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, Albert Lockhart, Diane Medina, Jeffrey Sosman, Gary B. Gordon, Mace L. Rothenberg

Research output: Contribution to journalArticle

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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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Antimitotic Agents
Sulfonamides
Pharmacokinetics
Safety
Maximum Tolerated Dose
Appointments and Schedules
Constipation
Abdominal Pain
Fatigue
ABT751
Ileus
Colchicine
Tubulin
Mitosis
Microtubules
Cell Division
Oral Administration
Neoplasms
Cell Cycle
Research Design

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

The pharmacokinetics and safety of ABT-751, a novel, orally bioavailable sulfonamide antimitotic agent : Results of a phase 1 study. / Hande, Kenneth R.; Hagey, Anne; Berlin, Jordan; Cai, Yingna; Meek, Kysa; Kobayashi, Hiro; Lockhart, Albert; Medina, Diane; Sosman, Jeffrey; Gordon, Gary B.; Rothenberg, Mace L.

In: Clinical Cancer Research, Vol. 12, No. 9, 01.05.2006, p. 2834-2840.

Research output: Contribution to journalArticle

Hande, KR, Hagey, A, Berlin, J, Cai, Y, Meek, K, Kobayashi, H, Lockhart, A, Medina, D, Sosman, J, Gordon, GB & Rothenberg, ML 2006, 'The pharmacokinetics and safety of ABT-751, a novel, orally bioavailable sulfonamide antimitotic agent: Results of a phase 1 study', Clinical Cancer Research, vol. 12, no. 9, pp. 2834-2840. https://doi.org/10.1158/1078-0432.CCR-05-2159
Hande, Kenneth R. ; Hagey, Anne ; Berlin, Jordan ; Cai, Yingna ; Meek, Kysa ; Kobayashi, Hiro ; Lockhart, Albert ; Medina, Diane ; Sosman, Jeffrey ; Gordon, Gary B. ; Rothenberg, Mace L. / The pharmacokinetics and safety of ABT-751, a novel, orally bioavailable sulfonamide antimitotic agent : Results of a phase 1 study. In: Clinical Cancer Research. 2006 ; Vol. 12, No. 9. pp. 2834-2840.
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T2 - Results of a phase 1 study

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AU - Hagey, Anne

AU - Berlin, Jordan

AU - Cai, Yingna

AU - Meek, Kysa

AU - Kobayashi, Hiro

AU - Lockhart, Albert

AU - Medina, Diane

AU - Sosman, Jeffrey

AU - Gordon, Gary B.

AU - Rothenberg, Mace L.

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N2 - 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.

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