Phase I study of epigenetic modulation with 5-azacytidine and valproic acid in patients with advanced cancers.
OBJECTIVE
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.


METHODS
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 mug/mL (therapeutic for seizures). Cycles were 28 days long. 5-AZA was started at 20 mg/m(2) 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/m(2) of 5-AZA in combination with valproic acid. Dose-limiting toxicities were neutropenic fever and thrombocytopenia, which occurred at a dose of 94 mg/m(2) 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.


CONCLUSIONS
The combination of 5-AZA and valproic acid is safe at doses up to 75 mg/m(2) for 5-AZA in patients with advanced malignancies.
Braiteh
Fadi
F
Department of Investigational Cancer Therapeutics (Phase I Program), Division of Cancer Medicine and Quantitative Sciences, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
Soriano
Andres O
AO
Garcia-Manero
Guillermo
G
Hong
David
D
Johnson
Marcella M
MM
Silva
Leandro De Padua
Lde P
Yang
Hui
H
Alexander
Stefanie
S
Wolff
Johannes
J
Kurzrock
Razelle
R
D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001374:Azacitidine / Q000008:administration & dosage*; D002648:Child; D015331:Cohort Studies; D018899:CpG Islands; D019175:DNA Methylation; D004357:Drug Synergism; D044127:Epigenesis, Genetic; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D014635:Valproic Acid / Q000008:administration & dosage*
D014635:Valproic Acid; D001374:Azacitidine