A Phase I trial of the kinesin spindle protein (Eg5) inhibitor AZD4877 in patients with solid and lymphoid malignancies
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Background This Phase I study assessed the safety and maximum tolerated dose (MTD) of the kinesin spindle protein inhibitor AZD4877 in patients with relapsed/refractory solid tumors and lymphoma. Methods In this multicenter study, a standard 3 + 3 dose-escalation design was used. AZD4877 was given as an intravenous infusion on days 1, 4, 8 and 11 of each 21-day cycle. Responses were assessed with CT scans +/− PET after 6 and 12 weeks, then every 12 weeks while on therapy. An additional four patients with lymphoma were enrolled at the MTD. Results 29 patients were enrolled and 22 patients received at least one dose of AZD4877 and were evaluable for safety. The MTD was 11 mg. Dose-limiting toxicity was neutropenia (n = 2 patients, 15 mg cohort). The most common adverse events were grade 1/2 fatigue, nausea, neutropenia and dyspnea. AZD4877 exposure generally increased with dose, with mean elimination half-life approximately 16 h at the MTD. Pharmacodynamic analyses demonstrated moderate correlation between plasma drug concentrations at 6 or 24 h and monoaster formation in peripheral blood mononuclear cells (PBMCs). Conclusions AZD4877 is generally well-tolerated with pharmacodynamic evidence of target inhibition in circulating PBMCs.
KeywordsAZD4877 Eg5 Solid tumors Safety Tolerability Pharmacokinetics
We thank Claire Routley PhD from Mudskipper Bioscience who provided editorial assistance funded by AstraZeneca. We also thank Linda Hylander-Gans from AstraZeneca R&D Boston for support and technical assistance with the monoaster analysis.
This study was funded by AstraZeneca.
Conflicts of interest
Nancy L. Lewis has attended advisory boards for Macrogenics. Anna Osmukhina, Jianguo Li, Zhiping You, Dennis Huszar and Jeffrey M. Skolnik are all employees at AstraZeneca. Kaida Wu was an employee of AstraZeneca at the time of the study. Anna Osmukhina, Dennis Huszar and Jeffrey M. Skolnik own stock in AstraZeneca.
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