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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

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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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Acknowledgements

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.

Author information

Author notes

  1. Anthony W. Tolcher

    Present address: NEXT Oncology, San Antonio, USA

  2. Antoinette R. Tan

    Present address: Levine Cancer Institute, Atrium Health, Charlotte, USA

  3. Cathrine Leonowens

    Present address: Cathrine Leonowens Consulting LLC, Sanford, USA

  4. Joseph F. Kleha

    Present address: Array Biopharma, Boulder, CO, USA

  5. Nageatte Ibrahim

    Present address: Merck & Co, Kenilworth, USA

  6. Li Yan

    Present address: Brii Biosciences Limited, San Francisco, USA

Authors and Affiliations

  1. South Texas Accelerated Research Therapeutics, San Antonio, TX, USA

    Anthony W. Tolcher

  2. Division of Hematology and Oncology, Moores Cancer Center, University of California, San Diego, CA, USA

    Razelle Kurzrock

  3. Division of Cancer Medicine, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Vincente Valero

  4. Division of Medical Oncology, Melanoma Research Clinics, University of Colorado Cancer Center, Aurora, CO, USA

    Rene Gonzalez

  5. Massachusetts General Hospital, Boston, MA, USA

    Rebecca S. Heist

  6. Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA

    Antoinette R. Tan

  7. Sarah Cannon Research Institute, Nashville, TN, USA

    Julie Means-Powell

  8. Division of Medical Oncology, Department of Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA

    Theresa L. Werner

  9. Texas Oncology, US Oncology-Baylor University Medical Center, Dallas, TX, USA

    Carlos Becerra

  10. GlaxoSmithKline, Collegeville, PA, USA

    Chenxi Wang, Cathrine Leonowens, Shanker Kalyana-Sundaram, Catherine Ellis, Nageatte Ibrahim & Li Yan

  11. Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA

    Joseph F. Kleha, Jennifer Gauvin & Anthony M. D’Amelio Jr.

  12. Texas Oncology, 5206 Research Drive, San Antonio, TX, 78240, USA

    Anthony W. Tolcher

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Corresponding author

Correspondence to Anthony W. Tolcher.

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Conflict of interest

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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