Publication Date:
2014-10-02
Description:
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 ( C max ), clearance (CL), volume of distribution at steady-state (Vd ss ), area under curve (AUC), and terminal elimination half-life ( t 1/2 ) 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. Clin Cancer Res; 20(19); 5032–40. ©2014 AACR .
Print ISSN:
1078-0432
Electronic ISSN:
1557-3265
Topics:
Medicine
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