PHASE-I AND PHARMACOLOGICAL STUDY OF 9-AMINOCAMPTOTHECIN COLLOIDAL DISPERSION FORMULATION GIVEN AS A 24-HOUR CONTINUOUS-INFUSION WEEKLY TIMES 4 EVERY 5 WEEKS

Purpose: 9-Aminocamptothecin (9-AC) is a water-insoluble camptothecin (CMP) derivative that inhibits normal topoisomerase I function, Schedu le dependency was noted, with the greatest activity seen in the settin g of greater than 24 hours exposure to lactone (L) concentrations grea ter than or equal to 10 nmol/L. In this phase I study 9-AC was given b y ct continuous intravenous infusion over 24 hours once weekly times f our every 5 weeks. Patients and Methods: Twenty patients, of whom 16 h ad fluorouracil-refractory colorectal cancer (CRC), entered the study Dose levels were 0.7 mg/m(2) (n = 4), 1.4 mg/m(2) (n = 3), 1.9 mg/m(2) (n = 6), and 1.65 mg/m(2) (n = 7). Detailed pharmacokinetic (PK) meas urements of 9-AC L and carboxylate (C) were performed on day 1 of cycl es 1 and 2. Results: At 1.9 mg/m(2), dose-limiting toxicity (DLT) was reached, with three of six patients having grade 4 neutropenia. At 1.6 5 mg/m(2), one of seven patients had grade 4 neutropenia, Nonhematolog ic toxicity was modest, with diarrhea greater than or equal to grade 3 in two patients and lethargy greater than or equal to grade 3 in eigh t PK/pharmacodynamic (PD) analyses showed marked interpatient variabil ity. Steady-state concentrations (Css) of 9-AC L greater than or equal to 10 nmol/L (3.6 mu g/L) were seen in five of seven patients at 1.65 mg/m(2) and five of six patients at 1.9 mg/m(2). Using the sigmoidal maximal effect (Emax) model, 9-AC L area under the concentration-time curve (AUC) and Css correlated with day 15 decrease in neutrophils (R- 2 = .47), but not platelets. Conclusion: The recommended phase II dose of 9-AC colloidal dispersion (CD) given as a 24-hour continuous infus ion weekly for 4 of every 5 weeks is 1.65 mg/m(2), (C) 1998 by America n Society of Clinical Oncology.