Phase I/II study of everolimus combined with mFOLFOX-6 and bevacizumab for first–line treatment of metastatic colorectal cancer

  • G. Weldon GilcreaseEmail author
  • David D. Stenehjem
  • Mark L. Wade
  • John Weis
  • Kimberly McGregor
  • Jonathan Whisenant
  • Kenneth M. Boucher
  • Kelli Thorne
  • Nicole Orgain
  • Ignacio Garrido-Laguna
  • Sunil Sharma


Background This phase I/II trial evaluated toxicity and antitumor activity of everolimus plus mFOLFOX6 + bevacizumab for first-line treatment of metastatic colorectal cancer (mCRC). Methods A phase I, modified 3 + 3 Fibonacci schema determined the maximum tolerated dose (MTD) of everolimus, followed by phase II dose expansion. The phase II primary objective was progression-free survival at 6 months (PFS-6 m). Results The everolimus MTD was 10 mg daily with mFOLFOX6 + bevacizumab based on safety from phase I (n = 22). Twenty-five patients were treated in the phase II at 10 mg everolimus daily. Frequent grade 3–4 adverse events were neutropenia (64%), leukopenia (28%) and hypokalemia (26%). Grade 2 stomatitis was observed in 62% of patients. Two dose-limiting toxicities were observed with one attributed to everolimus 10 mg daily (grade 3 diarrhea, hypokalemia, and anorexia) and grade 3 coronary vasospasm attributed to fluorouracil. The objective response rate was 53% and was higher (86%) in those with PTEN deficiency. PFS-6 m was 96% (95% CI 89–99.9%) at the MTD (n = 35). The everolimus recommended phase II dose of this regimen is 7.5 mg daily due to frequent stomatitis and dose reductions. Conclusions Everolimus plus mFOLFOX-6 + bevacizumab is tolerable and demonstrated preliminary efficacy for first-line mCRC. Further studies are warranted in PTEN deficiency.


Everolimus Colorectal cancer Phase I/II Investigational therapeutics FOLFOX 



This study was funded by Novartis Pharmaceuticals and the Huntsman Cancer Institute. clinical trial NCT01047293.

Compliance with ethical standards

Conflict of interest

Sunil Sharma received research support from Novartis Pharmaceuticals and has served on Novartis Pharmaceuticals advisory boards. All other authors have no financial interests to disclose surrounding this manuscript.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.


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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • G. Weldon Gilcrease
    • 1
    Email author
  • David D. Stenehjem
    • 2
  • Mark L. Wade
    • 3
  • John Weis
    • 1
  • Kimberly McGregor
    • 4
  • Jonathan Whisenant
    • 1
    • 5
  • Kenneth M. Boucher
    • 6
  • Kelli Thorne
    • 3
  • Nicole Orgain
    • 1
  • Ignacio Garrido-Laguna
    • 1
  • Sunil Sharma
    • 7
  1. 1.Department of Internal Medicine (Division of Oncology)Huntsman Cancer Institute at the University of UtahSalt Lake CityUSA
  2. 2.Department of Pharmacy Practice and Pharmaceutical Sciences, College of PharmacyUniversity of MinnesotaDuluthUSA
  3. 3.Department of Research Compliance: Huntsman Cancer InstituteSalt Lake CityUSA
  4. 4.Medical AffairsFoundation MedicineCambridgeUSA
  5. 5.Huntsman Intermountain Cancer Care ProgramSalt Lake CityUSA
  6. 6.Department of Internal Medicine (Epidemiology)University of UtahSalt Lake CityUSA
  7. 7. Division Clinical SciencesTranslational Genomics Research Institute (TGen)PhoenixUSA

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