Abstract LB-179: Phase I trial of relapsed neuroblastoma with DFMO alone and in combination with etoposide.
Authors: Sholler Giselle L. , Gerner Eugene W. , Bergendahl Genevieve , LaFleur Bonnie J. , VanderWerff Alyssa , Ashikaga Takamaru , Ferguson William , Roberts William , Eslin Don , Kaplan Joel , Kraveka Jacqueline M. , Mitchell Deanna , Neville Kathleen , Wada Randal , Parikh Nehal , Sender Leonard , Higgins Timothy , Bachmann Andre 
Published: August 2014

Abstract
Background: Neuroblastoma (NB) is the most common extracranial solid tumor in children. There is no curative treatment for children with relapsed NB, and the 5-year survival rate is &lt;10%. These more aggressive forms of NB respond poorly to chemotherapeutic approaches, and there is a need for agents with novel mechanisms of action. Ornithine decarboxylase (ODC), a gene encoding for the ODC enzyme that is pivotal in polyamine biosynthesis, has been shown to be upregulated in NB. High polyamine content and elevated ODC activities have been associated with poor prognosis in NB. Suppression of polyamines in NB has been shown in preclinical studies to be effective to reduce tumor. Methods: The primary aim of this phase I study was to determine the safety and maximum tolerated dose (MTD) of DFMO as a single agent and in combination with etoposide in pediatric patients with refractory or recurrent NB. The secondary aims were to evaluate the pharmacokinetics of DFMO, the treatment response and biological correlates in urine. A dose escalation trial of daily oral DFMO for one 21-day cycle, followed by four 21 day cycles of DFMO and oral etoposide was completed. Response was evaluated by CT or MRI and MIBG imaging. Measurement of urinary catecholamines and bone marrow disease were used to determine a clinical response. Urinary polyamines were measured at day 1 of each cycle. Results: Twenty-one patients were enrolled between Mar 2010 and Oct 2012. The median age was 10 years old, with a range of 1-17 years old. Patients were enrolled at one of four escalating doses (500mg/m2-1500mg/m2 BID). No dose-limiting toxicities (DLTs) or serious adverse events (SAEs) were seen. The biological effect of urinary polyamine normalization was seen at these dose levels, therefore this study did not escalate to a final MTD. While a phase I study is not powered to evaluate anti-tumor efficacy, seventeen patients with NB were evaluable. Of these; 15 had stable disease and 2 had progressive disease. Of note, 1 subject obtained a complete response in their bone marrow while four patients have been on study progression free for over a year. Spot urine samples from patients had measurable levels of polyamines monoacetylspermidine (MASpd) and diacetylspermine (DASpm). Treatment was associated with decreased urinary MASpd over the first cycle for all patients. Patients with disease progression during the first 3-months of treatment had average increases in urinary DASpm and histamine over this time, while this parameter decreased over time in those patients exhibiting 3-month stabilization of disease. Conclusion: The biologically active dose of DFMO is 500-1500 mg/m2 BID and is well tolerated by pediatric patients. Prolonged stabilization of disease was seen with clinical benefit in greater than 50% of patients. Urine polyamines appear to be a marker for response to DFMO therapy. This biological correlate will be further explored in a Phase II study currently underway.
Citation Format: Giselle L. Sholler, Eugene W. Gerner, Genevieve Bergendahl, Bonnie J. LaFleur, Alyssa VanderWerff, Takamaru Ashikaga, William Ferguson, William Roberts, Don Eslin, Joel Kaplan, Jacqueline M. Kraveka, Deanna Mitchell, Kathleen Neville, Randal Wada, Nehal Parikh, Leonard Sender, Timothy Higgins, Andre Bachmann. Phase I trial of relapsed neuroblastoma with DFMO alone and in combination with etoposide. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-179. doi:10.1158/1538-7445.AM2013-LB-179