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

Hanna Jean Khoury, Guillermo Garcia-Manero, Gautam Borthakur, Tapan Kadia, Maria Cielo Foudray, Martha Arellano, Amelia Langston, Beverly Bethelmie-Bryan, Selena Rush, Kevin Litwiler, Sharon Karan, Heidi Simmons, Adam I Marcus, Mieke Ptaszynski, Hagop Kantarjian, Hanna Jean Khoury, Guillermo Garcia-Manero, Gautam Borthakur, Tapan Kadia, Maria Cielo Foudray, Martha Arellano, Amelia Langston, Beverly Bethelmie-Bryan, Selena Rush, Kevin Litwiler, Sharon Karan, Heidi Simmons, Adam I Marcus, Mieke Ptaszynski, Hagop Kantarjian

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. (Clinicaltrials.gov identifier NCT00637052).

Conflict of interest statement

Conflict of Interest: Salena Rush and Mieke Ptaszynski – Array BioPharma Inc. Employment, Hagop Kantarjian-Commercial Research Funding, Gautam Borthakur – Consultant and Advisory Board Member.

Copyright © 2011 American Cancer Society.

Figures

Figure 1
Figure 1
Geometric Mean Plasma Concentration of ARRY-520 (with 1 Standard Deviation) for Schedule 1 (Panel A) and Schedule 2 (Panel B)
Figure 1
Figure 1
Geometric Mean Plasma Concentration of ARRY-520 (with 1 Standard Deviation) for Schedule 1 (Panel A) and Schedule 2 (Panel B)
Figure 2
Figure 2
Aberrant spindles are observed in PBMCs after ARRY-520 treatment. Confocal imaging of PBMCs from patients with (A) DAPI (B) tubulin and (C) merge of tubulin and DAPI staining.
Figure 2
Figure 2
Aberrant spindles are observed in PBMCs after ARRY-520 treatment. Confocal imaging of PBMCs from patients with (A) DAPI (B) tubulin and (C) merge of tubulin and DAPI staining.
Figure 2
Figure 2
Aberrant spindles are observed in PBMCs after ARRY-520 treatment. Confocal imaging of PBMCs from patients with (A) DAPI (B) tubulin and (C) merge of tubulin and DAPI staining.

Source: PubMed

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