In a phase I trial, the oral AKT inhibitor afuresertib demonstrated single-agent activity against hematologic malignancies, specifically multiple myeloma.
The oral AKT inhibitor afuresertib demonstrated single-agent activity against hematologic malignancies, specifically multiple myeloma, according to the results of a phase I open-label study published in Blood.
“From this first-time-in-human trial we conclude that afuresertib is safe, well tolerated, and has a favorable pharmacokinetic profile,” wrote Andrew Spencer, MD, of Alfred Hospital-Monash University, Melbourne Australia, and colleagues. “Based on two dose-limiting toxicities in the 150-mg cohort, the recommended monotherapy phase II dose from this study was established at a maximum tolerated dose of 125 mg daily.”
Modern treatments for multiple myeloma, such as carfilzomib and pomalidomide, currently provide patients with a 3- to 4-month increase in progression-free survival. However, researchers are still looking for treatment options that will offer patients with multiple myeloma long-term remission.
Previous studies of afuresertib in mice showed that the drug delayed various human tumor growth, and had a high frequency of sensitivity in T-cell acute lymphoblastic leukemia, B-cell ALL, chronic lymphocytic leukemia, and non-Hodgkin lymphoma.
In this study, Spencer and colleagues sought to evaluate afuresertib’s safety, pharmacokinetics and clinical activity in a variety of relapsed or refractory hematologic malignancies. The study included 73 patients who were treated at doses ranging from 25 mg per day to 150 mg per day.
Thirty-four of the patients had multiple myeloma. Of these patients, three at the 125-mg dose had a confirmed partial response and three patients were classified as having stable disease. The overall response rate for patients with multiple myeloma was 8.8% and the clinical benefit rate was 17.6%.
The maximum tolerated dose was established at 125-mg per day because of dose-limiting hepatotoxicity that occurred in two patients at the 150-mg dose.
“Study treatment was withdrawn from both patients and the liver enzyme abnormalities resolved within 33 days in the first one of the two patients,” the researchers wrote. “Subsequent review of the second patient revealed extensive liver involvement by lymphoma at the time of study enrollment, which confounded interpretation of the dose-limiting toxicity.”
Among the most frequently reported adverse events were nausea (35.6%), diarrhea (32.9%), and dyspepsia (24.7%). All patients on study experienced at least one adverse events and 83.6% were considered related or possibly related to the study treatment.
Some clinical activity was also observed in patients with other hematologic malignancies. One patient with non-Hodgkin lymphoma had a complete response, and six patients had disease stabilization for prolonged periods.
Based on the encouraging clinical activity seen in patients with multiple myeloma, these patients were preferentially enrolled into an expansion cohort.