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Anticancer Drugs. 2006 Jun;17(5):571-9.

Phase I trial of continuous infusion 9-aminocamptothecin in patients with advanced solid tumors: 21-day infusion is an active well-tolerated regimen.

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Division of Medical Oncology, Department of Medicine, Kaplan Comprehensive Cancer Center, New York University School of Medicine, New York, USA.


This study's objectives were to determine the maximum tolerated dose (MTD) of 9-aminocamptothecin (9-AC), given as a prolonged continuous infusion (CI) for 7-21 days, when formulated in dimethylacetamide/polyethylene glycol 400 (DMA) and then later as a colloidal dispersion (CD), and to determine the steady-state pharmacokinetics of 9-AC. Patients with solid tumors refractory to standard therapy were enrolled on this study. Total dose/cycle of 9-AC/DMA was initially escalated by duration (7-21 days), while keeping the dose rate constant at 6.2 microg/m/h (1.04-3.12 mg/m/4-week cycle). Then, the dose rate was escalated from 6.2 to 21.1 microg/m/h (3.12-10.6 mg/m/4-week cycle) while keeping the infusion duration constant at 21 days. CD formulation was escalated from 14.1 to 25 microg/m/h (7.11-12.60 mg/m/4-week cycle) while keeping the infusion duration constant at 21 days and then escalated from 28.1 to 37.5 microg/m/h (9.44-12.60 mg/m/3-week cycle) while keeping the infusion duration constant at 14 days. Sixty-two patients were evaluable for toxicity; 61 received prior chemotherapy (median 3 regimens/patient). No consistent dose-limiting toxicity (DLT) was encountered with the DMA formulation until dose level 10.60 mg/m/cycle, when two patients experienced DLTs. With the 21-day CD formulation, the MTD was 12.60 mg/m/cycle with three DLTs out of five patients. When 9-AC was given on the 14-day schedule, DLT was seen at 9.44, 11.20 and 12.60 mg/m/cycle, with consistent DLT at the two highest dose levels. All DLTs for both formulations were grade 4 hematologic toxicities (neutropenia and/or thrombocytopenia), while non-hematologic toxicities were relatively mild (including gastrointestinal toxicities and fatigue). One patient with ovarian cancer had a complete response and three had partial responses (PRs). One patient each with non-Hodgkin's lymphoma and cancer of unknown primary had a PR. Pharmacokinetic studies of both formulations of 9-AC revealed a linear relationship between increasing plasma 9-AC lactone concentration and dose. The median plasma 9-AC lactone concentration for 9-AC/CD was approximately twice that achieved by 9-AC/DMA for the same dose level. Both 9-AC formulations, given as a 21-day CI, were well tolerated with dose-limiting myelosupression at the MTD. This dose intensity exceeds that of other 9-AC phase I/II schedules. The recommended phase II dose (RPTD) is 9.42 mg/m/4-week cycle, given as a 21-day infusion. The 14-day schedule of 9-AC/CD was equally myelosuppressive with the RPTD of 9.44 mg/m/3-week cycle, although two heavily pre-treated patients (one with pelvic radiotherapy) could not tolerate this dose. Objective responses were observed in six out of 57 heavily pre-treated patients, most of which had ovarian cancer.

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