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

Milan G. Chheda, Patrick Y. Wen, Fred H. Hochberg, Andrew S. Chi, Jan Drappatz, April F. Eichler, Daniel Yang, Rameen Beroukhim, Andrew D. Norden, Elizabeth R. Gerstner, Rebecca Betensky, Tracy T. Batchelor

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)627-634
Number of pages8
JournalJournal of Neuro-Oncology
Volume121
Issue number3
DOIs
StatePublished - Jan 1 2015

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Sirolimus
Glioblastoma
Maximum Tolerated Dose
Cohort Studies
Disease-Free Survival
Appointments and Schedules
Hypophosphatemia
Cytochrome P-450 CYP3A
Vascular Endothelial Growth Factor Receptor-2
Lymphopenia
1-Phosphatidylinositol 4-Kinase
Aspartate Aminotransferases
N-(4-bromo-2-fluorophenyl)-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazolin-4-amine
Exanthema
Epidermal Growth Factor Receptor
Epidermal Growth Factor
Vascular Endothelial Growth Factor A
Fatigue
Cell Survival
Pharmaceutical Preparations

Keywords

  • Chemotherapy
  • Clinical trial
  • Glioblastoma

ASJC Scopus subject areas

  • Oncology
  • Neurology
  • Clinical Neurology
  • Cancer Research

Cite this

Chheda, M. G., Wen, P. Y., Hochberg, F. H., Chi, A. S., Drappatz, J., Eichler, A. F., ... Batchelor, T. T. (2015). Vandetanib plus sirolimus in adults with recurrent glioblastoma: results of a phase I and dose expansion cohort study. Journal of Neuro-Oncology, 121(3), 627-634. https://doi.org/10.1007/s11060-014-1680-2

Vandetanib plus sirolimus in adults with recurrent glioblastoma : results of a phase I and dose expansion cohort study. / Chheda, Milan G.; Wen, Patrick Y.; Hochberg, Fred H.; Chi, Andrew S.; Drappatz, Jan; Eichler, April F.; Yang, Daniel; Beroukhim, Rameen; Norden, Andrew D.; Gerstner, Elizabeth R.; Betensky, Rebecca; Batchelor, Tracy T.

In: Journal of Neuro-Oncology, Vol. 121, No. 3, 01.01.2015, p. 627-634.

Research output: Contribution to journalArticle

Chheda, MG, Wen, PY, Hochberg, FH, Chi, AS, Drappatz, J, Eichler, AF, Yang, D, Beroukhim, R, Norden, AD, Gerstner, ER, Betensky, R & Batchelor, TT 2015, 'Vandetanib plus sirolimus in adults with recurrent glioblastoma: results of a phase I and dose expansion cohort study', Journal of Neuro-Oncology, vol. 121, no. 3, pp. 627-634. https://doi.org/10.1007/s11060-014-1680-2
Chheda, Milan G. ; Wen, Patrick Y. ; Hochberg, Fred H. ; Chi, Andrew S. ; Drappatz, Jan ; Eichler, April F. ; Yang, Daniel ; Beroukhim, Rameen ; Norden, Andrew D. ; Gerstner, Elizabeth R. ; Betensky, Rebecca ; Batchelor, Tracy T. / Vandetanib plus sirolimus in adults with recurrent glioblastoma : results of a phase I and dose expansion cohort study. In: Journal of Neuro-Oncology. 2015 ; Vol. 121, No. 3. pp. 627-634.
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