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Journal of Neuro-Oncology

, Volume 144, Issue 2, pp 303–311 | Cite as

Phase I/II study of bevacizumab with BKM120, an oral PI3K inhibitor, in patients with refractory solid tumors (phase I) and relapsed/refractory glioblastoma (phase II)

  • John D. Hainsworth
  • Kevin P. Becker
  • Tarek Mekhail
  • Sajeel A. Chowdhary
  • Janice Faulkner Eakle
  • David Wright
  • Robert M. Langdon
  • Kathleen J. Yost
  • Gilbert Darin Anthony Padula
  • Kimberly West-Osterfield
  • Meredith Scarberry
  • Candice A. Shaifer
  • Mythili Shastry
  • Howard A. BurrisIII
  • Kent ShihEmail author
Clinical Study

Abstract

Background

Current bevacizumab-based regimens have failed to improve survival in patients with recurrent glioblastoma. To improve treatment efficacy, we evaluated bevacizumab + BKM120, an oral pan-class I PI3K inhibitor, in this patient population.

Methods

A brief phase I study established the optimal BKM120 dose to administer with standard-dose bevacizumab. BKM120 60 mg PO daily + bevacizumab 10 mg/kg IV every 2 weeks in 28-day cycles was then administered to patients with relapsed/refractory glioblastoma in the phase II portion.

Results

Eighty-eight patients enrolled (phase I, 12; phase II, 76). In phase I, BKM120 80 mg PO daily produced dose limiting toxicity in 3 of 6 patients; a BKM120 dose of 60 mg PO daily was established as the maximum tolerated dose. In phase II, the median progression-free survival (PFS) was 4.0 months (95% CI 3.4, 5.4), PFS at 6 months was 36.5%, and the overall response rate was 26%. Forty-two patients (57%) experienced one or more serious treatment related toxicities. The most common CNS toxicities included mood alteration (17%) and confusion (12%); however, these were often difficult to classify as treatment- versus tumor-related.

Conclusions

The efficacy seen in this study is similar to the efficacy previously reported with single-agent bevacizumab. This regimen was poorly tolerated, despite the low daily dose of BKM120. Further development of this combination for the treatment of glioblastoma is not recommended.

Keywords

BKM120 Glioblastoma Bevacizumab PI3K pathway Blood-brain barrier 

Notes

Acknowledgements

The authors would like to thank participating patients, their families, and site personnel for their very important contributions to this clinical trial.

Funding

Novartis Pharmaceuticals providing funding for this study and the study drug, BKM120.

Compliance with ethical standards

Conflict of interest:

The authors have no conflict of interest to disclose.

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • John D. Hainsworth
    • 1
  • Kevin P. Becker
    • 2
  • Tarek Mekhail
    • 3
  • Sajeel A. Chowdhary
    • 3
  • Janice Faulkner Eakle
    • 3
  • David Wright
    • 3
  • Robert M. Langdon
    • 4
  • Kathleen J. Yost
    • 5
  • Gilbert Darin Anthony Padula
    • 5
  • Kimberly West-Osterfield
    • 6
  • Meredith Scarberry
    • 6
  • Candice A. Shaifer
    • 6
  • Mythili Shastry
    • 6
  • Howard A. BurrisIII
    • 7
  • Kent Shih
    • 7
    Email author
  1. 1.Tennessee Oncology PLLCNashvilleUSA
  2. 2.Yale UniversityNew HavenUSA
  3. 3.Florida Cancer Specialists/SCRIFt. MyersUSA
  4. 4.Nebraska Methodist Cancer CenterOmahaUSA
  5. 5.Grand Rapids Oncology ProgramGrand RapidsUSA
  6. 6.Sarah CannonNashvilleUSA
  7. 7.Sarah Cannon Research Institute/Tennessee Oncology PLLCNashvilleUSA

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