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.

Autor: Tolcher AW; South Texas Accelerated Research Therapeutics, San Antonio, TX, USA. atolcher@nextsat.com.; NEXT Oncology, San Antonio, USA. atolcher@nextsat.com.; Texas Oncology, 5206 Research Drive, San Antonio, TX, 78240, USA. atolcher@nextsat.com., Kurzrock R; Division of Hematology and Oncology, Moores Cancer Center, University of California, San Diego, CA, USA., Valero V; Division of Cancer Medicine, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Gonzalez R; Division of Medical Oncology, Melanoma Research Clinics, University of Colorado Cancer Center, Aurora, CO, USA., Heist RS; Massachusetts General Hospital, Boston, MA, USA., Tan AR; Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA.; Levine Cancer Institute, Atrium Health, Charlotte, USA., Means-Powell J; Sarah Cannon Research Institute, Nashville, TN, USA., Werner TL; Division of Medical Oncology, Department of Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA., Becerra C; Texas Oncology, US Oncology-Baylor University Medical Center, Dallas, TX, USA., Wang C; GlaxoSmithKline, Collegeville, PA, USA., Leonowens C; GlaxoSmithKline, Collegeville, PA, USA.; Cathrine Leonowens Consulting LLC, Sanford, USA., Kalyana-Sundaram S; GlaxoSmithKline, Collegeville, PA, USA., Kleha JF; Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.; Array Biopharma, Boulder, CO, USA., Gauvin J; Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA., D'Amelio AM Jr; Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA., Ellis C; GlaxoSmithKline, Collegeville, PA, USA., Ibrahim N; GlaxoSmithKline, Collegeville, PA, USA.; Merck & Co, Kenilworth, USA., Yan L; GlaxoSmithKline, Collegeville, PA, USA.; Brii Biosciences Limited, San Francisco, USA.
Jazyk: angličtina
Zdroj: Cancer chemotherapy and pharmacology [Cancer Chemother Pharmacol] 2020 Apr; Vol. 85 (4), pp. 673-683. Date of Electronic Publication: 2020 Feb 15.
DOI: 10.1007/s00280-020-04038-8
Abstrakt: 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.
Databáze: MEDLINE
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