Phase I and pharmacologic study of high doses of the topoisomerase I inhibitor topotecan with granulocyte colony-stimulating factor in patients with solid tumors

E. K. Rowinsky, L. B. Grochow, S. E. Sartorius, M. K. Bowling, Scott H Kaufmann, D. Peereboom, R. C. Donehower

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Purpose: To evaluate the feasibility of escalating doses of the topoisomerase I (topo I) inhibitor topotecan (TPT) with granulocyte colony- stimulating factor (G-CSF) in minimally pretreated adults with solid tumors and to study whether G-CSF scheduling variably affects the ability to escalate TPT doses. Materials and Methods: Thirty-six patients received 121 courses of TPT as a 30-minute infusion daily for 5 days every 3 weeks at doses that ranged from 2.0 to 4.2 mg/m2/d. G-CSF 5 μg/kg/d subcutaneously (SC) was initiated concurrently with TPT (starting on day 1). Because the concurrent administration of TPT and G-CSF resulted in severe myelosuppression at the lowest TPT dose level, an alternate posttreatment G- CSF schedule in which G-CSF dosing began after TPT (starting on day 6) was subsequently evaluated. Plasma sampling was performed to characterize the pharmacologic behavior of high-dose TPT and to determine whether G-CSF altered the pharmacokinetic profile of TPT. Results: Severe myelosuppression precluded the administration of TPT at the first dose, 2.0 mg/m2/d, with G- CSF on the concurrent schedule. However, dose escalation of TPT with G-CSF on a posttreatment schedule proceeded to 4.2 mg/m2/d. The dose-limiting toxicities (DLTs) were thrombocytopenia and neutropenia. One partial response was noted in a patient with colorectal carcinoma refractory to fluoropyrimidines. Pharmacokinetics were linear within the dosing range of 2.0 to 3.5 mg/m2/d, but TPT clearance was lower at the 4.2-mg/m2/d dose level. At 3.5 mg/m2/d, which is the maximum-tolerated dose (MTD) and recommended dose for subsequent-phase studies of TPT with G-CSF, the area under the concentration-versus-time curves (AUCs) for total TPT and lactone averaged 2.2- and 2.3-fold higher, respectively, than the AUCs achieved at the lowest TPT dose, 2.0 mg/m2/d. The pharmacologic behavior of high-dose TPT was not significantly altered by the scheduling of G-CSF. Conclusion: G- CSF administered after 5 daily 30-minute infusions of TPT permits a 2.3-fold dose escalation of TPT above the MTD in solid-tumor patients, whereas concurrent therapy with G-CSF and TPT results in severe myelosuppression.

Original languageEnglish (US)
Pages (from-to)1224-1235
Number of pages12
JournalJournal of Clinical Oncology
Issue number4
StatePublished - Apr 1996
Externally publishedYes


ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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