title: A Phase I Trial of DFMO Targeting Polyamine Addiction in Patients with Relapsed/Refractory Neuroblastoma.
abstract: BACKGROUND
  Neuroblastoma (NB) is the most common cancer in infancy and most frequent cause of death from extracranial solid tumors in children. Ornithine decarboxylase (ODC) expression is an independent indicator of poor prognosis in NB patients. This study investigated safety, response, pharmacokinetics, genetic and metabolic factors associated with ODC in a clinical trial of the ODC inhibitor difluoromethylornithine (DFMO) ± etoposide for patients with relapsed or refractory NB.
  
  
  RESULTS
  Twenty-one patients participated in a phase I study of daily oral DFMO alone for three weeks, followed by additional three-week cycles of DFMO plus daily oral etoposide. No dose limiting toxicities (DLTs) were identified in patients taking doses of DFMO between 500-1500 mg/m2 orally twice a day. DFMO pharmacokinetics, single nucleotide polymorphisms (SNPs) in the ODC gene and urinary levels of substrates for the tissue polyamine exporter were measured. Urinary polyamine levels varied among patients at baseline. Patients with the minor T-allele at rs2302616 of the ODC gene had higher baseline levels (p=0.02) of, and larger decreases in, total urinary polyamines during the first cycle of DFMO therapy (p=0.003) and had median progression free survival (PFS) that was over three times longer, compared to patients with the major G allele at this locus although this last result was not statistically significant (p=0.07). Six of 18 evaluable patients were progression free during the trial period with three patients continuing progression free at 663, 1559 and 1573 days after initiating treatment. Median progression-free survival was less among patients having increased urinary polyamines, especially diacetylspermine, although this result was not statistically significant (p=0.056).
  
  
  CONCLUSIONS
  DFMO doses of 500-1500 mg/m2/day are safe and well tolerated in children with relapsed NB. Children with the minor T allele at rs2302616 of the ODC gene with relapsed or refractory NB had higher levels of urinary polyamine markers and responded better to therapy containing DFMO, compared to those with the major G allele at this locus. These findings suggest that this patient subset may display dependence on polyamines and be uniquely susceptible to therapies targeting this pathway.
  
  
  BACKGROUND
  Clinicaltrials.gov NCT#01059071.
authors.affiliation: Helen DeVos Children's Hospital, Grand Rapids, Michigan, United States of America; College of Human Medicine, Michigan State University, Grand Rapids, Michigan, United States of America.
authors.forename: Giselle L
authors.initials: GL
authors.lastname: Saulnier Sholler
authors.affiliation: Cancer Prevention Pharmaceuticals, Tucson, Arizona, United States of America.
authors.forename: Eugene W
authors.initials: EW
authors.lastname: Gerner
authors.affiliation: Helen DeVos Children's Hospital, Grand Rapids, Michigan, United States of America.
authors.forename: Genevieve
authors.initials: G
authors.lastname: Bergendahl
authors.affiliation: Cancer Prevention Pharmaceuticals, Tucson, Arizona, United States of America.
authors.forename: Robert B
authors.initials: RB
authors.lastname: MacArthur
authors.affiliation: Helen DeVos Children's Hospital, Grand Rapids, Michigan, United States of America.
authors.forename: Alyssa
authors.initials: A
authors.lastname: VanderWerff
authors.affiliation: Medical Biostatistics, University of Vermont, Burlington, Vermont, United States of America.
authors.forename: Takamaru
authors.initials: T
authors.lastname: Ashikaga
authors.affiliation: Department of Microbiology and Molecular Genetics, University of Vermont College of Medicine, Burlington, Vermont, United States of America.
authors.forename: Jeffrey P
authors.initials: JP
authors.lastname: Bond
authors.affiliation: Cardinal Glennon Children's Hospital, St. Louis, Missouri, United States of America.
authors.forename: William
authors.initials: W
authors.lastname: Ferguson
authors.affiliation: University of California San Diego School of Medicine and Rady Children's Hospital, San Diego, California, United States of America.
authors.forename: William
authors.initials: W
authors.lastname: Roberts
authors.affiliation: Kapiolani Medical Center for Women and Children, Honolulu, Hawaii, United States of America.
authors.forename: Randal K
authors.initials: RK
authors.lastname: Wada
authors.affiliation: Arnold Palmer Hospital for Children, Orlando, Florida, United States of America.
authors.forename: Don
authors.initials: D
authors.lastname: Eslin
authors.affiliation: Medical University of South Carolina, Charleston, South Carolina, United States of America.
authors.forename: Jacqueline M
authors.initials: JM
authors.lastname: Kraveka
authors.affiliation: Levine Children's Hospital, Charlotte, North Carolina, United States of America.
authors.forename: Joel
authors.initials: J
authors.lastname: Kaplan
authors.affiliation: Helen DeVos Children's Hospital, Grand Rapids, Michigan, United States of America.
authors.forename: Deanna
authors.initials: D
authors.lastname: Mitchell
authors.affiliation: Connecticut Children's Medical Center, Hartford, Connecticut, United States of America.
authors.forename: Nehal S
authors.initials: NS
authors.lastname: Parikh
authors.affiliation: Children's Mercy Hospitals and Clinics, Kansas City, Missouri, United States of America.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Neville
authors.affiliation: Children's Hospital of Orange County, Orange, California, United States of America.
authors.forename: Leonard
authors.initials: L
authors.lastname: Sender
authors.affiliation: Medical Biostatistics, University of Vermont, Burlington, Vermont, United States of America.
authors.forename: Timothy
authors.initials: T
authors.lastname: Higgins
authors.affiliation: Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
authors.forename: Masao
authors.initials: M
authors.lastname: Kawakita
authors.affiliation: Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Hiramatsu
authors.affiliation: Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
authors.forename: Shun-Suke
authors.initials: SS
authors.lastname: Moriya
authors.affiliation: College of Human Medicine, Michigan State University, Grand Rapids, Michigan, United States of America; University of Hawaii at Hilo, The Daniel K. Inouye College of Pharmacy, Hilo, Hawaii, United States of America.
authors.forename: André S
authors.initials: AS
authors.lastname: Bachmann
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D000518:Eflornithine / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D005047:Etoposide / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D009447:Neuroblastoma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000652:urine; D009955:Ornithine Decarboxylase / Q000378:metabolism; D065108:Ornithine Decarboxylase Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D010641:Phenotype; D011073:Polyamines / Q000378:metabolism* / Q000652:urine; D012008:Recurrence; D012449:Safety; D016896:Treatment Outcome
chemical_list: D065108:Ornithine Decarboxylase Inhibitors; D011073:Polyamines; D005047:Etoposide; D009955:Ornithine Decarboxylase; D000518:Eflornithine