AACR: Pan-AKT Inhibitor ARQ092 Shows Promise in Solid Tumors in First-in-Human Trial

April 11, 2013

The pan-AKT inhibitor ARQ092 was shown to be well-tolerated, avoiding dose-limiting toxicities that often haunt inhibitors of AKT signaling, according to results presented at the 2013 AACR meeting.

Washington, DC-The pan-AKT inhibitor ARQ092 was shown to be well-tolerated, avoiding dose-limiting toxicities that often haunt inhibitors of AKT signaling, according to results presented at the 2013 AACR meeting.

Mansoor Saleh, MD

ARQ092 is a novel pan-AKT inhibitor that targets the pleckstrin homology domain of all AKT isoforms to stabilize the closed conformation and arrest enzyme function. It had been previously shown to be effective in both cell and mouse xenografts models of cancer. The data were presented by Mansoor Saleh, MD, director of research at Georgia Cancer Specialists and professor at the University of Alabama Comprehensive Cancer Center, Birmingham, Alabama.

Twenty-eight patients with advanced metastatic disease who had failed standard chemotherapy were enrolled in the trial, which evaluated toxicity and tolerance as primary endpoints. Pharmacokinetics, pharmacodynamics, and determination of optimal and maximum-tolerated dose were secondary endpoints in this study. Doses started with 10 mg once every 2 days and escalated to 10, 20, 40, and then 80 mg daily. If toxicity was experienced at the 80 mg per day dose, the patients were stepped down to a 60 mg daily dose.

Adverse events for the trial included mild and reversible fatigue, loss of appetite, diarrhea, and nausea. The most significant toxicity noted during the talk was hyperglycemia, which was seen in four patients taking the 80 mg daily dose, which was attenuated when patients were stepped down to the 60 mg dose. Maculopapular rash was not seen until the 80 mg dose, as well. Three of the patients contracted a rash at this dosage, and this side effect was reversed by moving to the 60 mg dose. “Rash, which has been the Achilles’ heel of a variety of AKT inhibitors was not predominant in this particular agent,” noted Dr. Saleh. He also noted that the hyperglycemia tended to precede rash, suggesting doctors could use hyperglycemia as a predictor of future toxicity with ARQ092. Maximum-tolerated dose was unable to be determined, since toxicity experienced at 80 mg was completely ameliorated by moving to the 60 mg dosing schedule.

The pharmacokinetic profile suggested the drug had a 20- to 58-hour half-life, and the drug was still available in the body at 24 hours, suggesting ARQ092 could be useful in intermittent dosing schedules in the future. Nine patients total were also able to have their platelet-rich plasma tested for phosphorylation status of AKT. ARQ092 was shown to significantly reduce these levels, giving preliminary indication that the drug is working as expected in the body. Eleven patients of 20 who could be evaluated in the study also showed stable disease, but no partial or complete clinical response could be observed. “Disease stabilization clearly underscores the fact that patients were able to stay on the study for much longer in the presence of this particular agent,” said Dr. Saleh. Other clinical trials with ARQ092 are being planned in solid tumors and advanced lymphoma using intermittent dosing schedules. ARQ092 was developed by Arqule, Inc.