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

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

SUBMITTER: Doi T

PROVIDER: S-EPMC4515243 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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

Doi Toshihiko T Tamura Kenji K Tanabe Yuko Y Yonemori Kan K Yoshino Takayuki T Fuse Nozomu N Kodaira Makoto M Bando Hideaki H Noguchi Kazuo K Shimamoto Takashi T Ohtsu Atsushi A

Cancer chemotherapy and pharmacology 20150624 2

<h4>Purpose</h4>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.<h4>Methods</h4>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 ev ...[more]

PMID: 26104654

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Project description:BACKGROUND:The PI3K/AKT pathway is activated through PIK3CA or AKT1 mutations and PTEN loss in breast cancer. We conducted a phase II trial with an allosteric AKT inhibitor MK-2206 in patients with advanced breast cancer who had tumors with PIK3CA/AKT1 mutations and/or PTEN loss/mutation. METHODS:The primary endpoint was objective response rate (ORR). Secondary endpoints were 6-month progression-free survival (6?m PFS), predictive and pharmacodynamic markers, safety, and tolerability. Patients had pre-treatment and on-treatment biopsies as well as collection of peripheral blood mononuclear cells (PBMC) and platelet-rich plasma (PRP). Next-generation sequencing, immunohistochemistry, and reverse phase protein arrays (RPPA) were performed. RESULTS:Twenty-seven patients received MK-2206. Eighteen patients were enrolled into the PIK3CA/AKT1 mutation arm (cohort A): 13 had PIK3CA mutations, four had AKT1 mutations, and one had a PIK3CA mutation as well as PTEN loss. ORR and 6?m PFS were both 5.6% (1/18), with one patient with HR+ breast cancer and a PIK3CA E542K mutation experiencing a partial response (on treatment for 36?weeks). Nine patients were enrolled on the PTEN loss/mutation arm (cohort B). ORR was 0% and 6?m PFS was 11% (1/9), observed in a patient with triple-negative breast cancer and PTEN loss. The study was stopped early due to futility. The most common adverse events were fatigue (48%) and rash (44%). On pre-treatment biopsy, PIK3CA and AKT1 mutation status was concordant with archival tissue testing. However, two patients with PTEN loss based on archival testing had PTEN expression on the pre-treatment biopsy. MK-2206 treatment was associated with a significant decline in pAKT S473 and pAKT T308 and PI3K activation score in PBMC and PRPs, but not in tumor biopsies. By IHC, there was no significant decrease in median pAKT S473 or Ki-67 staining, but a drop was observed in both responders. CONCLUSIONS:MK-2206 monotherapy had limited clinical activity in advanced breast cancer patients selected for PIK3CA/AKT1 or PTEN mutations or PTEN loss. This may, in part, be due to inadequate target inhibition at tolerable doses in heavily pre-treated patients with pathway activation, as well as tumor heterogeneity and evolution in markers such as PTEN conferring challenges in patient selection. TRIAL REGISTRATION:ClinicalTrials.gov, NCT01277757 . Registered 13 January 2011.

Dataset Information

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

Publications

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

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