Methylation and histone deacetylase inhibition in combination with platinum treatment in patients with advanced malignancies. Invest New Drugs 2013 Oct;31(5):1192-200
Date
08/03/2013Pubmed ID
23907406Pubmed Central ID
PMC3809091DOI
10.1007/s10637-013-0003-3Scopus ID
2-s2.0-84884812613 (requires institutional sign-in at Scopus site) 49 CitationsAbstract
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.
Author List
Falchook GS, Fu S, Naing A, Hong DS, Hu W, Moulder S, Wheler JJ, Sood AK, Bustinza-Linares E, Parkhurst KL, Kurzrock RAuthor
Razelle Kurzrock MD Center Associate Director, Professor in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AcetylationAdult
Aged
Antineoplastic Agents
Antineoplastic Combined Chemotherapy Protocols
Azacitidine
Carboplatin
DNA Methylation
Female
Histone Deacetylase Inhibitors
Histones
Humans
Male
Middle Aged
Neoplasms
Receptors, TNF-Related Apoptosis-Inducing Ligand
Valproic Acid
