HDAC Inhibitor Vorinostat in Resistant BRAF V600 Mutated Advanced Melanoma

Activating mutations in the BRAF gene are present in about 50% of human melanomas. BRAF inhibitors (BRAFi) inhibit the serine-threonine protein kinase BRAF, which plays a dominant role in the MAPK pathway influencing cell growth. MEK inhibitors (MEKi) inhibit MEK1 and MEK2, two regulatory proteins downstream of BRAF. The clinical benefit of this treatment is limited due to development of drug resistance in 6-8 months for treatment with BRAFi and 9-14 months for treatment with BRAFi in combination with MEKi.This is often associated with secondary mutations in the MAPK pathway leading to re-activation of the pathway.Withholding from treatment with BRAFi and/or MEKi leads to a reversible hyperactivation of the MAPK pathway, causing a transient growth arrest. Chronic proliferation and growth arrest occur when there is a persistent hyperactivation of the MAPK pathway. Treatment of BRAFi and/or MEKi resistant melanoma with vorinostat, a histone deacetylase inhibitor (HDACi), leads to persistent hyperactivation of the pathway and a state of growth arrest with hallmarks of oncogene induced senescence.In these studies in mice with BRAFi resistant BRAF V600 mutated melanoma switch from a BRAFi to the HDACi vorinostat resulted in complete disappearance of the tumor after two months of treatment. HDACi cause accumulation of Reactive Oxygen Species (ROS) leading to apoptosis and upregulation of the MAPK-pathway. As seen by Wang et al hyperactivation of the MAPK-pathway is an important milestone in the anti-tumor treatment of BRAF V600 melanoma. This is a phase I, single-center, single-arm, non-randomized, open-label, clinical pharmacological proof of principal study to determine the safety of vorinostat as anti-tumor therapy in patients with advanced resistant BRAF V600 mutated melanoma. A total of 21 evaluable patients with BRAF V600 mutated melanoma who developed resistance to BRAFi and/or BRAFi+MEKi after at least 4 weeks of PR or CR response will be enrolled in this study. Vorinostat will be given at a single daily dose of 360 mg derived from the established and registered dose for treatment of cutaneous T-cell lymphoma. Treatment will be continuous in cycles of 28 days and doses will be reduced in steps of 90 mg per dose-reduction in case of unacceptable safety concerns.