Reference Detail

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	Vol	Issue	Date	Pages	Journal Short Title
Cancer chemotherapy and pharmacology	85	4	2020 Apr	673-683	Cancer Chemother Pharmacol

URL

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
Uprosertib	Uprosertib	2	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
Uprosertib		GSK2141795\|GSK-2141795\|GSK 2141795	Akt Inhibitor (Pan) 21 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