Phase 1 study of ABT-751, a novel microtubule inhibitor, in patients with refractory hematologic malignancies

Karen W.L. Yee, Anne Hagey, Srdan Verstovsek, Jorge Cortes, Guillermo Garcia-Manero, Susan M. O'Brien, Stefan Faderl, Deborah Thomas, William Wierda, Steven Kornblau, Alessandra Ferrajoli, Maher Albitar, Evelyn McKeegan, David R. Grimm, Toby Mueller, Rhonda R. Holley-Shanks, Leonardo Sahelijo, Gary B. Gordon, Hagop M. Kantarjian, Francis J. Giles

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72 Scopus citations

Abstract

Purpose: ABT-751 is an oral antimitotic agent that binds to the colchicine site on β-tubulin. A phase 1 study was conducted to determine the maximum tolerated dose and toxicities of ABT-751 in patients with advanced myelodysplastic syndrome and relapsed or refractory acute leukemias. Study Design: Thirty-two patients were treated: nine with 100 (n = 3), 125 (n = 3), or 150 mg/m2 (n = 3) of ABT-751 given orally once daily for 7 days every 3 weeks and 23 with 75 (n = 3), 100 (n = 3), 125 (n = 5), 150 (n = 5), 175 (n = 3), or 200 mg/m2 (n = 4) of ABT-751 given orally once daily for 21 days every 4 weeks. Consenting patients had pharmacogenetic sampling and enumeration of circulating endothelial cells (CEC). Results: Dose-limiting toxicity consisted of ileus in one patient at 200 mg/m2, with a subsequent patient developing grade 2 constipation at the same dose level. One patient with relapsed acute myelogenous leukemia achieved a complete remission that was sustained for 2 months. Four other patients had transient hematologic improvements, consisting of a decrease in peripheral blood blasts and improvements in platelet counts. CEC number was reduced in three patients with a concomitant reduction in peripheral blasts. A previously undescribed nonsynonymous single nucleotide polymorphism, encoding Ala185Thr, was identified in exon 4 of the β-tubulin gene, TUBB, in three other patients. The recommended phase 2 dose in hematologic malignancies is 175 mg/m 2 daily orally for 21 days every 4 weeks. Conclusion: Further assessment of ABT-751, especially in combination with other agents, in patients with acute leukemias is warranted.

Original languageEnglish (US)
Pages (from-to)6615-6624
Number of pages10
JournalClinical Cancer Research
Volume11
Issue number18
DOIs
Publication statusPublished - Sep 15 2005
Externally publishedYes

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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