title: Phase I Study of Vorinostat as a Radiation Sensitizer with 131I-Metaiodobenzylguanidine (131I-MIBG) for Patients with Relapsed or Refractory Neuroblastoma.
abstract: OBJECTIVE
  (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.
  
  
  METHODS
  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.
authors.affiliation: Department of Pediatrics, University of California San Francisco, San Francisco, California. duboiss@peds.ucsf.edu.
authors.forename: Steven G
authors.initials: SG
authors.lastname: DuBois
authors.affiliation: Department of Preventive Medicine, USC Keck School of Medicine and Children's Hospital Los Angeles, Los Angeles, California.
authors.forename: Susan
authors.initials: S
authors.lastname: Groshen
authors.affiliation: Department of Pediatrics, University of Washington School of Medicine, Seattle, Washington.
authors.forename: Julie R
authors.initials: JR
authors.lastname: Park
authors.affiliation: Department of Radiation Oncology, University of California San Francisco, San Francisco, California.
authors.forename: Daphne A
authors.initials: DA
authors.lastname: Haas-Kogan
authors.affiliation: Department of Radiation Oncology, University of California San Francisco, San Francisco, California.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California.
authors.forename: Ethan
authors.initials: E
authors.lastname: Geier
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California.
authors.forename: Eugene
authors.initials: E
authors.lastname: Chen
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California.
authors.forename: Kathy
authors.initials: K
authors.lastname: Giacomini
authors.affiliation: Department of Pediatrics, Cincinnati Children's Medical Center, Cincinnati, Ohio.
authors.forename: Brian
authors.initials: B
authors.lastname: Weiss
authors.affiliation: Department of Pediatrics, University of Chicago School of Medicine, Chicago, Illinois.
authors.forename: Susan L
authors.initials: SL
authors.lastname: Cohn
authors.affiliation: Department of Pediatrics, Cook Children's Hospital, Fort Worth, Texas.
authors.forename: M Meaghan
authors.initials: MM
authors.lastname: Granger
authors.affiliation: Department of Pediatrics, University of Michigan Medical School, Ann Arbor, Michigan.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Yanik
authors.affiliation: Department of Radiology, University of California San Francisco, San Francisco, California.
authors.forename: Randall
authors.initials: R
authors.lastname: Hawkins
authors.affiliation: Department of Radiology, University of California San Francisco, San Francisco, California.
authors.forename: Jesse
authors.initials: J
authors.lastname: Courtier
authors.affiliation: Department of Radiology, USC Keck School of Medicine and Children's Hospital Los Angeles, Los Angeles, California.
authors.forename: Hollie
authors.initials: H
authors.lastname: Jackson
authors.affiliation: Department of Radiology, USC Keck School of Medicine and Children's Hospital Los Angeles, Los Angeles, California.
authors.forename: Fariba
authors.initials: F
authors.lastname: Goodarzian
authors.affiliation: Department of Pathology, USC Keck School of Medicine and Children's Hospital Los Angeles, Los Angeles, California.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Shimada
authors.affiliation: Department of Pediatrics, USC Keck School of Medicine and Children's Hospital Los Angeles, Los Angeles, California.
authors.forename: Scarlett
authors.initials: S
authors.lastname: Czarnecki
authors.affiliation: Department of Preventive Medicine, USC Keck School of Medicine and Children's Hospital Los Angeles, Los Angeles, California.
authors.forename: Denice
authors.initials: D
authors.lastname: Tsao-Wei
authors.affiliation: Department of Pediatrics, USC Keck School of Medicine and Children's Hospital Los Angeles, Los Angeles, California.
authors.forename: Judith G
authors.initials: JG
authors.lastname: Villablanca
authors.affiliation: Department of Pediatrics, USC Keck School of Medicine and Children's Hospital Los Angeles, Los Angeles, California.
authors.forename: Araz
authors.initials: A
authors.lastname: Marachelian
authors.affiliation: Department of Pediatrics, University of California San Francisco, San Francisco, California.
authors.forename: Katherine K
authors.initials: KK
authors.lastname: Matthay
mesh_terms: D019797:3-Iodobenzylguanidine / Q000008:administration & dosage*; D000107:Acetylation; D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D002675:Child, Preschool; D016903:Drug Monitoring; D005260:Female; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D007457:Iodine Radioisotopes / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D009447:Neuroblastoma / Q000473:pathology* / Q000628:therapy*; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology / Q000627:therapeutic use*; D016896:Treatment Outcome; D000077337:Vorinostat; D055815:Young Adult
chemical_list: D006657:Histones; D006877:Hydroxamic Acids; D007457:Iodine Radioisotopes; D050484:Norepinephrine Plasma Membrane Transport Proteins; D011838:Radiation-Sensitizing Agents; C493227:SLC6A2 protein, human; D019797:3-Iodobenzylguanidine; D000077337:Vorinostat