474P - Phase 1 study of the selective AKT inhibitor MK-2206 in Japanese patients with advanced solid tumors

Date 01 October 2012
Event ESMO Congress 2012
Session Poster presentation III
Topics Drug Development
Presenter Yuko Tanabe
Authors Y. Tanabe1, T. Doi2, K. Tamura3, K. Yonemori1, M. Kodaira1, N. Fuse4, H. Bando5, Y. Maeda6, T. Shimamoto6, A. Ohtsu7
  • 1Breast And Medical Oncology Division, National Cancer Center Hospital, 104-0045 - Tokyo/JP
  • 2National Cancer Center Hospital East; Chiba, Japan, Chiba/JP
  • 3Outpatient Treatment Center, National Cancer Center Hospital, 104-0045 - Tokyo/JP
  • 4Gastroenterology & Gi Oncology Department, National Cancer Center Hospital East; Chiba, Japan, Chiba/JP
  • 5Department Of Gastroenterology And Gastrointestinal Oncology, National Cancer Center Hospital East; Chiba, Japan, 277-8577 - Chiba/JP
  • 6Japan Development, MSD K.K.; Tokyo, Japan, Tokyo/JP
  • 7Research Center For Innovative Oncology, National Cancer Center Hospital East; Chiba, Japan, JP-277-8577 - Chiba/JP



The AKT pathway, which mediates cell proliferation, survival, and angiogenesis, is commonly dysregulated in cancer. MK-2206 is an orally active, allosteric AKT 1/2 inhibitor with wide preclinical activity. This open-label, nonrandomized study investigated the safety, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity of MK-2206 in Japanese patients with solid tumors who were refractory to standard therapy.


Patients received once every other day (qod) or once-weekly (qw) doses of MK-2206 in 28-day treatment cycles, with a 1-week drug holiday following Cycle 1. Dose-limiting toxicities (DLTs) were evaluated during Cycle 1, with cohorts of 3, 6, or 9 patients, depending on the dose studied and adverse events (AEs) experienced by patients. Overall antitumor activity was assessed at designated time points every other treatment cycle after initial screening, following RECIST guidelines.


Treated patients (N = 24; male/female: 10/14; median age: 57 yrs; ECOG PS 0/1: 16/8) received MK-2206 45 mg or 60 mg qod (n = 12) and 135 mg or 200 mg qw (n = 12). Grade 3 rash was the DLT at both 60 mg qod (1 of 9 patients) and 200 mg qw (3 of 9 patients). Common reversible drug-related toxicities included rash (83.3%), stomatitis (58.3%), pyrexia (58.3%), and hyperglycemia (54.2%). MK-2206 terminal half-life did not differ from non-Japanese patients (69–80 h vs 60–90 h), but Cmax, AUC, and Ctroughwere generally higher in Japanese patients (1.5- to 1.7-fold). ANOVA models that adjusted for body weight suggested that PK differences could be mostly attributed to between-study body weight differences. PD assays demonstrated inhibition of blood pAKT at Day 15 (27.6%–61.4%). Modest antitumor activity was observed with a best response of stable disease (SD) lasting longer than 42 weeks; patients who achieved SD had various diagnoses, including neuroendocrine carcinoma and esophageal cancer.


MK-2206 at doses up to 60 mg or 200 mg has a long terminal half-life and can be safely administered on either qod or qw dosing schedules. Higher exposures were observed in Japanese patients, but this could be explained by body weight differences.


All authors have declared no conflicts of interest.