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

Cancer Chemother Pharmacol. 2020 Apr;85(4):673-683. doi: 10.1007/s00280-020-04038-8. Epub 2020 Feb 15.


Purpose: 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.

Methods: 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.

Results: 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).

Conclusions: Continuous and intermittent dosing of trametinib in combination with uprosertib was not tolerated, and minimal clinical activity was observed in all schedules tested.

Keywords: AKT inhibitor; BRAF-wild type melanoma; MEK inhibitor; Trametinib; Triple-negative breast cancer; Uprosertib.

Publication types

  • Clinical Trial, Phase I
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Combined Chemotherapy Protocols / pharmacokinetics*
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Cohort Studies
  • Diamines / administration & dosage
  • Dose-Response Relationship, Drug
  • Female
  • Follow-Up Studies
  • Humans
  • MAP Kinase Kinase 1 / antagonists & inhibitors*
  • MAP Kinase Kinase 2 / antagonists & inhibitors*
  • Male
  • Maximum Tolerated Dose
  • Melanoma / drug therapy*
  • Melanoma / pathology
  • Middle Aged
  • Prognosis
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors*
  • Pyrazoles / administration & dosage
  • Pyridones / administration & dosage
  • Pyrimidinones / administration & dosage
  • Tissue Distribution
  • Triple Negative Breast Neoplasms / drug therapy*
  • Triple Negative Breast Neoplasms / pathology
  • Young Adult


  • Diamines
  • GSK2141795
  • Pyrazoles
  • Pyridones
  • Pyrimidinones
  • trametinib
  • MAP2K2 protein, human
  • Proto-Oncogene Proteins c-akt
  • MAP Kinase Kinase 1
  • MAP Kinase Kinase 2
  • MAP2K1 protein, human