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Ref Type Journal Article
PMID (32062691)
Authors Tolcher AW, Kurzrock R, Valero V, Gonzalez R, Heist RS, Tan AR, Means-Powell J, Werner TL, Becerra C, Wang C, Leonowens C, Kalyana-Sundaram S, Kleha JF, Gauvin J, D'Amelio AM, Ellis C, Ibrahim N, Yan L
Title Phase I dose-escalation trial of the oral AKT inhibitor uprosertib in combination with the oral MEK1/MEK2 inhibitor trametinib in patients with solid tumors.
Journal Cancer chemotherapy and pharmacology
Vol 85
Issue 4
Date 2020 Apr
Abstract Text This study aimed to determine the safety, tolerability, and recommended phase II doses of trametinib plus uprosertib (GSK2141795) in patients with solid tumors likely to be sensitive to MEK and/or AKT inhibition.This was a phase I, open-label, dose-escalation, and dose-expansion study in patients with triple-negative breast cancer or BRAF-wild type advanced melanoma. The primary outcome of the expansion study was investigator-assessed response. Among 126 enrolled patients, 63 received continuous oral daily dosing of trametinib and uprosertib, 29 received various alternative dosing schedules, and 34 were enrolled into expansion cohorts. Doses tested in the expansion cohort were trametinib 1.5 mg once daily (QD) + uprosertib 50 mg QD.Adverse events (AEs) were consistent with those reported in monotherapy studies but occurred at lower doses and with greater severity. Diarrhea was the most common dose-limiting toxicity; diarrhea and rash were particularly difficult to tolerate. Overall, 59% and 6% of patients reported AEs with a maximum severity of grade 3 and 4, respectively. Poor tolerability prevented adequate delivery of uprosertib with trametinib at a concentration predicted to have clinical activity. The study was terminated early based on futility in the continuous-dosing expansion cohorts and a lack of pharmacological or therapeutic advantage with intermittent dosing. The objective response rate was < 5% (1 complete response, 5 partial responses).Continuous and intermittent dosing of trametinib in combination with uprosertib was not tolerated, and minimal clinical activity was observed in all schedules tested.


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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Uprosertib GSK2141795|GSK-2141795|GSK 2141795 Akt Inhibitor (Pan) 19 AKT Inhibitor (Pan) - ATP competitive 7 Uprosertib (GSK2141795) is an ATP-competitive inhibitor of AKT, which leads to inhibition of PI3K/AKT signaling potentially resulting in inhibition of cell proliferation and anti-tumor growth (PMID: 24978597, PMID: 32062691).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown Advanced Solid Tumor no benefit Trametinib + Uprosertib Phase I Actionable In a Phase I trial, the combination of Trametinib (GSK1120212) and Uprosertib (GSK2141795) was not well-tolerated and resulted in minimal efficacy in patients with advanced solid tumors (n=126), demonstrating an objective response rate of less than 5%, with one complete response and five partial responses (PMID: 32062691). 32062691