Phase 1 Study of ABT-751, a Novel Microtubule Inhibitor, in Patients with Refractory Hematologic Malignancies

• Published in: Clinical cancer research Vol. 11; no. 18; pp. 6615 - 6624
• Main Authors: YEE, Karen W. L, HAGEY, Anne, FERRAJOLI, Alessandra, ALBITAR, Maher, MCKEEGAN, Evelyn, GRIMM, David R, MUELLER, Toby, HOLLEY-SHANKS, Rhonda R, SAHELIJO, Leonardo, GORDON, Gary B, KANTARJIMI, Hagop M, GILES, Francis J, VERSTOVSEK, Srdan, CORTES, Jorge, GARCIA-MANERO, Guillermo, O'BRIEN, Susan M, FADERL, Stefan, THOMAS, Deborah, WIERDA, William, KORNBLAU, Steven
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.09.2005
• Subjects: AC133 Antigen; Acute Disease; acute leukemia; Adult; Aged; Antigens, CD - analysis; Antineoplastic agents; Antineoplastic Agents - adverse effects; Antineoplastic Agents - therapeutic use; Biological and medical sciences; CD146 Antigen; circulating endothelial cells; Constipation - chemically induced; Diarrhea - chemically induced; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Endothelial Cells - chemistry; Female; Glycoproteins - analysis; Hematologic Neoplasms - blood; Hematologic Neoplasms - drug therapy; Hematologic Neoplasms - genetics; Humans; Leukemia - blood; Leukemia - drug therapy; Leukemia - genetics; Leukocyte Common Antigens - analysis; Male; Medical sciences; microtubule inhibitor; Microtubules - metabolism; Middle Aged; Mutation; myelodysplasia; Myelodysplastic Syndromes - blood; Myelodysplastic Syndromes - drug therapy; Myelodysplastic Syndromes - genetics; Nausea - chemically induced; Neoplasm Recurrence, Local; Neoplastic Cells, Circulating - chemistry; Neural Cell Adhesion Molecules - analysis; Peptides - analysis; Pharmacology. Drug treatments; Platelet Endothelial Cell Adhesion Molecule-1 - analysis; Sulfonamides - adverse effects; Sulfonamides - therapeutic use; Treatment Outcome; Tubulin - genetics; tubulin polymorphisms; Vomiting - chemically induced; Human; Treatment resistance; Phase I trial; Cytoskeleton; Malignant hemopathy; Inhibitor; Microtubule
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-05-0650

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/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). Results: 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 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.