Clinical trial NCT04907539
Conditions: Colorectal Cancer
Keywords: Open label RXC004 Nivolumab Ring finger protein 43 R-spondin Efficacy Safety Pharmacokinetics
Sponsor: Redx Pharma Ltd
Start date: 2021-11-08; Completion date: 2024-04-02
Enrollment: 25 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This is a Phase II, open label, multicentre, multi-arm, study to evaluate the preliminary efficacy and safety of RXC004 as monotherapy and in combination with nivolumab in patients with Ring finger protein 43 (RNF43) or R-spondin (RSPO) aberrated, microsatellite stable (MSS), colorectal cancer (CRC), that have progressed following current standard of care treatment.

Detailed description:
The study is composed of two arms, RXC004 monotherapy (Arm A) and RXC004 in combination with nivolumab (Arm B). 20 evaluable patients will be enrolled in Arm A and 20 eligible patients in Arm B.

The study initially opened with Arm A; Arm B will be opened once a recommended Phase II dose (RP2D) for RXC004 in combination with nivolumab is established in the phase I dose escalation study (NCT03447470).

Once Arm B is opened, patients who are eligible for both Arm A and Arm B will be randomised 2:1 to Arm B: Arm A in an open-label manner.

Patients in Arm A may be treated with RXC004 + nivolumab if they have progressive disease on the 8 week scan, as long as they are eligible for Arm B and have Sponsor approval.

Arms: arm 1: Patients will receive RXC004 (2 mg once daily \[QD\], orally).

Patients in Arm A may crossover to Arm B treatment if they have progressive disease on the first Response Evaluation Criteria in Solid Tumours, (RECIST) scan (if Arm B is open at the time of progression). arm 2: Patients will receive RXC004 (1.5 mg QD, orally) in combination with nivolumab (480 mg every 4 weeks \[q4w\], intravenous \[IV\] infusion).

Arm B will be opened once a RP2D for RXC004 in combination with nivolumab is established in the phase I dose escalation study (NCT03447470). RXC004 dose to be used in combination with nivolumab will be based on data from the phase 1 study (NCT03447470).
Interventions: intervention 1: RXC004 intervention 2: Nivolumab intervention 3: Denosumab
Intervention descriptions: intervention 1: RXC004 will be administered orally, 2 mg QD (Monotherapy); and 1.5 mg QD (Combination therapy)

Dose Formulation: 0.5 mg or 1 mg capsules. intervention 2: Nivolumab will be administered via IV infusion, 480 mg q4w. intervention 3: Denosumab will be administered via subcutaneous (SC) injection, 120 mg once every month.

Use: Prophylactic

Protocol documents:
Prot_000.pdf: 
Cover page 
Protocol number: RXC004/0002 
Document title: A Multi-arm, Phase II, Open-Label, Multicentre Study to Assess the 
Preliminary Efficacy of RXC004 in Monotherapy and in Combination with Nivolumab, in 
Patients with Ring Finger Protein 43 (RNF43) or R-spondin (RSPO) Aberrated, 
Metastatic, Microsatellite Stable, Colorectal Cancer who have Progressed following 
Therapy with Current Standard of Care 
 
NCT number: NCT04907539 
Version number: 7.0 
Date of the document: 19 August 2022 


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Clinical Study Protocol  
Study Code 
RXC004/0002 
Version 
Final v7.0 
Date 
19 Aug 2022 
A Multi-arm, Phase II, Open-Label, Multicentre Study to Assess the
Preliminary Efficacy of RXC004 in Monotherapy and in Combination with 
Nivolumab, in Patients with Ring Finger Protein 43 (RNF43) or R-spondin 
(RSPO) Aberrated, Metastatic, Microsatellite Stable, Colorectal Cancer who
have Progressed following Therapy with Current Standard of Care 
Legal Registered Address:  
Redx Pharma Plc 
Block 33 
Mereside, Alderley Park 
Alderley Edge, Cheshire 
SK10 4TG, UK  
Regulatory Agency Identifier Number(s) 
EudraCT No.: 
2020-003132-24 
Protocol Number:   
 
RXC004/0002 
Amendment Number: Final Version 7.0 
Study Treatment: RXC004 monotherapy (Arm A) or RXC004 and nivolumab combination 
(Arm B) 
  
Study Phase: Phase 2 
Short Title: Phase II Study to Assess Efficacy of RXC004 +/- Nivolumab in RNF43/RSPO 
Aberrated mCRC MSS after Progression on SoC.  
PORCUPINE STUDY 


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SIGNATURES 
 
PROTOCOL TITLE: 
A Multi-arm, Phase II, Open-Label, Multicentre Study to Assess 
the Preliminary Efficacy of RXC004 in Monotherapy and in 
Combination with Nivolumab, in Patients with Ring Finger 
Protein 43 (RNF43) or R-spondin (RSPO) Aberrated, Metastatic, 
Microsatellite Stable, Colorectal Cancer who have Progressed 
following Therapy with Current Standard of Care 
PROTOCOL NO: 
 
RXC004/0002 
VERSION NO: 
 
7.0 
 
 
________ 
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Signature  
 
 
Date 
  
  
 
 
Medical Monitor Name and Contact Information will be provided separately 
International Co-ordinating investigators 
 
 
 
 
 
 
Phone: 
  
 
 
 
 
 
 
 
 
 
PPD
PPD
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PPD
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INVESTIGATOR SIGNATURES 
PROTOCOL TITLE: A Multi-arm, Phase II, Open-Label, Multicentre Study to Assess the 
Preliminary Efficacy of RXC004 in Monotherapy and in Combination with Nivolumab, in 
Patients with Ring Finger Protein 43 (RNF43) or R-spondin (RSPO) Aberrated, Metastatic, 
Microsatellite Stable, Colorectal Cancer who have Progressed following Therapy with Current 
Standard of Care 
PROTOCOL NUMBER: RXC004/0002 
VERSION NUMBER: 7.0 
 
 
This protocol is a confidential communication of Redx Pharma, plc. I confirm that I have read 
this protocol, I understand it, and I will work according to this protocol. I will also work 
consistently with the ethical principles that have their origin in the Declaration of Helsinki and 
that are consistent with good clinical practices and the applicable laws and regulations. 
Acceptance of this document constitutes my agreement that no unpublished information 
contained herein will be published or disclosed without prior written approval from Redx 
Pharma, plc.  
 
Signature of Investigator:      
__________________________            Date:  ________ 
 
Printed Name:                                ___________________________ 
Investigator Title:                           ___________________________ 
 
Name/Address of Centre:              ___________________________ 
 
___________________________ 
 
___________________________ 
 
Site Number:    ________ 


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VERSION HISTORY 
Version 7.0 – 19 August 2022 
This amendment is considered to be substantial based on the criteria set forth in Article 
10(a) of Directive 2001/20/EC of the European Parliament and the Council of the European 
Union. 
Substantial changes:  
The RXC004 dose to be used in combination therapy (1.5 mg QD) has been defined and 
justified by updated and new text, to support combination therapy. Supporting information 
has been added on the dose regimen and dose reductions.  
Sections updated: Section 4.4 and its subsections, Section 6.1.1, Section 6.6 
Details of allocation of patients to Arm A or Arm B by randomisation once Arm B has 
started enrolment have been added, following FDA advice.  
Sections updated: Section 1.2, Section 4.1, new Section 6.3  
Non-substantial changes:  
Selected Cycle 0 Day 1 pre-dose tests can be performed up to 24 hours prior to Cycle 0 
Day 1 treatment administration. Section updated: Section 1.2 
Clarification of timings for baseline biopsy and baseline 
 Section updated: 
Section 1.2 
Clarification of prophylactic treatment regimens with denosumab and calcium. Sections 
updated: Sections updated: Sections 1.2, 2.3.1.2, 6.2.3 
At selected sites, digital ECG collection may take place using ambulatory Holter monitoring 
equipment on Cycle 0 Day 1, and Cycle 1 Day 15. Sections updated: Section 1.2 and 8.2.4 
TSH (reflex T3/T4) sampling at Cycle 0 Day 1 was removed from the Part A schedule of 
assessment. Section updated: Section 1.2 
Background information has been updated. Sections updated: Sections 2.2.2, 2.2.3, and 
2.3.2 
Details of an SAE of ileitis reported in this study were added to the protocol, to provide 
investigators with details relevant to the safety of RXC004. Sections updated: Section 
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2.3.1.2 and Appendix J 
Clarifying language was added on the potential assessment of tumour gene and protein 
expression correlation with treatment response. Sections updated: Section 3 and 8.6.1 
In inclusion criterion 4, the requirement for documented radiological progression has been 
modified to clarify that the progression does not require having been defined by 
RECIST 1.1. Section updated: 5.1 
Exclusion criterion 10 and prohibited medication details have been updated to clarify 
vaccine requirements. Sections updated: Section 5.2 and 5.3.3.1 
Details on central genetic testing for required pre-screening tests have been updated 
according to the currently used tests and processes, and for consistency with other RXC004 
studies. Section updated: Section 5.5.1 
Table 13 (Investigational Products) has been updated to include the RXC004 dosage level 
for Part B. Section updated: Section 6.1.1 
Update to RXC004 dose modification guidance Section updated: Section 6.6 
Vitamin D and viral tests (HIV, hepatitis B/C) at baseline/screening have been added to the 
list of laboratory safety variables in Table 16 for consistency with the schedules of 
assessment. Section updated: Section 8.2.1 
A safety review of the combination data will be conducted after  patients have received the 
combination of RXC004 and nivolumab for at least 1 cycle. Sections updated: Section 4.1 
and 9.6 
Update to guidance on prohibited CYP3A4 inhibitors and inducers. Section updated: 
Appendix E 
Guidance on management of events of colitis has been updated. Section updated: 
Appendix J 
Minor edits have been made throughout the protocol to correct typographical errors and 
improve cross referencing within the protocol. 
Version 6.0 – 13th January 2022 
• Inclusion criteria #8, creatinine clearance amended to ≥60mL/min instead of > 
60mL/min following FDA advice.  Section updated: Section 5.1 
• RXC004 related colitis management guidelines revised to clarify the maximum time 
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a patient with Grade 1 colitis can continue RXC004 at a lower dose before switching 
to Grade 2 management and to clarify the maximum time that RXC004 treatment 
can be held before permanent discontinuation, following FDA advice.  Section 
updated: Appendix J 
• Dose modification table revised to include interruption of RXC004 if a patient has 
>5kg weight loss associated with dysgeusia and dysgeusia treatment guidelines 
modified to clarify management options following FDA advice.  Sections updated: 
Table 14 and Appendix I 
• Dose modification table revised to include permanent discontinuation of RXC004 in 
the event of a RXC004 related Grade 4 event following FDA advice.  Sections 
updated: Table 14 and Table 15 
• The following changes were made to the schedule of Assessments 
o ECG monitoring plan revised to include monitoring around the anticipated 
maximal RXC400 concentration on Cycle 0 Day 1 (first dose) and Cycle 1 
Day 15 (steady state) following FDA advice. 
o 
 a assessments changed from optional to mandatory unless 
unavailable at site to clarify the original intention that these assessments 
should be performed if the site has the capability to do so. 
o Footnote added to 
 
 
Sections updated: Table 1 and Table 2 
• Minor editorial changes were made throughout the protocol for consistency and 
clarity 
Version 5.0 – 14th September 2021 
1. The following updates were made to the eligibility criteria following FDA review: 
a. Exclusion criteria updated to exclude patients with QTcF  >470 ms 
b. Creatinine clearance inclusion criteria and monitoring added to enable future 
population PK analysis of effect of CLcr on PK of RXC004  
Sections updated – Section 5.1 and Section 5.2 
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2. Guidelines for management of colitis events updated after IB updated.  Dose 
modification tables, prohibited medications and safety labs also updated 
accordingly.  Discontinuation of RXC004 and nivolumab (for patients on the 
combination) for grade 3 colitis events added as per MHRA request.    Sections 
updated – Appendix J, Table 9, Section 5.3.3.1 and Section 6.6 
3. RXC004 background, risk assessment and dose justification updated to include data 
from the most recent IB.  Sections updated – Section 2.2.3, Section 2.3.1 and 
Section 4.4.1 
4.  Adverse Events of Potential Interest (AEPI) identified for monitoring: bone 
toxicities and colitis events. Sections Updated – Section 8.3.13  
5. Contraception requirements updated to include the definition of sexual abstinence, 
as per MHRA request.  Section added – Section 5.3.1 
6. Clarification for treating patients after RECIST1.1 progression added.  Sections 
updated 7.1.1 
7. RXC004 fasting requirements from Section 5.3.2 added to schedule of assessment 
footnotes and RXC004 handling instructions for clarity.  Sections updated - 
Table 1, Table 2 and Section 6.2.1  
8. Restrictions on the use of concomitant CYP3A4 inhibitors and inducers updated to 
include 2 weeks prior to first dose of study treatment, as well as throughout the 
study treatment following FDA feedback.  Section updated – Section 5.3.3.1 
9. Maximum 14 days RXC004 interruption without Sponsor approval’ language 
removed from protocol as a clarification for situations where it conflicts with advice 
for management of colitis in Appendix J.  Section updated - Section 6.6 
10. Optional collection of 
 i in the screening period (if not collected 
during pre-screening) added to Schedule of Assessments to allow for confirmation 
of the 
 a at the central laboratory.  Language also amended to 
allow MSI status of patients to be confirmed at the central laboratory.  Sections 
updated – Table 1, Table 2, Section 5.5 and Section 8.6 
11. Ability of patients to enrol in concomitant COVID-19 vaccination studies removed 
as per MHRA request.  Sections updated – Section 5.3.3.2 and 7.1 
12. Dysgeusia dose modifications from Table 10 also added to Table 9 for clarity.  
Sections updated – Table 9 
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13. Retention of ECG traces added as part of a programme initiative to enable future QT 
investigations if required.  Section updated – Section 8.2.4 
14.
 
 
    Sections updated - Table 1, Table 2, Table 3 and 
Section 8.6.2 
15. Arm A primary endpoint rationale updated for clarity.  Section updated – Section 
4.3.1 
Version 4.0 – 18th June 2021 
1. Dose of RXC004 in Arm A updated to 2 mg QD, due to recent data from Phase 1 
study and Safety Review Committee recommendations.  RXC004 background, 
risk/benefit, dose rationale and dose modification sections also updated with most 
recent data from the Phase 1 dose escalation study  Sections updated – Section 
2.2.3, Section 2.3.1, Section 4.4.1, Section 6.6, Table 1, Table 4, Table 13, and 
Table 7. 
2. Inclusion criteria for entry into the combination treatment phase in Arm A added, to 
clarify when crossover to combination treatment can occur.  Sections updated – 
Figure 1, Section 5.1 and Appendix D 
3. Acceptable methods of contraception in the lifestyle consideration updated to be 
consistent with the Clinical Trial Facilitation Group (CTFG) recommendations for 
highly effective methods of contraception. Sections updated – Section 5.3.1 
4. Management plan for RXC004 related diarrhoea/colitis events added after safety 
review of data from the Phase 1 study.  Sections added – Appendix J  
5. The following items have been added to the protocol as a result of the COVID-19 
vaccination risk assessment; 
a. receipt of live (capable of replication) vaccinations within 4 weeks of 
starting study treatment eligibility criteria moved from Arm B specific 
exclusion criteria to core exclusion criteria.  Sections updated – Section 5.2  
b. Clarification on permitted COVID-19 vaccinations. Sections updated – 
Section 5.3.3.1 and 5.3.3.2 
c. Interruption of RXC004 for COVID-19 infections added to dose interruption 
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and stopping criteria.  Sections updated – Table 14 
d. Clarification on collection of COVID-19 adverse events added.  Sections 
updated – Section 8.3.11 
6. The following changes have been made to the schedule of assessments; 
a. Permitted windows added to pharmacokinetic sample timepoints on Cycle 0 
Day 1 and Cycle 1 Day 15 for clarity.  Sections updated – Table 1 and 
Table 2 
b. HCV, HBV and HIV testing in Arm A moved from pre-first cycle of 
RXC004+Nivolumab to the screening period following feedback from Ethics 
Committees. Sections updated – Table 1 
c. 
 
 
.  .  Sections updated – Table 1 and Table 2 
d. MSI testing removed from pre-screening activities and local MSI test added 
to screening after feedback from sites on availability of local testing.  
Sections updated – Table 1 and Table 2 
e. Collection of 
 after Cycle 2 removed, based on 
emerging data from Phase 1 study which indicates that collection of samples 
after Cycle 2 is not required.  Sections updated – Table 1 and Table 2 
7. Assessments to characterise and guidelines to treat RXC004 related dysgeusia added 
to protocol to better define and clinically manage dysgeusia events.  Assessment of 
dysgeusia also added to Secondary safety objective.  Sections updated - Section 
8.3.12, Table 1, Table 2, Table 3 and Appendix I. 
8. 
 
 
  
 
  Additional details of the centralised pre-screening 
assays for RNF43 and RSPO also added to Section 5.5.  Sections updated – 
Section 5.5, Section 8.6.1, Table 1, Table 2 and Table 3. 
9. Details of a Safety Monitoring Committee for Redx Phase 2 RCX004 studies added 
to protocol to aid patient safety monitoring.  Sections updated – Section 9.6 
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10. Additional language added to sample size determination to ensure that the decision 
for stopping development is not based purely on patients with RNF43 mutation or  
RSPO fusions alone.  Sections updated – Section 9.2 
11. Following an update to the Nivolumab SmPC, approval for Nivolumab to treat 
oesophageal squamous cell carcinoma added to Section 2.2.4 and updates made to 
the Nivolumab toxicity management guidelines.  Sections updated – Section 2.2.4 
and Appendix G  
12. Language about collection of scans preformed before consent moved from Inclusion 
criteria #4 and added into Section 8.1.1 so that availability of theses scans does not 
affect patient eligibility for the study.  Sections updated – Section 5.1 and Section 
8.1 
13. Changes required for UK local version 3.0 (see below) added into Global protocol.  
Sections updated – Section 5.1, 5.3.1, 5.3.4, 8.3.1, 8.3.10, Table 1 and Table 2 
14. Minor editorial changes were made throughout the protocol for consistency and 
clarity 
UK Local Version 3.0 – 18 February 2021 
1. Duration of contraception for women of childbearing potential amended to take into 
account the requirements for patients using nivolumab and denosumab, as per 
MHRA request.  Sections updated - Section 5.1, 5.3.1 and 8.3.10. 
2. Lifestyle restrictions updated to include avoiding direct sunlight and use of tanning 
equipment, as per MHRA request,  Section updated - Section 5.3 (new Section 
5.3.4 added) 
3. Schedule of assessments and time period for collection of adverse events clarified to 
be from signature of the main study informed consent, as per MHRA request.  
Sections updated - Section 8.3.1, Table 1 and Table 2 
Version 2.0 – 30 November 2020 
Initial creation 
Version 1.0 – 18 August 2020 
Not submitted to Regulatory Authorities 


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TABLE OF CONTENTS 
TITLE PAGE ............................................................................................................................. 1 
VERSION HISTORY ................................................................................................................ 4 
TABLE OF CONTENTS ......................................................................................................... 11 
LIST OF FIGURES ................................................................................................................. 14 
LIST OF TABLES ................................................................................................................... 14 
LIST OF APPENDICES .......................................................................................................... 15 
1 
PROTOCOL SUMMARY .................................................................................... 16 
 
Synopsis ................................................................................................................ 16 
 
Schedule of Assessments ...................................................................................... 19 
2 
INTRODUCTION ................................................................................................ 32 
 
Study Rationale ..................................................................................................... 33 
 
Background ........................................................................................................... 33 
2.2.1 
Wnt signalling in colorectal cancer ...................................................................... 33 
2.2.2 
Role of Wnt signalling in the immune response to cancer ................................... 34 
2.2.3 
RXC004 ................................................................................................................ 35 
2.2.4 
Nivolumab ............................................................................................................ 36 
 
Benefit/Risk Assessment ...................................................................................... 36 
2.3.1 
RXC004 risks ....................................................................................................... 36 
2.3.1.1 
Risks associated with targeting the Wnt pathway ................................................ 36 
2.3.1.2 
Risks of RXC004 associated adverse events ........................................................ 37 
2.3.2 
Nivolumab Risks .................................................................................................. 40 
2.3.3 
Benefit assessment ................................................................................................ 41 
2.3.4 
Overall Benefit: Risk Conclusion ......................................................................... 42 
3 
OBJECTIVES AND ENDPOINTS ...................................................................... 43 
4 
STUDY DESIGN ................................................................................................. 45 
 
Overall Design ...................................................................................................... 45 
 
Scientific Rationale for Study Design .................................................................. 45 
 
Rationale for Study Endpoints .............................................................................. 46 
4.3.1 
Arm A Primary Endpoint ...................................................................................... 46 
4.3.2 
Arm B Primary Endpoint ...................................................................................... 48 
 
Justification for Doses of RXC004 and Nivolumab ............................................. 48 
4.4.1 
RXC004 ................................................................................................................ 48 
4.4.1.1 
RXC004 Clinical Safety Data (NCT03447470) – Monotherapy Module 1 ......... 48 
4.4.1.2 
RXC004 Clinical Safety Data (NCT03447470) – in Combination with 
Nivolumab Module 2)........................................................................................... 54 
4.4.1.3 
RXC004 pharmacokinetic profile ......................................................................... 59 
4.4.1.4 
RXC004 Pharmacodynamic and Efficacy Data ................................................... 60 
4.4.1.5 
RXC004 monotherapy dose .................................................................................. 61 
4.4.1.6 
RXC004 dose in combination with nivolumab .................................................... 61 


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4.4.2 
Nivolumab ............................................................................................................ 61 
 
End of Study Definition ........................................................................................ 61 
5 
STUDY POPULATION ....................................................................................... 62 
 
Inclusion Criteria .................................................................................................. 62 
 
Exclusion Criteria ................................................................................................. 64 
 
Lifestyle Considerations ....................................................................................... 66 
5.3.1 
Contraception ........................................................................................................ 66 
5.3.2 
Meals and Dietary Restrictions ............................................................................. 66 
5.3.3 
Concomitant treatments ........................................................................................ 66 
5.3.3.1 
Prohibited medications ......................................................................................... 66 
5.3.3.2 
COVID-19 Vaccinations ....................................................................................... 67 
5.3.4 
Other Lifestyle Considerations ............................................................................. 68 
 
Screen Failures...................................................................................................... 68 
 
Pre-Screening Genetic Testing.............................................................................. 68 
5.5.1 
Central Testing ...................................................................................................... 68 
5.5.2 
Local Testing......................................................................................................... 69 
5.5.3 
MSS/MSI Testing ................................................................................................. 69 
6 
STUDY TREATMENT ........................................................................................ 70 
 
Study Treatment(s) Administered ......................................................................... 70 
6.1.1 
Investigational Products........................................................................................ 70 
 
Preparation/Handling/Storage/Accountability of Study Treatments .................... 70 
6.2.1 
RXC004 ................................................................................................................ 70 
6.2.2 
Nivolumab ............................................................................................................ 71 
6.2.3 
Denosumab ........................................................................................................... 72 
 
Randomisation ...................................................................................................... 73 
 
Study Treatment Compliance ............................................................................... 73 
6.4.1 
RXC004 ................................................................................................................ 73 
6.4.2 
Nivolumab ............................................................................................................ 73 
 
Concomitant Therapy ........................................................................................... 73 
6.5.1 
Rescue Medicine ................................................................................................... 74 
 
Dose Modification ................................................................................................ 74 
 
Access to Study Treatment after the End of the Study ......................................... 79 
7 
DISCONTINUATION OF STUDY TREATMENT AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ............................................................. 79 
 
Discontinuation of Study Treatment ..................................................................... 79 
7.1.1 
Treatment of Symptomatically Stable Patients after RECIST 1.1 Defined 
Progression ........................................................................................................... 80 
 
Participant Withdrawal from the Study ................................................................ 81 
 
Lost to Follow up .................................................................................................. 81 
8 
STUDY ASSESSMENTS AND PROCEDURES ................................................ 83 
 
Efficacy Assessments ............................................................................................ 83 


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8.1.1 
Tumour assessments ............................................................................................. 83 
8.1.2 
Survival assessments ............................................................................................ 84 
 
Safety Assessments ............................................................................................... 84 
8.2.1 
Clinical Safety Laboratory Assessments .............................................................. 84 
8.2.2 
Physical Examinations .......................................................................................... 85 
8.2.3 
Vital Signs ............................................................................................................. 85 
8.2.4 
Electrocardiograms ............................................................................................... 86 
8.2.5 
ECOG performance status .................................................................................... 86 
8.2.6 
Other Safety Assessments ..................................................................................... 86 
 
Adverse Events and Serious Adverse Events ....................................................... 87 
8.3.1 
Time Period and Frequency for Collecting AE and SAE Information ................. 87 
8.3.2 
Follow-up of AEs and SAEs ................................................................................. 87 
8.3.3 
Causality Collection.............................................................................................. 88 
8.3.4 
Adverse Events Based on Signs and Symptoms .................................................. 88 
8.3.5 
Adverse Events Based on Examinations and Tests .............................................. 89 
8.3.6 
Hy’s Law ............................................................................................................... 89 
8.3.7 
Disease Progression .............................................................................................. 90 
8.3.8 
Disease Under study ............................................................................................. 90 
8.3.9 
Reporting of Serious Adverse Events ................................................................... 90 
8.3.10 
Pregnancy ............................................................................................................. 90 
8.3.10.1 
Maternal Exposure ................................................................................................ 91 
8.3.10.2 
Paternal Exposure ................................................................................................. 91 
8.3.11 
COVID-19 infections............................................................................................ 91 
8.3.12 
Dysgeusia .............................................................................................................. 92 
8.3.13 
Adverse Events of Potential Interest (AEPI) ........................................................ 92 
 
Overdose ............................................................................................................... 92 
 
Human Biological Samples .................................................................................. 93 
8.5.1 
Pharmacokinetics .................................................................................................. 93 
8.5.1.1 
Determination of Drug Concentration .................................................................. 94 
8.5.2 
Pharmacodynamics ............................................................................................... 95 
8.5.2.1 
Collection of Samples ........................................................................................... 95 
 
Human Biological Sample Biomarkers ................................................................ 96 
8.6.1 
Collection of mandatory samples for biomarker analysis .................................... 96 
8.6.2 
.................................................................. 97 
8.6.3 
.............................................................................................................. 98 
9 
STATISTICAL CONSIDERATIONS ................................................................... 99 
 
Statistical Hypotheses ........................................................................................... 99 
 
Sample Size Determination .................................................................................. 99 
 
Populations for Analyses .................................................................................... 100 
 
Statistical Analyses ............................................................................................. 100 
9.4.1 
General Considerations ....................................................................................... 101 
9.4.1.1 
Patient Disposition .............................................................................................. 101 
9.4.1.2 
Protocol Deviations ............................................................................................ 101 
9.4.1.3 
Demographic and other baseline characteristics................................................. 101 
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9.4.1.4 
Medical History .................................................................................................. 101 
9.4.1.5 
Prior and concomitant therapy ............................................................................ 102 
9.4.2 
Efficacy ............................................................................................................... 102 
9.4.2.1 
Primary Endpoint(s)............................................................................................ 102 
9.4.2.2 
Secondary Endpoint(s)........................................................................................ 102 
9.4.2.3 
Tertiary/Exploratory Endpoint(s) ........................................................................ 103 
9.4.3 
Safety .................................................................................................................. 103 
9.4.3.1 
Adverse events .................................................................................................... 104 
9.4.3.2 
Laboratory parameters ........................................................................................ 104 
9.4.3.3 
Vital signs ........................................................................................................... 104 
9.4.4 
Other Analyses .................................................................................................... 104 
 
Interim Analyses ................................................................................................. 104 
 
Safety Monitoring Committee ............................................................................ 105 
10 
APPENDICES .................................................................................................... 106 
11 
REFERENCES ................................................................................................... 142 
 
LIST OF FIGURES 
Figure 1 
Overall Design ............................................................................................ 18 
Figure 2 
Treatment after first progression (Arm A) ................................................ 120 
Figure 3 
Treatment after first progression (Arm B) ................................................ 121 
Figure 4 
Treatment after first progression for patients that remain on RXC004 
monotherapy (Arm A) ............................................................................... 122 
 
LIST OF TABLES 
Table 1 
Arm A Schedule of Assessments ................................................................ 19 
Table 2 
Arm B Schedule of Assessments ................................................................ 26 
Table 3 
Objectives and Endpoints ............................................................................ 43 
Table 4 
Grade 2 or higher RXC004 related adverse events, including DLTs 
observed in DLT evaluable patients as of 30 July 2021 (Phase 1 study 
RXC004/0001, monotherapy Module 1) ..................................................... 49 
Table 5 
Summary of Treatment-Emergent Adverse Events Phase 1 study 
RXC004/0001, monotherapy Module 1) ..................................................... 51 
Table 6 
Most common (occurring in at least 20% patients) treatment emergent 
AEs in Phase 1 study RXC004/0001 (monotherapy Module 1) ................. 52 
Table 7 
Most common (occurring in at least 20% patients) treatment related AEs 
in Phase 1 study RXC004/0001 (monotherapy Module 1) ......................... 53 


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Table 8 
Treatment-related AEs Grade 2 or higher including DLTs, observed in 
DLT evaluable patients as of 01 July 2022, Phase 1 study RXC004/0001 
(RXC004 + nivolumab Module 2) .............................................................. 55 
Table 9 
Summary of Treatment-Emergent Adverse Events as of 01 July 2022, 
Phase 1 study RXC004/0001 (RXC004 + Nivolumab Module 2) .............. 56 
Table 10 
Most common (occurring in at least 20% patients) TEAEs, as of 
01 July 2022, Phase 1 study RXC004/0001 (RXC004 + nivolumab 
Module 2) .................................................................................................... 57 
Table 11 
Most common (occurring in at least 20% patients) AEs considered 
related to RXC004 or nivolumab, as of 01 July 2022, Phase 1 study 
RXC004/0001 (RXC004 + nivolumab Module 2) ...................................... 58 
Table 12 
Steady state pharmacokinetic parameters, as of 01 July 2022, Phase 1 
study RXC004/0001 RXC004 monotherapy and combination with 
nivolumab (Module 1 and Module 2) ......................................................... 60 
Table 13 
Investigational Products .............................................................................. 70 
Table 14 
Dose Modification and Stopping Criteria ................................................... 75 
Table 15 
Guidance for dose reductions for RXC004-related adverse events ............ 78 
Table 16 
Laboratory safety variables ......................................................................... 85 
Table 17 
Definition of PK Parameters ....................................................................... 94 
Table 18 
Populations for Analysis ........................................................................... 100 
Table 19 
Nivolumab toxicity management and dose modifications ........................ 127 
Table 20 
Management of colitis events .................................................................... 139 
 
LIST OF APPENDICES 
Appendix A 
Regulatory, Ethical, and Study Oversight Considerations ........................ 107 
Appendix B 
Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ......................................................................... 111 
Appendix C 
Handling of Human Biological Samples ................................................... 116 
Appendix D 
RECIST 1.1 (Response Evaluation Criteria in Solid Tumours) Responses118 
Appendix E 
Prohibited CYP3A4 Inhibitors, and Inducers ........................................... 123 
Appendix F 
RNF43/RSPO aberrations ......................................................................... 125 
Appendix G 
Nivolumab Toxicity Management and Dose Modification Guidelines .... 127 
Appendix H 
Abbreviations ............................................................................................ 135 
Appendix I 
Dysgeusia treatment guidelines ................................................................. 137 
Appendix J 
Management of Colitis Events .................................................................. 139 
 


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1 
PROTOCOL SUMMARY 
 
Synopsis 
Protocol Title: A Multi-arm, Phase II, Open-Label, Multicentre Study to Assess the 
Preliminary Efficacy of RXC004 in Monotherapy and in Combination with Nivolumab, in 
Patients with Ring Finger Protein 43 (RNF43) or R-spondin (RSPO) Aberrated, Metastatic, 
Microsatellite Stable, Colorectal Cancer who have Progressed following Therapy with Current 
Standard of Care (PORCUPINE study)
Short Title: Phase II Study to Assess Efficacy of RXC004 +/- Nivolumab in RNF43/RSPO 
Aberrated mCRC MSS after Progression on SoC.   
Rationale: 
The Wnt signalling pathway plays an important role in tumourigenesis and has been shown to 
be elevated in both ring finger protein 43 (RNF43) and R-Spondin (RSPO) aberrated 
colorectal cancer (CRC).  There is also evidence that Wnt signalling may have a role in 
enabling cancers to avoid immunosurveillance and hence resistance to some immunotherapies.  
RXC004 is a small molecule porcupine (PORCN) inhibitor which reduces Wnt signalling and 
therefore may offer an opportunity to deliver clinical benefit by both a direct tumour targeting 
effect in genetically selected patients and by converting the tumour microenvironment from an 
immune “cold” to an immune “hot” signature making the tumour sensitive to anti-PD1/PD-L1 
inhibition. 
The PORCUPINE study will therefore evaluate RXC004 as monotherapy and in combination 
with anti-PD1 (nivolumab) in ! 2nd line metastatic MSS colorectal cancer patients who have 
either a RNF43 LoF mutation or a RSPO fusion/translocation. 
 
 


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Objectives and Endpoints 
 
Objectives 
Endpoints 
Primary 
To assess the anti-tumour activity of RXC004 
monotherapy and RXC004 + nivolumab  
Monotherapy : Disease control rate (DCR) using 
each patient’s Best Overall Response (BOR) 
according to RECIST 1.1  
Combination : Objective response rate (ORR) 
using each patient’s BOR according to 
RECIST 1.1 
Secondary 
To further assess the preliminary efficacy of 
RXC004 monotherapy and RXC004 + 
nivolumab  
% change in the sum of target lesions, duration 
of response (DoR), PFS, ORR (monotherapy) 
and DCR (combination) using investigator 
assessments according to RECIST 1.1 and OS. 
To assess the PK of RXC004 as monotherapy 
and in combination with nivolumab 
Maximum plasma concentration (Cmax) after 
Dose 1, Cmax at steady state, minimum observed 
plasma concentration (Cmin) at steady state as 
well as other relevant parameters (e.g. tmax, t½, 
λz, AUC0-∞, CL/F, and Vz/F).   
To assess the safety and tolerability profile of 
RXC004 monotherapy and RXC004 + 
nivolumab combination 
Incidence of AEs, SAEs, dose reductions, 
interruptions and discontinuations, and 
assessment of dysgeusia. 
 
A full list of objectives can be found in Table 3. 
 
 


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Figure 1 
Overall Design 
 
Patients in Arm A who have undergone dose reduction during monotherapy cannot have the RXC004 dose re-escalated if 
switching to RXC004 + nivolumab combination therapy. The RXC004 dose must be discussed with the Sponsor prior to 
starting combination therapy. 
DCR disease control rate, ECOG performance status, LoF, mCRC metastatic colorectal cancer; MSS Microsatellite stable; 
ORR objective response rate; OS Overall survival; PFS progression free survival; RNF43 Ring finger 43; RSPO R-Spondin; 
RXC004 Porcupine inhibitor 
 
Disclosure Statement: This is an open label study two Arms A & B  
Number of Participants: 
Approximately 
 patients will be enrolled in total to provide 20 evaluable patients in each 
arm. Patients who progress on Arm A will have the opportunity to cross over into the 
combination arm, once this is open to recruitment.  
Pre-screened for MSS status, RNF43 loss of 
function mutations and RSPO fusions 
Estimated 
 p patients 
Screened (Signed main ICF) 
Estimated 
 patients 
Enrolled (dosed) 
Estimated 
 patients 
Evaluable patients 
Estimated 
 patients 
 
Note: "Enrolled" means patients that receive a dose of RXC004. Potential patients who are 
screened (sign main ICF) for the purpose of determining eligibility for the study but are not 
enrolled are considered “screen failures”, unless otherwise specified by the protocol.  
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Schedule of Assessments 
Table 1 
Arm A Schedule of Assessments 
 
Table 1 – Arm A Schedule of assessments 
Treatment Phase 
Pre-treatment 
RXC004 monotherapy 
RXC004 + nivolumab 
combination j 
Post-treatment 
 
Pre-
Screening Screening 
Cycle 0 
(3-7 days) 
Cycle 1 
(28 day cycle) 
Cycle 2 
onwards 
(28 day cycles) 
Pre-first 
Cycle 
Cycle 1 
onwards 
(28 day cycles) 
IP 
Discontinuation 
30 day 
Follow-
upv 
90 day 
Follow-
upv 
Survival 
follow-up 
Window 
n/a 
-28 to –1 
D1 
D1 
D15 
+/- 1d 
D1 +/- 3d 
 
D1 +/- 3d 
Within 7 
days 
+/- 3d 
+/- 3d 
q8w +/- 
1wk 
Pre-Screening 
informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Genetic screening 
for RNF43/RSPO 
aberrations and 
MSI status t 
X 
 
 
 
 
 
 
 
 
 
 
 
Main study 
informed consent 
 
X 
 
 
 
 
 
 
 
 
 
 
Demography & 
baseline 
characteristics 
 
X 
 
 
 
 
 
 
 
 
 
 
Smoking history 
 
X 
 
 
 
 
 
 
 
 
 
 
Central MSI testing 
(if not completed in 
pre-screening) 
 
X 
 
 
 
 
 
 
 
 
 
 
&&,
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Table 1 – Arm A Schedule of assessments 
Treatment Phase 
Pre-treatment 
RXC004 monotherapy 
RXC004 + nivolumab 
combination j 
Post-treatment 
 
Pre-
Screening Screening 
Cycle 0 
(3-7 days) 
Cycle 1 
(28 day cycle) 
Cycle 2 
onwards 
(28 day cycles) 
Pre-first 
Cycle 
Cycle 1 
onwards 
(28 day cycles) 
IP 
Discontinuation 
30 day 
Follow-
upv 
90 day 
Follow-
upv 
Survival 
follow-up 
Window 
n/a 
-28 to –1 
D1 
D1 
D15 
+/- 1d 
D1 +/- 3d 
 
D1 +/- 3d 
Within 7 
days 
+/- 3d 
+/- 3d 
q8w +/- 
1wk 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Medical/ 
surgical history 
 
X 
 
 
 
 
 
 
 
 
 
 
Oral and dental 
assessmentw 
 
X 
Oral assessment at each visit - only if patient reports dysgeusia 
 
Inclusion/ exclusion 
criteria 
 
X 
 
 
 
 
Xk 
 
 
 
 
 
HepB, HepC and 
HIV testing 
 
X 
 
 
 
 
 
 
 
 
 
 
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Table 1 – Arm A Schedule of assessments 
Treatment Phase 
Pre-treatment 
RXC004 monotherapy 
RXC004 + nivolumab 
combination j 
Post-treatment 
 
Pre-
Screening Screening 
Cycle 0 
(3-7 days) 
Cycle 1 
(28 day cycle) 
Cycle 2 
onwards 
(28 day cycles) 
Pre-first 
Cycle 
Cycle 1 
onwards 
(28 day cycles) 
IP 
Discontinuation 
30 day 
Follow-
upv 
90 day 
Follow-
upv 
Survival 
follow-up 
Window 
n/a 
-28 to –1 
D1 
D1 
D15 
+/- 1d 
D1 +/- 3d 
 
D1 +/- 3d 
Within 7 
days 
+/- 3d 
+/- 3d 
q8w +/- 
1wk 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Physical 
examination 
 
X 
X 
X 
 
X 
X 
X 
X 
 
 
 
ECOG performance 
status 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Pregnancy test 
(WOCBP only) 
 
(X) 
(X)† 
(X) 
(X) 
(X) 
(X) 
(X) 
 
 
 
 
Baseline and ‘on 
treatment’ tumour 
biopsies 
(mandatory)a 
 
X 
 
 
Xg 
Xl 
 
Xl 
 
 
 
 
Vital signs 
(including height 
and weight)r 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Clinical chemistry / 
Haematology 
 
X 
X† 
X 
X 
X 
X 
X 
X 
X 
X 
 
TSH (reflex 
T3/T4)u 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
ECGc 
 
X 
X 
X 
X 
Xh 
X 
Xh 
X 
 
 
 
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Table 1 – Arm A Schedule of assessments 
Treatment Phase 
Pre-treatment 
RXC004 monotherapy 
RXC004 + nivolumab 
combination j 
Post-treatment 
 
Pre-
Screening Screening 
Cycle 0 
(3-7 days) 
Cycle 1 
(28 day cycle) 
Cycle 2 
onwards 
(28 day cycles) 
Pre-first 
Cycle 
Cycle 1 
onwards 
(28 day cycles) 
IP 
Discontinuation 
30 day 
Follow-
upv 
90 day 
Follow-
upv 
Survival 
follow-up 
Window 
n/a 
-28 to –1 
D1 
D1 
D15 
+/- 1d 
D1 +/- 3d 
 
D1 +/- 3d 
Within 7 
days 
+/- 3d 
+/- 3d 
q8w +/- 
1wk 
DXA scan 
 
X 
On Cycle 4 and Cycle 7 of RXC004 treatment and then every 7 
RXC004 cycles thereafter whilst on study treatment 
 
 
 
 
Blood samples for 
bone turnover 
biomarkers (β-
CTX) 
 
X 
 
 
X 
X 
 
X 
 
 
 
 
 
 
 
X 
 
X 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
X† 
 
X 
X 
 
X 
 
 
 
 
 
 
 
 
X† 
 
X 
X 
 
X 
 
 
 
 
 
 
 
 
X† 
 
X 
Cycle 2 
only 
 
Cycle 1 and 
2 only 
 
 
 
 
 
 
 
 
X† 
 
X 
X 
 
X 
X 
 
 
 
 
 
 
 
X† 
 
X 
X 
 
X 
X 
 
 
 
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Table 1 – Arm A Schedule of assessments 
Treatment Phase 
Pre-treatment 
RXC004 monotherapy 
RXC004 + nivolumab 
combination j 
Post-treatment 
 
Pre-
Screening Screening 
Cycle 0 
(3-7 days) 
Cycle 1 
(28 day cycle) 
Cycle 2 
onwards 
(28 day cycles) 
Pre-first 
Cycle 
Cycle 1 
onwards 
(28 day cycles) 
IP 
Discontinuation 
30 day 
Follow-
upv 
90 day 
Follow-
upv 
Survival 
follow-up 
Window 
n/a 
-28 to –1 
D1 
D1 
D15 
+/- 1d 
D1 +/- 3d 
 
D1 +/- 3d 
Within 7 
days 
+/- 3d 
+/- 3d 
q8w +/- 
1wk 
RECIST 1.1 
assessments 
(by CT/MRI)n 
 
X 
 
On study tumour 
assessments should occur 
q8w +/- 1 week (relative to 
first dose of IP) for the 
first 56 weeks, followed by 
q12w +/- 1 week until 
RECIST1.1 radiological 
progressionx 
On study tumour 
assessments should 
continue q8w +/- 1 week 
(relative to first dose of 
IP) for the first 56 weeks, 
followed by q12w +/- 1 
week until RECIST1.1 
radiological progression 
q, x.  
If a patient discontinues for a reason other 
than progression then tumour assessments 
should continue q8w +/- 1 week (relative to 
first dose of IP) for the first 56 weeks, 
followed by q12w +/- 1 week until 
RECIST1.1 radiological progression 
 
(manda
ndator
ory unless  
unavailable at site)i 
 
X* 
 
On study 
udy 
 
assessments should occur 
at week 8 and week 16 +/- 
1 week relative to first 
dose of IP. 
On study 
udy 
 
assessments should occur 
at week 8 and week 16 
+/- 1 week relative to 
first dose of combination 
 
 
 
 
Vitamin D3 and 
Calcium 
supplements 
 
Patients should commence 800 IU vitamin D3 (Cholecalciferol) daily and 
1000-1500 mg calcium daily supplements from ICF signature until RXC004 
discontinuation 
 
 
 
 
Denosumab dosingy 
 
 
120 mg sc Denosumab once every month from C0D1 until 
RXC004 discontinuation  
 
 
 
 
RXC004 dosingm 
 
 
X 
(2 mg 
single 
dose) 
Continuous daily dosing 
(2 mg QD) 
 
Continuous 
daily dosing 
(1.5 mg QD) 
 
 
 
 
RXC004 diary 
 
 
X 
Review at each visit 
 
 
 
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Table 1 – Arm A Schedule of assessments 
Treatment Phase 
Pre-treatment 
RXC004 monotherapy 
RXC004 + nivolumab 
combination j 
Post-treatment 
 
Pre-
Screening Screening 
Cycle 0 
(3-7 days) 
Cycle 1 
(28 day cycle) 
Cycle 2 
onwards 
(28 day cycles) 
Pre-first 
Cycle 
Cycle 1 
onwards 
(28 day cycles) 
IP 
Discontinuation 
30 day 
Follow-
upv 
90 day 
Follow-
upv 
Survival 
follow-up 
Window 
n/a 
-28 to –1 
D1 
D1 
D15 
+/- 1d 
D1 +/- 3d 
 
D1 +/- 3d 
Within 7 
days 
+/- 3d 
+/- 3d 
q8w +/- 
1wk 
Nivolumab dosing 
 
 
 
 
 
 
 
480 mg q4w 
+/- 3 dayso 
 
 
 
 
RXC004 PKf 
 
 
X 
 
X 
X 
 
X 
X 
 
 
 
Concomitant 
medication 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Taste assessmentz 
 
X 
At each visit – only if patient reports dysgeusia 
 
Survival status and 
post-
discontinuation 
anti-cancer therapyp 
 
 
 
 
 
 
 
 
 
X 
X 
X 
Once Arm B is opened, patients who are eligible for both Arm A and Arm B will be randomised 2:1 to Arm B: Arm A in an open-label manner on Day 1. Randomisation will be stratified by genetic 
alteration (RNF43, RSPO). 
a  
A baseline (pre-first dose IP) biopsy is a mandatory requirement, except in exceptional circumstances where biopsy is not technically feasible. All patients without a baseline sample must be 
approved by Sponsor before starting study treatment.  The baseline 
 can be a ‘fresh newly acquired’ biopsy or an 
 ( (preferably from the same organ site that ‘on 
treatment’ biopsy will be taken) and taken after completion of all prior s standard of c care treatments. In exceptional circumstances where b baseline b biopsy cannot be scheduled before C0D1, the 
procedure may be performed before C1D1 after a minimum of 4 days washout from C0D1. A second ‘on treatment’ biopsy at Cycle 1 Day 15 (+/- 1 day), is also mandatory providing that 
investigator judges the second biopsy to be technically and clinically feasible.  The Cycle 1 Day 15 biopsy should be collected post-dose and the time of collection should be accurately recorded.  
RECIST 1.1 target lesions should not be chosen for biopsies. 
b 
c 
Triplicat
cate E
e ECGs s should b be e co
collect
ected a as f follows; 
Cycle 0: 
 
Cycle 1, 
 
Cycle X, 
At selected s sites, ambulatory H
 Holter monitoring w
 will b be used on C
 Cycle 0 Day 1 and Cycle 1 Day 15 for central analysis of digital ECG information. 
d 
 
e 
 
 
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f 
Blood samples for PK analysis should be collected as follows (the actual time for each blood draw must be accurately recorded); 
Cycle 0: 
 
Cycle 1, 
 
Cycle X, 
 
g 
h 
ECGs arare e required at C2D1 and as clinically indicated from C3D1 onwards 
i 
 
 
j 
RXC004 +
 + n nivolumab combination treatment will be allowed for up to 20 patients that have progressed on RXC004 monotherapy.  This treatment phase will only be opened after the RP2D for 
RXC004 + nivolumab is determined 
k 
Patients that consent to RXC004 + nivolumab combination treatment will have eligibility re-assessed for RXC004 + nivolumab combination specific criteria 
l 
One ‘on treatment’ biopsy is required during cycle 3 of RXC004 monotherapy or RXC004 + nivolumab combination treatment, providing that investigator judges the biopsy to be technically and 
clinically feasible. The biopsy should be collected post-dose and the time of collection should be accurately recorded. 
m 
 Patients must fast (water to drink only) for at least 2 hours prior to taking a dose to at least 1-hour post-dose for all doses 
n 
CT (preferred) or MRI, each preferably with IV contrast.  It is strongly recommended to maintain use of the same imaging modality (CT or MRI), acquisition protocol, facility and scanner across 
all imaging time points per patient. 
o 
480 mg IV infusion over 60 minutes, q4w +/- 3 days, unless an infusion needs to held due to an adverse event.  Results for vital signs (including weight), performance status, chemistry, 
haematology and thyroid function labs must be available before commencing an infusion (within 3 days) and reviewed by the treating physician or Investigator prior to dosing 
p 
Survival and details of first and subsequent therapies for cancer, after discontinuation of treatment, will be collected. 
q 
Patients treated with RXC004 monotherapy that radiologically progress as per RECIST1.1 at the 8 week scan, may be treated with RXC004 + nivolumab combination, subject to meeting 
combination treatment eligibility criteria. The most recent scan that shows progression on RXC004 monotherapy treatment will be used as the baseline scan for the combination treatment (see 
Section 7.1.1 and Appendix D for more details).    
r 
Height is required at screening only 
s 
 
t 
 
 
 
 
u 
T3 a and T
 T4 will o only b be m
 measured i if TSH is abnormal or if t therere i
e is clinical suspicion of an AE related to the endocrine system 
v 
Follow up assessments should be performed 30 days after discontinuation of RXC004 and 90 days after last dose of nivolumab (for patients treated with RXC004 and nivolumab) 
w 
A dental examination with preventive dentistry if appropriate and an individual benefit-risk assessment is mandatory prior to treatment with denosumab.  An initial dental examination may be 
performed by a member of the clinical team who can assess the need for referral to a dentist for further assessment including any preventative dentistry.  A visual oral examination (including 
tongue, palate, uvula, tonsils, buccal mucosa, lips, gums and parotid duct) should also be performed at baseline and at each scheduled visit where dysgeusia is reported as an adverse event.     
x 
Symptomatically stable patients may continue study treatment after RECIST1.1 progression, until either symptomatic progression or second RECIST1.1 progression (relative to the first 
RECIST1.1 progression on a given study treatment).  Patients who continue study treatment after RECIST1.1 progression should continue RECIST1.1 assessments as per protocol until 
discontinuation of study treatment.  See Section 7.1.1 and Appendix D for more details. 
y 
All patients must receive denosumab before first dose of RXC004.  120 mg sc denosumab should be administered approximately once every month from C0D1 until RXC004 discontinuation.  
Investigators may delay subsequent denosumab doses until the next scheduled visit providing that there is no significant increase in β-CTX compared to baseline, according to Investigator 
judgement. 
z 
A taste assessment (consisting of a specific set of questions) will be performed at screening and at each study visit when patient reports dysgeusia.  Please see Section 8.3.12 for more details 
# 
Consent and collection of blood sample during screening is preferred, but patients can consent/sample collected at any time during study 
† 
These tests can be performed up to 24 hours before study treatment is administered on C0D1. They must be performed pre-dose.  
* 
 
 
 
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Table 2 
Arm B Schedule of Assessments 
 
Table 2 – Arm B (RXC004 + nivolumab combination) Schedule of assessments 
 
Pre-
Screening 
Screening 
Cycle 0 
(3-7 days) 
Cycle 1 
(28 day cycle) 
Cycle 2 
onwards 
(28 day cycles) 
IP 
Discontinuation 
30 day 
Follow-upr 
90 day 
Follow-upr 
Survival 
follow-up 
Window 
n/a 
-28 to –1 
D1 
D1 
D15 
+/- 1d 
D1 
+/- 3d 
Within 7 days of 
discontinuation 
+/- 3d 
+/- 3d 
q8w +/- 
1wk 
Pre-Screening 
informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Genetic screening for 
RNF43/RSPO 
aberrations and MSI 
statusp 
X 
 
 
 
 
 
 
 
 
 
Main study informed 
consent 
 
X 
 
 
 
 
 
 
 
 
Demography & 
baseline 
characteristics 
 
X 
 
 
 
 
 
 
 
 
Smoking history 
 
X 
 
 
 
 
 
 
 
 
Central MSI testing 
(if not completed in 
pre-screening) 
 
X 
 
 
 
 
 
 
 
 
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Table 2 – Arm B (RXC004 + nivolumab combination) Schedule of assessments 
 
Pre-
Screening 
Screening 
Cycle 0 
(3-7 days) 
Cycle 1 
(28 day cycle) 
Cycle 2 
onwards 
(28 day cycles) 
IP 
Discontinuation 
30 day 
Follow-upr 
90 day 
Follow-upr 
Survival 
follow-up 
Window 
n/a 
-28 to –1 
D1 
D1 
D15 
+/- 1d 
D1 
+/- 3d 
Within 7 days of 
discontinuation 
+/- 3d 
+/- 3d 
q8w +/- 
1wk 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Medical/surgical 
history 
 
X 
 
 
 
 
 
 
 
 
Oral and dental 
assessments 
 
X 
Oral assessment at each visit - only if patient reports dysgeusia 
 
Inclusion/exclusion 
criteria 
 
X 
 
 
 
 
 
 
 
 
HepB, HepC and 
HIV testing 
 
X 
 
 
 
 
 
 
 
 
 
 
 
(opt
optiona
onal)w 
 
X 
 
 
 
 
 
 
 
 
Physical examination 
 
X 
X 
X 
 
X 
X 
 
 
 
ECOG performance 
status 
 
X 
X 
X 
X 
X 
X 
 
 
 
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Table 2 – Arm B (RXC004 + nivolumab combination) Schedule of assessments 
 
Pre-
Screening 
Screening 
Cycle 0 
(3-7 days) 
Cycle 1 
(28 day cycle) 
Cycle 2 
onwards 
(28 day cycles) 
IP 
Discontinuation 
30 day 
Follow-upr 
90 day 
Follow-upr 
Survival 
follow-up 
Window 
n/a 
-28 to –1 
D1 
D1 
D15 
+/- 1d 
D1 
+/- 3d 
Within 7 days of 
discontinuation 
+/- 3d 
+/- 3d 
q8w +/- 
1wk 
Pregnancy test 
(WOCBP only) 
 
(X) 
(X)x 
(X) 
(X) 
(X) 
 
 
 
 
Baseline and ‘on 
treatment’ tumour 
biopsies (mandatory)a 
 
X 
 
 
X 
Xg 
 
 
 
 
Vital signs (including 
height and weight)m 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Clinical chemistry / 
Haematology 
 
X 
Xx 
X 
X 
X 
X 
X 
X 
 
TSH (reflex T3/T4)q 
 
X 
 
X 
X 
X 
X 
X 
X 
 
ECGv 
 
X 
X 
X 
X 
Xh 
X 
 
 
 
DXA scan 
 
X 
On Cycle 4 and Cycle 7 of RXC004 treatment 
and then every 7 RXC004 cycles thereafter 
whilst on study treatment  
 
 
 
 
Blood samples for 
bone turnover 
biomarkers (β-CTX) 
 
X 
 
 
X 
X 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
Xx 
 
X 
X 
 
 
 
 
 
 
 
 
Xx 
 
X 
X 
 
 
 
 
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Table 2 – Arm B (RXC004 + nivolumab combination) Schedule of assessments 
 
Pre-
Screening 
Screening 
Cycle 0 
(3-7 days) 
Cycle 1 
(28 day cycle) 
Cycle 2 
onwards 
(28 day cycles) 
IP 
Discontinuation 
30 day 
Follow-upr 
90 day 
Follow-upr 
Survival 
follow-up 
Window 
n/a 
-28 to –1 
D1 
D1 
D15 
+/- 1d 
D1 
+/- 3d 
Within 7 days of 
discontinuation 
+/- 3d 
+/- 3d 
q8w +/- 
1wk 
 
 
 
 
Xx 
 
X 
Cycle 2 only 
 
 
 
 
  
 
 
 
Xx 
 
X 
X 
X 
 
 
 
 
 
 
 
Xx 
 
X 
X 
X 
 
 
 
RECIST 1.1 
assessments (by 
CT/MRI)j 
 
X 
 
On study tumour assessments should occur q8w +/- 1 week (relative to first dose of IP) for the 
first 56 weeks, followed by q12w +/- 1 week until RECIST1.1 radiological progression n 
 
(manda
ndatory u
y unless 
unavailable at site)i 
 
Xy 
On study 
udy 
 assessments should occur at 
week 8 and week 16 +/- 1 week relative to first 
dose of IP. 
 
 
 
 
Vitamin D3 and 
Calcium supplements 
 
Patients should commence 800 IU vitamin D3 
(Cholecalciferol) daily and 1000-1500 mg calcium daily 
supplements from ICF signature until RXC004 
discontinuation 
 
 
 
 
Denosumab dosingt 
 
 
120 mg sc Denosumab once every month from 
C0D1 until RXC004 discontinuation  
 
 
 
 
RXC004 dosing 
 
 
X 
(1.5 mg 
single 
dose) 
Continuous daily dosing (1.5 mg 
QD) 
 
 
 
 
RXC004 diary 
 
 
X 
Review at each visit 
 
 
 
Nivolumab dosing 
 
 
 
480 mg q4w +/- 3 daysk 
 
 
 
 
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Table 2 – Arm B (RXC004 + nivolumab combination) Schedule of assessments 
 
Pre-
Screening 
Screening 
Cycle 0 
(3-7 days) 
Cycle 1 
(28 day cycle) 
Cycle 2 
onwards 
(28 day cycles) 
IP 
Discontinuation 
30 day 
Follow-upr 
90 day 
Follow-upr 
Survival 
follow-up 
Window 
n/a 
-28 to –1 
D1 
D1 
D15 
+/- 1d 
D1 
+/- 3d 
Within 7 days of 
discontinuation 
+/- 3d 
+/- 3d 
q8w +/- 
1wk 
RXC004 PKf 
 
 
X 
 
X 
X 
X 
 
 
 
Concomitant 
medication 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse events 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Taste assessmentu 
 
X 
At each visit – only if patient reports dysgeusia 
 
Survival status and 
post-discontinuation 
anti-cancer therapy l 
 
 
 
 
 
 
 
X 
X 
X 
Once Arm B is opened, patients who are eligible for both Arm A and Arm B will be randomised 2:1 to Arm B: Arm A in an open-label manner on Day 1. Randomisation will be stratified by genetic 
alteration (RNF43, RSPO). 
a  
A baseline (pre-first dose IP) biopsy is a mandatory requirement, except in exceptional circumstances where biopsy is not technically feasible. All patients without a baseline sample must be 
approved by Sponsor before starting study treatment.  The baseline 
 can be a ‘fresh newly acquired’ biopsy or an 
 (preferably from the same organ site that ‘on 
treatment’ biopsy will be taken) and taken after completion of all prior s standard of c care treatments. In exceptional circumstances w
 where baseline biopsy cannot be scheduled before C0D1, the 
procedure may be performed before C1D1 after a minimum of 4 days washout from C0D1. A second ‘on treatment’ biopsy at Cycle 1 Day 15 (+/- 1 day), is also mandatory providing that 
investigator judges the second biopsy to be technically and clincally feasible.  The Cycle 1 Day 15 biopsy should be collected post-dose and the time of collection should be accurately recorded.  
RECIST 1.1 target lesions should not be chosen for biopsies.  
b 
  
c 
 
d 
 
e 
 
 
f 
Blood s samples f for P
 PK analysis should be collected as follows (the actual time for each blood draw must be accurately recorded); 
Cycle 0: 
 
Cycle 1, 
 
Cycle X, 
 
g 
One ‘on treatment’ biopsy i is r requ
quired d during Cyclcle 3
e 3 o of treat
eatment, p prov
oviding
ng t that inv
nvestigator judges the biopsy to be technically and clinically feasible.  The biopsy should be collected post-dose 
and the time of collection should be accurately recorded. 
h 
ECGs are required at C2D1 and as clinically indicated from C3D1 onwards 
i 
 
 
 
j 
CT ( (preferred) o or M
 MRI, each preferably with IV contrast.  It is strongly recommended to maintain use of the same imaging modality (CT or MRI), acquisition protocol, facility and scanner across 
all imaging time points per patient. 
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k 
480 mg IV infusion over 60 minutes, q4w +/- 3 days, unless an infusion needs to held due to an adverse event.  Results for vital signs (including weight), performance status, chemistry, 
haematology, and thyroid function labs must be available before commencing an infusion (within 3 days) and reviewed by the treating physician or Investigator prior to dosing. 
l 
Survival and details of first and subsequent therapies for cancer, after discontinuation of treatment, will be collected 
m 
height is required at screening only 
n 
Symptomatically stable patients may continue RXC004 + nivolumab treatment after the RECIST1.1 progression on combination treatment, until symptomatic progression or second RECIST1.1 
progression (relative to the first RECIST1.1 progression).  Patients who continue study treatment after RECIST1.1 progression should continue RECIST1.1 assessments as per protocol until 
discontinuation of study treatment.  See Section 7.1.1 and Appendix D for more details. 
o 
 
p 
 
 
 
 
q 
T3 a and T
 T4 will o only b be m
 measured if T
 TSH i is a abnormal o or if t there i is clinical suspicion of an AE related to the endocrine system 
r 
Follow up assessments should be performed 30 days after discontinuation of IP and 90 days after last dose of Nivolumab 
s 
A dental examination with preventive dentistry if appropriate and an individual benefit-risk assessment is mandatory prior to treatment with denosumab.  An initial dental examination may be 
performed by a member of the clinical team who can assess the need for referral to a dentist for further assessment including any preventative dentistry.  A visual oral examination (including 
tongue, palate, uvula, tonsils, buccal mucosa, lips, gums and parotid duct) should also be performed at baseline and at each scheduled visit were dysgeusia is reported as an adverse event 
t 
All patients must receive first dose of denosumab before first dose of RXC004.  120 mg sc denosumab should be administered approximately once every month from C0D1 until RXC004 
discontinuation.  Investigators may delay subsequent denosumab doses until the next scheduled visit providing that there is no significant increase in β-CTX compared to baseline, according to 
Investigator judgement. 
u 
A taste assessment (consisting of a specific set of questions) will be performed at screening and at each study visit when patient reports dysgeusia.  Please see Section 8.3.12 for more details. 
Patients must fast (water to drink only) for at least 2 hours prior to taking a dose to at least 1-hour post-dose for all doses 
v 
Triplicate ECGs should be collected as follows; 
Cycle 0: 
 
Cycle 1, 
 
Cycle X, 
At selected s sites, ambulatory H
 Holter monitoring w
 will b be used on C
 Cycle 0 Day 1 and Cycle 1 Day 15 for central analysis of digital ECG information. 
w 
Consent and collection of blood sample during screening is preferred, but patients can consent/sample collected at any time during study 
x 
These tests can be performed up to 24 hours before study treatment is administered. They must be performed pre-dose. 
y 
 
 
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2 
INTRODUCTION 
Colorectal cancer (CRC) accounts for approximately 10% of all cancer related deaths 
worldwide (Bray et al 2018).  Approximately 20-25% of newly diagnosed CRC is metastatic 
at presentation and approximately 70% will eventually develop metastases (Ansa et al 2018, 
SEER cancer stats review 2015). 
Treatment of metastatic colorectal cancer is based on several factors including patient factors 
(e.g. performance status, age), treatment choice factors (e.g. QoL, toxicity profile), tumour 
molecular characteristics 
 an
 and tumour clinical characteristics (tumour burden 
and biology, related symptoms).  Expert treatment guidelines for metastatic colorectal cancer 
include those by the European society for Medical Oncology (ESMO) (Van Cutsem et al 
2016) and the U.S. National Comprehensive Cancer Network (NCCN) (NCCN clinical 
practice guidelines V3. 2020). 
According to the U.S. NCCN guidelines, first line treatment choice is based primarily on the 
patient’s performance status and ability to tolerate intensive versus non-intensive treatment.  
Typically, 1st line treatment encompasses doublet or triplet chemotherapy with or without 
targeted therapy with anti-VEGF or anti-EGFR agents. In patients with 
 
 wi
 wild-type disease or with left-sided tumours, oxaliplatin or irinotecan-based doublet 
chemotherapy treatment (FOLFOX/FOLFIRI) in combination with an anti-EGFR agent is 
recommended. In patients with 
 m
 mutated tumours, oxaliplatin- or 
irinotecan-based doublet or triplet chemotherapy (FOLFOX/FOLFIRI/FOLFOXIRI) in 
combination with anti-VEGF treatment (bevacizumab) is recommended. 
In patients with poor performance status or inability to tolerate intensive treatment, 1st line 
treatment is typically monotherapy chemotherapy with/without targeted treatment 
(anti-VEGF/EGFR) or targeted monotherapy or immunotherapy treatment. Treatment for 
patients with 
 w
 wild-type disease includes cetuximab or panitumumab. 
Patients with 
 w
 wild-type tumours may be offered 
Trastuzumab in combination with pertuzumab or lapatinib. Patients with MSI-H disease are 
offered anti-PD1 second line treatment. 
Second-line treatment is largely based on the 1st line treatment offered to patients with those 
who received platinum-based 1st line treatment receiving irinotecan based 2nd line treatment 
and vice-versa.  Recommended third-line treatments include monotherapy treatment with 
irinotecan, regorafenib (Grothey et al 2013) or TAS-102 (Trifluridine in combination with 
tipiracil) (Mayer et al 2015). 
The median survival of patients with metastatic CRC is 30 months (Van Cutsem et al 2016).  
One-year PFS and OS rates for patients treated with second line systemic therapy are 
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approximately 15% and 40% respectively (Cao et al 2020).  There is therefore still a 
significant unmet medical need for additional treatment options for metastatic CRC.
 
Study Rationale 
The Wnt signalling pathway plays an important role in tumourigenesis and has been shown to 
be elevated in both ring finger protein 43 (RNF43) and R-Spondin (RSPO) aberrated CRC.  
There is also evidence that Wnt signalling may have a role in enabling cancers to avoid 
immunosurveillance and hence resistance to some immunotherapies.  
Currently there remains a major unmet medical need in metastatic colorectal cancer. 
Immunotherapy with anti-PD1 has not demonstrated any efficacy in Microsatellite stable 
(MSS) colorectal cancer, which represents approximately 85% of colorectal cancer. 
RXC004 may offer an opportunity to deliver clinical benefit by both a direct tumour targeting 
effect (in patients with RNF43 LoF mutations or RSPO fusion/translocation) and an immune-
oncology effect, by converting the tumour microenvironment from an immune “cold” to an 
immune “hot” signature, making the tumour sensitive to anti-PD1/PD-L1 inhibition. This 
immune effect may be seen in genetically unselected patients as the target cells are the 
immune cells and not the tumour cells themselves. 
RXC004 will therefore be evaluated in ! 2nd line metastatic MSS colorectal cancer patients, 
who have either a RNF43 LoF mutation or a RSPO fusion/translocation. 
 
Background 
2.2.1 
Wnt signalling in colorectal cancer 
The Wnt signaling pathway plays an important role in tumourigenesis (Zhan et al 2016) and in 
immune evasion (Goldsberry et al 2019) in many common cancers.  The Wnt pathway is 
initiated by the binding of Wnt glycoproteins to Frizzled (Fz) and low-density lipoprotein 
receptor-related protein (LRP) 5 or 6 co-receptors, resulting in the phosphorylation of 
Dishevelled (DSH) which in turn recruits a destruction complex comprising axin, 
adenomatous polyposis coli (APC) and glycogen synthase kinase 3ȕGSK3ȕto the cell 
membrane.  The movement of these proteins inhibits the phosphorylation of ȕ-catenin 
allowing ȕ-catenin to accumulate near the cell nucleus and induces the transcription of target 
genes. 
RNF43 is an integral membrane E3 ubiquitin ligase that promotes degradation of Fz receptors.  
Loss of function (LoF) RNF43 mutations have been described in 3-13% of all colorectal 
cancers (cBioPortal for cancer genomics, Matsumoto et al 2020, Cerami et al 2012).  These 
LoF RNF43 mutations lead to increased Fz receptors at the cell surface and hence elevated 
Wnt signaling. 
RSPOs are secreted proteins that act as ligands for the LRP 4/5/6 receptors. RSPO binding to 


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LRPs potentiates Wnt signaling by sequestering RNF43, resulting in the accumulation of 
Fz/LRP-receptor complexes at the cell membrane (De Lau et al 2014 and Seshagiri et al 
2012).  Chromosome rearrangements of RSPO2 and RSPO3 have been described in 
approximately 5% of CRC (Seshagiri et al 2012, Shinmura et al 2014, Kleeman et al 2019).  
The rearrangements result in fusion transcripts that drive marked overexpression of the RSPO 
gene.  
PORCN is a membrane-bound protein-serine O-palmitoleoyltransferase which is required for 
the acetylation, activation and secretion of Wnt ligands.  RXC004 inhibits PORCN leading to 
reduced canonical and non-canonical Wnt signalling.  Blocking Wnt signalling with PORCN 
inhibitors has been shown to suppress the growth of RNF43 and RSPO aberrated CRC cancers 
in preclinical models (Madan et al 2016 and Koo et al 2015).   
2.2.2 
Role of Wnt signalling in the immune response to cancer 
Anti-PD-1 monoclonal antibodies such as nivolumab have been shown to improve survival in 
metastatic mis-match repair deficient (dMMR) and MSI-H CRC, but patients with MSS CRC 
are largely unresponsive to immune checkpoint inhibitor treatment (Overman et al 2017, Le et 
al 2015). 
There is strong scientific rationale, from both preclinical and clinical studies, that Wnt 
pathway activity drives the immune evasion of tumours (Spranger and Gajewski 2018, Wang 
et al 2018 and Luke et al 2019).  In order for immune cells to recognize cancer cells, they 
must first infiltrate the tumour and then remain activated.  Wnt pathway activated tumours 
have been shown to be poorly infiltrated by immune cells (Grasso et al 2018) and 
pharmacological inhibition of Wnt signaling promotes cytotoxic T cell infiltration sensitizing 
cancer cells to PD-1 inhibitors (Feng et al 2019, Xiao et al 2018). 
There are currently a number of ongoing clinical trials investigating Porcupine inhibitors 
combined with PD-1 checkpoint inhibitors, in genetically unselected patients with advanced 
tumours (e.g. NCT02521844, NCT01351103 and NCT02675946). 
The results from an ongoing Phase 1 study (NCT01351103) of the small molecule PORCN 
inhibitor WNT974, indicated WNT974 monotherapy had a manageable safety profile and the 
potential for antitumor activity in a molecularly selected population (Janku et al 2015, Rodon 
et al 2021).  Preliminary data from the dose escalation part of the study, in which patients with 
advanced solid tumours received WNT974 in combination with the anti-PD-1 monoclonal 
antibody, spartalizumab have been reported (Janku et al 2020).  Of 27 enrolled patients (as of 
02 September 2019), 63% had received prior anti-PD-1 therapy.  One patient (4%) had a 
partial response (PR), 11 (41%) had stable disease (SD), 13 (48%) had progressive disease, 
and response was unknown in 2 patients.  The combination of WNT974 + spartalizumab was 
reported as being well tolerated.  Dose-limiting toxicities were reported in 2 patients: Grade 2 


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spinal compression fracture that occurred in the setting of trauma and Grade 3 arthralgia. The 
most common treatment-related AE was hypothyroidism (19%).  Four patients (15%) had 
7 suspected-related Grade 3/4 AEs (arthralgia, atrial fibrillation, diabetes mellitus, diabetic 
ketoacidosis, hyperglycemia, hyponatremia, and maculopapular rash)..  
2.2.3 
RXC004 
RXC004 is a potent and selective small molecule inhibitor of Porcupine (PORCN) that is 
required for the post-translational modification of all Wnt ligands.  Inhibition of PORCN 
reduces both Wnt secretion and downstream canonical and non-canonical Wnt signaling.  
RXC004 has demonstrated in vitro and in vivo efficacy in preclinical models with RNF43 loss 
of function mutations and RSPO fusions. This data supports the genetic selection of patients 
with MSS CRC with upstream Wnt pathway aberrations such as RNF43 mutation and RSPO 
fusions. RXC004 was not effective in 3 human cancer cell lines with downstream Wnt 
pathway mutations such as 
 m
 mutations, however there is evidence to suggest that patients 
with 
 m
 mutated tumours may also benefit from a reduction in ligand drive because of 
PORCN inhibition.  It has been reported that many colorectal cancer cell lines with mutations 
in 
 r remain dependent on Wnt ligands (Voloshenenko et al 2013) and in these Wnt 
dependent cell lines, PORCN inhibition with a small molecule in resulted in decreased 
pathway activation, anti-proliferative effects and reduced cell viability.  Taken together these 
data suggest patients with genetically selected cancers bearing downstream mutations in the 
Wnt pathway, may also receive some therapeutic benefit from treatment with RXC004 
RXC004 has demonstrated an immune stimulant effect and efficacy in monotherapy and in 
combination with anti-PD1 in mouse syngeneic models, supporting testing of combination of 
RXC004 with nivolumab in MSS CRC patients.  
RXC004 is being assessed in the Phase 1 RXC004/0001 trial (NCT03447470) as monotherapy 
and also in combination with the anti-PD-1 monoclonal antibody nivolumab, for safety and 
tolerability in advanced malignancies.  RXC004 monotherapy at doses of 0.5, 1.0, 1.5, 2.0 mg, 
3.0 mg and 10 mg have been evaluated to date. RXC004 at doses of 1.0 and 1.5 mg has been 
evaluated in combination with nivolumab. 
In addition, RXC004 is being tested as monotherapy in patients with RNF43 mutated 
pancreatic cancer and biliary tract cancers, and is planned to be tested in combination with 
pembrolizumab in biliary tract cancers, following SOC therapies, in an ongoing Phase 2 study 
RXC004/0003. 
A detailed description of the chemistry, pharmacology, and pre-clinical efficacy, and safety of 
RXC004 is provided in the RXC004 Investigator’s Brochure 
As of the 30 July 2021 a total of 25 patients have been dosed with RXC004 monotherapy in 
the phase 1 study at doses between 0.5 mg and 10 mg QD. The most frequently occurring 
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treatment emergent adverse events (TEAEs) were fatigue (64%), nausea (56%), anorexia 
(48%), vomiting (40%), dysgeusia (36%), diarrhoea (32%), aspartate aminotransferase 
increased (28%) anaemia (20%) and constipation (20%).  The most frequently occurring 
treatment related AEs (TRAEs) of any grade were fatigue (52%), nausea (44%), decreased 
appetite (40%), dysgeusia (40%) and vomiting (24%). Doses up to 2 mg QD were considered 
safe and tolerable. Events of intestinal inflammation (colitis, enteritis or enterocolitis) were 
observed in 4 patients who started treatment with RXC004 at doses of 3 mg QD or higher and 
3 of these were dose-limiting toxicities. 
A detailed description of the Phase 1 study results is provided in Section 4.4.1.   
2.2.4 
Nivolumab 
Nivolumab is a human immunoglobulin G4 (IgG4) monoclonal antibody that binds to the 
programmed death receptor-1 (PD-1) receptor.  Binding of the PD-1 ligands, PD-L1 and 
PD-L2, to the PD-1 receptor found on T cells, inhibits T-cell proliferation and cytokine 
production. Upregulation of PD-1 ligands occurs in some tumours and signaling through this 
pathway can contribute to inhibition of active T-cell immune surveillance of tumours. 
Nivolumab blocks the interaction of PD-L1 and PD-L2 with the PD-1 receptor, releasing the 
inhibition of the immune response and hence generating an anti-tumour immune response.  
Nivolumab has been approved in the European Union (EU) for the treatment of multiple 
cancers including metastatic melanoma, metastatic non-small cell lung cancer, advanced renal 
cell carcinoma, metastatic or recurrent squamous cell head and neck cancer, metastatic 
urothelial cancer, unresectable, recurrent or metastatic oesophageal squamous cell carcinoma 
and classical Hodgkin lymphomas that have progressed or recurred after an autologous stem 
cell transplant.  Nivolumab has also been approved by the US Food and Drug Administration 
(FDA) for the treatment of chemoresistant microsatellite instability-high (MSI-H) or 
mismatch repair deficient metastatic colorectal cancer (CRC). 
A detailed description of the chemistry, pharmacology, efficacy, and safety of nivolumab is 
provided in the nivolumab prescribing information. 
 
Benefit/Risk Assessment 
2.3.1 
RXC004 risks 
2.3.1.1 
Risks associated with targeting the Wnt pathway 
The principal on-target adverse events of significant interest known to occur with porcupine 
inhibition include decreases in bone density (including bone fragility fractures) and loss of 
taste (dysgeusia).  Inhibiting the Wnt pathway may also predispose to inflammation in the 
gastrointestinal tract because of the role of Wnt in the immune micro-environment.  
The safety profile of RXC004 is similar to that reported for two other Porcupine inhibitors in 


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clinical trials: ETC-159 and WNT974.  Preliminary data from 16 patients in the ongoing 
Phase 1a/b, first in human (FIH), dose escalation study of PORCN inhibitor, ETC-159, in 
advanced or metastatic solid tumours [NCT02521844] were first reported in 2017. At that 
time, the maximum tolerated dose (MTD) was 30 mg every other day, with dose limiting 
toxicities of compression fractures and hyperbilirubinemia.  Adverse events (>20%) included 
vomiting (32%), anorexia and fatigue (31%) dysgeusia and constipation (25%) Elevations of 
serum β-CTX, a marker of bone turnover, were observed (Ng et al 2017). Subsequently, 
prophylactic denosumab was introduced during the first 2 cycles. Data from the completed 
Phase 1, open-label trial of WNT974, administered in monotherapy have recently been 
published [NCT01351103] (Rodon et al 2021). In this study, 94 patients received oral 
WNT974 at doses of 5–30 mg once-daily, plus intermittent dosing schedules. AEs suspected 
to be related to study treatment were reported for 75 patients (80%), with the most common 
(≥20%) being dysgeusia (44 patients; 47%), decreased appetite (27 patients; 29%), and nausea 
(23 patients; 24%). Six patients (6.4%) experienced seven bone related disorders, five of 
which were suspected to be related to study treatment: osteoporosis, pathological fracture, 
osteopenia, and 2 Grade 3 spinal fractures.  
2.3.1.2 
Risks of RXC004 associated adverse events 
As described in Section 4.4.1, RXC004 has been evaluated as a monotherapy in 25 patients in 
a phase 1 monotherapy dose-escalation trial at doses of 0.5–10 mg QD, in which doses of up 
to 2 mg QD were found to be tolerable and safe.  
At doses up to and including 2 mg QD, the most common treatment related AEs of any grade 
were fatigue (10/20 patients), nausea (7/20), anorexia (6/20), dysgeusia (6/20), and vomiting 
(4/20).  
Dysgeusia Events 
In the Phase 1 study, RXC004-related dysgeusia was observed in 5 out of 20 patients who 
received doses of up to 2 mg QD, 3 out of 4 patients receiving 3 mg QD, and by the 1 patient 
who received 10 mg QD RXC004.  This study protocol includes an assessment for the further 
characterisation of this event and include guidance for the management of dysgeusia 
(Appendix I)  Guidance for dose modifications of RXC004 and nivolumab for all toxicities 
are provided in Section 6.6.  
Colitis Events 
In the Phase 1 study, events of intestinal inflammation (colitis, enteritis or enterocolitis) were 
observed in 4 patients who started treatment with RXC004 at doses of 3 mg QD or higher and 
3 were dose-limiting toxicities. CTCAE Grade 3 RXC004 related colitis occurred in the one 
patient who received 10 mg and CTCAE Grade 3 enteritis occurred in one patient who 
received RXC004 3 mg QD. CTCAE Grade 2 colitis also developed in two more patients who 


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started treatment with 3 mg RXC004, both Grade 2 events presented during Cycle 2, 
Symptoms included abdominal pain, intermittent constipation, diarrhoea, nausea and/or 
vomiting. Blood and mucus in the stool were not apparent in any of the cases. Symptoms were 
usually accompanied by, and preceded by, a raised CRP. In two patients, the event recurred 
after initially responding to steroids, but responded again to further treatment.  
Colitis events were not observed in any patients who commenced treatment with doses of 
RXC004 2 mg QD and lower, and the 3 mg QD dose gave a disproportionately high exposure 
compared to 2 mg QD. However, at the time of writing this protocol, one SAE of ileitis had 
been reported in this Phase 2 study and, considering the known risk of colitis for patients 
receiving nivolumab, there is a potential risk for colitis in patients receiving RXC004 as a 
monotherapy in Arm A and as an overlapping toxicity in patients who receive RXC004 in 
combination with nivolumab in Arm B. 
Guidelines for the investigation and management of diarrhoea/colitis for RXC004 both as a 
monotherapy and in combination with nivolumab are provided in Appendix J. Guidance for 
dose modifications of RXC004 and nivolumab for all toxicities are provided in Section 6.6.  
Colitis events are also defined as an Adverse Event of Potential Interest (AEPI) for RXC004, 
requiring additional details to be recorded on routine safety reporting.   
Bone Events 
Since Wnt inhibition both reduces bone formation and increases bone resorption, the 
concomitant use of the anti-resorbing agent, denosumab is expected to prevent drug-induced 
bone loss, and this has been a successful approach in the Phase 1 study, along with patient 
selection, and monitoring. Patients with high risk of bone fractures are excluded study 
protocols and participating patients will be monitored for bone turnover biomarkers and bone 
mineral density while on study.  
In this study, patients will receive prophylactic denosumab (120 mg s.c. once every month) 
along with Vitamin D3 and Calcium supplements (800 IU vitamin D3 daily [Cholecalciferol] 
and 1000-1500 mg calcium daily supplements) from the time of signing the ICF and 
throughout the study until discontinuation of RXC004.  
Guidance for dose modifications of RXC004 and nivolumab for all toxicities are provided in 
Section 6.6.  Bone toxicity events are defined as an AEPI for RXC004, requiring additional 
details to be recorded on routine safety reporting.  


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Assessment of potential for other risks 
Potential for Drug-Drug Interactions with CYP3A4 inhibitors 
RXC004 has not shown the potential to induce or inhibit CYP enzymes or transporters at the 
dose to be investigated in this study but it is exclusively metabolised by CYP3A4 and as such 
has the potential to be a victim for drug-drug interactions with potent CYP inhibitors (which 
could increase levels of RXC004, leading to a higher risk of adverse events). As such, strong 
and moderate CYP3A4 inhibitors are contra indicated in this protocol (see Appendix E). 
Patients with colorectal cancers commonly require co-medication with analgesics, antibiotics, 
anti-emetics and anti-depressant or anxiolytic drugs, some of which are CYP3A4 inhibitors. 
The table in Appendix E highlights the CYP3A4 inhibitors which are also likely to be 
commonly used in colorectal cancer patients. These drugs should be avoided, and alternatives 
used wherever possible. If it is not possible to use an alternative (e.g. if a specific antibiotic or 
anti-fungal treatment is needed), RXC004 should be interrupted. 
Potential for QTc prolongation 
Based on preclinical data [hERG assay, ECG monitoring in 28-day GLP toxicology studies], 
RXC004 is not considered to have a significant potential to prolong the QTc interval. RXC004 
did not lead to cardiac adverse events including arrhythmias, or syncope in the Phase 1 study.  
Triplicate ECGs will be collected in this study and other studies of RXC004 so that the 
potential for QTc prolongation can be explored in future as part of a population PK analysis.  
Potential for an effect of food on RXC004 exposure 
It is not yet known whether food may increase or decrease the exposure of RXC004. Until 
such data are generated, RXC004 must be given in a fasted state, as described in Section 5.3.2, 
and this is explained to patients in the Information Sheet. 
Potential for risks in specific patient populations 
A preliminary analysis of data from the Phase 1 study showed no effect of age, sex, BMI or 
race on RXC004 pharmacokinetics.  
Pre-clinical development showed that RXC004 is exclusively metabolised by CYP3A4 and 
there was no renal clearance of RXC004. However, there is currently no information on the 
clearance of potential human metabolites of RXC004. While data are limited, the study 
inclusion criteria will restrict the use of RXC004 to patients with adequate renal and hepatic 
function  
More detailed information about the known and potential risks of RXC004 may be found in 


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the most recent Investigator’s Brochure and Development Safety Update Report. 
In summary the pre-clinical information and emerging PK and safety profile has not identified 
any risks that would preclude investigation of RXC004 at a dose of 2 mg QD in the advanced 
cancer setting.  
2.3.2 
Nivolumab Risks 
Checkpoint inhibitors including anti PD-1, as well as antibodies directed against PDL-1 and 
CTLA-4, boost the endogenous immune responses directed against tumours.  Adverse events 
seen with checkpoint inhibitors are frequently due to immune mediated mechanisms and can 
occur in any organ system.  The adverse events known to occur with nivolumab treatment (as 
monotherapy and in combination with various agents) are well documented (Haanen et al 
2017) and include gastrointestinal effects (e.g. diarrhoea or colitis), pneumonitis, hepatic 
events, skin rashes myocarditis and endocrinopathies (including hypo and hyper-thyroidism).   
The safety of nivolumab administered as a single agent or in combination with ipilimumab in 
patients with mCRC was evaluated in the CHECKMATE-142 study. (NCT02060188). The 
most frequent serious adverse reactions reported in at least 2% of patients treated with 
nivolumab monotherapy were colitis/diarrhoea, hepatic events, abdominal pain, acute kidney 
injury, pyrexia, and dehydration. The most common adverse reactions for single agent 
nivolumab (reported in at least 20% of patients) were fatigue, diarrhea, pyrexia, 
musculoskeletal pain, abdominal pain, pruritus, nausea, rash, decreased appetite, and vomiting 
(Overman et al 2017). 
Immune mediated adverse events that can occur during treatment with nivolumab can be seen 
weeks or months after discontinuation of treatment. Symptoms of these events will be 
monitored throughout treatment (e.g. diarrhoea, rash, and neuropathy). Laboratory 
assessments will check for elevated liver enzymes, kidney and thyroid function, electrolytes, 
glucose and blood counts. 
More detailed information about the known and expected benefits and potential risks of 
nivolumab may be found in the nivolumab Package Insert. 
The safety profile of RXC004 in combination with nivolumab has not been fully characterized 
in patients. The toxicity profiles of RXC004 and nivolumab as monotherapy are largely 
non-overlapping apart from gastrointestinal effects (diarrhoea/colitis), which were observed at 
the 3 mg dose of RXC004 but not at doses up to and including doses of 2 mg.  The porcupine 
inhibitor WNT974 has been combined with an anti-PD1 in a phase 1 trial (NCT01351103) in 
27 patients with metastatic solid tumours, most of whom (63%) had received prior anti-PD1 
treatment. DLTs of Grade 2 spinal compression fracture (in the setting of trauma) and Grade 3 
arthralgia were reported in 2 patients. The authors concluded that WNT974 + spartalizumab 
was well tolerated (Janku et al 2020). The safety profile of RXC004 in combination with 


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nivolumab, while unknown, is expected to be similar to that of WNT974 in combination with 
spartalizumab. 
2.3.3 
Benefit assessment 
This trial will evaluate RXC004 monotherapy and RXC004 in combination with nivolumab in 
Microsatellite Stable (MSS) metastatic colorectal cancer (CRC) patients with upstream WNT 
pathway aberrations (RNF43 LoF mutations and RSPO fusions). RXC004 monotherapy may 
offer clinical benefit by both a direct tumour targeting mechanism and by an 
immune-oncology mechanism.  
Wnt pathway activated tumours have been shown to be poorly infiltrated by immune cells 
(Grasso et al 2018) and pharmacological inhibition of Wnt signaling promotes cytotoxic T cell 
infiltration, sensitizing cancer cells to PD-1 inhibitors (Feng et al 2019, Xiao et al 2018). 
Thus, there is clear rationale for the combination of RXC004 with checkpoint inhibitors. 
The Phase 1 study of RXC004 enrolled unselected patients with advanced cancers with a 
median of 3 prior lines of treatment. Out of 18 RECIST-evaluable patients, 5 had stable 
disease, in one case lasting for up to 26 weeks. All five of these patients with stable disease 
had Wnt-ligand-dependent tumours, supporting the hypothesis that RXC004 will have clinical 
activity in selected tumours that are dependent on Wnt ligand signaling pathways. 
In the expansion cohort of the WNT 974 study (Rodon et al 2021), stable disease was 
observed in 10 out of 28 patients, which was enriched in patients with RNF43 mutations.  
WNT974 has also been combined with anti-PD1 (spartalizumab) in an ongoing Phase 1 trial 
in 27 patients (NCT01351103). The combination was well tolerated with efficacy being 
observed in some patients (DCR of 41%) (Janku et al 2020).  
In addition, in house data with RXC004 in mouse syngeneic models have demonstrated that 
RXC004 combined with anti-PD1 results in a more immunogenic tumour microenvironment.  
Currently the prognosis of previously treated MSS metastatic colorectal cancer patients is 
poor with current 3rd line standard of care agents (regorafenib and TAS-102) with a response 
rate of <5%, median PFS and OS of approximately 2 and 6 months respectively and a DCR of 
approximately 40% (Grothey et al 2013; Mayer et al 2015). MSS colorectal cancer represents 
approximately 85% of all colorectal cancer. Immunotherapy has, to-date, proved ineffective in 
MSS CRC with no efficacy observed with anti-PD1 treatment- in contrast to MSI-H CRC 
where anti-PD1 treatment is approved for use as a single agent.  
There is insufficient clinical data to reach a definitive conclusion about the efficacy of 
PORCN inhibitors or other treatments in genetically selected MSS CRC with RNF43 
mutations and RSPO fusions. However, there is some preliminary evidence to suggest that 


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patients with RNF43 mutations have a poor prognosis compared to the general patient 
population with MSS CRC, (Cerami et al 2012, Gao et al 2013) suggesting that alternative 
treatments are needed for this subset of patients. 
RXC004, both as a single agent and in combination with nivolumab in this genetically 
selected MSS metastatic colorectal cancer population has therefore the potential to 
demonstrate clinical benefit in this major patient population with a large unmet medical need. 
2.3.4 Overall Benefit: Risk Conclusion 
Considering the measures taken to minimise risk to participants participating in this study, the 
potential risks identified in association with study treatment seem justified by the anticipated 
benefits that may be afforded to participants with RNF43 or RSPO aberrated MSS mCRC. 


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3 
OBJECTIVES AND ENDPOINTS 
Table 3 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
To assess the anti-tumour activity of RXC004 
monotherapy and RXC004 +nivolumab  
Monotherapy : Disease control rate (DCR) using 
each patients Best Overall Response (BOR) 
according to RECIST 1.1  
Combination : Objective response rate (ORR) 
using each patients BOR according to 
RECIST 1.1 
Secondary 
To further assess the preliminary efficacy of 
RXC004 monotherapy and RXC004 + 
nivolumab  
% change in the sum of target lesions, duration 
of response (DoR), PFS, ORR (monotherapy) 
and DCR (combination) using investigator 
assessments according to RECIST 1.1 and OS. 
To assess the PK of RXC004 in monotherapy 
and in combination with nivolumab 
Maximum plasma concentration (Cmax) after 
Dose 1, Cmax at steady state, minimum observed 
plasma concentration (Cmin) at steady state as 
well as other relevant parameters (e.g. tmax, t½, 
λz, AUC0-∞, CL/F, and Vz/F).  
To assess the safety and tolerability profile of 
RXC004 monotherapy and RXC004 + 
nivolumab combination 
Incidence of AEs SAEs, dose reductions, 
interruptions and discontinuations, and 
assessment of dysgeusia. 
Exploratory 
 
 
 
 
 
 
 
    
 
 
 
 
 
 
 
 
 
 
 
 
 
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Objectives 
Endpoints 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
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4 
STUDY DESIGN 
 
Overall Design 
This is Phase II, open label, multicentre, multi-arm, study to evaluate the preliminary efficacy 
and safety of RXC004 as monotherapy and in combination with nivolumab in patients with 
Ring finger protein 43 (RNF43) or R-spondin (RSPO) aberrated, microsatellite stable (MSS), 
colorectal cancer (CRC), that have progressed following current standard of care treatment. 
The study is composed of two arms, RXC004 monotherapy (Arm A) and RXC004 in 
combination with nivolumab (Arm B).  20 evaluable patients will be enrolled in Arm A and 
20 evaluable patients in Arm B. 
The study initially opened with Arm A; Arm B will be opened once a recommended Phase II 
dose (RP2D) for RXC004 in combination with nivolumab is established in the Phase I dose 
escalation study (NCI 03447470).  A safety review of the combination data will be conducted 
after  patients have received the combination of RXC004 and nivolumab for at least 1 cycle. 
Once Arm B is opened, patients who are eligible for both Arm A and Arm B will be 
randomised 2:1 to Arm B: Arm A in an open-label manner. Randomisation will be stratified by 
genetic alteration (RNF43 vs RSPO).
Patients in Arm A may be treated with RXC004 + nivolumab if they have progressive disease 
on the 8-week scan, as long as they are eligible for Arm B and have Sponsor approval. 
Patients who have undergone dose reduction during monotherapy cannot have the RXC004 
dose re-escalated if switching to RXC004 + nivolumab combination therapy. The RXC004 
dose must be discussed with the Sponsor prior to starting combination therapy. 
The primary objectives of the study are to assess the preliminary efficacy of each treatment 
arm; RXC004 monotherapy and RXC004+nivolumab based on an individual patients best 
overall response.) Tumour assessment will be performed by Investigators every 8 weeks 
± 1 week (relative to the date of initiation of study treatment) for the first 56 weeks, followed 
by q12w weeks ± 1 until radiological disease progression (as defined by Response Evaluation 
Criteria in Solid Tumours, version 1.1 [RECIST1.1]).  The primary efficacy endpoint for 
RXC004 monotherapy is disease control rate (i.e. proportion of patients who achieve CR, PR 
or SD) and the primary efficacy endpoint for RXC004 + nivolumab is objective response rate.  
Following radiological progression, patients will be followed-up for safety and survival. 
The general study design is summarized in Figure 1.  
 
Scientific Rationale for Study Design 
The Wnt signaling pathway plays an important role in tumourigenesis (Zhan et al 2016) and in 
immune evasion (Goldsberry et al 2019) in many common cancers. RNF43 is an integral 
&&,


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membrane E3 ubiquitin ligase that promotes degradation of Fz receptors.  Loss of function 
(LoF) RNF43 mutations have been described in 3-13% of all colorectal cancers (cBioPortal 
for cancer genomics, Matsumoto et al 2020, and Cerami et al 2012).  These LoF RNF43 
mutations lead to increased Fz receptors at the cell surface and hence elevated Wnt signaling. 
RSPOs are secreted proteins that act as ligands for the LRP 4/5/6 receptors. RSPO binding to 
LRPs potentiates Wnt signaling by sequestering RNF43, resulting in the accumulation of 
Fz/LRP-receptor complexes at the cell membrane (De Lau et al 2014 and Seshagiri et al 
2012).  Chromosome rearrangements of RSPO2 and RSPO3 have been described in 
approximately 5% of CRC (Seshagiri et al 2012, Shinmura et al 2014, Kleeman et al 2019).  
The rearrangements result in fusion transcripts that drive marked overexpression of the RSPO 
gene.  
PORCN is a membrane-bound protein-serine O-palmitoleoyltransferase which is required for 
the acetylation, activation and secretion of Wnt ligands.  RXC004 inhibits PORCN leading to 
reduced canonical and non-canonical Wnt signalling.  Blocking Wnt signalling with PORCN 
inhibitors has been shown to suppress the growth of RNF43 and RSPO aberrated CRC cancers 
in preclinical models (Madan et al 2016 and Koo et al 2015). 
 
There is strong scientific rationale, from both preclinical and clinical studies, that Wnt 
pathway activity drives the immune evasion of tumours (Spranger and Gajewski 2018, Wang 
et al 2018 and Luke et al 2019).  In order for immune cells to recognize cancer cells, they 
must first infiltrate the tumour and then remain activated.  Wnt pathway activated tumours 
have been shown to be poorly infiltrated by immune cells (Grasso et al 2018) and 
pharmacological inhibition of Wnt signaling promotes cytotoxic T cell infiltration sensitizing 
cancer cells to PD-1 inhibitors (Feng et al 2019, Xiao et al 2018). 
There are currently a number of ongoing clinical trials investigating combining Porcupine 
inhibitors with PD-1 checkpoint inhibitors, in patients with advanced tumours.  This trial will 
therefore evaluate both the direct tumour targeting potential of RXC004 monotherapy and the 
dual potential of direct tumour targeting and reversal of immune evasion/restoration of 
sensitivity to anti-PD1 treatment in MicroSatellite Stable (MSS) metastatic colorectal cancer 
patients with upstream WNT pathway aberrations (RNF43 LoF and RSPO fusion). 
 
 
Rationale for Study Endpoints 
4.3.1 
Arm A Primary Endpoint 
RXC004 has shown efficacy in both RNF43 LoF and RSPO fusion human xenograft models. 
As part of these preclinical studies, it was observed that RXC004 did not show a clear dose 
response relationship when a calliper measurement was utilised for study endpoint.  The 
callipers measure the size of the tumour in the mouse similar to a RECIST scan in a cancer 


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patient. In addition to the calliper measurement Redx conducted immunohistochemistry (IHC) 
analysis and 
 s scanning on these RSPO fusion tumours.  By IHC a clear dose 
response relationship was shown on reduction of Ki67 staining, a marker of proliferation in 
tumour cells, and a dose dependent increase in Alcian Blue/Periodic acid-Schiff staining, 
markers of mucins in the tumour.  Therefore, in addition to the dramatic dose dependent 
reduction in tumour cell proliferation, RXC004 also resulted in a striking change in cell 
morphology. As indicated by Alcian blue/Period acid-Shiff staining, RXC004 treatment was 
shown to increase the presence of mucins in the extracellular space in a dose dependent 
manner.  This increase in mucin in the tumour microenvironment we believe is responsible for 
the lack of apparent dose response in the calliper tumour volume measurement in this model.  
Furthermore, 
 scanning in the same RSPO fusion tumour model showed a reduction 
in metabolic activity in the tumours, and when tumours were removed and implanted into 
secondary host animals, they had a significantly reduced rate of growth compared to tumours 
pre-treated with vehicle alone. This suggests potential continued benefit of RXC004 induced 
cell changes even post drug treatment.  
Based on these pre-clinical observations, and also taking into consideration the low published 
response rates 
%) with single agents TAS-102 and regorafenib in MSS CRC, it is 
considered unlikely that RXC004 as a monotherapy will deliver RECIST-confirmed clinical 
responses. The RECIST measurement on tumour size may be confounded if this cell 
differentiation and increase in mucous production in the tumour microenvironment that was 
seen in pre-clinical models is also observed in human tumours as this would result in a lack of 
tumour area shrinkage.  For these reasons, the exploratory objectives of the study include an 
 for IHC and an 
 s scan.  
Disease Control Rate (DCR; defined as CR+ PR+ durable stable disease lasting for at least 
16 weeks) was selected as the primary endpoint for the RXC004 monotherapy arm because it 
considers both tumour shrinkage and durable disease stabilisation. It is possible and more 
likely that RXC004 efficacy could result in prolonged stable disease rather than tumour 
shrinkage.  As complete ablation of tumour cell proliferation has been observed in preclinical 
models, this mechanism of action could still lead to patient benefit, increased progression free 
survival and ultimately an overall survival benefit for the patient.  
For this endpoint, a value of 
% DCR will be used as a reference, as this was consistently 
reported in the studies of TAS-102 and regorafenib in a similar but unselected patient 
population (Grothey et al 2013 and Mayer et al 2015) and an improvement over this value 
would be  considered relevant, firstly because the DCR rate in the reported studies was based 
on SD at   w
 weeks, whereas in this study at least 16 weeks of SD is required, and secondly  
because of the preliminary evidence that RNF43 mutated MSS CRC may have a poorer 
prognosis than the general MSS CRC population. 
However, acknowledging that Disease Control Rate is difficult to interpret in a single arm 
study, the secondary endpoints of the study include the best % change in the sum of target 
lesions from baseline, the ORR (monotherapy) and duration of response (DoR) according to 
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RECIST 1.1, as well as PFS and OS. All of these endpoints will be taken into account when 
determining whether RXC004 has demonstrated sufficient clinical activity to support further 
clinical development as a monotherapy. Further details are provided in sections 9.2 and 9.4. 
4.3.2 
Arm B Primary Endpoint 
The mechanism of action of RXC004 on the tumour epithelial cell could lead to prolonged 
stable disease and hence DCR is considered an appropriate primary endpoint for RXC004 
monotherapy.  In contrast, combination of RXC004 with nivolumab would be expected to 
have both a RXC004 effect on the growth of the tumour cells and a synergistic effect with 
nivolumab on the immune system.  RXC004 should reverse Wnt pathway induced immune 
evasion and nivolumab will allow activated CD8 T cells to function without the immune 
suppression resulting from tumour PD-L1 expression.  Therefore, it is believed that in 
combination, the active CD8 T cells will have the ability to destroy tumour cells and thus 
shrink the size of the tumour; hence ORR is thought to be a suitable endpoint for the 
combination arm. 
 
Justification for Doses of RXC004 and Nivolumab 
Patients who enrol in Arm A RXC004 monotherapy will receive 2.0 mg RXC004 orally once 
a day in a fasted state. This dose was chosen using the predicted efficacious dose ranges from 
pre-clinical pharmacology models, preclinical and clinical target engagement assays, 
information from toxicology and toxicokinetic studies, and safety, efficacy and 
pharmacokinetics data from the Phase 1 study of RXC004 in patients with advanced solid 
tumours (NCT03447470). 
Patients who receive combination therapy with RXC004 and nivolumab in Arm A or B will 
receive RXC004 1.5 mg orally once a day in combination with nivolumab 480 mg q4w. The 
RXC004 1.5 mg dose is supported by the available safety and PK data for this dose given in 
combination with nivolumab in the ongoing Phase 1 study RXC004/0001 (NCT03447470; see 
Sections 4.4.1.2 and 4.4.1.3). At a meeting held on 07 July 2022, the Phase 1 Safety Review 
Committee (SRC) determined that RXC004 1.5 mg in combination with nivolumab is a 
tolerated dose, based on safety and PK data (see Sections 4.4.1.2 and 4.4.1.3). 
4.4.1 
RXC004 
4.4.1.1 
RXC004 Clinical Safety Data (NCT03447470) – Monotherapy Module 1 
As of 30 July 2021, 25 patients had received treatment with RXC004 monotherapy, which 
completed the Module. This study opened in 2018 with a RXC004 dose of 10 mg once daily, 
but the dose was not tolerated, in the first patient who developed grade 3 diarrhoea, colitis and 
asymptomatic bone fragility fractures in a thoracic vertebra and clavicle, which are on-target 
toxicities of Wnt pathway inhibitors. Recruitment was halted to allow for the manufacture of 
lower doses of compound and to amend the protocol with a revised dose schedule and 
additional safety measures. The study restarted the dose escalation on 18th March, 2019 with 


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0.5 mg RXC004.   
As of the 30 July 2021, 24 additional patients had been dosed with RXC004 monotherapy in 
Module 1 of the study at doses of 0.5 mg, 1 mg, 1.5 mg, 2 mg and 3 mg, a six-fold dose range.  
Six patients received treatment at highest declared tolerated dose (2 mg), and all were 
evaluable for dose limiting toxicity (DLT) analysis. 
Table 4 
Grade 2 or higher RXC004 related adverse events, including DLTs 
observed in DLT evaluable patients as of 30 July 2021 (Phase 1 study 
RXC004/0001, monotherapy Module 1) 
Dose 
Patients 
dosed 
Patients 
evaluable 
for DLT 
Grade 2 or higher RXC004 related AEs in DLT 
evaluablea patients 
0.5 mg 
QD 
4 
3 
Tolerated dose 
RXC004 related AEs ≥ CTCAE G2 (2/3 patients); 
G2 fatigue (1/3 patients) 
G2 increase in β-CTX (1/3 patients) 
1 mg QD 
3 
3 
Tolerated dose 
RXC004 related AEs ≥ CTCAE G2 (1/3 patients); 
G2 fatigue (1/3 patients) 
G2 increase in β-CTX (1/3 patients) 
G2 loss of appetite (1/3 patients) 
G2 Nausea (1/3 patients) 
1.5 mg 
QD 
7 
6 
Tolerated dose 
RXC004 related AEs ≥ CTCAE G2 (4/6 patients); 
G2 fatigue (4/6 patients)b 
G2 loss of appetite/anorexia (2/6 patients)b 
G2 Nausea (1/6 patients), G3 Nausea (1/6 patients)b 
G2 Dysgeusia (1/6 patients)b 
G2 increased AST (1/6 patients)b 
G2 decreased sodium (1/6 patients)b 
G3 diarrhoea (1/6 patients)b 
G3 vomiting (1/6 patients)b 
G3 weight loss (1/6 patients)b 
2 mg QD 
6 
6 
Tolerated dose 
RXC004 related AEs ≥ CTCAE G2 (4/6 patients); 
G3 Pancreatitis (1/6 patients) [DLT] 


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Dose 
Patients 
dosed 
Patients 
evaluable 
for DLT 
Grade 2 or higher RXC004 related AEs in DLT 
evaluablea patients 
G2 Diarrhoea (2/6 patients) 
G2 Dysgeusia (1/6 patients)b 
3 mg QD 
4 
4 
Non-tolerated dose 
RXC004 related AEs ≥ CTCAE G2 (4/4 patients); 
G2 Fatigue (1/4 patients)b 
G2 Nausea (1/4 patients)b 
G2 Constipation (1/4 patients)b 
G2 Anorexia (2/4 patients)b 
G2 Colitis (2/4 patients)b [DLT] 
G2 Dysgeusia (1/4 patients)b 
G3 Enteritis (1/4 patients) [ DLT] 
G2 hyponatremia (1/4 patients) 
G2 Humerus fracture (1/4 patients) 
G5 Subdural Hematoma (1/4 patients) 
10 mg QD 
1 
1 
Non-tolerated dose 
One DLT – G3 Diarrhoea. 
G3 proctitis, G2 enterocolitis, dysgeusia and fragility 
bone fractures also reported by this patient 
a 
The DLT assessment period runs from the start of dosing with RXC004 (Cycle 0 Day 1) up to Cycle 1 Day 
21.  To be evaluable for DLT assessment patient must had received at least 66% of the intended dose of 
RXC004 during Cycle 1 or have experienced a DLT event in the assessment period 
b 
The start date of one or more events was outside of the DLT period.  However, AEs occurring in Cycle 2 
and beyond which meet the definition of a DLT or are considered clinically significant may also be 
considered by the Safety Review Committee, when making dose escalation decisions. 
 
No DLTs were observed in the patients dosed in the first three cohorts since the study was 
restarted (RXC004 doses from 0.5 mg to 1.5 mg).  One DLT of CTCAE grade 3 pancreatitis 
was observed at the 2 mg dose level.  At the 3 mg dose level, two DLTs of colitis and enteritis 
were observed in 2 out of 4 evaluable patients, which led to the SRC declaring 3 mg QD 
RXC004 as non-tolerated.   
Denosumab (XGEVA™ - 120 mg s.c. once every month) was administered prophylactically 
from Cycle 0 to all patients from cohort 3 (1.5 mg RXC004) onwards, to maximize bone 
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A summary of the treatment emergent adverse events (TEAEs) regardless of causality, 
reported for RXC004 monotherapy in the phase 1 RXC004/0001 study (NCT03447470) up to 
30 July 2021 is included in Table 5. 
Table 5 
Summary of Treatment-Emergent Adverse Events Phase 1 study 
RXC004/0001, monotherapy Module 1)  
 
Number of 
patients with: 
0.5 mg 
(N=4) 
N (%) 
1.0 mg 
(N=3) 
N (%) 
1.5 mg 
(N=7) 
N (%) 
2.0 mg 
(N=6) 
N (%) 
3.0 mg 
(N=4) 
N (%) 
10.0 mg 
(N=1) 
N (%) 
Overall 
(N=25) 
N (%) 
Any TEAE 
4 (100) 
3 (100) 
7 (100) 
6 (100) 
4 (100) 
1 (100) 
25 (100) 
Any Treatment-
Related TEAE 
4 (100) 
3 (100) 
5 (71) 
5 (83) 
4 (100) 
1 (100) 
22 (88) 
TEAE >= Grade 3 
0 (0) 
1 (33) 
6 (86) 
1 (17) 
3 (75) 
1 (100) 
12 (48) 
Treatment-Related 
TEAE >= Grade 3 
0 (0) 
0 (0) 
2 (29) 
1 (17) 
1 (25) 
1 (100) 
5 (20) 
Serious TEAE 
0 (0) 
1 (33) 
5 (71) 
117) 
3 (75) 
1 (100) 
11 (44) 
Serious Treatment-
Related TEAE 
0 (0) 
0 (0) 
1 (14) 
0 (0) 
2 (50) 
1 (100) 
4 (16) 
TEAE Leading to 
Discontinuation of 
Study Treatment 
1 (25) 
0 (0) 
2 (29) 
0 (0) 
2 (50) 
1 (100) 
6 (24) 
Treatment-Related 
TEAE Leading to 
Discontinuation of 
Study Treatment 
1 (25) 
0 (0) 
2 (29) 
0 (0) 
2 (50) 
1 (100) 
6 (24) 
TEAE Leading to 
Dose Modification 
0 (0) 
1 (33) 
3 (43) 
2 (33) 
2 (50) 
1 (100) 
9 (36) 
TEAE Leading to 
Death 
0 (0) 
0 (0) 
1 (14) 
0 (0) 
1 (25) 
0 (0) 
2 (8) 
TEAE = treatment-emergent adverse event 
 
The most common TEAEs and TRAEs (occurring in at least 20% patients) are summarised in 
Table 6 and Table 7.  The most frequently occurring TEAEs were fatigue (64%), nausea 
(56%), decreased appetite (48%), vomiting (40%), dysgeusia (36%), diarrhoea (32%), 
aspartate aminotransferase increased (28%), anaemia (20%), and constipation (20%).   


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Table 6 
Most common (occurring in at least 20% patients) treatment emergent 
AEs in Phase 1 study RXC004/0001 (monotherapy Module 1) 
 
  Preferred Term 
0.5 mg 
(N=4) 
1.0 mg 
(N=3) 
1.5 mg 
(N=7) 
2.0 mg 
(N=6) 
3.0 mg 
(N=4) 
10.0 mg 
(N=1) 
Overall 
(N=25) 
Patients with Any TEAEs 
4 (100) 
3 (100) 
7 (100) 
6 (100) 
4 (100) 
1 (100) 
25 (100) 
Fatigue 
2 (50) 
2 (67) 
6 (86) 
3 (50) 
2 (50) 
1 (100) 
16 (64) 
Nausea 
2 (50) 
2 (67) 
5 (71) 
1 (17) 
3 (75) 
1 (100) 
14 (56) 
Decreased appetite 
1 (25) 
2 (67) 
3 (43) 
2 (33) 
3 (75) 
1 (100) 
12 (48) 
Vomiting 
0 (0) 
2 (67) 
4 (57) 
2 (33) 
1 (25) 
1 (100) 
10 (40) 
Dysgeusia 
0 (0) 
0 (0) 
2 (29) 
3 (50) 
3 (75) 
1 (100) 
9 (36) 
Diarrhoea 
1 (25) 
2 (67) 
3 (43) 
1 (17) 
0 (0) 
1 (100) 
8 (32) 
AST increased 
1 (25) 
0 (0) 
3 (43) 
1 (17) 
1 (25) 
1 (100) 
7 (28) 
Anaemia 
1 (25) 
2 (67) 
2 (29) 
0 (0) 
0 (0) 
0 (0) 
5 (20) 
Constipation 
0 (0) 
0 (0) 
1 (14) 
1 (17) 
2 (50) 
1 (100) 
5 (20) 
 
The most common RXC004-related AEs reported were: fatigue (52%), nausea (44%), 
decreased appetite (40%), dysgeusia (40%) and vomiting (24%). At doses up to and including 
2 mg QD, the most common treatment related AEs were fatigue (10/20 patients), nausea 
(7/20), anorexia (6/20), dysgeusia (6/20), and vomiting (4/20), No grade 4/5 treatment related 
AEs or bone fragility events were reported at any dose levels up to and including 2 mg QD.  
Only dysgeusia appeared to be dose-related. 


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Table 7 
Most common (occurring in at least 20% patients) treatment related AEs 
in Phase 1 study RXC004/0001 (monotherapy Module 1) 
 
  Preferred Term 
0.5 mg 
(N=4) 
1.0 mg 
(N=3) 
1.5 mg 
(N=7) 
2.0 mg 
(N=6) 
3.0 mg 
(N=4) 
10.0 mg 
(N=1) 
Overall 
(N=25) 
Patients with Any TRAEs 
4 (100) 
3 (100) 
5 (71) 
5 (83) 
4 (100) 
1 (100) 
22 (88) 
Fatigue 
2 (50) 
1 (33) 
4 (57) 
3 (50) 
2 (55) 
1 (100) 
13 (52) 
Nausea 
1 (25) 
2 (67) 
3 (43) 
1 (17) 
3 (75) 
1 (100) 
11 (44) 
Decreased appetite 
1 (25) 
1 (33) 
2 (29) 
2 (33) 
3 (75) 
1 (100) 
10 (40) 
Dysgeusia 
0 (0) 
0 (0) 
2 (29) 
4 (66) 
3 (75) 
1 (100) 
10 (40) 
Vomiting 
0 (0) 
1 (33) 
2 (29) 
1 (17) 
1 (25) 
1 (100) 
6 (24) 
 
Five patients reported nine CTCAE Grade 3 events that were assessed as possibly or probably 
related to RXC004 by the investigator, and these patients all received doses of 1.5 mg or 
higher. These events were: weight loss (1 patient, 1.5 mg); nausea, vomiting and diarrhoea (all 
in one patient, 1.5 mg); pancreatitis (1 patient, 2 mg); enteritis (1 patient, 3 mg) and diarrhoea, 
proctitis and hyponatraemia (all in 1 patient, 10 mg). No Grade 4 events were reported. Two 
Grade 5 events were reported – COVID-19 infection (1 patient, 1.5 mg, not-related to 
RXC004) and subdural hematoma following a fall (1 patient, 3 mg QD, assessed as possibly 
related to RXC004).  See Table 4. 
A total of 16 Serious Adverse Events (SAEs) were reported in 11 patients. Nine of the 
16 SAEs reported were assessed as unrelated to the RXC004 by the investigator and the 
sponsor. These were: gastroenteritis viral (Grade 3, 1 patient, 1 mg), Escherichia urinary tract 
infection (Grade 3, 1 patient, 1.5 mg), pulmonary haemorrhage (Grade 1, 1 patient, 1.5 mg), 
melaena (2 SAEs in 1 patient at 1.5 mg – one Grade 1 then other Grade 3 – both due to a new 
primary malignancy), small intestinal obstruction (Grade 3, 1 patient 1.5 mg), COVID-19 
(Grade 5, 1 patient, 1.5 mg), Stoma site infection (Grade 2, 1 patient, 2 mg) and biliary track 
infection (Grade 3, 1 patient, 3 mg). 7 SAEs (which occurred in 4 patients) were assessed as 
possibly or probably related to RXC004 by the investigator and are described below: 
2. 2 SAEs of NCI CTCAE grade 3/2 diarrhoea that occurred in 1 patient at 10 mg QD RXC004 
(before the study was re-started) were both assessed as probably related to RXC004 and led 
to discontinuation of study drug.  The events subsequently resolved/recovered and 10 mg 
QD RXC004 was declared not tolerated by the Safety Review Committee (SRC). 
3. 1 SAE of NCI CTCAE grade 3 diarrhoea that occurred at 1.5 mg RXC004 was assessed as 
probably related to RXC004 and led to discontinuation of study drug.  The event was also 
associated with a clostridium difficile infection and subsequently resolved/recovered.  


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4. 1 SAE of NCI CTCAE grade 2 colitis that occurred at 3 mg QD RXC004 was assessed as 
probably related to RXC004.  The event subsequently resolved, and the patient continued 
study treatment at a lower dose (1.5 mg RXC004).  The 3 mg QD dose of RXC004 was 
subsequently declared not tolerated by the SRC. 
5. 1 SAE of NCI CTCAE grade 3 enteritis that occurred at 3 mg QD RXC004 was assessed as 
probably related to RXC004.  This patient also had a SAE of NCI CTCAE grade 2 humerus 
fracture (following a fall whilst hospitalised for enteritis) which was assessed as probably 
related to RXC004.  The enteritis and fracture events were both unresolved at the time that 
the patient subsequently died due to a CTCAE grade 5 subdural hematoma (following a 
fall).  The subdural hematoma was assessed as possibly related to RXC004 by investigator 
due to unknown mechanism as an association between the study drug and potential factors 
that could have contributed to this event, such as coagulation, had not been ruled out at the 
time of death. The 3 mg QD dose of RXC004 was subsequently declared not tolerated by 
the SRC. 
 
4.4.1.2 
RXC004 Clinical Safety Data (NCT03447470) – in Combination with 
Nivolumab Module 2) 
As of 01 July 2022, 13 patients have received RXC004 in combination with nivolumab 
480 mg q4w at doses of RXC004 1 mg and 1.5 mg in Module 2 of the ongoing Phase 1 study 
RXC004/0001. Eight of these patients received treatment at the highest declared tolerated 
dose (RXC004 1.5 mg). Treatment-related AEs of CTCAE ≥ Grade 2 reported in 
DLT-evaluable patients are summarised in Table 8.  
Overall, the AE profile of the RXC004 1.5 mg dose in combination with nivolumab is similar 
to the RXC004 2 mg monotherapy dose. More patients who received the 1.5 mg dose had 
treatment related AEs of Grade 2 or higher (4/6) than patients who received the 1 mg dose 
(2/5). One patient who received 1.5 mg in combination had drug-induced liver injury (DILI), 
which was considered drug-related and a DLT.  
The SRC determined at a meeting held on 07 July 2022, that both RXC004 1 mg and 1.5 mg 
QD in combination with nivolumab are tolerated doses. A decision was made not to further 
escalate the dose in the study, based on the safety and PK profiles of the 1.5 mg dose, as the 
combination of RXC004 2 mg with nivolumab was anticipated to lead to slightly higher 
exposure and potentially more AEs than the 2 mg monotherapy dose. 


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Table 8 
Treatment-related AEs Grade 2 or higher including DLTs, observed in 
DLT evaluable patients as of 01 July 2022, Phase 1 study RXC004/0001 
(RXC004 + nivolumab Module 2) 
Dose 
Number 
of patients 
dosed 
Patients 
evaluable 
for DLT 
Study treatment-related AEs, CTCAE ≥ Grade 2 in 
DLT-evaluable a patients 
1.0 mg QD RXC004 
+ nivolumab 480 mg 
q4w 
5 
5 
Tolerated dose 
 
Events ≥ Grade 2 in DLT-evaluable patients (2/5 patients): 
G2 back pain (1/5 patients) b 
G2 nausea (1/5 patients) b 
G2 fatigue (1/5 patients) c 
G2 poor appetite (1/5 patients) c 
G3 fatigue (1/5 patients) b  
1.5 mg QD RXC004 
+ nivolumab 480 mg 
q4w 
8 
6 e 
Tolerated dose 
 
Events ≥ Grade 2 in DLT evaluable patients (4/6 patients): 
G2 dysgeusia (2/6 patients) b 
G2 diarrhoea (1/6 patients) b 
G2 diarrhoea (1/6 patients) c 
G2 reduced appetite (1/6 patients) b 
G2 nausea (1/6 patients) b 
G2 constipation (1/6 patients) d 
G2 anorexia (1/6 patients) b 
G2 increased total bilirubin (1/6 patients) b 
G2 High TBL (1/6 patients) b 
G3 DILI (1/6 patients) [DLT] c 
a 
The DLT assessment period runs from the start of dosing with RXC004 (Cycle 0 Day 1) up to Cycle 1 Day 28. To be 
evaluable for DLT assessment patient must had received ≥ 66% of the intended dose of RXC004 and all of the 
nivolumab infusion during Cycle 1, or have experienced a DLT event in the assessment period. 
b 
Related to RXC004. 
c 
Related to RXC004 and nivolumab. 
d 
Related to nivolumab. 
e 
Two of the 8 patients who received RXC004 1.5 mg in combination with nivolumab discontinued prior to the end of 
Cycle 1 without meeting DLT criteria, and were replaced. 
AE, adverse event; CTCAE, Common Terminology Criteria for Adverse Events; DLT, dose-limiting toxicity; q4w, every 
4 weeks; QD, once daily. 
 
A summary of the treatment-emergent adverse events (TEAEs) reported in Module 2 
(RXC004 + nivolumab combination therapy) up to 01 July 2022 is presented in Table 9.  


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Table 9 
Summary of Treatment-Emergent Adverse Events as of 01 July 2022, 
Phase 1 study RXC004/0001 (RXC004 + Nivolumab Module 2) 
Number of patients with: 
RXC004 1.0 mg + 
nivolumab 
(N=5) 
RXC004 1.5 mg + 
nivolumab 
(N=8) 
Overall 
 
(N=13) 
TEAE 
5 (100) 
8 (100) 
13 (100) 
Treatment-Related TEAE 
5 (100) 
8 (100) 
13 (100) 
RXC004-Related TEAE 
5 (100) 
8 (100) 
13 (100) 
Nivolumab-Related TEAE 
3 (60) 
6 (75) 
9 (69) 
TEAE ≥ Grade 3 
3 (60) 
4 (50) 
7 (54) 
Treatment-Related TEAE ≥ Grade 3 
1 (20) 
3 (38) 
4 (31) 
RXC004-Related TEAE ≥ Grade 3 
1 (20) 
3 (38) 
4 (31) 
Nivolumab-Related TEAE ≥ Grade 3 
0 (0) 
2 (25) 
2 (15) 
TEAE ≥ Grade 4 
0 (0) 
0 (0) 
0 (0) 
Treatment-Related TEAE ≥ Grade 4 
0 (0) 
0 (0) 
0 (0) 
Serious TEAE 
3 (60) 
3 (38) 
6 (46) 
Serious Treatment-Related TEAE 
0 (0) 
1 (13) 
1 (8) 
Serious RXC004-Related TEAE 
0 (0) 
1 (13) 
1 (8) 
Serious nivolumab-Related TEAE 
0 (0) 
1 (13) 
1 (8) 
TEAE Leading to Discontinuation of Study 
Treatment (RXC004) 
0 (0) 
2 (25) 
2 (15) 
Treatment-Related TEAE Leading to 
Discontinuation of Study Treatment 
0 (0) 
2 (25) 
2 (15) 
TEAE Leading to RXC004 Dose Modification 
2 (40) 
5 (63) 
7 (54) 
Dose Reduced 
0 (0) 
1 (13) 
1 (8) 
Dose Interrupted 
2 (40) 
5 (63) 
7 (54) 
TEAE Leading to Death 
0 (0) 
0 (0) 
0 (0) 
TEAE of Dose Limiting Toxicity 
0 (0) 
1 (13) 
1 (8) 
Adverse events were coded using MedDRA Version 24.1. A TEAE was an AE with onset on or after date of first 
dose of study treatment and within 30 days of last dose. 
Treatment-related adverse event was an adverse event that had relationship to study drug designated by the 
investigator as Possibly Related or Probably Related. 
Treatment-Related: adverse events related to RXC004 and/or nivolumab. If the relationship to RXC004 or 
nivolumab was missing, the event was conservatively treated as related to the corresponding study treatment. 
AE, adverse event; MedDRA, Medical Dictionary for Regulatory Activities; TEAE, treatment-emergent adverse 
event. 
 
The most common TEAEs (that were reported by ≥ 20% of patients) are summarised by 
RXC004 dose level and overall in Table 10. The most common TEAEs were decreased 
appetite, fatigue, and nausea which were all reported for 6 patients each (46%).  


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Table 10 
Most common (occurring in at least 20% patients) TEAEs, as of 
01 July 2022, Phase 1 study RXC004/0001 (RXC004 + nivolumab 
Module 2) 
Preferred term 
Number (%) of patients 
RXC004 1.0 mg QD 
+ nivolumab  
(N = 5) 
RXC004 1.5 mg QD 
+ nivolumab  
(N = 8) 
Overall 
 
(N = 13) 
Patients with any TEAEs 
5 (100) 
8 (100) 
13 (100) 
Decreased appetite 
2 (40) 
4 (50) 
6 (46) 
Fatigue 
3 (60) 
3 (38) 
6 (46) 
Nausea 
2 (40) 
4 (50) 
6 (46) 
Dysgeusia 
1 (20) 
4 (50) 
5 (38) 
Constipation 
2 (40) 
2 (25) 
4 (31) 
Headache 
2 (40) 
2 (25) 
4 (31) 
Weight decreased 
1 (20) 
3 (38) 
4 (31) 
Abdominal distension 
1 (20) 
2 (25) 
3 (23) 
Blood bilirubin increased 
0 (0) 
3 (38) 
3 (23) 
Pruritus 
1 (20) 
2 (25) 
3 (23) 
Urinary tract infection 
0 (0) 
3 (38) 
3 (23) 
QD, once daily; TEAE, treatment-emergent adverse event. 
The most common AEs (that were reported by ≥ 20% of patients) related to study treatment 
(RXC004 or nivolumab) are summarised in Table 11. All 13 patients had at least one AE 
related to study treatment; all 13 patients had events related to RXC004, 9 patients (69%) had 
events related to nivolumab. The most common treatment-related AEs were nausea (46%), 
dysgeusia (38%), and fatigue (38%). With the exception of fatigue, all of these events were 
more frequently observed at the 1.5 mg dose than the 1 mg dose level. Dysgeusia is 
considered to be an on-target effect of Wnt inhibition. 
 


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Table 11 
Most common (occurring in at least 20% patients) AEs considered 
related to RXC004 or nivolumab, as of 01 July 2022, Phase 1 study 
RXC004/0001 (RXC004 + nivolumab Module 2) 
Preferred term 
Number (%) of patients 
RXC004 1.0 mg QD 
+ nivolumab  
(N = 5) 
RXC004 1.5 mg QD 
+ nivolumab  
(N = 8) 
Overall 
 
(N = 13) 
Patients with any TRAEs 
5 (100) 
8 (100) 
13 (100) 
Nausea 
2 (40) 
4 (50) 
6 (46) 
Dysgeusia 
1 (20) 
4 (50) 
5 (38) 
Fatigue 
2 (40) 
3 (38) 
5 (38) 
Decreased appetite 
1 (20) 
3 (38) 
4 (31) 
Weight decreased 
1 (20) 
3 (38) 
4 (31) 
Blood bilirubin increased 
0 (0) 
3 (38) 
3 (23) 
QD, once daily; TRAE, treatment-related adverse event. 
 
Three patients had CTCAE Grade 3 events that were assessed by the Investigator as possibly 
or probably related to RXC004: Grade 3 fatigue was reported by one patient who received 
RXC004 1 mg + nivolumab and one patient who received RXC004 1.5 mg. One patient who 
received RXC004 1.5 mg had Grade 3 events of aspartate aminotransferase increased, blood 
alkaline phosphatase increased, and DILI, which were considered to be related to both 
RXC004 and nivolumab. No other events of DILI were reported in either Module 1 or 
Module 2. A fourth patient who received RXC004 1.5 mg had a Grade 3 event of anaemia 
with missing relationship details. 
A total of 11 treatment-emergent SAEs were reported in 6 patients. Ten of the 11 SAEs 
reported were assessed by the Investigator and the Sponsor as unrelated to RXC004. These 
were as follows: infection (NOS), left leg weakness, and infection (all reported in one patient 
at 1 mg); kidney infection and liver pain (in one patient at 1 mg), and 2 events of ascites (in 
one patient at 1 mg); diarrhoea (in one patient at 1.5 mg); and chest infection and pneumonia 
(in one patient at 1.5 mg). 
One SAE was assessed as being related to RXC004 and nivolumab: this was Grade 3 DILI in 
a patient who had colorectal cancer with liver metastases, and was reported on Cycle 1 
Day 17. The event was considered to be a DLT, and study treatment was permanently 
discontinued. The liver function tests subsequently returned to baseline. The patient 
subsequently died due to disease progression. No other events of DILI were reported in either 
Module 1 or Module 2. 


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4.4.1.3 
RXC004 pharmacokinetic profile 
The data from the ongoing Phase 1 study (NCT03447470) have characterised the PK of 
RXC004 monotherapy in patients following single and multiple oral doses ranging from 
0.5 mg to 10 mg, and in combination with standard dose nivolumab at doses of RXC004 1 mg 
and 1.5 mg.   
RXC004 was rapidly absorbed following oral dosing in fasting conditions, with a peak plasma 
concentration observed typically after 1-2 hours post-dose and eliminated with a half-life of 
approximately 
 hours.  The exposures achieved in patients dosed with 0.5–2 mg were 
broadly dose proportional and predictable from the exposure observed in the patient dosed at 
10 mg in terms of half-life, Cmax, Cmin and AUC. There was limited accumulation to steady 
state and it is in line with expectations from the measured half-life. The 3 mg dose Cmax, Cmin 
and AUC were all disproportionately high compared to the 2 mg dose, giving an estimated 
 i in exposure for the 50% rise in dose.  
There was little difference in RXC004 plasma exposure between monotherapy and 
combination therapy on Cycle 0 Day 1. On Cycle 1 Day 15, the steady state RXC004 plasma 
exposure appeared to be slightly greater on combination therapy compared with monotherapy, 
although patient numbers are small. The mechanism for a potential small increase in exposure 
when RXC004 is given with nivolumab is unclear since a PK interaction with a monoclonal 
antibody is unlikely, but an increase in bioavailability cannot be ruled out. 
The plasma exposure of RXC004 when given at 1.5 mg in combination with nivolumab was 
no greater than that observed at 2 mg monotherapy and was around 
 t than that 
observed at 3 mg monotherapy. 
The steady state PK parameters of RXC004 from Study RXC004/0001, for RXC004 
monotherapy and in combination with nivolumab are summarised in Table 12. 
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Table 12 
Steady state pharmacokinetic parameters, as of 01 July 2022, Phase 1 
study RXC004/0001 RXC004 monotherapy and combination with 
nivolumab (Module 1 and Module 2) 
Parameter 
(units) 
 
RXC004  monotherapy 
RXC004 in combination 
with nivolumab 
1 mg 
1.5 mg 
2 mg 
1 mg 
1.5 mg 
Cmin  
(ng/mL) 
N 
3 
6 
4 
4 
4 
Geometric mean 
(%CV) 
7.15  
(120) 
12.6  
(142) 
26.8  
(134) 
8.62  
(163) 
13.6  
(48.4) 
Tmax (h) 
N 
3 
6 
5 
5 
6 
Median  
(min – max) 
1.00  
(1–2.00) 
2.00  
(1.00–4.00) 
1.00  
(0.5 – 2.00) 
2.00  
(0.5-6.0) 
1.50  
(0.5-2.00) 
Cmax 
(ng/mL) 
N 
3 
6 
5 
5 
5 
Geometric mean 
(%CV) 
42.4  
(89.1) 
56.6  
(53.7) 
68.5  
(61.6) 
58.2  
(46.3) 
76.4  
(57.6) 
AUC0-24 
(h*ng/mL) 
N 
3 
6 
4 
5 
5 
Geometric mean 
(%CV) 
392  
(42) 
630  
(76) 
931  
(61.1) 
544  
(65.5) 
706  
(40.1) 
AUC0-24, area under the plasma concentration-time curve from zero to 24 hours; Cmax, maximum observed plasma 
concentration; Cmin, minimum observed plasma concentration across the dosing interval; Tmax, time to maximum plasma 
concentration. 
4.4.1.4 
RXC004 Pharmacodynamic and Efficacy Data 
In pre-clinical pharmacology models, RXC004 demonstrated anti-tumour activity at steady 
state Cmin exposures of between 
 and 
 fold IC50, with evidence of improved efficacy at 
higher doses.  The target human exposure to achieve monotherapy efficacy is a Cmin value of 
fo
fold IC50. 
Pharmacodynamic effects (>50% reduction in AXIN2 expression in skin) were observed in 
patients who achieved Cmin exposure of 
fold IC50. 
As of 30 July 2021, 5/18 evaluable patients in the monotherapy module, with at least 
2 scheduled RECIST1.1 scans had achieved durable SD of 10 weeks or longer – 1 patient 
dosed at 1.0 mg QD (RNF43 LoF mCRC), 2 patients dosed at 1.5 mg (CCA and RSPO fusion 
mCRC) and 2 patients dosed at 3 mg (CCA and thymus cancer.  The CCA patient had a dose 
reduction to 1.5 mg RXC004 after experiencing colitis).  Of note all 5 patients who achieved 
SD had a type of cancer in which RXC004 is most likely to demonstrate clinical benefit based 
on its mechanism of action. These selected tumour types are CRC or PDAC with a RNF43 
LoF mutation or RSPO fusion, or biliary tract cancer or thymus cancer, both of which are 
reported to have high Wnt ligand activity (Boulter et al 2015, Loilome et al 2014, Vodicka et 
al 2020). All patients with RECIST SD also achieved Cmin exposures of 
-fold IC50. 
Efficacy data for the combination of RXC004 + nivolumab in Module 2 are not yet available. 
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4.4.1.5 
RXC004 monotherapy dose 
Based on all of the available information, patients who enrol in Arm A RXC004 monotherapy 
will receive 2.0 mg RXC004 orally once a day.   
The 2 mg QD dose was both tolerable and able to consistently deliver Cmin values of f 
fold 
IC50 in all patients, whereas the 1.5 mg QD dose did not consistently achieve the target Cmin 
values of 
fold IC50 in all patients.   
The 2 mg dose has been selected for Phase 2 development as the optimal dose to demonstrate 
an efficacy signal in patients with genetically selected tumours and to allow for potential dose 
reductions to manage adverse events.  
4.4.1.6 
RXC004 dose in combination with nivolumab 
Patients who receive combination therapy with RXC004 and nivolumab in Arm A or B will 
receive RXC004 1.5 mg orally once a day. Justification for the choice of doses and regimens 
is provided in Sections 4.4.1 and 4.4.2. 
4.4.2 
Nivolumab 
The nivolumab dose and regimen selected for this study are based on the FDA approved 
prescribing information for nivolumab.  Patients with MSI-H or dMMR metastatic colorectal 
cancer can receive 240 mg q2w or 480 mg q4w.  480 mg q4w was selected to complement a 
28-day cycle of RXC004 and reduce the number of patient visits required.  
 
End of Study Definition 
A participant is considered to have completed the study if he/she has completed all phases of 
the study (including the last visit and the last scheduled assessment shown in the Schedule of 
Assessments) or withdraws consent whichever occurs first. 
The end of the study is defined as the date of the last visit of the last participant in the study or 
the last scheduled assessment shown in the Schedule of Assessments for the last participant in 
the study before the data cut off (DCO).  
Sponsor may terminate this study at any time for reasons that include but are not limited to; 
x The discovery of an unexpected, significant, or unacceptable risk to the patients 
enrolled in the study 
x Inability to complete the trial in a meaningful timeframe due to a lack of recruitment.  
x A decision on the part of the Sponsor to modify/suspend or discontinue development 
of the drug 
&&,
&&,


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5 
STUDY POPULATION 
The study will recruit male or female patients aged 18 years or older with histologically 
documented, RNF43 or RSPO genetically aberrated, MSS mCRC (Stage IV), who have 
progressed after standard of care treatment(s), have a minimum life expectancy of 16 weeks 
and an Eastern Cooperative Oncology Group performance status of 0 or 1. 
Prospective approval of protocol deviations to recruitment and enrolment criteria, also known 
as protocol waivers or exemptions, is not permitted. 
 
Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
1 
Participant must be 18 years of age at the time of signing the informed consent.  
2 
Ability to give written informed consent and capable of understanding the protocol 
requirements listed in the informed consent form (ICF).  Written informed consent must 
be obtained prior to performing any protocol-related procedures, including screening and 
pre-screening evaluations Participants must be willing and able to comply with the study 
protocol procedures and restrictions.  
3 
Histological documentation of metastatic (Stage IV) CRC and;
(a) documented tumour tissue aberration in RNF43 and/or RSPO from central pre-
screening or from a recognised panel approved by the sponsor.  Please see 
Section 5.5 and Appendix F for more details 
(b) documented confirmation of MSS status, performed as a standard of care procedure 
at site. Please see Section 5.5 for more details 
4 
Patients must have had documented radiological progression following a minimum of 
1 prior standard of care treatment regimen for metastatic disease.  
5 
ECOG performance status 0 or 1 with no deterioration over the previous 2 weeks and an 
estimated life expectancy of greater than 16 weeks 
6 
At least one lesion that is measurable by RECIST 1.1 at baseline (within 28 days prior to 
start of study treatment).  The measurable lesion must not be chosen for the mandatory 
paired biopsies. 
7 
Mandatory paired biopsies*; Patients must have at least one lesion suitable for biopsy at 
screening (which must not be a target lesion for RECIST 1.1) and be willing to provide 
mandatory tumour biopsy samples as follows:  
Arm A: Baseline*; C1D15 (+ up to 7 days) and during Cycle 3 of monotherapy treatment 
(3 biopsies) 
Arm A combination treatment phase patients: Baseline*, C1D15 (+ up to 7 days) and 
during Cycle 3 of combination treatment (3 biopsies)  


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Arm B: Baseline**, C1D15 (+ up to 7 days) and during Cycle 3 of combination 
treatment (3 biopsies)  
*Baseline biopsy is mandatory except in exceptional circumstances where biopsy is not 
technically feasible.  All patients without a baseline sample must be approved by Sponsor 
before starting study treatment.  On treatment biopsies are also mandatory unless deemed 
not to be technically or clinically feasible by Investigator. 
**
, i, ideally from the same site of disease (e.g. liver, lymph node etc) that 
the ‘on treatment’ biopsy will be taken from, and taken after completion of all prior 
standard of care treatments will be accepted as a baseline biopsy. 
8 
Patients with adequate organ functions as described below; 
− 
AST/ALT ≤ 2.5X ULN (upper limit of normal) [with no underlying Liver Metastasis] 
− 
AST/ALT ≤ 5 X ULN [with underlying Liver Metastasis] 
− 
Total Bilirubin < 1.5 X ULN 
− 
Serum Creatinine ≤ 1.5 X ULN 
− 
ANC ≥ 1.5 x 109/L 
− 
Platelets > 100 x 109/L  
− 
Hb >8.5g/dL (with or without transfusional support) 
− 
Calculated creatinine clearance (CrCL) ≥60 mL/min as determined by Cockcroft 
Gault (using actual body weight).  
Males: 
CrCL =   
Weight (kg) × (140 - Age) 
(mL/min)  
72 × serum creatinine (mg/dL) 
Females: 
CrCL =  
 
Weight (kg) × (140 - Age)  
  
× 0.85 
(mL/min) 
 
72 × serum creatinine (mg/dL) 
− 
 
9 
Female patients of childbearing potential must have a negative pregnancy test prior to 
start of dosing 
10 Female patients of childbearing potential and male patients with female partners of 
childbearing potential must agree to use a highly effective method of contraception during 
the study and for at least 5 months after the last dose of study drug. See Section 5.3.1 for 
details of acceptable methods of contraception 
 
For patients on RXC004 monotherapy treatment (Arm A) the following inclusion 
criteria will also apply to enter the RXC004 + nivolumab treatment phase; 
CCI


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11. Patients must have had documented RECIST1.1 defined radiological progression on 
RXC004 monotherapy treatment on the first scheduled scan (week 8 +/- 1 week)
12. Patients must receive Cycle 1 Day 1 of combination study treatment within 28 days of 
the first scheduled scan (week 8 +/- 1 week) showing RECIST1.1 defined radiological 
progression, or for clinically stable patients that remain on RXC004 after RECIST1.1 
defined radiological progression, within 28 days of the most recent scan showing 
further radiological progression or confirmation of the week 8 RECIST1.1 progression 
(see Section 7.1.1 and Appendix D for more details) 
 
 
Exclusion Criteria  
Participants are excluded from the study if any of the following criteria apply: 
1 
Prior therapy with a compound of the same mechanism of action as RXC004. 
2 
Patients at higher risk of bone fractures, including; 
(a) Patients with Vitamin D [25(OH)D3] deficiency defined as < 30 nmol/L 
(<12 ng/mL). [Note - Patients who fail on this criteria can be retested within the 
screening window] 
(b) Patients with a corrected total serum calcium level of <2 mmol/L and serum 
magnesium level of < 0.60 mmol/L 
(c) Patients with osteoporosis (as defined by a T-score of < -2.5 at any of the 3 following 
sites, all of which must be assessed: L/R total hip, L/R femoral neck, lumbar spine 
(L1-4) by DEXA scan) or history of fragility fractures (any fracture occurring with 
low-level trauma or as a result of falling < standing height) 
(d) Patients with ongoing or a history of clinically significant hyperparathyroidism, 
Pagets disease or Osteomalacia. Patients with a prior diagnosis of 
hyperparathyroidism, Pagets disease or Osteomalacia, considered to have no 
increased bone fragility risk, may be included only after consultation with the 
Sponsor’s Medical Monitor. 
(e) Patients who have received treatment for type 2 Diabetes Mellitus with a 
Thiazolidinedione peroxisome proliferator-activated receptor gamma agonist (e.g. 
pioglitazone or rosiglitazone) within 4 weeks prior to study drug dosing. 
3 
Any known uncontrolled inter-current illness or persistent clinically significant toxicity 
related to prior anti-cancer treatment (as assessed by the Investigator) which in the 
investigator's opinion makes it undesirable for the patient to participate in the study 
4 
Patients who have any history of an active (requiring treatment) other malignancy (except 
any in-situ carcinoma, non-melanoma skin carcinoma and early prostate cancer with a 
normal PSA) within 2 years of study entry. 
5 
Patients with known or suspected brain metastases 


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6 
Use of anti-neoplastic agents (including immunotherapy), immunosuppressants and other 
investigational drugs within 3 weeks prior to the first dose of study treatment, or any 
residual AEs from prior anti-cancer therapies that have not resolved to Grade ≤1.  Note: 
COVID-19 vaccinations that are authorised but not approved should not be considered as 
investigational agents for the purposes of study eligibility assessment. 
7 
Patients with a known hypersensitivity to any RXC004 excipients. 
8 
Patients with a contra-indication for denosumab treatment including: 
• Known hypersensitivity to Denosumab or any of the excipients 
• Severe untreated hypocalcaemia 
• Unhealed lesions from dental or oral surgery 
9 
Patients who are pregnant or breast-feeding 
10 Use of any live or live-attenuated vaccines against infectious diseases (e.g., influenza 
nasal spray, varicella) within 4 weeks (28 days) of initiation of study treatment.  Note: 
Patients who require COVID-19 vaccination within 4 weeks of initiation of study 
treatment should receive a non-live vaccine (e.g. one based on mRNA or fully 
inactivated/genetically modified viruses incapable of replication) 
11  Judgment by the investigator that the participant should not participate in the study if the 
participant is unlikely to comply with study procedures, restrictions and requirements. 
12 Patients with a mean resting corrected QTcF  >470 ms, obtained from triplicate ECGs 
performed at screening 
 
For patients on RXC004 + nivolumab combination treatment (Arm B or Arm A RXC004 
+ nivolumab treatment phase) the following exclusion criteria will also apply; 
13 Patients with any contraindication to the use of nivolumab as per approved label 
(Summary of Product Characteristics or equivalent)  
14 Patients with active or prior documented autoimmune or inflammatory disorders within 
the past 5 years, including inflammatory bowel disease, rheumatoid arthritis, autoimmune 
hepatitis, Grave’s disease, lupus and celiac disease. The following are exceptions to this 
criterion;  
(a) Patients with vitiligo or alopecia 
(b) Patients with type I diabetes mellitus 
(c) Patients with residual hypothyroidism due to autoimmune condition only requiring 
hormone replacement 
(d) Patients with psoriasis not requiring systemic treatment, or conditions not expected to 
recur in the absence of an external trigger. 
(e) Patients with celiac disease controlled by diet alone 
15 Patients with active infections, including tuberculosis, hepatitis B, hepatitis C or human 
immunodeficiency virus.   Patients with a resolved HBV infection (defined as presence of 


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hepatitis B core antibody [HBcAb] and absence of HBV surface antigen [HBsAg] or 
negative on polymerase chain reaction [PCR] for HBV DNA) are eligible. Patients 
positive for HCV antibody are eligible only if PCR is negative for HCV RNA. 
16 Patients with body weight <40kg 
17 Patients with a history of allogeneic organ transplant or active primary immunodeficiency 
18 Patients with a known hypersensitivity to nivolumab or any of the excipients of the 
product  
 
 
Lifestyle Considerations 
5.3.1 
Contraception 
1 
Women must be 1 year post-menopausal, surgically sterile or must agree to using 
enhanced contraceptive measures for the duration of the study and for 5 months after the 
last dose of study drug, with all male sexual partners.  Highly effective methods of 
contraception must be used, which include having a vasectomised partner, sexual 
abstinence (defined as refraining from heterosexual intercourse during the study and for 5 
months after the last dose of study drug. The reliability of sexual abstinence needs to be 
evaluated by the Investigator, in relation to the duration of the study and the 
preferred/usual lifestyle of the subject), or one of the following: hormonal contraceptives 
which inhibit ovulation (oral, injectable, transdermal, intravaginal or implants), 
Intrauterine Device (IUD), Intrauterine Hormone-releasing System (IUS) (e.g., Mirena), 
or bilateral tubal occlusion.  
2 
Men must use a condom (with spermicide) during the study, and for 5 months after the 
last dose of study drug, with all sexual partners.   
3 
Men must not donate sperm for 5 months after the last dose of study drug. 
 
5.3.2 
Meals and Dietary Restrictions 
Patients must fast (water to drink only) from at least 2 hours prior to taking a dose to at least 
1-hour post-dose for all doses. Patients should abstain from eating large amounts of grapefruit 
and Seville oranges (and other products containing these fruits e.g. grapefruit juice or 
marmalade) during the study (e.g., no more than a small glass of grapefruit juice (120 mL) or 
half a grapefruit or 1-2 teaspoons (15g) of Seville orange marmalade daily). 
5.3.3 
Concomitant treatments 
5.3.3.1 
Prohibited medications 
The following concomitant medication is prohibited without approval from the Sponsor 
Physician; 
1 
The use of any natural/herbal products or other ‘folk remedies’. 


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2 
No other chemotherapy, hormonal therapy (contraception and hormone replacement 
therapy is acceptable), or other investigational product is permitted other than the study 
treatments. 
3 
Live or live-attenuated virus and bacterial vaccines should not be administered, e.g. 
yellow fever, measles, influenza nasal spray, COVID-19, rubella, mumps, typhoid, 
mycobacterium tuberculosis (BCG), Yersinia pestis (EV) within 4 weeks of starting study 
treatment, whilst the patient is receiving study medication and for 30 days following 
discontinuation of study treatment.  Patients who require COVID-19 vaccination whilst 
on study should receive a non-live vaccine (e.g. one based on mRNA or fully 
inactivated/genetically modified viruses incapable of replication). 
4 
The use of some CYP3A4 inhibitors and inducers should be restricted prior to first dose 
of study treatment and throughout the study treatment, as RXC004 is observed to be 
exclusively metabolised by CYP3A4. For a list of prohibited CYP3A4 inhibitors and 
inducers and the required washout periods, please refer to Appendix E. 
5 
Drugs that are immunosuppressive or may cause secondary osteoporosis should not be 
administered (e.g. corticosteroids, pioglitazone or rosiglitazone). 
  The following exceptions are allowed; 
• Use of immunosuppressive medication for the management of nivolumab-related 
AEs (as per Appendix G) or colitis events (as per Appendix J).  Steroids required 
for the management of RXC004 or nivolumab related AEs, should be tapered to 
doses ≤ 10 mg/day prednisone equivalent, before  re-starting study treatment. 
• Use of topical, inhaled or intranasal corticosteroids 
• Systemic steroids at doses ≤ 10 mg/day prednisone equivalent 
 
5.3.3.2 
COVID-19 Vaccinations 
 
COVID-19 vaccination is permitted before or during study treatment, with the exception of 
live-attenuated vaccines and replication-competent vector vaccines, which are prohibited 
within 4 weeks of starting study treatment and whilst on study treatment. 
As COVID-19 vaccines are often prioritised for cancer patients, vaccination prior to the first 
dose of study treatment is advisable.  Where possible, COVID-19 vaccinations should be 
given at least 72 hours before starting study treatment and study treatment should not 
commence until any acute adverse effects from vaccination have resolved to at least Grade 1.  
If this is not possible, investigators should follow their local prescribing information and 
policies when considering whether a patient on study treatment should receive a COVID-19 
vaccination.  If COVID-19 vaccination is given during the study (including the screening 
period), then please ensure that all the relevant information is recorded in the concomitant 
medication eCRF (i.e vaccine name, manufacturer, date(s) given and dose). 


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5.3.4 
Other Lifestyle Considerations 
Patients taking RXC004 are advised to avoid exposure to direct sunlight and the use of 
tanning equipment. 
 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently treated in the study. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the Consolidated 
Standards of Reporting Trials (CONSORT) publishing requirements and to respond to queries 
from regulatory authorities. Minimal information includes demography, screen failure details, 
eligibility criteria, and any serious adverse event (SAE). 
Individuals who do not meet the Calcium and/or Vitamin D3 laboratory criteria for 
participation in this study may be retested after starting Calcium/Vitamin D3 supplementation.  
Repeating laboratory tests within the screening period will not be considered as a rescreen. 
 
Pre-Screening Genetic Testing 
All enrolled patients’ tumours will be required to have a genetic mutation which is predicted 
to be loss of function in RNF43, or an RSPO fusion/translocation detectable in 
 
.  .  Eligible patients also need to have evidence of MSS status.  Eligible 
subjects will be identified by either a central genetics screening approach or local laboratory 
assessments.  
5.5.1 
Central Testing 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Data from central genetic screening will be shared with investigators to aid future treatment 
decisions. 
 
 
 
 
5.5.2 
Local Testing  
Patients with predicted loss of function RNF43 mutations or RSPO fusions from other local 
testing will also be eligible to enter the study, provided that the assay used for testing has 
adequate analytical validation for this purpose (i.e. fully 
 f for the purpose of 
investigating RNF43 mutations or RSPO fusions; partially 
 for their analytical 
performance or having achieved a minimum validation specification of >90% for Analytical 
Sensitivity / PPA and >95% for Analytical Specificity / NPA for the detection of the 
aberrations in the genes of interest and performed in an ISO accredited,  CLIA or CAP 
accredited lab). If aberrations are detected by local tests that are not included in the list in 
Appendix F, these may be included in the study on discussion with the Sponsor. 
 
 
 
 
5.5.3 
MSS/MSI Testing 
Tumour samples that test positive for RNF43 mutations or RSPO fusions will also be tested 
for MSI status at 
.  .  The MSI status from 
 
 is
 is not required for eligibility (which will be based on the local standard of care IHC, 
NGS or PCR test that has been taken at diagnosis to identify patients with Lynch Syndrome or 
patients with MSI CRC who may be eligible for treatment with a PD-1 inhibitor), but will be 
used to retrospectively evaluate the concordance between local and central MSI assays.  
 
 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI


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6 
STUDY TREATMENT 
 
Study Treatment(s) Administered 
6.1.1 
Investigational Products 
Table 13 
Investigational Products 
Treatment 
RXC004 
Nivolumab 
Denosumab 
ARM 
Arm A and B 
Arm B and Arm A 
combination treatment 
phase 
Arm A and B 
Type 
Drug
Biologic
Biologic
Dose 
Formulation 
0.5 mg or 1 mg capsules 
Ampule 
Ampule 
Dosage Level(s) 
Monotherapy: 2 mg QD 
Combination therapy: 
1.5 mg QD 
480 mg q4w 
120 mg once every 
month 
Route of 
Administration 
oral 
IV infusion 
SC injection 
Use 
Experimental  
Experimental 
Prophylactic 
IMP and NIMP 
IMP 
IMP 
IMP 
Sourcing 
Provided centrally by 
the Sponsor 
Provided centrally by 
the Sponsor 
Provided centrally by 
the Sponsor
Packaging and 
Labelling 
RXC004 will be 
provided in white 50 mL 
HDPE Duma bottles. 
Each bottle will be 
labelled as required per 
country requirement 
Study Intervention will 
be provided in packets 
of 240 mg/24 mL 
vials. Each packet will 
be labelled as required 
per country 
requirement 
Study Intervention will 
be provided in a vial  
containing 120 mg in 
1.7 mL solution 
Each vial will be 
labelled as required per 
country requirement 
HDPE, high-density polyethylene; IMP, investigational medicinal product; IV, intravenous; NIMP, non-investigational 
medicinal product; QD, once daily; q4w, once every 4 weeks; SC, subcutaneous. 
 
 
Preparation/Handling/Storage/Accountability of Study 
Treatments 
6.2.1 
RXC004 
RXC004 will be supplied by Redx as 0.5 and 1.0 mg capsules. A complete description of the 
chemistry and formulation may be found in the Investigational Medicinal Product Dossier. 


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The Quality Control Standards and requirements for RXC004 study medication are described 
in separate release protocols/ Certificate of Analysis. 
RXC004 is formulated as two dosage strengths capsules (0.5 mg and 1.0 mg), manufactured 
by Quay Pharma, Deeside Industrial Park, CH5 2NS, United Kingdom. The RXC004 capsules 
strengths are 0.5, 1.0 mg for oral administration.  Stability testing of RXC004 is ongoing. 
Please refer to the current IMP label for the Expiry Date associated with the current shelf-life 
of the product. 
Patients must fast (water to drink only) for at least 2 hours prior to taking a dose to at least 
1-hour post-dose for all doses. 
6.2.2 
Nivolumab 
Nivolumab will be supplied by 240 mg/24 mL vial solutions for infusion after dilution. Two 
(2) vials will be needed for the 480 mg dose. 
Storage; 
• Unopened vials must be stored in a refrigerator (2°C to 8°C). The vials must be kept 
in the original package in order to protect from light. Vials should not be frozen. The 
unopened vial can be stored at controlled room temperature up to 25°C with room 
light for up to 48 hours.  
• Infusion must be completed within 24 hours of preparation. If not used immediately, 
the solution may be stored under refrigeration conditions (2°C-8°C) and protected 
from light for up to 24 hours [a maximum of 8 hours of the total 24 hours can be at 
room temperature (20°C-25°C) and room light]. 
• Do not use after the expiry date which is stated on the carton and on the vial label 
after EXP. The expiry date refers to the last day of that month.  
•  Do not store any unused portion of the infusion solution for reuse. Any unused 
medicine or waste material should be disposed of in accordance with local 
requirements. 
 
Preparation and administration of nivolumab; 
• Visually inspect drug product solution for particulate matter and discoloration prior to 
administration. Nivolumab is a clear to opalescent, colourless to pale-yellow solution. 
Discard the vial if the solution is cloudy, discoloured, or contains extraneous 
particulate matter other than a few translucent-to-white, proteinaceous particles. Do 


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not shake the vial.  
• Withdraw the required volume of nivolumab and transfer into an intravenous 
container. Dilute nivolumab with either 0.9% Sodium Chloride Injection, USP or 5% 
Dextrose/Glucose Injection, USP to prepare an infusion with a final concentration 
ranging from 1 mg/mL to 10 mg/mL. The total volume of infusion must not exceed 
160 mL. For patients with body weights less than 40 kg, the total volume of infusion 
must not exceed 4 mL/kg of body weight.  
• Mix diluted solution by gentle inversion. Do not shake 
• The dose of nivolumab for administration must be prepared by the Investigator’s or 
site’s designated IP manager using aseptic technique.  Total time from needle puncture 
of the vial to the end of administration should not exceed; 
o 8 hours at room temperature  
o 24 hours under refrigeration at 2°C to 8°C (36°F to 46°F)  
• The infusion should be administered over 60 minutes through an intravenous line 
containing a sterile, non-pyrogenic, low protein binding in-line filter (pore size of 0.2 
micrometre to 1.2 micrometre). 
• Do not co-administer other drugs through the same intravenous line 
• The intravenous line should be flushed at the end of the infusion. 
 
6.2.3 
Denosumab 
Denosumab is a human monoclonal antibody (IgG2) that targets and binds with high affinity 
specifically to RANKL, preventing RANKL/RANK interaction from occurring and resulting 
in reduced osteoclast numbers and function, thereby decreasing bone resorption and cancer-
induced bone destruction. 
Denosumab is approved to be administered at 120 mg S.C. once monthly for use in the 
prevention of skeletal-related events in patients with advanced cancers with bone metastases 
(XGEVA). 
The use of denosumab in this trial is outside labelled use as patients may not have bone 
metastases. The rationale for its prophylactic use in all patients is as a bone protection 
measure based on the increased risk of bone fragility with RXC004 treatment.  


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Randomisation 
Once Arm B is opened, patients who are eligible for both Arm A and Arm B will be 
randomised 2:1 to Arm B: Arm A to ensure there is no conscious or unconscious selection 
bias. A 2:1 randomisation was selected to ensure that the combination and monotherapy arms 
will complete at approximately the same time and to maximise the number of patients 
recruited under randomisation conditions. Patients will be centrally assigned to a Study Arm 
using IRT. 
Randomisation will be open-label, and will be stratified by genetic alteration 
(RNF43 vs RSPO). 
 
Study Treatment Compliance 
6.4.1 
RXC004 
The first dose of RXC004 will be taken at the site under medical supervision.  The date and 
time of dose administered at site will be recorded in the source documents and recorded in the 
eCRF.  When patients self-administer RXC004 at home, compliance with study treatment will 
be assessed at each visit. Compliance will be assessed by collection of a patient diary cards 
and counting of returned capsules, during the site visits and documented in the source 
documents and eCRF. Deviation(s) from the prescribed dosage regimen should be recorded in 
the eCRF. 
A record of the number of RXC004 capsules dispensed to and taken by each participant must 
be maintained and reconciled with study treatment and compliance records. Treatment start 
and stop dates, including dates for treatment delays and/or dose reductions will also be 
recorded in the eCRF. 
6.4.2 
Nivolumab 
Nivolumab will be dosed at the site, directly from the investigator or designee, under medical 
supervision. The date, and time of dose administered at site will be recorded in the source 
documents and recorded in the eCRF. The dose of nivolumab and the study participant 
identification will be confirmed at the time of dosing by a member of the study site staff other 
than the person administering the study intervention.  
Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the participant is receiving at the time of enrolment or 
receives during the study must be recorded along with: 
x 
Reason for use 
x 
Dates of administration including start and end dates 


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x 
Dosage information including dose and frequency 
Concomitant medication may be given as medically indicated with the exception of prohibited 
concomitant medication (Section 5.3.3 and Appendix E).  The Medical Monitor should be 
contacted if there are any questions regarding concomitant or prior therapy. 
6.5.1 Rescue Medicine 
As a result of immune mediated AEs that could potentially be experienced by patients on 
nivolumab, steroids and other immunosuppressant rescue medication must be available to 
these patients. The two products that fall into the category of other immunosuppressants are 
infliximab (e.g., for colitis) and mycophenolate (e.g. for hepatitis).  Rescue medications for 
immune mediated adverse events will be obtained locally. 
The use of infliximab and mycophenolate are considered to be used as off-label for 
management of immunotherapy related toxicities.  These rescue medications must be 
receipted, controlled, and administered by the pharmacist and stored according to the labelled 
storage conditions. 
 
Dose Modification 
RXC004 dose reduction and interruption are permitted. Nivolumab dose reduction is not 
permitted but dose interruption/delay is permitted as per Appendix G. 
RXC004 may be dose interrupted (withheld) until a clinically significant (any grade) and/or a 
grade ! 3 related adverse event resolves to baseline or < grade 2. RXC004 may also be 
withheld if it is necessary to give a concomitant medication that is a moderate or strong 
CYP3A4 inhibitor. RXC004 related colitis events should be managed as per Appendix J. 
Adverse events that are assessed as being causally related nivolumab should be managed as 
per the Nivolumab Toxicity Management and Dose Modification Guidelines (Appendix G). If 
either agent is interrupted or discontinued for a related-AE the other agent (nivolumab or 
RXC004) may be continued if the patient is judged (by the investigator) to be receiving 
clinical benefit.
RXC004 and nivolumab dose interruption and stopping criteria are detailed in Table 14. 


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Table 14 
Dose Modification and Stopping Criteria 
Event  
Action  
Colitis events 
(e,g. Colitis, ileitis, enterocolitis etc) 
 
Grade 1 
 
 
 
If receiving RXC004, either as monotherapy or in 
combination with nivolumab; 
Reduce RXC004 to a lower dose (see Table 15 for dose 
reduction scheme) and manage as per Appendix J (and 
Appendix G if applicable) 
 
Grade 2  
If receiving RXC004, either as monotherapy or in 
combination with nivolumab 
Interrupt RXC004.  Manage as per Appendix J and  
Appendix G if applicable.  When event has resolved to 
Grade 1a and steroids tapered to ≤10 mg of prednisone per 
day (or equivalent), resume RXC004 at a lower dose (see 
Table 15 for dose reduction scheme) and nivolumab (if 
applicable) at 480 mg q4w. 
If event re-occurs after re-starting study treatment, then 
RXC004 and nivolumab (if applicable) should be 
permanently discontinued. 
 
Grade 3 
If receiving RXC004 monotherapy; 
Interrupt RXC004.  Manage as per Appendix J.  When event 
has resolved to Grade 1a and steroids tapered to ≤10 mg of 
prednisone per day (or equivalent), resume RXC004 at a 
lower dose (see Table 15 for dose reduction scheme). 
If event re-occurs after re-starting study treatment, then 
RXC004 should be permanently discontinued. 
 
If receiving RXC004 in combination with nivolumab; 
permanently discontinue both agents and manage as per 
Appendix J and  Appendix G. 
 
Grade 4 
If receiving RXC004, either as monotherapy or in 
combination with nivolumab; 
Permanently discontinue study treatment (both agents if 
applicable).  Manage as per Appendix J and  Appendix G 
 
 


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Event  
Action  
Dysgeusia events 
Grade 1/2 
 
RXC004 related; 
Consider dose reduction, depending on clinical symptoms 
Manage as per Appendix I 
Interrupt RXC004 treatment if dysgeusia is associated with 
>5kg weight loss from baseline 
 
Grade 2 associated with a 10-20% 
decrease in body weight 
RXC004 related; 
Manage as per Appendix I 
Reduce RXC004 to a lower dose (see Table 15 for dose 
reduction scheme). 
 
Grade 2 associated with a >20% 
decrease in body weight 
RXC004 related; 
Permanently discontinue RXC004.  Nivolumab can 
continue if clinical benefit is judged by investigator. 
 
Other adverse events 
Any event that meets discontinuation 
criteria 
for 
nivolumab 
(see 
Appendix G) 
 
Permanently discontinue nivolumab.  RXC004 can continue 
if clinical benefit is judged by investigator. 
 
Any event that meets nivolumab 
treatment hold (see Appendix G) 
Interrupt nivolumab and manage as per Appendix G.  
Nivolumab can be re-started when event is resolved to 
≤Grade 1 and any steroid taper completed (to ≤10 mg 
prednisone equivalent).  RXC004 can continue whilst 
nivolumab is held if the patient is judged (by the 
investigator) to be receiving clinical benefit. 
Grade 3 toxicity (1st event) 
RXC004 related; 
Interrupt RXC004 and provide supportive care, resume at a 
lower dose level when resolved (grade ≤ 2 or returns to 
baseline).  See Table 15 for dose reduction scheme.  
 
Nivolumab related; 
See guidelines in Appendix G.  
 
Grade 
3 
toxicity 
(subsequent 
recurrence of a previously experienced 
event)  
RXC004 and/or nivolumab related; 
Permanently discontinue the related study treatment. 


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Event  
Action  
Grade 4 toxicity 
 
RXC004 and/or nivolumab related; 
Permanently discontinue RXC004 and nivolumab (if 
applicable) 
All Grade events  
 
 
Study treatment can be interrupted or discontinued for any 
clinically significant AEs that in the investigator’s opinion 
warrants treatment interrupted or discontinuation. 
Bone events 
Confirmed (by imaging) RXC004 
related 
fragility 
bone 
fracture 
(excluding 
grade 
1 
vertebral 
deformities) 
 
Patients with a DXA scan showing 
> 7% worsening in BMD at lumbar 
spine or total hip compared to 
baseline 
 
An individual increase in β-CTX of 
pg/ml 
from 
the 
baseline 
(screening) value or an individual 
measurement of 
pg/
pg/ml 
 
 
Permanently discontinue RXC004.  Nivolumab can 
continue if the patient is receiving clinical benefit as judged 
by the investigator. 
 
 
Permanently discontinue RXC004.  Nivolumab can 
continue if the patient is receiving clinical benefit as judged 
by the investigator. 
 
 
 
Permanently discontinue study treatment unless the patient 
has received clinical benefit (investigator assessment) and 
continued treatment is warranted. 
COVID-19 infection 
Positive COVID-19 test 
 
Interrupt RXC004, until acute symptoms have resolved.  
Major surgery  
Interrupt RXC004, resume at full dose. Nivolumab does not 
need to be interrupted. 
No stoppage is required for biopsy procedures.  
Vomiting  
If vomiting occurs shortly after RXC004 is swallowed, the 
dose may be replaced if all of the intact capsules can be 
counted. Resume with the following scheduled dose. 
Missed RXC004 dose  
Allowed to take the scheduled dose up to 4 hours after the 
scheduled dose time. If greater than 4 hours, the missed dose 
should not be taken, and patient should continue with next 
dose at allotted time.  
 
 
a 
Attempts should be made to confirm that the colitis has resolved to Grade ≤ 1 (e.g. normalised CRP or fecal 
calprotectin if raised during event; GI appearance normalised on X-ray/CT or endoscopy) before restarting 
RXC004. 
AE, adverse event; BMD, bone mineral density; COVID-19, Coronavirus disease 2019; QD, once daily. 
CCI
CCI


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Toxicity will be assessed utilizing the NCI Common Terminology Criteria for Adverse Event 
(CTCAE) version 5.0, unless otherwise specified.  Every effort should be made to administer 
trial treatment at the planned dose and schedule.  However, patients experiencing RXC004 
related toxicities may have their RXC004 dose modified as outlined below. 
RXC004 related toxicities observed during the course of the study will be managed by 
interruption of RXC004 and initiation of appropriate treatment as judged by the Investigator.  
Upon re-starting treatment the guidance for dose reduction in RXC004 contained in Table 15 
should be followed.   
Patients in Arm A who have undergone dose reduction during monotherapy cannot have the 
RXC004 dose re-escalated if switching to  RXC004 + nivolumab combination therapy. The 
RXC004 dose must be discussed with the Sponsor prior to starting combination therapy. 
Table 15 
Guidance for dose reductions for RXC004-related adverse events 
Dose Level 
RXC004 (monotherapy) 
RXC004 (in combination 
therapy) 
Initial dose level 
2 mg QD 
1.5 mg QD 
1st dose reduction 
• Grade 3 toxicity (1st 
event) 
 
• Grade 2 dysgeusia 
associated with 10-20% 
weight lossa 
 
Hold RXC004b.  Upon 
resolution to ≤ grade 2, restart 
at 1.5 mg QD 
 
Dose reduce to 1.5 mg QD 
 
Hold RXC004b. Upon 
resolution to ≤ Grade 2, 
restart at 1.0 mg QD 
 
Dose reduce to 1.0 mg 
QD 
2nd dose reduction 
• Grade 3 toxicity (1st 
unique event) 
• Grade 3 toxicity 
(recurrence of a 
previously experienced 
Grade 3-4 event) 
• Grade 2 dysgeusia 
associated with >20% 
 
Hold RXC004b.  Upon 
resolution to ≤ grade 2, restart 
at 1 mg QD 
Permanently discontinue 
RXC004 
Permanently discontinue 
RXC004 
 
Hold RXC004b. Upon 
resolution to ≤ Grade 2, 
restart at 0.5 mg QD 
Permanently discontinue 
RXC004 
Permanently discontinue 
RXC004 


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Dose Level 
RXC004 (monotherapy) 
RXC004 (in combination 
therapy) 
weight lossa 
 
3rd dose reduction 
Not permitted.  Permanently 
discontinue RXC004 
Not permitted. 
Permanently discontinue 
RXC004 
a 
excluding other possible causes and despite optimal treatment 
b 
RXC004 can be resumed after an interruption, as long as no other treatment discontinuation criteria 
have been met.  Patients who experience disease progression whilst RXC004 is held, will not be eligible 
to be treated beyond progression.  
 
For patients treated with RXC004 and nivolumab, dose reductions in nivolumab are not 
allowed.  Patients experiencing nivolumab related toxicities may delay nivolumab infusions or 
permanently discontinue nivolumab as described in Appendix G and Table 14. 
 
Access to Study Treatment after the End of the Study 
Any patients still receiving investigational product at the time of the data cut off will be able 
to continue to receive investigational products within the current study, if in the Investigator’s 
opinion, they are deriving clinical benefits and not meeting any of the discontinuation 
criteria.  Assessments will revert to standard of care for each individual site.  Patients will 
continue to be monitored for all SAEs up to 30 days after the last dose of RXC004 (for 
patients treated with RXC004 monotherapy only) or 90 days after the last dose of nivolumab 
(for patients treated with RXC004 and nivolumab).  A paper form process will be used for 
SAE reporting.   
All SAEs, overdoses and pregnancies will be reported until 30 days after the last dose of 
RXC004 (for patients treated with RXC004 monotherapy only) or 90 days after the last dose 
of nivolumab (for patients treated with RXC004 and nivolumab).   The investigational product 
will be supplied to sites manually.  The investigational product dispensation and reconciliation 
will be handled by the study at each patient’s visit.  The investigational product accountability 
information must still be collected until all patients have completed treatment.   
7 
DISCONTINUATION OF STUDY TREATMENT AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
 
Discontinuation of Study Treatment 
An individual patient will not receive any further IP (RXC004 or nivolumab) if any of the 
following occur; 
x Patient decision to withdraw from further treatment with IP. The patient is, at any time, 


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free to discontinue treatment, without prejudice to further treatment 
• Clinical or RECIST 1.1-defined radiological progression (symptomatically/clinically 
stable patients may continue treatment until symptomatic/clinical progression or 
second RECIST 1.1 progression [relative to the first ‘on study treatment’ RECIST 1.1 
progression]).  See Section 7.1.1 for details for continuing study treatment after 
RECIST1.1 defined progression 
• An AE that meets discontinuation criteria in Appendix G or Table 14 
• Pregnancy or intent to become pregnant 
• Initiation of alternative anticancer therapy including another investigational agent  
• Non-compliance with the study protocol that, in the opinion of the Investigator or 
Sponsor, warrants withdrawal from treatment with IP 
Discontinuation from study treatment is NOT the same thing as a withdrawal from the study.  
If study treatment is permanently discontinued, the participant will remain in the study to be 
evaluated for safety, progression (if the patient discontinues for a reason other than 
progression) and survival. See the SoA for data to be collected at the time of discontinuation 
of study treatment and during follow-up. 
7.1.1 
Treatment of Symptomatically Stable Patients after RECIST 1.1 
Defined Progression 
Patients with symptomatically stable disease may continue treatment after the initial 
RECIST 1.1 – defined progression, until symptomatic/clinical progression or a second 
RECIST 1.1 PD assessment (relative to the initial RECIST1.1 progression, for a given study 
treatment).  
Patients who wish to continue study treatment after RECIST1.1 defined progression, should 
be informed of all other alternative treatment options available to them by the treating 
physician and sign an additional consent that they wish to continue study treatment. A decision 
to continue study treatment after initial progression must also be discussed and agreed by the 
treating physician and the Sponsor.   
The criteria for continuing treatment after initial RECIST 1.1-defined progression are as 
follows: 
• Signed patient consent for treatment after progression 
• The patient does not have any significant, unacceptable, or irreversible toxicities 
indicating that continuing treatment will not further harm the patient. 


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x There is absence of clinical symptoms or signs indicating clinically significant disease 
SURJUHVVLRQDFFRPSDQLHGE\DGHFOLQHLQ(&2*SHUIRUPDQFHVWDWXV!
x There is absence of rapid disease progression or threat to vital organs or critical 
anatomical sites (e.g. central nervous system metastasis, respiratory failure due to 
tumour compression, or spinal cord compression) requiring urgent alternative medical 
intervention. 
x Study treatment was not on hold/interrupted at time of progression   
Patients continuing study treatment after initial RECIST 1.1 defined progression should 
continue RECIST scans as per the Schedule of Assessments (the next tumour assessment 
should be at least 4 weeks after the first RECIST 1.1 defined progression and no later than the 
next regularly scheduled imaging timepoint).   
 
Participant Withdrawal from the Study 
x 
A participant may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioural, 
compliance, or administrative reasons. This is expected to be uncommon. 
x 
A participant who considers withdrawing from the study must be informed by the 
investigator about modified follow-up options (e.g., telephone contact, a contact with a 
relative or treating physician, or information from medical records). 
x 
If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent. 
x 
If a participant withdraws from the study, it should be confirmed if he/she is still agrees 
for existing samples to be used in line with the original consent. If he/she requests 
withdrawal of consent for use of samples, destruction of any samples taken and not tested 
should be carried in line with what was stated in the informed consent and local 
regulation. The investigator must document the decision on use of existing samples in the 
site study records and inform the Global Study Team. 
 
 
Lost to Follow up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
x 
The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 


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schedule and ascertain whether or not the participant wishes to and/or should continue in 
the study. 
• 
Before a participant is deemed lost to follow up, the investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, 
if necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record. 
 
 


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8 
STUDY ASSESSMENTS AND PROCEDURES 
x 
Study procedures and their timing are summarised in the SoA. Protocol waivers or 
exemptions are not allowed. 
x 
Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study intervention. 
x 
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct. 
x 
All screening evaluations must be completed and reviewed by Investigator to confirm that 
potential participants meet all eligibility criteria. The investigator will maintain a 
screening log to record details of all participants screened and to confirm eligibility or 
record reasons for screening failure, as applicable. 
x 
Procedures conducted as part of the participant’s routine clinical management (e.g., blood 
count) and obtained before signing of the ICF may be utilised for screening or baseline 
purposes provided the procedures met the protocol-specified criteria and were performed 
within 28 days of the first dose of study treatment. 
x 
The maximum amount of blood collected from each participant over the duration of the 
study, is expected to not exceed 500 mL. 
 
 
Efficacy Assessments 
The primary endpoint for the RXC004 monotherapy arm, will be the DCR using a patients 
best overall response, with secondary endpoints of % change in the sum of target lesions, 
ORR, DoR, PFS and OS.  For the RXC004 + nivolumab arm, the primary endpoint will be   
ORR using a patients BOR with secondary endpoints of % change in the sum of target lesions, 
DCR, DoR, PFS and OS. 
Efficacy assessments of DCR, ORR, % change in the sum of target lesions, DoR and PFS will 
be derived using investigator RECIST 1.1 assessments.  In addition, OS will also be 
evaluated. 
8.1.1 
Tumour assessments 
Tumour assessments utilize images from CT or MRI, collected during screening/baseline and 
at regular (follow-up) intervals during the study.  The same imaging method should be used 
throughout the study.  It is important to follow the tumour assessment schedule as per the 
SoA.  Tumour assessments will continue until RECIST1.1-defined radiological progression.  
Patients treated with RXC004+nivolumab that continue treatment after RECIST1.1 
progression, will continue tumour assessments until second RECIST1.1 defined radiological 
progression (relative to the initial RXC004+nivolumab progression event). 


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Sites will be required to store electronic copies of all scans, and the Sponsor may arrange for 
possible centralised storage of all imaging data.  Centralised storage of imaging data would be 
possible to support an independent centralized review of disease assessments. 
In addition, if available, the last 2 imaging scans taken prior to the screening scan for this 
study and/or their reports should be kept for possible central/sponsor review. 
8.1.2 
Survival assessments 
Assessments for survival must be made following treatment discontinuation, as indicated in 
the SoA. Survival information may be obtained via telephone contact with the patient or the 
patient’s family, or by contact with the patient’s current physician. The details of first and 
subsequent therapies for cancer, after discontinuation of treatment, will be collected. In 
addition, patients on treatment or in survival follow-up will be contacted within 7 days of the 
DCO for any survival analyses to provide complete survival data. 
 
Safety Assessments 
 
8.2.1 
Clinical Safety Laboratory Assessments 
Blood samples for determination of clinical chemistry and haematology will be taken at the 
visits indicated in the SoA.  Additional safety samples may be collected if clinically indicated 
at the discretion of the investigator. The date, time of collection and results (values, units and 
reference ranges) will be recorded on the appropriate eCRF. 
The clinical chemistry and haematology will be performed at a local laboratory at or near to 
the investigator site. Sample tubes and sample sizes may vary depending on laboratory 
method used and routine practice at the site. 
The following laboratory variables will be measured.  


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Table 16 
Laboratory safety variables 
Haematology/Haemostasis (whole blood) 
Clinical Chemistry (serum or plasma) 
Haemoglobin (Hb) 
Creatinine and creatinine clearancea 
Total white cell count 
Bilirubin, total 
Neutrophils (absolute count or %) 
Alkaline phosphatise (ALP) 
Platelet count 
Aspartate transaminase (AST) 
Lymphocytes (absolute count or %) 
Alanine transaminase (ALT) 
 
Albumin 
 
Potassium 
Other tests: 
Calcium, total 
HIV antibodiesc 
Phosphate 
Hepatitis B surface antigenc 
Sodium 
Hepatitis C antibodiesc 
Glucose 
 
Thyroid-stimulating hormone (TSH) 
 
Lipase 
 
Lactate dehydrogenase (LDH) 
 
Amylase 
 
T3 free (reflex)b 
 
T4 free (reflex)b 
 
C-reactive protein (CRP) 
 
Vitamin Dc 
a 
Creatinine clearance at baseline only  
b 
Free T3 or T4 only need to be measured if TSH is abnormal or if Investigator judges that there may be an 
AE related to the endocrine system 
c 
Required at baseline/screening only. 
 
 
8.2.2 
Physical Examinations 
A physical examination will include, at a minimum, assessments of the skin, lungs, 
cardiovascular system, and abdomen (liver and spleen). A neurological exam should also be 
conducted at screening/baseline and thereafter as clinically indicated. 
Physical examinations will be performed at timelines as specified in the SoA,  
8.2.3 
Vital Signs 
The following vital signs will be performed at timelines as specified in the SoA; 
• Blood pressure 


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• Pulse rate 
• Temperature 
• Respiration rate 
• Weight 
• Height (recorded at baseline only) 
8.2.4 
Electrocardiograms 
Triplicate 12-lead ECGs will be performed at timepoints as specified in the SoA.  ECGs 
should be obtained after the patient has been in a supine position for 5 minutes and recorded 
while the patient remains in that position.  Mean QT intervals corrected for heart rate should 
be calculated using Fridericia’s formula (QTcF).  
All ECG traces should be kept by site for possible central/sponsor review. 
At selected sites, digital ECG collection may take place using ambulatory Holter monitoring 
equipment for approximately 24 hours on Cycle 0 Day 1 and Cycle 1 Day 15. The information 
will be stored and analysed centrally. 
8.2.5 
ECOG performance status 
ECOG performance status will be assessed at the times specified in the assessment schedules 
based on the following: 
0. 
Fully active; able to carry out all usual activities without restrictions 
1. 
Restricted in strenuous activity, but ambulatory and able to carry out light work or 
work of a sedentary nature (e.g. light housework or office work) 
2. 
Ambulatory and capable of self-care, but unable to carry out any work activities; up 
and about more than 50% of waking hours 
3. 
Capable of only limited self-care; confined to bed or chair more than 50% of waking 
hours 
4. 
Completely disabled; unable to carry out any self-care and totally confined to bed or 
chair 
5 
Dead 
8.2.6 
Other Safety Assessments 


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Pregnancy tests 
All women of childbearing potential will have pregnancy tests (urine or serum) performed at 
timepoints as specified in the SoA 
Screening safety tests 
Tests for hepatitis B surface antigen, hepatitis C antibodies, and HIV antibodies will be 
performed for all patients at screening. 
 
Adverse Events and Serious Adverse Events 
The Principal investigator (PI) is responsible for ensuring that all staff involved in the study 
are familiar with the content of this section. 
The definitions of an AE or SAE can be found in Appendix B. 
AEs will be reported by the patient (or, when appropriate, by a caregiver, surrogate, or the 
participant’s legally authorised representative).  
The investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE. 
8.3.1 
Time Period and Frequency for Collecting AE and SAE Information 
Adverse Events will be collected from time of signature of the main study informed consent 
form throughout the treatment period and until 30 days after the last dose of RXC004 (for 
patients treated with RXC004 monotherapy only) or 90 days after the last dose of nivolumab 
(for patients treated with RXC004 and nivolumab). 
SAEs will be recorded from the time of signing of the main study informed consent form until 
the follow-up period is completed (30 days after the last dose of RXC004 [for patients treated 
with RXC004 monotherapy only] or 90 days after the last dose of nivolumab [for patients 
treated with RXC004 and nivolumab]).  If an event starts after the safety follow-up period 
defined above is considered to be a late-onset toxicity related to study treatment, then it should 
be reported as an AE or SAE, as applicable. 
If the investigator becomes aware of a serious adverse event with a suspected causal 
relationship to the investigational medicinal product that occurs after the end of the clinical 
study in a participant treated by him or her, the investigator shall, without undue delay, report 
the serious adverse event to the sponsor. 
8.3.2 
Follow-up of AEs and SAEs 
Any AEs that are unresolved at 90 days after last dose of IP should be followed up by the 


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investigator for as long as medically indicated, but without further recording in the eCRF.  
Redx retains the right to request additional information for any participant with ongoing 
AE(s)/SAE(s) at the end of the study, if judged necessary. 
Adverse event variables 
'The following variables will be collected for each AE; 
• 
AE (verbatim) 
• 
The date when the AE started and stopped 
• 
CTCAE grade changes 
• 
Whether the AE is serious or not 
• 
Investigator causality rating against the Investigational Product(s) (yes or no) 
• 
Action taken with regard to Investigational Product(s) 
• 
Outcome 
• 
Whether treatment was required 
 
In addition, the following variables will be collected for SAEs: 
• 
Date AE met criteria for serious AE 
• 
Date investigator became aware of serious AE 
• 
Serious criteria 
• 
Date of hospitalisation 
• 
Date of discharge 
• 
Probable cause of death 
• 
Date of death 
• 
Autopsy performed 
• 
Causality assessment in relation to Study procedure(s) 
• 
Causality assessment to other medication 
 
8.3.3 Causality Collection 
The investigator should assess causal relationship between Investigational Product and each 
Adverse Event, and answer ‘yes’ or ‘no’ to the question ‘Do you consider that there is a 
reasonable possibility that the event may have been caused by the investigational product?’ 
8.3.4 Adverse Events Based on Signs and Symptoms 
All AEs spontaneously reported by the patient or reported in response to the open question 


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from the study site staff: ‘Have you had any health problems since the previous visit/you were 
last asked?’, or revealed by observation will be collected and recorded in the eCRF. When 
collecting AEs, the recording of diagnoses is preferred (when possible) to recording a list of 
signs and symptoms. However, if a diagnosis is known and there are other signs or symptoms 
that are not generally part of the diagnosis, the diagnosis and each sign or symptom will be 
recorded separately. 
8.3.5 Adverse Events Based on Examinations and Tests 
The results from the Clinical Study Protocol mandated laboratory tests and vital signs will be 
summarised in the Clinical Study Report (CSR).  
Deterioration as compared to baseline in protocol-mandated, laboratory values, vital signs, 
bone turnover biomarkers and DXA scans, should therefore only be reported as AEs if they 
fulfil any of the SAE criteria, are the reason for discontinuation of treatment with the 
investigational product or are considered to be clinically relevant as judged by the investigator 
(which may include but not limited to consideration as to whether treatment or non-planned 
visits were required or other action was taken with the study treatment, e.g. dose adjustment or 
drug interruption).  
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign 
will be considered as additional information. Wherever possible the reporting investigator 
uses the clinical, rather than the laboratory term (e.g. anaemia versus low haemoglobin value). 
In the absence of clinical signs or symptoms, clinically relevant deteriorations in non-
mandated parameters should be reported as AE(s). 
Deterioration of a laboratory value, which is unequivocally due to disease progression, should 
not be reported as an AE/SAE. 
Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported as an AE unless unequivocally 
related to the disease under study. 
8.3.6 Hy’s Law 
If a patient demonstrates an AST or ALT ≥3x ULN together with total bilirubin ≥2x ULN, it must 
be reported to the Sponsor and/or designated CRO within 24 hours. Prompt reporting of cases 
meeting Hy’s Law criteria (via the SAE expedited reporting system) is required for compliance 
with regulatory guidelines. The Investigator is responsible for immediately determining whether a 
patient meets potential Hy’s Law criteria. The Investigator needs to perform additional 
examinations for this and confirm the results with the medical monitor. 


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8.3.7 Disease Progression 
Disease progression can be considered as a worsening of a patient’s condition attributable to 
the disease for which the investigational product is being studied. It may be an increase in the 
severity of the disease under study and/or increases in the symptoms of the disease. The 
development of new, or progression of existing metastasis from the primary cancer under 
study should be considered as disease progression and not an AE. Events, which are 
unequivocally due to disease progression, should not be reported as an AE during the study. 
8.3.8 Disease Under study 
Events which are unequivocally due to disease under study should not be reported as an AE 
during the study unless they meet SAE criteria or lead to discontinuation of the investigational 
product. 
8.3.9 
Reporting of Serious Adverse Events 
All SAEs must be reported, whether or not considered causally related to the investigational 
product, or to the study procedure(s). All SAEs will be recorded in the eCRF. 
If any SAE occurs in the course of the study, then investigators or other site personnel must 
inform the appropriate Sponsor representatives within one day i.e., immediately but no later 
than 24 hours of when he or she becomes aware of it. 
The designated Sponsor representative works with the investigator to ensure that all the 
necessary information is provided to Patient Safety within 1 calendar day of initial receipt 
for fatal and life-threatening events and within 5 calendar days of initial receipt for all other 
SAEs. 
For fatal or life-threatening adverse events where important or relevant information is missing, 
active follow-up is undertaken immediately. Investigators or other site personnel inform 
Sponsor representatives of any follow-up information on a previously reported SAE within 
one calendar day i.e., immediately but no later than 24 hours of when he or she becomes 
aware of it. 
For further guidance on the definition of a SAE, see Appendix B of the Clinical Study 
Protocol. 
The reference document for definition of expectedness is the IB for RXC004 and the 
EU/FDA/Local label for nivolumab.  
8.3.10 
Pregnancy 
All pregnancies and outcomes of pregnancy should be reported to Sponsor representative 
except for if the pregnancy is discovered before the study participant has received any study 


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drug. 
8.3.10.1 
Maternal Exposure 
The Sponsor and Sponsor designated Safety Services must be notified within 24 hours of the 
initial report and any follow-up reports of a female patient or a male patient’s female partner 
becoming pregnant during the course of the study and for 5 months after the last dose of the 
study drug(s) via the Pregnancy Report Form. Pregnancy itself is not regarded as an adverse 
event unless there is a suspicion that the investigational product under study may have 
interfered with the effectiveness of a contraceptive medication or a female patient or male 
patient’s female partner experiences signs or symptoms of pregnancy complications; 
congenital abnormalities/birth defects and spontaneous miscarriages should be reported as 
SAEs. The contact information for pregnancy reporting is the same as for SAE reporting. 
Female patient(s) who become pregnant will be followed until the outcome of the pregnancy 
is known. In order for the Sponsor or designee to collect pregnancy surveillance information, 
the pregnant patient or partner must sign an ICF. Pregnancy follow-up should describe the 
outcome of the pregnancy, including any voluntary or spontaneous termination, details of the 
birth, and the presence or absence of any congenital abnormalities or birth defects in the 
offspring. 
If a female patient becomes pregnant, administration of the study drug(s) must be 
discontinued immediately. 
8.3.10.2 
Paternal Exposure  
Male participants should refrain from fathering a child or donating sperm during the study and 
for at least 5 months following the last dose. 
Pregnancy of the participant’s partners is not considered to be an adverse event. However, the 
outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, 
normal birth or congenital abnormality), occurring from the date of the first dose until 5 
months after the last dose should, if possible, be followed up and documented in the 
Pregnancy Report Form. Consent from the partner must be obtained before the Pregnancy 
Report Form is completed.  
8.3.11 
COVID-19 infections 
COVID-19 infections occurring from the time of signature of the main study ICF until 30 days 
after discontinuation of study treatment should be reported as adverse events.  Patients who 
test positive for COVID-19, but do not have any symptoms should be reported as 
‘asymptomatic COVID-19’.  If COVID-19 is suspected but not confirmed by a diagnostic test, 
then ‘suspected COVID-19’ should be reported.  The AE term for the ‘suspected COVID-19’ 
should be updated when the results of the diagnostic test are known to reflect the confirmed 
COVID-19 or alternative diagnosis (e.g. common cold, influenza etc). 


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8.3.12 
Dysgeusia 
Loss of taste (dysgeusia) is an on-target adverse event known to occur with porcupine 
inhibition (Ng et al 2017, Janku et al 2015).  According to CTCAEv5, there are only two 
grades of dysgeusia; 
Grade 1 – Altered taste but no change in diet 
Grade 2 – Altered taste with change in diet (e.g., oral supplements); noxious or unpleasant 
taste; loss of taste. 
As dysgeusia is poorly characterized by CTCAE grade alone, site research personnel will 
complete a taste assessment (consisting of a specific set of questions and an oral examination) 
at screening for each patient enrolled, and for any patient who reports dysgeusia in response to 
the open question from the study site staff; ‘Have you had any health problems since the 
previous visit/you were last asked?. In such cases, the assessment will be performed at each 
visit until the adverse event has resolved. The information will be recorded and analysed as 
part of the overall safety objective of the study. 
8.3.13 
Adverse Events of Potential Interest (AEPI) 
As discussed in Section 2.3.1, Colitis events and Bone Toxicity events are classified as AEPIs 
for RXC004. This means that additional information will be captured on the case report forms 
for any CTCAE preferred terms that fall into these categories. These terms will be defined in 
the CRF Guidelines and reviewed at any update of the CTCAE definitions. 
 
Overdose 
For this study, any dose of RXC004 greater than the daily assigned dose will be considered an 
overdose. 
Investigators should be advised that any patient who receives an overdose should be 
monitored closely, managed with appropriate supportive care and followed up expectantly. 
There are no data regarding RXC004 overdose in humans. An overdose and AEs should be 
treated as per standard medical practice.  
Dosing details should be captured in the eCRF. If the subject receives a dose of a study drug 
that exceeds protocol specifications and the subject is symptomatic, then the symptom(s) 
should be documented as AEs in the eCRF and, if serious, submitted to the Sponsor’s 
designated safety contact on an SAE Report Form. Do not record the overdose as an AE if the 
subject is not symptomatic. 
Please refer to the local label for management of nivolumab overdoses. 


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Human Biological Samples 
Instructions for the collection and handling of biological samples will be provided in the study 
specific laboratory manual. Samples should be stored in a secure storage space with adequate 
measures to protect confidentiality. For further details on Handling of Human Biological 
Sample see Appendix C. 
Samples will be stored for a maximum of 15 years from the date of the issue of the CSR in 
line with consent and local requirements, after which they will be destroyed/repatriated.  
x 
Pharmacokinetic (PK) samples will be disposed of after the Bioanalytical Report 
finalization or six months after issuance of the draft Bioanalytical Report (whichever is 
earlier), unless consented for future analyses.  
 
Pharmacokinetic samples may be disposed of or anonymised by pooling. Additional 
analyses may be conducted on the anonymised, pooled pharmacokinetic samples to 
further evaluate and validate the analytical method. Any results from such analyses 
may be reported separately from the Clinical Study Report (CSR). 
 
8.5.1 
Pharmacokinetics 
RXC004 PK data will be summarised using descriptive statistics (N, mean, SD, median, min, 
max for all parameters, also geometric mean for Cmax and AUC) to determine the 
pharmacokinetic behaviour of RXC004 on multiple dosing and to confirm relevant exposure 
to RXC004. This may also permit investigation of any significant metabolites.  Venous blood 
samples (2 mL) for determination of concentrations of RXC004 in plasma will be taken at the 
times described in the schedule of assessments (Table 1 and Table 2).  The date and time that 
the last dose of RXC004 was administered before the PK assessment day, the date and time of 
the dose of RXC004 administered on the PK assessment day and the date and time of 
collection of each sample will be recorded.  
The date and time of collection of each sample will be recorded.  
The timing of the PK samples may be adjusted during the study, dependent on emerging data, 
in order to ensure appropriate characterisation of the plasma concentration-time profiles. The 
total number of samples and the total volume of blood taken from each patient will not exceed 
that outlined in the Lab Manual. 
If a patient misses any doses of RXC004 within 3 days of PK sampling, please contact the 
Sponsor representative as to any effect on the changes required on the timing of the PK 
assessments. All other assessments, including laboratory safety assessments, vital signs and 
RECIST should continue to be performed as per study plan, relative to baseline assessments. 
Samples will be collected, labelled, stored and shipped as detailed in the Laboratory Manual. 


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8.5.1.1 
Determination of Drug Concentration 
Samples for determination of RXC004 concentrations in plasma will be analysed using an 
appropriate bioanalytical method. Full details of the analytical method used will be described 
in a separate bioanalytical report. 
All samples still within the known stability of the analytes of interest at the time of receipt by 
the bioanalytical laboratory will be analysed. 
In addition, the pharmacokinetic samples may be subjected to further analyses in order to 
investigate the presence and/or identity of drug metabolites. Any results from such analyses 
will be reported separately from the Clinical Study Report.  
PK parameters will be estimated for each patient using WinNonlin® (Phoenix 64 V8 or 
higher) or suitable alternative. The following parameters will be derived, where appropriate, 
from the individual plasma concentration versus time profiles of RXC004. 
Table 17 
Definition of PK Parameters 
PARAMETER 
DEFINITION 
Cmax 
The maximum observed concentration. 
tmax 
The time at which Cmax was apparent. 
AUC0-t 
The area under the concentration versus time curve from time zero to the sampling time at 
the last quantifiable concentration (Ct) at tlast (the time of the last quantifiable concentration) 
calculated by the linear trapezoidal rule. 
λz 
The apparent terminal rate constant, estimated using the negative slope of the least square 
regression analysis of the log concentration versus time data for the terminal linear portion 
of the curve. 
t½ 
The apparent terminal half-life, calculated from Loge 2 / λz. 
AUC0-∞ 
The area under the concentration-time curve estimated from time zero to infinity as the sum 
of the two areas: AUC0-t and AUCextrap, where AUCextrap is calculated as Ct / λz. 
CL 
The systemic clearance calculated as: Dose/ AUC0-∞. 
Vss 
The 
apparent 
volume 
of 
distribution 
at 
steady 
state 
calculated 
as: 
 Dose/AUC x (AUMC/ AUC0-∞ - T/2) where T is the duration of intravenous injection. 
 
Where appropriate the following RXC004 plasm pharmacokinetic parameters will be estimated. 
include  
• 
 Cmax 
Maximum observed plasma concentration 
• 
tmax 
Time to Cmax 


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• 
Cmin 
Minimum observed concentration across the dosing 
interval 
• 
 λz 
Terminal rate constant 
• 
 t½ 
Terminal half-life 
• 
 AUC0-24  and from zero to infinity  Area under the plasma concentration-time curve from 
zero to 24 hours 
• 
AUC0-t 
Area under the plasma concentration-time curve from 
zero to the time of the last quantifiable concentration 
• 
AUC0-∞ 
Area under the plasma concentration-time curve from 
zero to infinity 
• 
AUCτ 
Area under the plasma concentration-time curve across 
the dosing interval 
• 
CL/F 
Total plasma clearance after oral administration 
• 
 Vz/F 
Apparent 
volume 
of 
distribution 
after 
oral 
administration 
• 
Vss/F 
The apparent volume of distribution at steady state  
  
• 
 MRT 
Mean residence time 
• 
Rac 
Accumulation ratio based on AUCτ and Cmin after the 
first and the last dose 
• 
Swing 
(Cmax-Cmin)/Cmin 
 
Dose proportionality of exposure parameters will be explored. In addition to dose normalisation of Cmax 
and AUC values. 
 
Additional PK parameters may be calculated as appropriate. 
Incurred sample reproducibility analysis, if any, will be performed alongside the bioanalysis 
of the test samples. The results from the evaluation, if performed, will be reported in a 
separate Bioanalytical Report. 
8.5.2 
Pharmacodynamics 
8.5.2.1 
Collection of Samples 
 
 
 
 
 
 
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Human Biological Sample Biomarkers 
8.6.1 
Collection of mandatory samples for biomarker analysis 
By consenting to participate in the study the subject consents to participate in the mandatory 
research components of the study.  
Samples for biomarker research are required and will be collected from all participants in this 
study as specified in the SoA.  
 
 
 
Details for collection, volumes, storage, and shipment of biologic samples will be detailed in a 
separate Laboratory Manual 
 
All enrolled patient’s tumours will be required to have a genetic mutation which is predicted 
to be loss of function in RNF43, or an RSPO fusion/translocation detectable in 
 
  Eligible patients also need to have documented MSS status.  Eligible 
subjects will be identified by either a central genetics screening approach or local laboratory 
assessments.  Please see Section 5.5 for more details 
If patients are enrolled in the study based on local laboratory assessments, then an 
 
 will be collected at screening and sent for central genetic screening as 
described in Section 5.5.  If an 
 i is not available or not consented to, then a 
sample of the study baseline tumour biopsy may be sent for the central genetic screening. 
Exploratory biomarkers include; 
 
The study mandates that 
 are collected at baseline and ‘on treatment’ at time 
points specified in the SoA.  
 t that may be assessed include (but are 
not limited to), 
 
.  .  The 
 of these 
may 
be correlated to clinical response.   
 
 may be prepared from whole blood samples obtained from patients 
at timepoints specified in the SoA.  Quantification of 
and/or 
 
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    Analysis may include (but is not limited to), the 
 
of f 
. C
. Correlations with outcome data may be 
performed on 
d on 
 w
 with the aim of identifying useful 
 thresholds for 
identifying patients likely to receive benefit. 
 
Blood samples for analysis of 
 or
 or 
 w
 will be 
obtained from all patients as specified in the SoA.  Overall 
or 
 and/or 
 i in 
 m
 may be assessed using 
 
 
 
Blood samples for analysis of 
 w
 will be obtained from patients at 
timepoints specified in the SoA.  The concentrations of a panel of relevant 
 
  Such measurements may be correlated with response. 
 
 will be taken from a subset of patients recruited by sites within close 
proximity to Redx Pharma.  
 
 w
 will be used for analysis of 
 u using 
 Such 
measurements may be correlated with response. 
 
 frequently increased in 
.  B
.  Blood samples for 
will be 
obtained from patients at timepoints specified in the SoA and analysed locally.  
may be correlated with response. 
8.6.2 
 
 
 
 
 
 
 
 
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8.6.3 
  
 
 
 
 
 
  
 
 
 
 
 
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9 
STATISTICAL CONSIDERATIONS 
 
Statistical Hypotheses 
The statistical hypotheses for testing the activity of monotherapy and the combination 
independently are: 
H0 : pS0 
H1 : SS1 
Where H0 is the null hypothesis, p is the observed response rate, p0 is the response rate for 
available treatment options – 
, , H1 is the alternative hypothesis and 
p1 is the target response rate – 
.  .  For RXC004 monotherapy the primary 
summary measure is the disease control rate (DCR) and the corresponding p0 and p1 are 
% 
and 
%.  For the combination of RXC004 and nivolumab the primary summary measure is 
objective response rate (ORR) and the corresponding p0 and p1 are 
% and 
%. 
6DPSOH6L]H'HWHUPLQDWLRQ
The method by Frewer et al (Frewer et al 2016), together with the totality of the data 
collected, will be used to guide go/no-go decision making:
For the combination RXC004+nivolumab arm, assuming a t t
 rate of 
% 
response rate which is considered to be clinically significant in the target population, against a 
reference value of 
% 
% response rate (Eng et al 2019) as a 
, then 
a sample size of 20 achieves greater than 
% power, at the 
  
 
 
  These hurdles will be used to 
guide the decision for onward development.  The totality of the data, including the population 
enrolled and the results from the secondary endpoints will be used for the final decision. 
For the monotherapy RXC004 arm, assuming a 
% disease control 
rate which is considered to be clinically significant improvement over standard of care in the 
target population, against a reference value of 
% DCR (Grothey et al 2013 and Mayer et al 
2015) as a 
, then a sample size of 20 achieves greater than 
% 
power, at the 
 
 
 These hurdles will be used to guide the decision for onward 
development.  The totality of the data, including the population enrolled and the results from 
the secondary endpoints will be used for the final decision. 
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Approximately 
 patients are expected to be enrolled in order for approximately 20 patients 
to be in the evaluable dataset in each treatment arm.
Note: "Enrolled" means the subject has signed the main study ICF, completed screening and 
been dosed. 
The intention of the trial is to recruit patients with tumours with either RNF43 LoF mutation 
or RSPO fusion/translocation tumours to ensure the optimum decision is made at the end of 
the trial.  If, after approximately half the patients have been recruited it is found that patients 
with tumours harbouring RNF43 LoF mutation or RSPO fusions dominate recruitment and at 
that time the results are such there is a 
% probability of the 
 b being met in 
patients with one of the aberrations then recruitment may be focussed on patients with the 
alternative aberration.  For example, if all 10 patients in both arms have RNF43 LoF mutation 
tumours  and no patients respond on the combination arm and/or 3 or less have disease control 
on the monotherapy arm then recruitment in one or both arms may be focussed on patients 
with RSPO fusion/translocation tumours and recruitment expanded to allow 20 patients with 
RSPO fusion/translocation tumours to be recruited. 
 
Populations for Analyses 
The following populations are defined: 
Table 18 
Populations for Analysis 
Population/Analysis set 
Description 
 Full analysis set / Safety 
analysis set 
All subjects who enrolled and received at least one dose of study drug 
(RXC004 in the case of the monotherapy arm and at least one of RXC004 
and nivolumab in the combination arm) 
 
 
 
 
 
 
 
 
PK analysis set 
All subjects in the safety analysis set who have had at least 1 blood sample 
 
 
Statistical Analyses 
A detailed description of the statistical summaries and analyses will be presented in the 
Statistical Analysis Plan (SAP) which will be finalised prior to DBL. 
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9.4.1 
General Considerations 
The study data is planned to be analysed and reported based on all subject data at the primary 
completion data cut-off date (approximately 24 weeks after cycle 1 day 1 for the last subject 
in), or at the End of Study, whichever comes first.  
All analyses, summaries and listings will be performed using SAS software (version 9.3 or 
higher).  For categorical variables the frequency and percentage will be presented.  For 
continuous variables, the sample size (n), mean, median, and standard deviation, as well as the 
minimum and maximum values will be presented.  Missing data will not be imputed unless 
otherwise stated. 
A baseline assessment will be defined as the last assessment performed prior to the first dose 
of study treatment.  While many of these assessments will be performed on the day of the first 
dose, others will be performed during screening.  If a patient is missing an assessment 
typically performed on the day of the first dose, screening values may be substituted as 
baseline 
Data will be presented separately for the monotherapy arm and the combination arm.  There 
will be no formal comparisons of the results in the two arms.  ORR, DCR and PFS will be 
presented separately for the patients who received RXC004+nivolumab as combination 
therapy as sequential therapy after progression on RXC004 monotherapy at first RECIST 
progression scan. 
9.4.1.1 
Patient Disposition 
Patient disposition will be presented together with withdrawals from treatments, withdrawals 
from the study, and the reason for withdrawal. 
9.4.1.2 
Protocol Deviations 
Protocol deviations will be collected and reviewed during the study. The final classification 
and effect of each protocol deviation as well as the composite effect of a set of protocol 
deviations on analysis populations will be assessed prior to the database lock.  
9.4.1.3 
Demographic and other baseline characteristics 
Demographic and baseline characteristics will be summarised.  For continuous demographic 
variables, results will be summarized and presented as n, mean, standard deviations, median 
and minimum and maximum values.  For categorical variables the frequency and percentage 
of subjects will be used. 
9.4.1.4 
Medical History 
Medical History will be coded according to the latest version of Medical Dictionary for 
Regulatory Activities (MedDRA). The number (percent) of patients reporting a history of any 
disease related medical condition, as recorded on the CRF, will be summarized by system 


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organ class (SOC) and preferred term (PT) for the FAS.   
9.4.1.5 
Prior and concomitant therapy 
All investigator terms for medications recorded in the eCRF will be coded to standard names 
using the World Health Organization Drug Dictionary and further coded to the appropriate 
Anatomical-Therapeutic-Chemical code. 
Prior medications will be defined as medications that stopped before the first dose of study 
drug and will be summarised and listed. 
Concomitant medications will be defined as medications that (1) started before the first dose 
of study drug and were continuing at the time of the first dose of study drug or (2) started on 
or after the date of the first dose of study drug.  Concomitant medications will be summarised 
and listed. 
9.4.2 
Efficacy  
9.4.2.1 
Primary Endpoint(s) 
The primary endpoint for the monotherapy arm is disease control rate and the primary 
endpoint for the combination arm is the objective response rate, both based on a individuals 
best overall response using investigator RECIST 1.1 assessments. 
Objective response rate is defined as the proportion of subjects with a best overall response of 
complete response or partial response, based on local investigator assessment, as defined in 
RECIST 1.1.  Confirmation of response is required for declaring PR or CR as the BOR.  A 
confirmed response is defined as a CR or PR followed by a CR or PR a least 4 weeks later.  
The ORR will be summarised with accompanying 90% confidence interval calculated using 
the Clopper Pearson method.  This will be calculated on the full analysis set and the evaluable 
analysis set with the evaluable analysis set calculation being considered primary. In the 
summary tables the incidence of unconfirmed responses will be presented as well as the 
patients with confirmed responses. 
Disease control rate (DCR) is defined as the proportion of patients with a BOR of either CR, 
PR or stable disease (SD) for at least 16 weeks post baseline (corresponding to SD for 2 
scheduled scans post baseline). A time window of 1 week around the week 16 visit will be 
applied.  The DCR and associated 90% confidence interval, calculated using the Clopper 
Pearson method will be presented.  This will be calculated on the full analysis set and the 
evaluable analysis set with the evaluable analysis set calculation being considered primary. 
9.4.2.2 
Secondary Endpoint(s) 
Progression free survival is defined as the time from first dose of study treatment until the date 
of disease progression or death (by any cause in the absence of progression), regardless 
whether the subject withdraws from the assigned study treatment or receives another 


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anticancer prior to progression.  Patients who have not progressed or died at the time of 
analysis will be censored at the time of the latest date of RECIST v1.1 assessment of their last 
evaluable scan, however if the subject progresses or dies after 2 or more missed scheduled 
scanning visits, the subject will be censored at the time of their last evaluable scan prior to the 
missing scan visits.  If the subject has no evaluable visits or does not have baseline data they 
will be censored at 0 days unless they die within 2 scan visits of baseline.  Progression free 
survival will be listed by subject and will be presented graphically using Kaplan-Meier plots. 
Median PFS, together with 3 month, 6 month and 12 months PFS rates will be estimated. 
Percentage change in tumour size will be derived at each visit by the percentage change from 
baseline in the sum of diameters of target lesions.  The best percentage change in tumour size 
will be the subjects value representing the largest decrease (or smallest increase) from baseline 
in tumour size. Best percentage change in tumour size will be presented in waterfall plots and 
percentage change in tumour size at each visit will be presented in a spider plot. 
 
  
 
  
 
 
 
Overall survival is defined as the time from first day of study treatment until death due to any 
cause.  Any subject not known to have died at the time of analysis will be censored based on 
the last recorded date on which the subject was known to be alive.  Overall survival will be 
listed by subject and presented graphically using Kaplan-Meier plots.  Median, 6 month and 
12 month OS rates will be estimated. 
9.4.2.3 
Tertiary/Exploratory Endpoint(s) 
 
 
 
 
 
 
 
  
9.4.3 
Safety 
In general, safety data will be reported according to treatment initially received – i.e. RXC004 
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monotherapy or RXC004 + nivolumab combination.  In order to explore any difference in the 
subjects who just received monotherapy compared to those who receive combination after 
progressing at the 8-week scan some safety data presentations will split the RXC004 into two 
groups – the monotherapy only subjects and the monotherapy followed by combination 
subjects as well as presenting them together.  The tables that will be produced this way will be 
detailed in the SAP. 
9.4.3.1 
Adverse events  
Treatment emergent AEs (TEAEs) are defined as those AEs with an onset after dosing and 
those pre-existing AEs that worsen after the start of dosing and within 30 days of stopping 
RXC004 monotherapy or 90 days after the last actual nivolumab dose (for patients on 
RXC004 and nivolumab combination).  For AEs, verbatim terms in the eCRF will be mapped 
to preferred terms and system organ class using the Medical Dictionary for Regulatory 
activities (version 22.0 or later) CTCAE criteria v5.0 will be used to grade the severity of AEs.  
The incidence of treatment emergent AEs will be summarised by preferred term and system 
organ class as well as severity.  Treatment related TEAEs will be summarised in the same way.  
Subject incidence of SAEs will also be produced. 
By subject listings of all AEs, deaths, SAEs and TEAEs leading to discontinuation will also be 
produced. 
9.4.3.2 
Laboratory parameters 
Shift tables to characterize changes from baseline to on treatment will be presented for 
haematology, clinical chemistry and coagulation parameters.  Laboratory tests with numerical 
grading criteria in the NCI CTCAE v5.0 will be graded accordingly.  Grade 0 will be assigned 
for all non-missing values not graded as 1 or higher.  For laboratory tests where grades are not 
defined by CTCAE v5.0 results will be classified as low, normal or high based on laboratory 
normal ranges, 
9.4.3.3 
 Vital signs 
Vital signs data will be presented in listings.  Abnormal vital signs values will be identified as 
those outside (above or below) the reference range.  Vital signs data will be summarized using 
descriptive statistics. 
9.4.4 
Other Analyses  
Other analyses that may be deemed necessary will be outlined and presented in the SAP. 
 
Interim Analyses  
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Safety Monitoring Committee 
A safety monitoring committee (SMC) will be appointed to review safety data from patients in 
this study and a second study of RXC004 in patients with pancreatic and biliary tract cancer 
(RXC004/0003).  
The SMC will comprise experts in the disease areas under investigation, who may be study 
investigators, a biostatistician and an independent bone metabolism expert. The SMC will be 
convened to review the safety and tolerability of RXC004 at regular intervals.   
 
The safety reviews will start when approximately y  patients across the phase 2 clinical trial 
programme have been dosed for at least 1 cycle of study treatment and will continue every 6 
months until the phase 2 studies close or last patient discontinues study treatment (whichever 
occurs first).  A safety review of the combination data will be conducted after  patients have 
received the combination of RXC004 and nivolumab for at least 1 cycle.  Additional safety 
reviews may be performed at other times as deemed appropriate by the Sponsor. 
 
Since the studies are open label, there are no blinding issues associated with performing 
interim safety reviews.  Full details of the SMC procedures, processes, and analyses can be 
found in the SMC Charter. 
 
 
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10 
APPENDICES 
 


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Appendix A 
Regulatory, Ethical, and Study Oversight Considerations 
A 1 
Regulatory and Ethical Considerations 
• 
This study will be conducted in accordance with the protocol and with the following: 
− 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines 
− 
Applicable ICH Good Clinical Practice (GCP) Guidelines 
− 
Applicable laws and regulations 
• 
The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents (e.g., advertisements) must be submitted to an IRB/IEC by the investigator 
and reviewed and approved by the IRB/IEC before the study is initiated. 
• 
Any amendments to the protocol will require IRB/IEC and applicable Regulatory 
Authority approval before implementation of changes made to the study design, except 
for changes necessary to eliminate an immediate hazard to study participants. 
• 
Redx will be responsible for obtaining the required authorisations to conduct the study 
from the concerned Regulatory Authority. This responsibility may be delegated to a CRO 
but the accountability remains with Redx. 
 
Regulatory Reporting Requirements for SAEs 
• 
Prompt notification by the investigator to the sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention under clinical investigation are met. 
• 
The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRB)/Independent Ethics Committees (IEC), and investigators. 
• 
For all studies except those utilizing medical devices investigator safety reports must be 
prepared for suspected unexpected serious adverse reactions (SUSAR) according to local 
regulatory requirements and sponsor policy and forwarded to investigators as necessary. 
• 
An investigator who receives an investigator safety report describing a SAE or other 
specific safety information (e.g., summary or listing of SAEs) from the sponsor will 
review and then file it along with the Investigator’s Brochure and will notify the IRB/IEC, 
if appropriate according to local requirements. 
A 2 
Financial Disclosure 
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 


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information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators 
are responsible for providing information on financial interests, this includes any changes to 
financial interests throughout the study and for 1 year after the final CSR. 
A 3 
Informed Consent Process 
• 
The investigator or his/her representative will explain the nature of the study to the patient 
or his/her legally authorised representative and answer all questions regarding the study. 
• 
Patients must be informed that their participation is voluntary and they are free to refuse 
to participate and may withdraw their consent at any time and for any reason during the 
study. Patients or their legally authorised representative will be required to sign a 
statement of informed consent that meets the requirements of 21 CFR 50, local 
regulations, ICH guidelines, Health Insurance Portability and Accountability Act 
(HIPAA) requirements, where applicable, and the IRB/IEC or study centre. 
• 
The medical record must include a statement that written informed consent was obtained 
before the patient was enrolled in the study and the date the written consent was obtained. 
The authorised person obtaining the informed consent must also sign the ICF. 
• 
Patients must be re-consented to the most current version of the ICF(s) during their 
participation in the study. 
• 
A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorised representative. 
 
The ICF will contain a separate section that addresses and documents the collection and use of 
any mandatory and/or optional human biological samples. The investigator or authorised 
designee will explain to each participant the objectives of the analysis to be done on the 
samples and any potential future use. Participants will be told that they are free to refuse to 
participate in any optional samples or the future use and may withdraw their consent at any 
time and for any reason during the retention period.  
A 4 
Data Protection 
• 
Patients will be assigned a unique identifier by the sponsor. Any patient records or 
datasets that are transferred to the sponsor will contain the identifier only; patient names 
or any information which would make the patient identifiable will not be transferred. 
• 
The patient must be informed that his/her personal study-related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure and use of 
their data must also be explained to the patient in the informed consent  


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• 
The patient must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorised personnel appointed by the sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
A 5 
Dissemination of Clinical Study Data 
A description of this clinical study will be available on http://www.clinicaltrials.gov, as will 
the summary of the main study results when they are available. The clinical study and/or 
summary of main study results may also be available on other websites according to the 
regulations of the countries in which the study is conducted. 
A 6 
Data Quality Assurance 
• 
All patient data relating to the study will be recorded on eCRF unless transmitted to the 
sponsor or designee electronically (e.g., laboratory data). The investigator is responsible 
for verifying that data entries are accurate and correct by physically or electronically 
signing the eCRF. 
• 
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF. 
• 
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
• 
The sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
• 
The sponsor assumes accountability for actions delegated to other individuals (e.g., 
Contract Research Organizations). 
• 
Study monitors will perform ongoing source data verification to confirm that data entered 
into the eCRF by authorised site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of patients are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements. 
• 
Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the investigator for 2 years after the last marketing application unless 
local regulations or institutional policies require a longer retention period. No records 
may be destroyed during the retention period without the written approval of the sponsor. 
No records may be transferred to another location or party without written notification to 
the sponsor. 
A 7 
Source Documents 
• 
Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site. 


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• 
Data reported on the eCRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available. 
A 8 
Study and Site Start and Closure 
The study start date is the date on which the clinical study will be open for recruitment of 
patients. 
The first act of recruitment is the first site open and will be the study start date. 
The sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to: 
• 
Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the sponsor's procedures, or GCP guidelines 
• 
Inadequate recruitment of participants by the investigator 
• 
Discontinuation of further study intervention development 
 
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organization(s) used in the study of the reason for termination or suspension, as specified by 
the applicable regulatory requirements. The investigator shall promptly inform the participant 
and should assure appropriate participant therapy and/or follow-up. 
A 9 
Publication Policy 
• 
The data generated by this study are confidential information of the Sponsor. The Sponsor 
will make the results of the study publicly available. The publication policy with respect 
to the Investigator and study centre will be set forth in the Clinical Trial Agreement. 
• 
The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally support 
publication of multicentre studies only in their entirety and not as individual site data. In 
this case, a coordinating investigator will be designated by mutual agreement. 


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Appendix B Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting 
B 1 
Definition of adverse events 
An adverse event is the development of any untoward medical occurrence in a patient or 
clinical study participant administered a medicinal product and which does not necessarily 
have a causal relationship with this treatment.  An AE can therefore be any unfavourable and 
unintended sign (e.g., an abnormal laboratory finding), symptom (for example nausea, chest 
pain), or disease temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product.  
The term AE is used to include both serious and non-serious AEs and can include a 
deterioration of a pre-existing medical occurrence. An AE may occur at any time, including 
run-in or washout periods, even if no Study treatment has been administered. 
B 2 
Definitions of serious adverse event 
A serious adverse event is an AE occurring during any study phase (i.e., run-in, treatment, 
washout, follow-up), that fulfils one or more of the following criteria: 
• 
Results in death 
• 
Is immediately life-threatening 
• 
Requires in-participant hospitalisation or prolongation of existing hospitalisation  
• 
Results in persistent or significant disability or incapacity 
• 
Is a congenital abnormality or birth defect 
• 
Is an important medical event that may jeopardise the participant or may require medical 
treatment to prevent one of the outcomes listed above. 
 
Adverse Events (AEs) for malignant tumours reported during a study should generally be 
assessed as Serious AEs. If no other seriousness criteria apply, the ‘Important Medical Event’ 
criterion should be used. In certain situations, however, medical judgement on an individual 
event basis should be applied to clarify that the malignant tumour event should be assessed 
and reported as a Non-Serious AE. For example, if the tumour is included as medical history 
and progression occurs during the study, but the progression does not change treatment and/or 
prognosis of the malignant tumour, the AE may not fulfil the attributes for being assessed as 
Serious, although reporting of the progression of the malignant tumour as an AE is valid and 
should occur. Also, some types of malignant tumours, which do not spread remotely after a 
routine treatment that does not require hospitalization, may be assessed as Non-Serious; 
examples in adults include Stage 1 basal cell carcinoma and Stage 1A1 cervical cancer 
removed via cone biopsy. 


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The above instruction applies only when the malignant tumour event in question is a new 
malignant tumour (i.e., it is not the tumour for which entry into the study is a criterion and that 
is being treated by the IP under study and is not the development of new or progression of 
existing metastasis to the tumour under study). Malignant tumours that – as part of normal, if 
rare, progression – undergo transformation (e.g., Richter's transformation of B cell chronic 
lymphocytic leukaemia into diffuse large B cell lymphoma) should not be considered a new 
malignant tumour. 
Life threatening 
‘Life-threatening’ means that the participant was at immediate risk of death from the AE as it 
occurred or it is suspected that use or continued use of the product would result in the 
participant’s death. ‘Life-threatening’ does not mean that had an AE occurred in a more severe 
form it might have caused death (e.g., hepatitis that resolved without hepatic failure). 
Hospitalisation 
Outpatient treatment in an emergency room is not in itself a serious AE, although the reasons 
for it may be (e.g., bronchospasm, laryngeal oedema). Hospital admissions and/or surgical 
operations planned before or during a study are not considered AEs if the illness or disease 
existed before the participant was enrolled in the study, provided that it did not deteriorate in 
an unexpected way during the study. 
Important medical event or medical treatment 
Medical and scientific judgement should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life threatening or result in 
death, hospitalisation, disability or incapacity but may jeopardise the participant or may 
require medical treatment to prevent one or more outcomes listed in the definition of serious. 
These should usually be considered as serious. 
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgement must be used. 
• 
Angioedema not severe enough to require intubation but requiring iv hydrocortisone 
treatment 
• 
Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment with 
N-acetylcysteine 
• 
Intensive treatment in an emergency room or at home for allergic bronchospasm 
• 
Blood dyscrasias (e.g., neutropenia or anaemia requiring blood transfusion, etc.) or 
convulsions that do not result in hospitalisation 
• 
Development of drug dependency or drug abuse 
 


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Intensity rating scale: 
The grading scales found in the revised National Cancer Institute CTCAE latest version will 
be utilised for all events with an assigned CTCAE grading. For those events without assigned 
CTCAE grades, the recommendation in the CTCAE criteria that converts mild, moderate and 
severe events into CTCAE grades should be used. A copy of the CTCAE can be downloaded 
from the Cancer Therapy Evaluation Program website (http://ctep.cancer.gov). The applicable 
version of CTCAE should be described clearly. 
B 3 
A Guide to Interpreting the Causality Question 
When making an assessment of causality consider the following factors when deciding if there 
is a ‘reasonable possibility’ that an AE may have been caused by the drug. 
• 
Time Course. Exposure to suspect drug. Has the participant actually received the suspect 
drug?  Did the AE occur in a reasonable temporal relationship to the administration of the 
suspect drug? 
• 
Consistency with known drug profile. Was the AE consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the same 
pharmacological class? Or could the AE be anticipated from its pharmacological 
properties? 
• 
De-challenge experience. Did the AE resolve or improve on stopping or reducing the dose 
of the suspect drug? 
• 
No alternative cause. The AE cannot be reasonably explained by another aetiology such 
as the underlying disease, other drugs, other host or environmental factors. 
• 
Re-challenge experience. Did the AE reoccur if the suspected drug was reintroduced after 
having been stopped?  
• 
Laboratory tests. A specific laboratory investigation (if performed) has confirmed the 
relationship. 
 
In difficult cases, other factors could be considered such as: 
• 
Is this a recognised feature of overdose of the drug? 
• 
Is there a known mechanism? 
 
Causality of ‘related’ is made if following a review of the relevant data, there is evidence for a 
‘reasonable possibility’ of a causal relationship for the individual case. The expression 
‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship. 
The causality assessment is performed based on the available data including enough 


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information to make an informed judgment. With no available facts or arguments to suggest a 
causal relationship, the event(s) will be assessed as ‘not related’. 
Causal relationship in cases where the disease under study has deteriorated due to lack of 
effect should be classified as no reasonable possibility. 
B 4 
Medication Error 
For the purposes of this clinical study a medication error is an unintended failure or mistake in 
the treatment process for a Redx study drug that either causes harm to the participant or has 
the potential to cause harm to the participant.  
A medication error is not lack of efficacy of the drug, but rather a human or process related 
failure while the drug is in control of the study site staff or participant. 
Medication error includes situations where an error.  
• 
occurred 
• 
was identified and intercepted before the participant received the drug 
• 
did not occur, but circumstances were recognised that could have led to an error 
 
Examples of events to be reported in clinical studies as medication errors: 
• 
Drug name confusion 
• 
Dispensing error e.g. medication prepared incorrectly, even if it was not actually given to 
the participant 
• 
Drug not administered as indicated, for example, wrong route or wrong site of 
administration 
• 
Drug not taken as indicated e.g. tablet dissolved in water when it should be taken as a 
solid tablet, tablet taken with food when it should be taken fasted.  
• 
Drug not stored as instructed e.g. kept in the fridge when it should be at room temperature  
• 
Wrong participant received the medication  
• 
Wrong drug administered to participant  
 
Examples of events that do not require reporting as medication errors in clinical studies: 
• 
Participant accidentally missed drug dose(s) e.g. forgot to take medication 
• 
Accidental overdose (will be captured as an overdose) 
• 
Participant failed to return unused medication or empty packaging 


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• 
Errors related to background and rescue medication, or standard of care medication in 
open label studies 
 
Medication errors are not regarded as AEs but AEs may occur as a consequence of the 
medication error. 
 


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Appendix C 
Handling of Human Biological Samples 
C 1 
Chain of custody 
A full chain of custody is maintained for all samples throughout their lifecycle. 
The investigator at each centre keeps full traceability of collected biological samples from the 
patients while in storage at the centre until shipment or disposal (where appropriate) and 
records relevant processing information related to the samples whilst at site. 
The sample receiver keeps full traceability of the samples while in storage and during use until 
used or disposed of or until further shipment and keeps record of receipt of arrival and onward 
shipment or disposal. 
Redx or delegated representatives will keep oversight of the entire life cycle through internal 
procedures, monitoring of study sites, auditing or process checks, and contractual 
requirements of external laboratory providers. 
Samples retained for further use will be stored in the Redx-assigned biobanks or other sample 
archive facilities and will be tracked by the appropriate Redx Team for the remainder of the 
sample life cycle. 
C 2 
Withdrawal of Informed Consent for donated biological samples  
Redx ensures that biological samples are returned to the source or destroyed at the end of a 
specified period as described in the informed consent. 
If a participant withdraws consent to the use of donated biological samples, the samples will 
be disposed of/destroyed/repatriated, and the action documented. If samples are already 
analysed, Redx is not obliged to destroy the results of this research. 
Following withdrawal of consent for biological samples, further study participation should be 
considered in relation to the withdrawal processes outlined in the informed consent. 
The investigator: 
• 
Ensures participant’s’ withdrawal of informed consent to the use of donated samples is 
highlighted immediately to Redx or delegate. 
• 
Ensures that relevant human biological samples from that participant, if stored at the 
study site, are immediately identified, disposed of as appropriate, and the action 
documented. 
• 
Ensures that the participant and Redx are informed about the sample disposal. 
 
Redx ensures the organization(s) holding the samples is/are informed about the withdrawn 


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consent as soon as reasonably possible and that samples are disposed of or repatriated as 
appropriate, and the action documented and study site notified. 
C 3 
International Airline Transportation Association (IATA) 6.2 
Guidance Document 
LABELLING AND SHIPMENT OF BIOHAZARD SAMPLES 
International Airline Transportation Association (IATA) 
(https://www.iata.org/whatwedo/cargo/dgr/Pages/download.aspx) classifies infectious 
substances into 3 categories: Category A, Category B or Exempt 
Category A Infectious Substances are infectious substances in a form that, when exposure to 
it occurs, is capable of causing permanent disability, life-threatening or fatal disease in 
otherwise healthy humans or animals.  
Category A pathogens are e.g., Ebola, Lassa fever virus. Infectious substances meeting these 
criteria which cause disease in humans or both in humans and animals must be assigned to UN 
2814. Infectious substances which cause disease only in animals must be assigned to UN 
2900: 
Category B Infectious Substances are infectious Substances that do not meet the criteria for 
inclusion in Category A. Category B pathogens are e.g., Hepatitis A, C, D, and E viruses. 
They are assigned the following UN number and proper shipping name 
• 
UN 3373 – Biological Substance, Category B 
• 
are to be packed in accordance with UN3373 and IATA 650 
 
Exempt - Substances which do not contain infectious substances or substances which are 
unlikely to cause disease in humans or animals are not subject to these Regulations unless they 
meet the criteria for inclusion in another class. 
• 
Clinical study samples will fall into Category B or exempt under IATA regulations 
• 
Clinical study samples will routinely be packed and transported at ambient temperature in 
IATA 650 compliant packaging 
(https://www.iata.org/whatwedo/cargo/dgr/Documents/DGR-60-EN-PI650.pdf). 
• 
Biological samples transported in dry ice require additional dangerous goods specification 
for the dry-ice content 
• 
files would remain physically separate. 
 
 


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Appendix D 
RECIST 1.1 (Response Evaluation Criteria in Solid 
Tumours) Responses 
 
 
Patients with symptomatically stable disease may continue study treatment after the initial 
RECIST 1.1 - defined progression until symptomatic progression or second RECIST 1.1 PD 
assessment (relative to the initial RECIST1.1 progression for a given study treatment).   A 
decision to continue study treatment after initial progression must be discussed and agreed by 
the treating physician and the Sponsor.   
The criteria for continuing treatment after initial RECIST 1.1-defined progression are as 
follows: 
• The patient does not have any significant, unacceptable, or irreversible toxicities 
indicating that continuing treatment will not further benefit the patient. 
• There is absence of clinical symptoms or signs indicating clinically significant disease 
progression accompanied by a decline in ECOG performance status>1. 
Term 
Definition 
Complete response (CR) 
Disappearance of all target lesions. Any pathological lymph nodes must 
have reduction in short axis to <10 mm. 
Partial response (PR) 
A ≥ 30% decrease in the sum of diameters of target lesions, taking as 
reference the baseline sum diameters. 
Progressive disease (PD) 
At least a 20% increase in the sum of diameters of target lesions, taking 
as reference the smallest sum on study (this includes the baseline sum if 
that is the smallest on study). In addition to the relative increase of 20%, 
the sum must also demonstrate an absolute increase of at least 0.5 cm. 
The appearance of one or more new lesions is also considered 
progression. 
Stable disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on 
study.  
New measureable lesions1 
Always represents progressive disease (PD) 
New non-measureable lesions 
Always represents progressive disease (PD) 
Non-index lesions 
Changes contribute to defining best overall response of CR, PR, SD, and 
PD 
From RECIST v1.1  
1) Measureable lesion must be accurately measured in at least one dimension (longest diameter in the plane 
of measurement is to be recorded) with a minimum size of 10 mm by CT scan (CT slice thickness no 
greater than 5 mm) 


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• There is absence of rapid disease progression or threat to vital organs or critical 
anatomical sites (e.g. central nervous system metastasis, respiratory failure due to 
tumour compression, or spinal cord compression) requiring urgent alternative medical 
intervention.   


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Figure 2 
Treatment after first progression (Arm A) 
 
 
 
 


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Figure 3 
Treatment after first progression (Arm B) 
 
 
 
 
 
 


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Figure 4 
Treatment after first progression for patients that remain on RXC004 monotherapy (Arm A) 
 


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Appendix E 
Prohibited CYP3A4 Inhibitors, and Inducers  
 
CYP3A4 Inhibitors  
[Bold text denotes commonly used co-medications in 
patients with colorectal cancer] 
CYP3A4 Inducers  
[None of these drugs are commonly used co-
medications in patients with colorectal cancer] 
Strong CYP3A4 Inhibitors 
Concomitant use of these drugs has the potential to increase 
the exposure of RXC004 over 5-fold  
These agents must not be given within 14 days of first dose of 
study treatment 
boceprevir, cobicistat, danoprevir and ritonavir, elvitegravir 
and ritonavir, grapefruit juice, indinavir and ritonavir, 
itraconazole, ketoconazole, lopinavir and ritonavir, 
paritaprevir and ritonavir and (ombitasvir and/or dasabuvir), 
posaconazole, ritonavir, saquinavir and ritonavir, telaprevir, 
tipranavir and ritonavir, troleandomycin, voriconazole, 
clarithromycin, idelalisib, nefazodone, nelfinavir, 
Strong CYP3A4 Inducers 
Concomitant use of these drugs has the potential 
to decrease the exposure of RXC004 by over 80%  
aptalutimide, carbamazepine, enzalutamide, 
mitotane, phenytoin, rifampin, St. John’s wort 
These agents must not be given within 14 days of 
first dose of study treatment 
Moderate CYP3A4 Inhibitors 
Concomitant use of these drugs has the potential to increase 
the exposure of RXC004 by 2-5-fold 
A washout period of 14 days is recommended and a minimum 
washout period of 5 half-lives (See SPC or USPI) is required 
before first dose of study treatment. 
aprepitant, ciprofloxacin, conivaptan, crizotinib, 
cyclosporine, diltiazem, dronedarone, erythromycin, 
fluconazole, fluvoxamine, imatinib, tofisopam, verapamil 
lansoprazole 
Moderate CYP3A4 Inducers 
Concomitant use of these drugs has the potential 
to decrease the exposure of RXC004 by 60-80% 
A washout period of 14 days is recommended and 
a minimum washout period of 5 half-lives (See 
SPC or USPI) is required before first dose of 
study treatment 
bosentan, efavirenz, etravirine, phenobarbital, 
primidone 
Weak CYP3A4 Inhibitors 
These are not prohibited but should be used with caution as 
they may increase the exposure of RXC004 by 1.25 -2- fold 
chlorzoxazone, cilostazol, cimetidine, clotrimazole, 
fosaprepitant, istradefylline, ivacaftor, lomitapide, 
ranitidine, ranolazine, ticagrelor, omeprazole 
Weak CYP3A4 Inducers 
These drugs are not prohibited- they have the 
potential to decrease the exposure of RXC004 by 
20-50% which is within the scope of the dose 
reduction allowances 


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armodafinil, modafinil, rufinamide 
For updated information, please refer to https://www.fda.gov/drugs/drug-interactions-
labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers 


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Appendix F 
RNF43/RSPO aberrations 
The study will recruit patients with documented RNF43 or RSPO genetically aberrated, MSS 
mCRC. 
Patients with the following RNF43 mutations are eligible for the study; 
Patients with documented loss of function RNF43 mutations other than those listed above may 
be allowed after consultation with Sponsor. 
Patients with the following RSPO fusions are eligible for the study: 
  
CCI
CCI


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Patients with documented RSPO fusions other than those listed above may be allowed after 
consultation with Sponsor. 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI


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Appendix G Nivolumab Toxicity Management and Dose Modification 
Guidelines 
Recommendations for nivolumab modifications are provided in the dose modification section 
of the nivolumab Prescribing Information and summarized here.   
Table 19 
Nivolumab toxicity management and dose modifications 
Adverse Event 
Severity 
Investigations, Treatment and Dose 
modification 
Colitis 
Grade 1 diarrhoea or colitis 
Investigations: FBC, UEC, LFTs, CRP, TFTs.  Stool 
microscopy for leucocytes/ova/parasites, culture, 
viral PCR, C. diff. toxin and cryptosporidia 
 
Treat with oral fluids and loperamide.  Avoid high 
fibre/lactose diet.  If Grade 1 symptoms persist for 
>14 days treat as per Grade 2 
 
Continue treatment 
Grade 2 diarrhoea or colitis 
Investigations as per Grade 1.  Exclude steatorrhea 
 
Consider abdominal X-ray and 
sigmoidoscopy/colonoscopy for signs of Colitis. 
 
Start prednisolone 0.5-1 mg/kg or consider oral 
budesonide 9 mg od if no bloody diarrhoea.  Once 
recovered to Grade 1, wean steroids over 2-4 weeks. 
If no improvement in 72hrs, treat as per Grade 3.   
 
Withhold dosea 
Grade 3 diarrhoea or colitis 
Investigations as per Grade 2 with daily FBC, UEC, 
LFTs and CRP 
 
Conduct Sigmoidoscopy/colonoscopy.  Early 
surgical review if bleeding, pain or distension.  
Review diet (e.g. nil by mouth, clear fluids, TPN) 
 
Treat with IV (methyl)prednisolone 1-2 mg/kg.  
Wean steroids over 4-8 weeks.  If no improvement in 
72 hours start Infliximab 5 mg/kg (if no 
perforation/sepsis/TB/hepatitis/congestive heart 
failure – Must have had 
flexsigmoidoscopy/colonoscopy prior)b 
Withhold dosea   
Grade 4 diarrhoea or colitis 
Investigations and treatment as per Grade 3 
 
Permanently discontinue 
Pneumonitis 
Grade 1 
Bloods (FBC/UEC/LFTs/Ca/ESR/CRP).  Consider 
sputum sample screening for viral/bacterial infection.   
 


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Adverse Event 
Severity 
Investigations, Treatment and Dose 
modification 
Chest X-ray 
 
Continue treatment  
Grade 2 
Investigations as per Grade 1. Monitor symptoms 
daily 
 
Start antibiotics if suspicion of infection.  If no 
evidence of infection or no improvement with 
antibiotics after 48hrs add in prednisolone 
1 mg/kg/day orally.  Once improved to baseline, 
wean steroids over at least 6 weeks.  If no 
improvement after 48hrs, manage as per Grade 3 
 
Consider Pneumocystis prophylaxis depending on 
the clinical context 
 
High resolution CT +/- bronchoscopy and BAL 
pending appearances 
 
Withhold dosea 
Grade 3 or 4 
Admit patient and perform investigations as per 
Grade 2.  
 
Treat with (methyl)prednisolone IV 2-4 mg/kg/day 
and cover with empiric antibiotics.  Once improved 
to baseline wean steroids over at least 8 weeks.  If no 
improvement after 48hrs add infliximab 5 mg/kg (or 
MMF if concurrent hepatic toxicity).   
 
High resolution CT +/- bronchoscopy and BAL 
pending appearances 
 
Permanently discontinue 
Hepatitis 
Grade 1: 
ALT or AST >ULN-3XULN 
If > ULN-3XULN repeat in 1 week 
 
Continue treatment 
Grade 2:  
ALT or AST 3-5XULN 
Re-check LFTs/INR/albumin every 3 days.  Review 
medications, e.g. statins, antibiotics and alcohol 
history. Perform liver screen: Hepatitis A/B/C 
serology, Hepatitis E PCR, anti-
ANA/SMA/LKM/SLA/LP/LCI, iron studies  
 
If rising ALT/AST when re-checked start oral 
prednisolone 1 mg/kg.  Once resolved to Grade 1, 
wean steroids over 2 weeks.  Re-escalate if 
worsening; nivolumab treatment may be resumed 
once prednisolone ≤ 10 mg 
 


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Adverse Event 
Severity 
Investigations, Treatment and Dose 
modification 
Consider imaging for metastases/clot 
 
Withhold dosea 
Grade 3:AST or ALT 5-
20XULN  
Re-check LFTs/INR/albumin every day.  Other 
investigation as per Grade 2. 
 
If ALT/AST < 400 and normal 
bilirubin/INR/albumin treat with oral prednisolone 
1 mg/kg.  If ALT/AST > 400 or raised 
bilirubin/INR/low albumin treat with i.v. 
(methyl)prednisolone 2 mg/kg.  Once improved to 
G2, can change to oral prednisolone and wean over 
4 weeks 
 
Perform US with Doppler.  Low threshold to admit if 
clinical concern 
 
Permanently discontinue 
Grade 4: ALT or AST 
>20xULN 
Investigations as per Grade 3 
 
Treat with i.v. (methyl)prednisolone 2 mg/kg.  If 
condition worsens despite steroids, add 
mycophenolate mofetil (MMF) 500-1000 mg bd.  If 
worse on MMF, consider addition of tacrolimus. 
 
Hepatology consult and consider liver biopsy 
 
Permanently discontinue 
Hypophysitis 
Grade 2 
Pituitary axis assessment, MRI pituitary protocol 
(also exclude brain metastases), visual ﬁeld 
assessment. Monitor TFTs. 
Start oral prednisolone 0.5-1 mg/kg od after pituitary 
axis assessment.  If no improvement in 48h, treat as 
severe with i.v. (methyl)prednisolone.  Wean steroids 
based on symptoms over 2-4 weeks to 5 mg 
prednisolone.  Do not stop steroids  
 
Refer to or consult endocrinologist  
 
Withhold dosec 
Grade  3 
Investigations as per Grade 2 
 
Initiate i.v. (methyl)prednisolone 1 mg/kg after 
sending bloods for pituitary axis assessment.  
Analgesia as needed for headache.  Aim convert to 
prednisolone and wean as symptoms allow over 4 
weeks to 5 mg 
 


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Adverse Event 
Severity 
Investigations, Treatment and Dose 
modification 
Refer to or consult endocrinologist  
 
Withhold dosec 
Grade 4 
Investigations as per Grade 1 
 
Treatment as per Grade 3 
 
Refer to or consult endocrinologist  
 
Permanently discontinue 
Adrenal 
Insufficiency 
Grade 2 
Consider management with corticosteroids (if needed 
for symptoms of acute inflammation)  
 
Withhold dosec 
Grade 3 or 4 
Permanently discontinue 
Type 1 Diabetes 
Mellitus 
Grade 3 
hyperglycaemia/diabetes 
Admit to hospital immediately and start treatment of 
newly onset type I DM. 
 
Consider management with corticosteroids (if needed 
for symptoms of acute inflammation)  
 
Withhold dosec 
Grade 4 
hyperglycaemia/diabetes 
Treat as per Grade 3  
 
Permanently discontinue 
Nephritis and Renal 
Dysfunction 
Grade 1 (creatinine 1.5 x 
baseline or > ULN-1.5x ULN) 
Review hydration status, medications, urine 
test/culture if urinary tract infection symptoms 
Dipstick urine and send for protein assessment 
UPCR.  Repeat creatinine weekly.  If worsens, 
manage as per Grade 2 
 
If obstruction suspected: renal ultrasound +/- doppler 
to exclude obstruction/clot 
 
Continue treatment 
Grade 2: creatinine > 1.5-3x 
baseline or > 1.5-3x ULN 
Investigation as per Grade 1 and review 
creatinine/K+ in 48h-72h; if not improving discuss 
with nephrologist and need for biopsy and if 
attributed to irAE, If proteinuria: for 24 h collection 
or UPCR 
If blood: phase contrast microscopy and GN screen* 
if nephrologist recommends 
 
Initiate steroids (oral prednisolone 0.5-1 mg/kg) 
 


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Adverse Event 
Severity 
Investigations, Treatment and Dose 
modification 
Renal ultrasound +/- doppler to exclude 
obstruction/clot 
 
Withhold dosea  - Repeat creatinine/K+ every 48h 
If returns to G1/baseline – recommence treatment (if 
on steroids, only once < 10 mg prednisolone) 
If not attributed to irAE - may continue treatment 
Grade 3: creatinine > 3x 
baseline or > 3-6x ULN Serum 
creatinine more than 1.5 and 
up to 6 times the ULN 
Investigation as per Grade 2, plus admit patient for 
monitoring and ﬂuid balance; repeat creatinine every 
24h; early discussion with nephrologist and need for 
biopsy; if worsening, initiate i.v. 
(methyl)prednisolone 1-2 mg/kg 
 
Withhold dosea 
Serum creatinine >6 x ULN 
Investigations as per G3, plus patient should be 
managed in hospital where renal replacement therapy 
is available 
 
initiate i.v. (methyl)prednisolone 1-2 mg/kg 
 
Permanently discontinue 
Skin 
Grade 1 (skin rash with or 
without symptoms, <10% 
BSA) 
Physical examination.  Exclude other causes e.g. 
viral illness, infection, other drug rash etc 
 
Topical steroids (mild strength) +/- oral or topical 
anti-histamines may be administered 
 
Continue treatment 
Grade 2 (10-30% BSA) 
Investigations as per Grade 1 
 
Topical steroids (moderate strength) +/- oral or 
topical anti-histamines may be administered 
 
Consider dermatology referral and skin biopsy 
 
Continue treatment 
Grade 3 rash (>30% BSA, or 
10-30% BSA with substantial 
symptoms) or suspected 
Stevens-Johnson syndrome 
(SJS) or toxic epidermal 
necrolysis (TEN) 
Investigations as per Grade 1 
 
Topical treatments as above (potent).  Initiate 
steroids: if mild to moderate 0.5-1 mg/kg 
prednisolone od for 3 days then wean over 1-2 
weeks; or if severe i.v. (methyl)prednisolone 
0.5-1 mg/kg and convert to oral steroids on response, 
wean over 2-4 weeks 
 
Dermatology referral and skin biopsy 
 


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Adverse Event 
Severity 
Investigations, Treatment and Dose 
modification 
Withhold dosea 
Grade 4 rash or confirmed SJS 
or TEN 
Investigations as per Grade 1 
 
i.v. (methyl)prednisolone  1-2 mg/kg 
 
Seek urgent dermatology review 
 
Permanently discontinue 
Peripheral 
neurological toxicity 
(For specific 
recommendations 
for Myasthenia 
Gravis and Guillain-
Barré syndrome, see 
‘other’) 
Grade 1 
Comprehensive neurological examination Diabetic 
screen, B12/folate, HIV, TSH, consider vasculitic & 
autoimmune screen, review alcohol history & other 
medications 
 
Consider need for MRI/MRA brain or spine (exclude 
CVA, structural cause) 
 
Continue treatment 
Grade 2 
Investigations as per Grade 1, plus consider 
NCS/EMG for lower motor neurone motor and/or 
sensory change 
 
Consider pulmonary function/sniff/diaphragmatic 
function tests and neurological consult 
 
Initial observation reasonable or initiate prednisolone 
0.5-1 mg/kg (if progressing, e.g. from mild) and/or 
pregabalin or duloxetine for pain.  Taper steroids 
over 4-8 weeks.  If worsening, treat as per Grade 3 
 
Withhold dosea 
Grade 3 
Admit patient.  Involve neurologist in care Daily 
neurological review +/- daily vital capacity 
 
MRI brain/spine advised NCS/EMG Lumbar 
puncture Pulmonary function assessment 
 
Initiate (methyl)prednisolone 2 mg/kg i.v.  Taper 
steroids over 4-8 weeks. 
 
Withhold dosea 
Encephalitis 
New-onset moderate or severe 
neurologic signs or symptoms 
Lumbar puncture, PCR for HSV, cytology and 
consider viral culture 
 
Oral prednisolone 0.5-1 mg/kg or i.v. 
(methyl)prednisolone 1-2 mg/kg if very unwell 
(Exclude bacterial and ideally viral infections prior 


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Adverse Event 
Severity 
Investigations, Treatment and Dose 
modification 
to high-dose steroids).  Consider concurrent empiric 
antiviral (i.v. acyclovir) and antibacterial therapy 
 
CNS imaging and consider neurological consult 
 
Withhold dosea 
Immune-mediated encephalitis 
Lumbar puncture, PCR for HSV, cytology and 
consider viral culture 
 
Oral prednisolone 0.5-1 mg/kg or i.v. 
(methyl)prednisolone 1-2 mg/kg if very unwell 
(Exclude bacterial and ideally viral infections prior 
to high-dose steroids).  Consider concurrent empiric 
antiviral (i.v. acyclovir) and antibacterial therapy 
 
CNS imaging  
 
Permanently discontinue 
Thyroid function 
Hypothyroidism: Low FT4 
with elevated TSH or TSH > 
10 with normal FT4 
Thyroxine 0.5-1.5 μg/kg (start low in elderly, if 
cardiac history) 
 
Continue treatment 
Thyrotoxicosis (DDx 
thyroiditis, Grave’s disease) 
 
Investigations: Anti-TSH Receptor Ab, anti-TPO Ab, 
nuclear medicine thyroid uptake scan  
 
Propranolol or atenolol for symptoms; consider 
carbimazole if anti-TSH Receptor Ab positive 
Painful thyroiditis – consider prednisolone 0.5 mg/kg 
and taper if unwell,  
 
Withhold dosec 
Grade 4 hypothyroidism or 
hyperthyroidism 
Investigations and treatments as above. 
 
Permanently discontinue 
Infusion reactions 
Grade 1 or 2 
Interrupt or slow rate of infusion 
Grade 3 or 4 
Permanently discontinue 
Other 
Other Grade 3AEs 
- 
First occurrence 
- 
Recurrence of same 
Grade 3 adverse 
events 
 
Withhold dosea 
Permanently discontinue 
Life-threatening or Grade 4 
adverse reaction 
Permanently discontinue 
Grade 3 myocarditis 
If myocarditis is suspected, admit the patient and 
immediately start high-dose (methyl)prednisone 
(1-2 mg/kg). In the case of deterioration, consider 


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Adverse Event 
Severity 
Investigations, Treatment and Dose 
modification 
adding another immunosuppressive drug (MMF or 
tacrolimus) 
 
Permanently discontinue 
Guillain-Barré syndrome 
(GBS) 
Nerve conduction studies (acute polyneuropathy) 
Lumbar puncture (elevated protein with normal 
WBC count).  Pulmonary function tests with vital 
capacity and maximum inspiratory/expiratory 
pressures. Antibody testing for GBS variants, e.g. 
GQ1b in Miller Fisher variant 
 
Use of steroids not recommended in idiopathic GBS 
If no improvement or worsening, plasmapheresis or 
intravenous immunoglobulin indicated. 
 
Neurological consult.  Consider location of care 
where ventilatory support available (required in 
15%-30% idiopathic cases) 
 
Permanently discontinue 
Myasthenia Gravis 
Check for ocular muscle and proximal muscle 
fatigability.  AChR and anti-MuSK antibodies 
Bedside tests, e.g. Tensilon test or ice pack test with 
neurological input.  Repetitive nerve stimulation and 
single ﬁbre EMG 
 
Steroids indicated (oral or i.v. depending on 
symptoms).  Pyridostigmine initial dose 30 mg tds.  
If no improvement or worsening, plasmapheresis or 
IVIG may be considered 
Additional immunosuppressants azathioprine, 
cyclosporine, mycophenolate 
Avoid certain medications, e.g. ciproﬂoxacin, beta-
blockers, that may precipitate cholinergic crisis 
 
Neurological consult 
 
Permanently discontinue 
Requirement for 10 mg per 
day or greater prednisone or 
equivalent for more than 12 
weeks 
Permanently discontinue 
Persistent Grade 2 or 3 
adverse event lasting 12 weeks 
or longer 
Permanently discontinue 
a 
Resume treatment when adverse reaction improves to Grade 0 or 1 
b 
Other immunosuppressive treatment options – MMF 500-1000 mg bid or tacrolimus 
c 
Withhold dose until symptoms resolve and any steroid treatment is complete.  Treatment should be continued in the presence of 
hormone replacement therapy as long as no symptoms are present 


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Appendix H Abbreviations 
Abbreviation or special 
term 
Explanation 
AE 
Adverse Event 
AUC 
Area under the concentration-time curve 
BOR 
Best Overall Response 
CCA 
Cholangiocarcinoma 
Cmax 
Maximum plasma concentration 
Cmin 
Minimum observed plasma concentration 
CR 
Complete response 
CRC 
Colorectal cancer 
CRO 
Contract Research Organisation 
CSR 
Clinical Study Report 
CT 
Clinical Trial 
CTCAE 
Common Terminology Criteria for Adverse Events (National Cancer Institute) 
DBL 
Data Base Lock 
DCO 
Data Cut Off 
DILI 
Drug-induced liver injury 
DLT 
Dose-limiting toxicity 
DNA 
deoxyribonucleic acid  
EC 
Ethics Committee, synonymous to Institutional Review Board (IRB) and 
Independent Ethics Committee (IEC) 
ECG 
Electrocardiogram 
eCRF 
electronic Case Report Form 
ESMO 
European Society for Medical Oncology 
EU 
European Union 
FDA 
U.S. Food and Drug Administration 
 
 
FSI 
First Subject In 
Fz 
Frizzled  
GCP 
Good Clinical Practice 
IB 
Investigator’s Brochure 
IC50 
Half maximal inhibitory concentration 
ICF 
Informed Consent Form 
IRT 
Interactive response technology 
LoF 
Loss of function 
LRP 
low-density lipoprotein receptor-related protein 
CCI
CCI


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Abbreviation or special 
term 
Explanation 
mCRC 
Metastatic colorectal cancer 
MSI-H 
Microsatellite instability high 
MSS 
Microsatellite stable 
NCCN 
National Comprehensive Cancer Network 
PD-1 
Programmed death receptor 1 
PDAC 
Pancreatic ductal adenocarcinoma 
PI 
Principal Investigator  
PORCN 
Porcupines 
PR 
Partial response 
QoL 
Quality of life 
RECIST 
Response Evaluation Criteria In Solid Tumours 
RNF43 
Ring finger protein 43 
RSPO 
R-Spondin 
SAE 
Serious Adverse Event  
SAP 
Statistical Analysis Plan 
SD 
Stable disease 
SmPC 
Summary of Product Characteristics 
SoA 
Schedule of Assessments 
SOC 
Standard of Care 
SRC 
Safety Review Committee 
TEAE 
Treatment-emergent adverse event 
TRAE 
Treatment-related adverse event 
TSH 
Thyroid-stimulating hormone 
 


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Appendix I 
Dysgeusia treatment guidelines 
As there are no recognised standard international guidelines for the management of this 
multifactorial event, investigators are advised to consult their local practice guidelines for the 
management of dysgeusia. Please refer to Table 14 and Section 6.6 for instructions on dose 
reductions and interruptions for dysgeusia. 
Some interventions may be effective in treating dysgeusia: 
• Treatment with oral pilocarpine and artificial saliva may help in cases where there is also dry 
mouth 
• Zinc supplements may help in cases where there is evidence of zinc deficiency 
• Alpha lipoic acid is an antioxidant capsule supplement which may improve flavour sensation 
• Good oral hygiene and chlorhexidine (or similar) mouthwashes 
 
Patients may be advised of some ways that they can manage dysgeusia, for example: 
• Cooking or eating food in non-metallic cookware 
• Avoiding foods that taste bitter or metallic 
• Flavouring foods with seasonings and spices 
• Eating food cold may help to reduce unpleasant flavour sensations 
• Frequently brushing teeth 
• Rinsing with mouth wash regularly 
• Using chewing gum. Lozenges or mints to stimulate saliva production 
 
A dysgeusia treatment algorithm has been developed by Sevryugin et al 2021 based on their 
review of published studies of dysgeusia interventions and is included to assist investigators 
with the management of dysgeusia that occurs during treatment with RXC004.  However, it is 
acknowledged that not all of the management suggestions may be readily available or 
applicable to patients in this study. 


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Figure from Sevryugin et al 2021 


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Appendix J 
Management of Colitis Events 
In the Phase 1 study of RXC004, events of colitis or enteritis were reported in 4 patients who 
commenced treatment at doses of 3 mg QD or 10 mg QD as a monotherapy. One event of 
ileitis has also been reported to date in this study.  
RXC004-related diarrhoea/colitis may present as abdominal pain with other symptoms 
including intermittent constipation, diarrhoea, nausea and/or vomiting. In some cases, 
symptoms may be minimal.  Blood and mucus in the stool may not be apparent. 
Symptoms may be preceded by or accompanied by a raised CRP and neutrophil count.  
If lower GI tract inflammation is suspected, infectious and other causes should be excluded, 
including CMV and C .difficile.  Attempts should be made to definitively diagnose the 
condition with a CT scan, and colonoscopy/sigmoidoscopy with biopsy, if clinically safe to do 
so. 
Nivolumab is known to cause Colitis (See Appendix G) so patients receiving the combination 
of RXC004 and nivolumab may be at higher risk of this event. These guidelines are consistent 
with guidance for nivolumab-related colitis. However, for patients who are receiving RXC004 
plus nivolumab, please also refer to the most current version of the nivolumab SPC/USPI. 
Management:  
Monitoring of CRP or fecal calprotectin levels may help to monitor the response to treatment.  
Table 20 
Management of colitis events 
Grade 
Management 
Grade 1 colitis 
[asymptomatic but evidence 
on CT scan] 
 
Continue RXC004 at a lower dose and repeat the CT scan 
within 4 weeks. 
No action is needed for nivolumab.  
No additional treatment is indicated. If the Grade 1 colitis is 
evident on the second scan despite the lower dose of 
RXC004, it should be managed as Grade 2 colitis and the 
scan should be repeated within 4 weeks. 
Grade 2 colitis [abdominal 
pain, mucus or blood in 
stool] 
Pause RXC004 (and nivolumab if applicable) 
Manage with corticosteroids at a dose of 0.5 mg/kg 
methylprednisolone equivalent. 
When symptoms have resolved, taper over 2-4 weeks. 


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Grade 
Management 
If symptoms recur during tapering, the steroid dose may 
need to be increased again.   
If no improvement in 72 hrs despite treatment, treat as 
Grade 3 
RXC004 can be restarted at a lower dose after colitis has 
resolved to Grade ≤ 1* and steroids tapered to physiological 
levels (<10 mg prednisone per day equivalent dose) over at 
least 1 month. 
If steroids cannot be tapered to physiological levels within 
12 weeks of commencing steroid treatment, then RXC004 
(and nivolumab if applicable) should be permanently 
discontinued. 
Grade 3 colitis [ severe or 
persistent abdominal pain, 
fever, ileus; peritoneal 
signs] 
Pause RXC004 (and nivolumab, if applicable) 
Seek specialist advice 
Manage with corticosteroids at a dose of 1 mg/kg 
methylprednisolone equivalent.   
When symptoms improve, taper steroids to physiological 
levels over 4-8 weeks and consider use of prophylactic 
antibiotics and anti-fungals 
If the patient is receiving RXC004 as a monotherapy, 
RXC004 can be restarted at a lower dose after colitis has 
resolved to Grade ≤ 1* and steroids tapered to physiological 
levels (<10 mg prednisolone equivalent dose). If the 
patient is receiving RXC004 in combination with 
nivolumab, both agents should be permanently 
discontinued 
If steroids cannot be tapered to physiological levels within 
12 weeks of commencing steroid treatment, then RXC004 
(and nivolumab, if applicable) should be permanently 
discontinued. 
Additional anti-inflammatory medications (e.g infliximab) 
may be indicated if no improvement in 48-72hrs. It is 


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Grade 
Management 
important to rule out bowel perforation and refer to 
infliximab SMPC/USPI for general guidance before 
using infliximab 
If anti-inflammatories are required, RXC004 (and 
nivolumab, if applicable) should be permanently 
discontinued. 
Grade 4 colitis [life 
threatening consequences] 
Manage as per Grade 3 Colitis. 
RXC004 and nivolumab (if applicable) should be 
permanently discontinued. 
*Attempts should be made to confirm that the colitis has resolved to Grade ≤ 1 (e.g normalised CRP or fecal 
calprotectin if raised during event; GI appearance normalised on X ray/ CT or endoscopy) before restarting 
RXC004. 
 
If there is any recurrence of colitis ≥ Grade 2 after recommencing RXC004, RXC004 and 
nivolumab, if applicable should be permanently discontinued. 
 


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11 
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RNF43 Mutation Is Associated With Aggressive Tumor Biology Along With BRAF V600E 


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SAP_001.pdf: 
Cover page 
Document title: A Multi-arm, Phase II, Open-Label, Multicentre Study to Assess the 
Preliminary Efficacy of RXC004 in Monotherapy and in Combination with Nivolumab, in 
Patients with Ring Finger Protein 43 (RNF43) or R-spondin (RSPO) Aberrated, 
Metastatic, Microsatellite Stable, Colorectal Cancer who have Progressed following 
Therapy with Current Standard of Care 
NCT number: NCT04907539 
Date of the Document: 30 May 2024 


Parexel International 
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 Statistical Analysis Plan 
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Parexel International 
Redx Pharma Plc 
Clinical Study Protocol RXC004/0002 
 
 
A Multi-arm, Phase II, Open-Label, Multicentre Study to Assess the Preliminary Efficacy of 
RXC004 in Monotherapy and in Combination with Nivolumab, in Patients with Ring Finger Protein 
43 (RNF43) or R-spondin (RSPO) Aberrated, Metastatic, Microsatellite Stable, Colorectal Cancer 
who have Progressed following Therapy with Current Standard of Care 
 
 
 
 
 
Statistical Analysis Plan 
Version: 4.0 
 
 
 
 
 
 
 
Parexel Project Number: 253582 
 
 


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SPONSOR SIGNATURE PAGE 
 
This document has been approved and signed electronically by the following: 
 
 
 
 
 
 
 
 
Signatory 
Reviewer 
 
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ole: 
 
 
  
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Parexel SIGNATURE PAGE 
Signatures below confirm that the Statistical Analysis Plan was developed in accordance with SOP-
GDO-WW-019 and that it is approved for release. 
This document has been approved and signed electronically by the following: 
 
 
 
 
 
 
Signatory 
Author 
 
Project Role: 
 
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TABLE OF CONTENTS 
1 
INTRODUCTION .................................................................................................................... 11 
2 
STUDY OBJECTIVES ............................................................................................................ 12 
3 
INVESTIGATIONAL PLAN................................................................................................... 13 
3.1 
Overall Study Design and Plan ........................................................................................ 13 
3.2 
Endpoints and Associated Variables ............................................................................... 14 
3.2.1 
Efficacy Variables ....................................................................................................... 14 
3.2.1.1 Best Overall Response (BOR) .................................................................................... 15 
3.2.1.2 Objective Response Rate (ORR) ................................................................................ 16 
3.2.1.3 Disease Control Rate (DCR) ....................................................................................... 16 
3.2.1.4 Percentage change in the sum of target lesions .......................................................... 16 
3.2.1.5 Progression Free Survival (PFS) ................................................................................. 17 
3.2.1.6 Overall Survival (OS) ................................................................................................. 17 
3.2.2 
Pharmacokinetic/Pharmacodynamic Variables .......................................................... 17 
3.2.3 
Safety Variables .......................................................................................................... 17 
3.2.4 
Exploratory Variables ................................................................................................. 18 
4 
STATISTICAL METHODS..................................................................................................... 18 
4.1 
Data Quality Assurance ................................................................................................... 18 
4.2 
General Presentation Considerations ............................................................................... 18 
4.2.1 
Study Days .................................................................................................................. 18 
4.2.2 
Visit Windowing ......................................................................................................... 18 
4.2.3 
Definition of Baseline and Post-baseline Assessments .............................................. 19 
4.2.4 
End of Study (EoS) ..................................................................................................... 20 
4.2.5 
Data Listings ............................................................................................................... 20 
4.2.6 
Data summaries ........................................................................................................... 21 
4.2.7 
Figures ........................................................................................................................ 21 
4.2.8 
Handling of Dropouts or Missing Data ....................................................................... 21 
4.2.9 
Analysis Conventions ................................................................................................. 21 
4.3 
Software 22 
4.4 
Study Patients .................................................................................................................. 22 
4.4.1 
Disposition of Patients ................................................................................................ 22 
4.4.2 
Protocol Deviations ..................................................................................................... 22 
4.5 
Analysis Sets.................................................................................................................... 23 
4.6 
Demographics and Baseline Characteristics .................................................................... 23 
4.7 
Medical History and Surgical History ............................................................................. 24 
4.8 
Prior and Concomitant Medications ................................................................................ 25 
4.9 
Prior and Concomitant Radiotherapy and Procedure ...................................................... 27 
4.10 Extent of Exposure .......................................................................................................... 27 
4.10.1 
RXC004 ...................................................................................................................... 27 


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4.10.2 
Nivolumab .................................................................................................................. 28 
4.11 Efficacy Evaluation ......................................................................................................... 29 
4.11.1 
Analysis and Data Conventions .................................................................................. 29 
4.11.1.1 Multi-centre Studies .................................................................................................... 29 
4.11.1.2 Adjustments for Covariates ........................................................................................ 29 
4.11.1.3 Handling of Dropouts or Missing Data ....................................................................... 29 
4.11.1.4 Multiple Comparisons/Multiplicity ............................................................................ 29 
4.11.1.5 Interim Analyses ......................................................................................................... 29 
4.11.1.6 Examination of Subgroups .......................................................................................... 29 
4.11.2 
Primary Efficacy Variable(s) ...................................................................................... 30 
4.11.2.1 Disease Control Rate (DCR) ....................................................................................... 30 
4.11.2.2 Objective Response Rate (ORR) ................................................................................ 30 
4.11.3 
Secondary Efficacy Variables ..................................................................................... 30 
4.11.3.1 Percentage change in sum of target lesions ................................................................ 31 
4.11.3.2 Progression Free Survival (PFS) ................................................................................. 31 
4.11.3.3 Overall Survival .......................................................................................................... 32 
4.11.4 
Pharmacokinetics/Pharmacodynamic ......................................................................... 32 
4.12 Safety Evaluation ............................................................................................................. 32 
4.12.1 
Adverse Events ........................................................................................................... 32 
4.12.2 
Dysgeusia .................................................................................................................... 35 
4.12.3 
Clinical Laboratory Evaluation ................................................................................... 35 
4.12.4 
Vital Signs, Physical Examinations and Other Observations Related to Safety ........ 36 
4.12.4.1 Vital Signs ................................................................................................................... 36 
4.12.4.1
 ............................................................................. 37 
4.12.4.2 Electrocardiograms (ECG) ......................................................................................... 37 
4.12.4.3 Performance Status ..................................................................................................... 38 
4.12.4.4 Bones Evaluation ........................................................................................................ 39 
4.12.4.5 Physical Examination ................................................................................................. 39 
4.12.5 
Safety Monitoring Committee .................................................................................... 39 
4.13 Exploratory Objectives .................................................................................................... 40 
4.14 Determination of Sample Size ......................................................................................... 40 
4.15 Changes in the Conduct of the Study or Planned Analysis ............................................. 40 
5 
REFERENCES ......................................................................................................................... 42 
6 
APPENDICES .......................................................................................................................... 44 
6.1 
Anti-Tumour Activity assessment ................................................................................... 44 
6.1.1 
Target Lesions (TLs) assessment ................................................................................ 45 
6.1.2 
Non-Target Lesions (NTLs) assessment ..................................................................... 45 
6.1.3 
New Lesions (NLs) assessment .................................................................................. 46 
6.1.4 
Overall Response (OR) ............................................................................................... 46 
6.2 
Summary of treatment arms to be considered for each endpoint .................................... 48 
 
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TABLE OF FIGURES 
Figure 1 - Overall Design................................................................................................................... 14 
 
TABLE OF TABLES 
Table 1 – Determination of Best Overall Response (RECIST 1.1 BOR determination in trials where 
confirmation of complete or partial response is required) ......................................... 15 
Table 2 – Vital Sign Criteria for Abnormalities ................................................................................ 37 
Table 3 - Time point response: patients with target (+/–non-target) disease ..................................... 46 
 
 


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REVISION HISTORY 
Version No. 
Effective Date 
Summary of Change(s) 
1.0 
25-Mar-2021 
New document 
2.0  
25-Jan-2022 
SMC meeting 
Revision of Adverse Events section (Outputs added, AEPI, 
Dysgeusia assessment) 
Add Bones evaluation 
Add eDISH plots  
Add Dysgeusia evaluation 
3.0 
21-Sep-2023 
Revision of Evaluable Set definition 
Add new variables in Baseline Characteristics 
Revision of RDI definitions 
Revision of sorting rules for AEs and ConMeds 
Add 
Add 
 analysis 
4.0 
24-May-2024 
Revision Objectives endpoints definition 
Revision Evaluable Set definition 
Revision Concomitant Medications imputation rules 
Add 
 im
 imputation rules 
Add Labs BLQ rules 
 
 
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LIST OF ABBREVIATIONS 
List and define all acronyms and abbreviations used in the document here.  Abbreviations should be 
spelled out in full and the abbreviation indicated in parentheses at first appearance in the text.  
Abbreviations should appear in alphabetical order. 
Abbreviation / Acronym 
Definition / Expansion 
AE 
Adverse event 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Transaminase 
AST 
Aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
AUC 
Area under the concentration-time curve 
AUC(0-inf)  
AUC from time zero extrapolated to infinity 
BMI 
Body Mass Index 
BOR 
Best Overall Response 
C0 
Cycle 0 
CI 
Confidence Interval 
CL/F 
Apparent clearance following oral administration 
eCRF 
electronic Case Report Form 
Cmax 
Maximum observed concentration 
Cmin 
Minimum observed concentration in the dosing interval 
CR 
Complete Response 
CRC 
Colorectal Cancer 
CT 
Computerized Tomography 
DCO 
Data Cut-Off 
DCR 
Disease Control Rate 
DMC 
Data Monitoring Committee 
DNA 
Deoxyribonucleic acid 
DoR 
Duration of Response 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group Performance Status 
EoS 
End of Study 
FAS 
Full Analysis Set 


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Abbreviation / Acronym 
Definition / Expansion 
Hb 
Hemoglobin 
ICF 
Informed consent form 
ICH 
The International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use 
IMP 
Investigational Medicinal Product 
LDH 
Lactate Dehydrogenase 
LRV 
Lower Reference Value 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic Resonance Imaging 
MSS 
Microsatellite stable 
NE 
Not evaluable 
NLs 
New Lesions 
NTL 
Non-Target Lesions 
OR 
Overall Response 
ORR 
Objective Response Rate 
OS 
Overall Survival 
PD 
Progressive disease only use one abbrev, do not use 
pharmacodynamics or protocol deviation, spell those out 
PFS 
Progression Free Survival 
PK 
Pharmacokinetic 
PR 
Partial Response 
PT 
Preferred Term 
QT 
The QT interval is measured from the beginning of the QRS 
complex to the end of the T wave 
QTc 
Corrected QT interval 
QTcB 
QT corrected using Bazzett’s formula 
QTcF 
QT corrected using Fridericia’s formula 
RDI 
Relative Dose Intensity 
RECIST 
Response Evaluation Criteria in Solid Tumours 
RNF43 
Right Finger Protein 43 
RP2D 
Recommended Phase 2 Dose 
RSPO 
R-spondin 


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Abbreviation / Acronym 
Definition / Expansion 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
Stable disease, do not use standard deviation or single dose, spell 
those out, they are not frequently mentioned in this document 
SI 
System of Units 
SoA 
Schedule of Assessments 
SOC 
System Organ Class 
SLD 
Sum of Longest Diameters 
TEAE 
Treatment-emergent adverse event 
TFLs 
Tables/Figures/Listings 
TLs 
Target Lesions 
tmax 
Time corresponding to occurrence of Cmax 
TSH 
Thyroid Stimulating Hormone 
TTR 
Time To Response 
TV 
Target Value 
UK, UKN, UNKN 
Unknown 
VS 
Vital signs 
Vz/F 
Apparent volume of distribution during terminal phase 
WHO-DD 
World Health Organization - Drug Dictionary 
Wnt 
Wingless Int-1 (pathway) 
λz 
Terminal elimination rate constant 
 


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1 
INTRODUCTION 
The analyses described in this statistical analysis plan (SAP) are based upon the following study 
documents: 
• 
Study Protocol, Version 7.0 (19-Aug-2022) 
• 
electronic Case Report Form (eCRF), Version 3.0 (09-Jun-2022) 
The structure and content are based upon International Conference on Harmonization (ICH) 
requirements as detailed in ICH E3 – Structure and Content of Clinical Study Reports [8]. 
 
 
 
 
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2 
STUDY OBJECTIVES 
Objectives 
Endpoints 
Primary 
To assess the anti-tumour activity of 
RXC004 monotherapy and RXC004 + 
Nivolumab  
Monotherapy: Disease control rate (DCR) 
using each patients Best Overall Response 
(BOR) according to RECIST 1.1  
Combination: Objective response rate 
(ORR) using each patients BOR according 
to RECIST 1.1 
Secondary 
To further assess the preliminary efficacy of 
RXC004 monotherapy and RXC004 + 
Nivolumab  
% change in the sum of target lesions, 
duration of response (DoR), PFS, ORR 
(monotherapy) and DCR (combination) 
using investigator assessments according to 
RECIST 1.1 and OS 
To assess the PK of RXC004 in 
monotherapy and in combination with 
Nivolumab 
Maximum plasma concentration (Cmax) 
after Dose 1, Cmax at steady state, 
minimum observed plasma concentration 
(Cmin) at steady state as well as other 
relevant parameters (e.g. tmax, t½, λz, 
AUC0-∞, CL/F, and Vz/F) 
To assess the safety and tolerability profile 
of RXC004 monotherapy and RXC004 + 
Nivolumab combination 
Incidence of AEs SAEs, dose reductions, 
interruptions and discontinuation and 
assessment of dysgeusia 
Exploratory 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Page 13 of 48 
 
 
 
 
 
 
 
 
 
 
3 
INVESTIGATIONAL PLAN 
3.1 
Overall Study Design and Plan 
This is a Phase II, open label, multicentre, multi-arm, study to evaluate the preliminary efficacy and 
safety of RXC004 as monotherapy and in combination with Nivolumab in patients with Ring finger 
protein 43 (RNF43) or R-spondin (RSPO) aberrated, microsatellite stable (MSS) colorectal cancer 
(CRC), who have progressed following current standard of care treatment. 
The study is composed of two arms: 
• RXC004 monotherapy (arm A). 
• RXC004 in combination with Nivolumab (arm B).  
20 eligible patients will be enrolled in arm A and 20 eligible patients in arm B. 
The study will initially open with arm A. arm B will be opened once a recommended Phase II dose 
(RP2D) for RXC004 in combination with Nivolumab is established in the Phase I dose escalation 
study (NCI 03447470).  
Patients in arm A may be treated with RXC004 + Nivolumab if they have progressive disease on the 
8-week scan (a protocol amendment with RP2D details of RXC004 + Nivolumab will be required 
before the arm A combination treatment phase can be opened). 
The primary objective of the study is to assess the preliminary efficacy of each treatment arm, 
RXC004 monotherapy (arm A) and RXC004 + Nivolumab (arm B), based on an individual patient’s 
best overall response (BOR). Tumour assessment will be performed by Investigators every 8 weeks 
(± 1 week) (relative to the date of initiation of study treatment) for the first 56 weeks, and then 
every 12 weeks (± 1 week) until radiological progressive disease (PD) (as defined by Response 
Evaluation Criteria in Solid Tumours, version 1.1 [RECIST 1.1] [9]). The primary efficacy endpoint 
for RXC004 monotherapy is the disease control rate (DCR) (i.e. the proportion of patients who 
achieve complete response [CR], partial response [PR] or stable disease [SD]), and the primary 
efficacy endpoint for RXC004 + Nivolumab is the objective response rate (ORR) (i.e. the proportion 
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 Statistical Analysis Plan 
TP-GDO-WW-133-02 
CONFIDENTIAL 
Project Document Version No.4.0 
Effective Date:  26 Nov 19 
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of patients who achieve CR or PR). Following radiological progression, patients will be followed-up 
for safety and survival. The general study design is summarized in Figure 1. 
Figure 1 - Overall Design 
 
 
3.2 
Endpoints and Associated Variables 
3.2.1 Efficacy Variables 
The following variables will be used to evaluate efficacy endpoints: 
• In accordance with RECIST 1.1 guidelines (see Section 6.1):  
o ORR based on each patient’s BOR 
o DCR based on each patient’s BOR 
o Percentage change at each visit and best overall percentage change in the sum of target 
lesions  
o Duration of Response (DoR) 
o Progression Free Survival (PFS) 
o Time to Response (TTR) 
• Overall Survival (OS) 
In case the RECIST 1.1 assessment is done across several days: 
• The first day of assessment will be considered in case of PD as Overall Response (OR). 
• The last day of assessment will be considered in case of response (CR, PR or SD) as OR. 
CCI


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3.2.1.1 Best Overall Response (BOR) 
BOR is defined as the best OR recorded from the start of the study treatment until PD or death for 
each patient. In case the progression event is death, the BOR takes into account all data collected until 
the last evaluable RECIST assessment before death. Only OR provided by Investigators at each 
RECIST 1.1 visit will be considered for variables derivation and analyses (for details, see Section 6.1).  
Confirmation of response is required for declaring PR or CR as BOR. BOR is determined once all data 
on OR for the patient are known. BOR will be computed as the key efficacy variable to determine ORR 
and DCR. 
A confirmed response is defined as a CR or PR followed by a CR or PR a least 4 weeks later (see Table 
1 – Determination of Best Overall Response). A requirement for SD is that it should be met at least 
once no less than 8 weeks after the first dose of trial treatment/baseline assessment, otherwise the best 
response will be considered as not evaluable (NE) according to RECIST 1.1 guidelines. As the 
protocol allows a window of 1 week for the scan, a scan at least 7 weeks from start of treatment will 
be acceptable for SD. 
Table 1 – Determination of Best Overall Response (RECIST 1.1 BOR determination in trials where confirmation 
of complete or partial response is required) 
Overall 
response first 
time point 
Overall 
response 
subsequent time 
point (at least 4-
weeks after) 
Best Overall Response 
 
 
 
CR 
CR 
CR 
CR 
PR 
see footnote (*) 
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 
  
  
  
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, NE = not 
evaluable 


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(*) If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease 
meeting PR criteria relative to baseline, makes the disease PD at that point (since disease must have 
reappeared after CR). Best response would depend on whether minimum duration for SD was met. However, 
sometimes ‘CR’ may be claimed when subsequent scans suggest small lesions were likely still present and 
in fact the patient had PR, not CR at the first time point. Under these circumstances, the original CR should 
be changed to PR and the best response is PR. 
 
3.2.1.2 Objective Response Rate (ORR) 
ORR is defined as the proportion of patients with a BOR of CR or PR. Confirmation of response is 
required for declaring PR or CR as the BOR. ORR was set as primary efficacy endpoint for arm B and 
secondary efficacy endpoint for arm A.  Responses on subsequent treatments after discontinuing will not 
be included. 
3.2.1.3 Disease Control Rate (DCR) 
DCR is defined as the proportion of patients with a BOR of either CR, PR or SD for at least 16 weeks 
post-baseline (corresponding to SD for 2 scheduled scans post-baseline). As the protocol allows a window 
of 1 week for the scan, a time window of 1 week before the Week 16 visit will be applied such that any 
scan that is at least 15 weeks after starting treatment will be considered acceptable for the evaluation of 
response. DCR was set as primary efficacy endpoint for arm A and secondary efficacy endpoint for arm 
B. As an additional analysis, DCR will also be defined as the proportion of patients with a BOR of either 
CR, PR or SD for at least 8 weeks post-baseline (corresponding to SD for 1 scheduled scan post-baseline). 
As the protocol allows a window of 1 week for the scan, a time window of 1 week before the Week 8 visit 
will be applied such that any scan that is at least 7 weeks after starting treatment will be considered 
acceptable for the evaluation of response. 
 
3.2.1.4 Percentage change in the sum of target lesions 
Percentage change in sum of diameters of target lesions from baseline for patients with measurable disease, 
will be calculated for each RECIST assessment visit, as follows: 
Percentage change in the sum of target lesions (%) = (Σ observed value after baseline - Σ observed value 
at baseline) * 100 / Σ observed value at baseline 
Percentage change in sum of diameters of target lesions was set as a secondary efficacy endpoint for both 
arm A and arm B. 


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The best overall percentage change in the sum of target lesions (%), representing the largest decrease (or 
smallest increase in the absence of a decrease) from baseline, will also be considered as an efficacy 
endpoint. 
3.2.1.5 Progression Free Survival (PFS)  
PFS is defined as the time from first dose of study treatment (Day 1) until the date of disease progression 
or death (by any cause in the absence of progression), regardless whether the patient withdraws from the 
assigned study treatment or receives another anticancer prior to progression.  
Patients who have not progressed or died at the time of analysis will be censored at the time of the latest 
date of RECIST 1.1 assessment of their last evaluable scan, however if the patient progresses or dies after 
2 or more missed scheduled scanning visits (Progression/Death date - Last available scan date>=16 +1 
weeks), the patient will be censored at the time of their last evaluable scan prior to the missing scan visits. 
If the patient has no evaluable visits or does not have baseline data, they will be censored at 0 days. 
However, if the patient dies within 2 scan visits of first dose (within 16 +1 weeks from first dose date 
without a post baseline scan) then its death date will be treated as their progression date. PFS was set as 
secondary efficacy endpoint both for arm A and arm B, and PFS time is defined as: 
PFS (days) = Date of documented PD, Death or last RECIST 1.1 assessment – first dose of study 
treatment (C0D1) + 1 
3.2.1.6 Overall Survival (OS)  
OS is defined as the time from the first day of study treatment (Day 1) until death due to any cause. Any 
patient not known to have died at the time of analysis will be censored based on the last recorded date on 
which the patient was known to be alive. OS was set as secondary efficacy endpoint both for arm A and 
arm B, and OS time is defined as: 
OS (days) = Date of death or last contact – first dose of study treatment (C0D1) + 1 
 
3.2.2 Pharmacokinetic/Pharmacodynamic Variables 
 
3.2.3 Safety Variables 
The following safety variables will be evaluated: 
• AEs and SAEs 
• Dysgeusia 
• Vital signs 
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• Electrocardiogram (ECG) 
• ECOG performance status 
• Prior and concomitant medications 
• Clinical laboratory evaluation 
• Bones evaluation 
3.2.4 Exploratory Variables 
Methods for evaluation of 
 will be provided in a separate SAP. 
4 
STATISTICAL METHODS 
4.1 
Data Quality Assurance 
Tables/Figures/Listings (TFLs) to be included in the report will be independently checked for 
consistency, integrity and in accordance with standard Parexel procedures. 
4.2 
General Presentation Considerations 
All tables, listings, and graphs will be produced to landscape orientation using Courier New 9pt font 
and will be incorporated into a MS Word document as a rich text file (RTF) (margins on standard A4: 
Margins (top, left, right, and bottom) 2.54 cm. 
4.2.1 Study Days 
Screening will be conducted between Day -28 and Day -1. The first day of treatment will be Cycle 0 
- Day 1 (C0D1). When calculating AEs/ConMeds/etc timing days will be calculated relative to day 
1. 
For patients in arm A, who have radiologically progressed at Week 8 and move to RXC004 + 
Nivolumab, count of days will re-start from the day of the first of intake of the combination a new 
Cycle 1 with D1, as reported in the Schedule of Activities (SoA) (see protocol).   
4.2.2 Visit Windowing 
By visit summaries will be made considering the windows as below. The visit windowing is assessed 
relative to C1D1 date (not C0D1 due to delays between C0D1 and C1D1). 
C0D1 
C0D1  
C1D1 
(C1D1 - Day 8) 
Day 15 
(Day 9 - Day 21) 
Day 29 
(Day 22 - Day 42) 
Day 57 
(Day 43 - Day 70) 
CCI


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Day 85 
(Day 71 - Day 98) 
Day 113 
(Day 99 - Day 126) 
Day 141 
(Day 127 - Day 154) 
Day 169 
(Day 155 - Day 182) 
Day 197 
(Day 183 - Day 210) 
Day 225 
(Day 211 - Day 238) 
Day 253 
(Day 239 - Day 266) 
Day 281 
(Day 267 - Day 294) 
Day 309 
(Day 295 - Day 322) 
Day 337 
(Day 323 - Day 350) 
Day 365 
(Day 351 - Day 378) 
Day 393 
(Day 379 - Day 406) 
Day 421 
(Day 407 - Day 434) 
Day 449 
(Day 435 - Day 462) 
Day 477 
(Day 463 - Day 490) 
The following visits will not be remapped: Screening, IP Discontinuation, 30/90 Day Follow-up, 
Survival Follow-up. 
In case several visits occur into the same windows the following rule is to be applied:  
• For by-visit table, we will consider the mean of available assessments. 
• For Shift table, we will consider either Minimum or Maximum available value depending on 
the direction. 
4.2.3 Definition of Baseline and Post-baseline Assessments 
A baseline assessment will be defined as the last assessment performed prior to the first dose of study 
treatment (C0D1). While many of these assessments will be performed on the day of the first dose, 
others will be performed during screening. If a patient is missing an assessment typically performed 
on the day of the first dose, screening values may be substituted as baseline. 
Patients treated with RXC004 monotherapy (arm A) that radiologically progress as per RECIST1.1 
at the first ‘on treatment’ scan, may be treated with RXC004 + Nivolumab combination. Accordingly, 
the following groups of analyses have to be defined to clarify which patients and which information 
in arm A will be utilized: 
• Arm A (RXC004 monotherapy): this group will include information for all patients 
enrolled in arm A.  
•  Arm A1 (RXC004 monotherapy): this group will include information of all patients 
enrolled in Arm A who were on monotherapy throughout the study - ie. subjects who did 
not radiologically progressed at the first scan (week 8) or who radiologically progressed 


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at the first scan (week 8) but remained on monotherapy or who withdrew before the first 
scan.  
• Arm A2 (RXC004 + Nivolumab): this group will include information of patients enrolled 
in arm A who radiologically progressed at the first scan (Week 8) and then switch to 
receive combination therapy of RXC004 + Nivolumab either at Week 8 or later. The last 
scan before the switch to combination treatment will be set as the arm A2 baseline 
RECIST1.1 scan for the combination treatment. The date of the last scan before switching 
to combination treatment will also be used to determine the arm A2 baseline date for all 
the efficacy endpoints except OS. OS will keep the same baseline regardless of the 
progression. For assessments other than efficacy, Arm A2 summaries, will include data 
from start of monotherapy until end of combination treatment. 
• Arm B (RXC004 + Nivolumab): this group will include information on all patients 
enrolled in arm B. 
Some patients with symptomatically stable disease may continue treatment after the initial 
RECIST 1.1 - defined progression, until symptomatic/clinical progression or a second RECIST 1.1 
PD assessment (relative to the initial RECIST1.1 progression, for a given study treatment).  
Change from baseline is derived where both baseline and post-baseline values are available: 
• Absolute Change from baseline = post-baseline value – baseline value 
• Relative Change from baseline (%) = [(post-baseline value – baseline value) / baseline 
value] * 100  
 
4.2.4 End of Study (EoS) 
A participant is considered to have completed the study if he/she has completed all phases of the 
study (including the last visit and the last scheduled assessment shown in the SoA) or withdraws 
consent whichever occurs first. 
The end of the study is defined as the date of the last visit of the last participant in the study or the 
last scheduled assessment shown in the SoA for the last participant in the study before the data cut 
off (DCO). 


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4.2.5 Data Listings 
All listings will contain information both for arm A and arm B (arm A patients followed by arm B 
patients). Patients who change treatment in arm A after radiological progression at week 8 will be 
flagged.  
All listings will include scheduled and unscheduled measurements. All listings will display the same 
number of decimals as in the source data. All raw data will be reported exactly as provided.  
4.2.6 Data summaries 
Summaries will be presented as follows: 
• Arm A and arm B in the same table, as detailed described in the following sections. A 
separate set of tables and figures on selected endpoints will be done for arm A1 and/or 
arm A2. 
• No formal comparisons will be performed between arms. 
4.2.7 Figures 
Figures for efficacy evaluation will be produced as detailed in Section 4.11. In selected presentations 
where specified, figures presenting arm A, arm A1, arm A2 and arm B will be produced. For arm A1 
and arm A2, KM curves will be presented provided there enough data to make it meaningful to do 
so: at least 8 events. 
4.2.8 Handling of Dropouts or Missing Data 
There will be no imputation of missing data, unless otherwise stated. 
4.2.9 Analysis Conventions 
Continuous data will be summarized in terms of the mean, standard deviation, median, minimum, 
maximum and number of observations, unless otherwise stated. 
The minimum and maximum will be reported to the same number of decimal places as the raw data 
recorded in the database.  The mean and median, will be reported to one more decimal place than the 
raw data recorded in the database.  The standard deviation will be reported to two more decimal places 
than the raw data recorded in the database.  In general, the maximum number of decimal places 
reported shall be four for any summary statistic. 
Categorical data will be summarized in terms of the number of patients providing data at the relevant 
time point (n), frequency counts and percentages. Any planned collapsing of categories will be 
detailed in the SAP text and the data displays.   


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Percentages will be presented to one decimal place. Percentages will not be presented for zero counts.  
Percentages will be calculated using n as the denominator.   
Changes from baseline in categorical data will be summarized using shift tables where appropriate. 
Confidence intervals will be presented to one more decimal place than the raw data. 
4.3 
Software 
TFLs and any non-descriptive statistical analysis will be produced using SAS® Software (Version 9.3 
or higher). The REPORT procedure (SAS PROC REPORT) will be used to produce all table and 
listings; SAS/GRAPH will be used to produce all figures. 
4.4 
Study Patients  
4.4.1 Disposition of Patients  
A clear accounting of the disposition of all patients who enter the study will be provided from 
screening to study completion. 
The number of patients who were screened (who signed main study ICF), were exposed to study 
treatment, who completed the study or discontinued and primary reason for end of treatment will be 
summarized for arm A and arm B in the FAS. The number of patients in arm A who switch from 
monotherapy to combination therapy will also be summarized. The number of patients in arm A and 
arm B who remained on original treatment despite disease progression will also be presented. 
The patient disposition including the date the informed consent was signed, date of first/last intake of 
study drug and the primary reason for End of Treatment will be listed. 
A listing of patients included into each of the analysis set will be presented, related summary statistics 
will be provided. Patients who did not meet the eligibility criteria or were screen failures will also be 
listed.  
4.4.2 Protocol Deviations 
Deviations from the protocol including violations of inclusion/exclusion criteria will be assessed as 
“minor” or “major” in cooperation with the Sponsor in an ongoing manner during protocol deviation 
review meetings. Major protocol deviations are defined as those deviations from the protocol likely 
to have an impact on the perceived efficacy and/or safety of study treatments. Protocol deviations are 
defined in the project-specific Protocol Deviation Specification. Whether a protocol deviation results 
in exclusion from a particular analysis set will be detailed in the protocol deviation specification and 
documented in the supporting protocol deviation review document. 


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The number and percentage of patients with major protocol deviations will be summarized by type of 
deviation for arm A and arm B in the FAS. The summary will be done separately for major protocol 
deviations leading to exclusion from the evaluable set and the other major protocol deviations. All 
protocol deviations will be listed. 
4.5 
Analysis Sets 
A summary of the number of patients included in each analysis population described below will be 
provided for arm A and arm B. Percentage of subjects in the evaluable set will be calculated based 
on the full analysis set (FAS). 
A listing of patients included into each of the analysis set will be presented will be provided. The 
patients who did not meet the eligibility criteria or were screen failures will also be listed.  
• Full analysis set (FAS) / Safety analysis set: All patients who enrolled and received at 
least one dose of study drug (RXC004 in the case of the monotherapy arm and at least one 
of RXC004 or nivolumab in the combination arm). 
• 
 
 
 
 
 
 
 
• PK analysis set: All patients in the safety analysis set who have had at least 1 blood sample. 
4.6 
Demographics and Baseline Characteristics 
Demographic and Baseline characteristics will be summarized and listed for the FAS. 
Demographics will be summarized for arm A and arm B, including: 
• Age (years) 
• Gender (Male or Female) 
• Race (American Indian or Alaska Native, Asian, Black or African, American, Native 
Hawaiian or Other Pacific Islander, White, Other) 
• Ethnicity (Hispanic or Latino, Not Hispanic or Latino, Not Stated, Unknown) 
Baseline characteristics will be summarized for arm A and arm B, including: 
CCI
CCI
CCI
CCI
CCI
CCI
CCI


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• Weight (kg) 
• Height (only screening visit) (cm) 
• Body Mass Index (BMI) result (kg/m2) 
• ECOG PS at Study Entry 
• Stage at Study Entry 
• Primary Location 
• Cancer Classification (Histology) 
• Histological Grade 
• TNM status 
• MSI status 
• WNT pathway genetic aberration (LoF RNF43 mutation, RSPO2/3 Fusion, Wild Type, 
No Results Available) 
• PD-L1 Tumor proportion score: as continuous and categorical variable (<1%, >=1% - 
49%, >50%) 
• PD-L1 Immune proportion score: as continuous and categorical variable (<1%, >=1% - 
49%, >50%) 
• Site of Local/Metastatic Disease  
• Number of prior lines of cancer therapy and indications 
• Best response achieved for the most recent treatment  
• Time from last Disease Progression disease to first dose of Study Drug (weeks)* 
• Time from Initial Metastatic Diagnosis to first dose of Study Drug (Months)* 
• Time from last most recent Dose of prior therapy to first dose of Study Drug (weeks)* 
• Sum of target lesions at Baseline  
 
(*) In case, last disease progression date, initial metastatic diagnosis date or most recent dose prior 
therapy date is incomplete, the following imputation rules will be implemented: 
• UK-MMM-YYYY: Assume 01-MMM-YYYY.  
• UK-UKN-YYYY: If the year is prior to the year of first dose of study drug, assume 01-JUL-
YYYY of the collected year. Otherwise, no imputation. 
• UK-UKN- UNKN: No imputation. Duration will be considered as missing. 
 


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4.7 
Medical History and Surgical History  
Medical history and Surgical history as pre-specified in the Medical and Surgical history eCRF will 
be presented in the patient data listings.   
4.8 
Prior and Concomitant Medications 
Prior and concomitant medications will be coded using the World Health Organization - Drug 
Dictionary (WHO-DD) Version March 2023 and will be classified by Anatomical Therapeutic 
Chemical (ATC) categories. Prior medications will be defined as medications that stopped before the 
first dose of study drug and will be listed only.  
For the purpose of categorizing medications as prior or concomitant, incomplete medication start and 
stop dates will be imputed as follows: 
Missing start dates (where UK, UKN and UNKN indicate unknown or missing day, month and year 
respectively):  
• UK-MMM-YYYY: Assume 01-MMM-YYYY. If the month and year are the same as the first 
dose of study drug month and year, then assume the date of first dose of study drug; 
• UK-UKN-YYYY:  
o If the year is prior to the year of first dose of study drug, assume 01-JUL-YYYY of 
the collected year. If the end date is before 01-JUL-YYYY, assume the first day of the 
year. 
o If the year is the same as the first dose of study drug year, then assume the date of first 
dose of study drug. If the End Date occurs before the first dose of study drug, then 
assume the first day of the year.  
o If the year is after the first dose of study drug year, then assume the first day of the 
year. 
• UK-UKN- UNKN: Assume date of first dose of study drug. In case end date is before first 
dose of study drug, assume the first day of the year of the CM end date. 
Missing stop dates for concomitant medications data will be handled as follows (where UK, UKN 
and UNKN indicate unknown or missing day, month and year respectively):  
• UK-MMM-YYYY: Assume the last day of the month; 
• UK-UKN-YYYY: Assume 31-DEC-YYYY; 
• UK-UKN- UNKN: Assume ongoing and leave it missing. 
Medications will be categorized as follows: 


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Medication start and stop dates will be compared to the date of first dose of study medication to allow 
medications to be classified as either Prior or Concomitant.   
Medications and treatments administered prior to the Investigational Medicinal Product (IMP) intake 
which stopped prior to IMP intake will be considered as prior medications. Medications and 
treatments which started before, on or after the IMP intake and which stopped after IMP intake of 
study drug (including medications and treatments which stopped the day of the IMP intake) will be 
considered as concomitant medications. If medication start and/or stop dates are missing or partial, 
the dates will be compared as far as possible with the date of IMP dosing. Medications will be 
assumed to be concomitant, unless there is clear evidence (through comparison of partial dates) to 
suggest that the medication stopped prior to the IMP dosing. If there is clear evidence to suggest that 
the medication stopped prior to the IMP dosing, the medication will be assumed to be Prior. 
Medications and treatments with a start date after the last dose of IMP will be considered as post-
study medication and will not be considered as concomitant medications. 
Concomitant medications will be analysed for arm A and arm B for the FAS.  
The number (n) and percentage (%) of patients taking concomitant medications will be summarized 
by ATC classification and Preferred Name. ATC Level 1 will be sorted by alphabetical order. 
Preferred Names, within each ATC Level 1, will be sorted by descending frequency of the total 
frequency. In the event of Preferred Names with equal total frequencies, the relevant Preferred Names 
will be sorted alphabetically. Similarly, if a patient reported more than one concomitant or post-
treatment medication within the same primary ATC Level 1, the patient will be counted only once.   
Prior and concomitant medications (ATC Level 1/ Preferred Name), dose, frequency and route, 
start/stop date (or ongoing) and type of indication as specified in the eCRF with medication category 
(Prior or Concomitant) will be presented in the by- patient data listing for FAS. 
Additional summaries and listing will be created specifically for Prior anti-cancer therapies.  
 
 


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4.9 
Prior and Concomitant Radiotherapy and Procedure 
Prior and concomitant radiotherapy will be summarized and listed for the FAS. 
The following prior radiotherapy variables will be described: 
• Number of patients having a history of radiotherapy 
• Intent of prior radiotherapy 
• Sites of prior radiotherapy 
The following concomitant radiotherapy variables will be described: 
• Number of patients having a concomitant radiotherapy 
• Intent of concomitant radiotherapy 
• Sites of concomitant radiotherapy 
Concomitant procedure will be listed for the FAS. 
 
4.10 Extent of Exposure 
FAS population set will be considered for the analysis. Extent of exposure will be summarized for 
arm A and arm B. The below derived parameters will be listed by arm and patient. 
4.10.1 RXC004 
Duration and compliance of the RXC004 exposure will be assessed by computing the following 
variables:  
• Number of cycles and number of doses per patient 
• RXC004 Duration of treatment (weeks) = (Date of last dose – Date of first dose + 1) / 7 
• Cumulative dose (mg) = Sum of all doses administered 
• RXC0004 RDI (%) = [Cumulative dose received (mg) / (RXC004 Duration of treatment 
(days) * 2mg)] * 100, for Arm A  
• RXC0004 RDI (%) = [Cumulative dose received (mg) / (RXC004 Duration of treatment 
(days) * 1.5mg)] * 100, for Arm A combination and Arm B  
For switching patients in arm A, RXC0004 RDI for Arm A combination should be considered from 
the start of the combination. 
 
• Number of patients with dose reduced and reason for reduction 
• Number of patients with dose interrupted and reason for interruption 


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Duration of the RXC004 duration, and Cumulative dose will be summarized as continuous variables. 
RDI will be summarized as continuous variable and by categories:] - ; 60%[, [60% ; 75%[, [75% ; 
90%[, [90% ; 100%], ] 100% ; + [).  
The number of patients who had dose reductions will be summarized by categories: (Any, 1, 2 times). 
Another summary will be produced excluding treatment cycles after the progression for the patients 
who remain on treatment despite PD. A swimmer plot will be produced presenting the duration of 
treatment. A tag will show the first PD and when patients achieve response. For the patients in arm 
A who switched to combination, a different colour will be used for the monotherapy and the 
combination treatment. Swimmer plots will be presented separately for arm A and arm B 
4.10.2 Nivolumab 
 
Duration and compliance of the Nivolumab exposure will be assessed by computing the following 
variables:  
• Number of cycles and number of doses per patient 
• Nivolumab Duration of treatment (weeks) = (Date of last dose – Date of first dose + 28) / 
7 
• Cumulative dose (mg) = Sum of all doses administered 
• Nivolumab RDI (%) = [(Cumulative dose received (mg) * 4 (weeks)) / (Nivolumab 
Duration of treatment (weeks) * 480 (mg))] * 100 
• Number of patients with dose interruption and reasons for interruption 
• Number of patients with dose delay and reasons for delay 
Duration of the Nivolumab duration, and Cumulative dose will be summarized as continuous 
variables. RDI will be summarized as continuous variable and by categories:] - ; 60%[, [60% ; 75%[, 
[75% ; 90%[, [90% ; 100%], ] 100% ; + [).  
The number of patients who had dose reduction/delay will be summarized by categories: (Any, 1, 2, 
3+ times). 
Another summary will be produced excluding treatment cycles after the progression for the patients 
that remain on treatment despite PD.  


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4.11 Efficacy Evaluation 
4.11.1 Analysis and Data Conventions 
The statistical hypotheses for testing the activity of monotherapy and the combination independently 
are: 
H0: p≤p0 
H1: p≥p1 
Where H0 is the null hypothesis, p is the observed response rate, p0 is the response rate for available 
treatment options – 
, , H1 is the alternative hypothesis and p1 is the target 
response rate – 
. . For RXC004 monotherapy the primary summary measure is the 
DCR and the corresponding p0 and p1 are 
% and 
%. For the combination of RXC004 and 
nivolumab the primary summary measure is the ORR and the corresponding p0 and p1 are 
% and 
%. 
4.11.1.1 Multi-centre Studies 
There will not be any adjustment for study centres, subgroup analysis based on study centres are not 
planned. 
4.11.1.2 Adjustments for Covariates 
No statistical model will be provided for the analysis of study endpoints.  
4.11.1.3 Handling of Dropouts or Missing Data 
Missing data will not be imputed.   
4.11.1.4 Multiple Comparisons/Multiplicity 
Not applicable in this study. 
4.11.1.5 Interim Analyses 
There is no formal interim analysis planned 
4.11.1.6 Examination of Subgroups 
Not applicable in this study.  
 
 
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4.11.2 Primary Efficacy Variable(s)  
All primary efficacy analyses will be conducted on the evaluable set.  
Primary objective of study will consider the overall tumour response provided by Investigators. A 
listing containing information on target, non-target lesions, new lesions, overall response will be 
provided (ordered by arm, patient and visit). 
4.11.2.1 Disease Control Rate (DCR)  
The definition of DCR is provided in Section 3.2.1.3. DCR will be based on a individuals BOR using 
investigator RECIST 1.1 assessment. DCR is set as primary efficacy endpoint for arm A and 
secondary efficacy endpoint for arm B.  
DCR and associated 90% confidence intervals (CIs), calculated using the Clopper Pearson method, 
will be summarized for arm A and arm B. For arm A, the patients who switched due to progression 
at first scan will be considered as having progressed. In addition, DCR will be summarized for arm 
A2 patients. 
DCR will be listed for all patients in the evaluable set. 
As an additional analysis, this analysis will be repeated considering the definition detailed in section 
3.2.1.3. 
4.11.2.2 Objective Response Rate (ORR)  
Definition of ORR is provided in Section 3.2.1.3. ORR will be based on a individuals BOR using 
investigator RECIST 1.1 assessment. ORR is set as primary efficacy endpoint for arm B and 
secondary efficacy endpoint for arm A.  
ORR and associated 90% CIs, calculated using the Clopper Pearson method, will be summarized for 
arm A and arm B. For arm A, the patients who switched due to progression at first scan will be 
considered as having progressed. In addition, ORR will be summarized for arm A2 patients. 
BOR will be listed for all patients in the evaluable set 
4.11.3 Secondary Efficacy Variables 
All secondary efficacy analyses will be conducted on the FAS and, where appropriate, on the 
evaluable set. 
 
 


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4.11.3.1 Percentage change in sum of target lesions 
The % change in sum of target lesions is defined in Section 3.2.1.4 .  
Percentage change in tumour size will be derived at each visit by the percentage change from 
baseline in the sum of diameters of target lesions will be provided for arm A and arm B. It will also 
be summarized for arm A2.  
In arm A and arm B, % change in sum of target lesions will be always computed considering screening 
sum of diameters as baseline. For patients in cluster arm A2, % change in sum of target lesion will be 
computed considering as reference the sum of diameters computed at Week 8. In case some individual 
lesions are not measured, the whole sum of target lesions will be considered as missing. 
Percentage change in tumour size will be listed per visit for all patients in FAS. 
The best percentage change in tumour size will be the patients value representing the largest decrease 
(or smallest increase) from baseline in tumour size.  
A waterfall-plot will be produced to report the best % change in sum of target lesions for each patient 
(considering the minimum observed value) ordered by largest increase to greatest decrease. In 
addition, two waterfall-plot will be produced to report the % change in sum of target lesions at Week 8 
and Week 16. Best overall responses (BOR) will be highlighted for each patient. The figure will be 
repeated considering RNF43 and RSPO2/3 Status instead of BOR. 
A Spider-plot will be drawn to describe the % change in sum of target lesion. Vertical axis will 
represent the % change in sum of target lesions (% change in tumour size) while the horizontal axis 
will represent days from screening, as follows: 
day (x-axis) = date of RECIST 1.1 assessment – first dose of study treatment (C0D1) 
Best overall responses (BOR) will be highlighted for each patient. The figure will be repeated 
considering RNF43 and RSPO2/3 Status instead of BOR. 
All plots will be provided for the FAS separately for arm A, arm A2 and arm B.  The spider plot for 
A2 will still use the original baseline to week 8 so it is clear what the changes were when the patient 
switched to the combination. 
4.11.3.2 Progression Free Survival (PFS) 
PFS is defined in Section 3.2.1.5.  
Kaplan-Meier analyses will be conducted for arm A and arm B (in the same plot) and separately for 
arm A2. For arm A, the patients who switched due to progression at first scan will be considered as 
having progressed. Survival plots will be produced to present Kaplan-Meier estimated curves. In 


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addition, the following parameters estimated from the Kaplan-Meier curves will be provided for each 
group: 
• median PFS and corresponding 95% CIs  
• PFS rate at 3, 6 and 12 months and corresponding 95% CIs (one month = 30.4375 days). 
PFS will be listed for all patients in the FAS. 
4.11.3.3 
Overall Survival 
OS is defined in Section 3.2.1.6.  
Kaplan-Meier analyses will be conducted for arm A and arm B (in the same plot) and separately for 
arm A2. Survival plots will be produced to present Kaplan-Meier estimated curves.  
OS will be listed for all patients in the FAS. 
 
4.11.4 Pharmacokinetics/Pharmacodynamic 
 
4.12 Safety Evaluation 
Safety summaries and analyses will be based on the FAS.  
4.12.1 Adverse Events 
Adverse Events will be collected from time of signature of informed consent form throughout the 
treatment period and until 30 days after the last dose of RXC004 (for patients treated with RXC004 
monotherapy only) or 90 days after the last dose of Nivolumab (for patients treated with RXC004 
and Nivolumab). 
SAEs will be recorded from the time of signing of informed consent form until the follow-up period 
is completed: 30 days after the last dose of RXC004 (for patients treated with RXC004 monotherapy 
only) or 90 days after the last dose of Nivolumab (for patients treated with RXC004 and Nivolumab).  
The following variables will be collected for each AE: 
• AE (verbatim) 
• Start/Stop date  
• CTCAE grade at onset and grade changes 
• Seriousness 
• Investigator causality rating against the Investigational Product(s)  
• Action taken with regard to Investigational Product(s) 
• Action taken with regards to AE 
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• Outcome 
In addition, the following variables will be collected for SAEs: 
• Date AE met criteria for SAE 
• Date investigator became aware of SAE 
• Hospitalisation  
• Life Threatening 
• Congenital Anomaly or Birth Defect 
• Disability or Permanent Damage 
• Other Medically Important Serious Event 
• Date of hospitalisation 
• Date of discharge 
• Causality assessment in relation to Study procedure(s) 
• Causality assessment to other medication 
Partially complete AE dates will not be imputed in the listings and the available day, month and year 
components will be used to determine if an adverse event is treatment- emergent taking the first 
dosing date last treatment date as references.  
More specifically: 
• Start date of AE missing: Assumed to be date of first treatment dose. 
• Start day and month of AE missing: Assumed to be date of first treatment dose (if same 
year for both dates), January 1st otherwise. 
• Start day of AE missing: Assumed to be date of first treatment dose (if same month and 
year for both dates), first day of the month otherwise. 
• End date for non-ongoing AE missing: Assumed to date of last treatment dose 
• End day and month for non-ongoing AE missing: Assumed to be date of last treatment 
dose (if same year for both dates), December 31st otherwise. 
• End day for non-ongoing AE missing: Assumed to be date of last treatment dose (if same 
month and year for both dates), last day of the month otherwise. 
Explain if first use TEAEs with missing relationship to the study drug will be considered as related. 
AEs will be coded using the MedDRA, latest version. Grading will be performed using CTCAE 
version 5.0. 


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TEAEs are defined as those AEs with an onset after dosing and those pre-existing AEs that worsen 
after the start of dosing and within 30 days of stopping RXC004 monotherapy or 90 days after the 
last actual Nivolumab dose (for patients on RXC004 and Nivolumab combination). 
An overview table of TEAEs will be provided showing the number of patients, the percentage of 
patients and the number of events for the following categories of events:  
• Any TEAE  
• Any treatment related TEAE to RXC004 
• Any treatment related TEAE to Nivolumab 
• Any grade >= 3 TEAE 
• Any grade >= 3 TEAE related to RXC004 
• Any grade >= 3 TEAE related to Nivolumab 
• Any serious TEAE (STEAE) 
• Any serious TEAE related to RXC004 
• Any serious TEAE related to Nivolumab 
• Any TEAE leading to death 
• Any TEAE leading to permanent discontinuation or reduction or interruption of RXC004 
• Any TEAE leading to permanent discontinuation of RXC004 
• Any TEAEs leading to RXC004 reduction  
• Any TEAEs leading to RXC004 interruption  
• Any TEAE leading to permanent discontinuation or interruption of Nivolumab 
• Any TEAE leading to permanent discontinuation of Nivolumab 
• Any TEAEs leading to Nivolumab interruption 
For TEAEs, TEAEs considered related (RXC004 and Nivolumab), STEAEs, STEAEs considered 
related (RXC004 and Nivolumab), TEAEs leading to study treatment discontinuation, TEAEs leading 
to RXC004 reduction, TEAEs leading to RXC004 interruption, TEAEs leading to Nivolumab 
interruption, TEAEs by maximum grade, TEAEs with grade >=3, TEAEs with grade >=3 related to 
RXC004, TEAEs with grade >=3 related to Nivolumab, death, detailed tables will be created showing 
the number of patients who experienced at least one TEAE, the corresponding percentage of patients 
and the number of events by SOC and PT. 
SOC will be sorted by alphabetical order. PTs, within each SOC, will be sorted by descending order 
of total frequency. In the event of PTs with equal total frequencies, the relevant PTs will be sorted 


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alphabetically.. In addition, a table summarizing TEAEs by decreasing frequency of Preferred Terms 
will be produced for all TEAEs and TEAEs related to RXC004/Nivolumab. 
A table will also be produced showing the details for every patient that die (death date, cause of death 
etc…).  
Listing of all AEs (including non-treatment-emergent events) will be provided. This listing will be 
presented, ordered by arm and patient. It will include patient identifier, AE (SOC, PT, and verbatim 
term), date of onset, date of resolution, duration, maximum grade, seriousness, action taken, outcome 
and causality. A listing detailing the serious TEAEs will also be produced. 
TEAEs summaries will be conducted for arm A and arm B and separately for arm A1 and arm A2 (in 
the same table) as applicable. 
4.12.2 Dysgeusia 
Loss of taste (dysgeusia) is an on-target adverse event known to occur with porcupine inhibition. A 
taste assessment questionnaire will be performed at screening and at each study visit when patient 
reports dysgeusia. 
A bar-chart will present the worst answers to the main questions after screening and a separate one 
illustrating the worst answers on the way the taste is altered.  In the event a patient answering in both 
directions of ‘more sensitive’ or ‘loss’ then loss will be considered worse. A by-patient listing will 
also be provided. 
 
4.12.3 Clinical Laboratory Evaluation 
Blood samples for determination of clinical chemistry and haematology will be taken at the visits 
indicated in the SoA (see protocol). Additional safety samples may be collected if clinically indicated 
at the discretion of the investigator. The date, time of collection and results (values, units and 
reference ranges) will be recorded on the eCRF. 
The clinical chemistry and haematology will be performed at a local laboratory at or near to the 
investigator site. Sample tubes and sample sizes may vary depending on laboratory method used and 
routine practice at the site.  
 
In case of BLQ values (eg “<5”, “<100”) for some assessments, the following rule will be considered:  
- 
If less than 50% of the assessments (across patients) are BLQ such as “<XXX”, then “XXX/2” 
will be considered for summaries. 


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- 
If 50% or more than 50% of assessments (across patients) are BLQ such as “<XXX” then “0” 
will be considered for summaries. 
 
The following laboratory variables will be measured: 
• Haematology (whole blood): Haemoglobin (Hb), Lymphocytes (absolute count and %), 
Neutrophils (absolute count and %), Platelet count, Total white cell count. , . 
• Clinical Chemistry (serum or plasma): Albumin, Alanine transaminase (ALT), Alkaline 
phosphatase (ALP), Amylase (only for arm B), Aspartate transaminase (AST), Calcium, 
Calcium corrected, Creatinine, CRP, Glucose, Lactate dehydrogenase (LDH), Lipase (only 
for arm B), Magnesium, Phosphate, Potassium, Sodium, Total bilirubin, Urea.   .  
The original lab test units will be converted using the International System of Units (SI) [11].  
Laboratory test with numerical grading criteria in the NCI CTCAE v5.0 will be graded accordingly. 
Grade 0 will be assigned for all non-missing values not graded as 1 or higher. For laboratory tests 
where grades are not defined by CTCAE v5.0 results will be classified as low, normal or high based 
on laboratory normal ranges.  
The following summaries will be provided for all parameters for arm A and arm B: 
• A summary of results by assessment visit (as per SoA) 
• Shift tables will be provided for all parameters to compare a patient’s baseline laboratory 
grade relative to worst post-baseline grade (Low and/or High abnormal direction will be 
considered for each parameter).   
By-patient listing will be provided for all patient in FAS by arm and visit, including changes from 
baseline, grade and reference range. All values outside the clinical reference ranges will also be 
flagged in the data listings. The abnormal values will be flagged with ‘L’ for values below the lower 
limit of the clinical reference range and ‘H’ for values above the upper limit of the clinical reference 
range. In addition, box plots presenting the results per visit will be presented for each lab parameters. 
eDISH plots will also be produced to assess the liver toxicity. 
 
4.12.4 Vital Signs, Physical Examinations and Other Observations Related to Safety 
4.12.4.1 Vital Signs 
The following vital signs will be recorded at baseline and post-baseline visit: 
• Weight (kg) 
• Systolic blood pressure (in mmHg) 


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• Diastolic blood pressure (in mmHg) 
• Pulse rate (beats/minute) 
• Temperature (°C or °F) 
• Respiratory rate (breaths per minute) 
A shift table from baseline systolic blood pressure and diastolic blood to worst on-treatment results 
will be presented. The normal/abnormal classification will be made using the criteria defined in table 
below:  
Table 2 – Vital Sign Criteria for Abnormalities 
Vital Sign Criteria for 
Abnormalities 
Criteria for Abnormalities 
(any of the following situation) 
Systolic blood pressure 
- 
value <80 mmHg 
- 
value >129 mmHg  
Diastolic blood pressure 
- 
value <60 mmHg 
- 
value >80 mmHg 
 
Vital signs data and clinically relevant abnormalities in vital signs will also be listed. 
4.12.4.1 
 
Blood samples for 
 will be obtained from patients at timepoints specified in the SoA. Summary 
statistics of values and relative change from baseline by visit will be presented for 
or 
 values. 
By-patient listing will be provided for all patient in FAS by visit, including values and changes from 
baseline. 
4.12.4.2 Electrocardiograms (ECG) 
Triplicate 12-lead ECGs will be performed at timepoints as specified in the SoA (see protocol). ECGs 
should be obtained after the patient has been in a supine position for 5 minutes and recorded while 
the patient remains in that position. Mean QT intervals corrected for heart rate should be calculated 
using Fridericia's formula (QTcF). The following variables will be collected: 
• PR Interval (msec) 
• RR Interval (msec) 
• QRS Complex (msec) 
• QT Interval (msec) 
• QTcF interval (msec) 
 
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Mean of the 3 measures (considering 1 decimal) will be considered at each timepoint (Pre-dose, 1-
hour dose, 12-hour dose). 
 
ECGs will be performed 3 times and an overall evaluation will be provided, as follows: 
• Overall ECG evaluation (normal, abnormal – not clinically significant, abnormal – 
clinically significant) 
 
 
A shift table of baseline QTcF to worst on-treatment results will be presented. For rating the worst 
on-treatment value, the following categories will be used based on the varying degrees of abnormality 
above, in the order of least to most severe (top to bottom): 
• Missing result 
• <=450 msec (i.e. ‘normal’) 
• >450-<=480 msec 
• >480-<=500 msec 
• >500 msec 
Baseline QTcF will be the pre-dose value at baseline. Worst on-treatment QTcF will be the worst 
post-baseline all timepoints considered.   
All ECG parameters will be listed.  
4.12.4.3 Performance Status 
Eastern Cooperative Oncology Group (ECOG) Performance Status will be assessed at the times 
specified in the SoA based on the following (see protocol):  
0. Fully active; able to carry out all usual activities without restrictions  
1. Restricted in strenuous activity, but ambulatory and able to carry out light work or work of a 
sedentary nature (e.g. light housework or office work)  
2. Ambulatory and capable of self-care, but unable to carry out any work activities; up and about 
more than 50% of waking hours  
3. Capable of only limited self-care; confined to bed or chair more than 50% of waking hours  
4. Completely disabled; unable to carry out any self-care and totally confined to bed or chair  
5 Dead 
 
A shift table will be presented to show worst changes from baseline separately for arm A and arm B. 
ECOG score results (including screening value) will be listed by arm and visit.  


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4.12.4.4 Bones Evaluation 
Blood Sample for
 and DXA scan assessments will be performed 
at timepoints as specified in the SoA (see protocol). The following variables will be collected: 
- 
 
 
 
 
 
 
 
  
 Bones Evaluation variables will also be listed.   
 
4.12.4.5 Physical Examination 
 
Physical Examination will be assessed at the times specified in the SoA. By-patient listing will be 
provided for all patient in FAS by visit, including details in abnormalities if any. 
 
4.12.5 Safety Monitoring Committee  
A safety monitoring committee (SMC) will be appointed to review safety data from patients in this 
study and a second study of RXC004 in patients with pancreatic and biliary tract cancer 
(RXC004/0003). 
The SMC is a group consisting of the country principal investigators (PI) from each of the phase 2 
studies and a statistician. An independent bone metabolism consultant will review the data and 
provide expert advice to the SMC meetings, but will not be a formal member of the SMC. 
The SMC will be convened to review the safety and tolerability of RXC004 at regular intervals. 
The safety reviews will start when approximately 
tely  patients across the phase 2 clinical trial program 
have been dosed for at least 1 cycle of study treatment and will continue every 6 months until the 
phase 2 studies close or last patient discontinues study treatment (whichever 
occurs first). Additional safety reviews may be performed at other times as deemed appropriate by 
the Sponsor. 
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Since the studies are open label, there are no blinding issues associated with performing interim safety 
reviews. Full details of the SMC procedures, processes, and analyses can be found in the SMC 
Charter.  
 
4.13 Exploratory Objectives 
 
 
4.14 Determination of Sample Size 
The method by Frewer et al [10], together with the totality of the data collected, will be used to guide 
go/no-go decision making: 
For the combination RXC004+nivolumab arm, assuming a 
% response rate which is 
considered to be clinically significant in the target population, against a reference value of 
% 
response rate (Eng C et al 2019) as 
, then a sample size of 20 achieves greater than 
% power, 
at the 
 
 
 These hurdles 
will be used to guide the decision for onward development. The totality of the data, including the 
results from the secondary endpoints will be used to in the final decision. 
For the monotherapy RXC004 arm, assuming a 
% disease control rate which is 
considered to be clinically significant in the target population, against a reference value of f 
% DCR 
[11 - 12] as a 
, then a sample size of 20 achieves greater than 
% power, at the 
 
 
 
 These hurdles 
will be used to guide the decision for onward development. The totality of the data, including the 
results from the secondary endpoints will be used to in the final decision. 
Approximately 
tely 
 patients are expected to be enrolled in order for approximately 20 patients to be in 
the evaluable dataset in each treatment arm. 
4.15 Changes in the Conduct of the Study or Planned Analysis 
In order to make the most appropriate assessment of efficacy for the compound and not be influenced 
by early dropouts not due to drug the Evaluable set will require at least 4 weeks of RXC004 intake 
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and at least one post dose radiographic tumour assessment or progressed/died ahead of the first 
radiographic assessment instead of one single dose as initially planned. 
After an ongoing review of the available data the following changes to the final outputs were made 
compared to the protocol 
• Medical History will not be summarized but will be listed. 
• 
 
• Overall Survival will not be summarized but will be listed. 
 
 
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5 
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2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 
countries. Cancer J Clin. 68;394-424 
 
[2]  
AnsaBE, Coughlin SS, Alema-Mensah E, Smith SA. Evaluation of Colorectal Cancer 
Incidence Trends in the United States (2000-2014) J Clin Med. 7(2):22 
 
[3]  
Van Cutsem E, Cervantes A, Adam R, Sobrero A, Van Krieken JH, Aderka D, Aranda Aguilar 
E, Bardelli A, Benson A, Bodoky G, Ciardiello F, D'Hoore A, Diaz-Rubio E, Douillard JY, 
Ducreux M, Falcone A, Grothey A, Gruenberger T, Haustermans K, Heinemann V, Hoff P, 
Köhne CH, Labianca R, Laurent-Puig P, Ma B, Maughan T, Muro K, Normanno N, Österlund 
P, Oyen WJ, Papamichael D, Pentheroudakis G, Pfeiffer P, Price TJ, Punt C, Ricke J, Roth A, 
Salazar R, Scheithauer W, Schmoll HJ, Tabernero J, Taïeb J, Tejpar S, Wasan H, Yoshino T, 
Zaanan A, Arnold D. ESMO consensus guidelines for the management of patients with 
metastatic colorectal cancer. Ann Oncol. 27(8); 1386-1422. 
 
[4]  
Grothey A, Van Cutsem E, Sobrero A, Siena S, Falcone A, Ychou M, Humblet Y, Bouché O, 
Mineur L, Barone C, Adenis A, Tabernero J, Yoshino T, Lenz HJ, Goldberg RM, Sargent DJ, 
Cihon F, Cupit L, Wagner A, Laurent D; CORRECT Study Group. Regorafenib Monotherapy 
for Previously Treated Metastatic Colorectal Cancer (CORRECT): An International, 
Multicentre, Randomised, Placebo-Controlled, Phase 3 Trial. Lancet. 381(9863):303-312 
 
[5]  
Mayer RJ, Van Cutsem E, Falcone A, Yoshino T, Garcia-Carbonero R, Mizunuma N, 
Yamazaki K, Shimada Y, Tabernero J, Komatsu Y, Sobrero A, Boucher E, Peeters M, Tran 
B, Lenz HJ, Zaniboni A, Hochster H, Cleary JM, Prenen H, Benedetti F, Mizuguchi H, Makris 
L, Ito M, Ohtsu A; RECOURSE Study Group. Randomized trial of TAS-102 for refractory 
metastatic colorectal cancer. N. Engl. J. Med. 372(20):1909-1919. 
 
[6]  
Van Cutsem E, Cervantes A, Adam R, Sobrero A, Van Krieken JH, Aderka D, Aranda Aguilar 
E, Bardelli A, Benson A, Bodoky G, Ciardiello F, D'Hoore A, Diaz-Rubio E, Douillard JY, 
Ducreux M, Falcone A, Grothey A, Gruenberger T, Haustermans K, Heinemann V, Hoff P, 
Köhne CH, Labianca R, Laurent-Puig P, Ma B, Maughan T, Muro K, Normanno N, Österlund 
P, Oyen WJ, Papamichael D, Pentheroudakis G, Pfeiffer P, Price TJ, Punt C, Ricke J, Roth A, 
Salazar R, Scheithauer W, Schmoll HJ, Tabernero J, Taïeb J, Tejpar S, Wasan H, Yoshino T, 
Zaanan A, Arnold D. ESMO consensus guidelines for the management of patients with 
metastatic colorectal cancer. Ann Oncol. 27(8); 1386-1422. 
 
[7]  
Cao M, Zhou M, Zhang J. Comparison of Efficacy and Safety for Patients With Beyond 
Second Line Treated Metastatic Colorectal Cancer: A Network Meta-Analysis of Randomized 
Controlled Trials J. Chemother. Feb 21;1-8; Epub ahead of print 
 
[8]  
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Recommended for Adoption at Step 4 (2020). 
 
[9]  
Eisenhauer, E. A., Therasse, P., Bogaerts, J., Schwartz, L. H., Sargent, D., Ford, R., ... & 
Rubinstein, L. (2009). New response evaluation criteria in solid tumours: revised RECIST 
guideline (version 1.1). European journal of cancer, 45(2), 228-247. 


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[10]  
Frewer P, Mitchell P, Watkins C, Matchman J. Decision-making in early clinical drug 
development. Pharmaceutical Statistics. 15:255-263. 
 
[11]  
Young, D.S and Huth, E.J; 1998;  SI Units for Clinical Measurement; American College of 
Physicians;  Philadelphia and Burtis, C.A, Ashwood, E.R and Bruns, D.E; 2008; 
Fundamentals of Clinical Chemistry; Saunders Elsevier; Missouri


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6 
APPENDICES 
6.1 
Anti-Tumour Activity assessment 
The anti-tumour activity of RXC004 monotherapy and RXC004+Nivolumab will be assessed by 
investigator at site by utilizing images from explain (CT) or explain (MRI), collected during 
screening/baseline and at regular (follow-up) intervals during the study. It is important to follow the 
tumour assessment schedule as per the SoA (see protocol). Patients treated with RXC004+Nivolumab 
that continue after RECIST 1.1 progression, will continue tumour assessment until second RECIST 
1.1 defined radiological progression (relative to the initial RCX004+Nivolumab progression event). 
Tumour assessments utilize images from CT or MRI, collected during screening/baseline and at regular 
(follow-up) intervals during the study. Tumour assessments will continue until RECIST 1.1-defined 
radiological progression. Patients treated with RXC004+Nivolumab that continue treatment after RECIST 
1.1 progression, will continue tumour assessments until second RECIST 1.1 defined radiological 
progression (relative to the initial RXC004+Nivolumab progression event).  
Sites will be required to store electronic copies of all scans, and the Sponsor may arrange for possible 
centralised storage of all imaging data. Centralised storage of imaging data would be possible to 
support an independent centralized review of disease assessments. 
At baseline, tumour lesions/lymph nodes will be categorized in measurable or non-measurable as 
follows: 
- 
Measurable tumour lesions: must be accurately measured in at least one dimension (longest 
diameter in the plane of measurement is to be recorded) with a minimum size of 10 mm by 
CT scan (CT scan slice thickness no greater than 5 mm). 
- 
Measurable malignant lymph nodes: to be considered pathologically enlarged and 
measurable, a lymph node must be ≥15mm in short axis when assessed by CT scan (CT scan 
slice thickness recommended to be no greater than 5 mm).  
- 
Non-measurable:  all other lesions, including small lesions (longest diameter <10 mm or 
pathological lymph nodes with ≥10 to <15 mm short axis) as well as truly non-measurable 
lesions. 
When more than one measurable lesion is present at baseline all lesions up to a maximum of five 
lesions total (and a maximum of two lesions per organ) representative of all involved organs should 
be identified as target lesions and will be recorded and measured at baseline. 
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 


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reproducible repeated measurements. All other lesions including pathological lymph nodes should be 
identified as non-target lesions. 
At each tumour assessment visit, the sum of the diameters (longest for non-nodal lesions, short axis 
for nodal lesions in mm) for all target lesions will be calculated. If lymph nodes are to be included in 
the sum, then as noted above, only the short axis is added into the sum.  
The baseline sum diameters will be used as reference to further characterise any objective tumour 
regression in the measurable dimension of the disease. The minimum observed sum of diameters is 
called “Nadir” and this includes the baseline sum if that is the smallest observed on study. If a lesion 
split into different components, it will be considered as single lesion where the diameter is obtained 
by the some of the longest diameter of each single component.  
RECIST 1.1 guideline will be followed to determine the overall tumour response based on target 
lesions, non-target and new lesions responses. Tumour assessment visits will be conducted, in 
accordance with SoA (see protocol), every 8 weeks ± 1 week (relative to the date of initiation of study 
treatment) for the first 56 weeks, followed by q12w weeks ± 1 until radiological disease progression 
(as defined by Response Evaluation Criteria in Solid Tumours, version 1.1 [RECIST 1.1]). 
 
6.1.1 Target Lesions (TLs) assessment 
At each tumour assessment visit, the response for TLs will be determined as follows: 
- 
Complete response (CR): disappearance of all target lesions i.e. explain (SLD) = 0. However, 
a CR can be achieved with SLD >0 if a pathological lymph node is identified as a target lesion 
and has a reduction in short axis to <10 mm.  
- 
Partial response (PR): A ≥30% decrease in the sum of diameters of target lesions, taking as 
reference the baseline sum diameters.  
- 
Progressive disease (PD): at least a 20% increase in the sum of diameters of target lesions, 
taking as reference the nadir. In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm.  
- 
Stable disease (SD): neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study.  
- 
Not all evaluated: if one or more than individual lesions is missing, the sum of longest 
diameters is also missing, nevertheless the available sum meets criteria for PD. 
 
6.1.2 Non-Target Lesions (NTLs) assessment 
At each tumour assessment visit, each NTL will be evaluated as follows: 


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- 
Complete Response (CR): Disappearance of all NTLs. All lymph nodes must be non-
pathological in size (<10 mm short axis). 
- 
Non-CR/Non-PD: Persistence of one or more NTLs and/or maintenance of tumour marker 
level above the normal limits. 
- 
Progressive Disease (PD): Unequivocal progression of existing NTLs.  
 
6.1.3 New Lesions (NLs) assessment 
The presence of new measurable lesions and new non-measurable lesions will be assessed at each 
tumour assessment visit (after baseline). The occurrence of NLs will be recorded as dichotomous 
response “Yes” or “No”. New measurable/non-measurable lesions will be assessed in accordance to 
baseline criteria for identification of measurable/non-measurable lesions. NLs identified in 
lymph nodes will be considered only if  lymph node is ≥15 mm in short axis. 
 
6.1.4 Overall Response (OR) 
At each tumour assessment visit, OR will be determined as defined in the RECIST 1.1 guideline. 
Table 3 shows rules to determine the OR outcome. For example, if a patient resulted in PR for TLs, 
not-evaluated for NTLs and without NLs (“No”), the overall response at the considered visit will be 
PR.  
Table 3 - Time point response: patients with target (+/–non-target) disease 
Target lesions 
Non-target lesions 
New lesions 
Overall response 
 
 
 
 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
  
  
  
  
(CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease and, NE = 
not-evaluable) 
 
Furthermore, PD can be also considered as a worsening of a patient’s condition attributable to the disease 
for which the investigational product is being studied. It may be an increase in the severity of the disease 
under study and/or increases in the symptoms of the disease. The development of new, or progression of 
existing metastasis from the primary cancer under study should be considered as disease progression and 


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not an AE. Events, which are unequivocally due to disease progression, should not be reported as an AE 
during the study. 
 
 


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6.2 
Summary of treatment arms to be considered for each endpoint 
 
. 
Endpoints 
Arms to consider 
DCR 
Arm A/B and arm A2 
ORR 
Arm A/B and arm A2 
PFS 
Arm A/B and arm A2 
Percentage change in tumor size 
Arm A/B and Arm A2 
AEs 
Arm A/B and Arm A1/A2 
Rest of endpoints 
Arm A/B unless otherwise specified 
 


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