Jp. Eder et al., PHASE-I TRIAL OF THE COLLOIDAL DISPERSION FORMULATION OF 9-AMINO-20(S)-CAMPTOTHECIN ADMINISTERED AS A 72-HOUR CONTINUOUS INTRAVENOUS-INFUSION, Clinical cancer research, 4(2), 1998, pp. 317-324
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.