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[Abstract]

PURPOSE:

(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.

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. 

©2015 American Association for Cancer Research.

[Author information]

DuBois SG1, Groshen S2, Park JR3, Haas-Kogan DA4, Yang X4, Geier E5, Chen E5, Giacomini K5, Weiss B6, Cohn SL7, Granger MM8, Yanik GA9, Hawkins R10, Courtier J10, Jackson H11, Goodarzian F11, Shimada H12, Czarnecki S13, Tsao-Wei D2, Villablanca JG13, Marachelian A13, Matthay KK14.

1 Department of Pediatrics, University of California San Francisco, San Francisco, California. duboiss@peds.ucsf.edu.

2 Department of Preventive Medicine, USC Keck School of Medicine and Children's Hospital Los Angeles, Los Angeles, California.

3 Department of Pediatrics, University of Washington School of Medicine, Seattle, Washington.

4 Department of Radiation Oncology, University of California San Francisco, San Francisco, California.

5 Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California.

6 Department of Pediatrics, Cincinnati Children's Medical Center, Cincinnati, Ohio.

7 Department of Pediatrics, University of Chicago School of Medicine, Chicago, Illinois.

8 Department of Pediatrics, Cook Children's Hospital, Fort Worth, Texas.

9 Department of Pediatrics, University of Michigan Medical School, Ann Arbor, Michigan.

10 Department of Radiology, University of California San Francisco, San Francisco, California.

11 Department of Radiology, USC Keck School of Medicine and Children's Hospital Los Angeles, Los Angeles, California.

12 Department of Pathology, USC Keck School of Medicine and Children's Hospital Los Angeles, Los Angeles, California.

13 Department of Pediatrics, USC Keck School of Medicine and Children's Hospital Los Angeles, Los Angeles, California.

14 Department of Pediatrics, University of California San Francisco, San Francisco, California.