Sunitinib to Treat Recurrent Brain Cancer

Background:

Solid tumors have multiple mechanisms for stimulating angiogenesis with the vascular
endothelial growth factor (VEGF)-kinase insert domain receptor (KDR) axis being only one of
them. Sunitinib, through its multiple tyrosine kinase receptor targets, represents an
attempt to capitalize on the concept of targeting multiple mechanisms responsible for
glioma-associated angiogenesis. Sunitinib inhibits platelet derived growth factor receptor
(PDGFR) and c-kit (stem cell factor (SCF) receptor) at nanomolar concentrations. The
combination blocks all three known major glioma-mediated angiogenic mechanisms (VEGF, c-kit,
PDGF). Based on this scientific rationale, the promising anti-glioma activity of sunitinib
in preclinical models, and the promising clinical data in patients with gliomas treated with
other VEGF inhibitors, we are now proposing a phase II trial of sunitinib in patients with
recurrent malignant gliomas.

Objectives:

To evaluate the anti-glioma activity of sunitinib in patients with recurrent malignant
gliomas who are either naive or resistant to prior bevacizumab therapy.

Eligibility:

Patients with recurrent malignant glioma are eligible for this study.

Design:

This is a phase II study with a target enrollment of 64 (32 with glioblastoma multiforme
(GBM) and 32 with anaplastic glioma (AG)) patients who have not progressed on prior
treatment with anti-VEGF therapy, and 64 (32 with GBM and 32 with AG)patients who have
progressed on prior bevacizumab therapy.

Sunitinib will be self-administered orally at 37.5 mg daily, with dose adjustments allowed
for toxicity and concomitant drug interactions.

The primary endpoint is six-month progression free survival for both arms of the study.

We performed an interim analysis (see below) and after consulting with the pharmaceutical
company (Pfizer) we believe that ending the study is the most appropriate course of action
to take.

In the original design of the trial, for the AG stratum, the agent will be considered
effective if at least 14 patients have not progressed by 6 months. Now, we have observed one
out 10 Bev-naïve who haven't progressed by 6 months. Then given one patient in the first 10
patients whose PFS >=6, the conditional probability of observing at least 14 out of 32
patients who are 6 month-PFS is only 43% even if the true 6 months-PFS is 55%. Since in the
first 10 patients, we only observed one patient with PFS>=6 months, it is unlikely that the
true 6 month-PFS is 55%. The conditional power would be close to zero, if the true 6
month-PFS close to 10% as observed so far. Based on the conditional probability, the chance
of a positive study is small, and hence the trial should be considered stopped for futility.

For Bev-resistant patients, because in the first 12 patients none had PFS >= 6 months the
conditional probability of declaring the agent being effective is even lower and equals 12%,
if the true PFS at 6 months is 55%. Essentially there is little chance that the agent can be
declared effective.

- INCLUSION CRITERIA:

1. Patients with histologically proven intracranial malignant glioma will be
eligible for this protocol. Malignant gliomas include glioblastoma multiforme
(GBM), gliosarcoma (GS), anaplastic astrocytoma (AA), anaplastic
oligodendroglioma (AO), anaplastic mixed oligoastrocytoma (AMO), or malignant
astrocytoma NOS (not otherwise specified).

2. Patients may have received prior therapy with bevacizumab, but not within six
weeks of starting treatment with sunitinib. Patients who received prior therapy
with bevacizumab must have demonstrated radiographic disease progression while
being treated with bevacizumab.

3. Patients must have progressed after radiation and temozolomide therapy and have
an interval of greater than or equal to 4 weeks from the completion of radiation
therapy to study entry. If the patient has had prior stereotactic radio surgery,
true tumor progression must be corroborated by fludeoxyglucose 18F
(FDG)-positron emission tomography (PET) or magnetic resonance (MR) spectroscopy
imaging.

4. Patients must have evidence of tumor progression by contrast enhanced perfusion
magnetic resonance imaging (MRI) or computed tomography (CT) scan. This scan
should be performed within 14 days prior to registration and on a five-day
stable dose of steroids. If the steroid dose is increased between the date of
imaging and registration, a new baseline MR/CT is required. The same type of
scan (i.e., MRI or CT) must be used throughout the period of protocol treatment
for tumor measurement.

5. Patients having undergone recent resection of recurrent or progressive tumor
will be eligible as long as all of the following conditions apply:

- They have recovered from the effects of surgery.

- Residual disease following resection of recurrent tumor is not mandated for
eligibility into the study. To best assess the extent of residual disease
post-operatively, a CT/MRI should be done:

- no later than 96 hours in the immediate post-operative period, or

- at least 4 weeks post-operatively, and

- within 14 days of registration, and

- on a steroid dosage that has been stable for at least 5 days.

f) Normal organ and marrow function defined as: total leukocyte count greater
than or equal to 3000 cells/ul, absolute neutrophil count (ANC) greater than or
equal to 1500 cells/ul, platelet count greater than or equal to 100,000
cells/ul, serum creatinine less than or equal to 2.0 times the upper limit of
normal, and bilirubin less than or equal to 1.5 times the upper limit of normal,
hemoglobin greater than or equal to 9.0 g/dL , serum calcium less than or equal
to 12.0 mg/dL, aspartate aminotransferase (AST)/alanine aminotransferase (ALT)
less than or equal to 1.5 times the upper limit of normal, prothrombin time (PT)
less than or equal to 1.5 upper limits of normal (ULN). Eligibility level for
hemoglobin may be reached by transfusion.

g) The effects of sunitinib on the developing human fetus at the recommended
therapeutic dose are unknown. Women of child-bearing potential and men must
agree to use adequate contraception (hormonal or barrier method of birth
control; abstinence) prior to study entry and for the duration of study
participation. Should a woman become pregnant or suspect she is pregnant while
participating in this study, she should inform her treating physician
immediately.

h) All patients or their previously designated durable power of attorney (DPA)
(if the patient is deemed by the treating physician to be impaired or
questionably impaired in such a way that the ability of the patient to give
informed consent is questionable) must sign an informed consent indicating that
they are aware of the investigational nature of this study.

i) Patients must be greater than or equal to 18 years old, and with a life
expectancy greater than 8 weeks.

j) Patients must have a Karnofsky performance status of greater than or equal to
60.

k) Patients must have recovered from the toxic effects of prior therapy: 2 weeks
from any investigational agent, two weeks from vincristine, 6 weeks from
nitrosoureas, 3 weeks from procarbazine, 1 week for non-cytotoxic agents, (e.g.,
interferon, tamoxifen, thalidomide, cis-retinoic acid, etc.), and 4 weeks from
other cytotoxic therapy. Any questions related to the definition of
non-cytotoxic agents should be directed to the Study Chair.

l) Patients must not have any significant medical illnesses that in the
investigator's opinion cannot be adequately controlled with appropriate therapy
or would compromise the patients' ability to tolerate this therapy.

m) This study was designed to include women and minorities, but was not designed
to measure differences of intervention effects. Males and females will be
recruited with no preference to gender. No exclusion to this study will be based
on race. Minorities will actively be recruited to participate.

EXCLUSION CRITERIA:

1. Patients who, in the view of the treating physician, have significant active cardiac,
hepatic, renal, or psychiatric diseases are ineligible.

2. Patients with a history of prior therapy directed against vascular endothelial growth
factor (VEGF) (e.g. sorafenib, pazopanib, Zactima (ZD6474), AZD2171), with the
exception of bevacizumab, will not be allowed to enroll.

3. Concurrent use of other standard chemotherapeutics or investigative agents.

4. Patients known to have a malignancy (other than their malignant glioma) that has
required treatment in the last 12 months and/or are expected to require treatment in
the next 12 months (except non-melanoma skin cancer or carcinoma in-situ in the
cervix).

5. Patients who have an active infection.

6. Pregnant (positive pregnancy test) or nursing women. Both fertile men and women must
agree to use adequate contraceptive measures during study therapy and for at least 3
months after the completion of sunitinib therapy.

7. Concurrent anti-coagulation or anti-platelet medication (including aspirin,
non-steroidal anti-inflammatory agents, cyclooxygenase -2 (COX-2) inhibitors).

8. Serious or non-healing wound, ulcer or bone fracture

9. History of any of the following within 6 months of study entry: abdominal fistula,
gastrointestinal perforation, intra-abdominal abscess, stroke, myocardial infarction
or unstable angina. Patients will not undergo diagnostic screening for any of these
conditions.

10. Invasive procedures defined as follows:

- Major surgical procedure, open biopsy or significant traumatic injury within 28
days prior to Day 1 therapy

- Anticipation of need for major surgical procedures during the course of the
study

- Core biopsy within 7 days prior to start of therapy

11. Uncontrolled hypertension (greater than 150/100 mmHg) while on antihypertensive
medications.

12. New York Heart Association class II or greater congestive heart failure.

13. Serious cardiac arrhythmia requiring medication.

14. Evidence of bleeding diathesis, coagulopathy, or international normalized ratio (INR)
greater than 1.5.

15. History of allergic reactions attributed to compounds of similar chemical or biologic
composition to sunitinib.

16. Patients receiving any enzyme inducing anti-epileptic drugs (EIAEDs) and other potent
cytochrome P450 3A4 (CYP3A4) modulators (per Appendixes B and C) within two weeks
prior to treatment start are ineligible.

17. Baseline echocardiogram with ejection fraction less than 50% or greater than or equal
to 20% decrease from a prior study

18. corrected QT interval(QTc) interval greater than 500 msec on baseline
electrocardiogram (EKG).

19. Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral
therapy are ineligible because of the potential for pharmacokinetic interactions with
sunitinib.