Journal
FUTURE ONCOLOGY
Volume 16, Issue 11, Pages 619-629Publisher
FUTURE MEDICINE LTD
DOI: 10.2217/fon-2020-0023
Keywords
BRAF inhibitor; BRAFV600E mutation; histone deacetylase inhibitor; MEK inhibitor; melanoma; metastatic; resistance
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Funding
- Oncode Institute
- ERC proof of concept grant
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The clinical benefit of treatment with BRAF- and MEK-inhibitors in melanoma is limited due to resistance associated with emerging secondary mutations. Preclinical and clinical studies have shown that short-term treatment with the HDAC inhibitor vorinostat can eliminate cells harboring these secondary mutations causing resistance. This proof of concept study is to determine the efficacy of sequential treatment with vorinostat and BRAFi/MEKi in resistant BRAF(V600E) mutant melanoma. The primary aim is demonstrating anti-tumor response of progressive lesions according to RECIST 1.1. Secondary end points are to determine that emerging resistant clones with a secondary mutation in the MAPK pathway can be detected in circulating tumor DNA and purged by short-term vorinostat treatment. Exploratory end points include pharmacokinetic, pharmacodynamic and pharmacogenetic analyses (NCT02836548).
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