Phase 1 study of single-agent WNT974, a first-in-class Porcupine inhibitor, in patients with advanced solid tumours.
Br J Cancer
; 125(1): 28-37, 2021 07.
Article
in En
| MEDLINE
| ID: mdl-33941878
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.
Full text:
1
Database:
MEDLINE
Main subject:
Pyrazines
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Pyridines
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Enzyme Inhibitors
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Axin Protein
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Neoplasms
Type of study:
Clinical_trials
Limits:
Adult
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Aged
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Female
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Humans
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Male
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Middle aged
Language:
En
Journal:
Br J Cancer
Year:
2021
Type:
Article
Affiliation country:
Spain