A phase I–II study of the histone deacetylase inhibitor valproic acid plus chemoimmunotherapy in patients with advanced melanoma

Abstract

We explored in a phase I/II clinical trial the combination of valproic acid (VPA), a clinically available histone deacetylase inhibitor, with standard chemoimmunotherapy in patients with advanced melanoma, to evaluate its clinical activity, to correlate the clinical response with the biological activity of VPA and to assess toxicity. Patients were treated initially with VPA alone for 6 weeks. The inhibition of the target in non-tumour peripheral blood cells (taken as a potential surrogate marker) was measured periodically, and valproate dosing adjusted with the attempt to reach a measurable inhibition. After the treatment with valproate alone, dacarbazine plus interferon-α was started in combination with valproate. Twenty-nine eligible patients started taking valproate and 18 received chemoimmunotherapy and are assessable for response. We observed one complete response, two partial remissions and three disease stabilisations lasting longer than 24 weeks. With the higher valproate dosages needed to reach a measurable inhibition of the target, we observed an increase of side effects in those patients who received chemoimmunotherapy. The combination of VPA and chemoimmunotherapy did not produce results overtly superior to standard therapy in patients with advanced melanoma and toxicity was not negligible, casting some doubts on the clinical use of VPA in this setting (at least in the administration schedule adopted).

Antileukemic activity of valproic acid in chronic lymphocytic leukemia B cells defined by microarray analysis

“…Moreover, VPA has already been used in phase I/II clinical trials in combination with other classical chemotherapies such as purine analogues, 23,24 anthracyclin 25 and chemoimmunotherapy. 26 VPA association with monoclonal antibodies is furthermore described in in vitro studies. 27,28 Finally, VPA is well tolerated, and its effective concentration can be easily achieved in humans.…”

Evaluation of melanogenesis in A-375 melanoma cells treated with 5,7-dimethoxycoumarin and valproic acid

“…Valproic acid ( Fig. 1A; VPA; a short-chain fatty acid) is a HDAC inhibitor [6,11]. The selective initiation of apoptosis through a mitochondrial pathway and the activation of death receptors in tumor cells are responsible for the anticancer action of HDACis.…”

Prolonged survival with valproic acid use in the EORTC/NCIC temozolomide trial for glioblastoma

“…Improved survival for patients with a number of tumors has been reported if HDAC-inhibitory agents including VPA are combined with one or more chemotherapeutic agents. 8,14,15 Previously, a prolonged survival of 14 months vs 11 months was observed in patients with glioblastoma treated with adjuvant CCNU who received antiepileptic therapy with a non-EIAED, mainly VPA, compared with patients who received an EIAED, mainly carbamazepine. 16 Exploratory trials using HDAC inhibitors more potent than VPA such as vorinostat in combination with TMZ radiochemotherapy are ongoing and may provide further support for this hypothesis.…”