Phase I dosage finding and pharmacokinetic study of intravenous topotecan and oral erlotinib in adults with refractory solid tumors

Purpose

Topotecan is widely used for refractory solid tumors but multi-drug resistance may occur due to tumor expression of ATP-binding cassette (ABC) transporters. Since erlotinib, an inhibitor of the epidermal growth factor receptor, also inhibits several ABC transporters, we performed a phase I study to evaluate the safety, efficacy, and pharmacokinetics of intravenous topotecan given in combination with erlotinib.

Methods

Patients received 150 mg of oral erlotinib daily and a 30 min intravenous infusion of topotecan on days 1–5 of a 21-day cycle. Dosage escalation of topotecan occurred with a starting dosage of 0.75 mg/m². The pharmacokinetics of topotecan was evaluated on day 1 of cycle 1 without erlotinib and on day 1 of cycle 2 or 3 with erlotinib.

Results

Twenty-nine patients were enrolled. The maximum tolerated dosage was determined to be 1.0 mg/m². Dose-limiting toxicities included neutropenia and thrombocytopenia. The average duration of treatment was 97 days. Two partial responses were observed. Topotecan clearance and exposure were similar with and without erlotinib.

Conclusions

The combination of topotecan and erlotinib is tolerable at clinically effective doses. Erlotinib does not affect the disposition of topotecan to a clinically significant extent.