Novel AKT inhibitor afuresertib shows favorable safety, pharmacokinetics, and clinical activity in multiple myeloma: Phase 1 study results
Mené sur 73 patients atteints d'un cancer hématologique de stade avancé, notamment d'un myélome multiple, cet essai de phase I évalue la dose maximale recommandée et l'activité clinique de l'afuresertib, un inhibiteur de AKT par voie orale
The PI3K/AKT pathway is constitutively active in multiple cancers, including hematologic malignancies, providing proliferative and anti-apoptotic signals and possibly contributing to drug resistance. We conducted an open-label phase 1 study to evaluate the maximum tolerated dose (MTD), safety, pharmacokinetics, and clinical activity of afuresertib—an oral AKT inhibitor—in patients with advanced hematologic malignancies. Seventy-three patients (median age: 63 years) were treated at doses ranging from 25 to 150mg/d. The MTD was established at 125mg/d due to two dose-limiting toxicities in the 150-mg cohort (liver function test abnormalities). Most frequent adverse events were nausea (35.6%), diarrhea (32.9%), and dyspepsia (24.7%). Cmax and AUC(0-24) were generally dose proportional at >75mg doses; the median time to peak plasma concentrations was 1.5-2.5h post-dose, with a half-life of approximately 1.7 days. Overall, three multiple myeloma patients attained partial response (PR); additional three attained minimal responses (MR). Clinical activity was also observed in non-Hodgkin's lymphoma (n=1 complete response; n=1 PR). One patient with Langerhan's histiocytosis attained PR; six with Hodgkin's disease had disease stabilization for prolonged periods of time. Single-agent afuresertib had a favorable safety profile and demonstrated clinical activity against hematologic malignancies, including multiple myeloma. Clinical trial information: NCT00881946.Submitted March 4, 2014.Accepted July 15, 2014.Copyright © 2014 American Society of Hematology