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

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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
Pages (from-to)2130-2137
Number of pages8
JournalMolecular Cancer Therapeutics
Volume5
Issue number8
DOIs
StatePublished - Aug 1 2006

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Etoposide
Type II DNA Topoisomerase
Topoisomerase I Inhibitors
Pharmacokinetics
Type I DNA Topoisomerase
Topoisomerase II Inhibitors
Blood Cells
Maximum Tolerated Dose
Neutropenia
Thrombocytopenia
Nausea
Vomiting
Fatigue
Diarrhea
Neoplasms
Research Design
Down-Regulation
rubitecan
Enzymes
Therapeutics

ASJC Scopus subject areas

  • Oncology
  • Drug Discovery
  • Pharmacology

Cite this

Simon, G. R., Lush, R. M., Gump, J., Tetteh, L., Williams, C., Cantor, A., ... 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

Sequential oral 9-nitrocamptothecin and etoposide : A pharmacodynamic- and pharmacokinetic-based phase I trial. / Simon, George R.; Lush, Richard M.; Gump, Jana; Tetteh, Leticia; Williams, Charles; Cantor, Alan; Antonia, Scott; Garrett, Christopher; Rocha-Lima, Caio; Fishman, Mayer; Sullivan, Daniel M.; Munster, Pamela N.

In: Molecular Cancer Therapeutics, Vol. 5, No. 8, 01.08.2006, p. 2130-2137.

Research output: Contribution to journalArticle

Simon, GR, Lush, RM, Gump, J, Tetteh, L, Williams, C, Cantor, A, Antonia, S, Garrett, C, Rocha-Lima, C, Fishman, M, Sullivan, DM & Munster, PN 2006, 'Sequential oral 9-nitrocamptothecin and etoposide: A pharmacodynamic- and pharmacokinetic-based phase I trial', Molecular Cancer Therapeutics, vol. 5, no. 8, pp. 2130-2137. https://doi.org/10.1158/1535-7163.MCT-06-0034
Simon, George R. ; Lush, Richard M. ; Gump, Jana ; Tetteh, Leticia ; Williams, Charles ; Cantor, Alan ; Antonia, Scott ; Garrett, Christopher ; Rocha-Lima, Caio ; Fishman, Mayer ; Sullivan, Daniel M. ; Munster, Pamela N. / Sequential oral 9-nitrocamptothecin and etoposide : A pharmacodynamic- and pharmacokinetic-based phase I trial. In: Molecular Cancer Therapeutics. 2006 ; Vol. 5, No. 8. pp. 2130-2137.
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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.",
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AU - Antonia, Scott

AU - Garrett, Christopher

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AU - Sullivan, Daniel M.

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N2 - 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.

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