A Phase I Trial of DFMO Targeting Polyamine Addiction in Patients with Relapsed/Refractory Neuroblastoma.
Publication/Presentation Date
1-1-2015
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.
METHODS AND FINDINGS: 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.
TRIAL REGISTRATION: Clinicaltrials.gov NCT#01059071.
Volume
10
Issue
5
First Page
0127246
Last Page
0127246
ISSN
1932-6203
Published In/Presented At
Saulnier Sholler, G. L., Gerner, E. W., Bergendahl, G., MacArthur, R. B., VanderWerff, A., Ashikaga, T., Bond, J. P., Ferguson, W., Roberts, W., Wada, R. K., Eslin, D., Kraveka, J. M., Kaplan, J., Mitchell, D., Parikh, N. S., Neville, K., Sender, L., Higgins, T., Kawakita, M., Hiramatsu, K., … Bachmann, A. S. (2015). A Phase I Trial of DFMO Targeting Polyamine Addiction in Patients with Relapsed/Refractory Neuroblastoma. PloS one, 10(5), e0127246. https://doi.org/10.1371/journal.pone.0127246
Disciplines
Medicine and Health Sciences | Pediatrics
PubMedID
26018967
Department(s)
Department of Pediatrics
Document Type
Article