Mja. De Jonge et al., Phase I pharmacologic study of oral topotecan and intravenous cisplatin: Sequence-dependent hematologic side effects, J CL ONCOL, 18(10), 2000, pp. 2104-2115
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 performe
d to assess the feasibility of the combination of oral topotecan and cispla
tin, the pharmacokinetic interaction, and sequence-dependent effects.
Patients and Methods: Topotecan was administered orally (PO) daily for 5 da
ys in escalating doses and cisplatin was given intravenously (IV) at a fixe
d dose of 75 mg/m(2) either before topotecan administration on day 1 (seque
nce 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 n
ot eligible. Sequence CT induced significantly more severe myelosuppression
than did sequence TC, and the maximum-tolerated dosage of topotecan in seq
uence CT was 1.25 mg/m(2)/d x 5. In sequence TC, the maximum-tolerated dosa
ge 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 precede
d 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 in
teraction could be discerned in our study. The antitumor efficacy of both s
chedules should be evaluated in a randomized phase II study. J Clin Oncol 1
8:2104-2115. (C) 2000 by American Society of Clinical Oncology.