Phase I Dose Escalation Study of Vandetanib w/ Hypofractionated Stereotactic Radiotherapy in Patients w/ Recurrent Malignant Gliomas

Screening Prior to receiving any treatment, tests will be performed to determine overall
medical condition. This will include blood tests, questions about your medical history, and
physical and neurological exams.

MRI scan of the brain, electrocardiogram (ECG) and chest X-ray will be performed as baseline
studies if they have not been performed in the last 28 days.

Women of child-bearing potential will also have a serum pregnancy test within 2 days before
taking the study drug.

During treatment If all of the study criteria are met and are enrolled in the study, you
will start taking the study drug at least 7 days before radiation therapy. You will take the
study drug once a day by mouth. You should take the study drug at about the same time each
day. If you forget to take a dose, take the missed dose as soon as you remember, as long as
it is at least 12 hours before the next dose is due. If it is less than 12 hours until the
next dose, do not take the dose you have missed. If you throw up within 30 minutes after
you take the study drug, you should take another dose, and use medicine to stop or relieve
your vomiting per your doctor's instruction. You will continue to take the study drug for a
total duration of one year. The study will be stopped if your disease progresses or there is
excessive toxicity. Your participation in the study will be for one year. However, we will
continue to follow your disease status, general health and possible treatment-related side
effects after one year and for as long as possible.

This is a Phase I study. These types of studies usually include a small number of subjects
and are often called dose-escalation studies. Subjects in the first dose group will be
receiving a small dose of the study drug. If no unacceptable side effects are observed in
these subjects, the next group of subjects will receive the next higher dose of study drug.
The study drug doses planned are as follows:

Dose Level Drug dose Level 1 100 mg once a day Level 2 200 mg once a day Level 3 300 mg once
a day

You will be assigned to one of three levels depending on when you enter the study.

You will also receive radiation therapy. The radiation dose is the same for all patients.
Radiation therapy will begin at least 7 days after you begin taking the study drug. The
radiation therapy will be once a day for 3 consecutive days. A special plastic mask will be
made for you and used to hold your head still during each radiation treatment.

Tests and procedures will be performed throughout your treatment to determine how your
cancer is responding and to monitor you for safety purposes. The tests and procedures will
be scheduled for you. The following tests and procedures will be performed:

- Physical examination, neurological examination, and ECG, right before, and in the
first, second, fourth, eighth and twelfth week of drug treatment; then once every three
months.

- Brain MRI and quality of life questionnaires at one month and three month after
radiation therapy, then once every three months.

- Chest X-ray as your doctor determines.

Follow-up You will also have follow-up visits with your doctor once a month for the first 6
months, then once every three months. You may also see your doctor anytime as needed.

Duration You will be on this study for up to 12 months.

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-irridiation.

- Recurrent tumor is not surgically resectable or patient is not medically operable.

- Prior chemotherapy is allowed, except prior therapy with anti-EGFR and/or anti-VEGFR
therapy.

- Age greater than 18 years at time of registration.

- 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, BUN less than 25 mg/dl, Bilirubin less than 2.0 mg/dl, SGPT
or SGOT less than 2 x normal range.

- Less than or equal to 3 recurrent tumors, and the 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.

- Patients must sign study-specific consent form prior to registration.

- Inclusion of Women and Minorities. Both men and women and members of all ethnic
groups are eligible for this trial.

Exclusion Criteria

- Prior therapy with any anti-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) which in the Investigator's opinion makes it
undesirable for the patient to participate in the trial or which would jeopardize
compliance with the protocol.

- As the effect of VANDETANIB on fetus and infant is unknown, pregnant and
breast-feeding women will be excluded from this study.

- Treated on any other clinical protocols or with a non-approved or investigational
drug within 30 days before Day 1 of study treatment. Conventional chemotherapy must
be stopped at least two weeks before the patient starts VANDETANIB.

- 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 such as myocardial infarction; New York Heart
Association (NYHA) classification of heart disease greater than 2 (see Appendix B)
within 3 months before entry; or presence of cardiac disease that, in the opinion of
the Investigator, increases the risk of ventricular arrhythmia.

- History of arrhythmia (multifocal premature ventricular contractions (PVCs),
bigeminy, trigeminy, ventricular tachycardia, or uncontrolled atrial fibrillation)
which is symptomatic or requires treatment (CTCAE grade 3) or asymptomatic sustained
ventricular tachycardia. Atrial fibrillation, controlled on medication is not
excluded.

- Previous history of 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 (LBBB.) 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.

- Any concomitant medication that may cause QTc prolongation, induce Torsades de
Pointes (see Appendix A) or induce CYP3A4 function (refer to section 6.6)
Hypertension not controlled by medical therapy (systolic blood pressure greater than
160 mm Hg or diastolic blood pressure greater than 100 mm Hg)

- Currently 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 such as phenytoin,
carbamazepine, rifampicin, barbiturates, or primadone. However, patients are eligible
for the study 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 (see Appendix A) or induce CYP3A4 function (refer to section
6.6).

- 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