Please select the eligibility criteria that correspond to the clinical trial below.
Title: Phase I/Randomized Phase II Double Blind Study of Either Dasatinib or Placebo Combined With Bevacizumab in Recurrent Glioblastoma
Brief Summary: 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.


Options:
A: Inclusion Criteria:

1. Patients with histologically proven recurrent malignant primary glioma will be eligible. Glioma type will be restricted to: GBM, gliosarcoma (GS), anaplastic gliomas \[anaplastic astrocytoma (AA), anaplastic oligodendroglioma (AO), anaplastic infiltrating glioma (AIG), mixed anaplastic glioma (MAG), anaplastic ependymoma\]
2. Patients must show unequivocal evidence for tumor recurrence or progression by MRI scan within 15 days prior to Day 0/Baseline procedure after failing prior surgical resection, biopsy, chemotherapy or radiation
3. For patients entered in Group A (see Treatment Plan) tumors must be accessible for stereotactic injection. Tumors must be between 1.0 - 5.0 cm in diameter
4. For patients entered in Group B (see Treatment Plan) tumors must be surgically resectable, and surgical resection must be indicated at the time of baseline evaluation. Tumors must be \>1.0 cm in diameter.
5. Patients will consent to have a biopsy taken at the time of the stereotactic injection to confirm the presence of malignant glioma (based on frozen section) before injection of DNX-2401
6. For each patient there must be a consensus between the physician investigators in this study that injection will not deliver DNX-2401 into the ventricular system. Patients must have a stable steroid regimen for at least 1 week prior to DNX-2401 administration
7. Patients may or may not have had prior chemotherapy
8. Patients must be willing and able to give informed consent
9. Age \> /= 18 years
10. Patients must have a Karnofsky performance status greater than or equal to 70
11. Patients must have recovered from the toxic effects of prior therapy (i.e., CTC grade 1 or less). For example, they must be at least two weeks after vincristine, 6 weeks after nitrosoureas, and 3 weeks after procarbazine or temozolomide administration
12. Patients must have adequate bone marrow function (absolute granulocyte count \> 1,500 and platelet count of \> 100,000), adequate liver function (SGPT and alkaline phosphatase \< 2 times institutional normals and bilirubin \<1.5 mg%), and adequate renal function (BUN or creatinine \<1.5 times institutional normal) prior to starting therapy
13. 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
14. No exclusion to this study will be based on race. Minorities will actively be recruited to participate. The malignant glioma patient population treated at MDACC over the past year is as follows: American Indian or Alaskan Native - 0, Asian or Pacific Islander - \<2%, Black, not of Hispanic Origin - 3%, Hispanic - 6%, White, not of Hispanic Origin - 88%, Other or Unknown - 2%, Total - 100%

Exclusion Criteria:

1. Any radiotherapy within 4 weeks prior to date of DNX-2401 administration.
2. Active uncontrolled infection or severe intercurrent medical conditions. All patients must be afebrile at baseline (i.e., \< 38.0 Celsius \[C\])
3. Evidence of bleeding diathesis or use of anticoagulant medication or any medication that may increase the risk of bleeding that cannot be stopped prior to surgery. If the medication can be discontinued , based on the clinical judgment of the surgeon, prior to DNX-2401 injection then patient may be eligible.
4. History or current diagnosis of any medical or psychological condition that in the Investigator's opinion, might interfere with the subject's ability to participate or inability to obtain informed consent because of psychiatric or complicating medical problems
5. Female who is pregnant and/or nursing. Because of the potential risk of a recombinant virus containing a gene involved in cellular growth regulation and differentiation which could potentially affect a developing fetus or growing infant, females who are pregnant, at risk of pregnancy, or breast feeding a baby during the study period are excluded
6. Tumor position that, in the Investigator's opinion, would pose the risk of penetration of the cerebral ventricular system during injection with study drug. If, during the DNX-2401injection procedure, penetration of the ventricular system is suspected or confirmed, DNX-2401 administration will be aborted
7. Immunocompromised subjects, subjects with autoimmune conditions, active hepatitis (B or C) or HIV seropositivity
8. Patients with Li-Fraumeni Syndrome or with a known germ line deficit in the retinoblastoma gene or its related pathways
9. Multiple intracranial malignant glioma lesions at the time of recurrence. Multiple enhancing areas within a single tumor will not be considered multiple glioma lesions
10. Tumor involvement which would require ventricular, brainstem or posterior fossa injection or access through a ventricle in order to deliver the virus
11. Tumor involving the subependyma or suspected cerebrospinal fluid (CSF) dissemination
12. Documented extracranial metastasis
13. Biologic/immunotherapy (e.g., IL-2, IL-12, interferon) within 4 weeks of DNX-2401 administration
14. Concurrent chemotherapy, radiation or biological therapy
15. Any contraindication for undergoing MRI such as: individuals with pacemakers, epicardial pacer wires, infusion pumps, surgical and/or aneurysm clips, shrapnel, metal prosthesis, implants with potential magnetic properties, metallic bodies in the eyes, etc.
16. White blood cell (WBC) \< 2.5 x 103/mm3, absolute neutrophil count (ANC) \< 1.5 x 103/mm3, platelet \< 100,000/mm3, hemoglobin (Hgb) \< 10.0 gm/dL, prothrombin time/international normalized ratio (PT/INR) or partial thromboplastin time (PTT) \> 1.8 x control
17. Grade 4 hematological toxicity
18. Serum creatinine \> 1.5 mg/dL
19. Liver transaminases (aspartate aminotransferase \[AST\] and/or alanine aminotransferase \[ALT\]) or total bilirubin \> 2x the upper limits of normal
20. Vaccinations of any kind within 30 days prior to Delta-24-RGD-4C administration
21. Current diagnosis of other cancer except curative cervical cancer in situ, basal or squamous cell carcinoma of the skin. Patients with a history of another cancer, but who are cancer free for a minimum of three years remain eligible
22. History of encephalitis, multiple sclerosis, other CNS infection or primary CNS disease that would interfere with subject evaluation
23. Patients with history of prior gene transfer therapy or prior therapy with cytolytic virus of any type, especially DNX-2401
24. Males or females who refuse to use a double-barrier form of birth control during the study and for up to 6 months after injection with DNX-2401
B: 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®).
C: Inclusion Criteria:

* Histological confirmed diagnosis of relapsed intracranial GB
* Progressive Disease (PD) following standard chemoradiation
* Prior surgical resection allowed
* Performance status Eastern Cooperative Oncology Group (ECOG) 0 or 1
* Adequate hematologic, hepatic and renal function
* Discontinued all prior cancer treatments for cancer \& recovered from the acute effects of therapy
* Tumor specimen must be available for a central pathology review and prognostic and predictive biomarker evaluation

Exclusion Criteria:

* Moderate or severe heart disease based on New York Heart Association (NYHA) criteria
* Prior nitrosurea therapy (including lomustine or Gliadel)
* Prior bevacizumab as 1st line treatment for GB (if treatment was concluded 12 months prior to enrollment, the patient may be eligible to participate in the trial)
* Current acute or chronic myelogenous leukemia
* Second primary malignancy that may affect the interpretation of results
* Serious concomitant systemic disorder
D: DISEASE CHARACTERISTICS:

* Histopathologically confirmed glioblastoma multiforme

  * Grade IV disease by WHO classification
  * Newly diagnosed disease
* Initial diagnostic surgery or biopsy performed within the past 4 weeks
* Not a candidate for standard radiotherapy (60Gy/30 fractions over 6 weeks) in combination with temozolomide

PATIENT CHARACTERISTICS:

* ECOG performance status 0-2
* Absolute granulocyte count ≥ 1,500/mm³
* Platelet count ≥ 100,000/mm³
* Creatinine ≤ 1.5 times upper limit of normal (ULN)
* Bilirubin ≤ 1.5 times ULN
* ALT and AST \< 2.5 times ULN
* No known hypersensitivity to temozolomide or compounds with similar chemical composition to temozolomide
* No history of other malignancies except adequately treated nonmelanoma skin cancer, curatively treated in situ cancer of the cervix, or other curatively treated solid tumors with no evidence of disease for at least 5 years
* No serious active infection (e.g., wound infection requiring parenteral antibiotics) or other serious underlying medical conditions that would preclude study treatment
* No other condition (e.g., psychological or geographical) that would preclude study compliance

PRIOR CONCURRENT THERAPY:

* No prior chemotherapy
* No prior radiotherapy
* No prior or concurrent investigational therapy
* No concurrent surgical procedures for tumor debulking
* No concurrent stereotactic boost radiotherapy
* No other concurrent chemotherapy, immunotherapy, or biological therapy
* No concurrent epoetin alfa
* Concurrent corticosteroids allowed provided the patient has been on a stable or decreasing dose for at least 14 days

Answer: B