• R R Thomas, W Dahut, N Harold, J L Grem, B P Monahan, M Liang, R A Band, J Cottrell, V Llorens, J A Smith, W Corse, S G Arbuck, J Wright, A P Chen, J D Shapiro, J M Hamilton, C J Allegra, and C H Takimoto.
• Developmental Therapeutics Department, Medicine Branch, Division of Clinical Sciences, National Cancer Institute, Bethesda, MD 20889, USA.
• Cancer Chemother. Pharmacol. 2001 Sep 1; 48 (3): 215-22.

PurposeTo define the toxicity profile and the recommended phase II doses of 9-aminocamptothecin (9-AC) administered as a weekly 120-h infusion.Methods9-AC was administered over 120 h weekly to 55 adult cancer patients with solid tumors over doses ranging from 0.41 to 0.77 mg/m2 per day in a phase I and pharmacologic study. 9-AC formulated in dimethylacetamide/polyethylene glycol (DMA) was administered on a 3 of 4-week schedule, and the newer colloidal dispersion (CD) formulation was given on a 2 of 3-week schedule.ResultsOverall, 193 courses of therapy were administered over 122 dose levels. On the 3 of 4-week schedule, 9-AC DMA infused at > or = 0.6 mg/m2 per day for 120 h weekly produced dose-limiting neutropenia, thrombocytopenia, and diarrhea, or resulted in 1-2-week treatment delays. Shortening treatments to 2 of 3 weeks resulted in dose-limiting neutropenia and fatigue at infusion rates > 0.72 mg/m2 per day. The ratio of 9-AC lactone to total (carboxylate + lactone) drug plasma concentrations at steady-state was 0.15 +/- 0.07. Clinical toxicities and drug pharmacokinetics were not substantially different between the DMA and CD formulations. One objective response was observed in a patient with bladder cancer and minor responses were observed in patients with lung and colon cancers. Plasma area under the concentration versus time curve for 9-AC lactone modestly correlated with the degree of thrombocytopenia (r=0.51) using a sigmoid Emax pharmacodynamic model.ConclusionThe recommended phase II dose for the 9-AC DMA formulation is 0.48 mg/m2 per h over 120 h for 3 of 4 weeks and for the 9-AC CD formulation is 0.6 mg/m2 per day over 120 h for 2 of 3 weeks. Both regimens were well tolerated and feasible to administer.

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