Methylation and histone deacetylase inhibition in combination with platinum treatment in patients with advanced malignancies

Abstract

Purpose: The combination of DNA methylation inhibitors and histone deacetylase inhibitors is synergistic in gene expression activation and may overcome platinum resistance. Sequential treatment with azacitidine and valproic acid (VPA) in combination with carboplatin may overcome resistance to platinum-based therapy, and we conducted a phase I trial to assess safety, maximum tolerated dose (MTD), and clinical correlates. Experimental Design Patients with advanced solid tumors refractory to standard therapy were eligible. In cohorts of escalating doses, patients received azacitidine for 5 days from days 1 to 5, VPA for 7 days from days 5 to 11, and carboplatin starting in the second cycle on days 3 and 10. Clinical correlates included evaluation of epigenetic changes, methylation patterns, and histone acetylation levels in peripheral blood mononuclear cells.

Results: Thirty-two patients were treated. The MTD was 75 mg/m(2) azacitidine, 20 mg/kg VPA, and AUC 3.0 carboplatin. Minor responses or stable disease lasting ≥ 4 months were achieved by six patients (18.8 %), including three with platinum-resistant or platinum-refractory ovarian cancer. The most common adverse events grade ≥ 3 were fatigue (81 %) and neutropenia (69 %). Dose-limiting toxicity occurred in six patients (18.8 %), including four patients with grade 3 altered mental status. Death receptor 4 (DR4) methylation was shown to decrease in a subset of patients, but there was no relationship with tumor response or number of cycles received.

Conclusions: Combination of azacitidine, VPA, and carboplatin demonstrates decreased DR4 methylation and modest evidence of antitumor activity in patients with heavily treated advanced malignancies.

Trial registration: ClinicalTrials.gov NCT00529022.

Conflict of interest statement

CONFLICT OF INTEREST

Dr. Falchook received research funding from Celgene. The other authors have no conflict of interest to disclose.

Figures

Fig. 1

Dose schema for azacitidine, carboplatin, and valproic acid (VPA). Abbreviations: AUC, area under the curve; D, day; MTD, maximum tolerated dose

Fig. 2

Dynamic changes in DR4 methylation in peripheral blood mononuclear cell (PBMC) DNA from patient #4, with ovarian cancer, who had stable disease and received 9 months of treatment (A). No correlation between valproic acid (VPA) dose and decrease in DR4 methylation in PBMC DNA (p = 0.3) (B). Abbreviations: M-DR4, Methylated DR4; UM-DR4, Unmethylated DR4