Phase I study assessing the safety and tolerability of barasertib (AZD1152) with low-dose cytosine arabinoside in elderly patients with AML

Abstract

Introduction: Barasertib is the pro-drug of barasertib-hydroxy-quinazoline pyrazole anilide, a selective Aurora B kinase inhibitor that has demonstrated preliminary anti-AML activity in the clinical setting.

Patients and methods: This Phase I dose-escalation study evaluated the safety and tolerability of barasertib, combined with LDAC, in patients aged 60 years or older with de novo or secondary AML. Barasertib (7-day continuous intravenous infusion) plus LDAC 20 mg (subcutaneous injection twice daily for 10 days) was administered in 28-day cycles. The MTD was defined as the highest dose at which ≤ 1 patient within a cohort of 6 experienced a dose-limiting toxicity (DLT) (clinically significant adverse event [AE] or laboratory abnormality considered related to barasertib). The MTD cohort was expanded to 12 patients.

Results: Twenty-two patients (median age, 71 years) received ≥ 1 treatment cycle (n = 6, 800 mg; n = 13, 1000 mg; n = 3, 1200 mg). DLTs were reported in 2 patients (both, National Cancer Institute Common Terminology Criteria for Adverse Events grade 3 stomatitis/mucositis; 1200 mg cohort). The most common AEs were infection (73%), febrile neutropenia (59%), nausea (50%), and diarrhea (46%). Barasertib plus LDAC resulted in an overall response rate (International Working Group criteria) of 45% (n = 10/22; according to investigator opinion).

Conclusion: The MTD of 1000 mg barasertib in combination with LDAC in older patients with AML was associated with acceptable tolerability and preliminary anti-AML activity.

Trial registration: ClinicalTrials.gov NCT00926731.

Keywords: Acute myeloid leukemia; Barasertib-hQPA; Dose-escalation study.

Conflict of interest statement

Conflicts of interest

Dr Kantarjian has received research grants from AstraZeneca; Dr Sekeres has attended advisory boards for Celgene and Amgen; Dr Ribrag has received research support from Servier, Bayer and Sanofi, and has served as a consultant for Takeda, Servier and AstraZeneca; Drs Owen, Stockman and Oliver are employees of and own stock in AstraZeneca. All other authors state that they have no conflicts of interest.

Copyright © 2013 Elsevier Inc. All rights reserved.

Figures

Figure 1. Study design

Footnote: SMC, safety monitoring committee

Figure 2. Plasma concentration–time curves for (A) barasertib; (B) barasertib-hQPA; and (C) LDAC

Figure 3. Exposure (AUC and Css) to barasertib-hQPA by barasertib dose