A Phase I Dose Escalation Study for Patients With Recurrent Malignant Gliomas

Recurrent malignant gliomas are uniformly fatal, and there has been no standard treatment in
this setting. Radiation therapy remains the main treatment. Although the efficacy of
systemic chemotherapy has not been well defined, studies have shown that some new agents
such as gefitinib and vandetanib have promising effects either as an antitumor agent or as a
radiation sensitizer.

To determine the maximum tolerated dose of hypofractionated stereotactic radiotherapy that
can be delivered with gefitinib to patients with recurrent malignant gliomas who have failed
prior combined therapy of surgery, chemotherapy and radiation therapy, we have been
conducting a phase I dose escalation study (COMIRB 03-1249) of hypofractionated stereotactic
radiotherapy.

Patients with pathologically proven malignant gliomas (WHO grade 3 or 4) that recurred after
initial surgery, chemotherapy and radiation therapy are eligible, provided that the
recurrent tumor is 6 cm in the largest diameter on MRI T1-weighted imaging; patients have
normal organ function and blood counts. Patients with a recurrent tumor in the brain stem,
or with more than three lesions were excluded. Patients started gefitinib at 250 mg once a
day 7 days before hypofractionated radiotherapy and continued during and after radiation for
a total duration of one year, or until disease progression. Radiation therapy was delivered
using Novalis BrainLab machine, in three fractions over three consecutive days. A removable
BrainLab mask was used for immobilization. The target volume was the T1 post-contrast
enhancing lesion on brain MRI with 2 mm margin. Radiation dose was prescribed to the 80-90%
isodose line that encompassed the target volume. Dose limiting toxicity was defined as any
grade 3 acute or delayed toxicity scored by NCI common toxicity criteria version 3. The
study schema is depicted in the following table.

Hypofractionated Stereotactic Radiotherapy Dose Escalation Dose level Dose

- of patients Tumor ≤ 6 cm Radiation a Total dose/fraction size Gefitinib b

3 patients Level 1 18 Gy/6 Gy 250 mg p.o. daily 3 patients Level 2 24 Gy/8 Gy 250 mg
p.o. daily 3 patients Level 3 30 Gy/10 Gy 250 mg p.o. daily 6 patients Level 4 36 Gy/12
Gy 250 mg p.o. daily a Radiation was given one fraction a day for three consecutive
days. b Doses for gefitinib are stated as exact dose in mg. Gefitinib started 7 days
before radiation and continued for 12 months, or until disease progression or
dose-limiting toxicities

15 patients were enrolled on the study with three patients on the first three dose
levels and 6 patients on the last dose level dose. There were 9 male and 6 female
patients. The median age was 45.5 years with a range of 23 to 65 years. 6 patients had
recurrent anaplastic astrocytoma and other 9 patients had recurrent glioblastoma
multiforme. All patients received prior radiation therapy to a total dose of 6000 cGy
except in one patient whose prior radiation dose was 5400 cGy. The median time interval
from prior radiation therapy was 13 months with a range of 3 to 56 months. All patients
received prescribed dose of hypofractionated stereotactic radiation. The median target
volume treated was 36 cc with a range of 8.4 cc to 121 cc. With a median follow-up time
of 8 months (range 3 to 16 months), there was no dose-limiting toxicity. One patient
with recurrent anaplastic astrocytoma treated on dose level 1 (1800 cGy) developed
seizures 6 moths after radiation and required surgery. Pathology showed radionecrosis
with no viable tumor cells. Grade 1 gefitinib-related skin reaction was observed in two
patients, and grade 1 diarrhea in one patient. Grade 2 skin reaction and diarrhea were
observed in one patient.

The preliminary results from our COMIRB 03-1249 study indicate that hypofractionated
stereotactic radiotherapy to a total dose of 3600 cGy (36 Gy) in three fractions is well
tolerated with gefitinib at daily dose of 250 mg. The results of this study were presented
at 2006 American Society of Therapeutic Radiology and Oncology annual meeting in
Philadelphia November 5-9, 2006.

VANDETANIB is a potent inhibitor of the tyrosine kinase activity of kinase insert
domain-containing receptor (KDR), VANDETANIB has demonstrated inhibition of both VEGFR and
EGFR tyrosine kinases in vitro.

VANDETANIB has shown excellent inhibition of tumor cell growth in a broad range of
preclinical models, including lung cancer xenografts. Regression of established tumors in
animals was observed following oral administration. VANDETANIB was considered to have an
acceptable preclinical toxicology profile for the proposed therapeutic indication.
VANDETANIB also inhibits EGF-stimulated cell proliferation, though at a concentration
approximately 3-fold higher than that required for inhibition of VEGF-stimulated cell
proliferation.

Rationale for this study The EGFR signal transduction pathway may play an important role in
tumor growth and therapy resistance of malignant gliomas. It is also well known that new
vasculature formation is one of the characteristics of malignant gliomas indicating that
angiogenesis plays a very important role in initial tumor growth, and tumor re-growth during
or after definitive treatment.

An EGFR and VEGFR dual inhibitor such as VANDETANIB holds tremendous promise in the
treatment of malignant gliomas.

Based on: 1) malignant glioma cells overexpress EGFR; 2) new vasculature formation is the
rule of malignant gliomas; 3) our preliminary results from COMIRB 03-1249 study indicating
that HSRT to 36 Gy in three fractions is well tolerated with gefitinib in patients with
recurrent malignant gliomas who were previously treated with full dose radiation (60 Gy) and
various regimens of chemotherapy, we propose a phase I dose escalation study of EGFR and
VEGFR dual inhibitor VANDETANIB in combination with HSRT at a fixed dose of 36 Gy.

Based on the phase I data once-daily dosing of VANDETANIB at 300 mg/day is well tolerated as
a monotherapy in patients with advanced solid tumor and pharmacokinetic analysis confirmed
that VANDETANIB was suitable for once-daily oral dosing.

This dose escalation study will evaluate the toxicity and safety of VANDETANIB at daily dose
of 100 mg/day, 200 mg/day and 300 mg/day in combination with hypofractionated stereotactic
radiotherapy to a total dose of 36 Gy in patients with recurrent malignant gliomas.

Inclusion Criteria:

- Patients with histopathologically confirmed malignant gliomas that recurred after
surgical resection and conventional radiation therapy.

- Tumor not located in the eloquent part of the brain and not touching the brainstem,
optic chiasm or optic nerve

- 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 > 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 > 10 gm/dl,

- absolute neutrophil count > 1500/ul,

- platelets > 100,000/ul,

- BUN < 25 mg/dl,

- Creatinine < 1.5 mg/dl,

- Bilirubin < 2.0 mg/dl,

- SGPT or SGOT < 2 x normal range. -≤ 3 recurrent tumors, and the combined largest
diameter of all tumors ≤ 6 cm.

- Recurrent tumor ≤ 6 cm in the largest diameter.

- 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 > 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

- 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.

- 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

- 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 <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 or induce 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)

- Currently active diarrhea that may affect the ability of the patient to absorb the
VANDETANIB or tolerate diarrhea.

- 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

- Laboratory results:

- Serum bilirubin >1.5 x the upper limit of reference range (ULRR)

- Serum creatinine >1.5 x ULRR or creatinine clearance < 50 mL/minute

- Potassium, <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) > 2.5 ULRR