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Phase I and Pharmacologic Study of Intermittently Administered 9-Nitrocamptothecin in Patients with Advanced Solid Tumors

¹ Program of Molecular Therapeutics and Drug Discovery and
² Biostatistics Facility, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, and
³ Department of Pharmaceutical Sciences, School of Pharmacy,
⁴ Division of Hematology/Oncology, Department of Medicine, School of Medicine, and
⁵ Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania

Purpose: 9-Nitrocamptothecin (9NC) is an oral camptothecin analogue currently administered at 1.5 mg/m²/day x 5 days/week in Phase III studies for pancreatic carcinoma. In an effort to increase the dose administered per day and determine whether the daily dose or number of days of treatment influence toxicity, we performed a Phase I study of 9NC using intermittent schedules of administration.

Experimental Design: On schedule A, 9NC was administered orally daily x 5 days for 2 weeks every 4 weeks (one cycle). On schedule B, 9NC was administered orally daily x 14 days every 4 weeks (one cycle). Dose levels were determined by adaptive dose finding. Serial blood samples were obtained on day 1 of each schedule for pharmacokinetic studies of 9NC and its 9-aminocamptothecin (9AC) metabolite, and lactone forms were measured by high-performance liquid chromatography.

Results: The recommended Phase II doses for schedules A and B were 2.43 and 1.70 mg/m²/day, respectively, each providing the same dose intensity (i.e., 24 mg/m²/cycle). The primary toxicities on schedules A and B were neutropenia, thrombocytopenia, and diarrhea. On schedule A, two patients with gastric cancer and two patients with pancreatic cancer had stable disease for more than six cycles. On schedule B, one patient with pancreatic cancer had stable disease for more than six cycles, and a patient with pancreatic cancer had a partial response. There was significant interpatient variability in the disposition of 9NC and 9AC. Most of the drug remained in the 9NC form with a ratio of 9NC to 9AC of 4 to 1.

Conclusions: These studies suggest that 9NC administered on an intermittent schedule is tolerable and may be an active regimen in patients with gastric or pancreatic cancers. Dosing 9NC on a mg/m² basis does not reduce pharmacokinetic variability.

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