Related Experiment Video
Updated: Jul 11, 2026
Assays for Validating Histone Acetyltransferase Inhibitors
Published on: August 6, 2020
Phase I trial of MS-275, a histone deacetylase inhibitor, administered weekly in refractory solid tumors and lymphoid
Shivaani Kummar1, Martin Gutierrez, Erin R Gardner
1Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, USA. kummars@exchange.nih.gov
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/m(2). 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/m(2) 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.
Insights
This Phase I trial found that oral MS-275, a histone deacetylase inhibitor, is well tolerated at 6 mg/m(2) weekly. Drug exposure increased linearly with dose, showing anticancer potential.
Area of Science:
- Pharmacology
- Oncology
- Clinical Trials
Background:
- MS-275 is a histone deacetylase inhibitor with demonstrated anticancer activity in preclinical studies.
- Histone deacetylase inhibitors represent a promising class of anticancer agents.
Purpose of the Study:
- To determine the dose-limiting toxicities and maximum tolerated dose (MTD) of oral MS-275.
- To evaluate the pharmacokinetics of oral MS-275 in patients with refractory malignancies.
- To assess the pharmacodynamic effects of MS-275 on protein acetylation.
Main Methods:
- A Phase I clinical trial involving patients with refractory solid tumors and lymphoid malignancies.
- Oral MS-275 administered weekly for 4 weeks in a 6-week cycle.
- Pharmacokinetic and pharmacodynamic analyses, including flow cytometry for protein acetylation.
Main Results:
- The MTD of oral MS-275 was determined to be 6 mg/m(2).
- Reversible grade 3 toxicities included hypophosphatemia, hyponatremia, and hypoalbuminemia; myelosuppression was also observed.
- Pharmacokinetics showed linear dose-proportionality in drug exposure (AUC) with considerable interpatient variability.
Conclusions:
- MS-275 is well tolerated at 6 mg/m(2) weekly with food in patients with refractory malignancies.
- Oral MS-275 demonstrates linear dose-proportional drug exposure.
- MS-275 effectively increased protein acetylation in peripheral blood mononuclear cells.
