PHASE-I CLINICAL AND PLASMA AND CELLULAR PHARMACOLOGICAL STUDY OF TOPOTECAN WITHOUT AND WITH GRANULOCYTE-COLONY-STIMULATING FACTOR

Topotecan, a semisynthetic water-soluble analogue of camptothecin, inh ibits human topoisomerase I (topo I). We performed a Phase I clinical and plasma pharmacological study of topotecan administered by 24-h con tinuous infusion without and with granulocyte colony-stimulating facto r (G-CSF). We also measured topo I-DNA complexes in peripheral blood m ononuclear cells (PBMCs) in an attempt to correlate formation of topo I-DNA complexes in patients treated with topotecan with toxicity and/o r response. One hundred four courses of topotecan at doses of 2.5-15.0 mg/m(2) were administered to 44 patients with solid tumors. The maxim um tolerated dose without G-CSF was 10.0 mg/m(2); granulocytopenia was the dose-limiting toxic effect. The maximum tolerated dose could not be increased with G-CSF because of severe thrombocytopenia. Plasma pha rmacology was obtained in 11 patients treated at 12.5 mg/m(2) and 15.0 mg/m(2). The topotecan lactone end-infusion plasma levels correlated strongly with the area under the curve. Lactone elimination was biexpo nential with a mean t(1/2)alpha of 28 min and a t(1/2)beta of 3.8 h at 12.5 mg/m(2). Topo I-DNA complexes were measured before and after tre atment in PBMCs from seven patients. Pretopotecan topo I-DNA complexes were available on two additional patients treated at 15 mg/m(2). The mean increase in topo I-DNA complexes at the end of the topotecan infu sion was 1.25 times the pretreatment value. There was a statistically significant relationship (P = 0.02) between lack of disease progressio n and the level of topo I-DNA complexes measured in PBMCs before thera py. For Phase II studies of minimally treated adults with solid tumors , the recommended topotecan starting dose administered by 24-h continu ous infusion is 10 mg/m(2) without G-CSF.