 8 and 15 of a 28-
day schedule. Protocol-specific guidelines for dose modifications and 
discontinuations due to adverse events are provided. Patients will continue to 
receive NUC-1031 until the occurrence of disease progression using RECIST or 
unmanageable drug-related adverse events despite dose modification.  
 
 
 


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Sample Size: 
Two dose levels of NUC-1031, 500 mg/m2 and 750 mg/m2, will be evaluated in 
parallel cohorts of up to 20 patients each in Part I of the study. One dose level will 
be selected for further evaluation in Part II of the study (based on ongoing safety, 
dosing intensity, PK and clinical activity observed during Part I), where enrollment 
shall continue until a total of 44 evaluable patients are recruited at the selected 
dose. The primary objective will be assessed in these 44 patients. 
The study will be considered to have met its primary endpoint if a minimum of 4 
responses (CR or PR) are observed. Based on 44 patients, if the true ORR is 15%, 
there is greater than an 80% probability of observing 4 or more responses. 
Furthermore, if the true response rate were only 5%, there would be less than a 7% 
probability of observing 4 or more responses.  
Data dependent, an efficacy update analysis may also be performed to provide 
more mature efficacy data, particularly for the longer term efficacy endpoints such 
as DOR, PFS and OS. The need for such an analysis, and its timing, will be 
determined by the DSMC following review of the primary analysis results. 
Upon review of the primary analysis data from Part II by the DSMC, the study may 
be further expanded at the selected dose level, which will be described in a protocol 
amendment. 
Inclusion 
Criteria: 
 
1. Provision of signed written informed consent. Patients with easily accessible 
tumor must also consent to the collection of fresh biopsy tumor tissue to 
participate in the study. Patients who do not have easily accessible tumor for 
biopsy should not be put at undue risk for sample collection and these patients 
remain eligible for the study. 
2. Original diagnosis and/or histological confirmation of high-grade serous, high-
grade endometrioid, epithelial ovarian, fallopian tube or primary peritoneal 
cancer.  
3. Platinum-free interval since last line of platinum of less than 6 months 
(182 days). 
4. Received at least 3 prior chemotherapy-containing regimens. Prior treatment 
with only non-cytotoxic agents (e.g. hormones, antibodies or PARP inhibitors) 
is permitted, but should not be considered as one of the ‘3 prior chemotherapy-
containing regimens’. Adjuvant chemotherapy should be counted as a prior line 
of chemotherapy. 
5. Age ≥18 years. 
6. ECOG performance status of 0 or 1. 
7. Measurable disease as defined by RECIST. 
8. Adequate bone marrow function as defined by: absolute neutrophil count 
(ANC) ≥1.5×109/l, platelet count ≥100×109/l and hemoglobin level ≥10.0 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 Cr <1.5×ULN or GFR ≥50 ml/min. 
11. Ability to comply with protocol requirements. 
12. Patients are assumed to be infertile as a consequence of treatment for their 
disease, however, in the event they are not, patients must be postmenopausal 
(12 months of amenorrhea), agree to be abstinent, or they must agree to use 
two forms of contraception, one of which must be a barrier method and the 
other must be a highly effective method. These forms of contraception must be 
used from the time of signing consent, throughout the treatment period, and for 
30 days following the last NUC-1031 dose administration. Oral or injectable 
contraceptive agents cannot be the sole method of contraception. See protocol 
Section 10.3.1 for more information. Patients of childbearing potential must 
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drug administration. This criterion does not apply to patients who have had a 
previous hysterectomy or bilateral oophorectomy. 
Exclusion 
Criteria: 
 
1. Disease classified as primary platinum refractory (i.e. progression while 
receiving initial line of platinum-based therapy or within 4 weeks of the last 
platinum dose of the initial regimen). 
2. Received fewer than 3 prior chemotherapy-containing regimens. 
3. Prior therapy with single-agent gemcitabine (prior gemcitabine plus 
carboplatin combination treatment is permitted). 
4. Prior history of hypersensitivity to gemcitabine. 
5. History of allergic reactions attributed to the components of the diluents used 
with NUC-1031. 
6. Mucinous, low-grade serous, low-grade endometrioid, carcinosarcoma, clear 
cell, or undifferentiated/unclassifiable histology. 
7. Symptomatic CNS or leptomeningeal metastases. 
8. Prior chemotherapy, radiotherapy (other than short cycle of palliative 
radiotherapy for bone pain), treatment with a VEGF inhibitor, PARP inhibitor 
or immunotherapy within 21 days of first receipt of study drug (within 6 weeks 
for nitrosoureas and mitomycin C); hormone therapy within 14 days of first 
receipt of study drug; or blood transfusion, or use of hematopoietic growth 
factors within 28 days of first receipt of study drug.  
9. Residual toxicities from chemotherapy or radiotherapy, which have not 
regressed to Grade ≤1 severity (NCI CTCAE v4.03), except for neuropathy 
(Grade 2 allowed) or alopecia. 
10. 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 or ductal carcinoma in situ 
(DCIS) of the breast. Patients with previous invasive cancers are eligible if 
treatment was completed more than 5 years prior to initiating the current study 
treatment, and the patient has had no evidence of recurrence since then. 
11. Presence of an uncontrolled concomitant illness or active infection requiring 
IV antibiotics. 
12. Presence of any serious illnesses, medical conditions, or other medical history, 
including laboratory results, which, in the Investigator’s opinion, would be 
likely to interfere with the patient’s participation in the study, or with the 
interpretation of the results. 
13. Known HIV positive or known active hepatitis B or C. 
14. 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. 
15. Currently pregnant, lactating or breastfeeding. 
16. QTc interval >450 milliseconds. 
17. Concomitant use of drugs known to prolong QT/QTc interval (Appendix 1). 
18. History of radiologically confirmed bowel obstruction (including sub-
occlusive disease) relating to ovarian cancer within 6 months prior to the first 
receipt of study drug. 
19. Patients who have received a live vaccination within 4 weeks of first planned 
NUC-1031 dose administration. 
Study 
Duration Per 
Patient: 
Patients will continue to receive NUC-1031 in the absence of disease progression 
or unmanageable drug-related toxicity. 


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SUMMARY SCHEDULE OF EVENTS 
 
Each Cycle 
End of 
Treatment 
Visit20 
 
Follow-
up Visit 
Q8 weeks 
(±7 days)2
1  
Survival 
Follow-up 
Q12 weeks 
(±7 days) 
Assessment 
Screening 
Up to 
28 days 
prior 
Day 1 
(±3) 
Day 2 
Days 8 & 15 
(±3) 
Day 16 
Informed consent 
X 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria confirmation 
X 
 
 
 
 
 
 
 
Patient registration 
X 
 
 
 
 
 
 
 
Medical and surgical 
history, including 
prior therapy for 
ovarian cancer1 
X 
 
 
 
 
 
 
 
BRCA testing2 
X 
 
 
 
 
 
 
 
ECOG performance 
status 
X 
X 
 
 
 
X 
X 
 
Physical 
examination, 
including vital signs3 
X 
X 
 
X 
 
X 
 
 
Height and weight4 
X 
X 
 
 
 
X 
 
 
Pregnancy test 
X 
X17 
 
 
 
X 
 
 
12-lead ECG5 
X 
X6 
 
X6 
 
X 
 
 
Patient 
demographics 
X 
 
 
 
 
 
 
 
Baseline symptoms 
X 
 
 
 
 
 
 
 
Hematology7 
X 
X 
 
X 
 
X 
 
 
Serum chemistry8 
X 
X 
 
X 
 
X 
 
 
Coagulation 
parameters: PT/INR 
and aPTT9 
X 
X 
 
 
 
X 
 
 
Urinanalysis10 
X 
X 
 
 
 
X 
 
 
Pharmacokinetic 
sampling11 
 
X 
X 
X 
X 
 
 
 
Serum tumor 
markers (CA125)12 
X 
X 
 
 
 
X 
X 
 
Tumor response 
assessment: CT, 
MRI and/or PET-CT 
(US only) scan13 
Scans performed at Screening then every 8 weeks (±7 days) from C1D1 until disease 
progression, regardless of treatment cycle. CRs and PRs must be confirmed by repeated 
images at least 4 weeks after initial documentation. 
Collection of tumor 
specimen14 
X 
X19 
 
 
 
 
 
 
Patient-Reported 
Outcomes15 
X 
X 
 
 
 
X 
 
 
NUC-1031 study 
drug administration16 
 
   X18 
 
X 
 
 
 
 
Adverse events 
 
X 
X 
X 
X 
X 
X22 
 
Concomitant 
medications 
X 
X 
X 
X 
X 
X 
 
 
Survival follow-up 
phone call 
 
 
 
 
 
 
 
X23 


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1. 
Medical history and prior therapy collected during Screening. Any changes from date 
of consent should be recorded as Adverse Events. 
2. 
Patients with unknown BRCA mutation status should undergo local BRCA mutation 
testing prior to study entry, according to local ethical procedures for genetic testing. 
Results are needed prior to randomization. 
3. 
Vital signs include measurement of pulse rate, respiratory rate, temperature and blood 
pressure, after the patient has been seated or in the supine position for 5 minutes. 
4. 
Height will be measured at Screening only. If a patient’s weight increases or decreases 
by ≥10% during the course of the study, the dose of NUC-1031 should be recalculated. 
5. 
12-lead ECG measurements must be obtained at screening, pre-infusion on each 
treatment day, and at the treatment completion visit. 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. The QTc interval 
should be calculated for each ECG using the Fridericia formula and averaged. 
Management of QT/QTc prolongation should be performed in accordance with 
institutional standard of care at the discretion of the treating physician. Digital and/or 
certified paper copies should be stored as part of the study documents in the event they 
need to be used in a future analysis. 
6. 
At C1D1, C1D15, C3D1 and C3D15 12-lead ECG measurements should be performed 
30-60 minutes pre-infusion and again 30-60 minutes post-infusion. 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. 
The QTc interval should be calculated for each ECG using the Fridericia formula and 
averaged. Management of QT/QTc prolongation should be performed in accordance 
with institutional standard of care at the discretion of the treating physician. Digital 
and/or certified paper copies should be stored as part of the study documents in the 
event they need to be used in a future analysis. 
7. 
Hematology includes white blood cell (WBC) count, differential WBC count, red blood 
cell count (RBC), hemoglobin, hematocrit and platelet count. 
8. 
Serum chemistry incudes sodium, potassium, magnesium, urea or blood urea nitrogen, 
creatinine, glucose, phosphate, total protein, albumin, adjusted calcium, total bilirubin, 
bicarbonate, chloride, uric acid, alkaline phosphatase, AST, ALT and LDH.  
9. 
Either PT or INR may be measured, depending on institutional standards.  
10. 
Urinalysis includes pH, specific gravity, ketones, leukocytes, protein, glucose, 
bilirubin, urobilinogen and occult blood. Dipstick testing is acceptable. 
11. 
Pharmacokinetic sampling (blood and urine) will be performed at a sub-set of sites 
specified by NuCana. At sites participating in the PK sample collection, blood samples 
are collected on Cycle 1 (Days 1 and 15), and Cycle 3 (Day 1) at pre-dose (T0), end of 
infusion (T1), T1 plus 10 minutes (T2), T1 plus 30 minutes (T3), T1 plus 1 hour (T4), T1 
plus 2 hours (T5), T1 plus 4 hours (T6), T1 plus 6 hours (T7) and T1 plus 24 hours (T8). 
See blood-sampling schedule in the protocol. 
Urine samples are collected on Cycle 1 (Days 1 and 15) at 0-6 hours, and 6-24 hours.  
12. 
CA125 to determine GCIG response. 
 
13. 
Baseline imaging of the thorax, abdomen, and pelvis is required within 28 days of 
randomization. CT, MRI and PET-CT (US only) scans are acceptable. In selected 


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situations, combination of CT/MRI is acceptable (i.e. CT of chest, MRI of abdomen). 
The same imaging modalities for each anatomic component be continued throughout 
the duration of the study. Objective responses using RECIST must be confirmed by 
repeat assessment performed ≥4 weeks after initial documentation of response. 
Progressive disease should be confirmed prior to stopping treatment.  
14. 
Patients must have consented to the submission of archival tumor, if available and 
collection of fresh biopsy tumor tissue to participate in the study. Patients who do not 
have easily accessible tumor for biopsy should not be put at undue risk for sample 
collection and these patients remain eligible for the study. Biopsied lesions should not 
be designated as target lesions for the purposes of RECIST. Archival tumor tissue, if 
available may be submitted as paraffin tissue block or at least 10 unstained slides. 
15. 
The FOSI-18 and EQ-5D-5L instruments must be completed prior to other scheduled 
study procedures and dosing (if applicable) at Screening, on Day 1 of each treatment 
cycle, at treatment discontinuation, and at the 28-day post-treatment discontinuation 
follow-up visit for all patients. 
16. 
Patients will receive NUC-1031 on Day 1, 8 and 15 (±3 days) of a 28-day cycle. 
17. 
For women of child-bearing potential, serum pregnancy testing must be performed 
within 72 hours prior to C1D1 and at End of Treatment visit. In addition, urine 
pregnancy tests will be performed pre-dose on Day 1 of each cycle. If any urine test 
result is positive, patient dosing will be postponed until the result is confirmed by a 
serum pregnancy test. Patients with a positive serum test will be discontinued from the 
study. 
18. 
Includes insertion of central venous access device, if not already present (if NUC-1031 
is centrally administered). 
19. 
Optional fresh biopsy tissue sample collection within 24 hours post administration of 
C1D1 dose for patients who consent. 
20. 
Includes treatment discontinuation due to disease progression or early treatment 
discontinuation for other reasons (e.g. withdrawal of consent). Progressive disease 
should be confirmed prior to stopping treatment. Visit to occur within 30 (±7) days of 
the last dose of NUC-1031. 
21. 
Patients withdrawing from the study with no radiological evidence of disease 
progression will receive scans every 8 weeks (±7 days) from C1D1 until disease 
progression, initiation of a new treatment or death in order to determine duration of 
overall response and PFS. 
22. 
Adverse events should be captured from the time of consent up to 30 days after the last 
dose of NUC-1031. SAEs deemed definitely, probably or possibly related to NUC-1031 
but outside of this window (>30 days from last dose of NUC-1031) should also be 
captured in the eCRF. 
23. 
Patients with evidence of disease progression as defined by RECIST criteria will 
receive a phone call at regular intervals (every 12 weeks ±7 days) until death, loss to 
follow-up, or study discontinuation in order to determine duration of Overall Survival. 


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ABBREVIATIONS 
°C 
Degrees Centigrade 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
AST 
Aspartate aminotransferase 
AUC 
Area under the curve 
AUC0-t 
Area under the plasma concentration-time curve from time zero to the last 
measurable concentration 
BICR 
Blinded Independent Central Reviewer 
BRCA 1/2 
Breast cancer (gene) 1/2 
BUN 
Blood urea nitrogen 
CA125 
Cancer Antigen 125 
CDA 
Cytidine deaminase 
CL 
Apparent clearance 
Cmax 
Maximum plasma concentration; peak plasma concentration 
CNS 
Central Nervous System 
CR 
Complete Response 
CRF 
Case report form  
CRO 
Clinical Research Organization 
CSR 
Clinical study report 
CT  
Computed tomography 
CTC 
Common toxicity criteria 
dCK 
Deoxycytidine kinase 
dFdC 
Di-fluoro-deoxycytidine (gemcitabine) 
dFdCDP 
Di-fluoro-deoxycytidine diphosphate 
dFdCMP 
Di-fluoro-deoxycytidine monophosphate 
dFdCTP 
Di-fluoro-deoxycytidine triphosphate 
dFdU 
Di-fluoro-deoxyuridine 
DMA 
Dimethylacetamide 
DNA 
Deoxyribonucleic acid 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EQ-5D-5L 
EuroQoL Five Dimensions, Five Level 
FDA 
(US) Food and Drug Administration  
FOSI-18 
FACT/NCCN-Ovarian Symptom Index (containing 18 items) 
GCIG 
Gynecologic Cancer InterGroup 
G-CSF 
Granulocyte colony stimulating factor 
GFR 
Glomerular filtration rate 
hENT1 
Human equilibrative nucleoside transporter 1 
HIV 
Human Immunodeficiency Virus 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH-GCP 
International Conference on Harmonization - Good Clinical Practice 
IHC 
Immunohistochemistry 
IMP 
Investigational medicinal product 
IND 
Investigational New Drug 
IRB/EC 
Institutional review board/ ethics committee 
IV 
Intravenous 
l 
Liter 


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LDH 
Lactate dehydrogenase 
LPLV 
Last patient last visit 
m2 
Meter2 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
µM 
Micromolar 
ml 
Milliliter 
mM 
Millimolar 
MRI 
Magnetic Resonance Imaging 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse 
Events 
ORR 
OS 
Objective Response Rate 
Overall Survival 
PARP 
Poly ADP ribose polymerase 
PBMC 
Peripheral blood mononuclear cell 
PD 
Progressive Disease 
PFI 
Platinum-Free Interval 
PFS 
Progression-Free Survival 
PK 
Pharmacokinetics 
PLD 
Pegylated liposomal doxorubicin 
PR 
Partial Response 
PRO 
Patient-Reported Outcome 
PS 
Performance Status 
RECIST 
Response Evaluation Criteria In Solid Tumors (version 1.1) 
RRM1 
Ribonucleotide reductase M1 
RRM2 
Ribonucleotide reductase M2 
RP2D 
Recommended Phase 2 Dose 
RSI 
Reference Safety Information 
SAE 
Serious adverse event 
SAR 
Serious adverse reaction 
SD 
Stable Disease  
SOC 
System Organ Class 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
t1/2 
Terminal half-life 
TEAE 
Treatment emergent adverse event 
ULN 
Upper limit of normal 
Vd 
Volume of distribution 
VEGF 
Vascular endothelial growth factor 
WBC 
White blood cell 
WHO DD 
World Health Organization Drug Dictionary 
 


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1 
INTRODUCTION AND STUDY RATIONALE 
1.1 
Treatment Options for Recurrent Ovarian Cancer 
Ovarian cancer is the most common cause of gynecologic cancer death and the fifth leading 
cause of death from cancer in women (Siegel et al, 2014). The majority of women present with 
advanced stage disease which is treated initially with optimal surgical debulking followed by 
systemic treatment with a platinum plus taxane chemotherapy regimen. Although complete 
response (CR) following this initial treatment is observed in 70% of patients, the majority will 
relapse generally within 2 years. As a result, the 5-year survival rate for women with ovarian 
cancer is only 30% (American Cancer Society, Cancer Facts and Figures, 2015). 
The selection of treatment for recurrent disease is governed by the period from cessation of 
primary platinum-based chemotherapy to disease recurrence or progression, known as the 
platinum-free interval (PFI; Friedlander et al, 2011). Patients with disease progression while 
receiving platinum-based therapy or within 4 weeks of last platinum dose are defined as having 
platinum-refractory disease; those with a PFI of more than 1 month and less than 6 months 
have platinum-resistant disease. For such patients, single-agent chemotherapy with or without 
bevacizumab is standard therapy. Patients with a PFI of 6-12 months have partial platinum 
resistance; and those with PFI more than 12 months have platinum-sensitive recurrence. For 
these patients, re-treatment with platinum-containing chemotherapy doublets is standard 
therapy. 
 
1.2 
Treatment for Platinum-Resistant Ovarian Cancer 
There are no highly effective treatments for patients with platinum-resistant ovarian cancer. A 
number of chemotherapeutic agents have demonstrated modest anti-tumor activity in these 
patients with response rates generally in the range of 10-20% and median times to progression 
of 3-4 months (Markman & Bookman, 2000). Standard treatment for patients with platinum-
resistant disease generally involves the sequential use of single-agent chemotherapy including, 
agents such as paclitaxel, topotecan, pegylated liposomal doxorubicin, and gemcitabine. 
Paclitaxel, topotecan, and pegylated liposomal doxorubicin (PLD) have been approved by 
global regulatory authorities in this population of patients, while gemcitabine is only approved 
for use in combination with carboplatin for patients with platinum-sensitive relapsed disease. 
Recent clinical data have demonstrated that the addition of bevacizumab to single-agent 
chemotherapy (either PLD, topotecan or weekly paclitaxel) in patients with platinum-resistant 
disease, who had received no more than 2 prior chemotherapy regimens, results in an improved 
outcome compared to chemotherapy alone. In this study, median progression-free survival 
(PFS) increased from 3.4 months to 6.7 months (HR=0.48, 95 % CI: 0.38 to 0.60, p<0.001), in 
patients treated with bevacizumab plus chemotherapy compared to chemotherapy alone 
(Pujade-Lauraine et al, 2014). 
The histologic subtype of ovarian cancer is a factor known to influence outcome and response 
to treatment. Mucinous, clear cell, and low-grade serous carcinomas are distinct entities, are 
less responsive to chemotherapy in both the primary and recurrent settings and have differing 
natural histories (Groen et al, 2015).  
BRCA1/2 mutation status has a significant impact on response to treatment (Yang et al, 2011). 
In the recurrent setting, ovarian cancer patients with a somatic or germline BRCA1/2 mutation 
are highly responsive to platinum and other DNA-damaging chemotherapy regimens. 
Recurrent ovarian cancer patients with BRCA1/2 mutations are also generally more responsive 
to other chemotherapy agents that induce direct DNA damage and specifically to targeted 
agents, such as PARP inhibitors.  


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PLD gives an enhanced time to treatment failure and improved overall survival to second and 
third-line treatments in recurrent ovarian cancer patients with a BRCA1/2 mutation (Safra et 
al, 2011; Kaye et al, 2012). An overall response rate of 31% was achieved with the PARP 
inhibitor olaparib in 193 recurrent ovarian cancer patients with a known deleterious germline 
BRCA1/2 mutation (Kaufman et al, 2015). 
Ovarian cancer patients are often currently managed with multiple sequential therapeutic 
regimens. The number of prior therapies might influence outcome. Also, it has been noted 
recently that ‘the designation of platinum-sensitive vs platinum-resistant on the basis of a time 
line in the patient with recurrent ovarian cancer beyond the third line of therapy may be less 
precise or important’ (Alvarez et al, 2016). 
In summary, while there are multiple chemotherapeutic options for patients with platinum-
resistant, recurrent ovarian cancer, there remains a clear unmet need for more effective agents 
to treat this population of women. 
 
1.3 
Gemcitabine in Ovarian Cancer 
Gemcitabine in combination with a platinum agent (cisplatin or carboplatin) is approved 
globally for women with platinum-sensitive recurrent ovarian cancer. In the AGO-OVAR 
study, 356 patients with platinum-sensitive recurrent ovarian cancer were assigned to either 
single-agent carboplatin AUC5 or carboplatin AUC4 in combination with gemcitabine 
1,000 mg/m2 on days 1 and 8 every 3 weeks (Pfisterer et al, 2006).  
After a median follow-up of 17 months, a median PFS of 8.6 months was observed for 
gemcitabine plus carboplatin, compared with 5.8 months for single-agent carboplatin 
(p=0.0031). An Objective Response Rate (ORR) of 47.2% was recorded for gemcitabine plus 
carboplatin compared with 30.9% for single-agent carboplatin (p=0.0016). In view of the 
improved response rate and duration of response, gemcitabine is usually given alongside 
carboplatin in the relapsed, platinum-sensitive setting. For these patients in the relapsed setting, 
the choice of gemcitabine is seen as advantageous over paclitaxel as gemcitabine does not 
cause hair loss or neurotoxicity. 
In patients with platinum-resistant recurrence, gemcitabine given in combination with 
carboplatin was shown in one study to have an ORR of 47% (Ledermann et al, 2010). However, 
in view of the likely resistance to carboplatin and relatively poor cellular uptake of gemcitabine 
in these patients, other non-platinum regimens are generally favored over carboplatin and 
gemcitabine.  
 
1.3.1 Gemcitabine Resistance 
Gemcitabine is associated with key cancer resistance mechanisms (Slusarczyk et al, 2014), 
which may result in limited efficacy in ovarian cancer patients. These resistance mechanisms 
include: 
• Inefficient uptake into cells requiring active membrane transporters, which limits the 
ability of the drugs to reach their site of action (Achiwa et al, 2004); 
• Poor intracellular conversion via intracellular kinases to the active di- and tri-
phosphates forms (Kroep et al, 1998); 
• Metabolism via deamination, thus rendering them inactive (Kroep et al, 1998). 


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1.4 
NUC-1031 
NUC-1031 (Acelarin®) is a new chemical entity resulting from the phosphoramidate 
transformation of gemcitabine. NUC-1031 is synthesized as a pre-activated molecule bearing 
one protected phosphate group, termed the phosphoramidate motif, imparting several potential 
advantages over gemcitabine: 
• NUC-1031 is more efficiently taken up by cells as it does not rely on nucleoside 
transporters to cross the cellular membrane; 
• NUC-1031 presents the cell with an already partially activated (monophosphate) form 
of the nucleoside, thereby obviating the need for the rate limiting initial kinase 
activation; 
• NUC-1031 is protected from enzymatic breakdown (especially by deaminases and 
phosphorylases) resulting in greater stability and a reduction in the generation of major 
metabolites. 
 
1.4.1 Nonclinical Data 
NUC-1031 has shown in vitro efficacy against a range of cancer cell lines including: pancreatic, 
bladder, prostate, breast, NSCL and colon. The in vitro studies showed a consistent increase in 
cytotoxicity of NUC-1031 compared to gemcitabine controls (EC50 values for NUC-1031 
showed 1.3 to 343-fold improvement over gemcitabine). 
In vivo, NUC-1031 has also demonstrated greater efficacy across a range of xenograft studies 
compared to gemcitabine. In all of the studies reported, NUC-1031 was more effective than 
gemcitabine at an equimolar dose. The increased effectiveness was in some cases related to 
improved tolerance to NUC-1031 allowing a higher dose to be administered. Where equivalent 
doses were tolerated, NUC-1031 showed a higher reduction in tumor growth over gemcitabine. 
Toxicology findings for NUC-1031 are consistent with the cytotoxic mechanism of action and 
are qualitatively similar to those reported for gemcitabine. Dose range finding and four-week 
toxicity studies have shown that NUC-1031 could be administered at a dose equivalent to four-
times the reported gemcitabine maximum tolerated dose in dog. The main findings included 
evidence of gastrointestinal mucosal irritation, suppression of the hematopoietic system, 
lymphoid atrophy and thymic atrophy. Data from genotoxicity studies suggest that NUC-1031 
is only weakly genotoxic and significantly less so than gemcitabine. Further nonclinical data 
can be found in the Investigator’s Brochure. 
 
1.4.2 Clinical Data 
The Phase I, first-in-human (FIH) dose escalation study of NUC-1031 as a single-agent has 
been completed in patients with advanced solid tumors (PRO-001). The Investigator-sponsored 
study enrolled a total of 68 patients with advanced solid tumors between October 2012 and 
October 2014. The dose range tested was from 500-1,000 mg/m2 in monthly cycles of 
administration, using a schedule derived from that used for gemcitabine (Day 1, 8 and 15 every 
28 days). 
The 68 patients treated on the study included 22 males and 46 females. The mean age of the 
patients was 56.3 years (range 20.3 to 83.5 years). The common cancer histories (>10%) 
included ovarian cancer (14.7%), pancreatic cancer (13.2%) and colorectal carcinoma (10.3%). 
The largest primary tumor (>30%) category was categorized as ‘other’, which included one 
patient with papillary serous carcinoma later classified as ovarian cancer. All the patients had 
been previously treated with chemotherapy with a mean (standard deviation) number of prior 


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chemotherapy regimens of 3.0 (1.77). A total of 34/68 patients (50.0%) received prior 
gemcitabine therapy. Across the range of doses tested on the study, the median number of 
NUC-1031 cycles received was 3 (range 0.3 to 19). A total of 14 patients received 6 or more 
cycles of treatment. 
NUC-1031 was generally well tolerated. Although treatment emergent adverse events were 
reported in all patients, the majority were Grade 1 or 2 in severity, were reversible, and were 
considered unrelated to the study drug. Likewise, the majority of Grade 3 or 4 adverse events 
were considered unrelated to the study drug and resolved without sequelae. 
The most commonly occurring treatment emergent and treatment related adverse events were 
laboratory abnormalities, specifically decreased blood cell counts (neutropenia, lymphopenia 
and thrombocytopenia), as well as elevations in liver function enzymes (alanine 
aminotransferase and aspartate aminotransferase). The most commonly occurring treatment 
related clinical adverse events were fatigue, nausea and vomiting and disturbance in taste 
(dysguesia). Within each cycle of therapy, these laboratory and clinical abnormalities were 
managed by withholding or delaying treatment. In addition, dose reductions were implemented 
in subsequent cycles of treatment for patients continuing on the protocol. 
Dose-limiting toxicities were observed at doses of 725 mg/m2 and above and occurred in 
4 patients. Reversible Grade 4 thrombocytopenia occurred in 1 patient at 750 mg/m2. 
Reversible Grade 4 thrombocytopenia and neutropenia occurred in 1 patient at 1,000 mg/m2. 
Reversible Grade 3 transaminase elevation occurred in 2 patients (1 at 725 mg/m2 and 1 at 
1,000 mg/m2). 
NUC-1031 demonstrated substantive anti-tumor activity at doses of 500 mg/m2 and above. 
Efficacy was evaluable in 49 of 68 patients (72%) who received two or more cycles of NUC-
1031 and were evaluated radiographically using RECIST criteria. PRs were reported in five 
patients (10%). The five patients achieving PRs included 3/7 patients (42.9%) from the 
750 mg/m2 group, 1/4 patients (25.0%) from the 1,000 mg/m2 group and 1/2 patients (50.0%) 
from the 625 mg/m2 treatment group. Confirmatory scans were not available for three patients 
(1 each in the 1,000 mg/m2, 750 mg/m2 and 625/m2 mg treatment groups). The two patients 
who received a confirmatory scan had durable responses of 7.5 months and 14.5 months. An 
additional 32 patients (65%) achieved Stable Disease, resulting in an overall Disease Control 
Rate (DCR) of 76% (37/49). In the efficacy evaluable patients, the duration of PFS ranged from 
0.5 to 18.7 months and the median PFS duration ranged from 1.8 to 9.2 months. Further clinical 
data can be found in the Investigator’s Brochure. 
 
1.4.3 Pharmacokinetics 
The disposition of NUC­1031 and its metabolites in plasma, peripheral blood mononuclear 
cells (PBMCs), and urine following IV administration of NUC-1031 was investigated in the 
PRO-001 study. 
Overall, plasma exposures of NUC-1031, di-fluoro-deoxycytidine (dFdC; gemcitabine) and the 
potentially toxic metabolite di-fluoro-deoxyuridine (dFdU) differed substantially. Median 
plasma AUC0-t values ranged from 22.3–272, 0.31–2.19, and 6.61–115 µg*h/mL, respectively. 
Median Cmax values ranged from 74.4–718, 0.18–2.49, and 0.36–5.81 µg/mL, respectively. 
Intracellular exposures were low for all analytes with the exception of the primary anti-cancer 
metabolite, dFdCTP. Median intracellular dFdCTP AUC0-t and Cmax estimates ranged from 
13.9– 87.8 µg*h/mL and 3.31–13.4 µg/mL, respectively.  
In urine, dFdU constituted the largest percentage of drug excretion; 21.7% and 27.3% of the 
NUC-1031 dose was excreted as dFdU over the 24 hours post-dose on Cycle 1, Day 1 and 


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Cycle 1, Day 15, respectively. Overall, less than 1% of the dose was excreted as dFdC or NUC-
1031. 
In summary, the PRO-001 PK analyses revealed the following: 
• After NUC-1031 administration over the dose range of 375 to 1,000 mg/m2, NUC-1031 
plasma concentrations and key exposure parameters (AUC0-t and Cmax) increased with 
increasing dose in an approximately dose proportional manner.  
• Plasma concentrations and key exposure parameters for the primary NUC-1031 
metabolites, dFdC, and dFdU, did not appear to increase in a dose proportional manner 
with increasing NUC-1031 dose. The lack of dose proportionality is not unexpected 
given that: 
o The PRO-001 study was not designed to show dose proportionality, and 
o There was a relatively small number of patients in each dose group. 
• The predominant intracellular metabolite generated was dFdCTP, both in terms of 
concentration and key intracellular exposure parameters. Compared to published 
gemcitabine literature (Grunewald et al, 1990; Abbruzzese et al, 1991; Grunewald et 
al, 1992; Cattel et al, 2006; Peters et al, 2007), on an equimolar basis: 
o The median intracellular dFdCTP Cmax following NUC-1031 administration 
was 217-times higher than that observed with gemcitabine. 
o The median intracellular dFdCTP AUC0-24 following NUC-1031 administration 
was 139-times higher than that observed with gemcitabine. 
o NUC-1031 administration results in intracellular dFdCTP concentrations 
throughout the following 24-hour period that are higher than that which is 
observed at the Cmax 2-hour time point after gemcitabine administration. 
• The predominant analyte found in excreted urine was dFdU; urinary excretion of NUC-
1031 and dFdC was minimal. 
The findings of the PRO-001 PK analyses are consistent with the clinical data, where 
NUC-1031 doses of 500 mg/m2 and above demonstrated marked anti-tumor activity. 
 
1.5 
Study Rationale 
Data from 18 patients in the PRO-001 study with gynecological cancer (11 ovarian, 3 
endometrial, 2 cervical and 2 fallopian tube) were encouraging. Of these patients with 
gynecological cancer, 10 had platinum-resistant disease, 5 were platinum refractory and 
14 were deemed evaluable for efficacy. The radiological evaluation shows that 2 of the 
14 patients (14.3%) achieved a PR. These patients received NUC-1031 at 625 mg/m2 and 750 
mg/m2. A further 11/14 (78.6%) patients achieved SD, resulting in a 92.9% DCR.  
Data from the ongoing PRO-002 study of NUC-1031 in combination with carboplatin in 
advanced ovarian cancer are equally encouraging. Of the 22 patients enrolled, 20 are evaluable 
for efficacy and there has been 1 CR, 5 PRs, and 13 SDs, resulting in a DCR of 95% (19/20). 
The data from these patients provides a strong rationale for further development of NUC-1031 
in Phase II studies in ovarian cancer. 
 
2 
STUDY OBJECTIVES AND ENDPOINTS 


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2.1 
Primary Objective 
The primary objective is to assess the anti-tumor activity of NUC-1031, as measured by 
Objective Response Rate (ORR) per RECIST criteria (Appendix 2) at the selected dose level 
(500 mg/m2 or 750 mg/m2). Primary assessment will be done by a blinded independent central 
reviewer (BICR). 
 
2.2 
Secondary Objectives 
The secondary objectives are: 
• To assess additional measures of anti-tumor activity of NUC-1031 including: 
o Change from baseline in tumor size. 
o Duration of Overall Response (per RECIST). 
o Progression-Free Survival (per RECIST). 
o Time to Disease Progression (per RECIST). 
o Disease Control Rate (CR+PR+SD, per RECIST).  
o Best GCIG Overall Response, combining the change in CA125 from 
baseline with RECIST assessment (per GCIG criteria). 
o Overall Survival. 
• To further assess the safety profile of NUC-1031 administered over multiple cycles. 
• To explore relationships between NUC-1031 PK, pharmacodynamics and clinical 
activity. 
• To describe the effects of NUC-1031 on ovarian cancer symptoms. 
 
2.3 
Exploratory Objectives 
• To establish the expression of genomic, transcriptomic and proteomic biomarkers 
in PBMCs and tissue samples, which may help predict patients who derive 
additional benefit from NUC-1031. 
• To explore the impact of treatment and disease state on health state utility by 
EuroQoL five dimensions, five level (EQ-5D-5L). 
 
2.4 
Primary Endpoint 
• ORR at the selected dose level (500 mg/m2 or 750 mg/m2) per RECIST criteria and 
assessed by a BICR. 
 


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2.5 
Secondary Endpoints 
The secondary endpoints are: 
• Efficacy 
o Change from baseline in tumor size. 
o Duration of Overall Response (per RECIST). 
o Progression-Free Survival (per RECIST). 
o Time to Disease Progression (per RECIST). 
o Disease Control Rate (CR+PR+SD, per RECIST). 
o Best GCIG Overall Response, combining the change in CA125 from 
baseline with RECIST assessment (per GCIG criteria). 
o Overall Survival. 
o Assessment of ovarian cancer symptoms using the FOSI-18 questionnaire 
(Appendix 3).  
• Safety 
o Treatment-emergent adverse events (per NCI CTCAE v4.03). 
o Clinically-significant laboratory parameters (per NCI CTCAE v4.03). 
o Changes in vital signs and serial ECGs. 
 
2.6 
Pharmacokinetics 
Pharmacokinetic sampling (blood and urine) will be performed at a sub-set of sites specified 
by NuCana. The PK of single and multiple-dose NUC-1031 will be assessed, including: 
• Maximum concentration (Cmax). 
• Area under the curve (AUC). 
• Half-life (T1/2). 
• Volume of distribution (Vd). 
• Clearance (CL). 
PK of the following analytes will be measured: 
• In plasma/urine: NUC-1031, dFdC and dFdU. 
• In peripheral blood mononuclear cells (PBMCs): NUC-1031, dFdC, dFdCMP, 
dFdCDP, dFdCTP and dFdU. 
 
2.7 
Exploratory Endpoints 
• Assessment of candidate genomic, transcriptomic and proteomic biomarkers of 
resistance/sensitivity to NUC-1031 in tumor specimens and/or plasma will be 
assessed. Examples of candidate markers include cytidine deaminase (CDA), 
deoxycytidine kinase (dCK), human equilibrative nucleoside transporter 1 
(hENT1), ribonucleotide reductase M1 (RRM1) and RRM2. 
• Assessment of the impact of treatment and disease state on health state utility by 
EuroQoL five dimensions, five level questionnaire (EQ-5D-5L; Appendix 4).  


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3 
INVESTIGATIONAL PLAN 
3.1 
Overall Study Design 
This is a randomized open-label, two-part clinical study of NUC-1031 in up to 64 patients with 
platinum-resistant ovarian cancer. Patients will be randomized to NUC-1031 500 mg/m2 or 750 
mg/m2 and will be evaluated in two parallel cohorts of up to 20 patients each in Part I of the 
study. The randomization will be stratified to ensure that key prognostic markers, including 
BRCA mutation status and number of prior lines of chemotherapy (3 or >3), are balanced 
between the 2 dose levels. The stratification procedure will be defined in the statistical analysis 
plan. 
On the basis of ongoing safety, dosing intensity, PK and clinical activity observed during Part I, 
one dose level will be selected for further evaluation in Part II of the study, where enrollment 
shall continue until a total of 44 response evaluable patients are recruited at the selected dose 
(Figure 1). 
 
 
 
 
Figure 1 
PRO-105 Study Schema 
 
The primary analysis of response rate will take place when 44 patients are enrolled at the 
selected dose and all active patients have undergone the required assessments for assessment 
of confirmed ORR by RECIST (i.e., approximately 16 weeks after the 44th patient starts 
treatment). Upon review of these data from Part II by the DSMC, the study may be further 
expanded at the selected dose level, which will be described in a protocol amendment. An 
efficacy update analysis may also be performed to provide more mature efficacy data.  
 
 


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3.2 
Rationale for the NUC-1031 Dose Selected 
Data from the PRO-001 study confirms the nonclinical rationale for the phosphoramidate 
transformation of gemcitabine. When compared to historical pharmacology data with 
gemcitabine, NUC-1031 generated substantially greater overall exposure to the active tri-
phosphate metabolite in PBMCs isolated from patients. This appears to be the case across 
essentially all of the dose range studied in the Phase I study. Indeed, some level of 
pharmacologic activity, either safety related or efficacy related, was observed at nearly every 
dose level. 
When dosing data are examined, it appears that the dose levels of 825 mg/m2 and above 
required more substantial dose delays, omissions and dose reductions in order to deliver 
repeated cycles of therapy. Conversely, patients dosed at 750 mg/m2 and below were largely 
able to maintain treatment intensity. It is also noteworthy that 4 of 5 PRs occurred in the 
625 mg/m2 to 750 mg/m2 dose range. Accordingly, a dose of 750 mg/m2 on days 1, 8 and 15 
of a 28-day cycle has been selected for this PRO-105 study. 
Furthermore, a dose of 500 mg/m2 has been added to the PRO-105 study in accordance with 
pre-IND recommendations from the US Food and Drug Administration (FDA) in which they 
suggested that a dose lower than 750 mg/m2 also be explored. Both patients enrolled at 
500 mg/m2 in PRO-001 achieved SD. In addition, the PK parameters were relatively constant 
across the dose range studied and NUC-1031 generated substantially greater intracellular levels 
of the active anti-cancer metabolite, dFdCTP, compared to historical data with gemcitabine. 
 
3.3 
Study Treatment 
In Part I, eligible consenting patients will be randomized to receive IV NUC-1031 at a dose of 
either 500 mg/m2 or 750 mg/m2 on a day 1, 8 and 15 of a 28-day schedule. Up to 20 patients 
will be enrolled in each arm. 
One dose level will be selected for further evaluation in Part II of the study (based on ongoing 
safety, dosing intensity, PK and clinical activity observed during Part I), where enrollment shall 
continue until a total of 44 evaluable patients are recruited at the selected dose. The study will 
be complete when all patients have reached the PFS endpoint or when 24 months have elapsed 
since the final patient was enrolled (whichever comes first). 
Criteria for inter-cycle and intra-cycle dose delay and dose modification are specified in 
Section 9 of this protocol. The reasons for dose delay or dose reduction should be captured as 
AEs in the patient medical record and noted on the case report form (CRF). 
 
3.4 
Duration of Patient Participation 
Patients will continue to receive NUC-1031 until the occurrence of disease progression by 
RECIST or unmanageable drug-related adverse events despite dose 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 
CRF. 
Should a patient discontinue treatment without radiological evidence of disease progression, 
the patient should continue to undergo tumor assessment every 8 weeks from C1D1 until such 
time as progression can be documented or new treatment is initiated. 


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3.5 
Patient Selection and Study Centers 
It is anticipated that up to 64 patients will be enrolled in this study at multiple study centers in 
the US and Europe. Patients are eligible for the study if all of the inclusion criteria are met and 
none of the exclusion criteria apply.  
 
4 
PATIENT SELECTION 
4.1 
Inclusion Criteria 
To be enrolled in this study, patients must meet the following criteria during the Screening 
period: 
1. Provision of signed written informed consent. Patients with easily accessible tumor 
must also consent to the collection of fresh biopsy tumor tissue to participate in the 
study. Patients who do not have easily accessible tumor for biopsy should not be put at 
undue risk for sample collection and these patients remain eligible for the study. 
2. Original diagnosis and/or histological confirmation of high-grade serous, high-grade 
endometrioid epithelial ovarian, fallopian tube or primary peritoneal cancer.  
3. Platinum-free interval since last line of platinum of less than 6 months (182 days). 
4. Received at least 3 prior chemotherapy-containing regimens. Prior treatment with only 
non-cytotoxic agents (e.g. hormones, antibodies or PARP inhibitors) is permitted, but 
should not be considered as one of the ‘3 prior chemotherapy-containing regimens’. 
Adjuvant chemotherapy should be counted as a prior line of therapy. 
5. Age ≥18 years. 
6. ECOG performance status of 0 or 1. 
7. Measurable disease as defined by RECIST. 
8. Adequate bone marrow function as defined by: absolute neutrophil count (ANC) 
≥1.5×109/l, platelet count ≥100×109/l and hemoglobin level ≥10.0 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 Cr <1.5×ULN or GFR ≥50 ml/min. 
11. Ability to comply with protocol requirements. 
12. Patients are assumed to be infertile as a consequence of treatment for their disease, 
however, in the event they are not, patients must be postmenopausal (12 months of 
amenorrhea), agree to be abstinent, or they must agree to use two forms of 
contraception, one of which must be a barrier method and the other must be a highly 
effective method. These forms of contraception must be used from the time of signing 
consent, throughout the treatment period, and for 30 days following the last NUC-1031 
dose administration. Oral or injectable contraceptive agents cannot be the sole method 
of contraception. See protocol Section 10.3.1 for more information. Patients of 
childbearing potential must have a negative serum pregnancy test within 72 hours prior 
to the first study drug administration. This criterion does not apply to patients who have 
had a previous hysterectomy or bilateral oophorectomy. 
 


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4.2 
Exclusion Criteria 
Patients who meet any of the following criteria at Screening will be excluded from the study: 
1. Disease classified as primary platinum refractory (i.e. progression while receiving 
initial line of platinum-based therapy or within 4 weeks of the initial regimen). 
2. Received fewer than 3 prior chemotherapy-containing regimens. 
3. Prior therapy with single-agent gemcitabine (prior gemcitabine plus carboplatin 
combination treatment is permitted). 
4. Prior history of hypersensitivity to gemcitabine. 
5. History of allergic reactions attributed to the components of the diluents used with 
NUC-1031. 
6. Mucinous, low-grade serous, low-grade endometrioid, carcinosarcoma, clear cell, or 
undifferentiated/unclassifiable histology. 
7. Symptomatic CNS or leptomeningeal metastases. 
8. Prior chemotherapy, radiotherapy (other than short cycle of palliative radiotherapy for 
bone pain), treatment with a VEGF inhibitor, PARP inhibitor or immunotherapy within 
21 days of first receipt of study drug (within 6 weeks for nitrosoureas and mitomycin 
C); hormone therapy within 14 days of first receipt of study drug; or blood transfusion, 
or use of any hematopoietic growth factors within 28 days of first receipt of study drug. 
9. Residual toxicities from chemotherapy or radiotherapy, which have not regressed to 
Grade ≤1 severity (NCI CTCAE v4.03), except for neuropathy (Grade 2 allowed) or 
alopecia. 
10. Patients who have a history of another malignancy diagnosed within the past 5 years, 
with the exception of adequately treated non-melanoma skin cancer or curatively 
treated carcinoma in situ of the cervix or ductal carcinoma in situ (DCIS) of the breast. 
Patients with previous invasive cancers are eligible if treatment was completed more 
than 5 years prior to initiating the current study treatment, and the patient has had no 
evidence of recurrence since then. 
11. Presence of an uncontrolled concomitant illness or active infection requiring IV 
antibiotics. 
12. Presence of any serious illnesses, medical conditions, or other medical history, 
including laboratory results, which, in the Investigator’s opinion, would be likely to 
interfere with the patient’s participation in the study, or with the interpretation of the 
results. 
13. Known HIV positive or known active hepatitis B or C. 
14. 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. 
15. Currently pregnant, lactating or breastfeeding. 
16. QTc interval >450 milliseconds. 
17. Concomitant use of drugs known to prolong QT/QTc interval (Appendix 1). 
18. History of radiologically confirmed bowel obstruction (including sub-occlusive 
disease) relating to ovarian cancer within 6 months prior to the first receipt of study 
drug. 


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19. Patients who have received a live vaccination within 4 weeks of first planned NUC-
1031 dose administration. 
 
4.3 
Waivers to Entry Criteria 
The Investigator at each study center is responsible for ensuring the accuracy and completeness 
of all research records, the accountability of study drug, and the conduct of clinical and 
laboratory evaluations as outlined in the protocol. Waivers will not be granted for a patient 
who does not satisfy the eligibility criteria. Investigators who are unsure whether the patient 
satisfies all the entry criteria and wish to clarify matters of clinical discretion must contact the 
Medical Monitor who will consult the Sponsor before responding to the enquiry. 
 
4.4 
Study Completion 
The study is considered complete when 44 response evaluable patients have been treated at the 
selected dose and all patients have reached the PFS endpoint or 24 months have elapsed since 
the final patient was enrolled (whichever comes first). Adverse events present at the time of 
study withdrawal should continue to be assessed for a minimum of 30 days following the last 
dose of study drug or until resolution to baseline values, whichever occurs first. This should 
ensure that sufficient information is available to enable assessment of the primary endpoint and 
other critical secondary endpoints including safety. In the weeks subsequent to a determination 
that sufficient information is available for these assessments, a date for database lock will be 
assigned, and any outstanding inquiries concerning data elements will be resolved.  
 
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. Please 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 designee who obtains consent must be suitably qualified and experienced. All 
designees must be authorized by the Investigator to obtain consent. The Investigator is 
responsible for ensuring that the study consent procedures comply with 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 
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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 Tumor Tissue Collection 
A fresh tumor biopsy and archival tumor tissue, if available are required assessments for this 
study. Patients who do not have easily accessible tumor for biopsy should not be put at undue 
risk for sample collection and these patients remain eligible for the study. Biopsied lesions 
should not be designated as target lesions for the purposes of RECIST.  
An optional tumor sample may also be collected within 24 hours of NUC-1031 administration 
on C1D1. Participation in this element of the research requires patients to sign an addendum to 
the ICF. For sampling procedures, storage conditions, and shipment instructions, please refer 
to the accompanying Tumor Tissue Laboratory Manual. 
 
5.2 
Patient Registration and Screening Procedures 
All screening activities must be performed within 28 days of randomization. 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 CRO upon 
request, but without patient identifiers. 
In Part I, patient randomization will be stratified according to BRCA mutation status and 
number of prior lines of chemotherapy (3 or >3). In Part II, sensitivity analyses will be 
conducted of efficacy endpoints according to BRCA mutation status. Patients known to have 
germline BRCA mutation(s) prior to randomization can enter the study based on this result. 
Patients who have had a tumor BRCA mutation identified in a certified laboratory may also be 
enrolled on the study based on this result. Patients with unknown BRCA mutation status should 
undergo local BRCA mutation testing prior to study entry, according to local ethical procedures 
for genetic testing.  
Before entering a patient onto the study, the Medical Monitor, in consultation with the Sponsor, 
will confirm eligibility according to the defined inclusion and exclusion criteria. Details of the 
query and outcome of the decision must be documented on the registration/ eligibility checklist. 
To register a patient to the study, the site must email a completed Registration Form, along 
with a copy of the blinded histology report, to the patient registration email address supplied. 
The site will be informed by email and fax of the approval to be treated. Treatment must not 
start until this registration process is complete and must start no later than 10 days after the day 
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5.3 
Screening Assessments 
Standard of care assessments that were completed prior to informed consent but are within the 
screening window may be used for screening assessments and do not have to be repeated.  All 
protocol required assessments that are not deemed standard of care should not be completed 
until after informed consent is signed. 
Screening assessments of consented patients will comprise the following: 
• Provision of written informed consent. 
• Eligibility confirmation, including histological diagnosis of ovarian cancer. 
• Patient registration. 
• Assessment of medical and surgical history, including prior therapy for ovarian cancer. 
• BRCA testing (if BRCA status is unknown). 
• ECOG performance score. 
• The FOSI-18 and EQ-5D-5L instruments must be completed prior to other scheduled 
study procedures and dosing (if applicable). 
• Routine physical 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. 
• Height and weight. 
• 12-lead ECG 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. The QTc interval should be calculated for each ECG using the 
Fridericia formula and averaged. Management of QT/QTc prolongation should be 
performed in accordance with institutional standard of care at the discretion of the 
treating physician. Digital and certified paper copies should be stored as part of the 
study documents in the event they need to be used in a future analysis. 
• Recording of demographic data. 
• Baseline assessment of symptoms. 
• Blood samples drawn for: 
o Hematology: WBC count, differential WBC count, RBC count, hemoglobin, 
hematocrit and platelets. 
o Coagulation parameters: PT/INR and aPTT. 
o Chemistry: sodium, potassium, magnesium, urea or blood urea nitrogen, 
creatinine, glucose, phosphate, total protein, albumin, adjusted calcium, total 
bilirubin, bicarbonate, chloride, uric acid, alkaline phosphatase, AST, ALT and 
LDH. 
o Pregnancy testing: For women of childbearing potential serum pregnancy must 
be performed within 72 hours prior to C1D1. 
o CA125 (for GCIG response determination). 
• Urinalysis: pH, specific gravity, ketones, leukocytes, protein, glucose, bilirubin, 
urobilirubin and occult blood. Dipstick testing is acceptable. 


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• Tumor imaging (CT, MRI and/or PET-CT [US only] of thorax, abdomen and pelvis) – 
performed within 28 days of randomization. Biopsied lesions should not be designated 
as target lesions for the purposes of RECIST. 
• Obtain fresh and archival tumor tissue. For sampling procedures, storage conditions, 
and shipment instructions, see the Tumor Tissue Laboratory Manual. Patients who do 
not have easily accessible tumor for biopsy should not be put at undue risk for sample 
collection and these patients remain eligible for the study. Biopsied lesions should not 
be designated as target lesions for the purposes of RECIST. 
• Recording of concomitant medication. 
 
5.4 
Re-Screening Patients Who Fail Inclusion/Exclusion Criteria 
If a patient does not meet the inclusion/exclusion criteria upon first assessment, she can be re-
screened within 14 days. Patients who fail at re-screening are ineligible and may not be re-
screened. 
 
5.5 
Evaluations to Be Performed During the Study 
During treatment, patients will be medically reviewed on dosing days. The following will be 
assessed: 
 
5.5.1 Each Cycle, Day 1 
All procedures to be completed prior to dosing except NUC-1031 administration and applicable 
PK samples. Safety laboratory assessments and weight measurement may be performed up to 
3 days prior to Day 1 of each cycle.  
• ECOG performance score. 
• The FOSI-18 and EQ-5D-5L instruments must be completed prior to other 
scheduled study procedures and dosing (if applicable). 
• Routine physical 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. 
• 12-lead ECGs should be performed pre-infusion. 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. The QTc 
interval should be calculated for each ECG using the Fridericia formula and 
averaged. Management of QT/QTc prolongation should be performed in 
accordance with institutional standard of care at the discretion of the treating 
physician. Digital and/or certified paper copies should be retained at site and stored 
as part of the study documents in the event they need to be used in a future analysis. 
• At C1D1 and C3D1 only the 12-lead ECGs should be performed 30-60 minutes pre-
infusion and again 30-60 minutes post-infusion. 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. The QTc 
interval should be calculated for each ECG using the Fridericia formula and 
averaged. Management of QT/QTc prolongation should be performed in 


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accordance with institutional standard of care at the discretion of the treating 
physician. Digital and/or certified paper copies should be retained at site and stored 
as part of the study documents in the event they need to be used in a future analysis. 
• Blood samples drawn for: 
o Hematology: WBC count, differential WBC count, RBC count, hemoglobin, 
hematocrit and platelets. 
o Coagulation parameters: PT/INR and aPTT. 
o Chemistry: sodium, potassium, magnesium, urea or blood urea nitrogen, 
creatinine, glucose, bicarbonate, chloride, uric acid, phosphate, total protein, 
albumin, adjusted calcium, total bilirubin, alkaline phosphatase, AST, ALT and 
LDH. 
o CA125. 
• 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-1031. 
• AE recording and causality assessment. 
• Recording of new or changes to concomitant medication. 
 
5.5.2 For Sites Collecting Optional Fresh Biopsy: Within 24 Hours of Cycle 1 Day 1  
• Obtain fresh tumor biopsy within 24 hours of the end of NUC-1031 infusion on 
C1D1. For sampling procedures, storage conditions, and shipment instructions, see 
the Tumor Tissue Laboratory Manual. Patients who do not have easily accessible 
tumor for biopsy should not be put at undue risk for sample collection and these 
patients remain eligible for the study. Biopsied lesions should not be designated as 
target lesions for the purposes of RECIST. 
 
5.5.3 For Sites Participating in PK Sample Collection: Cycles 1 & 3 – Days 1 & 2   
• PK: multiple blood samples will be taken during Cycles 1 and 3 on Days 1 and 2.  
Optional urine samples may be taken during Cycle 1 on Days 1 and 2. Refer to 
Section 7.2 for more details. 
• AE recording and causality assessment. 
• Recording of new or changes to concomitant medication. 
5.5.4 Each Cycle, Days 8 & 15 
All procedures to be completed prior to dosing except NUC-1031 administration and applicable 
PK samples. 
• Routine physical 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. 


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• 12-lead ECGs should be performed pre-infusion. 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. The QTc interval 
should be calculated for each ECG using the Fridericia formula and averaged. 
Management of QT/QTc prolongation should be performed in accordance with 
institutional standard of care at the discretion of the treating physician. Digital and/or 
certified paper copies should be stored as part of the study documents in the event they 
need to be used in a future analysis. 
• At C1D15 and C3D15 only the ECGs should be performed 30-60 minutes pre-infusion 
and again 30-60 minutes post-infusion. 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. The QTc interval should be 
calculated for each ECG using the Fridericia formula and averaged. Management of 
QT/QTc prolongation should be performed in accordance with institutional standard of 
care at the discretion of the treating physician. Digital and/or certified paper copies 
should be stored as part of the study documents in the event they need to be used in a 
future analysis. 
• Blood samples drawn for: 
o Hematology: WBC count, differential WBC count, RBC count, hemoglobin, 
hematocrit and platelets. 
o Chemistry: sodium, potassium, magnesium, urea or blood urea nitrogen, 
creatinine, glucose, bicarbonate, chloride, uric acid, phosphate, total protein, 
albumin, adjusted calcium, total bilirubin, alkaline phosphatase, AST, ALT and 
LDH. 
• IV administration of NUC-1031. 
• AE recording and causality assessment. 
• Recording of new or changes to concomitant medications. 
 
5.5.5 For Sites Participating in PK sample Collection: Cycle 1 Days 15 & 16 
• PK: multiple blood samples will be taken on Cycle 1 Days 15 and 16. Optional 
urine samples may be taken on Cycle 1 Days 15 and 16. Refer to Section 7.2 for 
more details. 
• AE recording and causality assessment. 
• Recording of new or changes to concomitant medications. 
 
 


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5.5.6 Every 8 Weeks (±7 days) from Cycle 1 Day 1 Until Disease Progression, Initiation 
of a New Treatment or Death  
• Tumor imaging (CT, MRI and/or PET-CT [US only] of thorax, abdomen and pelvis).  
• ECOG performance status should be assessed if the patient has stopped study treatment 
and is attending a Follow-Up Visit. 
 
5.5.7 End of Treatment Visit 
The assessments to be performed on discontinuation due to disease progression or early 
treatment discontinuation for other reasons (e.g. withdrawal of consent) are summarized below. 
The End of Treatment visit should occur within 30 days of the last administration of NUC-
1031. The following will be assessed: 
• ECOG performance status. 
• The FOSI-18 and EQ-5D-5L instruments must be completed prior to other scheduled 
study procedures. 
• Routine physical 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. 
• 12-lead ECG 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. The QTc interval should be calculated for each ECG using the 
Fridericia formula and averaged. Management of QT/QTc prolongation should be 
performed in accordance with institutional standard of care at the discretion of the 
treating physician. Digital and certified paper copies should be stored as part of the 
study documents in the event they need to be used in a future analysis. 
• Blood samples drawn for: 
o Hematology: WBC count, differential WBC count, RBC count, hemoglobin, 
hematocrit and platelets. 
o Coagulation parameters: PT/INR and aPTT. 
o Chemistry: sodium, potassium, magnesium, urea or blood urea nitrogen, 
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 CA125. 
• Urinalysis: pH, specific gravity, ketones, leukocytes, protein, glucose, bilirubin, 
urobilirubin and occult blood. Dipstick testing is acceptable. 
• AE recording and causality assessment. 
• Recording of new or changes to concomitant medication. 
 


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5.5.8 Follow-Up 
Patients who stop treatment with no evidence of disease progression as defined by RECIST 
criteria will continue to receive scans at regular intervals (every 8 weeks [±7 days] from C1D1) 
until disease progression or death (whichever comes first) in order to determine duration of 
overall response and PFS. 
Patients with evidence of disease progression as defined by RECIST criteria will receive a 
phone call at regular intervals (every 12 weeks [±7 days]) until death, loss to follow-up, or 
study discontinuation in order to determine duration of Overall Survival. 
 
6 
PATIENT WITHDRAWAL 
6.1 
End of Treatment 
Treatment with NUC-1031 is to be continued until one of the following occurs: 
• Progressive Disease (PD) as defined by RECIST criteria. Patients should not 
discontinue NUC-1031 because of raised CA125 or other clinical signs of PD until 
PD has been confirmed by RECIST. 
• Unmanageable toxicity defined as an AE that is considered by the Investigator to 
warrant permanent discontinuation of NUC-1031 including the following: 
o AE resulting in a dosing delay of more than 14 days in starting the next 
cycle, unless the patient is receiving clinical benefit. 
o Clinically significant drug-related AE that recurs despite dose reduction in 
two consecutive cycles. Patients may continue to receive treatment if the 
Principal Investigator and Medical Monitor agree that the patient is 
receiving a clinical benefit and the toxicity is manageable, reversible or 
transient. 
• Lack of further clinical benefit or unfavorable risk/benefit profile as judged by the 
Investigator. 
• Inter-current illness that prevents further administration of NUC-1031. 
• 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 further treatment with NUC-1031. 
• Patient non-compliance. 
• Lost to follow-up. 
• Patient withdrawal of consent. 
• Sponsor request. 


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All study procedures outlined for the End of Treatment visit are to be completed within 30 days 
(±7 days) of the last dose of study drug. The primary reason for study drug discontinuation is 
to be recorded in the CRF. 
 
6.2 
Follow-Up After Treatment Discontinuation 
Patients who have documented disease progression defined by RECIST criteria while receiving 
study medication will discontinue treatment but will enter the follow up period. Patients should 
not discontinue NUC-1031 because of raised CA125 or other clinical signs of PD until PD has 
been confirmed by RECIST. 
Patients who stop treatment with no evidence of disease progression will enter the follow-up 
period and should attend clinic every 8 weeks (±7 days) from C1D1 for follow-up scans and 
assessments. This should continue until disease progression, initiation of a new treatment or 
death. 
 
6.3 
Consent Withdrawal 
Patients will be informed that they have the right to withdraw from the study at any time for 
any reason, without prejudice to their medical care.  
Consent withdrawal means that a patient has expressed a wish to withdraw from the study 
altogether. Under these circumstances, the site personnel should document all relevant 
discussions in the patient notes and mark all future CRF pages as not applicable. Under these 
conditions, Investigators are still responsible to follow up any SAEs until resolution. 
 
6.4 
Patient Evaluability and Replacement 
Enrollment will continue until there are 44 patients evaluable for a response assessment at the 
selected dose level. All patients with measurable disease (defined by BICR) will be considered 
evaluable for response assessment. 
All eligible patients who receive at least one dose of NUC-1031 are considered evaluable for 
safety analysis.  
 
7 
SAMPLES FOR LABORATORY ANALYSIS 
7.1 
Clinical Laboratory Tests 
All clinical laboratory testing will be performed at local sites. A serum or urine 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, or during the 3 days prior to a treatment 
visit. 
 
7.2 
Pharmacokinetics 
PK sampling (blood and urine) will be performed at a sub-set of sites specified by NuCana. 
The PK schedule is designed to explore the relationship between NUC-1031 PK, 
pharmacodynamics and clinical activity. PK endpoints will include assessments of: 
• In plasma/urine: NUC-1031, dFdC and dFdU. 
• In PBMCs: NUC-1031, dFdC, dFdCMP, dFdCDP, dFdCTP and dFdU. 


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Blood samples will be collected at the following visits:  
• Cycle 1: Days 1 and 2 
• Cycle 1: Days 15 and 16 
• Cycle 3: Days 1 and 2 
 
The PK blood sampling schedule is summarized in Table 1 below: 
Table 1 
PK sampling schedule 
Sample 1 
T0 – pre-dose (before the start of the infusion) 
Sample 2 
T1 – end of infusion 
Sample 3 
T2 – T1 plus 10 minutes 
Sample 4 
T3 – T1 plus 30 minutes 
Sample 5 
T4 – T1 plus 1 hour 
Sample 6 
T5 – T1 plus 2 hours 
Sample 7 
T6 – T1 plus 4 hours 
Sample 8 
T7 – T1 plus 6 hours 
Sample 9 
T8 – T1 plus 24 hours  
 
Optional pooled urine collection for PK analysis will be taken 0-6 and 6-24 hours from the 
beginning of NUC-1031 infusion. Optional urine pooled urine collections will be collected at 
the following visits: 
• Cycle 1: Days 1 and 2 
• Cycle 1: Days 15 and 16 
 
Standard PK parameters for each compound of interest will then be derived from the measured 
plasma, urine and PBMC concentrations. The PK samples will be processed and analyzed at a 
central laboratory. Please refer to the Guidelines for Pharmacokinetic Sample Management for 
details regarding PK sample collection, processing and shipping. 
 
7.3 
Tumor Tissue Biopsies 
Fresh and archival tumor tissue will be submitted for laboratory analysis to understand the basis 
for response or resistance to treatment. Fresh and archival tumor (if available) samples are a 
requirement for participation in the study. However, patients who do not have easily accessible 
tumor for biopsy should not be put at undue risk for sample collection and these patients remain 
eligible for the study. Biopsied lesions must not be designated as target lesions for the purposes 
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An optional tumor sample may be collected within 24 hours of the end of the infusion of NUC-
1031 on C1D1. Specific instructions on the collection and shipment of tissue samples will be 
provided in the Tumor Tissue Laboratory Manual.  
Correlation of response to NUC-1031 with genomic, transciptomic and proteomic tissue 
biomarkers of tumor sensitivity and resistance will be assessed both in the freshly obtained 
tumor specimens and in archival samples obtained at screening. Markers of interest include 
cytidine deaminase (CDA), deoxycytidine kinase (dCK), human equilibrative nucleoside 
transporter 1 (hENT1), ribonucleotide reductase M1 (RRM1) and RRM2. 
 
7.4 
Labeling and Confidentiality of Biological Samples 
All biological samples (including blood, urine and tumor) sent to analytical laboratories will 
be labeled with the study number, patient number and date/time taken. Samples labels must not 
contain any personally identifiable information.  
 
7.5 
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 CRO 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 
anonymized, it would not be possible to destroy such samples. 
 
8 
INVESTIGATIONAL MEDICINAL PRODUCT 
8.1 
NUC-1031 Description 
The drug product, NUC-1031 (for injection), is presented as a sterile solution in clear glass 
vials at a concentration of 250 mg/ml formulated in dimethylacetamide (DMA) and Normal 
Saline (0.9%) in the ratio of 80:20. 
 
8.2 
NUC-1031 Supplies and Study Drug Packaging  
NUC-1031 will be supplied to the pharmacy of the investigative clinical site and will be 
supplied as a 7 ml fill volume in 10 ml clear glass vials. The vials are packaged in a labeled 
cardboard outer carton, each containing 6 vials. 
A Diluent Solution is supplied as a 10 ml volume in clear glass 20 ml vials. The Diluent 
Solution is comprised of 20% DMA, 40% Kolliphor ELP and 40% Tween 80. The Diluent 
Solution vials are packaged in labeled cardboard outer carton, each containing 3 vials. 
 
8.3 
Handling and Storage 
NUC-1031 and Diluent Solution must be stored in an appropriately secure Investigational 
Pharmacy at all times until dispensed for administration to patients on protocol. NUC-1031 
must be stored between 2-8°C (36-46°F) in a temperature-monitored refrigerated unit. The 
Diluent Solution must be stored at room temperature (15-25°C/59-77°F). Only adequately 
trained pharmacy staff are permitted to handle NUC-1031 and the Diluent Solution. The study 
medication should not be removed from the pharmacy except for the purposes of dispensing to 
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If NUC-1031 or the Diluent Solution contacts the skin or the mucous membranes, it should be 
washed immediately and thoroughly. For additional information on study drug handling 
including dispensing directions, please refer to the NUC-1031 Pharmacy Manual.  
 
8.4 
Preparation 
As with other cytotoxic substances, applicable local procedures should be used in the 
preparation and administration of NUC-1031. Please refer to the administration guidance in the 
current version of the Pharmacy Manual and Administration Guidelines for further information 
on the preparation of NUC-1031. 
8.5 
Study Drug Dosage and Administration 
NUC-1031 will be administered to each patient based on her body surface area (BSA) at 
baseline. If a patient’s weight increases or decreases by ≥10% during the course of the study, 
the dose of NUC-1031 should be recalculated. The Dubois & Dubois BSA calculation is the 
preferred method, however other standard calculations can also be used. Sites should document 
the method used in the eCRF. 
 
Dubois & Dubois BSA calculation: 
 
BSA (m2) = 0.007184 × Height (cm)0.725 × Weight (kg)0.425 
 
Patients will receive IV NUC-1031 at an initial dose of 500 mg/m2 or 750 mg/m2 on Days 1, 8 
and 15 of a 28-day schedule. Dose adjustments or dose delays are to be implemented within or 
between cycles based on drug related toxicities. The dose modification scheme to be employed 
is detailed in Section 9 of this protocol. 
The Diluent Solution (Kolliphor ELP; Tween 80; DMA) is provided for use by the hospital 
pharmacy to prepare NUC-1031 for administration by infusion in sterile saline for injection. 
The pharmacy will prepare the product for administration by mixing NUC-1031 and Diluent 
Solution and then further diluting the appropriate dose of this mixture in 0.9% sterile saline for 
injection. This preparation is then administered IV over 30 minutes. The administration time 
may be increased to 1 hour and then to 2 hours, if required. Please refer to the current Pharmacy 
Manual and Administration Guidelines for further information on NUC-1031 preparation and 
administration. 
 
8.6 
Drug Destruction 
Used vials 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. 
 
8.7 
Study Drug Accountability 
The FDA and other applicable regulatory authorities require accounting of all study drug 
received by each study center. Records of drug disposition required include the date received 
by the center, 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 center is to use a study drug 


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accountability log to document study drug disposition. All items on this form are to be 
completed in full. 
The Investigator identification number and patient initials (as allowed by local regulations) and 
identification number are to be recorded on each study drug accountability log. Each time study 
personnel dispense study drug for a patient, he or she is to record the date dispensed, amount 
of study drug dispensed, Lot number, and the dispenser’s initials. Study personnel are to 
monitor the inventory of clinical supplies and maintain a count of all used and unused study 
drug. The Sponsor’s designated site monitor will review study drug accountability records and 
remaining drug supplies during routine monitoring visits. 
 
8.8 
Management of NUC-1031 Overdose 
The dose of NUC-1031 intended for use on this protocol is 500 mg/m2 or 750 mg/m2. In the 
Phase I, FIH study, the highest dose studied was 1,000 mg/m2. Should a substantial overdose 
occur, there is no known antidote. Any patient, who inadvertently receives a higher dose than 
intended should be monitored closely, managed with appropriate supportive care, including 
transfusion and hematopoietic 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. 
 
9 
DOSE MODIFICATIONS 
Adverse events may be managed by dose delays and/or dose reductions according to the 
clinical situation. Advice on how to modify dosing for hematological and non-hematological 
toxicities is given below.  
Only one dose reduction is permitted within a cycle. This may be a temporary dose reduction, 
in which case the next cycle can revert to the starting dose of the previous cycle, or it may be 
a permanent dose reduction 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 will be discontinued. The lowest dose which may be administered is 275 mg/m2. 
Treatment between cycles can be delayed for up to 14 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-1031 and will 
be withdrawn from the study. 
 
9.1 
Hematological Toxicity – Dose Adjustment  
NUC-1031 administration should be given according to the absolute neutrophil count (ANC) 
and platelet count on the day of dosing. On Day 1 of each 28-day cycle, if the ANC is 
≥1.5×109/l and the platelet count is ≥75×109/l, then NUC-1031 should be given at full dose 
unless the patient has previously been permanently dose reduced. 
On Day 1 of each 28-day cycle, if the ANC is 1.5-1.0×109/l and the platelet count is 50-75×109/l 
without evidence of bleeding, then NUC-1031 should be given at a reduced dose unless the 
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Within a cycle, should patients experience neutropenia or thrombocytopenia, dosing on Day 8 
and Day 15 should be adjusted per Table 2. 
 
Table 2 
Dose adjustments within a cycle (Days 8 and 15) based on ANC and platelet 
counts 
ANC 
 
Platelets 
Starting dose 
(750 mg/m2) 
Starting dose 
(500 mg/m2) 
Starting dose 
(375 mg/m2) 
≥1.5×109/l 
AND 
≥75×109/l 
750 mg/m2 
500 mg/m2 
375 mg/m2 
1.5-1.0×109/l 
and afebrile 
AND/OR 
50-75×109/l 
without 
evidence 
of bleeding 
500 mg/m2 
375 mg/m2 
275 mg/m2 
<1.0×109/l, or 
<1.5×109/l with 
fever 
AND/OR 
<50×109/l, 
or 
<100×109/l 
with active 
bleeding 
Omit 
Omit 
Omit 
 
Should both the Day 8 and Day 15 doses be omitted for hematologic toxicity within the same 
cycle, the dose for all subsequent cycles should be permanently reduced to the next dose 
level.  
If a patient starts a treatment cycle at 500 mg/m2 and requires further dose reduction on Day 
8 or Day 15 of the following cycle due to hematologic toxicity, dose modification should 
follow the column second from the right of Table 2. 
If a patient has her dose permanently reduced to 375 mg/m2, and hematologic toxicity 
persists on any day that a dose is scheduled, dose modification should follow the far right 
column of Table 2.  
For all other hematologic toxicity, dose adjustments should be performed according to Table 3.  
 
 
 


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Table 3 
Dose adjustments for hematological toxicities (excluding toxicities relating to 
ANC and platelet counts) 
NCI CTCAE grade 
Dose adjustment 
Grade 1 toxicity  
If the patient was receiving 750 mg/m2 then 
reduce to 500 mg/m2.  
If the patient was receiving 500 mg/m2 then 
reduce to 375 mg/m2. 
If the patient was receiving 375 mg/m2 then 
reduce to 275 mg/m2. 
Grade 2, 3 and 4 toxicity  
 
Omit until resolution to ≤Grade 1 if the patient 
was receiving 750 mg/m2 then resume at the 
dose 500 mg/m2.  
If the patient was receiving 500 mg/m2 then 
resume at the dose 375 mg/m2. 
If the patient was receiving 375 mg/m2 then 
resume at the dose 275 mg/m2. 
 
 
9.2 
Non-Hematological Toxicity – Dose Adjustment 
Dose adjustment should be performed according to Table 4.  If dose omission is required, 
treatment should be delayed until the toxicity has resolved to ≤Grade 1. If this occurs, 
subsequent doses should be permanently reduced, without re-escalation. For significant 
pulmonary complications (e.g. pneumonitis and acute respiratory distress syndrome), study 
treatment should be stopped. 
 
Table 4 
Dose adjustment for non-hematological toxicities 
NCI CTCAE grade 
Dose adjustment 
Grade 0-2 toxicity or Grade 3 nausea/ 
vomiting/ alopecia 
100% dose (with escalation of anti-emetic 
prophylaxis for nausea and vomiting) 
Grade 3/4 toxicity  
(except nausea/vomiting/alopecia) 
Omit until resolution to ≤Grade 1 if the patient 
was receiving 750 mg/m2 then resume at the 
dose 500 mg/m2.  
If the patient was receiving 500 mg/m2 then 
resume at the dose 375 mg/m2. 
If the patient was receiving 375 mg/m2 then 
resume at the dose 275 mg/m2. 
 
 
 


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9.3 
Guidance for Dose Omissions 
Table 5 outlines the guidance for omission of doses on Day 1, 8 or 15. 
Table 5 
Dose omission guidance 
Day 1 missed dose 
Day 8 missed dose 
Day 15 missed dose 
If the dose omitted was due to 
be on Day 1 of the next cycle, 
that cycle will not be 
considered to start until the day 
the first dose is actually 
administered to the patient (i.e. 
1-2-3-Rest, X-1-2-3-Rest, etc). 
Cycle continues per protocol, 
with one dose not given (i.e. 
1-2-3-Rest, 1-X-3-Rest, 1-2-3-
Rest, etc). Day 15 is 
administered as per cycle 
calendar if blood results 
permit. 
That week becomes the week 
of rest. Next dose (if blood 
results permit) becomes Day 1 
of a new cycle, and the patient 
is considered to have had a 21-
Day cycle. 
 
10 OTHER TREATMENTS (NON-IMP) 
All prescription and non-prescription medications and therapies, including pharmacologic 
doses of vitamins, herbal medicines, or other non-traditional medicines, taken from 28 days 
prior to the first dose of NUC-1031 through the End of Treatment Visit must be recorded in 
the CRF. All prior anti-cancer therapies from initial diagnosis up until enrollment must be 
recorded in the CRF. 
 
10.1 
Support Medication 
Patients may receive standard prophylactic medical treatment for nausea and vomiting. During 
treatment, patients will be reviewed on a weekly basis during the first cycle and on each day 
of treatment for subsequent cycles. Additional visits may be arranged at the Investigator’s 
discretion. All support medication must be recorded in the CRF. 
 
10.2 
Hematopoietic Growth Factor Support 
The prophylactic use of hematopoietic growth factors (e.g. G-CSF) is not permitted in cycle 1. 
However, the Investigator may prescribe G-CSF as treatment for Grade 3 or higher  neutropenia 
according to local protocols and as prophylaxis after the first event of Grade 3 neutropenia or 
for any febrile neutropenic episode in order to enable the patient to continue on study. All 
hematopoietic growth factors used from 30 days prior to date of consent until 30 days after 
administration of last dose of NUC-1031 must be recorded in the CRF. Any blood or platelet 
transfusions should also be recorded in the CRF. 
 
10.3 
Concomitant Medication and Non-Drug Therapies 
Concomitant medication may be given as medically indicated. All concomitant medication and 
non-drug therapies used from 30 days prior to date of consent until 30 days after administration 
of last dose of NUC-1031 must be recorded in the CRF. 
 
 
 


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10.3.1 Contraception Methods 
Patients are assumed to be infertile as a consequence of treatment for their disease, or 
postmenopausal (12 months of amenorrhea).   
 
If patients are not infertile or post-menopausal, they must agree to: 
• Abstinence during her entire participation in the study and for 30 days post-last dose of 
study medication or  
• Use two forms of contraception, one of which must be a barrier method and one must 
be a highly effective form (less than 1% failure rate if used consistently and correctly).  
 
Acceptable barrier methods (which may not be considered highly effective): 
• Male or female condom, with or without spermicide 
• Cap, diaphragm or sponge with spermicide 
 
Highly effective forms of contraception include: 
• Oral, intravaginal or transdermal combined (estrogeen and progestogen containing) 
hormonal contraception associated with inhibition of ovulation 
• Oral, injectable, or implantable progestogen-only hormonal contraception associated 
with inhibition of ovulation 
• Surgical sterilization (bilateral occlusion, vasectomized partner) 
• Intrauterine device or intrauterine hormone-releasing system 
 
These forms of contraception must be used from the time of signing consent, throughout the 
treatment period, and for 30 days following the last NUC-1031 dose administration. Oral or 
injectable contraceptive agents cannot be the sole method of contraception. Patients of 
childbearing potential must have a negative serum pregnancy test within 72 hours prior to the 
first study drug administration. 
 
 
 


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10.4 
Prohibited Therapy and Concomitant Medications 
Use of the following therapies is prohibited during the study: 
• Cytotoxic chemotherapy 
• Radiotherapy 
• Immunotherapy including immunosuppressive therapy 
• Radioimmunotherapy 
• Hormone therapy (other than contraceptives, hormone-replacement therapy, or 
megestrol acetate) 
• Biologic agents intended for the treatment of ovarian cancer (other than hematopoietic 
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 ovarian cancer, whether approved by local 
regulatory authorities or investigational 
• Drugs that are known to prolong QTc interval (Appendix 1). 
• Live vaccines (must also be avoided for six weeks after last NUC-1031 dose 
administration). 
 
11 TUMOR RESPONSE ASSESSMENTS 
11.1 
Tumor Measurements and Assessment of Disease Response 
Patients must have at least one lesion that can be accurately assessed at baseline by CT, MRI 
or PET-CT (US only), 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, MRI or 
PET-CT (US only) scan. The same radiological methods at baseline must be used to follow 
lesions throughout the study. Disease must be measured according to RECIST criteria, with 
target and non-target lesions identified, measured and followed throughout the study 
(Appendix 2). Biopsied lesions should not be designated as target lesions for the purposes of 
RECIST. 
Whenever possible, the same qualified physician will interpret results to reduce variability. 
Radiographic images will be maintained at the study center, and Investigator’s findings will be 
filed in the patient’s source documents. 
In addition, digital copies of all radiographic images will be collected and stored in a central 
radiologic facility in order to allow for independent confirmation of the radiographic imaging 
results. Instructions for the collection, and submission of images are provided in a separate 
Imaging Manual. 
Tumor measurements and disease response assessments are to be performed every 8 weeks (±7 
days) from C1D1. If the patient stops study treatment for reasons other than radiologically 
confirmed PD, tumor measurements and disease response assessments should continue every 
8 weeks (±7 days) from C1D1 thereafter until PD is radiologically confirmed. 
Tumor measurements and disease response assessments also are to be performed any time 
disease progression is suspected. 
Patients should not discontinue NUC-1031 because of raised CA125 or other clinical signs of 
PD until PD has been confirmed by RECIST. 


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CRs and 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 6 weeks. 
A third-party central imaging vendor will review all study-related imaging. The imaging 
vendor will not be responsible for assessing images in real-time to inform on patient treatment 
decisions. This responsibility will remain with the Principal Investigator at the site. Please refer 
to the Imaging Manual for details on submission and review of images. 
 
12 SAFETY REPORTING 
12.1 
Definitions 
The Investigator is responsible for reporting all AEs that are observed or reported during the 
study, regardless of their relationship to study drug or their clinical significance. 
An AE is defined as any untoward medical occurrence in a patient enrolled into this study 
regardless of its causal relationship to study drug. Patients or their legally authorized 
representatives will be instructed to contact the Investigator or Sub-Investigator at any time 
after signing the ICF if any symptoms develop. 
A Treatment Emergent AE (TEAE) is defined as any event not present before exposure to 
study drug or any event already present that worsens in either intensity or frequency after 
exposure to study drug. 
A Serious AE (SAE) is defined as any event that: 
• Results in death, 
• Is immediately life-threatening, 
• Requires inpatient hospitalization or prolongation of existing hospitalization, 
• Results in persistent or significant disability/incapacity, 
• Is a congenital anomaly/birth defect, 
• Significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above) 
PD 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 NUC-1031. This means that a causal relationship between NUC-1031 and the AE is at 
least a reasonable possibility, i.e. the relationship cannot be ruled out. 
An Unexpected Drug Reaction is an adverse drug reaction, the nature or severity of which, is 
not consistent with applicable product information (referring to information in IB, see RSI). 
A Suspected Unexpected Serious Adverse Reaction (SUSAR) is a serious adverse drug 
reaction, the nature or severity of which is not consistent with the applicable product 
information (e.g. Investigator’s Brochure for an unapproved IMP). 
Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical judgment, 
they may jeopardize the patient and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood 


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dyscrasias, convulsions that do not result in inpatient hospitalization, 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 hospitalized, had any 
accidents, used any new medications, or changed concomitant medication regimens (both 
prescription and over-the-counter medications). In addition to patient observations, AEs will 
be documented from any data collected on the CRF or other documents that are relevant to 
patient safety. Any allergic reaction to the agents administered as study drug treatment must be 
reported as an AE. 
All AEs that occur from date of consent through 30 days after the last dose of study drug must 
be reported in detail on the AE CRF. Disease progression in the medical opinion of the 
physician and/or disease-related morbidity and mortality as a study endpoint will not be 
considered an AE or SAE but should be captured on the Death CRF. Information to be collected 
for each AE includes onset date, type of event, etiology, Investigator-specified assessment of 
severity and relationship to study drug, seriousness, any required treatment or evaluations, 
outcome and date of resolution. AEs resulting from concurrent illnesses, reactions to 
concurrent illnesses, reactions to concurrent medications, or progression of disease states must 
also be reported. All AEs will be followed for 30 days after the patient’s last dose, or until 
resolution, whichever comes first. 
Pre-existing conditions (present before the start of the AE collection period) are considered 
concurrent medical conditions and should not be recorded as AEs. However, if the patient 
experiences a worsening or complication of such a concurrent condition, the worsening or 
complication should be recorded as an AE. Pre-existing AEs that worsen should be followed 
until 30 days after the patient’s last dose or resolution to the AE level present at study entry. 
Investigators should ensure that the AE term recorded captures the change in the condition (e.g. 
“worsening of [condition]”). 
Insufficient clinical response, efficacy, or pharmacological action should NOT be recorded as 
an AE. The Investigator must make the distinction between exacerbation of pre-existing illness 
and lack of therapeutic efficacy. PD is NOT an AE; however, some sequelae of PD (i.e. pain, 
neurologic impairment) may be reported as AEs (generally not related to NUC-1031). 
Abnormal laboratory values or test results constitute AEs only if they induce clinical signs or 
symptoms, are considered clinically significant, require therapy or further diagnosis beyond 
repeat testing for confirmation, or (if not associated with clinical signs or symptoms) they 
remain at levels consistent with severe abnormalities despite appropriate medical intervention. 
It is requested that when reporting AEs for which potentially redundant NCI CTCAE terms 
exist, the Investigator utilizes the more clinically-oriented terminology (for example, ‘anemia’ 
is preferable to ‘hemoglobin decreased’). 
It is also requested that in the setting of an allergic reaction or suspected allergic reaction 
considered by the Investigator to be related to NUC-1031, that the Investigator reports both the 
specific symptoms associated with the reaction (i.e. ‘urticaria’, ‘dyspnea’) and also report the 
appropriate term indicating the allergic reaction (‘allergic reaction’ or ‘anaphylaxis’ if 
appropriate [Immune System Disorders; CTCAE v4.03]). 
 


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12.3 
Assessment of Causality 
The Investigator’s assessment of an AE's relationship to study drug is part of the documentation 
process, but it is not a factor in determining what is or is not 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 NUC-1031 should be classified using the following guidelines: 
Related: A temporal relationship exists between the event onset and administration of NUC-
1031. It cannot be readily explained by the patient’s clinical state, intercurrent illness, or 
concomitant therapies. In case of cessation or reduction of the dose, the event abates or resolves 
and reappears upon rechallenge. This includes events that are considered possibly, probably, 
or definitely related to NUC-1031.  
Not Related: Evidence exists that the AE has an etiology other than the study drug (e.g. pre-
existing condition, underlying disease, intercurrent illness, or concomitant medication). This 
includes events that are considered probably not or not related to NUC-1031. It should be 
emphasized that ineffective study drug treatment should not be considered as causally related 
in the context of AE reporting (in other words, PD is not considered an AE; however some 
sequelae of PD may be reported as AEs and should generally be reported as AEs not related to 
NUC-1031). 
 
12.4 
Assessment of Severity 
The severity of each AE is to be assessed by the Investigator according to NCI CTCAE, v4.03. 
If the AE is not included in the NCI CTCAE, then the Investigator is to determine the intensity 
of the AE according to the following criteria: 
 
Mild (Grade 1): 
AE that disappears or is easily tolerated on continuation of 
study drug. 
Moderate (Grade 2): 
AE sufficiently discomforting to cause interference with 
usual 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 that occurs from first administration of study drug through 30 days after last study drug 
dose must be reported to Chiltern Pharmacovigilance (PV) within 24 hours from the time study 
site personnel first learn about the event. The SAE report will be completed and emailed or 
faxed to Chiltern PV using the contact details in Table 6. 
Table 6 
Chiltern pharmacovigilance contact details 
Email 
GlobalSAEInbox@chiltern.com  
UK fax number 
(+44) 00 800-529-34043 
US fax number 
(+1) 888-726-8416 or (+1) 888-228-2837 
 
If the patient is hospitalized because of or during the course of an SAE, then a copy of the 
hospital discharge summary (if available) should be faxed to Chiltern PV, using the fax 
numbers listed above, as soon as it becomes available. Withdrawal from the study and all 
therapeutic measures will be performed at the discretion of the Investigator or sub investigator. 
NuCana, or Chiltern PV, will notify appropriate regulatory authorities of any unexpected, fatal, 
or life-threatening experience that is determined to be related to the use of the study drug. Refer 
to Section 12.7 for more details. 
The Investigator or sub investigator is responsible for informing the IRB/EC. Copies of SAE 
correspondence with all Investigators or sub-investigators, governing authorities, ethics 
committees, and NuCana must be submitted to Chiltern PV for filing. 
A patient experiencing one or more SAE will receive treatment and follow-up evaluations by 
the Investigator or sub-investigator or will be referred to another appropriate physician for 
treatment and follow-up. All SAEs must be followed to resolution or, if resolution is unlikely, 
to stabilization. 
Study endpoints in ovarian cancer patients include disease-related mortality and morbidity, 
which will not be reported as expedited IND safety reports, unless there is a serious and 
unexpected event with evidence of a causal relationship between study drug and the event. As 
appropriate and based on the frequency of occurrence, SAEs in the study will be reported to 
the FDA at an appropriate interval, such as inclusion in the periodic update IND annual report.  
The following SAEs will not be reported individually in an expedited manner because they are 
anticipated to occur in the ovarian cancer 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. 
 
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, a SAE 


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Report Form should be completed and faxed within 24 hours of Investigator awareness to the 
Chiltern PV contact details provided above. 
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 Institutional 
Review Boards/ Ethics Committees (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-1031 or be sufficient to change NUC-1031 
administration or the overall conduct of the study. 
NuCana, or Chiltern PV, will notify appropriate regulatory authorities by telephone or fax 
transmission of any fatal, or life-threatening experience that is determined to be related to the 
use of the study drug (expedited report) as soon as possible but no later than 7 calendar days 
after the initial receipt of the information. Initial notification will be followed by a written 
report within 15 calendar days.  
For unexpected events associated with the use of the study drug which are not fatal or life 
threatening, NuCana or Chiltern PV will notify the regulatory authorities as soon as possible, 
but no later than 15 days of the initial receipt of information.  
The Investigator or Sub-Investigator is responsible for informing the IRB/EC. Copies of SAE 
correspondence with all Investigators or Sub-Investigators, regulatory authorities, IRBs/ECs 
and NuCana must be submitted to Chiltern PV for filing. 
 
12.8 
Terms and Grading of Events 
All AEs and toxicities must be graded according to NCI CTCAE v4.03. 
 
12.9 
Pregnancy 
Patients who become pregnant should be withdrawn from study treatment immediately. 
Pregnancies (in a patient or partner) occurring during the study require expedited reporting. A 
Pregnancy Notification Report should be completed and submitted to Chiltern PV within the 
same timelines and using the same contact details as an SAE. All reported pregnancies should 
be followed up and the outcome reported using the Pregnancy Follow-up Report. If the 
outcome of the pregnancy meets any of the criteria for seriousness, it must also be reported as 
an SAE.  
Examples of pregnancy outcomes that are SAEs include reports of: 
• Congenital anomalies or developmental delay, in the fetus or the child. 


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• Fetal death and spontaneous abortion. 
• Suspected adverse reactions in the neonate that are classified as serious. 
 
12.10 
Events Exempt from Being Reported as AE/SAEs 
12.10.1  Progression of Underlying Disease 
Disease progression and resultant death will be captured on the CRF. AEs including 
hospitalization that are clearly consistent with disease progression will not be reported as 
individual AE/SAEs. Clinical symptoms of disease progression will only be reported as AEs if 
the symptom cannot be determined as exclusively due to the progression of the underlying 
malignancy, or does not fit the expected pattern of progression for 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 tumor 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-
1031 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 
NuCana will ensure that all Investigators are kept informed, in a timely manner, as new safety 
information becomes available. Investigators are responsible for briefing their study team as 
appropriate. 
 
 
 


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12.12 
Reference Safety Information (RSI) for Assessment of Expectedness 
The IB supplied by NuCana for NUC-1031 contains a defined table, which will act as the RSI 
for the 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 downgraded to ‘expected’, a 
justification for the changes will be included in the amendment request. Changes to the 
IB that impact on patient safety or alter the risk/benefit assessment may require changes 
to the study documentation such as the ICF. NuCana will identify any such required 
changes and ensure ICF revisions are made and approved by applicable Regulatory 
Authorities and IRBs/ECs, and patients re-consented as applicable. Significant updates 
to the IB shall be attached to the DSUR (once approved by applicable Regulatory 
Authorities and IRBs/ECs); however the IB in effect at the start of the DSUR reporting 
period serves at the RSI during the reporting period.  
• Non-Significant Changes to the RSI: If changes to the IB are minor and do not include 
new/removed expected reactions, do not impact on patient safety or alter the benefit/risk 
assessment, then sites will not receive the updated IB until the end of the DSUR 
reporting period and this decision will be made by NuCana. 
 
If the non-significant updated IB is to be implemented in the new DSUR reporting period, then 
Regulatory Authority and IRB/EC should be informed of the intention to implement the 
updated IB after the DSUR reporting period ends. The updated IB will be attached to the 
DSUR. If new expected reactions have been added to the IB or events have downgraded to 
‘expected’, then the updated IB must receive approval before it is implemented. The IB will be 
sent to the study sites with a covering letter documenting the changes. This will be circulated 
after the DSUR has been submitted at the start of the new DSUR reporting period. 
 
12.13 
Data Safety Monitoring Committee (DSMC) 
The DSMC will review the safety, dosing intensity, pharmacokinetic and clinical activity data 
from Part I of the study to decide on which dose should be used in Part II. Members of the 
DSMC will include:  
• Chief Investigators from the US and Europe   
• Selected Principal Investigators from participating sites  
• Chiltern Medical Monitors 
• NuCana Medical Director 
• Study management staff from NuCana. 
 
 
 


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13 STATISTICAL CONSIDERATIONS 
A Statistical Analysis Plan (SAP) will be finalized before database lock and conduct of the 
final analysis is undertaken. The main features of the planned statistical analysis are included 
below. 
 
13.1 
Sample Size 
The primary analysis of response rate will take place when 44 patients are enrolled at the 
selected dose and all active patients have undergone the required assessments for assessment 
of confirmed ORR by RECIST. The study will be considered to have met its primary endpoint 
if a minimum of 4 confirmed responses (CR or PR) is observed. Based on 44 patients, if the 
true ORR is 15%, there is greater than an 80% probability of observing 4 or more responses. 
Furthermore, if the true response rate were only 5%, there would be less than a 7% probability 
of observing 4 or more responses.   
Upon review of the data from Part II by the DSMC, the study may be further expanded at the 
selected dose level, which will be described in a protocol amendment. 
 
13.2 
Missing, Unused and Spurious Data 
All available safety, PK, and efficacy data will be included in tabulations and patient-level 
listings. No imputation of values for missing data will be performed. 
 
13.3 
Analysis Populations 
The analysis of time to progression, PFS, OS and health-related quality of life (HRQoL) data 
will be summarized and analyzed in all patients enrolled, regardless of treatment received (the 
full analysis set, FAS) on an intention-to-treat (ITT) basis. 
The primary analysis of response rate will be based on a blinded independent central review 
(BICR) of confirmed response rate by RECIST.  Only patients with measurable disease at 
baseline (defined by BICR) will be included in the Evaluable for Response population. This 
population will be analyzed for all related response measurements.  Sensitivity analyses will 
be performed including using the investigator-recorded assessment.  For the purposes of dose 
selection, unconfirmed responses will be taken into account but for all other analyses 
confirmation of response is required. 
As warranted by the data, efficacy may also be assessed in sub-populations, as defined by 
NuCana prior to database lock.  Any sub-group analyses will be exploratory and their purpose 
would be to 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.  
For the assessment of safety and tolerability, summaries will be produced based on the Safety 
Analysis Set.  This will include all patients who receive at least one dose of study treatment.  
PK analyses will be performed on the PK population, defined as all patients who receive any 
amount of NUC-1031 and have sufficient data for PK analysis. 
 
 
 


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13.4 
Patient Disposition 
Data tabulations will summarize the following patient numbers: 
• Enrolled 
• At least one dose of NUC-1031 received 
• Evaluable for safety and efficacy 
• Protocol violations 
• Withdrew from study due to: 
o AE 
o Investigator request   
o Withdrew consent 
o Lost to follow-up 
o Other reasons, as collected in the CRF. 
 
13.5 
Statistical Methods 
13.5.1   Demographics and Baseline Data 
Demographic and baseline characteristics of patients will be summarized using descriptive 
statistics: 
• Age 
• Sex 
• Race 
• Ethnicity 
• Baseline ECOG performance score 
• Primary diagnosis 
• Disease stage at diagnosis and baseline 
• Prior therapies, including systemic therapies, radiation, and surgeries 
• Other baseline characteristics, as collected in the CRF. 
 
13.5.2 Concomitant Medications 
The number and proportion of patients in the Safety analysis set using different concomitant 
medications will be tabulated and summarized by WHO DD anatomical, therapeutic, chemical 
class and preferred term. 
Use of hematopoietic growth factors and transfusions are of special interest. 
 
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. 
 


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13.5.4 Efficacy Analysis 
The primary response evaluation is based upon the determination of response using RECIST 
(Appendix 2) by a BICR: 
• ORR is defined as the number of patients achieving a confirmed response (CR or PR). 
Number and percentage of patients achieving a response, with confidence intervals, will 
be provided. In addition, the number and percentage of patients achieving individual 
best response criteria of CR, PR, SD, PD, or NE will be described. 
• Change from baseline in tumor size is measured as the percentage change in the total 
measurements of target lesions from the pre-treatment scan, measured at each 
scheduled scan.  
• Duration of Overall Response is measured from the time measurement criteria are 
first met for CR or PR (whichever is first recorded) until the first date that recurrent or 
PD is objectively documented (taking as reference for PD 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 duration of response will be censored at the date of last tumor 
assessment.  
• PFS is defined as the time from the date of study treatment initiation (start of treatment) 
to the first date of objectively determined PD or death from any cause. For patients who 
are still alive at the time of the data cut-off date and without evidence of tumor 
progression, PFS will be censored at the date of the most recent objective progression-
free observation. For patients who receive subsequent anticancer therapy prior to 
objective disease progression or death, PFS will be censored at the date of the last 
objective progression-free observation prior to the date of subsequent therapy. 
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. 
• Time to Disease Progression is measured from the start of the treatment until the 
criteria for progression are first met, taking as reference the smallest measurements 
recorded since the treatment started, including the baseline measurements. For patients 
who were lost to follow-up, or died without progression or reached the time point of 
analysis without a known record of progression, the time to progression will be 
censored at the date of last tumor assessment. 
The number of overall censored patients, number of patients with events and Kaplan-
Meier estimates median time will be provided. The results will also be presented 
graphically in Kaplan-Meier plots. 
• Disease Control Rate is defined as the number of patients achieving confirmed 
response (CR or PR) or SD as best overall response (as defined in RECIST). 
• Best GCIG Overall Response (CR, PR, SD, PD, NE): number and percentage of 
patients with responses defined per GCIG criteria will be described. 
• OS is defined as the time from randomization until death from any cause. All deaths 
will be included, whether they occur during the study or following treatment 
discontinuation. For patients who have not died, overall survival will be censored at the 
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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 PRO Analysis 
13.5.5.1 EQ-5D-5L 
Descriptive statistics, graphs and listings will be reported for health state utility values and 
visual analogue scale by visits as well as change in these scores from baseline. Further details 
will be included in the SAP. 
 
13.5.5.2 FOSI-18 
Descriptive statistics, graphs and listings will be reported to explore the impact of NUC-1031 
on symptoms and HRQoL. The relationship between PROs, efficacy and AEs will be explored 
using descriptive summaries. Further details of the exploratory analysis based on the FOSI-18 
will be outlined in the SAP. 
 
13.5.6   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-1031. 
 
13.5.6.1 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 
summarized by MedDRA™, Version 18.1 (or higher), System Organ Class (SOC) and 
preferred term (PT). The severity of AEs will also be summarized by NCI CTCAE v4.03 (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. 
 
The following summaries will be produced by dose cohort for all TEAEs: 
• An overview table of the incidence of TEAEs, Grade 3+ TEAEs, SAEs, TEAEs leading 
to treatment discontinuation and TEAEs leading to death, by dose and overall. 
• 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 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 SAEs by preferred term. 
 


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In addition, the following will be listed: 
• 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 AE is resolved), 
investigator’s assessment of severity and relationship to study drug. 
• 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.  
• 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. 
 
13.5.6.2 Laboratory Parameters 
Laboratory results (hematology, serum chemistry, coagulation parameters and urinalysis) will 
be classified according to NCI CTCAE v4.03 (or higher). Laboratory results not corresponding 
to an NCI CTCAE term will not be graded.  
Shift tables will be shown for intra-individual changes from Baseline in NCI CTCAE grade for 
each study visit. Laboratory parameters will also be listed. 
 
13.5.6.3 Vital Signs 
Vital sign parameters (including blood pressure and heart rate) and body weight will be listed. 
 
13.5.6.4 ECOG Performance Status 
ECOG performance status will be listed. The ECOG Performance Scale is provided in 
Appendix 5. 
13.5.6.5 Physical Examination 
Physical examination findings will be listed. 
 
13.5.6.6 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. 
 
 
 


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13.5.6.7 Pharmacokinetics 
The PK of single and multiple-dose NUC-1031 will be assessed, including: 
• Maximum concentration (Cmax) 
• Area under the curve (AUC) 
• Half-life (T1/2) 
• Volume of distribution (Vd) 
• Clearance (CL). 
 
PK of the following will be measured: 
• In plasma/urine: NUC-1031, dFdC and dFdU. 
• In peripheral blood mononuclear cells: NUC-1031, dFdC, dFdCMP, dFdCDP, 
dFdCTP and dFdU. 
 
All above PK parameters will be analyzed in the PK population. 
 
13.5.6.8 Exploratory Endpoints 
Assessment of candidate genomic, transcriptomic and proteomic biomarkers of 
resistance/sensitivity to NUC-1031 in tumor specimens will be analysed in the ITT population. 
The candidate genomic, transcriptomic and proteomic biomarkers will be defined in the SAP. 
 
13.5.7 Primary Analysis and Interim Analyses   
The primary analysis of Part II will take place when 44 patients are enrolled at the selected 
dose and all active patients have undergone the required assessments for assessment of 
confirmed ORR by RECIST (i.e, approximately 16 weeks after the 44th patient starts 
treatment). 
Up to three interim analyses may be performed during Part I in order to select a dose to take 
forwards into Part II. For the purpose of the dose selection analyses only, unconfirmed 
responses may be taken into account, provided that the response is unconfirmed due to 
insufficient follow-up data being available, rather than because the subsequent data is available 
and does not confirm the initial response. 
An additional efficacy update analysis may be performed following the primary analysis of 
Part II. The purpose of this analysis would be to provide more mature efficacy data. As such, 
the timing of such an analysis, if required, will be determined following review of the primary 
analysis. 
Timings of all analyses will be described in the statistical analysis plan. Upon review of the 
data from Part II by the DSMC, the study may be further expanded at the selected dose level, 
which will be described in a protocol amendment. 
 
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 clinical study report.  


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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 electronic CRF (eCRF) will be used, please refer to the CRF Completion Guidelines for 
further information. The Investigator must review each completed eCRF in a timely manner. 
The Investigator will be required to review and electronically sign and date the CRFs once the 
patient’s data is complete. 
 
14.2 
Monitoring of the Study 
Monitoring and auditing procedures developed by NuCana or designee will be followed, in 
order to comply with ICH-GCP guidelines. Before a study center can enter a patient into the 
study, a representative of NuCana or designee will visit the study center to: 
• Determine the adequacy of the facilities. 
• Discuss with the Investigator(s) and other personnel their responsibilities with regard 
to protocol adherence, and the responsibilities of NuCana or its representatives. This 
will be documented in a Clinical Study Agreement between NuCana and the 
Investigator. 
During the study, a monitor from NuCana or appointed CRO will have regular contacts with 
the study center, 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 NuCana. 
• Confirm AEs and SAEs have been properly documented in the eCRFs and confirm any 
SAEs have been forwarded to NuCana or designee, and those SAEs that met criteria 
for reporting have been forwarded to the IRB/EC. 
The monitor will be available between visits if the Investigator or other staff needs information 
or advice. 
 
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, initials and date of birth (or other 


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identified as appropriate to country regulations and agreed with NuCana) 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.  
 
15 ETHICAL AND REGULATORY CONSIDERATIONS 
15.1 
Good Clinical Practice Compliance 
NuCana, 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 Board/ Ethics Committees 
The applicable Institutional Review Boards/ Ethics Committees (IRBs/ECs) will review all 
appropriate study documentation in order 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 NuCana or appointed CRO before a 
study center can enroll 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 
Authorization 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/exclusion or primary endpoint criteria. 


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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 of Investigator has failed to adhere 
to significant protocol requirements (e.g. inclusion/exclusion 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. 
 
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 NuCana to submit the complete and accurate certification or disclosure 
statements required under 21 CFR 54. In addition, the Investigator and Sub-Investigators must 
provide NuCana with a commitment to update this information promptly if any relevant 
changes occur during the course of the investigation and for one year after study completion. 
Neither NuCana nor the CRO, Chiltern, 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 NuCana nor Chiltern 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. 
 


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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-1031 clinical development. These documents should be retained for a 
longer period, however, if required by the applicable regulatory requirements or by an 
agreement with NuCana. It is the responsibility of NuCana to inform the Investigator or Sub-
Investigator or institution as to when these documents no longer need to be retained. 
If the Investigator becomes unable for any reason to continue to retain study records for the 
required period, NuCana should be prospectively notified. The study records must be 
transferred to a designee acceptable to NuCana, such as another Investigator, another 
institution, or to an independent third party arranged by NuCana. The Investigator must obtain 
written permission from NuCana before disposing of any records, even if retention 
requirements have been met. Retention and storage of central laboratory records supporting PK 
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 NuCana, representatives of NuCana, the FDA, or other regulatory agency 
access to all study records. 
The Investigator should promptly notify NuCana and the appointed CRO of any audits 
scheduled by any regulatory authorities and promptly forward copies of any audit reports 
received to NuCana.  
 
16 PUBLICATION POLICY 
An ICH E3-compliant clinical study report (CSR) will be generated based on the final data 
listings of this study. The final CSR will be submitted to Regulatory Authorities and IRBs/ECs 
in accordance with the stipulated timelines. 
 
16.1 
Communication of Results by NuCana 
NuCana shall publicly disclose study results 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 will be submitted to ClinicalTrials.gov within one year of the primary 
completion date, which is defined as ‘the date that the final patient was examined or received 
an intervention for the purposes of final collection of data for the primary outcome, whether 
the clinical study concluded according to the pre-specified protocol or was terminated’. Final 
study results will be posted to EudraCT within one year of the end of study date, as defined in 
this protocol. 
16.2 
Publication by Investigators 
Investigators may not publish or disclose results until the study is completed. In addition, 
Investigators shall acknowledges 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 


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individual results, may not be sufficient from which to draw any meaningful scientific 
conclusion. 
NuCana 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 NuCana and each Institution. In addition, NuCana may form a publication 
committee to evaluate and give approval of any submission for publication. 
The proposed publication (manuscript, abstract or poster) or presentation will be provided to 
NuCana by the Investigator for review and comment at least 60 days prior to the planned 
submission. The Investigator understands and agrees that participation in the study may involve 
a commitment to publish the study results in a cooperative publication with other Investigators. 
No publication of confidential information shall be made without NuCana’s prior written 
approval. The Investigator agrees, upon NuCana’s request, to delete any confidential 
information that may impact intellectual property protection from the proposed publication. 
Investigators will comply with recognized ethical publications and authorship standards, 
including Section II of the ‘Ethical Considerations in the Conduct and Reporting of Research’ 
of the Uniform Requirements for Manuscripts Submitted to Biomedical Journals, established 
by 
the 
International 
Committee 
of 
Medical 
Journal 
Editors 
(http://www.icmje.org/index.html#authorship). 
 
 


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17 REFERENCES 
Abbruzzese JL et al. A phase I clinical, plasma, and cellular pharmacology study of 
gemcitabine. J Clin Oncol 1991; 9: 491–498. 
Achiwa H et al. Determinants of sensitivity and resistance to gemcitabine: the roles of human 
equilibrative nucleoside transporter 1 and deoxycytidine kinase in non-small cell lung cancer. 
Cancer Sci 2004; 95: 753–757. 
Alvarez R et al. Moving beyond the platinum sensitive/resistant paradigm for patients with 
recurrent ovarian cancer. Gynecol Oncol 2016; 141: 405–409. 
American Cancer Society, Cancer Facts and Figures, 2015. Accessed 01 December 2016. 
http://www.cancer.org/acs/groups/content/@editorial/documents/document/acspc-044552.pdf 
Cattel L et al. Pharmacokinetic evaluation of gemcitabine and 2’,2’-difluorodeoxyctidine-5’-
triphosphate after prolonged infusion in patients affected by different solid tumors. Ann Oncol 
2006; 17: 142–147. 
Eisenhauer EA et al. New response evaluation criteria in solid tumors: revised RECIST 
guideline (version 1.1). Eur J Cancer 2009; 45: 228–247. 
Friedlander M et al. Gynecologic Cancer InterGroup. Clinical trials in recurrent ovarian cancer. 
Int J Gynecol Cancer 2011; 21: 771–775. 
Groen R et al. Updates and emerging therapies for rare epithelial ovarian cancers: one size no 
longer fits all. Gynecol Oncol 2015; 136: 373–383. 
Grunewald R et al. Pharmacologically directed design of the dose rate and schedule of 2',2'-
difluorodeoxycytidine (Gemcitabine) administration in leukemia. Cancer Res 1990; 50: 6823–
6826. 
Grunewald R et al. Gemcitabine in leukemia: a phase I clinical, plasma, and cellular 
pharmacology study. J Clin Oncol 1992; 10: 406–413. 
Kaufman B et al. Olaparib monotherapy in patients with advanced cancer and a germline 
BRCA 1/2 mutation. J Clin Oncol 2015; 33: 244–250. 
Kaye SG et al. Phase II, open-label, randomized, multicenter study comparing the efficacy and 
safety of olaparib, a poly (ADP-ribose) polymerase inhibitor, and pegylated liposomal 
doxorubicin in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer. J Clin 
Oncol 2012; 30: 372–379. 
Kroep JR et al. Role of deoxycytidine kinase (dCK), thymidine kinase 2 (TK2), and 
deoxycytidine deaminase (dCDA) in the antitumor activity of gemcitabine (dFdC). Adv Exp 
Med Biol 1998; 431: 657–660. 
Ledermann JA et al. Inhibition of carboplatin-induced DNA interstrand cross-link repair by 
gemcitabine in patients receiving these drugs for platinum-resistant ovarian cancer. Clin 
Cancer Res 2010; 16: 4899–905. 
Markman M & Bookman MA. Second-line treatment of ovarian cancer. Oncologist 2000; 5: 
26–35. 
Peters GJ et al. Clinical phase I and pharmacology study of gemcitabine (2', 2'-
difluorodeoxycytidine) administered in a two-weekly schedule. J Chemother 2007; 19: 212–
221. 
 
 


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Pfisterer J et al; AGO-OVAR; NCIC CTG; EORTC GCG. Gemcitabine plus carboplatin 
compared with carboplatin in patients with platinum-sensitive recurrent ovarian cancer: an 
intergroup trial of the AGO-OVAR, the NCIC CTG, and the EORTC GCG. J Clin Oncol 2006; 
24: 4699–4707. 
Pujade-Lauraine E et al. Bevacizumab Combined With Chemotherapy for Platinum-Resistant 
Recurrent Ovarian Cancer: The AURELIA Open-Label Randomized Phase III Trial. J Clin 
Oncol 2014; 32: 1302-1308. 
Safra T et al. BRCA mutation status and determinant of outcome in women with recurrent 
epithelial ovarian cancer treated with pegylated liposomal doxorubicin. Mol. Cancer Ther 
2011; 10: 2000–2007. 
Siegel R et al. Cancer statistics, 2014. CA Cancer J Clin 2014; 64: 9–29. 
Slusarczyk M et al. Application of ProTide Technology to Gemcitabine: A Successful 
Approach to Overcome the Key Cancer Resistance Mechanisms Leads to a New Agent (NUC-
1031) in Clinical Development. J Med Chem 2014; 27: 513–42. 
Yang D et al. Association of BRCA 1 and BRCA 2 mutations with survival, chemotherapy 
sensitivity, and gene mutator phenotype in patients with ovarian cancer. JAMA 2011; 306: 
1557–1565. 
 
 


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18 APPENDICES 
Appendix 1: 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 1.  Table 1.  Drugs known to prolong QT/QTc interval 
 
Generic Name 
Brand Names (Partial List) 
Amiodarone 
Cordarone®, Pacerone®, Nexterone® 
Anagrelide 
Agrylin®, Xagrid® 
Arsenic trioxide 
Trisenox® 
Astemizole (removed from market) 
Hismanal® 
Azithromycin 
Zithromax®, Zmax® 
Bepridil (removed from market) 
Vascor® 
Chloroquine 
Aralen® 
Chlorpromazine 
Thorazine®, Largactil®, Megaphen® 
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 market) Tequin® 
Grepafloxacin 
Raxar® 
Halofantrine 
Halfan® 
Haloperidol 
Haldol® (US & UK), Aloperidin®, Bioperidolo®, Brotopon®, 
Dozic®, Duraperidol® (Germany), Einalon S®, Eukystol®, 
Halosten®, Keselan®, Linton®, Peluces®, Serenace®, 
Serenase®, Sigaperidol® 


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Generic Name 
Brand Names (Partial List) 
Ibutilide 
Corvert® 
Ibogaine (only on non-US market) 
None 
Levofloxacin 
Levaquin®, Tavanic® 
Levomepromazine (only on non-US 
market) 
Nosinan®, Nozinan®, Levoprome® 
Levomethadyl (removed from 
market) 
Orlaam® 
Levosulpiride (only on non-US 
market) 
Lesuride®, Levazeo®, Enliva® (with rabeprazole) 
Mesoridazine (removed from 
market) 
Serentil® 
Methadone 
Dolophine®, Symoron®, Amidone®, Methadose®, 
Physeptone®, Heptadon® 
Moxifloxacin 
Avelox®, Avalox®, Avelon® 
Ondansetron 
Zofran®, Anset®, Ondemet®, Zuplenz®, Emetron®, 
Ondavell®, Emeset®, Ondisolv®, Setronax® 
Oxaliplatin 
Eloxatin® 
Papaverine HCl 
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®  
Sevoflurane 
Ulane®, Sojourn® 
Sotalol 
Betapace®, Sotalex®, Sotacor® 
Sparfloxacin (removed from 
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 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® 
 
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.  
 
 


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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 February 
2017], 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 2: Response Evaluation Criteria in Solid Tumors (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 tumors: revised RECIST guideline 
(version 1.1). Eur J Cancer 2009; 45: 228–247. 
 
Measurability of Tumor 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 – tumor 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 tumor 
measurements must be recorded in millimeters (or decimal fractions of centimeters) by use of 
a ruler or callipers. Tumor 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 tumor 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 tumor lesions plus short axis of 
lymph nodes: overall maximum of 5) is to be calculated and recorded. 
 


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Non-target lesions – all non-measurable lesions (or sites of disease) including pathological 
nodes (those with short axis ≥10 mm but <15 mm), plus any measurable lesions over and above 
those listed as target lesions are considered non-target lesions. Measurements are not required 
but these lesions should be noted at baseline and should be followed as “present” or “absent”. 
 
All baseline evaluations should be performed as closely as possible to the beginning of 
treatment and never more than 4 weeks before the beginning of the treatment. 
 
Methods of Measurements 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Assessments should be 
identified on a calendar schedule and should not be affected by delays in therapy, which may 
be treatment arm dependent. While on study, all target lesions recorded at baseline should have 
their actual measurements recorded on the CRF at each subsequent evaluation, even when very 
small (e.g. 2 mm). If it is the opinion of the radiologist that the lesion has likely disappeared, 
the measurement should be recorded as 0 mm. If the lesion is believed to be present and is 
faintly seen but too small to measure, a default value of 5 mm should be assigned. For lesions 
which fragment/split add together the longest diameters of the fragmented portions; for lesions 
which coalesce, measure the maximal longest diameter for the “merged lesion”. 
 
Clinical lesions – clinical lesions will only be considered measurable when they are superficial 
and ≥10 mm as assessed using callipers (e.g. skin nodules). For the case of skin lesions, 
documentation by color photography including a ruler to estimate the size of the lesion is 
recommended. If feasible, imaging is preferred. 
 
Chest X-ray – chest CT is preferred over chest X-ray, particularly when progression is an 
important endpoint, since CT is more sensitive than X-ray, particularly in identifying new 
lesions. However, lesions ≥20 mm on chest X-ray may be considered measurable if they are 
clearly defined and surrounded by aerated lung. 
 
CT, MRI – CT is the best currently available and reproducible method to measure lesions 
selected for response assessment. This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT slice thickness is 5 mm or less. When CT scans have 
slice thickness greater than 5 mm, the minimum size for a measurable lesion should be twice 
the slice thickness. MRI is also acceptable in certain situations (e.g. for body scans). While 
PET scans are not considered adequate to measure lesions, PET-CT scans may be used 
providing that the measures are obtained from the CT scan and the CT scan is of identical 
diagnostic quality to a diagnostic CT (with IV and oral contrast). 
 
Ultrasound – ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement. If new lesions are identified by ultrasound in the course of the study, 
confirmation by CT should be obtained. 
 
Endoscopy, Laparoscopy – the utilization of these techniques for objective tumor evaluation 
is not advised. However, they can be useful to confirm complete pathological response when 


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biopsies are obtained or to determine relapse in studies where recurrence following complete 
response or surgical resection is an endpoint. 
 
Tumor markers – tumor markers alone cannot be used to assess objective tumor response. If 
markers are initially above the upper normal limit, however, they must normalize for a patient 
to be considered in complete response. 
 
Cytology, Histology – these techniques can be used to differentiate between PR and CR in rare 
cases if required by protocol (for example, residual lesions in tumor types such as germ cell 
tumors, where known residual benign tumors 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 tumor has met criteria for response or stable 
disease is advised to differentiate between response or stable disease and progressive disease. 
 
Tumor 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 Tables 1 and 2 
below. 
 
Complete Response (CR) – disappearance of all target and non-target lesions and 
normalization of tumor markers. Pathological lymph nodes must have short axis measures <10 
mm (Note: continue to record the measurement even if <10 mm and considered CR). Tumor 
markers must have normalized. Residual lesions (other than nodes <10 mm) thought to be non-
malignant should be further investigated (by cytology or PET scans) before CR can be 
accepted.  
 
Partial Response (PR) – at least a 30% decrease in the sum of measures (longest diameter for 
tumor lesions and short axis measure for nodes) of target lesions, taking as reference the 
baseline sum of diameters. Non-target lesions must be non-PD.  
 
Stable Disease (SD) – neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD taking as reference the smallest sum of diameters on study. 
 
 
 


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Progressive Disease (PD) – at least a 20% increase in the sum of diameters of measured lesions 
taking as references the smallest sum of diameters recorded on study (including baseline) AND 
an absolute increase of ≥5 mm. Appearance of new lesions will also constitute PD (including 
lesions in previously unassessed areas). In exceptional circumstances, unequivocal progression 
of non-target disease may be accepted as evidence of disease progression, where the overall 
tumor burden has increased sufficiently to merit discontinuation of treatment, for example 
where the tumor 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. 
 
Appendix 2.  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 
Normalization of tumor markers 
All tumor 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 2 Table 2 on the next page. 
 
 


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Appendix 2.  Table 2.  Response Assessment after Subsequent Scan 
Response: First 
Time Point 
Subsequent 
Time Point 
BEST Overall Response 
Also Requires 
CR 
CR 
CR 
Normalization of tumor 
markers. All tumor 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 Tumor Re-Evaluation 
Tumors 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 Tumor 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 tumor 
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 3: FOSI-18 Questionnaire 
Below is a list of statements that other people with your illness have said are important.  
Please circle or mark one number per line to indicate your response as it applies to the 
past 7 days. 
 
 
 
 
 
Not at 
all 
A little 
bit 
Some-
what 
Quite 
a bit 
Very 
much 
GP1 
I have a lack of energy
 .....................................................................  
0 
1 
2 
3 
4 
GP4 
I have pain
 .....................................................................  
0 
1 
2 
3 
4 
GP6 
I feel ill
 .....................................................................  
0 
1 
2 
3 
4 
O3 
I have cramps in my stomach area
 .....................................................................  
0 
1 
2 
3 
4 
HI7 
I feel fatigued
 .....................................................................  
0 
1 
2 
3 
4 
Cx6 
I am bothered by constipation
 .....................................................................  
0 
1 
2 
3 
4 
O1 
I have swelling in my stomach area
 .....................................................................  
0 
1 
2 
3 
4 
C3 
I have control of my bowels
 .....................................................................  
0 
1 
2 
3 
4 
GF5 
I am sleeping well
 .....................................................................  
0 
1 
2 
3 
4 
GE6 
I worry that my condition will get worse
 .....................................................................  
0 
1 
2 
3 
4 
GP2 
I have nausea
 .....................................................................  
0 
1 
2 
3 
4 
B5 
I am bothered by hair loss
 .....................................................................  
0 
1 
2 
3 
4 
GP5 
I am bothered by side effects of treatment
 .....................................................................  
0 
1 
2 
3 
4 
O2 
I have been vomiting
 .....................................................................  
0 
1 
2 
3 
4 
BMT15 
I am bothered by skin problems
 .....................................................................  
0 
1 
2 
3 
4 
D
R
S-
P 
T
S
E 
D
R
S-
E 


PRO-105 
 
Version 2.5, 11 October 2017_FINAL 
 
NuCana plc 
 75 
BMT5 
I am able to get around by myself
 .....................................................................  
0 
1 
2 
3 
4 
GF3 
I am able to enjoy life
 .....................................................................  
0 
1 
2 
3 
4 
GF7 
I am content with the quality of my life 
right now
 .....................................................................  
 
0 
 
1 
 
2 
 
3 
 
4 
 
 
F 
W 
B 


PRO-105 
 
Version 2.5, 11 October 2017_FINAL 
 
NuCana plc 
 76 
Appendix 4: EQ-5D-5L Questionnaire 
Under each heading, please tick the ONE box that best describes your health TODAY. 
 
MOBILITY 
I have no problems in walking about  
 
 
 
 
 
I have slight problems in walking about 
 
 
 
 
 
I have moderate problems in walking about  
 
 
 
 
I have severe problems in walking about 
 
 
 
 
 
I am unable to walk about 
 
 
 
 
 
 
 
SELF-CARE 
I have no problems washing or dressing myself 
 
 
 
 
I have slight problems washing or dressing myself  
 
 
 
I have moderate problems washing or dressing myself 
 
 
 
I have severe problems washing or dressing myself  
 
 
 
I am unable to wash or dress myself  
 
 
 
 
 
USUAL ACTIVITES (e.g. work, study, housework, family or leisure activities) 
I have no problems doing my usual activities 
 
 
 
 
I have slight problems doing my usual activities 
 
 
 
 
I have moderate problems doing my usual activities  
 
 
 
I have severe problems doing my usual activities 
 
 
 
 
I am unable to do my usual activities  
 
 
 
 
 
PAIN/DISCOMFORT 
I have no pain or discomfort  
 
 
 
 
 
 
I have slight pain or discomfort 
 
 
 
 
 
 
I have moderate pain or discomfort  
 
 
 
 
 
I have severe pain or discomfort 
 
 
 
 
 
 
I have extreme pain or discomfort 
 
 
 
 
 
 
ANXIETY/DEPRESSION 
I am not anxious or depressed 
 
 
 
 
 
 
I am slightly anxious or depressed 
 
 
 
 
 
 
I am moderately anxious or depressed 
 
 
 
 
 
I am severely anxious or depressed  
 
 
 
 
 
I am extremely anxious or depressed  
 
 
 
 
 
 
 


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Version 2.5, 11 October 2017_FINAL 
 
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 77 
• We would like to know how good or bad your health is TODAY. 
• This scale is numbered from 0 to 100. 
o 100 means the best health you can imagine. 
o 0 means the worst health you can imagine. 
• Mark an X on the scale to indicate how your health is TODAY. 
 
 
 
Now, please write the number you marked on the scale in the box below. 
 
YOUR HEALTH TODAY = 
 
 
 
 


PRO-105 
 
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 78 
Appendix 5: ECOG Performance Scale 
 
Activity Performance Description 
Score 
Fully active, able to carry out all on all pre-disease performance without restriction. 
0 
 
 
Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature, e.g. light housework, office work. 
1 
 
 
Ambulatory and capable of all self-care, but unable to carry out any work activities.  
Up and about more than 50% of waking hours.  
2 
 
 
Capable of only limited self-care. Confined to bed or chair more than 50% of waking 
hours.  
3 
 
 
Completely disabled. Cannot carry out any self-care. Totally confined to bed or chair. 
4 
 
 
Dead 
5 
 

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN 
A Phase II Open-Label Study of NUC-1031 in Patients 
with Platinum-Resistant Ovarian Cancer 
NCT Number: 
Date: 
NCT03146663 
26 May 2020 


 
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NuCana plc 
 
 
 
Protocol: PRO-105 
 
EUDRACT: 2016-003287-39 
IND: 130348 
 
Treatment: NUC-1031 
 
 
A Phase II Open-Label Study of NUC-1031 in Patients with Platinum-
Resistant Ovarian Cancer  
 
 
 
Author(s): 
 Nicolas Ramon 
Document Status: 
Version 1 Final Draft 
Version Dates: 
Version 1 Draft 1: 06Apr2017 
Version 1 Draft 2: 12May2017 
Version 1 Draft 3: 28Aug2017 
Version 1 Draft 4: 30May2019 
 
Version 1 Draft 5: 24Jan2020 
 
Version 1 Draft 6: 04Mar2020 
Final Version: 26May2020 
Pages: 
96 
 
 
 
STATEMENT OF CONFIDENTIALITY  
The information contained herein is expressly patient to the terms and conditions of the Confidentiality Agreement 
dated by and between Covance and NuCana plc. 
 
 
TMF Filing Code: 
 
 
 


 
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STATISTICAL ANALYSIS PLAN 
 
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Protocol Number: 
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Approvals  
The undersigned agree that all required reviews of this document are complete, and approve this Statistical 
Analysis Plan as final. Programming of the tables and listings based upon the specifications within this document 
can proceed. 
Covance Approval 
 
 
 
 
Signature 
 
Date 
 
 
Nicolas Ramon / Principal Biostatistician 
 
 
 
NuCana plc: 
 
 
 
 
Signature 
 
Date 
 
 
Bryn Dixon / Senior Project Manager 
 
Reviewers 
The following reviews of the Statistical Analysis Plan (SAP) were conducted: 
Name and Title  
Role 
Version Last 
Reviewed 
Company/ 
Organization 
Yolène Acin, Principal Biostatistician 
Peer Statistician 
Draft v1.6 
Covance 
Elena Raimondi, Senior Statistical 
Programmer 
Lead Statistical 
Programmer 
Final v1.0 
Covance 
Rodrigo Maccari, Project Manager 
Project Manager 
Final v1.0 
Covance 
John Paul Gallivan, Medical Affairs 
Medical Affairs 
Final v1.0 
NuCana plc 


 
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Contents 
ABBREVIATIONS .................................................................................................................. 7 
1 
INTRODUCTION.......................................................................................................... 10 
2 
STUDY OBJECTIVES .................................................................................................. 11 
2.1 
PRIMARY ENDPOINT ................................................................................................. 11 
2.2 
SECONDARY ENDPOINTS ........................................................................................... 11 
2.3 
SAFETY ENDPOINTS .................................................................................................. 12 
2.4 
PHARMACOKINETIC ENDPOINTS ................................................................................ 12 
2.5 
EXPLORATORY ENDPOINTS ....................................................................................... 13 
3 
STUDY DESIGN ............................................................................................................ 14 
3.1 
DISCUSSION OF STUDY DESIGN ................................................................................. 14 
3.2 
STUDY TREATMENT .................................................................................................. 15 
3.2.1 Study Treatment .................................................................................................. 15 
3.2.2 NUC-1031 Description ........................................................................................ 15 
3.2.3 Study Drug Dosage and Administration ............................................................ 15 
3.2.4 Dose Modifications ............................................................................................. 16 
3.2.4.1 
Hematological Toxicity – Dose Adjustment ................................................ 16 
3.2.4.2 
Non-Hematological Toxicity – Dose adjustment ........................................ 18 
3.2.4.3 
Guidance for Dose Omissions ..................................................................... 19 
3.3 
STUDY SCHEDULE ..................................................................................................... 19 
3.3.1 Patient Registration and Screening Procedures ................................................ 19 
3.3.2 Screening Assessments ....................................................................................... 20 
3.3.3 Re-Screening Patients who fail Inclusion/Exclusion Criteria .......................... 21 
3.3.4 Evaluations to be performed during the study ................................................... 21 
3.3.4.1 
Each Cycle, Day 1 ........................................................................................ 21 
3.3.4.2 
For sites Collecting Optional Fresh Biopsy: Within 24 Hours of Cycle 1 
Day 1 
22 
3.3.4.3 
For Sites Participating in PK Sample Collection: Cycles 1 & 3 – Days 1 & 2
 
23 
3.3.4.4 
Each Cycle, Days 8 & 15 ............................................................................. 23 
3.3.4.5 
For Sites Participating in PK Sample Collection: Cycle 1 Days 15 & 16 ... 24 
3.3.4.6 
Every 8 Weeks (± 7 days) from Cycle 1 Day 1 until Disease Progression, 
Initiation of a New Treatment or Death ....................................................................... 24 
3.3.4.7 
End of Treatment Visit................................................................................. 24 
3.3.4.8 
Follow-Up .................................................................................................... 25 
3.4 
CONCOMITANT MEDICATION .................................................................................... 29 
3.4.1 Support Medication ............................................................................................. 29 
3.4.2 Hematopoietic Growth Factor Support .............................................................. 29 
3.4.3 Concomitant Medication and Non-Drug Therapies .......................................... 29 
3.4.4 Prohibited Therapy and Concomitant Medications ........................................... 30 


 
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3.5 
STUDY ANALYSIS POPULATIONS ............................................................................... 31 
3.5.1 Randomized Set (RS) .......................................................................................... 31 
3.5.2 Safety Analysis Set (SS) ...................................................................................... 31 
3.5.3 Full Analysis Set (FAS) ...................................................................................... 31 
3.5.4 Evaluable For Response Set (EFR) ................................................................... 31 
3.5.5 GCIG Analysis Set (GCIGAS) ............................................................................ 32 
3.5.6 Other Populations Defined for Tables and Listings .......................................... 32 
3.5.7 Subgroups ............................................................................................................ 32 
3.6 
WITHDRAWN PATIENTS ............................................................................................ 33 
3.6.1 End of Treatment ................................................................................................ 33 
3.6.2 Follow-Up after Treatment Discontinuation ..................................................... 34 
3.6.3 Consent Withdrawal ............................................................................................ 34 
3.6.4 Study Completion ................................................................................................ 34 
3.7 
RANDOMIZATION ...................................................................................................... 35 
3.8 
BLINDING .................................................................................................................. 35 
3.9 
SAMPLE SIZE ............................................................................................................. 35 
4 
STATISTICAL METHODOLOGY ............................................................................ 36 
4.1 
PLANNED ANALYSES ................................................................................................ 36 
4.2 
INTERIM ANALYSES .................................................................................................. 37 
4.2.1 Dose Selection Analysis ...................................................................................... 38 
4.2.2 Efficacy Update Analysis .................................................................................... 39 
4.3 
DISPOSITION OF PATIENTS ........................................................................................ 39 
4.4 
BASELINE AND DEMOGRAPHIC CHARACTERISTICS ................................................... 40 
4.4.1 Baseline and Demographic Characteristics ....................................................... 40 
4.4.2 Medical/ Surgical History ................................................................................... 42 
4.4.3 Ovarian Cancer History ...................................................................................... 42 
4.4.4 Prior Ovarian Cancer Therapy........................................................................... 43 
4.5 
EXPOSURE ................................................................................................................. 45 
4.5.1 Study Drug Administration ................................................................................. 45 
4.5.2 Relative Dose Intensity (RDI) and Percent Intended Dose (PID) .................... 46 
4.5.3 Relative Doses Received (RDR) and Percentage Intended Doses Received 
(PIDR) ............................................................................................................................. 47 
4.5.4 Treatment Delays ................................................................................................ 48 
4.6 
PRIOR AND CONCOMITANT MEDICATION .................................................................. 48 
4.7 
CONCOMITANT PROCEDURES/ SURGERIES/ THERAPIES ............................................. 49 
4.8 
EFFICACY / PRIMARY AND SECONDARY ANALYSIS ................................................... 50 
4.8.1 Primary Endpoint ................................................................................................ 50 
4.8.1.1 
Normality Assumption Checking ................................................................ 50 
4.8.1.2 
Closed Testing Procedure for Primary Analysis .......................................... 50 
4.8.2 Method of Analysis for Primary Outcome ......................................................... 50 
4.8.3 Secondary Endpoints .......................................................................................... 53 
4.8.4 Methods of Analysis for Secondary Outcomes .................................................. 53 
4.8.4.1 
BOR according to RECIST v1.1 Assessment .............................................. 54 
4.8.4.2 
DCR ............................................................................................................. 54 


 
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4.8.4.3 
PFS ............................................................................................................... 55 
4.8.4.4 
OS ................................................................................................................ 58 
4.8.4.5 
DOR ............................................................................................................. 58 
4.8.4.6 
TTP .............................................................................................................. 59 
4.8.4.7 
TTR .............................................................................................................. 60 
4.8.4.8 
Percentage Change from Baseline in Tumor Size ....................................... 60 
4.8.4.9 
Best GCIG Overall Response, combining the Change CA125 from Baseline 
with RECIST Assessment (per GCIG criteria) ............................................................ 60 
4.8.4.10 
Percentage Change of CA125 .................................................................. 65 
4.8.4.11 
Time on Treatment ................................................................................... 65 
4.8.4.12 
FOSI-18 Questionnaire ............................................................................ 65 
4.9 
EXPLORATORY ENDPOINTS ....................................................................................... 68 
4.9.1 EQ-5D-5L Questionnaire ................................................................................... 68 
4.9.1.1 
Analysis of Dimensions (Health profiles).................................................... 69 
4.9.1.2 
EQ VAS ....................................................................................................... 69 
4.9.1.3 
EQ-5D-5L Index Value ................................................................................ 69 
4.10 
SAFETY ANALYSIS .................................................................................................... 70 
4.10.1 
Adverse Events ................................................................................................ 70 
4.10.1.1 
Definition ................................................................................................. 70 
4.10.1.2 
Reporting.................................................................................................. 71 
4.10.1.3 
Assessment of Causality .......................................................................... 72 
4.10.1.4 
Assessment of Severity ............................................................................ 72 
4.10.1.5 
Description of Analyses ........................................................................... 73 
4.10.2 
Laboratory Findings ....................................................................................... 75 
4.10.2.1 
Hematology and Biochemistry ................................................................ 77 
4.10.2.2 
Urinalysis ................................................................................................. 79 
4.10.2.3 
Coagulation .............................................................................................. 79 
4.10.3 
Physical Examinations ................................................................................... 79 
4.10.4 
Vital Signs ....................................................................................................... 80 
4.10.5 
ECG ................................................................................................................. 80 
4.10.6 
ECOG .............................................................................................................. 81 
4.11 
ADJUSTMENT FOR COVARIATES ................................................................................ 81 
4.11.1 
Center Effects .................................................................................................. 81 
4.12 
PROTOCOL VIOLATIONS OR DEVIATIONS .................................................................. 81 
4.12.1 
Violation Criteria ............................................................................................ 82 
4.12.2 
Protocol Deviations ......................................................................................... 82 
4.13 
MISSING VALUES – MISSING VISITS ......................................................................... 82 
4.13.1 
Adverse Events ................................................................................................ 82 
4.13.2 
Concomitant medication ................................................................................. 84 
4.13.3 
Initial Diagnosis Date ..................................................................................... 84 
4.13.4 
Treatment Intake dates and PD dates for prior ovarian cancer therapies ... 84 
4.13.5 
Birth Date ........................................................................................................ 85 
4.14 
DEVIATIONS FROM SAP ............................................................................................ 86 
4.15 
CHANGES IN CONDUCT OR PLANNED ANALYSES FROM THE PROTOCOL ................... 86 
4.16 
ALGORITHMS/SAS CODES ........................................................................................ 87 


 
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5 
TABLES AND LISTINGS ............................................................................................ 89 
5.1 
TABLE FORMAT ........................................................................................................ 89 
5.2 
CONVENTIONS .......................................................................................................... 89 
5.3 
TABLES ..................................................................................................................... 90 
5.3.1 Section 14.1: Demographic and Baseline .......................................................... 90 
5.3.2 Section 14.2: Primary ......................................................................................... 90 
5.3.3 Section 14.2: Secondary ...................................................................................... 91 
5.3.4 Section 14.2: Exploratory – EQ-5D-5L .............................................................. 92 
5.3.5 Section 14.3: Safety ............................................................................................. 92 
5.3.5.1 
Adverse Events ............................................................................................ 92 
5.3.5.2 
Laboratory Results ....................................................................................... 92 
5.3.5.3 
Electrocardiogram ........................................................................................ 92 
5.4 
LISTINGS ................................................................................................................... 93 
5.5 
FIGURES .................................................................................................................... 94 
5.6 
APPENDICES .............................................................................................................. 94 
5.7 
REFERENCES ............................................................................................................. 95 
 


 
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Abbreviations 
 
AE 
Adverse Event 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase  
ANC 
Absolute Neutrophil Count 
aPTT 
activated Partial Thromboplastin Time 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Classification 
BICR 
Blinded Independent Central Reviewer 
BMI 
Body Mass Index 
BOR 
Best Overall Response 
BPM 
Beats Per Minutes 
BRCA 
Breast Cancer 
BRCA 1/2 
Breast Cancer (gene) 1/2 
BSA 
Body Surface Area 
BUN 
Blood Urea Nitrogen 
C1D1 
Cycle 1 Day 1 
C1D15 
Cycle 1 Day 15 
C2D15 
Cycle 2 Day 15 
C3D1 
Cycle 3 Day 1 
C3D15 
Cycle 3 Day 15 
CA125 
Cancer Antigen 125 
CDA 
Cytidine DeAminase  
CI 
Confidence Interval 
CR 
Complete Response 
CS 
Clinically Significant 
CSR 
Clinical Study Report 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Event 
DBP 
Diastolic Blood Pressure 
dCK 
deoxyCytidine Kinase  
DCO 
Data Cut Off 
DCR 
Disease Control Rate 
dFdCTP 
di-fluoro-deoxyCytidine TriPhosphate 
DI 
Dose Intensity 
DMA 
Dimethylacetamide 
DOR 
Duration of Overall Response 
DRM 
Data Review Meeting 
DSD 
Duration of Stable Disease 
DSMC 
Data Safety Monitoring Committee 
ECG 
Electrocardiogram 


 
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ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic Case Report Form 
EFR 
Evaluable For Response 
EQ-5D-5L 
EuroQoL Five Dimensions, Five Levels 
EuroQoL 
Euro Quality of Life 
FACT 
Functional Analysis of Cancer Therapy 
FAS 
Full Analysis Set 
FDA 
(US) Food and Drug Administration 
FOSI-18 
FACT/NCCN-Ovarian Symptom Index (containing 18 items) 
FOSI-DRS-E 
FOSI-Disease Related Symptoms-Emotional 
FOSI-DRS-P 
FOSI-Disease Related Symptoms-Physical 
FOSI-F/WB 
FOSI-Function/Well Being 
FOSI-TSE 
FOSI-Treatment Side Effects 
G-CSF 
Granulocyte Colony-Stimulating 
GCIG 
Gynecologic Cancer InterGroup 
hENT1 
human Equilibrative Nucleoside Transporter 1 
INR 
International Normalized Ratio 
IV 
Intravenous 
kg 
Kilogram 
KM 
Kaplan-Meier 
LDH 
Lactate dehydrogenase 
m² 
Meter² 
Max 
Maximum 
MedDRA  
Medical Dictionary for Regulatory Activities  
mg 
milligram 
mL 
milliliter 
mmHg 
MilliMeters of Mercury 
MRI 
Magnetic Resonance Imaging 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NCI-CTCAE 
National Cancer Institute-Common Terminology Criteria for Adverse 
Event 
NCS 
Non Clinically Significant 
NE 
Not Evaluable 
ORR 
Objective Response Rate 
OS 
Overall Survival 
PARP 
Poly ADP Ribose Polymerase 
PBMC 
Peripheral Blood Mononuclear Cells 
PD 
Progressive Disease 
PDI 
Planned Dose Intensity 
PET 
Positron Emission Tomography 
PFS 
Progression-Free Survival 
PFS4 
Progression-Free Survival at 4 months 


 
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PFS6 
Progression-Free Survival at 6 months 
PFS6KM 
Progression-Free Survival at 6 months for Kaplan-Meïer analysis 
PID 
Percent Intended Dose 
PIDR 
Percentage Intended Doses Received 
PK 
Pharmacokinetic 
 
PPS 
Per Protocol Set 
PR 
Partial Response 
PRO 
Patient Reported Outcome 
PT/INR 
Prothrombin Time/ International Normalized Ratio 
RBC 
Red Blood Cells 
RDI 
Relative Dose Intensity 
RDR 
Relative Doses Received 
RECIST v1.1 
Response Evaluation Criteria In Solid Tumors version 1.1 
RRM1 
Ribonucleotide Reductase M1 
RRM2 
Ribonucleotide Reductase M2 
RS 
Randomized Set 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
SD 
Stable Disease 
SDTM 
Study Data Tabulation Model 
SI 
International System 
SLD 
Sum of Lesion Diameters 
SOC 
System Organ Class 
SS 
Safety analysis set 
StD 
Standard Deviation 
TEAE 
Treatment Emergent Adverse Event 
TTP 
Time to Disease Progression 
TTR 
Time to Response 
ULN 
Upper Limit of Normal 
ULRR 
Upper Limit of Response Range 
US 
United States 
VAS 
Visual Analogue Scale 
VEGF 
Vascular Endothelial Growth Factor 
VEGFR 
Vascular Endothelial Growth Factor Receptor 
WBC 
White Blood Cell 
wk 
Week 
 


 
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1 Introduction 
This document presents the statistical analysis plan (SAP) for NuCana plc (NuCana), Protocol 
No. PRO-105: A Phase II Open-Label Study of NUC-1031 in Patients with Platinum-Resistant 
Ovarian Cancer.  
This analysis plan is based on the final protocol dated 11Oct2017; incorporating amendment 
no. 1, dated 06Mar2017 and amendment no. 2, dated 20Apr2017 
The SAP provides the description of the analysis for the dose selection analysis, primary 
analysis and a potential efficacy update analysis. Depending on the results of the primary 
analysis, the study could be expanded. Thus, a possible expansion analysis could be added. 
Following a preliminary analysis of the top-line data from Part I, the dose intensity was lower 
than expected and the decision was made not to proceed with Part II. Therefore, no dose will 
be selected. 
 


 
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2 Study Objectives 
The primary objective is to assess the anti-tumor activity of NUC-1031, as measured by 
Objective Response Rate (ORR) per Response Evaluation Criteria In Solid Tumors version 1.1 
(RECIST v1.1) criteria at the selected dose level (500 milligrams (mg)/meter² (m²) or 750 
mg/m²).  
Primary assessment will be done by a Blinded Independent Central Reviewer (BICR). 
 
The secondary objectives are:  
- 
To assess additional measures of anti-tumor activity of NUC-1031 including:  
o Change from baseline in tumor size. 
o Duration of Overall Response (DOR, per RECIST). 
o Progression-Free Survival (PFS, per RECIST). 
o Time to Disease Progression (TTP, per RECIST). 
o Disease Control Rate (DCR) (Complete Response (CR) + Partial Response (PR) 
+ Stable Disease (SD) which lasts at least 6 weeks from baseline, per RECIST). 
o Best Gynecologic Cancer InterGroup (GCIG) Overall Response, combining the 
change in Cancer Antigen 125 (CA125) from baseline with RECIST assessment 
(per GCIG criteria).  
o Overall Survival (OS). 
- 
To further assess the safety profile of NUC-1031 administered over multiple cycles. 
- 
To 
explore 
relationships 
between 
NUC-1031 
Pharmacokinetic 
(PK), 
pharmacodynamics and clinical activity.  
- 
To describe the effects of NUC-1031 on ovarian cancer symptoms.  
 
The exploratory objectives are: 
- 
To establish the expression of genomic, transcriptomic and proteomic biomarkers in 
Peripheral Blood Mononuclear Cells (PBMCs) and tissue samples, which may help 
predict patients who derive additional benefit from NUC-1031.  
- 
To explore the impact of treatment and disease state on health state utility by Euro 
Quality of Life (EuroQoL) five dimensions, five levels (EQ-5D-5L).  
2.1 Primary Endpoint 
The primary endpoint of this study is: 
• ORR at the selected dose level (500 mg/m² or 750 mg/m²) defined per RECIST v1.1 
and assessed by a BICR. 
2.2 Secondary Endpoints 
The secondary endpoints of this study are: 
• Change from baseline in tumor size.  
• DOR.  


 
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• PFS.  
• TTP.  
• Time To Response (TTR). 
• DCR.  
• Best Overall Response (BOR). 
• Best GCIG Overall Response, combining the change in Cancer Antigen 125 (CA125) 
from baseline with RECIST assessment.  
• OS.  
• Assessment of ovarian cancer symptoms using Functional Analysis of Cancer Therapy 
(FACT)/ National Comprehensive Cancer Network (NCCN)-Ovarian Symptom Index 
(containing 18 items) (FOSI-18) questionnaire. 
• Time on treatment. 
2.3 Safety Endpoints 
The safety endpoints of this study are the followings: 
• Treatment-emergent adverse events per National Cancer Institute-Common 
Terminology Criteria for Adverse Event version 4 (NCI CTCAE v4).  
• Laboratory parameters 
• Changes in vital signs. 
• Changes in serial Electrocardiograms (ECG). 
2.4 Pharmacokinetic Endpoints 
The pharmacokinetic (PK) endpoints of this study are the followings: 
• Maximum concentration (Cmax). 
• Area under the curve (AUC). 
• Half-life (T1/2). 
• Volume of distribution (Vd). 
• Clearance (CL). 
In addition, PK of the following analytes will be measured: 
• In plasma/urine: NUC-1031, dFdC and dFdU. 
• In PBMCs: NUC-1031, dFdC, dFdCMP, dFdCDP, dFdCTP and dFdU. 
PK analyses will not be described in this Statistical Analysis Plan but in a separate document. 


 
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2.5 Exploratory Endpoints 
The following exploratory endpoint will be summarized: 
• Assessment of the impact of treatment and disease state on health state utility by 
EuroQoL five dimensions, five level questionnaire. 
 
The following exploratory endpoint will be described separately: 
• Assessment of candidate genomic, transcriptomic and proteomic biomarkers of 
resistance/sensitivity to NUC-1031 in PBMCs and tissue samples. Examples of 
candidate markers include cytidine deaminase (CDA), deoxycytidine kinase (dCK), 
human equilibrative nucleoside transporter 1 (hENT1), ribonucleotide reductase M1 
(RRM1) and Ribonucleotide Reductase M2 (RRM2). 


 
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3 Study Design 
3.1 Discussion of Study Design 
This is a randomized open-label, two-part clinical study of NUC-1031 in up to 64 patients with 
platinum-resistant ovarian cancer. Patients will be randomized to NUC-1031 500 mg/m² or 750 
mg/m² and will be evaluated in two parallel cohorts of up to 20 patients each in Part I of the 
study. The randomization will be stratified to ensure that key prognostic markers, including 
Breast Cancer (BRCA) mutation status and number of prior lines of chemotherapy (3 or >3), 
are balanced between the 2 dose levels. Thus, the stratification factors are BRCA mutation 
status (Yes/No) and Number of prior lines of chemotherapy (=3/>3). 
On the basis of ongoing safety, dosing intensity, PK and clinical activity observed during Part 
I, one dose level will be selected for further evaluation in Part II of the study, where enrolment 
shall continue until a total of 44 response evaluable patients are recruited at the selected dose 
(Figure 1). 
Figure 1: Study Design 
 
It is anticipated that up to 64 patients will be enrolled in this study at multiple study centers (24) in 
the United States (US) (16) and Europe (8). Patients are eligible for the study if all of the inclusion 
criteria are met and none of the exclusion criteria apply. 
The primary analysis of response rate will take place when 44 patients are enrolled at the 
selected dose and all active patients have undergone the required assessments for assessment 
of confirmed ORR by RECIST (i.e., approximately 16 weeks after the 44th patient starts 
treatment). Upon review of the data from Part II by the Data Safety Monitoring Committee 
(DSMC), the study may be further expanded at the selected dose level, which will be described 


 
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in a protocol amendment. A further efficacy update analysis may be performed at a later date 
to provide more mature efficacy data. 
The study will be deemed complete following the efficacy update analysis. If the efficacy 
update analysis is not required, the study will be considered complete following the Data Cut 
Off (DCO) for the primary analysis. 
Following a preliminary analysis of top-line data in 51 randomised patients from Part I, the 
dose intensity was lower than expected and the decision was made not to proceed with Part II. 
As a consequence, database lock will occur sooner than initially planned and the primary 
analysis of response rate described above will not be produced. 
In addition, the efficacy update analysis described above will not be performed. 
3.2 Study Treatment 
3.2.1 Study Treatment 
In Part I, eligible consenting patients will be randomized to receive Intravenous (IV) NUC-
1031 at a dose of either 500 mg/m² or 750 mg/m² on a day 1, 8 and 15 of a 28-day schedule. 
Up to 20 patients will be enrolled in each arm.  
One dose level will be selected for further evaluation in Part II of the study (based on ongoing 
safety, dosing intensity, PK and clinical activity observed during Part I), where enrolment shall 
continue until a total of 44 evaluable patients are recruited at the selected dose. The study will 
be complete when all patients have reached the PFS endpoint or when 24 months have elapsed 
since the final patient was enrolled (whichever occurs first).  
Criteria for inter-cycle and intra-cycle dose delay and dose modification are specified in 
Section 3.2.4. The reasons for dose delay or dose reduction should be captured as Adverse 
Events (AE) in the patient medical record and noted on the electronic Case Report Form 
(eCRF).  
3.2.2 NUC-1031 Description 
The drug product, NUC-1031 (for injection), is presented as a sterile solution in clear glass 
vials at a concentration of 250 mg/milliliter (ml) formulated in dimethylacetamide (DMA) and 
Normal Saline (0.9%) in the ratio of 80:20. 
3.2.3 Study Drug Dosage and Administration 
NUC-1031 will be administered to each patient based on her Body Surface Area (BSA) at 
baseline. If a patient’s weight increases or decreases by ≥10% during the course of the study, 
the dose of NUC-1031 should be recalculated. The Dubois & Dubois BSA calculation is the 
preferred method, however other standard calculations can also be used. Sites should document 
the method used in the electronic Case Report Form (eCRF). 
Dubois & Dubois BSA calculation: 


 
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𝐵𝐵𝐵𝐵𝐵𝐵(𝑚𝑚2) = 0.007184 × 𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻ℎ𝑡𝑡(𝑐𝑐𝑐𝑐)0.725 × 𝑊𝑊𝑊𝑊𝑊𝑊𝑊𝑊ℎ𝑡𝑡(𝑘𝑘𝑘𝑘)0.425 
Patients will receive IV NUC-1031 at an initial dose of 500 mg/m² or 750 mg/m² on Days 1, 8 
and 15 of a 28-day schedule. Dose adjustments or dose delays are to be implemented within or 
between cycles based on drug related toxicities. The dose modification scheme to be employed 
is detailed in the section below. 
3.2.4 Dose Modifications 
Adverse events may be managed by dose delays and/or dose reductions according to the clinical 
situation. Advice on how to modify dosing for hematological and non-hematological toxicities 
is given below.  
Only one dose reduction is permitted within a cycle. This may be a temporary dose reduction, 
in which case the next cycle can revert to the starting dose of the previous cycle, or it may be 
a permanent dose reduction 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 will be discontinued. The lowest dose which may be administered is 275 mg/m².  
Treatment between cycles can be delayed for up to 14 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-1031 and will 
be withdrawn from the study. 
3.2.4.1 Hematological Toxicity – Dose Adjustment 
NUC-1031 administration should be given according to the Absolute Neutrophil Count (ANC) 
and platelet count on the day of dosing. On Day 1 of each 28-day cycle, if the ANC is 
≥1.5×109/l and the platelet count is ≥75×109/l, then NUC-1031 should be given at full dose 
unless the patient has previously been permanently dose reduced.  
On Day 1 of each 28-day cycle, if the ANC is 1.5-1.0×109/l and the platelet count is 50-75×109/l 
without evidence of bleeding, then NUC-1031 should be given at a reduced dose unless the 
patient has received 2 prior dose reductions.  
Within a cycle, should patients experience neutropenia or thrombocytopenia, dosing on Day 8 
and Day 15 should be adjusted per Table 1 below. 


 
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Table 1.  Dose adjustments within a cycle (Days 8 and 15) 
ANC 
 
Platelets 
Starting dose 
(750 mg/m²) 
Starting dose 
(500 mg/m²) 
Starting dose 
(375 mg/m²) 
≥1.5×109/l 
AND 
≥75×109/l 
750 mg/m² 
500 mg/m² 
375 mg/m² 
1.5-1.0×109/l 
and afebrile 
AND/OR 
50-75×109/l 
without 
evidence 
of bleeding 
500 mg/m² 
375 mg/m² 
275 mg/m² 
<1.0×109/l, or 
<1.5×109/l with 
fever 
AND/OR 
<50×109/l, 
or 
<100×109/l 
with active 
bleeding 
Omit 
Omit 
Omit 
Should both the Day 8 and Day 15 doses be omitted for hematologic toxicity within the same 
cycle, the dose for all subsequent cycles should be permanently reduced the next dose level. 
If a patient starts a treatment cycle at 500 mg/m² and requires further dose reduction on Day 8 
or Day 15 of the following cycle due to hematologic toxicity, dose modification should follow 
the column second from the right of Table 1.  
If a patient has her dose permanently reduced to 375 mg/m², and hematologic toxicity persists 
on any day that a dose is scheduled, dose modification should follow the far right column of 
Table 1. 
For  all other hematological toxicities, dose adjustments should be performed according to 
Table 2. 


 
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Table 2.  Dose adjustments for haematological toxicities (excluding toxicities relating to 
ANC and platelet counts) 
NCI CTCAE 
grade 
Dose adjustment 
Grade 1 toxicity  
If the patient was receiving 750 mg/m2 then reduce to 500 mg/m2.  
If the patient was receiving 500 mg/m2 then reduce to 375 mg/m2. 
If the patient was receiving 375 mg/m2 then reduce to 275 mg/m2. 
Grade 2, 3 and 4 
toxicity  
Omit until resolution to ≤Grade 1 if the patient was receiving 750 mg/m2 then 
resume at the dose 500 mg/m2.  
If the patient was receiving 500 mg/m2 then resume at the dose 375 mg/m2. 
If the patient was receiving 375 mg/m2 then resume at the dose 275 mg/m2. 
3.2.4.2 Non-Hematological Toxicity – Dose adjustment 
Drug adjustment should be performed according to Table 3. If dose omission is required, 
treatment should be delayed until the toxicity has resolved to ≤ Grade 1. If this occurs, 
subsequent doses should be permanently reduced, without re-escalation. For significant 
pulmonary complications (e.g. pneumonitis and acute respiratory distress syndrome), study 
treatment should be stopped. 


 
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Table 3.  Dose adjustment for non-hematological toxicities 
NCI CTCAE grade 
Dose adjustment 
Grade 0-2 toxicity or Grade 3 nausea/ 
vomiting/ alopecia 
100% dose (with escalation of anti-emetic 
prophylaxis for nausea and vomiting) 
Grade 3/4 toxicity  
(except nausea/vomiting/alopecia) 
Omit until resolution to ≤ Grade 1 if the patient 
was receiving 750 mg/m² then resume at the 
dose 500 mg/m².  
If the patient was receiving 500 mg/m² then 
resume at the dose 375 mg/m². 
If the patient was receiving 375 mg/m² then 
resume at the dose 275 mg/m². 
3.2.4.3 Guidance for Dose Omissions 
Table 4 outlines the guidance for omission of doses on Day 1, 8 or 15. 
Table 4.  Dose omission guidance 
Day 1 missed dose 
Day 8 missed dose 
Day 15 missed dose 
If the dose omitted was due 
to be on Day 1 of the next 
cycle, that cycle will not be 
considered to start until the 
day the first dose is actually 
administered to the patient 
(i.e. 1-2-3-Rest, X-1-2-3-
Rest, etc). 
Cycle 
continues 
per 
protocol, with one dose not 
given (i.e. 1-2-3-Rest, 1-X-
3-Rest, 1-2-3-Rest, etc).  Day 
15 is administered as per 
cycle 
calendar 
if 
blood 
results permit. 
That week becomes the week 
of rest. Next dose (if blood 
results permit) becomes Day 
1 of a new cycle, and the 
patient is considered to have 
had a 21-Day cycle. 
3.3 Study Schedule 
3.3.1 Patient Registration and Screening Procedures 
All screening activities must be performed within 28 days of randomization. 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 CRO upon 
request, but without patient identifiers.  
In Part I, patient randomization will be stratified according to BRCA mutation status and 
number of prior lines of chemotherapy (3 or >3). In Part II, sensitivity analyses will be 
conducted on ORR according to BRCA mutation status and number of prior lines of 
chemotherapy (see details in Section 4.8.2). Patients known to have germline BRCA 
mutation(s) prior to randomization can enter the study based on this result. Patients who have 


 
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had a tumor BRCA mutation identified in a certified laboratory may also be enrolled on the 
study based on this result. Patients with unknown BRCA mutation status should undergo local 
BRCA mutation testing prior to study entry, according to local ethical procedures for genetic 
testing.  
Before entering a patient onto the study, the investigator will confirm eligibility according to 
the defined inclusion and exclusion criteria. Then, this confirmation is sent to Covance project 
manager and clinical team leader in a patient registration form and they will confirm that patient 
may be randomized. Details of the query and outcome of the decision must be documented on 
the registration/ eligibility checklist. To register a patient to the study, the site must email a 
completed Registration Form, along with a copy of the blinded histology report, to the patient 
registration email address supplied. The patient will then be registered to the study. The site 
will be informed by email and fax of the approval to be treated. Treatment must not start until 
this registration process is complete and must start no later than 10 days after the day of 
registration. 
3.3.2 Screening Assessments 
Standard of care assessments that were completed prior to informed consent but are within the 
screening window may be used for screening assessments and do not have to be repeated. All 
protocol required assessments that are not deemed standard of care should not be completed 
until after informed consent has been signed. 
Screening assessments of consented patients will comprise the following:  
- 
Provision of written informed consent.  
- 
Eligibility confirmation, including histological diagnosis of ovarian cancer.  
- 
Patient registration.  
- 
Assessment of medical and surgical history, including prior therapy for ovarian cancer.  
- 
BRCA testing (if BRCA status is unknown).  
- 
ECOG performance status.  
- 
The FOSI-18 and EQ-5D-5L instruments must be completed prior to other scheduled 
study procedures and dosing (if applicable).  
- 
Routine physical 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.  
- 
Height and weight.  
- 
12-lead ECG 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. The QTc interval should be calculated for each ECG using the 
Fridericia formula and averaged. Management of QT/QTc prolongation should be 
performed in accordance with institutional standard of care at the discretion of the 
treating physician. Digital and certified paper copies should be stored as part of the 
study documents in the event they need to be used in a future analysis.  
- 
Recording of demographic data.  
- 
Baseline assessment of symptoms.  
- 
Blood samples drawn for: 
o Hematology: white blood cell (WBC) count, red blood cell (RBC) count, 


 
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differential WBC count, including hemoglobin, hematocrit and platelets. 
o Coagulation parameters: prothrombin time (PT)/ international normalized ratio 
(INR) and activated partial thromboplastin time (aPTT).  
o Chemistry: sodium, potassium, magnesium, urea or Blood Urea Nitrogen (BUN), 
creatinine, glucose, phosphate, total protein, albumin, adjusted calcium, total 
bilirubin, bicarbonate, chloride, uric acid, alkaline phosphatase, Aspartate 
Aminotransferase (AST), Alanine Aminotransferase (ALT) and Lactate 
dehydrogenase (LDH).  
o Pregnancy testing: For women of childbearing potential serum pregnancy must be 
performed within 72 hours prior to Cycle 1 Day 1.  
o CA125 (for GCIG response determination).  
- 
Urinalysis: pH, specific gravity, ketones, leukocytes, protein, glucose, bilirubin, 
urobilirubin and occult blood. Dipstick testing is acceptable.  
- 
Tumor imaging (Computed Tomography (CT), Magnetic Resonance Imaging (MRI) 
and/or Positron Emission Tomography (PET)-CT [US only] of thorax, abdomen and 
pelvis) – performed within 28 days of randomization. Biopsied lesions should not be 
designated as target lesions for the purposes of RECIST.  
- 
Obtain fresh and archival tumor tissue. For sampling procedures, storage conditions, 
and shipment instructions, see the Tumor Tissue Laboratory Manual. Patients who do 
not have easily accessible tumor for biopsy should not be put at undue risk for sample 
collection and these patients remain eligible for the study. Biopsied lesions should not 
be designated as target lesions for the purposes of RECIST.  
- 
Recording of concomitant medication.  
3.3.3 Re-Screening Patients who fail Inclusion/Exclusion Criteria 
If a patient does not meet the inclusion/exclusion criteria upon first assessment, she can be re-
screened within 14 days. Patients who fail at re-screening are ineligible and may not be re-
screened. 
3.3.4 Evaluations to be performed during the study 
During treatment, patients will be medically reviewed on dosing days. The following will be 
assessed:   
3.3.4.1 Each Cycle, Day 1 
All procedures to be completed prior to dosing except NUC-1031 administration and applicable 
PK samples. Safety laboratory assessments and weight measurement may be performed up to 
3 days prior to Day 1 of each cycle. 
- 
ECOG performance status.  
- 
The FOSI-18 and EQ-5D-5L instruments must be completed prior to other scheduled 
study procedures and dosing (if applicable).  
- 
Routine physical 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.  


 
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- 
12-lead ECGs should be performed pre-infusion. 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. The QTc interval 
should be calculated for each ECG using the Fridericia formula and averaged. 
Management of QT/QTc prolongation should be performed in accordance with 
institutional standard of care at the discretion of the treating physician. Digital and 
certified paper copies should be retained at site and stored as part of the study 
documents in the event they need to be used in a future analysis.  
- 
At Cycle 1 Day 1 (C1D1) and Cycle 3 Day 1 (C3D1) only the 12-lead ECGs should be 
performed 30-60 minutes pre-infusion and again 30-60 minutes post-infusion. 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. The QTc interval should be calculated for each ECG using the Fridericia 
formula and averaged. Management of QT/QTc prolongation should be performed in 
accordance with institutional standard of care at the discretion of the treating physician. 
Digital and certified paper copies should be 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 Hematology: WBC count, RBC count, differential WBC count, including 
hemoglobin, hematocrit and platelets.  
o Coagulation parameters: PT/INR and aPTT.  
o Chemistry: sodium, potassium, magnesium, urea or BUN, creatinine, glucose, 
bicarbonate, chloride, uric acid, phosphate, total protein, albumin, adjusted 
calcium, total bilirubin, alkaline phosphatase, AST, ALT and LDH.  
o CA125.  
- 
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-1031.  
- 
AE recording and causality assessment.  
- 
Recording of new or changes to concomitant medication.  
3.3.4.2 For sites Collecting Optional Fresh Biopsy: Within 24 Hours of Cycle 1 
Day 1 
- 
Obtain fresh tumor biopsy within 24 hours of the end of NUC-1031 infusion on C1D1.. 
For sampling procedures, storage conditions, and shipment instructions, see the Tumor 
Tissue Laboratory Manual. Patients who do not have easily accessible tumor for biopsy 
should not be put at undue risk for sample collection and these patients remain eligible 
for the study. Biopsied lesions should not be designated as target lesions for the 
purposes of RECIST.  
 


 
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3.3.4.3 For Sites Participating in PK Sample Collection: Cycles 1 & 3 – Days 1 & 
2 
- 
PK: multiple blood samples will be taken on Cycles 1 and 3 on Days 1 and 2, 24 hours 
after NUC-1031 administration. Optional urine samples may be taken during Cycle 1 
on Days 1 and 2.. 
- 
AE recording and causality assessment. 
- 
Recording of new or changes to concomitant medication. 
3.3.4.4 Each Cycle, Days 8 & 15 
All procedures to be completed prior to dosing except NUC-1031 administration and applicable 
PK samples.  
- 
Routine physical 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 pre-infusion. 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. The QTc interval 
should be calculated for each ECG using the Fridericia formula and averaged. 
Management of QT/QTc prolongation should be performed in accordance with 
institutional standard of care at the discretion of the treating physician. Digital and 
certified paper copies should be stored as part of the study documents in the event they 
need to be used in a future analysis. 
- 
At Cycle 1 Day 15 (C1D15) and Cycle 3 Day 15 (C3D15) only the ECGs should be 
performed 30-60 minutes pre-infusion and again 30-60 minutes post-infusion. 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. The QTc interval should be calculated for each ECG using the Fridericia 
formula and averaged. Management of QT/QTc prolongation should be performed in 
accordance with institutional standard of care at the discretion of the treating physician. 
Digital and certified paper copies should be stored as part of the study documents in the 
event they need to be used in a future analysis. 
- 
Blood samples drawn for: 
o Hematology: WBC count, RBC count, differential WBC count, including 
hemoglobin, hematocrit 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 NUC-1031.  
- 
AE recording and causality assessment.  
- 
Recording of new or changes to concomitant medications  
 


 
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3.3.4.5 For Sites Participating in PK Sample Collection: Cycle 1 Days 15 & 16 
- 
PK: multiple blood samples will be taken on Cycle 1 Days 15 and 16. Optional urine 
samples may be taken on Cycle 1 Days 15 and 16. 
- 
AE recording and causality assessment. 
- 
Recording of new or changes to concomitant medication. 
3.3.4.6 Every 8 Weeks (± 7 days) from Cycle 1 Day 1 until Disease Progression, 
Initiation of a New Treatment or Death 
- 
Tumor imaging (CT, MRI and/or PET-CT [US only] of thorax, abdomen and pelvis).  
- 
ECOG performance status should be assessed if the patient has stopped study treatment 
and is attending a Follow-Up Visit.  
3.3.4.7 End of Treatment Visit 
The assessments to be performed on discontinuation due to disease progression or early 
treatment discontinuation for other reasons (e.g. withdrawal of consent) are summarized below. 
The End of Treatment visit should occur within 30 days of the last administration of NUC-
1031. The following will be assessed:  
- 
ECOG performance status.  
- 
The FOSI-18 and EQ-5D-5L instruments must be completed prior to other scheduled 
study procedures.  
- 
Routine physical 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. 
- 
12-lead ECG 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. The QTc interval should be calculated for each ECG using the 
Fridericia formula and averaged. Management of QT/QTc prolongation should be 
performed in accordance with institutional standard of care at the discretion of the 
treating physician. Digital and certified paper copies should be stored as part of the 
study documents in the event they need to be used in a future analysis. 
- 
Blood samples drawn for: 
o Hematology: WBC count, RBC count, differential WBC count, including 
hemoglobin, hematocrit and platelets.  
o Coagulation parameters: PT/INR and aPTT.  
o Chemistry: sodium, potassium, magnesium, urea or BUN, creatinine, glucose, 
bicarbonate, chloride, uric acid, phosphate, total protein, albumin, adjusted 
calcium, total bilirubin, alkaline phosphatase, AST, ALT and LDH.  
o Pregnancy testing for women of child-bearing potential.  
o CA125.  
- 
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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- 
Recording of new or changes to concomitant medication.  
3.3.4.8 Follow-Up 
Patients who stop treatment with no evidence of disease progression as defined by RECIST 
criteria will continue to receive scans at regular intervals (every 8 weeks [±7 days] from C1D1) 
until disease progression or death (whichever comes first) in order to determine duration of 
overall response and progression-free survival.  
Patients with evidence of disease progression as defined by RECIST criteria while receiving 
study medication will discontinue treatment but will enter the follow up period.  They will 
receive a phone call at regular intervals (every 12 weeks [±7 days]) until death, loss to follow-
up, or study discontinuation in order to determine duration of Overall Survival. 


 
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All above information are summarized in the study schedule (see Table 5 below). 
Table 5.  Summary schedule of events 
 
Each Cycle 
End of 
Treatment 
Visit20 
 
Follow-
up Visit 
Q8 weeks 
(±7 days)2
1  
Survival 
Follow-up 
Q12 weeks 
(±7 days) 
Assessment 
Screening 
Up to 
28 days 
prior 
Day 1 
(±3) 
Day 2 
Days 8 & 15 
(±3) 
Day 16 
Informed consent 
X 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria confirmation 
X 
 
 
 
 
 
 
 
Patient registration 
X 
 
 
 
 
 
 
 
Medical and surgical 
history, including 
prior therapy for 
ovarian cancer1 
X 
 
 
 
 
 
 
 
BRCA testing2 
X 
 
 
 
 
 
 
 
ECOG performance 
status 
X 
X 
 
 
 
X 
X 
 
Physical 
examination, 
including vital signs3 
X 
X 
 
X 
 
X 
 
 
Height and weight4 
X 
X 
 
 
 
X 
 
 
Pregnancy test 
X 
X17 
 
 
 
X 
 
 
12-lead ECG5 
X 
X6 
 
X6 
 
X 
 
 
Patient 
demographics 
X 
 
 
 
 
 
 
 
Baseline symptoms 
X 
 
 
 
 
 
 
 
Hematology7 
X 
X 
 
X 
 
X 
 
 
Serum chemistry8 
X 
X 
 
X 
 
X 
 
 
Coagulation 
parameters: PT/INR 
and aPTT9 
X 
X 
 
 
 
X 
 
 
Urinanalysis10 
X 
X 
 
 
 
X 
 
 
Pharmacokinetic 
sampling11 
 
X 
X 
X 
X 
 
 
 
Serum tumor 
markers (CA125)12 
X 
X 
 
 
 
X 
X 
 
Tumor response 
assessment: CT, 
MRI and/or PET-CT 
(US only) scan13 
Scans performed at Screening then every 8 weeks (±7 days) from C1D1 until disease 
progression, regardless of treatment cycle. CRs and PRs must be confirmed by repeated 
images at least 4 weeks after initial documentation. 
Collection of tumor 
specimen14 
X 
X19 
 
 
 
 
 
 
Patient-Reported 
Outcomes15 
X 
X 
 
 
 
X 
 
 
NUC-1031 study 
drug administration16 
 
   X18 
 
X 
 
 
 
 
Adverse events 
 
X 
X 
X 
X 
X 
X22 
 
Concomitant 
medications 
X 
X 
X 
X 
X 
X 
 
 
Survival follow-up 
phone call 
 
 
 
 
 
 
 
X23 


 
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1. 
Medical history and prior therapy collected during Screening. Any changes from date of consent should 
be recorded as Adverse Events. 
2. 
Patients with unknown BRCA mutation status should undergo local BRCA mutation testing prior to 
study entry, according to local ethical procedures for genetic testing. Results are needed prior to 
randomization. 
3. 
Vital signs include measurement of pulse rate, respiratory rate, temperature and blood pressure, after the 
patient has been seated or in the supine position for 5 minutes. 
4. 
Height will be measured at Screening only. If a patient’s weight increases or decreases by ≥10% during 
the course of the study, the dose of NUC-1031 should be recalculated. 
5. 
12-lead ECG measurements must be obtained at screening, pre-infusion on each treatment day, and at 
the treatment completion visit. 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. The QTc interval should be calculated for each ECG using the Fridericia formula and 
averaged. Management of QT/QTc prolongation should be performed in accordance with institutional 
standard of care at the discretion of the treating physician. Digital and/or certified paper copies should 
be stored as part of the study documents in the event they need to be used in a future analysis. 
6. 
At C1D1, C1D15, C3D1 and C3D15 12-lead ECG measurements should be performed 30-60 minutes 
pre-infusion and again 30-60 minutes post-infusion. 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. The QTc interval should be calculated for each ECG using the Fridericia 
formula and averaged. Management of QT/QTc prolongation should be performed in accordance with 
institutional standard of care at the discretion of the treating physician. Digital and/or certified paper 
copies should be stored as part of the study documents in the event they need to be used in a future 
analysis. 
7. 
Hematology includes white blood cell (WBC) count, differential WBC count, red blood cell count 
(RBC), hemoglobin, hematocrit and platelet count. 
8. 
Serum chemistry incudes sodium, potassium, magnesium, urea or blood urea nitrogen, creatinine, 
glucose, phosphate, total protein, albumin, adjusted calcium, total bilirubin, bicarbonate, chloride, uric 
acid, alkaline phosphatase, AST, ALT and LDH.  
9. 
Either PT or INR may be measured, depending on institutional standards.  
10. 
Urinalysis includes pH, specific gravity, ketones, leukocytes, protein, glucose, bilirubin, urobilinogen 
and occult blood. Dipstick testing is acceptable. 
11. 
Pharmacokinetic sampling (blood and urine) will be performed at a sub-set of sites specified by NuCana. 
At sites participating in the PK sample collection, blood samples are collected on Cycle 1 (Days 1 and 
15), and Cycle 3 (Day 1) at pre-dose (T0), end of infusion (T1), T1 plus 10 minutes (T2), T1 plus 30 minutes 
(T3), T1 plus 1 hour (T4), T1 plus 2 hours (T5), T1 plus 4 hours (T6), T1 plus 6 hours (T7) and T1 plus 24 
hours (T8). See blood-sampling schedule in the protocol. 
Urine samples are collected on Cycle 1 (Days 1 and 15) at 0-6 hours, and 6-24 hours.  
12. 
CA125 to determine GCIG response. 
 


 
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13. 
Baseline imaging of the thorax, abdomen, and pelvis is required within 28 days of randomization. CT, 
MRI and PET-CT (US only) scans are acceptable. In selected situations, combination of CT/MRI is 
acceptable (i.e. CT of chest, MRI of abdomen). The same imaging modalities for each anatomic 
component be continued throughout the duration of the study. Objective responses using RECIST must 
be confirmed by repeat assessment performed ≥4 weeks after initial documentation of response. 
Progressive disease should be confirmed prior to stopping treatment.  
14. 
Patients must have consented to the submission of archival tumor, if available and collection of fresh 
biopsy tumor tissue to participate in the study. Patients who do not have easily accessible tumor for 
biopsy should not be put at undue risk for sample collection and these patients remain eligible for the 
study. Biopsied lesions should not be designated as target lesions for the purposes of RECIST. Archival 
tumor tissue, if available may be submitted as paraffin tissue block or at least 10 unstained slides. 
15. 
The FOSI-18 and EQ-5D-5L instruments must be completed prior to other scheduled study procedures 
and dosing (if applicable) at Screening, on Day 1 of each treatment cycle, at treatment discontinuation, 
and at the 28-day post-treatment discontinuation follow-up visit for all patients. 
16. 
Patients will receive NUC-1031 on Day 1, 8 and 15 (±3 days) of a 28-day cycle. 
17. 
For women of child-bearing potential, serum pregnancy testing must be performed within 72 hours prior 
to C1D1 and at End of Treatment visit. In addition, urine pregnancy tests will be performed pre-dose on 
Day 1 of each cycle. If any urine test result is positive, patient dosing will be postponed until the result 
is confirmed by a serum pregnancy test. Patients with a positive serum test will be discontinued from the 
study. 
18. 
Includes insertion of central venous access device, if not already present (if NUC-1031 is centrally 
administered). 
19. 
Optional fresh biopsy tissue sample collection within 24 hours post administration of C1D1 dose for 
patients who consent. 
20. 
Includes treatment discontinuation due to disease progression or early treatment discontinuation for other 
reasons (e.g. withdrawal of consent). Progressive disease should be confirmed prior to stopping 
treatment. Visit to occur within 30 (±7) days of the last dose of NUC-1031. 
21. 
Patients withdrawing from the study with no radiological evidence of disease progression will receive 
scans every 8 weeks (±7 days) from C1D1 until disease progression, initiation of a new treatment or 
death in order to determine duration of overall response and PFS. 
22. 
Adverse events should be captured from the time of consent up to 30 days after the last dose of NUC-
1031. SAEs deemed definitely, probably or possibly related to NUC-1031 but outside of this window 
(>30 days from last dose of NUC-1031) should also be captured in the eCRF. 
23. 
Patients with evidence of disease progression as defined by RECIST criteria will receive a phone call at 
regular intervals (every 12 weeks ±7 days) until death, loss to follow-up, or study discontinuation in 
order to determine duration of Overall Survival. 
 


 
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3.4 Concomitant Medication 
All prescription and non-prescription medications and therapies, including pharmacologic 
doses of vitamins, herbal medicines, or other non-traditional medicines, taken from 28 days 
prior to the first dose of NUC-1031 through the End of Treatment Visit must be recorded in 
the eCRF.  All prior anti-cancer therapies from initial diagnosis up until enrolment must be 
recorded in the eCRF. 
3.4.1 Support Medication 
Patients may receive standard prophylactic medical treatment for nausea and vomiting.  During 
treatment, patients will be reviewed on a weekly basis during the first cycle and on each day of 
treatment for subsequent cycles.  Additional visits may be arranged at the Investigator’s 
discretion.  All support medication must be recorded in the eCRF. 
3.4.2 Hematopoietic Growth Factor Support 
The prophylactic use of hematopoietic growth factors [e.g. Granulocyte Colony-Stimulating 
(G-CSF)] is not permitted in cycle 1.  However, the Investigator may prescribe G-CSF as 
treatment for Grade 3 or higher neutropenia according to local protocols and as prophylaxis 
after the first event of Grade 3 or higher neutropenia or for any febrile neutropenic episode in 
order to enable the patient to continue on study.  All hematopoietic growth factors used from 
30 days prior to date of consent until 30 days after administration of last dose of NUC-1031 
must be recorded in the eCRF.  Any blood or platelet transfusions should also be recorded in 
the eCRF. 
3.4.3 Concomitant Medication and Non-Drug Therapies 
Concomitant medication may be given as medically indicated. All concomitant medication and 
non-drug therapies used from 30 days prior to date of consent until 30 days after administration 
of last dose of NUC-1031 must be recorded in the eCRF. 


 
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3.4.4 Prohibited Therapy and Concomitant Medications 
Use of the following therapies is prohibited during the study: 
- 
Cytotoxic chemotherapy 
- 
Radiotherapy 
- 
Immunotherapy including immunosuppressive therapy 
- 
Radioimmunotherapy 
- 
Hormone therapy (other than contraceptives, hormone-replacement therapy, or 
megestrol acetate) 
- 
Biologic agents intended for the treatment of ovarian cancer (other than hematopoietic 
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 ovarian cancer, whether approved by local 
regulatory authorities or investigational 
- 
Drugs that are known to prolong QTc interval. 
 
 


 
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3.5 Study Analysis Populations 
There will be 5 analysis populations defined for the study analyses: 
3.5.1 Randomized Set (RS) 
The RS will correspond to all patients who provided informed consent and were randomized 
into the study in Part I.  
It will be used for the dose selection analysis, only for patients in Part I. 
3.5.2 Safety Analysis Set (SS) 
The SS will correspond to all patients who received at least one dose of study treatment (NUC-
1031 500 mg/m² or 750 mg/m²). 
This will be the primary analysis set for the assessment of safety parameters. Patients will be 
analysed according to the dose initially received (the dispensed treatment even if there was 
randomization error). 
3.5.3 Full Analysis Set (FAS) 
Based on the intention-to-treat principle, the FAS will be defined as all enrolled patients: 
- 
who received at least one dose of study treatment (NUC-1031 500 mg/m² or 750 mg/m²) 
For the purposes of the analyses, patients of part I will be included according to the dose they 
were randomized to, regardless of any subsequent dose modifications or errors. For part II, 
patients will be included in the FAS according to the intended dose level, regardless of any 
dosing errors or subsequent dose modifications. 
This will be the primary analysis set for the assessment of PFS and OS, and all quality of life 
and symptom-related endpoints. 
3.5.4 Evaluable For Response Set (EFR) 
The EFR will be defined as all patients from the FAS who have measurable disease at baseline 
based on BICR. 
For the purposes of the analyses, patients in Part I will be included according to the dose they 
were randomized to, regardless of any subsequent dose modifications. For Part II, patients will 
be included in the EFR according to the intended dose level, regardless of any dosing errors or 
subsequent dose modifications. 
This will be the primary analysis set for the assessment of all efficacy parameters related to 
response measurements (ORR, DOR, TTP, TTR, DCR, BOR). PFS and OS will also be 
generated in the EFS set. 


 
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3.5.5 GCIG Analysis Set (GCIGAS) 
The GCIGAS will correspond to all patients from the FAS with: 
- 
Measurable disease at baseline, as determined by BICR 
- 
A baseline CA125 reading ≥ 2 x the upper reference range (taken within 2 weeks of 
C1D1) 
For the purposes of the analyses, patients in Part I will be included according to the dose they 
were randomized to, regardless of any subsequent dose modifications or errors. For Part II, 
patients will be included in the GCIGAS according to the intended dose level, regardless of 
any dosing errors or subsequent dose modifications. 
3.5.6 Other Populations Defined for Tables and Listings 
For the purposes of tables and listings (for example, patient disposition) another population is 
defined: 
• Screened population (all screened patients). 
3.5.7 Subgroups 
For the primary endpoint, the analyses will also be produced in the following subgroups: 
- 
By BRCA mutation status (Yes/ No) 
- 
By number of prior lines of chemotherapy (3/ >3) 
Dependent of the results of the primary analysis, additional subgroup explorations will be 
considered exploratory only and are not covered by this SAP. 
Following the decision to stop the study, no subgroup analysis of primary endpoint will be 
performed. 
However, BOR, PFS and OS analyses will be also performed in the following subgroups 
- 
Co-morbidities at baseline (Yes/No) 
- 
Prior gemcitabine intake (Yes/No) 
- 
Time on prior gemcitabine in months (≤ 1/ >1-3/ >3-6/ >6-12/ >12) 
- 
Time to progression from end of last prior platinum-based chemotherapy in months (≤ 
1/ >1-3/ >3-6/ >6) 
- 
BRCA mutation status (Yes/No) 
- 
Time to progression from start of last prior therapy (≤ 1/ >1-3/ >3-6/ >6) 


 
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3.6 Withdrawn Patients 
Patients will continue to receive NUC-1031 until the occurrence of disease progression by 
RECIST or unmanageable drug-related adverse events despite dose modification. Patients may 
also decline treatment at any time for any reason, or they may meet any of the other reasons 
for treatment withdrawal. Reasons for treatment discontinuation must be captured in the patient 
medical record and on the Treatment Discontinuation page of the eCRF.  
Should a patient discontinue treatment without radiological evidence of disease progression, 
the patient should continue to undergo tumor assessment every 8 weeks from C1D1 until such 
time as progression can be documented or new treatment is initiated. 
3.6.1 End of Treatment 
Treatment with NUC-1031 is to be continued until one of the following occurs: 
- 
PD as defined by RECIST criteria. Patients should not discontinue NUC-1031 because 
of raised CA125 or other clinical signs of PD until PD has been confirmed by RECIST. 
- 
Unmanageable toxicity defined as an AE that is considered by the Investigator to 
warrant permanent discontinuation of NUC-1031 including the following: 
o AE resulting in a dosing delay of more than 14 days in starting the next cycle, 
unless the patient is receiving clinical benefit. 
o Clinically significant drug-related AE that recurs despite dose reduction in two 
consecutive cycles. Patients may continue to receive treatment if the Principal 
Investigator and Medical Monitor agree that the patient is receiving a clinical 
benefit and the toxicity is manageable, reversible or transient.  
- 
Lack of further clinical benefit or unfavorable risk/benefit profile as judged by the 
Investigator.  
- 
Inter-current illness that prevents further administration of NUC-1031.  
- 
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 further treatment with NUC-1031.  
- 
Patient non-compliance.  
- 
Lost to follow-up.  
- 
Patient withdrawal of consent.  
- 
Sponsor request.  
All study procedures outlined for the End of Treatment visit are to be completed within 30 days 
(±7 days) of the last dose of study drug. The primary reason for study drug discontinuation is 
to be recorded in the eCRF. 


 
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3.6.2 Follow-Up after Treatment Discontinuation 
Patients who have documented disease progression defined by RECIST criteria while receiving 
study medication will discontinue treatment but will enter the follow up period. Patients should 
not discontinue NUC-1031 because of raised CA125 or other clinical signs of PD until PD has 
been confirmed by RECIST. 
Patients who stop treatment with no evidence of disease progression will enter the follow-up 
period and should attend clinic every 8 weeks (±7 days) from C1D1 for follow-up scans and 
assessments. This should continue until disease progression, initiation of a new treatment or 
death. 
3.6.3 Consent Withdrawal 
Patients will be informed that they have the right to withdraw from the study at any time for 
any reason, without prejudice to their medical care.  
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 electronic Case Report Form (eCRF) pages 
as not applicable. Under these conditions, Investigators are still responsible to follow up any 
Serious Adverse Events (SAE) until resolution. 
3.6.4 Study Completion 
The study is considered complete when 44 response evaluable patients have been treated at the 
selected dose and all patients have reached the PFS endpoint or 24 months have elapsed since 
the final patient was enrolled (whichever occurs first).  
Adverse events present at the time of study withdrawal should continue to be assessed for a 
minimum of 30 days following the last dose of study drug or until resolution to baseline values, 
whichever occurs first. This should ensure that sufficient information is available to enable 
assessment of the primary endpoint and other critical secondary endpoints including safety. In 
the weeks subsequent to a determination that sufficient information is available for these 
assessments, a date for database lock will be assigned, and any outstanding inquiries 
concerning data elements will be resolved. 
The data cut-off for the primary analysis will be performed 16 weeks after the 44th patient is 
enrolled at the selected dose. All endpoints will be reported at the time of the primary analysis. 
Data dependent, a further efficacy update analysis may be performed at a later date, to provide 
more mature efficacy data for PFS, OS and DOR data. ORR may also be updated at this time 
point. The timing of this analysis, if required, will be determined upon review of the primary 
analysis. 
Following a preliminary analysis of top-line data in 51 randomised patients from Part I, the 
dose intensity was lower than expected and the decision was made not to proceed with Part II.  


 
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As a consequence, database lock will happen sooner than initially planned and the primary 
analysis mentioned above won’t be produced. 
In addition, the efficacy update analysis described above will not be performed. 
3.7 Randomization 
For Part I of the study, patients will be randomized to NUC-1031 500 mg/m² or 750 mg/m² and 
will be evaluated in two parallel cohorts of up to 20 patients each. The randomization with a 
ratio 1:1 will be stratified on BRCA mutation status (Yes/No) and number of prior lines of 
chemotherapy (=3/>3). The randomization will be conducted centrally using RAVE module in 
Medidata system and will have 4 separate randomisation sequences. 
After the dose selection (based on ongoing safety, dosing intensity, PK and clinical activity 
observed during Part I), in Part II, patients will be enrolled to the selected dose without 
randomization in order to recruit 44 evaluable patients, as required for the main analysis. 
3.8 Blinding 
This is an open label study.  
3.9 Sample Size 
The primary analysis of response rate will take place when 44 patients at the selected dose have 
undergone the required assessments for assessment of confirmed ORR by RECIST. The study 
will be considered to have met its primary endpoint if a minimum of 4 confirmed responses 
(CR or PR) are observed. Based on 44 patients, if the true ORR is 15%, there is greater than an 
80% probability of observing 4 or more responses. Furthermore, if the true response rate were 
only 5%, there would be less than a 7% probability of observing 4 or more responses out of 44 
patients. 


 
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4 Statistical Methodology 
4.1 Planned Analyses 
Demographic analyses will be carried out using the randomised set, the safety analysis set, or 
full analysis set,. Some of them will also be performed in the randomized set for dose selection 
analysis. 
The efficacy analyses will be carried out on the FAS and the EFR (for response assessments). 
GCIG criteria will be analysed with the GCIG Analysis Set. 
Unless otherwise stated, summary statistics will be presented for continuous variables, by way 
of n, mean, standard deviation (StD), median, minimum and maximum and by way of group 
frequencies and percentages for categories of categorical variables. Percentages will be 
calculated using the total patients per dose group, and overall.  
The primary endpoint, ORR, will be summarised to show the number and percentage of 
responders, along with the corresponding 80% and 95% Clopper-Pearson (exact) and Mid-p 
confidence intervals. In addition, the number and percentage of patients achieving individual 
best response criteria of CR, PR, SD, PD, or NE will be described. Due to the decision not to 
continue the study, this analysis of ORR with a dedicated table will not be produced. Only the 
number and percentages of responder/ non responder patients will be provided in the table of 
BOR. 
DCR will be summarized as described above for ORR. Due to the decision not to continue the 
study, this analysis will not be produced. 
Kaplan-Meier (KM) plot of PFS, OS, DOR, TTR and TTP will be produced (for DOR and 
TTR, these will only include the subset of patients defined as responders by the BICR). 
Descriptive statistics (median, 25th percentile, 75th percentile, minimum and maximum) will 
also be produced based on the KM estimates. Due to the decision not to continue the study, 
DOR, TTR and TTP will not be analysed. 
Percentage changes from baseline to each visit of the Sum of Lesion Diameters (SLD) (mm) 
as well as best percentage change will be summarized. In addition, waterfall plots will be 
provided for sum of lesion diameters at week 8, week 16 and for the best percentage change. 
In addition, descriptive statistics will be summarized by dose groups at the same timepoints. 
For CA125, percentage changes from baseline to each visit (Cycle X Day 1) and best 
percentage change from baseline will be summarized and presented with a waterfall plot (Cycle 
3 Day 1 – Baseline and Cycle 5 Day1 – Baseline only). Different bar types will be used to 
distinguish between the two dose levels. 
Exploratory endpoints will be summarised using the FAS. Due to the decision not to continue 
the study, this analysis will not be produced. 
Safety endpoints will be presented using descriptive statistics based on the Safety Analysis Set. 
No baseline testing will be performed. 
Statistics will be displayed for the following: 


 
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• NUC-1031 500 mg/m² 
• NUC-1031 750 mg/m² 
Notes:  
• Where a percentage change, a relative change or a change from baseline is presented, 
results for baseline are the most recent assessments prior to the first day of NUC-1031 
(500 mg/m² or 750 mg/m²) infusion (or pre-dose on C1D1 if applicable). 
• All data will be listed. 
4.2 Interim Analyses 
Interim analyses are planned to aid the dose selection for Part I of the study. There may be up 
to 3 dose selection analysis timepoints (see Section 4.2.1). 
Data from the dose selection analyses will be reviewed by a DSMC. Members of DSMC will 
include:  
• Chief Investigators from US and Europe   
• Selected Principal Investigators from participating sites  
• Covance Medical Monitors 
• NuCana Medical Director 
• Study management staff from NuCana. 
Except PK analyses, all other analyses will be provided by the statistician and described in this 
document. 
For each dose selection analysis, according to the Data Management Plan, 15 business days 
prior to the DSMC meeting, data management will send a raw data extract to the statistical 
team (lead statistician and lead statistical programmer) in order to produce and send the results 
to the DSMC members 5 business days prior the DSMC meeting. No database lock will be 
performed, but a defined data cut-off date will be determined based on study enrolment and 
DSMC member availability. The raw data will be “as clean as possible”: all queries closed, 
100% medical coding complete, all critical data Source Data Verified and Data Management 
Review completed. 
This extract will be stored by the statistical team and used to develop CDISC (SDTM and 
ADaM datasets). 
An update efficacy analysis may also be performed after the primary analysis, to provide more 
mature efficacy data. The same process as described above for dose selection analysis will be 
followed. 
Thus, different data cut-offs will be used to correspond to the different protocol objectives: 
- 
dose selection 
- 
primary analysis 


 
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- 
efficacy update analysis. 
It will let us show and present the data that was available at the time of the analysis (dose 
selection, primary analysis or efficacy update analysis, if necessary) and use those different 
results for the Clinical Study Report. 
4.2.1 Dose Selection Analysis 
Two dose levels of NUC-1031, 500 mg/m² and 750 mg/m², will be evaluated in parallel cohorts 
of up to 20 patients in each in Part I of the study.  One dose level will be selected for further 
evaluation in Part II of the study (based of ongoing safety, dosing intensity, PK and clinical 
activity observed during Part I), where enrolment shall continue until a total of 44 evaluable 
patients are recruited at the selected dose.   
The decision to determine the Part II dose (500 mg/m² or 750 mg/m²) will be made by the 
DSMC after review of all required data as outlined below.  This analysis could be performed 
once, twice or three times depending on whether a decision can be made at the time of the 
initial analysis: 
- 
once 10 patients are enrolled in each arm and have undergone at least one post treatment 
scan 
- 
once 15 patients are enrolled in each arm and have undergone at least one post treatment 
scan 
- 
at the end of the randomization: once 20 patients are enrolled in each arm and have 
undergone at least one post treatment scan 
The DSMC will review the safety, dosing intensity, pharmacokinetic and clinical activity data 
from Part I of the study to decide on which dose should be used in Part II.  
The following analyses will be provided for all patients randomized in Part I: 
- 
Patient disposition 
- 
Baseline and Demographic Characteristics 
- 
Ovarian Cancer History 
- 
Prior Ovarian Cancer Therapies 
- 
Exposure 
- 
Prior and Concomitant Medications (only listed) 
- 
Best Overall Response according to RECIST v1.1 assessment based on BICR  as well 
as based on Investigator-Recorded Assessment (including unconfirmed responses) 
- 
Percentage change from baseline in tumor size at week 8 and at week 16 and best 
percentage change from baseline 
- 
Percentage change of CA125 at Cycle 3 Day 1 and Cycle 5 Day 1 and best percentage 
change from baseline 
- 
Best GCIG Overall Response, combining the change CA125 from baseline with 
RECIST assessment (only listed). 
- 
Adverse Events 
- 
Laboratory Findings 
- 
Physical Examination (only listed) 


 
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- 
Vital Signs (only listed) 
- 
ECG 
- 
ECOG Performance Status (only listed) 
 
Only descriptive statistics without inferential (no statistical test) will be provided. 
4.2.2 Efficacy Update Analysis 
An efficacy update analysis may be performed after the primary analysis, to provide more 
mature efficacy data.  
The same process as described for dose selection analysis regarding extract of the data and 
output delivery will be followed. 
The following analyses will be provided: 
- 
ORR based on BICR 
- 
BOR 
- 
DCR 
- 
PFS 
- 
OS 
- 
DOR 
- 
TTP 
- 
TTR 
- 
Best GCIG Overall Response, combining the change CA125 from baseline with 
RECIST assessment (per GCIG criteria). 
Due to the decision not to proceed with Part II,  the study will be stopped and no efficacy update 
analysis will be produced. 
 
4.3 Disposition of Patients 
The number of patients receiving study treatment, in each analysis population, who continued  
treatment, who continued into follow-up, who continued into Survival Follow-up, who died 
and the primary reasons for ending treatment and the primary reasons for ending study 
participation will be presented by dose group. 
In addition, the number of patients in each analysis set with reasons for exclusion will be 
described. 
Moreover, the number and percentages of patients with each major protocol violation will be 
summarized too. 
These analyses will be produced for the dose selection analysis and the primary analysis in all 
screened patients for patient disposition and major protocol violations, and in patients from the 
Safety Analysis Set for the description of analysis sets. 


 
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Patient disposition, Inclusion/ Exclusion criteria descriptions, patients’ eligibility, and protocol 
violations/ deviations will be presented in data listings. 
Due to the decision not to proceed with Part II, the patient eligibility listing will not be 
provided. 
 
4.4 Baseline and Demographic Characteristics 
4.4.1 Baseline and Demographic Characteristics 
All baseline and demographic characteristics will be summarised by treatment group. This will 
include:  
- 
gender,  
- 
race,  
- 
ethnicity,  
- 
age group (<55, 55-<66, 66-75, >75),  
- 
ECOG performance status,  
- 
BRCA mutation status,  
- 
number of prior lines of chemotherapy,  
- 
time to progression from start of last chemotherapy in months (≤3/>3),  
- 
time to progression from start of last platinum based chemotherapy in months (≤1/>1-
3/>3-6/>6), 
- 
time to progression from end of last platinum based chemotherapy in months (≤1/>1-
3/>3-6/>6),  
- 
patients who received prior gemcitabine,  
- 
patients who received prior gemcitabine and had a best response of PD,  
- 
patients who had gemcitabine intake as last prior chemotherapy,  
- 
Time on prior gemcitabine in months (≤1/>1-3/>3-6/>6-12/>12) 
- 
patients with a co-morbidity at baseline,  
- 
time to progression from start of last prior therapy in months (≤1/>1-3/>3-6/>6). 
In addition, all co-morbidities at baseline will be described. 
All demographic data and baseline characteristics will be summarized in output tables by 
treatment groups and presented in data listings for the dose selection analysis and the primary 
analysis in all patients from the Randomized Set. 
Notes: 
• Age groups are defined as: <55, 55-<66, 66-75, >75 years of age. If birth date is 
partially missing, substituting rules defined in Section 4.13.5 will be applied. 


 
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• Listing will also present women with childbearing potential, age, weight (kilograms 
(kg)), BSA (m²), Body Mass Index (BMI) (kg/m²). 
• BMI will be calculated as weight(kg)/height2(m) 
• BSA at screening will be calculated as (Dubois & Dubois BSA calculation) 
𝐵𝐵𝐵𝐵𝐵𝐵(𝑚𝑚2) = 0.007184 × 𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻ℎ𝑡𝑡(𝑐𝑐𝑐𝑐)0.725 × 𝑊𝑊𝑊𝑊𝑊𝑊𝑊𝑊ℎ𝑡𝑡(𝑘𝑘𝑘𝑘)0.425 
• Time to Progression from start of last chemotherapy (defined as the one received 
immediately before coming on study) (months) = (Progression date – Start date of last 
chemotherapy + 1)/30.4375 
• Time to Progression from start of last platinum-based chemotherapy (defined as the one 
received immediately before coming on study) (months) = (Progression date – Start 
date of last platinum based chemotherapy + 1)/30.4375 
• Time to Progression from end of last platinum-based chemotherapy (defined as the one 
received immediately before coming on study) (months) = (Progression date – Last 
intake date of last platinum-based chemotherapy + 1)/30.4375 
• Time on prior gemcitabine (months) = (Last intake date of last prior gemcitabine – First 
intake date of last prior gemcitabine + 1)/30.4375 
• Time to Progression from start of last prior therapy (defined as the one received 
immediately before coming on study) (months)= (Progression date – First intake date 
of last prior therapy + 1)/30.4375 
• A co-morbidity at baseline is defined as at least one LLT present at the time of first 
intake among the LLT list below extracted from medical history: 
o Anorexia 
o Arthralgia 
o Arthritis 
o Asthma 
o Atrial fibrillation 
o Chronic kidney disease 
o Chronic kidney disease stage 3 
o Chronic renal insufficiency 
o Diabetes 
o Hypertension 
o Hypotension 
o Myalgia 
o Neuropathy 
o Neuropathy peripheral 
o Osteoarthritis 
o Osteoporosis 


 
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o Peripheral sensory neuropathy 
o Pleural effusion 
o Polymyalgia 
o Polymyalgia rheumatica 
o Pulmonary embolism 
o Rheumatoid arthritis 
o Sensory neuropathy 
o Tachycardia 
o Type II diabetes mellitus 
o Ureteral stent insertion 
o Urinary tract infection 
o UTI 
o Vaginal haemorrhage 
o Venous thrombosis 
4.4.2 Medical/ Surgical History 
Medical history will be presented in a data listing with System Organ Class (SOC) and 
Preferred Term for the primary analysis in patients from the Safety Analysis set. 
Notes:  
• Medical history will be coded (System Organ Class (SOC) and Preferred Term) 
according to MedDRA version 18.1 or higher. 
4.4.3 Ovarian Cancer History 
Ovarian Cancer History will be summarized by treatment groups for the dose selection analysis 
as well as the primary analysis in patients from the randomized set. 
The following criteria will be described: 
- 
Time since initial diagnosis (days) defined as Screening date – Diagnosis date + 1 
- 
Original diagnosis (Ovarian/ Fallopian Tube/ Primary Peritoneal/ Other) 
- 
Histology (High Grade Serous/ High Grade Endometrioid/ Undifferentiated Epithelial/ 
Unclassifiable Epithelial/ Mixed Epithelial/ Other) 
- 
Stage at initial diagnosis (Stage I (IA/ IB/ IC) / Stage II (IIA/ IIB) / Stage III (IIIA1/ 
IIIA2/ IIIB/ IIIC) / Stage IV (IVA/ IVB) / Unknown) 
- 
Current stage at screening visit (Stage I (IA/ IB/ IC) / Stage II (IIA/ IIB) / Stage III 
(IIIA1/ IIIA2/ IIIB/ IIIC) / Stage IV (IVA/ IVB) / Unknown) 
- 
Documented deleterious BRCA mutation? (Yes/ No) 
- 
Type of BRCA mutation, if BRCA mutation=Yes (BRCA 1/ BRCA 2/ BRCA 1/2) 
- 
Any current known metastatic disease sites (Yes/ No) 
- 
Metastatic disease sites (Abdomen/ Adrenals/ Bone Marrow/…/Other) 


 
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Ovarian Cancer History will also be listed. 
Note: 
• In case of missing initial diagnosis date, substituting rules defined in Section 4.13.3 will 
be applied. 
4.4.4 Prior Ovarian Cancer Therapy 
Prior Ovarian Cancer Therapy will be summarized by treatment group. 
The following descriptive statistics will be provided for the dose selection analysis 
(Randomized set) as well as the primary analysis (Safety analysis set): 
- 
Number of prior lines of therapy for Ovarian Cancer:  
o Number and percentage of patients in each category: < 3, 3, 4, 5, 6, 7, 8, > 8 
o Quantitative description: n, Mean (SD), Median, Min, Max 
- 
Number and percentage of patients who have received a prior gemcitabine-containing 
regimen (Yes/ No)  
- 
Number and percentage of patients who have shown resistance to prior Gemcitabine-
containing regimens (i.e., who have had a documented best response of PD) (Yes/ No), 
- 
Time to Progression post starting last platinum-containing regimen (months) in classes 
(≤ 6, >6-9, >9-12, > 12) defined as (Progression date – Start date of last platinum 
containing regimen + 1) / 30.4375 
- 
Time to Progression post completion of last platinum-containing regimen (months) in 
classes (≤ 1, >1-6, > 6) defined as (Progression date – Last date of last platinum 
containing regimen + 1) / 30.4375 
- 
Time to Progression post starting most recent chemotherapy (regardless of agent) 
(months) in classes (≤ 1, >1-6, >6-9, >9-12, > 12) defined as (Progression date – Start 
date of most recent chemotherapy + 1) / 30.4375. It corresponds to the one received 
immediately before coming on study 
- 
Treatment-Free Interval from completion of most recent chemotherapy treatment 
(months) in classes (≤ 1, >1-3, >3-6, >6-9, > 9) defined as (First study treatment intake 
date – Last date of last prior treatment regimen + 1) / 30.4375 
They will also be listed. 
In addition, descriptive statistics of each agent name as prior therapies will be performed for 
the dose selection analysis as well as the primary analysis (Safety analysis set). 
Moreover, the following items will be listed for the primary analysis: 
- 
Any prior systemic cancer therapy (Yes/ No) 
- 
Agent Type (Chemotherapy/ Radiotherapy/ Hormonal Therapy/ Immunotherapy/ 
PARP Inhibitor/ Vascular Endothelial Growth Factor (VEGF) or Vascular Endothelial 
Growth Factor Receptor (VEGFR)/ Other) 


 
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- 
For each Agent Type: 
o Reason for Administration (Radio Sensitizing/ Radiation Indicated/ Neoadjuvant/ 
Adjuvant/ Other) 
o Number of Cycles 
o Best Response 
o Reason for Discontinuation (Progressive or Relapse Disease/ Unmanageable 
Toxicity/ Completed Treatment/ Lack of Efficacy/ Other) 
o Time to Progression/ Relapse defined as Progression/ Relapse date – Start Date of 
regimen + 1 
- 
If Agent Type=Radiotherapy: 
o Field of radiation (site) (Abdomen/ Chest/ GI tract/ Kidney/ Liver/ Lung/ Lymph 
Nodes/ Spleen/ Other) 
o Estimated total dose of radiation 
However, following the decision not to proceed to Part II, those listings won’t be produced. 
Note: 
• In case of partially missing first or last intake dates of prior ovarian cancer therapies or 
in case of partially missing PD dates of prior ovarian cancer therapies for patients whose 
discontinuation reason is “Progressive/ Relapse Disease” in the CRF, substituting rules 
defined in Section 4.13.4 will be applied. 
• If PD date or first intake date of the last platinum-containing regimen is completely 
missing (so not substituted), “Time to Progression post starting last platinum-
containing regimen (months)” will not be derived, and patient will be counted as 
missing in the table. 
• If PD date or last intake date of the last platinum-containing regimen is completely 
missing (so not substituted), “Time to Progression post completion of last platinum-
containing regimen (months)” will not be derived, and patient will be counted as 
missing in the table. 
• If PD date or first intake date of the most recent chemotherapy is completely missing 
(so not substituted), “Time to Progression post starting most recent chemotherapy 
(regardless of agent) (months)” will not be derived, and patient will be counted as 
missing in the table. 
• If last intake date of the most recent chemotherapy is completely missing (so not 
substituted), “Treatment-Free Interval from completion of most recent chemotherapy 
treatment (months)” will not be derived, and patient will be counted as missing in the 
table. 


 
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• Platinum-containing regimen corresponds to treatments include in the following list: 
o Carboplatin (ATC Code = L01XA01) 
o Cisplatin (ATC Code = L01XA02) 
o Oxaliplatin (ATC Code = L01XA03) 
o Satraplatin (ATC Code = L01XA04) 
o Polyplatillen (ATC Code = L01XA05) 
4.5 Exposure 
Exposure will be described by treatment group and presented in a data listing for the dose 
selection analysis as well as the primary analysis in patients from the Full Analysis Set. 
4.5.1 Study Drug Administration 
The following endpoints will be described: 
- 
Number of NUC-1031 doses received throughout study as a continuous variable # 
- 
Total dose received: overall and by cycle # 
- 
Number of cycles by patients # 
- 
Number of patients by cycle* 
- 
Dose reduction*: overall and by cycle 
- 
Missing Dose * (visit without administration according to schedule):  overall and by 
cycle 
- 
Duration of exposure (in days)* to NUC-1031 as a continuous variable. This will be 
calculated as the date of last administration - date of first administration + 1 day 
throughout study. 
According to table 4 (see Section 3.2.4.3 Guidance for Dose Omissions), the following rules 
will be applied for the description of missing dose: 
- 
Day 1 missed dose (If day 1 is missed but day 8 is given then the day 8 dose is 
considered to be the day 1 dose for the  new cycle):  no missed dose to be considered 
for Day 1 as in the cycle patient will be dosed 3 times 
- 
Day 8 missed dose: to be considered as a missing dose 
- 
Day 15 missed dose (If day 15 is missed then this is considered the week off and the 
next dose becomes day 1 of a new cycle and the previous cycle is abbreviated to 3 
weeks):  the patient will only be dosed twice in the cycle. So a missing dose will be 
considered for this cycle (corresponding to day 15 dose). 
Note:  
- 
For dose selection analysis, only endpoints flagged with a star (*) will be described. 
- 
Due to the decision not to proceed with Part II, endpoints flagged with a # will not be 
described. 


 
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4.5.2 Relative Dose Intensity (RDI) and Percent Intended Dose (PID) 
The RDI is defined as: 
RDI at cycle i = (d at cycle i/D at cycle i)*100 
where: 
- 
where d is the actual cumulative dose (in mg/m²) delivered up to the earlier of 
progression (or a censoring event) or the actual last day of dosing, 
- 
D is the intended cumulative dose (in mg/m²) up to the earlier of progression (or a 
censoring event) or the actual last day of dosing. 
Dose intensity (DI) (mg/m²/week (wk)) and RDI (%) will be calculated by cycle. Descriptive 
statistics will be provided. 
The actual cumulative dose received (mg/m²) at cycle i is equal to the actual dose received 
(mg) at cycle i divided by the BSA at the beginning of the cycle i. 
Actual dose intensity by cycle i is defined as follows 
Actual DI at cycle i = Actual dose received (mg/m²) at cycle i
Actual duration of cycle i (wks)
 
With  
Actual duration of cycle i (wks) = [(Course date at cycle i+1) − (Course date at cycle i)]/7 
If cycle i is the last cycle, then the time is taken to be 28. 
 
The percentage of RDI at cycle i is the ratio of the actual dose intensity (mg/m2/wk) at cycle i 
to the Planned Dose Intensity (PDI) (mg/m2/wk), that is to say: 
RDI at cycle i = ((Actual DI at cycle i)/ PDI)*100 
With PDI=Planned dose (mg/m²)/4 
RDI will be calculated with one decimal. 
 
The same analyses will be performed for the PID. It will be defined as: 
PID at cycle i = (d at cycle i/D at cycle i)*100 
where: 
- 
d is the actual cumulative dose (in mg/m²) delivered up to progression (or a censoring 
event), 
- 
D is the intended cumulative dose up to progression (or a censoring event).  D is the 
total dose (in mg/m²) that would be delivered, if there were no modification to dose or 
schedule. 
Notes:  


 
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- 
If a patient records an early termination visit, the early termination date is used as the 
end date of that last visit interval. 
- 
For Dose Selection Analysis, these parameters will be described at different timepoints: 
o For all patients for a fixed planned 2 cycles 
o For a fixed planned 3 cycles only in patients who completed them 
o For a fixed planned 4 cycles only in patients who completed them 
o Rule: If there are fewer than 3 patients in an arm who completed a cycle (3 or 4 
for the 2 previous analyses), then the corresponding analysis won’t be performed. 
- 
For the Primary Analysis, these analyses will be performed twice: 
o once for a fixed planned 4 cycles in all patients 
o once for all cycles up to progression in all patients 
- 
Following a preliminary analysis of top-line data in 51 randomised patients from Part 
I, the dose intensity was lower than expected and the decision was made not to proceed 
to Part II . Consequently, the same analyses as those performed at the time of Dose 
Selection Analysis will be performed for the primary analysis. Nevertheless, analyses 
for all patients for a fixed planned 2 cycles will be repeated in patients with at least one 
co-morbidity at baseline and in patients with no co-morbidity at baseline. 
4.5.3 Relative Doses Received (RDR) and Percentage Intended Doses Received (PIDR) 
Same calculations will be performed for the RDR and the PIDR. Instead of the cumulative 
doses, the number of doses will be considered. 
RDR will be defined as 
RDR = 100 * d/D, 
where  
- 
d is the number of doses actually received up to the earliest of progression (or 
censoring event) or last dose, 
- 
D is the number of doses that should have been received if there were no interruptions 
or delays in treatment, up to the earliest of progression (or censoring event) or last 
dose. 
PIDR will be defined as 
PIDR = 100 * d/D, 
where  
- 
d is the number of doses actually received up to progression (or censoring event), 
- 
D is the number of doses that should have been received if there were no interruptions 
or delays in treatment, up to progression (or censoring event). 


 
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Notes: 
- 
If a patient records an early termination visit, the early termination date is used as the 
end date of that last visit interval. 
- 
For Dose selection analysis, those two parameters won’t be described. 
- 
For the Primary Analysis, these analyses will be performed twice: 
o once for a fixed planned 4 cycles in all patients 
o once for all cycles up to progression 
- 
Following the decision not to proceed to Part II, the same analyses as those performed 
at the time of Dose Selection Analysis will be performed for the primary analysis; that 
means that RDR and PIDR will only be listed. 
4.5.4 Treatment Delays 
Deviations from treatment visit intervals (Treatment delay) will also be described:  
- 
The number of cycles delayed will be presented by cycle number and overall at Day 1 
of each cycle. 
- 
The number of patients with one or more treatment delays in each cycle will be 
summarized 
A treatment delay is defined as a delay > 3 days from the target interval of 28 days. 
The delay will be categorized as (3-7 days], (7-14 days], (14-21 days], > 21 days.  
According to Table 4 (see Section 3.2.4.3 Guidance for Dose Omissions), the following rules 
will be applied for the description of treatment delay: 
- 
Day 1 missed dose (If day 1 is missed but day 8 is given then the day 8 dose is 
considered to be the day 1 dose for the  new cycle):  a treatment delay will be calculated 
since a cycle is planned to last 28 days 
- 
Day 15 missed dose (If day 15 is missed then this is considered the week off and the 
next dose becomes day 1 of a new cycle and the previous cycle is abbreviated to 3 
weeks):  no treatment delay. 
Note: 
- 
For Cycle 1 Day1, as stated in the protocol, the visit has to be performed within 28 days 
after screening visit.  
4.6 Prior and Concomitant Medication 
Incidence of concomitant medication will be presented by treatment groups, WHO DD 
anatomical, therapeutic and chemical class (Anatomical Therapeutic Classification (ATC) 


 
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levels 1,2 and 4) and preferred drug name for the primary analysis in patients from the safety 
analysis set. 
Number of events/medications will be presented too. 
Prior medication will be listed only. 
Prior medications are those that started and stopped before exposure to study medication; 
concomitant medications are all medications taken during the study period, including those 
started before but on going at first dose. 
Where a medication start date is partially or fully missing, and it is unclear as to whether the 
medication is prior or concomitant, it will be assumed that it is concomitant.  
Prior and concomitant medications will also be listed for dose selection analysis as well as 
primary analysis. 
Note: 
Medications are coded using World Health Organization Drug dictionary. 
4.7 Concomitant Procedures/ Surgeries/ Therapies 
Concomitant Procedures/ Surgeries/ Therapies will be listed by treatment groups at the time of 
the primary analysis. The following criteria will be listed: 
- 
Procedure, surgery or therapy date 
- 
Procedure, surgery or therapy description 
- 
Indication (Medical History/ AE/ Other) 
- 
If indication is an AE, AE selected 
- 
If indication is a Medical History, Medical History selected 
- 
If indication is other, specify 
- 
Study drug suspended for this procedure? (Yes/ No) 
 
 


 
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4.8 Efficacy / Primary and Secondary Analysis 
All efficacy analyses will be performed in patients from either the EFR (for response 
assessments) or the FAS. 
4.8.1 Primary Endpoint 
The primary efficacy endpoint of this study is the ORR at the selected dose level (500 mg/m2 
or 750 mg/m2) per RECIST criteria and assessed by a BICR. 
ORR is defined as the proportion of patients achieving a confirmed response: CR or PR. 
4.8.1.1 Normality Assumption Checking 
Not applicable 
4.8.1.2 Closed Testing Procedure for Primary Analysis 
The primary analysis will be performed when all 44 patients at the selected dose have 
completed at least 16 weeks of treatment. A further efficacy update analysis may be performed 
at a later timepoint to provide more mature efficacy data. As the primary endpoint is ORR, and 
4 confirmed responses are required to declare that the study has met its primary endpoint, no 
adjustment for multiplicity is planned to account for the primary and update analyses, because 
once 4 responses have been achieved, the threshold will have been met and further analyses 
will not inflate the false positive risk. 
Following a preliminary analysis of top-line data in 51 randomised patients from Part I, the 
dose intensity was lower than expected and the decision was made not to proceed with Part II  
Consequently, the primary analysis described above as well as the efficacy update analysis will 
not be performed. 
4.8.2 Method of Analysis for Primary Outcome 
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: CR, PR, SD, PD, Not Evaluable (NE). 
Patients’ response will also be classified as "unknown" if insufficient data were collected to 
allow evaluation per these criteria. 
According to RECIST v1.1, the following table provides a summary of the overall response 
status calculation at each time point for patients who have measurable disease at baseline: 


 
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Table 6: Integration of target, non-target and new lesions into response assessment 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Response for this Category Also 
Requires 
Patients with target lesions ± non-target lesions 
CR 
CR 
No 
CR 
Normalization of tumor markers 
All tumor nodes <10 mm 
Documented on 2 successive or more 
post-baseline scans with at least 
4 weeks interval 
CR 
Non-CR/Non-PD 
No 
PR 
Documented on 2 successive or more 
post-baseline scans with at least 
4 weeks interval 
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. 
The overall response will be determined for all protocol specified assessments, ie scheduled 
assessments (with or without missing information) and also for all unscheduled assessments 
with non-missing information. 
If a scheduled assessment is completely missing (target, non-target, new lesion), the overall 
response will be NE. 
The BOR according to RECIST v1.1 is defined as the best response recorded from the initiation 
of treatment until disease progression. 
When SD is believed to be the BOR, it needs to be assessed a minimum of 6 weeks after 
randomization (Part I) or start of treatment (Part II). Otherwise, the BOR will be NE, unless 
any PD was further documented, in which case BOR will be PD. 
If a patient progressed before this first assessment, he will be considered as ‘early progressive’. 
If this event occurs, the overall response of the patient will be presumed as progression. 


 
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Confirmation of CR and PR (assessed a minimum of 4 weeks after the first assessment of CR 
or PR) is needed to deem either one the BOR. 
Complete response [CR] and partial response [PR] would be confirmed 4 weeks later at a 
subsequent time point.  
Table 7: BOR when confirmation of CR and PR required 
Response: 
First Time 
Point 
Subsequent 
Time Point 
BOR 
Also Requires 
CR 
CR 
CR 
Normalization of tumor 
markers. All tumor 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 should result in the subsequent assessment being classified 
as a PD rather than a PR. The BOR would then be SD provided the initial CR were observed 
at least 6 weeks after start of treatment, or PD otherwise. 
Patients for whom response is not confirmed will be classified as "NE", unless they meet the 
criteria for stable disease (or the criteria for partial response in case of an unconfirmed complete 
response).  
ORR is defined as the number of patients achieving a confirmed CR or PR as the BOR. 
Number and percentage of patients achieving a response according to BICR will be presented 
along with its two-sided 80% and 95% Clopper-Pearson and Mid-p CI.  
In addition, two sensitivity analyses will be performed for ORR: 
- 
A sensitivity analysis will be performed using investigator-recorded assessment of 
response instead of BICR (based on the subset of the FAS deemed to have measurable 
disease by the investigators) 


 
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- 
A sensitivity analysis of ORR based on BICR using the PPS, to investigate the impact 
of major deviations on the primary endpoint. 
These analyses will be performed in patients from the Evaluable For Response Set and Per 
Protocol Set at the time of Primary Analysis.  
ORR based on BICR may also be updated at the time of the efficacy update analysis (if 
performed). 
Following the decision not to proceed to Part II, the analysis of ORR mentioned above will not 
be performed. However, descriptive statistics of responder/non responder patients will be 
provided in the same table as BOR. 
4.8.3 Secondary Endpoints 
The secondary endpoints of this study are: 
• BOR according to RECIST v1.1 assessment. 
• DCR.  
• PFS.  
• OS.  
• DOR.  
• TTP.  
• TTR.  
• Change from baseline in tumor size.  
• Best GCIG Overall Response, combining the change CA125 from baseline with 
RECIST assessment (per GCIG criteria).  
• Relative Change of CA125. 
• Time on treatment. 
• FOSI-18 questionnaire. 
4.8.4 Methods of Analysis for Secondary Outcomes 
All tables by weeks or listings based on BICR will apply the following rules: 
- 
Cycle 2 will correspond to week 8 
- 
Cycle 4 will correspond to week 16 
- 
Cycle 6 will correspond to week 24 
- 
Cycle 8 will correspond to week 32 
- 
Cycle 10 will correspond to week 40 
- 
Cycle 12 will correspond to week 48 
- 
Unscheduled assessments will be considered as unscheduled 


 
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- 
Follow-up assessments will be considered as Follow-up 
 
In addition, all tables by weeks or listings based on investigator recorded assessment will apply 
the following rules: 
- 
A scan will be considered as week 8 scan if the tumor assessment date is in the 
windows of Cycle 1 Day 1 date + 49 days and Cycle 1 Day 1 date + 63 days. 
- 
A scan will be considered as week 16 scan if the tumor assessment date is in the 
windows of Cycle 1 Day 1 date + 105 days and Cycle 1 Day 1 date + 119 days. 
- 
A scan will be considered as week 24 scan if the tumor assessment date is in the 
windows of Cycle 1 Day 1 date + 161 days and Cycle 1 Day 1 date + 175 days. 
- 
A scan will be considered as week 32 scan if the tumor assessment date is in the 
windows of Cycle 1 Day 1 date + 217 days and Cycle 1 Day 1 date + 231 days. 
- 
A scan will be considered as week 40 scan if the tumor assessment date is in the 
windows of Cycle 1 Day 1 date + 273 days and Cycle 1 Day 1 date + 287 days. 
- 
A scan will be considered as week 48 scan if the tumor assessment date is in the 
windows of Cycle 1 Day 1 date + 329 days and Cycle 1 Day 1 date + 343 days. 
4.8.4.1 BOR according to RECIST v1.1 Assessment 
The BOR will be assessed by providing number and percentage of patients achieving each 
individual best response criteria (CR, PR, SD, PD, or NE). 
The BOR will be assessed for both BICR and Investigator assessed responses. 
This analysis will be performed in patients from the Evaluable For Response Set at the time of 
dose selection analysis and primary analysis. 
Following the decision not to proceed to Part II, the BOR primary analysis will be performed 
in the same way as the dose selection analysis without confirmation rule of CR and PR 
responses. 
Moreover, same BOR analyses will be performed in the following subgroups: 
- 
Co-morbidities at baseline (Yes/No) 
- 
Prior gemcitabine intake (Yes/No) 
- 
Time on prior gemcitabine in months (≤ 1/ >1-3/ >3-6/ >6-12/ >12) 
- 
Time to progression from end of last prior platinum-based chemotherapy in months (≤ 
1/ >1-3/ >3-6/ >6) 
- 
BRCA mutation status (Yes/No) 
- 
Time to progression from start of last prior therapy (≤ 1/ >1-3/ >3-6/ >6) 
4.8.4.2 DCR 
DCR is defined as the proportion of patients achieving as BOR a confirmed response (CR or 
PR) or SD whose SD duration from baseline lasts at least of 6 weeks based on BICR. 


 
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Summary statistics showing the number and percentage of patients with disease control will be 
presented. The presentation will show the overall disease control figures, along with the 
category of disease control achieved (CR, PR, SD ≥ 6 weeks (-5 days), SD < 6 weeks (-5 days).  
DCR will be evaluated in patients from the Evaluable For Response Set at the time of primary 
analysis. 
Same analysis with DCR based on Investigator-Recorded Assessment will also be provided. 
Following the decision not to proceed to Part II, this endpoint will not be described but only 
listed. 
4.8.4.3 PFS 
PFS is defined as the time from the date of study treatment initiation (start of treatment) or 
randomization (if randomized) to the first date of objectively determined PD or death from any 
cause (in the absence of progression) based on BICR.  
Event dates are assigned to:  
 The first time when confirmed progressive disease was noted, or  
 Date of death.  
In case of progressive disease followed by death, the first event will be considered in the 
analysis. 
The progressive disease date is assigned to the first time at which progressive disease can be 
declared. 
For patients who are still alive at the time of the data cut-off date and without evidence of tumor 
progression, PFS will be censored at the date of the most recent objective progression-free 
observation (last tumor assessment date).  
For patients who receive subsequent anticancer therapy prior to objective disease progression 
or death, PFS will be censored at the date of the last objective progression-free observation 
(last tumor assessment date) prior to the date of subsequent therapy. 
For patients without any scan and without death, PFS will be censored at the day after the first 
treatment intake date. 
When tumor assessment visits are completely missing, FDA Guidance “Clinical Trial 
Endpoints for the Approval of Cancer Drugs and Biologics” [4] states that "events occurring 
after two or more missed radiological assessments will be censored in the analysis at the last 
adequate assessment’.  
This will be implemented as follows: 
PD occurring after two or more missed radiological assessments will be censored in the 
analysis at the last adequate assessment before the missing assessments. 
If a patient has one missed radiological assessment before a PD, the PD event will be analyzed 
as an event. 
The PFS time will be calculated as the time from first administration of NUC-1031 (for Part II 
patients) or randomization (for Part I patients) to either progressive disease or death as follows: 


 
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PFS (months) = [(Date of event – date of randomization/ first administration) + 1]/30.4375 
The number of overall censored patients, number of patients with events and Kaplan-Meier 
estimates median time will be provided with 25th percentile and 75th percentile. In addition, the 
results will be presented graphically in Kaplan-Meier plots including count for numbers of 
patients at risk. 
Moreover, same PFS analyses will be performed in the following subgroups: 
- 
Co-morbidities at baseline (Yes/No) 
- 
Prior gemcitabine intake (Yes/No) 
- 
Time on prior gemcitabine in months (≤ 1/ >1-3/ >3-6/ >6-12/ >12) 
- 
Time to progression from end of last prior platinum-based chemotherapy in months (≤ 
1/ >1-3/ >3-6/ >6) 
- 
BRCA mutation status (Yes/No) 
- 
Time to progression from start of last prior therapy (≤ 1/ >1-3/ >3-6/ >6) 
In addition, analysis of PFS with a cut-off date at 6 months using the KM method (PFS6KM) 
will also be carried out on all patients in the analysis population, but only considering data 
between first treatment intake date and first treatment intake date + 183 days (6 months). 
For the analysis of PFS6KM, the following censoring rules will be applied: 
- 
If the patient doesn’t miss any visit and has not died before 6 months or has not 
documented progression before 6 months, he will be censored at the 6 months date. 
- 
If the patient misses a visit and has not died before 6 months or has not documented 
progression before 6 months, he will be censored at the last non-missing tumor 
assessment date. 
- 
For patients who receive subsequent anticancer therapy prior to objective disease 
progression or death in the 6 month period, PFS will be censored at the date of the last 
objective progression-free observation (last tumor assessment date) prior to the date of 
subsequent therapy. 
- 
For patients without any scan and without death in the 6 month period, PFS will be 
censored at the day after the first treatment intake date.  
These analyses will be produced in patients from the FAS at the time of the primary analysis. 
Moreover, number and percentage of patients with PFS at 4 months as binary data (Yes/ No/ 
Missing, where “Yes” corresponds to not progressing) will be presented in patients from the 
FAS, EFR at the time of the primary analysis. The same analysis will be performed for PFS at 
6 months only in patients randomized/included prior to the last 6 months of the trial. 
For PFS4 and PFS6 considered as binary variables, the following rules will be applied: 
- 
If the patient receives any other anti-cancer treatment prior to 4/6 months then he will 
be counted as a "No" (i.e., counted as being a progressing). 


 
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- 
If the patient is missing his last scheduled tumor assessment (and he has not died before 
4/6 months, nor has documented progression before 4/6 months) then he will be counted 
as "missing". 
- 
For patients not randomized in the last 6 months of the trial, PFS6 will be displayed as 
Not Applicable (NA) in the listing. 
Due to the decision not to proceed to Part II, only classic PFS with Kaplan-Meier based on 
BICR will be performed. However, KM plots of PFS will. not be displayed. 
Analysis based on Investigator Recorded assessment will not be produced. Only listings will 
be produced for Investigator Recorded assessments as well as for PFS4, PFS6 and PF6KM 
endpoints. 
Note: 
 PFS will be calculated with one decimal. 
 Methodology of Kaplan-Meier estimator
∧
t
S  
The survival function is defined as 
[
]
0
),
(
1
≥
−
=
>
=
t
t
F
t
T
P
St
 
Assume 2 timepoints 
it  and 
1
+
it
 (
1
+
it
>
it ) then, 
S(ti+1)=P[T>ti+1]=P[T> ti+1 and T>ti] 
 
With conditional probability theorem we obtain: 
[
]
[
]
[
]
i
i
i
i
t
T
P
T
T
T
T
P
t
T
P
>
×
>
>
=
>
+
+
/
1
1
 
With:  
 
[
]
i
i
T
T
T
T
P
>
>
+ /
1
 can be estimated by 
1
1
1
+
+
−
i
i
t
t
n
d
 where 
1
+
itd
is the number of patients 
with the events at ti+1 and 
1
+
itn
is the number of patients at risk at ti+1. 
 
[
]
)
( i
i
t
S
t
T
P
=
>
 by definition 
Thus we obtain 
)
(
1
)
(
1
1
1
i
t
t
i
t
S
n
d
t
S
i
i


×






−
=
+
+
+
 
Knowing that 
1
0 =
∧
S
, we obtain the Kaplan-Meier estimator ( )
∧
t
S
: 


 
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∏
≤
∧





−
=
t
t
i
i
i
KM
i
n
d
t
S
/
1
)
(
 
4.8.4.4 OS 
OS is defined as the time from first administration of NUC-1031 or randomization (if 
randomized) until death from any cause. All deaths will be included, whether they occur during 
the study or following treatment discontinuation.  
For patients who have not died, overall survival will be censored at the date of last contact (date 
the patient was last known to be alive).  
OS time (in months) = [(date of death/ date patient last known to be alive - date of 
randomization/ first administration) + 1]/30.4375. 
The OS will be analysed as described for PFS. 
The number of overall censored patients, number of patients with events and Kaplan-Meier 
estimates median time will be provided with 25th percentile, 75th percentile. In addition, the 
results will be presented graphically in Kaplan-Meier plots. 
OS analysis will be produced in patients from the FAS at the time of the primary analysis. 
Moreover, same PFS analyses will be performed in the following subgroups: 
- 
Co-morbidities at baseline (Yes/No) 
- 
Prior gemcitabine intake (Yes/No) 
- 
Time on prior gemcitabine in months (≤ 1/ >1-3/ >3-6/ >6-12/ >12) 
- 
Time to progression from end of last prior platinum-based chemotherapy in months (≤ 
1/ >1-3/ >3-6/ >6) 
- 
BRCA mutation status (Yes/No) 
- 
Time to progression from start of last prior therapy (≤ 1/ >1-3/ >3-6/ >6) 
Due to the decision not to proceed to Part II, KM plots will not be displayed. 
4.8.4.5 DOR 
DOR will be evaluated for the subset of patients categorized as responders for the assessment 
of ORR (Section 4.8.1).  
DOR is defined as the period from the date of initial confirmed PR or CR (whichever occurs 
first) until the date of PD or death from any cause (whichever occurs first). 
Only responses that were later confirmed, will be considered when calculating the DOR. 
DOR will be calculated as follows: 
DOR (months) = ((Date of PD or death – Date of first confirmed PR or CR) + 1) /30.4375 


 
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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 duration of response will be 
censored at the date of last tumor assessment. 
For patients who receive subsequent anticancer therapy prior to objective disease progression, 
DOR will be censored at the date of the last tumor assessment date prior to the date of 
subsequent therapy. 
Only patients with BOR of CR or PR (i.e., responders) will be included in the analysis of DOR. 
The analysis and presentation of DOR will be described as for PFS, at the time of the primary 
analysis and will be based on the subset of the Evaluable For Response Set categorized as 
responders for ORR based on BICR. 
The number of overall censored patients, number of patients with events and Kaplan-Meier 
estimates median time will be provided with 25th percentile and 75th percentile. In addition, the 
results will be presented graphically in Kaplan-Meier plots. 
Same analysis with DOR based on Investigator-Recorded Assessment will also be provided. 
Due to the decision not to proceed to Part II, DOR will only be listed. 
4.8.4.6 TTP 
TTP is measured with the Duration of Stable Disease (DSD), from the randomization date (Part 
I patients) or start of the treatment (Part II patients) until the criteria for progression are first 
met, taking as reference the smallest measurements recorded since the treatment started, 
including the baseline measurements.  
TTP (months) = ((Date of progression of disease – Randomization date/ Time from first dose) 
+ 1) /30.4375 
For patients who were lost to follow-up without progression or reached the time point of 
analysis without a known record of progression, the time to progression will be censored at the 
date of last tumor assessment.  
For patients who died without documented progression, the time to progression will be 
censored at the date of last tumor assessment. 
For patients who receive subsequent anticancer therapy prior to objective disease progression, 
TTP will be censored at the date of the last tumor assessment date prior to the date of 
subsequent therapy 
The analysis and presentation of TTP will be as described for PFS in patients from the EFR 
and PPS at the time of primary analysis. 
The number of overall censored patients, number of patients with events and Kaplan-Meier 
estimates median time will be provided with 25th percentile and 75th percentile. The results will 
also be presented graphically in Kaplan-Meier plots. 
Due to the decision not to proceed to Part II, TTP will only be listed. 


 
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4.8.4.7 TTR 
TTR will be evaluated for the subset of patients categorized as responders for the assessment 
of ORR (Section 4.8.1).  
TTR is measured from the randomization date (Part I patients) or start of the treatment (Part II 
patients) until the first documentation of confirmed PR or CR (whichever occurs first).  
TTR (months) = ((Date of first confirmed response - time from randomization/ first dose) + 1) 
/30.4375 
The analysis and presentation of TTR will be described as for PFS in responder patients from 
the Evaluable for Response Set at the time of the primary analysis. 
Kaplan-Meier estimates median time to response, 25th and 75th percentiles and the range (min-
max) will be provided with 25th percentile and 75th percentile. The results will also be presented 
graphically in Kaplan-Meier plots. 
Due to sponsor decision after dose selection analysis to stop the study, DOR will only be listed. 
4.8.4.8 Percentage Change from Baseline in Tumor Size 
Percentage changes from baseline to each visit of the Sum of Lesion Diameters (SLD) (mm) 
as well as best percentage change will be summarized by dose group in patients from the 
Evaluable for Response Set at the time of the dose selection analysis as well as the primary 
analysis. 
In addition, the following waterfall plots of percentage change from baseline of SLD will be 
presented: 
- 
Percentage change from baseline to week 8, 
- 
Percentage change from baseline to week 16 
- 
Best percentage change from baseline 
4.8.4.9 Best GCIG Overall Response, combining the Change CA125 from 
Baseline with RECIST Assessment (per GCIG criteria) 
 
The GCIG recommends that for trials of relapsed ovarian cancer the following definition for 
response according to CA125 be used in addition to the standard RECIST response criteria. 
Definition of response according to CA125.  
A response according to CA125 has occurred if there is at least a 50% reduction in CA125 
levels from a pretreatment sample. The response must be confirmed and maintained for at least 
28 days. Patients can be evaluated according to CA125 only if they have a pretreatment sample 
that is at least twice the Upper Limit of Normal (ULN) and within 2 weeks prior to starting 
treatment. 
To calculate CA125 responses accurately, the following rules apply: 


 
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- 
intervening samples and the 28-day confirmatory sample must be less than or equal to 
(within an assay variability of 10%) the previous sample. 
- 
variations within the normal range of CA125 levels will not interfere with the response 
definition. 
- 
For each patient, the same assay method must be used and the assay must be tested in 
a quality-control scheme. 
- 
Patients are not evaluable by CA125 if they have received mouse antibodies (unless the 
assay used has been shown not to be influenced by Human Anti-Mouse Antibody 
(HAMA)) or if there has been medical and/or surgical interference with their 
peritoneum or pleura during the previous 28 days. If assessing therapy that includes two 
treatment modalities for relapse (e.g., surgery and chemotherapy), any CA125 response 
results from both treatments modalities. CA125 cannot distinguish between the effects 
of the two treatments. 
 
The date when the CA125 level is first reduced by 50% is the date of the CA125 response.  
In addition, those patients who have both a CA125 response and whose CA125 level falls to 
within the normal range, can be classified as CA125 complete responders. Patients who have 
a fall of CA125 to within the normal range but whose initial CA125 was less than twice the 
upper limit of normal, have not had a CA125 response and cannot therefore be classified as a 
CA125 complete responder. 
Definition of Progression on first line therapy and Recurrence after first line therapy 
according to CA125. 
Progression is defined according to RECIST but can also be based upon serum CA125 (defined 
below) but tumor measurements should take precedence over CA125.  
If measurable disease is shrinking during treatment, but the CA125 indicates progression (as 
defined below) the patient should continue to receive protocol treatment. If measurable disease 
shows stable disease but CA125 indicates progression after a minimum of 3 courses of 
chemotherapy, protocol treatment should be changed.  
If the GCIG definition based on CA125 is used to define progression after relapse therapy it 
should be noted that it has not been validated. 
Evaluation of progression according to CA125 
Progression or Recurrence based on serum CA125 levels will be defined on the basis of a 
progressive serial elevation of serum CA125, according to the following criteria and table 8: 
A) Patients with elevated CA-125 pretreatment and normalization of CA125 must show 
evidence of CA125 greater than, or equal to, two times the upper limit of the reference 
range on two occasions at least one week apart  
or 


 
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B) Patients with elevated CA125 before treatment, which never normalizes must show 
evidence of CA125 greater than, or equal to, two times the nadir value on two occasions 
at least one week apart  
or 
C) Patients with CA125 in the reference range before treatment must show evidence of 
CA125 greater than, or equal to, two times the upper limit of the reference range on two 
occasions at least one week apart. 
Elevated values must be confirmed by two separate measurements obtained at least one week 
apart. CA125 Progression will be assigned the date of the first measurement that meets the 
criteria as noted. Patients are not evaluable by CA125 if they have received mouse antibodies 
(unless the assay used has been shown not to be influenced by HAMA) or if there has been 
medical and/or surgical interference with their peritoneum or pleura (eg, paracentesis) during 
the previous 28 days. 
A patient may be declared to have progressive disease on the basis of either the objective 
RECIST 1.1 criteria or the CA125 criteria. The date of progression will be the date of the 
earlier of the two events if both are documented. 


 
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Table 8: Definition of progression after first-line therapy in ovarian cancer as proposed 
by GCIG 
GCIG 
subcategorized 
group 
RECIST 
Measurable/ Non-measurable 
disease 
 
CA125 
A 
Compared to baseline (or lowest 
sum while on study if less than 
baseline), a 20% increase in sum of 
longest 
diameters 
(RECIST 
definition) 
Or 
Any new lesions (measurable or 
non-measurable) 
Or 
Unequivocal increase in non target 
disease 
 
PD date: date of documentation of 
increase or new lesions 
 
 
AND 
 
 
 
 
 
/ 
 
 
 
CA125 ≥ 2 x Upper Limit 
of Response Range 
(ULRR) documented on 
two occasions # 
 
 
 
 
 
 
 
PD date: first date of the 
CA125 elevation to ≥ 2 x 
ULRR 
B 
As for A 
OR 
CA 125 ≥ 2 x nadir value 
on 2 occasions # 
C 
As for A 
 
As for A 
GCIG groups A, B & C defined above 
# Repeat CA125 any time, but normally not less than 1 week after the first elevated CA125 
level. 
CA125 levels sampled after patients received mouse antibodies (unless the assay used has 
been shown not to be influenced by HAMA) or if there has been medical and /or surgical 
interference with their peritoneum or pleura during the previous 28 days, should not be taken 
into account. 
Evaluation of BOR in patients with initial measurable disease and who are also evaluable 
by CA125 
A report that combines both CA125 and RECIST criteria, is likely to include patients that are 
measurable by one or both of the criteria, who may have events at different time points. In 
patients that are measurable by both criteria the date of response will be the earlier date of the 
two events.  
The following rules apply when determining the BOR: 
- 
If patients have PD according to RECIST within 28 days of CA125 response they are 
classified as PD.  
- 
If the PD according to RECIST is > 28 days after the CA125 response they are classified 
as PR. 
- 
Patients whose best response according to RECIST is SD but who have a CA125 
response are classified as CA125 responders. 


 
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The following table presents the BOR combining RECIST and CA125. 
Table 9: BOR in patients with initial measurable disease and who are also evaluable by 
CA125, combining both criteria 
Target 
Lesions ~ 
Non-Target 
Lesions # 
New 
Lesions 
CA125 
BOR 
Best RECIST 
response for this 
category also 
requires it to be 
confirmed and 
maintained for at 
least 28 days 
CR 
CR 
No 
Normal 
CR 
CR 
Non-CR/Non-
PD 
No 
Not PD 
PR 
CR 
CR 
No 
PR not 
normal 
PR 
CR 
NE 
No 
PR 
PR 
PR 
Non-PD or Not 
All Evaluated 
No 
Not PD 
PR 
Not All 
Evaluated 
Non-PD 
No 
PR 
PR 
(PD or New) > 28 days from CA125 PR * 
PR 
PR 
SD 
Non-PD 
No 
PR 
PR 
SD 
Non-PD or Not 
All Evaluated 
No 
Not PR and 
not PD 
SD 
(PD or New) ≤ 28 days from CA125 PR * 
PR 
PD 
PD 
Any 
Yes or No 
Any 
PD 
NE or 
Any 
PD 
Yes or No 
Any 
PD 
NE or 
Any 
Any 
Yes 
Any 
PD 
NE or 
Any 
Any 
Yes or No 
PD 
PD 
Notes: 
~ target lesions include up to 5 measurable lesions (2 per organ) as defined by RECIST 1.1 
# non-target lesions include ascites and peritoneal thickening which are not measurable 
according to RECIST 1.1 
* patients who have a CA125 response that occurs more than 28 days from PD according 
to RECIST 1.1 are considered as PR according to best response, but PD if the RECIST 1.1 
PD is within 28 days of CA125 response 


 
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Best GCIG Overall Response, combining the change CA125 from baseline with RECIST 
assessment (per GCIG criteria) will be summarized in patients from the GCIG Analysis Set at 
the time of primary. 
It will also be presented in a data listing for the dose selection analysis and primary analysis. 
Due to the decision not to proceed to Part II, Best GCIG Overall Response will not be 
summarized and will only be listed. 
4.8.4.10 Percentage Change of CA125 
Percentage changes from baseline to each visit of CA125 value (U/mL) will be summarized in 
patients from the GCIG Analysis Set at the time of the dose selection analysis as well as the 
primary analysis. 
In addition, waterfall plots of relative change of CA125 value in patients with measurable 
CA125 value at baseline will be presented at each visit and for the best percentage change from 
baseline. Percentage changes from baseline to Cycle 3 Day 1 and to Cycle 5 Day 1 will be of 
special interest in order to be able to compare the results with percentage changes of tumor size 
(SLD) from baseline to Week 8 and to Week 16. 
4.8.4.11 Time on Treatment 
A Swimmer plot of time on Treatment by Response Category will be presented at the time of 
the primary analysis for the 2 following evaluations: 
- 
BOR according to RECIST v1.1 based on BICR in patients from the Evaluable for 
Response Set 
- 
Best GCIG Overall Response combining the change CA125 from baseline with 
RECIST assessment (per GCIG criteria) in patients from the GCIG Analysis Set 
Time on treatment will be calculated as the date of last administration - date of first 
administration + 1 day throughout study. 
Due to sponsor decision after dose selection analysis to stop the study, these figures won’t be 
displayed. 
4.8.4.12 FOSI-18 Questionnaire 
The FOSI-18 questionnaire will be filled by the patient at screening visit, days 1 of each cycle, 
end of treatment visit and follow-up visits (every 8 weeks). 
The following endpoints will be evaluated: 
- 
Lack of energy (coded as GP1) 
- 
Pain (coded as GP4) 
- 
Ill (coded as GP6) 
- 
Cramps in stomach area (coded as O3) 


 
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- 
Fatigue (coded as HI7) 
- 
Bothered by constipation (coded as Cx6) 
- 
Swelling in stomach area (coded as O1) 
- 
Control of bowels (coded as C3) 
- 
Sleeping well (coded as GF5) 
- 
Worries about conditions (coded as GE6) 
- 
Nausea (coded as GP2) 
- 
Bothered by hair loss (coded as B5) 
- 
Bothered by side effects of treatment (coded as GP5) 
- 
Vomiting (coded as O2) 
- 
Bothered by skin problems (coded as BMT15) 
- 
Ability to get around by herself (coded as BMT5) 
- 
Ability to enjoy life (coded as GF3) 
- 
Content with the quality of life right now (coded as GF7) 
The possible evaluations are Not at all, A little bit, Somewhat, Quite a bit, Very much. 
Number and percentage of patients with each response category at each visit will be 
summarized from the Full Analysis Set at the time of primary analysis. 
In addition, 5 scores can be developed based on the FOSI-18 item questionnaire: one scale on 
the overall questionnaire named FOSI-18 Total (score range: 0-72) and 4 subscales named: 
- 
FOSI-Disease Related Symptoms-Physical (FOSI-DRS-P) (score range: 0-36) 
composed of 
o GP1 
o GP4 
o GP6 
o O3 
o HI7 
o Cx6 
o O1 
o C3 
o GF5 
- 
FOSI-Disease Related Symptoms-Emotional (FOSI-DRS-E) (score range: 0-4) 
corresponding to GE6 item, 


 
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- 
FOSI-Treatment Side Effects (FOSI-TSE) (score range: 0-20) composed of 
o GP2 
o B5 
o GP5 
o O2 
o BMT15 
- 
FOSI-Function/Well Being (FOSI-F/WB) (score range: 0-12) composed of  
o BMT5 
o GF3 
o GF7. 
For the calculation of the scores, responses to items GP1, GP4, GP6, O3, HI7, Cx6, O1, GE6, 
GP2, B5, GP5, O2, BMT15 are coded as follows: 
- 
Not at all = 4 
- 
A little bit = 3 
- 
Somewhat = 2 
- 
Quite a bit = 1 
- 
Very much = 0 
Conversely, responses to items C3, GF5, BMT5, GF3, and GF7 are coded as follows: 
- 
Not at all = 0 
- 
A little bit = 1 
- 
Somewhat = 2 
- 
Quite a bit = 3 
- 
Very much = 4 
 
The following formulas describe the calculation of each score: 
- 
FOSI-18 Total Score 
FOSI-18 Total Score = 18 * (Sum of all individual item scores) / (Number of items answered) 
- 
FOSI-DRS-P Score 
FOSI-DRS-P Score = 9 * (Sum of individual item scores) / (Number of items answered) 
- 
FOSI-DRS-E Score 
FOSI-DRS-E Score = GE6 Score 
- 
FOSI-TSE Score 


 
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FOSI-TSE Score = 5 * (Sum of individual item scores) / (Number of items answered) 
- 
FOSI-F/WB Score 
FOSI-F/WB Score = 3 * (Sum of individual item scores) / (Number of items answered) 
 
Thus, a high score is good. Therefore, a score of “0” is a severely symptomatic patient and the 
highest possible score is an asymptomatic patient. 
Each Score will be described at each visit in patients and graphically represented in patients 
from the Full Analysis Set at the time of primary analysis. 
In addition, changes from baseline to each visit of each score will be provided in patients from 
the Full Analysis Set at the time of primary analysis. 
FOSI-18 questionnaire will be listed too. 
Due to the decision not to proceed to Part II, FOSI-18 questionnaire will not be described, nor 
listed. 
4.9 Exploratory Endpoints 
4.9.1 EQ-5D-5L Questionnaire 
The EQ-5D-5L questionnaire will be filled by the patient at screening visit, days 1 of each 
cycle, end of treatment visit and follow-up visits (every 8 weeks). 
The following endpoints will be evaluated: 
- Dimensions  
o Mobility (No problems/ Slight problems/ Moderate problems/ Severe problems/ 
Unable) 
o Self-Care (No problems/ Slight problems/ Moderate problems/ Severe 
problems/ Unable) 
o Usual Activities (No problems/ Slight problems/ Moderate problems/ Severe 
problems/ Unable) 
o Pain/ Discomfort (No problems/ Slight problems/ Moderate problems/ Severe 
problems/ Unable) 
o Anxiety/ Depression (No problems/ Slight problems/ Moderate problems/ 
Severe problems/ Unable) 
- Visual Analogue Scale (VAS) 
Notes: 
• There should be only one response for each dimension  


 
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• For dimensions, ambiguous values (e.g, several boxes are ticked for a single dimension) 
should be treated as missing values 
The following analyses will be performed in patients from the Full Analysis Set at the time of 
primary analysis. 
EQ-5D-5L endpoints will also be presented in a data listing. 
4.9.1.1 Analysis of Dimensions (Health profiles) 
The number and percentage of patients in each level of each dimension will be provided at each 
visit by treatment group in patients from the Full Analysis Set.  
It will also be graphically represented using bar charts. 
4.9.1.2 EQ VAS 
VAS will be described at each visit by treatment group in patients from the Full Analysis Set. 
It will also be graphically represented using line charts. 
4.9.1.3 EQ-5D-5L Index Value 
For each patient, a 5L profile will be derived with 5 digits (one digit by dimension). For each 
dimension, the following code will be computed: 
- No problems=1 
- Slight problems=2 
- Moderate problems=3 
- Severe problems=4 
- Unable=5 
Then using the “EQ-5D-5L Crosswalk Index Value Calculator” downloaded from the EuroQol 
website, an index value for the patient will be calculated according to his country. 
Once these index values are calculated, descriptive statistics at each visit will be provided as 
well as changes from baseline.  
Mean values will also be graphically represented at each visit. 
Notes: 
• If a patient has a missing value for one dimension, her 5 L profile won’t be derived. 
• The Interim scoring for the EQ-5D-5L: Mapping the EQ-5D-5L to EQ-5D-3L value sets. 
Q-5D-5L Index Value Calculator developed by the EuroQol Group document developed 
by Van Hout B, Janssen MF, et al (EuroQol Group) has index values calculated for 
Denmark, France, Germany, Netherlands, Spain and United Kingdom. If one other 
European country is included in the study, index values for US patients will be used for all 
patients of the study. 


 
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• Due to the decision not to proceed to part II, EQ-5D-5L questionnaire will not be described 
or listed. 
4.10 Safety Analysis 
Safety data will include AE, Clinical Laboratory Evaluations (chemistry, hematology, urine 
and coagulation), Physical Examinations, Vital Signs, ECG and ECOG. 
All safety analyses will be presented by treatment group in patients from the safety analysis set 
for dose selection analysis as well as the primary analysis. 
4.10.1 Adverse Events 
All AE will be recorded and graded by investigators using the National Cancer Institute-
Common Terminology Criteria for Adverse Event (NCI-CTCAE) classification (Version 4.0) 
and will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) Version 
18.1 or higher, and will be classified by MedDRA Preferred Term and SOC. 
The Investigator is responsible for reporting all AEs that are observed or reported during the 
study, regardless of their relationship to study drug or their clinical significance. 
4.10.1.1 Definition 
For FDA regulated studies the FDA defines an adverse event as the following: 
“Adverse event means any untoward medical occurrence associated with the use of a drug in 
humans whether or not considered drug related.” 
An AE is defined as any untoward medical occurrence in a patient enrolled into this study 
regardless of its causal relationship to study drug. Patients or their legally authorized 
representatives will be instructed to contact the Investigator or Sub-Investigator at any time 
after signing the ICF if any symptoms develop. 
A Treatment Emergent Adverse Event (TEAE) is defined as: 
- any event not present before exposure to study drug, thus occurring between first study 
drug dose intake date and last study dose drug intake date + 30 days 
- or any event already present that worsens in either intensity or frequency after exposure 
to study drug; thus worsening between first study drug dose intake date and last study 
dose drug intake date + 30 days 
AE are classified as serious or non-serious. A SAE is defined as any event that: 
• Results in death, 
• Is immediately life-threatening, 
• Requires inpatient hospitalization or prolongation of existing hospitalization, 
• Results in persistent or significant disability/incapacity, 
• Is a congenital anomaly/birth defect, 


 
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• Significant medical event in the investigator's judgment (e.g., may jeopardize the patient 
or may require medical/surgical intervention to prevent one of the outcomes listed above) 
PD and disease-related death will not be considered as an AE or SAE. 
Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical judgment, 
they may jeopardize the patient and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias, convulsions that do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse. 
4.10.1.2 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 hospitalized, 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 eCRF or other documents that are relevant to patient 
safety. Any allergic reaction to the agents administered as study drug treatment must be 
reported as an AE. 
All AEs that occur from date of consent through 30 days after the last dose of study drug must 
be reported in detail on the AE eCRF. 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 eCRF. Information to be 
collected for each AE includes onset date, type of event, etiology, 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. 
Preexisting conditions (present before the start of the AE collection period) are considered 
concurrent medical conditions and should not be recorded as AEs. However, if the patient 
experiences a worsening or complication of such a concurrent condition, the worsening or 
complication should be recorded as an AE. Pre-existing AEs that worsen should be followed 
until 30 days after the patient’s last dose or resolution to the AE level present at study entry. 
Investigators should ensure that the AE term recorded captures the change in the condition (e.g. 
“worsening of [condition]”). 
Insufficient clinical response, efficacy, or pharmacological action should NOT be recorded as 
an AE. The Investigator must make the distinction between exacerbation of preexisting illness 
and lack of therapeutic efficacy. PD is NOT an AE; however, some sequelae of PD (i.e. pain, 
neurologic impairment) may be reported as AEs (generally not related to NUC-1031). 
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 


 
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repeat testing for confirmation, or (if not associated with clinical signs or symptoms) they 
remain at levels consistent with severe abnormalities despite appropriate medical intervention. 
It is requested that when reporting AEs for which potentially redundant NCI CTCAE terms 
exist, the Investigator utilizes the more clinically-oriented terminology (for example, ‘anemia’ 
is preferable to ‘hemoglobin decreased’). 
It is also requested that in the setting of an allergic reaction or suspected allergic reaction 
considered by the Investigator to be related to NUC-1031, that the Investigator reports both the 
specific symptoms associated with the reaction (i.e. ‘urticaria’, ‘dyspnea’) and also report the 
appropriate term indicating the allergic reaction (‘allergic reaction’ or ‘anaphylaxis’ if 
appropriate [Immune System Disorders; CTCAE v4]). 
4.10.1.3 Assessment of Causality 
The Investigator’s assessment of an AE's relationship to study drug is part of the documentation 
process, but it is not a factor in determining what is or is not 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 NUC-1031 should be classified using the following guidelines: 
Related: A temporal relationship exists between the event onset and administration of NUC-
1031. It cannot be readily explained by the patient’s clinical state, intercurrent illness, or 
concomitant therapies. In case of cessation or reduction of the dose, the event abates or resolves 
and reappears upon rechallenge. This includes events that are considered possibly, probably, 
or definitely related to NUC-1031.  
Not Related: Evidence exists that the AE has an etiology other than the study drug (e.g. pre-
existing condition, underlying disease, intercurrent illness, or concomitant medication). This 
includes events that are considered probably not or not related to NUC-1031. It should be 
emphasized that ineffective study drug treatment should not be considered as causally related 
in the context of AE reporting (in other words, PD is not considered an AE; however some 
sequelae of PD may be reported as AEs and should generally be reported as AEs not related to 
NUC-1031). 
4.10.1.4 Assessment of Severity 
The severity of each AE is to be assessed by the Investigator according to NCI CTCAE, v4. If 
the AE is not included in the NCI CTCAE, then the Investigator is to determine the intensity 
of the AE according to the following criteria: 
Mild (Grade 1): 
AE that disappears or is easily tolerated on continuation of 
study drug 
Moderate (Grade 2): 
AE sufficiently discomforting to cause interference with 
usual work activities. 
Severe (Grade 3): 
AE that is incapacitating, with inability to work or perform 
daily 
Life-Threatening (Grade 4): 
AE that is potentially life-threatening* 


 
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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. 
4.10.1.5 Description of Analyses 
Missing severity, relationship or outcome will be classed as unknown. 
A patient with more than one occurrence of the same adverse event in a particular system organ 
class will be counted only once in the total of those experiencing adverse events in that 
particular system organ class.  
If a patient experiences the same adverse event at more than one severity, or with more than 
one relationship to study drug, the most severe rating or the stronger causal relationship to 
study drug will be given precedence.  
Any missing severity, causality, or outcome will not be imputed and classed as unknown. 
Summaries classifying events according to severity and relationship will be presented. 
The denominator used to calculate incidence percentages consists of patients in the Safety 
analysis set.  
AEs will be grouped by System Organ Class and Preferred Term and sorted in descending 
frequency in the overall group.   
For tables by NCI-CTCAE grade, if a patient has more than one AE the worst grade will be 
summarized.  
Hence, the following summaries will be presented by dose for the safety analysis set: 
• Summary of Adverse Events*: number of AEs, number of TEAEs, number of TEAEs 
related to study drug, number of Infusion Reaction TEAEs (or a component of one), 
number of serious TEAEs, number of TEAEs leading to dose modification (reduction 
or increase or drug interrupted or drug withdrawn), number of TEAEs leading to 
treatment discontinuation, number of TEAEs with grade 3 or higher, TEAEs by severity 
grade, TEAEs by relationship to study treatment (related/ not related), TEAE last 
outcome, TEAE last action taken with study drug. 
• Summary of Deaths*: number of deaths, number of deaths within 30 days of starting 
treatment, number of deaths with Progressive Disease as the Primary Cause, number of 
AEs whose outcome=Death. 
Table of summary of Adverse Events will also be produced in the following subgroups: 
- 
Patients with at least one co-morbidity at baseline 
- 
Patients with no co-morbidity at baseline 
 
The following description of Adverse Events will also be provided (incidence of) with number 
and percentage of patients and the number of events: 


 
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• Treatment Emergent Adverse Events by System Organ Class and Preferred Term* 
• Serious Treatment Emergent Adverse Events by System Organ Class and Preferred 
Term* 
• Most frequent (≥10% of patients) Treatment Emergent Adverse Events by Preferred 
Term in Order of Frequency 
• Most frequent (≥10% of patients) Serious Treatment Emergent Adverse Events by 
Preferred Term in Order of Frequency 
• Treatment Emergent Adverse Events Leading to Treatment Discontinuation by 
Preferred Term in Order of Frequency * 
• Treatment Emergent Adverse Events Leading to Death by Preferred Term in Order of 
Frequency * 
• Treatment Emergent Adverse Events Leading to Dose Modification (Action Taken = 
“Dose reduced” or “Dose increased” or “Drug interrupted” or “Drug withdrawn”) by 
Preferred Term in Order of Frequency 
• Treatment Emergent Adverse Events by System Organ Class and Preferred Term and 
Worst NCI-CTCAE Grade 
• Serious Treatment Emergent Adverse Events by System Organ Class and Preferred 
Term and Worst NCI-CTCAE Grade* 
• Treatment Related Emergent Adverse Events by System Organ Class and Preferred 
Term and Worst NCI-CTCAE Grade 
• Serious Treatment Related Emergent Adverse Events by System Organ Class and 
Preferred Term and Worst NCI-CTCAE Grade 
• Treatment Emergent Adverse Events with a Grade Greater Than or Equal to 3 by 
System Organ Class and Preferred Term and Worst NCI-CTCAE Grade 
• Deaths* will be listed with time interval between date of death and first/last study dose 
drug intake date (in days) = death date – first/last study dose drug intake date + 1 
 
Related events will be defined as events that are ticked as “related” in the eCRF. 
All other information collected (e.g. action taken) will be listed as appropriate.  
Only treatment emergent adverse events will be included in the adverse event and serious 
adverse event tables. Non-treatment emergent events (starting prior first study drug dose intake 
date) will be included in the patient listings and flagged but not included in the above 
summaries.  
Where an AE start date is partially or fully missing, and it is unclear as to whether the AE is 
treatment emergent, it will be assumed that it is. 


 
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All AE safety analyses will be presented by dose group in patients from the safety analysis set 
at the time of primary analysis. Those flagged with a * will also be provided for the dose 
selection analysis. 
Listings will be presented and sorted by treatment group, patient and AE number for all adverse 
events recorded during the study. 
The following listings will be provided: 
- 
Adverse events*,  
- 
Grade 3 or 4 adverse events*, 
- 
Adverse events leading to dose modifications (Action Taken = “Dose reduced” or 
“Dose increased” or “Drug interrupted” or “Drug withdrawn”), 
- 
Adverse events leading to treatment discontinuation*, 
- 
Adverse Events leading to death*,  
Those flagged with a * will also be provided for the dose selection analysis. 
Due to the decision not to proceed to Part II, only tables and listings already produced for dose 
selection analysis will be edited for the primary analysis, with the addition of the following 
tables: 
- 
Summary table of AE in patients with at least one co-morbidity at baseline 
- 
Summary table of AE in patients with no co-morbidity at baseline 
- 
Treatment Related Emergent Adverse Events by System Organ Class and Preferred 
Term 
- 
Treatment Related Emergent Adverse Events by System Organ Class and Preferred 
Term and Worst NCI-CTCAE Grade 
4.10.2 Laboratory Findings 
The following laboratory parameters will be studied: 
Hematology: 
- 
RBC,  
- 
Hemoglobin,  
- 
Hematocrit,  
- 
Platelet count,  
- 
WBC,  
- 
Neutrophils (Absolute and/or Differentials),  
- 
Lymphocytes (Absolute and/or Differentials),  
- 
Monocytes (Absolute and/or Differentials),  
- 
Eosinophils (Absolute and/or Differentials),  
- 
Basophils (Absolute and/or Differentials). 
Biochemistry: 
- 
Sodium,  


 
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- 
Potassium,  
- 
Magnesium,  
- 
Urea or BUN,  
- 
Creatinine,  
- 
Glucose,  
- 
Phosphate,  
- 
Total Protein,  
- 
Albumin,  
- 
Adjusted Calcium,  
- 
Total Bilirubin,  
- 
Bicarbonate,  
- 
Chloride,  
- 
Uric Acid,  
- 
Alkaline Phosphatase (ALP),  
- 
AST,  
- 
ALT,  
- 
LDH. 
Hematology and Biochemistry parameters will be collected at the following visits: screening 
visit, Days 1 of each cycle, Days 8 of each cycle, Days 15 of each cycle and at end of treatment 
visit. 
Urine: 
- 
pH,  
- 
Specific gravity,  
- 
Ketones,  
- 
Leukocytes,  
- 
Protein,  
- 
Glucose,  
- 
Bilirubin,  
- 
Urobilinogen 
- 
Occult blood. 
Coagulation 
- 
Prothrombin Time 
- 
INR  
- 
aPTT 
Urine and Coagulation parameters will be collected at screening visit, Days 1 of each cycle, 
and at end of treatment visit. 
Categorical and numeric variables will be presented separately. 
All laboratory parameters (hematology, chemistry, urinary and coagulation) will be also listed. 
The following analyses will be performed in patients of the safety analysis set for the dose 
selection analysis and the primary analysis. 
Notes: 


 
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• For analyses of changes from baseline to worst value according to the NCI CTCAE grade, 
all emergent (on treatment values with grade > baseline grade) values will be considered 
(repeat results within a visit or unscheduled visit). In case of several values with the same 
worst grade, the first one will be taken into account 
• For shift table analyses from baseline to worst/ last value, repeat laboratory results within 
a visit or unscheduled visit will be taken into account. 
• Unscheduled and repeat results will also be listed. 
• All results outside predefined normal ranges will be flagged in the data listings. 
• Any other laboratory results will be listed only.  
• If a laboratory result is missing, the observation will not be taken into account and will not 
be listed. 
• All laboratory values will be converted to International System (SI) of units. 
• All laboratory parameters will be graded using SI values and the NCI-CTCAE 
classification Version 4.0 (or higher). Laboratory results not corresponding to an NCI 
CTCAE term will not be graded. For some parameters, grade can be derived for low values 
and high values. In that situation, the shift table will be produced for the 2 cases (high grade 
and low grade). 
• Some Blood Urea Nitrogen (BUN) values may be filled for Urea in the eCRF. So for Urea 
analyses, the following conversion rules will be applied: 
o BUN [mmol/L] = BUN [mg/dL] * 0.3571 (to get the SI value of BUN) and BUN 
[mmol/L]= urea [mmol/L] 
o Urea [mmol/L] = BUN [mg/dL of nitrogen] x 10 [dL/L] / 14x2 [mg N/mmol urea] 
(the mass of nitrogen within urea is used) 
o To convert BUN to urea in mg/dL by using following formula: Urea [mg/dL]= BUN 
[mg/dL] * 2.14 
o Essentially: 
• BUN (mg/dL) = Urea (mg/dL) / 2.1428 
• Urea (mmol/L) = BUN (mg/dL) * 0.357 
4.10.2.1 Hematology and Biochemistry 
Shift tables presenting worst post baseline grade according to baseline grade will also be 
displayed for the following parameters: 
- 
Haematology 


 
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o Hemoglobin (Low) 
o Hemoglobin (High) 
o Leukocytes (Low) 
o Leukocytes (High) 
o Neutrophils (Low) 
o Platelets (Low) 
o Lymphocytes (Low) 
o Lymphocyte (High) 
- 
Biochemistry 
o Phosphate (Low) 
o Alanine Aminotransferase (High) 
o Albumin (Low) 
o Alkaline Phosphatase (High) 
o Aspartate Aminotransferase (High) 
o Bilirubin (High) 
o Calcium Corrected (Low) 
o Calcium Corrected (High) 
o Creatinine (High) 
o Glucose (Low) 
o Glucose (High) 
o Magnesium (Low) 
o Magnesium (High) 
o Potassium (Low) 
o Potassium (High) 
o Sodium (Low) 
o Sodium (High) 
Box plots over time will be produced for all Hematology and Biochemistry parameters. 
In addition, for all Hematology and Biochemistry parameters, scatter plots displaying the mean 
within-patient percentage change from baseline over the study (one data point per patient) 
according to the dose received will be presented. 
Scatter plots of maximum Total Bilirubin by maximum ALT (respectively AST) by patient will 
also be provided, where ALT, AST and Total Bilirubin will be presented in multiples of the 
ULN, with reference lines at 3xULN for ALT (and AST) and 2xULN for Total Bilirubin. 


 
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In addition, for patients with Potential Hy’s law, values of ALT, AST, ALP and Bilirubin 
according to ULN (Value/ULN) will be graphically represented over time by patient, 
presenting all 4 liver function test on the same plot. 
The following laboratory abnormalities define potential Hy’s law cases: 
- 
Post-baseline AST and/or ALT elevations that are > 3 × ULN 
And 
- 
Elevation of Total Bilirubin > 2 × ULN (or clinical jaundice if total bilirubin measures 
are not available), regardless of whether this occurs at the same time as the ALT/ AST 
elevation 
Due to the decision not to proceed to Part II, only shift tables produced for dose selection 
analysis will be repeated for primary analysis. No box plot, scatter plot or Hy’s law plot will 
be displayed. 
4.10.2.2 Urinalysis 
Urinary parameters will be listed only. 
4.10.2.3 Coagulation 
Coagulation parameters will be listed only. 
4.10.3 Physical Examinations 
Physical examination will be performed at screening, Day 1 of each cycle, Day 8 of each cycle, 
Day 15 of each cycle as well as at end of treatment visit. 
The following endpoints will be listed: 
- 
Physical Examination performed? (Yes/ No) 
- 
General appearance (Normal/ Abnormal, Non Clinically Significant (NCS)/ Abnormal 
Clinically Significant (CS)/ Not Evaluated) 
- 
Head and Neck (including Eyes, Ears and Throat) (Normal/ Abnormal, NCS/ Abnormal 
CS/ Not Evaluated)  
- 
Cardiovascular (Normal/ Abnormal, NCS/ Abnormal CS/ Not Evaluated) 
- 
Respiratory (Normal/ Abnormal, NCS/ Abnormal CS/ Not Evaluated) 
- 
Abdomen or Gastrointestinal (Normal/ Abnormal, NCS/ Abnormal CS/ Not Evaluated) 
- 
Musculoskeletal Extremities (Normal/ Abnormal, NCS/ Abnormal CS/ Not Evaluated) 
- 
Lymph Nodes (Normal/ Abnormal, NCS/ Abnormal CS/ Not Evaluated) 
- 
Neurological Systems (Normal/ Abnormal, NCS/ Abnormal CS/ Not Evaluated) 
- 
Skin (Normal/ Abnormal, NCS/ Abnormal CS/ Not Evaluated) 
- 
Other (Normal/ Abnormal, NCS/ Abnormal CS/ Not Evaluated) 


 
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Physical examination will be presented in a data listing in patients from the safety analysis set 
for the dose selection analysis as well as the primary analysis. 
4.10.4 Vital Signs 
Vital signs will be evaluated at screening, Day 1 of each cycle, Day 8 of each cycle, Day 15 of 
each cycle as well as at end of treatment visit. 
The following criteria will be presented with box plots over time: 
- Systolic Blood Pressure (mmHg)  
- Diastolic Blood Pressure (mmHg)  
- Pulse Rate (beats per minutes (bpm))  
- Weight (kg)  
Box plots will be produced at each visit by treatment group and all vital sign parameters will 
be listed in patients from the safety analysis set for the primary analysis. 
Then, scatter plots displaying by parameter the mean percentage change from baseline over the 
study by patient according to the dose received will be presented at the time of the primary 
analysis. 
Vital sign parameters will also be presented in a data listing at the time of dose selection 
analysis. 
Due to the decision not to proceed to Part II, only the listings produced for dose selection 
analysis will be edited for primary analysis. No box plot or scatter plot will be displayed. 
4.10.5 ECG 
ECG parameters will be evaluated at screening, Day 1 of each cycle, Day 8 of each cycle, Day 
15 of each cycle as well as at end of treatment visit. 
The following endpoints will be summarized by visit. 
- QTc Average (msec) 
- QTc Average (Derived) (msec) 
The following endpoints will only be listed: 
- Investigator’s overall assessment (Nomal/ Abnormal Clinically Significant/ Abnormal 
Not Clinically Significant/ Incomplete Analysis/ Un-interpretable/ Not Done) 
- Heart Rate (beats/ min) 
- PR Interval (msec) 
- RR Interval (sec) 
- QRS Interval (msec) 


 
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- QT Interval (msec) 
ECG parameters will be described at each visit by treatment group and listed in patients from 
the safety analysis set for the dose selection analysis as well as the primary analysis. 
In addition, Box Plots for QTc Average and QTc Average (Derived) values over time will be 
presented for the primary analysis. 
Then, scatter plots displaying for QTc Average and QTc Average (Derived) values, the mean 
percentage change from baseline over the study by patient according to the dose received will 
be presented for the primary analysis. 
Moreover, profile plots for QTc Average and QTc Average (Derived) changes pre and post 
dose at Cycle 1 Day 1, Cycle 1 Day 15, Cycle 3 Day 1 and Cycle 3 Day 15 will be displayed 
at the time of the dose selection analysis as well as the primary analysis. 
Due to the decision not to proceed to Part II, the table, the listing and the profile plot produced 
for dose selection analysis will be performed for primary analysis. No box plot or scatter plot 
will be displayed. 
4.10.6 ECOG 
ECOG performance status is measured at Screening and on Day 1 of each cycle and at End of 
Study visit.  
ECOG performance status will be presented in a data listing at the time of dose selection 
analysis and primary analysis. 
4.11 Adjustment for Covariates 
Not applicable. 
4.11.1 Center Effects 
This study will be conducted in up to 24 sites: approximately 16 sites in the US and 
approximately 8 in Europe. The randomization of the study was not stratified by site. No center 
effect is expected. 
4.12 Protocol Violations or Deviations 
A Data Review Meeting (DRM) will be held prior to database lock before the primary analysis. 
The primary purpose of this meeting will be to identify important deviations from the protocol 
and discuss any data cleaning or statistical analysis issues. Detailed definitions of important 
deviations and how they are to be identified will be documented in a separate specifications 
document which will be approved prior to the DRM. Deviations will be classified as minor or 
major. 
Where possible, deviations from the protocol are to be identified programmatically.  


 
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The major protocol deviations will be fully defined and documented.   
A list of patients with important deviations from the observational plan will be agreed upon 
during the DRM and will be documented in the “Analysis Set Specifications” document. 
If protocol violations do occur as outlined in the criteria below, then the data from complete 
individual patients, individual visits or individual evaluations will be excluded from this 
analysis. The finalisation of protocol violations and excluded data will be made prior to the 
database lock. 
4.12.1 Violation Criteria 
Patients who meet any of the following criteria will be listed and presented in the study report: 
• Non-compliance with inclusion criteria 
• Non-compliance with exclusion criteria 
• Non-compliance with study treatment; 
• Treatment administration deviation; 
• Unauthorised concomitant therapy 
• Other, e.g. consent not signed 
Note: Other reasons for violation may be added to this list, but will be done so prior to database 
lock of the study. 
4.12.2 Protocol Deviations 
Deviations from the protocol, as defined in the protocol, will be documented on an ongoing 
basis by the study monitors and project manager throughout the study period.  
At the time of database lock, while the protocol violations are being reviewed, the project 
manager will forward all relevant documentation highlighting protocol deviations to the study 
statistician. These deviations will be included in the protocol violation document for agreement 
and will be listed with the protocol violations in the Clinical Study Report (CSR). 
4.13 Missing Values – Missing Visits 
For partially missing dates for efficacy endpoints, the following imputation rules will be used: 
if the day of the month is missing, but month and year are known (UN-MMM-YYYY), it will 
be imputed by the 1st of the month (01-MMM-YYYY). If this implementation rule produces a 
date before start of treatment, then the date of start of treatment is used. 
4.13.1 Adverse Events 
In case of missing information for AEs, this will be treated as described in section 4.8.1. 


 
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For missing or partially missing start/stop dates of AE, the following rules will be applied: 
Table 10: Substituting rules for (partially) missing AE start/stop dates 
Missing start 
or stop date 
Substituted start date 
Substituted stop date (recovery 
date if AE outcome is “Resolved 
without sequelae” or “Resolved 
with sequelae” or if AE is not 
ongoing) 
.. 
/mmm/yyyy 
(= missing 
day) 
If same month and year than first 
administration date, then: 
First administration date + 1  
 
Else: 
01/mmm/yyyy 
If same month and year than last visit 
date, then: 
Last visit date 
 
Else: 
Last day of the month 
/mmm/yyyy 
../…/yyyy 
(= missing 
day and 
month) 
If 
same 
year 
than 
first 
administration date, then: 
First administration date + 1  
 
Else: 
01/JAN/yyyy 
If same year than last visit date, then: 
Last visit date 
 
Else: 
31/DEC/yyyy 
.. /… /.… 
(= completely 
missing date) 
First administration date + 1  
Last visit date 
 


 
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4.13.2 Concomitant medication 
In case of missing or partially missing dates for concomitant medication, the following rules 
will be applied: 
Table 11: Substituting rules for concomitant medication with (partially) missing dates 
Missing start or 
stop date 
Substituted start date 
Substituted stop date 
../mmm/yyyy 
 
(= missing day) 
If same month and year than first 
administration date then: 
First administration date + 1  
 
Else: 
01/mmm/yyyy 
- the completion/withdrawal date 
if the patient is 
completed/withdrawn the same 
month and year 
 
otherwise 
- the last day of the month (28-29-
30-31/mmm/yyyy)  
../…/yyyy 
 
(= missing day 
and month) 
If 
same 
year 
than 
first 
administration date, then: 
First administration date + 1  
 
Else: 
01/JAN/yyyy 
- the completion/withdrawal date 
if the patient is 
completed/withdrawn the same 
year 
 
otherwise 
- the last day of the year : 
31/DEC/yyyy otherwise. 
../.../…. 
 
(= completely 
missing date) 
First administration date + 1  - No substitution (i.e., treatment 
considered as still ongoing) 
4.13.3 Initial Diagnosis Date 
In case of missing or partially missing dates for initial diagnosis, the following rules will be 
applied: 
- If initial diagnosis date=../mmm/yyyy (= missing day), then it will be substituted by 
01/mmm/yyyy 
- If initial diagnosis date=.../.../yyyy (= missing day and month), then it will be substituted 
by 01/JAN/yyyy 
- If initial diagnosis date=.../.../…. (= completely missing), then it won’t be substituted. 
4.13.4 Treatment Intake dates and PD dates for prior ovarian cancer therapies 
In case of missing or partially missing dates for first or last intake dates of prior ovarian cancer 
therapies, the following rules will be applied: 


 
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Table 12: Substituting rules for partially missing first/ last intake dates of prior 
ovarian cancer therapies 
Missing first or last intake 
date 
Substituted first intake 
date 
Substituted last intake date  
.. /mmm/yyyy 
(= missing day) 
01/mmm/yyyy 
Last day of the month mmm/yyyy 
../…/yyyy 
(= missing day and month) 
01/JAN/yyyy 
31/DEC/yyyy 
.. /… /.… 
(= completely missing date) 
No substitution 
No substitution 
 
In case of missing or partially missing PD dates of prior ovarian cancer therapies for patients 
whose discontinuation reason is “Progressive/ Relapse Disease” in the CRF, the following rules 
will be applied: 
Table 13: Substituting rules for prior ovarian cancer therapies with (partially) missing 
PD dates 
Missing PD date 
Substituted PD date 
../mmm/yyyy 
 
(= missing day) 
If same month and year than first intake date of the 
corresponding prior ovarian cancer therapy then: 
First prior ovarian cancer therapy intake date + 1  
 
Else: 
01/mmm/yyyy 
../…/yyyy 
 
(= missing day and month) 
If same year than first intake date of the corresponding prior 
ovarian cancer therapy, then: 
First prior ovarian cancer therapy intake date + 1  
 
Else: 
01/JAN/yyyy 
../.../…. 
 
(= completely missing date) 
No substitution  
 
4.13.5 Birth Date 
In case of partially missing birth dates, the following rules will be applied: 
- If birth date=../mmm/yyyy (= missing day), then it will be substituted by 01/mmm/yyyy 
- If birth date=.../.../yyyy (= missing day and month), then it will be substituted by 
01/JAN/yyyy 


 
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- If birth date=.../.../…. (= completely missing), then it won’t be substituted. 
 
4.14 Deviations from SAP 
Any deviations from the original statistical plan will be described and justified in the final CSR, 
whether written post dose selection or primary analysis. 
4.15 Changes in Conduct or Planned Analyses from the Protocol 
 Vital Signs 
Abnormal values of vital signs won’t be tabulated although it was planned in the protocol 
because it was not deemed useful. 
Due to the decision to stop the study, this SAP has been updated in order to reflect what will 
really be provided after database lock for an abbreviated clinical study report. 
Below are the list of updates following this decision: 
- 
No dose selection was performed and part II will not take place; 
- 
No efficacy update analysis will be performed; 
- 
No PPS will be developed, 5 analysis populations will be defined instead of 6; 
- 
No subgroup will be defined for ORR but BOR, PFS and OS analyses will be performed 
in 6 subgroups ; 
- 
DSMC analyses will be repeated for primary analysis in addition to some other outputs; 
- 
Patients eligibility listing will not be provided; 
- 
Demographic and baseline characteristics outputs will not be displayed in the SS, FAS, 
EFR Set and GCIG set; 
- 
Ovarian Cancer history results will not be displayed in the SS; 
- 
For study drug administration, some items will not be described (see section 4.5.1); 
- 
RDR and PIDR endpoints will not be studied and will only be listed; but RDI and PID 
will also be described in co-morbidity subgroups; 
- 
No ORR analysis will be displayed in a specific table. Only a description of 
responder/non responder patients will be provided in the BOR table; 
- 
BOR will not be described with the confirmatory rule for CR and PR responses. Same 
analysis as Dose selection analysis will be done; 


 
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- 
DCR, DOR, TTP and TTR endpoints will only be listed; 
- 
PFS based on BICR will not be analysed in EFR. PFS based on Investigator Recorded 
assessment won’t be produced as well as PFS4, PFS6 and PF6KM endpoint analyses. 
In addition, no KM plot will be displayed; 
- 
OS analyses will not be performed in EFR and no KM plot will be displayed; 
- 
Best GCIG Overall Response will only be listed; 
- 
Swimmer plot of time of Treatment will not be edited; 
- 
FOSI-18 and EQ-5D-5L questionnaires will not be described, nor listed; 
- 
AE analyses will be the same as those provided for dose selection analysis but summary 
table of adverse events will be repeated in co-morbidity subgroups; 
- 
No box plot, scatter plot or Hy’s law plot will be displayed for laboratory parameters; 
- 
No box plot or scatter plot will be displayed for vital signs or ECG; 
4.16 Algorithms/SAS Codes 
• Tables that need descriptive statistics – continuous variables: 
PROC UNIVARIATE DATA=dset NOPRINT; 
    VAR var1 var2 var3 …varn; 
   BY byvar; (optional) 
   OUTPUT OUT=outname 
   N=n MEAN=mean MIN=min MAX=max MEDIAN=median STD=std; 
RUN; 
• Tables that need frequency counts: 
PROC FREQ DATA=dset NOPRINT; 
  
BY byvar; (optional) 
   TABLES var1*var2; 
  
OUTPUT OUT=outname; 
RUN; 
• Tables that need 95% CIs within group for binomial proportions: 
PROC FREQ DATA=dset; 
  
BY byvar; (optional) 
   TABLES var1; 
  
EXACT BINOMIAL; 
RUN; 
• Tables that need number of events/censored and probabilities of failure/survival at 
cut off times: 
PROC LIFETEST DATA=dset OUTSURV=LIFE METHOD=LT INTERVALS=12, 24,; 


 
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TIME duration*censor (0 or 1); 
 
ID patient; 
 
STRATA treatment; 
RUN; 
• Tables that need life table with estimates of survival, with CIs and log rank test:  
PROC LIFETEST DATA=dset OUTSURV=LIFE METHOD=KM; 
 
 TIME duration*censor (0 or 1); 
 
ID patient; 
 
STRATA treatment; 
RUN; 
• Tables that need 95% CIs within group for continuous variables: 
DATA outdata;  
 SET outname; 
   LCL=mean-(TINV(0.975,n-1)*(std/SQRT(n))); 
   UCL=mean+(TINV(0.975,n-1)*(std/SQRT(n))); 
RUN; 
 
 


 
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5 Tables and Listings 
5.1 Table Format 
All output will be produced using SAS version 9.2 or a later version. 
In the top left portion of each table/listing, a table/listing number followed by the title of the 
table/listing will be presented. After the title line, optional sub-title or population information 
can be presented. Horizontal lines will appear before and after the column heading of the 
table/listing. Footnotes will be put under the main body of text at the bottom of the page.  
The sponsor name, protocol number, programmers User ID, status of the table/listing (i.e. draft 
or final) and SAS program name will appear bottom left in a string and the page number will 
appear on the bottom right corner of each table/listing. The date and time of creation of 
table/listing will appear bottom left under the sponsor name. The source listing number will 
appear bottom left.  
A landscape layout is proposed for both table and listing presentations. 
The left and right margins of all tables and listings will be a minimum of 2.1 cm from the left 
and 1.9cm from the right. The top and bottom margins will be a minimum 2.92cm. Header and 
footer will be both 1.27 cm. 
There is no special requirement of font type and size, but an 8-point font size for tables and 7or 
8-point for listings is proposed using Courier New font. A maximum SAS line size=141 and 
page size=44 for 8-point font size, and line size=161 and page size=50 for 7-point will be used 
so as to fit on both UK and US paper sizes. 
In a listing, in the case that a patient’s record has been continued to the next page, an appropriate 
identification (e.g., the patient ID number) must be presented at the beginning of that page. 
5.2 Conventions 
Unless otherwise specified, in summary tables of continuous variables, the minimum and 
maximum values will be displayed to the same number of decimal places as the raw data, the 
mean and median will be presented to one extra decimal place compared to the raw data, and 
the standard deviation will be displayed to two extra decimal places compared to the raw data. 
Wherever possible data will be decimal aligned. 
Unless otherwise specified frequency tabulations will be presented by number and percentage, 
where the percentage is presented in brackets to 1 decimal place. 
P-values, if applicable, will be presented to 3 decimal places. If a p-value is less than 0.05 but 
is greater than or equal to 0.01, then an asterisk (*) will be added next to this value. If a p-value 
is less than 0.01 but is greater than or equal to 0.001, then two asterisks (**) will be added next 
to this value. Finally, if the p-value is less than 0.001 then three asterisks (***) will be added 
next to this value and it will be presented as <0.001. If the rounded result is a value of 1.000, it 
will be displayed as >0.999. Any date information in the listing will use the date9. format, for 
example, 07MAY2002. In the listing, a unit associated with a variable will be presented only 


 
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Protocol Number: 
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once within parentheses either below or next to that variable in the heading portion. If a 
parameter has multiple units, each unit will be displayed only once, as applicable. 
All tables will have their source listing referenced in a footnote. Listings should be sorted by 
treatment group, patient and visit and have the Study Data Tabulation Model (SDTM) data 
referenced in a footnote. All tables, listings and figures will be converted into Microsoft Word 
documents and collated into three complete documents.  
5.3 Tables 
Tables flagged with a * will be also produced for the Dose Selection Analysis. Those flagged 
with a # will be also produced for the Efficacy Update Analysis (if performed). 
Due to the decision not to proceed to Part II, no efficacy update analysis will be performed and 
several analyses scheduled for primary analysis will not be produced. 
5.3.1 Section 14.1: Demographic and Baseline 
Table 14.1.1.1 
Patient Disposition (All screened patients)*  
Table 14.1.1.2 
Analysis Sets (All screened patients) *  
Table 14.1.1.3 
Major Protocol Violations (All screened Patients) 
Table 14.1.2.1 
Demographics and Baseline Characteristics (Randomized Set) * 
Table 14.1.2.2 
 Baseline co-morbidities (Randomized Set) 
Table 14.1.3 
Ovarian Cancer History (Randomized Set) *  
Table 14.1.4.1 
Prior Ovarian Cancer Therapy – Agent Names (Randomized Set ) *  
Table 14.1.4.2 
Prior Ovarian Cancer Therapy – Baseline Characteristics Details 
(Randomized Set) *  
Table 14.1.5.1.1 
Exposure and Study Drug Administration (Full Analysis Set) *  
 
 
Table 14.1.5.2.1 
Exposure and Dose Intensity (Full Analysis Set) *  
Table 14.1.5.2.2 
Exposure and Dose Intensity in patients with at least one co-morbidity at 
baseline (Full Analysis Set) 
Table 14.1.5.2.3 
Exposure and Dose Intensity in patients with no co-morbidity at baseline 
(Full Analysis Set) 
Table 14.1.5.3.1 
Exposure and Treatment Delay Intervals (Full Analysis Set) *  
 
 
Table 14.1.6.1 
Concomitant Medications (Safety Analysis set)   
5.3.2 Section 14.2: Primary 
Following the decision not to proceed to Part II, the analysis of primary endpoint will not be 
performed. However, descriptive statistics of responder/non responder patients will be 
provided in the same table as BOR. 


 
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5.3.3 Section 14.2: Secondary 
Table 14.2.2.1 
Best Overall Response according to RECIST v1.1 based on BICR 
(Evaluable For Response Set) * 
Table 14.2.2.2 
Best Overall Response according to RECIST v1.1 based on Investigator-
Recorded Assessment (Evaluable For Response Set) *   
Table 14.2.2.3 
Best Overall Response according to RECIST v1.1 based on BICR 
according to co-morbidities at baseline (Evaluable for Response Set) 
Table 14.2.2.4 
Best Overall Response according to RECIST v1.1 based on BICR 
according to prior gemcitabine intake (Evaluable for Response Set) 
Table 14.2.2.5 
Best Overall Response according to RECIST v1.1 based on BICR 
according to time on prior gemcitabine (Evaluable for Response Set) 
Table 14.2.2.6 
Best Overall Response according to RECIST v1.1 based on BICR 
according to time to progression from end of last prior platinum based 
chemotherapy (Evaluable for Response Set) 
Table 14.2.2.7 
Best Overall Response according to RECIST v1.1 based on BICR 
according to BRCA mutation status (Evaluable for Response Set) 
Table 14.2.2.8 
Best Overall Response according to RECIST v1.1 based on BICR 
according to time to progression from start of last prior therapy 
(Evaluable for Response Set) 
Table 14.2.4.1 
Progression Free Survival based on BICR (Full Analysis Set)   
Table 14.2.4.2 
Progression Free Survival based on BICR according to co-morbidities at 
baseline (Full Analysis Set) 
Table 14.2.4.3 
Progression Free Survival based on BICR according to prior gemcitabine 
intake (Full Analysis Set) 
Table 14.2.4.4 
Progression Free Survival based on BICR according to time on prior 
gemcitabine (Full Analysis Set) 
Table 14.2.4.5 
Progression Free Survival based on BICR according to time to 
progression from end of last prior platinum based chemotherapy (Full 
Analysis Set) 
Table 14.2.4.6 
Progression Free Survival based on BICR according to BRCA mutation 
status (Full Analysis Set) 
Table 14.2.4.7 
Progression Free Survival based on BICR according to time to 
progression from start of last prior therapy (Full Analysis Set) 
Table 14.2.5.1 
Overall Survival (Full Analysis Set)    
Table 14.2.5.2 
Overall Survival according to co-morbidities at baseline (Full Analysis 
Set) 
Table 14.2.5.3 
Overall Survival according to prior gemcitabine intake (Full Analysis 
Set) 
Table 14.2.5.4 
Overall Survival according to time on prior gemcitabine (Full Analysis 
Set) 
Table 14.2.5.5 
Overall Survival according to time to progression from end of last prior 
platinum based chemotherapy (Full Analysis Set) 
Table 14.2.5.6 
Overall Survival according to BRCA mutation status (Full Analysis Set) 


 
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Protocol Number: 
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Table 14.2.5.7 
Overall Survival according to time to progression from start of last prior 
therapy (Full Analysis Set) 
Table 14.2.9.1 
Sum of Lesion Diameters – Percentage Change from Baseline based on 
BICR (Evaluable for Response Set) *  
Table 14.2.11.1 
CA125 – Percentage Change from Baseline (GCIG Analysis Set) *  
5.3.4 Section 14.2: Exploratory – EQ-5D-5L 
Not Applicable, following the decision not to proceed to Part II. 
5.3.5 Section 14.3: Safety 
5.3.5.1 Adverse Events  
Table 14.3.1.1 
Summary of Adverse Events*  
Table 14.3.1.1.1 
Summary of Adverse Events in patients with at least one co-morbidity at 
baseline 
Table 14.3.1.1.2 
Summary of Adverse Events in patients with no co-morbidity at baseline 
Table 14.3.1.2 
Summary of Deaths*  
Table 14.3.1.3.1 
Treatment Emergent Adverse Events by System Organ Class and 
Preferred Term *  
Table 14.3.1.3.2 
Serious Treatment Emergent Adverse Events by System Organ Class and 
Preferred Term *  
Table 14.3.1.3.3 
Treatment Related Emergent Adverse Events by System Organ Class and 
Preferred Term 
Table 14.3.1.5.1 
Treatment 
Emergent 
Adverse 
Events 
Leading 
to 
Treatment 
Discontinuation by Preferred Term in Order of Frequency *  
Table 14.3.1.5.2 
Treatment Emergent Adverse Events Leading to Death by Preferred Term 
in Order of Frequency *  
Table 14.3.1.6.2 
Serious Treatment Emergent Adverse Events by System Organ Class and 
Preferred Term and Worst NCI-CTCAE Grade *  
Table 14.3.1.6.3 
Treatment Related Emergent Adverse Events by System Organ Class and 
Preferred Term and Worst NCI-CTCAE Grade 
5.3.5.2 Laboratory Results 
Table 14.3.5.1.1 
Laboratory results – Hematology – Shift Table of Worst Post Baseline 
Grade according to Baseline Grade *  
Table 14.3.5.2.1 
Laboratory Results – Biochemistry – Shift Table of Worst Post 
Baseline Grade according to Baseline Grade *  
5.3.5.3 Electrocardiogram 
Table 14.3.6 
Electrocardiogram *  
 
All safety tables will be produced using the Safety Analysis Set. 


 
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Sponsor: 
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5.4 Listings 
Listings flagged with a * will also be produced for the Dose Selection Analysis. Those flagged 
with a # will also be produced for the Efficacy Update Analysis (if performed). 
Due to the  decision not to proceed to Part II, no efficacy update analysis will be performed 
and several analyses scheduled for primary analysis will not be produced. 
Listing 14.3.2 
Listing of Deaths (Safety Analysis Set) *  
Listing 16.1.7    
Randomization (Randomized Patients) * 
Listing 16.2.1.1 
Patient Disposition (Safety Analysis Set) *  
Listing 16.2.1.2 
Inclusion/Exclusion Criteria Descriptions  (All screened Patients) 
Listing 16.2.2.1 
Protocol Violations  (Safety Analysis Set) 
Listing 16.2.4.1   
Demographics and Baseline Characteristics (Safety Analysis Set) *  
Listing 16.2.4.2   
Medical/ Surgical History, including reported and coded terms  (Safety 
Analysis Set) 
Listing 16.2.4.3 
Ovarian Cancer History (Randomized Set)*  
Listing 16.2.4.4.1 
Prior Ovarian Cancer Therapy – Baseline Details (Randomized Set) *  
Listing 16.2.4.5 
Prior & Concomitant Medications including reported and coded terms 
(Safety Analysis Set) *  
Listing 16.2.4.6 
Concomitant Procedures/ Surgeries/ Therapies (Safety Analysis Set) 
Listing 16.2.5.1 
Study Treatment Administration (Safety Analysis Set) *  
Listing 16.2.5.2 
Extent of Exposure (Safety Analysis Set) *  
Listing 16.2.6.1.1 
Tumor Assessment – Target Lesions according to BICR (Full Analysis 
Set) 
Listing 16.2.6.1.2 
Tumor Assessment – Target Lesions according to Investigator-
Recorded Assessment (Full Analysis Set) 
Listing 16.2.6.2.1 
Tumor Assessment – Non-Target Lesions according to BICR (Full 
Analysis Set) 
Listing 16.2.6.2.2 
Tumor Assessment – Non-Target Lesions according to Investigator-
Recorded Assessment (Full Analysis Set) 
Listing 16.2.6.3.1 
Tumor Assessment – New Lesions according to BICR (Full Analysis 
Set) 
Listing 16.2.6.3.2 
Tumor Assessment – New Lesions according to Investigator-Recorded 
Assessment (Full Analysis Set) 
Listing 16.2.6.4 
Assessment of Anti-Tumor Activity based on BICR (RECIST criteria) 
(Full Analysis Set) * # 
Listing 16.2.6.5 
Assessment of Anti-Tumor Activity based on Investigator-Recorded 
Assessment (RECIST criteria) (Full Analysis Set) *  
Listing 16.2.6.6.1 
Assessment of Anti-Tumor Activity – Derived Efficacy Endpoints based 
on BICR (RECIST criteria) (Full Analysis Set) * # 
Listing 16.2.6.6.2 
Assessment of Anti-Tumor Activity – Derived Efficacy Endpoints based 
on Investigator-Recorded Assessment (RECIST criteria) (Full Analysis 
Set) * # 


 
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Sponsor: 
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Protocol Number: 
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Listing 16.2.6.7 
Best GCIG Overall Response, combining the Change CA125 from 
Baseline with RECIST Assessment (per GCIG criteria) (GCIG Analysis 
Set) * # 
Listing 16.2.7.1 
Adverse Events (Safety Analysis Set) *  
Listing 16.2.7.2 
Adverse Events Leading to Treatment Discontinuation (Safety Analysis 
Set) *  
Listing 16.2.7.3 
Adverse Events Leading to Death (Safety Analysis Set) *  
Listing 16.2.7.4 
Grade 3 or 4 Adverse Events (Safety Analysis Set) *  
Listing 16.2.8.1 
Laboratory Results: Hematology (Safety Analysis Set) *  
Listing 16.2.8.2 
Laboratory Results: Biochemistry (Safety Analysis Set) *  
Listing 16.2.8.3 
Laboratory Results: Urinalysis (Safety Analysis Set) *  
Listing 16.2.8.4 
Laboratory Results: Coagulation (Safety Analysis Set) *  
Listing 16.2.9 
Physical Examination (Safety Analysis Set) *  
Listing 16.2.10 
Vital Signs (Safety Analysis Set) *  
Listing 16.2.11   
Electrocardiogram (Safety Analysis Set) *  
Listing 16.2.12 
ECOG Performance Status (Safety Analysis Set) *  
 
5.5 Figures 
Figures flagged with a * will also be produced for the Dose Selection Analysis. Those flagged 
with a # will also be produced for the Efficacy Update Analysis (if performed). 
Due to the decision not to proceed to Part II, no efficacy update analysis will be performed and 
several analyses scheduled for primary analysis will not be produced. 
Figure 14.2.8.1 
Waterfall Plots of Percentage Changes from Baseline of SLD (Evaluable 
For Response Set) *  
Figure 14.2.10.1 
Waterfall Plots of Percentage Changes from Baseline of CA125 (GCIG 
Analysis Set) *  
Figure 14.3.9.3 
Electrocardiogram – Profile Plots of QTc Changes Pre and Post Dose 
(Safety Analysis Set) * 
Tables, 
Listings, 
and 
Figures 
will 
follow 
the 
format 
of: 
PRO-
105_NuCana_35679_shell_Final_26May2020.doc  
 
5.6 Appendices 
The following appendices are for internal use only and not for inclusion into the CSR. {Note: 
ALL analyses will require raw SAS output}. 
Due to the decision not to proceed to Part II, only 14 tables with inferential statistics will be 
produced. Thus, only 14 corresponding appendices will be needed. 
Appendix 14.2.4.1 
Progression Free Survival based on BICR (Full Analysis Set) 
Appendix 14.2.4.2 
Progression Free Survival based on BICR according to co-
morbidities at baseline (Full Analysis Set) 


 
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Appendix 14.2.4.3 
Progression Free Survival based on BICR according to prior 
gemcitabine intake (Full Analysis Set) 
Appendix 14.2.4.4 
Progression Free Survival based on BICR according to time on prior 
gemcitabine (Full Analysis Set) 
Appendix 14.2.4.5 
Progression Free Survival based on BICR according to time to 
progression from end of last prior platinum based chemotherapy 
(Full Analysis Set) 
Appendix 14.2.4.6 
Progression Free Survival based on BICR according to BRCA 
mutation status (Full Analysis Set) 
Appendix 14.2.4.7 
Progression Free Survival based on BICR according to time to 
progression from start of last prior therapy (Full Analysis Set) 
Appendix 14.2.5.1 
Overall Survival (Full Analysis Set) 
Appendix 14.2.5.2 
Overall Survival according to co-morbidities at baseline (Full 
Analysis Set) 
Appendix 14.2.5.3 
Overall Survival according to prior gemcitabine intake (Full 
Analysis Set) 
Appendix 14.2.5.4 
Overall Survival according to time on prior gemcitabine (Full 
Analysis Set) 
Appendix 14.2.5.5 
Overall Survival according to time to progression from end of last 
prior platinum based chemotherapy (Full Analysis Set) 
Appendix 14.2.5.6 
Overall Survival according to BRCA mutation status (Full Analysis 
Set) 
Appendix 14.2.5.7 
Overall Survival according to time to progression from start of last 
prior therapy (Full Analysis Set) 
 
5.7 References 
E.A. Eisenhauer, P. Therasse, J. Bogaerts, L.H. Schwartz, D. Sargent, R. Ford, J. Dancey, S. 
Arbuck, S. Gwyther, M. Mooney, L. Rubinstein, L. Shankar, L. Dodd, R. Kaplanj, D. Lacombe, 
J. Verweij (2008). New response evaluation criteria in solid tumors: Revised RECIST guideline 
(version 1.1). 
Gynecological Cancer Intergroup (GCIG) Members (November 2005). CA 125 definitions 
agreed by GCIG November 2005. 
Gordon John Sampson Rustin, Ignace Vergote, Elizabeth Eisenhauer, Eric Pujade-Lauraine, 
Michael Quinn, Tate Thigpen, Andreas du Bois, Gunnar Kristensen, Anders Jakobsen, Satoru 
Sagae, Kathryn Greven, Mahesh Parmar, Michael Friedlander, Andres Cervantes and Jan 
Vermorken (February 2011). Definitions for Response and Progression in Ovarian Cancer 
Clinical Trials Incorporating RECIST 1.1 and CA 125 Agreed by the Gynecological Cancer 
Intergroup (GCIG). International Journal of Gynecological Cancer: Volume 21 – Issue 2 – 
pp419-423 
Mandy Van Reenen, Bas Janssen 1 (April 2015). EQ-5D-5L User Guide Basis information on 
how to use the EQ-5D-5L instrument, Version 2.1. 


 
TPBS001 Version 5 – 9th October 2016 
 
 
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Sponsor: 
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Protocol Number: 
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Distribution: 
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Sally E.Jensen, and al . FOSI-18 scoring template, 2008. NCNN/FACT Ovarian Symptom 
Index-18 (FOSI-18) Scoring Guidelines (Version 2). 
Sally E.Jensen, Karen Kaiser, Lelilan Lacson, Julian Schink, David Cella (08 December 2014). 
Content validity of the NCCN-FACT Ovarian Sympton. 
Sally E.Jensen, Sarah K. Rosenbloom, Jennifer L.Beaumont, Amy Abernethy, Paul 
B.Jacobsen, Karen Syrjala, David Cella (13 November 2010). A new index of priority symptoms 
in advanced ovarian cancer. 
U.S. Department of health and human services, National Institutes of Health, National Cancer 
Institute, May 28, 2009 (v4.03: June 14, 2010). Common Terminology Criteria for Adverse 
Events (CTCAE). 
Van Hout B, Janssen MF, et al (EuroQol Group). Interim scoring for the EQ-5D-5L: Mapping 
the EQ-5D-5L to EQ-5D-3L value sets. Q-5D-5L Index Value Calculator developed by the 
EuroQol Group, Version 1.1.Value in Health  2012 Jul-Aug;15(5):708-15.