13036 Background: The histone deacetylase (HDAC) inhibitor MS-275, a synthetic benzamide derivative, has demonstrated antitumor activity in vitro & in vivo. After determining maximum tolerable dose (MTD = 2 mg/m2) & dose limiting toxicity (DLT) for MS-275 given to fasting patients (pts) weekly ×4 q6 weeks, we explored toxicity profile, MTD, & pharmacokinetics (PK) of MS-275 when given po on the same schedule with food. Methods: MS-275 at 2, 4, or 6 mg/m2 was administered to pts with advanced malignancy & PS ≤2, LFTs ≤2.5 × normal, adequate hematopoietic & renal function, & normal resting MUGA. PK samples were analyzed by LC-MS. Data for pts in the fed state were compared to data obtained in previous cohorts of pts treated in the fasting state. Protein acetylation assessed by a novel flow cytometric assay & HDAC enzymatic activity were measured in peripheral blood mononuclear cells (PBMC). Results: 16 pts received a median of 2 cycles (1–5) of MS-275 2–6 mg/m2 with food. No DLT occurred on 2 or 6 mg/m2 (n = 3 each), while 1 pt on 4 mg/m2 (n = 10) had a DLT: grade 3 hypophosphatemia. For 2–6 mg/m2 other grade 3 toxicities were neutropenia & lymphopenia. Grade 1–2 toxicities in >1 pt were leucopenia, anemia, thrombocytopenia, fatigue, nausea, vomiting, headache, hypoalbuminemia, hypophosphatemia, hyponatremia, & hypocalcemia. MTD has not been reached; current dose level is 8 mg/m2. Comparing PK for fasting & fed pts on 2–4 mg/m2, there was no difference in Tmax (0.5h); average Cmax & AUC were 35% & 25% lower, respectively, in fed pts; this difference is not statistically significant. Interindividual variability in exposure to MS-275 increased from 52% in fasting pts to 100% in fed pts. PBMC protein acetylation & HDAC inhibition were seen at all dose levels (2–6 mg/m2) in fed pts. Of 9 pts evaluable for response (2–4 mg/m2), 2 of 6 pts on 4 mg/m2 had stable disease. Conclusions: MTD has not yet been established for MS-275 given with food on this schedule but is ≥4 mg/m2 weekly x4 q6 weeks. Interindividual variability in exposure increases with food. Whether intestinal absorption is decreased when MS-275 is given with food requires further evaluation with additional patients. Drug-related protein hyperacetylation & HDAC inhibition were observed. [Table: see text]