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- Title
Phase 1 study of single-agent WNT974, a first-in-class Porcupine inhibitor, in patients with advanced solid tumours.
- Authors
Rodon, Jordi; Argilés, Guillem; Connolly, Roisin M.; Vaishampayan, Ulka; de Jonge, Maja; Garralda, Elena; Giannakis, Marios; Smith, David C.; Dobson, Jason R.; McLaughlin, Margaret E.; Seroutou, Abdelkader; Ji, Yan; Morawiak, Jennifer; Moody, Susan E.; Janku, Filip
- Abstract
<bold>Background: </bold>This Phase 1 study assessed the safety and efficacy of the Porcupine inhibitor, WNT974, in patients with advanced solid tumours.<bold>Methods: </bold>Patients (n = 94) received oral WNT974 at doses of 5-30 mg once-daily, plus additional dosing schedules.<bold>Results: </bold>The maximum tolerated dose was not established; the recommended dose for expansion was 10 mg once-daily. Dysgeusia was the most common adverse event (50% of patients), likely resulting from on-target Wnt pathway inhibition. No responses were seen by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1; 16% of patients had stable disease (median duration 19.9 weeks). AXIN2 expression by RT-PCR was reduced in 94% of paired skin biopsies (n = 52) and 74% of paired tumour biopsies (n = 35), confirming inhibition of the Wnt pathway. In an exploratory analysis, an inverse association was observed between AXIN2 change and immune signature change in paired tumour samples (n = 8).<bold>Conclusions: </bold>Single-agent WNT974 treatment was generally well tolerated. Biomarker analyses suggest that WNT974 may influence immune cell recruitment to tumours, and may enhance checkpoint inhibitor activity.<bold>Clinical Trial Registration: </bold>NCT01351103.
- Subjects
PROTEINS; PYRIDINE; CLINICAL trials; HETEROCYCLIC compounds; ORAL drug administration; CELLULAR signal transduction; TREATMENT effectiveness; GENES; TUMORS; ENZYME inhibitors
- Publication
British Journal of Cancer, 2021, Vol 125, Issue 1, p28
- ISSN
0007-0920
- Publication type
journal article
- DOI
10.1038/s41416-021-01389-8