Dasatinib and Bevacizumab in Treating Patients With Recurrent or Progressive High-Grade Glioma or Glioblastoma Multiforme
Condition: Glioblastoma Multiforme
MeSH terms: Glioblastoma
Intervention: bevacizumab; dasatinib; placebo
Intervention description: Given intravenously; Given orally; Given orally
Intervention MeSH terms: Bevacizumab; Dasatinib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 144.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: adult giant cell glioblastoma; adult glioblastoma; adult gliosarcoma; adult mixed glioma; recurrent adult brain tumor; adult anaplastic oligodendroglioma; adult oligodendroglioma; adult anaplastic astrocytoma

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.
    

Eligibility criteria:

        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®).