Phase I Evaluation of Sequential Topoisomerase Targeting with Irinotecan/Cisplatin Followed by Etoposide in Patients with Advanced Malignancy

Purpose: To investigate pharmacologically guided addition of etoposide to a weekly irinotecan/cisplatin chemotherapy. Patients and Methods: Patients with advanced nonhematologic malignancies were eligible. Treatment consisted of i.v. administration of 50 mg/m 2 irinotecan and 20 mg/m 2 cisplatin on days 1, 8, 15, and 22 of a 42-day cycle or on days 1 and 8 of a 21-day cycle. Etoposide was administered in a dose-escalating fashion 2 days after each dose of irinotecan/cisplatin, either i.v. as a single dose or p.o. as two doses administered 12 h apart. Pharmacologic analyses included measurement of plasma concentrations of irinotecan, SN-38, and SN-38 glucuronide, as well as quantitation of topoisomerase protein levels in peripheral blood mononuclear cells (PBMNCs). Results: A total of 40 patients with a variety of malignancies received 122 cycles of therapy. Dose-limiting toxicities included neutropenia and diarrhea, with the 21-day cycle tolerated better than the 42-day cycle. For the 21-day cycle, the maximum tolerated dose was 75 mg/m 2 for i.v. etoposide and 85 mg/m 2 for oral etoposide. Objective responses were observed in four patients with previously treated mesothelioma, gastric, breast, and ovarian cancer, respectively. PBMNC levels of topoisomerase IIα were increased at the time of etoposide administration in two patients, with these patients having the highest SN-38 glucuronide peak-plasma-concentration and area-under-the-curve values among 15 patients with available pharmacokinetic data. One of these patients had a partial response to therapy. Conclusions: Pharmacologically guided administration of etoposide in combination with irinotecan/cisplatin using a 21-day cycle is associated with acceptable toxicity and significant antitumor activity. The finding that PBMNC topoisomerase IIα protein levels increased after irinotecan/cisplatin treatment in two of six patients supports the continued development of sequential topoisomerase targeting in the treatment of malignancy.