Phase I trial of MS-275, a histone deacetylase inhibitor, administered weekly in refractory solid tumors and lymphoid malignancies

Shivaani Kummar, Martin Gutierrez, Erin R. Gardner, Erin Donovan, Kyunghwa Hwang, Joo Chung Eun, Min Jung Lee, Kim Maynard, Mikhail Kalnitskiy, Alice Chen, Giovanni Melillo, Qin C. Ryan, Barbara Conley, William D. Figg, Jane B. Trepel, James Zwiebel, James H. Doroshow, Anthony J. Murgo

Research output: Contribution to journalArticlepeer-review

102 Scopus citations

Abstract

Purpose: MS-275 is a histone deacetylase inhibitor that has shown potent and unique anticancer activity in preclinical models. The aims of this phase I trial were to determine the dose-limiting toxicities and maximum tolerated dose of oral MS-275 in humans administered with food on a once weekly schedule and to study the pharmacokinetics of oral MS-275. Experimental Design: Patients with refractory solid tumors and lymphoid malignancies were treated with oral MS-275 on a once weekly schedule for 4 weeks of a 6-week cycle. Samples for pharmacokinetic and pharmacodynamic analyses were collected during cycle 1. Protein acetylation in subpopulations of peripheral blood mononuclear cells was measured using a multivariable flow cytometry assay. Results: A total of 22 patients were enrolled, and 19 were considered evaluable for toxicity. The maximum tolerated dose was 6 mg/m2. No National Cancer Institute Common Toxicity Criteria grade 4 toxicities were observed. Dose-limiting grade 3 toxicities were reversible and consisted of hypophosphatemia, hyponatremia, and hypoalbuminemia. Non-dose-limiting grade 3 myelosuppression was also observed. The mean terminal half-life of MS-275 was 33.9 ± 26.2 and the T max ranged from 0.5 to 24 h. Although there was considerable interpatient variability in pharmacokinetics, the area under the plasma concentration versus time curve increased linearly with dose. Conclusions: MS-275 is well tolerated at a dose of 6 mg/m2 administered weekly with food for 4 weeks every 6 weeks. Drug exposure increases linearly with dose, and protein acetylation increased in all the subpopulations of peripheral blood mononuclear cells following MS-275 administration.

Original languageEnglish (US)
Pages (from-to)5411-5417
Number of pages7
JournalClinical Cancer Research
Volume13
Issue number18
DOIs
StatePublished - Sep 15 2007
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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