Cancer Therapy: Clinical Interrogating Two Schedules of the AKT Inhibitor MK-2206 in Patients with Advanced Solid Tumors Incorporating Novel Pharmacodynamic and Functional Imaging Biomarkers
نویسندگان
چکیده
Purpose: Multiple cancers harbor genetic aberrations that impact AKT signaling. MK-2206 is a potent pan-AKT inhibitor with amaximum tolerated dose (MTD) previously established at 60mg 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-enhancedMRI, diffusion-weighted imaging, magnetic resonance spectroscopy, and intrinsic susceptibility-weighted MRI. Results: A total of 71 patients were enrolled; 38 patients had 60mgMK-2206QOD, 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 followingdose-limiting rash at 250 and300mg.QWdosing appeared tobe similarly tolerated toQOD,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 QWschedules. The intermittent dose of 200mgQWis currently used inphase IIMK-2206monotherapy and combination studies (NCT00670488). Clin Cancer Res; 20(22); 5672–85. 2014 AACR.
منابع مشابه
Interrogating two schedules of the AKT inhibitor MK-2206 in patients with advanced solid tumors incorporating novel pharmacodynamic and functional imaging biomarkers.
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 cancer...
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تاریخ انتشار 2014