Phase I and pharmacologic study of i.p. 9-aminocamptothecin given as six fractions over 14 days

Franco M. Muggia, Leonard Liebes, Maitreyee Hazarika, Scott Wadlere, Anne Hamilton, Gila Hornreich, Joan Sorich, Chung Chiang, Elliot Newman, Milan Potmesil, Howard Hochster

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11 Scopus citations

Abstract

We sought to define the tolerance of 9-amino-20(S)-camptothecin (9-AC) when given by the i.p. route to patients with cancer in the peritoneal cavity consisting of nodules that did not exceed 1 cm in maximum diameter. 9-AC was given in six fractions over 12 days, at doses ranging from 1.25 to 13.5 mg/m2 in cycles repeated every 28 days. Dose escalations after the first two dose levels took place in cohorts of three patients, with expansion of the dose level once a dose-limiting toxicity (DLT) was encountered. All patients had blood and i.p. pharmacokinetic (PK) analysis during cycle 1 of each dose level. Topoisomerase (Topo) I signal was serially measured in peripheral blood mononuclear cells (PBMCs) in blood and cells collected in i.p. cytologic washings. Twelve patients received 31 cycles of 9-AC. Tolerance to repeated i.p. drug administration was generally excellent. The DLT was neutropenia encountered at the highest dose level in two patients, whereas the dose of 9 mg/ m2 was well tolerated. The DLTs were associated with peak plasma levels ranging from 47 to 81 ng/ml and also depletion of Topo I in PBMCs. The i.p.:plasma AUC ratio (± SD) was 11.5 (±3.8). Two patients had objective evidence of clinical benefit and only one of seven patients deemed evaluable for response had progressive disease. We conclude that i.p. 9-AC demonstrates excellent local tolerance at a dose and schedule associated with evidence of systemic effects. A dose of 9 mg/m2/cycle administered in a schedule of six divided fractions is suitable for further evaluation against tumors involving primarily the peritoneal cavity.

Original languageEnglish (US)
Pages (from-to)819-825
Number of pages7
JournalAnti-Cancer Drugs
Volume13
Issue number8
DOIs
StatePublished - Sep 2002

All Science Journal Classification (ASJC) codes

  • Pharmacology (medical)
  • Oncology
  • Cancer Research
  • Pharmacology

Keywords

  • 9-Aminocamptothecin
  • Intraperitoneal
  • Topoisomerase I

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