Abstract
3055 Background: Preclinical studies suggest that histone deacetylase (HDAC) inhibitors may restore tumor sensitivity to retinoids. The objective of this study was to determine the maximum-tolerated dose (MTD), the dose-limiting toxicity (DLT), and the pharmacokinetic (PK)/pharmacodynamic (PD) profiles of the HDAC inhibitor MS-275 in combination with 13-cis retinoic acid (CRA). Methods: Patients (pts) with advanced solid tumors were treated with MS-275 orally once weekly and CRA orally twice daily x 3 weeks every 4 weeks. The starting dose for MS-275 was 4 mg/m2 and the dose was escalated based on toxicity assessments. The fixed dose for CRA was 1 mg/kg/day. PK concentrations of MS-275 and CRA were determined by LC/MS/MS. Western Blot analysis on peripheral-blood mononuclear cells (PBMCs) and tumor samples (when feasible) were performed to evaluate target inhibition. Results: To date thirteen pts have been enrolled. Tumor types include prostate (4 pts), bladder and renal cell (2 pts), and others. The MTD was exceeded at the 5 mg/m2 dose level (G3 hyponatremia, neutropenia and anemia). Fatigue (G1 or G2) is a common side effect. MS-275 peak concentrations were 141.6±75.7ng/mL at 4mg/m2 and 139.5±30.9 ng/mL at 5mg/m2. MS-275 half-life and clearance were 108.2±47.9h and 9.4±6.0L/h/m2, which is consistent with prior reports for MS-275 as single agent. Median CRA steady-state trough levels were 182.4 ng/mL. The MTD was 4 mg/m2 MS-275 and 1 mg/kg CRA. Five pts remained on treatment for ≥ 4 months including pts with prostate cancer (3), pancreatic cancer (6 months) and a pt with renal cell carcinoma (12 months) who presented a partial response in the lungs. Histones isolated from PBMCs showed transient but consistent protein acetylation post-therapy. Tumor biopsy of a liver lesion from prostate carcinoma revealed post-therapy induced histone acetylation and decreased phosphorylated ERK and STAT3 protein expression consistent with HDAC inhibitory activity. Conclusions: Combination of MS-275 with CRA is reasonably well tolerated and 4 mg/m2 is the Phase II recommended dose for MS-275 in combination with CRA. Tumor response and PD data suggest clinical and biological activity for this combination strategy. [Table: see text]
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