Originally published as JCO Early Release 10.1200/JCO.2005.02.188 on April 25 2005

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Phase I and Pharmacokinetic Study of MS-275, a Histone Deacetylase Inhibitor, in Patients With Advanced and Refractory Solid Tumors or Lymphoma

Qin C. Ryan, Donna Headlee, Milin Acharya, Alex Sparreboom, Jane B. Trepel, Joseph Ye, William D. Figg, Kyunghwa Hwang, Eun Joo Chung, Anthony Murgo, Giovanni Melillo, Yusri Elsayed, Manish Monga, Mikhail Kalnitskiy, James Zwiebel, Edward A. Sausville

From the Clinical Trials Unit, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis; Clinical Pharmacology Research Core, Medical Oncology Clinical Research Unit; Center for Cancer Research; Investigational Drug Branch, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda; and Developmental Therapeutics Program, SAIC Frederick Inc, National Cancer Institute at Frederick, Frederick, MD

Address reprint requests to Edward Sausville, MD, PhD, FACP, Greenebaum Cancer Center, University of Maryland, 22 S. Greene St, Baltimore, MD 21201; e-mail: esausville{at}umm.edu.

PURPOSE: The objective of this study was to define the maximum-tolerated dose (MTD), the recommended phase II dose, the dose-limiting toxicity, and determine the pharmacokinetic (PK) and pharmacodynamic profiles of MS-275.

PATIENTS AND METHODS: Patients with advanced solid tumors or lymphoma were treated with MS-275 orally initially on a once daily x 28 every 6 weeks (daily) and later on once every-14-days (q14-day) schedules. The starting dose was 2 mg/m² and the dose was escalated in three- to six-patient cohorts based on toxicity assessments.

RESULTS: With the daily schedule, the MTD was exceeded at the first dose level. Preliminary PK analysis suggested the half-life of MS-275 in humans was 39 to 80 hours, substantially longer than predicted by preclinical studies. With the q14-day schedule, 28 patients were treated. The MTD was 10 mg/m² and dose-limiting toxicities were nausea, vomiting, anorexia, and fatigue. Exposure to MS-275 was dose dependent, suggesting linear PK. Increased histone H3 acetylation in peripheral-blood mononuclear-cells was apparent at all dose levels by immunofluorescence analysis. Ten of 29 patients remained on treatment for 3 months.

CONCLUSION: The MS-275 oral formulation on the daily schedule was intolerable at a dose and schedule explored. The q14-day schedule is reasonably well tolerated. Histone deacetylase inhibition was observed in peripheral-blood mononuclear-cells. Based on PK data from the q14-day schedule, a more frequent dosing schedule, weekly x 4, repeated every 6 weeks is presently being evaluated.

Terms in blue are defined in the glossary, found at the end of this issue and online at www.jco.org.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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