Sequential oral 9-nitrocamptothecin and etoposide: A pharmacodynamic- and pharmacokinetic-based phase I trial

George R. Simon, Richard M. Lush, Jana Gump, Leticia Tetteh, Charles Williams, Alan Cantor, Scott Antonia, Christopher Garrett, Caio Rocha-Lima, Mayer Fishman, Daniel M. Sullivan, Pamela N. Munster

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

Purpose: Resistance to topoisomerase (topo) I inhibitors has been related to down-regulation of nuclear target enzyme, whereas sensitization to topo II inhibitors may result from induction of topo II by topo I inhibitors. Here, we evaluated a sequence-specific administration of a topo I inhibitor followed by a topo II inhibitor. Experimental Design: Twenty-five patients with advanced or metastatic malignancies were treated with increasing doses (0.75, 1.0, 1.25, 1.5, 1.75, or 2.0 mg/m2) of 9-nitrocamptothecin (9-NC) on days 1 to 3, followed by etoposide (100 or 150 mg/d) on days 4 and 5. At the maximally tolerated dose, 20 additional patients were enrolled. The median age was 60 years (range, 40-84 years). Endpoints included pharmacokinetic analyses of 9-NC and etoposide, and treatment-induced modulations of topo I and II expression in peripheral blood mononuclear cells. Results: Neutropenia, thrombocytopenia, nausea, vomiting, diarrhea, and fatigue were dose-limiting toxicities and occurred in six patients. Despite a median number of four prior regimens (range 1-12), 2 (4%) patients had an objective response and 13 (29%) patients had stable disease. In contrast to the expected modulation in topo I and IIα levels, we observed a decrease in topo IIα levels, whereas topo I levels were not significantly altered by 9-NC treatment. Conclusions: Sequence-specific administration of 9-NC and etoposide is tolerable and active. However, peripheral blood mononuclear cells may not be a predictive biological surrogate for drug-induced modulation of topo levels in tumor tissues and should be further explored in larger studies.

Original languageEnglish (US)
Pages (from-to)2130-2137
Number of pages8
JournalMolecular cancer therapeutics
Volume5
Issue number8
DOIs
StatePublished - Aug 1 2006

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Simon, G. R., Lush, R. M., Gump, J., Tetteh, L., Williams, C., Cantor, A., Antonia, S., Garrett, C., Rocha-Lima, C., Fishman, M., Sullivan, D. M., & Munster, P. N. (2006). Sequential oral 9-nitrocamptothecin and etoposide: A pharmacodynamic- and pharmacokinetic-based phase I trial. Molecular cancer therapeutics, 5(8), 2130-2137. https://doi.org/10.1158/1535-7163.MCT-06-0034