• Anthony W Tolcher, Razelle Kurzrock, Vincente Valero, Rene Gonzalez, Rebecca S Heist, Antoinette R Tan, Julie Means-Powell, Theresa L Werner, Carlos Becerra, Chenxi Wang, Cathrine Leonowens, Shanker Kalyana-Sundaram, Joseph F Kleha, Jennifer Gauvin, Anthony M D'Amelio, Catherine Ellis, Nageatte Ibrahim, and Li Yan.
• South Texas Accelerated Research Therapeutics, San Antonio, TX, USA. atolcher@nextsat.com.
• Cancer Chemother. Pharmacol. 2020 Apr 1; 85 (4): 673-683.

PurposeThis 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.MethodsThis 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.ResultsAdverse 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).ConclusionsContinuous 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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