A phase I and pharmacologic study of 9-aminocamptothecin administered as a120-h infusion weekly to adult cancer patients

Purpose: To define the toxicity profile and the recommended phase II doses of 9-aminocamptothecin (9-AC) administered as a weekly 120-h infusion. Meth ods: 9-AC was administered over 120 h weekly to 55 adult cancer patients wi th solid tumors over doses ranging from 0.41 to 0.77 mg/m(2) per day in a p hase I and pharmacologic study. 9-AC formulated in dimethylacetamide/polyet hylene glycol (DMA) was administered on a 3 of 4-week schedule, and the new er colloidal dispersion (CD) formulation was given on a 2 of 3-week schedul e. Results: Overall, 193 courses of therapy were administered over 122 dose levels. On the 3 of 4-week schedule, 9-AC DMA infused at greater than or e qual to0.6 mg/m(2) per day for 120 h weekly produced dose-limiting neutrope nia, thrombocytopenia, and diarrhea, or resulted in 1-2-week treatment dela ys. Shortening treatments to 2 of 3 weeks resulted in dose-limiting neutrop enia and fatigue at infusion rates > 0.72 mg/m(2) per day. The ratio of 9-A C lactone to total (carboxylate + lactone) drug plasma concentrations at st eady-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 are a under the concentration versus time curve for 9-AC lactone modestly corre lated with the degree of thrombocytopenia (r=0.51) using a sigmoid Ena, pha rmacodynamic model. Conclusion: The recommended phase II dose for the 9-AC DMA formulation is 0.48 mg/m(2) per h over 120 h for 3 of 4 weeks and for t he 9-AC CD formulation is 0.6 mg/m(2) per day over 120 h for 2 of 3 weeks. Both regimens were well tolerated and feasible to administer.