Phase I and pharmacologic study of sequential topotecan, carboplatin, and etoposide

Abstract

Inhibition of topoisomerase I by topotecan results in a compensatory increase in topoisomerase II levels associated with increased in vitro sensitivity of tumors to etoposide. Maximum synergy has been observed for the sequence of topotecan followed by etoposide. This is the pharmacologic rationale for the sequence of topotecan 0.4 mg/m(2) per day for 7 days continuous i.v. infusion, carboplatin i.v. on day 8, and etoposide 50 mg per day p.o. days 9 through 20. The carboplatin dosage was escalated from an AUC of 4 to 5 to 6 (Calvert formula). Up to six treatment cycles were administered at 28-day intervals. Eligible patients had metastatic non-small cell lung cancer (NSCLC) or extensive disease small lung cell lung cancer (SCLC), no prior chemotherapy, performance status 0-2, and adequate organ function. Follow-up was twice weekly in the first cycle for CBC and for topotecan and etoposide concentrations. Follow-up, thereafter, was weekly. Tumor response was assessed after two and six cycles and then as clinically indicated. At carboplatin AUCs of 4 and 5, no NCI grade 4 toxicity was observed in cycle 1 in cohorts of three patients each. At the AUC of 5, two patients experienced dose-limiting events after cycle 3, one grade 4 neutropenia lasting >3 days (no fever) and one failure to recover an absolute neutrophil count >1500/microl by day 35. This was, therefore, deemed the maximal tolerable dose. Number of treatment cycles per patient ranged between 1 and 6, and three patients completed six cycles. All patients were male, age 47-71, with NSCLC in one and SCLC in six. The patient with NSCLC had progressive disease after one cycle. One complete and three partial responses were observed in five patients with SCLC. Mean steady-state plasma concentrations during topotecan infusion ranged from 0.73 to 1.69 ng/ml, and mean etoposide concentrations ranged from 60 to 230 ng/ml. This sequence of topotecan, carboplatin, and etoposide appeared tolerable and active. Neutropenia was the dose-limiting toxicity.