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Clinical Trial Protocol

Vorinostat in patients with resistant BRAFV600E mutated advanced melanoma: a proof of concept study

    Sanne Huijberts

    *Author for correspondence:

    E-mail Address: s.huijberts@nki.nl

    Department of Clinical Pharmacology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands

    ,
    Liqin Wang

    Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands

    ,
    Rodrigo Leite de Oliveira

    Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands

    ,
    Hilde Rosing

    Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands

    ,
    Bastiaan Nuijen

    Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands

    ,
    Jos Beijnen

    Department of Clinical Pharmacology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands

    Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands

    Faculty of Science, Utrecht University, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands

    ,
    Rene Bernards

    Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands

    Faculty of Science, Utrecht University, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands

    ,
    Jan Schellens

    Faculty of Science, Utrecht University, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands

    &
    Sofie Wilgenhof

    Department of Medical Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands

    Published Online:https://doi.org/10.2217/fon-2020-0023

    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 BRAFV600E 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).

    Papers of special note have been highlighted as: • of interest

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