Phase I pharmacologic study of oral topotecan and intravenous cisplatin : Sequence-dependent hematologic side effects

Purpose: In in vitro studies, synergism and sequence-dependent effects were reported for the combination of topotecan and cisplatin. Recently, an oral formulation of topotecan became available. This phase I study was performed to assess the feasibility of the combination of oral topotecan and cisplatin, the pharmacokinetic interaction, and sequence-dependent effects. Patients and Methods: Topotecan was administered orally (PO) daily for 5 days in escalating doses and cisplatin was given intravenously (IV) at a fixed dose of 75 mg/m2 either before topotecan administration on day 1 (sequence CT) or after topotecan administration on day 5 (sequence TC) once every 3 weeks. Patients were treated in a randomized cross-over design. Results: Forty-nine patients were entered onto the study; one patient was not eligible. Sequence CT induced significantly more severe myelosuppression than did sequence TC, and the maximum-tolerated dosage of topotecan in sequence CT was 1.25 mg/m2/d x 5. In sequence TC, the maximum-tolerated dosage of topotecan was 2.0 mg/m2/d x 5. Dose-limiting toxicity consisted of myelosuppression and diarrhea. Pharmacokinetics of topotecan and cisplatin were linear over the dose range studied; no sequence-dependent effects were observed. In addition, topotecan did not influence the protein binding of cisplatin or the platinum-DNA adduct formation in peripheral leukocytes in either sequence. Conclusion: The recommended dosages for phase II studies involving patients like the patients in our study are topotecan 1.25 mg/m2/d PO x 5 preceded by cisplatin 75 mg/m2 IV day 1 once every 3 weeks, and topotecan 2.0 mg/m2/d PO followed by cisplatin 75 mg/m2 IV day 5. No pharmacokinetic interaction could be discerned in our study. The antitumor efficacy of both schedules should be evaluated in a randomized phase II study.