RT, Temozolomide, and Bevacizumab Followed by Bevacizumab/Everolimus in First-line Treatment of GBM
Condition: Glioblastoma Multiforme
MeSH terms: Glioblastoma
Intervention: Radiation therapy; Temozolomide; Bevacizumab; Bevacizumab; Everolimus
Intervention description: Radiation therapy, 2.0 Gy daily, 5 days per week by single daily dose, to a total of 60 Gy over 6 weeks; Temozolomide 75mg/m2 by mouth daily, beginning day 1 of radiation therapy and continuing through the last day of radiation therapy; Bevacizumab 10mg/kg IV, every 2 weeks, beginning day 1 of radiation therapy; Bevacizumab 10mg/kg IV, every 2 weeks, beginning Week 11; Everolimus 10mg by mouth daily, beginning Week 11
Intervention MeSH terms: Bevacizumab; Everolimus; 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: Glioblastoma Multiforme; Radiation Therapy; Temozolomide; Bevacizumab; Everolimus

Summary:

      In this phase II trial the investigators plan to incorporate two targeted agents, bevacizumab
      and everolimus, into the first-line multimodality therapy of glioblastoma. In the first
      portion of the treatment, bevacizumab will be added to standard concurrent radiation therapy
      plus temozolomide. After completing radiation therapy, patients will continue treatment with
      the combination of bevacizumab and everolimus.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Age >=18 years.

          -  Histologically confirmed intracranial glioblastoma multiforme (WHO grade 4).

          -  Patients who have had partial or complete surgical debulking are eligible, as are
             those with inoperable glioblastoma.

          -  No previous treatment with radiotherapy or systemic therapy. Local therapy with a
             Gliadel wafer placed at the time of surgical debulking is permitted.

          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

          -  Adequate bone marrow function

          -  Adequate liver function:

          -  Serum creatinine <=1.5 x institutional ULN.

          -  Ability to swallow whole pills.

          -  Women of child-bearing potential must have a negative serum pregnancy test performed
             within 7 days prior to start of treatment. Women of child-bearing potential and men
             must agree to use adequate contraception (barrier method of birth control) while
             receiving study treatment and for 6 months after the last study treatment. Hormonal
             contraceptives are not acceptable as a sole method of contraception. Female patients
             must not breast feed.

          -  INR <1.3 or PT/PTT within normal limits in patients not receiving anticoagulation.
             However, patients receiving anticoagulation treatment with an agent such as warfarin
             or heparin are also eligible. For patients on warfarin, the INR should be measured
             prior to initiation of everolimus and monitored at least weekly, or as defined by the
             local standard of care, until INR is stable.

          -  Fasting serum cholesterol <=300 mg/dL OR <=7.75 mmol/L AND fasting triglycerides <=
             2.5 x institutional ULN.

        Exclusion Criteria:

          -  New York Heart Association (NYHA) grade II or greater congestive heart failure (see
             Appendix B) or symptomatic congestive heart failure.

          -  Inadequately controlled hypertension (defined as systolic blood pressure >150 mmHg
             and/or diastolic blood pressure >100 mmHg).

          -  History of myocardial infarction or unstable angina within 6 months prior to beginning
             study treatment.

          -  History of stroke or transient ischemic attack within 6 months prior to beginning
             study treatment.

          -  Significant vascular disease (e.g., aortic aneurysm, requiring surgical repair or
             recent peripheral arterial thrombosis) within 6 months prior to beginning study
             treatment.

          -  Prior history of hypertensive crisis or hypertensive encephalopathy.

          -  History of hemoptysis (>=1/2 teaspoon of bright red blood per episode) within 1 month
             prior to beginning study treatment.

          -  Evidence of bleeding diathesis or significant coagulopathy (in the absence of
             therapeutic anticoagulation).

          -  History of abdominal fistula or gastrointestinal perforation within 6 months prior to
             Day 1.

          -  Serious, non-healing wound, active ulcer, or untreated bone fracture.

          -  Proteinuria as demonstrated by urine dipstick for proteinuria >=2+. For patients with
             >=2+ proteinuria on dipstick urinalysis, a urine protein: creatinine (UPC) ratio will
             be determined or a 24-hour urine collection will be done. Patients with a UPC ratio <1
             or a 24-hour urine protein <1 gram are eligible.

          -  Minor surgical procedures (excluding placement of a vascular access device),
             fine-needle aspirations, or core biopsies within 7 days prior to starting treatment.

          -  Major surgical procedure, open biopsy, or significant traumatic injury within 28 days
             prior to starting protocol treatment or anticipation of need for major surgical
             procedure during the course of study treatment. Patients who have not recovered from
             the side effects of any major surgery are not eligible.

          -  Treatment with any investigational agents within 4 weeks of study entry.

          -  Chronic, systemic treatment with corticosteroids or other immunosuppressive agents.
             Topical or inhaled steroids are allowed.

          -  Other malignancies within the past 3 years except for adequately treated carcinoma in
             situ of the cervix or basal cell or superficial squamous (skin cell) carcinomas.