Modulation of autophagy: a Phase II study of vorinostat plus hydroxychloroquine versus regorafenib in chemotherapy-refractory metastatic colorectal cancer (mCRC).
Journal
British journal of cancer
ISSN: 1532-1827
Titre abrégé: Br J Cancer
Pays: England
ID NLM: 0370635
Informations de publication
Date de publication:
10 2022
10 2022
Historique:
received:
28
01
2022
accepted:
09
06
2022
revised:
15
05
2022
pubmed:
24
6
2022
medline:
16
9
2022
entrez:
23
6
2022
Statut:
ppublish
Résumé
In metastatic colorectal cancer (mCRC), regorafenib (RGF), a multi-kinase inhibitor with angiogenic inhibition has modest effects on survival. We reported that autophagy modulation using hydroxychloroquine (HCQ), enhances the anticancer activity of the histone deacetylase inhibitor, vorinostat (VOR), in mCRC, is well tolerated, and has comparable activity to RGF. Thus, we conducted a prospective study of VOR/HCQ versus RGF in mCRC. This is a randomised, controlled trial of VOR 400 mg and HCQ 600 mg orally daily versus RGF 160 mg orally daily (3 weeks on/1 week off), every 4 weeks, in patients with mCRC. median progression-free survival (mPFS). Secondary endpoints: median overall survival (mOS); adverse events; pharmacodynamic analyses. From 2/2015-10/2017, 42 patients were randomised to VOR/HCQ and RGF. Median age was 58.4 years. mPFS on VOR/HCQ was 1.9 months versus 4.35 months with RGF (P = 0.032). There was no difference in mOS (P = 0.9). Treatment was tolerated in both arms. In both arms, there was improved anti-tumour immunity. VOR/HCQ had an inferior PFS when compared to RGF, although there was an increase in anti-tumour immunity in mCRC. VOR/HCQ has a favourable safety profile, and immune or tumour biomarkers may be used to identify clinical benefit of autophagy modulation in mCRC. NCT02316340.
Sections du résumé
BACKGROUND
In metastatic colorectal cancer (mCRC), regorafenib (RGF), a multi-kinase inhibitor with angiogenic inhibition has modest effects on survival. We reported that autophagy modulation using hydroxychloroquine (HCQ), enhances the anticancer activity of the histone deacetylase inhibitor, vorinostat (VOR), in mCRC, is well tolerated, and has comparable activity to RGF. Thus, we conducted a prospective study of VOR/HCQ versus RGF in mCRC.
METHODS
This is a randomised, controlled trial of VOR 400 mg and HCQ 600 mg orally daily versus RGF 160 mg orally daily (3 weeks on/1 week off), every 4 weeks, in patients with mCRC.
PRIMARY ENDPOINT
median progression-free survival (mPFS). Secondary endpoints: median overall survival (mOS); adverse events; pharmacodynamic analyses.
RESULTS
From 2/2015-10/2017, 42 patients were randomised to VOR/HCQ and RGF. Median age was 58.4 years. mPFS on VOR/HCQ was 1.9 months versus 4.35 months with RGF (P = 0.032). There was no difference in mOS (P = 0.9). Treatment was tolerated in both arms. In both arms, there was improved anti-tumour immunity.
CONCLUSIONS
VOR/HCQ had an inferior PFS when compared to RGF, although there was an increase in anti-tumour immunity in mCRC. VOR/HCQ has a favourable safety profile, and immune or tumour biomarkers may be used to identify clinical benefit of autophagy modulation in mCRC.
CLINICAL TRIAL REGISTRATION
NCT02316340.
Identifiants
pubmed: 35739299
doi: 10.1038/s41416-022-01892-6
pii: 10.1038/s41416-022-01892-6
pmc: PMC9470553
doi:
Substances chimiques
Phenylurea Compounds
0
Pyridines
0
regorafenib
24T2A1DOYB
Hydroxychloroquine
4QWG6N8QKH
Vorinostat
58IFB293JI
Banques de données
ClinicalTrials.gov
['NCT02316340']
Types de publication
Clinical Trial, Phase II
Journal Article
Randomized Controlled Trial
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1153-1161Subventions
Organisme : NIA NIH HHS
ID : P30 AG044271
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA054174
Pays : United States
Informations de copyright
© 2022. The Author(s), under exclusive licence to Springer Nature Limited.
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