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A phase 1 dose-escalation study of ARRY-520, a kinesin spindle protein inhibitor, in patients with advanced myeloid leukemias†
Article first published online: 2 DEC 2011
Copyright © 2011 American Cancer Society
Volume 118, Issue 14, pages 3556–3564, 15 July 2012
How to Cite
Khoury, H. J., Garcia-Manero, G., Borthakur, G., Kadia, T., Foudray, M. C., Arellano, M., Langston, A., Bethelmie-Bryan, B., Rush, S., Litwiler, K., Karan, S., Simmons, H., Marcus, A. I., Ptaszynski, M. and Kantarjian, H. (2012), A phase 1 dose-escalation study of ARRY-520, a kinesin spindle protein inhibitor, in patients with advanced myeloid leukemias. Cancer, 118: 3556–3564. doi: 10.1002/cncr.26664
Presented as a Poster at the 51st Annual Meeting of the American Society of Hematology; December 5-8, 2009; New Orleans, Louisiana.
- Issue published online: 2 JUL 2012
- Article first published online: 2 DEC 2011
- Manuscript Accepted: 19 SEP 2011
- Manuscript Received: 19 JUL 2011
- Manuscript Revised:
- kinesin spindle protein inhibitor;
- phase 1;
- maximum tolerated dose;
- advanced myeloid leukemia;
- myelodysplastic syndrome;
ARRY-520 selectively inhibits the mitotic kinesin spindle protein (KSP), which leads to abnormal monopolar spindle formation and apoptosis.
A phase 1 trial was conducted to establish the safety and the maximum tolerated dose (MTD) of ARRY-520 given as a 1-hour infusion in either a single dose or on a day 1, 3, and 5 divided-dose schedule per cycle in patients with advanced or refractory myeloid leukemias. Additional objectives were to characterize pharmacokinetics, assess preliminary clinical activity, and explore biomarkers of KSP inhibition with ARRY-520. A total of 36 patients with acute myelogenous leukemia (n = 34) or myelodysplastic syndromes (n = 2) with a median age of 66 years (range, 21-88 years) were enrolled: 15 in the single-dose schedule (dose levels: 2.5, 3.75, 4.5, and 5.6 mg/m2) and 21 in the divided-dose schedule (dose levels: 0.8, 1.2, 1.5, and 1.8 mg/m2/day).
The MTD was 4.5 mg/m2 total dose per cycle for both dose schedules. Dose-limiting toxicities included mucositis, exfoliative rash, hand-foot syndrome, and hyperbilirubinemia. Grades 3 or 4 reversible drug-related myelosuppression were observed in 33 of 36 patients. Plasma pharmacokinetic analyses revealed low clearance of ARRY-520 (∼3 L/hour), a volume of distribution of ∼450 L, and a median terminal half-life of >90 hours. Monopolar spindles were observed in blood mononuclear cells, through use of 4′,6-diamidino-2-phenylindole nucleic acid stain and antitubulin antibodies.
On the basis of the relative lack of clinical activity, further development of ARRY-520 as an antileukemic agent was halted. (Clinicaltrials.gov identifier NCT00637052). Cancer 2012;3556–3564. © 2011 American Cancer Society.