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Phase 1 trial of dasatinib plus erlotinib in adults with recurrent malignant glioma

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Abstract

To determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of dasatinib, an inhibitor of the Src family kinase proteins, with erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor, among recurrent malignant glioma patients. Once daily dasatinib was escalated in successive cohorts while erlotinib was administered daily at established doses based on concurrent CYP3A-inducing anticonvulsant (EIAEDS) use. Dasatinib pharmacokinetic analyzes were performed. Forty-seven patients enrolled including 37 (79 %) with grade IV and 10 (21 %) with grade III malignant glioma. Thirty patients (64 %) were at ≥second recurrence, while 27 (57 %) had received prior bevacizumab. The dasatinib MTD was 180 mg when combined with either 150 mg of erlotinib for patients not on EIAEDs, or 450 mg of erlotinib for patients on EIAEDs. The most common DLTs were diarrhea and fatigue, while most adverse events were grade 2. Pharmacokinetic data suggests that dasatinib exposure increased with increased dasatinib dose and concurrent erlotinib administration, while concurrent EIAED use diminished dasatinib exposure. No radiographic responses were observed, and only one patient (2 %) remained progression-free at 6 months. We demonstrate that dasatinib plus erlotinib can be safely co-administered on a continuous, daily dosing schedule with erlotinib, and established the recommended dose level of this combination.

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Acknowledgments

This work was supported by NIH Grants P50 NS20023 and CA11898; NIH Grant MO1 RR 30, GCRC Program, NCRR and SPORE in Brain Cancer 2 P50 CA108786. The authors thank Wendy Gentry for her excellent secretarial support in the development of this manuscript.

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Authors and Affiliations

  1. Center for Neuro-Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, SW-430, Boston, MA, 02215, USA

    David A. Reardon

  2. Departments of Surgery, The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC, USA

    David A. Reardon, Stevie Threatt, John H. Sampson & Henry S. Friedman

  3. Departments of Pediatrics, The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC, USA

    David A. Reardon & Henry S. Friedman

  4. Departments of Medicine, The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC, USA

    James J. Vredenburgh, Annick Desjardins & Katherine B. Peters

  5. Departments of Cancer Center Biostatistics, The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC, USA

    James E. Herndon II, April Coan & Frances McSherry

  6. Departments of Pathology, The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC, USA

    Roger E. McLendon

  7. Department of Clinical Pharmacology and Pharmacometrics, Bristol-Myers Squibb, Princeton, NJ, USA

    Steven Zhang

  8. Department of Medicine (Neurology), Faculty of Medicine at Siriraj Hospital, Mahidol University, Bangkok, Thailand

    Sith Sathornsumetee

  9. Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic, Cleveland, OH, USA

    Jeremy N. Rich

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  1. David A. Reardon
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Correspondence to David A. Reardon.

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Reardon, D.A., Vredenburgh, J.J., Desjardins, A. et al. Phase 1 trial of dasatinib plus erlotinib in adults with recurrent malignant glioma. J Neurooncol 108, 499–506 (2012). https://doi.org/10.1007/s11060-012-0848-x

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