Phase I and pharmacokinetic study of MS-275, a histone deacetylase inhibitor, in patients with advanced and refractory solid tumors or lymphoma
| Autor: | William D. Figg, James A. Zwiebel, Alex Sparreboom, Yusri A. Elsayed, Jane B. Trepel, Joseph Z. Ye, Edward A. Sausville, Manish Monga, Donna Headlee, Anthony J. Murgo, Giovanni Melillo, Mikhail Kalnitskiy, Milin Acharya, Eun Joo Chung, Kyunghwa Hwang, Qin C. Ryan |
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| Rok vydání: | 2005 |
| Předmět: |
Adult
Male Cancer Research Lymphoma Maximum Tolerated Dose Nausea medicine.drug_class Pyridines Administration Oral Pharmacology Drug Administration Schedule chemistry.chemical_compound Pharmacokinetics Neoplasms medicine Humans Enzyme Inhibitors Histone H3 acetylation Aged Entinostat business.industry Histone deacetylase inhibitor Middle Aged Histone Deacetylase Inhibitors Oncology chemistry Pharmacodynamics Immunology Toxicity Benzamides Vomiting Female medicine.symptom Neoplasm Recurrence Local business |
| Zdroj: | Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 23(17) |
| ISSN: | 0732-183X |
| Popis: | 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 × 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 × 4, repeated every 6 weeks is presently being evaluated. |
| Databáze: | OpenAIRE |
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