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A phase I, open-label, two-stage study to investigate the safety, tolerability, pharmacokinetics, and pharmacodynamics of the oral AKT inhibitor GSK2141795 in patients with solid tumors


Background We sought to determine the recommended phase II dose (RP2D) and schedule of GSK2141795, an oral pan-AKT kinase inhibitor. Patients and Methods Patients with solid tumors were enrolled in the dose-escalation phase. Pharmacokinetic (PK) analysis after a single dose (Cycle 0) informed dose escalation using accelerated dose titration. Once one grade 2 toxicity or dose-limiting toxicity was observed in Cycle 1, the accelerated dose titration was terminated and a 3 + 3 dose escalation was started. Continuous daily dosing was evaluated along with two intermittent regimens (7 days on/7 days off and 3 times per week). In the expansion phase at RP2D, patients with endometrial or prostate cancer, as well as those with select tumor types with a PIK3CA mutation, AKT mutation or PTEN loss, were enrolled. Patients were evaluated for adverse events (AEs), PK parameters, blood glucose and insulin levels, and tumor response. Results The RP2D of GSK2141795 for once-daily dosing is 75 mg. The most common (>10%) treatment-related AEs included diarrhea, fatigue, vomiting, and decreased appetite. Most AEs were low grade. The frequency of hyperglycemia increased with dose; however, at the RP2D, grade 3 hyperglycemia was only reported in 4% of patients and no grade 4 events were observed. PK characteristics were favorable, with a prolonged half-life and low peak-to-trough ratio. There were two partial responses at the RP2D in patients with either a PIK3CA mutation or PTEN loss. Conclusion GSK2141795 was safe and well-tolerated, with clinical activity seen as monotherapy at the RP2D of 75 mg daily. NCT00920257.

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Editorial assistance was provided by SciMentum and funded by GlaxoSmithKline.

Investigators performed the human investigations after approval by a local Human Investigations Committee and in accord with an assurance filed with and approved by the Department of Health and Human Services. The investigators obtained informed consent from each participant or each participant’s guardian.

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Corresponding author

Correspondence to Carol Aghajanian.

Ethics declarations

Conflicts of interest

C. Aghajanian declares she participated on a Focus Study Steering Committee for Mateon Therapeutics and has served on the Advisory Boards of Clovis, Cerulean Pharma, Bayer, and VentiRx at various time points since July 2015. K. M. Bell-McGuinn declares she is currently an employee and stockholder of Eli Lilly. H. A. Burris III declares he has no conflict of interest. L. L. Siu declares she has received research funding from GlaxoSmithKline. L. Stayner declares she has no conflict of interest. J. J. Wheler declares she has no conflict of interest. D. S. Hong declares he has received research funding from Adaptimmune, Abbvie, Amgen, AstraZeneca, Bayer, BMS, Daiichi-Sanko, Eisai, Genentech, Genmab, Ignyta, Infinity, Kite, Kyowa, Eli Lilly, LOXO, Mirati, Merck, Medimmune, Molecular Template, Novartis, Pfizer, and Takeda; D. S. Hong has also received consulting fees from Bayer, Baxter, Guidepoint Global, and Janssen; D. S. Hong has also received travel accommodations from LOXO and Mirna, and has ownership interest in Molecular Match and Oncoresponse. C. Kurkjian declares she has no conflict of interest. S. Pant declares he has no conflict of interest. A. Santiago-Walker declares she has received personal fees from GlaxoSmithKline. J. L. Gauvin declares she has received personal fees and has stock in GlaxoSmithKline. J.M. Antal declares she holds stock in GlaxoSmithKline and is an employee and holds stock in G1 Therapeutics. J.B. Opalinska declares she was an employee and owns stock in GlaxoSmithKline. S.R. Morris declares she was an employee of and has patent interest with GlaxoSmithKline. J.R. Infante declares he is an employee of Johnson & Johnson.

Financial support

This study was funded by GlaxoSmithKline (NCT number: NCT00920257).

Drs. Aghajanian and Bell-McGuinn (while at MSK) are supported in part by the NIH/NCI Cancer Center Support Grant P30 CA008748.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This article does not contain any studies with animals performed by any of the authors.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Additional information

Previous presentation of the manuscript

Presented as an oral abstract at the 2011 ASCO Annual Meeting. Citation: J Clin Oncol 29: 2011 (suppl; abstr 3003)

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Aghajanian, C., Bell-McGuinn, K.M., Burris, H.A. et al. A phase I, open-label, two-stage study to investigate the safety, tolerability, pharmacokinetics, and pharmacodynamics of the oral AKT inhibitor GSK2141795 in patients with solid tumors. Invest New Drugs 36, 1016–1025 (2018).

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  • GSK2141795
  • Akt
  • PIK3
  • PTEN
  • Endometrial cancer