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Pharmacokinetic drug interaction between AEE788 and RAD001 causing thrombocytopenia in patients with glioblastoma

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Abstract

Purpose

Treating glioblastoma through the simultaneous inhibition of multiple transduction pathways may prove more effective than single-pathway inhibition. We evaluated the safety, biologic activity, and pharmacokinetic profile of oral AEE788, a selective inhibitor of epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF), plus oral RAD001, a mammalian target of rapamycin inhibitor, in glioblastoma patients.

Methods

This phase IB/II, open-label, multicenter, 2-arm, dose-escalation study enrolled adult glioblastoma patients at first or second recurrence/relapse. Primary objective was to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of AEE788 combined with RAD001. Secondary objectives included determining the safety/tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity of the combination.

Results

Sixteen patients were enrolled (AEE788 200 mg/day + RAD001 5 mg/day, 2 patients; AEE788 150 mg/day + RAD001 5 mg every other day [qod], 14); all patients discontinued the study most commonly because of disease progression. Four patients experienced DLT (AEE788 200 mg/day + RAD001 5 mg/day, 1 patient; AEE788 150 mg/day + RAD001 5 mg qod, 3). Both patients receiving AEE788 (200 mg/day) plus RAD001 (5 mg/day) experienced clinically significant thrombocytopenia requiring a dose reduction/interruption. AEE788 appeared to inhibit the metabolism of RAD001. The study was terminated prematurely before an MTD was determined because of safety findings in other studies evaluating AEE788 monotherapy.

Conclusions

The coadministration of AEE788 and RAD001 in glioblastoma patients caused a clinically significant thrombocytopenia and a higher-than-expected RAD001 area under the curve concentration when dosed at 200 and 5 mg/day, respectively. After a dose reduction to AEE788 (150 mg/day) and RAD001 (5 mg qod), the combination appeared to be better tolerated.

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Acknowledgments

We are indebted to the patients who participated in this study and study coordinators. We thank Syntaxx Communications, Inc. for assistance with manuscript development and editing. Research support by Novartis Pharmaceuticals Corporation, East Hanover, NJ.

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Authors and Affiliations

  1. Center for Neuro-Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, SW-460F, Boston, MA, 02215, USA

    David A. Reardon

  2. University of California, Los Angeles, Los Angeles, CA, USA

    Timothy Cloughesy

  3. Cleveland Clinic Lerner Research Institute, Cleveland, OH, USA

    Jeremy Rich

  4. University of Texas MD Anderson Cancer Center, Houston, TX, USA

    W. K. Alfred Yung & Charles Conrad

  5. Celgene Corporation, Summit, NJ, USA

    Lotus Yung

  6. Novartis Pharmaceutical Corporation, East Hanover, NJ, USA

    Clifford DiLea, Jerry Huang, Margaret Dugan, William Mietlowski & Andrea Maes

Authors
  1. David A. Reardon
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  2. Timothy Cloughesy
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  3. Jeremy Rich
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  4. W. K. Alfred Yung
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  5. Lotus Yung
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  6. Clifford DiLea
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  7. Jerry Huang
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  8. Margaret Dugan
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  9. William Mietlowski
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  10. Andrea Maes
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  11. Charles Conrad
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Corresponding author

Correspondence to David A. Reardon.

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Reardon, D.A., Cloughesy, T., Rich, J. et al. Pharmacokinetic drug interaction between AEE788 and RAD001 causing thrombocytopenia in patients with glioblastoma. Cancer Chemother Pharmacol 69, 281–287 (2012). https://doi.org/10.1007/s00280-011-1754-1

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  • DOI: https://doi.org/10.1007/s00280-011-1754-1

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