Phase I Study to Assess the Safety, Tolerability and Pharmacokinetics of AZD4877 in Japanese Patients with Solid Tumors

Abstract

IntroductionAZD4877 is a potent Eg5 inhibitor that has been shown to have an acceptable tolerability profile in a Phase I study of Western patients with solid tumors. This study was conducted to evaluate the safety, pharmacokinetic (PK) profile, maximum tolerated dose (MTD) and efficacy of AZD4877 in a Japanese population with solid tumors.MethodsIn this Phase I, open-label, dose-escalation study, AZD4877 (10, 15, 20 or 25 mg) was administered as a 1-hour intravenous infusion on days 1, 8 and 15 of repeated 28-day cycles to Japanese patients with advanced solid tumors. Adverse events (AEs) were evaluated according to Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. PK variables were assessed pre- and post dosing. The MTD of AZD4877 was determined by evaluating dose-limiting toxicities (DLTs). Efficacy was evaluated by assessing best response according to Response Evaluation Criteria In Solid Tumors version 1.0.ResultsOf the 21 patients enrolled, 18 received at least one dose of AZD4877 (N = 3 in both the 10 and 15 mg cohorts, N = 6 in both the 20 and 25 mg cohorts). The most commonly reported AEs were fatigue and nausea (39% of patients each). One patient in each of the 20 and 25 mg cohorts experienced a DLT (neutropenia and febrile neutropenia). Dose escalation was halted at 25 mg and the MTD was not defined in this population. CTCAE grade ≥3 abnormal laboratory findings/vital signs were reported in 12 patients, with neutropenia (56%) and leukopenia (44%) being the most commonly reported. Exposure to AZD4877 was not fully dose proportional and AZD4877 clearance and elimination half-life appeared independent of dose. The best response to AZD4877 was stable disease in five of 16 evaluable patients.ConclusionAZD4877 up to doses of 25 mg was well tolerated in Japanese patients. There was little evidence of clinical efficacy.

The structure of the ternary Eg5–ADP–ispinesib complex

“…Ispinesib (also named SB-715992 or CK0238273) is a potent and selective inhibitor of Eg5 that is currently in multiple phase II clinical trials (Burris et al, 2011;Souid et al, 2010) and is one of the most advanced drug candidates. The importance of the quinazolin-4-one scaffold targeting Eg5 is further underlined by the fact that three structurally related compounds are in various stages of clinical development: SB-743921, a second-generation ispinesib analogue (Holen et al, 2011), AZD4877 (Esaki et al, 2011) and Arq621 (Chen et al, 2011). A greater understanding of the molecular details of the protein-inhibitor interactions of this class of compounds is therefore crucial.…”

Second-Generation Antimitotics in Cancer Clinical Trials

“…Overall, the results were disappointing. In the phase I trials in solid tumor patients (NCT00613652 and NCT00389389), neutropenia was the most common DLT [ 217 , 218 ]. No objective responses were observed, with 31% and 27% of patients achieving SD, respectively [ 217 , 218 ].…”

“…In the phase I trials in solid tumor patients (NCT00613652 and NCT00389389), neutropenia was the most common DLT [ 217 , 218 ]. No objective responses were observed, with 31% and 27% of patients achieving SD, respectively [ 217 , 218 ]. Other trials with AML (NCT00486265) and urothelial cancer (NCT00661609) patients demonstrated similar efficacy.…”

Resistance by Allostery: A Novel Perspective for Eg5-Targeted Drug Design

“…SB743921, a derivative of ispinesib and found to be 5-fold more potent against ATPase activity of Eg5, is undergoing phase II clinical trials . AZD4877, − MK0731, ARQ621, and ARRY520 have progressed to various stages of clinical development.…”