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Phase 1/1b dose escalation and expansion study of BEZ235, a dual PI3K/mTOR inhibitor, in patients with advanced solid tumors including patients with advanced breast cancer

Cancer Chemotherapy and Pharmacology volume 82, pages 285–298 (2018)Cite this article

Abstract

Purpose

To determine the maximum tolerated dose (MTD) of BEZ235, an oral inhibitor of class I PI3K and mTOR complexes 1 and 2.

Methods

We performed a phase I/Ib, multicenter, open-label study of oral BEZ235 administered in a continuous daily schedule. The study consisted of two parts: dose-escalation part and safety-expansion part. BEZ235 was administered as a single agent to patients with solid tumors or in combination with trastuzumab for HER2+ advanced breast cancer (aBC). Primary end points were MTD, safety, and tolerability. The secondary end point was pharmacokinetics. Other formulations of BEZ235, solid dispersion system (SDS) sachet, and SDS capsules were also assessed.

Results

One hundred and eighty-three patients were enrolled; single-agent BEZ235 was administered as hard gelatin capsule (n = 59), SDS capsules A and B (n = 33), and SDS sachet (n = 61), amongst which SDS sachet was chosen as the preferred formulation. The monotherapy MTD for capsule A and SDS sachet was determined to be 1000 and 1200 mg/day, respectively. Thirty patients with HER2+ aBC received BEZ235 in combination with trastuzumab. The MTD of BEZ235 in combination with trastuzumab was 600 mg/day. A total of four patients (13.3%) achieved partial response across the different groups. Most frequent AEs in single agent and combination cohorts included nausea (80.3 and 93.3%), diarrhea (75.4 and 80.0%), and vomiting (63.9 and 63.3%).

Conclusions

The MTD of BEZ235 as single agent was 1200 and 600 mg/day with trastuzumab. Pharmacokinetic profiles showed low-to-moderate variability at low dose (10 mg) and high variability at high doses (100 mg and above). Gastrointestinal AEs were frequent at high doses.

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Acknowledgements

We thank the patients who participated in this trial and their families, as well as staff members at individual trial centers who provided support; Amirtha Ganesh, PhD and Avinash Yerramsetti (Novartis Healthcare Pvt Ltd) for providing medical editorial assistance with this manuscript.

Funding

The study was initiated, funded, and sponsored by Novartis Pharmaceuticals Corporation.

Author information

Affiliations

  1. Medical Oncology Department, Vall d’Hebrón University Hospital, Barcelona, Spain

    Jordi Rodon

  2. INCLIVA Biomedical Research Institute, Valencia, Spain

    Alejandro Pérez-Fidalgo

  3. Dana-Farber Cancer Institute, Boston, MA, USA

    Ian E. Krop

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

    Howard Burris

  5. Instituto Valenciano de Oncología, Valencia, Spain

    Angel Guerrero-Zotano

  6. Medical University of South Carolina, Charleston, SC, USA

    Carolyn D. Britten

  7. Texas Oncology, Dallas, TX, USA

    Carlos Becerra & Donald A. Richards

  8. The Netherlands Cancer Institute, Amsterdam, The Netherlands

    Jan Schellens

  9. West German Cancer Center, University Hospital Essen, Essen, Germany

    Martin Schuler

  10. Thomas Jefferson University, Philadelphia, PA, USA

    Maysa Abu-Khalaf

  11. MD Anderson Cancer Center, Houston, TX, USA

    Faye M. Johnson

  12. Manchester University, Manchester, UK

    Malcolm Ranson

  13. Greenville Memorial Hospital, Greenville, SC, USA

    Jeff Edenfield

  14. Novartis Pharma AG, Basel, Switzerland

    Antonio P. Silva, Wolfgang Hackl, Cornelia Quadt, David Demanse & Vincent Duval

  15. Memorial Sloan Kettering Cancer Center, New York, USA

    Jose Baselga

Authors
  1. Jordi Rodon
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  2. Alejandro Pérez-Fidalgo
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  3. Ian E. Krop
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  4. Howard Burris
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  5. Angel Guerrero-Zotano
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  6. Carolyn D. Britten
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  7. Carlos Becerra
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  8. Jan Schellens
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  9. Donald A. Richards
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  10. Martin Schuler
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  11. Maysa Abu-Khalaf
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  12. Faye M. Johnson
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  13. Malcolm Ranson
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  14. Jeff Edenfield
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  15. Antonio P. Silva
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  16. Wolfgang Hackl
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  17. Cornelia Quadt
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  18. David Demanse
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  19. Vincent Duval
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  20. Jose Baselga
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Corresponding author

Correspondence to Jordi Rodon.

Ethics declarations

Conflict of interest

J. Rodon reports grants and personal fees from Novartis during the conduct of the study; grants from Bayer and personal fees from Peptomyc, Orion, and Servier outside the submitted work. I. Krop reports personal fees from Genentech/Roche, Daiichi/Sankyo and Macrogenics outside the submitted work; research grants from Genentech/Roche. H. Burris reports other fees Novartis during the conduct of the study. C. Britten reports grants from Novartis during the conduct of the study; grants from Amgen, Boston Biomedical, Eli Lilly, Five Prime, Plexxikon, Keystone Nano, EMD Serono, Roche, Tesaro, Regeneron, Pfizer and Halozyme outside the submitted work; non-financial support from Five Prime; personal fees from Cleave outside the submitted work. M. Schuler reports other fees from University Hospital Essen, University Duisburg-Essen and Ruhrlandklinik outside the submitted work; personal fees from AstraZeneca, Celgene, Roche, Abbvie, Eli Lilly, Alexion, and MSD outside the submitted work; personal fees and grants from Boehringer Ingelheim, Bristol-Myers Squibb, and Novartis outside the submitted work. M. Abu-Khalaf reports grants from Novartis during the conduct of the study and outside the submitted work. A. Silva is employee of Novartis Pharma AG and hold Novartis stock options. W. Hackl is employee of Novartis Pharma AG and hold Novartis stock options. C. Quadt is employee of Novartis Pharma AG and hold Novartis stock options. D. Demanse is employee of Novartis Pharma AG. V. Duval is employee of Novartis Pharma AG. A. Pérez-Fidalgo, A. Guerrero-Zotano, C. Becerra, sJ. Schellens, D. Richards, F. Johnson, M. Ranson, J. Edenfield and J. Baselga have nothing to disclose.

Ethical approval

This study was conducted in accordance with Good Clinical Practice guidelines and the Declaration of Helsinki. An independent ethics committee and institutional review boards approved the study protocol and any subsequent amendments at each participating center. A study steering committee monitored study conduct in line with the protocol.

Informed consent

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

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Rodon, J., Pérez-Fidalgo, A., Krop, I.E. et al. Phase 1/1b dose escalation and expansion study of BEZ235, a dual PI3K/mTOR inhibitor, in patients with advanced solid tumors including patients with advanced breast cancer. Cancer Chemother Pharmacol 82, 285–298 (2018). https://doi.org/10.1007/s00280-018-3610-z

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  • DOI: https://doi.org/10.1007/s00280-018-3610-z

Keywords

  • PI3K
  • mTORC1/2
  • Breast cancer
  • BEZ235
  • Inhibitor