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

Abstract

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/m(2) 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/m(2)/d x 5. In sequence TC, the maximum-tolerated dosage of topotecan was 2.0 mg/m(2)/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/m(2)/d PO x 5 preceded by cisplatin 75 mg/m(2) IV day 1 once every 3 weeks, and topotecan 2.0 mg/m(2)/d PO followed by cisplatin 75 mg/m(2) 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.

• Authors: M J de Jonge, W J Loos, H Gelderblom, A S Planting, M E van der Burg, A Sparreboom, E Brouwer, V van Beurden, M A Mantel, E Doyle, S Hearn, G Ross, J Verweij
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 18 Issue 10 Pg. 2104-15 (May 2000) ISSN: 0732-183X [Print] United States
• PMID: 10811676 (Publication Type: Clinical Trial, Clinical Trial, Phase I, Journal Article, Randomized Controlled Trial)

Chemical References

• Topotecan
• Cisplatin

Topics

• Adult
• Aged
• Antineoplastic Combined Chemotherapy Protocols (administration & dosage, adverse effects, pharmacokinetics)
• Area Under Curve
• Cisplatin (administration & dosage, adverse effects, pharmacokinetics)
• Cross-Over Studies
• Drug Administration Schedule
• Drug Interactions
• Feasibility Studies
• Female
• Humans
• Infusions, Intravenous
• Male
• Middle Aged
• Neoplasms (drug therapy)
• Neutropenia (chemically induced)
• Thrombocytopenia (chemically induced)
• Topotecan (administration & dosage, adverse effects, pharmacokinetics)