PHASE-I AND PHARMACOLOGICAL STUDY OF IRINOTECAN IN COMBINATION WITH CISPLATIN FOR ADVANCED LUNG-CANCER

We have conducted a Phase I trial to determine the maximum tolerated d ose of CPT-11 together with a fixed dose of cisplatin in patients with advanced lung cancer, and the dose-limiting toxicities of this combin ation. Fourteen previously untreated patients with stage IIIB or IV di sease were treated with CPT-11 (90-min intravenous infusion on days 1, 8, and 15) plus cisplatin (60 mg m-2, intravenously on day 1). The st arting dose of CPT-11 was 60 mg m-2, and diarrhea was the dose-limitin g toxicity at the 90 mg m-2 dose level. All three patients (all four c ycles) given 90 mg m-2 of CPT-11 experienced grade 3 diarrhea. Hematol ogic toxicity was relatively mild. Elimination of CPT-11 was biphasic with a mean (+/- s.d.) beta half-life of 11.36 +/- 7.26 h. The mean te rminal half-life of the major metabolite (7-ethyl-10-hydroxycamptothec in; SN-38) was 22.13 +/- 13.28 (s.d.) h, and modest escalation of the CPT-11 dose from 80 mg m-2 to 90 mg m-2 resulted in a statistically si gnificant apparent increase in the plasma concentrations of SN-38. The re were one complete response (7%) and five partial responses (36%) am ong the 14 patients for an overall response rate of 43%. The recommend ed dose for Phase 11 studies is 80 mg m-2 of CPT-11 and 60 mg m-2 of c isplatin.