Summary
Purpose: XK469, a member of the quinoxaline family of antitumor agents, is believed to be unique in its ability to selectively target topoisomerase IIβ. Based on encouraging pre-clinical data, a phase I trial was conducted to determine the dose limiting toxicity (DLT) and the maximum tolerated dose (MTD).
Methods: A 2B accelerated titration schema was employed. XK469 was administered as a 5 or 20 min IV infusion on days 1–5 every 21 days. The starting dose was 9 mg/m2. Pharmacokinetics (PK) were conducted in cycles 1–3.
Results: 22 patients (21 evaluable, mean age: 56 years, median performance status: 1) were enrolled. At dose level 11 (260 mg/m2/daily X 5), 1/6 patients experienced a DLT of grade 4 neutropenia. At 346 mg/m2/daily X 5, 2/2 patients experienced DLT's with one episode of febrile neutropenia and one grade 3 infection. The MTD was identified as 260 mg/m2/day. XK469 peak plasma levels and systemic exposure were proportional to dose indicating linear pharmacokinetics. However, secondary peaks in the PK profiles and a rapid decline in drug level from 23 to 24 h occurred in some patients. Drug infusion in the afternoon followed by dense sampling of levels during the elimination phase supported the hypothesis that the drug was being sequestered. No anti-tumor activity was identified.
Conclusions: Traditional PK sampling designs were inadequate to describe XK469 disposition. XK469 and related structures work through a unique mechanism of action. A further understanding of the specific mechanism of these compounds might uncover a unique avenue for future drug development.
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This study was supported by NIH grant UO1-CA062487.
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Alousi, A.M., Boinpally, R., Wiegand, R. et al. A phase 1 trial of XK469: Toxicity profile of a selective topoisomerase IIβ inhibitor. Invest New Drugs 25, 147–154 (2007). https://doi.org/10.1007/s10637-006-9024-5
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DOI: https://doi.org/10.1007/s10637-006-9024-5