Interrogating Two Schedules of the AKT Inhibitor MK-2206 in Patients with Advanced Solid Tumors Incorporating Novel Pharmacodynamic and Functional Imaging Biomarkers

Abstract

Purpose: Multiple cancers harbor genetic aberrations that impact AKT signaling. MK-2206 is a potent pan-AKT inhibitor with a maximum tolerated dose (MTD) previously established at 60 mg on alternate days (QOD). Due to a long half-life (60-80 hours), a weekly (QW) MK-2206 schedule was pursued to compare intermittent QW and continuous QOD dosing.Experimental Design: Patients with advanced cancers were enrolled in a QW dose-escalation phase I study to investigate the safety and pharmacokinetic-pharmacodynamic profiles of tumor and platelet-rich plasma (PRP). The QOD MTD of MK-2206 was also assessed in patients with ovarian and castrationresistant prostate cancers and patients with advanced cancers undergoing multiparametric functional magnetic resonance imaging (MRI) studies, including dynamic contrast-enhanced MRI, diffusion-weighted imaging, magnetic resonance spectroscopy, and intrinsic susceptibility-weighted MRI.Results: A total of 71 patients were enrolled; 38 patients had 60 mg MK-2206 QOD, whereas 33 received MK-2206 at 90, 135, 150, 200, 250, and 300 mg QW. The QW MK-2206 MTD was established at 200 mg following dose-limiting rash at 250 and 300 mg. QW dosing appeared to be similarly tolerated to QOD, with toxicities including rash, gastrointestinal symptoms, fatigue, and hyperglycemia. Significant AKT pathway blockade was observed with both continuous QOD and intermittent QW dosing of MK-2206 in serially obtained tumor and PRP specimens. The functional imaging studies demonstrated that complex multiparametric MRI protocols may be effectively implemented in a phase I trial.Conclusions: Treatment with MK-2206 safely results in significant AKT pathway blockade in QOD and QW schedules. The intermittent dose of 200 mg QW is currently used in phase II MK-2206 monotherapy and combination studies (NCT00670488). Clin Cancer Res; 20(22); 5672-85. Ó2014 AACR.

A Phase I Trial of Combined Ridaforolimus and MK-2206 in Patients with Advanced Malignancies

“…Ridaforolimus strongly and rapidly reduces 4E-BP1 protein levels (indicating mTOR inhibition) in peripheral blood mononuclear cells at doses down to 10 mg QD Â 28 days (16). MK-2206 monotherapy has demonstrated antitumor activity in hormone receptor-positive breast cancer at a reduced dose of 150 mg QW (27). The need to lower ridaforolimus dose when combining with other agents has been reported previously.…”

“…The ridaforolimus starting dose was selected to be 50% of the MTD for oral ridaforolimus as a single agent (40 mg per os QD Â 5/week) in the phase I/II single-agent, dose-escalation trial (16), and 20 mg per os QD Â 5/week was below doses of ridaforolimus that produced minimal to low toxicity as a single agent (16). The starting dose for MK-2206 of 90 mg per os QW was selected, as it had not been associated with any DLTs in a previous dose-finding trial (27) and was less than half the single-agent MTD of 200 mg QW, allowing for dose escalation (27).…”

“…MK-2206 is a highly selective, oral allosteric Akt inhibitor, which is equally potent toward purified recombinant human Akt1 and Akt2 and approximately 5-fold less potent against human Akt3 (IC 50 ¼ 8, 12, and 65 nmol/L, respectively) in enzyme assays and is well tolerated as a single agent (25)(26)(27). In the first-in-humans clinical trial of MK-2206 in advanced solid tumors, 33 patients received MK-2206 at 30, 60, 75, or 90 mg on alternating days.…”

“…Dose-limiting toxicities (DLT) included skin rash and stomatitis, establishing the maximum tolerated dose (MTD) at 60 mg every other day (26). In another phase I trial, a onceweekly (QW) schedule of MK-2206 was found to cause doselimiting rash at 250 and 300 mg, establishing the MTD as 200 mg QW (27).…”

Clinical Trials that Utilize MRS as a Biomarker

“…Finally, one study used MRS to monitor abdominal and pelvic tumors. 2 The mean number of subjects in each study was 37, with a range of 7-154 subjects. Of the studies, 11 had 50 or more subjects, and 65% of the studies showed significant differences and were therefore sufficiently powered.…”