Bevacizumab and Temozolomide Following Radiation and Chemotherapy for Newly Diagnosed Glioblastoma Multiforme
Condition: Glioblastoma Multiforme
MeSH terms: Glioblastoma
Intervention: Bevacizumab and Temozolomide
Intervention description: This is an open-label, single arm, multi-center, phase II study involving 48 subjects with newly diagnosed supra-tentorial GBM. Following surgery, subjects with radiographically evaluable disease will receive external beam radiotherapy (59.4 - 60 Gy in 30 - 33 fractions) with daily temozolomide (75 mg/m2). Two to three weeks later, subjects will begin treatment with temozolomide (150-200 mg/m2 daily for five of 28 consecutive days) in conjunction with Avastin (10 mg/kg, every 14 days).
Intervention MeSH terms: Bevacizumab; Temozolomide
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 62.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      This study is being conducted to help determine whether the addition of Avastin (an
      anti-cancer drug), when given along with temozolomide during the monthly cycles that follow
      radiation, is able to delay tumor growth, shrink tumors, or impact how long people with GBM
      live. This study is sponsored by Genentech, Inc., the manufacturer of Avastin.

      Avastin is the experimental drug being administered in this research study. Avastin binds a
      protein called vascular endothelial growth factor, or VEGF. VEGF is produced by tumors and
      circulates in the blood. One of VEGF's main roles is to support the growth of new blood
      vessels. During cancer, VEGF promotes the growth of blood vessels that bring nutrients to
      tumor cells and help them grow. Avastin binds to VEGF, which then prevents VEGF from
      functioning. In laboratory studies, Avastin prevented the growth of several different types
      of cancer cells grown in animals. Avastin was approved by the Food and Drug Administration
      (FDA) for the treatment of metastatic colorectal cancer in combination with chemotherapy.
      Avastin has not been approved by the FDA for the treatment of GBM and is, therefore,
      considered experimental. Avastin is currently undergoing testing (alone and in combination
      with another anti-cancer drug, irinotecan) in persons with GBM that have come back after
      conventional treatment.

      Temozolomide (Temodar) is an anti-cancer drug that works by interfering with the growth of
      cells (including cancer cells) by stopping their division. Temozolomide was approved by the
      U.S. FDA for the treatment of newly diagnosed GBM in 2005.

      Avastin and temozolomide are currently being used together in several research studies
      involving people with newly diagnosed GBM. Limited information is available about either the
      safety or effectiveness of this drug combination.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Disease-Specific Concerns Histologically confirmed GBM as determined by central
             pathology review Supratentorial location

          2. General Medical Concerns 18 years of age; Karnofsky performance status > 60;
             Tumor-related contrast enhancement on initial and post-operative Gd-MRI; Recovery from
             effects of surgery and/or its complications prior to initiating radiotherapy;
             Radiotherapy must begin < 5 weeks following surgery; Pre-and post-operative Gd-MRI
             prior to the initiation of radiotherapy; Adequate hematological, renal, and hepatic
             function:hemoglobin > 10 grams hematocrit > 30%, platelets > 100,000 per mm3, BUN < 25
             mg/dl, Creatinine < 1.5 mg/dl, Total bilirubin < 1.5 mg/dl, SGOT or SGPT < twice
             institutional normal range, Subjects must not be pregnant or nursing, Use of effective
             means of contraception (men and women) in subjects of child-bearing (women) and at all
             ages (men), Study-specific signed informed consent, Ability to comply with study
             follow-up procedures.

             -

        Exclusion Criteria:

          -  a. Disease-Specific Concerns: malignant gliomas graded less than GBM; infratentorial
             tumor location; recurrent disease; intra-tumoral hemorrhage; Placement of Gliadel®
             wafers; b. Bevacizumab-Specific Concerns: Inadequately controlled hypertension
             (defined as systolic blood pressure 150 and/or diastolic blood pressure > 100 mmHg on
             antihypertensive medications); Any prior history of hypertensive crisis or
             hypertensive encephalopathy; History of myocardial infarction or unstable angina
             within 6 months prior to study enrollment; History of stroke or transient ischemic
             attack within 6 months prior to study enrollment; New York Heart Association (NYHA)
             Grade II or greater CHF (see Appendix E); Significant vascular disease (e.g., aortic
             aneurysm, aortic dissection); Symptomatic peripheral vascular disease; Evidence of
             bleeding diathesis or coagulopathy; History of abdominal fistula, gastrointestinal
             perforation, or intra-abdominal abscess within 6 months prior to study enrollment;
             History of intracerebral abscess within 6 months prior to study enrollment; Major
             surgical procedure, open biopsy, or significant traumatic injury within 28 days prior
             to study enrollment (exclusive of craniotomy); anticipation of need for major surgical
             procedure during the course of the study; Core biopsy or other minor surgical
             procedure, excluding placement of a vascular access device, within 7 days prior to
             study enrollment; Serious non-healing wound, ulcer, or bone fracture; Proteinuria at
             screening as demonstrated by either; Urine protein:creatinine (UPC) ratio 1.0 at
             screening OR Urine dipstick for proteinuria ≥ 2+ (patients discovered to have ≥2+
             proteinuria on dipstick urinalysis at baseline should undergo a 24 hour urine
             collection and must demonstrate ≤ 1g of protein in 24 hours to be eligible); Known
             hypersensitivity to any component of Avastin. c. General Medical Exclusions

        Subjects meeting any of the following criteria are ineligible for study entry:

        Current, recent (within 4 weeks of the first infusion of this study), or planned
        participation in an experimental drug study other than a Genentech-sponsored Avastin cancer
        study; History of any other malignancy within 5 years (except non-melanoma skin cancer or
        carcinoma in situ of the cervix);Pregnant or nursing females; Unstable systemic disease,
        including active infection, uncontrolled hypertension, or serious cardiac arrhythmias
        requiring medication;

        Screening clinical laboratory values:

        Absolute neutrophil count < 1500/ul, Platelet count < 100,000/ul, Total bilirubin > 1.6
        mg.dl, AST/ALT > 1.5 x the upper limit of normal ( ULN), Creatinine > 1.2 x ULN, Urine
        protein/creatinine ratio > 1.0, International normalized ration (INR) > 1.5 and activated
        partial thromboplastin time (aPTT) > 1.5 x ULN (except for subjects receiving
        anticoagulation therapy) in the absence of therapeutic intent to anticoagulate the subject.
        Therapeutic anticoagulation is permitted.