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

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

Journal: Clinical cancer research : an official journal of the American Association for Cancer Research 2016;21(12):2715-21

PMID: 25695691

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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.

Address: Department of Pediatrics, University of California San Francisco, San Francisco, California. [email protected].; Department of Preventive Medicine, USC Keck School of Medicine and Children's Hospital Los Angeles, Los Angeles, California.; Department of Pediatrics, University of Washington School of Medicine, Seattle, Washington.; Department of Radiation Oncology, University of California San Francisco, San Francisco, California.; Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California.; Department of Pediatrics, Cincinnati Children's Medical Center, Cincinnati, Ohio.; Department of Pediatrics, University of Chicago School of Medicine, Chicago, Illinois.; Department of Pediatrics, Cook Children's Hospital, Fort Worth, Texas.; Department of Pediatrics, University of Michigan Medical School, Ann Arbor, Michigan.; Department of Radiology, University of California San Francisco, San Francisco, California.; Department of Radiology, USC Keck School of Medicine and Children's Hospital Los Angeles, Los Angeles, California.; Department of Pathology, USC Keck School of Medicine and Children's Hospital Los Angeles, Los Angeles, California.; Department of Pediatrics, USC Keck School of Medicine and Children's Hospital Los Angeles, Los Angeles, California.; Department of Pediatrics, University of California San Francisco, San Francisco, California.

DOI: 10.1158/1078-0432.CCR-14-3240

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MeSH Terms: 3-Iodobenzylguanidine, Acetylation, Adolescent, Adult, Aged, Child, Child, Preschool, Drug Monitoring, Female, Histones, Humans, Hydroxamic Acids, Iodine Radioisotopes, Male, Middle Aged, Neoplasm Recurrence, Local, Neuroblastoma, Norepinephrine Plasma Membrane Transport Proteins, Radiation-Sensitizing Agents, Treatment Outcome, Vorinostat, Young Adult