The novel AKT inhibitor afuresertib shows favorable safety, pharmacokinetics, and clinical activity in multiple myeloma

Andrew Spencer, Sung-Soo Yoon, Simon Harrison, Shannon R Morris, Deborah A Smith, Richard A Brigandi, Jennifer Lynn Shannon Gauvin, Rakesh Kumar, Joanna B Opalinska, Christine Chen

Research output: Contribution to journalArticleResearchpeer-review

86 Citations (Scopus)

Abstract

The PI3K/AKT pathway is constitutively active in hematologic malignancies, providing proliferative and antiapoptotic 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 were treated at doses ranging from 25 to 150 mg per day. The MTD was established at 125 mg per day because of 2 dose-limiting toxicities in the 150-mg cohort (liver function test abnormalities). The most frequent adverse events were nausea (35.6 ), diarrhea (32.9 ), and dyspepsia (24.7 ). Maximum plasma concentrations and area under the plasma concentration-time curves from time 0 to 24 hours were generally dose proportional at >75-mg doses; the mediantime to peak plasma concentrationswas1.5 to 2.5 hours post dose, with a half-life of approximately 1.7 days. Three multiple myeloma patients attained partial responses; an additional 3 attained minimal responses. Clinical activity was also observed in non-Hodgkin lymphoma, Langerhan s cell histiocytosis, and Hodgkin disease. Single-agent afuresertib showed a favorable safety profile and demonstrated clinical activity against hematologic malignancies, including multiple myeloma. This trial was registered at www.clinicaltrials.gov as NCT00881946. (Blood. 2014;124(14):2190-2195).
Original languageEnglish
Pages (from-to)2190 - 2195
Number of pages6
JournalBlood
Volume124
Issue number14
DOIs
Publication statusPublished - 2014

Cite this