title: Phase I and pharmacologic study of i.p. 9-aminocamptothecin given as six fractions over 14 days.
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/m(2) 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/m(2) 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/m(2)/cycle administered in a schedule of six divided fractions is suitable for further evaluation against tumors involving primarily the peritoneal cavity.
authors.affiliation: NYU Cancer Institute, Division of Medical Oncology, New York University School of Medicine, New York, NY 10016, USA. muggif01@gcrc.med.nyu.edu
authors.forename: Franco M
authors.initials: FM
authors.lastname: Muggia
authors.forename: Leonard
authors.initials: L
authors.lastname: Liebes
authors.forename: Maitreyee
authors.initials: M
authors.lastname: Hazarika
authors.forename: Scott
authors.initials: S
authors.lastname: Wadler
authors.forename: Anne
authors.initials: A
authors.lastname: Hamilton
authors.forename: Gila
authors.initials: G
authors.lastname: Hornreich
authors.forename: Joan
authors.initials: J
authors.lastname: Sorich
authors.forename: Chung
authors.initials: C
authors.lastname: Chiang
authors.forename: Elliot
authors.initials: E
authors.lastname: Newman
authors.forename: Milan
authors.initials: M
authors.lastname: Potmesil
authors.forename: Howard
authors.initials: H
authors.lastname: Hochster
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D002166:Camptothecin / Q000008:administration & dosage* / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*
chemical_list: D000970:Antineoplastic Agents; C080125:9-aminocamptothecin; D002166:Camptothecin