A phase I and pharmacologic study of 9-aminocamptothecin administered as a 120-h infusion weekly to adult cancer patients

• Published in: Cancer chemotherapy and pharmacology 2001-09, Vol.48 (3), p.215-222
• Main Authors: THOMAS, Rebecca R, DAHUT, William, CORSE, William, ARBUCK, Susan G, WRIGHT, John, CHEN, Alice P, SHAPIRO, Jeremy D, HAMILTON, J. Michael, ALLEGRA, Carmen J, TAKIMOTO, Chris H, HAROLD, Nancy, GREM, Jean L, MONAHAN, Brian P, LIANG, Michael, BAND, Roger A, COTTRELL, Jeff, LLORENS, Victor, SMITH, Judith A
• Format: Article
• Language: English
• Subjects: Adult; Aged; Antineoplastic agents; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - pharmacokinetics; Area Under Curve; Biological and medical sciences; Camptothecin - administration & dosage; Camptothecin - analogs & derivatives; Camptothecin - pharmacokinetics; Chemotherapy; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Hematologic Tests; Humans; Infusions, Intravenous; Male; Medical sciences; Metabolic Clearance Rate; Middle Aged; Neoplasms - drug therapy; Neoplasms - metabolism; Pharmacology. Drug treatments; Platelet Count
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s002800100329

To define the toxicity profile and the recommended phase II doses of 9-aminocamptothecin (9-AC) administered as a weekly 120-h infusion. 9-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. Overall, 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. The 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.