Pharmacokinetically guided phase I trial of topotecan and etoposide phosphate in recurrent ovarian cancer

Abstract

A pharmacokinetically guided phase I study of topotecan and etoposide phosphate was conducted in recurrent ovarian cancer. The scheduling of the topoisomerase I and II inhibitors was determined using in vitro activity data. All patients had recurrent disease following prior platinum-containing chemotherapy. Patients had a World Health Organisation performance status of 0-2 and adequate bone marrow, renal and hepatic function. Treatment was with topotecan intravenously for 5 days followed immediately by a 5-day intravenous infusion of etoposide phosphate (EP), with pharmacokinetically guided dose adjustment. Plasma etoposide levels were measured on days 2 and 4 of the infusion. A total of 21 patients entered the study. In all, 48% were platinum resistant and 71% had received prior paclitaxel. The main toxicities were haematological, short lived and reversible. A total of 29% of patients experienced grade 4 thrombocytopenia and 66% grade 4 neutropenia after the first cycle. Neutropenia and thrombocytopenia was dose limiting. The maximum-tolerated dose was topotecan 0.85 mg m(-2) day(-1) days 1-5 followed immediately by a 5-day infusion of EP at a plasma concentration of 1 mug ml(-1). The response rate (RR) was 28% in 18 evaluable patients. There was marked interpatient variability in topoisomerase IIalpha levels measured from peripheral lymphocytes, with no observed increase following topotecan. This regimen of topotecan followed by EP demonstrated good activity in recurrent ovarian cancer and was noncrossresistant with paclitaxel. Both the toxicity and RR was higher than would be expected from the single agent data, in keeping with synergy of action.

Figure 1

Etoposide clearance. Relationship between etoposide clearance and EDTA clearance (renal function) prior to treatment, shown as a regression curve (A) and as a scatter graph for EDTA clearance below and above 60 ml min⁻¹ (B).

Figure 2

Difference from target concentration. Graph demonstrating the variability of plasma etoposide concentrations, measured on days 2 and 4 of the infusion, for each cycle.

Figure 3

European Organisation for Research and Treatment of Cancer (EORTC) score. Mean EORTC QOL scores (±1 s.d.) calculated at baseline, before cycles 3 and 6 and after cycle 6.

Figure 4

Percentage of apoptotic cells. Apoptosis (mean+s.d.) induced by combinations of etoposide and SN-38 in SKOV-3 (A), OVCAR-3 (B) and A2780 (C) ovarian cancer cell lines. The treatments were; Control, SN-38+etoposide concurrently for 3 days (S+E), SN-38 for days 1–3 immediately followed by etoposide for days 3–6 (SE), etoposide for days 1–3 immediately followed by SN-38 for days 3–6 (ES), SN-38 for days 1–3 followed by 1 day drug free, then etoposide for days 4–7 (S0E), etoposide for days 1–3 followed by 1 day drug free, then SN-38 for days 4–7 (E0S).

Figure 5

Topoisomerase IIα levels/arbitrary units. Topoisomerase IIα levels in peripheral blood. An example Western blot of topoisomerase IIα (A). Lymphopreps were made from peripheral blood samples taken pretreatment (1), post-topotecan (2) and post-etoposide (3) administration. Western blotting was performed on proteins from the lymphocyte cell pellet. Blots were probed with a monoclonal anti-topoisomerase IIα antibody. β Tubulin was used as a loading control. Scatter graph of topoisomerase IIα levels in peripheral lymphocytes for all 10 patients at baseline, after topotecan and at the end of treatment (B).