Tandutinib Plus Bevacizumab to Treat Recurrent Brain Tumors

* INCLUSION CRITERIA:
* Patients with histologically proven intracranial malignant glioma will be eligible for this protocol.

Malignant glioma includes glioblastoma multiforme (GBM), gliosarcoma, anaplastic astrocytoma (AA), anaplastic oligodendroglioma (AO), anaplastic mixed oligoastrocytoma (AMO), or malignant astrocytoma NOS (not otherwise specified).

* Patients must have evidence for tumor progression by magnetic resonance imaging (MRI) or computed tomography (CT) scan.

This scan should be performed within 14 days prior to registration and on a fixed dose of steroids for at least 5 days.

If the steroid dose is increased between the date of imaging and registration a new baseline MRI/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.

* 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.

  * If the 96 hour scan is more than 21 days before registration, the scan needs to be repeated.

If the steroid dose is increased between the date of imaging and registration, a new baseline MRI/CT is required on a stable steroid dosage for at least 5 days.

* Patients must have progressed after radiation therapy and must have an interval of greater than or equal to 4 weeks from the completion of radiation therapy to study entry.
* 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.
* Patients must be greater than or equal to 18 years old, and with a life expectancy greater than 8 weeks.
* Patients must have a Karnofsky performance status of greater than or equal to 60.
* Patients must have recovered from the toxic effects of prior therapy: 2 weeks from any investigational agent, 4 weeks from prior cytotoxic therapy, two weeks from vincristine, 6 weeks from nitrosoureas, 3 weeks from procarbazine administration, and 1 week for non-cytotoxic agents, e.g., interferon, tamoxifen, thalidomide, cis-retinoic acid, etc. (radiosensitizer does not count). Any questions related to the definition of non-cytotoxic agents should be directed to the Study Chair.
* Patients must have adequate bone marrow function (white blood cell (WBC) greater than or equal to 3,000/microl, Absolute neutrophil count (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 (serum glutamic oxaloacetic transaminase (SGOT) and bilirubin less than 2 times upper limit of normal (ULN)), and adequate renal function (creatinine less than 1.5 mg/dL and/or creatinine clearance greater than or equal to 60 cc/min) before starting therapy.

Serum sodium, calcium, potassium, chloride, and magnesium must be in normal limits.

These tests must be performed within 14 days prior to registration. Eligibility level for hemoglobin may be reached by transfusion.

* 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
* 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.
* Creatinine clearance or calculated creatinine clearance greater than or equal to 60 mL/minute.
* Patients must practice adequate contraception.
* Head CT Scan without contrast (to rule out significant acute hemorrhage) within 7 days prior to starting treatment.
* A 12 lead electrocardiogram (ECG) to be performed within 2 weeks of trial entry with corrected QT interval (QTc) less than 460 msec.

EXCLUSION CRITERIA:

* Patients who, in the view of the treating physician, have significant active cardiac, hepatic, renal, or psychiatric diseases are ineligible.
* No concurrent use of other standard chemotherapeutics or investigative agents.
* Patients known to have a malignancy that has required treatment in the last 12 months and/or is expected to require treatment in the next 12 months (except non-melanoma skin cancer or carcinoma in-situ in the cervix).
* Patients who have an active infection.
* Pregnant (positive pregnancy test) or nursing women. Fertile men and women must agree to use adequate contraceptive measures during study therapy and for at least 6 months after the completion of tandutinib plus bevacizumab therapy.
* Patients who have any disease that will obscure toxicity (i.e. vasculitis, congenital hypercoaguability syndromes, uncontrolled primary hypertension, idiopathic thrombocytopenia).
* Evidence of significant recent hemorrhage on mandatory CT scan (defined as 1 cm or more of acute blood) of the brain within 7 days of patient accrual with the following exceptions: resolving hemorrhagic changes related to surgery, and/or presence of punctate hemorrhages in the tumor.
* Concurrent anti-coagulation or anti-platelet medication (including aspirin, non-steroidal anti-inflammatories, cyclooxygenase -2 (COX-2) inhibitors).
* Serious or non-healing wound, ulcer or bone fracture.
* Proteinuria at screening as demonstrated by either:
* Urine protein:creatinine (UPC) ratio greater than or equal to 1.0 at screening OR
* Urine dipstick for proteinuria greater than or equal to 2+ (patients discovered to have greater than or equal to 2+ proteinuria on dipstick urinalysis at baseline should undergo a 24 hour urine collection and must demonstrate less than or equal to 1g of protein in 24 hours to be eligible).
* History of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess within 6 months
* 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 D1 therapy
* Patients with clinically significant cardiovascular disease
* History of cerebrovascular accident (CVA) or transient ischemic attack within 6 months
* Inadequately controlled hypertension (defined as systolic blood pressure greater than 160 and/or diastolic blood pressure greater than 100 mmHg on antihypertensive medications)
* Any prior history of hypertensive crisis or hypertensive encephalopathy
* Myocardial infarction or unstable angina within 6 months
* New York Heart Association Grade II or greater congestive heart failure
* Serious cardiac arrhythmia requiring medication
* Unstable angina pectoris
* Symptomatic peripheral vascular disease
* Evidence of bleeding diathesis or coagulopathy
* Prothrombin time (PT)/partial thromboplastin time (PTT) greater than1.5 time the upper limit of normal
* Patients with known hypersensitivity of Chinese hamster ovary cell products or other recombinant human antibodies
* Inability to take oral medication
* Known gastrointestinal disease or history of gastrointestinal surgery that could interfere with the absorption of orally administered medication.
* Ongoing vomiting
* 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 (Common Terminology Criteria for Adverse Events (CTCAE) grade 3), or asymptomatic sustained ventricular tachycardia.
* 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- 1 first 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, acquired immune deficiency (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.
* Known or suspected primary muscular or neuromuscular disease (e.g. muscular dystrophy, myasthenia gravis). This does not include steroid myopathy.
* Prior treatment with bevacizumab is not permitted.
* Concurrent use of other drugs that have been shown to potentially prolong the QTc interval.