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Tumor Treating Field Therapy in Combination with Bevacizumab for the Treatment of Recurrent Glioblastoma
Published on: October 27, 2014
A phase I/II trial of vandetanib for patients with recurrent malignant glioma
Teri N Kreisl1, Katharine A McNeill, Joohee Sul
1Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA. kreislt@mail.nih.gov
Abstract:
Vandetanib is a once-daily multitargeted tyrosine kinase inhibitor of vascular endothelial growth factor receptor-2, epidermal growth factor receptor, and the rearranged-during-transfection oncogene. A phase I trial was conducted to describe the pharmacokinetics of vandetanib in patients with recurrent glioma on enzyme-inducing anti-epileptic drugs (EIAEDs) and to identify the maximum tolerated dose (MTD) in this population. A phase II trial evaluated the efficacy of vandetanib in patients with recurrent malignant glioma not on EIAEDs as measured by 6-month progression-free survival (PFS6). In the phase I trial, 15 patients were treated with vandetanib at doses of 300, 400, and 500 mg/day, in a standard dose-escalation design. The MTD in patients on EIAEDs was 400 mg/day, and steady-state levels were similar to those measured in patients not on EIAEDs. Dose-limiting toxicities were prolonged QTc and thromboembolism. Thirty-two patients with recurrent glioblastoma multiforme (GBM) and 32 patients with recurrent anaplastic gliomas (AGs) were treated in the phase II trial, at a dosage of 300 mg/day on 28-day cycles. Six patients (4 GBM, 2 AG) had radiographic response. PFS6 was 6.5% in the GBM arm and 7.0% in the AG arm. Median overall survival was 6.3 months in the GBM arm and 7.6 months in the AG arm. Seizures were an unexpected toxicity of therapy. Vandetanib did not have significant activity in unselected patients with recurrent malignant glioma.
Insights
Vandetanib, a tyrosine kinase inhibitor, showed limited efficacy in recurrent malignant glioma patients. The maximum tolerated dose was 400 mg/day, with toxicities including QTc prolongation and thromboembolism.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- Vandetanib is a multitargeted tyrosine kinase inhibitor impacting VEGFR-2, EGFR, and RET.
- Recurrent glioma presents a significant challenge in neuro-oncology treatment.
Purpose of the Study:
- To determine the pharmacokinetics and maximum tolerated dose (MTD) of vandetanib in recurrent glioma patients on enzyme-inducing anti-epileptic drugs (EIAEDs).
- To evaluate the efficacy of vandetanib in recurrent malignant glioma patients not on EIAEDs, measured by 6-month progression-free survival (PFS6).
Main Methods:
- Phase I trial: Dose escalation of vandetanib (300, 400, 500 mg/day) in 15 patients on EIAEDs to find MTD.
- Phase II trial: 300 mg/day vandetanib in 64 patients (32 glioblastoma multiforme, 32 anaplastic gliomas) not on EIAEDs.
Main Results:
- The MTD for vandetanib in patients on EIAEDs was 400 mg/day. Dose-limiting toxicities included QTc prolongation and thromboembolism.
- In the phase II trial, PFS6 was 6.5% for glioblastoma multiforme and 7.0% for anaplastic gliomas. Radiographic response was observed in 6 patients.
- Unexpected toxicity of seizures was noted. Vandetanib demonstrated limited activity in unselected recurrent malignant glioma patients.
Conclusions:
- Vandetanib at 300 mg/day did not show significant efficacy in recurrent malignant glioma.
- The MTD was established at 400 mg/day in patients on EIAEDs, with notable toxicities.
- Further investigation may be warranted for specific glioma subtypes or in combination therapies.
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