Phase I Trial of MS-275, a Histone Deacetylase Inhibitor, Administered Weekly in Refractory Solid Tumors and Lymphoid Malignancies

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/m 2 . No National Cancer Institute CommonToxicity 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 F 26.2 and the T max ranged from 0.5 to 24 h. Although there was considerable interpatient variability in pharmacokinetics, the areaunder the plasma concentrationversus time curveincreasedlinearly withdose. 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.

Randomized Phase II, Double-Blind, Placebo-Controlled Study of Exemestane With or Without Entinostat in Postmenopausal Women With Locally Recurrent or Metastatic Estrogen Receptor-Positive Breast Cancer Progressing on Treatment With a Nonsteroidal Aromatase Inhibitor

“…[14][15][16][17][18][19][20][21] These consisted of fatigue, gastrointestinal disturbances, and hematologic toxicities and were easily addressed by entinostat dose reductions or interruptions, with only one patient using growth factor support for neutropenia. Though cardiovascular and electrocardiographic effects including QT (interval corrected for heart rate) prolongation have been previously reported with HDACi, [22][23][24][25][26] in our study, 31% of the population had previously Progression-Free Survival (probability)…”

Chemical targeting of the innate antiviral response by histone deacetylase inhibitors renders refractory cancers sensitive to viral oncolysis

“…MS-275 was chosen for the treatment of all models because of the noticeable enhancing effects demonstrated in vitro (Fig. S5 A and B), and the safety profile demonstrated in multiple phase I clinical trials (24,37,38). In all cases, the drug was administered i.p.…”

miR-449a targets HDAC-1 and induces growth arrest in prostate cancer

“…Dysregulation of miRNA expression has been identified in a number of cancers (Pan et al, 2001;Lu et al, 2005;Volinia et al, 2006;Blenkiron et al, 2007;Chen and Stallings, 2007;Fulci et al, 2007;Gaur et al, 2007;Kummar et al, 2007;Meng et al, 2007;Porkka et al, 2007;Wedel et al, 2008) and an accumulating data indicate that some miRNAs can function as tumor suppressors or oncogenes and are important in cancer development. Deletion or loss of function of a tumor-suppressing miRNA results in overexpression of target oncogenes.…”