Abstract 27: First dose-finding study in cancer patients (pts) of a potent, selective, allosteric AKT inhibitor MK2206 (MK), incorporating pharmacodynamic (PD) and predictive biomarkers and showing profound pathway blockade

Abstract

Background: Akt signaling plays a key role in cell proliferation, growth and survival, and is commonly deregulated in human cancers. MK inhibits Akt1/2/3, with nanomolar IC50 and has broad preclinical antitumor activity. Methods: MK was administered either every second day (QOD) or weekly (QW), due to a predicted long elimination half-life, in a Phase I dose escalation trial. Detailed pharmacokinetic-pharmacodynamic (PK-PD) studies were pursued. At MTD, mandatory pre- and post-MK tumor biopsies (n=12) were carried out to confirm target inhibition; expanded cohorts of ovarian (n=12) and prostate cancers (n=12) were also assessed. Archival tumor and circulating nucleic acid were analyzed for PTEN loss and PIK3CA mutations respectively. PD studies included Meso Scale Discovery (MSD) ELISA and immunohistochemical (IHC) analyses of Akt phosphorylation and of its downstream targets in tumor; MSD in platelet-rich plasma (PRP); and immunofluorescence in hair follicles. Results: 58 pts (25 F/33 M; median age 60 years; ECOG PS 0/1: 16/42) received MK in either QOD or QW schedules. 45 pts received MK at 30, 60, 75 or 90 mg QOD. The QOD MTD was 60 mg, with dose limiting toxicities (DLT) of CTCAE G3/4 skin rash and G3 mucositis. QW MTD is currently being established; to date, 13 pts have received MK at 90, 135, 200 and 300 mg QW. 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 135 mg QW. Median Tmax was 6-8 hours and mean t1/2 ranged from 55 to 78 hours. Plasma concentrations of MK achieved preclinically established PK targets for significant phosphorylated Ser473 AKT (pAKT) inhibition. Robust pAKT inhibition of ∼70% by MSD was observed in paired tumor biopsies (6 of 9 pts) in the 60 mg QOD biopsy cohort, confirming target modulation at this MTD dose. At 60 mg QOD, these tumor PD effects correlated with statistically significant decreases in pAKT in PRP (p<0.001) and phosphorylated Thr246 PRAS40 (pPRAS40) in hair follicles (p<0.05) following MK. In QW cohorts, doses from 90 mg showed decreases in pAKT in PRP and pPRAS40 in hair follicles. Reversible G1-3 hyperglycemia and G1 insulin c-peptide elevation were also reported. An advanced pancreatic cancer pt with PTEN loss (60 mg QOD) had a 23% decrease in RECIST tumor measurements and ∼60% decrease in CA19-9 tumor marker, with target modulation confirmed in tumor and hair follicles. Other antitumor activity included: minor tumor responses (metastatic melanoma, neuroendocrine cancer), CA125 declines, PSA stabilization, central tumor necrosis and decreased ascites. Conclusions: MK is generally well tolerated at the MTD of 60 mg QOD. Profound AKT signaling blockade was reported, including antitumor activity in a pt with PTEN loss. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 27.

Genomic Complexity and AKT Dependence in Serous Ovarian Cancer

“…The AKT-1/2 inhibitor (AKTi-1/2) inhibits AKT1 and AKT2 with EC 50 s of 3.5 nM and 42.1 nM, respectively, and is significantly less potent against AKT3, with an EC 50 of 1.9 µM in in vitro kinase assays (15). The pan-AKT-1/2/3 inhibitor (hereafter referred to by its clinical name, MK2206) potently inhibits all three AKT isoforms with EC 50 values of 8, 12 and 65 nM for AKT1, -2 and -3, respectively (16, 17). As depicted in Fig.…”

“…AKT1/2 inhibitor (AKTi-1/2, compound 17) (15) and pan-AKT1/2/3 inhibitor (MK2206) (16, 17) were obtained from Merck. PD0325901 (PD901) was synthesized as reported (26–29).…”

Preclinical Pharmacology, Antitumor Activity, and Development of Pharmacodynamic Markers for the Novel, Potent AKT Inhibitor CCT128930

“…In the future, this technique may potentially be developed further to include the analyses of multiple biomarkers per hair follicle through the use of antibodies directly labeled with distinct fluorophores. This hair follicle assay is currently being employed as a pharmacodynamic readout in the Phase I clinical trial of the allosteric AKT inhibitor MK2206 (20).…”

“…In this paper, we present the preclinical pharmacology of the novel AKT inhibitor CCT128930 and demonstrate its effects on appropriate pharmacodynamic biomarkers, both in vitro and in vivo , as well as promising antitumor efficacy in human tumor xenograft models with PI3K-AKT-mTOR pathway activation. Using CCT128930 as a preclinical tool, we have also developed a robust and sensitive, non-invasive pharmacodynamic biomarker assay using hair follicles, which is currently being employed in a clinical trial of an AKT inhibitor (20).…”