Inclusion Criteria

- ELIGIBILITY CRITERIA :

INCLUSION CRITERIA PHASE I:

Patients with histologically proven malignant primary gliomas will be eligible for this
protocol. These include glioblastoma multiforme (GBM), gliosarcoma, anaplastic
astrocytoma (AA), anaplastic oligodendroglioma (AO), anaplastic mixed oligoastrocytoma
(AMO), and malignant glioma/astrocytoma NOS. Additionally, patients with progressive
low-grade gliomas and patients with infiltrative brain stem gliomas, diagnosed
radiographically rather than by biopsy.

Patients must have an MRI scan performed within 14 days prior to registration.

Patients having undergone recent resection of a recurrent or progressive tumor, will be
eligible four weeks after surgery.

Patients must have failed prior radiation therapy.

All patients or their PREVIOUSLY DESIGNATED DPA (if the patient is deemed by the treating
physician to be cognitively impaired or questionably impaired is 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.

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

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

Patients must be at least six weeks from radiation therapy. Additionally, patients must be
at least 6 weeks from nitrosoureas, 4 weeks from temozolomide or carboplatin, 3 weeks from
procarbazine, and 2 weeks from last vincristine administration. Patients must be at least
4 weeks from other cytotoxic therapies not listed above and 2 weeks for non-cytotoxic
agents (e.g., interferon, tamoxifen) including investigative agents.

Patients must have adequate bone marrow function (WBC greater than or equal to
3,000/microliter ANC greater than or equal to 1,500/mm(3), platelet count of greater than
or equal to 100,000/mm(3), and hemoglobin greater than or equal to 10 gm/dl), adequate
liver function (SGOT and bilirubin less than or equal to 2 times ULN), and adequate renal
function (creatinine less than or equal to 1.5 mg/dL and/or creatinine clearance greater
than or equal to 60 cc/min) before starting therapy. These tests must be performed within
14 days prior to registration. Eligibility level for hemoglobin may be reached by
transfusion.

Patients must either not be receiving steroids, or be on a stable dose of steroids for at
least five days prior to registration.

Patients with a history of any other cancer (except non-melanoma skin cancer or carcinoma
in-situ of the cervix), unless in remission and off of all therapy for that disease for a
minimum of 1 year are ineligible.

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.

Patients must not be pregnant or nursing, and all patients (both men and women) must be
willing to practice birth control during and for 2 months after treatment with ZD6474.
Women of childbearing potential (WCBP) must have a negative serum or urine pregnancy test.
In addition, sexually active WCBP must agree to use adequate contraceptive methods (oral,
injectable, or implantable hormonal contraceptive; tubal ligation; intra-uterine device;
barrier contraceptive with spermicide; or vasectomized partner).

A 12 lead electrocardiogram (ECG) to be performed within 2 weeks of trial entry with QTc
less than 460 msec.

Only patients on EIAEDs are to be included in Phase I.

A normal echocardiogram to be performed within 2 weeks of trial entry.

EXCLUSION CRITERIA PHASE I:

Any of the following is regarded as a criterion for exclusion from the study:

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

Active cardiac disease as defined by:

- Significant cardiac event (including symptomatic heart failure or evidence of cardiac
ischemia within 3 months of first dose or presence of any cardiac disease that in the
opinion of the Investigator increases the risk of ventricular arrhythmia.

- Clinically significant arrhythmia (multifocal premature ventricular contraction
[PVC], bigeminy, trigeminy, ventricular tachycardia, bradycardia) that is symptomatic
or requires treatment (CTCAE v3.0 grade 3), or asymptomatic sustained ventricular
tachycardia, at the discretion of the investigator.

- Any concurrent medication that may cause QTc prolongation or induce Torsades de
Pointes (See Appendix C, Table 1). Drugs listed in Appendix C, Table 2, that in the
investigator's opinion cannot be discontinued are allowed; however, must be monitored
closely with additional ECGs and laboratory assessments of electrolytes to ensure the
patient's safety.

- Previous history of QTc prolongation with other medication.

- Congenital long QT syndrome.

- QTc with Bazett's correction that is unmeasurable, or greater than or equal to 460
msec on screening ECG. If a patient has QTc greater than or equal to 460 msec on
screening ECG, a second screen ECG may be repeated at least 24 hours apart. The
average QTc from the 2 screening ECGs must be less than 460 msec in order for the
patient to be eligible for the study. If the patient meets eligibility requirements
in this way, the "baseline" QTc for this patient will be the average of the 3 ECGs
(screen 1, screen 2, and pre-1st dose).

- Previous history of left ventricular ejection fraction (LVEF) less than 45 percent as
measured by multi-gated acquisition scan (MUGA) or by echocardiogram (ECHO) for
patients with previous anthracycline therapy (total dose greater than 450 mg/m(2)) or
significant cardiovascular disease or chest irradiation, as determined by the
investigator.

- A cardiac arrhythmia serious enough to require therapy (i.e. drugs, AID), angina,
symptomatic congestive heart failure and/or a cardiac ejection fraction less than 45
percent.

Prior serious cardiac disease defined as prior coronary bypass surgery, angioplasty, or
prior myocardial infarction unless a recent cardiac evaluation (within the last 3 months)
demonstrated no significant coronary artery disease (i.e. a negative stress test) and no
myocardial wall dysfunction.

Concurrent use of other standard chemotherapeutics or investigative agents or
vasoconstrictors for the treatment of migraine (ergotamine, zolmitriptan, sumatriptan)
because of the potential for exacerbation of coronary vasoconstriction.

Laboratory results sustained at:

Neutrophils less than 1.5 10(9)/L or platelets less than 100,000/mm(3). Serum creatinine
greater than 1.5 x ULRR. Potassium, calcium (ionized calcium or adjusted for albumin), or
magnesium concentrations outside normal limits. Supplementation of electrolytes is
permitted. Aspartate aminotransferase (AST/SGOT) greater than 2 times ULRR, or AST
greater than 5.0 ULRR if judged by the investigator to be related to liver metastases.

Evidence of severe or uncontrolled systemic disease or any concurrent condition 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.

Hypertension not controlled by medical therapy (systolic blood pressure greater than 160
mm Hg or diastolic blood pressure greater than 100 mm Hg).

Any currently active gastrointestinal disease with diarrhea that may affect the ability of
the patient to absorb the ZD6474 or tolerate diarrhea.

Currently pregnant or breast feeding.

Participation in a clinical trial of any investigational agents within 14 days prior to
commencing study treatment.

Patients must be at least six weeks from radiation therapy. Additionally, patients must be
at least 6 weeks from nitrosoureas, 4 weeks from temozolomide or carboplatin, 3 weeks from
procarbazine, and 2 weeks from last vincristine administration. Patients must be at least
4 weeks from other cytotoxic therapies not listed above and 2 weeks for non-cytotoxic
agents (e.g., interferon, tamoxifen) including investigative agents.

Any unresolved toxicity greater than CTC (Version 3.0) grade 1 from previous anti-cancer
therapy.

INCLUSION CRITERIA PHASE II:

Patients with histologically proven malignant primary gliomas will be eligible for this
protocol. These include glioblastoma multiforme (GBM), gliosarcoma, anaplastic
astrocytoma (AA), anaplastic oligodendroglioma (AO), anaplastic mixed oligoastrocytoma
(AMO), and malignant glioma/astrocytoma NOS.

Patients must have an MRI scan performed within 14 days prior to registration.

Patients having undergone recent resection of a recurrent or progressive tumor, will be
eligible four weeks after surgery.

Patients with high-grade gliomas must have failed prior radiation therapy.

All patients or their PREVIOUSLY DESIGNATED DPA (if the patient is deemed by the treating
physician to be cognitively 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.

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

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

Patients must be at least six weeks from radiation therapy. Additionally, patients must be
at least 6 weeks from nitrosoureas, 4 weeks from temozolomide or carboplatin, 3 weeks from
procarbazine, and 2 weeks from last vincristine administration. Patients must be at least
4 weeks from other cytotoxic therapies not listed above and 2 weeks for non-cytotoxic
agents (e.g., interferon, tamoxifen) including investigative agents.

Patients must have adequate bone marrow function (WBC greater than or equal to
3,000/microl, ANC greater than or equal to 1,500/mm(3), platelet count of greater than or
equal to 100,000/mm(3), and hemoglobin greater than or equal to 10 gm/dl), adequate liver
function (SGOT and bilirubin less than or equal to 2 times ULN), and adequate renal
function (creatinine less than or equal to 1.5 mg/dL and/or creatinine clearance greater
than or equal to 60 cc/min) before starting therapy. These tests must be performed within
14 days prior to registration. Eligibility level for hemoglobin may be reached by
transfusion.

Patients must either not be receiving steroids, or be on a stable dose of steroids for at
least five days prior to registration.

Patients with a history of any other cancer (except non-melanoma skin cancer or carcinoma
in-situ of the cervix), unless in remission and off of all therapy for that disease for a
minimum of 1 year are ineligible.

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.

Patients must not be pregnant or nursing, and all patients (both men and women) must be
willing to practice birth control during and for 2 months after treatment with ZD6474.
Women of childbearing potential (WCBP) must have a negative serum or urine pregnancy test.
In addition, sexually active WCBP must agree to use adequate contraceptive methods (oral,
injectable, or implantable hormonal contraceptive; tubal ligation; intra-uterine device;
barrier contraceptive with spermicide; or vasectomized partner).

A 12 lead electrocardiogram (ECG) to be performed within 2 weeks of trial entry with QTc
less than 460 msec.

Only patients taking NEIAEDs are to be included in Phase II.

A normal echocardiogram to be performed within 2 weeks of trial entry.

EXCLUSION CRITERIA PHASE II:

Any of the following is regarded as a criterion for exclusion from the study:

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

Active cardiac disease as defined by:

- Significant cardiac event (including symptomatic heart failure or evidence of cardiac
ischemia within 3 months of first dose or presence of any cardiac disease that in the
opinion of the Investigator increases the risk of ventricular arrhythmia.

- Clinically significant arrhythmia (multifocal premature ventricular contraction
[PVC], bigeminy, trigeminy, ventricular tachycardia, bradycardia) that is symptomatic
or requires treatment (CTCAE grade 3), or asymptomatic sustained ventricular
tachycardia.

- Any concurrent medication that may cause QTc prolongation or induce Torsades de
Pointes (See Appendix C, Table 1). Drugs listed in Appendix C, Table 2, that in the
investigator's opinion cannot be discontinued are allowed; however, must be monitored
closely with additional ECGs and laboratory assessments of electrolytes to ensure the
patient's safety.

- Previous history of QTc prolongation with other medication.

- Congenital long QT syndrome

- QTc with Bazett's correction that is unmeasurable, or greater than or equal to 460
msec on screening ECG. If a patient has QTc greater than or equal to 460 msec on
screening ECG, a second screen ECG may be repeated at least 24 hours apart. The
average QTc from the 2 screening ECGs must be less than 460 msec in order for the
patient to be eligible for the study. If the patient meets eligibility requirements
in th...