Phase 1 study of single-agent WNT974, a first-in-class Porcupine inhibitor, in patients with advanced solid tumours.
Administration, Oral
Adult
Aged
Axin Protein
/ genetics
Enzyme Inhibitors
/ administration & dosage
Female
Gene Expression Regulation, Neoplastic
/ drug effects
Humans
Male
Middle Aged
Neoplasms
/ drug therapy
Pyrazines
/ administration & dosage
Pyridines
/ administration & dosage
Treatment Outcome
Wnt Signaling Pathway
/ drug effects
Journal
British journal of cancer
ISSN: 1532-1827
Titre abrégé: Br J Cancer
Pays: England
ID NLM: 0370635
Informations de publication
Date de publication:
07 2021
07 2021
Historique:
received:
29
10
2020
accepted:
31
03
2021
revised:
17
03
2021
pubmed:
5
5
2021
medline:
15
12
2021
entrez:
4
5
2021
Statut:
ppublish
Résumé
This Phase 1 study assessed the safety and efficacy of the Porcupine inhibitor, WNT974, in patients with advanced solid tumours. Patients (n = 94) received oral WNT974 at doses of 5-30 mg once-daily, plus additional dosing schedules. 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). 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. NCT01351103.
Sections du résumé
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.
Identifiants
pubmed: 33941878
doi: 10.1038/s41416-021-01389-8
pii: 10.1038/s41416-021-01389-8
pmc: PMC8257624
doi:
Substances chimiques
AXIN2 protein, human
0
Axin Protein
0
Enzyme Inhibitors
0
Pyrazines
0
Pyridines
0
LGK974
U27F40013Q
Banques de données
ClinicalTrials.gov
['NCT01351103']
Types de publication
Clinical Trial, Phase I
Journal Article
Multicenter Study
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
28-37Subventions
Organisme : NCATS NIH HHS
ID : UL1 TR003167
Pays : United States
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