Conditions: Cancer Solid Tumor
Keywords: Biliary tract cancers Thymus cancers
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 46
Healthy volunteers: no

Brief summary:
The purpose of this study is to determine the safety and tolerability of RXC004 as monotherapy and in combination with Nivolumab in patients with advanced malignancies. In order to define the doses and schedules for further clinical evaluation.

Detailed description:
The study will consist of an ascending monotherapy dose, the doses are pre-defined.

The decision to escalate will be made upon the assessment of safety and tolerability data in the first cycle of treatment.

Module 1 will commence with a 3+3 dose escalation design up to a recommended Phase 2 monotherapy dose. Patients being monitored for dose limiting toxicities at each dose level.

Characterisation of the PK profile, MTD and/or recommended Phase 2 dose will be defined on the emerging data.

Module 2: RXC004 and Nivolumab - Follows a similar 3+3 dose escalation design using RXC004 plus Nivolumab. The MTD and/or Phase 2 dose will be defined based on the PK profile, emerging safety and the appearance of any dose limiting toxicities.

Module 3: Intermittent dose schedules of RXC004 will be investigated. The intermittent schedules will utilize the module 1 dose which was shown to be safe and tolerated when used continuously. Characterisation of the PK profile; Wnt pathway inhibition; incidence/severity of Wnt pathway related AEs and anti-tumor activity will be evaluated at 2 different dosing schedules.

Arms:
arm 1: Patients were given 0.5 mg RXC004 and monitored for Dose Limiting Toxicities. arm 2: Patients were given 1.0 mg RXC004 in combination with a standard dose of Nivolumab and monitored for Dose Limiting Toxicities. arm 3: Patients were given 2.0 mg RXC004. The patients were treated for 2 weeks at the same dose, followed by 1 week off for a 21 day cycle. arm 4: Patients were given 1.0 mg RXC004 and monitored for Dose Limiting Toxicities. arm 5: Patients were given 1.5 mg RXC004 and monitored for Dose Limiting Toxicities. arm 6: Patients were given 2.0 mg RXC004 and monitored for Dose Limiting Toxicities. arm 7: Patients were given 3.0 mg RXC004 and monitored for Dose Limiting Toxicities. arm 8: Patients were given 10.0 mg RXC004 and monitored for Dose Limiting Toxicities. arm 9: Patients were given 1.5 mg RXC004 in combination with a standard dose of Nivolumab and monitored for Dose Limiting Toxicities.

Interventions: intervention 1: RXC004 intervention 2: Nivolumab
Intervention descriptions: intervention 1: RXC004 is taken orally, inhibits porcupine (PORCN) and interacts with the wnt signalling pathway. intervention 2: RXC004 is taken orally, inhibits porcupine (PORCN) and interacts with the wnt signalling pathway.

Nivolumab is a fully human monoclonal immunoglobulin G4 antibody to PD-1

Protocol document:
Prot_000.pdf: 


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SIGNATURES 
 
 
PROTOCOL TITLE: 
A Modular, Multi-Arm, Phase1, Adaptive Design Study to 
Evaluate the Safety and Tolerability of RXC004, Alone and in 
Combination with Anti-cancer Treatments, in Patients with 
Advanced Malignancies 
PROTOCOL NO: 
RXC004/0001 
 
 
 
 
 
 
 
 
 
 
Signature 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Overview of Study  
 
 
 
 
 
 
 
 
 
 
 
 
 


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TABLE OF CONTENTS 
 
TABLE OF CONTENTS ....................................................................................................... 4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................... 10 
1 
INTRODUCTION – CORE ..................................................................................... 14 
1.1 
Investigational Agent .................................................................................... 14 
1.2 
Disease Linkage ............................................................................................. 16 
1.2.1 
Genetic Alterations in the Wnt Pathway in Colorectal, 
Gastric and Pancreatic Cancers ........................................................ 16 
1.2.2 
Wnt Signalling and Biliary Tract Cancer ......................................... 17 
1.2.3 
Wnt Pathway in Other Cancers ........................................................ 18 
1.2.4 
Wnt Pathway as an Immune Oncology Target ................................. 18 
1.2.5 
Clinical Precedence with Target ....................................................... 19 
1.2.6 
Tolerability of Targeting Porcupine ................................................. 22 
1.3 
Non-clinical Information and Correlative Studies ..................................... 22 
1.3.1 
Pre-clinical Primary Pharmacology Studies ..................................... 22 
1.3.2 
Pre-clinical Toxicology and Safety Pharmacology 
Studies .............................................................................................. 24 
1.4 
Overall Study Design and Flow Chart ........................................................ 26 
1.5 
Blinding .......................................................................................................... 27 
1.6 
Rationale ........................................................................................................ 27 
1.7 
Overall Study Benefit-Risk and Ethical Assessment ................................. 28 
1.7.1 
RXC004 Monotherapy ..................................................................... 28 
1.7.2 
RXC004 in Combination with Nivolumab ....................................... 33 
1.8 
Study Timetable and End of Study ............................................................. 36 
1.9 
Study Objectives ............................................................................................ 36 
1.9.1 
Primary Objectives ........................................................................... 36 
1.9.2 
Secondary Objectives ....................................................................... 37 
1.9.3 
Exploratory Objectives ..................................................................... 37 
2 
SELECTION OF STUDY POPULATION AND RESTRICTIONS.................... 39 
2.1 
Inclusion Criteria .......................................................................................... 39 
2.1.1 
Core Inclusion Criteria ..................................................................... 39 
2.1.2 
Inclusion Criteria for Genetics Research .......................................... 40 
2.1.3 
Module 3-Specific Inclusion Criteria ............................................... 40 
2.2 
Exclusion Criteria ......................................................................................... 40 
2.2.1 
Core Exclusion Criteria .................................................................... 40 
2.2.2 
Module 2: RXC004- and Nivolumab-Specific Exclusion 
Criteria .............................................................................................. 42 
2.3 
Subject Restrictions ...................................................................................... 42 


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Concomitant Treatments................................................................... 43 
3 
STUDY TREATMENT, CONDUCT, WITHDRAWAL – CORE ....................... 47 
3.1 
Study Treatment ........................................................................................... 47 
3.1.1 
Starting Dose (Module 1) for Study Re-start ................................... 47 
3.1.2 
Dose Escalation Scheme (Modules 1 and 2) .................................... 49 
3.1.3 
Definition of Maximum Tolerated Dose (Modules 1 and 
2) ....................................................................................................... 50 
3.1.4 
Definition of Maximum Feasible Dose (Modules 1 and 2) .............. 50 
3.1.5 
Definition of MBAD  (Modules 1 and 2) ......................................... 51 
3.2 
Safety Review Committee ............................................................................. 51 
3.3 
Dose Modifications and Individual Stopping Criteria .............................. 52 
3.4 
Adverse Event Management Plan ............................................................... 52 
3.4.1 
Bone Management plan (All Modules) ............................................ 52 
3.4.2 
Diarrhoea/Colitis Management and Treatment Guidelines .............. 57 
3.4.3 
Nivolumab Toxicity Management and Dose Modification 
(for Module 2 patients) ..................................................................... 57 
3.5 
Treatment Compliance and Accountability ............................................... 58 
3.5.1 
Treatment Accountability ................................................................. 58 
3.6 
Subject Withdrawal ...................................................................................... 58 
4 
SAFETY – CORE ..................................................................................................... 60 
4.1 
Definitions of Adverse Events and Serious Adverse Events ..................... 60 
4.2 
Reporting of Adverse Events, Serious Adverse Events and 
Dose Limiting Toxicities ............................................................................... 63 
4.2.1 
Reporting of SAEs and Suspected Unexpected Serious 
AEs to Regulatory Authorities, Ethics Committees and 
Investigators ..................................................................................... 64 
4.2.2 
Follow-Up of Adverse Events .......................................................... 65 
4.3 
Medical Emergencies and Sponsor Contacts ............................................. 65 
4.3.1 
Safety Reporting and Medical Management .................................... 65 
4.3.2 
Emergency Sponsor Contact ............................................................ 65 
4.3.3 
Overdose ........................................................................................... 66 
4.3.4 
Pregnancy ......................................................................................... 66 
5 
STUDY DESIGN ....................................................................................................... 67 
5.1 
Introduction ................................................................................................... 67 
5.2 
Module 1 – RXC004 Monotherapy ............................................................. 67 
5.2.1 
Module 1: Study Objectives ............................................................. 68 
5.2.2 
Module 1  Eligibility Criteria ........................................................... 68 
5.2.3 
Ascending Monotherapy SAD/MAD ............................................... 68 
5.2.4 
Selection of Doses ............................................................................ 70 
5.2.5 
Selection and Timing of Dose for Each Patient ............................... 71 
5.2.6 
Dose-Limiting Toxicity for Module 1 (RXC004 
Monotherapy) ................................................................................... 72 


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RXC004 Monotherapy: Dose Modifications .................................... 73 
5.2.8 
Study Treatment Discontinuation Criteria ........................................ 74 
5.2.9 
Biomarker Samples .......................................................................... 76 
5.2.10 
Exploratory Assessments .................................................................. 77 
5.3 
Module 2 – RXC004 and Nivolumab Combination ................................... 77 
5.3.1 
Module 2 Objectives ......................................................................... 79 
5.3.2 
Module 2 Eligibility Criteria ............................................................ 79 
5.3.3 
Module 2: Ascending Combination MAD ....................................... 80 
5.3.4 
Selection of Doses for Module 2 ...................................................... 80 
5.3.5 
Selection and Timing of Dose for Each Subject............................... 80 
5.3.6 
Dose-Limiting Toxicity for RXC004 + Nivolumab 
Combination (Module 2) .................................................................. 82 
5.3.7 
Dose Modifications .......................................................................... 83 
5.3.8 
Study Treatment discontinuation Criteria......................................... 84 
5.3.9 
Biomarker Samples .......................................................................... 88 
5.3.10 
Exploratory Assessments .................................................................. 88 
5.4 
Module 3 ........................................................................................................ 88 
5.4.1 
Module 3: Study Objectives ............................................................. 89 
5.4.2 
Module 3  Eligibility Criteria ........................................................... 89 
5.4.3 
Dose Rationale .................................................................................. 91 
5.4.4 
RXC004 Intermittent Schedules ....................................................... 91 
5.4.5 
Intermittent Schedule Rationale ....................................................... 92 
5.4.6 
RXC004 Dose Modifications ........................................................... 94 
5.4.7 
Study Treatment Discontinuation Criteria ........................................ 94 
5.4.8 
Biomarker Samples .......................................................................... 97 
5.4.9 
Exploratory Assessments .................................................................. 97 
6 
STUDY TREATMENT ............................................................................................ 98 
6.1 
Method of Assigning Subjects to Treatment .............................................. 98 
6.2 
Identity of Investigational Product(s) ......................................................... 98 
6.2.1 
RXC004 ............................................................................................ 98 
6.2.2 
Nivolumab ........................................................................................ 98 
6.3 
Packaging, Labelling and Storage ............................................................... 99 
6.3.1 
RXC004 ............................................................................................ 99 
6.3.2 
Nivolumab ...................................................................................... 100 
6.4 
Selection of Doses in the Study .................................................................. 100 
6.5 
Selection and Timing of Dose for Each Subject ....................................... 100 
7 
STUDY ENDPOINTS ............................................................................................. 101 
7.1 
Efficacy ......................................................................................................... 101 
7.2 
Safety ............................................................................................................ 103 
7.2.1 
Adverse Events ............................................................................... 104 
7.2.2 
Clinical Laboratory Evaluations ..................................................... 104 
7.2.3 
Vital Signs, Physical Findings and Other Safety 
Assessments .................................................................................... 106 
7.3 
Pharmacokinetics and Pharmacodynamics .............................................. 106 


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Pharmacokinetic Endpoints ............................................................ 106 
7.3.2 
Determination of Drug Concentration in Pharmacokinetic 
Samples ........................................................................................... 107 
7.3.3 
Pharmacodynamic Endpoints ......................................................... 109 
7.4 
Appropriateness of Measurements ............................................................ 115 
8 
QUALITY CONTROL AND QUALITY ASSURANCE – CORE .................... 116 
8.1.1 
Monitoring ...................................................................................... 116 
8.1.2 
Data Management/Coding .............................................................. 117 
8.1.3 
Quality Assurance .......................................................................... 118 
9 
STATISTICS ........................................................................................................... 120 
9.1 
Determination of Sample Size .................................................................... 120 
9.2 
Statistical Methods ...................................................................................... 120 
9.2.1 
Efficacy Analyses ........................................................................... 121 
9.2.2 
Safety Analyses .............................................................................. 123 
9.2.3 
Data to be Analysed ........................................................................ 123 
9.2.4 
Missing Data ................................................................................... 123 
9.3 
Subject Disposition ...................................................................................... 124 
9.4 
Subject Characteristics ............................................................................... 124 
9.5 
Efficacy Analyses ........................................................................................ 124 
9.6 
Safety ............................................................................................................ 124 
9.6.1 
Adverse Events ............................................................................... 124 
9.6.2 
Clinical Laboratory Evaluations ..................................................... 125 
9.6.3 
Vital Signs Measurements, Physical Exams, ECG and 
Other Safety Evaluations ................................................................ 125 
9.7 
Health Outcomes Analyses ......................................................................... 125 
9.8 
Pharmacokinetic and Pharmacogenetic Analyses ................................... 125 
9.9 
Interim Analyses ......................................................................................... 125 
10 
ETHICS ................................................................................................................... 126 
10.1 
Institutional Review Board or Independent Ethics Committee ............. 126 
10.2 
Ethical Conduct of the Study ..................................................................... 126 
10.3 
Subject Information and Informed Consent ............................................ 127 
10.4 
Subject Data Protection .............................................................................. 127 
11 
STUDY ADMINISTRATION – CORE ................................................................ 128 
11.1 
Data Handling and Record Keeping ......................................................... 128 
11.2 
Direct Access to Source Data/Documents ................................................. 128 
11.3 
Investigator Information ............................................................................ 128 
11.3.1 
Investigator Obligations ................................................................. 128 
11.3.2 
Protocol Signatures ......................................................................... 129 
11.3.3 
Publication Policy ........................................................................... 129 
11.4 
Financing and Insurance ............................................................................ 129 


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REFERENCES ........................................................................................................ 130 
13 
APPENDICES ......................................................................................................... 135 
14 
SIGNATURE OF INVESTIGATOR .................................................................... 169 
 
 


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LIST OF TABLES 
Table 1 
Wnt Pathway Clinical Trials ........................................................................... 21 
Table 2 
Interventions for patients with increasing bone fracture risk .......................... 57 
Table 3: 
Indicative Dose-Escalation Scheme for Module 1 .......................................... 72 
Table 4   
Module 1 Dose Interruption and Stopping Criteria ........................................ 74 
Table 5  
Indicative Dose Escalation Scheme for Module 2 .......................................... 82 
Table 6 
Module 2 Dose Interruption and Stopping Criteria ........................................ 84 
Table 7   
Module 3 Dose-Interruption and Stopping Criteria ........................................ 94 
Table 8:  
Laboratory Test: Required Analytes ............................................................. 105 
Table 9:  
Definition of PK Parameters ......................................................................... 107 
Table 10:  
PK Plasma Sampling Schedule ..................................................................... 109 
Table 11: 
Module 1 : Pharmacodynamic samples / Tumour Collection 
Schedule ........................................................................................................ 109 
Table 12:  
Module 2: Pharmacodynamic samples / Tumour Collection 
Schedule ........................................................................................................ 112 
 
LIST OF FIGURES 
Figure 1: 
Interaction Between Porcupine and the Canonical Wnt Pathway .................. 15 
Figure 2  
Overall Study Design ...................................................................................... 26 
Figure 3  
Bone Remodeling Schematic .......................................................................... 53 
Figure 4 
Module 1 RXC004 monotherapy SAD/MAD ................................................ 70 
Figure 5 
Module 2 dose escalation ................................................................................ 78 
Figure 6 
Dose-dependent effects of RXC004 in B16F10/C27BL/6 
syngeneic model and the SNU-1411 xenograft model. .................................. 92 
 
LIST OF APPENDICES 
Appendix 1  
Schedule of Assessments - Module 1 ........................................................... 136 
Appendix 2 
Schedule of Assessments - Module 2 ........................................................... 139 
Appendix 3 
Performance Status Scale .............................................................................. 144 
Appendix 4 
Response Evaluation Criteria for Solid Tumours (RECIST) ........................ 145 
Appendix 5 
Colitis Management and Treatment Guidelines ........................................... 146 
Appendix 6 
Dysgeusia treatment guidelines .................................................................... 150 
Appendix 7 
Prohibited CYP3A4 Inhibitors and Inducers ................................................ 152 
Appendix 8 
Nivolumab Toxicity Management and Dose Modification 
Guidelines (Patients enrolled onto Module 2 only) ...................................... 154 
Appendix 9 
Module 3 Schedule of Assessments .............................................................. 163 
Appendix 10 RNF43/RSPO aberrations ............................................................................. 167 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation or 
special term 
Explanation 
ADR 
Adverse drug reaction 
AE 
Adverse event  
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
APC 
Adenomatous polyposis coli 
APTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
AUCss 
Area under the curve at steady state 
BAD 
Biologically active dose 
BCG 
Bacillus Calmette–Guérin vaccine 
BID 
Twice daily 
BMI 
Body mass index 
BP 
Blood pressure 
CBP 
CREB binding protein 
CFR 
Code of Federal Regulations 
CHL 
Classical Hodgkin’s lymphoma 
CIOMS 
Council for International Organisations of Medical Sciences 
Cmax 
Maximum plasma concentration  
CMO 
Chief Medical Officer 
CPMP 
Committee for proprietary medicinal products 
CR 
Complete response 
CRF 
Case report form (electronic/paper) 
CRO 
Contract research organisation 
CSP 
Clinical study protocol 
CSR 
Clinical study report 
CT 
Computerised tomography 
CTC 
Circulating tumour cells 
CTCAE 
Common Terminology Criteria for Adverse Events 
ctDNA 
Circulating tumour deoxyribonucleic acid 
DC 
Dendritic cell 
DCR 
Disease control rate 
DLT 
Dose-limiting toxicity 
DNA 
Deoxyribonucleic acid 
DOR 
Duration of response 
DSH 
Dishevelled 
ECG 
Electrocardiogram 


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Abbreviation or 
special term 
Explanation 
ECOG 
Eastern Co-operative Oncology group 
EDC 
Electronic data capture 
EF 
Ejection fraction  
ELISA 
Enzyme-linked immunosorbent assay 
EU 
European Union 
FDA 
Food and Drug Administration 
FSH 
Follicle-stimulating hormone 
FTIH 
First time in human 
Fz 
Frizzled co-receptor 
GCP 
Good Clinical Practice 
GCSF 
Granulocyte-colony stimulating factor 
GEJ 
Gastro-oesophageal junction 
GI 
Gastro-intestinal 
GnRH 
Gonadotropin-releasing hormone  
GSK3β 
Glycogen synthase kinase 3β 
HDPE 
High-density polyethylene 
HRT 
Hormone replacement therapy 
HSCT 
Hematopoietic stem cell transplantation 
IB 
Investigator’s Brochure 
ICH 
International Council for Harmonisation 
ICF  
Informed Consent Form 
IEC 
Independent Ethics Committee 
IgG 
Immunoglobulin G 
IHC 
Immunohistochemistry 
IMP 
Investigational medicinal product 
INR 
International normalised ratio 
IRB 
Institutional Review Board 
IUD 
Intra-uterine device 
LH 
Luteinising hormone 
LoF 
Loss of function 
LRP5/6 
Low-density lipoprotein receptor-related protein 5/6 
LRV 
Lower reference value 
mAbs 
Monoclonal antibodies 
MAD 
Multiple ascending dose 
MBAD 
Minimal biologically active dose 
MDSC 
Myeloid-derived suppressor cell 
MFD 
Maximum feasible dose 
MHRA 
Medicines and Healthcare products Regulatory Agency 
MedDRA 
Medical Dictionary for Regulatory Activities 


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Abbreviation or 
special term 
Explanation 
MRI 
Magnetic resonance imaging 
MMTV 
Mouse mammary tumour virus 
mRNA 
Messenger RNA 
MTD 
Maximum tolerated dose 
NA 
Not applicable 
NCI 
National Cancer Institute 
NE 
Not evaulable 
NK 
Natural killer 
NSCLC 
Non-small cell lung cancer 
NTL 
Non-target lesion 
ORR 
Objective response rate 
OS 
Overall survival 
PCWG3 
Prostate Cancer Working Group 3 
PD 
Progression of disease 
PD-1 
Programmed death receptor-1 
PDAC 
Pancreatic ductal adenocarcinoma 
PI 
Principal investigator 
pIC50 
Negative log of half maximal inhibitory concentration 
PFS 
Progression-free survival  
PK 
Pharmacokinetics 
PDL 1 
Programmed death-ligand 1 
PoC 
Proof of concept (defined as evidence of clinical benefit, such as reduction in 
tumour size)  
PoM 
Proof of mechanism (defined as evidence that the compound has a potential 
mechanism of action in humans such as inhibition of target enzyme or 
receptor) 
PoP 
Proof of principle (defined as proof of not only engagement with the 
biological target but also that the downstream consequneces of this target 
action have changed) 
PORCN 
Protein-serine O-palmitoleoyltransferase porcupine 
PR 
Partial response 
QTc 
QT interval corrected for heart rate 
RECIST 
Response Evaluation Criteria in Solid Tumours  
RNA 
Ribonucleic acid 
RNF43 
Ring finger protein 43 
SAE 
Serious adverse event 
SAD 
Single ascending dose 
SAP 
Statistical Analysis Plan 
SCCHN 
Squamous-cell carcinoma of the head and neck 
SD 
Stable disease 


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Abbreviation or 
special term 
Explanation 
SDV 
Source data verification 
SFRP 
Secreted frizzled-related protein 
SoC 
Standard of care 
SOP 
Standard operating procedures 
SRC 
Safety Review Committee 
SUSAR 
Suspected unexpected serious adverse reaction 
TGI 
Tumour growth inhibition 
TIL 
Tumour infiltrating lymphocytes 
Tmax 
Maximum plasma concentration  
T½ 
The time taken for any concentration point in the elimination phase to fall to 
half its value 
TL 
Target lesion 
TV 
Target value 
UK 
United Kingdom 
ULN 
Upper limit of normal 
WHO 
World Health Organization 
WHODrug 
World Health Organization Drug Dictionary 
 
 
 
 


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1 INTRODUCTION – CORE  
1.1 Investigational Agent 
The investigational agent RXC004 is a novel, small-molecule inhibitor of the membrane 
bound protein-serine O-palmitoleoyltransferase porcupine (PORCN). PORCN is required for 
the post-translational modification of all Wnts ligands and is vital for Wnt secretion and 
initiation of downstream canonical and non-canonical signalling. {Herr, 2012 Ref 16} 
 
The Wnt signaling pathway plays an instrumental role in animal development and in the 
regulation of cellular proliferation, migration, morphology, apoptosis, differentiation, and stem 
cell self-renewal. Dysregulation and aberrant activation of the Wnt pathway is known to play 
a critical role in the development of a variety of malignancies {Logan, 2004 Ref 24}. 
The interaction between porcupine and the canonical Wnt pathway is illustrated in Figure 1. 
 


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Figure 1: 
Interaction Between Porcupine and the Canonical Wnt Pathway  
 
 
 
 
 
PORCN is required for the post-translational modification of all Wnt proteins, and is vital for Wnt secretion.The Wnt 
pathway is initiated by the binding of Wnt glycoproteins to co-receptors frizzled (Fz) and low-density lipoprotein 
receptor-related protein (LRP) 5 or 6 resulting in the phosphorylation of dishevelled (DSH), which in turn recruits a 
destruction complex comprising axin, adenomatous polyposis coli (APC) and glycogen synthase kinase 3β (GSK3β) to 
the cell membrane. The movement of these proteins inhibits the phosphorylation of β-catenin allowing β-catenin to 
accumulate near the cell nucleus and induces the transcription of target genes. 
 
Aberrant activation of the pro-survival Wnt signalling pathway is a key determinant in 
numerous cancers {Nusse, 2012 Ref 31} and therefore constituents of this pathway are 
potentially promising therapeutic targets.{Artem Blagodatski1†, 2014 Ref 2} 
The investigational agent RXC004 is a novel, orally bioavailable small-molecule inhibitor of 
porcupine (PORCN). The mechanism of action of RXC004 provides the potential to afford 
monotherapy efficacy as well as efficacy in combination (either via synergistic or additive 
effects) with a number of anti-cancer treatments. This study is, therefore, an adaptive modular 
study in design, allowing evaluation of the safety, tolerability, PK and anti-tumour activity of 


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RXC004 at increasing doses, initially as monotherapy and then in combination with different 
anti-cancer treatments, in patients with advanced malignancies. 
1.2 Disease Linkage 
1.2.1 Genetic Alterations in the Wnt Pathway in Colorectal, Gastric and 
Pancreatic Cancers 
Recurrent chromosome rearrangements involving members of the R-Spondin (RSPO) family, 
RSPO2 and RSPO3, have been described in colorectal cancer (CRC). {Seshagiri, 2012 Ref 
36}  The rearrangements result in fusion transcripts that drive marked overexpression of the 
RSPO gene. RSPOs are secreted proteins that act as ligands for the leucine rich repeat 
containing G-protein coupled receptor LRP family (LRP 4/5/6). RSPO binding to LRPs 
potentiates Wnt signalling by sequestering the E3 ubiquitin ligases RNF43 and ZNRF3, 
resulting in the accumulation of Fz/LRP-receptor complexes at the cell membrane. All reported 
RSPO-fusion events in CRCs are mutually exclusive of APC mutations and other activating 
mutations in the Wnt pathway, indicating RSPO rearrangements are likely key genetic drivers 
in CRC. RSPO proteins can stabilise cytosolic β-catenin and dramatically synergize with Wnt 
ligands resulting in increased pathway activity.{Seshagiri, 2012 Ref 36;de Lau, 2014 Ref 6}  
 
Redx has demonstrated an anti-proliferative effect of RXC004 in the SNU-1411 cell line, a 
human CRC cell line containing an RSPO fusion. RNF43 is an integral membrane E3 ubiquitin 
ligase that promotes degradation of Fz receptors (Figure 1). A number of mutations in this 
ligase have been identified in cancer patients and are predicted to result in RNF43 LoF leading 
to increased Fz expression at the cell surface and elevated Wnt signalling. A significant 
incidence of RNF43 mutations has been reported in CRC, gastric and pancreatic cancers. 
Sensitivity to PORCN inhibitors has been demonstrated in tumour cell lines with RNF43 LoF 
mutations.{Madan, 2016 Ref 26}  
 
This sensitivity has been corroborated in in vivo studies; Redx has also demonstrated efficacy 
of RXC004 in a CAPAN 2 xenograft study (Section 1.3.1) that carries an RNF43 loss of 
function mutation. 
 
Bioinformatics analysis of The Cancer Genome Atlas (TCGA) and cBioPortal databases has 
confirmed that the RNF43 mutation prevalence in pancreatic cancer is around 4%. Due to this 
low incidence it is likely that patient selection for this indication will require Redx to be part 
of a larger platform based  trial. Redx is actively engaged with the Precision Panc initiative (a 


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UK wide pancreatic cancer trial led by CRUK). In gastric cancer and CRC, bioinformatics has 
revealed a higher incidence of RNF43 mutation: approximately 9% and 6%, respectively.  In 
addition, RSPO fusions are found in approximately 10% of CRC, thus genetic alteration of 
upstream Wnt pathway is likely to occur in ~16% of CRC in total  Redx has developed assays 
in order to detect RNF43 LoF mutations and RSPO fusions in patients tumour samples (seee 
Section 5.4.2.4 for more details) 
As discussed above, RXC004 has shown efficacy in both RNF43 LoF and RSPO fusion human 
xenograft models. As part of these pre-clinical studies it was observed that RXC004 did not 
show a clear dose-repose relationship when a caliper measurement was used for study 
endpoint. The calipers measure simply the size of the tumour in the mouse similar to a RECIST 
scan in a cancer patient. In addition to the caliper measurement Redx has also conducted IHC 
analysis on these RSPO fusion tumours.  By IHC, a clear dose-response relationship was shown 
on Ki67 staining, which shows an antiproliferative effect of RXC004.  In addition to the 
dramatic dose-dependent reduction in tumour cell proliferation, RXC004 also resulted in a 
striking change in cell morphology.   By Alcian blue staining,  RXC004 treatment was shown 
to increase the presence of mucins in the extracellular space in a dose-dependent manner.  Redx 
believes that this increase in mucin in the tumour microenvironment is responsible for the lack 
of dose response in the caliper tumour volume measurement in this model. A RECIST 
measurement on tumour size maybe confounded if this cell differentiation and increase in 
mucus production in the tumour microenvironment results in a lack of tumour area shrinkage.  
For these reasons, DCR is the primary endpoint for the RXC004 monotherapy arm because it 
is possible that RXC004 efficacy could result in prolonged stable disease rather than tumour 
shrinkage. As complete ablation of tumour cell proliferation has been observed in pre-clinical 
models,  this mechanism of action could still lead to patient benefit, increased progression free 
survival and ultimately an overall survival benefit for the patient.  
 
1.2.2 Wnt Signalling and Biliary Tract Cancer 
Patient samples from biliary-tract cancer (BTC) patients have been shown to have high 
expression of both Wnt ligands and Fz receptors. {Boulter, 2015 Ref 3} In addition to this high 
expression, there are no reports of downstream pathway mutations that would render these 
patients resistant to PORCN inhibition. BTC cell-line xenograft models in mice and chemically 
induced models of cholangioma in rats have been demonstrated to be sensitive to PORCN 
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1.2.3 Wnt Pathway in Other Cancers 
In addition to the upstream genetic mutations in the Wnt pathway and increased Wnt ligand 
production described above in gastric, pancreatic, colorectal and biliary tract cancers, there is 
also a potentially much wider role for PORCN inhibition in other solid tumours. 
Abnormal expression of regulatory proteins in the pathway by epigenetic alteration has been 
described. For example, the reduced activity or absence of extracellular Wnt antagonists, the 
secreted frizzled-related proteins (SFRPs), has been reported in colorectal, breast, prostate, and 
lung cancers and thus evidence exists for therapeutic utility of a PORCN inhibitor in a wider 
range of solid tumours.{Caldwell, 2004 Ref 4;Lee, 2004 Ref 23;Suzuki, 2004 Ref 42;Fukui, 
2005 Ref 10;Zou, 2005 Ref 51}. 
In addition, although it could be assumed that mutations downstream in the Wnt pathway, such 
as APC mutations (prevalent in up to 90% of CRC) would render tumours resistant to PORCN 
inhibition, evidence in the literature exists to suggest such patients may also benefit from a 
reduction in ligand drive via PORCN inhibition.{Voloshanenko, 2013 Ref 47} A small-
molecule PORCN inhibitor in CRC cell lines bearing APC mutations resulted in decreased 
pathway activation, anti-proliferative effects and reduced cell viability. These data suggest 
patients with cancers bearing downstream mutations in the Wnt pathway, traditionally 
expected to be insensitive to PORCN inhibitors may well in fact receive therapeutic benefit 
from treatment with a PORCN inhibitor.  
1.2.4 Wnt Pathway as an Immune Oncology Target 
There is strong scientific rationale, from both pre-clinical and clinical studies, that Wnt 
pathway activity drives the immune evasion of tumours.{Spranger, 2018 Ref 41;Wang, 2018 
Ref 48}  Porcupine inhibition has the potential to block two of the five critical mechanisms of 
tumour-cell immune evasion.  High β-catenin protein levels (i.e. high Wnt pathway activation) 
were also recently reported to correlate with lack of immune signature across 22 different 
cancer types. {Luke, 2019 Ref 25}  The lack of immune signature has been linked to a lack of 
response to immune checkpoint inhibitors (such as anti-PD-1). Redx has demonstrated efficacy 
by an immune system-mediated mechanism with RXC004 in combination with an anti-PD1 
antibody in a CT26 mouse syngeneic CRC tumour model. RXC004/anti-PD-1 combination 
therapy results in a significant decrease in Treg cells and a significant increase in the cytotoxic 
T cell to Treg cell ratio in this model compared to either agent alone. In addition, RXC004 has 
monotherapy efficacy in the B16 melanoma mouse syngeneic model. This efficacy is 
dependent on an intact immune system and correlates with RXC004 causing a decrease in 
myeloid derived suppressor cells (MDSCs) in the tumours of this model. 
 
As described above, blockade of Wnt by RXC004 would be expected therefore to reverse Wnt 
induced immune evasion in the tumour microenvironment and result in a decrease in MDSCs 


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and Tregs and an increase in CD8 T cells. In a patient with PDL1 +ve disease then in order for 
these newly acquired CD8 T cells to function optimally an anti-PD1/antiPDL1 immunotherapy 
will be required and therefore in these PDL1 +ve patients we would expect to see synergy 
between the action of RXC004 to bring in the T cells to the TME and the anti-PD(L)1 agent to 
release the inhibition on these T cells. 
 
1.2.5 Clinical Precedence with Target 
As of yet there are no Wnt pathway inhibitors approved for therapeutic use.  A number of 
companies are investigating porcupine inhibitors in Phase 1/2 clinical trials, these compounds 
are;: WNT974, ETC-159 and XNW7201, CGX1321. (Table 1) 
 
Data from the completed Phase 1, open-label trial of WNT974, administered in monotherapy 
have recently been published (NCT01351103). {Rodon, 2021 Ref 35} In this study, 94 
patients received oral WNT974 at doses of 5–30 mg QD, 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 two Grade 3 spinal fractures. No OR evaluation criteria 
in solid tumors (RECIST) responses were reported but 15 patients (16%) had stable disease 
(median duration 19.9 weeks). In the expansion cohort, SD was observed in 10/28 patients 
(36%), which was enriched in patients with RNF43 mutations.  
 
WNT974 is also being evaluated in an ongoing Phase 1 dose-escalation study (NCT01351103) 
in combination with spartalizumab, an anti-PD1 antibody.{Janku, 2020 Ref 19}  At the time 
of the last report, 32 patients with advanced/metastatic solid tumours have been enrolled 
including cutaneous melanoma, uveal melanoma, lung SCC, HNSCC, pancreatic cancer, 
cervical cancer and TNBC. Seventeen patients (melanoma, lung SCC, HNSCC) were 
refractory (best response was PD) to prior anti-PD1. WNT974 was administered orally QD and 
administered either on Days 1-8 or 1-15 in Cycle 1 (28-day cycle) only or in Cycles 1-4. 
Spartalizumab was administered at 400 mg QD every 28 days starting on Day 1. The safety of 
the combination was largely consistent with either agent administered as monotherapy. Two 
DLTs were reported (Grade 2 spinal compression fracture [study Day 9] after 2.5 mg Day 1-8 
Cycles 1-4) and Grade 3 arthralgia (2.5 mg Days1-15 Cycle 1 only). No MTD had been 
established.{Janku, 2020 Ref 19} 
The DCR (SD + PR + CR) reported was 41% (13/32), which included 12 patients who achieved 
SD and one (TNBC) who achieved a PR. Of patients who received prior anti-PD1, 47% 
achieved SD (9/19). The majority of these patients were refractory to prior anti-PD1 treatment 
(17/19). All five patients with uveal melanoma achieved durable SD of > 24 weeks duration. 


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The study is ongoing with further recruitment of uveal melanoma patients planned in addition 
to evaluating whether AXIN2 mRNA levels may be predictive of clinical benefit. 
Phase 1a safety data from an ongoing FTIM clinical study of the small molecule PORCN 
inhibitor ETC-159 (NCT02521844), were presented in a poster at the ASCO 2017 annual 
meeting {Ng, 2017 #10270}.  Twenty advanced solid tumour patients were treated in the dose-
escalation phase (1–40 mg ETC-159, QOD in a 28-day cycle).  Two DLTs were reported 
(hyperbilirubinemia at 16 mg and a skeletal fragility fracture at 30 mg) and the most common 
AEs (irrespective of causality) were anorexia (30%), fatigue (30%), vomiting (30%), dysgeusia 
(30%), increased β-CTX (30%), nausea (20%) and constipation (20%). In the 30 mg cohort, 
two of five patients experienced bone-fragility fractures (one of these was classed as a DLT 
while the other was outside the DLT period) and four out of five patients experienced a 
doubling from baseline and increase to >1000 pg/mL in serum β-CTX levels.  These patients 
with increased β-CTX (defined as a doubling from baseline to a level above 1000 pg/mL) were 
given bone protective treatments (denosumab or bisphosphonate), which normalised β-CTX 
levels.  The MTD was therefore declared at 30 mg.  Efficacy analysis in the first twenty patients 
showed that five had SD. 
CGX1321 (Curegenix Inc) is a porcupine inhibitor in Phase 1 development in Asia as 
monotherapy in advanced solid tumours and in Phase 1b in combination with pembrolizumab 
in patients with advanced GI tumours (CRC, gastric, pancreatic, bile duct, hepatocellular, 
oesophageal and GI cancers). No clinical data have been reported to date on CGX1321. 
 


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Table 1 
Wnt Pathway Clinical Trials 
PORCN 
Inhibitor  
Global Status, 
Trial ID, 
Location 
Tumor Type 
Drugs tested 
Patient 
segment 
Prior SoC 
treatment  
CGX-1321 
 
Phase1/1b 
(recruiting) 
 
NCT02675946, 
US and OUS 
Colorectal, 
esophageal, 
gastric, liver, 
pancreatic, 
unspecific solid 
tumors 
CGX-1321; 
pembrolizumab1  
Second line 
Stage III, IV 
 
Patients who have 
relapsed, are 
refractory to, or are 
not considered 
medically suitable to 
receive SoC 
treatment. 
Phase 1 
(recruiting) 
 
NCT03507998, 
OUS 
Colorectal, 
esophageal, 
gastric, liver, 
pancreatic, 
unspecified 
solid tumors2 
CGX-1321 
Second line 
Stage III, IV 
 
Histologically 
diagnosed tumors 
that have relapsed, 
are refractory to, or 
are not considered 
medically suitable to 
receive SoC 
treatment. 
ETC-159 
Phase 1a/b 
(recruiting)  
 
NCT02521844, 
US and OUS 
Colorectal, 
endometrial, 
ovarian, 
unspecified 
solid tumors 
ETC-159; 
pembrolizumab1  
RSPO fusion 
for MMS 
colorectal 
cancer; MMS-
ovarian, 
MMS-
endometrial  
 
Second line 
Stage III, IV 
 
Histologically or 
cytologically 
confirmed advanced 
or metastatic tumors, 
that are unresectable 
solid malignancies, 
and that are 
refractory, intolerant 
or not suitable to 
available treatment. 
WNT-974/ 
LGK-974 
Phase 1 
(recruiting) 
 
NCT01351103, 
US and OUS 
Breast, 
cervical, 
colorectal, 
esophageal, 
head/neck, 
lung, non-
small-cell, 
melanoma, 
pancreatic2 
LGK-974; 
spartalizumab1,5 
BRAF, HER2-
negative, 
Second line 
Stage II, III, 
IV, triple 
receptor-
negative 
 
Patients who have 
progressed despite 
standard therapy or 
for which no 
effective standard 
therapy exists. 
Phase 1b/2 
(completed) 
 
NCT02278133, 
US and OUS 
Colorectal2 
LGK-974, 
cetuximab3, 
encorafenib4 
BRAF 
second line 
Stage IV 
 
Patients with 
BRAFV600-mutant 
KRAS wild type 
with RNF43 
mutation and/or 
RSPO fusion in 
metastatic colorectal 
cancer who have 
progressed after at 


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least one prior SoC 
regimen or are 
intolerant to 
irinotecan-based 
regimens. 
XNW-
7201 
Phase 1 
(recruiting) 
NCT03901950, 
OUS 
 
Unspecified 
solid tumors  
 
XNW-7201 
Second line 
Stage III 
Stage IV 
 
Patients with 
histologically or 
cytologically 
confirmed advanced 
solid tumors after 
failure of SoC, or 
intolerability to SoC, 
or with no SoC. 
1Anti-PD-1 antibody; 2 includes evaluation of PORCN in tumors with aberrations in the WNT signalling 
pathway (RSPO fusion or RNF43); 3 EGFR antagonist; 4 BRAF kinase inhibitor; 5Unapproved product; US = 
United States; MMS = microsatellite stable; OUS = Out of the United States, SoC=standard of care. 
 
 
1.2.6 Tolerability of Targeting Porcupine 
An update of the tolerability of RXC004 in the current study can be found in Section  1.7.1.2. 
The safety profile of RXC004 monotherapy is similar to that reported for two other porcupine 
inhibitors, ETC-159 and WNT974, in clinical trials, which demonstrated a tolerable safety 
profile for this pharmacological class at doses with confirmed Wnt pathway inhibition, as 
described in Section 1.2.5. {Janku, 2020 Ref 19;Ng, 2017 #10831}(Janku et al 2015 Ref 18, 
Rodon Ref 35 and Ng et al 2017 Ref 30) 
As well as having a role in tumour development the Wnt pathway is involved in tissue 
homeostasis in the GI tract and in bone. Pre-clinical studies have demonstrated a therapeutic 
margin between the exposure levels required for anti-cancer efficacy and the emergence of on-
target GI side effects with porcupine inhibitors. This is in contrast to other approaches targeting 
the Wnt pathway such as tankyrase inhibition, in which the therapeutic window was shown to 
be <1. {Zhong, 2016 Ref 50}  
1.3 Non-clinical Information and Correlative Studies 
1.3.1 Pre-clinical Primary Pharmacology Studies 
In vitro cellular assays were used to define the Wnt pathway inhibitory activity of RXC004. 
RXC004 was tested for its ability to reduce production of Wnt ligand from Wnt producing 
mouse L-cells. The amount of Wnt released from these cells was then quantitated by use of a 
reporter assay. Reporter cells are transfected with the luciferase gene under the control of 


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β-catenin transcriptional response elements. RXC004 was shown to potently inhibit release of 
Wnt from the mouse L cells; RXC004 had a pIC50 of 10.2 in this reporter assay. In addition, it 
was also demonstrated that addition of exogenous recombinant Wnt ligand had the ability to 
“rescue” the inhibition of Wnt pathway by RXC004 in this reporter assay which supports that 
RXC004 is inhibiting Wnt signalling upstream of Wnt ligand production by inhibiting 
PORCN. To further confirm the mechanism of action of RXC004 Wnt palmitoylation was 
directly monitored in HEK293 cells. It was demonstrated that 100 nM RXC004 decreased 
detectable labelled palmitic acid conjugated to Wnt, supporting that RXC004 directly inhibits 
PORCN.  
The anti-proliferative activity of RXC004 was tested in HPAF-II and Capan-2 human 
pancreatic ductal adenocarcinoma (PDAC) and SNU-1411 human CRC cell lines.  HPAF-II 
and Capan-2 cell lines harbour RNF43 mutations that are predicted to result in LoF of RNF43, 
while the SNU-1411 cell line harbours a RSPO fusion. RXC004 was shown to be anti-
proliferative in Capan-2, HPAF-II and SNU-1411 cell lines with pIC50 of 9.4, 8.8 and 8.6, 
respectively.  
Pre-clinical anti-tumour efficacy of RXC004 as a single agent was evaluated in a Capan-2 and 
a SNU1411 tumour xenograft model, and a gastric cancer PDX model. Both the Capan and the 
gastric PDX models have RNF43 LoF mutations, The SNU1411 model has an RSPO fusion. 
In the Capan-2 xenograft model RXC004 caused significant TGI when dosed at 1.5 mg/kg 
BID, TGI = 65.6%; and at 5 mg/kg QD, TGI= 67.6%. RXC004 was demonstrated to cause 
tumour regression (-16.9%) when dosed at 5 mg/kg BID in this model. In the gastric cancer 
PDX model RXC004 caused significant tumour growth inhibition when dosed at 5 mg/kg QD 
(TGI=49%). In the SNU-1411 model, RXC004 at 1.5 mg/kg QD, 5 mg/kg QD, 1.5 mg/kg BID 
and 1.5 mg/kg BID 5 on/2 off significantly slowed the growth of SNU-1411 tumours compared 
with vehicle-treated animals with T/C values of 53.4% (p<0.05), 64.0% (p<0.01), 58.2% 
(p<0.01) and 64.1% (p<0.01), respectively. 
In addition to single-agent monotherapy efficacy in gastric, colorectal and pancreatic cancer 
models, RXC004 has been tested in the immune competent mouse syngeneic models CT26 
and B16. Redx has demonstrated efficacy by an immune system-mediated mechanism with 
RXC004 in combination with an anti-PD1 antibody in the CT26 mouse syngeneic colorectal 
tumour model. RXC004/anti-PD-1 combination therapy results in a significant decrease in 
Treg cells and a significant increase in the cytotoxic to Treg T cell ratio compared to either 
agent alone. In addition, RXC004 has monotherapy efficacy in the B16 melanoma mouse 
syngeneic model. This efficacy is dependent on an intact immune system and correlates with 
RXC004 causing a decrease in MDSCs in the tumours of this model. 


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1.3.2 Pre-clinical Toxicology and Safety Pharmacology Studies 
The preclinical safety studies conducted with RXC004 included oral GLP toxicology studies 
in rats and dogs for up to 28 days, in vitro genetic toxicology studies, secondary and safety 
pharmacology studies and an assessment of phototoxicity. 
Oral dosing of RXC004 to rats and dogs for up to one month was associated primarily with 
dose-dependent effects on the GI tract and bone.  Effects on mobility, food consumption and 
body weight were dose limiting.   
In the one-month rat GLP toxicity study, animals were dosed orally with 1, 3 or 5 mg/kg/day. 
Dose-dependent growth plate dysplasia, reduced trabecular bone, and fractures were variably 
present in the femur and femoro-tibial joint in both sexes at all dose levels. Decreased bone 
was present in the sternum of males administered 3 or 5 mg/kg/day and females at all dose 
levels.  Higher marrow fat levels were variably observed in the femur and sternum of both 
sexes at all dose levels. Degeneration, inflammation, erosion and ulceration were recorded in 
the large and small intestine of both sexes. Acinar dilatation was present in the prostate of 
males administered 5 mg/kg/day. At the end of the recovery phase, findings in the small 
intestines and prostate had fully reversed with partial recovery of the findings in the femur, 
femoro-tibial joint, and sternum.   
In the dog one-month GLP toxicity study, animals were dosed orally with 5, 10, or 
15 mg/kg/day. Administration of 15 mg/kg/day RXC004 to dogs was associated with impaired 
mobility (stiff gait) with intermittent tremors, slow movements, subdued behaviour, and 
swollen wrist joints noted in several animals. Two female dogs were removed from the study 
at the end of Week 1, due to the severity of these signs.  Bone lesions (growth-plate dysplasia) 
were considered to be the cause of these observations.  At the recovery sacrifice, growth plate 
dysplasia was still present in the carpus of one male administered 15 mg/kg/day. The dose level 
of 5 mg/kg/day is considered the ‘no-observed AE-level’ (NOAEL).  
The majority of the findings in both rats and dogs were considered to be related to on-target 
pharmacology, resulting from inhibition of porcupine and reduction of Wnt pathway 
signalling. 
An in vivo cardiovascular assessment was conducted in a group of telemetered beagle dogs.  
No test article-related effects on ECG, haemodynamics or body temperature were observed 
following single oral administration of RXC004 up to 50 mg/kg. 
 
RXC004 absorbs light above 290 nm in the UV/visible spectrum and is therefore considered 
to be potentially phototoxic. RXC004 was not genotoxic in vitro in the Ames test or 
micronucleus assay. 
Overall, the results from the toxicology studies support the progression into clinical trials in 
patients with advanced cancer. 


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For additional details, please refer to the IB. 


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1.4 Overall Study Design and Flow Chart 
The design is summarised as follows: 
Figure 2  
Overall Study Design 
 
 
 
The study is a modular Phase1, dose-escalation, open-label study to assess the safety, 
tolerability, PK and preliminary anti-tumour activity of RXC004 in monotherapy and in 
combination in patients with advanced malignancies.  
The study started with the RXC004 monotherapy module (Module 1), a monotherapy dose 
escalation to identify the MBAD, MTD or MFD in multiple patient cohorts.  The recommended 
RXC004 monotherapy dose for further development was 2 mg QD.  A summary of the 
monotherapy data is provided in Section 1.7.1.2. A RXC004 and nivolumab combination 
module (Module 2) was added to the protocol using a fixed-dose nivolumab (anti PD-1) 
monoclonal antibody. Nivolumab will be given at the FDA-approved dose/schedule for MSI-
H CRC, while RXC004 will be dose escalated up to a MTD for the combination. 
An RXC004 monotherapy scheduling module (Module 3) was added with this amendment.  
Module 3 will investigate whether alternative dosing schedules are tolerated in selected Wnt 
pathway activated patients. Two different RXC004 monotherapy schedules will initially be 


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investigated in Module 3 – 2 mg QD for 4 days, followed by three days off each week (Arm 
1), and 2 mg QD for 2 weeks  followed by one week off  (Arm 2).  Additional arms with 
alternative schedules may be added, after review by the SRC. 
 
Further modules may be added following a substantial protocol amendment to explore the 
following in patients with locally advanced, unresectable and/or metastatic solid malignancies: 
• Combination of RXC004 with SoC therapy 
• RXC004 formulation switches 
• Potential effects of food on the PK of RXC004 
 
1.5 Blinding 
This is an open-label, non-comparative study so blinding is not required. 
1.6 Rationale  
The mechanism of action of RXC004 provides the potential for monotherapy efficacy but 
also to combine with a number of anti-cancer treatments, to result in either synergistic or 
additive activity. This study is, therefore, an adaptive modular study in design, allowing 
evaluation of the safety, tolerability, PK and anti-tumour activity of RXC004 at increasing 
doses, initially as monotherapy and then in combination with nivolumab, an anti-PD1 
immune-checkpoint inhibitor. Other combinations may be evaluated e.g. RXC004 with SoC 
chemotherapeutic and/or targeted treatments in patients with advanced 
malignancies.{Biankin, 2015 Ref 1; Emens, 2016 Ref 8; Sharma, 2016 Ref 38}. Additional 
modules may be added to explore formulation switches or potential food effects at a later 
date. 
Key aspects of the study, such as the revised starting dose of RXC004 in Module 1 (0.5mg), 
and the dose escalation and cohort size of all study modules, are based upon the clinical PK 
data from Patient 001/001(10mg) and also accepted methodology from other porcupine 
inhibitor Phase 1 oncology studies.{Ivy, 2010 Ref 17} 
The collection of samples is included to allow characterisation of the PK of RXC004, and, if 
appropriate, investigation of the presence of and/or identity of metabolites of RXC004 to allow 
the Sponsor to fulfil regulatory requirements related to the testing of the safety of RXC004 and 
its metabolites. 
As part of the clinical drug-development programme for RXC004, the Sponsor plans to include 
investigations into variations in pharmacodynamic and exploratory biomarker profiles and 
their relationship to drug effect. These biomarkers may be derived from DNA, RNA), proteins 
and/or metabolites. There are many potential benefits of this exploratory research, including 
the possibility to identify patients most likely to benefit from treatment, explain outliers or 


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non-responders or explain adverse reactions related to drug exposure. This research may result 
in an understanding of the impact of variation between individuals and how this information 
can be used to bring better drugs to the clinic. 
The results from this study will form the basis for decisions regarding future studies. 
1.7 Overall Study Benefit-Risk and Ethical Assessment 
RXC004, in this current study, is considered to have a positive benefit-risk profile for patients 
with advanced cancers with high Wnt ligand dependency, when given at doses up to and 
including 2 mg QD as a monotherapy.  RXC004 also has the potential to enhance the activity 
of immune checkpoint inhibitors e.g. PD-1 or PD-L1 antibodies in patients with advanced 
cancers. 
 
1.7.1 RXC004 Monotherapy 
1.7.1.1 Potential Benefits 
Although there can be no certainty of clinical benefit to patients, particularly in this initial 
study in patients with locally advanced and unresectable or metastatic tumours, non-clinical 
data with RXC004 support the hypothesis that as a PORCN inhibitor, RXC004 would be 
expected to have utility as a therapeutic agent initially in advanced malignancies and, in due 
course, for earlier stages of disease management. 
RXC004 monotherapy treatment may offer the potential of clinical benefit in cancer patients 
by two different mechanisms of action. First it may benefit patients who have a specific Wnt 
pathway alteration (including RNF43 mutation or RSPO fusion) and second it may act as an 
immune-oncology agent facilitating an immune response by converting immunogenically 
“cold” tumours to immunogenically “hot” tumours.  
At the initiation of this study, the potential for monotherapy clinical benefit in unselected 
patients (patients without RNF43 LoF or RSPO fusion and cholangiocarcinoma patients) was 
unknown but was considered to be likely significantly less than in selected patients (RNF43 
LoF or RSPO fusion patients and cholangiocarcinoma patients). In Modules 1 and 2  , patients 
were able to  participate in an optional pre-screen, in which archival tumours could be 
genetically screened for upstream Wnt signalling pathway aberrations. The data from this 
screening could be used to retrospectively correlate presence of RNF43 LoF or RSPO fusions 
to response to study treatment.  
One of the important emerging opportunities is the growing evidence that Wnt signalling 
may subvert cancer immunosurveillance, hence promoting immunoevasion and resistance to 
multiple immunotherapeutics, including immune checkpoint blockers.{Wang, 2018 Ref 


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48;Galluzzi, 2018 Ref 11;Spranger, 2015 Ref 39;Luke, 2019 Ref 25} Redx therefore believes 
that  RXC004, used as a monotherapy or in combination with an immune checkpoint blocker, 
could be of benefit to a broader unselected metastatic cancer patient population through this 
mechanism.  
 In Module 1, 5/18 RECIST-evaluable patients had SD, in one case lasting for up to 26 
weeks. All five of these patients had Wnt-ligand-dependent tumours . None of the patients 
with Wnt ligand–independent tumours had SD. Following this observation, Module 3 
(intermittent monotherapy doses) was designed to enrol only patients with Wnt ligand-
dependent tumours to receive RXC004 monotherapy, in order for patients to have the best 
chance of experiencing clinical efficacy.  
Potential patients will be fully informed of the risks and requirements of the study. During 
the study patients will be given any new information that may affect their decision to 
continue participation. They will be informed that their consent to participate in the study is 
voluntary and may be withdrawn at any time with no reason given and without penalty or 
loss of benefits to which they would otherwise be entitled. Only patients who are fully able to 
understand the risks, benefits, and potential AEs of the study, and provide their consent 
voluntarily will be enrolled. 
Please refer to IB for further information. 
 
1.7.1.2 Potential Risks 
As of 30th July 2021, 25 patients have been dosed with RXC004 in Module 1 of the current 
study, at doses of 0.5mg-10mg QD, in which doses of up to 2 mg QD were found to be 
tolerable and safe. The most frequently occurring TEAEs were fatigue (64%), nausea (56%), 
decreased appetite (48%), vomiting (40%), dysgeusia (40%), diarrhoea (32%), aspartate 
aminotransferase increased (28%), and constipation (20%).    
Five patients reported ≥Grade 3 AEs that were assessed by the Investigators as possibly or 
probably related to RXC004: Grade 3 weight loss (1.5 mg); Grade 3 
nausea/vomiting/diarrhoea (1.5 mg); Grade 3 pancreatitis (2 mg); Grade 3 enteritis and Grade 
5 subdural hematoma from a fall (3 mg); Grade 3 diarrhoea/proctitis/hyponatreamia (10mg). 
Three DLTs have been reported in the study: Grade 3 diarrhoea in a patient at RXC004 10 
mg QD (before the study was re-started at RXC004 0.5 mg), Grade 3 enteritis in a patient at 
RXC004 3 mg and Grade 2 colitis in patient at  RXC004 3 mg.   


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As of 30th July 2021, a total of 16 SAEs were reported in 11 patients. Apart from diarrhoea, 
which occurred in two patients, and colitis/enteritis, which are similar events and occurred in 
two patients, no SAEs were reported in more than one patient. Nine of the 16 SAEs reported 
in patients who received RXC004 monotherapy were assessed by the investigator and the 
Sponsor as unrelated to RXC004. The other seven SAEs were assessed by the Investigator as 
possibly or probably related to RXC004.  Six of these treatment-related SAEs occurred at 
RXC004 daily doses that were subsequently declared SRC to be not tolerated (RXC004 3 mg 
and 10 mg QD): 
• 
Two SAEs of NCI CTCAE Grade 3/2 diarrhoea that occurred in one patient at RXC004 
10 mg QD (before the study was re-started) that led to discontinuation of study drug. 
• 
One SAE of NCI CTCAE Grade 3 diarrhoea that occurred at RXC004 1.5 mg QD and 
led to discontinuation of study drug. The event was also associated with a Clostridium difficile 
infection and subsequently resolved/recovered.  
• 
One SAE of NCI CTCAE Grade 2 colitis that occurred at RXC004 3 mg QD.  The 
event subsequently resolved and the patient continued study treatment at a lower dose 
(RXC004 1.5 mg). 
• 
One SAE of NCI CTCAE Grade 3 enteritis that occurred at RXC004 3 mg QD.  The 
event was unresolved at the time that the patient subsequently died due to a subdural hematoma 
following a fall (Patient 0003/019). 
• 
One SAE of NCI CTCAE Grade 2 humerus fracture (following a fall while hospitalised 
for enteritis – Patient 0003/019) occurred at RXC004 3 mg QD.  The event was unresolved at 
the time that the patient subsequently died due to a subdural hematoma (Patient 0003/019). 
• 
One NCI CTCAE Grade 5 SAE of subdural hematoma (following a fall while 
hospitalised for enteritis – Patient 0003/019) occurred at RXC004 3 mg QD. 
 
The MTD for Module 1 has been declared as RXC004 2 mg QD.  At doses up to and 
including 2 mg QD, the most common TRAEs were fatigue (10/20 patients), nausea (7/20), 
anorexia (6/20), dysgeusia (6/20), and vomiting (4/20). 
The principal on-target AEs 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 GI tract 
because of the role of Wnt in the immune micro-environment.  


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More detailed information about the RXC004 clinical data may be found in the most recent 
IB and Development Safety Update Report. 
1.7.1.2.1  
Bone Effects 
Wnt signalling is known to play a prominent role controlling many aspects of skeletal 
development and homeostasis. It promotes bone formation whereas its inactivation leads to 
more osteopenic phenotypes. It is recognised that blockade of Wnt signalling, for example 
through PORCN inhibition, would be expected to lead to a movement of the bone remodelling 
balance in a catabolic direction..{Kahn, 2014 Ref 21}  Following dosing with RXC004, it is 
not surprising therefore that toxicology studies in both rats and dogs have identified bone as a 
pharmacodynamic target organ in a dose-dependent manner. These changes are considered to 
be a direct consequence of on-target pharmacology.   
In this study, bone fractures (vertebral [T9] and clavicular in normal bone [non-metastatic]) 
occurred in Patient 001/001, treated with RXC004 10 mg QD, which led to a trial interruption. 
PK analysis indicated that RXC004 exposure levels in this patient were significantly higher 
than had been predicted pre-clinically due to a longer than predicted half life. As bone fractures 
were observed in the first patient dosed on study RXC004/0001 (10 mg) and other Phase 1 
clinical trials of Wnt inhibitors, a comprehensive bone-management plan was implemented in 
the protocol. Patients at significant risk of bone fracture are excluded from study entry, patients 
are given prophylactic denosumab and bone turnover biomarkers are monitored to identify any 
increased risk of bone fractures. The bone management plan (Section 3.4.1) includes: 
• Exclusion of patients with bone metastases  
• Exclusion of patients at higher risk of bone fractures 
• Monitoring of blood bone-turnover markers and BMD 
• Intervention measures for patients with increased bone-fracture risk on RXC004 
treatment 
• Use of prophylactic denosumab (anti-RANKL monoclonal antibody) in all patients to 
maintain BMD from the RXC004 1.5-mg monotherapy cohort (Module 1, Cohort 3). 
Importantly, the amended starting dose of RXC004 was reduced 20-fold from the original 
study first dose to a dose of 0.5 mg QD. 
In this study, all patients from the 1.5-mg dosing group have received prophylactic 
denosumab (120 mg s.c. QM) from cohort 3 (1.5mg) along with vitamin D3 (cholecalciferol 
800 IU QD) and calcium (1000-1500 mg QD) supplements from the time of signing the ICF 
and throughout the RXC004 treatment.  
Since prophylactic denosumab was introduced for all patients, β-CTX levels have remained at 
or below the baseline levels observed and no patient has lost significant BMD (>7% decrease 


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in BMD) on DEXA scanning while receiving RXC004. One patient who received a dose of 3 
mg QD experienced a bone fracture after a fall. No spontaneous fractures were reported. 
 
1.7.1.2.2  
Diarrhoea and Colitis 
Wnt signalling is known to play a prominent role in adult intestinal homeostasis.{Gregorieff, 
2005 Ref 14} Reversible degeneration and inflammation of the GI mucosa was also observed 
in the pre-clinical toxicology studies conducted with RXC004.  Other molecules that reduce 
Wnt pathway activity have previously been dosed in man and have also been associated with 
GI AEs.{Artem Blagodatski1†, 2014 Ref 2}   
RXC004-related diarrhoea has been observed in 4 /25 patients treated with RXC004 and in 
two cases it was an SAE. One patient who received 10 mg (the highest RXC004 dose 
administered) developed an SAE of Grade 3 diarrhoea in Cycle 1, which responded to 
treatment with corticosteroids but recurred as Grade 2 diarrhoea three weeks after stopping 
treatment, possibly due to steroids being stopped.  One patient who received RXC004 1.5 mg 
developed an SAE of Grade 3 diarrhoea on Cycle 2 Day 10, which lasted for 10 days.   
 
Based on data up 30th July 2021, intestinal inflammation events (colitis, enteritis or 
enterocolitis) have been reported in four (4) patients. CTCAE Grade 3 RXC004-related 
colitis occurred in the patient who received 10 mg and CTCAE Grade 3 enteritis occurred in 
a patient who received 3 mg. CTCAE Grade 2 colitis developed in two more patients, who 
started treatment with RXC004 3 mg RXC004 QD. One Grade 2 event presented 
symptomatically in Cycle 2 and, in the fourth case, Grade 2 colitis was discovered on the 
RECIST staging scan in Cycle 2. Symptoms included abdominal pain, intermittent 
constipation, diarrhoea, nausea and/or vomiting. Blood and mucus in the stool were not 
apparent in the cases reported to date. 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, events of ileitis and colitis were subsequently 
reported in the ongoing Phase 2 studies (RXC004/0002 and RXC004/0003), at doses of 2mg 
QD, so there is a potential risk for colitis in patients receiving RXC004 2mg QD as a 
monotherapy. It is hoped that the intermittent dosing  schedules to be studies in Module 3 
may reduce the risk of this event.  


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The RXC004/0001 study protocol excludes patients with persistent ≥Grade 2 or higher 
diarrhoea (any cause) that has not resolved or improved with appropriate treatment prior to 
study enrolment and contains guidelines for investigation and management diarrhoea/colitis 
(Appendix 5).  
1.7.1.2.3  
Dysgeusia Events 
RXC004-related dysgeusia was observed in 6/20 patients who received doses of ≤ 2 mg QD, 
in 3/4 patients receiving 3 mg QD, and by the one patient who received 10 mg QD. An 
assessment for further characterisation of this event in Module 3, and guidance for the 
management of dysgeusia has been added to this protocol (Appendix 6) 
1.7.1.2.4 Reproductive and Teratogenic Toxicity 
No reproductive toxicology or teratogenic studies have been conducted with RXC004 to date, 
and it is unknown whether the drug is excreted in human milk. Therefore, WOCPB and men 
should agree to use adequate contraception prior to study entry and for the duration of study 
participation, and women who are breast feeding are excluded from the study. Both women 
and men should be fully informed of the lack of reproductive toxicity testing, and women must 
have a negative pregnancy test prior to enrolment. 
Please refer to the IB for further information. 
1.7.2 RXC004 in Combination with Nivolumab  
1.7.2.1 Potential Benefits 
The Wnt pathway has been widely described as being a key pathway in immune evasion in 
various common tumours.{Galluzzi, 2018 Ref 11} {Spranger, 2015 Ref 39} Wnt pathway-
activated tumours have been shown to be poorly infiltrated by immune cells {Grasso, 2018 
#Ref 13} and pharmacological inhibition of Wnt signalling promotes cytotoxic T cell 
infiltration sensitising cancer cells to PD-1 inhibitors.{Feng, 2019 Ref 9;Xiao, 2018 Ref 49}  
Wnt pathway activation has been linked to resistance to checkpoint inhibitors such as anti-
PDL1 and anti-PD1. {Spranger, 2018 Ref 41;Wang, 2018 Ref 48;Galluzzi, 2018 Ref 11} 
Spranger and colleagues stratified 266 human metastatic melanoma tumour samples by 
cytotoxic T cell burden (CD8 +ve T cells).{Spranger, 2015 Ref 39}  Wnt pathway activation 
(β-catenin positive cells) correlated with reduced cytotoxic CD8 +ve T cell infiltrate in 
melanoma patients. These initial data in melanoma linking Wnt pathway activation to 
exclusion of tumour fighting T cells from the microenvironment have now been extended to 
bladder cancer {Sweis, 2016 Ref 43} and in a recent presentation at ASCO “most solid 
tumours”.{Luke, 2016 Ref 25}  


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WNT974, a PORCN inhibitor has been combined with anti-PD1 (spartalizumab) in an ongoing 
Phase1 trial in 32 patients.{Janku, 2020 Ref 19} The combination was well tolerated with 
efficacy being observed in patients (DCR of 41%) (see section  1.2.5 for details). Durable SD 
was observed in patients who were refractory to prior anti-PD1 treatment. 
In-house data with RXC004 in mouse syngeneic models have demonstrated that RXC004 
combined with anti-PD1 results in an increase in the ratio of cytotoxic CD8 positive cells to 
regulatory T cells. Thus, there is a clear rationale for the combination of RXC004 with 
checkpoint inhibitors. 
Nivolumab, is currently licensed for use as treatment for patients with the following: 
• Unresectable or metastatic melanoma in monotherapy or in combination with 
ipilimumab (approved by EMA and FDA). 
• Adjuvant treatment of melanoma with lymph node involvement or metastatic disease 
that has undergone complete resection (approved by EMA and FDA). 
• Locally advanced or metastatic non-small cell lung cancer (NSCLC) with progression 
on or after platinum-based chemotherapy (approved by EMA and FDA). 
• Metastatic small-cell lung cancer (SCLC) in combination with ipilimumab for first-line 
treatment in adults with PD-L1 and no other EGFR or ALK genomic alterations) ; it is 
also indicated after progression on platinum-based chemotherapy and at least one other 
line of therapy (approved by FDA and EMA). Patients with EGFR/ALK genomic 
alterations should have disease progression on FDA-approved therapy 
• Advanced renal cell cancer;  after prior anti-angiogenic therapy (monotherapy) or as 
first line treatment for intermediate/poor-risk patients (in combination with 
ipilimumab); or in combination with cabozantinib for first-line treatment in adults.  
(approved by EMA and FDA). 
• Classical Hodgkin’s lymphoma (cHL) that has relapsed or progressed after autologous 
hematopoietic stem cell transplantation (HSCT) and post-transplantation brentuximab 
vedotin, or ≥3 lines of systemic therapy including HSCT (approved by EMA and FDA). 
• Recurrent or metastatic squamous-cell carcinoma of the head and neck (SCCHN) with 
disease progression on or after a platinum-based therapy (approved by EMA and FDA). 
• Locally advanced unresectable or metastatic urothelial carcinoma who have disease 
progression during or following platinum-containing chemotherapy (approved by 
EMA and FDA). 
• Treatment of patients with hepatocellular carcinoma who have previously received 
sorafenib (approved by FDA). 
• Treatment of patients with metastatic, mismatch repair deficient (dMMR) or 
microsatellite instability-high (MSI-H) CRC, as single agent or in combination with 


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ipilimumab who have progressed after fluoropyrimidine, oxaliplatin and irinotecan 
(single agent approved by FDA, combination approved by EMA and FDA). 
• Unresectable advance, recurrent or metastatic oesophageal squamous-cell carcinoma 
after prior therapy with fluoropyrimidine-and platinum-based chemotherapy (approved 
by EMA and FDA). 
• Gastric cancer, gastroesophageal junction cancer and adenocarcinoma, in combination 
with fluoropyrimidine- and platinum-based chemotherapy in patients with advanced or 
metastatic gastric cancer, gastroesophageal junction cancer and esophageal 
adenocarcinoma (approved by EMA and FDA). 
 
1.7.2.2 Potential Risks 
The clinical, pre-clinical and emerging safety profile has not identified any risks that would 
preclude investigation of a RXC004 and nivolumab combination in an advanced cancer setting. 
At high exposures of RXC004 the preclinical toxicities that overlap with those commonly seen 
with PD-1 inhibitors are those that affect the gut mucosa. 
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. AEs seen with 
checkpoint inhibitors are frequently due to immune-mediated mechanisms and can occur in 
any organ system. The most commonly seen immune-mediated effects include GI effects (e.g. 
diarrhoea or colitis), pneumonitis, hepatic events, skin rashes and dermatitis 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). For 
single-agent nivolumab, the most frequent SAEs reported in ≥2% of patients were 
colitis/diarrhea, hepatic events, abdominal pain, acute kidney injury, pyrexia, and dehydration. 
The most common AEs reported in monotherapy (in ≥20% of patients) were fatigue, diarrhoea, 
pyrexia, musculoskeletal pain, abdominal pain, pruritus, nausea, rash, decreased appetite, and 
vomiting.{Overman, 2017 Ref 34} 
Immune-mediated AEs 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. 
A detailed description of the chemistry, pharmacology, efficacy, and safety of nivolumab is 
provided in the nivolumab prescribing information. 


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The safety profile of RXC004 in combination with nivolumab is currently being investigated 
in Module 2.  Up to 30th July 2021, three patients had received treatment with a combination 
of RXC004 1 mg QD and nivolumab 480 mg i.v. Q4W.  Eight SAEs were reported in these 
three patients, all of which were assessed as unrelated to both RXC004 and nivolumab. These 
were: Grade-2 left-leg weakness and two Grade 2 infections (not otherwise specified) SAEs in 
one patient; a Grade-3 kidney infection and Grade 3 hepatic pain in another patient; and a 
Grade-2 hepatic pain and two Grade 3 ascites SAEs in the third patient. One patient 
discontinued treatment with RXC004 due to an SAE of ascites, NCI CTCAE Grade 3, which 
was unrelated to RXC004 or nivolumab. No Grade 4/5 events or DLTs have been reported in 
Module 2 to date. 
A modest and predictable safety profile was observed with another porcupine inhibitor, 
WNT974, in combination with the anti-PD1 agent spartalizumab (NCT01351103) in 32 
patients with metastatic solid tumours. All related AEs were Grade 1-2. One Grade 3 related 
AE of arthralgia was reported. The study authors concluded that the safety profile was 
consistent with that observed during treatment with either agent as a single agent.{Janku, 2020 
Ref 19} 
There is the potential for synergistic effect on gut mucosal toxicity for the combination of 
RXC004 and nivolumab treatment; careful monitoring of GI-related AEs and their sequelae 
will take place in this potential study module. 
 
 
1.8 Study Timetable and End of Study 
The end of the study is when the last module has been completed (last patient, last visit). 
The Sponsor may terminate this study at any time for reasons that include but are not limited 
to: 
− The discovery of an unexpected, significant, or unacceptable risk to the patients 
enrolled in the study 
− Failure of the Investigators to enter patients at an acceptable rate 
− A decision on the part of the Sponsor to modify/suspend or discontinue development 
of the drug. 
 
1.9 Study Objectives 
1.9.1 Primary Objectives 
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• To assess the safety and tolerability of RXC004 when given to patients with advanced 
malignances alone or in combination with anti-cancer treatments, and to define the 
doses and schedules for further clinical evaluation. 
1.9.2 Secondary Objectives 
The following secondary objectives apply to all modules of the study: 
• To characterise the PK profile of RXC004, following a single dose and at steady state 
after multiple dosing, when given orally alone or in combination with anti-cancer 
treatments. 
• To obtain a preliminary assessment of RXC004 activity by evaluation of 
pharmcodynamic  biomarker changes which may include, but are not limited to, Wnt 
pathway inhibition, gene expression signatures, and ctDNA levels. 
• To obtain a preliminary assessment of the anti-tumour activity of RXC004 as a single 
agent or in combination with anti-cancer treatments (to include assessment of ORR, 
DCR, DoR and PFS). 
1.9.3 Exploratory Objectives 
The following exploratory objectives apply to all modules of the study: 
• To obtain a preliminary assessment of RXC004 activity by evaluation of 
pharmacodynamic biomarkers from blood skin, and tumour, which may include, but 
are not limited to normal and tumour cell signalling pathway targets and modulation of 
gene expression, and measures of tumour infiltrating lymphocyte population.  
• 
To explore the relationship between PK and efficacy, safety, and blood borne and tissue 
biomarkers. 
• 
To collect and store pre-dose plasma and serum sample and/or analyse surplus blood 
or tissue including patient specific archival tumour tissue, if available, for potential 
future exploratory research into factors that may influence the development of agents 
to treat human disease and/or response to RXC004 (where response is defined broadly 
to include efficacy, tolerability or safety). This may include the analysis of tumour 
specific and circulating biomarkers, such as tumour DNA, mRNA, proteins or 
metabolites. In the event that additional tumour molecular profiling is required to 
understand further any response to RXC004, Redx may request a sample of the most 
recent tumour biopsy for additional research. 
• 
To investigate predictive markers and acquired resistance to RXC004 that may be 
observed in tumour from patients treated with RXC004. 
• 
To investigate the per-patient concordance between potential patient selection 
biomarker (and/or other molecular aberrations) and pharmacodynamic biomarkers as 
determined either by Redx or local test methods, in comparison to potential patient 


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selection biomarkers and pharmacodynamic biomarkers levels obtained by central 
laboratory tests. 
• 
Characterisation in paired tumour biopsies samples of the effect of RXC004 on changes 
in the tumour microenvironment including but not limited to effects on immune cell 
subpopulations. 
 
 


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2 SELECTION 
OF 
STUDY 
POPULATION 
AND 
RESTRICTIONS   
2.1 Inclusion Criteria 
2.1.1 Core Inclusion Criteria 
For inclusion in all modules of the study, all patients must fulfil all of the following criteria: 
1. Ability to give written informed consent prior to any study-specific screening 
procedures, sampling and analyses; including access to all archival tumour tissue 
taken within the last 18 months, with the understanding that the consent may be 
withdrawn by the patient at any time without prejudice 
2. Capable of understanding the protocol requirements, is willing and able to comply 
with the study protocol procedures, restrictions (Section 2.3) and has signed and 
dated the informed consent document 
3. Aged at least 18 years at time of screening. 
4. Patients must have histological or cytological confirmation of advanced 
malignancy not considered to be appropriate for further conventional treatment 
5. Evaluable disease, either measurable on imaging, or with informative tumour 
marker(s), as assessed by RECIST 1.1 (Appendix 4) or other relevant response 
assessment criteria for tumour type.  For RECIST 1.1, patients should have at least 
1 lesion that qualifies as a RECIST 1.1 target lesion at baseline (within 28 days of 
the first dose).  The use of scans obtained as part of standard clinical practice, prior 
to informed consent, will be accepted if they comply with RECIST 1.1 criteria and 
have been performed within the 28-day screening period. 
6. Patients must have recovered from toxicities of prior therapies. (i.e. to CTCAE 
≤ grade 2) apart from alopecia 
7. Eastern Cooperative Oncology Group (ECOG) (Appendix 3) or World Health 
Organisation (WHO) performance status 0 or 1 with no deterioration over the 
previous 2 weeks and an estimated life expectancy of greater than 12 weeks 
8. Organ Function Requirements - Patients must have adequate organ functions as 
defined below: 
− AST/ALT ≤ 2X ULN (upper limit of normal) [with no underlying Liver Metastasis] 
− AST/ALT ≤ 3X ULN [with underlying Liver Metastasis] 
− Total Bilirubin within normal range 
− Serum Creatinine ≤ 1.5X ULN 
− ANC ≥ 1500/μL 
− Platelets > 100,000/μL 
− Hb >9g/dL 


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9. Females must be using adequate contraceptive measures, must not be breast feeding 
and must have a negative pregnancy test prior to start of dosing if of child-bearing 
potential or must have evidence of non-child-bearing potential by fulfilling one of 
the following criteria at screening: 
− Post-menopausal defined as aged more than 50 years and amenorrhoeic for at least 
12 months following cessation of all exogenous hormonal treatments 
− Documentation of irreversible surgical sterilisation by hysterectomy, bilateral 
oophorectomy or bilateral salpingectomy but not tubal ligation 
− Amenorrhoeic for 12 months and serum follicle-stimulating hormone (FSH), 
luteinizing hormone (LH) and plasma oestradiol levels in the postmenopausal range 
for the institution 
10. Ability to swallow and retain oral medication  
 
2.1.2 Inclusion Criteria for Genetics Research 
For inclusion in the optional genetics research study patients must fulfil the following criteria: 
11. Provision of optional genetics research informed consent 
If a patient declines to participate in any optional component of the study, there will be no 
penalty or loss of benefit to the patient, and they will not be excluded from any other aspect of 
the main study 
2.1.3 Module 3-Specific Inclusion Criteria 
For inclusion in Module 3 study patients must also fulfil the following criteria: 
12. Patients with Wnt ligand-dependent solid tumours, defined as: 
• 
Biliary tract cancers 
• 
Thymus cancers (thymic and thymoma WHO classification) 
• 
Any solid tumour with documented aberration in RNF43 and/or RSPO from central 
pre-screening or from a recognised panel approved by the Sponsor.  See Section 
5.4.2.4 and Appendix 10 for more details  
Patients willing to have mandatory skin biopsies at baseline and on one occasion while on 
study treatment. See schedule of assessments (Appendix 9) for details.  
2.2 Exclusion Criteria 
2.2.1 Core Exclusion Criteria  
For inclusion in all modules of the study, all patients must not enter the study if any of the 
following exclusion criteria are fulfilled:  
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2. No other anti-cancer therapy, or other investigational product is permitted other than the 
agent(s) described in the relevant study module. 
• During the study period, patients using allowed hormonal therapy should maintain a 
constant dose and should not change existing regimen. 
• If a change in hormonal therapy is indicated, e.g. due to intolerable adverse effects, the 
regimen may be modified but change should be minimized thereafter. 
3. Patients with persistent grade 2 or higher diarrhoea (any cause) that has not resolved or 
improved with appropriate treatment prior to study enrolment 
4. Patients at higher risk of bone fractures, including; 
• Patients with bone metastases 
• Patients with β-CTX (bone turnover marker) of > 1000 pg/mL 
• 
Patients with Vitamin D [25(OH)D3] deficiency defined as < 30nmol/L (<12ng/mL). 
[Note - Patients who fail on this criteria alone can be retested within the screening 
window (see Sec 3.4.1.2)]   
• Patients with a corrected total serum calcium level of <2 mmol/L and serum magnesium 
level of < 0.60 mmol/L 
• Patients with osteoporosis (as defined by a T-score of < -2.5 at L/R total hip, L/R 
femoral neck, or 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 
and any ≥ grade 2 vertebral fracture on VFA) 
• 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. 
• 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. 
• Patients who have received oral or intravenous (i.v.) glucocorticoids for > 4weeks at 
daily doses equivalent to >7.5 mg of oral (p.o.) prednisolone within 6 weeks prior to 
study drug dosing 
5. Patients receiving radiation to more than 30% of the bone marrow, direct radiation to their 
spine or pelvis, or with a wide field of radiation within 4 weeks of the first dose of study 
treatment.  
6. Female patients who are pregnant or breast-feeding at entry 
7. QTcF prolongation (> 470 msec) 
8. Patients with any known uncontrolled inter-current illness including ongoing or active 
clinically significant infections, symptomatic congestive heart failure (with an Ejection 
Fraction (EF) ≤ 50% or the institutional lower limit of normal whichever is lower), 
hypertension, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social 
situations that would limit compliance with study requirements 
9. Patients with any of the following medications within 4 weeks prior to enrolment: 
− Anti-neoplastic agents 


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− Immunotherapy (mAbs, Interferons, Cytokines [except GCSF]) 
− Immunosuppressants (e.g. cyclosporin, rapamycin, tacrolimus, rituximab, 
alemtuzumab, natalizumab, etc.). 
− Another investigational drug 
 
10. Patients with any known severe allergies (e.g. anaphylaxis) to any active or inactive 
ingredients in the study drugs 
 
2.2.2 Module 2: RXC004- and Nivolumab-Specific Exclusion Criteria 
In addition to the core exclusion criteria, patients must not enter Module 2 if any of the 
following exclusion criteria are fulfilled: 
11. Patients with any contraindication to the use of Nivolumab as per approved county label 
(Summary of Product Characteristics or equivalent)  
12. Patients with active or prior documented autoimmune disorders, drug-induced immune 
disorders, or inflammatory disorders within the past 5 years, including inflammatory 
bowel disease, rheumatoid arthritis, immune hepatitis, pneumonitis, 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 
13. Patients with active infections, including tuberculosis, hepatitis B, hepatitis C or human 
immunodeficiency virus 
14. Use of any live vaccines against infectious diseases (eg, influenza nasal formulation, 
varicella) within 4 weeks (28 days) of initiation of study treatment 
15. Patients with body weight <40kg 
16. Patients with a history of allogeneic organ transplant or active primary immunodeficiency 
17. Patients with a known hypersensitivity to Nivolumab or any of the excipients of the 
product  
2.3 Subject Restrictions 
The following restrictions apply while the patient is receiving study treatment and for the 
specified times before and after: 


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• 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 taking RXC004 are advised to avoid exposure to direct sunlight and the use of 
tanning equipment. 
Male patients: 
• Men must use a condom (with spermicide) during the study, and for 1 week after the 
last dose of study drug, with all sexual partners 
• Where a sexual partner of a male participant is a WOCBP who is not using effective 
contraception, men must use a condom (with spermicide) during the study and for 6 
months after the last dose of a study drug 
• Must not donate sperm for 6 months after the last dose of study drug 
 
Female patients 
• Women with evidence of non-child-bearing potential at screening have no restrictions 
around contraception 
Women of child-bearing potential must use enhanced contraception during the 
study, and for 6 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 patient) 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.  
2.3.1 Concomitant Treatments 
All medications used during the study and taken within 30 days of the screening visit will be 
recorded on the CRF. 
Information on any treatment in the 4 weeks prior to starting study treatment and all 
concomitant treatments given during the study, with reasons for the treatment, will be recorded 
in the CRF. If medically feasible, patients taking regular medication should be maintained on 
it throughout the study period. 
Concomitant medication may be given as medically indicated within 30 days prior to 
administration of the study drug or within 5 half-lives of the chemical entity prior to 


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administration of the study drug, whichever is longer with the exception of prohibited 
concomitant medication (see Section Prohibited Concomitant Medication2.3.1.1) 
2.3.1.1 Prohibited Concomitant Medication 
The following concomitant medication is prohibited without approval from the Sponsor 
Physician: 
• The use of any natural/herbal products or other ‘folk remedies’ should be discouraged; 
approval required by Sponsor Physician 
• No growth factor support, blood products or prophylactic antibiotics are permitted 
during the DLT assessment periods in the study. Following this, it may be permitted 
following discussion with the PI and the Sponsor 
• No other chemotherapy, hormonal therapy (HRT and stable treatment of > 6 months 
with GnRH analogues are acceptable), or other investigational product is permitted 
other than the combination agent(s) described in the relevant study module 
• Live virus and bacterial vaccines should not be administered, e.g. yellow fever, 
measles, influenza nasal spray, rubella, mumps, typhoid, Mycobacterium tuberculosis 
(BCG), Yersinia pestis (EV series) whilst the patient is receiving study medication and 
during the 28-day follow-up period following IP discontinuation. An increased risk of 
infection by the administration of these vaccines has been observed with conventional 
chemotherapy and the effects with RXC004 are unknown. The administration of killed 
vaccines is allowed. Examples of killed vaccines are cholera, bubonic plague, polio, 
hepatitis A and rabies 
• Patients must not receive any other investigational drugs while on this study, other than 
the combination agent(s) described in the relevant study module   
• The use of some CYP3A4 inhibitors and inducers should be restricted throughout the 
study, as RXC004 is observed to be exclusively metabolised by CYP3A4. For a  list of 
prohibited CYP3A4 inhibitors and inducers please refer to Appendix 7. 
• For patients enrolled in Module 2, patients should not receive concurrent 
immunosuppressive medications.  The following exceptions are allowed: 
o Use of immunosuppressive medication for the management of IP-related AEs 
(as per Appendix 8) or colitis events (as per Appendix 5) 
o Use of topical, inhaled or intranasal corticosteroids. 
o Systemic steroids at doses less than 10 mg/day prednisone equivalent. 
 
2.3.1.2 Allowed medication 
Patients will be permitted to receive appropriate supportive care measures as deemed necessary 
by the treating physician including but not limited to the items outlined below: 


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• 
Opiates may be used for pain control and patients can receive preventive treatment for 
constipation 
• 
Hormone therapies are allowed for patients who have been identified as a hormone therapy 
user at the start of the study 
• 
Anticoagulant Therapy: patients who are taking warfarin may participate in this trial; 
however, it is recommended that prothrombin time (international normalised ratio (INR) 
and activated partial thromboplastin time (APTT)) be monitored carefully at least once per 
week for the first month, then monthly if the INR is stable. Subcutaneous heparin is 
permitted. 
• 
Diarrhoea: Diarrhoea should be promptly treated in line with the colitis  management and 
treatment guidelines Appendix 5. Anti-diarrheal agents should not be taken 
prophylactically. 
• 
Corticosteroids: Patients may receive on-study treatment oral or intravenous (i.v.) 
glucocorticoids for up to 4 weeks (at daily doses equivalent to <10 mg of oral (p.o.) 
prednisolone).  If steroids are required for treatment of colitis (as per Appendix 5), then 
study treatment should be held until steroids are tapered to  ≤10mg per day prednisone or 
equivalent.  .  Patients enrolled on Module 2 (RXC004 and nivolumab) may also receive 
treatment with steroids for immune-mediated AEs (as per Appendix 8.  Steroids should be 
tapered to ≤10 mg/day prednisone or equivalent before re-starting nivolumab.  Patients 
who require treatment with ≥10mg per day prednisone or equivalent for >8 weeks should 
permanently discontinue study treatment (RXC004 and nivolumab if applicable). 
• 
Patients may receive immunosuppressant (e.g. infliximab for colitis or mycophenolate for 
hepatitis) rescue medication required for colitis (as per Appendix 5) or nivolumab related 
immune mediated adverse events (as per Appendix 8).  Steroid refractory patients that 
require immunosuppressant treatment should permanently discontinue study treatment  
(RXC004 and nivolumab if applicable). 
• 
Nausea/vomiting: Anti-emetic treatment can be administered if required according to the 
guidelines of the participating centres, except for the first dose each patient takes. Nausea 
and vomiting should be treated aggressively, and strong consideration should be given to 
the administration of prophylactic anti-emetic therapy. 
• 
According to standard institutional practice. Patients should be strongly encouraged to 
maintain liberal oral fluid intake.  
• 
Anaemia: Transfusions may be used as clinically indicated for the treatment of anaemia, 
but should be clearly noted as concurrent medications. 
• 
Neutropenia: Colony-stimulating factors including G-CSF, pegylated G-CSF or GM-CSF 
according to Institutional Standards are allowed after the first cycle of therapy, following 
discussion with the PI and the Sponsor physician. 


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• 
Patients already receiving erythropoietin at the time of screening for the study may 
continue it providing they have been receiving it for more than one month at the time study 
treatment is started. Prophylactic erythropoietin should not be started during the DLT 
period but may be started during Cycle 2 and after, following discussion with the PI and 
Sponsor physician. 
 
2.3.1.3 Subsequent Therapies for Cancer 
Details of first and subsequent therapies for cancer and/or details of surgery for the treatment 
of the cancer, after discontinuation of treatment, will be collected. Reasons for starting 
subsequent anti-cancer therapies including access to other PORCN/Wnt pathway inhibitors 
or investigational drugs will be collected and included in the exploratory assessments. 
2.3.1.4 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 AEs 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 all relevant information should be recorded in the concomitant medication CRF 
(i.e. vaccine name, manufacturer, date(s) given and dose). 
 


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3 STUDY TREATMENT, CONDUCT, WITHDRAWAL – CORE 
3.1 Study Treatment  
Module-specific study treatment details are outlined in Section 5.2 (Module 1) Section 5.3 
(Module 2) and Section 5.4 (Module 3). 
Additional modules may be added at a later date (following a protocol amendment) to 
investigate combinations with anti-cancer treatments, and to investigate the effects of dosing 
with and without food on RXC004 PK parameters. RXC004 will be given as a flat dose at each 
dose level, based on a 60 Kg patient. Eligible participants will be enrolled in sequential cohorts 
treated with study treatment, while being monitored for safety and DLTs. 
During the dose escalation, patients will receive a single dose on the first day of doing (Cycle 
0, Day 1) followed by a washout of 6-10 days for the assessment of PK, then once daily 
(Modules 1 and 2) or scheduled (Module 3) dosing from Cycle 1 onwards. Patients may 
continue to receive the study treatment until progression, unacceptable toxicity or withdrawal. 
Dose levels will not be weight adjusted. 
3.1.1 Starting Dose (Module 1) for Study Re-start 
On 29th March 2018, recruitment in clinical study RXC004/001 was temporarily halted, 
following clinically significant AEs observed in the first patient dosed, assessed as related to 
RXC004 on-target effects and Wnt pathway inhibition.  Analysis of the PK data from Patient 
001/001 indicated that systemic RXC004 exposure was significantly higher than that predicted 
from pre-clinical studies.  Following manufacture of lower doses of RXC004 and inclusion of 
additional safety measures to the study protocol, RXC004 was restarted at 0.5 mg which was 
based on several considerations including: 
 
• Clinical PK observed in Patient 001/001 
• Cover required to cause tumour growth inhibition in pre-clinical cancer models 
• Exposure over IC50 achieved by competitor PORCN inhibitors in their reported Phase1 
studies 
 
3.1.1.1 Clinical PK/Pharmacodynamics  
The PK for Patient 001/001 showed that the maximum plasma concentration (Cmax) was in line 
with expectations but the terminal half-life (T1/2) was significantly longer than predicted, due 
to the evidence of biphasic PK resulting in a long elimination phase and a significantly higher 
Cmin than expected.  The calculated T1/2 was approximately 20 h following multiple doses to 
steady state.  This contributed to an approximately 3-fold accumulation of AUC at steady state 
and an approximately 50-fold increase in Cmin compared to the prediction from modelling.  The 


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expected T1/2 was previously predicted using modelling in a one-compartment analysis and was 
calculated to be 3.5 h.  Additionally, RXC004 reduced AXIN2 mRNA expression in the skin 
of Patient 001/001 to approximately 19% of the baseline measurement on Day 8 of Cycle 1, 
indicating significant Wnt pathway inhibition. The patient was not taking any concomitant 
medication expected to have caused a DDI with RXC004.  
Emerging data show that the exposures achieved in patients dosed with 0.5–2.0 mg are 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, with accumulation at steady state in line with the 
measured half-life (range of 8-16 h after a single dose). Pathway engagement, inhibition of 
AXIN2 in patient skin biopsies has also been confirmed in all dose cohorts tested. 
Additional PK sample times at later time-points up to 96 h have been included in the study 
protocol (see Table 10) in Cycle 0, to more accurately determine the half-life of RXC004 in 
patients.   
PK samples will be analysed for each patient before commencing continuous dosing (Cycle 
1), until Redx judges that the human PK parameters for RXC004 are reliably established.  In 
the event of the Cmin value being outside the expected tolerated range, a different dosing 
schedule at the same dose (e.g. 0. 5mg QD dosing) will be considered.  If the Cmin is within the 
expected tolerated range and the dose is clinically tolerated, Redx will plan to initially increase 
the dose to 1 mg QD and be led by the emerging data and SRC for all further dose escalations. 
 
3.1.1.2 Free-Drug Exposure Required for Efficacy in Pre-clinical Studies 
The proposed new starting dose of 0.5 mg QD (or a dose and schedule that provides equivalent 
exposure) should provide free exposure of approximately 2 times the pharmacological IC50 
over the dosing interval, based on the PK from Patient 001/001 and assuming dose linearity.  
This Cmin cover is a similar starting point to the cover originally expected for the 10 mg dose 
based on original predictions from preclinical species and in vitro assays (Capan-2 
proliferation IC50).   
In pre-clinical models of cancer, RXC004 has achieved significant tumour-growth inhibition 
with the free exposure range of 1 x IC50 Cmin to 10 x IC50 Cmin.  The proposed starting dose 
should be within this range of Cmin exposures and thus we expect to deliver potential patient 
benefit.   
3.1.1.3 Free Exposure over IC50 Achieved by Competitor 
PORCN Inhibitors 
The Novartis PORCN inhibitor WNT974 has been dosed in patients between 5 mg QD and 30 
mg QD {Janku, 2020 Ref 19}  These doses of WNT974 produce free exposure at Cmin of 
between 3 x and 24 x the pharmacological IC50 of the compound and additionally a higher Cmax 
and AUC than expected for RXC004 0.5 mg.  WNT974 was well tolerated in this study and 
did not reach an MTD.   
The A-Star PORCN inhibitor ETC-159 has been dosed at a range of 1–30 mg QOD in an 
ongoing Phase 1a/b clinical trial.  Phase 1a has completed.{Ng, 2017 Ref 30}   ETC-159 has 


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an MTD defined as 30 mg QOD (Cmin free exposure >50 x IC50), two of five patients dosed at 
30 mg experienced fragility fractures while no fractures were observed at any of the lower 
doses. A dose of 16 mg QOD (Cmin free exposure ~20 x IC50) has been selected for evaluation 
in Phase 1b. 
By modelling the published PK data with both ETC-159 and WNT974 we have demonstrated 
that RXC004 dosed at 0.5 mg, will result in significantly less exposure than both ETC159 at 
16mg and WNT974 at 10 mg, both of which were tolerated doses in man. 
The starting dose/schedule of further modules will be the decision of the SRC based on 
emerging safety and tolerability data, however, will not exceed the equivalent maximum 
exposure found to be tolerated in Module 1 at that point. Dose increments will be guided by 
safety data observed during Cycle 1, as well as on-going assessment of safety beyond Cycle 1 
in earlier cohorts, plus PK and pharmacodynamic data as available. Every new dose cohort 
will be evaluated for the occurrence of a DLT during Cycle 1 of treatment. 
Based on emerging data, including available biomarker data and/or safety data and/or pre-
clinical data, the SRC may consider alternative treatment schedules or dose intervals (for 
example, twice daily dosing or intermittent treatment), in consultation with the Sponsor. Please 
refer to the IB and relevant study protocol module for further details. 
3.1.2 Dose Escalation Scheme (Modules 1 and 2) 
RXC004 starting dose and dose-escalation plans for Module 1 are in Section 5.2.  The details 
for the starting dose of RXC004 in combination with nivolumab and dose-escalation plans 
are in Section 5.3. 
Dose, frequency and schedule in subsequent cohorts may increase or decrease in response to 
safety, tolerability, PK and emerging non-clinical data. 
There will be no intra-patient dose escalations. 
Every new dose cohort will be evaluated for the occurrence of a DLT during Cycle 1 of study 
treatment. Dose escalation and de-escalation will follow a standard ‘3+3’ scheme for Modules 
1 and 2. There will be no dose escalations in  Module 3. If no DLT is observed in a cohort, 
then dose escalation may occur.  
Cohort Expansion 
If one patient experiences a DLT in a group of 3 or more evaluable patients, then the cohort 
will be expanded to include 6 evaluable patients. Note: cohort expansion to more than 3 
patients per cohort (> 4 patients) may occur also if more than 3 patients are screened in a single 
cohort and are deemed eligible; in such cases dose escalation to the next higher dose will not 
occur until all patients (e.g. 3 or 4 patients) have completed the DLT assessment period with 
no DLT observed. If only one DLT is observed in the complete cohort of 6 evaluable patients, 
then dose escalation may occur, once all patients in the expanded cohort have completed their 
first cycle of treatment with RXC004. If 2 or more patients experience a DLT in a group of up 


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to 6 evaluable patients (including those in the dose expansion arms), irrespective of the number 
of patients enrolled, the dose will be considered not tolerated and recruitment to the cohort and 
dose escalation will cease. A lower, intermediate dose (de-escalation) may be considered in 
order to better define the MTD. 
The highest dose where ≤ 1 DLT is seen in 6 patients will be termed the MTD. 
 
If a patient becomes unevaluable following dose administration they may be replaced, if 
required, to ensure at least 3 patients are evaluable for an assessment of safety and tolerability 
at that dose.  There will be no minimum time period required between completion of dosing in 
the last evaluable patient from one cohort and the start of dosing in the subsequent cohort.  
 
After each dose level during the dose escalation phase of the study, a SRC will evaluate the 
safety and tolerability and pharmacokinetics of RXC004 to decide the next dose and/or 
schedule. 
3.1.3 Definition of Maximum Tolerated Dose (Modules 1 and 2) 
A dose will be considered non-tolerated and dose escalation will cease if 2 or more of up to 6 
evaluable patients experience a DLT at a dose level. Once the non-tolerated dose is defined the 
MTD may be confirmed at the previous dose-level below the non-tolerated dose or a dose 
between the non-tolerated dose and the last tolerated dose may be investigated.  
Definition of Evaluable Patient for Modules 1 and 2 
For decisions on dose escalation, an evaluable patient is defined as a patient who has received 
study treatment and either: 
• Has completed minimum safety evaluation requirements and has received 100% of the 
specified RXC004 dose in Cycle 0 and at least 66% of the intended dose of RXC004 
during Cycle 1 (Patients in Module 2 must also receive 100% of the nivolumab infusion 
on Cycle 1 Day 1) 
• Has experienced a DLT during Cycle 0 and/ or Cycle 1 
 
Any patient that is withdrawn and is not evaluable will be replaced to ensure a minimum 
number of evaluable patients. 
3.1.4 Definition of Maximum Feasible Dose (Modules 1 and 2) 
A dose and schedule will be considered non-feasible and escalation will cease where PK 
parameters determine that a maximum absorbable dose has been reached, or where a 
formulation that would allow administration of RXC004 in a reasonable number of capsules 
of an acceptable size is not achievable. 


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3.1.5 Definition of MBAD  (Modules 1 and 2) 
• A biologically relevant PK exposure (i.e. dose predicted to sustain free plasma 
concentration >IC50). The estimated biologically relevant PK exposure is calculated to 
be achieved by a dose of 0.5 mg QD; 
And/or 
• Biomarker (AXIN2) target engagement in either normal or tumour tissue; 
And/or  
• Clinical response (RECIST 1.1). 
 
3.2 Safety Review Committee 
Following the completion of each dose escalation cohort of Modules 1 and 2, the SRC will 
meet by telephone to evaluate the safety and tolerability and, where available, PK and 
pharmacodynamic of RXC004 to decide the next dose and/or schedule. Any dose interruptions 
and reductions will be taken into account. AEs occurring in Cycle 2 and beyond which meet 
the definition of a DLT or are considered clinically significant may also be considered in 
making dose escalation decisions (refer to RXC004 Safety Review Committee Remit, which 
has been provided as a separate document). Other AEs, or possible trends in AEs, during the 
dose escalation phase may inform dose escalation decisions. 
The SRC will consist of the following: 
• Principal Investigator or delegate 
• IQVIA Project Manager, who will chair the committee, or delegate 
• Redx Chief Medical Officer  
• Redx Project Manager 
• Investigator or delegate from other investigational sites 
 
The Clinical Pharmacology Scientists, Study Statisticians, Pharmacovigilance representatives, 
Study Leaders and other Sponsor and non-Sponsor technical experts may also be invited as 
appropriate. The SRC Remit document for this study will define the exact membership and 
who should be present for decisions to be made. Further Sponsor or non-Sponsor experts may 
be consulted by the SRC as necessary. 
The SRC decisions may be to: 
• 
Proceed with dose escalation either to next defined dose escalation step or justify the 
rationale for reduced escalation step based on available safety, PK and pharmacodynamic 
data 
• 
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• 
De-escalate the dose of RXC004 either to a previous lower dose level (up to a maximum 
of 6 evaluable patients) or to an intermediate lower dose level  
• 
Stop the dose escalation part of a study module 
• 
Adjust the dosing frequency/schedule/sequence of RXC004, with or without a concurrent 
change in dose 
• 
Advise on any adjustment to study assessment time points e.g. PK sampling, based on data 
available during the trial and protocolled limit on blood volumes and number of samples 
permissible in a given period. 
 
Following establishment of the monotherapy dose in Module 1 (MBAD/ MTD/ MFD), the 
SRC decisions may be to: 
• 
Confirm the MTD, MFD, and/or MBAD 
• 
Advise on (and approve where appropriate) required pre-medication 
• 
Advise on any adjustment to study assessment time points e.g. PK sampling, based on data 
available during the trial and protocolled limit on blood volumes and number of samples 
permissible in a given period. 
 
When there are other patients who are ongoing within a cohort at the time of a review, the SRC 
may decide to defer their decision until data from these further patients become evaluable. 
Any patient started on treatment in error, as he/she failed to comply with all of the selection 
criteria but meets the criteria of an evaluable patient, will be reviewed on a case by case basis 
by the SRC to determine if the patient should be included or excluded in the decision for dose 
escalation. The decisions and decision-making of the SRC on the next dose level will be 
documented and provided to the Investigators prior to dosing any new patients. 
3.3 Dose Modifications and Individual Stopping Criteria 
The module specific dose modification guidelines and individual stopping criteria in found in 
Section 5.2 (Module 1) Section 5.3 (Module 2), and Section 5.4 (Module 3)  respectively. 
3.4 Adverse Event Management Plan 
3.4.1 Bone Management plan (All Modules) 
Bone Metabolism Overview 
Bone is a metabolically active structure which undergoes continuous remodelling throughout 
life.{Crockett, 2011 Ref 5}  After attaining peak bone mass, bone undergoes constant 
remodelling through bone resorption followed by formation sequentially by a basic 
multicellular unit of bone called a “bone remodelling unit”.  Various biomolecules, released 


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into the circulation during bone resorption and formation, are called bone turnover markers 
(BTMs).  Under optimal physiological conditions, bone resorption takes place in around 10 
days. 
Figure 3  
Bone Remodeling Schematic 
Schematic representation of the bone remodelling cycle, increased bone resorption is 
accompanied by an increases in β-CTX.  
 
 
The BTMs are grouped into two categories based on the metabolic phase during which they 
are produced as: 
• Bone formation markers 
• Bone resorption markers 
 
N-terminal propeptide of type 1 collagen (P1NP) is a recognised by the International 
Osteoporosis Foundation (IOF) as a bone formation marker, in view of its predictable response 
to treatment and the reliability of P1NP assays as evidenced by low intra-individual variability, 
smaller circadian variation, stability at room temperature, and a good assay precision.  C-
terminal telopeptides of type 1 collagen (CTX-1) are degradation products of Type 1 collagen 
of bone generated by the activity of the enzyme cathepsin K. The native CTX exists in two 
forms, α and β isomerised forms, with the latter being released from the resorption of mature 
bone.  
 
Serum β–CTX is a well-characterised, established biochemical marker of bone resorption and 
is recommended in guidelines and advice from authorities such as the International Federation 
of Clinical Chemistry and the International Osteoporosis Foundation.{Vasikaran, 2018 Ref 
46;Johansson, 2014 Ref 20;Vasikaran, 2011 Ref 44} While it is recognised that increased bone 
resorption is associated with increased fracture risk, the relationship in prospective studies is a 
relatively weak one and there is no internationally validated thresholds or criteria that identify 
a high risk of fracture. A number of studies have recently derived reference intervals for β–
CTX and a proposed threshold of 1000 pg/ml is comparable to the upper limit in a number of 


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these studies.{Vasikaran, 2014 Ref 45;Michelsen, 2013 Ref 27;Gossiel, 2014 Ref 12}  
Currently in this study all patients are required to have a β–CTX level of <1,000 pg/mL to be 
eligible to receive RXC004. All eligible patients will receive prophylactic denosumab (Anti-
RANKL antibody) to minimise bone mineral density loss. 
 
The revised dose escalation range of 0.5–3.0 mg daily is expected to result in exposure levels 
lower than those observed at tolerated doses of WNT974 and ETC-159 (10 mg and 16 mg 
respectively; levels at which no fractures were reported).  
To further reduce the potential for bone effects Redx will ensure that all patients receive 
calcium and vitamin D supplementation [vitamin D3 (cholecalciferol)]. In recognition of the 
fact that increased bone resorption is currently a potentially reversible effect of RXC004 at 
higher exposures, Redx will introduce treatment with denosumab in patients showing 
significant increases in β-CTX (increase of ≥350 pg/mL β-CTX from baseline or to a level 
above 1,000 pg/mL).  
 
3.4.1.1 Exclusion of Patients at High Risk of Bone Fractures 
The following patients are deemed to be at high risk of bone fractures and will be excluded 
from the study: 
• 
Patients with bone metastases 
• 
Patients with osteoporosis (as defined by a T-score of < -2.5 at L/R total hip, L/R 
femoral neck, or lumbar spine (L1-4) by DXA scan) or history of fragility fractures 
(any fracture occurring with low-level trauma or as a result of falling < standing height) 
• 
Patients with a β-CTX (bone turnover marker) of > 1000 pg/ml 
• 
Patients with Vitamin D [25(OH)D3] deficiency defined as < 30nmol/L (<12ng/mL)  
 
• 
Patients with history of hyperparathyroidism, Paget’s disease or Osteomalacia 
• 
Patients with a corrected total serum calcium level of <2 mmol/L and serum magnesium 
level of < 0.60 mmol/L 
• 
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 
• 
Patients who have received oral or intravenous (i.v.) glucocorticoids for > 4 weeks at 
daily doses > 7.5 mg of oral (p.o.) prednisolone (or equivalent) within 12 weeks prior 
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3.4.1.2 Prophylactic Supplements 
The following supplements should be started at screening and continue throughout the 
RXC004 treatment 
• Vitamin D supplements 800 IU daily  
• Calcium supplements 1000-1500 mg daily 
Vitamin D3 (cholecalciferol) should be used as it is thought to be a more effective 
supplement.  
Patient who fail screening due solely to 25 (OH)D3 level <12 ng/mL (30 nmol/L) should 
be given a single dose of oral cholecalciferol 300,000 IU and the levels rechecked 
approximately 3 weeks later (and within the 28-day screening window) 
Those with values >12 ng/ml can then enter the study if all other entry criteria are fulfilled 
and will receive the long term prophylactic daily cholecalciferol 800 IU as maintenance 
throughout the study treatment period. 
All patients will receive prophylactic denosumab (120 mg s.c. QM) along with vitamin D3 
(cholecalciferol 800 IU QD) and calcium (1000-1500 mg QD) supplements from the time of 
signing the ICF and throughout the- RXC004 treatment.  
 
3.4.1.3 Monitoring of Blood-Bone Turnover Markers and BMD 
BMD 
Osteoporosis and osteopenia are defined based on assessment of BMD using DEXA scan, with 
osteoporosis defined as a T-score of < 2.5 SD and osteopenia as a T-score of <- 1 and > -2.5 
SD.  However, BMD has low sensitivity with osteoporotic fractures occurring in both 
osteoporotic and osteopenic individuals. 
BMD will be assessed by DEXA scan at Screening, Cycle 2, and every 3 cycles from Cycle 4 
onwards i.e. Cycles 4, 7, 10 etc). 
In addition to a baseline (pre-treatment) DEXA scan all patients will have a vertebral fracture 
assessment (VFA) scan (a lateral T & L spine assessment if a VFA cannot be performed 
locally) to document any asymptomatic moderate/severe vertebral fractures which occur in a 
significant minority of patients aged 50 years or older. .{O'Neill, 1996 Ref 33}  Patients who 
have an asymptomatic, mild (Grade 1) vertebral fracture but who fulfil all inclusion/exclusion 
criteria will not be excluded from study.{Johansson, 2014 Ref 20} 
 
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Blood samples for monitoring of the bone turnover markers beta C-terminal telopeptide of type 
1 collagen (β-CTX) and P1NP will be routinely collected for patients. 
Bone turnover biomarkers will be collected* at the timepoints detailed in the Schedule of 
assessments (Appendix 1 for Module 1, Appendix 2 for Module 2 and Appendix 9 for Module 
3) 
*note that due to circadian variations and effects of food intake on CTX measurements, β –CTX samples will be collected in 
the morning after an overnight fast. 
The major benefit of using biochemical markers is that treatment induced changes occur much 
earlier than DEXA measured BMD, and the magnitude of the changes are usually much greater 
(i.e. a greater signal to noise ratio) than those detected by BMD.  Therefore, serum β –CTX 
levels will be routinely monitored as a resorption marker.  Samples will also be stored for 
subsequent measurement of other bone markers (e.g. P1NP) if indicated, during or at the end 
of the study.  
 
3.4.1.4 Intervention Measures for Patients with Increased Bone-Fracture Risk 
on RXC004 Treatment 
The interventions detailed in Table 2 should be followed for all patients on RXC004 study treatment, in the 
event of increased bone fracture risk. 
 
Patients with a DEXA scan showing >7% worsening in BMD at lumbar spine or total hip 
compared to baseline will permanently discontinue study treatment.  The change in BMD that 
can be confidently detected is termed the least significant change (LSC). A 7% decrease in 
BMD is approximately the 99% confidence limit for LSC and is considered as an indicator of 
failure to respond to treatment.{Diez-Perez, 2012 Ref 7}. 
 
Prophylactic denosumab (XGEVATM - 120 mg s.c. QM per approved label for prevention of 
skeletal-related events (SREs) in patients with bone metastases) will be administered to all 
patients (from the 1.5mg RXC004 monotherapy Module 1, Cohort 3). This denosumab dose 
and schedule is being adopted to maximise bone safety.  Patients with advanced/metastatic 
malignancies are at potential increased risk of bone fragility if treated with a porcupine 
inhibitor such as RXC004. In addition, while patients with bone metastases are excluded from 
the protocol currently it is the intention (based on safety data and appropriate expert and 
regulatory review and approval) to administer RXC004 to patients with bone metastases as 
part of the RXC004 development programme as a significant minority of patients with 
metastatic disease will have bone metastases). The XGEVATM approved dose and schedule of 
denosumab will be used in all patients both to maximize bone safety and allow a uniform and 
accurate assessment of denosumab use in combination with RXC004.  Denosumab, as it is a 
more potent inhibitor of bone resorption compared to bisphosphonates, leads to greater 
increases in bone mineral density.{Miller, 2016 Ref 28}  
 


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Prophylactic use of denosumab was not adopted from start of study treatment as the 
significantly lower starting dose of RXC004 0.5mg (previously this was 10 mg) and the other 
bone protection measures reduced the potential for bone toxicity. However, as a significant 
number of patients (3 of 6) required denosumab treatment by the end of Cycle 1 based on 
reaching protocol-defined increases in β-CTX levels indicative of increasing risk of bone 
fragility, prophylactic denosumab is now administered to all patients (from the 1.5 mg RXC004 
monotherapy cohort) based on a review of the data and advice by an independent expert in 
bone metabolism.  
 
Table 2 
Interventions for patients with increasing bone fracture risk 
 
Event 
Intervention 
Confirmed RXC004 related 
fragility bone fracture 
• 
Permanently discontinue study treatment 
Patients with a DEXA scan 
showing > 7% worsening in 
BMD at lumbar spine or 
total 
hip 
compared 
to 
baseline 
• 
Permanently discontinue study treatment 
An individual increase in β-
CTX of ≥350 pg/mL from  
baseline (screening) and/or 
an individual measurement 
≥1000 pg/mL β-CTX 
  
• 
If serum β-CTX  > 1,000 pg/mL or ≥350 pg/mL higher than the 
baseline level - permanently discontinue study treatment unless the 
patient has received clinical benefit (Investigator assessment) and 
continued treatment is warranted. 
 
3.4.2 Diarrhoea/Colitis Management and Treatment Guidelines 
Please refer to Appendix 5, for the treatment of diarrhoea/colitis for patients enrolled in all 
Modules 
3.4.3 Nivolumab Toxicity Management and Dose Modification (for Module 2 
patients) 
Guidelines for the management of immune-mediated reactions and infusion-related reactions, 
for patients treated with nivolumab therapy (Module 2 – RXC004 + nivolumab combination) 
are provided in the Nivolumab Toxicity Management and Dose Modification guidelines 
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3.5 Treatment Compliance and Accountability 
Study drug administration must be performed by study site staff and documented in source 
documents and the CRF. 
The prescribed dosage, timing, and mode of administration may not be changed. Any 
departures from the intended regimen must be recorded in the eCRFs.   
At each visit, prior to dispensing study medication, previously dispensed study medication will 
be retrieved by the Investigator and compliance assessed. Subjects exhibiting poor compliance 
as assessed by capsule counts should be counseled on the importance of good compliance to 
the study dosing regimen.   
Noncompliance is defined as taking less than 80% or more than 120% of RXC004 study 
medication during any evaluation period (visit to visit) or less than 100% of nivolumab at each 
infusion. 
3.5.1 Treatment Accountability 
The Investigator, a member of the investigational staff, or a hospital pharmacist must maintain 
an adequate record of the receipt and distribution of all study medication using the Drug 
Accountability Form. These forms must be available for inspection at any time. 
All study medication supplies should be accounted for at the termination of the study and a 
written explanation provided for discrepancies. All unused study medication supplies and 
packaging materials are to be inventoried and returned to IQVIA by the Investigator. The 
Investigator is not permitted to return or destroy unused clinical drug supplies or packaging 
materials unless authorized by IQVIA. 
3.6 Subject Withdrawal 
Patients may withdraw from any aspects of the voluntary exploratory research at any time, 
without prejudice to further treatment and independent of any decision concerning 
participation in other aspects of the main study. Patients may be discontinued from 
investigational product in the following situations: 
• 
Patient decision. The patient is at any time free to withdraw his/her participation in the 
study, without prejudice 
• 
Adverse events requiring permanent discontinue as detailed in Table 4 
• 
Severe non-compliance to this protocol as judged by the Investigator and/or Sponsor 
• 
Confirmed disease progression 
• 
Patients incorrectly initiated on investigational product 


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• 
Life threatening or other unacceptable toxicity 
• 
The discovery of an unexpected, significant, or unacceptable risk to the patients enrolled 
in the study 
• 
Lack of evaluable and/or complete data 
• 
Decision to modify the development plan of the drug 
• 
A decision on the part of the Sponsor to suspend or discontinue development of the drug 
• 
Extraordinary medical circumstances: Subject who, in the opinion of the Investigator 
should be discontinued for their well-being or if at any time the treatments prescribed by 
this protocol are detrimental to the subject’s health, the subject may be withdrawn from the 
study. In this event, reasons for withdrawal should be clearly documented on the case report 
form (CRF). 
• 
If subject becomes pregnant during the treatment period 
 
Any patient who permanently discontinues investigational product should be followed up for 
at least 28 days and until disease progression. 
Procedures for handling patients incorrectly initiated on investigational product: 
Patients who do not meet the inclusion/exclusion criteria should not, under any circumstances, 
be enrolled or receive study medication. There can be no exceptions to this rule. 
Where patients that do not meet the inclusion/exclusion criteria are enrolled in error or 
incorrectly started on treatment, or where patients subsequently fail to meet the study criteria 
post initiation, the Investigator should inform the Study Physician immediately.  
Any patient who is found to have failed to comply with all the selection criteria, but has not 
started treatment, will be removed from the study following completion of safety follow-up 
activities. 
Any patient started on treatment in error, as he/she has subsequently been found to have failed 
to comply with all the selection criteria, will undergo a risk/benefit assessment by the SRC; if 
the patient is judged to be receiving clinical benefit, the investigator may choose to continue 
to dose them with the investigational drug. 
Every effort should be made to keep all patients, whether eligible or ineligible, in the study 
until completion of safety follow-up activities. 
The Study Physician is to ensure all such contacts are appropriately documented. 


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4 SAFETY – CORE  
4.1 Definitions of Adverse Events and Serious Adverse Events 
The Investigator is responsible for recording all AEs observed during the study (from time of 
signed consent, washout, treatment, and follow-up) period. 
Definition of AE: An AE is any new untoward medical occurrence or worsening of a pre-
existing medical condition in a subject or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this 
treatment. 
 
Treatment-emergent adverse events: An AE occurring after dosing and within 30 days of last 
dose. 
 
Definition of Serious Adverse Event (SAE): An SAE, experience or reaction, is any untoward 
medical occurrence (whether considered to be related to study drug or not) that at any dose: 
• Results in death. 
• Is life-threatening (the subject is at a risk of death at the time of the event; it does not 
refer to an event which hypothetically might have caused death if it were more severe). 
• Requires inpatient hospitalization or prolongation of existing hospitalization: 
Hospitalizations are defined as initial or prolonged admissions that include an overnight 
stay. Hospitalization or prolonged hospitalization for technical, practical or social 
reasons, in the absence of an adverse event is not an SAE. Hospital admissions and/or 
surgical operations planned before or during a study are not considered AEs if the 
illness or disease existed before the subject was enrolled in the study, provided that it 
did not deteriorate in an unexpected way during the study. 
• Results in persistent or significant disability/incapacity. 
• Is a congenital abnormality/birth defect. 
• Other:  Medically significant events, which do not meet any of the criteria above, but 
may jeopardize the subject and may require medical or surgical intervention to prevent 
one of the other serious outcomes listed in the definition above. Examples of such 
events are blood dyscrasias (e.g. neutropenia or anemia requiring blood transfusion, 
etc.) or convulsions that do not result in hospitalization. 
 
An Adverse Drug Reaction (ADR) is defined as all noxious and unintended responses to a 
medicinal product related to any dose.  An Unexpected Adverse Drug Reaction is defined as 
any adverse reaction, the nature of which is not consistent with the applicable product 
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Each AE is to be evaluated for duration, severity, seriousness and causal relationship to the 
investigational drug. The action taken and the outcome must also be recorded. 
 
Severity 
The severity of the AE will be characterized as “mild, moderate or severe” according to the 
following definitions: 
• 
Mild (Grade 1) events are usually transient and do not interfere with the subject’s daily 
activities. 
• 
Moderate (Grade 2) events introduce a low level of inconvenience or concern to the subject 
and may interfere with daily activities. 
• 
Severe (Grade 3) events interrupt the subject’s usual daily activity. 
• 
Life-threatening (Grade 4) - Life-threatening consequences; urgent intervention indicated. 
• 
Death (Grade 5) related to AE. 
 
Relationship 
The causal relationship between the study medication and the AE has to be characterized as 
unrelated, unlikely, possible, probable or unknown (unable to judge).  
Events can be classified as “unrelated” if there is not a reasonable possibility that the study 
medication caused the AE. An “unlikely” relationship suggests that only a remote connection 
exists between the study drug and the reported AE. Other conditions, including chronic illness, 
progression or expression of the disease state or reaction to concomitant medication, appear to 
explain the reported AE. 
A “possible” relationship suggests that the association of the AE with the study medication is 
unknown; however, the AE is not reasonably supported by other conditions. 
A “probable” relationship suggests that a reasonable temporal sequence of the AE with drug 
administration exists and, in the Investigator’s clinical judgment, it is likely that a causal 
relationship exists between the drug administration and the AE, and other conditions 
(concurrent illness, progression or expression of disease state or concomitant medication 
reactions) do not appear to explain the AE. 
Adverse Events Based on Signs and Symptoms 
All AEs spontaneously reported by the patient, in diary or reported in response to the open-
ended and non-leading verbal questioning from the study personnel (e.g., “How are you 
feeling?” “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 CRF. When collecting AEs, it 
is preferred to record the diagnoses (when possible) instead of recording a list of signs and 


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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. 
Adverse Events Based on Examinations and Tests 
The results from protocol mandated laboratory tests, vital signs, ECGs and other safety 
assessments will be summarised in the Clinical Study Report. Deterioration as compared to 
baseline in these parameters will therefore only be reported as AEs if they fulfil any of the 
criteria for a SAE, a DLT or are the reason for discontinuation of treatment with the 
investigational product unless clearly due to progression of disease under study (see Disease 
progression). 
If deterioration in a laboratory value, vital sign, ECG or other safety assessment is associated 
with clinical signs and symptoms, the sign or symptom will be reported as an AE and the 
associated laboratory result or other finding 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 and symptoms, 
clinically relevant deteriorations in non-mandated parameters should be reported as AE(s). 
Deterioration of a laboratory value that is unequivocally due to disease progression should not 
be reported as an AE. 
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. 
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 to the primary cancer under study 
should be considered as disease progression and not an AE. Events that are unequivocally due 
to disease progression should not be reported as AEs during the study. 
New Cancers 
The development of a new cancer should be regarded as an AE and will generally meet at least 
one of the serious criteria. New cancers are those that are not the primary reason for the 
administration of the study treatment and have been identified after the patient’s inclusion in 
this study. They do not include metastases of the original cancer. 
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COVID-19 infections occurring from 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). 
Taste Disturbances 
Loss or altered taste (dysgeusia) is an on-target AE known to occur with porcupine inhibition 
(Ref 30, Ref 18).  According to CTCAE v5, 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 characterised 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 in Module 3, and for any patient in 
Module 3 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 AE has resolved. The 
information will be recorded and analysed as part of the overall safety objective of the study. 
 
4.2 Reporting of Adverse Events, Serious Adverse Events and 
Dose Limiting Toxicities 
TEAEs reported during the study will be coded using a Medical Dictionary for Regulatory 
Activities (MedDRA) dictionary. Incidence of treatment-emergent adverse events will be 
summarised by disease and cohort and the following: 
• System organ class and preferred term 
• System organ class, preferred term and severity 
 
These summaries will be presented for the following subsets: 


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• SAEs 
• All AEs 
• Drug-related AEs 
• AEs leading to treatment discontinuation 
 
For tables reporting AEs by severity, if a patient has multiple occurrences of an AE with the 
same organ class and preferred term, the most severe event will be presented. 
All SAEs will be recorded on the SAE Report form, the Adverse Events form in the CRF, and 
source documents. Criteria for documenting the relationship to study drug as well as severity 
and outcome will be the same as those previously described.   
All SAEs that are spontaneously reported within 30 days of a patient's last dose of RXC004 
(for Module 1) or 90 days of a patient's last dose of nivolumab (for Module 2) are to be 
collected and reported as previously described. 
The original CRF pages should be returned immediately to the CRF binder. The information 
must include at least the following: 
• 
Name, address and telephone number of the reporting Investigator. 
• 
Investigational product and study code. 
• 
Patient identification number, sex and age at study entry. 
• 
Description of the AE, measures taken and outcome. 
• 
Preliminary classification of causal relationship by the Investigator.   
 
The Principal Investigator (or designee) will notify IQVIA within 24 hours of identifying a 
DLT or SAE, whether related or unrelated to investigational drug, see Section 3. 
Additional follow-up information should be completed on an SAE follow-up form with a copy 
sent to the Sponsor or IQVIA and the original placed in the SAE section of the CRF binder. 
4.2.1 Reporting of SAEs and Suspected Unexpected Serious AEs to 
Regulatory Authorities, Ethics Committees and Investigators 
In accordance with the European Commission Clinical Trials Directive (2001/20/EC), the 
delegated CRO is responsible for submitting reports of AEs associated with the use of the drug 
that are both serious and unexpected to the regulatory authorities and Independent Ethics 
Committees / Institution Review Boards (IEC/ IRB) according to local laws and regulations. 
All investigators participating in clinical studies with the study medication will receive copies 
of these reports - Council for International Organisations of Medical Sciences (CIOMS) for 
prompt submission to their local institution / regulatory bodies. Other SAEs (i.e. expected or 
unrelated SAEs) should be reported per the relevant institution’s procedures. Investigators 
should provide written documentation of notification for each report to IQVIA.  


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Until such time that an AE is included in the IB reference safety information, it should be 
considered unexpected, regardless of whether the AE has been the subject of a previous Safety 
Update. All expectedness assessments will be made by the Sponsor or designee. 
Suspected Unexpected Serious Adverse Reactions (SUSARs) are required to be reported 
within 7 calendar days for life-threatening events and those resulting in death, or 15 calendar 
days for all others. These timeframes begin with the first notification of the SUSAR to IQVIA 
or Redx from the Investigator. 
4.2.2 Follow-Up of Adverse Events 
Any AEs observed from the time of consent/randomisation up to the end of the study will be 
followed up to resolution. Resolution means that the patient has returned to a baseline state of 
health or the Investigator does not expect any further improvement or worsening of the AE. 
All AEs that occur after the patient completed a clinical study should also be reported to IQVIA 
Clinical within 30 days of the last dose of study drug.   
4.3 Medical Emergencies and Sponsor Contacts 
4.3.1 Safety Reporting and Medical Management 
Following the completion of each dose-escalation cohort of Modules 1 and 2, the SRC will 
meet to evaluate the safety and tolerability and, where available, PK of RXC004 to decide the 
next dose and/or schedule as previously discussed in SRC Section 3.2. Dose interruptions and 
reductions will be taken into account. AEs occurring in Cycle 2 and beyond which meet the 
definition of a DLT or are considered clinically significant may also be considered in making 
dose escalation decisions. Other AEs, or possible trends in AEs, during the dose escalation 
phase may inform on dose escalation. 
4.3.2 Emergency Sponsor Contact 
In emergency situations, the Investigator or designee should contact the Sponsor’s study 
contact: 
  
 
  
  
 
 
 


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4.3.3 Overdose 
Investigators should be advised that any patient who receives a higher dose than that intended 
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 per standard medical practice.  
Dosing details should be captured in the CRF. If the patient receives a dose of a study drug 
that exceeds protocol specifications and the patient is symptomatic, then the symptom(s) 
should be documented as AEs in the CRF 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 patient is 
not symptomatic. 
4.3.4 Pregnancy 
A Pregnancy Report Form (or equivalent) must be completed for all pregnancies that occur 
from the time of first study drug dose until 6 months after the last dose of study drug(s) 
received, including any pregnancies that occur in the female partner of a male study patient. 
Additionally, all pregnancies should be reported that occur in a male patient’s partner if the 
estimated date of conception occurred after the male patient’s first dose of study drug. The 
form must be transmitted to the Drug Safety Department of IQVIA within 48 hours of 
becoming aware of the pregnancy. All pregnancies will be monitored for the full duration; all 
perinatal and neonatal outcomes should be reported. Infants should be followed for a minimum 
of 8 weeks after their delivery.  
Collection of data on the CRF: All pregnancies (as described above) that occur within 30 days 
of the last dose of study drug(s) will also be recorded as an AE. Abortion (whether spontaneous, 
therapeutic, or planned) should be reported as an SAE. Congenital anomalies or birth defects 
should be reported as SAEs. 
 


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5 STUDY DESIGN 
5.1 Introduction 
The study is a modular Phase 1, dose-escalation, open-label study to assess the safety, 
tolerability, PK and preliminary anti-tumour activity of RXC004 in monotherapy and in 
combination in patients with advanced malignancies.  
The study started with the RXC004 monotherapy module (Module 1, a monotherapy dose 
escalation to identify the minimum biologically active dose (MBAD), maximum tolerated dose 
(MTD) or maximum feasible dose (MFD), in multiple patient cohorts. Module 2 was added 
with protocol amendment v5, a RXC004 and nivolumab combination dose escalation to 
identify the MTD or MFD of RXC004 in combination with nivolumab. 
Module 3 will determine whether RXC004 2 mg QD monotherapy intermittent schedules are 
safe/tolerated.  This Module will initially start with two Arms – RXC004 2 mg QD taken for 
4 days, followed by 3 days off, repeated weekly for 21-day cycles (Arm 1) and RXC004 2 
mg QD taken for 2 weeks, followed by 1 week off (Arm 2).The option to start further 
modules will be the decision of the SRC, based on emerging pre-clinical data and, safety and 
tolerability information from the initial module. A substantial protocol amendment with 
relevant preclinical and clinical data will be put in place before starting any further modules. 
 
The dose escalation and dose escalation cohort size and the stopping criteria for Modules 1 
and 2  are based upon accepted methodologies for Phase 1 oncology studies.  Module 3 has a 
single cohort for each intermittent schedule. 
 
5.2 Module 1 – RXC004 Monotherapy 
The reason for conducting this study module is to provide the first cancer patient safety and 
tolerability data with RXC004.  
Treatment, conduct, and withdrawal, which include starting dose and the dose escalation 
scheme, can be found in Section 3.1.2 
Module 1 will commence by enrolling patients with advanced solid tumours into a SAD/MAD 
monotherapy dose-escalation arm. Eligible participants will be enrolled in sequential cohorts 
treated with RXC004 given as an oral capsule dose while being monitored for safety and DLTs. 
Dose levels will not be weight-adjusted and the starting dose for the study will be RXC004 0.5 
mg QD on Days 1-21 inclusive (for Cycle 1 and subsequent cycles). Dose increments will be 
guided by safety data observed during Cycle 1, as well as on-going assessment of safety beyond 


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Cycle 1 in earlier cohorts, plus PK and pharmacodynamic data as available. Every new dose 
cohort will be evaluated for the occurrence of a DLT during Cycle 0 or Cycle 1 of treatment. 
Patients will receive a single dose of RXC004 (Cycle 0) followed by a washout period (6-10 
days) before receiving 21 continuous days dosing of RXC004 capsules (refer to Figure 4). 
Module 1 will evaluate the safety and tolerability of RXC004 as monotherapy to provide 
dose(s) and schedules(s) for further modules, each evaluating the safety and tolerability of 
a specific combination agent. Module 1 will also provide preliminary efficacy readouts.  
 
 
5.2.1 Module 1: Study Objectives 
The study objectives are detailed in Section 1.9 
 
5.2.2 Module 1  Eligibility Criteria 
5.2.2.1 Module 1-Specific Inclusion Criteria  
There are no Module 1-specific inclusion criteria.  Patients must fulfill all of the core inclusion 
criteria in order to be eligible to receive study treatment in Module 1. The core inclusion criteria 
are detailed in Section 2.1.1 
5.2.2.2 Module 1-Specific Exclusion Criteria 
There are no Module 1-specific exclusion criteria.  Patients must not meet any of the core 
exclusion criteria in order to be eligible to receive study treatment in Module 1. The core 
exclusion criteria are detailed in Section 2. 
5.2.2.3 Restrictions 
Study restrictions are explained in Section 2.3 and prohibited concomitant treatments are 
explained in Section 2.3.1. 
 
5.2.3 Ascending Monotherapy SAD/MAD  
Module 1 will commence with an accelerated dose-escalation schedule and enrol three patients 
into a cohort with follow-up for AEs and DLT.  
Patients will receive a single dose of RXC004 on Day 1 followed by a 6-10 days’ washout 
period (Cycle 0) [this washout period may change based upon emerging data]. Cycles of 21 


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days of multiple dosing will then begin until the patient is withdrawn from the study (Cycle 1 
onwards). 
Dose escalation will continue in a 3+3 design until MBAD (as defined in Section 3.1.5) has 
been found to be tolerated. Subsequent dose escalation will continue in a 3+3 design until 
MTD/MFD has been reached. 
 
The decision to dose escalate will be made upon the assessment of the safety and tolerability 
data collected up until the time of study drug administration on Cycle 2, Day 1. This DLT 
assessment period was selected as any acute toxicities leading to cessation of dose escalation 
in this study are anticipated to present within this duration. Doses and/or schedules of RXC004 
will be defined by the SRC. 
Optional skin-punch biopsies will be taken from all patients in Module 1 at baseline and while 
receiving treatment for analysis of pharmacodynamic markers of Wnt pathway inhibition (see 
Schedule of Assessments in Appendix 1).  




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The study will start with Module 1 (monotherapy), in which the selected RXC004 starting dose 
of 0.5 mg QD (for the multiple dosing schedule) will be used, based on the clinical PK observed 
in Patient 001/001, the cover required for tumour efficacy in pre-clinical studies and the 
exposure over IC50 achieved by competitor PORCN inhibitors in their reported Phase1 studies 
(see Section 3.1.1). Eligible participants will be enrolled in sequential cohorts treated with 
RXC004, given as an oral capsule dose while being monitored for safety and DLTs. 
5.2.5 Selection and Timing of Dose for Each Patient 
The doses and duration of treatment for Module 1 is detailed in Section 5.2.3. The exact times 
the study drug was administered and comments are to be recorded directly on the appropriate 
page of the CRF. 
5.2.5.1 Dose Regimen 
The pre-clinical toxicology data support continuous dosing of RXC004 in humans, and Module 
1 will start with this schedule. However, based on emerging data, the SRC may decide to 
propose the exploration of intermittent schedules in some modules.  
5.2.5.2 Dose-Escalation Plan 
A general description of the study dose-escalation scheme can be found in Section 3.1 
The dose-escalation scheme will not exceed doubling of the dose, in principle. However, up to 
a quadrupling of the dose may be permitted in the first two escalations only, if the drug 
concentrations of the first or second level are immeasurable or below the predicted target drug 
exposure for biological effect (for example more than 2-fold) and there have been no 
significant safety or tolerability issues. This will ensure that the fewest possible cohorts are 
exposed to RXC004 below the presumed therapeutic dose. The planned dose escalation scheme 
has the flexibility to be amended in light of emerging data. 
Redx will interpret the single dose PK data before continuous dosing commences. If exposure 
levels indicate that a continuous schedule is not appropriate the patient may be discontinued or 
referred to the SRC to whether an alternative dosing schedule should be considered. 
Table 3 shows an indicative dose escalation scheme for Module 1. All dose levels beyond 
Cohort 1 may change in light of emerging safety, tolerability, and PK data, and also evolving 
relevant pre-clinical data. 
 
 


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Table 3: 
Indicative Dose-Escalation Scheme for Module 1  
Planned Dose levels 
Dose 
1 
0.5 mg QD 
2 
1.0 mg QD 
3 
1.5 mg QD 
4 
2.0 mg QD 
5 
2.5 mg QD 
6 
3.0 mg QD 
Note: This indicative dose and schedule optimisation scheme subject to SRC recommendation. 
 
The pre-clinical toxicology data support continuous dosing of RXC004 in humans, and Module 
1 will start with this schedule. However, based on emerging data, the SRC may decide to 
propose the exploration of intermittent schedules in some modules.  
Please see IB for further details. 
5.2.6 Dose-Limiting Toxicity for Module 1 (RXC004 Monotherapy) 
The DLT assessment period runs from the start of dosing with RXC004 (Cycle 0 Day 1) up to 
Cycle 1 Day 21 for patients enrolled in Module 1.  
A DLT is defined as an AE or abnormal laboratory value that occurs from the first dose of 
study treatment up to Cycle 1 Day 21, assessed as unrelated to disease progression, intercurrent 
illness, or concomitant medications that despite optimal therapeutic intervention meets any of 
the following criteria: 
1. Haematological toxicity that is: 
• CTCAE ≥Grade 4 present for more than 4 consecutive days  
• Grade 3 neutropenia (ANC ≥ 500 to < 1000 cells/mm3) of any duration 
accompanied by fever (≥ 38.5°C) and/or systemic infection 
• Grade 3 thrombocytopaenia (25,000 to < 50,000/mm3) with clinical 
evidence of bleeding 
2. Any other confirmed haematological toxicity CTCAE ≥Grade 4 (a repeat may be 
required for confirmation of an isolated abnormality in the absence of clinical signs, 
symptoms or other abnormal investigations, i.e. a suspected spurious value) 
3. Non-haematological toxicity CTCAE ≥Grade 3 including: 


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• Laboratory abnormalities that are considered clinically significant by the 
investigator (with or without clinical symptoms or signs)  
• QTc prolongation (> 500 msec or 60 msec above baseline) 
4. Any other toxicity that: 
• Is greater than that at baseline, is clinically significant and/or unacceptable, 
and is judged to be a DLT by the SRC 
• Is a protocol defined stopping criterion and is suspected to be RXC004 
related  
• Results in an interruption of dosing schedule of more than 14 days 
A DLT excludes:  
1. 
Inadequately treated ≤Grade 3 nausea and/or vomiting and ≤Grade 3 diarrhoea  
2. 
Any toxicity clearly unrelated to RXC004 e.g. solely related to the disease or disease-
related process under investigation 
3. 
Isolated laboratory changes of any grade without clinical sequelae or clinical 
significance 
 
The incidence and type of DLT-type toxicity emerging from treatment beyond Cycle 1 Day 21 
will be taken into account by the SRC in determining dose-escalation steps. 
 
5.2.7 RXC004 Monotherapy: Dose Modifications 
If a patient experiences a clinically significant and/or unacceptable event including a DLT not 
attributable to the disease or disease-related processes under investigation, RXC004 dosing 
may be interrupted or the dose reduced and supportive therapy administered as required. 
If the event resolves or reverts to ≤ CTCAE grade 2, treatment with RXC004 may be restarted 
using the rules below for dose modifications, only following agreement with the Sponsor 
Physician. Patients who are at the lowest possible dose, i.e., in Cohort 1 or who have their dose 
previously reduced to the Cohort 1 dose and who have demonstrated an acceptable response 
to the dose interruption may be permitted to restart at the lowest dose level at the discretion of 
the Investigator.   
For all other events, if the event does not resolve to ≤ CTCAE grade 2 or the patient is not 
showing clinical benefit, then the patient should be discontinued from treatment and observed 
until resolution of the event. 
Maximum tolerated dose will be defined in the presence of optimal supportive care for the 
event in question. 


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5.2.8 Study Treatment Discontinuation Criteria 
RXC004 dose interruption and stopping criteria are detailed  in Table 4 
Table 4   
Module 1 Dose Interruption and Stopping Criteria 
  
Event  
Action  
Diarrhoea 
 
1st incidence of diarrhoea ≥ grade 2 
(suspected RXC004 related):  
Treat as per Diarrhoea/Colitis Management and Treatment 
Guidelines 
Please refer to Appendix 5  
Temporarily interrupt RXC004 for up to 14 days*. 
Consider restarting at lower dose if resolved to < grade 1 
2nd occurrence of ≥ grade 2 diarrhoea 
Temporarily interrupt RXC004 for up to 14 days*. 
Consider restarting at lower dose if resolved to < grade 1 
3rd occurrence of ≥ grade 2 diarrhoea 
Permanently discontinue study treatment 
Bone events 
Confirmed 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 
 
 
Permanently discontinue study treatment 
 
 
Permanently discontinue study treatment 
An individual increase in β-CTX of 
≥350pg/ml 
from 
the 
baseline 
(screening) value or in individual 
measurement of ≥1000pg/ml 
  
Permanently discontinue study treatment unless the patient 
has received clinical benefit (investigator assessment) and 
continued treatment is warranted. 
Hepatic events 
Grade 3 increases in ALT or AST or 
ALP (> 5 x ULN if baseline normal, >5 
x baseline, if baseline abnormal) 
 
Permanently discontinue study treatment 
Grade 2 increases in ALT or AST or 
ALP (> 3 x ULN if baseline normal, >3 
x baseline, if baseline abnormal) with 
the 
appearance 
of 
symptoms 
associated with a clinical diagnosis of 
hepatitis 
including 
right 
upper 
quadrant pain or tenderness, fever, rash 
or eosinophilia (>5%) 
Permanently discontinue study treatment 


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Event  
Action  
Grade 2 increases in ALT or AST (> 3 
x ULN if baseline normal, >3 x 
baseline, if baseline abnormal) and 
total bilirubin > 2 x ULN or INR* > 1.5 
or other evidence of impairment to the 
synthesis function of the liver] 
*Unless patient is receiving warfarin 
Permanently discontinue study treatment 
Other adverse events 
Grade 3-4 toxicity (1st event^) 
 
Interrupt RXC004 (max. 14 days*), resume at the next 
lowest dose level when resolved (grade ≤ 2 or returns to 
baseline).  
Grade 
3-4 
toxicity 
(subsequent 
events^)  
Permanently discontinue study treatment 
Grade < 3 toxicity (all events^)  
 
^ Excluding diarrhoea 
Decision to interrupt RXC004 (max. 14 days*) is at the 
Investigator’s discretion. Resume at same dose prior to 
interruption.  
Surgery  
Interrupt RXC004 (max. 14 days*), resume at full dose. 
RXC004 should be stopped 3 days prior to surgery and 
resumed approx. 10 days later. If the wound has not healed 
a further 7 days are permitted prior to re-starting RXC004 
at the discretion of the Investigator and with approval of 
Sponsor Physician.  
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 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.  


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Event  
Action  
Corticosteroid use 
Patients receiving corticosteroids for treatment of diarrhoea 
should hold RXC004 (for max. 14 days*) as per 
Diarrhoea/Colitis Management and Treatment Guidelines 
(please refer to Appendix 5) 
Patients receiving corticosteroids for any indication other 
than diarrhoea, should continue RXC004 at current dose 
level. 
Patients who require on-study oral or intravenous (i.v.) 
glucocorticoids for > 4weeks at daily doses equivalent to 
≥7.5 mg of oral (p.o.) prednisolone (for any indication 
other than diarrhoea) should temporarily interrupt RXC004 
(for a maximum of 14 days*) if receiving clinical benefit 
(in the opinion of the investigator) and resume at full 
RXC004 dose once the daily corticosteroid dose equivalent 
falls to <7.5 mg PO prednisolone.  
RXC004 should be permanently discontinued for patients 
who require on-study oral or intravenous (i.v.) 
glucocorticoids for > 4weeks at daily doses equivalent to 
≥7.5 mg of oral (p.o.) prednisolone and are not receiving 
clinical benefit from RXC004 (in the opinion of the 
investigator)  
* RXC004 interruptions of greater than 14 days may be allowed for patients judged by investigator to be clinically 
benefiting from study treatment, and only after consultation with Sponsor 
 
The dose of RXC004 must not be adjusted under any other circumstances unless prior 
agreement is given by the Sponsor. All dose modification and interruptions (including any 
missed doses) and the reasons for the modifications/interruptions are to be recorded in the 
CRF. 
 
5.2.9 Biomarker Samples 
An archival or a newly acquired tumour biopsy will be requested from every patient enrolled 
in the study.  Archived/newly acquired biopsies are optional (but encouraged) in the Module 1  
dose escalation.  


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Optional Skin biopsies to assess downstream markers of Wnt expression may be taken from 
all consenting patients in Module 1. (see Appendix 1 Schedule of Assessments).  
In all patients participating in the study, the taking of non-mandatory tumour biopsies will be 
encouraged and can be taken from each patient at up to 3 time points during the study; 
1. At baseline (prior to first dose of RXC004) 
2. During RXC004 dosing (see SoA for biopsy timings) 
At the time of tumour biopsy, blood samples for assessment of PK and blood borne biomarkers  
will be taken; Analysis of these samples will include, but not be restricted to, PORCN/Wnt 
status and functional PORCN/Wnt inhibition, e.g. phosphorylation and/or expression of 
downstream markers. 
5.2.10 Exploratory Assessments 
Plasma and PBMC pharmacodynamic samples (all sites) will be obtained at C0D1 (prior to 
first dose) and at C1D8, C1D15, Day 1 of each cycle thereafter and treatment discontinuation.  
These samples may be used to examine gene and protein expression changes, including 
measurement of inflammatory markers.  Fresh whole blood (from selected sites of close 
proximity) will be obtained at C0D1 (prior to first dose), and pre-dose at C1D8, C1D15 and 
C2D1.  Fresh whole blood may be stained for cell surface markers to identify immune cell 
populations present in the circulation before and after treatment. Circulating tumour DNA 
(ctDNA) will be collected pre-dose at C0D1 and post-dose on C2D1, C4D1 and at treatment 
discontinuation. Analysis of total amounts and/or tumour mutations (including Wnt pathway 
aberrations) in ctDNA samples may be evaluated and correlated to patient response. 
 
5.3 Module 2 – RXC004 and Nivolumab Combination 
Based on the safety profile observed to date, a decision has been made by Redx and the SRC 
to start Module 2. 
The reason for conducting this study module is to provide the first cancer patient safety and 
tolerability data with RXC004 in combination with nivolumab.  
Module 2 will commence by enrolling patients with advanced solid tumours into a SAD/MAD 
monotherapy dose escalation arm. Eligible participants will be enrolled in dose-escalation 
cohorts treated with RXC004 given as an oral capsule dose in combination with a PD1 infusion. 
The dose of nivolumab will be a fixed dose of (480 mg every 4 weeks, and will remain at this 
dose level throughout the study. The dose of RXC004 will be escalated. The RXC004 starting 
dose for combination with nivolumab will be a lower dose than the highest confirmed safe and 
tolerated dose from the monotherapy study (Module 1). The RXC004 dose will be dose-
escalated to the MTD in combination in as few dose-cohorts as possible.  The RXC004 dose 


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used in Module 2 will not be escalated to exceed the MTD for RXC004 in monotherapy (2mg 
RXC004 QD). 
Patients will take a single dose of RXC004 to evaluate single dose PK, then start on continuous 
RXC004 dosing up 3-7 days later in combination with nivolumab every 28 days (Cycle 1). 
Each cycle will be 28 days from Cycle 1, Day 1.  
Dose increments will be guided by safety data observed during Cycle 1, as well as on-going 
assessment of safety beyond Cycle 1 in earlier cohorts, plus PK and pharmacodynamic data as 
available. Every new dose cohort will be evaluated for the occurrence of a DLT during Cycle 
0 or Cycle 1 of treatment. (Figure 5) 
Patients will have the option to have their tumour tissue (primarily from an archival source) 
tested for genetic aberrations (including upstream Wnt pathway aberrations such as RNF43 
mutations and RSPO-fusion) by next generation sequencing (NGS) or MassArray 
technologies. 
RXC004 will be administered orally in combination with anti PD1 infusion in patients with 
advanced solid malignancies. There will be escalation of the RXC004 dose in each cohort with 
intensive safety monitoring to ensure the safety of the patients. The design of this Module 2 
also allows the RXC004 & anti-PD1 combination tolerability and PK to be characterised in an 
unselected population of patients.  
 
 
Figure 5 
Module 2 dose escalation 
 


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5.3.1 Module 2 Objectives 
The  objectives are detailed in Section 1.9 
5.3.2 Module 2 Eligibility Criteria 
5.3.2.1 Module 2 Specific Inclusion Criteria  
The core inclusion are detailed in Section 2.1.1.  There are no Module 2 specific inclusion 
criteria.  Patients must fulfill all of the core inclusion criteria in order to be eligible to receive 
study treatment in Module 2. 
5.3.2.2 Module 2 Specific Exclusion Criteria 
The core and Module 2 specific exclusion are detailed in Sections 2.2.1 and 2.2.2 respectively.  
Patients must not receive study treatment in Module 2 if any of the Core or Module 2 specific 
exclusion criteria are fulfilled. 


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5.3.2.3 Restrictions 
Study restrictions are explained in Section 2.3 and prohibited concomitant treatments are 
explained in Section 2.3.1. 
5.3.3 Module 2: Ascending Combination MAD  
Module 2 will enroll three patients into a cohort with follow up for AEs and DLT.  
Patients will start with a single dose of RXC004 followed by a washout of 3-7 days (Cycle 
0).  RXC004 and nivolumab will commence at Cycle 1.  The first cohort will be daily 
RXC004 and 480 mg nivolumab every 4 weeks (28 days). 
 
The DLT period will be until the end of Cycle 1.  Dose escalation will continue in a 3+3 
design until MTD/MFD has been reached in the combination.  Decisions on doses and/or 
schedules of RXC004 in combination will be made in discussion with the SRC. 
 
5.3.4 Selection of Doses for Module 2 
In Module 2, the starting dose of RXC004 will be at a lower dose than the highest confirmed 
safe and tolerated dose from the ongoing monotherapy study (Module 1).  The RXC004 dose 
used in Module 2 will not be escalated to exceed the MTD for RXC004 in monotherapy (2mg 
RXC004 QD). 
Nivolumab will be administered at 480mg q4w, which is an approved dose and regimen from 
the nivolumab prescribing information.  The dose of nivolumab will not be modified in this 
module. 
5.3.5 Selection and Timing of Dose for Each Subject 
The doses and duration of treatment for Module 2, is detailed below.  The exact times the study 
drug was administered and comments are to be recorded directly on the appropriate page of 
the CRF. 
5.3.5.1 Dose Regimen 
Module 2 will start with a continuous dose of RXC004 that is  lower than the highest confirmed 
safe and tolerated dose from the ongoing monotherapy study (Module 1).   
All patients will start with a single RXC004 dose in Cycle 0, followed by a 3-7 day washout.  
Nivolumab will commence on Cycle 1, Day 1 concurrently with daily RXC004.  Cycle 1 
onwards will be 28 days in length. 


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The RXC004 and nivolumab combination dose escalation will start with continuous dosing of 
RXC004, but based on emerging data the SRC may decide to propose the exploration of 
intermittent combination schedules. 
5.3.5.2 The nivolumab dose and regimen selected for this study are based on 
the approved prescribing information for nivolumab.  The 
recommended dosage for nivolumab is 240 mg Q2W or 480 mg Q4W. 
480 mg Q4W has been selected to complement a 28-day cycle of 
RXC004 and reduce the number of patient visits required.  If a patient 
continues in the study on nivolumab alone, this treatment may be 
continued for a maximum of 12 months in total.Dose-Escalation Plan 
The dose-escalation scheme will not exceed doubling of the dose. 
Dose, frequency and schedule in subsequent cohorts may increase or decrease in response to 
safety, tolerability, pharmacokinetic and emerging non-clinical data.  The RXC004 dose used 
in Module 2 will not be escalated to exceed the MTD for RXC004 in monotherapy (2mg 
RXC004 QD). 
After each dose level during the dose escalation phase of the study, a SRC will evaluate the 
safety and tolerability and pharmacokinetics of RXC004 in combination with nivolumab to 
decide the next dose and/or schedule. 
Table 5 shows an indicative dose escalation scheme for Module 2. All dose levels beyond 
cohort 1 may change in light of emerging safety, tolerability, and pharmacokinetic data, and 
also evolving relevant pre-clinical data. 
 
 


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Table 5  
Indicative Dose Escalation Scheme for Module 2 
  
Planned Dose levels 
RXC004 Dose 
(Starting Cycle 0) 
Nivolumab Dose/Regimen 
(Starting Cycle 1) 
1 
1 mg QD 
480mg q4w 
2 
1.5 mg QD 
480mg q4w 
3 
2 mg QD 
480mg q4w 
Note: This indicative dose and schedule optimisation scheme is subject to SRC recommendation. 
 
The pre-clinical toxicology data supports continuous dosing of RXC004 in humans, and 
Module 2 will start with this schedule. However, based on emerging data the SRC may decide 
to propose the exploration of intermittent RXC004 in combination with nivolumab schedules. 
The nivolumab dose and regimen will not be adjusted in this module. 
Please see RXC004 IB and nivolumab prescribing information for further details. 
5.3.6 Dose-Limiting Toxicity for RXC004 + Nivolumab Combination (Module 2) 
The DLT assessment period runs from the start of dosing with RXC004 and nivolumab (Cycle 
1 Day 1) up to Cycle 1 Day 28 where nivolumab treatment is administered every 28 days 
starting on C1D1.  
A DLT is defined as an AE or abnormal laboratory value that occurs from cycle 1 day 1 up to 
Cycle 1 Day 28, assessed as unrelated to disease progression, intercurrent illness, or 
concomitant medications and is possibly related to RXC004, nivolumab or both agents and 
that despite optimal therapeutic intervention meets any of the following criteria; 
1. Haematological toxicity that is: 
• ≥ CTCAE grade 4 neutropenia present for more than 4 consecutive days  
• Grade 3 neutropenia (ANC ≥ 500 to < 1000 cells/mm3) of any duration 
accompanied by fever ≥ 38.5°C and/or systemic infection 
• Grade 3 thrombocytopenia (25,000 to < 50,000/mm3) with clinical evidence of 
bleeding 
2. Any other confirmed haematological toxicity ≥ CTCAEv4 grade 4 (a repeat may be 
required for confirmation of an isolated abnormality in the absence of clinical signs, 
symptoms or other abnormal investigations, i.e. a suspected spurious value) 
3. Non-haematological toxicity ≥ CTCAE grade 3 including: 


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• Laboratory abnormalities that are considered clinically significant by the 
investigator (with or without clinical symptoms or signs) 
• 
QTc prolongation (> 500 msec or 60 msec above baseline) 
 
4. Any other toxicity that: 
• Is greater than that at baseline, is clinically significant and/or unacceptable, and is 
judged to be a DLT by the SRC 
• Is a protocol defined stopping criteria and is suspected to be RXC004 or Nivolumab 
related  
5. Any grade 3 or higher immune-related adverse events 
 
A DLT excludes:  
1. 
Inadequately treated grade ≤3 nausea and/or vomiting and grade ≤3 diarrhoea  
2. 
Any toxicity clearly unrelated to RXC004 and/or Nivolumab e.g. solely related to the 
disease or disease-related process under investigation. 
3. 
Isolated laboratory changes of any grade without clinical sequelae or clinical 
significance 
 
5.3.7 Dose Modifications 
RXC004 dose reduction and interruption are permitted. Nivolumab dose reduction is not 
permitted but dose interruption/delay is permitted. 
RXC004 may be dose interrupted (withheld) for up to 14 days until a clinically significant 
(any grade) and/or a grade > 3 related adverse event resolves to baseline or < grade 1. 
Patients that experience a RXC004 related adverse events that do not resolve to baseline or < 
grade 1 after 14 days of dose interruption/delay despite appropriate treatment must be 
discussed with Sponsor, before re-starting RXC004.  
Adverse events that are assessed as being causally related nivolumab should be managed as 
per the Nivolumab Toxicity Management and Dose Modification Guidelines (Appendix 8). If 
either agent alone 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.  If a patient continues in the study on nivolumab alone, this treatment may be 
continued for a maximum of 12 months in total. 


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5.3.8 Study Treatment discontinuation Criteria 
RXC004 and nivolumab dose interruption and stopping criteria are detailed for in Table 6 
Table 6 
Module 2 Dose Interruption 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 and manage as per 
Appendix 5 (and Appendix 8 if applicable) 
 
 
Grade 2  
If receiving RXC004, either as monotherapy or in 
combination with nivolumab 
Interrupt RXC004.  Manage as per Appendix 5 and  
Appendix 8 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 and 
nivolumab (if applicable) at 480 mg once every month. 
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 5  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. 
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 5 and  Appendix 8. 
 


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Event  
Action  
Grade 4 
 If receiving RXC004, either as monotherapy or in 
combination with nivolumab; 
Permanently discontinue study treatment (both agents 
if applicable).  Mange as per Appendix 5 and  Appendix 8 
 
 
Dysgeusia events 
Grade  1 or 2 
 
RXC004 related; 
Consider dose reduction, depending on clinical symptoms 
Manage as per Appendix 6 
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 6 
Reduce RXC004 to a lower dose. 
 
Grade 2 associated with a >20% 
decrease in body weight 
RXC004 related; 
Manage as per Appendix 6 
Permanently discontinue RXC004.  Nivolumab can 
continue if clinical benefit is judged by investigator for a 
maximum of 12 months total treatment. 
 
 
 
 
 
Other adverse events 
Any event that meets discontinuation 
criteria for nivolumab (see Appendix 
8) 
 
Permanently discontinue nivolumab.  RXC004 can 
continue, if clinical benefit is judged by investigator. 
 


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Event  
Action  
Any event that meets nivolumab 
treatment hold (see Appendix 8) 
Interrupt nivolumab and manage as per Appendix 8.  
Nivolumab can be re-started when event is resolved to 
≤Grade 1 and any steroid taper completed (to 10mg 
prednisone equivalent).  RXC004 can continue whilst 
nivolumab is held, if the patient is judged (by the 
investigator) to be receiving clinical benefit. 
 
Grade 3-4 toxicity (1st event) 
RXC004 related; 
Interrupt RXC004 and provide supportive care, resume at 
the next lowest dose level when resolved (grade ≤ 2 or 
returns to baseline).  Interruptions >14 days should be 
discussed with Sponsor before re-starting. 
 
Nivolumab related; 
See guidelines in Appendix 8 
 
Grade 3-4 toxicity (subsequent 
recurrence 
of 
a 
previously 
experienced event)  
RXC004 and/or nivolumab related; 
Permanently discontinue study treatment 
All Grade events  
 
 
Study treatment can be discontinued for any clinically 
significant AEs that in the investigator’s opinion warrants 
treatment discontinuation. 


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Event  
Action  
Bone events 
Confirmed 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 
≥350pg/ml 
from 
the 
baseline 
(screening) value or in individual 
measurement of ≥1000pg/ml 
 
 
Permanently discontinue RXC004.  Nivolumab can 
continue, if clinical benefit is judged by investigator for a 
maximum of 12 months total treatment. 
 
Permanently discontinue RXC004.  Nivolumab can 
continue, if clinical benefit is judged by investigator for a 
maximum of 12 months total treatment. 
 
 
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. 
Interruptions >14 days should be discussed with Sponsor 
before re-starting. 
 
 
Surgery  
Interrupt RXC004 (max. 14 daysb), resume at full dose. 
RXC004 should be stopped 3 days prior to surgery and 
resumed approx. 10 days later. If the wound has not healed 
a further 7 days are permitted prior to re-starting RXC004 
at the discretion of the Investigator and with approval of 
Sponsor Physician.  
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.  
b.  RXC004 interruptions of greater than 14 days may be allowed for patients judged by investigator to be 
clinically benefiting from study treatment, and only after consultation with Sponsor 


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AE, adverse event; BMD, bone mineral density; COVID-19, Coronavirus disease 2019 
 
5.3.9 Biomarker Samples 
An archival or a newly acquired tumour biopsy will be requested from every patient enrolled 
in the study.  Archived/newly acquired biopsies are optional (but encouraged) in the Module 2  
dose escalation.  
In all patients participating in the study, the taking of non-mandatory tumour biopsies will be 
encouraged and can be taken from each patient at up to 3 time points during the study;  
1. At baseline (prior to first dose of study treatment) 
2. During study treatment dosing (see SoA for biopsy timings) 
At the time of tumour biopsy, blood samples for assessment of PK and blood borne biomarkers  
will be taken; Analysis of these samples will include, but not be restricted to, functional Wnt 
pathway inhibition, immune gene signature and immune cell infiltration. 
5.3.10 Exploratory Assessments 
The circulating soluble factors and PBMC pharmacodynamic samples (all sites) will be 
obtained at C0D1 (prior to first dose) and on C1D15 and Day 1 of each cycle thereafter.  These 
samples may be used to examine gene and protein expression changes, including measurement 
of inflammatory markers.  Fresh whole blood (from selected sites of close proximity) will be 
obtained at C0D1 (prior to first dose), and pre-dose at C1D15 and C2D1.  Fresh whole blood 
may be stained for cell surface markers to identify immune cell populations present in the 
circulation before and after treatment. Circulating tumour DNA (ctDNA) and RNA (ctRNA) 
will be collected pre-dose at C0D1, post-dose on C1D15 and Day 1 of each subsequent cycle 
and at treatment discontinuation. Analysis of total amounts and/or tumour mutations (including 
Wnt pathway aberrations) in ctDNA samples may be evaluated and correlated to patient 
response. 
5.4 Module 3 
Module 3 will investigate the PK, Wnt pathway inhibition, incidence/severity of Wnt 
pathway related adverse events and anti-tumour activity of RXC004 when given at 2 
different intermittent dosing schedules, in a selected group of patients with Wnt ligand 
dependent advanced solid tumours. 
Following the completion of Module 1, the 2mg QD dose was selected as the recommended 
starting dose for Phase 2 studies, with options of interruptions and dose reductions to manage 
potential toxicities. The most frequently occurring treatment related AEs in module 1 (all 
doses) were fatigue (52%), nausea (44%), decreased appetite (40%), dysgeusia (40) and 


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vomiting (24%). The median RXC004 exposure in Module 1 was approximately 7 weeks so 
these adverse events were generally observed during the first two treatment cycles.  Of the 
observed adverse events, only dysgeusia, a known on-target toxicity of Wnt pathway 
inhibitors, was observed to be dose-related and 4 out of 6 patients in the 2mg cohort reported 
dysgeusia within the first 2 treatment cycles. Module 3 will explore whether intermittent 
dosing schedules have the potential to deliver clinical anti-tumour activity in selected patients 
with Wnt ligand dependent tumours and whether intermittent dosing, giving short treatment 
breaks, has the potential to reduce incidence of treatment related toxicities such as dysgeusia. 
If so, an intermittent dosing schedule could be a future alternative to dose reduction in the 
management of treatment related adverse events. 
 
5.4.1 Module 3: Study Objectives 
The study objectives are detailed in Section 1.9 
5.4.2 Module 3  Eligibility Criteria 
5.4.2.1 
Module 3 Specific Inclusion Criteria  
Module 3 specific inclusion criteria can be found in Section 2.1.3.  Patients must fulfill all of 
the core and Module 3 specific inclusion criteria in order to be eligible to receive study 
treatment in Module 3.  The core inclusion criteria are detailed in Section 2.1.1 
5.4.2.2 Module 3 Specific Exclusion Criteria 
There are no Module 3 specific exclusion criteria.  Patients must not meet any of the core 
exclusion criteria in order to be eligible to receive study treatment in Module 3.  The core 
exclusion criteria are detailed in Section 2. 
5.4.2.3 Restrictions 
Study restrictions are explained in Section 2.3 and prohibited concomitant treatments are 
explained in Section 2.3.1. 
5.4.2.4 Pre-screening for tumours with RNF43 mutations and RSPO fusions 
All patients enrolled into Module 3 must have Wnt dependent solid tumours, defined as; 
• Any solid tumour with a predicted loss of function RNF43 mutation (see Appendix 
10 for details). 
• Any solid tumour with a RSPO fusion (see Appendix 10 for details) 
• Biliary tract cancer 


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• Thymus cancers (thymic and thymoma WHO Classification) 
Eligible patients with RNF43 mutations or RSPO fusions, detected either in a tumour sample 
or in circulating tumour DNA (CTDNA), will be identified by either a central genetics 
screening approach or local laboratory assessments.  Patients with colorectal, pancreatic, 
gastric, prostate or squamous non-small cell lung cancers may submit archival tumour 
samples to the central genetic screening (study pre-screening). 
Diagnostic/archival tumour FFPE samples may be sent to Northern Genetics Service for 
central genetic screening for RNF43 mutations and RSPO fusions. This is an ISO 15189 
accredited NHS laboratory and part of the Newcastle NHS Trust, UK. During analytical 
validation, the RNF43 iPLEX assay, that detects 33 known RNF43 loss-of-function variants, 
performed at 100% for Analytical Sensitivity / Positive agreement (PPA) and 100% for 
Analytical Specificity/ Negative agreement (NPA). During analytical validation, the RSPO 
iPLEX assay, that detects 7 known RSPO gene fusions, performed at 100% for Analytical 
Sensitivity / PPA and 100% for Analytical Specificity / NPA. See Appendix 10 for a list of 
the mutations and fusions covered by these iPLEX tests. In addition, patient 
diagnostic/archival tumour biopsy samples will also be tested in a mini-panel DNAseq for 
the following genes: RNF43, APC, CTNNB1, AXIN1, AXIN2, BRAF, MLH1 and KRAS. 
During analytical validation the custom 8 gene DNAseq panel, analyzed on an Illumina 
MiSeq platform and processed through a SOPHiA DDM pipeline (CCCP_A_QIA_v1), 
performed with an Analytical Sensitivity / PPA of 99.03%, and an Analytical Specificity / 
NPA of 100%. RNF43 predicted loss-of-function mutations detected in this DNAseq assay 
will also be eligible, and could include mutations or aberrations in RNF43 beyond those 
listed in Appendix 10.  As RNF43 is a tumour suppressor gene in context of the Wnt 
pathway, further screening is likely to identify previously unseen RNF43 loss-of-function 
mutations. The remaining 7 genes on the DNAseq panel will be used to retrospectively 
investigate whether aberrations in these genes correlate with response to therapy (exploratory 
analysis). 
Data from central genetic screening will be shared with investigators to aid future treatment 
decisions. 
Patients with any solid tumours with predicted loss of function RNF43 mutations or RSPO 
fusions from other local testing of blood or tumour 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 CE-marked for the purpose of investigating RNF43 mutations or RSPO fusions; 
partially CE-marked for their analytical performance or having achieved a minimum 


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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 10, these may be included in the study on 
discussion with the Sponsor. 
5.4.3 Dose Rationale  
In Module 3, intermittent schedules of RXC004 will be investigated.  The intermittent 
schedules will use 2mg QD RXC004, which has already shown to be safe and tolerated when 
used continuously in Module 1 of this study.  This dose delivers Cmin values > 3-fold IC50 in 
patients, which is expected to lead to >50% Wnt pathway inhibition, while also being safe and 
tolerable.   
Module 1 opened in 2018 with a RXC004 dose of 10mg once daily, but the dose was not 
tolerated in the first patient and the Module 1 dose escalation was restarted on 18th March, 
2019 with 0.5mg RXC004.  As of the 30th July, 25 patients have been dosed with RXC004 
monotherapy in Module 1 of the study at doses of 0.5mg (4), 1mg (3), 1.5mg (7), 2mg (6), 
3mg (4) and 10mg (1) 
At doses up to and including 2 mg QD, the most common treatment related AEs were fatigue 
(10/20 patients), nausea (7/20), decreased appetite (6/20), dysgeusia (6/20), and vomiting 
(4/20). Of these, only dysgeusia appeared to be dose related. No Grade 4/5 treatment related 
AEs or bone fragility events were reported at any of these dose levels of RXC004. 
A detailed description of the RXC004 risks is provided in Section 1.7.1.  Details of the 
pharmacology, efficacy, and safety of RXC004 is also provided in the RXC004 Investigator’s 
Brochure. 
 
5.4.4 RXC004 Intermittent Schedules 
Module 3 will enroll 6 evaluable patients per Arm, with follow up for PK, pharmcodynamics 
and AEs.  
 
An evaluable patient in Module 3 is defined as a patient that has received study treatment and 
either: 
• Has completed minimum safety evaluation requirements and has received 100% of the 
specified RXC004 dose in Cycle 0 and at least 80% of the intended dose of RXC004 
during Cycles 1 and 2.  


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• Has permanently discontinued study treatment due to a related adverse event 
 
Subjects will start with a single dose of RXC004 followed by a washout of 3-7 days (Cycle 
0).  RXC004 schedules will commence on Cycle 1, Day 1.  Each treatment cycle will be 21 
days.  Study treatment will continue until disease progression, intolerable toxicity or 
withdrawal of consent.   Module 3 will start with two treatment Arms of intermittent 
RXC004 schedules; 
• Arm 1 – 2mg QD RXC004 for 4 days, followed by 3 days off, repeated weekly for 21 
day treatment cycles 
• Arm 2 – 2mg QD RXC004 for 2 weeks, followed by 1 week off (21 day treatment 
cycles) 
Patient enrolment into Arms 1 and 2 will run concurrently. 
Further RXC004 monotherapy arms may be opened after review of safety and tolerability 
information from Arms 1 and 2, relevant data from Modules 1 and 2 and any emerging 
preclinical data.  
Mandatory skin punch biopsies will be taken from all patients in Module 3 at baseline and 
while receiving treatment for analysis of pharmacodynamic markers of Wnt pathway 
inhibition, alongside PK sampling (see Schedule of Assessments in Appendix 9).  
 
5.4.5 Intermittent Schedule Rationale 
Redx have previously demonstrated that RXC004 is efficacious when delivered on a 5 days 
on/2 days off schedule in multiple mouse oncology models (see Figure 6 below).  Due to 
differences in half-life between mouse and human, with RXC004 having a significantly 
longer half-life in man ( 11 to 13 h compared to 2.4 to 3.4 h in mice) this pre-clinical 
schedule is most closely matched by the 4 days on/3 days off schedule in man. 
Figure 6 
Dose-dependent effects of RXC004 in B16F10/C27BL/6 syngeneic model and 
the SNU-1411 xenograft model.  
 
 




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treatment cycle these respectively give 14% and 24% of time below the IC50 for Wnt 
pathway inhibition and at least 72 % of time above the target Cmin of >3-fold IC50 in patients. 
5.4.6 RXC004 Dose Modifications 
If a patient experiences a clinically significant and/or unacceptable event not attributable to the 
disease or disease-related processes under investigation, RXC004 dosing may be interrupted, 
the dose reduced and supportive therapy administered as required. 
If the event resolves or reverts to CTCAE ≤Grade 2, treatment with RXC004 may be restarted 
using the rules below for dose modifications, only following agreement with the Sponsor 
physician.  
If the event does not resolve to CTCAE ≤Grade 2, or the patient is not showing clinical benefit, 
then the patient should be discontinued from treatment and observed until resolution of the 
event. 
5.4.7 Study Treatment Discontinuation Criteria 
RXC004 dose-interruption and stopping criteria are detailed in Table 7 
Table 7   
Module 3 Dose-Interruption and Stopping Criteria 
  
Event  
Action  
Colitis events 
(e,g. Colitis, ileitis, enterocolitis etc.) 
 
Grade 1 
 
 
 
Reduce RXC004 to a lower dose and manage per Appendix 
5 
Grade 2  
Interrupt RXC004.  Manage per Appendix 5.  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. 
If event recurs after re-starting study treatment, then 
RXC004 should be permanently discontinued. 
 


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Event  
Action  
Grade 3 
Interrupt RXC004. Manage per Appendix 5.  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. 
If event recurs after re-starting study treatment, then 
RXC004 should be permanently discontinued. 
 
Grade 4 
Permanently discontinue RXC004.  Manage per 
Appendix 5 
 
 
Dysgeusia events 
Grade 1/2 
 
RXC004 related; 
Consider dose reduction, depending in clinical symptoms 
Manage per Appendix 6 
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 per Appendix 6 
Reduce RXC004 to a lower dose. 
 
Grade 2 associated with a >20% 
decrease in body weight 
RXC004 related; 
Manage per Appendix 6 
Permanently discontinue RXC004. 
 
Bone events 
Confirmed RXC004-related fragility 
bone fracture (excluding Grade 1 
vertebral deformities) 
 
Patients with a DEXA scan showing > 
7% worsening in BMD at lumbar spine 
or total hip compared to baseline 
 
 
Permanently discontinue study treatment 
 
 
Permanently discontinue study treatment 


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Event  
Action  
An individual increase in β-CTX of 
≥350 
pg/mL 
from 
the 
baseline 
(screening) value or in individual 
measurement of ≥1000 pg/mL 
  
Permanently discontinue study treatment unless the patient 
has received clinical benefit (Investigator assessment) and 
continued treatment is warranted. 
Other adverse events 
Grade 3-4 toxicity (1st event) 
 
RXC004 related: 
Interrupt RXC004 (max. 14 daysb), resume at the next 
lowest dose level when resolved (≤Grade 2 or returns to 
baseline).  
 
Grade 
3-4 
toxicity 
(subsequent 
recurrence of a previously experienced 
event)  
 
RXC004 related; 
Permanently discontinue study treatment 
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. 
COVID-19 infection 
Positive COVID-19 test 
 
Interrupt RXC004, until acute symptoms have resolved. 
Interruptions >14 days should be discussed with Sponsor 
before re-starting. 
Surgery  
Interrupt RXC004 (max. 14 daysb), resume at full dose. 
RXC004 should be stopped 3 days prior to surgery and 
resumed approx. 10 days later. If the wound has not healed 
a further 7 days are permitted prior to re-starting RXC004 
at the discretion of the Investigator and with approval of 
Sponsor Physician.  
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 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.  


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b.  RXC004 interruptions of greater than 14 days may be allowed for patients judged by investigator to be 
clinically benefiting from study treatment, and only after consultation with Sponsor 
AE, adverse event; BMD, bone mineral density; COVID-19, Coronavirus disease 2019 
 
The dose of RXC004 must not be adjusted under any other circumstances unless prior 
agreement is given by the Sponsor. All dose/schedule modifications and interruptions 
(including any missed doses) and the reasons for the modifications/interruptions are to be 
recorded in the CRF. 
 
5.4.8 Biomarker Samples 
An archival or a newly acquired tumour biopsy will be requested from every patient enrolled 
in the study.  Archived/newly acquired biopsies are optional (but encouraged) in the Module 3 
In all patients participating in the study, the taking of non-mandatory tumour biopsies will be 
encouraged and can be taken from each patient at up to 2 time points during the study; 
• At baseline (prior to first dose of RXC004) 
• During RXC004 dosing (see SoA for biopsy timings) 
 
Two mandatory skin biopsies to assess downstream markers of Wnt expression will also be 
taken from all patients in Module 3 (see Appendix 9 Schedule of Assessments for timing).  
At the time of tumour and skin biopsies, blood samples for assessment of PK and blood borne 
biomarkers will also be taken; Analysis of these samples will include, but not be restricted to, 
genetic screening for tumour samples only, RXC004 plasma concentrations, Wnt pathway 
activation status and functional PORCN/Wnt inhibition, e.g. phosphorylation and/or 
expression of downstream markers. 
5.4.9 Exploratory Assessments 
Plasma and PBMC pharmacodynamic samples (all sites) will be obtained at C0D1 (prior to 
first dose) and during treatment (see Appendix 9 specific tumour mutations (including Wnt 
pathway aberrations) in samples may be evaluated and correlated to patient response. 


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6 
STUDY TREATMENT   
Detailed information describing the preparation, administration, and storage of RXC004 is 
located in the Pharmacy Manual. 
Detailed information describing the preparation, administration, and storage of Nivolumab is 
located in the Nivolumab Prescribing Information 
6.1 Method of Assigning Subjects to Treatment 
Upon approval of subject registration, the sponsor or designee will assign each subject to a 
Module, Arm and dose cohort. The cohort assignment decisions will be documented in the 
clinical trial master file. 
6.2 Identity of Investigational Product(s) 
6.2.1 RXC004 
RXC004 drug product is provided in 0.5 and 1.0mg. A complete description of the chemistry 
and formulation may be found in the Investigational Medicinal Product Dossier. 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 (0.5mg & 1.0mg), manufactured by 
Quay Pharma, Deeside Industrial Park, CH5 2NS, United Kingdom. The RXC004 capsules 
strengths are 0.5, 1.0mg 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. 
Reformulation to the lower doses required for the clinical study is currently underway. When 
the development is complete the IMPD will be updated accordingly and submitted to the 
relevant regulatory authority. 
6.2.2 Nivolumab 
Nivolumab will be supplied as 240mg or 480mg  vial solutions for infusion after dilution. 
480mg of nivolumab will be used per administration (one 480mg vial or two 240mg vials)  
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 


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particulate matter other than a few translucent-to-white, proteinaceous particles. Do 
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 
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 designed 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 
micrometer to 1.2 micrometer). 
• Do not co-administer other drugs through the same intravenous line 
• The intravenous line should be flushed at the end of the infusion. 
 
6.3 Packaging, Labelling and Storage 
6.3.1 RXC004 
The capsules will be supplied in white 50 mL HDPE Duma bottles, 24 capsules per bottle, 
which are labelled appropriately as required by regulatory bodies and should be stored in the 
site pharmacy at ambient temperature, 20°±5°C. Full details of daily dispensing will be 
captured in the Pharmacy manual. 


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6.3.2 Nivolumab 
Nivolumab will be centrally supplied by RedX as two 240mg/24mL vial solutions for 
infusion after dilution. 
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. 
 
6.4 Selection of Doses in the Study 
The starting dose for Modules are described in sections 5.2, 5.3, and 5.4 for Module 1, 2 and 
3, respectively. 
The starting dose/schedule of further modules will be the decision of the SRC based on 
emerging safety and tolerability data, however will not exceed the equivalent maximum 
exposure found to be tolerated in Module 1 at that point. 
6.5 Selection and Timing of Dose for Each Subject 
The doses and duration of treatment for each Module are detailed in the appropriate Module 
specific study design section.  The doses and duration of treatment for Module 1,  2 and 3 are 
detailed in Section 5.2.5, Section 5.3.5 and Section 5.4.3., respectively. The exact date and 
times the study drug was administered and comments are to be recorded directly on the 
appropriate page of the eCRF. 


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7 STUDY ENDPOINTS   
7.1  Efficacy  
The preliminary assessment of efficacy is a secondary objective of the study. The efficacy 
measures for this study include objective response rate, duration of response disease control 
rate and PFS based on the RECIST version 1.1 guidelines.  
Tumour Assessments 
RECIST 1.1 guidelines for measurable, non-measurable, target lesions (TLs) and non-target 
lesions (NTLs) and the objective tumour response criteria are presented in Appendix 4 of this 
Clinical Study Protocol. 
Baseline scans for RECIST should be performed within 28 days of first dose (the use of scans 
obtained as part of standard clinical practice, prior to informed consent, but within the 28-day 
period should be detailed in the consent form).  Baseline tumour assessments should 
encompass all areas of known predilection for metastases in the disease under evaluation and 
should additionally investigate areas that may be involved based on signs and symptoms of 
individual patients. Baseline assessments should be performed no more than 28 days before 
the start of study treatment, and ideally should be performed as close as possible to the start of 
study treatment.  
Tumour assessments will be performed using full body (chest, abdomen and pelvis) CT/ MRI 
for soft-tissue lesion only and bone scan (with additional confirmatory imaging – plain x-ray, 
CT/ MRI) for bone metastasis (in patients who develop bone metastasis after study start). The 
methods of assessment used at baseline should be used at each subsequent follow-up 
assessment.  
Scans will take place at timepoints detailed in the Schedule of assessments (Appendix 1, 
Appendix 20 and Appendix 9). Scans may be performed at other times, as clinically indicated. 
Imaging tumour assessments will cease at objective progression.  In the event of a patient 
discontinuing treatment for reasons other than progression they should continue to be followed 
for progression unless there is withdrawal of consent. Progression criteria for imaging tumour 
assessment will be determined by the following assessments: 
• 
RECIST criteria for soft-tissue lesions only (lymph nodes, visceral metastasis, prostate) 
• 
Bone Scans will be conducted at screening/baseline to rule out bone metastasis and 
during treatment if investigator suspects disease progression/development of bone 
metastasis 
Any other sites at which new disease is suspected should also be appropriately imaged. If an 
unscheduled assessment is performed and the patient has not progressed, every attempt should 


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be made to perform subsequent assessments at the scheduled visits whilst the patient remains 
on study treatment. 
Categorisation of objective tumour response assessment will be based on the RECIST 1.1 
guidelines for response: CR (complete response), PR (partial response), SD (stable disease) 
and PD (progression of disease). In order for a patient to be considered in disease control the 
patient must have at least stable disease for the first 2 scheduled scans (12 weeks for Module 
1 or 16 weeks for Module 2).  In addition the disease control rate at 18 or 24 weeks will be 
presented (for patients who have at least stable disease for the first 3 scheduled scans on 
Module 1 or 2 respectively).    
For patients who only have non-measurable disease at baseline, categorisation of objective 
tumour response assessment will be based on the RECIST 1.1 guidelines for response for 
NTLs: CR, PD and Non CR/Non PD. 
If the Investigator is in doubt as to whether progression has occurred, particularly with response 
to NTLs or the appearance of a new lesion, it is advisable to continue treatment and reassess 
the patient’s status at the next scheduled assessment or sooner if clinically indicated. 
To achieve ‘unequivocal progression’ on the basis of non-target disease, there must be an 
overall level of substantial worsening in non-target disease such that, even in presence of SD 
or PR in target disease, the overall tumour burden has increased sufficiently to merit 
discontinuation of therapy. A modest ‘increase’ in the size of one or more NTLs is usually not 
sufficient to qualify for unequivocal disease progression status. 
It is important to follow the assessment schedule as closely as possible. Please refer to the study 
plan and Schedule of Assessments (Appendix 1 for Module 1, Appendix 2 for Module 2, 0 for 
Module 3) 
Calculation or Derivation of Tumour Response Variables 
At each tumour assessment response will be based on RECIST 1.1 criteria RECIST 1.1 based 
on the status of their disease compared with baseline and previous visit assessments. 
 
Progression of target lesions (TLs) will be calculated in comparison to when the tumour burden 
was at a minimum (i.e., smallest sum of diameters previously recorded on study, including 
baseline). In the absence of progression, tumour response (CR, PR, SD) will be calculated in 
comparison to the baseline tumour measurements obtained before starting treatment. 
If a patient has had a tumour assessment which cannot be evaluated, then the patient will be 
assigned a visit response of not evaluable (NE) unless there is evidence of progression in which 
case the response will be assigned as PD. 


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For TL measurements, if ≤ 1/3 of the TL sizes are missing then a scaling up rule will be applied 
as follows: 
• 
If ≤ 1/3 of lesions recorded at baseline are missing then the results will be scaled up (based 
on the nadir sizes, including baseline) to give an estimated sum of diameters and this will 
be used in calculations (this is equivalent to comparing the visit sum of diameters of the 
non-missing lesions to the nadir sum of diameters excluding the lesions that are missing 
and determining at what rate the lesions are changing) 
• 
If > 1/3 of lesions recorded at baseline are missing then the TL response will be NE. 
However, if the sum of non-missing TL diameters would result in PD (i.e., if using a value 
of 0 for missing lesions the sum of diameters has still increased by > 20% or more 
compared to the smallest sum of diameters on study), PD takes precedence over NE 
• 
A visit response of CR will not be allowed if any of the TL data is missing 
A visit response of CR is defined when all TL and NTL lesions present at baseline have 
disappeared (with the exception of lymph nodes which must be < 10mm to be considered non-
pathological) and no new lesions have developed since baseline. 
A visit response of PR is defined when the sum of diameters of the TLs has decreased by 30% 
or more compared to baseline (with no evidence of progression) and the NTLs are at least 
stable with no evidence of new lesions. 
To be considered a PR or CR in the clinical trial report, changes in tumour measurements must 
be confirmed by repeat assessments that should be performed no less than 4 weeks after the 
criteria for response are first met. 
Stable disease is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase 
to qualify for PD. In the case of SD, follow-up measurements must have met the SD criteria at 
least once after study entry at a minimum interval of not less than 35 days. 
When the Investigator is in doubt as to whether progression of disease has occurred and 
therefore reassesses the patient at a later date, the date of the initial scan should be declared as 
the date of progression if the repeat scans confirm progression. 
For further details see Appendix 4  
7.2 Safety 
Safety assessments will include physical examination, vital signs, biochemistry and 
haematology, laboratory screens (including bone turnover markers) (see Schedule of Study 
Assessments in Appendix 1). Adverse events will also be noted at every clinical visit and 
recorded at least every week. For all administrations in hospital, the patients must wait for at 
least 60 minutes from the time of the RXC004 administration for observation and repeat vital 


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signs. Performance status will be measured weekly in Cycle 1, thereafter at the beginning of 
each cycle. 
7.2.1 Adverse Events 
Investigator and study personnel will report all AEs and SAEs elicited during subject 
questioning; discovered during physical examination; revealed by diagnostic or laboratory 
testing; or found by other means. These events must be recorded on the CRF and/or SAE form, 
as appropriate. 
Use open-ended or non-directed method of questioning at each study visit to elicit the reporting 
of AEs. 
Use the National Cancer Institute’s Common Terminology Criteria for Adverse Events (NCI 
CTCAE), version 5.0 to grade adverse event severity. These criteria are provided in the study 
manual. When CTCAE criteria cannot be used, the event should be graded as mild, moderate, 
severe or fatal. 
7.2.2 Clinical Laboratory Evaluations 
The Investigator, IQVIA Clinical Medical Monitor, and Redx Chief Medical Officer (CMO) 
will review clinical laboratory tests for results of potential clinical significance at all the time 
points throughout the study. The Investigator will evaluate any change in laboratory values. 
If the Investigator determines a laboratory abnormality to be clinically significant, it is 
considered a laboratory AE; however, if the abnormal laboratory value is consistent with a 
current diagnosis, it may be documented accordingly.  
Table 8 includes a list of analytes to be collected during the study. 
 
 




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Bone monitoring: Blood samples (fasted) at time points detailed in the Schedule of 
Assessments (Appendix 1Error! Reference source not found. for Module 1, Appendix 2 for 
Module 2 and 0 for Module 3) and serum harvested for analysis.  
 
7.2.3 Vital Signs, Physical Findings and Other Safety Assessments 
Safety assessments will include physical examination, vital signs, biochemistry, haematology 
and urinalysis laboratory screens (see Schedule of Study Assessments, Appendix 1 for Module 
1, Appendix 2 for Module 2 and Appendix 9 for Module 3). Measurements of heart rate, body 
temperature, blood pressure and respiratory rate will be made after the patient has been resting 
supine for a minimum of 5 minutes. Adverse events will also be noted at every clinical visit 
and recorded at least every week. For all administrations in hospital, the patients must wait for 
at least 60 minutes from the time of the RXC004 administration for observation and repeat 
vital signs. Performance status will be measured weekly in cycle 1, thereafter at the beginning 
of each cycle. 
7.3 Pharmacokinetics and Pharmacodynamics  
7.3.1 Pharmacokinetic Endpoints 
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 presented in Table 10. The date and time of collection of each sample will be recorded. 
Samples will be split, one for RXC004 and one for the metabolite identification work. 
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. After 
2 or more cohorts have been completed the timing of later PK samples will be re-assessed 
based on emerging PK data and the desire to characterise 80% of the AUC in all patients. The 
total number of samples and the total volume of blood taken from each patient will not exceed 
that presented in Table 10. 
If a patient misses any doses of RXC004 within 3 days of PK sampling, please contact the 
IQVIA 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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Where appropriate the following pharmacokinetic parameters will be estimated  
Single dose: 
 
Plasma 
 
• 
Maximum plasma concentration (Cmax) 
 
• 
Time to Cmax (tmax) 
 
• 
Concentration at 24 hours (C24) (and 
concentration at 12 hours (C12) if start with 
twice daily dosing) 
 
• 
Terminal rate constant (λz) 
 
• 
Terminal half-life (T½) 
 
• 
Area under the plasma concentration-time 
curve from zero to 24 hours (AUC0-24), from 
zero to the time of the last measurable 
concentration (AUC0-t) and from zero to 
infinity (AUC) 
 
• 
 Plasma clearance (CL/F) 
 
• 
Apparent volume of distribution (Vz/F) 
 
• 
Mean residence time (MRT) 
 
 
Multiple dose: 
 
Plasma: 
 
• 
Maximum plasma concentration at steady-
state (Css,max) 
 
• 
Time to Css,max (tss,max) 
 
• 
Minimum concentration at steady-state (Css, 
min) 
 
• 
Area under the plasma concentration-time 
curve in the dosing interval (AUCtau) 
 
• 
 Plasma clearance at steady-state (CLss/F) 
 
• 
Mean residence time at steady-state (MRTss) 
• 
Swing 
 
 
PK Analysis for Day 1 and Cycle 2 Day 1 (pre-dose): 
• 
Dose proportionality 
• 
 
• 
Accumulation Ratio (Rac) 
• 
Dose normalised Cmax 
• 
Dose normalised AUCs 
• 
 
 




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Tissue samples 
Blood samples 
Study Visit 
Skin punch 
biopsy 
Tumour 
Collection 
(optional) 
PBMC 
Plasma 
ctDNA 
Fresh 
whole 
blooda 
C0D1 
Pre-doseb 
Pre-doseb 
Pre-dose 
Pre-dose 
Pre-dose 
Pre-dose 
C1D8 
N/A 
N/A 
Approx. 4-
6hr post 
dose 
Approx 4-
6hrs post 
dose 
N/A 
Pre-dose 
C1D15 
Approx. 4-
6hr post 
dose 
N/A 
Approx. 4-
6hr post 
dose 
Approx 4-
6hrs post 
dose 
N/A 
pre-dose 
C2D1 
N/A 
Post dosee 
Approx. 4-
6hr post 
dose 
Approx 4-
6hrs post 
dose 
Approx 4-
6hrs post 
dose 
Pre-dose 
CXD1c 
N/A 
Cy4 (+/- 1 
Cy)e  
Approx. 4-
6hr post 
dose 
Approx. 4-
6hr post 
dose 
Cycle 4 
Day 1 only.  
Approx. 4-
6hr post 
dose 
N/A 
End of 
treatment/disease 
progressiond 
N/A 
Post dose 
Post dose 
Post dose 
Post dose 
N/A 
a Whole blood samples will be collected from sites of close proximity to Redx laboratory only 
b Baseline tissue samples can be taken at any time after initial consent up to the first dosing. Investigator 
discretion should be used on likelihood of a patient being eligible 
c CXD1 is Day 1 of each subsequent cycle 
d Samples should be taken at the Final Study Visit, which should be performed as soon as practically possible 
after discontinuation of study drug (ideally within 7 days) 
e Between 4-12 hours post dose 
 
7.3.3.1.1 Exploratory endpoints from pharmacodynamic samples 
Skin punch biopsies will be collected in Module 1.  These samples may be analysed for gene 
and protein expression to determine target engagement of the Wnt pathway.  


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PBMC pharmacodynamic samples will be collected for all patients. These samples may be 
analysed for the effect of drug administration on induced PORCN/Wnt or related pathway 
activity. 
Plasma samples may be used to analyse circulating soluble factors, such as relevant tumour 
markers and markers of immune function, in baseline and on-treatment samples. These may 
be analysed by enzyme linked immunosorbent assay (ELISA), or other relevant methods.  
ctDNA samples may be used to analyse circulating tumour DNA/RNA (ctDNA/RNA).  Total 
amounts and/or analysis of mutations/genetic alterations in ctDNA/RNA may be analysed and 
associated with response to treatment. 
Fresh whole blood pharmacodynamic samples may be analysed by flow cytometry for changes 
in markers of immune cell populations, including, but not limited to, markers for immune cell 
subsets. In addition, assays of immune function such as stimulated cell activation (assessed by 
marker expression, cytokine secretion, proliferation, etc.) may be conducted using whole blood 
samples. 
Paired tumour biopsies may be monitored for gene/protein changes.  This data may be used to 
examine changes in Wnt pathway activation and/or immune cell changes in the tumour 
microenvironment.  
Additional pharmacodynamic markers, (e.g., monitoring other inflammatory markers, 
measuring specific cell populations, RNA profiles of specific cell populations, or measuring 
cell surface markers that can be measured by flow cytometry, Western blot, or ELISA) may be 
evaluated at the discretion of the sponsor using excess pharmacodynamic or PK samples. 
 
Tumour Samples  
An archival or a newly acquired biopsy will be requested from every patient enrolled in the 
study.  These archived/newly acquired biopsies are optional (but encouraged) in the study.  
Candidate biomarkers, e.g. upstream Wnt pathway aberrations (RNF43 mutation, RSPO 
fusion) will be analysed in archived/newly acquired tumour samples to investigate the 
relationship between these biomarkers and efficacy outcomes following treatment. 
Paired tumour biopsy samples, where available, will be analysed for exploratory 
pharmacodynamic endpoint measurements as described in Section 7.3.3.1.1 
 
 


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7.3.3.2 Module 2 
Blood and tumour Sample Collection 
PBMC, circulating soluble factors, ctDNA and ctRNA samples for pharmacodynamic analysis 
will be collected from all patients at baseline and on treatment, according to the table of 
scheduled assessments. 
Fresh whole blood will be collected from a subset of patients at baseline and on treatment, 
according to the table of scheduled assessments (depending on proximity of site for analysis 
of this fresh sample). 
Optional paired tumour biopsies will be also collected, where possible, from any suitable 
patient enrolled into module 2. 
As pharmacodynamic data become available, the timing of pharmacodynamic sampling may 
be adjusted, but the frequency of blood samples obtained will not increase. 
 
Table 12:  
Module 2: Pharmacodynamic samples / Tumour Collection Schedule  
 
Tumour 
Samples 
Blood Samples 
Study Visit 
Paired 
tumour 
biopsiesf 
PBMC 
Circulating 
soluble 
factors 
ctDNA 
ctRNA 
Fresh whole 
blooda 
C0D1 
(Optional) 
predoseb 
predose 
predose 
predose 
predose 
predose 
C1D15 
(Optional) 
post dose 
Approx. 
4-6hr 
post 
dose 
Approx 4-
6hrs post 
dose 
Approx 
4-6hrs 
post 
dose  
Approx 4-
6hrs post 
dose  
predose 
C2D1 
N/A 
Approx. 
4-6hr 
post 
dose 
Approx 4-
6hrs post 
dose 
Approx 
4-6hrs 
post 
dose 
Approx 4-
6hrs post 
dose 
Predose 
CXD1c 
(Optional) 
During 
Cycle 3 of 
treatment 
Approx. 
4-6hr 
post 
dose 
Approx. 4-
6hr post 
dose 
Approx. 
4-6hr 
post 
dose 
Approx. 
4-6hr post 
dose 
N/A 


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End of 
treatment/disease 
progressiond 
N/A 
N/A 
N/A 
Post 
final 
dose 
Post final 
dose 
N/A 
a Whole blood samples will be collected from sites of close proximity to Redx laboratory only 
b Baseline tumour samples can be taken at any time after initial consent up to the first dosing. Investigator 
discretion should be used on likelihood of a patient being eligible 
c CXD1 is Day 1 of each subsequent cycle 
d Samples should be taken at the IP discontinuation visit 
 
7.3.3.2.1  
Exploratory endpoints from pharmacodynamic samples 
PBMC pharmacodynamic samples will be collected for all patients. These samples may be 
analysed for the effect of drug administration on induced PORCN/Wnt or related pathway 
activity. 
Plasma samples may be used to analyse circulating soluble factors, such as relevant tumour 
markers and markers of immune function, in baseline and on-treatment samples. These may 
be analysed by enzyme linked immunosorbent assay (ELISA), or other relevant methods.  
ctDNA and ctRNA samples may be used to analyse circulating tumour DNA/RNA 
(ctDNA/RNA).  Total amounts and/or analysis of mutations/genetic alterations in ctDNA/RNA 
may be analysed and associated with response to treatment. 
Fresh whole blood pharmacodynamic samples may be analysed by flow cytometry for changes 
in markers of immune cell populations, including, but not limited to, markers for immune cell 
subsets. In addition, assays of immune function such as stimulated cell activation (assessed by 
marker expression, cytokine secretion, proliferation, etc.) may be conducted using whole blood 
samples. 
Paired tumour biopsies may be monitored for gene/protein changes.  This data may be used to 
examine changes in Wnt pathway activation and/or immune cell changes in the tumour 
microenvironment.  
Additional pharmacodynamic markers, (e.g., monitoring other inflammatory markers, 
measuring specific cell populations, RNA profiles of specific cell populations, or measuring 
cell surface markers that can be measured by flow cytometry, Western blot, or ELISA) may be 
evaluated at the discretion of the sponsor using excess pharmacodynamic or PK samples. 
 
7.3.3.2.2 Tumour Samples  


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An archival or a newly acquired biopsy will be requested from every patient enrolled in the 
study.  These archived/newly acquired biopsies are optional (but encouraged) in the study.  
Candidate biomarkers, e.g. upstream Wnt pathway aberrations (RNF43 mutation, RSPO 
fusion) will be analysed in archived/newly acquired tumour samples to investigate the 
relationship between these biomarkers and efficacy outcomes following treatment. 
Paired tumour biopsy samples, where available, will be analysed for exploratory 
pharmacodynamic endpoint measurements as described in Section 7.3.3.2.1 
 
7.3.3.3 Module 3  
Skin punch biopsy samples will be collected in Module 3, at baseline and on treatment 
according to the schedule of assessments (Appendix 9).  Skin punch biopsies are mandatory in 
Module 3. 
PBMC, circulating soluble factors, ctDNA and ctRNA samples for pharmacodynamic analysis 
will be collected from all patients at baseline and on treatment, according to the table of 
scheduled assessments (Appendix 9). 
Fresh whole blood will be collected from patients from UK sites at baseline and on treatment, 
according to the table of scheduled assessments (Appendix 9) 
Optional paired tumour biopsies will be also collected, where possible, from any suitable 
patient enrolled into module 3. 
As pharmacodynamic data become available, the timing of pharmacodynamic sampling may 
be adjusted, but the frequency of blood samples obtained will not increase. 
7.3.3.3.1 Exploratory endpoints from pharmacodynamic samples 
PBMC pharmacodynamic samples will be collected for all patients. These samples may be 
analysed for the effect of drug administration on immune cell composition, PORCN/Wnt or 
related pathway activity. 
Plasma samples may be used to analyse circulating soluble factors, such as relevant tumour 
markers and markers of immune function, in baseline and on-treatment samples. These may 
be analysed by enzyme linked immunosorbent assay (ELISA), or other relevant methods.  
ctDNA and ctRNA samples may be used to analyse circulating tumour DNA/RNA 
(ctDNA/RNA).  Total amounts and/or analysis of mutations/genetic alterations in ctDNA/RNA 
may be analysed and associated with response to treatment. 
Fresh whole blood pharmacodynamic samples may be analysed by flow cytometry for changes 
in markers of immune cell populations, including, but not limited to, markers for immune cell 
subsets. In addition, assays of immune function such as stimulated cell activation (assessed by 
marker expression, cytokine secretion, proliferation, etc.) may be conducted using whole blood 
samples. 


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Paired skin punch biopsies may be monitored for Wnt pathway activity through gene or protein 
expression changes. 
Paired tumour biopsies may be monitored for gene/protein changes.  This data may be used for 
example, to examine changes in Wnt pathway activation and/or immune cell changes in the 
tumour microenvironment.  
Additional pharmacodynamic markers, (e.g., monitoring other inflammatory markers, 
measuring specific cell populations, RNA profiles of specific cell populations, or measuring 
cell surface markers that can be measured by flow cytometry, Western blot, or ELISA) may be 
evaluated at the discretion of the sponsor using excess pharmacodynamic or PK samples. 
7.3.3.3.2 Tumour Samples  
An archival or a newly acquired biopsy will be requested from every patient enrolled in the 
study.  These archived/newly acquired biopsies are optional (but encouraged) in the study. 
These archival samples may be collected at screening and may be sent for central genetic 
screening as described in Section 5.4.2 and/or analysed for exploratory endpoint 
measurements as described in Section 7.3.3.3.1. 
Candidate biomarkers may also be analysed in archived/newly acquired tumour samples to 
investigate the relationship between these biomarkers and efficacy outcomes following 
treatment. 
Paired tumour biopsy samples, where available, will be analysed for exploratory 
pharmacodynamic endpoint measurements as described in Section 7.3.3.3.1 
7.4 Appropriateness of Measurements 
The safety measures that will be used in this trial are considered standard procedures for 
evaluating the potential adverse effects of study medications. Adverse events and, when 
applicable, clinical laboratory data will be graded using NCI CTCAE, version 5.0.  
Response will be assessed according to RECIST v1.1 (Appendix 4) which includes standard 
criteria for evaluating response in solid tumours. Prostate cancer responses will be assessed via 
PCWG3 criteria, which are standard accepted modifications of RECIST. The intervals of 
evaluation in this protocol are appropriate for disease management. 
 


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8 QUALITY CONTROL AND QUALITY ASSURANCE – 
CORE  
According to the Guidelines of Good Clinical Practice (CPMP/ICH/135/95), the Sponsor is 
responsible for implementing and maintaining quality assurance and quality control systems 
with written Standard Operating Procedures (SOPs).   
Quality control will be applied to each stage of data handling.   
The following QC checkpoints will be taken to ensure the accuracy, consistency, completeness, 
and reliability of the data: 
• Investigator meeting(s). 
• Central laboratories for biomarker analysis. 
• Local laboratories for clinical laboratory parameters and ECGs. 
• Centre Initiation visit. 
• Early centre visits post-enrollment. 
• Routine centre monitoring. 
• Ongoing centre communication and training. 
• Data management quality control checks. 
• Continuous data acquisition and cleaning. 
• Internal review of data. 
• Quality control check of the final clinical study report. 
In addition, Sponsor and/or IQVIA Quality Assurance Department may conduct periodic 
audits of the study processes, including, but not limited to study centre visits, central 
laboratories, vendors, clinical database, and final clinical study report. When audits are 
conducted, access must be authorized for all study related documents including medical history 
and concomitant medication documentation to authorized Sponsor’s representatives and 
regulatory authorities. 
8.1.1 Monitoring 
The Sponsor has engaged the services of a contract research organization (CRO), IQVIA, to 
perform all monitoring functions within this clinical study. IQVIA’s clinical monitors will 
work in accordance with SOPs and have the same rights and responsibilities as monitors from 
the Sponsor organization. Monitors will establish and maintain regular contact between the 
Investigator and the Sponsor. 
Monitors will evaluate the competence of each study centre, informing the Sponsor about any 
problems relating to facilities, technical equipment or medical staff. During the study, monitors 
will check that written informed consent has been obtained from all patients correctly and that 


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data are recorded correctly and completely. Monitors will also compare entries in eCRFs with 
corresponding source data prior to data cleaning by IQVIA Data Management and inform the 
Investigator of any errors or omissions. Monitors will also control adherence to the protocol at 
the study centre. They will arrange for the supply of investigational product and ensure 
appropriate storage conditions are maintained. 
Monitoring visits will be conducted according to all applicable regulatory requirements and 
standards. Regular monitoring visits will be made to each centre while patients are enrolled in 
the study. The monitor will make written reports to the Sponsor on each occasion contact with 
the Investigator is made, regardless of whether it is by phone or in person. 
The Investigator is responsible for maintaining source documents. These will be made 
available for inspection by the study monitor at each monitoring visit. To allow sufficient time 
to assemble documentation for the study monitor, monitoring visits will be confirmed in 
advance of planned visits. The Investigator must submit a completed eCRF for each subject 
who receives study medication, regardless of duration. All supportive documentation 
submitted with the eCRF, such as laboratory or hospital records, should be clearly identified 
with the study and subject number. Any personal information, including subject name, should 
be removed or rendered illegible to preserve individual confidentiality. 
During monitoring visits, entries in the eCRFs will be compared with the original source 
documents (source data verification). For the following items, this check will be 100%:  
• Subject identification number. 
• Subject consent obtained. 
• Subject eligibility criteria (inclusion and exclusion criteria). 
• Efficacy variables. 
• Medical record of AE. 
For all other items, 100% of the data will be checked. 
8.1.2 Data Management/Coding 
Data generated within this clinical study will be handled according to the relevant SOPs of the 
Data Management and Biostatistics departments of IQVIA. Single data entry with source data 
verification (SDV) will be performed for EDC. 
A validated and 21 CFR Part 11 compliant Electronic Data Capture (EDC) system will be used 
for this study, meaning that all eCRF data will be entered in electronic forms at the study centre. 
Data collection will be completed by authorized study centre staff designated by the 
Investigator. Appropriate training and security measures will be completed with the 
Investigator and all authorized study centre staff prior to the study being initiated and any data 
being entered into the system for any study patients. 


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All data must be entered in English. The eCRFs should always reflect the latest observations 
on the patients participating in the study. Therefore, the eCRFs are to be completed as soon as 
possible during or after the subject’s visit. To avoid inter-observer variability, every effort 
should be made to ensure that the same individual who made the initial baseline determinations 
completes all efficacy and safety evaluations. The Investigator must verify that all data entries 
in the eCRFs are accurate and correct. If some assessments are not done, or if certain 
information is not available or not applicable or unknown, the Investigator should indicate this 
in the eCRF. The Investigator will be required to electronically sign off on the clinical data.   
The monitor will review the eCRFs and evaluate them for completeness and consistency. The 
eCRF will be compared with the source documents to ensure that there are no discrepancies 
between critical data. All entries, corrections and alterations are to be made by the responsible 
Investigator or his/her designee. The monitor cannot enter data in the eCRFs. Once clinical 
data of the eCRF have been submitted to the central server, corrections to the data fields will 
be audit trailed, meaning that the reason for change, the name of the person who performed the 
change, together with time and date will be logged. Roles and rights of the site staff responsible 
for entering the clinical data into the eCRF will be determined in advance. If additional 
corrections are needed, the responsible monitor or Data Manager will raise a query in the EDC 
application. The appropriate study centre staff will answer queries sent to the Investigator. This 
will be audit trailed by the EDC application meaning that the name of investigational staff, 
time and date stamp are captured. 
The eCRF is essentially considered a data entry form and should not constitute the original (or 
source) medical records unless otherwise specified. Source documents are all documents used 
by the Investigator or hospital that relate to the subject’s medical history, that verify the 
existence of the subject, the inclusion and exclusion criteria and all records covering the 
subject’s participation in the study. They include laboratory notes, electrocardiogram (ECG) 
results, memoranda, pharmacy dispensing records, subject files, etc. 
Electronic case report form records will be automatically appended with the identification of 
the creator, by means of their unique UserID. Specified records will be electronically signed 
by the Investigator to document his/her review of the data and acknowledgement that the data 
are accurate. This will be facilitated by means of the Investigator’s unique UserID and 
password; date and time stamps will be added automatically at time of electronic signature. If 
an entry on an eCRF requires change, the correction should be made in accordance with the 
relevant software procedures. All changes will be fully recorded in a protected audit trail, and 
a reason for the change will be required. 
8.1.3 Quality Assurance  
Study centres, the study database and study documentation may be subject to Quality 
Assurance audit during the course of the study by the Sponsor or IQVIA on behalf of Redx. In 
addition, inspections may be conducted by regulatory bodies at their discretion.   
All required data will be entered into the clinical and/or safety database in accordance with 
Code of Federal Regulations (CFR) 21 Part 11 compliance. The database will include an audit 


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trail to document any evidence of data processing or activity on each data field by each user. 
Users will be given restricted access based on their role in the study through a password 
protected environment. All missing data will be explained.  
Data entered in the system must be verifiable against source documents and will be reviewed 
manually for validity and completeness against the source documents by a clinical monitor 
from Redx or its designee. If necessary, the study site will be contacted for corrections or 
clarifications. 


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9 STATISTICS  
9.1 Determination of Sample Size 
The sample size for Module 1 is not based on a formal sample size calculation, as no formal 
statistical hypothesis is being tested. The estimated maximum number of patients (n=30) has 
been based on the expected number of cohorts and the desire to obtain adequate tolerability, 
safety, pharmacokinetic and pharmacodynamic data while exposing as few patients as possible 
to the IMP and procedures. The total number of patients required will depend upon the 
toxicities encountered and the number of dose cohorts required. 
 
For Module 2, there will approximately 18 patients. 
Module 3 will recruit 6 patients who are evaluable for DLT assessment per cohort. 
9.2 Statistical Methods 
All analyses, summaries, and listings will be performed using SAS® software (version 9.3 or 
higher). Modules will be summarized separately. 
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. 
Patient disposition, demographics, and baseline characteristics will be summarised using 
descriptive statistics.  
In general, all efficacy, safety, and PK variables will be summarised using descriptive statistics. 
Continuous variables will be summarised by descriptive statistics (sample size [n], mean, 
standard deviation [SD], median, minimum and maximum). Categorical variables will be 
summarised in frequency tables (n, frequencies, and percentages). Individual subject data will 
be presented in listings. Missing data will not be imputed unless otherwise stated 
The study data from each module will be analyzed and reported based on all patient data up to 
the time when all module patients have completed at least 6 cycles of treatment or have 
discontinued study treatment. Data will be listed, summarized, and analyzed by dose level and 
overall.   
 
 


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Analysis Populations 
Four analysis populations will be defined for use with various analyses.   
• The Safety Population will consist of all patients who enrolled and receive at least one 
dose of study drug.   
• The PK Evaluable Population will consist of those patients deemed by the sponsor or 
pharmacokineticist to have sufficient PK concentration data to be meaningfully 
included in the PK analysis summaries.   
• The PD Evaluable Population will consist of those patients deemed by the sponsor or 
translational scientist to have sufficient PD assessment data to be meaningfully 
included in the PD analysis summaries. 
• The Efficacy Evaluable Population will include patients who receive a radiographic 
assessment at baseline, received at least one dose of study treatment, and at least one 
post-dose radiographic tumour assessment, or progressed ahead of the first scan. 
Adverse events and medical history will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) version 20.0 or greater. Concomitant medications will be coded using 
the World Health Organization Drug Dictionary (WHODrug: March 2017 or later version).  
9.2.1 Efficacy Analyses 
Overall Response Rate (ORR) (CR+PR), Duration of Response (DoR), Disease Control Rate 
(DCR) (CR+PR+SD) will be calculated for the efficacy evaluable population based on 
modified RECIST guidelines (Appendix 4).   
At each tumour assessment visit patients will be programmatically assigned a RECIST 1.1 visit 
response of CR, PR, SD, PD or NE depending on the status of their disease compared with 
baseline and previous visit assessments. 
Progression of target lesions (TLs) will be calculated in comparison to when the tumour burden 
was at a minimum (i.e., smallest sum of diameters previously recorded on study, including 
baseline). In the absence of progression, tumour response (CR, PR, SD) will be calculated in 
comparison to the baseline tumour measurements obtained before starting treatment. 
The best overall response will be determined programmatically for each patient as CR, PR, 
SD, PD or NE, based on the best response recorded from start of study treatment to end of 
treatment, including any assessments for confirmation after the end of treatment. 
Objective Response Rate 
Objective response rate is defined as the number of patients who have at least one response of 
CR or PR prior to any evidence of progression (as defined by RECIST 1.1) that is confirmed 
at least 4 weeks later divided by the number of response evaluable patients. 


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Disease Control rate 
Disease control rate is defined as the proportion of all patients dosed that have a visit response 
of at least SD, PR or CR at the second schedule scan post baseline, scheduled at week 12 for 
module 1 or week 16 for module 2. Therefore, earlier visit responses of CR, PR that become 
PD at the second post baseline scan or NE responses at the second post baseline scan do not 
constitute disease control. A time window of 1 week around the visit will be applied and it is 
recommended that any visits occurring within 1 week of the scheduled time  will be acceptable; 
however, if an earlier visit is defined as PD then the visit response at the second post baseline 
scan would also be defined as PD. If the second post baseline scan is missing or NE, but the 
next evaluable response is SD or better, then the patient will be defined as having non-
progressive disease at the second post baseline scan visit.  Disease control rate will also be 
assessed for patients who have at least SD for the first 3 scheduled post baseline scans (ie 18 
weeks for module 1 and 24 weeks for module 2. 
Percentage Change in Tumour Size 
Percentage change in tumour size will be determined for patients with measurable disease at 
baseline and is derived at each visit by the percentage change from baseline in the sum of the 
diameters of TLs. 
The best percentage change in tumour size will be the patient’s value representing the largest 
decrease (or smallest increase for those patients whose tumour target lesions do not show a 
decrease) from baseline in tumour size. 
Duration of response 
Duration of response will be defined as the time from the date of first documented response 
until date of documented progression or death in the absence of disease progression, the end 
of response should coincide with the date of progression or death from any cause used for the 
PFS endpoint. The time of the initial response will be defined as the latest of the dates 
contributing towards the first visit response of PR or CR. 
If a subject does not progress following a response, then their duration of response will use the 
PFS censoring time. 
Progression Free Survival 
Progression-free survival (PFS) will also be assessed.  Analyses will be done at the RP2D and 
pooled for all patients in a module. 
Progression free survival (PFS) is defined as the time from start of treatment (first dose of 
RXC004, or combination agent if relevant, whichever is first) until the date of objective disease 
progression or death (by any cause in the absence of progression) regardless of whether the 
subject withdraws from therapy or receives another anti-cancer therapy prior to progression. 


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Patients who have not progressed or died at the time of analysis will be censored at the time of 
the latest date of assessment from their last evaluable RECIST assessment. However, if the 
patient progresses or dies after two or more missed visits, the patient will be censored at the 
time of the latest evaluable RECIST assessment. If the patient has no evaluable visits or does 
not have baseline data they will be censored at 0 days unless they die within two visits of 
baseline. 
The PFS time will always be derived based on scan/assessment dates not visit dates. 
RECIST assessments/scans contributing towards a particular visit may be performed on 
different dates. The following rules will be applied: 
• 
Date of progression will be determined based on the earliest of the dates of the component that 
triggered the progression 
• 
When censoring a subject for PFS the subject will be censored at the latest of the dates contributing 
to a particular overall visit assessment 
 
9.2.2 Safety Analyses 
The Safety Population will be used to summarize the safety endpoints for this study. Safety 
and tolerability will be assessed by: 
• physical examination (including BP, Pulse, skin assessment),  
• evaluation of laboratory parameters - clinical chemistry, haematology and urinalysis 
(including urea creatinine and specific gravity)  
• ECG 
• number of withdrawals, discontinuations and dose reductions 
• number of DLTs 
• assessment of AEs (graded by CTCAE): adverse events will be summarized by 
MedDRA system organ class and preferred term based on the worst grade observed for 
each patient. If the intensity or seriousness of the AE changes, the overall intensity or 
seriousness will be the maximum intensity or seriousness of the multiple occurrences 
• SAEs 
9.2.3 Data to be Analysed 
All details regarding the statistical analysis and the preparation of tables, listings and figures 
will be described in the Statistical Analysis Plan prepared by IQVIA and approved by the 
Sponsor prior to database lock. 
9.2.4 Missing Data 
Missing data will not be imputed unless otherwise stated.  


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9.3 Subject Disposition 
The disposition summary will include all dosed patients. 
9.4 Subject Characteristics 
Patient characteristics will be obtained at screening and will be summarised for all patients 
administered RXC004. Summaries will include descriptive statistics for continuous variables 
(sample size, mean, standard deviation, median, minimum, and maximum) and for categorical 
variables (sample size, frequency and percent). Subject characteristics may include, but are not 
limited to: age, gender, race/ethnicity, height, weight, and body mass index (BMI). 
Subject characteristics will be summarised using the Safety Population. 
9.5 Efficacy Analyses 
Objective response rate and disease control rate will be summarized per dose level and pooled 
by module.  
Duration of response will only be evaluated for the subgroup of patients with an ORR using 
the Kaplan-Meier method, provided there are sufficient response to make it meaningful. 
Best change in tumor size whilst on treatment (ie greatest decrease or smallest increase for 
subjects whose tumors do not show a decrease) will be presented in the form of waterfall plots, 
with the bars being colour coded by dose level. 
Changes in tumor size for individual patients across time will also be presented by spider plots. 
PFS will be analyzed using the method of Kaplan-Meier, for patients who receive the 
recommended Phase 2 dose, and also pooling together all doses within a module.   
9.6 Safety 
9.6.1 Adverse Events 
Treatment-emergent adverse events are defined as AEs that first occurred or worsened in 
severity after the first administration of the study drug and within 30 days of last dose of 
RXC004 in the case of module 1 and within 90 days of last dose of nivolumab for module 2. 
Adverse event summaries will include incidence of treatment-emergent AEs by MedDRA 
preferred term and system organ class, SAEs including deaths, AEs that led to study drug 
discontinuation, AEs leading to death, treatment related AEs and AEs by maximum severity..   


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9.6.2 Clinical Laboratory Evaluations 
Shift tables to characterize changes from baseline will be presented for graded haematology, 
clinical chemistry, and coagulation parameters. All data will be presented in listings. Other 
summaries will be presented on a data-driven basis. 
9.6.3 Vital Signs Measurements, Physical Exams, ECG and Other Safety 
Evaluations 
All data will be presented in listings. Shift tables for change from baseline for ECG parameters 
and vital signs measurements based on ranges specified in the SAP will be provided 
9.7 Health Outcomes Analyses 
No health outcomes analyses will be conducted in this study. 
9.8 Pharmacokinetic and Pharmacogenetic Analyses 
Blood samples will be collected and stored to assess any potential differences in PK or toxicity 
that may be reflected in host genetics.  The results of the PK and pharmacogenetic analyses 
may be presented in reports separate to the CSR. 
9.9 Interim Analyses 
No formal interim analysis is planned. 


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10 ETHICS  
10.1 Institutional Review Board or Independent Ethics Committee 
An Ethics Committee should approve the final protocol, including the final version of the 
Informed Consent Form (ICF) and any other written information and/or materials to be 
provided to the patients. The Investigator will provide the Redx or IQVIA with documentation 
of IRB/IEC approval of the protocol and informed consent before the study may begin at the 
study centre(s). The Investigator should submit the written approval to Redx via IQVIA before 
enrolment of any subject into the study. 
Redx and IQVIA should approve any modifications to the ICF that are needed to meet local 
requirements. The Investigator will supply documentation to Redx via IQVIAas required 
IRB/IEC’s annual renewal of the protocol, and any approvals of revisions to the informed 
consent document or amendments to the protocol. 
The Investigator will report promptly to the IRB/IEC, any new information that may adversely 
affect the safety of patients or the conduct of the study. Similarly, the Investigator will submit 
written summaries of the study status to the IRB/IEC annually, or more frequently if requested 
by the IRB/IEC. Upon completion of the study, the Investigator will provide the ethics 
committee with a brief report of the outcome of the study, if required. 
Redx via IQVIA will provide Regulatory Authorities, Ethics Committees and Investigators 
with safety updates/reports according to local requirements, including Suspected Unexpected 
Serious Adverse Reactions, where relevant. 
Any investigator-initiated changes to the protocol (with the exception of changes to eliminate 
an immediate hazard to a study subject) must be approved by the sponsor prior to seeking 
approval from the IRB/IEC, and prior to implementing. The investigator is responsible for 
enrolling subjects who have met protocol eligibility criteria. Protocol deviations must be 
reported to the sponsor and the local IRB/IEC in accordance with IRB/IEC policies. 
The sponsor may terminate the study at any time. The IRB/IEC must be advised in writing of 
study completion or early termination. 
10.2 Ethical Conduct of the Study 
This study will be conducted and the informed consent will be obtained according to the ethical 
principles stated in the Declaration of Helsinki, the principles of Good Clinical Practice 
(current ICH guidelines) and the applicable drug and data protection laws and regulations of 
the countries where the study will be conducted. 
Good Clinical Practice (GCP) is an international ethical and scientific quality standard for 
designing, conducting, recording and reporting studies that involve the participation of human 


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patients. The study will be conducted in compliance with GCP and the applicable national 
regulations to assure that the rights, safety and well-being of the participating study patients 
are protected consistent with the ethical principles that have their origin in the Declaration of 
Helsinki. 
10.3 Subject Information and Informed Consent 
The ICF will be used to explain the risks and benefits of study participation to the subject in 
simple terms before the subject will be entered into the study. The informed consent form 
contains a statement that the consent is freely given, that the subject is aware of the risks and 
benefits of entering the study, and that the subject is free to withdraw from the study at any 
time. Written consent must be given by the subject and/or legal representative, after the receipt 
of detailed information on the study. 
The Investigator is responsible for ensuring that informed consent is obtained from each 
subject or legal representative and for obtaining the appropriate signatures and dates on the 
informed consent document prior to the performance of any protocol procedures and prior to 
the administration of study medication. The Investigator will provide each subject with a copy 
of the signed and dated consent form.   
10.4 Subject Data Protection 
The ICF will incorporate (or, in some cases, be accompanied by a separate document 
incorporating) wording that complies with relevant data protection and privacy legislation. 
Redx or their representative(s) will not provide individual genotype results to patients, any 
insurance company, any employer, their family members, general physician or any other third 
party, unless required to do so by law. 
Extra precautions are taken to preserve confidentiality and prevent genetic data being linked 
to the identity of the subject. In exceptional circumstances, however, certain individuals might 
see both the genetic data and the personal identifiers of a subject. For example, in the case of 
a medical emergency, a Redx or representative physician or an Investigator might know a 
subject’s identity and also have access to his or her genetic data. Also, regulatory authorities 
may require access to the relevant files. 


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11 STUDY ADMINISTRATION – CORE  
11.1 Data Handling and Record Keeping 
It is the Investigator’s responsibility to maintain essential study documents (protocol and 
protocol amendments, completed eCRFs, signed informed consent forms, relevant 
correspondence, and all other supporting documentation). The study site should plan on 
retaining such documents for approximately 15 years after study completion. The study site 
should retain such documents until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or at least 2 years after the formal discontinuation of clinical 
development of the investigational product. These documents should be retained for a longer 
period if required by the applicable regulatory requirements or the hospital, institution, or 
private practice in which the study is being conducted. Subject identification codes (subject 
names and corresponding study numbers) will be retained for this same period of time. These 
documents may be transferred to another responsible party, acceptable to Sponsor, who agrees 
to abide by the retention policies. Written notification of transfer must be submitted to Sponsor. 
The Investigator must contact Sponsor prior to disposing of any study records.   
11.2 Direct Access to Source Data/Documents 
The Investigator will prepare and maintain adequate and accurate source documents to record 
all observations and other pertinent data for each subject randomized into the study.   
The Investigator will allow the Sponsor, IQVIA, and authorized regulatory authorities to have 
direct access to all documents pertaining to the study, including individual subject medical 
records, as appropriate. 
11.3 Investigator Information 
11.3.1 Investigator Obligations 
This study will be conducted in accordance with the ICH Harmonized Tripartite Guideline for 
GCP (GCP, 1997; and European Legislation; and the ethical principles that have their origin 
in the Declaration of Helsinki.  
The Investigator agrees to conduct the clinical study in compliance with this protocol after the 
approval of the protocol by the IEC/IRB in compliance with local regulatory requirements. 
The Investigator and the Sponsor will sign the protocol to confirm this agreement. 


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11.3.2 Protocol Signatures 
After reading the protocol, each Investigator will sign the protocol signature page and send a 
copy of the signed page to the Sponsor or representative (Section 14). By signing the protocol, 
the Investigator confirms in writing that he/she has read, understands and will strictly adhere 
to the study protocol and will conduct the study in accordance with ICH Tripartite Guidelines 
for Good Clinical Practice and applicable regulatory requirements. The study will not be able 
to start at any centre where the Investigator has not signed the protocol. 
11.3.3 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. 
11.4 Financing and Insurance  
Sponsor will provide insurance in accordance with local guidelines and requirements as a 
minimum for the patients participating in this study. The terms of the insurance will be kept in 
the study files. 
 


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Ref 45 VASIKARAN ET AL 2014, Vasikaran, S.D., et al., Harmonised Australian Reference 
Intervals for Serum PINP and CTX in Adults. The Clinical Biochemist Reviews, 2014. 35(4): 
p. 237-242. 
Ref 46 VASIKARAN ET AL 2018, Vasikaran, S., Assessment of bone turnover in osteoporosis: 
harmonization of the total testing process, in Clinical Chemistry and Laboratory Medicine 
(CCLM). 2018. p. 1603. 
Ref 47 VOLOSHANENKO ET AL 2013, Voloshanenko, O., et al., Wnt secretion is required to 
maintain high levels of Wnt activity in colon cancer cells. Nat Commun, 2013. 4: p. 2610. 
Ref 48 WANG ET AL 2018, Wang, B., et al., Targeting Wnt/beta-Catenin Signaling for Cancer 
Immunotherapy. Trends Pharmacol Sci, 2018. 
Ref 49 XIAO ET AL 2018, Xiao Q, Wu J, Wang WJ, Chen S, Zheng Y, Yu X, Meeth K, 
Sahraei M, Bothwell ALM, Chen L, Bosenberg M, Chen J, Sexl V, Sun L, Li L, Tang W, 
Wu D.  DKK2 imparts tumor immunity evasion through β-catenin-independent suppression 
of cytotoxic immune-cell activation.  Nat. Med.  24(3):262-270 
Ref 50 ZHONG ET AL 2016, Zhong, Y., et al., Tankyrase Inhibition Causes Reversible 
Intestinal Toxicity in Mice with a Therapeutic Index < 1. Toxicol Pathol, 2016. 44(2): p. 267-
78. 
Ref 51 ZOU ET AL 2005, Zou, H., et al., Aberrant methylation of secreted frizzled-related 
protein genes in esophageal adenocarcinoma and Barrett's esophagus. International Journal of 
Cancer, 2005. 116(4): p. 584-591. 
 
 
 


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13 APPENDICES 
Appendix 1  
Schedule of Assessments - Module 1 ........................................................... 136 
Appendix 2 
Schedule of Assessments - Module 2 ........................................................... 139 
Appendix 3 
Performance Status Scale .............................................................................. 144 
Appendix 4 
Response Evaluation Criteria for Solid Tumours (RECIST) ........................ 145 
Appendix 5 
Colitis Management and Treatment Guidelines ........................................... 146 
Appendix 6 
Dysgeusia treatment guidelines .................................................................... 150 
Appendix 7 
Prohibited CYP3A4 Inhibitors and Inducers ................................................ 152 
Appendix 8 
Nivolumab Toxicity Management and Dose Modification 
Guidelines (Patients enrolled onto Module 2 only) ...................................... 154 
Appendix 9 
Module 3 Schedule of Assessments .............................................................. 163 
Appendix 10 RNF43/RSPO aberrations ............................................................................. 167 
 
 
 






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Each schedule will not exceed 12 samples taken out to 96 hours post RXC004 administration. The SRC may advise on adjusted time-points. The actual time for each blood draw must 
be accurately recorded.  
10. The Final Study Visit should be performed as soon as practically possible after discontinuation of study drug (ideally within 7 days) 
11. Vitamin D (800 IU OD) and calcium (1000 to 1500 mg OD) supplementation should commence at screening and continue throughout the treatment period 
12. Fresh blood may be requested from investigator sites in close proximity to RedX laboratories.  All  samples should be taken predose  
13. Blood samples will be taken to obtain ctDNA, pre-dose at C0D1 visit, approx. 4-6hrs post dose at C2D1 and C4D1 visits, and at disease progression/discontinuation of study 
treatment 
14. Day 1 and Day 15 bone markers will be assessed on Cycle 2 and Cycle 3 for the first 3 cohorts only (0.5mg, 1mg and 1.5mg RXC004).  All subsequent cohorts will have bone 
markers assessed on Day 1 only of Cycle 2 and Cycle 3 
 
 










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o 
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  


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Appendix 3 
Performance Status Scale 
 
ECOG 
Score 
Description 
0 
Normal activity. Fully active, able to 
carry on all pre-disease performance 
without restriction. 
1 
Symptoms, but ambulatory. Restricted in 
physically strenuous activity, but 
ambulatory and able to carry out work of 
a light or sedentary nature (e.g., light 
housework, office work). 
2 
In bed <50% of the time. Ambulatory and 
capable of all self-care, but unable to 
carry out any work activities. Up and 
about more than 50% of waking hours. 
3 
In bed >50% of the time. Capable of only 
limited self-care, confined to bed or chair 
more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. 
Cannot carry on any self-care. Totally 
confined to bed or chair. 
5 
Dead. 
 
 
 


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Appendix 4 
Response Evaluation Criteria for Solid Tumours (RECIST) 
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 nonmeasureable 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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Appendix 5 
Colitis Management and Treatment Guidelines  
Events of colitis or enteritis were reported in four patients who commenced treatment at 
doses of 3 mg QD or 10 mg QD.  Events of ileitis and colitis were subsequently reported in 
the ongoing Phase 2 studies (RXC004/0002 and RXC004/0003), at doses of 2mg QD, so 
there is a potential risk for colitis in patients receiving RXC004 2mg QD as a monotherapy.   
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 8) 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.  
 
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 


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Grade 
Management 
Grade 2 colitis (abdominal pain, 
mucus or blood in stool) 
Pause RXC004 (and nivolumab if applicable) 
Manage with corticosteroids at a dose of 0.5mg/kg 
methylprednisolone equivalent. 
When symptoms have resolved, taper over 2-4 weeks. 
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 (<10mg 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 1mg/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 
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Grade 
Management 
physiological levels (<10mg prednisolone equivalent 
dose) over at least 1 month.. 
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 
48-72 hrs. It is 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 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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Appendix 6 
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 7 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 
• 
Flavoring foods with seasonings and spices 
• 
Eating food cold may help to reduce unpleasant flavor sensations 
• 
Frequently brushing teeth 
• 
Rinsing with mouth wash regularly 
• 
Using chewing gum. Lozenges or mints to stimulate saliva production  


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A dysgeusia treatment algorithm has been developed by Sevryugin et al.{Sevryugin, 2021 
Ref 36} 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. 
Figure from {Sevryugin, 2021 Ref 36} 
 


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Appendix 7 
Prohibited CYP3A4 Inhibitors and Inducers 
  
CYP 3A4 Inhibitors  
CYP 3A4 Inducers  
Strong CYP 3A4 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 CYP 3A4 Inducers 
Concomitant use of these drugs has the potential 
to decrease the exposure of RXC004 by over 80%  
These agents must not be given within 14 days of 
first dose of study treatment 
 
aptalutimide, carbamazepine, enzalutamide, 
mitotane, phenytoin, rifampin, St. John’s wort 
 
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 SMPC 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 CYP 3A4 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 
SMPC 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 
armodafinil, modafinil, rufinamide 
 


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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 8 
Nivolumab Toxicity Management and Dose Modification Guidelines 
(Patients enrolled onto Module 2 only) 
Recommendations for nivolumab modifications are provided in the dose-modification 
section of the nivolumab Prescribing Information and summarised here.   
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 0.5-1mg/kg or consider oral 
budesonide 9mg 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 and consider 
biopsy.  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 5mg/kg (if no 
perforation/sepsis/TB/hepatitis/congestive heart 
failure – Must have had 
flexsigmoidoscopy/colonoscopy prior)b 
 
Withhold dosea   


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Adverse Event 
Severity 
Investigations, Treatment and Dose modification 
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.   
 
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 
1mg/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 5mg/kg 
(or MMF if concurrent hepatic toxicity).   
 
High resolution CT +/- bronchoscopy and BAL 
pending appearances 
 
Permanently discontinue 
Hepatitis 
(non-HCC) 
Grade 1: 
ALT or AST >ULN-3XULN 
If > ULN-3XULN repeat in 1 week 
 
Continue treatment 


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Adverse Event 
Severity 
Investigations, Treatment and Dose modification 
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 
 
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 
Hepatitis (HCC) 
ALT/AST within normal 
limits at baseline and 
increases to >3-5XULN 
Or 
Re-check LFTs/INR/albumin every 1-3 days 
 
If rising ALT/AST when re-checked start oral 
prednisolone 1 mg/kg.  If no improvement within 3-
5 days on oral prednisolone 1 mg/kg, consider 
additional workup (liver biopsy, liver US) and 


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Adverse Event 
Severity 
Investigations, Treatment and Dose modification 
AST/ALT is more than 1-
3XULN at baseline and 
increases to 5-10XULN 
treatment with methylprednisolone 2-4mg/kg/day.  
Immunosuppressives (e.g.MMF) should be 
considered if no improvement on steroids. 
 
If toxicity resolves to Grade ≤1 or baseline, wean 
steroids over 2 weeks.  Re-escalate if worsening; 
nivolumab treatment may be resumed once 
prednisolone ≤ 10 mg. 
 
Consider hepatologist consult and US with Doppler 
 
Withhold dosea 
AST/ALT increased to 
>10XULN or total bilirubin 
increases to >3XULN 
Investigations and treatment as above. 
 
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 dosea 
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 
 
Refer to or consult endocrinologist  
 
Withhold dosea 
Grade 4 
Investigations as per Grade 1 
 
Treatment as per Grade 3 
 
Refer to or consult endocrinologist  
 


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Adverse Event 
Severity 
Investigations, Treatment and Dose modification 
Permanently discontinue 
Adrenal 
Insufficiency 
Grade 2 
Withhold dosea 
Grade 3 or 4 
Permanently discontinue 
Type 1 Diabetes 
Mellitus 
Grade 3 hyperglycemia 
Admit to hospital immediately and start treatment of 
newly onset type I DM. 
 
Withhold dosea 
Grade 4 hyperglycemia 
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) 
 
Renal ultrasound +/- doppler to exclude 
obstruction/clot 
 
Withhold dosea  - Repeat creatinine/K+ every 48h 
If returns to Grade 1/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 per Grade 2, plus admit patient for 
monitoring and ﬂuid balance; repeat creatinine every 
24 h; early discussion with nephrologist and need 
for biopsy; if worsening, initiate 
(methyl)prednisolone 1-2 mg/kg i.v. 
 


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Adverse Event 
Severity 
Investigations, Treatment and Dose modification 
Withhold dosea 
Serum creatinine >6 x ULN 
Investigations per Grade 3, 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 
 
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 


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Adverse Event 
Severity 
Investigations, Treatment and Dose modification 
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 consultation 
 
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 
to high-dose steroids).  Consider concurrent empiric 
antiviral (i.v. acyclovir) and antibacterial therapy 
 
CNS imaging and consider neurological 
consultation 
 


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Adverse Event 
Severity 
Investigations, Treatment and Dose modification 
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 atenonol for symptoms; consider 
carbimazole if anti-TSH Receptor Ab positive 
Painful thyroiditis – consider prednisolone 0.5 
mg/kg and taper if unwell,  
 
Withhold dosea 
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–
2mg/kg). In the case of deterioration, consider 
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 


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Severity 
Investigations, Treatment and Dose modification 
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 consultation.  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 consultation 
 
Permanently discontinue 
Requirement for 10mg 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 
 








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Assessments made on Day 1 of each cycle are to be conducted prior to RXC004 administration, unless specified otherwise. 
Additional assessments may be conducted as clinically indicated. 
A tolerance of +/-1 day will be permitted for all study visits and a tolerance of -1 day for all assessments relative to the study visit, unless specified otherwise. 
* Female patients, if fertile, will require a serum pregnancy test at Screening and urine pregnancy on Day 1 of each cycle 
**Eligibility criteria to be re-checked at Cycle 1 prior to dose administration. 
***A lateral T & L spine assessment if a Vertebral Fracture Assessment (VFA) cannot be completed locally 
 
a  
A full physical examination is required at Screening and prior to Day 1 of each cycle ; Symptom-directed physical examination is acceptable at other time-points 
b 
Vital signs (heart rate, BP, temperature and respiration rate) will be assessed pre-dose and up to 1 hour after the RXC004 administration.  Patient status will be monitored during RXC004 
administration and repeat vital signs will be taken if needed.  Height is required at screening only.  Weight will be recorded at Screening and on Day 1 of each cycle. 
c 
All samples should be collected pre-dose  
d 
Fresh blood samples to be collected from UK sites only.  All samples should be collected pre-dosing. 
e 
Samples should be collected pre-dose for all samples.   
f 
Patients will have PK blood sampling conducted at the following sample times 
Cycle 0: Day 1 - Predose, then 30 mins, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, 12 h, 24 h, and 48 h post-dose. 
C1D11: Predose, then 30 mins, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, 12 h & 24 h 
Cycle X, Day 1 - A single pre-dose sample will also be taken on subsequent samples on Day 1. 
The SRC may advise on adjusted time-points. The actual time for each blood draw must be accurately recorded.  
g 
An optional ‘on treatment’ biopsy during Cycle 1 Day 11 treatment visit, preferably 4-6hrs post dose and from the same site as the baseline biopsy sample.  The actual time of collection should be 
accurately recorded. 
h 
Triplicate ECGs should be collected as follows; 
Cycle 0: Day 1 – Pre-dose (within 30 mins of first dose), then 1 h ± 10 mins and 12 h ± 30 mins post-dose 
Cycle 1, Day 11- Predose (within 30 mins of dose), then 1 h ± 10 mins and 12 h ± 30 mins post-dose 
Cycle X, Day 1 - Pre-dose (within 30 mins of dose)  
i 
Consenting patients will have a 10 mL blood sample taken for preparation of a germ-line DNA sample at Screening (recommended time-point only). 
j 
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.  Note that where there is a rationale for assessment of bone lesions that develop after study start, these assessments will be performed as part of the CT or MRI 
assessment and will not require additional radiological bone scan assessment.  Additional scans may be performed to confirm a Complete Response (CR) or Partial Response (PR) or disease 
progression (PD) as per appropriate response assessment guidelines. Any requirement for confirmatory scans will typically be performed at the next protocolled assessment time point. Other 
assessments e.g. whole body MRI or PET, are not protocol mandated, but may be performed as clinically indicated and at request of Investigator. 
k 
Arm 1 treatment schedule is 2mg QD RXC004 for 4 days, followed by 3 days off, repeated for 21 days per cycle of treatment.  Arm 2 treatment schedule is 2mg QD RXC004 for 2 weeks, followed by 
1 week off.  Further arms investigating other intermittent schedules may be added after review by SRC.  Results for chemistry and haematology labs must be available before starting a new treatment 
cycle (within 3 days) and reviewed by the treating physician or Investigator prior to dosing 
l 
Follow up assessments should be performed 30 days after last dose of RXC004 
m 
Mandatory skin punch biopsies will be collected from all patients.  All patients should consent to two skin punch biopsies – pre-dose on C0D1 (baseline) and one ‘on study treatment’ biopsy on either 
C1D11 or C2D1.  The first 3 patients in a given Arm will also have a skin punch biopsy on C1D11 (RXC004 dosing day sample) and the last 3 patients will have a skin punch biopsy pre-dose on 
C2D1 (off RXC004 sample).  Patients will have skin punch biopsies conducted at the following sample times (the actual time of collection should be accurately recorded); 
- All patients - C0D1 - Predose 
- Patients 1 to 3 within an Arm - C1D11 - 4-6 hrs post dose 
- Patients 4 to 6 within an Arm - C2D1 - Predose 
n 
 A taste assessment (consisting of a specific set of questions) will be performed at screening and at each study visit when patient reports a taste disturbance.  Please see Section 4.2 for more details 
o 
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 
 


Redx Pharma plc 
 
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Version 7.0 
Appendix 10 RNF43/RSPO aberrations 
In Module 3 of the study patients must have a Wnt dependent tumour, defined as: 
• Any solid tumour with a predicted loss of function RNF43 mutation 
• Any solid tumour with a RSPO fusion 
• Biliary tract cancer 
• Thymus cancers 
 
Patients with the following RNF43 mutations are eligible for the study: 
Nucleotide  
 Protein  
 c.64C>T  
 p.(Gln22Ter)  
 c.85G>T  
 p.(Gly29Ter)  
 c.122C>G  
 p.(Ser41Ter)  
 c.122C>A  
 p.(Ser41Ter)  
 c.137C>T  
 p.(Ala46Val)  
 c.207delT  
 p.(Phe69LeufsTer7)  
 c.245T>C  
 p.(Leu82Ser)  
 c.337C>T  
 p.(Arg113Ter)  
 c.349_350insC  
 p.(Arg117ProfsTer8)  
 c.349delC  
 p.(Arg117AlafsTer41)  
 c.394C>T  
 p.(Arg132Ter)  
 c.433C>T  
 p.(Arg145Ter)  
 c.454C>T  
 p.(Arg152Ter)  
 c.457C>T  
 p.(Gln153Ter)  
 c.461C>T  
 p.(Pro154Leu)  
 c.476G>A  
 p.(Trp159Ter)  
 c.477G>A  
 p.(Trp159Ter)  
 c.484G>A  
 p.(Val162Met)  
 c.505G>A  
 p.(Ala169Thr)  
 c.557T>C  
 p.(Ile186Thr)  
 c.599_600insC  
 p.(Trp200SerfsTer60)  
 c.599G>A  
 p.(Trp200Ter)  
 c.600G>A  
 p.(Trp200Ter)  
 c.647C>A  
 p.(Ser216Ter)  
 c.673delC  
 p.Arg225AlafsTer194)  
 c.776G>A  
 p.(Trp259Ter)  


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 c.777G>A  
 p.(Trp259Ter)  
 c.931delC  
 p.(LeuL311SerfsTer108)  
 c.988C>T  
 p.(Arg330Ter)  
 c.1009C>T   p.(Arg337Ter)  
 c.1111C>T   p.(Arg371Ter)  
Patients with documented LoF 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: 
PTPRK (NM_001291981.1) exon 1 :: RSPO3 (NM_032784.4) exon 2  
PTPRK (NM_001291981.1) exon 2 :: RSPO3 (NM_032784.4) exon 2  
PTPRK (NM_001291981.1) exon 7 :: RSPO3 (NM_032784.4) exon 2  
PTPRK (NM_001291981.1) exon 13 :: RSPO3 (NM_032784.4) exon 2  
EIF3F (NM_001568.2) exon 1 :: RSPO2 (NM_178565.4) exon 1  
EIF3F (NM_001568.2) exon 1 :: RSPO2 (NM_178565.4) exon 2  
NRIP1 (NM_003489.3) 5’ UTR :: RSPO2 (NM_178565.4) exon 1  
HNF4G (NM_001330561.1) 5’ UTR :: RSPO2 (NM_178565.4) exon 1  
PVT1 (NR_00367.3) exon 1 :: RSPO2 (NM_178565.4) exon 1  
PVT1 (NR_00367.3) exon 1 :: RSPO2 (NM_178565.4) exon 2  
Exon numbering based on the stated reference sequences using sequential numbering where the first coding 
exon is defined as exon 1.  
Patients with documented RSPO fusions other than those listed above may be allowed after consultation with 
Sponsor. 
 
 


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14 SIGNATURE OF INVESTIGATOR 
PROTOCOL TITLE:  A Modular, Multi-Arm Phase 1, Adaptive Design Study To Evaluate 
The Safety And Tolerability Of RXC004, Alone And In 
Combination With Anti-Cancer Treatments, In Patients With 
Advanced Malignancies 
PROTOCOL NO: 
RXC004/0001 
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. 
Instructions to the Investigator: Please SIGN and DATE this signature page. PRINT your name, title, and the 
name of the centre in which the study will be conducted. Return the signed copy to CRO.  
 
I have read this protocol in its entirety and agree to conduct the study accordingly: 
 
Signature of Investigator:      
__________________________            Date:  ________ 
Printed Name:                                ___________________________ 
Investigator Title:                           ___________________________ 
 
Name/Address of Centre:               
___________________________ 
 
___________________________ 
 
___________________________ 
 
 
 
 

SAP_001.pdf: 
Redx Pharma plc / Protocol: RXC004/0001
Novella Clinical (Confidential) Project #
Redx RXC004_0001 Statistical Analysis Plan v3.0 Final 20230317
Document last saved: 8/11/2023 7:36 AM
p. 1
Redx Pharma plc
Protocol #: RXC004/0001
A Modular multi-Arm, Phase 1, Adaptive Design Study to Evaluate the Safety and 
Tolerability of RXC004, Alone and in Combination with Anti-cancer Treatments, in Patients 
with Advanced Malignancies
Statistical Analysis Plan
Version 3.0; Amendment 2
Document last saved: 8/11/2023 7:36 AM
Prepared for:
Senior Project Manager
Redx Pharma plc
Prepared by:
Biostatistician II 
IQVIA Biotech
PPI
PPI




Redx Pharma plc / Protocol:  RXC004/0001 
Novella Clinical (Confidential) Project # 
Redx RXC004_0001 Statistical Analysis Plan v3.0 Final 20230317 
Document last saved: 8/11/2023 7:36 AM 
p. 3 
 
 
 
Revision History: Version 3.0; Amendment 2 (Previous: Version 2.0) 
 
Date  
Reason for 
update  
Modifications 
 
Original 
version 1.0 
NA 
07/20/2022 Amendment 1 
version 2.0 
1. Section VII; Prior Therapies: Summary tables for Best overall 
response of the immune checkpoint inhibitor regimens added.  
2. Section VII; Cancer history and classification: Summary of 
RNF43 and RSPO status and Wnt Ligand Dependency added. 
3. Section VIII; PFS will not be summarized using KM method with  
cohorts of n=3. 
4. Separate plot for diameter of TLs by dose level and wnt ligand 
dependency added. 
5. Section IX, Cumulative dose of RXC004 removed. 
6. Cumulative dose and any dose reduction summary table for 
Nivolumab removed. 
7. Section IX, Subsection B-Adverse Events: Separate listing of 
Serious AE, TEAEs leading to discontinuation of RXC004 and 
Nivolumab removed. 
8. Summary table of any Grade 3 or higher TEAE , related TEAEs 
for RXC004 and Nivolumab added. 
9. Summary table related to RXC004 and Nivolumab added. 
10. Summary table of TEAE leading to Nivolumab reduction 
removed. 
11. Summary table related to TEAE by PT added. 
12. Section IX, subsection C: Overlaying Line plot for lab data for all 
subjects added 
13. Section IX, subsection I: ECOG shift table by visit is  removed. 
14. Section IX, subsection J: Post anti-cancer therapy changed to Post-
Treatment Anti-Cancer Therapy. 
15. Section IX, subsection K: Summary table of B-CTX added. 
03/09/2023 Amendment 2 
version 3.0 
1. Section II, subsection A: Protocol version and date were updated. 
2. Section II, subsection C: One of the endpoints was removed as per 
the new protocol v7.0.  
3. Section III, subsection C: Dysgeusia Questionnaire endpoint was 
added for Module 3. 
4. Section IV, subsection A: Actual dose for Module 2 updated. 
Details regarding Module 3 study design overview added 
5. Section IV, subsection B: Study population for Module 3 added 
6. Section IV, subsection C: Sample size for Module 3 added 
7. Section IV, subsection E: Schedule of Assessments for Module 3 
added  
8. Section VI, subsection J, point #5:  Evaluable for Safety 
Population for Module 3 added.  
9. Section VIII, subsection B: Duration of Response and Time to 


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Response analysis excluded for Module 3.   
10. Section IX, subsection A: Number of Completed Cycles’ 
calculation for Module 3 added. 
 
 


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Novella Clinical (Confidential) Project # 
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TABLE of CONTENTS 
 
 
List of Abbreviations ...................................................................................................................... 7 
I. 
Introduction ............................................................................................................................. 8 
II. Protocol Objectives ................................................................................................................. 8 
A. Primary Objectives ................................................................................................................. 8 
B. Secondary Objectives ............................................................................................................. 8 
C. Exploratory Objectives ........................................................................................................... 8 
III. Study Endpoints ...................................................................................................................... 9 
A. Efficacy Endpoints .................................................................................................................. 9 
B. Safety Endpoints ..................................................................................................................... 9 
IV. Study Design ........................................................................................................................ 10 
A. Design Overview .................................................................................................................. 10 
B. Study Population ................................................................................................................... 12 
C. Sample Size........................................................................................................................... 13 
D. Treatment Randomization..................................................................................................... 13 
E. Assessment Schedule ............................................................................................................ 13 
V. Interventions ......................................................................................................................... 13 
A. Clinical Trial Material .......................................................................................................... 13 
B. Study Procedures .................................................................................................................. 13 
VI. General Analytical Considerations ...................................................................................... 13 
A. Data Sources and General Rules ........................................................................................... 13 
B. Definition of Baseline ........................................................................................................... 14 
C. Missing Data ......................................................................................................................... 14 
D. Nominal Timepoints ............................................................................................................. 14 
E. Definition of study day ......................................................................................................... 14 
F. Multiple Study Centers ......................................................................................................... 15 
G. Interim Analyses or Timing of Analyses .............................................................................. 15 
H. Test Sizes .............................................................................................................................. 15 
I. Multiple Comparisons........................................................................................................... 15 
J. Analysis Populations ............................................................................................................ 15 
1. Safety Population .................................................................................................................. 15 
2. Efficacy Evaluable Population.............................................................................................. 15 


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3. Pharmacokinetic (PK) Evaluable Population ....................................................................... 15 
4. Dose Limiting Toxicity (DLT) Evaluable Population .......................................................... 16 
K. Data Display Characteristics ................................................................................................. 16 
VII. Patient Accountability .......................................................................................................... 17 
A. Patient Characteristics........................................................................................................... 17 
B. Medical History .................................................................................................................... 18 
C. Disposition ............................................................................................................................ 18 
D. Protocol Deviations .............................................................................................................. 18 
VIII. Efficacy Analyses ............................................................................................................... 18 
A. Efficacy Endpoints ................................................................................................................ 18 
1. Best Overall Response (BOR) .............................................................................................. 19 
3. Disease Control Rate (DCR)................................................................................................. 20 
4. Duration of response (DoR) .................................................................................................. 21 
5. Progression Free Survival (PFS)........................................................................................... 21 
B. Efficacy Endpoint Analyses.................................................................................................. 22 
IX. Safety Analyses .................................................................................................................... 22 
A. Exposure ............................................................................................................................... 22 
B. Adverse Events ..................................................................................................................... 24 
C. Clinical Laboratory Results .................................................................................................. 26 
D. Vital Signs ............................................................................................................................ 27 
E. Physical Examination ........................................................................................................... 27 
F. Electrocardiogram (ECG) ..................................................................................................... 27 
G. Prior and Concomitant Medications ..................................................................................... 27 
H. Prior and Concomitant Procedures ....................................................................................... 28 
I. Eastern Cooperative Oncology Group Performance Status (ECOG PS) .............................. 28 
J. Post Treatment Anti-Cancer Therapy ................................................................................... 28 
K. β -CTX ……………………………………………………………………………………..28 
L. Other Assessments ................................................................................................................ 29 
X. Pharmacokinetics Analyses .................................................................................................. 29 


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List of Abbreviations 
 
Abbreviation or 
Specialist Term 
 
Definition 
AE 
Adverse Event 
BMD 
Bone Mineral Density 
BMI 
Body Mass Index 
CM 
Concomitant Medication 
CR 
Complete Response 
ctDNA 
Circulating tumor deoxyribonucleic acid 
DCR 
Disease Control Rate 
DLT 
Dose-limiting toxicity 
DNA 
Deoxyribonucleic acid 
DoR 
Duration of response 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
ECOG PS 
Eastern Cooperative Oncology Group Performance Status 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
ICF 
Informed Consent Form 
KM 
Kaplan-Meier 
MBAD 
Minimum Biologically Active Dose 
MedDRA 
Medical Dictionary for Regulatory Activities 
MFD 
Maximum Feasible Dose 
mRNA 
Messenger RNA 
MTD 
Maximum Tolerated Dose 
NCI CTCAE 
National Cancer Institute’s Common Terminology Criteria for Adverse Events 
NE 
Not Evaluable 
ORR 
Objective Response Rate 
PD 
Progressive Disease 
PDc 
Pharmacodynamic 
PFS 
Progression-free Survival 
PK 
Pharmacokinetic 
PR 
Partial Response 
PT 
Preferred Term 
QD 
Once a day 
QTcF 
QT with Fridericia's correction 
RDI 
Relative Dose Intensity 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP2D 
Recommended Phase 2 Dose 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Stable Disease 
SOC 
System Organ Class 
TEAE 
Treatment-emergent Adverse Event 
TL 
Target Lesion 
WHO 
World Health Organization 
 


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Redx Pharma plc / Protocol:  RXC004/0001 
Novella Clinical (Confidential) Project # GYA03429 
 
 
 
I. 
Introduction 
 
The Statistical Analysis Plan (SAP) is based on Protocol RXC004/0001 Version 7.0 
dated September 16th, 2022. 
 
This SAP will not repeat all the definitions given in the protocol but will provide 
further details of the summaries and analyses planned therein. The plan may be 
modified until the study clinical database is locked. Modules will be reported 
separately, so changes to the SAP specific for  module 2 and module 3 have been  
made after the database is locked in module 1.  Any deviations from the analysis 
plan, including any after the database lock, will be documented as such in the study 
report. 
 
This SAP will govern the analysis of efficacy and safety data from this study as well 
as descriptive summaries of the pharmacokinetic (PK) and key pharmacodynamic 
(PDc) data to be included in the CSR. 
 
II. 
Protocol Objectives 
 
A. Primary Objectives 
 
The protocol lists the following primary objectives which applies to all Modules of the 
study: 
x To assess the safety and tolerability of RXC004 when given to patients 
with advanced malignances alone or in combination with anti-cancer 
treatments, and to define the doses and schedules for further clinical 
evaluation. 
 
B. Secondary Objectives 
 
The protocol lists the following secondary objectives which apply to all Modules of 
the study: 
x To characterize the PK profile of RXC004, following a single dose and at 
steady state after multiple dosing, when given orally alone or in 
combination with anti-cancer treatments. 
x To obtain a preliminary assessment of RXC004 activity by evaluation of 
pharmacodynamic (PDc) biomarker changes which may include, but are 
not limited to, Wnt pathway inhibition, gene expression signatures, and 
ctDNA levels. 
x To obtain a preliminary assessment of the anti-tumor activity of RXC004 
as a single agent or in combination with anti-cancer treatments (to include 
assessment of objective response rate [ORR], disease control rate [DCR], 
duration of response [DoR], and progression-free survival [PFS]) 
 
C. Exploratory Objectives 
 
The protocol lists the following exploratory objectives which apply to all Modules of 


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Redx Pharma plc / Protocol:  RXC004/0001 
Novella Clinical (Confidential) Project # GYA03429 
 
 
the study: 
 
x To obtain a preliminary assessment of RXC004 activity by evaluation of 
PD biomarkers from blood skin, and tumor, which may include, but are 
not limited to normal and tumor cell signaling pathway targets and 
modulation of gene expression, and measures of tumor infiltrating 
lymphocyte population. 
x To explore the relationship between PK and efficacy, safety, and blood 
borne and tissue biomarkers. 
x To collect and store pre-dose plasma and serum sample and/or analyze 
surplus blood or tissue including patient specific archival tumor tissue, if 
available, for potential future exploratory research into factors that may 
influence the development of agents to treat human disease and/or 
response to RXC004 (where response is defined broadly to include 
efficacy, tolerability or safety). This may include the analysis of tumor 
specific and circulating biomarkers, such as tumor DNA, mRNA, proteins, 
or metabolites. In the event that additional tumor molecular profiling is 
required to understand further any response to RXC004, Redx may request 
a sample of the most recent tumor biopsy for additional research. 
x To investigate predictive markers and acquired resistance to RXC004 that 
may be observed in tumor from patients treated with RXC004. 
x To investigate the per-patient concordance between potential patient 
selection biomarker (and/or other molecular aberrations) and PDc 
biomarkers as determined either by Redx or local test methods, in 
comparison to potential patient selection biomarkers and PDc biomarkers 
levels obtained by central laboratory tests. 
x Characterization in paired tumor biopsies samples of the effect of RXC004 
on changes in the tumor microenvironment including but not limited to 
effects on immune cell subpopulations 
 
III. 
Study Endpoints 
 
Pharmacokinetics parameter derivation will be handled by PharmaKinetic Ltd. and is 
not described in this analysis plan.   
 
A. Efficacy Endpoints 
 
x The endpoints for assessment of efficacy include ORR, DoR, DCR, PFS 
based on the response evaluation criteria in solid tumors (RECIST) 
Version 1.1 
 
B. Safety Endpoints 
 
x Incidence and severity of AEs and SAEs 
x Incidence and severity of dose limiting toxicity (DLT) 
x Observed values and change from baseline in clinical laboratory test 
results which include serum chemistry, hematology, urinalysis, thyroid 


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function monitoring, lipid panel, liver function tests (LFT) monitoring, 
bone monitoring (β-CTX). 
x Observed values in bone mineral density (BMD) data by using DXA scan. 
x Observed values and change from baseline in vital signs 
x Observed values and change from baseline in electrocardiogram (ECG) 
parameters 
x Frequency counts and percentages of physical examination findings 
 
C. Dysgeusia questionnaire endpoints* 
x Grades for each question – main questions and how taste is altered 
questions 
 
* Dysgeusia questionnaire data reporting is outside the scope of the SAP. 
 
IV. 
Study Design 
 
A. Design Overview 
 
The study is a modular Phase 1, dose escalation, open-label study to assess the safety, 
tolerability, pharmacokinetics (PK) and preliminary anti-tumor activity of RXC004 in 
monotherapy and in combination in patients with advanced malignancies. 
 
The study has three modules: the RXC004 monotherapy module (Module 1),the 
RXC004 and Nivolumab combination module (Module 2) and the RXC004 
monotherapy scheduling module in selected Wnt pathway activated patients (Module 3). 
 
Based on emerging preclinical data and, safety and tolerability information from the 
initial modules, a Module 4 may be added with a protocol amendment. Thus, this 
SAP covers modules 1, 2 and 3. Any changes needed for future modules will be 
covered by an SAP amendment. 
 
For Module 1 – RXC004 Monotherapy: 
 
Module 1 opened in 2018 with a RXC004 dose of 10mg once daily, but the dose was 
not tolerated in the first patient who developed grade 3 diarrhea, colitis and 
asymptomatic bone fragility fractures in a thoracic vertebra and clavicle, which are 
on-target toxicities of Wnt pathway inhibitors. The T1/2 in humans was found to be 
longer than predicted from preclinical models, due to an extended terminal 
elimination phase resulting in a high Cmin level. 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 Module 1 dose escalation 
was restarted on 18th March 2019 with 0.5mg and was to commence with an 
accelerated dose escalation schedule and enroll three patients into a cohort with 
follow up for adverse events and DLT according to the dose levels in table 1. For the 
purposes of reporting the 10mg patient will be included in all safety tables and will 
appear as the top dose studied in the tables. 
 


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Dose escalation was to continue in a 3+3 design until the minimally biological active 
dose (MBAD) has been found to be tolerated. Subsequent dose escalation was to 
continue in a 3+3 design until maximum tolerated dose/maximum feasible dose 
(MTD/MFD) has been reached. 
 
Table below shows an indicative dose escalation scheme for Module 1. 
 
Table 1. Indicative Dose Escalation Scheme for Module 1 
 
Dose levels 
Planned Dose 
Actual Dose 
1 
0.5 mg QD 
0.5 mg QD 
2 
1.0 mg QD 
1.0 mg QD 
3 
1.5 mg QD 
1.5 mg QD 
4 
2.0 mg QD 
2.0 mg QD 
5 
2.5 mg QD 
3.0 mg QD 
6 
3.0 mg QD 
 
 
 
For Module 2 – RXC004 and Nivolumab Combination: 
 
The reason for conducting Module 2 is to provide the first cancer patient safety and 
tolerability data with RXC004 in combination with Nivolumab. 
 
Module 2 will commence by enrolling patients with advance solid tumors into a 
single ascending dose/multiple ascending dose (SAD/MAD) monotherapy dose 
escalation arm. Eligible patients will be enrolled in dose-escalation cohorts treated 
with RXC004 given as an oral capsule dose in combination with a PD1 infusion. The 
dose of Nivolumab will be a fixed dose of 480 mg every 4 weeks and will remain at 
this dose level throughout the study. The dose of RXC004 will be escalated. The 
RXC004 starting dose for combination with Nivolumab will be at a minimum of 2 
dose levels below the MTD of the monotherapy regimen. The RXC004 dose will be 
dose-escalated to the MTD in combination in as few dose-cohorts as possible. 
 
Table below shows an indicative dose escalation scheme for Module 2. All dose 
levels beyond cohort 1 may change in light of emerging safety, tolerability, and 
pharmacokinetic data, and also evolving relevant pre-clinical data. 
 
Table 2. Indicative Dose Escalation Scheme for Module 2 
 
Dose 
levels 
Planned  
RXC004 Dose  
(Starting Cycle 0) * 
Planned 
Nivolumab 
Dose/Regimen 
(Starting Cycle 1) 
Actual  
RXC004 Dose  
(Starting Cycle 0) * 
Actual 
Nivolumab 
Dose/Regimen 
(Starting Cycle 1) 
1 
1 mg QD 
480mg q4w 
1 mg QD 
480mg q4w 
2 
1.5 mg QD 
480mg q4w 
1.5 mg QD 
480mg q4w 
3 
2 mg QD 
480mg q4w 
N/A 
N/A 


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* The first cohort will start with a dose of RXC004 at a minimum 2 dose levels below 
the MTD of the monotherapy regimen. 
 
 
For Module 3 – RXC004 Monotherapy Scheduling: 
 
Module 3 will investigate the PK, Wnt pathway inhibition, incidence/severity of Wnt 
pathway related adverse events and anti-tumor activity of RXC004 when given at 2 
different intermittent dosing schedules, in a selected group of patients with Wnt ligand 
dependent advanced solid tumors. 
 
Following the completion of Module 1, the 2mg QD dose was selected as the 
recommended starting dose for Phase 2 studies, with options of interruptions and dose 
reductions to manage potential toxicities. The most frequently occurring treatment 
related AEs in module 1 (all doses) were fatigue (52%), nausea (44%), decreased 
appetite (40%), dysgeusia (40%) and vomiting (24%). The median RXC004 exposure 
in Module 1 was approximately 7 weeks so these adverse events were generally 
observed during the first two treatment cycles. Of the observed adverse events, only 
dysgeusia, a known on-target toxicity of Wnt pathway inhibitors, was observed to be 
dose-related and 4 out of 6 patients in the 2mg cohort reported dysgeusia within the 
first 2 treatment cycles.  
 
Module 3 will explore whether intermittent dosing schedules have the potential to 
deliver clinical anti-tumor activity in selected patients with Wnt ligand dependent 
tumors and whether intermittent dosing, giving short treatment breaks, has the potential 
to reduce incidence of treatment related toxicities such as dysgeusia. If so, an 
intermittent dosing schedule could be a future alternative to dose reduction in the 
management of treatment related adverse events. 
 
Table below shows an Intermittent Dose Schedule for Module 3. 
 
Table 3. Intermittent Dose Schedule for Module 3 
 
Planned Dose Planned Dose Schedule Actual Dose 
Actual Dose Schedule 
2.0 mg QD 
2 weeks on/1 week off 
2.0 mg QD 
2 weeks on/1 week off 
 
 
B. Study Population 
 
The patient population for this study will include men and women, 18 years or older 
at the time of screening, with histological or cytological confirmation of advanced 
malignancy not considered to be appropriate for further conventional treatment. 


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Additionally, for  Module 3, patients with Wnt ligand-dependent solid tumors, defined 
as Biliary tract cancers, Thymus cancers (thymic and thymoma WHO classification) or 
any solid tumor with documented aberration in RNF43 and/or RSPO,  will be included.  
 
See Protocol Section 2 for a complete list of inclusion/exclusion criteria. 
 
C. Sample Size 
 
The sample size for Module 1 is not based on a formal sample size calculation, as no 
formal statistical hypothesis is being tested. The estimated maximum number of 
patients (n=30) has been based on the expected number of cohorts and the desire to 
obtain adequate tolerability, safety, pharmacokinetic and pharmacodynamic data 
while exposing as few patients as possible to the IMP and procedures. The total 
number of patients required will depend upon the toxicities encountered and the 
number of dose cohorts required. 
 
For Module 2, there will approximately 18 patients. 
 
Module 3 will recruit 6 evaluable patients per Arm.  
 
D. Treatment Randomization 
 
This is an open-label non comparative study and as such randomization is not 
required. 
 
E. Assessment Schedule 
 
See Protocol Appendices 1, 2 and 9 for the study schedule of assessments. 
 
V. 
Interventions 
 
A. Clinical Trial Material 
 
The RXC004 capsules are provided in 0.5 and 1.0mg strength for oral administration. 
 
Nivolumab will be supplied as 240mg/24mL vial solutions for infusion after dilution. 
2 vials will be used per administration (480mg). 
 
B. Study Procedures 
 
Details of study procedures are described in Section 7 of the protocol. 
 
VI. 
General Analytical Considerations 
 
A. Data Sources and General Rules 
 


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Data generated within this clinical study will be handled according to the relevant 
SOPs of the Data Management and Biostatistics departments of IQVIA. Data will be 
captured on eCRFs. Single data entry with source data verification (SDV) will be 
performed for electronic data capture (EDC). PK and selected PDc data will be 
transferred to IQVIA. Other PDc, Biopsy, and Biomarker data will be collected and 
reported from a vendor database for this study. 
 
All statistical analysis will be performed following IQVIA Biotech standard operating 
procedures and on the IQVIA Biotech computer network. All statistical analysis will be 
performed using SAS® Version 9.4 with program code prepared specifically for the 
project by qualified IQVIA Biotech statisticians and programmers. 
 
Tables, listings, and figures will be presented separately for each module of the study. 
Tables will have separate columns for each dose level and overall, unless otherwise 
specified. Some summaries and analyses will only be performed at the maximum 
tolerated dose level (referred as RP2D in below section VIII B) 
 
B. Definition of Baseline 
 
A baseline assessment will be defined as the last assessment performed prior to the 
first dose of study treatment (RXC004 or Nivolumab if relevant, whichever is earlier). 
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. 
 
Change from baseline is calculated as post-baseline value – baseline value. Percent 
change from baseline is calculated as (post-baseline value – baseline value) / baseline 
value * 100. 
 
C. Missing Data 
 
Missing safety and efficacy data will not be imputed unless otherwise stated in the 
sections below. 
 
D. Nominal Timepoints 
 
Except response rate and data presented on continuous timescale, all by-visit 
summaries and analyses will be performed on nominal visits (i.e., actual visit as 
specified on the eCRF). 
 
E. Definition of study day 
 
There will be no study day 0. Day 1 is defined as the date of first study treatment. The 
study day for assessments occurring on or after Day 1 will be calculated as: 
 
x Study day = Date of the assessment/event – Day 1 + 1. 
 


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The study day for assessments occurring prior to Day 1 will be negative and 
calculated as: 
 
x Study day = Date of the assessment/event – Day 1. 
 
The study day will be displayed in all relevant data listings. 
 
F. Multiple Study Centers 
 
No adjustment for study center is planned. 
 
G. Interim Analyses or Timing of Analyses 
 
No formal interim analyses are planned for this study. However, a review of safety 
data and available PK and PD data will be performed after completion of each dose 
escalation cohort. 
 
H. Test Sizes 
 
Not applicable as formal statistical hypothesis testing will not be performed. 95% 
confidence intervals will be provided where specified. 
 
I. 
Multiple Comparisons 
 
Not applicable. 
 
J. Analysis Populations 
 
Analysis populations will be defined as following: 
 
1. Safety Population 
The Safety Population will consist of all patients who enrolled and received at 
least one dose of any study treatment. The safety population will be used for the 
safety analyses. 
 
2. Efficacy Evaluable Population 
The Efficacy Evaluable Population will include patients who receive a 
radiographic assessment at baseline, received at least one dose of any study 
treatment, and at least one post-dose radiographic tumor assessment, or 
progressed or died ahead of the first scan. The efficacy evaluable population will 
be used for the efficacy analyses. 
 
3. Pharmacokinetic (PK) Evaluable Population 
The PK Evaluable Population will consist of those patients deemed by the sponsor 
pharmacokineticist to have sufficient PK concentration data to be meaningfully 
included in the PK analysis summaries. 


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4. Dose Limiting Toxicity (DLT) Evaluable Population (Module 1 and 2) 
For Module 1 and 2, DLT evaluable population is defined as a patient that has 
received  study treatment and either: 
 
x Has completed minimum safety evaluation requirements and has 
received 100% of the specified RXC004 dose in Cycle 0 and at least 
66% of the intended dose of RXC004 during Cycle 1 (Patients in 
Module 2 must also receive 100% of the nivolumab infusion on Cycle 
1 Day 1).  
x Has experienced a DLT during Cycle 0 and/ or Cycle 1 
 
5. Evaluable for Safety Population(Module 3) 
For Module 3, the evaluable population is defined as a patient that has received  
study treatment and either: 
 
x Has completed minimum safety evaluation requirements and has 
received 100% of the specified RXC004 dose in Cycle 0 and at least 
80% of the intended dose of RXC004 during Cycle 1 and 2.  
x Has permanently discontinued study treatment due to a RXC004-related 
adverse event  
 
K. Data Display Characteristics 
 
Data displays produced for this study will include three types—summary tables, data 
listings, and figures. Unless stated otherwise, data listings will be produced for all 
recorded data. Summary tables will be produced as specified in the following 
sections. Additional data listings will be produced for outcome measures that involve 
extensive procedures to derive the analyzed outcomes. Figures will be produced when 
specified in sections to follow. 
 
Data listings will simply list the data recorded on the eCRF or derived for each 
patient. They will be ordered by module, dose cohort, site, patient number, and 
date/time of assessment. When expedient, additional levels of ordering hierarchy may 
reflect subsets of assessments within patient. Data listings will not display patient 
initials. 
 
Summary tables will display summary statistics calculated for each module and dose 
cohort, as well as overall within each module, unless described otherwise in following 
sections. 
 
Unless stated otherwise in relevant sections to follow, continuous data will be 
summarized descriptively with the number of non-missing values, mean, standard 
deviation, minimum, median, and maximum. Categorical data will be summarized 
using frequency counts and percentages. 
 


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VII. Patient Accountability 
 
A. Patient Characteristics 
 
Demographic and baseline characteristics, cancer history and classification, prior 
therapy will be summarized by dose cohort for each module separately in the Safety 
Population as appropriate. 
 
Demography and Baseline Characteristics: Data collected about the following 
patient characteristics at the screening visit will be summarized: 
x Age. Age will be calculated as the number of years elapsed between the birth 
date and the informed consent date. 
x Sex and childbearing potential (yes/no) 
x Ethnicity 
x Race 
x Height 
x Weight 
x Body Mass Index (BMI) 
 
Cancer History and Classification: A summary of the following elements will be 
provided: 
x Duration of Cancer (years). If the full initial diagnosis date is known, duration 
of cancer is calculated as (date of informed consent minus date of initial 
diagnosis) / 365.25. For partial initial diagnosis dates, if only month and year 
is available, the duration will be calculated as (number of months difference 
between the initial diagnosis year/month and inform consent year/month) / 12. 
If only year is available for initial diagnosis date, then the initial diagnosis 
month will be imputed to June that year and the duration will be calculated 
following the same calculation described above. Stage at Initial Diagnosis 
x Primary Location 
x Cancer Classification 
x Histologic Grade 
x RNF43 and RSPO status 
x Wnt Ligand Dependency: Wnt Ligand Dependent, Wnt Ligand 
Independent, Unknown 
x TNM Staging at Time of Study Entry 
x Baseline Eastern Cooperative Oncology Group (ECOG) performance status 
 
Prior Therapies:  Summary tables of the following elements will also be provided: 
x Prior Anti-Cancer Therapy 
x Number of lines of prior anti-cancer therapies. Combination therapies 
will be counted as 1 line of therapy. 
x Best overall response to the last anti-cancer regimen prior to the study 
entry (i.e., date of informed consent). 
x Best overall response among all reported prior anti-cancer regimens. 


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x Best overall response of the immune checkpoint inhibitor regimens. 
x All prior regimens will be coded using the WHO Drug (WHO-DD) 
version September 2021, B3 Format. The numbers and percentages 
of patients with prior anti-cancer therapy will be summarized by 
WHO- DD Anatomical-Therapeutic-Chemical (ATC) classification 
and preferred term 
x Prior Radiotherapy 
 
All data described above will also be provided in the listings. 
 
B. Medical History 
 
Medical histories will be coded using the MedDRA version 24.1 and summarized by 
System Organ Class (SOC) and Preferred Term (PT) by dose cohort for each module 
separately. 
 
A data listing will also be provided. 
 
C. Disposition 
 
Disposition will be summarized as the number and percentage of patients enrolled, 
dosed, discontinued from study treatment along with the reason for discontinuation 
and discontinued from the study along with the reasons for discontinuation by dose 
cohort and overall, for each module separately. The number of subjects in each 
analysis population will be summarized separately. 
 
Enrollment and disposition will be listed in a data listing. Screen failures will also be 
listed. 
 
D. Protocol Deviations 
 
A summary of number and percentage of patients with any protocol deviation by dose 
cohort and module based on the Safety Population will be present. 
 
Protocol deviation would be classified into major and minor. protocol deviation will 
be summarized by major/minor category. In addition, COVID-19 related protocol 
deviations will be summarized. 
 
VIII. Efficacy Analyses 
 
Efficacy analyses will be based on the Efficacy Evaluation Population. 
 
A. Efficacy Endpoints 
 
The preliminary assessment of efficacy will be assessed via tumor responses and 
lesion parameters based on the RECIST version 1.1. guidelines. The efficacy analyses 
of responses including best overall response (BOR), objective response rate (ORR), 


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duration of response (DoR), disease control rate (DCR) and progression free survival 
(PFS). The lesion parameters include change and percent change from baseline in the 
sum of the diameters of target lesions (TLs), presence/absence of non-target lesions 
and/or new lesions. 
 
All efficacy endpoints will be summarized and analyzed by dose cohorts for Module 
1, Module 2 and Module 3 separately unless otherwise specified below. 
 
1. Best Overall Response (BOR) 
Categorization of objective tumor response based on RECIST 1.1. guidelines 
for target lesions include CR (complete response), PR (partial response), SD 
(stable disease), PD (progression of disease), and NE (not evaluable). 
 
Best overall response is determined based on the RECIST overall responses 
as assessed by the investigator from the start of first study treatment 
(RXC004 or Nivolumab if relevant, whichever is earlier) until the end of last 
study treatment, including any required RECIST scans/assessments for 
confirmation post the last study treatment. 
 
CR and PR can only be considered as the best overall response if the initial 
CR or PR is confirmed by a scan that shows the same response or better at 
least 4 weeks after the initial response. If the repeat scan following the initial 
response is NE, but the next evaluable response confirms the initial CR/PR 
response, the BOR of CR/PR will be claimed. For example, a patient with 
time point responses assessed as PR-NE-PR will be considered as a confirmed 
PR. 
 
SD does not require confirmation. If SD is the best response ever seen and it 
meets the minimum criteria for SD duration (at least 35 days from date of first 
study treatment), SD will be claimed to be the best response overall response. 
 
Below table illustrates the determination of the best overall response when CR 
or PR confirmation is required. 
 
Table 3. Best Overall Response When Confirmation of CR and PR Required 
 
Overall response 
Initial response 
Overall response 
Subsequent response 
Best overall response 
CR 
CR 
CR 
CR 
PR 
PR 
CR 
SD 
SD provided minimum criteria 
for SD duration met, otherwise 
PD 
CR 
PD 
SD provided minimum criteria 
for SD duration met, otherwise 
PD 


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CR 
NE 
SD provided minimum criteria 
for SD duration met, otherwise 
NE 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD provided minimum criteria 
for SD duration met, otherwise 
PD 
PR 
PD 
SD provided minimum criteria 
for SD duration met, otherwise 
PD 
PR 
NE 
SD provided minimum criteria 
for SD duration met, otherwise 
NE 
SD 
SD 
SD provided minimum criteria 
for SD duration met, otherwise 
NE 
SD 
PD 
SD provided minimum criteria 
for SD duration met, otherwise 
PD 
SD 
NE/Missing 
SD provided minimum criteria 
for SD duration met, otherwise 
NE 
PD 
Not applicable 
PD 
NE 
NE 
NE 
 
2. Objective Response Rate (ORR) 
Objective response rate is defined as proportion of patients with a BOR of CR 
or PR prior to any evidence of progression (as defined by RECIST 1.1). 
 
3. Disease Control Rate (DCR) 
Disease control rate is defined as the proportion of all patients dosed that have 
a visit response of at least SD, PR, or CR at the second schedule scan post  
baseline, scheduled at week 12 for module 1 and module 3 or week 16 for 
module 2. Therefore, earlier visit responses of CR, PR that become PD at the 
second post baseline scan or NE responses at the second post baseline scan do 
not constitute disease control. A time window of 1 week around the visit will 
be applied and any visits occurring within 1 week of the scheduled time will 
be acceptable for inclusion in the assessment; however, if an earlier visit is 
defined as PD, then the visit response at the second post baseline scan would 
also be defined as PD. If the second post baseline scan is missing or NE, but 
the next evaluable response is SD or better, then the patient will be defined as 
having non-progressive disease at the second post baseline scan visit. Disease 
control rate will also be assessed separately for the first 3 scheduled post 
baseline scans (i.e., 18 weeks for module 1 and 3 and 24 weeks for module 2. 
A separate line in the ORR table will be presented to show the DCR for the 


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first 2 scan visits and DCR for the first 3 scan visits. 
 
4. Duration of response (DoR) 
Duration of response is defined as the time from the date of first documented 
overall response of confirmed CR or PR until date of first documented 
progression or death (from any cause), whichever occurs first. The first date 
at which a CR or PR response was noted will be used to calculate DOR, not 
the 
 
date of the confirmatory tumor assessment. Unconfirmed response will not be 
included. 
 
Patients who do not experience disease progression or death following a response 
at the time of analysis will be censored at the date of last tumor assessment by 
RECIST 1.1 criteria. 
 
Duration of response will only be evaluated for patients who have a best overall 
response of CR or PR. 
 
5. Progression Free Survival (PFS) 
Progression free survival (PFS) is defined as the time from the date of first study 
treatment (first dose of RXC004 or Nivolumab if relevant, whichever is first) 
until the date of objective disease progression or death (by any cause in the 
absence of progression) regardless of whether the patient withdraws from study 
treatment or receives another anti-cancer therapy prior to progression/death. Date 
of progression will be determined based on the date of first radiological 
assessment indicating progression (i.e., first scan date when an overall response 
is determined to be progressive disease as assessed by the investigator per 
RECIST overall response CRF page). 
 
Patients who have not progressed or died at the time of analysis will be censored 
at the time of the latest date of scan/assessment from their last evaluable RECIST 
assessments. However, if the patient progresses or dies after two or more missed 
visits, the patient will be censored at the time of the latest evaluable RECIST 
scan/assessment prior to the missed visits. If the patient has no evaluable visits or 
does not have baseline data, they will be censored at 1 day unless they die within 2 
scan visits of baseline. 
 
Lesion parameters will be assessed at each RECIST assessment, including target 
lesion diameter (for lymph nodes, the shortest diameter will be collected; for soft 
tissue lesions, the longest diameter will be collected), presence/absence of non- 
target lesions; and presence/absence of new lesions. 
 
The sum of the diameter of target lesions will be calculated at each RECIST 
assessment. Change and percent change from baseline in the sum of diameter of 
TLs will also be calculated. 
 


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The best percentage change in tumor size while on treatment will be the patient’s 
value representing the largest decrease (or smallest increase for those patients 
whose target lesions do not show a decrease) from baseline in the sum of 
diameter of TLs. 
 
 
B. Efficacy Endpoint Analyses 
ORR and DCR will be summarized for all dose levels. The two-sided 95% 
confidence interval (CI) using the Clopper-Pearson method will only be provided 
at RP2D and overall. 
 
PFS, and DoR will be summarized using the Kaplan-Meier (KM) method at by 
treatment group and overall. Estimates of median and PFS at 6 and 12 months, 
with the corresponding 95% CI will be reported for RP2D and overall. Swim 
lane plot for all time to event analysis by dose level and by wnt ligand 
dependency (DOR, PFS and duration of treatment).  
 
Time to response, defined as (date of first documented response of CR or PR for 
patients who have a confirmed CR or PR – date of first treatment + 1) / 7, will 
be summarized descriptively among patients who reported a response. 
 
Percent change from baseline in the sum of diameters of TLs will be 
summarized descriptively. Percent change from baseline in the sum of diameters 
of TLs for individual patient will be present in the spider plots – separate plots 
will be done by dose level and by Wnt ligand dependency. The best percent 
change in tumor size while on treatment will be presented in two waterfall plots. 
In one plot the bars will be color coded by dose level and in a separate plot by 
Wnt ligand dependency. 
 
ORR and percent change in the sum of TL diameters will only be evaluated 
among patients with measurable disease (i.e., with target lesion identified) at 
baseline. All efficacy data as collected on the eCRF along with the derived 
parameters will be presented in data listings. 
 
Given the small sample size in module 3, Duration of Response (DoR) and 
Time to Response will not be summarized for module 3 patients.  
 
IX. 
Safety Analyses 
 
Safety analyses will be based on the Safety Population. 
 
A. 
Exposure 
 
Exposure to RXC004 and Nivolumab will be summarized by dose cohorts and 
overall, for each module separately. All exposure parameters as well as all 
exposure data collected on the eCRF will be present in data listings. 
 
The following exposure parameters of RXC004 will be summarized from the 


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start of Cycle 0. 
x Total duration of exposure (weeks): calculated as (last RXC004 dosing 
date – first RXC004 dosing date + 1) / 7 
x Total number of doses received: defined as number of doses received as 
collected on the RXC004 dose administration eCRF page from the first 
RXC004 dosing date to the last RXC004 dosing date. 
x Any dose modifications: patients who have at least 1 RXC004 dose 
change (including dose reduction, missed dose or dose permanently 
withdrawn) along with the reason for dose modification will be 
summarized using frequency counts and percentages. 
x Any dose reductions: patients with any dose reductions will be 
summarized using frequency counts and percentages by the following 
categories: any dose reductions, 1 dose reduction, 2 dose reductions. 
 
The following exposure parameters of RXC004 will be summarized based on 
continuous dosing period (i.e., start from Cycle 1 Day 1). Cycle 0 dosing is 
excluded: 
x Total duration of exposure (weeks) on continuous dosing: calculated as 
(last RXC004 dosing date – first RXC004 dosing date of C1D1 + 1) / 7  
x Number of cycles for RXC004 on continuous dosing excluding Cycle 0: 
will be determined based on the last nominal visit as collected on CRF 
x Number of completed cycles: a cycle will be considered complete if 
they have 14 days of therapy within a 3-week period from C1D1. The 
total number of completed cycles will be calculated as the total number 
of days the dose was received divided by 14 (Module 3 only).  
x Cumulative actual dose received (mg): defined as total amount of actual 
dose (mg) received as collected on the RXC004 dose administration 
eCRF page from the first RXC004 dosing date to the last RXC004 dosing 
date. 
x Cumulative planned dose (mg): defined as total amount of planned dose 
(mg) as recorded on the RXC004 dose administration eCRF page from 
the first RXC004 dosing date to the last RXC004 dosing date. 
x Actual dose intensity (mg/week): defined as cumulative actual dose (mg) 
divided by total duration of exposure (weeks)  
x Planned dose intensity (mg/week): defined as cumulative planned dose 
(mg) divided by total duration of exposure (weeks). If a patient had a 
reduced dose per investigator’s assessment, then reduced dose will be 
considered as planned dose for the calculation of RDI. 
x Relative dose intensity (%): calculated as (actual dose intensity / planned 
dose intensity) * 100%. 
x Relative dose intensity category: the calculated % relative dose intensity 
above will be summarized by the following categories using frequency 
counts and percentages: <60%; 60% ≤ and < 75%; 75% ≤ and < 90%; 
90%≤ and ≤ 100%; > 100%. 
 
The number of capsules dispensed, returned and taken at each visit as collected 
on the RXC004 drug accountability eCRF page will be presented in data listings. 


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Duration of the RXC004, will be summarized as continuous variables. 
 
For patients in Module 2, the following exposure parameters of Nivolumab will 
also be summarized: 
x Total number of doses received: defined as number of doses received as 
collected on the Nivolumab dose administration eCRF page from the first 
Nivolumab dosing date to the last Nivolumab dosing date. 
x Any cycle delay: patients who have any cycle delay, 1 cycle delay, 2 
cycle delays, >= 3 cycle delays will be summarized using frequency 
counts and percentages. 
x Any infusion interruption: patients who have any infusion interruption 
along with the reason will be summarized using frequency counts and 
percentages. 
 
Number of Nivolumab doses will be summarized as continuous variables. 
 
B. Adverse Events 
 
Adverse events will be coded using MedDRA version 24.1. AEs are graded using 
the National Cancer Institute (NCI) Common Terminology Criteria for Adverse 
Events (CTCAE) Version 5.0. 
 
A treatment-emergent AE (TEAE) is defined as AEs that first occurred or 
worsened in severity after the first administration of the study treatment 
(RXC004 or Nivolumab) and within 30 days of last dose of RXC004 in the case 
of Module 1 and Module 3 and within 90 days of last dose of Nivolumab for 
Module 2. 
 
If relationship to RXC004 or Nivolumab is missing, the event will be 
conservatively treated as related to the corresponding study treatment. Missing 
CTCAE grade will be summarized as separate category. 
 
All AEs will be listed by module, dose cohort and patient, detailing the verbatim 
term given by the investigator, the preferred term (PT), system organ class 
(SOC), onset date, stop date, CTCAE grade, relationship to RXC004, 
relationship to Nivolumab (Module 2 only), action taken with RXC004, action 
taken with Nivolumab (Module 2 only), other action taken, dose limiting toxicity 
(Y/N), caused by disease progression (Y/N) and seriousness. Dose limiting 
toxicity. 
 
An overall AE summary will be present by the number and percent of patients 
for each module separately with the following: 
x All AEs 
x All TEAEs 
x Dose limiting toxicity (DLTs) (Module 1 and 2 
only) 
x RXC004-related TEAEs 


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x Any TEAE of CTCAE of grade 3 or higher 
x Any TEAE of CTCAE of grade 3 or higher related 
to RXC004  
x Nivolumab-related TEAEs (Module 2 only) 
x Any TEAE of CTCAE of grade 3 or higher related 
to Nivolumab (Module 2 only) 
x Serious AEs 
x RXC004-related SAEs 
x Nivolumab-related SAEs (Module 2 only) 
x TEAEs leading to RXC004 withdrawal 
x TEAEs leading to Nivolumab withdrawal 
x TEAEs leading to RXC004 reduction 
x RXC004 related adverse event  leading to death 
x Nivolumab-related adverse event  leading to death (Module 2 only) 
x TEAEs leading to RXC004 interruption 
x TEAEs leading to Nivolumab interruption 
x AEs leading to death 
 
The following AE summaries will be produced by system organ class 
(alphabetical order) and preferred term (descending order of the overall 
frequency) for each module separately: 
x All TEAEs 
x Serious AEs 
x Grade 3 or higher TEAEs 
x TEAEs leading to RXC004 withdrawal. This subset includes TEAEs with 
an Action Taken with RXC004 of “Drug Permanently Withdrawn” on the 
AE form. 
x TEAEs leading to RXC004 reduction. This subset includes TEAEs with 
an Action Taken with RXC004 of “Dose reduced” on the AE form 
x TEAEs leading to RXC004 interruption. This subset includes TEAEs with 
an Action Taken with RXC004 of “Dose interrupted” on the AE form 
x TEAEs leading to Nivolumab withdrawal (Module 2 only). This subset 
includes TEAEs with an Action Taken with Nivolumab of “Drug 
Permanently Withdrawn” on the AE form. 
x TEAEs leading to Nivolumab interruption (Module 2 only). This subset 
includes TEAEs with an Action Taken with Nivolumab of “Dose 
interrupted” on the AE form 
x TEAEs related to RXC004. This table will include TEAEs with a drug 
relationship of “Possibly Related” or “Probably Related” to RXC004. 
x TEAEs related to Nivolumab (Module 2 only). This table will include 
TEAEs with a drug relationship of “Related” to Nivolumab. 
x SAEs related to RXC004 
x SAEs related to Nivolumab (Module 2 only) 
x Grade 3 or higher TEAEs related to RXC004 
x Grade 3 or higher TEAEs related to Nivolumab (Module 2 only) 
x AEs leading to death 


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x AEs considered as dose-limiting toxicity (DLT) (Module 1 and 2 only) 
x TEAEs by maximum CTCAE grade 
x TEAE by PT  
x Treatment Related TEAE by PT.   
 
At each level of summarization, a patient will be counted once if he/she reported 
one or more events. The maximum CTCAE grade will be taken for the purposes 
of the summaries by grade. 
 
In addition, all deaths as collected on the Death eCRF page will be present in a 
data listing. 
 
C. Clinical Laboratory Results 
 
Laboratory test results (including serum chemistry, hematology, urinalysis, lipid 
panel, bone monitoring, liver function testing and thyroid panel [Module 2 only]) 
and abnormal laboratory values will be presented in data listings. CTCAE 
version 5.0 lab grades will also be presented where applicable. CTCAE grades 
will be derived based on laboratory results and will not factor in clinical 
evaluations. 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 version 
5.0 results will be classified as low, normal, or high based on laboratory normal 
ranges. 
 
Overlay line plot of observed values of lab data (including serum chemistry, 
hematology, urinalysis, lipid panel, bone monitoring, liver function testing and 
thyroid panel [Module 2 only]) will be presented for all subjects and by study 
module. Hys law eDISH plot will also be presented. 
 
Shift tables will be used to summarize the changes from baseline in severity of 
lab CTCAE grades for will be provided for serum chemistry, hematology, and 
urinalysis parameters by module, dose cohorts and visit, starting from the first 
post-baseline visit. The shift from baseline to worst low lab grades and to worst 
high lab grades will be summarized by module and dose cohorts. Clinical 
evaluations (normal, abnormal not clinically significant, and abnormal, clinically 
significant) will be summarized using frequency counts and percentages for each 
visit as applicable. For numeric laboratory test results, summaries of actual 
values, changes from baseline, and percent change from baseline will also be 
summarized using continuous descriptive statistics at each visit. 
 
By-patient listing will be provided by visit, including changes from baseline, 
grade and reference range. All values outside the 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. 
 
Results from pregnancy tests and HIV status will be provided in data listings. 
 


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D. Vital Signs 
 
Actual values and change from baseline of vital signs data (weight, temperature, 
pulse, respiratory rate, systolic blood pressure, and diastolic blood pressure) will 
be summarized using descriptive statistics at each visit. A listing of the vital 
signs data will also be provided. 
 
E. Physical Examination 
 
A full physical examination is assessed at screening and prior to Day 1 of each 
cycle. Abnormal physical examination findings will be presented in data listings. 
 
F. Electrocardiogram (ECG) 
 
Actual values and change from baseline of ECG parameters (PR interval, RR 
interval, QRS duration, QT interval, QTcB, QTcF) will be summarized 
descriptively by module, dose cohorts and timepoints. Note that ECGs are 
collected in triplicate and analyses of numeric results will be based on the 
average of the triplicate results. 
 
All ECG results along with the overall evaluation [i.e., Normal, Abnormal, Not 
Clinically Significant, and Abnormal, Clinically Significant]) will be presented in 
data listings. 
 
QTcF interval absolute values will also be tabulated by the following groups: 
x <=450 
x >450-<=480 msec 
x >480-<=500 msec 
x >500 msec 
Change from baseline in QTcF interval will be classified as: 
x <=30 msec increase from baseline 
x >30-<=60 msec increase from baseline 
x >60 msec increase from baseline 
 
Frequency and percentage of QTcF categorical analysis will be summarized by 
module and dose cohorts. 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): 
x Missing result 
x <=450 msec (i.e. ‘normal’) 
x >450-<=480 msec 
x >480-<=500 msec 
x >500 msec 
 
G. Prior and Concomitant Medications 
 


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Prior medications are defined as medications with a stop date prior to the first 
dose of any study treatment. Concomitant medications are defined as medications 
ongoing or with stop dates on or after the first dose of any study treatment. Prior 
and concomitant medications will be coded using WHO Drug version March 
2021, B3 Format. 
 
To distinguish prior vs. concomitant medications, the following rules for stop 
dates will apply: 
x If only year is recorded, and it is before Day 1, it is a prior medication; if 
year is same or after Day 1, it is assumed to be a concomitant medication. 
x If day is missing, but month and year are before Day 1, it is a prior 
medication; if month and year are the same as Day 1, it is assumed to be a 
concomitant medication; if month and year are after Day 1, it is a 
concomitant medication. 
x If start date is after Day 1, it is a concomitant medication regardless. 
 
Concomitant medications will be summarized by module, dose cohort, WHO-DD 
ATC classification, and PT. 
 
All prior and concomitant medications will be displayed in data listings as well. 
 
H. Prior and Concomitant Procedures 
 
Prior procedures are defined as procedures with a procedure date that is prior to 
the first dose of any study treatment. Concomitant procedures are defined as 
procedures with a procedure date on or after the first dose of any study treatment. 
 
Prior and concomitant procedures will be coded using MedDRA version 24.1. 
Concomitant procedures will be summarized by SOC and PT by dose cohort for 
each module separately. 
 
All prior and concomitant procedures will be displayed in data listings as well. 
 
I. 
Eastern Cooperative Oncology Group Performance Status (ECOG PS) 
 
A shift table of ECOG performance status from baseline to worst on-treatment 
value will be provided by dose cohort for each module separately. 
 
A listing of ECOG performance status results will also be generated. 
 
J. Post Treatment Anti-Cancer Therapy 
 
Post treatment Anti-Cancer therapy data will be summarized by ATC and PT in 
the summary table and presented in the data listing. 
 
K. β -CTX 
 
Absolute and change from baseline of β -CTX will be summarized and listed by 


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dose level and study module. β -CTX results below the lower limit of 
 
quantification will be imputed as 0 in descriptive summaries. Subjects who 
received denosumab will be summarized and flagged in the listings and if clear 
distinction between cohorts will be noted as a footnote in the summary table. 
 
L. Other Assessments 
 
DXA scan results, including change from baseline in BMD, concomitant 
radiotherapy, and concomitant transfusions will be presented in the data listings. 
 
X. 
Pharmacokinetics Analyses 
 
Plasma concentration data will be listed and summarized descriptively by 
analyte, module, dose level and nominal time points. 
 
Descriptive statistics will include the number of patients (n), mean, SD, 
coefficient of variation (CV%), median, minimum, and maximum. Concentration 
values below the limit of quantification (BLOQ) will be treated as 0 for the 
computation of descriptive statistics. 
 
The detailed derivation for the pharmacokinetic parameters based on plasma 
concentration data will be described in a separate analysis plan. All reported PK 
parameters will be listed and summarized descriptively similar to the 
concentration data. Geometric mean will also be presented for PK parameters 
such as AUC, Cmax and other parameters as appropriate and medians for Tmax. 
Plots of mean PK concentrations will be done with a different line and color for 
each dose level. Individual subject concentration data will be plotted with 
separate plots for each dose level.