Phase 1 pharmacokinetic study of the oral pan-AKT inhibitor MK-2206 in Japanese patients with advanced solid tumors

Toshihiko Doi, Kenji Tamura, Yuko Tanabe, Kan Yonemori, Takayuki Yoshino, Nozomu Fuse, Makoto Kodaira, Hideaki Bando, Kazuo Noguchi, Takashi Shimamoto, Atsushi Ohtsu, Toshihiko Doi, Kenji Tamura, Yuko Tanabe, Kan Yonemori, Takayuki Yoshino, Nozomu Fuse, Makoto Kodaira, Hideaki Bando, Kazuo Noguchi, Takashi Shimamoto, Atsushi Ohtsu

Abstract

Purpose: MK-2206 is an oral, highly selective inhibitor of AKT. The safety, tolerability, pharmacokinetics (PK), and anti-tumor activity of MK-2206 was evaluated in Japanese patients with advanced solid tumors.

Methods: Patients received a single oral dose of MK-2206 according to an every other day (QOD) dosing schedule or a once weekly (QW) dosing schedule in repeating 28-day treatment cycles, with a 7-day rest after only the first cycle. The dose-limiting toxicities (DLTs) were evaluated during Cycle 1. Full PK sampling was performed during Cycle 1.

Results: Twenty-four patients were treated at 45 mg (n = 3) or 60 mg (n = 9) QOD or at 135 mg (n = 3) or 200 mg (n = 9) QW. One patient experienced a DLT at 60 mg QOD, and three patients experienced DLTs at 200 mg QW. No DLTs were observed at 45 mg QOD or at 135 mg QW. The DLTs included mucosal inflammation, hyponatremia, face edema, erythema multiforme, and hyperglycemia. Common adverse events related to MK-2206 included rash, an elevated insulin c-peptide level, stomatitis, pyrexia, eosinophilia, leukopenia, and hyperglycemia. PK differences in MK-2206 exposure were observed between Japanese patients and non-Japanese patients. The higher exposure in Japanese patients was likely caused by the relatively lower weight of Japanese patients versus non-Japanese patients. No tumor responses were observed, but six patients exhibited stable disease lasting longer than 4 months.

Conclusions: MK-2206 has an acceptable safety profile in Japanese patients with advanced solid tumors and warrants further investigation.

Figures

Fig. 1
Fig. 1
Mean MK-2206 plasma concentration profiles for Japanese patients receiving multiple oral doses of 45 or 60 mg of MK-2206 every other day (QOD) for 4 weeks or 135 or 200 mg of MK-2206 once weekly (QW) for 4 weeks (semi-log scale)
Fig. 2
Fig. 2
Weight versus AUC0–168-h (a first dose: Day 1, b last dose: Day 22) of MK-2206 for Japanese and non-Japanese patients receiving 200 mg of MK-2206 QW

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