Phase I first-in-human study of CUDC-101, a multitargeted inhibitor of HDACs, EGFR, and HER2 in patients with advanced solid tumors.

PURPOSE: This first-in-human phase I study evaluated dose-limiting toxicities (DLT) and defined a phase II recommended dose (RD) for CUDC-101, a multitargeted inhibitor of HDACs, EGFR, and HER2 as a 1-hour intravenous (i.v.) infusion for 5 consecutive days every 2 weeks.

EXPERIMENTAL DESIGN: Twenty-five patients with advanced solid tumors received escalating doses of CUDC-101 (range, 75-300 mg/m(2)/day) following a standard 3 + 3 dose escalation design.

RESULTS: The MTD was determined to be 275 mg/m(2). Common grade 1/2 adverse events included nausea, fatigue, vomiting, dyspnea, pyrexia, and dry skin. DLTs occurred in 1 patient in the 275-mg/m(2) dose cohort (grade 2 serum creatinine elevation, n = 1) and 3 patients in the 300-mg/m(2) dose cohort (grade 2 serum creatinine elevation, n = 2; pericarditis, n = 1), all of which were transient and reversible. CUDC-101 exposure increased linearly with the mean maximum concentration (Cmax), clearance (CL), volume of distribution at steady-state (Vdss), area under curve (AUC), and terminal elimination half-life (t1/2) at the MTD dose of 9.3 mg/L, 51.2 L/h, 39.6 L, 9.95 h·ng/mL and 4.4 hours, respectively. Acetylated histone H3 induction was observed in posttreatment skin samples from 3 patients in the 275-mg/m(2) dose cohort, suggesting adequate systemic exposure and target inhibition. One patient with gastric cancer had a partial response and 6 patients had stable disease.

CONCLUSION: CUDC-101 administered by 1-hour i.v. infusion for 5 consecutive days every 2 weeks was generally well tolerated with preliminary evidence of antitumor activity. A dose of 275 mg/m(2) is recommended for further clinical testing.