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      A Phase I Trial of DFMO Targeting Polyamine Addiction in Patients with Relapsed/Refractory Neuroblastoma

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          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 500-1500mg/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

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          Most cited references 46

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          Recent advances in neuroblastoma.

           J Maris,  Anna Maris (2010)
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            Polyamines and cancer: old molecules, new understanding.

            The amino-acid-derived polyamines have long been associated with cell growth and cancer, and specific oncogenes and tumour-suppressor genes regulate polyamine metabolism. Inhibition of polyamine synthesis has proven to be generally ineffective as an anticancer strategy in clinical trials, but it is a potent cancer chemoprevention strategy in preclinical studies. Clinical trials, with well-defined goals, are now underway to evaluate the chemopreventive efficacy of inhibitors of polyamine synthesis in a range of tissues.
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              Nifurtimox-eflornithine combination therapy for second-stage African Trypanosoma brucei gambiense trypanosomiasis: a multicentre, randomised, phase III, non-inferiority trial.

              Human African trypanosomiasis (HAT; sleeping sickness) caused by Trypanosoma brucei gambiense is a fatal disease. Current treatment options for patients with second-stage disease are toxic, ineffective, or impractical. We assessed the efficacy and safety of nifurtimox-eflornithine combination therapy (NECT) for second-stage disease compared with the standard eflornithine regimen. A multicentre, randomised, open-label, active control, phase III, non-inferiority trial was done at four HAT treatment centres in the Republic of the Congo and the Democratic Republic of the Congo. Patients aged 15 years or older with confirmed second-stage T b gambiense infection were randomly assigned by computer-generated randomisation sequence to receive intravenous eflornithine (400 mg/kg per day, every 6 h; n=144) for 14 days or intravenous eflornithine (400 mg/kg per day, every 12 h) for 7 days with oral nifurtimox (15 mg/kg per day, every 8 h) for 10 days (NECT; n=143). The primary endpoint was cure (defined as absence of trypanosomes in body fluids and a leucocyte count
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                27 May 2015
                2015
                : 10
                : 5
                Affiliations
                [1 ]Helen DeVos Children’s Hospital, Grand Rapids, Michigan, United States of America
                [2 ]College of Human Medicine, Michigan State University, Grand Rapids, Michigan, United States of America
                [3 ]Cancer Prevention Pharmaceuticals, Tucson, Arizona, United States of America
                [4 ]Medical Biostatistics, University of Vermont, Burlington, Vermont, United States of America
                [5 ]Department of Microbiology and Molecular Genetics, University of Vermont College of Medicine, Burlington, Vermont, United States of America
                [6 ]Cardinal Glennon Children's Hospital, St. Louis, Missouri, United States of America
                [7 ]University of California San Diego School of Medicine and Rady Children's Hospital, San Diego, California, United States of America
                [8 ]Kapiolani Medical Center for Women and Children, Honolulu, Hawaii, United States of America
                [9 ]Arnold Palmer Hospital for Children, Orlando, Florida, United States of America
                [10 ]Medical University of South Carolina, Charleston, South Carolina, United States of America
                [11 ]Levine Children's Hospital, Charlotte, North Carolina, United States of America
                [12 ]Connecticut Children's Medical Center, Hartford, Connecticut, United States of America
                [13 ]Children's Mercy Hospitals and Clinics, Kansas City, Missouri, United States of America
                [14 ]Children’s Hospital of Orange County, Orange, California, United States of America
                [15 ]Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
                [16 ]University of Hawaii at Hilo, The Daniel K. Inouye College of Pharmacy, Hilo, Hawaii, United States of America
                National Cancer Institute, UNITED STATES
                Author notes

                Competing Interests: The authors of this manuscript have the following competing interests: E.W.G. is a paid employee of Cancer Prevention Pharmaceuticals (CPP). He has an ownership interest in, and serves on the board of, CPP. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

                Conceived and designed the experiments: GS ASB GB EWG DE TA. Performed the experiments: GS EWG MK KH SM DE AV WF WR RW J. Kraveka J. Kaplan DM NP KN LS JB TH. Analyzed the data: GS ASB GB EWG MK RBM TA TH. Contributed reagents/materials/analysis tools: TA WF WR RW J. Kraveka J. Kaplan DM NP KN LS JB. Wrote the paper: GS ASB GB EWG DE AV WF WR RW J. Kraveka J. Kaplan DM NP KN LS MK SM KH JB TH.

                Article
                PONE-D-14-46586
                10.1371/journal.pone.0127246
                4446210
                26018967

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

                Page count
                Figures: 5, Tables: 6, Pages: 20
                Product
                Funding
                The Neuroblastoma and Medulloblastoma Translational Research Consortium (NMTRC) supported this work in collaboration with Cancer Prevention Pharmaceuticals. This trial was funded by the Beat NB Foundation, Max’s Ring of Fire, Meryl and Charles Witmer Foundation, Owen Moscone Foundation and many other donations from the families of children with neuroblastoma. PD measurements were supported in part by NIH grants CA095060 (EWG PI) and CA123065 (EWG PI). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Custom metadata
                All relevant data are within the paper and its Supporting Information files.

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