Cancer Chemotherapy and Pharmacology

, Volume 67, Issue 2, pp 465–474 | Cite as

A phase I study of bevacizumab (B) in combination with everolimus (E) and erlotinib (E) in advanced cancer (BEE)

  • Karen E. Bullock
  • William P. Petros
  • Islam Younis
  • Hope E. Uronis
  • Michael A. Morse
  • Gerard C. Blobe
  • S. Yousuf Zafar
  • Jon P. Gockerman
  • Joanne J. Lager
  • Roxanne Truax
  • Kellen L. Meadows
  • Leigh A. Howard
  • Margot M. O’Neill
  • Gloria Broadwater
  • Herbert I. Hurwitz
  • Johanna C. Bendell
Clinical Trial Report

Abstract

Purpose

VEGF, mTOR, and EGFR inhibitors have demonstrated anti-tumor and anti-angiogenic effects alone and in combination with each other. This study evaluated the safety, tolerability, and pharmacokinetics of bevacizumab, everolimus, and erlotinib combination.

Methods

Doublet therapy consisted of bevacizumab at 10 mg/kg every 14 days and everolimus 5 mg daily which escalated to 10 mg daily. Erlotinib 75 mg daily was added to the phase II dose recommended phase II dose (RPTD) of bevacizumab and everolimus. Dose-limiting toxicity (DLT) was assessed in cycle 1.

Results

Forty-eight patients with advanced solid malignancies were evaluable for DLT and efficacy. No DLTs were observed in the doublet dose escalation. Two DLTs (grade 3 mucositis and grade 3 rash) were observed with the addition of erlotinib 75 mg daily. Consequently, triplet doses were adjusted and were better tolerated. Four patients had a partial response. Median progression-free survival (PFS) for the doublet therapy was 6.0 months (0.5 to 32+ months) and 5.5 months (0.8 to 27+ months) for the triplet therapy. Systemic exposure of everolimus was significantly higher in combination with erlotinib (476 ± 161 ng h/mL) compared to when given alone (393 ± 156 ng h/mL; P = 0.020).

Conclusions

The RPTD for the doublet therapy is bevacizumab 10 mg/kg every 14 days and everolimus 10 mg daily, and the RPTD for the triplet therapy is bevacizumab 5 mg/kg every 14 days, everolimus 5 mg and erlotinib 75 mg daily. Prolonged disease stability was demonstrated in tumors known to respond to mTOR inhibition and potentially resistant to VEGF blockade.

Keywords

Bevacizumab Everolimus Erlotinib Phase I Advanced cancer 

Notes

Acknowledgments

The authors would like to thank the patients, their families, and our phase I research staff: Shawna Savage, Jill Ashton, Christy Arrowood, Dorris Lockamy, Catherine Lowe, Sharon Norman, Neal Kaplan, Kathy Coleman, and Denise Morgan.

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Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Karen E. Bullock
    • 1
    • 3
  • William P. Petros
    • 2
  • Islam Younis
    • 2
    • 4
  • Hope E. Uronis
    • 1
  • Michael A. Morse
    • 1
  • Gerard C. Blobe
    • 1
  • S. Yousuf Zafar
    • 1
  • Jon P. Gockerman
    • 1
  • Joanne J. Lager
    • 1
    • 5
  • Roxanne Truax
    • 1
  • Kellen L. Meadows
    • 1
  • Leigh A. Howard
    • 1
  • Margot M. O’Neill
    • 1
  • Gloria Broadwater
    • 1
  • Herbert I. Hurwitz
    • 1
  • Johanna C. Bendell
    • 1
    • 6
  1. 1.Duke University Medical CenterDurhamUSA
  2. 2.Mary Babb Randolph Cancer CenterWest Virginia UniversityMorgantownUSA
  3. 3.United States NavyPortsmouthUSA
  4. 4.United States Food and Drug AdministrationSilver SpringUSA
  5. 5.Sanofi-aventisMalvernUSA
  6. 6.Sarah Cannon Research InstituteNashvilleUSA

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