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

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

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17 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)482-489
Number of pages8
JournalInvestigational New Drugs
Issue number3
StatePublished - Jun 15 2019

Bibliographical note

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

Publisher Copyright:
© 2018, Springer Science+Business Media, LLC, part of Springer Nature.


  • Colorectal cancer
  • Everolimus
  • Investigational therapeutics
  • Phase I/II


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