Perlmutter Cancer Center

High risk Neuroblastoma (HR NB) remains a challenge in pediatric oncology, accounting for 15% of all pediatric cancer deaths. While most patients are able to attain remission, approximately 50% will relapse. Once relapse occurs, there is currently no curative treatment for these children, and the 5-year survival rate for these children is <10%. As such, new therapeutic approaches are needed to treat these children. Relapsed patients who are able to obtain a second remission are not eligible for relapse therapeutic trials since they have no evidence of disease and yet they are likely to relapse within 6 months-1year. Prevention of relapse is one such approach to improve outcome in these patients. The NMTRC recently conducted a phase II trial of DFMO in HR NB patients in complete remission which demonstrated a markedly decreased rate of relapse compared to historical controls. Patients in first CR who were enrolled at the end of upfront therapy had a 2-year EFS of 91%, and those enrolled in CR following treatment for relapsed or primary /refractory disease had a 2-year EFS of 48%. The current study will prospectively confirm these results while providing additional safety and pharmacokinetic data required for FDA approval of this medication.These more aggressive forms of NB respond poorly to conventional chemotherapeutic approaches, and therefore, there is a great need for development of antineoplastic agents with novel mechanisms of action. DFMO is an enzyme-activated inhibitor of ornithine decarboxylase (ODC), which is the rate-limiting enzyme for polyamine biosynthesis. Both high polyamine content and elevated ODC expression has been shown in NB as well as many other tumors, and high polyamine levels appear to promote several aspects of malignant behavior, therefore, suppression of polyamines in cancer cells is an effective means to reduce tumor cell proliferation. DFMO, through inhibition of ODC, decreases LIN28 and increases Let7 levels, reversing this important cancer stem cell pathway. In addition, specific polyamine inhibitors such as DFMO have been evaluated in adult clinical cancer trials and shown to prevent formation of polyps and colon cancer. DFMO will be evaluated in this pediatric NB trial as a preventative single agent therapy.