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 beta-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 T(max) 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 microg/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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Authors | 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 |
Journal | Clinical cancer research : an official journal of the American Association for Cancer Research
(Clin Cancer Res)
Vol. 12
Issue 9
Pg. 2834-40
(May 01 2006)
ISSN: 1078-0432 [Print] United States |
PMID | 16675578
(Publication Type: Clinical Trial, Phase I, Journal Article)
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Chemical References |
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Topics |
- Administration, Oral
- Adult
- Aged
- Biological Availability
- Cell Division
(drug effects)
- Drug Administration Schedule
- Female
- Humans
- Male
- Middle Aged
- Neoplasms
(blood, urine)
- Safety
- Sulfonamides
(pharmacokinetics, therapeutic use, toxicity)
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