First-in-class phase I trial of a selective Akt inhibitor, MK2206 (MK), evaluating alternate day (QOD) and once weekly (QW) doses in advanced cancer patients (pts) with evidence of target modulation and antitumor activity.

Abstract

3009 Background: Akt mediates cell proliferation, survival, and angiogenesis and is deregulated in cancer. MK is a potent, allosteric Akt1/2/3 inhibitor, with wide preclinical antitumor activity and a predicted long terminal elimination half-life (t1/2). Methods: MK was initially given QOD; due to the observed long t1/2, a QW schedule was also evaluated. Archival tumor and circulating nucleic acid were analyzed for PTEN and PIK3CA aberrations. Pharmacodynamic (PD) analyses of AKT and downstream target phosphorylation (p) were conducted in tumor (mandatory biopsies at MTD), platelet-rich plasma (PRP) and hair follicles (HF). Circulating endothelial cell (CEC) and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) studies were conducted. Results: 70 pts (41 M; median age 60 yr; ECOG PS 0/1: 23/47) received MK. 55 pts received MK at 30, 60, 75 or 90 mg QOD; G3/4 rash (n=6) and G3 mucositis (n=1) were dose-limiting at 75 and 90 mg QOD. 15 pts received MK at 90, 135, 200 or 300 mg QW; G3 rash (n=3) was dose-limiting at 300 mg QW. Common reversible drug-related toxicities included rash (48.6%), nausea (20.0%), fatigue (17.1%) and hyperglycemia (12.9%). Pharmacokinetics were dose proportional; median Tmax was 6-8 hrs; mean t1/2 was 55-78 hrs. 9 pts at 60 mg QOD had serial tumor biopsies demonstrating pAKT inhibition following MK (>90% in 4/9; >70% in 7/9). This correlated with sustained falls in pAKT in PRP (p<0.001) and pPRAS40 in HF (p<0.05). A PTEN-negative (immunohistochemistry) pancreatic cancer pt (60 mg QOD) had 23% RECIST tumor shrinkage and 60% CA19-9 decline, with PD effects in tumor and HF. Minor tumor regressions (melanoma, neuroendocrine cancer), CA125 declines, PSA stabilization, tumor necrosis, and decreased ascites were seen following MK administration. Moreover, 18 of 23 (78.3%) evaluable pts had post-MK CEC declines of up to −100% (median change −69%); DCE-MRI studies (n≥12) are ongoing. Conclusions: MK has a long t1/2 and can be administered either on a QOD or QW schedule that is well tolerated and can induce sustained AKT blockade. MK also has antitumor activity and may be antiangiogenic. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Merck Merck Merck Chemotherapy Foundation, Merck Merck