The pharmacokinetics and safety of ABT-751, a novel, orally bioavailable sulfonamide antimitotic agent: Results of a phase 1 study

Kenneth R. Hande, Anne Hagey, Jordan Berlin, Yingna Cai, Kysa Meek, Hiro Kobayashi, A. Craig Lockhart, Diane Medina, Jeffrey Sosman, Gary B. Gordon, Mace L. Rothenberg

Research output: Contribution to journalArticle

75 Scopus citations

Abstract

Purpose: Microtubules play a critical role in many cellular functions, including cell division and mitosis. ABT-751 is a novel sulfonamide antimitotic that binds to the colchicine site on β-tubulin that leads to a block in the cell cycle at the G2M phase, resulting in cellular apoptosis. ABT-751 was investigated in this phase 1 trial designed to assess its maximum tolerated dose (MTD), dose-limiting toxicity (DLT), tolerability, and pharmacokinetics. Experimental Design: ABT-751 was administered on a daily (q.d.) or twice daily (b.i.d.) oral schedule for 7 days every 3 weeks to 39 patients with refractory solid tumors. Toxicity was monitored weekly. Plasma and urine ABT-751 and metabolite pharmacokinetics were determined. Results: The MTD for the q.d. schedule was 250 mg/d. DLTs during cycle 1 were abdominal pain, constipation, and fatigue. The MTD on the b.i.d. schedule was 150 mg. Cycle 1 of therapy with the 175 mg b.i.d. schedule was tolerated without DLT. However, six of seven patients reported grade 3 toxicity (ileus, constipation, abdominal pain, or fatigue), which occurred in cycle 2 or 3. ABT-751 was absorbed after oral administration with an overall mean Tmax of about 2 hours. The pharmacokinetics of ABT-751 were dose-proportional and time-independent. There was minimal accumulation of ABT-751 after multiple q.d. and b.i.d. doses. Efficacious concentrations, as determined from preclinical models (0.5-1.5 μg/mL), were achieved in all subjects. ABT-751 metabolism occurred primarily by glucuronidation and sulfation. No complete or partial tumor responses were noted, but one patient had a minor response, and four patients had stable disease lasting at least 6 months. Conclusions: The MTD and recommended phase 2 doses for ABT-751 were 250 mg q.d. and 150 mg b.i.d. on a 7-day schedule given every 3 weeks, due to subsequent cycle toxicities at 175 mg b.i.d. dosing. Toxicities were abdominal pain, constipation, and neuropathy.

Original languageEnglish (US)
Pages (from-to)2834-2840
Number of pages7
JournalClinical Cancer Research
Volume12
Issue number9
DOIs
StatePublished - May 1 2006
Externally publishedYes

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Hande, K. R., Hagey, A., Berlin, J., Cai, Y., Meek, K., Kobayashi, H., Lockhart, A. C., Medina, D., Sosman, J., Gordon, G. B., & Rothenberg, M. L. (2006). The pharmacokinetics and safety of ABT-751, a novel, orally bioavailable sulfonamide antimitotic agent: Results of a phase 1 study. Clinical Cancer Research, 12(9), 2834-2840. https://doi.org/10.1158/1078-0432.CCR-05-2159