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

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.

Phase I and pharmacokinetic study of MS-275, a histone deacetylase inhibitor, in patients with advanced and refractory solid tumors or lymphoma.

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 > or = 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.

A phase I and pharmacokinetic study of oral perifosine with different loading schedules in patients with refractory neoplasms.

PURPOSE: To determine the maximum tolerated dose (MTD) of perifosine (NSC 639966), an alkylphospholipid modulator of signal transduction, using different oral loading and maintenance regimens in an effort to avoid gastrointestinal toxicity while seeking maximal sustained plasma concentrations. METHODS: Thirty-one patients with advanced neoplasms were treated with monthly cycles of perifosine loading doses of 300, 600, 900, 1,200 and 1,500 mg (dose levels 1 through 5, respectively) on days 1-2 depending on the actual dose of the initial cycle. For subsequent cycles, perifosine loading doses were reduced to 100, 200, 300, 400 and 1,000 mg at the respective corresponding dose levels. Daily perifosine "maintenance" doses of 50, 100, 150, 200 and 250 mg for levels 1 through 5, respectively, commenced on days 2 or 3 and continued for a total of 21 days. No treatment was given for days 22-27. The pharmacokinetics of perifosine with these schedules was characterized. RESULTS: Dose-limiting diarrhea developed at or above dose level 4. The MTD and recommended phase II dose was dose level 3B, with a loading dose of 900 mg on day 1 divided into two doses of 450 mg administered 6 h apart and a maintenance dose of 150 mg on day 2 through 21. On subsequent cycles, the loading dose was reduced to 300 mg. Non-gastrointestinal toxicities included three episodes of gout or gout-like syndromes observed at doses above the MTD. The median peak plasma concentration of perifosine achieved at the MTD was approximately 8.3 µg/mL. Four patients had stable disease ranging from 167 to 735 days. CONCLUSIONS: Perifosine given according to a loading and maintenance schedule can safely sustain concentrations of drug, approaching concentrations achieved in preclinical models with evidence of anti-tumor effect.