Abstract CT101: Final results of the first-in-human study of the porcupine (PORCN) inhibitor zamaporvint (RXC004) in patients with advanced solid tumors

Abstract

Abstract Background Dysregulated Wnt signalling drives several cancers through effects on proliferation, fibrosis and immune evasion. RXC004 is a novel oral small molecule inhibitor of protein-serine O-palmitoyltransferase (PORCN), which is required for the post-translational modification and activation of Wnt ligands. RXC004 has potential for efficacy in upstream Wnt pathway activated tumours: ~5% pancreatic cancer and ~8% microsatellite stable colorectal (CRC) cancer with RNF43 mutations or RSPO fusions, and tumors with high Wnt ligand expression. Methods In this Phase I study of RXC004 (NCT03447470), Module 1 investigated continuous monotherapy dosing, Module 2 investigated combination with nivolumab 480mg s.c. Q4W and Module 3 investigated intermittent monotherapy dosing (2 weeks on 1 week off). Patients received denosumab 120 mg s.c Q4W to prevent loss of bone mineral density (BMD), a known effect of Wnt inhibition. The primary objectives were safety and tolerability. Secondary objectives were PK and RECIST response. PD markers included on-treatment changes in: Wnt pathway and fibrosis biomarkers in paired skin biopsies; circulating immune subsets by flow cytometry; cytokine changes by Luminex, and changes in circulating-tumor DNA (ctDNA) levels by ddPCR. Results In Module 1, 25 patients (pts) with unselected advanced solid tumors (AST) received RXC004 between 0.5mg and 10mg QD. The RP2D was 2mg QD; at this dose the most common AEs were fatigue, diarrhoea, dysgeusia and decreased appetite; no grade 4/5 AEs or bone fragility events were reported whilst 1 pt had a RXC004-related grade 3 AE, 3 pts (50%) had a dose interruption and 1 had a dose reduction. The median T1/2 of RXC004 was 14.5h. 5 pts with upstream Wnt pathway activated tumors had stable disease (SD), in 1 case for 26 weeks with sustained reduction in ctDNA and no BMD loss. In Module 2, 14 patients with unselected AST received RXC004 at 1mg QD or 1.5mg QD with nivolumab. The AE profile was similar to Module 1. The RP2D was 1.5mg QD; at this dose 3 pts had a RXC004-related grade 3 AE, 6 pts (75%) had a dose interruption and 3 had a dose reduction, and 4 pts had SD. PK was similar to Module 1. In Module 3, 7 patients with upstream Wnt-activated AST received RXC004 2mg QD, 2 weeks on, 1 week off. The AE profile was similar to Modules 1 and 2. There were no RXC004-related Grade 3 AEs, 2 pts (29%) had a dose interruption and there were no dose reductions. PK and PD analyses confirmed time off target. 2 pts had SD; 1 pt with RSPO fusion small intestinal adenocarcinoma remained on treatment for 36 weeks, with sustained reduction in ctDNA and no BMD loss. Conclusions In patients with AST, RXC004 was safe and tolerated at doses up to 2mg QD as monotherapy and 1.5mg QD in combination with nivolumab, demonstrating differential disease control in upstream Wnt pathway activated tumours. Denosumab prevented loss of BMD. Intermittent RXC004 dosing was well tolerated with no detrimental impact on efficacy. Citation Format: Natalie Cook, Sarah Blagden, Juanita Lopez, Debashis Sarker, Alastair Greystoke, Noor MD Haris, Farasat Kazmi, Kaiser Anam, Ana Ortego Franco, Rille Pihlak, Louise Goodwin, David Wilson, Caroline Phillips, Jane Robertson, Helen Timmis, Craig Tilston, Simon A. Woodcock, Ruth Plummer. Final results of the first-in-human study of the porcupine (PORCN) inhibitor zamaporvint (RXC004) in patients with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT101.