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

• Published in: Clinical cancer research 2015-06, Vol.21 (12), p.2715-2721
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: 3-Iodobenzylguanidine - administration & dosage; Acetylation; Adolescent; Adult; Aged; Child; Child, Preschool; Drug Monitoring; Female; Histones - metabolism; Humans; Hydroxamic Acids - pharmacology; Hydroxamic Acids - therapeutic use; Iodine Radioisotopes - pharmacology; Iodine Radioisotopes - therapeutic use; Male; Middle Aged; Neoplasm Recurrence, Local; Neuroblastoma - pathology; Neuroblastoma - therapy; Norepinephrine Plasma Membrane Transport Proteins - genetics; Norepinephrine Plasma Membrane Transport Proteins - metabolism; Radiation-Sensitizing Agents - pharmacology; Radiation-Sensitizing Agents - therapeutic use; Treatment Outcome; Young Adult
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-14-3240

(131)I-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. 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. 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. 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.