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Vandetanib plus sirolimus in adults with recurrent glioblastoma: results of a phase I and dose expansion cohort study

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Abstract

Targeting specific molecular alterations in glioblastoma (GBM) might more effectively kill tumor cells and increase survival. Vandetanib inhibits epidermal growth factor receptor and vascular endothelial growth factor receptor 2. Sirolimus inhibits mammalian target of rapamycin (mTOR), a member the phosphoinositide 3-Kinase signaling pathway. We sought to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of vandetanib combined with sirolimus. Twenty-two patients (14 men; 8 women) with recurrent GBM enrolled. Median age and KPS were 52.5 years and 90 %, respectively. Patients were naive to anti-VEGF and anti-EGF therapy and mTOR inhibitors, and not on CYP3A4-inducing drugs. Vandetanib and sirolimus were orally administered on a continuous daily dosing schedule in escalating dose cohorts. Ten patients enrolled in the dose escalation phase. Twelve more enrolled at the MTD to explore progression-free survival at 6 months (PFS6) in a single arm, single stage phase II-type design. In total, 19 patients received at least one dose at the MTD, and 15 completed at least 1 cycle at MTD. MTD was 200 mg vandetanib plus 2 mg sirolimus. The DLT was elevated AST/SGOT. The most common toxicities were lymphopenia, fatigue, rash, and hypophosphatemia. For 19 patients who received at least one dose at the MTD, including seven from the phase I group, two had a partial response [10.5 %; 95 % CI (1, 33 %)] and PFS6 was 15.8 % [95 % CI (3.9, 34.9 %)]. Vandetanib and sirolimus can be safely co-administered on a continuous, daily dosing schedule.

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Acknowledgments

We gratefully acknowledge Faye Safavi and Karly Griffin for aiding with data collection. This research was conducted with support from the Investigator-Sponsored Study Program of AstraZeneca. Authors received grant support from the NIH (K08 NS062907 and K12 CA090354 Career Development Awards to MGC; K24 CA125440 and K12 CA090354 to TTB), Brain Tumor Center of Memorial Sloan-Kettering Cancer Center, American Brain Tumor Association Fellowship, and American Association for Cancer Research/National Brain Tumor Foundation Fellowship to MGC; and Richard Floor Bequest (FHH). These data were presented in part at the annual meeting of the American Academy of Neurology (2012).

Conflict of interest

This research was conducted with support from the Investigator-Sponsored Study Program of AstraZeneca. PYW receives research support from AstraZeneca. RB owns shares in AstraZeneca. TTB receives research support from AstraZeneca. All other authors have no conflict of interest.

Ethical standards

All studies comply with the laws of the United States. The study was approved by the institutional review board at Dana-Farber/Harvard Cancer Center (Protocol 07-396).

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Author notes

  1. Milan G. Chheda

    Present address: Department of Neurology and Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA

Authors and Affiliations

  1. Stephen E. and Catherine Pappas Center for Neuro-Oncology, Massachusetts General Hospital, Yawkey 9 East, 55 Fruit Street, Boston, MA, 02114, USA

    Milan G. Chheda, Fred H. Hochberg, Andrew S. Chi, April F. Eichler, Daniel Yang, Elizabeth R. Gerstner & Tracy T. Batchelor

  2. Center for Neuro-Oncology, Dana-Farber/Brigham and Women’s Cancer Center, 450 Brookline Avenue, Boston, MA, 02215, USA

    Patrick Y. Wen, Rameen Beroukhim & Andrew D. Norden

  3. Division of Neurosurgery, University of California at San Diego, Mailcode 8893, 200 West Arbor Drive, San Diego, CA, 92103, USA

    Fred H. Hochberg

  4. Division of Hematology and Oncology, Departments of Neurology and Medicine, and Neuro-Oncology Program, University of Pittsburg Medical Center, Hillman Cancer Center, 5115 Centre Avenue, Pittsburgh, PA, 15232, USA

    Jan Drappatz

  5. Department of Cancer Biology and Center for Cancer Genome Characterization, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA, 02215, USA

    Rameen Beroukhim

  6. UpToDate, Wolters Kluwer Health, 95 Sawyer Road, Waltham, MA, 02453, USA

    April F. Eichler

  7. Department of Biostatistics, Harvard School of Public Health, 655 Huntington Avenue, Building II Room 421, Boston, MA, 02115, USA

    Rebecca A. Betensky

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  1. Milan G. Chheda
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Correspondence to Tracy T. Batchelor.

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Clinicaltrials.gov identifier: NCT00821080.

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Chheda, M.G., Wen, P.Y., Hochberg, F.H. et al. Vandetanib plus sirolimus in adults with recurrent glioblastoma: results of a phase I and dose expansion cohort study. J Neurooncol 121, 627–634 (2015). https://doi.org/10.1007/s11060-014-1680-2

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