Dose Escalation Study of Vandetanib With Hypofractionated Stereotactic Radiotherapy in Recurrent Malignant Gliomas

Inclusion Criteria:

* Patients with histopathologically confirmed malignant gliomas that recurred after surgical resection and conventional radiation therapy
* Tumor is not located in the eloquent part of the brain and not touching the brainstem, optic chiasm or optic nerve so that these critical structures will not receive full dose of re-irradiation
* Recurrent tumor is not surgically resectable or patient is not medically operable
* Age \> 18 years.
* Radiographical evidence of local recurrence on brain MRI, with or without histopathological confirmation.
* Estimated survival of at least 3 months
* Zubrod Performance Scale of 0-2
* Hgb greater than 10 gm/dl, absolute neutrophil count greater than 1500/ul, platelets greater than 100,000/ul, blood urea nitrogen (BUN) less than 25 mg/dl, Bilirubin less than 2.0 mg/dl, serum glutamate pyruvate transaminase (SGPT) or serum glutamate oxaloacetate transaminase (SGOT) less than 2 x normal range
* Less than or equal to 3 recurrent tumors, and combined largest diameter of all tumors less than or equal to 6 cm
* Single recurrent tumor less than or equal to 6 cm in the largest diameter

Exclusion Criteria:

* Prior therapy with any anti-Epidermal growth factor receptor(EGFR) and/or anti-VEGFR therapies
* Recurrent tumor greater than 6 cm in the largest diameter
* Recurrent tumor located in the brainstem.
* Prior radiation therapy to the brain within 2 months.
* Evidence of severe or uncontrolled systemic disease or any concurrent condition (such as severe cognitive impairment)
* pregnant and breast-feeding women will be excluded
* Treated on any other clinical protocols or with a non-approved or investigational drug within 30 days before Day 1 of study treatment.
* Any evidence of clinically active interstitial lung disease (patients with chronic stable radiographic changes who are asymptomatic need not be excluded)
* Clinically significant cardiac event
* History of arrhythmia. Atrial fibrillation, controlled on medication is not excluded.
* Previous history of corrected electrocardiogram QT interval (QTc)prolongation as a result from other medication that required discontinuation of that medication.
* Congenital long QT syndrome, or 1st degree relative with unexplained sudden death under 40 years of age
* Presence of left bundle branch block QTc with Bazett's correction that is unmeasurable, or 480 msec on screening ECG. If a patient has QTc 480 msec on screening ECG, the screen ECG may be repeated twice (at least 24 hours apart). The average QTc from the three screening ECGs must be less than 480 msec in order for the patient to be eligible for the study.
* Concomitant medication that may cause QTc prolongation, induce Torsades de Pointes or induce cytochrome P450 3A4 (CYP3A4) function Hypertension not controlled by medical therapy (systolic blood pressure greater than 160 mm Hg or diastolic blood pressure greater than 100 mm Hg)
* Active diarrhea that may affect the ability of the patient to absorb the VANDETANIB.
* Major surgery within 4 weeks, or incompletely healed surgical incision before starting study therapy
* Clinical and/or radiographic evidence of bleeding in the recurrent brain tumor.
* Patients currently on enzyme inducing anticonvulsants. However, patients are eligible if the enzyme inducing anticonvulsants can be discontinued or switched to non- enzyme inducing anticonvulsants one week before study entry. Non-enzyme inducing anticonvulsants cannot be those which may cause QTc prolongation, induce Torsades de Pointes or induce CYP3A4 function
* Laboratory results:

  * Serum bilirubin greater than 1.5 x the upper limit of reference range (ULRR)
  * Serum creatinine greater than 1.5 x ULRR or creatinine clearance less than 50 mL/minute (calculated by Cockcroft-Gault formula)
  * Potassium, less than 4.0 mmol/L despite supplementation; serum calcium (ionized or adjusted for albumin,) or magnesium out of normal range despite supplementation
  * Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) greater than 2.5 X ULRR