Bevacizumab Beyond Progression (BBP)
Condition: Malignant Glioma; Grade 4 Malignant Glioma; Glioblastoma; Gliosarcoma
MeSH terms: Glioblastoma; Glioma; Gliosarcoma
Intervention: Radiation Therapy; Temozolomide; Bevacizumab
Intervention MeSH terms: Bevacizumab; Temozolomide
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 68.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: malignant glioma; Grade 4 malignant glioma; glioblastoma; gliosarcoma; adult brain tumor

Summary:

      Studies which have separately studied bevacizumab for recurrent gliomas and bevacizumab for
      newly-diagnosed glioma have shown good results and the regimens have been well-tolerated by
      patients. This study seeks to investigate the use of bevacizumab with the standard therapy
      (radiation therapy and temozolomide) in newly diagnosed patients, followed by bevacizumab and
      temozolomide with the continuation of bevacizumab following progression. Two critical
      questions remain- the role of bevacizumab maintenance and bevacizumab at the time of
      progression in a patient previously treated with bevacizumab at the time of initial
      diagnosis.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Patients with histologically confirmed WHO Grade IV primary malignant glioma
             (glioblastoma or gliosarcoma);

          -  Patients ≥ 18 years of age;

          -  An interval of at least 2 weeks, but not ≥ 8 weeks between prior surgical procedure
             and initiation of treatment;

          -  Karnofsky Performance Status (KPS) ≥ 60%

          -  Laboratory Values:

               -  Platelet Count ≥ 125,000 cells/µL

               -  Absolute neutrophil count (ANC) ≥ 1,500 cells/µL

               -  Adequate renal function indicated by all of the following:

                    -  Serum creatinine ≤ 1.25 x upper limit of normal (ULN) or calculated
                       creatinine clearance ≥ 50 ml/min

                    -  Urine dipstick for proteinuria < 2+ unless a 24-hour urine protein < 1 g of
                       protein is demonstrated

               -  internationalized normalized ratio (INR) ≤ 1.5 and activated partial
                  thromboplastin time (aPTT) ≤ 1.5 x upper limit of normal (ULN) within 7 days
                  prior to first study treatment for patients not receiving anti-coagulation. The
                  use of full-dose oral or parenteral anticoagulants is permitted as long as the
                  INR or aPTT is within therapeutic limits (according to the medical standard of
                  the enrolling institution) and the patient has been on a stable dose of
                  anticoagulants for at least two weeks prior to the first study treatment.

          -  Patients will sign an Institutional Review Board-approved informed consent form.

          -  Female patients must not be pregnant or breast-feeding. Female patients of
             childbearing potential (defined as < 2 years after last menstruation or not surgically
             sterile) must use a highly effective contraceptive method (allowed methods of birth
             control, [i.e. with a failure rate of < 1% per year] are implants, injectables,
             combined oral contraceptives, intra-uterine device [Intrauterine Device (IUD); only
             hormonal], sexual abstinence or vasectomized partner) during the trial and for a
             period of > 6 months following the last administration of trial drug(s). Female
             patients with an intact uterus (unless amenorrhea for the last 24 months) must have a
             negative serum pregnancy test within 7 days prior to first study treatment.

          -  Fertile male patients must agree to use a highly effective contraceptive method
             (allowed methods of birth control [i.e. with a failure rate of < 1% per year] include
             a female partner using implants, injectables, combined oral contraceptives,
             Intrauterine Device (IUDs) [only hormonal], sexual abstinence or prior vasectomy)
             during the trial and for a period of > 6 months following the last administration of
             trial drugs.

        Exclusion Criteria:

          -  Any prior treatment for any grade glioma, including, but not limited to gliadel
             wafers, immunotherapy (including vaccine therapy), radiation therapy or chemotherapy,
             irrespective of grade of the tumor (NOTE: 5-aminolevulinic acid (ALA)-mediated
             photodynamic therapy administered prior to surgery to aid in optimal surgical
             resection is not considered a chemotherapy agent.);

          -  Co-medication that may interfere with study results; e.g. immuno-suppressive agents
             other than corticosteroids;

          -  Active infection requiring intravenous antibiotics;

          -  Prior or current treatment with bevacizumab or other anti-angiogenic treatment (i.e.
             anti-vascular endothelial growth factor (VEGF) or vascular endothelial growth factor
             receptor (VEGFR) therapies or tyrosine kinase inhibitors) for any condition;

          -  Treatment with any other investigational agent within 28 days or 2 investigational
             agent half-lives (whichever is longer) prior to first study treatment;

          -  Prior, unrelated malignancy requiring current active treatment with the exception of
             cervical carcinoma in situ and adequately treated basal cell or squamous cell
             carcinoma of the skin;

          -  Evidence of > Grade 1 central nervous system (CNS) hemorrhage on post-operative MRI
             scan, unless repeat MRI or CT performed prior to initiating bevacizumab shows stable
             grade 1 or resolving (< grade 1) CNS hemorrhage.

        Bevacizumab-Specific Exclusion Criteria:

          -  Inadequately controlled hypertension (defined as systolic blood pressure > 150 mmHg
             and/or diastolic blood pressure > 100 mmHg) within 28 days of first study treatment;

          -  Prior history of hypertensive crisis, hypertensive encephalopathy, reverse posterior
             leukoencephalopathy syndrome (RPLS);

          -  Prior history of gastrointestinal perforation or abscess;

          -  Clinically significant (i.e. active) cardiovascular disease, for example
             cerebrovascular accidents ≤ 6 months prior to study enrollment, myocardial infarction
             ≤ 6 months prior to study enrollment, unstable angina, New York Heart Association
             (NYHA) Grade II or greater congestive heart failure (CHF), or serious cardiac
             arrhythmia uncontrolled by medication or potentially interfering with protocol
             treatment;

          -  History or evidence upon physical/neurological examination of central nervous system
             disease (e.g. seizures) unrelated to cancer unless adequately controlled by medication
             or potentially interfering with protocol treatment;

          -  Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or
             recent arterial thrombosis) within 6 months prior to start of study treatment. Any
             previous venous thromboembolism > NCI common toxicity criteria adverse event (CTCAE)
             Grade 3;

          -  History of pulmonary hemorrhage/hemoptysis ≥ grade 2 (defined as ≥ 2.5 mL bright red
             blood per episode) within 1 month of first study treatment;

          -  History or evidence of inherited bleeding diathesis or significant coagulopathy at
             risk of bleeding (i.e. in the absence of therapeutic anticoagulation);

          -  Current or recent (within 10 days of study enrollment) use of aspirin (>325 mg/day),
             clopidogrel (>75 mg/day) or equivalent. Prophylactic use of anticoagulants is allowed;

          -  Surgical procedure (including open biopsy, surgical resection, wound revision, or any
             other major surgery involving entry into a body cavity) or significant traumatic
             injury within 28 days prior to first study treatment, or anticipation of need for
             major surgical procedure during the course of the study;

          -  Minor surgical procedure, e.g. stereotactic biopsy, within 7 days of first study
             treatment; placement of a vascular access device, within 2 days of first study
             treatment;

          -  History of intracranial abscess within 6 months prior to first study treatment;

          -  History of active gastrointestinal bleeding within 6 months prior to first study
             treatment;

          -  Serious, non-healing wound, active ulcer, or untreated bone fracture;

          -  Known hypersensitivity to any component of bevacizumab or any of the study drugs;