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


METHODS
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 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.


CONCLUSIONS
Further assessment of ABT-751, especially in combination with other agents, in patients with acute leukemias is warranted.
Yee
Karen W L
KW
Department of Leukemia, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Hagey
Anne
A
Verstovsek
Srdan
S
Cortes
Jorge
J
Garcia-Manero
Guillermo
G
O'Brien
Susan M
SM
Faderl
Stefan
S
Thomas
Deborah
D
Wierda
William
W
Kornblau
Steven
S
Ferrajoli
Alessandra
A
Albitar
Maher
M
McKeegan
Evelyn
E
Grimm
David R
DR
Mueller
Toby
T
Holley-Shanks
Rhonda R
RR
Sahelijo
Leonardo
L
Gordon
Gary B
GB
Kantarjian
Hagop M
HM
Giles
Francis J
FJ
D000071916:AC133 Antigen; D000208:Acute Disease; D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000032:analysis; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use; D051929:CD146 Antigen; D003248:Constipation / Q000139:chemically induced; D003967:Diarrhea / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D042783:Endothelial Cells / Q000737:chemistry; D005260:Female; D006023:Glycoproteins / Q000032:analysis; D019337:Hematologic Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000235:genetics; D006801:Humans; D007938:Leukemia / Q000097:blood / Q000188:drug therapy / Q000235:genetics; D017493:Leukocyte Common Antigens / Q000032:analysis; D008297:Male; D008870:Microtubules / Q000378:metabolism; D008875:Middle Aged; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000097:blood / Q000188:drug therapy / Q000235:genetics; D009325:Nausea / Q000139:chemically induced; D009364:Neoplasm Recurrence, Local; D009360:Neoplastic Cells, Circulating / Q000737:chemistry; D019006:Neural Cell Adhesion Molecules / Q000032:analysis; D010455:Peptides / Q000032:analysis; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000032:analysis; D013449:Sulfonamides / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome; D014404:Tubulin / Q000235:genetics; D014839:Vomiting / Q000139:chemically induced
C490492:ABT751; D000071916:AC133 Antigen; D015703:Antigens, CD; D000970:Antineoplastic Agents; D051929:CD146 Antigen; D006023:Glycoproteins; D019006:Neural Cell Adhesion Molecules; D010455:Peptides; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D013449:Sulfonamides; D014404:Tubulin; D017493:Leukocyte Common Antigens