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.
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The authors thank all participating patients and their families. The authors also thank William Fazzone, Ph.D., of ArticulateScience, LLC, for editorial assistance, which was funded by Novartis Pharmaceuticals Corporation.
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A. W. T. has received fees for consulting and board memberships, as well as research funding (paid to NEXT Oncology) from AbbVie, ADC Therapeutics, Adagene, Agenus, Aminex, AroBioTX, Arrys, Asana, Ascentage, Aximmune, Bayer, Biolnvent, Birdie, Boston Bio, CStone, Deciphera, EMD Serono, Forbius, GSK, HBM Partners, Ignyta, Inhibrx, Immunome, Immunomet, Innate, Jazz Pharmaceuticals, Kiromet, Mekanistic, Mersana, Nanobiotix, NatureWise, NBE Therapeutics, NextCure, Nitto Biopharma, Nuvalent, Pelican, Pfizer, Pierre Fabre, Pieris, Ridgeway, Scitemex, Sesen Bio, Seattle Genetics, Sunshine Guojian, Symphogen, Syndax, Syneos, Tizone, and Zymeworks. R. K. has received research funding from Boehringer Ingelheim, DeBiopharm, Foundation Medicine, Genentech, Grifols, Guardant Health, Incyte, Konica Minolta, Merck Serono, OmniSeq, Pfizer, and Sequenom; has consulting or advisory role in Actuate Therapeutics, Gaido, LOXO, NeoMed, Pfizer, Roche, Soluventis, and X-Biotech; has received speaker fees from Roche; is a board member of CureMatch, Inc.; and has stock and other equity interests in CureMatch, Inc., IDbyDNA, and Soluventis. V. V. received grant and honorarium from Novartis. R. G. received research funding from Novartis, GSK and grant and personal fees from Array, Bristol-Myers Squibb, Merck, and Roche/Genentech. R. S. H. received consulting honoraria from Boehringer Ingelheim, Novartis, Tarveda, Apollomics and received research funding (to his institution) from Daiichi Sankyo, Agios, Novartis, Corvus, Mirati, Millennium, Genentech Roche, AbbVie, Exelixis, Celgene, and Incyte. A. R. T. received research funding from GSK. C. W. and S. K-S. are employees of GSK. C. L. and L. Y. were former employees of GSK. J. F. K. was an employee of Novartis. J. G. and A. M. D. Jr. are employees of Novartis Pharmaceuticals and have stock ownership in Novartis and GSK. C. E. is an employee and stock owner of GSK. N. I. was an employee of GSK and currently is an employee of Merck. All remaining authors have declared no conflicts of interest. All authors received assistance with manuscript preparation from ArticulateScience, LLC.
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Tolcher, A.W., Kurzrock, R., Valero, V. et al. 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 85, 673–683 (2020). https://doi.org/10.1007/s00280-020-04038-8
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DOI: https://doi.org/10.1007/s00280-020-04038-8