A. Hauschild, U. Trefzer, C. Garbe
Jun 20, 2006
Citations
1
Influential Citations
23
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Quality indicators
Journal
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
Abstract
8044 Background: The acetylation of histones is a key component of gene regulation, which plays an important role in tumor initiation and progression. MS-275, an inhibitor of the benzamide series, is a synthetic orally available inhibitor of HDACs which showed anti-tumor activity in 3 phase 1 trials. METHODS A phase II, multicenter, randomized, parallel-group study of oral MS-275 evaluated the efficacy and toxicity in patients with non-resectable metastatic melanoma. Patients should have received at least one, but not more than two previous systemic therapies (chemo- and/or immunotherapy) for stage IV melanoma. Patients were stratified to receive either 3 mg MS-275 biweekly (days 1+15 of a 4-week cycle) or 7 mg MS-275 weekly (days 1+8+15 of a 4-week cycle) until disease progression or unacceptable toxicity. Study endpoints were the assessment of tumor response and toxicity. RESULTS A total of 28 patients have been randomized equally to the two dosing groups. Patients were classified as belonging to AJCC stage IVa (n=0), IVb (n=9; 32%), and IVc (n=19; 68%). In general, MS-275 was very well tolerated. No treatment-related SAEs have been observed. Most frequently reported side effects were nausea (CTC Grade 1+2, 32%) hypophosphatemia (CTC Grade 1-3, 29%), and diarrhea (CTC Grade 1+2, 18%). Stable diseases lasting from 8 wks to more than 48 wks have been observed in 4 pts (29%) in the 3 mg and 3 pts (21%) in the 7 mg dose group. Stabilizations occurred in these metastatic localizations: skin, peripheral and visceral lymph nodes, lung and bone, respectively. However, objective tumor responses were not observed. CONCLUSIONS The results suggest that MS-275 is well tolerated and shows long-lasting tumor stabilizations in patients with pre-treated metastatic melanoma. The failure of objective tumor responses in the single-agent treatment with MS-275 warrants further evaluation also in combinational settings. [Table: see text].