耐火材料(行星科学)
伏立诺他
医学
临床研究阶段
相(物质)
神经母细胞瘤
肿瘤科
内科学
核医学
毒性
材料科学
化学
组蛋白脱乙酰基酶
生物化学
遗传学
生物
基因
组蛋白
细胞培养
有机化学
复合材料
作者
Steven G. DuBois,Susan Groshen,Julie R. Park,Daphne A. Haas‐Kogan,Xiao-Dong Yang,Ethan G. Geier,Eugene Chen,Kathy Giacomini,Brian Weiss,Susan L. Cohn,M. Meaghan Granger,Gregory A. Yanik,Randall A. Hawkins,Jesse Courtier,Hollie Jackson,Fariba Goodarzian,Hiroyuki Shimada,Scarlett Czarnecki,Denice Tsao‐Wei,Judith G. Villablanca,Araz Marachelian,Katherine K. Matthay
标识
DOI:10.1158/1078-0432.ccr-14-3240
摘要
Abstract Purpose: 131I-metaiodobenzylguanidine (MIBG) is a radiopharmaceutical with activity in neuroblastoma. Vorinostat is a histone deacetylase inhibitor that has radiosensitizing properties. The goal of this phase I study was to determine the MTDs of vorinostat and MIBG in combination. Experimental Design: Patients ≤ 30 years with relapsed/refractory MIBG-avid neuroblastoma were eligible. Patients received oral vorinostat (dose levels 180 and 230 mg/m2) daily days 1 to 14. MIBG (dose levels 8, 12, 15, and 18 mCi/kg) was given on day 3 and peripheral blood stem cells on day 17. Alternating dose escalation of vorinostat and MIBG was performed using a 3+3 design. Results: Twenty-seven patients enrolled to six dose levels, with 23 evaluable for dose escalation. No dose-limiting toxicities (DLT) were seen in the first three dose levels. At dose level 4 (15 mCi/kg MIBG/230 mg/m2 vorinostat), 1 of 6 patients had DLT with grade 4 hypokalemia. At dose level 5 (18 mCi/kg MIBG/230 mg/m2 vorinostat), 2 patients had dose-limiting bleeding (one grade 3 and one grade 5). At dose level 5a (18 mCi/kg MIBG/180 mg/m2 vorinostat), 0 of 6 patients had DLT. The most common toxicities were neutropenia and thrombocytopenia. The response rate was 12% across all dose levels and 17% at dose level 5a. Histone acetylation increased from baseline in peripheral blood mononuclear cells collected on days 3 and 12 to 14. Conclusions: Vorinostat at 180 mg/m2/dose is tolerable with 18 mCi/kg MIBG. A phase II trial comparing this regimen to single-agent MIBG is ongoing. Clin Cancer Res; 21(12); 2715–21. ©2015 AACR.
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