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Final results of a translational phase l study assessing a QOD schedule of the potent AKT inhibitor MK-2206 incorporating predictive, pharmacodynamic (PD), and functional imaging biomarkers.
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2011
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Drug TargetEngineeringOncologic ImagingImmunologyPathologyPharmacotherapyQod ScheduleNovel Allosteric InhibitorTumor BiologyPharmacodynamic ModelingTranslational PharmacologyFunctional Imaging BiomarkersTranslational MedicineTheranosticsAnti-cancer AgentMolecular DiagnosticsFinal ResultsTumor BiopsiesMolecular OncologyCancer ResearchTherapeutic Drug MonitoringMedicinePten ExpressionTumor TargetingPharmacologyImmune Checkpoint InhibitorOncology
3001^ Background: MK-2206 is a novel allosteric inhibitor of all 3 isoforms of AKT, which are targets implicated in malignant progression. Methods: The investigational agent MK-2206 was given orally QOD to patients (pt) with advanced solid tumors. PD studies of AKT and downstream protein phosphorylation (p) were carried out in tumor biopsies and platelet-rich plasma with MesoScale Discovery (MSD) ELISA, and hair follicles with immunofluorescence. Tumor biopsies were sequenced with Sequenom Oncocarta panel for putative predictive biomarkers and stained with IHC for PTEN expression. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), MR spectroscopy (MRS) and diffusion weighted imaging (DWI) were conducted. Results: 71 pt (37 M; median age 59y; ECOG PS 0/1: 22/49) received MK-2206 at 30, 60, 75, 90 mg QOD. G3 rash (n=6) was dose limiting at 75-90 mg QOD, establishing MTD at 60mg QOD. Four MTD expansion cohorts were then undertaken: paired tumor biopsies (n=14), functional imaging (n=13), ovarian cancer (n=11) and castration resistant prostate cancer (n=14). MK-2206 related toxicities included rash, nausea, fatigue, and hyperglycemia. C-peptide levels increased on MK-2206. No G5 toxicities were seen. PK was dose proportional. Steady state trough MK-2206 concentrations ≥60mg QOD were above those required for both pAKT inhibition and antitumor activity in preclinical models. PD studies in patients treated at the MTD demonstrated that on commencement of MK-2206: 1) pAKT was inhibited in all on-treatment tumor biopsies (p=.002); 2) pAKT, pPRAS40, and pGSK3β were suppressed in platelet-rich plasma from 3h to 48h (all p<.05); 3) pPRAS40 was inhibited 6h to day 15 in hair follicles (p=.03). Median tumor DWI apparent diffusion coefficients increased significantly in 4 pt at day 7 and 2 pt at Day 21 of MK-2206, supporting intratumoral necrosis; DCE-MRI and MRS did not change post MK-2206. 9 pt had RECIST stable disease >4 months with minor responses in 3 pt and CA125 declines observed. Conclusions: MK-2206 can safely induce significant and sustained AKT pathway blockade at the MTD with early signs of clinical activity observed.