PHASE-I AND PHARMACOLOGICAL STUDY OF IRINOTECAN AND ETOPOSIDE WITH RECOMBINANT HUMAN GRANULOCYTE-COLONY-STIMULATING FACTOR SUPPORT FOR ADVANCED LUNG-CANCER

Purpose: We conducted a phase I trial of irinotecan (CPT-11), a topois omerase I inhibitor, combined with etoposide, a topoisomerase II inhib itor, and recombinant human granulocyte colony-stimulating factor (rhG -CSF) support because of the overlapping neutrophil toxicity of both d rugs. The aim was to determine the maximum-tolerated dose of CPT-11 co mbined with a fixed dose of etoposide in patients with advanced lung c ancer, as well as the dose-limiting toxicities of this combination. Pa tients and Methods: Twenty-five patients with stage III or IV lung can cer, 15 (60%) with prior chemotherapy, were treated at 4-week interval s using CPT-11 (90-minute intravenous infusion on days 1, 8, and 15) p lus etoposide (80 mg/m(2) intravenously on days 1 to 3). In addition, rhG-CSF (2 mu g/kg/d) was given from day 4 to day 21, except on the da ys of CPT-11 administration. The starting dose of CPT-11 was 60 mg/m(2 ), and it was escalated in 10-mg/m(2) increments until the maximum-tol erated dose was reached. Results: The maximum-tolerated dose of CPT-11 was 90 mg/m(2), since two of the three patients developed grade 3 to 4 leukopenia or grade 3 to 4 diarrhea during the first cycle of treatm ent at this dose level. Diarrhea and leukopenia were the dose-limiting toxicities, while thrombocytopenia was only a moderate problem. Elimi nation of CPT-11 was biphasic, with a mean +/- SD beta half-life of 18 .17 +/- 9.09 hours. The mean terminal half-life of 7-ethyl-10-hydroxyc amptothecin (SN-38; the major metabolite of CPT-11) was 43.40 +/- 37.8 4 hours. There was one complete response (5%) and eight partial respon ses (38%) among 21 assessable patients, for an overall response rare o f 43%. The response rates for small-cell lung cancer (SCLC) and non-sm ell-cell lung cancer (NSCLC) were 58% (seven of 12 patients) and 22% ( two of nine patients), respectively. Conclusion: The combination of CP T-11 and etoposide with rhG-CSF support seems to be active against lun g cancer, especially SCLC, with acceptable toxicity. The recommended d ose for phase H studies in previously untreated patients is 80 mg/m(2) of CPT-11 (days 1, 8, and 15) and 80 mg/m(2) of etoposide (days 1 to 3) plus 2 mu g/kg of rhG-CSF (days 4 to 21, except when CPT-11 is give n). In addition, 70 mg/m(2) of CPT-11 appears to be the appropriate do se for previously treated patients receiving this regimen. (C) 1994 by American Society of Clinical Oncology.