Faculty Collaboration Database

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

Date

02/18/2020

Pubmed ID

32062691

DOI

10.1007/s00280-020-04038-8

Scopus ID

2-s2.0-85079720073 (requires institutional sign-in at Scopus site)   41 Citations

Abstract

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.

Author List

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 Jr, Ellis C, Ibrahim N, Yan L

Author

Razelle Kurzrock MD Center Associate Director, Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adult
Aged
Aged, 80 and over
Antineoplastic Combined Chemotherapy Protocols
Cohort Studies
Diamines
Dose-Response Relationship, Drug
Female
Follow-Up Studies
Humans
MAP Kinase Kinase 1
MAP Kinase Kinase 2
Male
Maximum Tolerated Dose
Melanoma
Middle Aged
Prognosis
Proto-Oncogene Proteins c-akt
Pyrazoles
Pyridones
Pyrimidinones
Tissue Distribution
Triple Negative Breast Neoplasms
Young Adult