Phase I Study of Vorinostat as a Radiation Sensitizer with I-131-Metaiodobenzylguanidine (I-131-MIBG) for Patients with Relapsed or Refractory Neuroblastoma

作者：DuBois Steven G^*; Groshen Susan; Park Julie R; Haas Kogan Daphne A; Yang Xiaodong; Geier Ethan; Chen Eugene; Giacomini Kathy; Weiss Brian; Cohn Susan L; Granger M Meaghan; Yanik Gregory A; Hawkins Randall; Courtier Jesse; Jackson Hollie; Goodarzian Fariba; Shimada Hiroyuki; Czarnecki Scarlett; Tsao Wei Denice; Villablanca Judith G; Marachelian Araz; Matthay Katherine K

来源：Clinical Cancer Research, 2015, 21(12): 2715-2721.

DOI：10.1158/1078-0432.CCR-14-3240

Purpose: I-131-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/m(2)) 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/m(2) vorinostat), 1 of 6 patients had DLT with grade 4 hypokalemia. At dose level 5 (18 mCi/kg MIBG/230 mg/m(2) vorinostat), 2 patients had dose-limiting bleeding (one grade 3 and one grade 5). At dose level 5a (18 mCi/kg MIBG/180 mg/m(2) 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/m(2)/dose is tolerable with 18 mCi/kg MIBG. A phase II trial comparing this regimen to single-agent MIBG is ongoing.

• 出版日期2015-6-15