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

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 median time to peak plasma concentrations was 1.5 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.

Trial registration: ClinicalTrials.gov NCT00881946.

© 2014 by The American Society of Hematology.

Figures

Figure 1

Mean afuresertib plasma concentration-time profiles following repeat dose (day 8). Mean (± standard deviation) day 8 plasma concentration profiles at each dose are shown. Error bars shown represent standard deviation.

Figure 2

Duration of study treatment of 34 patients with MM. Arrows indicate patients who were still ongoing at the time of study closure. Those patients are continuing treatment with afuresertib on a continuation protocol. Two patients were enrolled in dose escalation (part 1) and were administered 100 mg per day (indicated by *); the remaining patients were administered 125 mg per day. NE, not evaluable; PD, progressive disease; SD, stable disease.