e-7010 and Constipation

ABT-751 is an oral antimitotic agent that binds to the colchicine site on beta-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.. Thirty-two patients were treated: nine with 100 (n = 3), 125 (n = 3), or 150 mg/m(2) (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/m(2) (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).. Dose-limiting toxicity consisted of ileus in one patient at 200 mg/m(2), 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 Ala(185)Thr, was identified in exon 4 of the beta-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.. Further assessment of ABT-751, especially in combination with other agents, in patients with acute leukemias is warranted.

Topics: AC133 Antigen; Acute Disease; Adult; Aged; Antigens, CD; Antineoplastic Agents; CD146 Antigen; Constipation; Diarrhea; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Endothelial Cells; Female; Glycoproteins; Hematologic Neoplasms; Humans; Leukemia; Leukocyte Common Antigens; Male; Microtubules; Middle Aged; Mutation; Myelodysplastic Syndromes; Nausea; Neoplasm Recurrence, Local; Neoplastic Cells, Circulating; Neural Cell Adhesion Molecules; Peptides; Platelet Endothelial Cell Adhesion Molecule-1; Sulfonamides; Treatment Outcome; Tubulin; Vomiting