Phase I pharmacokinetic-pharmacodynamic trial of weekly MS-275, an oral histone deacetylase inhibitor

3094 Background: MS-275, a synthetic benzamide derivative, is a histone deacetylase (HDAC) inhibitor with in vitro & in vivo antitumor activity. Based on our q2 week dosing results, we explored maximum tolerable dose (MTD) & dose limiting toxicity (DLT) for a weekly schedule with 2 oral formulations & 2 administration conditions. Methods: MS-275 uncoated (“A” with meal) or coated (“B” fasting) tablets were given weekly x4 q6 weeks to patients (pts) with advanced malignancy & PS≤2, LFTs≤2.5x normal, adequate hematopoetic & renal function, & normal resting MUGA. Pharmacokinetics (PK) (validated LCMS method) & histone H3 acetylation (H3Ac) in peripheral blood mononuclear cells (PBMC) (IHC image analysis and novel flow cytometric assay for protein acetylation) were assessed. Results: 13 pts, ECOG PS =1 (0–2) received median of 1 (1–4) course. 4 “A” (4–6 mg/m2) pts & 7 “B” (2–4 mg/m2) pts were evaluable for cycle 1 toxicity (CTC v2.0). “A” grade 3 toxicities were hypoalbuminemia, neutropenia & vomiting. On “B”...