Abstract
Abstract Background: Akt is a key mediator of cell proliferation, growth and survival, and is deregulated in a range of human cancers. MK-2206 is a highly selective, potent allosteric non-ATP competitive inhibitor of Akt1, 2 and 3, with nanomolar IC50 and broad preclinical antitumor activity. Methods: MK-2206 was administered on alternate days (QOD) and weekly (QW) in 28-day cycles, with assessment of safety, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary antitumor efficacy. PD studies included mesoscale discovery ELISA (MSD) and immunohistochemical (IHC) analyses of Akt and downstream substrates in tumor biopsies, as well as in platelet-rich plasma (PRP) by MSD and plucked hair follicles by immunofluorescence. Once MTD was established, paired pre- and post-treatment tumor biopsies were mandated in a separate cohort of 12 pts to confirm target inhibition. The MTD is currently being explored in ovarian cancer (n=12) and CRPC (n=12) cohorts. Circulating nucleic acid and tumor tissue were analyzed for PIK3CA mutations and PTEN status respectively and correlated with antitumor efficacy. Results: 48 pts (23 F/25 M; median age 57 years; ECOG performance status 0/1: 24/24) received MK-2206 in either QOD or QW schedules. Following evaluation of 19 pts at doses 30, 60, 75 and 90 mg, the QOD MTD was established at 60 mg, with dose limiting toxicities (DLT) of CTCAE G3/4 skin rash and G3 mucositis. QW dose escalation is ongoing (doses 90, 135 and 200 mg) with no DLT observed. Common drug-related toxicities include hyperglycemia (42.9%), skin rash (39.6%), nausea and fatigue (27.1%), and diarrhea (20.8%). PK (AUC0–48hr and Cmax) was dose proportional up to 60 mg QOD and at 90 mg QW. Median Tmax was 6–8 hrs and mean t1/2 ranged from 55 to 78 hr. The observed MK-2206 plasma concentrations achieved preclinically established PK targets for significant phosphorylated AKT (pAKT) inhibition in blood. Robust pAKT inhibition of approximately 90% was observed in paired tumor biopsies (5 of 7 pts) at 60 mg QOD, confirming target modulation at this dose level. This was supported by substantial decreases in pAKT and downstream biomarker signals e.g. pGSK3 in PRP in pts tested in the 60 mg QOD and 90 mg and higher QW cohorts, as well as asymptomatic reversible G1-3 hyperglycemia and G1 insulin c-peptide elevation. Observed antitumor activity included: tumor regression, CA125 declines, PSA stabilization, central tumor necrosis, liver function normalization, and decreased ascites. Conclusions: MK-2206 is generally well tolerated at the MTD of 60 mg QOD with dose proportional PK, substantial and sustained pAKT inhibition in tumor with supporting evidence in surrogate tissue confirming target modulation, and preliminary clinical activity. Dose escalation continues with the QW schedule. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B135.
Published Version
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