RATIONALE: Dasatinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Bevacizumab may also block the growth of the tumor by blocking blood flow to the tumor. It is not yet known whether bevacizumab together with dasatinib are more effective than a placebo in treating patients with recurrent or progressive high-grade glioma or glioblastoma multiforme.

PURPOSE: This randomized phase I/II trial (Phase I completed) is studying the side effects and best dose of dasatinib when given together with bevacizumab and to see how well it works compared to placebo in treating patients with recurrent or progressive high-grade glioma or glioblastoma multiforme.

OUTLINE: This is a multicenter, phase I, dose-escalation study (Phase I completed) of dasatinib followed by a phase II randomized study. Patients are grouped according to study (1 vs 2). Patients in the phase II portion are stratified according to age (> 70 years of age vs ≤ 70 years of age), and ECOG performance status (0 vs 1 or 2).

Phase I: Patients receive bevacizumab IV over 30-90 minutes on day 1. Patients also receive oral dasatinib once or twice daily on days 1-14 until the maximum-tolerated dose (MTD) is determined. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity. (Phase I completed) Please see the Arms section for the Phase II treatment regimens.

OBJECTIVES:

PRIMARY OBJECTIVES:

1. Determine the maximum tolerated dose (MTD) of dasatinib in combination with bevacizumab in high grade glioma patients. (Phase I)
2. To assess the safety and adverse events of the dasatinib in combination with bevacizumab in this patient population. (Phase I)
3. To estimate the efficacy of the bevacizumab combination with dasatinib in recurrent glioblastoma multiforme as measured by progression free survival at six months and compare it with the efficacy of bevacizumab alone. (Phase II)

SECONDARY OBJECTIVES:

1. To describe the overall toxicity associated with the dasatinib/bevacizumab combination. (Phase I)
2. To describe any preliminary evidence of antitumor activity. (Phase I)
3. To assess the time to disease progression. (Phase II)
4. To assess the safety and toxicity of the bevacizumab combination with dasatinib in this patient population. (Phase II)
5. To estimate the efficacy of the bevacizumab combination with dasatinib in recurrent glioblastoma multiforme as measured by overall survival time and compare it with the efficacy of bevacizumab alone. (Phase II)
6. To assess the impact of the treatment on the patient's quality of life (QOL) using the overall score from the FACT-Br (Phase II)

Patient Eligibility:

I. Pre-registration:

1. Central pathology review submission. This review is mandatory prior to registration to confirm eligibility.

II. Registration Inclusion Criteria:

1. ≥18 years of age

2. Study 1: Histologic confirmation of grade 3 or 4 glioma, including astrocytoma, oligodendroglioma, and mixed gliomas, as determined by pre-registration central pathology review.

3. Study 2: Histological confirmation of glioblastoma multiforme (grade 4 astrocytoma) as determined by pre-registration central pathology review. NOTE: Variant gliosarcomas are eligible

4. Evidence of tumor progression by MRI or CT scan following RT or following the most recent anti-tumor therapy. Patients who had surgical treatment at recurrence are eligible if there is imaging evidence of disease progression as compared to the first postoperative scan.

5. Bidimensionally measurable or evaluable disease by MRI or CT scan.

6. ECOG Performance Status (PS) 0, 1, or 2.

7. Patient willing to discontinue use of aspirin or medications that inhibit platelet function ≥ 1 week prior to registration.

8. Previous RT and ≥12 weeks since the completion of RT prior to registration.

9. The following laboratory values obtained ≤ 21 days prior to registration.

   • ANC ≥1500
   • PLT ≥100,000
   • Hgb >9.0 g/dL
   • T. bili ≤1.5 x ULN
   • SGOT (AST) ≤ 3 x ULN
   • Creatinine ≤ ULN

10. UPC ratio <1. NOTE: Urine protein must be screened by urine analysis for Urine Protein Creatinine (UPC) ratio. For UPC ratio ≥1.0, 24-hour urine protein must be obtained and the level should be <1000 mg

11. Negative pregnancy test done ≤7 days prior to registration, for women of childbearing potential only.

12. Ability to complete questionnaire(s) by themselves or with assistance.

13. Provide informed written consent

14. Willingness to return to enrolling institution for follow-up.

15. Patient willing to provide mandatory tissue samples for research purposes

16. Study 1: Any number of prior chemotherapy regimens for recurrent disease. Study 2: Up to 2 prior chemotherapy regimens with ≤1 regimen for recurrent disease.

III. Exclusion Criteria:

1. Pregnant women, nursing women and men or women of childbearing potential who are unwilling to employ adequate contraception during this study and for up to 6 months after bevacizumab treatment has ended. NOTE: bevacizumab and dasatinib are investigational agents whose genotoxic effects on the developing fetus and newborn are unknown.

2. Prior intratumoral therapy, stereotactic radiosurgery, or interstitial brachytherapy.

   EXCEPTION: Separate lesion on MRI which is not part of the previous treatment field, or convincing evidence of recurrent disease, based on biopsy, MRI spectroscopy, or PET scan.

3. Prior treatment with bevacizumab or VEGF-Trap (Aflibercept).

4. Inadequately controlled hypertension (systolic blood pressure of >150 mmHg or diastolic pressure >100 mmHg on anti-hypertensive medications).

   NOTE: Patients with well-controlled hypertension are eligible.

5. Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens.

6. Immunocompromised patients (other than that related to the use of corticosteroids). NOTE: Patients known to be HIV positive, but without clinical evidence of an immunocompromised state, are eligible for this study.

7. Any condition (e.g., gastrointestinal tract disease resulting in an inability to take oral medication or a requirement for IV alimentation, or prior surgical procedures affecting absorption) that impairs ability to swallow pills.

8. Receiving therapeutic anticoagulation with Warfarin. NOTE: Prophylactic anticoagulation (i.e., low dose warfarin) of venous or arterial access devices is allowed, provided that INR <1.5. Therapeutic anti-coagulation with low molecular weight heparin is allowed at time of registration.

9. Evidence of bleeding diathesis (greater than normal risk of bleeding) or coagulopathy (in the absence of therapeutic anticoagulation).

10. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, or psychiatric illness/social situations that would limit compliance with study requirements.

11. Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm.

12. Other active malignancy ≤3 years prior to registration. EXCEPTIONS: Non-melanotic skin cancer or carcinoma in-situ of the cervix. Note: If there is a history of prior malignancy, they must not be receiving other specific treatment (other than hormonal therapy) for their cancer.

13. History of myocardial infarction or unstable angina ≤6 months prior to registration.

14. New York Heart Association (NYHA) classification II, III or IV congestive heart failure.

15. Core biopsy or other minor surgical procedures ≤7 days prior to registration. Note: Placement of a vascular access device is allowed.

16. Major surgical procedure, open biopsy, or significant traumatic injury ≤28 days prior to registration or anticipation of need for major surgical procedure during the course of the study.

17. Significant vascular disease (e.g., aortic aneurysm, aortic dissection) or recent peripheral arterial thrombosis ≤6 months prior to registration.

18. History of hypertensive crisis or hypertensive encephalopathy.

19. Known hypersensitivity to any of the components of dasatinib or bevacizumab.

20. Serious, non-healing wound, active ulcer, or untreated bone fracture

21. History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess ≤6 months prior to registration.

22. Active or recent history of hemoptysis (≥ ½ teaspoon of bright red blood per episode) ≤30 days prior to registration.

23. History of stroke or transient ischemic attack (TIA) ≤6 months prior to registration.

24. Any evidence of CNS hemorrhage on baseline CT or MRI

25. Any of the following Category I drugs that are generally accepted to have a risk of causing Torsades de Pointes ≤7 days prior to registration (patients must discontinue drug 7 days prior to starting dasatinib)

    • Quinidine, procainamide, disopyramide
    • Amiodarone, sotalol, ibutilide, dofetilide
    • Erythromycin, clarithromycin
    • Chlorpromazine, haloperidol, mesoridazine, thioridazine, pimozide
    • Cisapride, bepridil, droperidol, methadone, arsenic, chloroquine, domperidone, halofantrine, levomethadyl, pentamidine, sparfloxacin, lidoflazine
    • Prochlorperazine

26. Diagnosed congenital long QT syndrome

27. Any history of clinically significant ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or Torsades de Pointes)

28. Prolonged QTc interval on pre-entry electrocardiogram (>450 msec)

29. Patients may not have any clinically significant cardiovascular disease including the following:

    • Myocardial infarction or ventricular tachyarrhythmia within 6 months.
    • Prolonged QTc ≥ 480 msec (Fridericia correction)
    • Ejection fraction less than institutional normal
    • Major conduction abnormality (unless a cardiac pacemaker is present)

    Note: Patients with any cardiopulmonary symptoms of unknown cause (e.g., shortness of breath, chest pain, etc.) should be evaluated by a baseline echocardiogram with or without stress test as needed in addition to electrocardiogram (ECG) to rule out QTc prolongation. The patient may be referred to a cardiologist at the discretion of the principal investigator. Patients with underlying cardiopulmonary dysfunction should be excluded from the study.

30. Subjects with hypokalemia or hypomagnesemia if it cannot be corrected prior to dasatinib administration

31. Known pleural or pericardial effusion of any grade

32. Concomitant use of H2 blockers or proton pump inhibitors that cannot be discontinued or switched to locally acting agents (i.e. famotidine or omeprazole.)

33. Use of the following Enzyme Inducing Anti-Convulsive (EIAC) medications is prohibited ≤ 7 days prior to registration: carbamazepine (Tegretol®, Tegretol XR®, Carbatrol®), phenytoin (Dilantin®, Phenytek®), fosphenytoin (Cerebyx®), phenobarbital, pentobarbital and primidone (Mysoline®). Note: Many antiepileptic drugs induce hepatic enzymes. Because dasatinib is metabolized by hepatic enzymes, patients taking antiepileptic medications that induce hepatic enzymes (EIACs) are ineligible for this trial. To be eligible for this trial, patients taking EIACs must be switched to non-EIACs ≥ 7 days prior to registration. The following agents are not known to affect dasatinib metabolism and are acceptable for use: valproic acid (Depakote®, Depacon®), gabapentin (Neurontin®), lamotrigine (Lamictal®), topiramate (Topamax®), tiagabine (Gabitril®), zonisamide (Zonegran®), levetiracetam (Keppra®), clonazepam (Klonopin®) and clobazam (Frisium®).