A phase 1 dose-escalation study of ARRY-520, a kinesin spindle protein inhibitor, in patients with advanced myeloid leukemias

• Type of Material: Article
• Authors: Hanna Khoury, Emory University; Guillermo Garcia-Manero, University of Texas; Gautam Borthakur, University of Texas; Tapan Kadia, University of Texas; Maria Cielo Foudray, University of Texas; Martha Arellano, Emory University; Amelia Langston, Emory University; Beverly Bethelmie-Bryan, Emory University; Selena Rush, Array BioPharma; Kevin Litwiler, Array BioPharma; Sharon Karan, Array BioPharma; Heidi Simmons, Array BioPharma; Adam Marcus, Emory University; Mieke Ptaszynski, Array BioPharma; Hagop Kantarjian, University of Texas
• Language: English
• Date: 2012-07-15
• Publisher: Wiley: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: @ 2011 American Cancer Society.
• Final Published Version (URL): http://dx.doi.org/10.1002/cncr.26664
• Title of Journal or Parent Work: Cancer
• ISSN: 0008-543X
• Volume: 118
• Issue: 14
• Start Page: 3556
• End Page: 3564
• Grant/Funding Information: This article was funded by P30 CA016672.
• Keywords: kinesin spindle protein inhibitor; Life Sciences & Biomedicine; myelodysplastic syndrome; advanced myeloid leukemia; PREPARATIVE REGIMEN; SMALL-MOLECULE INHIBITOR; ONCOLOGY; CONSOLIDATION THERAPY; relapsed; Oncology; ACUTE NONLYMPHOBLASTIC LEUKEMIA; maximum tolerated dose; MITOTIC KINESIN; Science & Technology; ARRY-520; phase 1; ACUTE NONLYMPHOCYTIC LEUKEMIA; ACUTE MYELOGENOUS LEUKEMIA; BONE-MARROW-TRANSPLANTATION; CYTOSINE-ARABINOSIDE THERAPY; POSTREMISSION CHEMOTHERAPY
• Research Categories: Health Sciences, Oncology; Biology, Microbiology

Abstract

BACKGROUND: ARRY-520 selectively inhibits the mitotic kinesin spindle protein (KSP), which leads to abnormal monopolar spindle formation and apoptosis. METHODS: 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/m 2) and 21 in the divided-dose schedule (dose levels: 0.8, 1.2, 1.5, and 1.8 mg/m 2/day). RESULTS: The MTD was 4.5 mg/m 2 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. CONCLUSIONS: On the basis of the relative lack of clinical activity, further development of ARRY-520 as an antileukemic agent was halted. © 2011 American Cancer Society.