Updated results of a phase I study of low dose decitabine and valproic acid (VA) in patients with acute myeloid leukemia (AML): Gene reexpression, demethylation, and clinical response

6515 Background: Decitabine, an inhibitor of DNA methyltransferase (DNMT) enzymes, has activity in myeloid malignancies at doses >1 log below the MTD of 2250mg/m2/course which may be optimal for DNA demethylation and minimize cytotoxicity. Methods: We designed a two step trial for AML patients (pts) to determine: Step 1, the lowest dose of decitabine to induce 100% increase in or re-expression of epigenetically silenced genes in 5/6 pts treated at a dose level; and Step 2, the MTD of the histone deacetylase (HDAC) inhibitor VA given with this dose of decitabine, and whether this MTD or a lower dose leads to 90% decrease in HDAC activity. Results: Decitabine was administered to 17 pts at two dose levels. Pts had relapsed/refractory AML (N=10) or age>60 and ineligible/refused standard therapy (N=7) and ranged in age from 36–83 years. Pts received decitabine at 15–20mg/m2/IV over 1 hr daily for 10 days (d) (3 pts also had VA 15mg/kg on days 5–21), every 28 d. Mean plasma decitabine Cmax (by a validated LC-MS...