Phase I clinical trial of weekly combined topotecan and irinotecan

Combining antineoplastic analogues may increase efficacy by increasing the serum and intracellular concentration of the cytotoxic moiety shared by the analogues. Topotecan and irinotecan are two camptothecan analogues that ar e active in different human tumors (topotecan in ovary; irinotecan in colon ) and in different experimental tumor systems. These data suggest that diff erent mechanisms of drug resistance may be operative for the two agents, an d if incomplete cross-resistance exists between analogues, concomitant admi nistration may be advantageous. The objectives of this phase I study were 1 ) to determine in a phase trial design whether topotecan and irinotecan adm inistered concomitantly on a weekly schedule can be delivered at the same d ose intensity as that of single-agent topotecan or irinotecan delivery; and 2) to determine whether hematologic and/or nonhematologic toxicity is incr eased with topotecan and irinotecan administered together as a prelude to a possible phase II trial in responsive tumor categories. Irinotecan was adm inistered for 30 to 45 minutes weekly X 4 at four dose levels: 50, 75, 100, and 125 mg/m(2)/wk. Topotecan was administered for 30 minutes (after irino tecan administration) at two dose levels within each of the irinotecan dose levels (1.0 and 1.5 mg/m(2)). Concomitant single-dose granulocyte-macropha ge colony-stimulating factor (G-CSF) was used for leukocyte counts between 1,000 cells/mm(3) and 3,500 cells/ mm(3) to maintain schedule. Maximum tole rated dosage (MTD) for the topotecan and irinotecan combination was defined as that which permitted 4 weeks of topotecan and irinotecan administration with G-CSF at or near the dose intensity reported for each single agent. T wenty-one patients received 32 4-week cycles. Dose-limiting toxicity was he matologic with grade IV leukopenia and neutropenia occurring at all dose le vels. There was no apparent increase in the diarrhea syndrome associated wi th irinotecan. The MTD for irinotecan (at 125 mg/m(2)/wk) is the same MTD a s with single-agent irinotecan use. The MTD for concomitant topotecan 0.5 m g/m(2)/wk) is 60% of the single-agent topotecan dose for the 5-day topoteca n schedule (at 2.5 mg/m(2)/wk) but only 30% of the single-agent topotecan d ose for the weekly schedule (5 mg/m(2)/wk). The topoisomerase I inhibitor d ose is increased minimally when the analogues are administered concomitantl y on a weekly schedule. Comparative trials of single-agent topotecan and ir inotecan versus the combination of topotecan and irinotecan would be necess ary to provide the proof of principle that combining analogues can increase therapeutic effectiveness.