Jordi Rodon1,2, Guillem Argilés3, Roisin M Connolly4,5, Ulka Vaishampayan6, Maja de Jonge7, Elena Garralda8, Marios Giannakis9, David C Smith10, Jason R Dobson11, Margaret E McLaughlin11, Abdelkader Seroutou12, Yan Ji13, Jennifer Morawiak11, Susan E Moody11, Filip Janku14. 1. Vall d'Hebron University Hospital and Universitat Autònoma de Barcelona, Barcelona, Spain. JRodon@mdanderson.org. 2. The University of Texas MD Anderson Cancer Center, Houston, TX, USA. JRodon@mdanderson.org. 3. Vall d'Hebron University Hospital and Universitat Autònoma de Barcelona, Barcelona, Spain. 4. Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA. 5. CancerResearch@UCC, College of Medicine and Health, University College Cork, Cork, Ireland. 6. Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA. 7. Department of Medical Oncology, Erasmus Medical Center Cancer Institute, Rotterdam, The Netherlands. 8. START Madrid, Hospital Universitario Madrid Sanchinarro, Madrid, Spain. 9. Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA. 10. University of Michigan, Ann Arbor, MI, USA. 11. Novartis Institutes for BioMedical Research, Cambridge, MA, USA. 12. Novartis Pharma AG, Basel, Switzerland. 13. Novartis Institutes for BioMedical Research, East Hanover, NJ, USA. 14. Department of Investigational Cancer Therapeutics (Phase 1 Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Abstract
BACKGROUND: This Phase 1 study assessed the safety and efficacy of the Porcupine inhibitor, WNT974, in patients with advanced solid tumours. METHODS: Patients (n = 94) received oral WNT974 at doses of 5-30 mg once-daily, plus additional dosing schedules. RESULTS: 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). CONCLUSIONS: 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. CLINICAL TRIAL REGISTRATION: NCT01351103.
BACKGROUND: This Phase 1 study assessed the safety and efficacy of the Porcupine inhibitor, WNT974, in patients with advanced solid tumours. METHODS: Patients (n = 94) received oral WNT974 at doses of 5-30 mg once-daily, plus additional dosing schedules. RESULTS: 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). CONCLUSIONS: 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. CLINICAL TRIAL REGISTRATION: NCT01351103.
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