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Phase I Study of Epigenetic Modulation with 5-Azacytidine and Valproic Acid in Patients with Advanced Cancers

Authors' Affiliations: ¹ Department of Investigational Cancer Therapeutics (Phase I Program), and ² Department of Leukemia, ³ Division of Cancer Medicine and Quantitative Sciences, and ⁴ Division of Pediatrics, University of Texas M. D. Anderson Cancer Center, Houston, Texas

Requests for reprints: Razelle Kurzrock, Department of Investigational Cancer Therapeutics, Phase I Program, 1515 Holcombe Boulevard, Box 0422, Houston, TX 77030. Phone: 713-794-1226; Fax: 713-745-2374; E-mail: rkurzroc{at}mdanderson.org.

Purpose: 5-Azacytidine (5-AZA) is a DNA-hypomethylating agent. Valproic acid is a histone deacetylase inhibitor. Combining hypomethylating agents and histone deacetylase inhibitors produces synergistic anticancer activity in vitro and in vivo. On the basis of this evidence, we conducted a phase I study of the combination of 5-AZA and valproic acid in patients with advanced cancers.

Experimental Design: 5-AZA was administered s.c. daily for 10 days. Valproic acid was given orally daily with a goal to titrate to plasma levels of 75 to 100 µg/mL (therapeutic for seizures). Cycles were 28 days long. 5-AZA was started at 20 mg/m² and escalated using an adaptive algorithm based on the toxicity profile in the prior cohort (6 + 6 design). Peripheral blood mononuclear cell global DNA methylation and histone H3 acetylation were estimated with the long interspersed nucleotide elements pyrosequencing assay and Western blots, respectively, on days 1 and 10 of each cycle when patients agreed to provide them.

Results: Fifty-five patients were enrolled. Median age was 60 years (range, 12-77 years). The maximum tolerated dose was 75 mg/m² of 5-AZA in combination with valproic acid. Dose-limiting toxicities were neutropenic fever and thrombocytopenia, which occurred at a dose of 94 mg/m² of 5-AZA. Stable disease lasting 4 to 12 months (median, 6 months) was observed in 14 patients (25%). A significant decrease in global DNA methylation and induction of histone acetylation were observed.

Conclusion: The combination of 5-AZA and valproic acid is safe at doses up to 75 mg/m² for 5-AZA in patients with advanced malignancies.

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