9 research outputs found
A Phase I Trial of DFMO Targeting Polyamine Addiction in Patients with Relapsed/Refractory Neuroblastoma
<div><p>Background</p><p>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.</p><p>Methods and Findings</p><p>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).</p><p>Conclusions</p><p>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.</p><p>Trial Registration</p><p>Clinicaltrials.gov <a href="https://clinicaltrials.gov/ct2/show/NCT01059071" target="_blank">NCT#01059071</a></p></div
Rank-ordered PFS by DFMO dose, ODC genotype and urinary polyamines.
<p>*PF = progression free, PD = progressive disease</p><p>2<sup>nd</sup> Leukemia = secondary leukemia</p><p>**Substrates for the tissue polyamine exporter SLC3A2 include the sum of putrescine, N1AcSpd, N8AcSpd and DAS; D1C1 = day 1, cycle 1, D8C1 = day 8 cycle 1</p><p>***NA = samples not available</p><p>Rank-ordered PFS by DFMO dose, ODC genotype and urinary polyamines.</p
NMTRC002 CONSORT Flow Diagram- modified for non-randomized trial design.
<p>NMTRC002 CONSORT Flow Diagram- modified for non-randomized trial design.</p
Characteristics of patients enrolled in NMTRC 002.
<p>Characteristics of patients enrolled in NMTRC 002.</p
Serum DFMO concentration versus time measurements for three patients receiving 750 mg/m<sup>2</sup> PO BID during cycle 1 of therapy.
<p>Serum DFMO concentration versus time measurements for three patients receiving 750 mg/m<sup>2</sup> PO BID during cycle 1 of therapy.</p
Progression free survival (PFS) and overall survival (OS) rates in patients enrolled in NMTRC 002 (N = 21).
<p>The number of patients shown at risk for disease progression (PFS) or death (OS) is shown in the figure.</p
Flowchart of NMTRC 002—Safety Study for Refractory or Relapsed Neuroblastoma With DFMO Alone and in Combination With Etoposide.
<p>Flowchart of NMTRC 002—Safety Study for Refractory or Relapsed Neuroblastoma With DFMO Alone and in Combination With Etoposide.</p
Association of ODC genotypes with polyamine markers and treatment responses.
<p>Association of ODC genotypes with polyamine markers and treatment responses.</p
Urinary polyamine metabolites from patients at baseline and during first two weeks of DFMO therapy.
<p>C1D1 = cycle 1 day 1 (defined as baseline)</p><p>C1D8 = cycle 1 day 8 after starting DFMO on day1</p><p>C1D15 = cycle 1 day 15 after starting DFMO on day 1</p><p>*Determined by Friedman two-way analysis of variance</p><p>**Not significant</p><p>Urinary polyamine metabolites from patients at baseline and during first two weeks of DFMO therapy.</p