PMID- 29611022 OWN - NLM STAT- MEDLINE DCOM- 20190610 LR - 20191201 IS - 1573-0646 (Electronic) IS - 0167-6997 (Print) IS - 0167-6997 (Linking) VI - 36 IP - 6 DP - 2018 Dec TI - 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. PG - 1016-1025 LID - 10.1007/s10637-018-0591-z [doi] AB - 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. FAU - Aghajanian, Carol AU - Aghajanian C AD - Gynecologic Medical Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center (MSK), 300 East 66th Street, New York, NY, 10065, USA. aghajanc@mskcc.org. AD - Department of Medicine, Weill Cornell Medical College, New York, NY, USA. aghajanc@mskcc.org. FAU - Bell-McGuinn, Katherine M AU - Bell-McGuinn KM AD - Gynecologic Medical Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center (MSK), 300 East 66th Street, New York, NY, 10065, USA. AD - Department of Medicine, Weill Cornell Medical College, New York, NY, USA. AD - Eli Lilly and Company, Indianapolis, IN, USA. FAU - Burris, Howard A 3rd AU - Burris HA 3rd AD - Sarah Cannon Research Institute, Nashville, TN, USA. AD - Tennessee Oncology, Nashville, TN, USA. FAU - Siu, Lillian L AU - Siu LL AD - Princess Margaret Cancer Centre, Toronto, Canada. FAU - Stayner, Lee-Ann AU - Stayner LA AD - Princess Margaret Cancer Centre, Toronto, Canada. FAU - Wheler, Jennifer J AU - Wheler JJ AD - The University of Texas MD Anderson Cancer Center, Houston, TX, USA. FAU - Hong, David S AU - Hong DS AD - The University of Texas MD Anderson Cancer Center, Houston, TX, USA. FAU - Kurkjian, Carla AU - Kurkjian C AD - Sarah Cannon Research Institute, Nashville, TN, USA. AD - Stephenson Cancer Center, University of Oklahoma, Oklahoma City, OK, USA. FAU - Pant, Shubham AU - Pant S AD - Sarah Cannon Research Institute, Nashville, TN, USA. AD - Stephenson Cancer Center, University of Oklahoma, Oklahoma City, OK, USA. FAU - Santiago-Walker, Ademi AU - Santiago-Walker A AD - GlaxoSmithKline, Collegeville, PA, USA. AD - Janssen, Lansdale, PA, USA. FAU - Gauvin, Jennifer L AU - Gauvin JL AD - GlaxoSmithKline, Collegeville, PA, USA. AD - Novartis Pharmaceuticals, Orlanda, Florida, USA. FAU - Antal, Joyce M AU - Antal JM AD - GlaxoSmithKline, Collegeville, PA, USA. AD - MedImmune, Gaithersburg, MD, USA. FAU - Opalinska, Joanna B AU - Opalinska JB AD - GlaxoSmithKline, Collegeville, PA, USA. AD - Boehringer-Ingelheim, Ridgefield, CT, USA. FAU - Morris, Shannon R AU - Morris SR AD - GlaxoSmithKline, Collegeville, PA, USA. AD - MedImmune, Gaithersburg, MD, USA. FAU - Infante, Jeffrey R AU - Infante JR AD - Sarah Cannon Research Institute, Nashville, TN, USA. AD - Tennessee Oncology, Nashville, TN, USA. LA - eng SI - ClinicalTrials.gov/NCT00920257 GR - P30 CA008748/CA/NCI NIH HHS/United States PT - Clinical Trial, Phase I PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20180403 PL - United States TA - Invest New Drugs JT - Investigational new drugs JID - 8309330 RN - 0 (Diamines) RN - 0 (GSK2141795) RN - 0 (Protein Kinase Inhibitors) RN - 0 (Pyrazoles) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) SB - IM MH - Administration, Oral MH - Adult MH - Aged MH - Aged, 80 and over MH - Cohort Studies MH - Diamines/administration & dosage/adverse effects/*pharmacokinetics/*therapeutic use MH - Dose-Response Relationship, Drug MH - Female MH - Humans MH - Male MH - Middle Aged MH - Mutation/genetics MH - Neoplasms/*drug therapy MH - Protein Kinase Inhibitors/administration & dosage/adverse effects/*pharmacokinetics/*therapeutic use MH - Proto-Oncogene Proteins c-akt/*antagonists & inhibitors/metabolism MH - Pyrazoles/administration & dosage/adverse effects/*pharmacokinetics/*therapeutic use PMC - PMC6170741 MID - NIHMS956643 OTO - NOTNLM OT - Akt OT - Endometrial cancer OT - GSK2141795 OT - PIK3 OT - PTEN COIS- Disclosure of potential 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. EDAT- 2018/04/04 06:00 MHDA- 2019/06/14 06:00 PMCR- 2019/12/01 CRDT- 2018/04/04 06:00 PHST- 2018/02/15 00:00 [received] PHST- 2018/03/15 00:00 [accepted] PHST- 2018/04/04 06:00 [pubmed] PHST- 2019/06/14 06:00 [medline] PHST- 2018/04/04 06:00 [entrez] PHST- 2019/12/01 00:00 [pmc-release] AID - 10.1007/s10637-018-0591-z [pii] AID - 10.1007/s10637-018-0591-z [doi] PST - ppublish SO - Invest New Drugs. 2018 Dec;36(6):1016-1025. doi: 10.1007/s10637-018-0591-z. Epub 2018 Apr 3.