Background: The Wnt pathway is a critical driver of cancer. RXC004 is a potent, selective, orally active inhibitor of the key Wnt pathway regulator, Porcupine. Inhibition of Porcupine blocks the release of all Wnt ligands from cells, preventing both tumour growth and tumour immune evasion. Wnt pathway alterations, including loss-of-function (LoF) RNF43 mutations and RSPO gene fusions, increase expression of the Wnt receptor Frizzled (Fzd) on the tumour cell surface, driving Wnt-ligand signalling. These alterations are present in ̃8% (Gao, 2013; Cerami, 2012; Shesagiri, 2012; Shinmura, 2014; Kleeman, 2019)of colorectal cancers (CRC). LoF RNF43 mutations are associated with poor prognosis in MSS CRC (Yaeger, 2018). Preclinical genetically selected CRC models showed disease stabilisation, differentiation towards a normal colonic phenotype with increased mucin secretion, and reduced metabolic activity on FDG-PET. In a Phase 1 study in patients with advanced solid tumours (NCT03447470), RXC004 was safe and tolerated at doses up to 2mg QD, the recommended phase 2 dose (RP2D), and showed a differentiated efficacy signal in Wnt-ligand dependent tumours (Cook, 2021). Methods: The PORCUPINE (NCT04907539) trial is a 2-arm Phase 2 trial of RXC004 monotherapy (Arm A) and RXC004 in combination with nivolumab (Arm B). 20 evaluable patients will be enrolled into each Arm. The study initially opened with Arm A; Arm B will be opened once the RP2D for RXC004 in combination with nivolumab is established in a separate phase 1 study. Once Arm B is opened, patients in Arm A may be treated with RXC004 + nivolumab if they have progressive disease on the first RECIST assessment scan. To be eligible for this study, patients must have metastatic microsatellite stable (MSS) CRC that has progressed following standard therapies. Tumours must have a LoF RNF43 mutation, or an RSPO2/3 fusion. As Wnt inhibition can affect bone metabolism, patients undergo a screening DEXA scan and receive prophylactic denosumab throughout the treatment period. The primary endpoint for Arm A is the disease control rate (DCR= CR+PR+SD at 16 wks), and for Arm B is objective response rate (ORR). Secondary endpoints are Safety and PK. Exploratory endpoints include FDG-PET changes and on-treatment changes in protein and gene expression in tumour biopsies. For Arm A, a target value (TV) of 60% DCR is considered a clinically significant improvement over standard of care against a lower reference value (LRV) of 40% DCR (Grothey, 2013; Mayer, 2015). For Arm B, a TV of 30% ORR is considered clinically significant against a LRV of 10% ORR (Eng, 2019). RXC004 is also being investigated in a second Phase 2 trial, PORCUPINE 2 (NCT04907851), in Biliary Tract Cancers and RNF-43 mutated Pancreatic Cancers. Clinical trial information: NCT04907539.