Phase 1/2 study to assess the safety, efficacy, and pharmacokinetics of barasertib (AZD1152) in patients with advanced acute myeloid leukemia.

The primary objective of this 2-part phase 1/2 study was to determine the maximum-tolerated dose (MTD) of the potent and selective Aurora B kinase inhibitor barasertib (AZD1152) in patients with newly diagnosed or relapsed acute myeloid leukemia (AML). Part A determined the MTD of barasertib administered as a continuous 7-day infusion every 21 days. In part B, the efficacy of barasertib was evaluated at the MTD. In part A, 32 patients were treated with barasertib 50 mg (n = 3), 100 mg (n = 3), 200 mg (n = 3), 400 mg (n = 4), 800 mg (n = 7), 1200 mg (n = 6), and 1600 mg (n = 6). Dose-limiting toxicities (stomatitis/mucosal inflammation events) were reported in the 800 mg (n = 1), 1200 mg (n = 1), and 1600 mg (n = 2) groups. The MTD was defined as 1200 mg. In part B, 32 patients received barasertib 1200 mg. In each part of the study, 8 of 32 patients had a hematologic response according to Cheson AML criteria. The most commonly reported grade ≥ 3 events were febrile neutropenia (n = 24) and stomatitis/mucosal inflammation (n = 16). We concluded that the MTD of barasertib is 1200 mg in patients with relapsed or newly diagnosed AML. Toxicity was manageable and barasertib treatment resulted in an overall hematologic response rate of 25%. This study is registered at www.ClinicalTrials.gov as NCT00497991.

Empirical assessment suggests that existing evidence could be used more fully in designing randomized controlled trials.

BACKGROUND: Meta-analyses of randomized controlled trials (RCTs) provide the highest level of evidence regarding the effectiveness of interventions. Less is known about how they are used to inform the design and reporting of RCTs. METHODS: A sample of RCTs published in leading medical journals in 2007 was assessed to establish whether authors considered previous trials in the design of their trial. An approach to calculate the sample size required for a significant pooled effect in an updated meta-analysis was applied to a subsample of the RCTs to illustrate the ways in which the results of an existing meta-analysis can be incorporated into the planning and reporting of new RCTs. RESULTS: Six of the 27 trials assessed (22%) reported the use of previous trial(s) for sample size calculations. Meta-analyses relating the results of the trial to previous research were cited in 37% (10 out of 27) of the report discussion sections. Previous evidence is formally incorporated into retrospective sample size calculations for three of the trials. DISCUSSION/CONCLUSION: Consulting previous research before embarking on a new trial and basing decisions about future research on the impact on an updated meta-analysis will make the reporting of research more coherent and the design of new RCTs more efficient.