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A phase 1 trial of XK469: Toxicity profile of a selective topoisomerase IIβ inhibitor

  • Phase I Studies
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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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Acknowledgment

This study was supported by NIH grant UO1-CA062487.

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Authors and Affiliations

  1. Karmanos Cancer Institute, Wayne State University School of Medicine, 4th Floor HWCRC, 4100 John R, Detroit, MI, 48201, USA

    Amin M. Alousi, Ramesh Boinpally, Richard Wiegand, Ralph Parchment, Shirish Gadgeel, Lance K. Heilbrun, Antionette J. Wozniak, Pamela DeLuca & Patricia M. LoRusso

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  1. Amin M. Alousi
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  2. Ramesh Boinpally
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  3. Richard Wiegand
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  4. Ralph Parchment
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  5. Shirish Gadgeel
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  6. Lance K. Heilbrun
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  7. Antionette J. Wozniak
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  8. Pamela DeLuca
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  9. Patricia M. LoRusso
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Corresponding author

Correspondence to Patricia M. LoRusso.

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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

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