PHASE-I TRIAL OF THE COLLOIDAL DISPERSION FORMULATION OF 9-AMINO-20(S)-CAMPTOTHECIN ADMINISTERED AS A 72-HOUR CONTINUOUS INTRAVENOUS-INFUSION

The camptothecins are a class of potent cytotoxic anti-cancer agents t hat interact with the nuclear enzyme topoisomerase I to produce lethal DNA strand cleavages, 9-Amino-20(S)-camptothecin (9AC) was introduced into Phase I clinical trials in dimethylacetamide and polyethylene gl ycol 400 in a 10 mM phosphoric acid vehicle for i,v, solubility, A lyo philized colloidal dispersion (CD) of 9AC for reconstitution with 20% dextrose in normal saline was developed as an alternative formulation, Patients (ages 25-75 years) with normal liver and kidney function, Ea stern Cooperative Oncology Group performance status less than or equal to 2, and up to two prior chemotherapy regimens were treated, The ini tial infusion rate was 37.5 mu g/m(2)/h as a 72-h continuous infusion (2.7 mg/m(2) total dose), Patient cohorts were treated with escalating infusion rates until grade 4 hematological or other grade 3 toxicity developed, Pharmacokinetic sampling was performed on all patients, and 9AC lactone concentrations in plasma were determined by a high-perfor mance liquid chromatographic assay, Twenty-five patients received a to tal of 65 courses of 9AC CD at doses from 2.70 to 4.65 mg/m(2), The do se-limiting toxicity was neutropenia, with little nonhematological tox icity, Nonlinear regression analysis of pooled patient data yielded a total plasma clearance of 30.3 +/- 4.5 liters/h/m(2), a half-life of 2 2.5 +/- 8.5 h, a mean residence time of 9.7 +/- 3.5 h, and a steady-st ate volume of distribution of 325 +/- 145 liters/m(2), Although no obj ective responses were seen, 9 of 25 patients exhibited stable disease for 2-6 months, The plasma pharmacokinetics of 9AC lactone in cancer p atients were comparable between the 9AC CD and soluble formulations, T he dosing regimen recommended for Phase II trials of the 9AC CD formul ation is 54.2 mu g/m(2)/h, given as a 72-h continuous i,v, infusion ev ery 3 weeks.